SI9300104A - Sulphonamidocarboxamides - Google Patents

Description

SulfonamidokarboksamidiSulfonamidocarboxamides

Izum se nanaša na nove sulfonamidokarboksamide s formuloThe invention relates to novel sulfonamidocarboxamides of formula

v kateri pomenijoin which they mean

X skupino s formulo χΐ ali ;X is a group of formula χΐ or;

T CH₂ ali O,T CH ₂ or O,

Rl, R2, Ril in R^l neodvisno drug od drugega H ali COO-nižji alkil,R 1, R 2, R 1 and R 1 are independently H or COO-lower alkyl,

Y H ali, če je X skupina χ2 ali če je X skupina χΐ, v kateri vsaj eden izmedY H or if X is a group χ2 or if X is a group χΐ in which at least one of

Rl in ni H, lahko stoji Y tudi za CH2COOH ali SO₂-A’,R1 and not H may also be Y for CH2COOH or SO ₂ -A ',

A in A’ aril, heteroaril, heterociklil, alkil ali cikloalkil,A and A 'aryl, heteroaryl, heterocyclyl, alkyl or cycloalkyl,

Q H, nižji alkil ali nižji alkil(OH, COOH ali COO-nižji alkil),Q H, lower alkyl or lower alkyl (OH, COOH or COO-lower alkyl),

M skupino s formulo M³, ali kadar je X skupina X², ali kadar je X skupina χΐ in vsaj eden izmed Rl, R² in Q ni H, in/ali kadar je A alkil ali cikloalkil, tedaj je M lahko tudi skupina z eno izmed formul M² - M⁸ M is a group of the formula M ³ , or when X is an X ² group or when X is a group χΐ and at least one of R 1, R ² and Q is not H, and / or when A is alkyl or cycloalkyl, then M may also be a group using one of the formulas M ² - M ⁸

—ch-ch₂(M¹) c=o ₄ VS» R³ —Ch-ch ₂ (M ¹ ) c = o ₄ VS »R ³ —CH-CH (M²) C=O N(R⁶)—CH-CH (M ² ) C = O N (R ⁶ ) -CH₂CH(NH(CO)₁.₂R⁷)--CH ₂ CH (NH (CO) _{1. 2} R ⁷ ) - (M³)(M ³ ) -CH₂CH(NHC(O)O-benzil)--CH ₂ CH (NHC (O) O-benzyl) - (M⁴)(M ⁴ ) =CH(CH₂)i-₂R⁷ = CH (CH ₂ ) i- ₂ R ⁷ (M⁵)(M ⁵ ) =CHCH₂C(O)R⁸ = CHCH ₂ C (O) R ⁸ (M6) (M6) =CHCH₂NH(CO)₁.₂R⁷ = CHCH ₂ NH (CO) ₁ . ₂ R ⁷ (M?) (M?) =CHCH₂NHC(O)O-benzil= CHCH ₂ NHC (O) O-benzyl (M⁸)(M ⁸ )

R³ H, nižji alkil ali alkenil, aril, heteroaril, cikloalkil ali (aril, heteroaril ali cikloalkil)-nižji alkil,R ^{3 is} H, lower alkyl or alkenyl, aryl, heteroaryl, cycloalkyl or (aryl, heteroaryl or cycloalkyl) lower alkyl,

R⁴ H, nižji alkil, aril, cikloalkil, ali (aril ali cikloalkil)-nižji alkil,R ^{4 is} H, lower alkyl, aryl, cycloalkyl, or (aryl or cycloalkyl) lower alkyl,

R³ H, nižji alkil ali v danem primeru preko nižjega alkilena vezan COOH, COOnižji alkil, nižji alkanoil, OH, nižji-alkanoiloksi, nižji-alkoksi, aril-nižji alkoksi, CONH₂, CONHCH2CH2OH, CONHOH, CONHOCH3,R ³ H, lower alkyl or optionally via lower alkylene bound COOH, COO lower alkyl, lower alkanoyl, OH, lower-alkanoyloxy, lower-alkoxy, aryl-lower alkoxy, CONH ₂ , CONHCH2CH2OH, CONHOH, CONHOCH3,

CONHO-benzil, CONHSO2-nižji alkil, CONHCH2CH2-aril, CONH cikloalkil, CONHCH₂-heteroaril, NH₂, NHCOO-nižji alkil, NHCOO-nižji aralkil, NHSO3H, (NHSO2 ali NHSO3)-nižji alkil, NH-nižji alkanoil, NHCOCOOH, NHCOCOO-nižji alkil, NH-cikloalkil,CONHO-benzyl, CONHSO2-lower alkyl, CONHCH2CH2-aryl, CONH cycloalkyl, CONHCH ₂ -heteroaryl, NH ₂ , NHCOO-lower alkyl, NHCOO-lower aralkyl, NHSO3H, (NHSO2 or NHSO3) -alkyl, NH-lower alkanoyl, NHCOCOOH, NHCOCOO-lower alkyl, NH-cycloalkyl,

NH-(3,4-diokoso-2-hidroksi-ciklobut-l-enil), NH-[2-nižji-(alkoksi ali alkeniloksi)-3,4-dioksociklobut- Ι-enil], NHCH2-heteroaril, NHCOCO-(aril ali nižji alkil), NHCOCH₂C1, NHCOCH₂O-aril, NHCOCH₂-aril, NHCO(aril ali heteroaril), NHPO3(R9, RlO), heteroaril, ali v danem primeru z O ali S prekinjen in v danem primeru z do 2 substituentoma iz skupine nižji-alkil, COOH, COO-nižji alkil, CH2OH in CH2O-benzil obročno substituiran CON(CH₂)₄-9, in RlO H, nižji-alkil ali fenil, pri čemer v primeru, da so Q, R¹, R², R² in R⁵ istočasno H, R^ ne sme biti fenil, N(R6) benzilamino ali v danem primeru z O ali S prekinjen in v danem primeru z do 2 substituentoma iz skupine nižji alkil, COOH, COO-nižji alkil, CH2OH, CH2O-benzil, obročno substituiran N(CH2)4-9,NH- (3,4-dioxo-2-hydroxy-cyclobut-1-enyl), NH- [2-lower- (alkoxy or alkenyloxy) -3,4-dioxocyclobut-Ι-enyl], NHCH2-heteroaryl, NHCOCO- (aryl or lower alkyl), NHCOCH ₂ C1, NHCOCH ₂ O-aryl, NHCOCH _2- aryl, NHCO (aryl or heteroaryl), NHPO3 (R9, R10), heteroaryl, or optionally interrupted by O or S and optionally case with up to 2 substituents from the group lower-alkyl, COOH, COO-lower alkyl, CH2OH and CH2O-benzyl, ring-substituted CON (CH _{2) 4} -9,; and Rio is H, lower-alkyl or phenyl, whereby in the case that Q, R ¹ , R ² , R ² and R ^{5 are} simultaneously H, R 4 must not be phenyl, N (R 6) benzylamino or optionally interrupted by O or S and optionally by up to 2 substituents from the group lower alkyl , COOH, COO-lower alkyl, CH2OH, CH2O-benzyl, ring-substituted N (CH2) 4-9,

R⁷ in r8 aril, heteroaril, cikloalkil ali heterociklil, ali r8 v danem primeru z do 2 substituentoma iz skupine okso, COO-nižji alkil, (CH2)o-lOH, (CH2)0-lOCO-nižji alkil, CONH2, CONH-nižji alkil aliR ⁷ and R 8 are aryl, heteroaryl, cycloalkyl or heterocyclyl, or R8, optionally with up to 2 substituents from the group of oxo, COO-lower alkyl, (CH 2) Loh, (CH2) 0-loco-lower alkyl, CONH2, CONH lower alkyl or

CON(nižji-alkil)2, substituiran N(CH2)4-9, kot tudi na njihove hidrate ali solvate in njihove fiziološko prenesljive soli.CON (lower-alkyl) 2 substituted N (CH 2) 4-9, as well as their hydrates or solvates and their physiologically tolerated salts.

Nadalje se izum nanaša na postopek za pripravo zgornjih spojin, na farmacevtske preparate, ki vsebujejo take spojine, kot tudi na pripravo teh spojin pri pripravi farmacevtskih preparatov.The invention further relates to a process for the preparation of the above compounds, to pharmaceutical preparations containing such compounds, as well as to the preparation of these compounds in the preparation of pharmaceutical preparations.

Primeri za fiziološko uporabne soli spojin s formulo I so soli s fiziološko prenesljivimi mineralnimi kislinami kot solno, žveplovo, žveplasto ali fosforovo kislino, ali z organskimi kislinami kot metansulfonsko, p-toluensulfonsko, ocetno, trifluorocetno, citronsko, fumarovo, maleinsko, vinsko, jantarno ali salicilno kislino. Spojine s formulo I s kislimi skupinami kot karboksilno skupino, lahko tvorijo tudi soli s fiziološko prenesljivimi bazami. Primeri takih soli so soli z alkalijskimi kovinami, zemljoalkalijskimi kovinami, amonijeve in alkilamonijeve soli, kot Na-, K-, Ca- ali tetrametil-amonijeve soli. Spojine s formulo I lahko nastopajo tudi v obliki ionskih parov (zwitter-ioni).Examples of physiologically useful salts of the compounds of formula I are salts with physiologically tolerable mineral acids such as hydrochloric, sulfuric, sulfuric or phosphoric acids, or with organic acids such as methanesulfonic, p-toluenesulfonic, acetic, trifluoroacetic, citric, fumaric, fumaric or salicylic acid. Compounds of formula I with acidic groups as a carboxyl group may also form salts with physiologically tolerable bases. Examples of such salts are salts with alkali metals, alkaline earth metals, ammonium and alkylammonium salts, such as Na-, K-, Ca- or tetramethyl-ammonium salts. The compounds of formula I may also be present in the form of ion pairs (zwitter ions).

Spojine s formulo I so lahko solvatizirane, zlasti hidratizirane. Hidratiziranje lahko poteka v teku postopka priprave, ali pa se pojavlja postopoma kot posledica higroskopnih lastnosti na začetku brezvodne spojine s formulo 1.The compounds of formula I may be solvated, in particular hydrated. Hydration may occur during the preparation process, or may occur gradually as a result of the hygroscopic properties at the beginning of the anhydrous compound of Formula 1.

Spojine s formulo I vsebujejo najmanj 2 asimetrična C-atoma in zato lahko nastopajo kot zmes diastereomerov ali kot optično čista spojina.Compounds of formula I contain at least 2 asymmetric C atoms and can therefore act as a mixture of diastereomers or as an optically pure compound.

V okviru izuma označuje izraz nižji skupine, ki vsebujejo 1 do 6, prednostno 1 do 4In the context of the invention, the term lower groups containing 1 to 6, preferably 1 to 4, is denoted

C-atome. Tako označuje nižji alkil sam ali v kombinaciji ravne ali razvejene skupine, ki vsebujejo 1 do 6, prednostno 1 do 4 C-atome, kot so metil, etil, propil, izopropil, butil, izobutil, t-butil, 2-butil in pentil. Kot alkilne skupine A so prednostne nižje alkilne skupine. Primer za nižji alkenil je alil.C-atoms. Thus, it denotes lower alkyl alone or in combination of straight or branched groups containing 1 to 6, preferably 1 to 4 C atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, 2-butyl and pentyl . Lower alkyl groups are preferred as alkyl groups A. An example of lower alkenyl is allyl.

Aril označuje skupine kot fenil in 1- ali 2-naftil, v danem primeru z 1 ali več substituenti, kot halogen, npr. klor, ali nižji alkil ali alkoksi, npr. CH₃, t-butil, OH, OCH₃, fenil, CF₃, OCF₃, ciklopentil, CN, COOH, COOCH₃, COOC2H5, CONH₂ ali tetrazolil.Aryl denotes groups as phenyl and 1- or 2-naphthyl, optionally with 1 or more substituents, such as halogen, e.g. chlorine or lower alkyl or alkoxy, e.g. CH ₃ , t-butyl, OH, OCH ₃ , phenyl, CF ₃ , OCF ₃ , cyclopentyl, CN, COOH, COOCH ₃ , COOC2H5, CONH ₂ or tetrazolyl.

Heteroarilne skupine so 5- do 10-členske aromatske skupine, ki obstajajo iz i ali 2 obročev in vsebujejo 1 ali več N- in/ali O- atomov. Primeri zanje so 2-, 3- ali 4-piridil, tudi v obliki njihovih N-oksidov, tetrazolil,-oksadiazolil, pirazinil in kinolil. Lahko so tudi substituirani, npr. z nižjim alkilom kot CH₃, ali halogenom kot klorom.Heteroaryl groups are 5- to 10-membered aromatic groups consisting of i or 2 rings and containing 1 or more N and / or O atoms. Examples of these are 2-, 3- or 4-pyridyl, also in the form of their N-oxides, tetrazolyl, -oxadiazolyl, pyrazinyl and quinolyl. They may also be substituted, e.g. with lower alkyl than CH ₃ or halogen as chlorine.

Cikloalkilne skupine vsebujejo 3 do 8 C-atomov. Primeri zanje so ciklopropil, ciklopentil in cikloheksil.Cycloalkyl groups contain 3 to 8 C atoms. Examples of these are cyclopropyl, cyclopentyl and cyclohexyl.

Heterociklil označuje 5- do 10-členske nearomatske, delno ali popolnoma nasičene skupine kot tetrahidrokinolil, ki vsebujejo 1 ali 2 obroča in vsaj en heteroatom, npr. N-atom, in so v danem primeru substituirani z 1 ali več substituenti kot nižjim alkilom, npr. metilom.Heterocyclyl designates 5- to 10-membered non-aromatic, partially or fully saturated groups as tetrahydroquinolyl containing 1 or 2 rings and at least one heteroatom, e.g. N-atom, and optionally substituted by 1 or more substituents than lower alkyl, e.g. methyl.

Primera za v danem primeru z O prekinjene tetra- do nona-metileniminske skupine N(CH₂)₄_9 sta heksahidroazepin in morfolino.Examples of the optionally discontinued tetra- to nona-methylenimine group N (CH ₂ ) ₄ _9 are hexahydroazepine and morpholino.

Primeri za spojine s formulo I so tisti, kjer pomenijoExamples of compounds of formula I are those where they are meant

X skupino X^, v kateri je gvanidino skupina nezaščitena,X is an X ^ group in which the guanidino group is unprotected,

Y H,Y H,

A aril, heteroaril ali heterociklil,A is aryl, heteroaryl or heterocyclyl,

Q ima zgornji pomen inQ has the above meaning and

M pomeni bodisi skupino IVp, v kateri imata R⁴ in R⁴ zgornji pomen, pri čemer v primeru, da sta Q, R⁴ in R⁵ iztočasno H, R⁴ ne sme biti H ali fenil, inM represents either the group IVp in which R ⁴ and R ^{4 have the} above meaning, where, if Q, R ⁴ and R ^{5 are} simultaneously H, R ⁴ must not be H or phenyl, and

R⁵ pomeni H, nižji alkil, ali v danem primeru preko nižjega alkilena vezan COOH, COO-nižji alkil, nižji alkanoil, OH, nižji alkanoiloksi, NH₂, NHCOO-nižji alkil, NHSO₃H, (NHSO₂ ali NHSO₃)-nižji alkil, NH-nižji alkanoil, NHCOCOOH, NHCOCOO-nižji alkil ali NHPO₃(R9,RlO), ali, če Q ni H, tedaj jeR ⁵ represents H, lower alkyl, or optionally via lower alkylene bound COOH, COO-lower alkyl, lower alkanoyl, OH, lower alkanoyloxy, NH ₂ , NHCOO-lower alkyl, NHSO ₃ H, (NHSO ₂ or NHSO ₃ ) lower alkyl, NH lower alkanoyl, NHCOCOOH, NHCOCOO lower alkyl or NHPO ₃ (R9, R10), or, if Q is not H, then

M lahko tudi skupina M², v kateri je N(R^) v danem primeru s COOH ali COOnižjim alkilom substituiran N(CH2)4-9Nadaljni primeri spojin s formulo I so tisti, kjer Y stoji za H, X je skupina X^ in M je skupina M^, in v primeru, da vsaj eden izmed Rl in R² (v χΐ) ni H, in/ali v primeru, da Q ni H, in/ali v primeru, daje A alkil ali cikloalkil, tedaj je lahko M tudi skupina M².M may also be a group M ² in which N (R ^) is optionally substituted by COOH or COO lower alkyl N (CH2) 4-9 Further examples of compounds of formula I are those wherein Y is H, X is group X ^ and M is a group M ^, and in case at least one of R 1 and R ² (in χΐ) is not H, and / or in case Q is not H, and / or in case A is alkyl or cycloalkyl, then M may also be an M ² group.

Nadaljni primeri spojin s formulo I so tisti, kjer Y stoji za H, X je skupina X² in M je skupina ali M²;Further examples of compounds of formula I are those wherein Y is H, X is group X ² and M is group or M ² ;

nadalje tiste, kjer Y stoji za H, X je skupina χΐ in M skupina ali M^, pod pogojem, da vsaj eden izmed R^ in R² (v χΐ) ni H in/ali Q ni H in/ali, daje A alkil ali cikloalkil;further those where Y stands for H, X is a group χΐ and M is a group or M ^, provided that at least one of R ^ and R ² (in χΐ) is not H and / or Q is not H and / or that A alkyl or cycloalkyl;

nadalje tiste, kjer Y stoji za H, X je skupina in M skupina M² ali M², pod pogojem, da vsaj eden izmed R^ in R² (v χΐ) ni H in/ali Q ni H in/ali, daje A alkil ali cikloalkil;further those where Y stands for H, X is a group and M is a group M ² or M ² , provided that at least one of R ^ and R ² (in χΐ) is not H and / or Q is not H and / or that A is alkyl or cycloalkyl;

nadalje tiste, kjer Y in Q stojita za H, X je skupina XI in M skupina M^, in pod pogojem, da vsaj eden izmed R' in R² (v X1) ni H in/ali je A alkil ali cikloalkil, je M lahko tudi skupina M².further those where Y and Q are H, X is a group XI and M is a group M, and provided that at least one of R 'and R ² (in X1) is not H and / or A is alkyl or cycloalkyl, M can also be an M ² group.

Prednostne spojine s formulo I so tiste, kjer Y stoji za H, Q za nižji alkil(OH, COOH ali COO-nižji alkil), X skupino χΐ in M skupino ali M²;Preferred compounds of formula I are those wherein Y stands for H, Q for lower alkyl (OH, COOH or COO-lower alkyl), X group χΐ and M group or M ² ;

nadalje tiste, kjer je X skupina χΐ, T je CH², eden izmed Rl in R² je H in drugi H ali COO-(metil, etil, izobutil ali t-butil);further, where X is a group χΐ, T is CH ² , one of R 1 and R ² is H and the other H or COO- (methyl, ethyl, isobutyl or t-butyl);

nadalje tiste, kjer je X skupina χΐ, T je O, eden izmed Rl in R² je H in drugi H ali COOC₂H₅;further those in which X is a group χΐ, T is O, one of R, and R ² is H and the other is H or COOC ₂ H _5;

nadalje tiste, kjer je X skupina X² in R¹¹ in R²! stojita za H.further those where X is group X ² and R ¹¹ and R ² ! stand for H.

Nadalje je A prednostno naftil, metilkinolil, metiltetrahidrokinolil, metil, piridil ali s t-butilom, CF3, fenilom, ciklopentilom, karboksi, metoksikarbonilom, etoksikarbonilom, OCF3, CN, CONH2 ali tetrazolilom substituiran fenil, in je Q prednostno H, CH3, CH₂COOH, CH₂CH₂OH ali CH2COOC2H5.Further, A is preferably naphthyl, methylquinolyl, methyltetrahydroquinolyl, methyl, pyridyl or t-butyl, CF3, phenyl, cyclopentyl, carboxy, methoxycarbonyl, ethoxycarbonyl, OCF3, CN, CONH2 or tetrazolyl substituted phenyl, and Q is preferably H, CH3, CH. ₂ COOH, CH ₂ CH ₂ OH or CH ₂ COOC ₂ H 5.

Če je M skupina M^, je prednostno H, CH3, propil, izopropil, butil, pentil, alil, ciklopropil, ciklopentil, cikloheksil, ciklopropilmetil, cikloheksilmetil, piridilmetil ali v danem primeru s klorom ali metoksi substituiran benzil in R^ stoji za H, izopropil,If M is a group M, preferably H, CH 3, propyl, isopropyl, butyl, pentyl, allyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclohexylmethyl, pyridylmethyl or optionally chlorine or methoxy substituted benzyl and R 4 stands for H , isopropyl,

2-butil, izobutil, fenil, benzil ali cikloheksil.2-butyl, isobutyl, phenyl, benzyl or cyclohexyl.

V skupini je nadalje R^ prednostno skupina (CH₂)q.₂-R^® *ⁿ H, OH, C(CH₃)₂OH, COCH3, OCOCH3, COO(H, CH3 ali C₂H₅), NHCOOCH3, NHCOCH3, tetrazolil, CONH₂, metiloksadiazolil, OCH3, benziloksi, morfolinokarbonil, CONHOCH3, CONHO-benzil, CONHSO₂CH₃, CONHCH₂piridil, CONH-ciklopropil, CONHCH₂CH₂-C₆H₃(OH)₂, CONHCH₂CH₂OH, NHCOCOOH, NHCOCOOCH3, NHCOCOOC₂H₅, NHSO3H, NHSO₂CH₃, NHCOO-benzil, NHCOCH₂C1, NHCOCH₂OC₆H₅, NHCOCOC₆H₅, NHCOCOCH3, NHCO-piridil, NHCO-piridil-N-oksid, NHCO-pirazinil, NHCOCH₂C₆H₃(OH)₂, NHPO(OC₆H₅)₂, NHPO(OC₂H₅)₂, NH-(3,4-diokso2-hidroksiciklobut-l-enil) ali NH-(2-aliloksi-3,4-dioksociklobut-l-enil).In the group, further R4 is preferably the group (CH ₂ ) q. ₂ -R ^ ® * ⁿ H, OH, C (CH ₃ ) ₂ OH, COCH3, OCOCH3, COO (H, CH3 or C ₂ H ₅ ), NHCOOCH3, NHCOCH3, tetrazolyl, CONH ₂ , methyloxadiazolyl, OCH3, benzyloxy. morpholinocarbonyl, CONHOCH3, CONHO-benzyl, CONHSO ₂ CH ₃ , CONHCH ₂ pyridyl, CONH-cyclopropyl, CONHCH ₂ CH ₂ -C ₆ H ₃ (OH) ₂ , CONHCH ₂ CH ₂ OH, NHCOCOOH, NHCOCOOCH3, NHCOCOOC ₂ H ₅ , NHSO3H, NHSO ₂ CH ₃ , NHCOOO-benzyl, NHCOCH ₂ C1, NHCOCH ₂ OC ₆ H ₅ , NHCOCOC ₆ H ₅ , NHCOCOCH3, NHCO-pyridyl, NHCO-pyridyl-N-oxide, NHCO-pyrazinyl, NHCOCH ₂ C ₆ H ₃ (OH) ₂ , NHPO (OC ₆ H ₅ ) ₂ , NHPO (OC ₂ H ₅ ) ₂ , NH- (3,4-dioxo-2-hydroxycyclobut-1-enyl) or NH- (2-allyloxy-3,4 -dioxocyclobut-1-enyl).

Če je M skupina M^, je N(R^) prednostno heksametilenimino.If M is a group M ^, N (R ^) is preferably hexamethylenimino.

Primeri za prednostne spojine s formulo I so naslednji:Examples of preferred compounds of Formula I are as follows:

(S)-N4-[(S)-l-(amino-imino-metil)piperidin-3-ilmetil]-Nl-karboksimetil-Nlciklopentil-2-(naftalin-2-sulfonilamino)sukcinamid, [(S)-3-[(S)-2-(amino-imino-metil)piperidin-3-ilmetilkarbamoil]-2-(naftalen-2sulfonilamino)propionil]-propil-aminoocetna kislina,(S) -N4 - [(S) -1- (amino-imino-methyl) piperidin-3-ylmethyl] -Nl-carboxymethyl-Ncyclopentyl-2- (naphthalene-2-sulfonylamino) succinamide, [(S) -3 - [(S) -2- (amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -2- (naphthalene-2-sulfonylamino) propionyl] -propyl-aminoacetic acid,

N-[N4-[[(S)-l-(amidino-3-piperidinil]metil]-N2-(2-naftilsulfonil)-L-asparaginil]-N(o-klorbenzil)glicin, [2-[[(S)-3-[(S)-l-(amino-imino-metil)piperidin-3-ilmetilkarbamoil]-2-(naftalen-2sulfonilamino)propionil]-butil-amino]etil]oksamska kislina, (S)-N4-[(S)-l-(amino-imino-metil)piperidin-3-ilmetil]-Nl-butil-2-(naftalen-2sulfonilamino)-Nl-(2-sulfoamino-etil)-sukcinamid, [(S)-3-[(S)-l-(amino-imino-metil)piperidin-3-ilmetilkarbamoil]-2-(4-tbutilfenilsulfonilamino)-propionil-ciklopropil-amino]-ocetna kislina,N- [N4 - [[(S) -1- (amidino-3-piperidinyl] methyl] -N2- (2-naphthylsulfonyl) -L-asparaginyl] -N (o-chlorobenzyl) glycine, [2 - [[( S) -3 - [(S) -1- (amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -2- (naphthalene-2-sulfonylamino) propionyl] -butyl-amino] ethyl] oxamic acid, (S) -N4 - [(S) -1- (amino-imino-methyl) piperidin-3-ylmethyl] -Nl-butyl-2- (naphthalene-2sulfonylamino) -Nl- (2-sulfoamino-ethyl) -succinamide, [(S) -3 - [(S) -1- (amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -2- (4-tbutylphenylsulfonylamino) -propionyl-cyclopropyl-amino] -acetic acid,

2- [(S)-2-[(S)-l-amino-imino-metil)piperidin-3-ilmetilkarbamoil]-l-[ciklopropil-(2etoksikarbonil-etil)-karbamoil]-etilsulfamoil]-benzojska kislina,2- [(S) -2 - [(S) -1-amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -1- [cyclopropyl- (2ethoxycarbonyl-ethyl) -carbamoyl] -ethylsulfamoyl] -benzoic acid,

3- [[(S)-3-[(S)-l-amino-imino-metil)-piperidin-3-ilkarbamoil]-2-(4-cianofenilsulfonilamino)-propionil]-ciklopropil-amino]-propionska kislina, (S)-N(4)-[4-(amino-imino-metil)-morfolin-2-ilmetil]-N(l)-ciklopropil-N(l)-[2(tetrazol-5-il)-etil]-2-(naftalin-2-ilsulfonil)-sukcinamid, etil ester [[(S)-3-[4-(amino-imino-metil)-morfolin-2-ilmetilkarbamoil]-2-(naftalin-2-il sulfonil)-propionil]-ciklopropil-amino]-ocetne kisline, [[(S)-3-[4-(amino-imino-metil)-morfolin-2-ilmetilkarbamoil]-2-(naftalen-2-ilsulfonil)-propionil]-ciklopropil-amino]-ocetna kislina,3 - [[(S) -3 - [(S) -1-amino-imino-methyl) -piperidin-3-ylcarbamoyl] -2- (4-cyanophenylsulfonylamino) -propionyl] -cyclopropyl-amino] -propionic acid, (S) -N (4) - [4- (amino-imino-methyl) -morpholin-2-ylmethyl] -N (1) -cyclopropyl-N (1) - [2 (tetrazol-5-yl) -ethyl ] -2- (Naphthalin-2-ylsulfonyl) -succinamide, ethyl ester [[(S) -3- [4- (amino-imino-methyl) -morpholin-2-ylmethylcarbamoyl] -2- (naphthalin-2-yl) sulfonyl) -propionyl] -cyclopropyl-amino] -acetic acid, [[(S) -3- [4- (amino-imino-methyl) -morpholin-2-ylmethylcarbamoyl] -2- (naphthalen-2-ylsulfonyl) - propionyl] -cyclopropyl-amino] -acetic acid,

2- [[(S)-3-[(S)-l-(amino-imino-metil)-piperidin-3-ilmetilkarbamoil]-2-[naftalen-2ilsulfonilamino)-propionil]ciklopropil-amino]-etil-sulfaminska kislina, (S)-N4-[(S)-l-(amino-imino-metil)piperidin-3-ilmetil]-Nl-2-(kloroacetilamino-etil)Nl-ciklopropil-2-(naftalen-2-ilsulfonilamino)-sukcinamid, (S)-N4-[(S)-l-(amino-imino-metil)-piperidin-3-ilmetil]-Nl-ciklopropil-2-(naftalen-2ilsulfonilamino)-Nl-(2-fenoksiacetilamino-etil)-sukcinamid, (S)-N4-[(S)-l-(amino-imino-metil)-piperidin-3-ilmetil]-Nl-ciklopropil-2-(naftalen-2ilsulfonilamino)-Nl-[2-(2-okso-2-fenil-acetilamino)-etil]-sukcinamid, (S)-N4-[(S)-l-(amino-imino-metil)-piperidin-3-ilmetil]-Nl-ciklopropil-2-(naftalen-2ilsulfonilamino)-Nl-[2-(2-okso-propionilamino)-etil]-sukcinamid, (S)-N4-[(S)-l-(amino-imino-metil)-piperidin-3-ilmetil]-Nl-ciklopropil~2-(naftalen-2ilsulfonilamino)-Nl-[2-piridin-3-ilkarbonilamino)-etil]-sukcinamid, (S)-N4-[(S)-l-(amino-imino-metil)-piperidin-3-ilmetil]-Nl-ciklopropil-2-naftalen-2ilsulfonilamino-Nl-[2-(l-oksi-nikotinoilamino)-etil]-sukcinamid,2- [[(S) -3 - [(S) -1- (amino-imino-methyl) -piperidin-3-ylmethylcarbamoyl] -2- [naphthalen-2ylsulfonylamino) -propionyl] cyclopropyl-amino] -ethyl-sulfamine acid, (S) -N4 - [(S) -1- (amino-imino-methyl) piperidin-3-ylmethyl] -Nl-2- (chloroacetylamino-ethyl) N1-cyclopropyl-2- (naphthalen-2-ylsulfonylamino ) -succinamide, (S) -N4 - [(S) -1- (amino-imino-methyl) -piperidin-3-ylmethyl] -Nl-cyclopropyl-2- (naphthalen-2ylsulfonylamino) -Nl- (2-phenoxyacetylamino) -ethyl) -succinamide, (S) -N4 - [(S) -1- (amino-imino-methyl) -piperidin-3-ylmethyl] -Nl-cyclopropyl-2- (naphthalen-2ylsulfonylamino) -Nl- [2 - (2-oxo-2-phenyl-acetylamino) -ethyl] -succinamide, (S) -N4 - [(S) -1- (amino-imino-methyl) -piperidin-3-ylmethyl] -Nl-cyclopropyl- 2- (Naphthalen-2ylsulfonylamino) -Nl- [2- (2-oxo-propionylamino) -ethyl] -succinamide, (S) -N4 - [(S) -1- (amino-imino-methyl) -piperidine-3 -ylmethyl] -Nl-cyclopropyl ~ 2- (naphthalen-2ylsulfonylamino) -Nl- [2-pyridin-3-ylcarbonylamino) -ethyl] -succinamide, (S) -N4 - [(S) -1- (amino-imino) -methyl) -piperidin-3-ylmethyl] -N1-cyclopropyl-2-naphthalen-2ylsulfonylamino-N1- [2- (1-oxy- nicotinoylamino) -ethyl] -succinamide,

Posebno prednostne so:Particularly preferred are:

N-N4-[[(S)-l-amidino-3-piperidinil]metil]-N2-(2-naftilsulfoniI)-L-asparaginil]-Nciklopropilglicin, (S)-[[3-[(S)-l-(amino-imino-metil)-piperidin-3-ilmeti]karbamoil]-2-(naftalin-2sulfonilamino)propionil]ciklopropilamino]propionska kislina, [(S)-3-[(S)-l-(amino-imino-metil)-piperidin-3-ilmetilkarbamoil]-2-(4-trifluormetilfenilsulfonilamino)-propionil-ciklopropil-amino]ocetna kislina,N-N4 - [[(S) -1-amidino-3-piperidinyl] methyl] -N2- (2-naphthylsulfonyl) -L-asparaginyl] -Ncyclopropylglycine, (S) - [[3 - [(S) -1 - (amino-imino-methyl) -piperidin-3-ylmethyl] carbamoyl] -2- (naphthalin-2-sulfonylamino) propionyl] cyclopropylamino] propionic acid, [(S) -3 - [(S) -1- (amino-imino) -methyl) -piperidin-3-ylmethylcarbamoyl] -2- (4-trifluoromethylphenylsulfonylamino) -propionyl-cyclopropyl-amino] acetic acid,

3- [[(S)-3-[(S)-l-(amino-imino-metil)-piperidin-3-ilkarbamoil]-2-(4-karbamoilfenilsulfonilamino)-propionil]-ciklopropil-amino]propionska kislina, (S)-N4-[(S)-l-(amino-imino-metil)-piperidin-3-ilmetil]-Nl-ciklopropil-2-(naftalen-2ilsulfonilamino)’Nl-[2-(pirazin-2-ilkarbonilamino)-etil]-sukcinamid, (S)-N4-[(S)-l-(amino-imino-metil)-piperidin-3-ilmetil]-Nl-ciklopropil-Nl-[2-(3,4dihidroksi-fenil)-etilkarbamoilmetil]-2-(naftalen-2-ilsulfonilamino)-sukcinamid.3 - [[(S) -3 - [(S) -1- (amino-imino-methyl) -piperidin-3-ylcarbamoyl] -2- (4-carbamoylphenylsulfonylamino) -propionyl] -cyclopropyl-amino] propionic acid, (S) -N4 - [(S) -1- (amino-imino-methyl) -piperidin-3-ylmethyl] -N1-cyclopropyl-2- (naphthalen-2ylsulfonylamino) -1'- [2- (pyrazin-2- ylcarbonylamino) -ethyl] -succinamide, (S) -N4 - [(S) -1- (amino-imino-methyl) -piperidin-3-ylmethyl] -Nl-cyclopropyl-N1- [2- (3,4-dihydroxy- phenyl) -ethylcarbamoylmethyl] -2- (naphthalen-2-ylsulfonylamino) -succinamide.

Spojine s formulo I pripravimo na sam po sebi znan način tako, daThe compounds of formula I are prepared in a manner known per se in such a way that

a) kislino s formuloa) an acid of formula

COOH iCOOH i

YY

II pretvorimo z aminom s formuloII is converted by an amine of the formula

Q-NHCH₂-XQ-NHCH ₂ -X

III ali njegovo soljo ob intermediami zaščiti funkcionalnih skupin, kijih vsebujejo skupine A, Y in M (v II) in Q (v III), aliIII or its salt at the intermediates of protecting functional groups containing groups A, Y and M (in II) and Q (in III), or

b) amin s formulob) an amine of formula

QQ

X³ IVX ³ IV

I III II

Y O v kateri je skupina X^1 ali X^2·:Y O in which the group is X ^ 1 or X ^ 2 ·:

pretvorimo z amidirnim sredstvom inis converted by an amidating agent and

c) po želji funkcionalno pretvorimo reakcije sposobno skupino, ki se nahaja v skupini M ali Q spojine s formulo I, inc) optionally functionally converting the reaction-capable group contained in the group M or Q of a compound of formula I, and

d) po želji prevedemo spojino s formulo I v njeno fiziološko prenesljivo sol ali sol spojine s formulo I v prosto kislino ali bazo.d) optionally converting a compound of Formula I into its physiologically tolerated salt or salt of a compound of Formula I into a free acid or base.

Smotrno pretvorimo kislino II v topilu kot dimetilformamidu (DMF) ali metilenkloridu, v prisotnosti baze kot 4-etilmorfolina, trietilamina, etildiizopropilamina ali l,8-diazabiciklo[5.4.0]undec-7-ena (DBU), s soljo spojine s formulo III, npr. trifluoracetatom, bisulfitom, nitratom, hidrokloridom ali hidrojodidom, in z benzotriazol-l-iloksi-tris(dimetilamino)fosfonijevega heksafluorofosfata (BOP) pri sobni temperaturi. Funkcionalne skupine kot COOH, NH₂ in OH, ki se nahajajo v spojinah II in III, in jih je treba intermediarno zaščititi, se dajo zaščititi v obliki nižjih alkil-OCO-skupin, kot benzil-OCO- ali azidnih skupin oz. benziloksi skupin. Cepitev zaščitene karboksi skupine kot COOCH3 ali COOC2H5, v COOH, lahko poteka z natrijevim lugom v etanolu. Prevedba benzil-OCONH- ali N3- skupine v prosto amino skupino lahko izvedemo s katalitskim (paladij na oglju) hidriranjem v etanolu.It is advantageous to convert acid II in a solvent such as dimethylformamide (DMF) or methylene chloride, in the presence of a base such as 4-ethylmorpholine, triethylamine, ethyldiisopropylamine or 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), with a salt of a compound of the formula III, e.g. trifluoroacetate, bisulfite, nitrate, hydrochloride or hydroiodide, and with benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP) at room temperature. Functional groups such as COOH, NH ₂ and OH, which are present in compounds II and III, and which are to be intermediate protected, can be protected in the form of lower alkyl-OCO groups, such as benzyl-OCO or azide groups or. benzyloxy groups. Cleavage of a protected carboxy group, such as COOCH3 or COOC2H5, in COOH may be carried out with sodium hydroxide in ethanol. Conversion of the benzyl-OCONH- or N3-group to the free amino group can be carried out by catalytic (palladium on carbon) hydrogenation in ethanol.

V varianti b) postopka lahko pretvorimo spojino IV v topilu kot dimetilformamidu ali metanolu, v prisotnosti baze kot trietilamina, s formamidinsulfonsko kislino ali 3,5-dimetil-l-pirazolil-formamidinijevim nitratom, smotrno pri temperaturi do 50 °C.In variant b) of the process, compound IV can be converted in the solvent as dimethylformamide or methanol, in the presence of a base as triethylamine, with formamidinsulfonic acid or 3,5-dimethyl-1-pyrazolyl-formamidinium nitrate, preferably at a temperature of up to 50 ° C.

Kot funkcionalne pretvorbe variante c) lahko omenimo naslednje:As functional transformations of variant c) the following can be mentioned:

1. umiljenje estrske skupine kot etoksikarbonila, npr. v etanolu ali metanolu, s pomočjo baze kot vodnega NaOH, ali umiljenje estrske skupine kot acetoksi, npr. v tetrahidrofuranu, s pomočjo baze kot vodnega LiOH;1. saponification of an ester group as ethoxycarbonyl, e.g. in ethanol or methanol, using a base such as aqueous NaOH, or saponification of an ester group such as acetoxy, e.g. in tetrahydrofuran, using the base as aqueous LiOH;

2. hidriranje dvojne vezi v alkilenski skupini, npr. v etanolu in vodi v prisotnosti paladija na oglju;2. Hydrogenation of the double bond in the alkylene group, e.g. in ethanol and water in the presence of palladium on charcoal;

3. hidriranje arilne skupine v ustrezno cikloalkilno skupino, npr. v etanolu v prisotnosti ocetne kisline in paladija na oglju;3. hydrogenating the aryl group to a suitable cycloalkyl group, e.g. in ethanol in the presence of acetic acid and palladium on charcoal;

4. cepitev etra kot benziletra, v ustrezen alkohol, npr. s pomočjo raztopine borovega tribromida v metilenkloridu;4. splitting the ether as benzyl ether into the corresponding alcohol, e.g. by means of a solution of boron tribromide in methylene chloride;

5. zaetrenje alkohola, npr. z nižjim alkilhalogenidom kot metil jodidom, v prisotnosti raztopine DBU v tetrahidrofuranu;5. alcohol etching, e.g. with a lower alkyl halide than methyl iodide, in the presence of a DBU solution in tetrahydrofuran;

6. prevedbo karboksilne kisline v amid karboksilne kisline z reakcijo z aminom kot morfolinom, npr. v dimetilformamidu v prisotnosti BOP in6. the conversion of a carboxylic acid to a carboxylic acid amide by reaction with an amine as morpholine, e.g. in dimethylformamide in the presence of BOP and

4-etilmorfolina;4-ethylmorpholine;

7. a) pretvorbo amina v derivat quadrat kisline, npr. z reakcijo s 3,4-bis(2propeniloksi)-3-ciklobuten-l,2-diona v tetrahidrofuranu pri 0 °C in po želji7. a) conversion of an amine into a quadratic acid derivative, e.g. by reaction with 3,4-bis (2-propenyloxy) -3-cyclobutene-1,2-dione in tetrahydrofuran at 0 ° C and optionally

b) katalitsko odcepitev 2-propenilne skupine iz derivata quadrat kisline, dobljene pri a), npr. s pomočjo paladijevega(II)-acetata v acetonitrilu in vodi v prisotnosti trietil fosfita in nato natrijevega 2-etilkapronata.b) catalytic cleavage of the 2-propenyl group from the quadratic acid derivative obtained in a), e.g. using palladium (II) -acetate in acetonitrile and water in the presence of triethyl phosphite and then sodium 2-ethylcapronate.

N-sulfonirane amino kisline s formulo II se da pripraviti z reakcijo ustreznega reakcije sposobnega derivata sulfonake kisline kot sulfoklorida A-SO₂C1, z ustreznim, intermediarno zaščitenim derivatom amino-kisline HN(Y)-M-COO-tbutil, npr. tako, kot je opisano v EP-A-468231. Cepitev t-butil estra v želeno kislino II lahko izvedemo s trifluorocetno kislino v CH₂C1₂ ^s solno kislino v etilacetatu.The N-sulfonated amino acids of formula II can be prepared by the reaction of a suitable reaction of a capable sulfonic acid derivative such as sulfur chloride A-SO ₂ C1, with the corresponding, intermediate protected amino acid derivative HN (Y) -M-COO-tbutyl, e.g. as described in EP-A-468231. The cleavage of t-butyl ester into the desired acid II can be carried out with trifluoroacetic acid in CH ₂ C1 ₂ ^with hydrochloric acid in ethyl acetate.

Nadalje se da pripraviti amino kisline II, kjer je M skupina Ml, po naslednji Reakcijski shemi (1), (2) in (3):It is further possible to prepare amino acids II, where M is a group Ml, according to the following Reaction Schemes (1), (2) and (3):

R⁴ R⁴ (D R³-NH₂ + Br^ -- HN—R ⁴ R ⁴ (DR ³ -NH ₂ + Br ^ - HN-

R⁵ ^3 R⁵ R ⁵ ^ 3 R ⁵

Boc_x (2) V + NCHCH₂COO—tBuBoc _x (2) V + NCHCH ₂ COO — tBu

C IC I

C=OC = O

OHOH

Boc.Boc.

NCHCHoCOO—tBuNCHCHoCOO — tBu

NN

R³ R ³

R⁴ R ⁴

R⁵ R ⁵

VI (tBu = t-butoksi, Boc = tBu-OCO) (3) VIVI (tBu = t-butoxy, Boc = tBu-OCO) (3) VI

O z°O z °

XX

A^Z ''NCHCHoCOO —tBu ^z IA ^Z '' NCHCHoCOO —tBu ^with I

YY

VIIVII

II (M=MbII (M = Mb

Reakcijo (1) lahko izvedemo v topilu kot toluenu pri zvišani temperaturi. Reakcijo (2) izvedemo smotrno tako, kot više zgoraj opisano reakcijo II z III.Reaction (1) can be carried out in the solvent as toluene at elevated temperature. Reaction (2) is suitably carried out as described above with reaction II with III.

Reakcijo VI—> VII izvedemo tako, da najprej odcepimo v VI vsebovano Boc skupino od N-atoma, npr. v acetonitrilu ali dioksanu s p-toluensulfonsko kislino, in pretvorimo dobljeno spojino s sulfokloridom A-SO₂C1 v dioksanu. Hidroliza estrov VII v kisline II lahko poteka s trifluorocetno kislino v metilenkloridu.The reaction VI—> VII is carried out by first cleaving into the VI-containing Boc group of the N atom, e.g. in acetonitrile or dioxane with p-toluenesulfonic acid, and the resulting compound is converted with sulfochloride A-SO ₂ C1 in dioxane. Hydrolysis of esters VII to acids II can be carried out with trifluoroacetic acid in methylene chloride.

Priprava estra VII, v katerem je tetrazolil, poteka preko ustreznega estra, v katerem stoji za ciano. Pretvorbo ciano skupine v tetrazolilno skupino lahko izvedemo v dimetilformamidu s pomočjo amonijevega klorida in natrijevega azida.The preparation of ester VII, which is tetrazolyl, is carried out via the corresponding ester containing cyano. The conversion of the cyano group to the tetrazolyl group can be carried out in dimethylformamide using ammonium chloride and sodium azide.

Izhodne gvanidine III, kjer je X skupina X² in stoje Rl, R² in Q za H, lahko pripravimo tako, kot je opisano v EP-A-468231, npr. izhajajoč iz 3-pikolilamina oz. 2-aminometil-4-benziImorfolina, v odvisnosti od tega, ali želimo gvanidine III, s T = CH₂ oz. T = O. Za pripravo optično aktivnega gvanidina III lahko delamo tako, kot je opisano v Primeru 36B. N-(3-piridilmetil)benzamid katalitsko (paladij na oglju) hidriramo v etanolu in solni kislini v (RS)-N-piperidin-3-ilmetil-benzamid.Output guanidines III, wherein X is a group X ² and standing R, R ² and Q are H can be prepared as described in EP-A-468231, for example. starting from 3-picolylamine or Of 2-aminomethyl-4-benzylmorpholine, depending on whether guanidine III is desired, with T = CH ₂ or. T = O. The preparation of optically active guanidine III can be done as described in Example 36B. N- (3-pyridylmethyl) benzamide is catalytically (palladium on carbon) hydrated in ethanol and hydrochloric acid in (RS) -N-piperidin-3-ylmethyl-benzamide.

S tvorbo soli z d-mandljevo kislino v metilenkloridu lahko z dodatkom dietil etra kristaliziramo (R)N-piperidin-3-ilmetil-benzamid-mandelat. Le-tega lahko zatem v dimetilformamidu amidiramo s trietilaminom in formamidinsulfonsko kislino. S segrevanjm raztopine dobljenega mandelata v koncentrirani solni kislini lahko dobimo (S)-gvanidin s formulo III, kjer je X skupina in so Q = Rl = R² = H.By forming a salt of d-almond acid in methylene chloride, (R) N-piperidin-3-ylmethyl-benzamide-mandelate can be crystallized by the addition of diethyl ether. It can then be amidated in dimethylformamide with triethylamine and formamidinsulfonic acid. By heating a solution of the obtained mandelate in concentrated hydrochloric acid, (S) -guanidine of formula III can be obtained, where X is a group and Q = R 1 = R ² = H.

Gvanidin III z X = X² in Q, R¹¹ in R^l = H se da pripraviti analogno tistemu z X = χΐ, T = CH₂ in Q, R¹ in R² = H, npr. po naslednji reakcijski shemi (IV) in kot je opisano v Primeru 67a)b) v nadaljevanju:Guanidine III with X = X ² and Q, R ¹¹ and R ^ l = H can be prepared analogously to X = χΐ, T = CH ₂ and Q, R ¹ and R ² = H, e.g. according to the following reaction scheme (IV) and as described in Example 67a) b) below:

Gvanidine III, pri katerih eden izmed Rl in R² oz. R¹¹ in R²^ ni H, se da pripraviti npr. preko spojin tipa VIII, IX, X v naslednji reakcijski shemi (V) in tako, kot je opisano v Primeru 48a)b)c):Guanidines III, in which one of R, and R ² respectively. R ¹¹ and R ^{2 are} not H, e.g. via the compounds of type VIII, IX, X in the following reaction scheme (V) and as described in Example 48a) b) c):

Tako pretvorimo amin VIII v heksanu in vodi s tetrabutilamonijevim hidrogensulfatom in IN natrijevim lugom in nato z benzilkloroformiatom. Iz dobljene spojine IX odcepimo Boc-skupino z raztopino solne kisline v ocet estru. Produkt prevedemo v dimetilformamidu s trietilaminom in formamidinsulfonsko kislino v spojino X. Za zaščito amidinske skupine v spojini X slednjo pretvorimo npr. v metilenkloridu z etil estrom klormravljinčne kisline. S hidrokatalitsko odcepitvijo skupine Z dobimo derivat piperidina III, kjer je X skupina X^ in eden izmed Rl in R² stoji za etoksikarbonil. Na analogen način lahko pripravimo ustrezni morfolinski derivat III (T = O).Consequently, amine VIII is converted into hexane and water with tetrabutylammonium hydrogen sulphate and 1N sodium hydroxide and then with benzyl chloroformate. From the obtained compound IX, the Boc group is cleaved with a solution of hydrochloric acid in vinegar ester. The product is converted into dimethylformamide with triethylamine and formamidinsulfonic acid into compound X. To protect the amidine group in compound X, the latter is converted e.g. in methylene chloride with hydrochloric acid ethyl ester. With hidrokatalitsko cleavage of the Z group to give the piperidine derivative III in which X is X ^ and one of R, and R ² represents ethoxycarbonyl. The corresponding morpholine derivative III (T = O) can be prepared in an analogous manner.

Za zaščito amidinske skupine vsebovane v gvanidinu III z Boc- skupino lahko pretvorimo gvanidin tipa X z di-t-butildikarbonatom (namesto z etil estrom klormravljinčne kisline ) v dioksanu.To protect the amidine group contained in guanidine III with the Boc group, guanidine of type X can be converted with di-t-butyldicarbonate (instead of hydrochloric acid ethyl ester) in dioxane.

Gvanidine III s Q ni H, se da pripraviti npr. po naslednjih reakcijah (6) in (7), kotje opisano v naslednjem Primeru 9a) do d):Q guanidine III with Q is not H, e.g. by the following reactions (6) and (7) as described in the following Example 9a) to d):

Gvanidin III s Q ni H in T = O dobimo zGuanidine III with Q is not H and T = O is obtained by

a) pretvorbo 2-aminometil-4-benzilmorfolina (J. Med. Chem. 33,1990, 1406 1413) z di-t-butildikarbonatom v dioksanu,a) conversion of 2-aminomethyl-4-benzylmorpholine (J. Med. Chem. 33,1990, 1406 1413) with di-t-butyldicarbonate in dioxane,

b) pretvorbo dobljenega amina, zaščitenega z Boc, z NaH in bromidom Q-Br v dimetilformamidu,b) conversion of the resulting Boc protected amine with NaH and Q-Br bromide to dimethylformamide,

c) odcepitvijo benzilne skupine iz dobljenega produkta s hidriranjem v etanolu v prisotnosti paladija na oglju inc) the separation of the benzyl group from the product obtained by hydrogenation in ethanol in the presence of palladium on charcoal; and

d) amidiranjem dobljenega morfolinskega derivata, kotje više zgoraj opisano za spojino IV in odcepitvijo Boc skupine.d) amidating the morpholine derivative obtained as described above for compound IV and cleaving the Boc group.

Izhodne amine IV pripravimo npr. po naslednji reakciji (8), kjer je W zaščitna skupina kot Boc ali Z.The starting amines IV are prepared e.g. following reaction (8), wherein W is a protecting group such as Boc or Z.

Za pripravo spojine IV kjer Q ni H, pretvorimo primaren amin XII, [ki se da pripraviti iz 3-hidroksimetilpiperidina, kot je opisano v EP-A-468231 in v sledečem Primeru 12a) do g)] v topilu kot metilenkloridu, z bazo kot Hunigovo bazo in bromidom Q-Br v sekundaren amin XIII. Kislino II nato pripajamo s tem aminom XIII (kot je opisano pri zgornjem pripajanju II + III). Zaščitno skupino Boc nato odcepimo s trifluorocetno kislino v metilenkloridu, p-toluensulfonski kislini v acetonitrilu ali raztopini klorovodika v etil acetatu. Odcepitev zaščitne skupine Z izvedemo s hidriranjem v etanolu v prisotnosti paladija na oglju. Za pripravo spojine IV, kjer je Q = H, pripajamo kislino II z aminom XII (namesto XIII).To prepare compound IV where Q is not H, the primary amine XII [which can be prepared from 3-hydroxymethylpiperidine as described in EP-A-468231 and in the following Example 12a) to g) is converted into a solvent such as methylene chloride, with a base as Hunig base and Q-Br bromide into secondary amine XIII. Acid II is then coupled with this amine XIII (as described in II + III above). The Boc protecting group is then cleaved with trifluoroacetic acid in methylene chloride, p-toluenesulfonic acid in acetonitrile or a solution of hydrogen chloride in ethyl acetate. Cleavage of protecting group Z is carried out by hydrogenation in ethanol in the presence of palladium on charcoal. To prepare compound IV, where Q = H, acid II is added with amine XII (instead of XIII).

Priprava izhodnega amina IV, kjer je M skupina Ml in stoji za NHCOCOO-nižji alkil, poteka preko spojine s formulo IV, v kateri stoji za azido skupino. Pretvorba azido v NHCOCOO-nižji alkil lahko poteka s katalitskim hidriranjem (Pd/C v metanolu) čemur sledi pretvorba nastale amino skupine v NHCOCOO-nižji alkil z reakcijo z mono-nižji alkil ester kloridom oksalne kisline v prisotnosti piridina v metilen kloridu. Če namesto mono-nižji alkil ester klorida oksalne kisline uporabimo pirazinkarboksilno kislino v prisotnosti Hunigove baze v metilenkloridu, dobimo spojino IV, v kateri je M = Ml in R^ = NHCO-pirazinil.The preparation of the starting amine IV, where M is a group M1 and stands for NHCOCOO-lower alkyl, is carried out via a compound of formula IV in which it stands for an azide group. The conversion of azido to NHCOCOO-lower alkyl can be carried out by catalytic hydrogenation (Pd / C in methanol) followed by conversion of the resulting amino group to NHCOCOO-lower alkyl by reaction with oxalic acid mono-lower alkyl ester in the presence of pyridine in methylene chloride. If pyrazincarboxylic acid is used instead of the mono-lower alkyl ester of oxalic acid chloride in the presence of Hunig's base in methylene chloride, compound IV is obtained wherein M = M1 and R ^ = NHCO-pyrazinyl.

Vrhu tega vsebujejo nekateri izmed naslednjih primerov podrobne podatke, ki se nanašajo na pripravo določenih spojin s formulami II, III in IV. Spojine s formulo III, kjer je X skupina χΐ in vsaj eden izmed Rl, R^ in Q ni H, ali kjer je X skupina X^, kot tudi spojine s formulo IV, kjer je M skupina Ml, ali, če je skupina X·^^, ali, če je X skupina Χ^Ι, in istočasno Q ni H in/ali, če je A alkil ali cikloalkil, tedaj je M lahko tudi ena od skupin M^ do M$ so nove in kot take prav tako predmet predloženega izuma.In addition, some of the following examples provide detailed information relating to the preparation of certain compounds of formulas II, III and IV. Compounds of formula III wherein X is a group χΐ and at least one of R1, R4 and Q is not H, or where X is a group X ^, as well as compounds of formula IV, where M is a group Ml, or, if a group is X · ^^, or, if X is a group Χ ^ Ι, and at the same time Q is not H and / or if A is alkyl or cycloalkyl, then M may also be one of the groups M ^ to M $ are new and, as such, the subject of the present invention.

Spojine s formulo I, njihovi solvati in njihove soli zavirajo tako s trombinom izzvano agregacijo ploščic kot tudi s trombinom izzvano strjevanje fibrinogena v krvni plazmi. Navedene spojine vplivajo tako na s ploščicami izzvano kot tudi na plazmatsko strjevanje krvi. S tem preprečujejo zlasti nastanek strjevalnih trombov kot tudi na ploščicah bogatih trombov in se jih da uporabiti pri terapiji oz. profilaksi bolezni kot tromboze, apopleksije, srčnega infarkta, vnetij in arterioskleroze. Nadalje učinkujejo te spojine na tumorske celice in preprečujejo tvorbo metastaz. Torej se jih da uporabiti tudi kot sredstva proti tumorjem.The compounds of formula I, their solvates and their salts inhibit both thrombin-induced platelet aggregation and thrombin-induced clotting of fibrinogen in blood plasma. These compounds affect both platelet-induced and plasma blood clotting. This prevents, in particular, the formation of clotting thrombi as well as platelet-rich thrombi and can be used in therapy or therapy. prophylaxis of diseases such as thrombosis, apoplexy, heart attack, inflammation and arteriosclerosis. They further effect these compounds on tumor cells and prevent the formation of metastases. Therefore, they can also be used as anti-tumor agents.

Različno zaviranje trombina in drugih serin-proteaz z zgornjimi spojinami je zaželeno, da dobimo spojine s po možnosti veliko specifičnostjo in se s tem izognemo možnim stranskim učinkom. Poleg drugih testiranih serin-proteaz smo razmerje zaviranja tripsina proti zaviranju trombina vzeli kot splošno merilo za specifičnost spojine (q v naslednji tabeli), ker se da tripsin kot najmanj specifično serin-proteazo zlahka zavirati z najrazličnejšimi zaviralci. Da bi mogli direktno primerjati zaviranje pri trombinu in tripsinu kljub uporabi najrazličnejših substratov, smo kot merilo za zaviranje ugotovili zaviralno konstanto Ki, neodvisno od koncentracije substrata in encima.Different inhibition of thrombin and other serine proteases by the above compounds is desirable in order to obtain compounds with possibly high specificity, thus avoiding possible side effects. Among the other serine proteases tested, the ratio of trypsin inhibition to thrombin inhibition was taken as the general criterion for the specificity of the compound (q in the following table), because trypsin can be easily inhibited by a variety of inhibitors as the least specific serine protease. In order to be able to directly compare inhibition of thrombin and trypsin despite the use of a wide variety of substrates, we determined the inhibition constant Ki as a measure of inhibition, independent of substrate concentration and enzyme.

Za dokaz zaviranja katalitske aktivnosti zgornjih proteaz se da uporabiti specifične kromogene peptidne substrate. Zaviranje amidolitične aktivnosti trombina in tripsina z zgornjimi spojinami smo dokazali tako, kot bo opisano v nadaljevanju.Specific chromogenic peptide substrates can be used to demonstrate inhibition of the catalytic activity of the above proteases. Inhibition of the amidolytic activity of thrombin and trypsin by the above compounds was demonstrated as described below.

Meritve smo izvedli na mikrotitrirnih ploščah pri sobni temperaturi. Pri tem smo na vdolbinico v plošči pomešali 150 μϊ pufra (50 mM Tris, 100 mM NaCl, 0.1% polietilenglikola; pH 7.8) s 50 μ\ zaviralne snovi, raztopljene v DMSO in razredčene s pufrom, ter dodali 25 μ\ humanega trombina (0.5 nM končna koncentracija). Po 10 minutah inkubacije smo reakcijo sprožili z dodatkom kromogenega substrata S-2238(H-D-Phe-Pip-Arg-paranitroanilina od Kabivitrum; 10 ali 50 μΜ končna koncentracija) in zasledovali hidrolizo substrata spektrofotometrično v teku 5 minut na kinetičnem odčitovalniku za mikrotitrirne plošče. Po grafični predstavitvi zaviralnih krivulj smo določili Ki- vrednosti po metodi, opisani v Biochem. J. 55,The measurements were performed on microtiter plates at room temperature. To this, 150 μϊ of buffer (50 mM Tris, 100 mM NaCl, 0.1% polyethylene glycol; pH 7.8) was mixed per well in a plate with 50 μ \ inhibitors dissolved in DMSO and diluted with buffer, and 25 μ \ human thrombin added ( 0.5 nM final concentration). After 10 minutes of incubation, the reaction was initiated by the addition of the chromogenic substrate S-2238 (H-D-Phe-Pip-Arg-paranitroaniline from Kabivitrum; 10 or 50 μΜ final concentration) and followed the hydrolysis of the substrate spectrophotometrically over 5 minutes on a microtiter plate kinetic reader. Following the graphical representation of the inhibitory curves, Ki values were determined according to the method described in Biochem. J. 55,

1955, 170-171. Zaviranje tripsina je poteklo analogno, vendar ob uporabi substrata S-2251 (H-D-Val-Leu-Lys-paranitroanilin) v 200 in 750 μΜ končne koncentracije; rezultati so razvidni iz naslednje Tabele;1955, 170-171. Trypsin inhibition expired in analogy but using S-2251 (H-D-Val-Leu-Lys-paranitroaniline) substrate at 200 and 750 μΜ final concentrations; the results are shown in the following Table;

Produkt iz Primera Product from For example Kj (nM) trombin Kj (nM) thrombin Kj (nM) tripsin Kj (nM) trypsin q q 2k 2k 0.40 0.40 7700 7700 19250 19250 4a 4a 0.27 0.27 1900 1900 7143 7143 4i 4i 0.82 0.82 5000 5000 6098 6098 4k 4k 0.30 0.30 8100 8100 27000 27000 41 41 0.56 0.56 5000 5000 8929 8929 5 5 0.22 0.22 4300 4300 19545 19545 15a 15a 0.85 0.85 6100 6100 7176 7176 15b 15b 0.99 0.99 2100 2100 2121 2121 16 16 0.81 0.81 2100' 2100 ' 2593 2593 26b 26b 0.25 0.25 130 130 524 524 29 29 0.44 0.44 1800 1800 4091 4091 30 30 0.75 0.75 2400 2400 3200 3200 31c 31c 2.20 2.20 7700 7700 3500 3500

Spojine s formulo I imajo neznatno toksičnost. Tako imajo produkti iz Primerov, naštetih v Tabeli, pri intravenoznem dajanju miši LD50 125 do 500 mg/kg.The compounds of formula I have little toxicity. Thus, the products of the Examples listed in the Table have 125 to 500 mg / kg for intravenous administration of LD50 mice.

Kot smo uvodoma omenili, so zdravila, ki vsebujejo spojino s formulo I, njen solvat ali sol, prav tako predmet predloženega izuma, nadalje tudi postopek za pripravo tovrstnih zdravil, ki je značilen po tem, da eno ali več drugih, terapevtsko dragocenih snovi prevedemo v galensko dajalno obliko. Dražeji, trde in mehke želatinske kapsule, raztopine, emulzije ali suspenzije, se dajo dajati oralno, ali pa rektalno, npr. v obliki supozitorijev, ali pa kot spraye. Dajanje pa lahko poteka tudi parenteralno, npr. v obliki injekcijskih raztopin.As mentioned above, medicaments containing a compound of Formula I, a solvate or salt thereof, are also an object of the present invention, and further a process for the preparation of such medicaments, characterized in that one or more other therapeutically valuable substances are translated into galenic administration form. Dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions may be administered orally or rectally, e.g. in the form of suppositories, or as sprays. However, administration may also occur parenterally, e.g. in the form of injection solutions.

Za pripravo tablet, lakiranih tablet, dražejev in trdih želatinskih kapsul lahko učinkovino pomešamo s farmacevtsko inertnimi anoraganskimi ali organskimi dodatki (polnili). Kot taki dodatki se dajo uporabiti pri tabletah, lakiranih tabletah, dražejih in trdih želatinskih kapsulah npr. laktoza, koruzni škrob ali njuni derivati, smukec, stearinska kislina ali njene soli. Za mehke želatinske kapsule so kot polnila primerna npr. rastlinska olja, voski, maščobe, poltrdni in tekoči polioli; v odvisnosti od strukture učinkovine pa pri mehkih želatinskih kapsulah sploh niso potrebni dodatki (polnila). Za pripravo raztopin in sirupov so kot dodatki primerni npr. voda, polioli, saharoza, invertni sladkor in glukoza; za injekcijske raztopine so primerni npr. voda, alkoholi, polioli, glicerin in rastlinska olja; za supozitorije pa so primerna npr. naravna ali trdena olja, voski, masti, poltekoči ali tekoči polioli. Farmacevtski pripravki pa lahko vsebujejo še konzervirna sredstva, posredovalce topnosti, stabilizirna sredstva, omočila, emulgirna sredstva, sladila, barvila, aromatizirna sredstva, soli za spremembo osmotskega tlaka, pufre, preslojevalna sredstva ali antioksidante.For the preparation of tablets, lacquer tablets, dragees and hard gelatin capsules, the active ingredient may be mixed with pharmaceutically inert inorganic or organic additives (fillers). As such, additives can be used in tablets, lacquer tablets, dragees and hard gelatin capsules, e.g. lactose, maize starch or derivatives thereof, talc, stearic acid or its salts. For soft gelatin capsules, e.g. vegetable oils, waxes, fats, semi-solid and liquid polyols; Depending on the structure of the active substance, no additives (fillers) are required at all in soft gelatin capsules. For the preparation of solutions and syrups, suitable additives are e.g. water, polyols, sucrose, invert sugar and glucose; for injection solutions are suitable e.g. water, alcohols, polyols, glycerin and vegetable oils; for suppositories, for example, natural or solid oils, waxes, greases, semi-liquid or liquid polyols. Pharmaceutical preparations may also contain preservatives, solubilizers, stabilizing agents, wetting agents, emulsifying agents, sweeteners, colorants, flavoring agents, osmotic pressure salts, buffers, coating agents or antioxidants.

Za terapijo oz. preventivo više zgoraj navedenih bolezni lahko doziranje učinkovine variira v širokih mejah in gaje seveda v vsakem posameznem primeru treba prilagoditi individualnim okoliščinam. Na splošno pa bo pri oralnem ali parenteralnem, npr. inravenoznem ali subkutanem dajanju primerna doza okoliFor therapy or. the prevention of several of the abovementioned diseases can vary the dosage of the active ingredient within wide limits and, of course, must be adapted to the individual circumstances in each individual case. In general, oral or parenteral, e.g. intravenous or subcutaneous administration of a suitable dose around

0.1 do 20 mg/kg, prednostno okoli 0.5 do 4 mg/kg dnevno za odrasle, pri čemer pa lahko pravkar navedeno zgornjo mejo tudi prekoračimo ali zmanjšamo, če bi se to izkazalo kot priporočljivo.0.1 to 20 mg / kg, preferably about 0.5 to 4 mg / kg, per day for adults, but the upper limit may also be exceeded or reduced if deemed appropriate.

Primer 1Example 1

Raztopini 0.85 g t-butil-(S)-N-cikloheksil-N-[(etoksikarbonil)-metil]-3-(2naftilsulfonamido)sukcinamata v 21 ml metilenklorida dodamo pri 0 °C 2.4 ml trifluorocetne kisline in mešamo pri sobni temperaturi. Peno, dobljeno po uparjenju raztopine, raztopimo v 13 ml dimetilformamida, nato dodamo 0.98 ml 4-etilmorfolina, 0.68 g benzotriazol-l-iloksi-tris(dimetilamino)fosfonijevega heksafluorfosfata in 0.43 g (S)-l-amidino-3-(aminometil)piperidin-dihidroklorida in mešamo pri sobni temperaturi. Reakcijsko zmes uparimo in ostanek kromatografiramo z ocet estrom, nato pa z ocetestrom/acetonom/ocetno kislino/vodo 16:2:1:1 na kremeničnem gelu. Izoliramo 0.85 g etil ester diacetata N-[N4-[[(S)-l-amidino-3piperidinil]metil]-N2-(2-naftilsuIfonil)-L-asparaginil]-N-cikloheksilglicina;To a solution of 0.85 g of t-butyl- (S) -N-cyclohexyl-N - [(ethoxycarbonyl) -methyl] -3- (2-naphthylsulfonamido) succinamate in 21 ml of methylene chloride was added at 0 ° C 2.4 ml of trifluoroacetic acid and stirred at room temperature. The foam obtained after evaporation of the solution is dissolved in 13 ml of dimethylformamide, then 0.98 ml of 4-ethylmorpholine, 0.68 g of benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate and 0.43 g of (S) -1-amidino-3- (aminomethyl) are added of piperidine dihydrochloride and stirred at room temperature. The reaction mixture was evaporated and the residue was chromatographed with ethyl acetate and then with 16: 2: 1: 1 acetone / acetone / acetic acid / water on silica gel. 0.85 g of N- [N4 - [[(S) -1-amidino-3-piperidinyl] methyl] -N2- (2-naphthylsulfonyl) -L-asparaginyl] -N-cyclohexylglycine ethyl ester is isolated;

Fab-MS: 629.3 (M + H) + .Fab-MS: 629.3 (M + H) < + >.

Priprava izhodnega materiala:Preparation of starting material:

a) Raztopini 2.89 g 0-t-butil estra N-boc-L-asparaginske kisline v 50 ml dimetilformamida dodamo 3.78 ml 4-etiImorfolina, 4.42 g benzotriazol-l-iloksitris(dimetilamino)fosfonijevega heksafluorfosfata (BOP) in raztopino 2.25 g etil estra N-cikloheksilglicina (J. Heterocykl. Chem. 23, 1986, 929-933) v 8 ml dimetilformamida. Reakcijsko zmes mešamo pri sobni temperaturi, nato uparimo in ostanek porazdelimo med ocetestrom in vodo. Organsko fazo sušimo, uparimo in ostanek kromatografiramo z ocetestrom/heksanom 1:1 na kremeničnem gelu. Izoliramo 4.5 g t-butil-(S)-3-(l-t-butoksiformamido)-N-cikloheksil-N-[(etoksikarbonil)metil]sukcinamata, Fab-MS: 457 (M + H) ⁺ .a) To a solution of 2.89 g of N-boc-L-aspartic acid 0-t-butyl ester in 50 ml of dimethylformamide was added 3.78 ml of 4-ethylmorpholine, 4.42 g of benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP) and a solution of 2.25 g of N-cyclohexylglycine ester (J. Heterocycle. Chem. 23, 1986, 929-933) in 8 ml of dimethylformamide. The reaction mixture was stirred at room temperature, then evaporated and the residue partitioned between acetone and water. The organic phase was dried, evaporated and the residue was chromatographed with 1: 1 ethyl acetate / hexane on silica gel. Isolate 4.5 g of t-butyl- (S) -3- (lt-butoxyformamido) -N-cyclohexyl-N - [(ethoxycarbonyl) methyl] succinamate, Fab-MS: 457 (M + H) ⁺ .

b) Raztopini 2.1 g produkta iz a) v 22 ml acetonitrila dodamo 2.2 g monohidrata ptoluensulfonske kisline ob mešanju. Nato raztopino uparimo in sušimo. 2.4 g ostanka raztopimo v 45 ml dioksana in dodamo raztopino 1.56 g b-naftilsulfoklorida v 15 ml dioksana. Dodamo 1.9 g natrijevega hidrogen karbonata v 19 ml vode. Po mešanju izlijemo reakcijsko zmes na led in ekstrahiramo z ocetestrom. Organsko fazo izperemo z vodo, nato sušimo in uparimo. Preostanek kromatografiramo s heksanom/ocetestrom 4:1 na kremeničnem gelu. Dobimo 0.85 g t-butil-(S)-Ncikloheksil-N-[(etoksikarbonil)metil]-3-(2-naftilsulfonamido)sukcinamata,b) To a solution of 2.1 g of the product from a) in 22 ml of acetonitrile is added 2.2 g of ptoluenesulfonic acid monohydrate while stirring. The solution was then evaporated and dried. Dissolve 2.4 g of the residue in 45 ml of dioxane and add a solution of 1.56 g of b-naphthylsulfochloride in 15 ml of dioxane. 1.9 g of sodium hydrogen carbonate in 19 ml of water are added. After stirring, pour the reaction mixture onto ice and extract with acetone. The organic phase is washed with water, then dried and evaporated. The residue was chromatographed with hexane / acetone 4: 1 on silica gel. 0.85 g of t-butyl- (S) -Ncyclohexyl-N - [(ethoxycarbonyl) methyl] -3- (2-naphthylsulfonamido) succinamate is obtained,

Fab-MS: 547 (M+H) + .Fab-MS: 547 (M + H) < + >.

Primer 2Example 2

2.A) Analogno Primeru 1 pripravimo naslednje spojine:2.A) The following compounds were prepared analogously to Example 1:

a) Etil ester acetat N-[N4-[[(S)-l-amidino-3-piperidinil]metil]-N2-(2-naftilsulfonil)L-asparaginil]-N-ciklopropilglicina, MS (ionski spray): 587,3 (M+H)⁺,a) N- [N4 - [[(S) -1-amidino-3-piperidinyl] methyl] -N2- (2-naphthylsulfonyl) L-asparaginyl] -N-cyclopropylglycine ethyl ester, MS (ion spray): 587 , 3 (M + H) < ⁺ >,

b) Etil ester acetat [[(S)-3-[(S)-l-(amino-imino-metil)piperidin-3-ilmetilkarbamoil]2-(naftalin-2-sulfonilamino)propionil]benzilamino] ocetne kisline, MS (ionski spray): 637,3 (M+H)+,b) [[(S) -3 - [(S) -1- (amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] 2- (naphthalene-2-sulfonylamino) propionyl] benzylamino] acetic acid ethyl ester, MS (ion spray): 637.3 (M + H) +,

c) Metil ester acetat N-[N4-[[(S)-l-amidino-3-piperidinil]metil]-N2-(2-naftilsulfonil) L-asparaginil]-N-cikloheksilglicina, MS (ionski spray): 629,4 (M + H) ⁺ ,c) N- [N4 - [[(S) -1-amidino-3-piperidinyl] methyl] -N2- (2-naphthylsulfonyl) L-asparaginyl] -N-cyclohexylglycine methyl ester, MS (ion spray): 629 , 4 (M + H) < ⁺ >,

d) Etil ester hidroklorid N-[N4-[[(S)-l-amidino-3-piperidinil]metil]-N2-(2naftilsulfonil)-L-asparaginil]-N-metilglicina, MS (ionski spray): 561,5 (M + H)⁺,d) N- [N4 - [[(S) -1-amidino-3-piperidinyl] methyl] -N2- (2-naphthylsulfonyl) -L-asparaginyl] -N-methylglycine ethyl ester hydrochloride, MS (ion spray): 561. 5 (M + H) < ⁺ >,

e) Etil ester hidroklorid N-[N4-[[(S)-l-amidino-3-piperidinil]metiI]-N2-(2naftilsulfonil)-L-asparaginil]-N-izopropilglicina, MS (ionski spray): 589,0 (M + H)⁺,e) N- [N4 - [[(S) -1-Amidino-3-piperidinyl] methyl] -N2- (2-naphthylsulfonyl) -L-asparaginyl] -N-isopropylglycine ethyl ester hydrochloride, MS (ion spray): 589, 0 (M + H) < ⁺ >,

f) Etil ester hidroklorid (S)-[N-alil-[3-[(S)-l-(amino-imino-metil)piperidin-3ilmetilkarbamoil]-2-(naftalin-2-sulfonilamino)propionil]amino] ocetne kisline,f) (S) - [N-allyl- [3 - [(S) -1- (amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -2- (naphthalene-2-sulfonylamino) propionyl] amino] acetic acid ethyl ester acids,

MS (ionski spray); 587,0 (M + H)+,MS (ion spray); 587.0 (M + H) < + >,

g) Etil ester hidroklorid N-[(S)-3-[(S)-l-(amino-imino-metil)piperidin-3ilmetilkarbamoil]-2-(naftalin-2-sulfonilamino)propionil]butilamino]ocetne kisline, MS (ionski spray): 603,2 (M + H) ⁺ ,g) N - [(S) -3 - [(S) -1- (amino-imino-methyl) piperidin-3ylmethylcarbamoyl] -2- (naphthalene-2-sulfonylamino) propionyl] butylamino] acetic acid ethyl ester hydrochloric acid, MS (ion spray): 603.2 (M + H) ⁺ ,

h) Etil ester hidroklorid N-[N4-[[(S)-l-amidino-3-piperidinil]metilj-N2-(2naftilsulfonil)-L-asparaginil]-N-ciklopropi!metil)glicina,h) N- [N4 - [[(S) -1-amidino-3-piperidinyl] methyl-N2- (2-naphthylsulfonyl) -L-asparaginyl] -N-cyclopropylmethyl) glycine ethyl ester hydrochloride,

MS (ionski spray): 601,2 (M + H) ⁺ ,MS (ion spray): 601.2 (M + H) ⁺ ,

i) Hidroklorid S-N4-[(S)-l-(amino-imino-metil)piperidin-3-ilmetil]-N 1-etoksikarbonilmetil-Nl-ciklopentil-2-(naftalin-2-sulfonilamino)sukcinamida,i) S-N4 hydrochloride - [(S) -1- (amino-imino-methyl) piperidin-3-ylmethyl] -N 1-ethoxycarbonylmethyl-N 1 -cyclopentyl-2- (naphthalene-2-sulfonylamino) succinamide,

MS (ionski spray): 615,2 (M + H),MS (ion spray): 615.2 (M + H),

j) Etil ester hidroklorid N-[N4-[[(S)-l-amidino-3-piperidinil]metil]-N2-(2naftilsulfonil)-L-asparaginil]-L-levcina, MS (ionski spray): 603,0 (M+H)+,j) N- [N4 - [[(S) -1-amidino-3-piperidinyl] methyl] -N2- (2-naphthylsulfonyl) -L-asparaginyl] -L-leucine ethyl ester hydrochloride, MS (ion spray): 603, 0 (M + H) < + >,

k) Etil ester hidroklorid N-[N4-[[(S)-l-amidino-3-piperidinil]metil]-N2-(2naftilsulfonil)-L-asparaginil]-N-ciklopropil-/?-alanina,k) N- [N4 - [[(S) -1-amidino-3-piperidinyl] methyl] -N2- (2-naphthylsulfonyl) -L-asparaginyl] -N-cyclopropyl -? - alanine ethyl ester hydrochloride,

MS (ionski spray): 601,3 (M+H)⁺,MS (ion spray): 601.3 (M + H) ⁺ ,

l) Etil ester hidroklorid (S)-3-[alil-[3-[(S)-l-amino-imino-metil)piperidin-3ilmetilkarbamoil]-2-(naftalin-2-sulfonilamino)propionil]amino]propionske kisline,l) (S) -3- [Allyl- [3 - [(S) -1-amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -2- (naphthalene-2-sulfonylamino) propionyl] amino] propionic acid ethyl ester hydrochloride ,

MS (ionski spray): 601,2 (M+H)⁺,MS (ion spray): 601.2 (M + H) ⁺ ,

m) Hidroklorid (S)-N4-[(S)-l-amino-imino-metil)piperidin-3-ilmetil]-Nl-butil-Nl-(2etoksikarboniletil)-2-(naftalen-2-ilsulfonilamino)-sukcinamida,m) Hydrochloride (S) -N4 - [(S) -1-amino-imino-methyl) piperidin-3-ylmethyl] -Nl-butyl-N1- (2ethoxycarbonylethyl) -2- (naphthalen-2-ylsulfonylamino) -succinamide ,

MS (ionski spray): 617,5 (M + H) + ,MS (ion spray): 617.5 (M + H) +,

n) Etil ester hidroklorid (S)-3-[(S)-l-amino-imino-metil)piperidin-3ilmetilkarbamoil]-2naftalen-2-ilsulfonilamino)-N-pentil-propionilamino-ocetne kisline, (1:1), MS (ionski spray): 617,5 (M + H)⁺,n) (S) -3 - [(S) -1-amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -2-naphthalen-2-ylsulfonylamino) -N-pentyl-propionylamino-acetic acid ethyl ester hydrochloride, (1: 1) , MS (ion spray): 617.5 (M + H) ⁺ ,

2.B) Priprava izhodnih materialov:2.B) Preparation of starting materials:

2.B)a) Raztopini 15.4 ml ciklopropilamina v 100 ml toluena dodamo 14.0 ml etil estra 3-brompropionske kisline in segrevamo reakcijsko zmes 3 ure na 90 °C. Zatem filtriramo od izločene soli in filtrat destiliramo. Dobimo 9.5 g etil estra N-ciklopropil3-alanina, Fab-MS: 157(M+H) + .2.B) a) To a solution of 15.4 ml of cyclopropylamine in 100 ml of toluene is added 14.0 ml of 3-bromopropionic acid ethyl ester and the reaction mixture is heated to 90 ° C for 3 hours. It is then filtered off from the recovered salt and the filtrate distilled. 9.5 g of N-cyclopropyl3-alanine ethyl ester, Fab-MS: 157 (M + H) +, are obtained.

2.B)b) Analogno postopku iz 2.B)a) pripravimo ob uporabi alilamina oz. butilamina namesto ciklopropilamina naslednje spojine:2.B) b) In analogy to the procedure in 2.B) a), prepared using allylamine or butylamine instead of cyclopropylamine the following compounds:

1) Etil ester N-alil-j8-alanina, Fab-MS: 157 (M ⁺ ),1) N-allyl-18-alanine ethyl ester, Fab-MS: 157 (M ⁺ ),

2) etil ester 3-butilaminopropionske kisline, Fab-MS: 173 (M ⁺ ).2) 3-Butylaminopropionic acid ethyl ester, Fab-MS: 173 (M ⁺ ).

2.B)c) Analogno Primeru (la), vendar ob uporabi N-substituiranega glicin estra namesto etil estra N-cikloheksilglicina dobimo naslednje triestre:2.B) c) Analogous to Example (1a), but using the N-substituted glycine ester instead of the N-cyclohexylglycine ethyl ester, the following triesters are obtained:

2.B)c)l) t-butil-(S)-2-(2-t-butoksiformamido)-N-ciklopropil-N[(etoksikarbonil)metiljsukcinamat, Fab-MS: 415 (M + H) ⁺ ,2.B) c) 1) t-butyl- (S) -2- (2-t-butoxyformamido) -N-cyclopropyl-N [(ethoxycarbonyl) methylsuccinamate, Fab-MS: 415 (M + H) ⁺ .

2.B)c)2) t-butil ester (S)-N-benzil-3-t-butoksikarbonilamino-N-etoksikarbonilmetilsukcinamske kisline, MS (ionski spray): 465.2 (M+H)⁺,2.B) c) (S) -N-Benzyl-3-t-butoxycarbonylamino-N-ethoxycarbonylmethylsuccinic acid t-butyl ester, MS (ion spray): 465.2 (M + H) ⁺ .

2.B)c)3) t-butil-ester (S)-3-t-butoksikarbonilamino-N-cikloheksilmetil-N-metoksikarbonilmetil-sukcinamske kisline, MS (ionski spray): 457.3 (M + H)⁺,2.B) c) 3) (S) -3-t-Butoxycarbonylamino-N-cyclohexylmethyl-N-methoxycarbonylmethyl-succinic acid t-butyl ester, MS (ion spray): 457.3 (M + H) ⁺ .

2.B)d) Analogno Primeru (lb) dobimo naslednje podatke:2.B) d) Analogous to Example (lb), the following information is obtained:

2.B)d) 1) t-butil ester (S)-N-ciklopropil-N-etoksikarbonilmetil-3-(naftalen-2sulfonilaminojsukcinamske kisline, Fab-MS : 505 (M + H) ⁺ ,2.B) d) (S) -N-Cyclopropyl-N-ethoxycarbonylmethyl-3- (naphthalene-2-sulfonylaminosuccinic acid) t-butyl ester, Fab-MS: 505 (M + H) ⁺ .

2.B)d)2) t-butil ester (S)-N-benzil-N-etoksikarbonilmetil-3-(nafta!en-2ilsulfonilamino)sukcinamske kisline, MS (ionski spray): 555,2 (M + H)⁺,2.B) d) (S) -N-Benzyl-N-ethoxycarbonylmethyl-3- (naphthalen-2ylsulfonylamino) succinic acid t-butyl ester, MS (ion spray): 555.2 (M + H) ⁺ ,

2.B)d)3) t-butil ester (S)-N-cikloheksilmetil-N-metoksikarbonilmetil-3-(naftalen-2ilsulfonilaminojsukcinamske kisline, MS (ionski spray): 547,2 (M + H)⁺,2.B) d) (S) -N-Cyclohexylmethyl-N-methoxycarbonylmethyl-3- (naphthalene-2ylsulfonylamino succinic acid) t-butyl ester, MS (ion spray): 547.2 (M + H) ⁺ .

2.B)e) Raztopini 5.78 g /5-t-butil estra N-boc-L-asparaginske kisline v 100 ml metilenklorida dodamo zapored 10.6 ml 4-etilmorfolina, 4.6 g N(dimetilaminopropil)-N’-etilkarbodiimid-hidroklorida, 244 mg 4dimetilaminopiridina in 3.1 g etil ester hidroklorida sarkozina. Po mešanju izlijemo reakcijsko zmes v ledenomrzlo raztopino 5% kalijevega hidrogen sulfata/10% kalijevega sulfata in ekstrahiramo z ocetestrom. Organsko fazo izperemo z vodo, nato sušimo, uparimo in ostanek kromatografiramo s heksanom/ocetestrom (3:1) na kremeničnem gelu. Dobimo 6.8 g t-butil estra (S)-3-t-butoksikarbonilamino-Netoksikarbonilmetil-N-metilsukcinamske kisline, MS (ionski spray): 389,4 (M + H) ⁺ ,2.B) e) To a solution of 5.78 g of N-boc-L-aspartic acid 5-t-butyl ester in 100 ml of methylene chloride, 10.6 ml of 4-ethylmorpholine, 4.6 g of N (dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride are added successively. 244 mg of 4-dimethylaminopyridine and 3.1 g of sarcosine hydrochloride ethyl ester. After stirring, pour the reaction mixture into an ice-cold solution of 5% potassium hydrogen sulphate / 10% potassium sulphate and extract with acetone. The organic phase was washed with water, then dried, evaporated and the residue was chromatographed with hexane / acetone (3: 1) on silica gel. 6.8 g of tert-butyl ester of (S) -3-t-butoxycarbonylamino-Netoxycarbonylmethyl-N-methylsuccinic acid are obtained, MS (ion spray): 389.4 (M + H) ⁺ .

2.B)f) Analogno 2.B)e), vendar ob uporabi N-substituiranih glicinestrov namesto etil estra sarkozina dobimo naslednje triestre:2.B) f) Analogous to 2.B) e), but using N-substituted glycine esters instead of the sarcosine ethyl ester, the following triesters are obtained:

2.B)f) 1) t-butil ester (S)-3-t-butoksikarbonilamino-N-etoksikarbonilmetil-nizopropil-sukcinamske kisline, MS (ionski spray): 417,1 (M + H) ⁺ ,2.B) f) (S) -3-t-Butoxycarbonylamino-N-ethoxycarbonylmethyl-nizopropyl-succinic acid t-butyl ester, MS (ion spray): 417.1 (M + H) ⁺ .

2.B)f)2) t-butil-(S)-N-alil-N-[(etokosikarbonil)metil]-3-( 1-tbutoksiformamido)sukcinamat, MS (ionski spray): 415,2 (M+H) ⁺ ,2.B) f) 2) t-Butyl- (S) -N-allyl-N - [(ethocosicarbonyl) methyl] -3- (1-tbutoxyformamido) succinamate, MS (ion spray): 415.2 (M + H) ⁺ ,

2.B)f)3) Etil ester N-[N,3-bis-(t-butoksikarbonil)-L-alanil-]-N-butilglicina,2.B) f) 3) N- [N, 3-bis- (t-butoxycarbonyl) -L-alanyl -] - N-butylglycine ethyl ester,

MS (ionski spray): 431,2 (M+H)⁺,MS (ion spray): 431.2 (M + H) ⁺ ,

2.B)f)4) Etil ester N-[N,3-bis-(t-butoksikarbonil)-L-alanil-]-N(ciklopropilmetil)glicina, MS (ionski spray): 428,2 M⁺,2.B) f) 4) N- [N, 3-bis- (t-butoxycarbonyl) -L-alanyl -] - N (cyclopropylmethyl) glycine ethyl ester, MS (ion spray): 428.2 M ⁺ .

2.B)f)5) t-butil ester (S)-3-t-butoksikarbonilamino-N-ciklopentil-Netoksikarbonilmetil-sukcinamske kisline, MS (ionski spray): 443,3 (M+H)+,2.B) f) 5) (S) -3-t-Butoxycarbonylamino-N-cyclopentyl-Netoxycarbonylmethyl-succinic acid t-butyl ester, MS (ion spray): 443.3 (M + H) +.

2.B)f)6) t-butil ester (S)-3-t-butoksikarbonilamino-N4-ciklobutil-N4etoksikarbonilmetil-sukcinamske kisline, MS (ionski spray): 429,2 (M+H)⁺,2.B) f) (S) -3-t-Butoxycarbonylamino-N4-cyclobutyl-N4ethoxycarbonylmethyl-succinic acid t-butyl ester, MS (ion spray): 429.2 (M + H) ⁺ .

2.B)f)7) t-butil ester (S)-3-t-butoksikarbonilamino-N-t-butil-N-etoksikarbonilmetil sukcinamske kisline, MS (ionski spray): 431,2 (M+H) ⁺ ,2.B) f) 7) (S) -3-t-Butoxycarbonylamino-Nt-butyl-N-ethoxycarbonylmethyl succinic acid t-butyl ester, MS (ion spray): 431.2 (M + H) ⁺ .

2.B)f)8) t-butil ester (S)-3-t-butoksikarbonilamino-N-etoksikarbonilmetil-N-pentilsukcinamske kisline, MS (ionski spray): 445,3 (M+H)+,2.B) f) 8) (S) -3-t-Butoxycarbonylamino-N-ethoxycarbonylmethyl-N-pentylsuccinic acid t-butyl ester, MS (ion spray): 445.3 (M + H) +.

2.B)g) Analogno 2.B)e), le ob uporabi etil estra L-levcina namesto etil estra sarkozina, dobimo etil ester N-[N,3-bis(t-butoksikarbonil)-L-alanil]-L-levcina, FabMS :431.2 (M+H) + .2.B) g) Analogous to 2.B) e) only using L-leucine ethyl ester instead of sarcosine ethyl ester gives N- [N, 3-bis (t-butoxycarbonyl) -L-alanyl] -L ethyl ester -leucine, FabMS: 431.2 (M + H) +.

2.B)h) analogno 2.B)e) le ob uporabi po Primeru 2.B)a) in b) pripravljenih estrov dobimo naslednje triestre:2.B) h) Analogous 2.B) e) Only when used according to Example 2.B) a) and b) prepared esters the following triesters are obtained:

2.B)h) 1) t-butil ester (S)-3-t-butoksikarbonilamino-N-ciklopropil-N-(2etoksikarbonil-etiljsukcinamske kisline, MS : 429 (M+H)+.2.B) h) (S) -3-t-Butoxycarbonylamino-N-cyclopropyl-N- (2ethoxycarbonyl-ethyl-succinamic acid) t-butyl ester, MS: 429 (M + H) +.

2.B)h)2) t-butil ester (S)-3-t-butoksikarbonilamino-N-alil-N-(2-etoksikarboniletil)sukcinamske kisline, MS : 429 (M + H) ⁺ .2.B) h) (S) -3-t-Butoxycarbonylamino-N-allyl-N- (2-ethoxycarbonylethyl) succinic acid t-butyl ester, MS: 429 (M + H) ⁺ .

2.B)h)3) t-butil ester (S)-3-t-butoksikarbonilamino-N-butil-N-(2-etoksikarboniletiljsukcinamske kisline, MS (ionski spray): 445.6 (M + H) ⁺ .2.B) h) (S) -3-t-Butoxycarbonylamino-N-butyl-N- (2-ethoxycarbonylethylsuccinic acid) t-butyl ester, MS (ion spray): 445.6 (M + H) ⁺ .

2.B)i) Raztopini 6.7 g t-butil estra (S)-3-t-butoksikarbonilamino-N-etoksikarbonilmetil-N-metilsukcinamske kisline v 80 ml dioksana dodamo 8.2 g monohidrata p-toluensulfonske kisline. Po mešanju dodamo 43.1 ml IN natrijevega luga, 4.34 g natrijevega hidrogen karbonata in raztopino 7.8 g 2-naftilsulfoklorida v 37 ml dioksana. Po mešanju izlijemo reakcijsko zmes v ledenomrzlo raztopino 5% kalijevega hidrogen sulfata/10% kalijevega sulfata in ekstrahiramo z ocetestrom. Organsko fazo izperemo z razredčeno raztopino kuhinjske soli, nato sušimo in uparimo. Po kromatografiji na kremeničnem gelu s heksanom/ocetestrom (3:1) izoliramo 2.0 g t-butil-(S)-N-[(etoksikarbonil)-metil]-N-metil-3-(2-naftilsulfonamido) sukcinamata, MS (ionski spray): 479,9 (M+H)⁺.2.B) i) To a solution of 6.7 g of (S) -3-t-butoxycarbonylamino-N-ethoxycarbonylmethyl-N-methylsuccinamic acid t-butyl ester in 80 ml of dioxane is added 8.2 g of p-toluenesulfonic acid monohydrate. After stirring, 43.1 ml of 1 N sodium hydroxide, 4.34 g of sodium hydrogen carbonate and a solution of 7.8 g of 2-naphthylsulfochloride in 37 ml of dioxane are added. After stirring, pour the reaction mixture into an ice-cold solution of 5% potassium hydrogen sulphate / 10% potassium sulphate and extract with acetone. The organic phase is washed with dilute salt solution, then dried and evaporated. After chromatography on silica gel with hexane / acetone (3: 1), 2.0 g of t-butyl- (S) -N - [(ethoxycarbonyl) -methyl] -N-methyl-3- (2-naphthylsulfonamido) succinamate, MS, were isolated, MS ( ion spray): 479.9 (M + H) ⁺ .

2.B)j) Analogno 2.B)i), vendar ob uporabi triestrov iz Primerov 2.B)f), g) in h) namesto triestrov iz Primera 2.B)e), dobimo naslednje diestre:2.B) j) Analogous to 2.B) i), but using the triesters of Examples 2.B) f), g) and h) instead of the triesters of Example 2.B) e), the following diesters are obtained:

2.B)j)l) etil ester N-[3-(t-butoksikarbonil)-N-(2-naftilsulfonil)-L-alanil]-Nizopropilglicina, Fab-MS: 433 (M-t-butoksi),2.B) N- [3- (t-Butoxycarbonyl) -N- (2-naphthylsulfonyl) -L-alanyl] -Nisopropylglycine ethyl ester, Fab-MS: 433 (M-t-butoxy).

2.B)j)2) etil ester N-alil-N-[3-(t-butoksikarbonil)-N2-(2-naftilsulfonil)-Lalaniljglicina, MS (ionski spray): 505.0 (M+H)⁺,2.B) j) 2) N-allyl-N- [3- (t-butoxycarbonyl) -N2- (2-naphthylsulfonyl) -Lalanylglycine ethyl ester, MS (ion spray): 505.0 (M + H) ⁺ .

2.B)j)3) t-butil ester (s)-N-butil-N-etoksikarbonilmetil-3-(naftalen-2sulfonilaminojsukcinamske kisline, MS (ionski spray): 54.3 (M + H)⁺,2.B) j) (S) -N-Butyl-N-ethoxycarbonylmethyl-3- (naphthalene-2-sulfonylamino succinic acid) t-butyl ester, MS (ion spray): 54.3 (M + H) ⁺ .

2.B)j)4) etil ester N-(ciklopropilmetil)-N-[4-t-butoksikarbonil)-N-(2-naftilsulfonil)L-alanil]glicina, Fab-MS: 445 (M-t-butoksi),2.B) j) 4) N- (cyclopropylmethyl) -N- [4-t-butoxycarbonyl) -N- (2-naphthylsulfonyl) L-alanyl] glycine ethyl ester, Fab-MS: 445 (M-t-butoxy),

2.B)j)5) t-butil ester (S)-N-ciklopentil-N-etoksikarbonilmeti]-3-(naftalen-2sulfonilaminojsukcinamske kisline, MS (ionski spray): 533.0 (M + H) ⁺ ,2.B) j) 5) (S) -N-Cyclopentyl-N-ethoxycarbonylmethyl] -3- (naphthalene-2-sulfonylamino succinic acid t-butyl ester, MS (ion spray): 533.0 (M + H) ⁺ .

2.B)j)6) t-butil ester (S)-N-ciklobutil-N-etoksikarbonilmetil-3-(naftalen-2sulfonilaminojsukcinamske kisline, MS (ionski spray): 519.1 (M + H) ⁺ ,2.B) j) (S) -N-Cyclobutyl-N-ethoxycarbonylmethyl-3- (naphthalene-2-sulfonylaminosuccinic acid) t-butyl ester, MS (ion spray): 519.1 (M + H) ⁺ .

2.B)j)7) t-butil ester (S)-N-t-butil-N-etoksikarbonilmetil-3-(naftalen-2sulfonilaminojsukcinamske kisline, MS (ionski spray): 521.1 (M + H)⁺,2.B) j) 7) (S) -Nt-Butyl-N-ethoxycarbonylmethyl-3- (naphthalene-2-sulfonylaminosuccinic acid t-butyl ester, MS (ion spray): 521.1 (M + H) ⁺ .

2.B)j)8) etil ester (S)-2-[(S)-3-t-butoksikarbonil-2-(naftalen-2-sulfonilamino)propionilamino]-4-metilpentanske kisline, MS (ionski spray): 521.0 (M+H)⁺,2.B) j) 8) (S) -2 - [(S) -3-t-butoxycarbonyl-2- (naphthalene-2-sulfonylamino) propionylamino] -4-methylpentanoic acid ethyl ester, MS (ion spray): 521.0 (M + H) < ⁺ >,

2.B)j)9) etil ester N-[3-(t-butoksikarbonil)-N-(2-naftilsulfonil)-L-alanil-]-Ncikopropil-)3-alanina, MS (ionski spray): 517.1 (M-H)^-,2.B) j) 9) N- [3- (t-Butoxycarbonyl) -N- (2-naphthylsulfonyl) -L-alanyl] - N-cyclopropyl-) 3-alanine ethyl ester, MS (ion spray): 517.1 ( MH) ^- ,

2.B)j) 10) etil ester N-alil-N-[O-t-butil-N-(naftalen-2-il-sulfonil)-L-aspartil-/3-alanina, MS (ionski spray): 519.4 (M+H) ⁺ ,2.B) j) 10) N-Allyl-N- [Ot-butyl-N- (naphthalen-2-yl-sulfonyl) -L-aspartyl- / 3-alanine ethyl ester, MS (ion spray): 519.4 ( M + H) ⁺ ,

2.B)j) 11) t-butil ester (S)-N-butil-N-(2-etoksikarboniletil)-3-(nafatlen-2ilsulfonilamino)-sukcinamske kisline, Fab-MS: 479.0 (M-izobutil ester ),2.B) j) 11) (S) -N-Butyl-N- (2-ethoxycarbonylethyl) -3- (naphthalen-2ylsulfonylamino) -succinic acid t-butyl ester, Fab-MS: 479.0 (M-isobutyl ester) ,

2.B)j)12) t-butil ester (S)-N-etoksikarbonilmetil-3-(naftalen-2-ilsulfonilamino)-Npentilsukcinamske kisline, Fab-MS: 479 (M-izobutil ester).2.B) j) (S) -N-Ethoxycarbonylmethyl-3- (naphthalen-2-ylsulfonylamino) -pentylsuccinamic acid t-butyl ester, Fab-MS: 479 (M-isobutyl ester).

Primer 3Example 3

Raztopini 0.85 g etil ester diacetata N-[N4-[[(S)-2-amidino-3-piperidinil]metil]N2-(2-naftiIsulfonil)-L-asparaginil]-N-cikloheksilglicina (Primer 1) v 6 ml etanola dodamo 6.0 ml IN natrijevega luga. Po mešanju dodamo 6.0 ml IN solne kisline, raztopino uparimo in ostanek kromatografiramo z acetonitrilom/vodo na koloni RP-18. Dobimo 0.25 g N-[N4-[[(S)-l-amidino-3-piperidinil]metil]-N2-(2-naftilsulfonil)-L-asparaginil]-N-cikloheksilglicina, MS (ionski spray): 601.3 (M+H) ⁺ .A solution of 0.85 g of N- [N4 - [[(S) -2-amidino-3-piperidinyl] methyl] N2- (2-naphthylsulfonyl) -L-asparaginyl] -N-cyclohexylglycine (Example 1) diacetate ethyl ester (Example 1) in 6 ml of ethanol was added to 6.0 ml of 1N sodium hydroxide. After stirring, 6.0 ml of 1N hydrochloric acid are added, the solution is evaporated and the residue is chromatographed with acetonitrile / water on RP-18 column. 0.25 g of N- [N4 - [[(S) -1-amidino-3-piperidinyl] methyl] -N2- (2-naphthylsulfonyl) -L-asparaginyl] -N-cyclohexylglycine are obtained, MS (ion spray): 601.3 ( M + H) ⁺ .

Primer 4Example 4

Analogno Primeru 3, le izhajajoč iz estrov Primera 2.A), dobimo naslednje kisline:Analogous to Example 3, only starting from the esters of Example 2.A), the following acids are obtained:

a) N-[N4-[[(S)-l-amidino-3-piperidinil]metil]-N2-(2-naftilsulfonil)-L-asparaginil]-N ciklopropilglicin, MS (ionski spray): 559.0 (M + H) ⁺ ,a) N- [N4 - [[(S) -1-amidino-3-piperidinyl] methyl] -N2- (2-naphthylsulfonyl) -L-asparaginyl] -N cyclopropylglycine, MS (ion spray): 559.0 (M + H) ⁺ ,

b) [[(S)-3-[(S)-l-(amino-imino-metil)piperidin-3-ilmetilkarbamoil]-2-(naftalin-2sulfonilamino)propionil]-benzilamino]ocetno kislino,b) [[(S) -3 - [(S) -1- (amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -2- (naphthalene-2-sulfonylamino) propionyl] -benzylamino] acetic acid,

MS (ionski spray): 609.1 (M+H) ⁺ ,MS (ion spray): 609.1 (M + H) < ⁺ >,

c) N-[N4-[[(S)-l-amidino-3-piperidinil]metiI]-N2-(2-naftiIsulfoniI)-L-asparaginiI]-N· cikloheksilglicin, MS (ionski spray): 615.4 (M+H)⁺,c) N- [N4 - [[(S) -1-amidino-3-piperidinyl] methyl] -N2- (2-naphthylsulfonyl) -L-asparaginyl] -N · cyclohexylglycine, MS (ion spray): 615.4 (M + H) ⁺ ,

d) N-(N4-[[(S)-l-amidino-3-piperidinil]metil]-N2-(2-naftilsulfonil)-L-asparaginil]-N metilglicin, MS (ionski spray): 532.9 (M+H)⁺,d) N- (N4 - [[(S) -1-amidino-3-piperidinyl] methyl] -N2- (2-naphthylsulfonyl) -L-asparaginyl] -N methylglycine, MS (ion spray): 532.9 (M + H) ⁺ ,

e) N-[N4-[[(S)-l-amidino-3-piperidinil]metil]-N2-(2-naftilsulfonil)-L-asparaginil]-N izopropilglicin, MS (ionski spray): 561.2 (M+H)⁺,e) N- [N4 - [[(S) -1-amidino-3-piperidinyl] methyl] -N2- (2-naphthylsulfonyl) -L-asparaginyl] -N isopropylglycine, MS (ion spray): 561.2 (M + H) ⁺ ,

f) [[(S)-3-[(S)-l-(amino-imino-metil)piperidin-3-ilmetilkarbamoil]-2-(naftalin-2sulfonilamino)propionil]alilamino]ocetno kislino, MS (ionski spray): 557.2 (M-H)^- f) [[(S) -3 - [(S) -1- (amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -2- (naphthalen-2-sulfonylamino) propionyl] allylamino] acetic acid, MS (ion spray) : 557.2 (MH) ^-

g) [[(S)-3-[(S)-l-(amino-imino-metil)piperidin-3-ilmetilkarbamoil]-2-(naftalin-2sulfonilamino)propionil]butilamino]ocetno kislino,g) [[(S) -3 - [(S) -1- (amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -2- (naphthalen-2-sulfonylamino) propionyl] butylamino] acetic acid,

MS (ionski spray): 575.3 (M + H)⁺,MS (ion spray): 575.3 (M + H) ⁺ ,

h) N-[N4-[[(S)-l-amidino-3-piperidinil]metil]-N2-(2-naftilsulfonil)-L-asparaginil]-N ciklopropilmetil)glicin, MS (ionski spray): 573.3 (M+H)⁺,h) N- [N4 - [[(S) -1-amidino-3-piperidinyl] methyl] -N2- (2-naphthylsulfonyl) -L-asparaginyl] -N cyclopropylmethyl) glycine, MS (ion spray): 573.3 ( M + H) ⁺ ,

i) (S)-N4-[(S)-l-(amino-imino-metil)piperidin-3-ilmetil]-Nl-karboksimetil-Nlciklopentil-2-(naftalin-2-sulfonilamino)sukcinamid,i) (S) -N4 - [(S) -1- (amino-imino-methyl) piperidin-3-ylmethyl] -Nl-carboxymethyl-Ncyclopentyl-2- (naphthalene-2-sulfonylamino) succinamide,

MS (ionski spray): 587.2 (M + H) + ,MS (ion spray): 587.2 (M + H) < + >,

j) N-[N4-[[(S)-l-amidino-3-piperdinil]rnetil]-N2-(2-naftilsulfonil)-L-asparaginil]-Llevcin, MS (ionski spray); 575.1 (M + H) ⁺ ,j) N- [N4 - [[(S) -1-amidino-3-piperidinyl] phenyl] -N2- (2-naphthylsulfonyl) -L-asparaginyl] -leucine, MS (ion spray); 575.1 (M + H) < ⁺ >,

k) [[(S)-3-[(S)-l-(amino-imino-metil)piperidin-3-ilmetilkarbamoil]-2-(naftalin-2sulfonilamino)propionil]ciklopropilamino]propionsko kislino,k) [[(S) -3 - [(S) -1- (amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -2- (naphthalen-2-sulfonylamino) propionyl] cyclopropylamino] propionic acid,

MS (ionski spray): 573.2 (M + H) ⁺ ,MS (ion spray): 573.2 (M + H) ⁺ ,

l) (S)-3-[aliI-[3-[(S)-l-(amino-imino-metil)piperidin-3-ilmetilkarbamoil]-2-(naftalin2-sulfonilamino)propionil]amino]propionsko kislino,l) (S) -3- [or N- [3 - [(S) -1- (amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -2- (naphthalene 2-sulfonylamino) propionyl] amino] propionic acid,

MS (ionski spray): 573.3 (M+H)⁺,MS (ion spray): 573.3 (M + H) ⁺ ,

m) 3-[(S)-3-[(S)-[l-(amino-imino-metil)piperidin-3-ilmetilkarbamoil]-N-butil-2(naftalen-2-ilsulfonilamino)propionilamino]propionsko kislino,m) 3 - [(S) -3 - [(S) - [1- (amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -N-butyl-2 (naphthalen-2-ylsulfonylamino) propionylamino] propionic acid,

MS (ionski spray): 589.4 (M+H)⁺,MS (ion spray): 589.4 (M + H) < ⁺ >,

n) [(S)-3-[(S)-[l-(amino-imino-metil)piperidin-3-ilmetilkarbamoil]-2-(naftalen-2ilsulfonilamino)propionil]pentil aminoocetno kislino,n) [(S) -3 - [(S) - [1- (amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -2- (naphthalen-2ylsulfonylamino) propionyl] pentyl aminoacetic acid,

MS (ionski spray): 589.5 (M+H)⁺,MS (ion spray): 589.5 (M + H) ⁺ ,

Primer 5Example 5

Raztopini 50 mg [[(S)-3-[(S)-[l-(amino-imino-metil)piperidin-3-ilmetilkarbamoil]2- (naftalin-2-sulfonilamino)propionil]alilamino]ocetne kisline (Primer 4.f) v ml etanola in 1 ml vode dodamo 10 mg paladija na oglju in hidriramo ob normalnih pogojih. Po 4 urah filtriramo od katalizatorja in filtrat uparimo. Dobimo 50 mg [(S)3- [(S)-[2-(amino-imino-metil)piperidin-3-ilmetilkarbamoil]-2-(naftalen-2-sulfonilamino)propionil]propil aminoocetne kisline, MS (ionski spray): 561.3 (M+H)⁺.50 mg [[(S) -3 - [(S) - [1- (amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] 2- (naphthalene-2-sulfonylamino) propionyl] allylamino] acetic acid solution (Example 4) .f) 10 mg of palladium-on-charcoal are added to ml of ethanol and 1 ml of water and hydrated under normal conditions. After 4 hours, it was filtered off from the catalyst and the filtrate was evaporated. 50 mg of [(S) 3- [(S) - [2- (amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -2- (naphthalene-2-sulfonylamino) propionyl] propyl aminoacetic acid, MS (ion spray), are obtained ): 561.3 (M + H) < ⁺ >.

Primer 6Example 6

Analogno Primeru 5 dobimo iz (S)-3-[alil-[3-[(S)-l-(amino-imino-metil)piperidin-3-ilmetilkarbamoil]-2-(naftalin-2sulfonilamino)propioniljamino]propionske kisline (Primer 4.1) 3-[(S)-3-[(S)-[l-(amino-imino-metil)piperidin-3-ilmetilkarbamoil]-2-(naftalen-2sulfonil-amino)propionil]propilamino]propionsko kislino,Analogous to Example 5 was obtained from (S) -3- [allyl- [3 - [(S) -1- (amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -2- (naphthalene-2sulfonylamino) propionylamino] propionic acid ( Example 4.1) 3 - [(S) -3 - [(S) - [1- (amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -2- (naphthalene-2-sulfonyl-amino) propionyl] propylamino] propionic acid,

MS (ionski spray): 575.2 (M+H)+.MS (ion spray): 575.2 (M + H) +.

Primer 7Example 7

A) Analogno Primeru 1 dobimo iz diestrov Primerov 2.B)i) in j) po eni strani in namesto (S)-l-amidino-3-(aminometil)piperidindihidroklorida: iz rac-2-aminometil4-morfolinkarboksamidintrifluoracetata po drugi strani naslednje estre:A) Analogous to Example 1 is obtained from the diesters of Examples 2.B) i) and j), on the one hand, and instead of (S) -1-amidino-3- (aminomethyl) piperidinedihydrochloride: from rac-2-aminomethyl4-morpholinecarboxamidintrifluoroacetate, on the other esters:

a) Etil ester trifluoracetat 3-[N-[(S)-3-[R,S)-4-(amino-imino-metil)morfolin-2ilmetilkarbamoil]-2-(naftalen-2-sulfoni)amino)propionil]ciklopropilamino]propionske kisline, (1:1), MS (ionski spray): 603.4 (M + H) ⁺ .a) Trifluoroacetate ethyl ester 3- [N - [(S) -3- [R, S] -4- (amino-imino-methyl) morpholin-2ylmethylcarbamoyl] -2- (naphthalene-2-sulfonylamino) propionyl] cyclopropylamino] propionic acid, (1: 1), MS (ion spray): 603.4 (M + H) ⁺ .

b) Etil ester trifluoracetat 3-[N-alil-[(S)-3-[R,S)-4-(amino-imino-metil)morfolin-2ilmetilkarbamoil]-2-(naftalen-2-sulfonilamino)propionil]amino]-propionske kisline, (1:1), MS (ionski spray): 603.5 (M+H)⁺.b) 3- [N-Allyl - [(S) -3- [R, S) -4- (amino-imino-methyl) morpholin-2ylmethylcarbamoyl] -2- (naphthalene-2-sulfonylamino) propionyl ethyl ester trifluoroacetate] amino] -propionic acids, (1: 1), MS (ion spray): 603.5 (M + H) ⁺ .

B) Izhodni trifluoracetat pripravimo kot sledi:B) The starting trifluoroacetate is prepared as follows:

a) Raztopini 23.3 g rac-2-(aminometil)-4-benzilmorfolina v 250 ml dioksana dodamo 27,1 g di-t-butildikarbonata v 250 ml dioksana. Po mešanju odparimo topilo in ostanek kromatografiramo z metilenkloridom/ocetestrom (3:1) na kremeničnem gelu. Produkt prekristaliziramo iz metilenklorida/heksana. Dobimo 25.6 g t-butil-rac[(4-benzil-2-morfolinil)metilj-karbamata. ·a) To a solution of 23.3 g of rac-2- (aminomethyl) -4-benzylmorpholine in 250 ml of dioxane was added 27.1 g of di-t-butyldicarbonate in 250 ml of dioxane. After stirring, the solvent was evaporated and the residue was chromatographed with methylene chloride / acetone (3: 1) on silica gel. The product was recrystallized from methylene chloride / hexane. 25.6 g of t-butyl-rac [(4-benzyl-2-morpholinyl) methyl-carbamate are obtained. ·

b) Raztopini produkta a) v 500 ml ocetestra in 50 ml ocetne kisline dodamo 2.6 g paladija na oglju in hidriramo 5 ur pri normalnih pogojih. Po filtriranju in uparjenju raztopimo ostanek v 230 ml dimetilformamida, dodamo 46 ml trietilamina in 10.8 g formamidinsulfonske kisline. Po mešanju uparimo reakcijsko zmes in ostanek porazdelimo med ocetestrom in vodo. Po sušenju organske faze in uparjenju dobimo t-butil-rac-[(4-amidino-2-morfolinil)metil]-karbamat-hemisulfit.b) To a solution of product a) 2.6 g of palladium on charcoal are added to 500 ml of acetic acid and 50 ml of acetic acid and hydrated for 5 hours under normal conditions. After filtration and evaporation, the residue is dissolved in 230 ml of dimethylformamide, 46 ml of triethylamine and 10.8 g of formamidinsulfonic acid are added. After stirring, the reaction mixture was evaporated and the residue was partitioned between acetone and water. After drying the organic phase and evaporating, t-butyl-rac - [(4-amidino-2-morpholinyl) methyl] -carbamate-hemisulfite is obtained.

c) 6.5 g pod b) dobljenega materiala suspendiramo v 50 ml metilenklorida in pri 0 °C dodamo 20 ml TFA. Nato uparimo reakcijsko zmes in azeotropno obdelamo z etilenkloridom in toluenom. Izoliramo rac-2-(aminometil)-4-morfolino-karboksamidintrifluoracetat.c) Suspend 6.5 g under b) of the resulting material in 50 ml of methylene chloride and add 20 ml of TFA at 0 ° C. The reaction mixture was then evaporated and azeotropically treated with ethylene chloride and toluene. Rac-2- (aminomethyl) -4-morpholino-carboxamidintrifluoroacetate is isolated.

Primer 8Example 8

Analogno Primeru 3 dobimo iz estrov Primera 7 naslednje kisline:Analogous to Example 3, the following acids are obtained from the esters of Example 7:

a) 3-[(S)-3-(R,S)-4-amino-imino-metilmorfolin-2-ilmetilkarbamoil]-2-(naftalen-2sulfonilamino)-N-ciklopropil-propionilamino]-propionsko kislino,a) 3 - [(S) -3- (R, S) -4-amino-imino-methyl-morpholin-2-ylmethylcarbamoyl] -2- (naphthalene-2-sulfonylamino) -N-cyclopropyl-propionylamino] -propionic acid,

MS (ionski spray): 575.5 (M + H) ⁺ .MS (ion spray): 575.5 (M + H) ⁺ .

b) 3-[N-alil-[(S)-3-(R,S)-4-(amino-imino-metil)morfolin-2-iImetiIkarbamoil]-2(naftalen-2-sulfonilamino)-propionil]-amino]-propionsko kislino,b) 3- [N-allyl - [(S) -3- (R, S) -4- (amino-imino-methyl) morpholin-2-ylmethylcarbamoyl] -2 (naphthalene-2-sulfonylamino) -propionyl] - amino] -propionic acid,

MS (ionski spray): 575.4 (M + H)+.MS (ion spray): 575.4 (M + H) +.

Primer 9Example 9

Raztopini 1.4 g etil estra N-[3-(t-butoksikarbonil)-N-(2-naftilsulfonil)-L-alanil]-Nciklopropil-/3-alanina Primer 2B)j)9) in 23 ml metilenklorida dodamo pri 2 °C 4.1 ml trifluorocetne kisline. Po 5 urah mešanja pri sobni temperaturi raztopino uparimo, ostanek raztopimo v 23 ml dimetilformamida in dodamo 1.7 ml 4-etilmorfolina, 1.2 g BOP in 0.8 g rac-3-[(2-hidroksietil)amino)metil]-l-piperidinkarboksamidindihidroklorida. Po mešanju uparimo reakcijsko raztopino in ostanek kromatografiramo z vodo/acetonitrilom na koloni RP-18. Dobimo 0.7 g etil ester hidroklorida 3-[(S)-3-[(R,S)-N-(l-amino-imino-metil-piperidin-3-ilmetiI)-2-hidroksi-etiIkarbamoil]-2-(naftalen-2-sulfonilamino)-N-ciklopropil-propionilamino]-propionske kisline (1:1), MS (ionski spray): 645,5 (M+H) ⁺ .To a solution of 1.4 g of N- [3- (t-butoxycarbonyl) -N- (2-naphthylsulfonyl) -L-alanyl] -Ncyclopropyl- / 3-alanine ethyl ester Example 2B) (9) and 23 ml of methylene chloride were added at 2 ° C 4.1 ml of trifluoroacetic acid. After stirring at room temperature for 5 hours, the solution was evaporated, the residue dissolved in 23 ml of dimethylformamide and 1.7 ml of 4-ethylmorpholine, 1.2 g of BOP and 0.8 g of rac-3 - [(2-hydroxyethyl) amino) methyl] -1-piperidinecarboxamidine dihydrochloride were added. After stirring, the reaction solution was evaporated and the residue was chromatographed with water / acetonitrile on RP-18 column. 0.7 g of 3 - [(S) -3 - [(R, S) -N- (1-amino-imino-methyl-piperidin-3-ylmethyl) -2-hydroxy-ethylcarbamoyl] -2- (0.7 g) ethyl ester is obtained. Naphthalene-2-sulfonylamino) -N-cyclopropyl-propionylamino] -propionic acid (1: 1), MS (ion spray): 645.5 (M + H) ⁺ .

Priprava izhodnega piperidinkarboksamidina:Preparation of the starting piperidinecarboxamidine:

a) Raztopini 20 g N-(2-hidroksietil)-3-pikolilamina v 250 ml dioksana dodamo raztopino 31.6 g di-t-butil-dikarbonata v 100 ml dioksana. Po mešanju uparimo reakcijsko zmes in kromatografiramo ostanek z ocetestrom na kremeničnem gelu. Dobimo 29.8 g t-butil-(2-hidroksietil)(3-piridilmetil)karbamata,a) To a solution of 20 g of N- (2-hydroxyethyl) -3-picolylamine in 250 ml of dioxane is added a solution of 31.6 g of di-t-butyl dicarbonate in 100 ml of dioxane. After stirring, the reaction mixture was evaporated and the residue was chromatographed with silica gel acetate. 29.8 g of t-butyl- (2-hydroxyethyl) (3-pyridylmethyl) carbamate are obtained,

EI-MS: 253 (M+H)+.EI-MS: 253 (M + H) < + >.

b) Pri a) dobljeni material raztopimo v 150 ml etanola, dodamo 3 g rutenija na aluminijevem oksidu in hidriramo 24 ur pri 60 °C in pri 100 bar. Po filtraciji dobimo kvantitativno t-butil-rac-(2-hidroksietil)(3-piperidinilmetil)karbamat,b) In a) the material obtained is dissolved in 150 ml of ethanol, 3 g of ruthenium on aluminum oxide are added and hydrated for 24 hours at 60 ° C and at 100 bar. Filtration gave t-butyl-rac- (2-hydroxyethyl) (3-piperidinylmethyl) carbamate quantitatively,

EI-MS: 259(M+H) + .EI-MS: 259 (M + H) < + >.

c) Raztopini produkta b) v 500 ml dimetilformamida dodamo 51 ml trietilamina in 12.1 g formamidinsulfonske kisline. Po mešanju odfiltriramo izločeni material, ga raztopimo v etanolu/vodi 1:1, filtriramo in filtrat uparimo ter azeotropno obdelamo z etanolom. Ostanek naplavimo z etrom in odnučamo. Dobimo 24.1 g t-butil-rac-[( 1amidino-3-piperidinil)metil](2-hidroksietil)karbamat-hemisulfita,c) To a solution of product b) 51 ml of triethylamine and 12.1 g of formamidinsulfonic acid are added in 500 ml of dimethylformamide. After stirring, the separated material is filtered off, dissolved in ethanol / water 1: 1, filtered and the filtrate is evaporated and azeotroped with ethanol. The residue was washed with ether and filtered off. 24.1 g of t-butyl-rac - [(1 amidino-3-piperidinyl) methyl] (2-hydroxyethyl) carbamate-hemisulfite are obtained,

Fab-MS: 301 (M+H).Fab-MS: 301 (M + H).

d) 10.0 g pri c) dobljenega produkta raztopimo v 90 ml metilenklorida in 10 ml metanola in pri 0 °C dodamo 100 ml 4M raztopine solne kisline v ocetestru. Po mešanju reakcijsko zmes uparimo in dobimo kvantitativno rac-3-[[(2-hidroksietil)amino]metil]-l-piperidinkarboksamidin dihidroklorid, Fab-MS: 201(M+H)⁺.d) Dissolve 10.0 g of the product obtained in 90 ml of methylene chloride and 10 ml of methanol, and at 0 ° C add 100 ml of 4M hydrochloric acid solution in acetic acid. After stirring, the reaction mixture was evaporated to give quantitative rac-3 - [[(2-hydroxyethyl) amino] methyl] -1-piperidinecarboxamidine dihydrochloride, Fab-MS: 201 (M + H) ⁺ .

Primer 10Example 10

Analogno Primeru 3 dobimo iz estra Primera 9 (S)-N4-(R,S)- l-amino-imino-metil-piperidin-3-ilmetil]-Nl-(2-karboksietil)-N 1ciklopropil-N4-(2-hidroksietil)-2-(naftalen-2-ilsulfonilamino)-sukcinamid,Analogous to Example 3 was obtained from the ester of Example 9 (S) -N4- (R, S) -1-amino-imino-methyl-piperidin-3-ylmethyl] -N1- (2-carboxyethyl) -N1cyclopropyl-N4- (2 -hydroxyethyl) -2- (naphthalen-2-ylsulfonylamino) -succinamide,

MS (ionski spray): 617,5 (M+H) ⁺ .MS (ion spray): 617.5 (M + H) ⁺ .

Primer 11Example 11

Raztopini 0.45 g t-butil-(S)-heksahidro-/?-(2-naftilsulfonamido)-7-okso-lH-azepin-lbutirata v 3 ml metilenklorida dodamo pri 0 °C 1.5 ml trifluorocetne kisline. Po mešanju raztopino uparimo, azeotropno obdelamo s toluenom in sušimo. Ostanek raztopimo v 8 ml dimetilformamida in dodamo 0.38 ml 4-etilmorfolina, 0.49 g BOP in 0.3 g rac-3-[[(2-hidroksietil)amino]metil]-l-piperidinkarboksamidin dihidroklorida (Primer 9d). Po mešanju reakcijsko zmes uparimo in kromatografiramo na kremeničnem gelu z ocetestrom/acetonom/ocetno kislino/vodo (6:2:1:1). Frakcije, ki vsebujejo produkt, uparimo in ostanek filtriramo z metanolom/vodo (9:1) preko Dowex (acetatna oblika). Dobimo 0.4 g (S)-N-[[(RS)-l-amidino-3-piperidinil]metil]N-(2-hidroksietil)heksahidro-/3-2-naftilsulfonamido-lH-l-azepinbutiramid diacetata, MS (ionski spray): 587,2 (M+H) ⁺ .To a solution of 0.45 g of t-butyl- (S) -hexahydro-N- (2-naphthylsulfonamido) -7-oxo-1H-azepine-butyrate in 3 ml of methylene chloride was added at 0 ° C 1.5 ml of trifluoroacetic acid. After stirring, the solution was evaporated, azeotroped with toluene and dried. The residue was dissolved in 8 ml of dimethylformamide and 0.38 ml of 4-ethylmorpholine, 0.49 g of BOP and 0.3 g of rac-3 - [[(2-hydroxyethyl) amino] methyl] -1-piperidinecarboxamidine dihydrochloride (Example 9d) were added. After stirring, the reaction mixture was evaporated and chromatographed on silica gel with acetic acid / acetone / acetic acid / water (6: 2: 1: 1). The product containing fractions were evaporated and the residue filtered with methanol / water (9: 1) over Dowex (acetate form). 0.4 g of (S) -N - [[(RS) -1-amidino-3-piperidinyl] methyl] N- (2-hydroxyethyl) hexahydro- / 3-2-naphthylsulfonamido-1H-1-azepinbutyramide diacetate is obtained, MS ( ion spray): 587.2 (M + H) ⁺ .

Priprava izhodnega materiala:Preparation of starting material:

a) Raztopini 2.89 g /3-t-butil estra N-boc-L-asparaginske kisline v 50 ml metilenklorida dodamo 1.37 ml heksametilenimina, 2.3 g N-(dimetilaminopropil)-N’etilkarbodiimid-hidroklorida in 122 mg dimetilaminopiridina. Po mešanju izlijemo reakcijsko zmes v ledenomrzlo raztopino 5% kalijevega hidrogen sulfata/10% kalijevega sulfata in ekstrahiramo z metilenkloridom. Organsko fazo izperemo z vodo, nato sušimo in uparimo. Ostanek kromatografiramo s heksanom/ocetestrom na kremeničnem gelu. Dobimo 2.9 g t-butil-(S)-/3-(l-t-butoksiformamido)heksahidro-7-okso-lH-azepin-l-butirata, Fab-MS: 371,2 (M + H) ⁺ .a) To a solution of 2.89 g / 3-t-butyl ester of N-boc-L-aspartic acid in 50 ml of methylene chloride was added 1.37 ml of hexamethylenimine, 2.3 g of N- (dimethylaminopropyl) -N'ethylcarbodiimide hydrochloride and 122 mg of dimethylaminopyridine. After stirring, pour the reaction mixture into an ice-cold solution of 5% potassium hydrogen sulfate / 10% potassium sulfate and extract with methylene chloride. The organic phase is washed with water, then dried and evaporated. The residue was chromatographed with hexane / acetone on silica gel. 2.9 g of t-butyl- (S) - / 3- (lt-butoxyformamido) hexahydro-7-oxo-1H-azepine-1-butyrate are obtained, Fab-MS: 371.2 (M + H) ⁺ .

b) Raztopini 1.02 g produkta iz a) v 10 ml dioksana dodamo 1.31 g monohidrata ptoluensulfonske kisline. Po mešanju dodamo ob hlajenju z ledom zapored 6.9 ml IN natrijevega luga, raztopino 0.93 g 2-naftilsulfoklorida v 5 ml dioksana in 0.7 g natrijevega hidrogen karbonata. Po mešanju izlijemo reakcijsko zmes v ledenomrzlo raztopino 5% kalijevega hidrogen sulfata/10% kalijevega sulfata in ekstrahiramo z ocetestrom. Organsko fazo izperemo z vodo, nato sušimo in uparimo. Po kromatografiji s heksanom/ocetestrom (2:1) na kremeničnem gelu izoliramo 0.55 g t-butil-(S) heksahidro-/3-(2-naftilsulfonamido)-7-okso-lH-azepin-l-butirata,b) To a solution of 1.02 g of the product from a) in 10 ml of dioxane is added 1.31 g of ptoluenesulfonic acid monohydrate. After stirring, 6.9 ml of 1N sodium hydroxide, a solution of 0.93 g of 2-naphthylsulfochloride in 5 ml of dioxane and 0.7 g of sodium hydrogen carbonate were added successively under ice-cooling. After stirring, pour the reaction mixture into an ice-cold solution of 5% potassium hydrogen sulphate / 10% potassium sulphate and extract with acetone. The organic phase is washed with water, then dried and evaporated. After chromatography with hexane / acetone (2: 1), 0.55 g of t-butyl- (S) hexahydro- / 3- (2-naphthylsulfonamido) -7-oxo-1H-azepine-1-butyrate is isolated on silica gel.

MS (ionski spray): 483,1 (M+H)⁺.MS (ion spray): 483.1 (M + H) ⁺ .

Primer 12Example 12

Raztopini 1.9 g t-butil estra (S)-3-[N-[(S)-4-(azepan-l-il)-3-(naftalin-2-sulfonilamino)-4-oksobutiril]-N-etoksikarbonilmetilaminometil]-piperidin-l-karboksilne kisline v 20 ml acetonitrila dodamo 1.3 g monohidrata p-toluensulfonske kisline. Po mešanju raztopino uparimo, ostanek sušimo, raztopimo v 25 ml dimetilformamida in dodamo 1.9 ml trietilamina in 450 mg formamidinsulfonske kisline. Po mešanju reakcijsko zmes uparimo in ostanek kromatografiramo z vodo/acetonitrilom na koloni RP-18. Dobimo 0.7 g etil ester hemisulfita [[(R)-l-(amino-imino-metil)piperidin-3-ilmetil-]-[(S)-4-(azepan-l-il)-3-(naftil-2-sulfonilamino)-4-oksobutiriljaminoj ocetne kisline, MS (ionski spray): 629,2 (M + H) ⁺ .A solution of 1.9 g of tert-butyl ester (S) -3- [N - [(S) -4- (azepan-1-yl) -3- (naphthalene-2-sulfonylamino) -4-oxobutyryl] -N-ethoxycarbonylmethylaminomethyl] -piperidine-1-carboxylic acid in 20 ml of acetonitrile was added 1.3 g of p-toluenesulfonic acid monohydrate. After stirring, the solution was evaporated, the residue was dried, dissolved in 25 ml of dimethylformamide and 1.9 ml of triethylamine and 450 mg of formamidinsulfonic acid were added. After stirring, the reaction mixture was evaporated and the residue was chromatographed with water / acetonitrile on RP-18 column. 0.7 g of hemisulfite ethyl ester [[((R) -1- (amino-imino-methyl) piperidin-3-ylmethyl)] - [(S) -4- (azepan-1-yl) -3- (naphthyl-2) is obtained -sulfonylamino) -4-oxobutyrylamino acetic acid, MS (ion spray): 629.2 (M + H) ⁺ .

Priprava izhodnega estra:Preparation of the ester output:

a) Raztopini 92.9 g rac-3-hidroksimetiIpiperidina v 1500 ml dioksana dodamo raztopino 211.2 g di-t-butil-dikarbonata v 500 ml dioksana, tako, da temperatura ne prekorači 25 °C. Reakcijsko zmes mešamo in nato uparimo. Ostanek naplavimo v 800 ml heksana in filtriramo. Dobimo 120.7 g rac-N-t-butiloksikarbonil-3-hidroksimetilpiperidina, tal. 78 °C.a) To a solution of 92.9 g of rac-3-hydroxymethylpiperidine in 1500 ml of dioxane, a solution of 211.2 g of di-t-butyl dicarbonate in 500 ml of dioxane is added so that the temperature does not exceed 25 ° C. The reaction mixture was stirred and then evaporated. The residue was poured into 800 ml of hexane and filtered. 120.7 g of rac-N-t-butyloxycarbonyl-3-hydroxymethylpiperidine are obtained, m.p. 78 ° C.

b) Raztopini 100 g produkta a) v 4000 ml metilenklorida dodamo 56.2 ml piridina in ohladimo na 0 °C. K temu dokapavamo 58.3 ml klorida maslene kisline, tako, da temperatura ne prekorači 10 °C. Po mešanju suspenzijo odfiltriramo. Filtrat uparimo in ostanek prevzamemo v ocetestru. Organsko fazo izperemo z vodno 10% raztopino CUSO4, sušimo in uparimo. Ostanek filtriramo skozi kremenični gel in eluiramo s heksanom/ocetestrom (8:2). Dobimo 119.7 g t-butil estra rac-3(butiroksimetil)-l-piperidinkarboksilne kisline.b) To a solution of 100 g of product a) 56.2 ml of pyridine are added in 4000 ml of methylene chloride and cooled to 0 ° C. Add to this 58.3 ml of butyric acid chloride so that the temperature does not exceed 10 ° C. After stirring, the suspension is filtered off. The filtrate was evaporated and the residue was taken up in ethyl acetate. The organic phase was washed with aqueous 10% CUSO4 solution, dried and evaporated. The residue was filtered through a silica gel and eluted with hexane / acetone (8: 2). 119.7 g of rac-3 (butyroxymethyl) -1-piperidinecarboxylic acid t-butyl ester are obtained.

c) 116.6 g produkta iz b) emulgiramo v 2 1 0.1 M raztopine natrijevega klorida in ml 0.1M natrijevega fosfatnega pufra pri pH 7.0. Nastavimo pH z 1.0N natrijevim lugom na 7.0 in reakcijo sprožimo z dodatkom 1.00 g iz Pseudomonas fluorescens pridobljene lipoproteinlipaze (Lipase P-30, Amano) v 10 ml 0.1M raztopine natrijevega klorida. Ob mešanju vzdržujemo pH z dodatkom 2.0N natrijevega luga pri 7.0. Po 14 urah končamo reakcijo z dodatkom 500 ml metilenklorida, ekstrahiramo reakcijsko zmes z metilen kloridom in organsko fazo sušimo in uparimo. Kromatografija ostanka preko kremničnega gela s heksanom/ocetestrom da 36.6 g t-butil estra (S)-3-hidroksimetil-l-piperidinkarboksilne kisline, tal. 89 do 90 °C, [a]_S65 ²⁵ = +53.5° (c=1.0, EtOH).c) 116.6 g of the product from b) were emulsified in 2 1 0.1 M sodium chloride solution and ml of 0.1 M sodium phosphate buffer at pH 7.0. Adjust the pH with 1.0N sodium hydroxide to 7.0 and start the reaction by adding 1.00 g of Pseudomonas fluorescens-derived lipoproteinlipase (Lipase P-30, Amano) in 10 ml of 0.1M sodium chloride solution. While stirring, the pH was maintained by adding 2.0N sodium hydroxide at 7.0. After 14 hours, complete the reaction with 500 ml of methylene chloride, extract the reaction mixture with methylene chloride and dry the organic phase and evaporate. Chromatography of the residue on a silica gel with hexane / acetone afforded 36.6 g of (S) -3-hydroxymethyl-1-piperidinecarboxylic acid t-butyl ester, m.p. 89 to 90 ° C, [α] _S65 ²⁵ = + 53.5 ° (c = 1.0, EtOH).

d) 65.7 g estrske frakcije iz c) emulgiramo v 1.15 L 0.1 M raztopine natrijevega klorida in 45 ml 0.1M natrijevega fosfatnega pufra (pH 7.0) in dodamo 0.50 g lipaze P-30 v 5 ml 0.1M raztopine natrijevega klorida. Ob mešanju vzdržujemo pH pri 7.0 z dodajanjem 2.0 N natrijevega luga. Po 40 urah končamo reakcijo z dodatkomd) 65.7 g of the ester fraction from c) are emulsified in 1.15 L of 0.1 M sodium chloride solution and 45 ml of 0.1M sodium phosphate buffer (pH 7.0) and 0.50 g of P-30 lipase is added in 5 ml of 0.1M sodium chloride solution. While stirring, the pH was maintained at 7.0 by the addition of 2.0 N sodium hydroxide. After 40 hours, complete the reaction with the addition

400 ml metilenklorida, reakcijsko zmes ekstrahiramo z metilenkloridom in organsko fazo sušimo in uparimo. Kromatogarfija ostanka preko kremeničnega gela s heksanom/ocetestrom da 49.5 g t-butil estra (R)-3-(butiril-oksimetil)- 1-piperidinkarboksilne kisline. Le-tega raztopimo v 250 ml etanola, dodamo 88 ml 2N natrijevega luga, mešamo čez noč in nato uparimo. Ostanek prevzamemo v 200 ml metilenklorida in izperemo z vodo, vodno fazo ekstrahiramo z metilenkloridom in organsko fazo sušimo in uparimo. Kromatografija ostanka preko kremeničnega gela s heksanom/ocetestrom da 33.7 g t-butil estra (R)-3-hidroksimetil-l-piperidinkarboksilne kisline, [a]_%5 ²⁵= —60.7° (c=1.0, EtOH).400 ml of methylene chloride, the reaction mixture is extracted with methylene chloride and the organic phase is dried and evaporated. Chromatography of the residue via quartz gel with hexane / ethyl acetate afforded 49.5 g of (R) -3- (butyryloxymethyl) -1-piperidinecarboxylic acid t-butyl ester. It was dissolved in 250 ml of ethanol, 88 ml of 2N sodium hydroxide was added, stirred overnight and then evaporated. The residue was taken up in 200 ml of methylene chloride and washed with water, the aqueous phase was extracted with methylene chloride and the organic phase was dried and evaporated. Chromatography of the residue on silica gel with hexane / acetone afforded 33.7 g of (R) -3-hydroxymethyl-1-piperidinecarboxylic acid t-butyl ester, [a] _{% 5} ²⁵ = -60.7 ° (c = 1.0, EtOH).

e) Raztopini 5.0 g produkta iz d) v 100 ml piridina dodamo 5.4 g p-klorsulfonilklorida. Reakcijsko zmes mešamo, nato uparimo, prevzamemo v 200 ml ocetestra in izperemo z vodo in vodno 10% raztopino CUSO4. Organsko fazo sušimo in uparimo Ostanek filtriramo preko kremeničnega gela in eluiramo s heksanom/-ocetestrom (8:2). Dobimo 6.5 g t-butil estra (R)-3-(p-klorfenilsulfonil-oksimetil)-l-piperidinkarboksilne kisline.e) To a solution of 5.0 g of the product from d) in 100 ml of pyridine is added 5.4 g of p-chlorosulfonyl chloride. The reaction mixture was stirred, then evaporated, taken up in 200 ml of acetone and washed with water and aqueous 10% CUSO4 solution. The organic phase was dried and evaporated. The residue was filtered through a silica gel and eluted with hexane / -acetester (8: 2). 6.5 g of (R) -3- (p-chlorophenylsulfonyl-oxymethyl) -1-piperidinecarboxylic acid t-butyl ester is obtained.

f) Raztopini produkta iz e) v 50 ml dimetilformamida dodamo 3.25 g natrijevega azida. Reakcijsko zmes mešamo 15 ur pri 50 °C in uparimo. Ostanek prevzamemo v vodi in etru in izperemo z vodo. Etrno fazo sušimo in uparimo. Dobimo 4.0 g t-butil estra (R)-3-azidometil-l-piperidinkarboksilne kisline.f) To a solution of the product of e) 3.25 g of sodium azide are added to 50 ml of dimethylformamide. The reaction mixture was stirred for 15 hours at 50 ° C and evaporated. The residue was taken up in water and ether and washed with water. The ether phase is dried and evaporated. 4.0 g of (R) -3-azidomethyl-1-piperidinecarboxylic acid t-butyl ester is obtained.

g)l) Raztopino produkta f) v 100 ml etanola hidriramo v prisotnosti 0.6 g platinovega oksida pod 1 bar vodika. Nato reakcijsko zmes filtriramo preko kremeničnega gela in eluiramo z metanolom. Dobimo 3.4 g t-butil estra (S)-3-aminometil-l-piperidinkarboksilne kisline, [a]_D ²⁵ - 17.7°C (c=0.6, EtOH).g) l) A solution of product f) is hydrated in 100 ml of ethanol in the presence of 0.6 g of platinum oxide under 1 bar of hydrogen. The reaction mixture was then filtered through silica gel and eluted with methanol. 3.4 g of (S) -3-Aminomethyl-1-piperidinecarboxylic acid t-butyl ester, [α] _D ²⁵ - 17.7 ° C (c = 0.6, EtOH) is obtained.

g) 2) Analogno e), f) in g) 1), dobimo iz t-butil estra (S)-3-hidroksimetil-lpiperidinkarboksilne kisline t-butil ester (R)-3-aminometil-l-piperidinkarboksilne kisline, [a]_D ²⁵ +23.0° (c=0.4, EtOH).g) 2) Analogous to e), f) and g) 1), is obtained from (S) -3-hydroxymethyl-1-piperidinecarboxylic acid t-butyl ester (R) -3-aminomethyl-1-piperidinecarboxylic acid t-butyl, [ a] _D ²⁵ + 23.0 ° (c = 0.4, EtOH).

h) Raztopini 4.0 g produkta iz g) v 300 ml metilenklorida dodamo pod argonijm 9.6 ml Hunigove baze in 2.08 ml etil estra bromocetne kisline. Po mešanju uparimo raztopino, naplavimo ostanek v ocetestru, filtriramo in filtrat iztresemo z vodo. Organsko fazo sušimo, uparimo in ostanek kromatografiramo s heksanom/ocetestrom (1:1) na kremeničnem gelu. Dobimo 2.3 g etil estra N-[[(S)-l-t-butoksikarbonil)-3-piperidinil]metil]glicina, EI-MS : 243 (M-t-butil).h) To a solution of 4.0 g of the product from g) in 300 ml of methylene chloride was added under argon 9.6 ml of Hunig's base and 2.08 ml of bromoacetic acid ethyl ester. After stirring, evaporate the solution, float the residue in the acetone, filter and shake the filtrate with water. The organic phase was dried, evaporated and the residue was chromatographed with hexane / acetone (1: 1) on silica gel. 2.3 g of N - [[((S) -1-t-butoxycarbonyl) -3-piperidinyl] methyl] glycine, EI-MS: 243 (M-t-butyl) are obtained.

i) Raztopini 1.65 g t-butil-(S)-heksahidro-j3-(2-naftilsulfonamido)-7-okso-lH-azepin1-butirata (Primer llb) v 50 ml metilenklorida dodamo pri 0 °C 5.5 ml trifluorocetne kisline. Po mešanju uparimo. Ostanek raztopimo v 31 ml dimetilformamida, dodamo 2.3 ml 4-etil-morfolina, 1.60 g BOP in raztopino 1.3 g produkta h) v 2 ml dimetilformamida. Po mešanju uparimo reakcijsko zmes, prevzamemo ostanek v ocetestru in iztresemo z vodo. Po sušenju organske faze, uparjenju in kromatografiji ostanka s heksanom/ocetestrom na kremeničnem gelu, dobimo 2.0 g t-butil estra (S)-3-[N-[(S)4-(azepan-l-il-)-3-(naftalin-2-sulfonilamino)-4-oksobutiril]-N-etoksikarbonilmetilaminometil]-piperidin-l-karboksilne kisline, MS (ionski spray): 687,3 (M + H) ⁺ .i) A solution of 1.65 g of t-butyl- (S) -hexahydro-3- (2-naphthylsulfonamido) -7-oxo-1H-azepinyl-butyrate (Example 11b) in 50 ml of methylene chloride was added at 0 ° C to 5.5 ml of trifluoroacetic acid. Evaporate after stirring. Dissolve the residue in 31 ml of dimethylformamide, add 2.3 ml of 4-ethyl-morpholine, 1.60 g of BOP and a solution of 1.3 g of product h) in 2 ml of dimethylformamide. After stirring, the reaction mixture was evaporated, the residue was taken up in acetone and shaken with water. After drying the organic phase, evaporation and chromatography of the residue with hexane / acetone on silica gel, 2.0 g of t-butyl ester (S) -3- [N - [(S) 4- (azepan-1-yl -) - 3- are obtained (Naphthalene-2-sulfonylamino) -4-oxobutyryl] -N-ethoxycarbonylmethylaminomethyl] -piperidine-1-carboxylic acid, MS (ion spray): 687.3 (M + H) ⁺ .

Primer 13Example 13

Raztopini 1.0 g estrskega produkta iz Primera 12 v K) ml metanola dodamo 9.0 ml IN natrijevega luga. Po mešanju dodamo 9.0 ml IN solne kisline, uparimo raztopino, kromatografiramo ostanek z vodo/acetonitrilom na koloni RP-18 in tako dobimo 0.5 g [[(R)-l-(amino-imino-metil)piperidin-3-ilmetil]-[(S)-4-(azepan-l-il-)-3-(naftil-2sulfonilamino)-4-oksobutiril]amino] ocetne kisline,To a solution of 1.0 g of the ester product of Example 12 in K) ml of methanol was added 9.0 ml of 1N sodium hydroxide. After stirring, 9.0 ml of 1N hydrochloric acid are added, the solution is evaporated, the residue is chromatographed with water / acetonitrile on RP-18 column to give 0.5 g [[(R) -1- (amino-imino-methyl) piperidin-3-ylmethyl] - [(S) -4- (Azepan-1-yl -) - 3- (naphthyl-2-sulfonylamino) -4-oxobutyryl] amino] acetic acid,

MS (ionski spray): 601,2 (M+H)+.MS (ion spray): 601.2 (M + H) +.

Primer 14Example 14

A) Analogno Primeru 1 dobimo:A) Analogous to Example 1 we get:

a) iz t-butil estra (S)-N-ciklopropil-N-etoksikarbonilmetil-3-(4-trifluormetilfenilsulfonilamino)-sukcinamske kisline, etil ester acetat [(S)-3-[(S)-l-(amino-imino-metil)piperidin-3-ilmetilkarbamoil]-2-(4trifluormetil-fenilsulfonilamino)propionil-ciklopropil-amino]ocetne kisline (1:1),a) From (S) -N-cyclopropyl-N-ethoxycarbonylmethyl-3- (4-trifluoromethylphenylsulfonylamino) -succinic acid t-butyl ester, acetate [(S) -3 - [(S) -1- (amino- imino-methyl) piperidin-3-ylmethylcarbamoyl] -2- (4trifluoromethyl-phenylsulfonylamino) propionyl-cyclopropyl-amino] acetic acid (1: 1),

MS (ionski spray): 605,4 (M+H) ⁺ .MS (ion spray): 605.4 (M + H) ⁺ .

b) iz t-butil estra (S)-3-(4-t-butil-fenilsulfonilamino)-N-ciklopropil-N-etoksikarbonilmetil-sukcinamske kisline, etil ester acetat [(S)-3-[(S)-l-(amino-imino-metil)piperidin-3-ilmetilkarbamoil]-2-(4t-butilfenilsulfonilamino)propionil-ciklopropil-amino]ocetne kisline (1:1),b) from (S) -3- (4-t-butyl-phenylsulfonylamino) -N-cyclopropyl-N-ethoxycarbonylmethyl-succinic acid t-butyl ester, acetate [(S) -3 - [(S) -1 - (amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -2- (4t-butylphenylsulfonylamino) propionyl-cyclopropyl-amino] acetic acid (1: 1),

MS (ionski spray): 593,5 (M+H) + .MS (ion spray): 593.5 (M + H) +.

c) iz t-butil estra (S)-3-(bifenil-4-ilsulfonilamino)-N-ciklopropil-N-etoksikarbonilmetil-sukcinamske kisline, etil ester hidroklorid [(S)-3-[(S)-l-(amino-imino-metil)piperidin-3-ilmetilkarbamoil]2-(bifenil-4-ilsulfonilamino)-N-ciklopropil-propionilamino ocetne kisline (1:2),c) from (S) -3- (biphenyl-4-ylsulfonylamino) -N-cyclopropyl-N-ethoxycarbonylmethyl-succinic acid t-butyl ester, ethyl ester hydrochloride [(S) -3 - [(S) -1- ( amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] 2- (biphenyl-4-ylsulfonylamino) -N-cyclopropyl-propionylamino acetic acid (1: 2),

MS (ionski spray): 613,4 (M + H) + .MS (ion spray): 613.4 (M + H) +.

d) iz t-butil estra (S)-N-ciklopropil-N-etoksikarbonilmetil-3-(3-metilkinolin)-8-ilsulfonilamino)-sukcinamske kisline, etil ester acetat [(S)-3-[(S)-l-(amino-imino-metil)piperidin-3-ilmetilkarbamoil]-Nciklopropil-2-(3-metilkinolin-8-ilsulfonilamino)-propionilamino ocetne kisline (1:1), MS (ionski spray): 602,2 (M + H) ⁺ .d) (S) -N-cyclopropyl-N-ethoxycarbonylmethyl-3- (3-methylquinoline) -8-ylsulfonylamino) -succinic acid t-butyl ester, acetate [(S) -3 - [(S) - 1- (amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -Ncyclopropyl-2- (3-methylquinolin-8-ylsulfonylamino) -propionylamino acetic acid (1: 1), MS (ion spray): 602.2 (M + H) ⁺ .

B) Izhodni diester dobimo iz t-butil-(S)-2-(l-t-butoksiformamido)-N-ciklopropil-N[(etoksikarbonil)metil]sukcinamata (Primer 2B)c)l)), analogno Primeru lb), vendar ob uporabi ustreznih arilsultokloridov namesto β-naftilsulfoklorida:B) The starting diester is obtained from t-butyl- (S) -2- (lt-butoxyformamido) -N-cyclopropyl-N [(ethoxycarbonyl) methyl] succinamate (Example 2B) c)), analogous to Example 1b), but using appropriate arylsultochlorides instead of β-naphthylsulfochloride:

a) t-butil ester (S)-N-ciklopropil-N-etoksikarbonilmetil-3-(4-trifluormetilfenilsulfonilamino)-sukcinatnske kisline, MS (ionski spray): 523,0 (M+H) ⁺ .a) (S) -N-Cyclopropyl-N-ethoxycarbonylmethyl-3- (4-trifluoromethylphenylsulfonylamino) -succinic acid t-butyl ester, MS (ion spray): 523.0 (M + H) ⁺ .

b) t-butil ester (S)-3-(4-t-butil-fenilsulfonamino)-N-ciklopropil-N-etoksikarbonilmetil-sukcinamske kisline, MS (ionski spray): 511,1 (M+H)⁺.b) (S) -3- (4-t-Butyl-phenylsulfonamino) -N-cyclopropyl-N-ethoxycarbonylmethyl-succinic acid t-butyl ester, MS (ion spray): 511.1 (M + H) ⁺ .

c) t-butil ester (S)-3-(bifenil-4-ilsulfonilamino)-N-ciklopropil-N-etoksikarbonilmetilsukcinamske kisline, MS (ionski spray): 531,4 (M+H)+.c) (S) -3- (Biphenyl-4-ylsulfonylamino) -N-cyclopropyl-N-ethoxycarbonylmethylsuccinic acid t-butyl ester, MS (ion spray): 531.4 (M + H) +.

d) t-butil ester (S)-N-ciklopropil-N-etoksikarbonilmetil-3-(3-metiIkinolin-8-iIsulfonilamino)-sukcinamske kisline, MS (iqnski spray): 520,2 (M + H) ⁺ .d) (S) -N-Cyclopropyl-N-ethoxycarbonylmethyl-3- (3-methylquinolin-8-ylsulfonylamino) -succinic acid t-butyl ester, MS (iqic spray): 520.2 (M + H) ⁺ .

Primer 15Example 15

Analogno Primeru 3 dobimo iz estrov Primera 14a) naslednje kisline:Analogous to Example 3, the following acids are obtained from the esters of Example 14a):

a) [(S)-3-[(S)-l-(amino-imino-metil)piperidin-3-ilmetilkarbamoil]-2-(4-trifluorometil fenilsulfonilaminoj-propionil-ciklopropil-aminojocetno kislino,a) [(S) -3 - [(S) -1- (amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -2- (4-trifluoromethylphenylsulfonylamino-propionyl-cyclopropyl-aminoacetic acid,

MS (ionski spray): 577,4 (M + H) ⁺ .MS (ion spray): 577.4 (M + H) ⁺ .

b) [(S)-3-[(S)-l-(amino-imino-metil)piperidin-3-ilmetilkarbamoil]-2-(4-t-butilfenilsulfonilaminoj-propionil-ciklopropil-aminojocetno kislino,b) [(S) -3 - [(S) -1- (amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -2- (4-t-butylphenylsulfonylamino-propionyl-cyclopropyl-aminoacetic acid,

MS (ionski spray); 565,2 (M + H) ⁺ .MS (ion spray); 565.2 (M + H) ⁺ .

c) [(S)-3-[(S)-l-(amino-imino-metil)piperidin-3-ilmetilkarbamoil]-2-(bifenil-4-ilsulfonilamino)-N-ciklopropil-propionilamino-ocetno kislino,c) [(S) -3 - [(S) -1- (amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -2- (biphenyl-4-ylsulfonylamino) -N-cyclopropyl-propionylamino-acetic acid,

MS (ionski spray): 585,4 (M+H) ⁺ .MS (ion spray): 585.4 (M + H) ⁺ .

d) [(S)-3-[(S)-l-(amino-imino-metil)piperidin-3-ilmetilkarbamoil]-N-ciklopropil-2(3-metilkinolin-8-ilsulfonilamino)-propionilamino-ocetno kislino,d) [(S) -3 - [(S) -1- (amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -N-cyclopropyl-2 (3-methylquinolin-8-ylsulfonylamino) -propionylamino-acetic acid,

MS (ionski spray): 574,4 (M + H) ⁺ .MS (ion spray): 574.4 (M + H) ⁺ .

Primer 16Example 16

Raztopini 0.34 g produkta iz Primera 15Ajd) v 25 ml etanola dodamo 1 ml ocetne kisline in 0.1 g paladija na oglju ter hidriramo pri normalnih pogojih. Po filtraciji in uparjenju filtrata dobimo 0.12 g acetata N-[(S)-3-[(S)-l-(amino-imino-metiljpiperidin-3-ilmetilkarbamoil]-2-(3-metil-1,2,3,4-tetrahidrokinolin-8-ilsulfonilamino)propionil]-N-ciklopropil-aminoocetne kisline (1:1),To a solution of 0.34 g of the product of Example 15Ajd) in 25 ml of ethanol was added 1 ml of acetic acid and 0.1 g of palladium on charcoal and hydrated under normal conditions. Filtration and evaporation of the filtrate gave 0.12 g of acetate N - [(S) -3 - [(S) -1- (amino-imino-methylpiperidin-3-ylmethylcarbamoyl] -2- (3-methyl-1,2,3, 4-Tetrahydroquinolin-8-ylsulfonylamino) propionyl] -N-cyclopropyl-aminoacetic acid (1: 1),

MS (ionski spray): 578,4 (M + H) ⁺ .MS (ion spray): 578.4 (M + H) ⁺ .

Primer 17Example 17

Analogno Primeru 1 dobimo iz t-butil estra (S)-N-cikIopropiI-3-(naftaIen-2ilsulfonilamino)-N-(3-okso-butil)-sukcinamske kisline, [(S)-N4-[(S)-l-(amino-imino-metil)piperidin-3-ilmetil]-Nl-ciklopropil-2-(naftalen-2ilsulfonilamino)-Nl-(3-oksobutil)-sukcinamid hidroklorid (1:1),Analogous to Example 1 was obtained from (S) -N-cyclopropyl-3- (naphthalen-2ylsulfonylamino) -N- (3-oxo-butyl) -succinic acid t-butyl ester, [(S) -N4 - [(S) - 1- (amino-imino-methyl) piperidin-3-ylmethyl] -Nl-cyclopropyl-2- (naphthalen-2ylsulfonylamino) -Nl- (3-oxobutyl) -succinamide hydrochloride (1: 1),

MS (ionski spray): 571,2 (M+H)⁺.MS (ion spray): 571.2 (M + H) ⁺ .

Priprava izhodnega materiala:Preparation of starting material:

a) Raztopini etil estra 10 g N-ciklopropil-/Lalanina v 100 ml dioksana dokapavamo ob hlajenju raztopino 13.9 g di-t-butil-dikarbonata v 140 ml dioksana. Po mešanju reakcijsko zmes uparimo. Po sušenju ostanka dobimo 16 g etil estra 3-(t-butoksikarbonil-ciklopropil-aminojpropionske kisline; Fab-MS: 201 (M-izobutilen).a) A solution of 13.9 g of di-t-butyl dicarbonate in 140 ml of dioxane is added dropwise to a solution of ethyl ester of 10 g of N-cyclopropyl- / Lalanine in 100 ml of dioxane. After stirring, the reaction mixture was evaporated. Drying the residue afforded 16 g of 3- (t-butoxycarbonyl-cyclopropyl-aminopropionic acid ethyl ester; Fab-MS: 201 (M-isobutylene).

b) Raztopini 15. 7 g produkta iz a) v 160 ml tetrahidrofurana dokapavamo pri 0° do 3 °C 42 ml 1.6 M raztopine metillitija v etru. Po mešanju pri sobni temperaturi ohladimo na 0° C in dokapavamo nadaljnjih 34.5 ml 1.6M raztopine metillitija v etru. Po mešanju izlijemo reakcijsko raztopino v ledenomrzlo raztopino 5% kalijevega hidrogen sulfata/10% kalijevega sulfata in ekstrahiramo z ocetestrom. Organsko fazo izperemo z raztopino kuhinjske soli, nato sušimo in uparimo ter ostanek kromatografiramo s heksanom/ocetestrom (4:1) na kremeničnem gelu. V prvi frakciji dobimo 8.3 g t-butil estra ciklopropil-(3-hidroksi-3-metilbutil)karbamidne kisline, Fab-MS: 187 (M-izobutilen).b) To a solution of 15. 7 g of the product from a) in 160 ml of tetrahydrofuran are added dropwise at 0 ° to 3 ° C 42 ml of a 1.6 M solution of methyllithium in ether. After stirring at room temperature, it was cooled to 0 ° C and a further 34.5 ml of 1.6M methyl ether solution in ether was added dropwise. After stirring, pour the reaction solution into an ice-cold solution of 5% potassium hydrogen sulphate / 10% potassium sulphate and extract with acetone. The organic phase was washed with brine, then dried and evaporated, and the residue was chromatographed with hexane / acetone (4: 1) on silica gel. In the first fraction 8.3 g of t-butyl ester of cyclopropyl- (3-hydroxy-3-methylbutyl) carbamic acid were obtained, Fab-MS: 187 (M-isobutylene).

c) Iz kromatograma b) izoliramo v drugi frakciji 1.7 g t-butil estra ciklopropil-3oksobutil karbamidne kisline, Fab-MS: 171 (M-izobutilen).c) From chromatogram b), 1.7 g of cyclopropyl-3-isobutyl carbamic acid t-butyl ester, Fab-MS: 171 (M-isobutylene), were isolated in the second fraction.

d) Raztopini 18.2 g produkta iz b) v 80 ml ocetestra dodamo 40 ml 4M raztopine solne kisline v ocetestru. Po mešanju odfiltriramo izločeni material in ga izperemo z ocetestrom. Po sušenju dobimo 3.6 g 4-ciklopropilamino-2-metilbutan-2-olhidroklorida, Fab-MS: 143 M+.d) To a solution of 18.2 g of the product of b) in 80 ml of acetic acid is added 40 ml of a 4M hydrochloric acid solution in acetic acid. After stirring, the separated material is filtered off and washed with acetone. After drying 3.6 g of 4-cyclopropylamino-2-methylbutan-2-olhydrochloride are obtained, Fab-MS: 143 M +.

e) Raztopini 3.1 g produkta iz c) v 30 ml ocetestra dodamo 30 ml 4M raztopine solne kisline v ocetestru. Po mešanju uparimo in sušimo. Dobimo 2.3 g 4-ciklopropilaminobutan-2-ona.e) To a solution of 3.1 g of the product from c) in 30 ml of acetone is added 30 ml of 4M hydrochloric acid solution in acetate. After stirring, evaporate and dry. 2.3 g of 4-cyclopropylaminobutan-2-one are obtained.

f) Raztopini 3.9 g β-t-butil estra N-Boc-L-asparaginske kisline v 40 ml metilenklorida dodamo 5,5 ml 4-etilmorfolina, 3.1 g N-(dimetilaminopropil)-N’-etilkarbodiimidhidroklorida in 0.17 g 4-dimetilaminopiridina. Tej raztopini dodamo pri e) dobljeni material, raztopljen v 20 ml metilenklorida. Po mešanju izlijemo reakcijsko raztopino v ledenomrzlo raztopino 5% kalijevega hidrogensulfata/10% kalijevega sulfata in ekstrahiramo z metilenkloridom. Organsko fazo izperemo z raztopino kuhinjske soli, nato sušimo in uparimo in ostanek kromatografiramo s heksanom/metil acetatom 2:1 na kremeničnem gelu. Dobimo 3.7 g t-butil estra (S)-N-(2-acetiletil)-3-t-butoksikarbonilamino-N-ciklopropil-sukcinamske kisline,f) To a solution of 3.9 g of N-Boc-L-aspartic acid β-t-butyl ester in 40 ml of methylene chloride was added 5.5 ml of 4-ethylmorpholine, 3.1 g of N- (dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride and 0.17 g of 4-dimethylaminopyridine . To this solution was added at e) the material obtained dissolved in 20 ml of methylene chloride. After stirring, pour the reaction solution into an ice-cold solution of 5% potassium hydrogen sulphate / 10% potassium sulphate and extract with methylene chloride. The organic phase was washed with brine, then dried and evaporated, and the residue was chromatographed with hexane / methyl acetate 2: 1 on silica gel. 3.7 g of (S) -N- (2-acetylethyl) -3-t-butoxycarbonylamino-N-cyclopropyl-succinic acid t-butyl ester is obtained,

MS (ionski spray): 399,3 (M+H) ⁺ .MS (ion spray): 399.3 (M + H) ⁺ .

g) Iz produkta f) dobimo analogno Primeru 2B)i) t-butil ester (S)-N-ciklopropil-3(naftalen-2-ilsulfonilamino)-N-(3-okso-butil) sukcinamske kisline,g) From product f), analogous to Example 2B) (S) -N-cyclopropyl-3 (naphthalen-2-ylsulfonylamino) -N- (3-oxo-butyl) succinic acid, t-butyl ester,

Fab-MS: 433 (M-izobutilen).Fab-MS: 433 (M-isobutylene).

Primer 18Example 18

Analogno Primeru 17 dobimo iz 4-ciklopropilamino-2-metilbutan-2-ol-hidroklorida (Primer 17 d), prekoAnalogous to Example 17 was obtained from 4-cyclopropylamino-2-methylbutan-2-ol-hydrochloride (Example 17 d), via

a) t-butil estra (S)-3-t-butoksikarbonilamino-N-ciklopropil-N-(3-hidroksi-3metilbutilj-sukcinamske kisline, MS (ionski spray): 415,4 (M + H)⁺ ina) (S) -3-t-Butoxycarbonylamino-N-cyclopropyl-N- (3-hydroxy-3methylbutyl-succinic acid) t-butyl ester, MS (ion spray): 415.4 (M + H) ⁺ and

b) t-butil estra (S)-N-ciklopropil-N-(3-hidroksi-3-metil-butil)-2-naftalen-2sulfonilaminoj-sukcinamske kisline, MS (ionski spray): 505,3 (M + H)⁺, (S)-N4-[(S)-l-(amino-imino-metil)-piperidin-3-ilmetil-Nl-ciklopropil-Nl-(3-hidroksi'b) (S) -N-cyclopropyl-N- (3-hydroxy-3-methyl-butyl) -2-naphthalene-2-sulfonylamino-succinic acid t-butyl ester, MS (ion spray): 505.3 (M + H) ) ⁺ , (S) -N4 - [(S) -1- (amino-imino-methyl) -piperidin-3-ylmethyl-N1-cyclopropyl-N1- (3-hydroxy)

3-metil-butil)-2-(naftalen-2-ilsulfonilamino)-sukcinamid hidroklorid (1:1),3-methyl-butyl) -2- (naphthalen-2-ylsulfonylamino) -succinamide hydrochloride (1: 1),

MS (ionski spray): 587,4 (M + H) ⁺ ·MS (ion spray): 587.4 (M + H) ⁺ ·

Primer 19Example 19

Analogno Primeru 7A), vendar izhajajoč iz diestrov Primera 14B)a), b) oz. e) dobimo naslednje estre:Analogous to Example 7A) but based on the diesters of Example 14B) a), b) and e) the following esters are obtained:

a) etil ester acetat [(S)-3-[(R,S)-4-(amino-imino-metil)morfolin-2-ilmetilkarbamoil]2-(4-trifluormetil-fenilsulfonilamino)-propionil-ciklopropil-amino]-ocetne kisline (1:1), MS (ionski spray): 607,2 (M + H)⁺,a) Acetyl ethyl ester [(S) -3 - [(R, S) -4- (amino-imino-methyl) morpholin-2-ylmethylcarbamoyl] 2- (4-trifluoromethyl-phenylsulfonylamino) -propionyl-cyclopropyl-amino] -acetic acids (1: 1), MS (ion spray): 607.2 (M + H) ⁺ ,

b) etil ester trifluoracetat [(S)-3-[(R,S)-4-(amino-imino-metil)morfolin-2ilmetilkarbamoil]-2-(4-t-butil-fenilsulfonilamino)-propionil-ciklopropil-aminojocetne kisline (1:1), MS (ionski spray): 595,3 (M + H)⁺, oz.b) trifluoroacetate [(S) -3 - [(R, S) -4- (amino-imino-methyl) morpholin-2ylmethylcarbamoyl] -2- (4-t-butyl-phenylsulfonylamino) -propionyl-cyclopropyl-aminoacetate ethyl ester acids (1: 1), MS (ion spray): 595.3 (M + H) ⁺ , resp.

c) etil ester trifluoracetat [(S)-3-[(R,S)-4-(amino-imino-metil)morfolin-2ilmetilkarbamoil]-2-(bifenil-4-ilsulfonilamino)-N-ciklopropil-propionilamino]-ocetne kisline (1:1), MS (ionski spray): 615,3 (M t H) ⁺ .c) trifluoroacetate ethyl ester [(S) -3 - [(R, S) -4- (amino-imino-methyl) morpholin-2ylmethylcarbamoyl] -2- (biphenyl-4-ylsulfonylamino) -N-cyclopropyl-propionylamino] - acetic acids (1: 1), MS (ion spray): 615.3 (M t H) ⁺ .

Primer 20Example 20

Analogno Primeru 3 dobimo izhajajoč iz estrov Primera 19 naslednje kisline:Analogous to Example 3, the following acids are obtained from the esters of Example 19:

a) [(S)-3-[(R,S)-4-(amino-imino-metil)morfolin-2-ilmetilkarbamoil]-2-(4-trifluormetil-fenilsulfonilamino)-propionil-ciklopropil-amino]-ocetno kislino,a) [(S) -3 - [(R, S) -4- (amino-imino-methyl) morpholin-2-ylmethylcarbamoyl] -2- (4-trifluoromethyl-phenylsulfonylamino) -propionyl-cyclopropyl-amino] -acetone acid,

MS (ionski spray): 579,1 (M + H) ⁺ .MS (ion spray): 579.1 (M + H) ⁺ .

b) [(S)-3-[(R,S)-4-(amino-imino-metil)morfolin-2-ilmetilkarbamoil]-2-(t-butillfenilsulfonilamino)-N-ciklopropil-propionilaminoj-ocetno kislino,b) [(S) -3 - [(R, S) -4- (amino-imino-methyl) morpholin-2-ylmethylcarbamoyl] -2- (t-butylphenylsulfonylamino) -N-cyclopropyl-propionylamino-acetic acid,

MS (ionski spray): 567,4 (M + H) + .MS (ion spray): 567.4 (M + H) +.

c) [(S)-3-[(R,S)-4-(amino-imino-metil)morfolin-2-ilmetilkarbamoil]-2-(bifenil-4ilfenilsulfonilamino)-N-ciklopropil-propionilamino]-ocetno kislino,c) [(S) -3 - [(R, S) -4- (amino-imino-methyl) morpholin-2-ylmethylcarbamoyl] -2- (biphenyl-4-phenylsulfonylamino) -N-cyclopropyl-propionylamino] -acetic acid,

MS (ionski spray): 587,3 (M + H) ⁺ .MS (ion spray): 587.3 (M + H) ⁺ .

Primer 21Example 21

Analogno Primeru 9, le izhajajoč iz N-metil-3-pikolilamina (namesto N-(2-hidroksietil)-3-pikolilamina), dobimo preko t-butilmetil (3-piridinmetiI)karbamata, t-butil-rac-metil (3-piperidinilmetil)karbamata, t-butil-rac-[(l-amidino-3-piperidinil)metil]metilkarbamat bisulfita in rac-3-[(metilamino)metil]metil]l-lpiperidinkarboksamidin dihidroklorida,Analogous to Example 9, only starting from N-methyl-3-picolylamine (instead of N- (2-hydroxyethyl) -3-picolylamine) is obtained via t-butylmethyl (3-pyridinmethyl) carbamate, t-butyl-rac-methyl (3 -piperidinylmethyl) carbamate, t-butyl-rac - [(1-amidino-3-piperidinyl) methyl] methylcarbamate bisulfite and rac-3 - [(methylamino) methyl] methyl] -1-piperidinecarboxamidine dihydrochloride,

Fab-MS: 171 (M + H)+,Fab-MS: 171 (M + H) < + >,

a) ob uporabi t-butil estra (S)-N-butil-N-(2-etoksikarboniletil-3-(naftalen-2ilsulfonilaminsukcinamske kisline (Primer 2.B)j) 11) etil ester hidroklorid 3-[(S)-3-[(R,S)-[l-(amino-imino-metil)piperidin-3-ilmetil]-Nmetilkarbamoil]-N-butil-2-(naftalen-2-ilsulfonilamino)-propionilamino]-propionske kisline (1:1), MS (ionski spray): 631,5 (M + H) ⁺ .a) using (S) -N-butyl-N- (2-ethoxycarbonylethyl-3- (naphthalene-2ylsulfonylaminosuccinic acid) t-butyl ester (Example 2.B) j) 11) ethyl ester hydrochloride 3 - [(S) - 3 - [(R, S) - [1- (amino-imino-methyl) piperidin-3-ylmethyl] -Nmethylcarbamoyl] -N-butyl-2- (naphthalen-2-ylsulfonylamino) -propionylamino] -propionic acid (1 : 1), MS (ion spray): 631.5 (M + H) ⁺ .

b) ob uporabib) when used

N-[3-(t-butoksikarbonil)-N-(2-naftilsulfonil)-L-alanilj-N-ciklopropil-/3-alanina (Primer 2.B)j)9) etil ester hidroklorid 3-[(S)-3-[(R,S)-[l-(amino-imino-metil)piperidin-3-ilmetiljmetilkarbamoilj-2-(naftalen-2-sulfonilamino)-propionil]-ciklopropilaminojpropionske kisline (1:1), MS (ionski spray): 615,4 (M + H) ⁺ .N- [3- (t-butoxycarbonyl) -N- (2-naphthylsulfonyl) -L-alanyl-N-cyclopropyl- / 3-alanine (Example 2.B) j) 9) ethyl ester hydrochloride 3 - [(S) -3 - [(R, S) - [1- (amino-imino-methyl) piperidin-3-ylmethylmethylcarbamoyl-2- (naphthalene-2-sulfonylamino) -propionyl] -cyclopropylamino-propionic acid (1: 1), MS (ionic spray): 615.4 (M + H) < ⁺ >.

Primer 22Example 22

Analogno Primeru 3 dobimo iz estrov Primera 21 naslednje kisline:Analogous to Example 3, the following acids are obtained from the esters of Example 21:

3-[(S)-3-[(R,S)-[l-(amino-imino-metil)piperidin-3-ilmetil]-N-metilkarbamoil]-Nbutil-2-(naftalen-2-sulfonilamino)-propionilamino]-propionsko kislino, MS (ionski spray): 603,5 (M + H)+.3 - [(S) -3 - [(R, S) - [1- (amino-imino-methyl) piperidin-3-ylmethyl] -N-methylcarbamoyl] -N-butyl-2- (naphthalene-2-sulfonylamino) - propionylamino] -propionic acid, MS (ion spray): 603.5 (M + H) +.

3-[(S)-3-[(R,S)-[l-(amino-imino-metil)piperidin-3-ilmetiI]-metil]-metilkarbamoil]-2(naftaIen-2-suIfonilamino)-propionil]-ciklopropil-amino]-propionsko kislino,3 - [(S) -3 - [(R, S) - [1- (amino-imino-methyl) piperidin-3-ylmethyl] -methyl] -methylcarbamoyl] -2 (naphthalen-2-sulfonylamino) -propionyl] -cyclopropyl-amino] -propionic acid,

MS (ionski spray): 587,4 (M + H) ⁺ .MS (ion spray): 587.4 (M + H) ⁺ .

Primer 23Example 23

Raztopini t-butil estra (S)-3-[(S)-3-[(4-kIorbenzil)-metoksikarbonilmetilkarbamoilj3-(naftalen-2-sulfonilamino)-propionilaminometilpiperidin-l-karboksilne kisline v 20 ml metilenklorida dodamo 4 ml trifluorocetne kisline. Po mešanju uparimo, ostanek raztopimo v 2.7 ml metanola in dodamo 0.93 ml trietilamina in 330 mg formamidinsulfonske kisline. Nato ponovno dodamo 165 mg formamidinsulfonske kisline in 0.19 ml trietilamina. Po mešanju uparimo reakcijsko zmes in kromatografiramo ostanek na kremeničnem gelu z ocetestrom/acetonom/ocetno kislino/vodo 6:2:1:1. Doimo 516 mg N-[N4-[[(S)-l-amidino-3-piperidinil]metil]-N2-(naftilsulfoniI) L-asparaginil]-N-(p-klorbenzil)glicina (1:1), MS (ionski spray): 657 (M + H) ⁺ .(S) -3 - [(S) -3 - [(4-chlorobenzyl) -methoxycarbonylmethylcarbamoyl] 3- (naphthalene-2-sulfonylamino) -propionylaminomethylpiperidine-1-carboxylic acid t-butyl ester solution was added 4 ml of trifluoroacetic acid in 20 ml of methylene chloride. . After stirring, the residue was dissolved in 2.7 ml of methanol and 0.93 ml of triethylamine and 330 mg of formamidinsulfonic acid were added. 165 mg of formamidinsulfonic acid and 0.19 ml of triethylamine are then added again. After stirring, the reaction mixture was evaporated and the residue was chromatographed on silica gel with acetone / acetone / acetic acid / water 6: 2: 1: 1. About 516 mg of N- [N4 - [[(S) -1-amidino-3-piperidinyl] methyl] -N2- (naphthylsulfonyl) L-asparaginyl] -N- (p-chlorobenzyl) glycine (1: 1), MS (ion spray): 657 (M + H) < ⁺ >.

Priprava izhodnega materiala:Preparation of starting material:

a) Suspenziji b-t-butil estra 10 g L-asparaginske kisline in 11.98 g naftalin-2sulfoklorida v 100 ml dioksana pri 6 do 10°C dokapavamo 52,85 ml 2N natrijevega luga. Po mešanju dokapavamo 53 ml IN solne kisline. Reakcijsko zmes takoj prevzamemo v 800 ml etra in izperemo fazo etra/dioksana z vodo. Po sušenju in uparjenju organskih faz kristaliziramo ostanek v etru. Po odfiltriranju kristalov dobimo 13.7 g 4-t-butil ester N-(2-naftilsulfonil)-L-asparaginske kisline, tal. 141°C.a) Suspensions of b-t-butyl ester of 10 g of L-aspartic acid and 11.98 g of naphthalene-2 sulfoxide in 100 ml of dioxane at 6 to 10 ° C were added dropwise to 52.85 ml of 2N sodium hydroxide. After stirring, 53 ml of 1N hydrochloric acid are added dropwise. The reaction mixture was immediately taken up in 800 ml of ether and the ether / dioxane phase was washed with water. After drying and evaporation of the organic phases, the residue is crystallized in ether. Filtration of the crystals gave 13.7 g of N- (2-naphthylsulfonyl) -L-aspartic acid 4-t-butyl ester, m.p. 141 ° C.

b) K 20 g metil ester hidroklorid in 34,8 g di-t-butil-dikarbonata v 300 ml metilenklorida in 10 ml vode dokapavamo 22.2 ml trietilamina. Po mešanju uparimo reakcijsko zmes. Ostanek prevzamemo v etru in izperemo etrno fazo po dodatku 5 ml IN solne kisline z vodo do nevtralnega. Po sušenju in uparjenju etrne faze dobimo 30.2 g N-BOC-glicin metil estra Rf=0.33 (eter/heksan 1:1).b) 22.2 ml of triethylamine are added dropwise to 20 g of methyl ester hydrochloride and 34.8 g of di-t-butyl dicarbonate in 300 ml of methylene chloride and 10 ml of water. After stirring, the reaction mixture was evaporated. The residue was taken up in ether and the ether phase was washed after addition of 5 ml of 1N hydrochloric acid with water to neutral. After drying and evaporating the ether phase, 30.2 g of N-BOC-glycine methyl ester is obtained Rf = 0.33 (ether / hexane 1: 1).

c) K 1.0 g surovega produkta iz b) in 937 mg 4-klor-benzilklorida v 10 ml dimetilformamida dodamo ob hlajenju z ledom 242 mg natrijevega hidrida (55% v olju). Po mešanju prevzamemo reakcijsko zmes v 100 ml etra in izperemo z vodo. Po sušenju in uparjenju etrne faze kromatografiramo ostanek preko kremeničnega gela z eterom/heksanom 1:2 . Dobimo 1.27 g N-BOC-N-(4-klorbenzil)-glicin metil estra Rf=0.33 (eter/heksan 1:2).c) To 1.0 g of the crude product of b) and 937 mg of 4-chloro-benzyl chloride in 10 ml of dimethylformamide were added while cooling with ice 242 mg of sodium hydride (55% in oil). After stirring, the reaction mixture was taken up in 100 ml of ether and washed with water. After drying and evaporating the ether phase, chromatograph the residue over silica gel with ether / hexane 1: 2. 1.27 g of N-BOC-N- (4-chlorobenzyl) -glycine methyl ester is obtained Rf = 0.33 (ether / hexane 1: 2).

d) 1.275 g produkta iz c) dodamo 5 ml 10N solne kisline v metanolu. Metanol odparimo in ostanek naplavimo v 20 ml etra in odfiltriramo. Po izpranju ostanka z etrom dobimo 0.93 g N-(4-klorbenzil)-glicin metil ester hidroklorida, Rf=0.59 (ocetester/aceton/voda/ledocet 6:2:1:1).d) 1.275 g of the product from c) is added 5 ml of 10N hydrochloric acid in methanol. The methanol was evaporated and the residue was taken up in 20 ml of ether and filtered off. Washing the residue with ether afforded 0.93 g of N- (4-chlorobenzyl) -glycine methyl ester hydrochloride, Rf = 0.59 (Acetester / acetone / water / glacial 6: 2: 1: 1).

e) 567 mg produkta iz a), 394 mg produkta iz d), 636 mg BOP in 0.5 ml Hiinigove baze raztopimo v 8 ml metilenklorida. Po mešanju prevzamemo reakcijsko zmes v 100 ml etra in izperemo etrno fazo s solno kislino in vodo. Po sušenju in uparjenju etrne faze kromatografiramo ostanek preko kremeničnega gela z etrom/heksanom 2:1. Dobimo 926 mg t-butil estra (S)-N-(4-klorbenzil)-N-metoksikarbonilmetil-3(naftalen-2-sulfonilamino)-sukcinamske kisline, MS (ionski sprav): 575 (M 4- H) ⁺ .e) 567 mg of product from a), 394 mg of product from d), 636 mg of BOP and 0.5 ml of Hiinig base were dissolved in 8 ml of methylene chloride. After stirring, the reaction mixture was taken up in 100 ml of ether and the ether phase was washed with hydrochloric acid and water. After drying and evaporating the ether phase, chromatograph the residue over silica gel with ether / hexane 2: 1. 926 mg of (S) -N- (4-chlorobenzyl) -N-methoxycarbonylmethyl-3 (naphthalene-2-sulfonylamino) -succinic acid t-butyl ester is obtained, MS (ionic apparatus): 575 (M 4H) ⁺ .

f) 926 mg produkta iz e) dodamo 6 ml 5-M solne kisline v dioksanu. Po mešanju prevzamemo reakcijsko zmes v 100 ml etra in izperemo etrno fazo z vodo. Po sušenju in uparjenju 877 mg (S)-N-(4-klorbenzil)-N-metoksikarbonilmetil-3-(naftalen-2sulfonilamino)-sukcinamske kisline, Rf=0.7 (ocetester/ledocet 99:1)f) 926 mg of the product from e) 6 ml of 5-M hydrochloric acid in dioxane are added. After stirring, the reaction mixture was taken up in 100 ml of ether and the ether phase was washed with water. After drying and evaporating 877 mg of (S) -N- (4-chlorobenzyl) -N-methoxycarbonylmethyl-3- (naphthalene-2-sulfonylamino) -succinic acid, Rf = 0.7 (acetic acid / glacial 99: 1)

g) 877 mg produkta f), 435 mg t-butil estra [S]-3-aminometil-l-piperidinkarboksilne kislin, 785 mg BOP in 0.58 ml Hunigove baze mešamo v 12 ml metilenklorida. Reakcijsko zmes prevzamemo v 100 ml etra in izperemo etrno fazo z ln solno kislino in vodo. Po sušenju in uparjenju etrnih faz kromatografiramo ostanek preko kremeničnega gela z ocetestrom/heksanom 4:1. Dobimo 958 mg t-butil estra (S)-3[(S)-3-[(4-klorbenzil)-metoksikarbonilmetil-karbamoil]-3-(naftalen-2-sulfonilamino)propionilaminometil]piperidin-l-karboksilne kisline,g) 877 mg of product f), 435 mg of [S] -3-aminomethyl-1-piperidinecarboxylic acid t-butyl ester, 785 mg of BOP and 0.58 ml of Hunig's base were stirred in 12 ml of methylene chloride. The reaction mixture was taken up in 100 ml of ether and the ether phase was washed with hydrochloric acid and water. After drying and evaporation of the ether phases, the residue is chromatographed over silica gel with 4: 1 acetone / hexane. 958 mg of (S) -3 [(S) -3 - [(4-chlorobenzyl) -methoxycarbonylmethyl-carbamoyl] -3- (naphthalene-2-sulfonylamino) propionylaminomethyl] piperidine-1-carboxylic acid t-butyl ester is obtained.

MS (ionski spray): 715 (M + H)⁺.MS (ion spray): 715 (M + H) ⁺ .

Primer 24Example 24

Raztopini 300 mg estrskega produkta iz Primera 23 v 3 ml tetrahidrofurana dodamo 1.25 ml IN LiOH. Po mešanju in dodatku 2 ml ocetne kisline uparimo in ostanek kromatografiramo na kremeničnem gelu z ocetestrom/acetonom/ocetno kislino/vodo 6:2:1:1. Dobimo 154.5 mg N-[N4-[[(S)-l-amidino-3-piperidinil]metil]-N2-(2naftilsulfonil)-L-asparaginil]-N-(p-klorbenzil)glicina,To a solution of 300 mg of the ester product of Example 23 in 3 ml of tetrahydrofuran was added 1.25 ml of IN LiOH. After stirring and adding 2 ml of acetic acid, the residue was evaporated and the residue was chromatographed on silica gel with acetone / acetone / acetic acid / water 6: 2: 1: 1. 154.5 mg of N- [N4 - [[(S) -1-amidino-3-piperidinyl] methyl] -N2- (2-naphthylsulfonyl) -L-asparaginyl] -N- (p-chlorobenzyl) glycine is obtained.

MS (ionski spray): 641 (M + H)⁺.MS (ion spray): 641 (M + H) ⁺ .

Primer 25Example 25

Analogno Primeru 23 pripravimo naslednje estre:The following esters were prepared analogously to Example 23:

a) metil ester acetat N-[N4-[[(S)-l-amidino-3-piperidinil]metil]-N2-(2-naftilsulfonil)L-asparaginil]-N-(m-klorbenzil)glicina (1:1), MS (ionski spray): 657 (M + H)⁺,a) N- [N4 - [[(S) -1-amidino-3-piperidinyl] methyl] -N2- (2-naphthylsulfonyl) L-asparaginyl] -N- (m-chlorobenzyl) glycine methyl ester (1: 1), MS (ion spray): 657 (M + H) ⁺ ,

b) metil ester acetat N-[N4-[[(S)-l-amidino-3-piperidinil]metil]-N2-(2-naftilsulfonil)L-asparaginil]-N-(o-klorbenzil)glicina (1:1), MS (ionski spray): 657 (M + H)⁺,b) N- [N4 - [[(S) -1-amidino-3-piperidinyl] methyl] -N2- (2-naphthylsulfonyl) L-asparaginyl] -N- (o-chlorobenzyl) glycine methyl ester (1: 1), MS (ion spray): 657 (M + H) ⁺ ,

c) metil ester acetat [N-[(S)-3-[(S)-l-amidino-piperidin-3-il-metilkarbamoil]-2(naftalen-2-sulfonilamino)-propionil]-N-(4-metoksibenzil)-amino]-ocetne kisline (1:1), MS (ionski spray): 653 (M + H)⁺,c) Methyl ester acetate [N - [(S) -3 - [(S) -1-amidino-piperidin-3-yl-methylcarbamoyl] -2 (naphthalene-2-sulfonylamino) -propionyl] -N- (4- methoxybenzyl) -amino] -acetic acid (1: 1), MS (ion spray): 653 (M + H) ⁺ ,

d) metil ester acetat [N-[(S)-3-[(S)-l-amidino-piperidin-3-il-metilkarbamoil]-2(naftalen-2-sulfonilamino)-propionil]-N-(piperidin-2-ilmetil)-amino]-ocetne kisline (1:1), MS (ionski spray): 624 (M + H)⁺,d) acetate [N - [(S) -3 - [(S) -1-amidino-piperidin-3-yl-methylcarbamoyl] -2 (naphthalene-2-sulfonylamino) -propionyl] -N- (piperidine- 2-ylmethyl-amino] -acetic acid (1: 1), MS (ion spray): 624 (M + H) ⁺ ,

e) metil ester acetat [N-[(S)-3-[(S)-l-amidino-piperidin-3-il-metilkarbamoil]-2(naftalen-2-sulfonilamino)-propionil]-(3-metoksi-benzil)-amino]-ocetne kisline (1:1), MS (ionski spray): 653 (M + H)⁺.e) acetate [N - [(S) -3 - [(S) -1-amidino-piperidin-3-yl-methylcarbamoyl] -2 (naphthalene-2-sulfonylamino) -propionyl] - (3-methoxy- benzyl) -amino] -acetic acid (1: 1), MS (ion spray): 653 (M + H) ⁺ .

Primer 26Example 26

Analogno Primeru 24 dobimo iz estrov Primera 25 naslednje kisline:Analogous to Example 24, the following acids are obtained from the esters of Example 25:

a) N-[N4-[[(S)-l-amidino-3-piperidinil]metil]-N2-(2-naftilsulfonil)-L-asparaginil]-N(m-klorbenzil)glicin, MS (ionski spray): 641 (M + H)⁺.a) N- [N4 - [[(S) -1-amidino-3-piperidinyl] methyl] -N2- (2-naphthylsulfonyl) -L-asparaginyl] -N (m-chlorobenzyl) glycine, MS (ion spray) : 641 (M + H) < ⁺ >.

b) N-[N4-[[(S)-l-amidino-3-piperidinil]metil]-N2-(2-naftilsulfonil)-L-asparaginil]-N(o-klorbenzil)glicin, MS (ionski spray): 641 (M + H) ⁺ .b) N- [N4 - [[(S) -1-amidino-3-piperidinyl] methyl] -N2- (2-naphthylsulfonyl) -L-asparaginyl] -N (o-chlorobenzyl) glycine, MS (ion spray) : 641 (M + H) < ⁺ >.

c) [N-[(S)-3-[(S)-l-amidino-3-piperidin-3-il-metilkarbamoil]-2-(naftalen-2sulfonilamino)-propionil]-N-(4-metoksibenzil)-amino]ocetno kislino,c) [N - [(S) -3 - [(S) -1-amidino-3-piperidin-3-yl-methylcarbamoyl] -2- (naphthalene-2-sulfonylamino) -propionyl] -N- (4-methoxybenzyl) -amino] acetic acid,

MS (ionski spray): 639 (M + H)+.MS (ion spray): 639 (M + H) +.

d) [N-[(S)-3-[(S)-l-amidino-3-piperidin-3-il-metilkarbamoil]-2-(naftalen-2sulfonilamino)-propionil]-N-(piridin-2-ilmetil)-amino]ocetne kisline,d) [N - [(S) -3 - [(S) -1-amidino-3-piperidin-3-yl-methylcarbamoyl] -2- (naphthalene-2-sulfonylamino) -propionyl] -N- (pyridin-2- ylmethyl) -amino] acetic acid,

MS (ionski spray): 610 (M + H)+.MS (ion spray): 610 (M + H) +.

e) [[(S)-3-[(S)-l-(amino-imino-metil)piperidin-3-ilmetilkarbamoil]-2-(naftalen-2sulfonilamino)-propionil]-(3-metoksibenzil)-amino]ocetno kislino,e) [[(S) -3 - [(S) -1- (amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -2- (naphthalene-2-sulfonylamino) -propionyl] - (3-methoxybenzyl) -amino] acetic acid,

MS (ionski spray): 639 (M + H) ⁺ .MS (ion spray): 639 (M + H) ⁺ .

Primer 27Example 27

Analogno Primeru 23, le ob uporabi ustreznih estrov aminokarboksilne kisline namesto metil ester hidroklorida N-(4-klorbenzil)glicina (Primer 23 d), dobimo naslednje estre:Analogous to Example 23, only using the appropriate aminocarboxylic acid esters instead of the N- (4-chlorobenzyl) glycine hydrochloride ester (Example 23 d) gave the following esters:

a) metil ester acetat L-N-[N4-[[(S)-l-amidino-3-piperidinil]metil]-N2-(2naftilsulfonil)-L-asparaginil]-l-fenilglicina (1:1),a) L-N- [N4 - [[(S) -1-amidino-3-piperidinyl] methyl] -N2- (2naphthylsulfonyl) -L-asparaginyl] -1-phenylglycine methyl ester (1: 1),

MS (ionski spray): 609 (M + H) ⁺,MS (ion spray): 609 (M + H) < ⁺ >,

b) metil ester acetat N-[N4-[[(S)-l-amidino-3-piperidinil]metil]-N2-(2-naftilsulfonil)L-asparaginil]-L-izolevcina (1:1), MS (ionski spray): 589 (M + H)+,b) N- [N4 - [[(S) -1-amidino-3-piperidinyl] methyl] -N2- (2-naphthylsulfonyl) L-asparaginyl] -L-isoleucine (1: 1), MS ( ion spray): 589 (M + H) < + >,

c) metil ester acetat N-[N4-[[(S)-l-amidino-3-piperidinil]metil]-N2-(2-naftilsulfonil)L-asparaginil]-L-ivalina (1:1), MS (ionski spray): 575 (M + H)⁺,c) N- [N4 - [[(S) -1-amidino-3-piperidinyl] methyl] -N2- (2-naphthylsulfonyl) L-asparaginyl] -L -valine (1: 1), MS ( ion spray): 575 (M + H) < ⁺ >,

d) metil ester acetat N-[N4-[[(S)-l-amidino-3-piperidinil]metil]-N2-(2-naftilsulfonil)L-asparaginil]-D-levcina (1:1), MS (ionski spray): 589 (M + H) ⁺ ,d) N- [N4 - [[(S) -1-amidino-3-piperidinyl] methyl] -N2- (2-naphthylsulfonyl) L-asparaginyl] -D-leucine methyl ester acetate (1: 1), MS ( ion spray): 589 (M + H) < ⁺ >,

e) metil ester acetat N-[N4-[[(S)-l-amidino-3-piperidinil]metil]-N2-(2-naftilsulfonil)L-asparaginil]-N-metil-L-valina (1:1), MS (ionski spray): 589 (M + H)⁺,e) N- [N4 - [[(S) -1-Amidino-3-piperidinyl] methyl] -N2- (2-naphthylsulfonyl) L-asparaginyl] -N-methyl-L-valine methyl ester acetate (1: 1 ), MS (ion spray): 589 (M + H) < ⁺ >,

f) metil ester acetat N-[N4-[[(S)-l-amidino-3-piperidinil]metil]-N2-(2-naftilsulfonil)L-asparaginil]-N-metil-L-izolevcina (1:1), MS (ionski spray): 603 (M + H)+,f) N- [N4 - [[(S) -1-Amidino-3-piperidinyl] methyl] -N2- (2-naphthylsulfonyl) L-asparaginyl] -N-methyl-L-isoleucine methyl acetate (1: 1 ), MS (ion spray): 603 (M + H) < + >,

g) (R)-2-[[(S)-3-[(S)-l-(amino-imino-metil)piperidin-3-ilmetilkarbamoil]-2-(naftalen 2-sulfonilamino)-propionilamino]-3-fenil-propionsko kislino, MS (ionski spray):g) (R) -2 - [[(S) -3 - [(S) -1- (amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -2- (naphthalene 2-sulfonylamino) -propionylamino] -3 -phenyl-propionic acid, MS (ion spray):

623 (M + H)+.623 (M + H) < + >.

Primer 28Example 28

Analogno Primeru 24 pripravimo izhajajoč iz estrov Primera 27 naslednje kisline:Analogously to Example 24, the following acids were prepared from the esters of Example 27:

a) L-N-[N4-[[(S)-l-amidino-3-piperidinil]metil]-N2-(2-naftilsulfonil)-L-asparaginil]2-metil-fenilglicin-acetat (1:1), MS (ionski spray): 595 (M + H) ⁺ ,a) LN- [N4 - [[(S) -1-amidino-3-piperidinyl] methyl] -N2- (2-naphthylsulfonyl) -L-asparaginyl] 2-methyl-phenylglycine acetate (1: 1), MS (ion spray): 595 (M + H) ⁺ ,

b) N-[N4-[[(S)-l-amidino-3-piperidinil]metil]-N2-(2-naftilsulfonil)-L-asparaginil]-Lizolevcin, MS (ionski spray): 575 (M + H)+,b) N- [N4 - [[(S) -1-amidino-3-piperidinyl] methyl] -N2- (2-naphthylsulfonyl) -L-asparaginyl] -Lysoleucine, MS (ion spray): 575 (M + H) ) +,

c) N-[N4-[[(S)-l-amidino-3-piperidinil]metil]-N2-(2-naftilsulfonil)-L-asparaginil]-Lvalin, MS (ionski spray): 561 (M + H) ⁺ ,c) N- [N4 - [[(S) -1-amidino-3-piperidinyl] methyl] -N2- (2-naphthylsulfonyl) -L-asparaginyl] -valin, MS (ion spray): 561 (M + H) ) ⁺ ,

d) N-[N4-[[(S)-l-amidino-3-piperidinil]metil]-N2-(2-naftilsulfonil)-L-asparaginil]-D levcin, MS (ionski spray): 575 (M + H) ⁺ ,d) N- [N4 - [[(S) -1-amidino-3-piperidinyl] methyl] -N2- (2-naphthylsulfonyl) -L-asparaginyl] -D leucine, MS (ion spray): 575 (M + H) ⁺ ,

e) N-[N4-[[(S)-l-amidino-3-piperidinil]metil]-N2-(2-naftilsulfonil)-L-asparaginil]-Nmetil-L-izolevcin, MS (ionski spray): 589 (M + H)⁺,e) N- [N4 - [[(S) -1-amidino-3-piperidinyl] methyl] -N2- (2-naphthylsulfonyl) -L-asparaginyl] -Nmethyl-L-isoleucine, MS (ion spray): 589 (M + H) ⁺ ,

f) N-[N4-[[(S)-l-amidino-3-piperidinil]metil]-N2-(2-naftilsulfonil)-L-asparaginil]-Nmetil-L-valin, MS (ionski spray): 575 (M + H)⁺,f) N- [N4 - [[(S) -1-amidino-3-piperidinyl] methyl] -N2- (2-naphthylsulfonyl) -L-asparaginyl] -Nmethyl-L-valine, MS (ion spray): 575 (M + H) ⁺ ,

g) (R)-2-[[(S)-3-[(S)-l-(amino-imino-metil)piperidin-3-ilmetilkarbamoil]-2-(naftalen2-sulfonilamino)-propionilamino]-3-fenil-propionsko kislino, MS (ionski spray):g) (R) -2 - [[(S) -3 - [(S) -1- (amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -2- (naphthalene 2-sulfonylamino) -propionylamino] -3- phenyl-propionic acid, MS (ion spray):

609 (M + H)+.609 (M + H) < + >.

Primer 29Example 29

Raztopini 1.09 g (S)-3-[butil-[2-(etoksalilamino-etil)]-karbamoil]-3-(naftalen-2sulfonilamino)-propionilaminometil]-piperidin-l-karboksilne kisline v 20 ml metilenklorida dodamo 4 ml trifluorocetne kisline. Po mešanju uparimo, naplavimo ostanek z etrom in nato dekantiramo eter. Ostanku dodamo 3 ml metanola, 1.06 trietilamina in 377 mg formamidinsulfonske kisline. Po mešanju ponovno dodamo po 1 ekvivalent formamidinsulfonske kisline in trietilamina. Zmes uparimo in kromatografiramo na kremeničnem gelu z ocetestrom/acetonom/ocetno kislino/vodo 6:2:1:1. Dobimo 962 mg metil ester acetata [2-[[(S)-3-[(S)l-(amino-imino-metil)piperidin-3-ilmetilkarbamoil]-2-(naftalen-2-sulfonilamino)-propionil]butilamino]etil]oksamske kisline (1:1), MS (ionski spray): 646 (M + H) ⁺ .To a solution of 1.09 g of (S) -3- [butyl- [2- (ethoxalylamino-ethyl)] -carbamoyl] -3- (naphthalene-2-sulfonylamino) -propionylaminomethyl] -piperidine-1-carboxylic acid in 20 ml of methylene chloride was added 4 ml of trifluoroacetic acid acid. After stirring, the residue was taken up in ether and the ether was decanted. To the residue was added 3 ml of methanol, 1.06 triethylamine and 377 mg formamidinsulfonic acid. After stirring, 1 equivalent of formamidinsulfonic acid and triethylamine are added again. The mixture was evaporated and chromatographed on silica gel with acetic acid / acetone / acetic acid / water 6: 2: 1: 1. Acetate [2 - [[(S) -3 - [(S) 1- (amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -2- (naphthalene-2-sulfonylamino) -propionyl] butylamino] is obtained 962 mg ] ethyl] oxamic acids (1: 1), MS (ion spray): 646 (M + H) ⁺ .

Priprava izhodnega materiala:Preparation of starting material:

a) 7.0 g 2-butilamino-etilklorid-hidroklorida (Org. Synth. Iv 1963, 333) mešamo skupaj s 7.9 g natrijevega azida v 50 ml dimetilformamida pri 50 °C. Po ohlajenju dokapavamo 82 ml ln natrijevega luga. Zmes prevzamemo v 700 ml etra, izperemo z vodo in po sušenju etrne faze dodamo 25 ml solne kisline (5 molarne v dioksanu). Po uparjenju etrne faze naplavimo ostanek v etru, odfiltriramo kristale in jih izperemo z etrom. Dobimo 5 g 2-butilamino-etilazid hidroklorida, Rf=0.14.a) 7.0 g of 2-butylamino-ethyl chloride hydrochloride (Org. Synth. iv 1963, 333) was mixed together with 7.9 g of sodium azide in 50 ml of dimethylformamide at 50 ° C. After cooling, 82 ml of ln sodium hydroxide are added dropwise. The mixture was taken up in 700 ml of ether, washed with water and after drying the ether phase 25 ml of hydrochloric acid (5 molars in dioxane) were added. After evaporation of the ether phase, the residue is taken up in ether, the crystals are filtered off and washed with ether. 5 g of 2-butylamino-ethylazide hydrochloride are obtained, Rf = 0.14.

b) K 8.85 g 4-t-butil estra N-(2-naftilsulfonil)-L-asparaginske kisline (Primer 23e) v 120 ml metilenklorida dodamo 5.0 g 2-butilamino-hidroklorida,10.8 g BOP in 11.98 ml Hunigove baze. Po mešanju prevzamemo v 600 ml etra in izperemo etrno fazo z ln solno kislino in z vodo. Po sušenju in uparjenju etrne faze kromato43 grafiramo ostanek preko kremeničnega gela z metilenkloridom/etrom 19:1 in dobimo 6.18 g t-butil estra (S)-3-[(2-azidoetil)-butil-karbamoil]-3-naftalen-2sulfonilamino)propionske kisline, Rf=0.42 (metilenklorid/eter 9:1).b) To 8.85 g of N- (2-naphthylsulfonyl) -L-aspartic acid 4-t-butyl ester (Example 23e) in 120 ml of methylene chloride was added 5.0 g of 2-butylamino hydrochloride, 10.8 g of BOP and 11.98 ml of Hunig's base. After stirring, it is taken up in 600 ml of ether and the ether phase is washed with hydrochloric acid and water. After drying and evaporating the ether phase of chromato43, graph the residue over silica gel with methylene chloride / ether 19: 1 to give 6.18 g of (S) -3 - [(2-azidoethyl) -butyl-carbamoyl] -3-naphthalene-2-sulfonylamino t-butyl ester. ) propionic acid, Rf = 0.42 (methylene chloride / ether 9: 1).

c) 6.18 g produkta iz b) dodamo 60 ml 5N solne kisline v dioksanu. Po mešanju prevzamemo v 400 ml etra ini izperemo etrno fazo z vodo. Po sušenju in uparjenju dobimo 5.58 g (S)-3-[(2-azidoetil)-butil-karbamoil]-3-naftalen-2-sulfonilaminojpropionske kisline, Rf=0.21 (ocetester).c) 6.18 g of the product of b) is added 60 ml of 5N hydrochloric acid in dioxane. After stirring, it is taken up in 400 ml of ether and the ether phase is washed with water. After drying and evaporation, 5.58 g of (S) -3 - [(2-azidoethyl) -butyl-carbamoyl] -3-naphthalene-2-sulfonylaminopropionic acid are obtained, Rf = 0.21 (acetester).

d) 5.57 g Produkta iz c), 3.3 g t-butil-estra (S)-3-aminometil-l-piperidinkarboksilne kisline, 5.97 g BOP in 4.4 ml Hiinigove baze mešamo v 80 ml metilenklorida. Nato prevzamemo zmes v etru in izperemo etrno fazo z ln solno kislino in z vodo. Po sušenju in uparjenju kromatografiramo produkt na kremeničnem gelu z ocetestrom/heksanom 4:1 in dobimo 6.43 g t-butil estra (S)-3-[(S)-3-[(2-azidoetil)-butilkarbamoil]-3-naftalen-2-sulfonilamino)-propionilaminometil]piperidin-l-karboksilne kisline, (ocetester/heksan 4:1).d) 5.57 g of the product from c), 3.3 g of (S) -3-aminomethyl-1-piperidinecarboxylic acid t-butyl ester, 5.97 g of BOP and 4.4 ml of Hiinig base are mixed in 80 ml of methylene chloride. Then the mixture is taken up in ether and the ether phase is washed with hydrochloric acid and water. After drying and evaporation, the product was chromatographed on silica gel with 4: 1 acetone / hexane to give 6.43 g of (S) -3 - [(S) -3 - [(2-azidoethyl) -butylcarbamoyl] -3-naphthalene t-butyl ester. -2-sulfonylamino) -propionylaminomethyl] piperidine-1-carboxylic acid, (acetester / hexane 4: 1).

e) 6.43 g produkta iz d) dodamo v 60 ml metanola 650 mg 5% paladija na oglu in hidriramo pri normalnih pogojih, katalizator odfiltriramo in uparimo filtrat. Dobimo 5.86 g t-butil estra (S)-3-[(S)-3-[(2-aminoetil)-butil-karbamoil]-3-naftalen-2sulfonilamino)-propionilaminometil]piperidin-l-karboksilne kisline, Rf=0.33 (ocetester/aceton/voda/ocetna kislina 6:2:1:1).e) 6.43 g of the product from d) is added to 60 ml of methanol 650 mg of 5% palladium on carbon and hydrated under normal conditions, the catalyst is filtered off and the filtrate is evaporated. 5.86 g of (S) -3 - [(S) -3 - [(2-aminoethyl) -butyl-carbamoyl] -3-naphthalene-2-sulfonylamino) -propionylaminomethyl] piperidine-1-carboxylic acid t-butyl ester is obtained, Rf = 0.33 (acetic acid / acetone / water / acetic acid 6: 2: 1: 1).

f) K 1.2 g produkta iz e) in 0.32 ml piridina dokapavamo pri 0 do 5 °C raztopino 0.23 ml mono-etil ester klorida oksalne kisline v 6 ml metilenklorida. Po mešanju prevzamemo v 100 ml etra in iperemo etrno fazo z IN solno kislino in z vodo.Po sušenju in uparjenju očistimo produkt na kremeničnem gelu z ocetestrom.f) A solution of 0.23 ml of oxalic acid chloride mono-ethyl ester in 6 ml of methylene chloride is added dropwise to 1.2 g of the product from e) and 0.32 ml of pyridine. After stirring, the mixture is taken up in 100 ml of ether and the ether phase is washed with 1N hydrochloric acid and water. After drying and evaporation, the product is purified on silica gel with acetone.

Dobimo 1.09 g t-butil estra (S)-3-[(S)-3-[butil-[2-(etoksalilamino etil]karbamoil]-3naftalen-2-sulfonilamino)-propionilaminoetil]piperidin-l-karboksilne kisline,(S) -3 - [(S) -3- [butyl- [2- (ethoxalylamino ethyl] carbamoyl] -3-naphthalene-2-sulfonylamino) -propionylaminoethyl] piperidine-1-carboxylic acid 1.09 g is obtained.

MS (ionski spray): 718 (M + H) + .MS (ion spray): 718 (M + H) +.

Primer 30Example 30

672 g estrskega produkta iz Primera 29 in 6.7 ml tetrahidrofurana mešamo z raztopino 2.8 ml IN litijevega hidroksida. Nato dodamo zmesi 4 ml ocetne kisline in uparimo. Ostanek očistimo na kremeničnem gelu z ocetestrom/acetonom/ocetno kislino/vodo 6:2:1:1, 461 mg [2-[[(S)-3-[(S)-l-(amino-imino-metil)piperidin-3ilmetilkarbamoilj-2-(naftalen-2-sulfonilamino)-propioniljbutil-amino]etiloksamsko kislino, MS (ionski spray): 632 (M + H)⁺.672 g of the ester product of Example 29 and 6.7 ml of tetrahydrofuran are mixed with a solution of 2.8 ml of IN lithium hydroxide. Then 4 ml of acetic acid was added to the mixture and evaporated. The residue was purified on silica gel with acetic acid / acetone / acetic acid / water 6: 2: 1: 1, 461 mg [2 - [[(S) -3 - [(S) -1- (amino-imino-methyl) piperidine] -3-Methylcarbamoyl-2- (naphthalene-2-sulfonylamino) -propionylbutyl-amino] ethyloxamic acid, MS (ion spray): 632 (M + H) ⁺ .

Primer 31Example 31

Analogno Primeru 29, le ob uporabi a) acetanhidrida, b) metansulfoklorida, c) SO3N(CH3)2-kompleksa oz. d) metilestra klormravljinčne kisline namesto v PrimeruAnalogous to Example 29, only using a) acetanhydride, b) methanesulfochloride, c) SO3N (CH3) 2-complex, or. d) hydrochloric acid methyl ester instead of Example

f) uporabljenega mono-etil ester klorida oksalne kisline, dobimo naslednje produkte:f) the oxalic acid chloride mono-ethyl ester used, the following products are obtained:

a) (S)-Nl-(2-acetilaminoetil)-N4-[(S)-l-(amino-imino-metil)piperidin-3-ilmetil]-Nlbutil-l-(naftalen-2-sulfonilamino)-sukcinamid-acetat (1:1), MS (ionski spray):a) (S) -Nl- (2-acetylaminoethyl) -N4 - [(S) -1- (amino-imino-methyl) piperidin-3-ylmethyl] -Nbutyl-1- (naphthalene-2-sulfonylamino) -succinamide -acetate (1: 1), MS (ion spray):

602 (M + H)+.602 (M + H) < + >.

b) (S)-N4-[(S)-l-(amino-imino-metiI)piperidin-3-ilmetil]-Nl-butil-Nl-(2-metansulfonilamino)-sukcinamid-acetat (1:1), MS (ionski spray): 638 (M + H) + .b) (S) -N4 - [(S) -1- (amino-imino-methyl) piperidin-3-ylmethyl] -Nl-butyl-N1- (2-methanesulfonylamino) -succinamide-acetate (1: 1), MS (ion spray): 638 (M + H) +.

c) (S)-N4-[(S)-l-(amino-imino-metil)piperidin-3-ilmetil]-N l-butil-2-(naftalen-2sulfonilamino)-Nl-(2-sulfoaminoetil)-sukcinamid, MS (ionski spray): 640 (M + H) ⁺ c) (S) -N4 - [(S) -1- (amino-imino-methyl) piperidin-3-ylmethyl] -N 1-butyl-2- (naphthalene-2sulfonylamino) -Nl- (2-sulfoaminoethyl) - succinamide, MS (ion spray): 640 (M + H) ⁺

d) [2-[[(S)-3-[(S)-l-(amino-imino-metiI)piperidin-3-ilmetilkarbamoil]-2-(naftalen-2sulfonilaminoj-propioniljbutil-aminojetilj metil ester acetat karbamske kisline (1:1), MS (ionski spray): 618 (M + H)+.d) [2 - [[(S) -3 - [(S) -1- (amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -2- (naphthalene-2-sulfonylamino-propionylbutyl-aminoethyl methyl ester carbamic acid acetate ( 1: 1), MS (ion spray): 618 (M + H) +.

Primer 32Example 32

A) Analogno Primeru 29 oz. 30 pripravimo naslednje produkte:A) Analogous to Example 29 oz. 30 we prepare the following products:

a) 3-[(S)-3-[(S)-l-amino-imino-metiI)piperidin-3-ilmetilkarbamoil]-2-(naftalen-2sulfonilaminoj-propionil-ciklopropil-aminoj-propilester acetat ocetne kisline (1:1), MS (ionski spray): 601,3 (M + H)+.a) 3 - [(S) -3 - [(S) -1-amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -2- (naphthalene-2sulfonylamino-propionyl-cyclopropyl-amino-propyl ester acetic acid (1 : 1), MS (ion spray): 601.3 (M + H) +.

b) (S)-N4-[(S)-l-(amino-imino-metil)piperidin-3-ilmetil]-Nl-ciklopropil-Nl-(3hidroksipropil)-2-(naftalen-2-sulfonilamino)-sukcinamid acetat (1:1), MS (ionski spray): 559 (M + H) + .b) (S) -N4 - [(S) -1- (amino-imino-methyl) piperidin-3-ylmethyl] -Nl-cyclopropyl-N1- (3-hydroxypropyl) -2- (naphthalene-2-sulfonylamino) -succinamide acetate (1: 1), MS (ion spray): 559 (M + H) +.

B) Priprava namesto 2-butilamino-etilazid-hidroklorida (Primer 29 a) uporabljenega izhodnega amina:B) Preparation of the starting amine used instead of 2-butylamino-ethylazide hydrochloride (Example 29 a):

a) K raztopini iz 6.86 g N-Boc-ciklopropilamina in 13.27 g 3-8t-butil-dimetilsililoksi)propilbromida v 70 ml dimetilformamida dodamo pri 0 do 5 °C 2.0 g natrijevega hidrida (55% v olju). Po mešanju prevzamemo v etru in izperemo etrno fazo z vodo. Po sušenju in uparjenju etrne faze in kromatografiji na kremeničnem gelu z etrom/heksanom 1:9 dobimo 11.73 g t-butil estra [3-(t-butil-dimetil-silaniloksi)propil]ciklopropilkarbamidne kisline, Rf=0.38 (eter/heksan 1:4).a) To a solution of 6.86 g of N-Boc-cyclopropylamine and 13.27 g of 3-8t-butyl-dimethylsilyloxy) propyl bromide in 70 ml of dimethylformamide was added at 0 to 5 ° C 2.0 g of sodium hydride (55% in oil). After stirring, the mixture is taken up in ether and the ether phase is washed with water. Drying and evaporation of the ether phase and chromatography on silica gel with ether / hexane 1: 9 gave 11.73 g of [3- (t-butyl-dimethyl-silanyloxy) propyl] cyclopropylcarbamic acid t-butyl ester, Rf = 0.38 (ether / hexane 1 : 4).

b) 11.73 g produkta iz a) raztopimo v 42.7 ml IM raztopine tetrabutilamonijevega fluorida v tetrahidrofuranu. Po mešanju prevzamemo v etru in izperemo etrno fazo z vodo. Po sušenju in uparjenju dobimo 7.02 g N-boc-3-ciklopropilamino-propanola, Rf=0.47 (metilenklorid/eter/1:1).b) Dissolve 11.73 g of the product from a) in 42.7 ml of IM solution of tetrabutylammonium fluoride in tetrahydrofuran. After stirring, the mixture is taken up in ether and the ether phase is washed with water. After drying and evaporation, 7.02 g of N-boc-3-cyclopropylamino-propanol were obtained, Rf = 0.47 (methylene chloride / ether / 1: 1).

c) Raztopini 1.92 g produkta iz b) v 19 ml metilenklorida dodamo 1.44 ml piridina in 0.89 ml acetanhidrida. Po mešanju prevzamemo v etru in izperemo etrno fazo z ln solno kislino in z vodo. Po sušenju in uparjenju etrne faze in kromatografiji na kremeničnem gelu z etrom/heksanom 1:2 dobimo 2.3 g N-Boc-3-ciklopropilaminopropilacetata, Rf=0.18 (eter/heksan 1:2).c) To a solution of 1.92 g of the product from b) in 1.44 ml of methylene chloride was added 1.44 ml of pyridine and 0.89 ml of acetanhydride. After stirring, the mixture is taken up in ether and the ether phase is washed with hydrochloric acid and water. After drying and evaporating the ether phase and chromatography on silica gel with ether / hexane 1: 2, 2.3 g of N-Boc-3-cyclopropylaminopropyl acetate are obtained, Rf = 0.18 (ether / hexane 1: 2).

d) 2.3 g Produkta c) dodamo 23 ml 4.3 M solne kisline v dioksanu. Po odparjenju topila naplavimo ostanek z etrom in zatem dekantiramo eter. Po sušenju dobimo 1.61 g metil ester hidroklorida 3-ciklopropilamino-propionske kisline (1:1),d) 2.3 g of Product c) 23 ml of 4.3 M hydrochloric acid in dioxane are added. After evaporation of the solvent, the residue was washed with ether and the ether was then decanted. Drying gave 1.61 g of 3-cyclopropylamino-propionic acid methyl ester hydrochloride (1: 1),

Rf=0.17 (ocetester/aceton/oeetna kislina/voda 6:2:1:1).Rf = 0.17 (acetic acid / acetone / acetic acid / water 6: 2: 1: 1).

Primer 33Example 33

Analogno Primeru 12 dobimo iz t-butil estra (R)-3-[[(S)-3-benzil-metilkarbamoil)-3(naftalen-2-sulfonilamino-propionil]etoksikarbonil-metil-aminometil]piperidin-lkarboksilne kisline etil ester sulfit [[(R)-l-(amino-imino-metil)piperidin)-3-ilmetil]-[(S)-3-(benzil-metilkarbamoil)-3-(naftalen-2-sulfonilamino)propionil]amino-3-ocetne kisline (2:1),Analogous to Example 12, (R) -3 - [[((S) -3-benzyl-methylcarbamoyl) -3 (naphthalene-2-sulfonylamino-propionyl] ethoxycarbonyl-methyl-aminomethyl] piperidine-carboxylic acid ethyl ester) was obtained from t-butyl ester sulfite [[(R) -1- (amino-imino-methyl) piperidin) -3-ylmethyl] - [(S) -3- (benzyl-methylcarbamoyl) -3- (naphthalene-2-sulfonylamino) propionyl] amino- 3-acetic acid (2: 1),

MS (ionski spray): 651,3 (M + H) ⁺ .MS (ion spray): 651.3 (M + H) ⁺ .

Priprava izhodnega materiala:Preparation of starting material:

a) Raztopini 7.6 g 4-t-butil estra N-(2-naftilsulfonil)-L-asparaginske kisline (Primer 23a) v 80 ml metilenklorida dodamo 8.1 ml 4-etilmorfolina, 4.6 g N-(dimetilaminopropil)-N’-etilkarbodiimid hidroklorida, 0.24 g 4-dimetilaminopiridina in 2.6 ml N-benzilmetilamina. Po mešanju izlijemo reakcijsko zmes v ledenomrzlo raztopino 5% kalijevega hidrogen sulfata/-10% kalijevega sulfata in ekstrahiramo z metilenkloridom. Organsko fazo izperemo z raztopino kuhinjske soli, sušimo in uparimo. Oszanek kromatografiramo s eksanom/-ocetestrom (3:1) na kremeničnem gelu. Izoliramo 3.4 g 1-t-butil estra (S)-N-benzil-N-metil-3-(naftalen-2-ilsulfonilamino) sukcinamidne kisline, MS (ionski spray): 483,4 (M + H) ⁺ .a) To a solution of 7.6 g of N- (2-naphthylsulfonyl) -L-aspartic acid 4-t-butyl ester (Example 23a) in 80 ml of methylene chloride was added 8.1 ml of 4-ethylmorpholine, 4.6 g of N- (dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride, 0.24 g of 4-dimethylaminopyridine and 2.6 ml of N-benzylmethylamine. After stirring, pour the reaction mixture into an ice-cold solution of 5% potassium hydrogen sulfate / -10% potassium sulfate and extract with methylene chloride. The organic phase is washed with brine, dried and evaporated. The residue was chromatographed with an exane / -acetester (3: 1) on silica gel. Isolated 3.4 g of (S) -N-benzyl-N-methyl-3- (naphthalen-2-ylsulfonylamino) succinamic acid 1-t-butyl ester, MS (ion spray): 483.4 (M + H) ⁺ .

b) Iz produkta a) dobimo analogno Primeru 12i) t-butil ester (R)-3-[[(S)-3-benzilmetilkarbamoil)-3-(naftalen-2-sulfonilamino-propionil]etoksikarbonilmetil-aminometil]piperidin-l-karboksilne kisline, MS (ionski spray): 709,5 (M 4- H) + .b) From product a), analogous to Example 12i (t) butyl ester of (R) -3 - [[(S) -3-benzylmethylcarbamoyl) -3- (naphthalene-2-sulfonylamino-propionyl] ethoxycarbonylmethyl-aminomethyl] piperidin-1 -carboxylic acids, MS (ion spray): 709.5 (M 4H) +.

Primer 34Example 34

Raztopini 0.2 g estra iz Primera 33 v 10 ml metanola dodamo 1.4 ml IN natrijevega luga. Po me{anju dodamo reakcijski raztopini 6 ml IN solne kisline in uparimo. Oszanek kromatografiramo z gradientom vode/acetonitrila na RP-18. Izoliramo 0.1 g hidroklorida [[(R)-l-(amino-imino-metil)piperidin-3-ilmetil]-[(S)-3-(benzilmetil-karbamoil)-3-(naftalen-2-sulfonilamino)propionil]amino-3-ocetne kisline (1:1), MS (ionski spray): 623,3 (M 4- H)+.To a solution of 0.2 g of the ester of Example 33 in 10 ml of methanol was added 1.4 ml of 1N sodium hydroxide. After stirring, 6 ml of 1N hydrochloric acid are added to the reaction solution and evaporated. The residue was chromatographed with a water / acetonitrile gradient on RP-18. 0.1 g of hydrochloride [[((R) -1- (amino-imino-methyl) piperidin-3-ylmethyl] - [(S) -3- (benzylmethyl-carbamoyl) -3- (naphthalene-2-sulfonylamino) propionyl) is isolated amino-3-acetic acids (1: 1), MS (ion spray): 623.3 (M 4H) +.

Primer 35Example 35

Analogno Primeru 9, vendar izhajajoč iz 1-t-butil estra (S)-N-benzil-N-metil-3(naftalen-2-iIsulfonilamino) sukcinamidne kisline (Primer 33 a), dobimo (S)-N4-[(R,S)-l-(amino-imino-metil)piperidin-3-iImetil]-Nl-benzil-N4-(2hidroksietil)-Nl-metil-2-(naftalen-2-sulfonilamino)-sukcinamid hidroklorid (1:1), MS (ionski spray): 609,3 (M 4- H) ⁺ .Analogous to Example 9, but starting from 1-t-butyl ester of (S) -N-benzyl-N-methyl-3 (naphthalen-2-ysulfonylamino) succinamic acid (Example 33 a), (S) -N4 - [( R, S) -1- (Amino-imino-methyl) piperidin-3-ylmethyl] -Nl-benzyl-N4- (2hydroxyethyl) -Nl-methyl-2- (naphthalene-2-sulfonylamino) -succinamide hydrochloride (1: 1) MS (ion spray): 609.3 (M 4H) ⁺ .

Primer 36Example 36

Analogno Primeru 1 pripravimo iz t-butil estra (S)-N-ciklopropil-N-(2-tetrazol-5-iletil)-3-naftalin-2-ilsulfonilamino-sukcinamske kisline in iz (S)-l-amidino-3-(aminometil)piperidin dihidroklorida (S)-N4-[(S)-l-(amino-imino-metil)piperidin-3-ilmetil]-Nl-ciklopropil-Nl-(2-tetrazol5-il-etil)-2-(naftil-2-ilsulfonilamino)-sukcinamid, MS (ISP): 597,4 (M + H) ⁺ .Analogous to Example 1 was prepared from (S) -N-cyclopropyl-N- (2-tetrazol-5-ylethyl) -3-naphthalin-2-ylsulfonylamino-succinic acid t-butyl ester and from (S) -1-amidino-3 - (Aminomethyl) piperidine dihydrochloride (S) -N4 - [(S) -1- (amino-imino-methyl) piperidin-3-ylmethyl] -Nl-cyclopropyl-N1- (2-tetrazol5-yl-ethyl) -2 - (Naphthyl-2-ylsulfonylamino) -succinamide, MS (ISP): 597.4 (M + H) ⁺ .

Priprava izhodnih materialov:Preparation of starting materials:

Aa) Analogno Primeru 2B)e), vendar ob uporabi 3-ciklopropilamino-propionitrila namesto sarkozinetil estra dobimo t-butil ester (S)-3-terc-butoksikarbonilamino-Nciklopropil-N-2-(ciano-etil)-sukcinamske kisline, MS (ISP): 382,2 (M + H) ⁺ .Aa) Analogous to Example 2B) e), but using 3-cyclopropylamino-propionitrile instead of the sarcosinethyl ester, (S) -3-tert-butoxycarbonylamino-N-cyclopropyl-N-2- (cyano-ethyl) -succinic acid t-butyl ester is obtained. MS (ISP): 382.2 (M + H) ⁺ .

Ab) Analogno Primeru 2B)i), vendar ob uporabi estra a) namesto t-butil estra (S)-3t-butoksikarbonilamino-N-etoksikarbonilmetil-N-metilsukcinamske kisline, dobimo t-butil ester (S)-N-ciklopropil-N-(2-ciano-etil)-3-naftalin-2-sulfonilaminosukcinamske kisline, MS (FAB): 414 (M-izobutilen).Ab) Analogous to Example 2B) i), but using ester a) instead of (S) -3t-butoxycarbonylamino-N-ethoxycarbonylmethyl-N-methylsuccinic acid t-butyl ester, t-butyl ester (S) -N-cyclopropyl- N- (2-cyano-ethyl) -3-naphthalene-2-sulfonylaminosuccinic acid, MS (FAB): 414 (M-isobutylene).

Ac) Raztopini 2.3 g pri b) dobljenega materiala v 25 ml dimetilformamida dodamo zapored 0.7 g amonijevega klorida in 0.86 g natrijevega azida. Reakcijsko zmes mešamo 24 ur pri 80 °C, ohladimo, filtriramo in filtrat uparimo. Po kromatografiji ostanka na kremeničnem gelu z ocetestrom + 0.5% ocetne kisline dobimo 0.3 g t-butil estra (S)-N-ciklopropil-N-(2-tetrazol-5-il-etil)-3-naftalin-2-ilsulfonilaminosukcinamske kisline, MS (ISP); 515,4 (M+H) + .Ac) To a solution of 2.3 g in b) of the material obtained in 25 ml of dimethylformamide is added successively 0.7 g of ammonium chloride and 0.86 g of sodium azide. The reaction mixture was stirred for 24 hours at 80 ° C, cooled, filtered and the filtrate evaporated. Chromatography of the residue on silica gel with acetic acid + 0.5% acetic acid gave 0.3 g of (S) -N-cyclopropyl-N- (2-tetrazol-5-yl-ethyl) -3-naphthalin-2-ylsulfonylaminosuccinic acid t-butyl ester , MS (ISP); 515.4 (M + H) +.

Ba) Raztopini 42.5 g N-(3-piridinilmetil)-benzamida v 220 ml etanola in 220 ml IN solne kisline dodamo 4.2 g paladija na oglju in hidriramo 24 ur pod 100 bar vodika pri sobni temperaturi. Nato filtriramo od katalizatorja in filtrat uparimo. Ostanke prevzamemo v metilenkloridu in iztresemo z IN natrijevim lugom Organsko fazo izperemo z vodo, sušimo in uparimo. Dobimo 36.1 g (RS)-N-piperidin-3-ilmetilbenzamida, MS (FAB): 218 M ⁺ .Ba) To a solution of 42.5 g of N- (3-pyridinylmethyl) -benzamide in 220 ml of ethanol and 220 ml of IN hydrochloric acid was added 4.2 g of palladium on charcoal and hydrogenated for 24 hours under 100 bar of hydrogen at room temperature. Then it was filtered off from the catalyst and the filtrate was evaporated. The residues were taken up in methylene chloride and shaken off with 1N sodium hydroxide solution. The organic phase was washed with water, dried and evaporated. 36.1 g of (RS) -N-piperidin-3-ylmethylbenzamide are obtained, MS (FAB): 218 M ⁺ .

Bb) 36.1 g pri Ba) dobljenega materiala raztopimo v 800 ml metilenklorida in dodamo 25.2 g D-mandljeve kisline. K nastali raztopini dokapavamo ob mešanjuBb) Dissolve 36.1 g of the material obtained in Ba) in 800 ml of methylene chloride and add 25.2 g of D-almond acid. The resulting solution was added dropwise with stirring

380 ml etra. Po vcepljenju izkristallizira 32.5 g soli. Ponovna prekristalizacija iz 420 ml metilenklorida, 10 ml metanola in 140 ml etra da 19.5 g (R)-N-piperidin3-ilmetil-benzamid-(R)-hidroksi-fenil-acetata (1:1), tal. od 75 °C, razpad.380 ml of ether. After inoculation, 32.5 g of salt are crystallized. Recrystallization from 420 ml of methylene chloride, 10 ml of methanol and 140 ml of ether gave 19.5 g of (R) -N-piperidin3-ylmethyl-benzamide- (R) -hydroxy-phenyl-acetate (1: 1), m.p. from 75 ° C, decomposition.

Bc) 19.3 g pri Bb) dobljene soli mandljeve kisline suspendiramo v 193 ml dimetilformamida, dodamo 21.7 ml trietilamina in 7.75 g formamidinsulfonske kisline ter mešamo pri sobni temperaturi. Reakcijsko zmes uparimo in ostanek kromatografiramo na kremeničnem gelu RP-18 z gradientom vode/acetonitrila. Izoliramo 13.4 g (S)-N-[l-(amino-imino-metil)piperidin-3-ilmetil]-benzamid-(R)-hidroksifenilacetata (1:1), MS (FAB): 218 M-(H2N-CN).Bc) 19.3 g of Bb) of the obtained almond acid salt was suspended in 193 ml of dimethylformamide, 21.7 ml of triethylamine and 7.75 g of formamidinsulfonic acid were added and stirred at room temperature. The reaction mixture was evaporated and the residue chromatographed on a RP-18 silica gel with a water / acetonitrile gradient. Isolated 13.4 g of (S) -N- [1- (amino-imino-methyl) piperidin-3-ylmethyl] -benzamide- (R) -hydroxyphenylacetate (1: 1), MS (FAB): 218 M- (H2N- CN).

Bd) 13.4 g pri Bc) dobljene soli mandljeve kisline raztopimo v 267 ml koncentrirane solne kisline in kuhamo ob refluksu. Po ohlajenju ekstrahiramo raztopino z etrom, nato uparimo vodno fazo in azeotropno obdelamo z etanolom. Ostanek naplavimo v 50 ml etanola, ohladimo v ledeni kopeli in odnučamo. Dobimo 4.6 g (S)-l-amidino-3 (aminometil)piperidin dihidroklorida, [a]_D -16.3 °C. (c=1.0, voda).Bd) 13.4 g at Bc) of the obtained almond acid salt was dissolved in 267 ml of concentrated hydrochloric acid and boiled under reflux. After cooling, the solution was extracted with ether, then the aqueous phase was evaporated and azeotroped with ethanol. The residue was taken up in 50 ml of ethanol, cooled in an ice bath and filtered off. 4.6 g of (S) -1-amidino-3 (aminomethyl) piperidine dihydrochloride, [α] _D -16.3 ° C are obtained. (c = 1.0, water).

Primer 37Example 37

Analogno Primeru 1, le ob uporabi nitrila iz Primera 36Ab) namesto t-butil-(S)-Ncikloheksil-N-(etoksikarbonil)-metil]-3-(2-naftilsulfonamido)sukcinamata, dobimo:Analogous to Example 1, only using the nitrile of Example 36Ab) instead of t-butyl- (S) -Ncyclohexyl-N- (ethoxycarbonyl) -methyl] -3- (2-naphthylsulfonamido) succinamate, we obtain:

(S)-N4-[(S)-l-(amino-imino-metil)piperidin-3-ilmetil]-Nl-(2-karbamoil-etil)-Nlciklopropil-2-(naftil-2-sulfonilamino)-sukcinamid hidroklorid,(S) -N4 - [(S) -1- (amino-imino-methyl) piperidin-3-ylmethyl] -N1- (2-carbamoyl-ethyl) -Nlcyclopropyl-2- (naphthyl-2-sulfonylamino) -succinamide hydrochloride,

MS (ISP): 572.3 (M + H)+.MS (ISP): 572.3 (M + H) < + >.

Primer 38Example 38

38A) Analogno Primeru 1 dobimo naslednje spojine:38A) Analogous to Example 1, the following compounds were obtained:

38Aa) iz t-butil estra (S)-3-(4-ciklopentil-benzensulfonilamino)-N-ciklopropil-N(2-etoksikarbonil-etil)sukcinamske kisline etil ester hidroklorid 3-[ciklopropil-[(S)-3-[(S)-l-(amino-imino-metil)piperidin-3ilmetil]-2-(4-ciklopentil-fenilsulfonilamino)-propionil]-amino]propionske kisline, MS (FAB): 619,2 (M + H) +38Aa) from (S) -3- (4-cyclopentyl-benzenesulfonylamino) -N-cyclopropyl-N (2-ethoxycarbonyl-ethyl) succinic acid t-butyl ester ethyl ester hydrochloride 3- [cyclopropyl - [(S) -3- [(S) -1- (amino-imino-methyl) piperidin-3ylmethyl] -2- (4-cyclopentyl-phenylsulfonylamino) -propionyl] -amino] propionic acid, MS (FAB): 619.2 (M + H) +

38Ab) iz metil estra (S)-2-[2-terc-butoksikarbonil-l-[ciklopropil-(2-etoksikarboniletil)-karbamoil]etilsulfamoil]benzojske kisline metil ester hidroklorid 2-[(S)-2-[(S)-l-(amino-imino-metil)piperidin-3-ilmetilkarbamoil]-l-[ciklopropil-(2-etoksikarbonil-etil)karbamoil]etilsulfamoil]benzojske kisline, MS (ISP): 609,4 (M + H)+.38Ab) from (S) -2- [2-tert-butoxycarbonyl-1- [cyclopropyl- (2-ethoxycarbonylethyl) -carbamoyl] ethylsulfamoyl] benzoic acid methyl ester methyl ester hydrochloride 2 - [(S) -2 - [(S ) -1- (amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -1- [cyclopropyl- (2-ethoxycarbonyl-ethyl) carbamoyl] ethylsulfamoyl] benzoic acid, MS (ISP): 609.4 (M + H) +.

38Ac) iz t-butil estra (S)-N-ciklopropil-N-etoksikarbonilmetil-3-naftalin-l-ilsulfonilamino-sukcinamske kisline etil ester hidroklorid [[(S)-3-[(S)-(l-amino_:imino-metil)piperidin-3-ilmetilkarbamoil]-2-(naftalen-l-ilsulfonilamino)-propionil]-ciklopropil-amino]ocetne kisline, MS (FAB): 587,4 (M + H) + .38Ac) (S) -N-cyclopropyl-N-ethoxycarbonylmethyl-3-naphthalin-1-ylsulfonylamino-succinic acid t-butyl ester ethyl ester hydrochloride [[(S) -3 - [(S) - (1-amino _: imino-methyl) piperidin-3-ylmethylcarbamoyl] -2- (naphthalen-1-ylsulfonylamino) -propionyl] -cyclopropyl-amino] acetic acid, MS (FAB): 587.4 (M + H) +.

38Ad) iz t-butil estra (S)-N-ciklopropil-N-(2-etoksikarbonil-etil-3-(4-trifluormetoksibenzensulfonilamino)sukcinamske kisline etil ester hidroklorid 3-[[(S)-3-[(S)-l-(amino-imino-metil)piperidin-3-ilmetilkarbamoil-2-(4-trifluormetoksi-benzensulfonilamino)-propionil]-ciklopropil-amino]propionske kisline, MS (ISP): 635,5 (M + H) ⁺ .38Ad) from (S) -N-cyclopropyl-N- (2-ethoxycarbonyl-ethyl-3- (4-trifluoromethoxybenzenesulfonylamino) succinic acid t-butyl ester ethyl ester hydrochloride 3 - [[(S) -3 - [(S) -1- (amino-imino-methyl) piperidin-3-ylmethylcarbamoyl-2- (4-trifluoromethoxy-benzenesulfonylamino) -propionyl] -cyclopropyl-amino] propionic acid, MS (ISP): 635.5 (M + H) ⁺ .

38Ae) iz t-butil estra (S)-3-(4-ciano-benzensulfonilamino)-N-ciklopropil-N-(2-etoksi karbonil-etil)sukcinamske kisline etil ester hidroklorid 3-[[(S)-3-[(S)-l-(amino-imino-metil)piperidin-3-ilmetilkarbamoil]-2-(4-ciano-fenilsulfonilamino)-propionil]-ciklopropil-amino]propionske kisline, MS (ISP): 576,7 (M + H) + .38Ae) from (S) -3- (4-cyano-benzenesulfonylamino) -N-cyclopropyl-N- (2-ethoxy carbonyl-ethyl) succinic acid t-butyl ester ethyl ester hydrochloride 3 - [[(S) -3- [(S) -1- (amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -2- (4-cyano-phenylsulfonylamino) -propionyl] -cyclopropyl-amino] propionic acid, MS (ISP): 576.7 ( M + H) +.

38Af) iz t-butil estra (S)-N-ciklopropil-N-(2-etoksikarbonil-etil-3-metansulfonilaminosukcinamske kisline etil ester hidroklorid 3-[[(S)-3-[(S)-l-(amino-imino-metil)-piperidin-3-ilmetilkarbamoil]-2-metlilsulfonilamino)-propionil]-cikIopropil-amino]propionske kisline, MS (ISP): 489,4 (M + H) + .38Af) (S) -N-cyclopropyl-N- (2-ethoxycarbonyl-ethyl-3-methanesulfonylaminosuccinic acid t-butyl ester ethyl ester hydrochloride 3 - [[(S) -3 - [(S) -1- (amino) -imino-methyl) -piperidin-3-ylmethylcarbamoyl] -2-methylsulfonylamino) -propionyl] -cyclopropyl-amino] propionic acid, MS (ISP): 489.4 (M + H) +.

38Ag) iz t-butil estra (S)-N-ciklopropil-N-(2-etoksikarbonil-etil)-3-(piridin-3ilsulfonilamino)sukcinamske kisline etil ester trifluoracetat 3-[[(S)-3-[(S)-l-(amino-imino-metil)-piperidin-3-ilmetilkarbamoil]-2-piridin-3-ilsulfonilamino-propionil]-ciklopropil-amino]propionske kisline, MS (ISP): 552,6 (M + H)+.38Ag) (S) -N-cyclopropyl-N- (2-ethoxycarbonyl-ethyl) -3- (pyridine-3ylsulfonylamino) succinic acid t-butyl ester ethyl trifluoroacetate 3 - [[(S) -3 - [(S ) -1- (Amino-imino-methyl) -piperidin-3-ylmethylcarbamoyl] -2-pyridin-3-ylsulfonylamino-propionyl] -cyclopropyl-amino] propionic acid, MS (ISP): 552.6 (M + H) +.

38B) Priprava izhodnega materiala:38B) Preparation of starting material:

Izhodni diester dobimo analogno postopku v Primeru 2B)i) iz t-butil estra (S)-3-tbutoksikarbonilamino-N-ciklopropil-N-(2-etoksikarbonil-etil)sukcinamske kisline (Primer 2B)h)l) z uporabo ustreznih arilsulfokloridov namesto 2-naftilsulfoklorida:The starting diester was obtained analogously to the procedure in Example 2B) i) from (S) -3-tbutoxycarbonylamino-N-cyclopropyl-N- (2-ethoxycarbonyl-ethyl) succinic acid t-butyl ester (Example 2B) h) 1) using the appropriate arylsulfochlorides instead of 2-naphthylsulfochloride:

38Ba) t-butil ester (S)-3-(4-ciklopentil-benzensulfonilamino)-N-ciklopropil-N(2-etoksikarbonil-etil)-sukcinamske kisline, MS (FAB): 481 (M-izobutilen)(S) -3- (4-Cyclopentyl-benzenesulfonylamino) -N-cyclopropyl-N (2-ethoxycarbonyl-ethyl) -succinic acid t-butyl ester, MS (FAB): 381 (M-isobutylene)

38Bb) metil ester (S)-2-[2-terc-butoksikarbonil-l-[ciklopropil-(2-etoksikarbonil-etil) karbamoil]etilsulfamoil]benzojske kisline, MS (FAB): 471 (M-izobutilen)(S) -2- [2-tert-butoxycarbonyl-1- [cyclopropyl- (2-ethoxycarbonyl-ethyl) carbamoyl] ethylsulfamoyl] benzoic acid methyl ester, MS (FAB): 381 (M-isobutylene)

38Bc) t-butil ester (S)-N-ciklopropil-N-etoksikarbonilmetil-3-naftalin-lilsulfonilamino-sukcinamske kisline, MS (ISP): 505.3 (M + H) ⁺ .(S) -N-Cyclopropyl-N-ethoxycarbonylmethyl-3-naphthalin-lylsulfonylamino-succinic acid t-butyl ester, MS (ISP): 505.3 (M + H) ⁺ .

38Bd) t-butil ester (S)-N-ciklopropil-N-(2-etoksikarbonil-etil)-3-(4-trifluormetoksibenzensulfonilamino)sukcinamske kisline, MS (FAB): 497 (M-izobutilen)(S) -N-Cyclopropyl-N- (2-ethoxycarbonyl-ethyl) -3- (4-trifluoromethoxybenzenesulfonylamino) succinic acid t-butyl ester, MS (FAB): 387 (M-isobutylene)

38Be) t-butil ester (S)-3-(4-ciano-benzensulfonilamino)-N-ciklopropil-N(2-etoksikarbonil-etil)-sukcinamske kisline, MS (ISP): 494.2 (M + H) ⁺ .(S) -3- (4-Cyano-benzenesulfonylamino) -N-cyclopropyl-N (2-ethoxycarbonyl-ethyl) -succinic acid t-butyl ester, MS (ISP): 494.2 (M + H) ⁺ .

38Bf) t-butil ester (S)-N-ciklopropil-N-(2-etoksikarbonil-etil)-3-metansulfonilamino sukcinamske kisline, MS (FAB): 361 (M ⁺ -OEt)(S) -N-Cyclopropyl-N- (2-ethoxycarbonyl-ethyl) -3-methanesulfonylamino succinic acid t-butyl ester, MS (FAB): 381 (M ⁺ -OEt)

38Bg) t-butil ester (S)-N-ciklopropil-N-(2-etoksikarbonil-etil)-3-(piridin-3ilsulfonilamino)-sukcinamske kisline, MS (ISP); 470.2 (M + H) ⁺ .(S) -N-cyclopropyl-N- (2-ethoxycarbonyl-ethyl) -3- (pyridine-3ylsulfonylamino) -succinic acid t-butyl ester, MS (ISP) 38Bg); 470.2 (M + H) < ⁺ >.

Primer 39Example 39

Analogno Primeru 3, le izhajajoč iz estrov Primera 38A, dobimo naslednje kisline:Analogous to Example 3, only starting from the esters of Example 38A, the following acids are obtained:

a) 3-[ciklopropil-[(S)-3-[(S)-l-(amino-imino-metil)-piperidin-3-ilmetil]-251 (4-ciklopentil-fenilsulfonilamino)-propionil]-amino]propionsko kislino,a) 3- [cyclopropyl - [(S) -3 - [(S) -1- (amino-imino-methyl) -piperidin-3-ylmethyl] -251 (4-cyclopentyl-phenylsulfonylamino) -propionyl] -amino] propionic acid,

MS (FAB); 591.3 (M + H) + .MS (FAB); 591.3 (M + H) < + >.

b) 2-[(S)-2-[(S)-l-(amino-imino-metil)-piperidin-3-ilmetilkarbamoil]-l-[ciklopropil(2-etoksikarbonil-etil)-karbamoil]-etilsulfamoil]benzojsko kislino,b) 2 - [(S) -2 - [(S) -1- (amino-imino-methyl) -piperidin-3-ylmethylcarbamoyl] -1- [cyclopropyl (2-ethoxycarbonyl-ethyl) -carbamoyl] -ethylsulfamoyl] benzoic acid,

MS (ISP): 567.2 (M + H)+.MS (ISP): 567.2 (M + H) < + >.

c) [[(S)-3-[(S)-l-(amino-imino-metil)-piperidin-3-ilmetilkarbamoil]-2-naftalen-lilsulfonilamino-propionil]-ciklopropil-amino]-ocetno kislino,c) [[(S) -3 - [(S) -1- (amino-imino-methyl) -piperidin-3-ylmethylcarbamoyl] -2-naphthalen-lylsulfonylamino-propionyl] -cyclopropyl-amino] -acetic acid,

MS (FAB): 559.4 (M + H)+MS (FAB): 559.4 (M + H) < + >.

d) 3-[N-ciklopropil-N-[(S)-3-[(S)-l-(amino-imino-metil)-piperidin-3-ilmetilkarbamoil]-2-(4-trifluorometoksi-fenilsulfonilamino)-propionil]-amino]-propionsko kislino, MS (FAB): 607.2 (M + H) + ^e) l) 3-[[(S)-3-[(S)-l-(amino-imino-metil)-piperidin-3-ilmetilkarbamoil]-2-(4-cianofenilsulfonilamino)-propionil]-ciklopropil-amino]propionsko kislino,d) 3- [N-cyclopropyl-N - [(S) -3 - [(S) -1- (amino-imino-methyl) -piperidin-3-ylmethylcarbamoyl] -2- (4-trifluoromethoxy-phenylsulfonylamino) - propionyl] -amino] -propionic acid, MS (FAB): 607.2 (M + H) + ^e ) 1) 3 - [[(S) -3 - [(S) -1- (amino-imino-methyl) - piperidin-3-ylmethylcarbamoyl] -2- (4-cyanophenylsulfonylamino) -propionyl] -cyclopropyl-amino] propionic acid,

MS (ISP): 548.5 (M + H) +MS (ISP): 548.5 (M + H) < + >.

e) 2) 3-[[(S)-3-[(S)-l-(amino-imino-metil)-piperidin-3-ilkarbamoil]-2-(4-karbamoilfenilsulfonilamino)-propionil]-ciklopropil-amino]-propionsko kislino,e) 2) 3 - [[(S) -3 - [(S) -1- (amino-imino-methyl) -piperidin-3-ylcarbamoyl] -2- (4-carbamoylphenylsulfonylamino) -propionyl] -cyclopropyl-amino ] -propionic acid,

MS (ISP): 566.5 (M + H) +MS (ISP): 566.5 (M + H) < + >.

f) 3-[[(S)-3-[(S)-l-(amino-imino-metil)-piperidin-3-ilmetilkarbamoil]-2-metilulfonilamino)-propionil]-ciklopropil-amino]propionsko kislino,f) 3 - [[(S) -3 - [(S) -1- (amino-imino-methyl) -piperidin-3-ylmethylcarbamoyl] -2-methylsulfonylamino) -propionyl] -cyclopropyl-amino] propionic acid,

MS (ISP): 461.3 (M + H)+MS (ISP): 461.3 (M + H) < + >.

g) 3-[[(S)-3-[(S)-l-(amino-imino-metil)-piperidin-3-ilmetilkarbamoiI]-2-piridin3-ilsulfonilamino)-propionil]-ciklopropil-amino]propionsko kislino,g) 3 - [[(S) -3 - [(S) -1- (amino-imino-methyl) -piperidin-3-ylmethylcarbamoyl] -2-pyridin3-ylsulfonylamino) -propionyl] -cyclopropyl-amino] propionic acid ,

MS (ISP); 524.3 (M + H) +MS (ISP); 524.3 (M + H) < + >.

Primer 40Example 40

Analogno Primeru 1 pripravimo etil ester acetat 3-[[(S)-3-[(S)-l-(amino-iminometil)-piperidin-3-ilmetilkarbamoil]-N-ciklopropil-2-(4-tetrazol-5-il-fenilsulfonilamino)-propionilamino]-propionske kisline, MS (ISP): 619.4 (M + H) ⁺ Analogous to Example 1, ethyl acetate 3 - [[(S) -3 - [(S) -1- (amino-iminomethyl) -piperidin-3-ylmethylcarbamoyl] -N-cyclopropyl-2- (4-tetrazol-5-) was prepared yl-phenylsulfonylamino) -propionylamino] -propionic acid, MS (ISP): 619.4 (M + H) ⁺

Priprava izhodnega materiala:Preparation of starting material:

1.4 g diestra, pripravljenega pri Primeru 38B)e), raztopimo v 14 ml dimetilformamida, dodamo 410 mg amonijevega klorida in 500 mg natrijevega azida in mešamo 24 ur pri 80 °C . Po ohlajenju na sobno temperaturo reakcijsko zmes filtriramo in filtrat uparimo. Izoliramo 1.8 g t-butil estra (S)-N-ciklopropil-N-(2etoksikarbonil-etil)-3-(4-tetrazol-5-il-fenil-sulfonilamino)-sukcinamske kisline, MS (ISP): 537,4 (M + H)+.1.4 g of the diester prepared in Example 38B) e) were dissolved in 14 ml of dimethylformamide, 410 mg of ammonium chloride and 500 mg of sodium azide were added and stirred at 80 ° C for 24 hours. After cooling to room temperature, the reaction mixture was filtered and the filtrate was evaporated. 1.8 g of (S) -N-cyclopropyl-N- (2ethoxycarbonyl-ethyl) -3- (4-tetrazol-5-yl-phenyl-sulfonylamino) -succinic acid 1.8 g is isolated, MS (ISP): 537.4 (M + H) < + >.

Primer 41Example 41

Analogno Primeru 3 dobimo iz estra Primera 40 3-[[(S)-3-[(S)-l-(amino-iminometil)-piperidin-3-ilmetilkarbamoil]-N-ciklopropil-2-[4-tetrazol-5-il)-fenilsulfonilaminoj-propionilaminoj-propionsko kislino, MS (ISP): 591.4 (M + H) ⁺ Analogous to Example 3 was obtained from the ester of Example 40 3 - [[(S) -3 - [(S) -1- (amino-iminomethyl) -piperidin-3-ylmethylcarbamoyl] -N-cyclopropyl-2- [4-tetrazol-5 -yl) -phenylsulfonylamino-propionylamino-propionic acid, MS (ISP): 591.4 (M + H) ⁺

Primer 42Example 42

Analogno Primeru 1, le ob uporabi naslednjih enantiomerov, pripravimo naslednje spojine:In analogy to Example 1, only using the following enantiomers, the following compounds were prepared:

a) Iz -β-butil estra N-Boc-D-asparaginske kisline namesto 0-t-butil estra N-Boc-Lasparaginske kisline:a) From N-Boc-D-aspartic acid -β-butyl ester instead of N-Boc-Laspartic acid 0-t-butyl ester:

etil ester hidroklorid [[(R)-3-[(S)-(l-amino-imino-metil)piperidin-3-ilmetilkarbamoil]-2-(naftalen-2-ilsulfonilamino)-propionil]-ciklopropil-amino]-ocetne kisline, MS (ISN); 585.4 (M + H) + .[[(R) -3 - [(S) - (1-amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -2- (naphthalen-2-ylsulfonylamino) -propionyl] -cyclopropyl-amino] - ethyl ester hydrochloride - acetic acids, MS (ISN); 585.4 (M + H) < + >.

b) iz (R)-l-amidino-3-(aminometil)-piperidin-dihidroklorida namesto (S)-l-amidino 3-(aminometil)-piperidin-dihidroklorida:b) from (R) -1-amidino-3- (aminomethyl) -piperidine dihydrochloride instead of (S) -1-amidino 3- (aminomethyl) -piperidine dihydrochloride:

etil ester hidroklorid [[(S)-3-[(R)-(l-amino-imino-metil)piperidin-3-ilmetilkarbamoil]-2-(naftalen-2-ilsulfonilamino)-propionil]-ciklopropil-amino]-ocetne kisline, MS (ISN): 585.7 (M + H) + .[[(S) -3 - [(R) - (1-amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -2- (naphthalen-2-ylsulfonylamino) -propionyl] -cyclopropyl-amino] - ethyl ester hydrochloride - acetic acids, MS (ISN): 585.7 (M + H) +.

c) iz t-butil estra N-Boc-D-asparaginske kisline namesto t-butil estra N-Boc-Lasparaginske kisline in (R)-l-amidino-3-(aminometil)-piperidin-dihidroklorida namesto (S)-l-amidino-3-(aminometil)-piperidin-dihidroklorida etil ester hidroklorid [[(R)-3-[(R)-(l-amino-imino-metil)piperidin-3-ilmetilkarbamoil]-2-(naftalen-2-ilsulfonilamino)-propionil]-ciklopropil-amino]-ocetne kisline, MS (ISP): 587.6 (M + H) + .c) from N-Boc-D-aspartic acid t-butyl ester instead of N-Boc-Laspartic acid t-butyl ester and (R) -1-amidino-3- (aminomethyl) -piperidine dihydrochloride instead of (S) -l -amidino-3- (aminomethyl) -piperidine dihydrochloride ethyl ester hydrochloride [[(R) -3 - [(R) - (1-amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -2- (naphthalen-2 -ylsulfonylamino) -propionyl] -cyclopropyl-amino] -acetic acid, MS (ISP): 587.6 (M + H) +.

Priprava izhodnega gvanidina iz Primera 42b):Preparation of starting guanidine from Example 42b):

Po postopku analogno Primeru 36B), vendar ob uporabi L-mandljeve kisline namesto D-mandljeve kisline, dobimo preko:Following the procedure analogous to Example 36B), but using L-mandelic acid instead of D-mandelic acid, it is obtained by:

a) (S)-N-piperidin-3-ilmetil-benzamid-(S)-hidroksi-fenil-acetata (1:1),a) (S) -N-piperidin-3-ylmethyl-benzamide- (S) -hydroxy-phenyl-acetate (1: 1),

MS (FAB): 218 M+.MS (FAB): 218 M < + >.

b) (R)-N-[l-(amino-imino-metil)-piperidin-(3)-ilmetil]benzamid-(S)-hidroksi-fenilacetata (1:1), MS (ISP): 261.4 (M + H)+.b) (R) -N- [1- (amino-imino-methyl) -piperidin- (3) -ylmethyl] benzamide- (S) -hydroxy-phenylacetate (1: 1), MS (ISP): 261.4 (M + H) +.

(R)-l-amidino-3-(aminometil)-piperidin dihidroklorid, [a]_D ²⁰= +17.6 °C (c=1.0, voda).(R) -1-Amidino-3- (aminomethyl) -piperidine dihydrochloride, [α] _D ²⁰ = +17.6 ° C (c = 1.0, water).

Primer 43Example 43

Analogno Primeru 3 pripravimo iz estrov Primera 42 naslednje kisline:The following acids were prepared analogously to Example 3 from the esters of Example 42:

a) [[(R)-3-[(S)-(l-amidino-imino-metil)piperidin-3-ilmetilkarbamoil]-2-(naftalen-2ilsulfonilamino)-propionil]-ciklopropil-amino]-ocetno kislino,a) [[(R) -3 - [(S) - (1-amidino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -2- (naphthalen-2ylsulfonylamino) -propionyl] -cyclopropyl-amino] -acetic acid,

MS (ISP): 559.5 (M + H) + .MS (ISP): 559.5 (M + H) < + >.

b) [[(S)-3-[(R)-(l-amidino-imino-metil)piperidin-3-ilmetilkarbamoil]-2-(naftalen-2ilsulfonilamino)-propionil]-ciklopropil-amino]-ocetno kislino,b) [[(S) -3 - [(R) - (1-amidino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -2- (naphthalen-2ylsulfonylamino) -propionyl] -cyclopropyl-amino] -acetic acid,

MS (ISP): 559.5 (M + H)+ .MS (ISP): 559.5 (M + H) < + >.

c) [[(R)-3-[(R)-(l-amidino-imino-metil)piperidin-3-ilmetilkarbamoil]-2-(naftalen-2ilsulfonilamino)-propionil]-eiklopropil-amino]-ocetno kislino,c) [[(R) -3 - [(R) - (1-amidino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -2- (naphthalen-2ylsulfonylamino) -propionyl] -cyclopropyl-amino] -acetic acid,

MS (ISP): 559.5 (M + H)+.MS (ISP): 559.5 (M + H) < + >.

Primer 44Example 44

Analogno Primeru 1 dobimo iz ustreznih t-butil estrov in ob uporabi rac-2(aminometil)-4-morfolinokarboksamidin-trifluoracetata (Primer 7Bc) namesto (S)amidino-3-(aminometil)-piperidin-dihidroklorida, naslednje produkte:Analogously to Example 1, the following products were obtained from the corresponding t-butyl esters and using rac-2 (aminomethyl) -4-morpholinocarboxamidine-trifluoroacetate (Example 7Bc) instead of (S) amidino-3- (aminomethyl) -piperidine dihydrochloride:

a) iz t-butil estra (S)-N-ciklopropil-N-(2-tetrazol-5-il-etil)-3-naftalin-2ilsulfonilamino-sukcinamske kisline (Primer 36Ac)):a) From (S) -N-cyclopropyl-N- (2-tetrazol-5-yl-ethyl) -3-naphthalin-2ylsulfonylamino-succinic acid t-butyl ester (Example 36Ac)):

(S)-N(4)-[4-(amino-imino-metil)-morfolin-2-ilmetil]-N(l)-ciklopropil-N(l)-[2(tetrazol-5-il)-etil]-2-(naftalin-2-ilsulfonil)-sukcinamid (1:1) epimerna zmes,(S) -N (4) - [4- (amino-imino-methyl) -morpholin-2-ylmethyl] -N (1) -cyclopropyl-N (1) - [2 (tetrazol-5-yl) -ethyl ] -2- (Naphthalin-2-ylsulfonyl) -succinamide (1: 1) epimeric mixture,

MS (ISP): 599.5 (M+H)+.MS (ISP): 599.5 (M + H) < + >.

b) iz t-butil estra (S)-N-ciklopropil-N-[2-(5-metil-l,2,4-oksadiazol-3-il)-etil]-3naftalen-2-ilsulfonilamino-sukcinamske kisline (Primer 47e)):b) from (S) -N-cyclopropyl-N- [2- (5-methyl-1,2,4-oxadiazol-3-yl) -ethyl] -3-naphthalen-2-ylsulfonylamino-succinic acid t-butyl ester ( Example 47e)):

(S)-N(4)-[4-(amino-imino-metil)-morfolin-2-ilmetil]-N(l)-ciklopropil-N(l)-[2-(5metil-l,2,4-oksadiazol-3-il)-etil]-2-(naftalen-2-ilsulfonilamino-sukcinamid hidroklorid (1:1), (1:1) epimerna zmes, MS (ISP): 613.7 (M + H) ⁺ .(S) -N (4) - [4- (amino-imino-methyl) -morpholin-2-ylmethyl] -N (1) -cyclopropyl-N (1) - [2- (5methyl-1,2,4) -oxadiazol-3-yl) -ethyl] -2- (naphthalen-2-ylsulfonylamino-succinamide hydrochloride (1: 1), (1: 1) epimer mixture, MS (ISP): 613.7 (M + H) ⁺ .

Primer 45Example 45

Analogno Primeru 1 dobimo iz ustreznih estrov ob uporabi rac-2-(aminometil)-4morfolinokarboksamidin trifluoracetata namesto (S)-l-amidino-3-(aminometil)piperidin dihidroklorida, naslednje produkte:Analogous to Example 1, the following products were obtained from the corresponding esters using rac-2- (aminomethyl) -4-morpholinocarboxamidine trifluoroacetate instead of (S) -1-amidino-3- (aminomethyl) piperidine dihydrochloride:

a) iz t-butil estra (S)-N-ciklopropil-N-etoksikarbonilmetil-3-(naftalen-2sulfonilaminoj-sukcinamske kisline (Primer 2B)d) 1)):a) From (S) -N-cyclopropyl-N-ethoxycarbonylmethyl-3- (naphthalene-2-sulfonylamino-succinic acid t-butyl ester (Example 2B) d) (1)):

etil ester hidroklorid [[(S)-3-[4-(amino-imino-metil)-morfolin-2-ilmetilkarbamoil]-2(naftalin-2-il-sulfonil)-propionil]-ciklopropil]-amino]-ocetne kisline (1:1), (1:1) epimerna zmes, MS (ISP): 589.5 (M + H) ⁺ .[[(S) -3- [4- (amino-imino-methyl) -morpholin-2-ylmethylcarbamoyl] -2 (naphthalin-2-yl-sulfonyl) -propionyl] -cyclopropyl] -amino] -acetyl ester hydrochloride acids (1: 1), (1: 1) epimeric mixture, MS (ISP): 589.5 (M + H) ⁺ .

b) iz estra iz Primera 38Bb):b) from the ester of Example 38Bb):

metil ester trifluoracetat 2-[(S)-2-[4-(amino-imino-metil)morfolin-2-ilmetilkarbamoil]-l-[(2-etoksikarbonil-etil)-ciklopropil-karbamoil]etilsulfamoil]-benzojske kisline (1:1), (1:1) epimerna zmes, MS (ISP): 611.6 (M + H) ⁺ .2 - [(S) -2- [4- (amino-imino-methyl) morpholin-2-ylmethylcarbamoyl] -1 - [(2-ethoxycarbonyl-ethyl) -cyclopropyl-carbamoyl] ethylsulfamoyl] -benzoic acid methyl ester trifluoroacetate ( 1: 1), (1: 1) epimeric mixture, MS (ISP): 611.6 (M + H) ⁺ .

Primer 46Example 46

Analogno Primeru 3, le izhajajoč iz estrov Primera 45, dobimo naslednje kisline:Analogous to Example 3, only starting from the esters of Example 45, the following acids are obtained:

a) [[(S)-3-[4-(amino-imino-metil)-morfolin-2-ilmetilkarbamoil]-2-(naftalen-2-ilsulfonil)-propionil]-ciklopropil]-amino]-ocetno kislino (1:1) epimerna zmes,a) [[(S) -3- [4- (amino-imino-methyl) -morpholin-2-ylmethylcarbamoyl] -2- (naphthalen-2-ylsulfonyl) -propionyl] -cyclopropyl] -amino] -acetic acid ( 1: 1) epimeric mixture,

MS (ISP): 561.4 (M+H) + .MS (ISP): 561.4 (M + H) < + >.

b) l) 2-[(S)-2-[4-(amino-imino-metil)-morfolin-2-ilmetilkarbamoil]-l-[ciklopropil-(2 etoksi-karbonil-etiljkarbamoiljetilaminosulfonilj benzojsko kislino (1:1) epimerna zmes, MS (ISP): 597.5 (M + H) + .b) 1) 2 - [(S) -2- [4- (amino-imino-methyl) -morpholin-2-ylmethylcarbamoyl] -1- [cyclopropyl- (2 ethoxy-carbonyl-ethylcarbamoylethylaminosulfonylbenzoic acid) (1: 1) epimer mixture, MS (ISP): 597.5 (M + H) +.

b)2) 2-[(S)-2-[4-(amino-imino-metil)-morfolin-2-ilmetilkarbamoil]-l-[(2-karboksietil)-ciklopropil-karbamoil]etilaminosulfonil] benzojska kislina (1:1) epimerna zmes MS (ISP): 569.4 (M + H)+ .b) 2) 2 - [(S) -2- [4- (amino-imino-methyl) -morpholin-2-ylmethylcarbamoyl] -1 - [(2-carboxyethyl) -cyclopropyl-carbamoyl] ethylaminosulfonyl] benzoic acid (1 : 1) epimer mixture of MS (ISP): 569.4 (M + H) +.

Primer 47Example 47

Analogno Primeru 1 pripravimo (S)-N4[(S)-l-(amino-imino-metil)-piperidin-3ilmetil]-N(l)-ciklopropil-N(l)-[2-(5-metil-l,2,4-oksadiazol-3-il)-etil]-2-(naftil-2ilsulfonilaminoj-sukcinamid hidroklorid, MS (ISP): 597.4 (M + H) ⁺ .Analogously to Example 1, (S) -N4 [(S) -1- (amino-imino-methyl) -piperidin-3ylmethyl] -N (1) -cyclopropyl-N (1) - [2- (5-methyl-1) was prepared , 2,4-Oxadiazol-3-yl) -ethyl] -2- (naphthyl-2ylsulfonylamino-succinamide hydrochloride, MS (ISP): 597.4 (M + H) ⁺ .

Priprava izhodnega materiala:Preparation of starting material:

a) raztopini 29.2 g 3-ciklopropilamino-propionitrila v 300 ml dioksana dokapavamo pri sobni temperaturi raztopino 57.8 g di-terc-butil dikarbonata v 300 ml dioksana. Raztopino mešamo čez noč pri sobni temperaturi in nato uparimo. Dobimo 58.1 g surovega t-butil estra (2-ciano-etil)-ciklopropil-karbaminske kisline,a) A solution of 57.8 g of di-tert-butyl dicarbonate in 300 ml of dioxane was added dropwise at a solution of 29.2 g of 3-cyclopropylamino-propionitrile in 300 ml of dioxane. The solution was stirred overnight at room temperature and then evaporated. 58.1 g of crude (2-cyano-ethyl) -cyclopropyl-carbamic acid t-butyl ester is obtained,

MS (FAB): 154 (M-izobutilen).MS (FAB): 154 (M-isobutylene).

b) Raztopini 20.0 g pri a) dobljenega nitrila v 57 ml etanola in 23 ml vode dodamob) To a solution of 20.0 g in a) of the resulting nitrile in 57 ml of ethanol and 23 ml of water is added

6.6 g hidroksilamin hidroklorida in 13.6 g natrijevega karbonata dekahidrata. Reakcijsko zmes kuhamo ob refluksu, uparimo, ostanek suspendiramo v vročem etanolu in filtriramo. Filtrat uparimo in ostanek prekristaliziramo iz izopropanola/heksana. Dobljene kristale raztopimo v 10 ml acetanhidrida in mešamo pri 80 °C. Zatem uparimo reakcijsko zmes, ostanku dodamo nasičeno raztopino natrijevega karbonata in ekstrahiramo z ocetestrom. Organske faze uparimo in ostanek kromatografiramo s heksanom/ocetestrom (3:1) na kremeničnem gelu. Dobimo 5.4 g t-butil estra ciklopropil-2-(5-metil-l,2,4-oksadiazol-3-il)-etil-karbaminske kisline,6.6 g of hydroxylamine hydrochloride and 13.6 g of sodium carbonate decahydrate. The reaction mixture was boiled under reflux, evaporated, the residue was suspended in hot ethanol and filtered. The filtrate was evaporated and the residue was recrystallized from isopropanol / hexane. The crystals obtained were dissolved in 10 ml of acetanhydride and stirred at 80 ° C. The reaction mixture was then evaporated, a saturated solution of sodium carbonate was added to the residue, and extracted with ethyl acetate. The organic phases were evaporated and the residue was chromatographed with hexane / acetone (3: 1) on silica gel. 5.4 g of cyclopropyl-2- (5-methyl-1,2,4-oxadiazol-3-yl) -ethyl-carbamic acid t-butyl ester are obtained,

MS (FAB): 211 (M-izobutilen).MS (FAB): 211 (M-isobutylene).

c) 5.2 g pri b) dobljenega materiala raztopimo v 30 ml ocetestra, dodamo 4M raztopino solne kisline v ocetestru in mešamo pri sobni temperaturi. Raztopino uparimo, ostanek naplavimo v ocetestru in odfiltriramo. Izoliramo 3.7 g ciklopropil2-(5-metil-l,2,4-oksadiazol-3-il)-etilamin hidroklorida, MS (FAB): 167 (M ⁺ ).c) 5.2 g in b) of the material obtained is dissolved in 30 ml of acetic acid, 4M hydrochloric acid solution in acetic acid is added and stirred at room temperature. The solution was evaporated, the residue was taken up in acetone and filtered off. 3.7 g of cyclopropyl2- (5-methyl-1,2,4-oxadiazol-3-yl) -ethylamine hydrochloride were isolated, MS (FAB): 167 (M ⁺ ).

d) Analogno postopku iz Primera 2.B)e), vendar ob uporabi pri c) dobljenega aminhidroklorida namesto sarkozinetil ester hidroklorida dobimo t-butil ester (S)-3-tercbutoksikarbonilamino-N-ciklopropil-N-[2-(5-metil-l,2,4-oksadiazol-3-il)-etilsukcinamske kisline, MS (ISP): 439.6 (M + H) ⁺ .d) Analogous to the procedure of Example 2.B) e), but using c) the resulting aminhydrochloride instead of the sarcosinethyl ester of hydrochloride, t-butyl ester of (S) -3-tert-butoxycarbonylamino-N-cyclopropyl-N- [2- (5- methyl-1,2,4-oxadiazol-3-yl) -ethylsuccinic acid, MS (ISP): 439.6 (M + H) ⁺ .

e) Analogno postopku iz Primera 2B)i), vendar ob uporabi pri d) dobljenega diestra namesto t-butil estra (S)-3-t-butoksikarbonilamino-N-etoksi-karboniImetil-N-metil sukcinamske kisline pripravimo t-butil ester ((S)-N-ciklopropil-N-[2-(5-metil-l,2,4oksadiazol-3-il)-etil]-3-(naftalen-2-ilsulfonilamino)-sukcinamske kisline,e) Analogous to the procedure in Example 2B) i), but using (d) the diester obtained instead of the (S) -3-t-butoxycarbonylamino-N-ethoxy-carbonylmethyl-N-methyl succinic acid t-butyl ester ((S) -N-cyclopropyl-N- [2- (5-methyl-1,2,4oxadiazol-3-yl) -ethyl] -3- (naphthalen-2-ylsulfonylamino) -succinic acid,

MS (FAB): 473 (M -izobutilen).MS (FAB): 473 (M -isobutylene).

Primer 48Example 48

Analogno Primeru 1 dobimo iz t-butil estra (S)-N-ciklopropil-N-etoksikarbonilmetil3-(naftalen-2-sulfonilamino)-sukcinamske kisline (Primer 2.B)d)l)) ob uporabi etil ester hidroklorida (S)-(3-aminometil-piperidin-l-il)-imino-metilkarbaminske kisline namesto (S)-l-amidino-3-(aminometil)piperidin-dihidroklorida etil ester [ciklopropil-[(S)-3-[(S)-l-(etoksikarbonil-amino-imino-metil)piperidin-3ilmetilkarbamoil]-2-(naftalen-2-ilsulfonilamino)-propionil]-amino]-ocetne kisline,Analogous to Example 1 was obtained from (S) -N-cyclopropyl-N-ethoxycarbonylmethyl 3- (naphthalene-2-sulfonylamino) -succinic acid t-butyl ester (Example 2.B) d)) using hydrochloride (S) ethyl ester - (3-Aminomethyl-piperidin-1-yl) -imino-methylcarbamic acid instead of (S) -1-amidino-3- (aminomethyl) piperidine dihydrochloride ethyl ester [cyclopropyl - [(S) -3 - [(S) -1- (ethoxycarbonyl-amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -2- (naphthalen-2-ylsulfonylamino) -propionyl] -amino] -acetic acid,

MS (ISP): 659.6 (M + H)+.MS (ISP): 659.6 (M + H) < + >.

Priprava izhodnega materiala:Preparation of starting material:

a) Raztopini t-butil estra 10.0 g (S)-3-aminometil-l-piperidinkarboksilne kisline v 400 ml heksana in 100 ml vode dodamo 3.7 g tetrabutil-amonijevega hidrogen sulfata in 100 ml IN natrijevega luga. Tej raztopini dokapavamo 9.3 ml benzilkloroformiata in mešamo 3 ure pri sobni temperaturi. Zatem odločimo organsko fazo, jo izperemo z vodo, 10% citronsko kislino, vodo in nasičeno raztopino natrijevega hidrogen karbonata, sušimo in uparimo. Dobimo t-butil-(S)-3-[(l-benziloksi)formamido]metil]-l-piperidinkarboksilat.a) To a solution of t-butyl ester 10.0 g of (S) -3-aminomethyl-1-piperidinecarboxylic acid in 400 ml of hexane and 100 ml of water was added 3.7 g of tetrabutyl-ammonium hydrogen sulfate and 100 ml of IN sodium hydroxide. 9.3 ml of benzyl chloroformate are added to this solution and stirred at room temperature for 3 hours. The organic phase is then determined, washed with water, 10% citric acid, water and saturated sodium hydrogen carbonate solution, dried and evaporated. T-Butyl- (S) -3 - [(1-benzyloxy) formamido] methyl] -1-piperidinecarboxylate is obtained.

b) 11.3 g pri a) dobljenega materiala raztopimo v 120 ml ocetestra, pri 4 °C dodamo 120 ml 4M raztopine solne kisline v ocetestru in mešamo 5 ur pri sobni temperaturi. Zatem reakcijsko raztopino uparimo, raztopimo ostanek v 265 ml dimetilformamida, dodamo 18 ml trietilamina in 4.3 g formamidinsulfonske kisline in mešamo 17 ur pri sobni temperaturi. Topilo uparimo, ostanku dodamo IN solno kislino, ponovno uparimo in kromatografiramo z vodo/acetonitrilom na koloni RP-18. Tako izoliramo 5.4 g benzil-[[(S)-l-amidino-3-piperidinil]metil]karbamat hidroklorida.b) Dissolve 11.3 g of the material obtained in 120 ml of acetic ester, add 120 ml of 4M hydrochloric acid solution in acetic acid at 4 ° C and stir for 5 hours at room temperature. The reaction solution was then evaporated, the residue dissolved in 265 ml of dimethylformamide, 18 ml of triethylamine and 4.3 g of formamidinsulfonic acid were added and stirred at room temperature for 17 hours. The solvent was evaporated, the residue was added AND hydrochloric acid, re-evaporated and chromatographed with water / acetonitrile on RP-18 column. 5.4 g of benzyl - [[(S) -1-amidino-3-piperidinyl] methyl] carbamate hydrochloride are thus isolated.

c) Raztopini 2.0 g benzil-[[(S)-l-amidino-3-piperidinil]metil]karbamat hidroklorida v 200 ml metilenklorida dokapavamo 0.55 ml etil estra klormravljinčne kisline. Reakcijsko zmes ohladimo na 0 °C. Ob mešanju dokapavamo 113 ml 0.1N natrijevega luga. Zatem mešamo v ledeni kopeli, fazi ločimo, organsko fazo pa izperemo z vodo, sušimo in uparimo. Dobimo 1.5 g benzil estra (S)-l-(etoksikarbonilamino-imino-metil)-piperidin-3-ilmetilkarbaminske kisline,c) A solution of 2.0 g of benzyl - [[(S) -1-amidino-3-piperidinyl] methyl] carbamate hydrochloride in 200 ml of methylene chloride was added dropwise with 0.55 ml of hydrochloric acid ethyl ester. The reaction mixture was cooled to 0 ° C. 113 ml of 0.1N sodium hydroxide were added dropwise with stirring. The mixture is then stirred in an ice bath, the phases are separated and the organic phase is washed with water, dried and evaporated. 1.5 g of (S) -1- (ethoxycarbonylamino-imino-methyl) -piperidin-3-ylmethylcarbamic acid benzyl ester is obtained,

MS (FAB): 363.2 (M + H) + .MS (FAB): 363.2 (M + H) < + >.

d) 1.5 g pri c) dobljenega materiala raztopimo v 30 ml etanola in 30 ml IN solne kisline, dodamo 0.2 g paladija na oglju in hidriramo. Dobimo 1.4 g etil ester hidroklorida (S)-(3-aminometil-piperidin-l-il)-imino-metilkarbaminske kisline,d) dissolve 1.5 g of the material obtained in 30 ml of ethanol and 30 ml of 1N hydrochloric acid, add 0.2 g of palladium on charcoal and hydrate. 1.4 g of (S) - (3-Aminomethyl-piperidin-1-yl) -imino-methylcarbamic acid ethyl ester hydrochloride is obtained,

MS (ISP): 229.4 (M + H) + .MS (ISP): 229.4 (M + H) < + >.

Primer 49Example 49

Analogno Primeru 48, vendar ob uporabi izobutil estra klormravljinčne kisline namesto etil estra klormravljinčne kisline (v Primeru 48c), dobimo preko izobutil estra (S)-(3-benziloksikarbonilaminometil-piperidin-l-il)-imino-metilkarbaminske kisline, MS (FAB): 390 M+ in preko izobutil ester hidroklorida [(S)-(3-aminometil-piperidin-l-il)-iminometilkarbaminske kisline (1:1), MS (termo spray); 257 (M + H)⁺, etil ester [ciklopropil-[(S)-3-[(S)-l-(izobutoksikarbonilamino-imino-metil)piperidin3-ilmetilkarbamoil]-2-(naftalen-2-ilsulfonilamino)-propionil]-amino]-ocetne kisline ali tavtomer amidino skupine; MS (ISP): 687.7 (M + H) ⁺ .Analogous to Example 48, but using hydrochloric acid isobutyl ester instead of hydrochloric acid ethyl ester (in Example 48c), isobutyl ester (S) - (3-benzyloxycarbonylaminomethyl-piperidin-1-yl) -imino-methylcarbamic acid, MS (FAB) ): 390 M + and via isobutyl ester hydrochloride [(S) - (3-aminomethyl-piperidin-1-yl) -iminomethylcarbamic acid (1: 1), MS (thermal spray); 257 (M + H) ⁺ , [cyclopropyl - [(S) -3 - [(S) -1- (isobutoxycarbonylamino-imino-methyl) piperidin3-ylmethylcarbamoyl] -2- (naphthalen-2-ylsulfonylamino) -propionyl ethyl ester ] -amino] -acetic acid or tautomer of the amidino group; MS (ISP): 687.7 (M + H) < ⁺ >.

Primer 50Example 50

Analogno Primeru 48 le ob uporabi etil ester hidroklorida (RS)-(2-aminometilmorfolin-4-il)-imino-metilkarbaminske kisline namesto etil ester hidroklorida (S)-(3-aminometil-piperidin-l-il)-imino-metilkarbaminske kisline dobimo etil ester [ciklopropil-[(S)-3-[4-etoksikarbonilamino-imino-metil)morfolin-2ilmetilkarbamoil]-2-(naftalen-2-ilsulfonilamino)-propionil]-amino]-ocetne kisline, (1:1) epimerno zmes, MS (ISP): 661.5 (M + H) + .Analogous to Example 48 only using (RS) - (2-aminomethylmorpholin-4-yl) -imino-methylcarbamic acid ethyl ester instead of (S) - (3-aminomethyl-piperidin-1-yl) -imino-methylcarbamic acid ethyl ester acids give [cyclopropyl - [(S) -3- [4-ethoxycarbonylamino-imino-methyl) morpholin-2-ylmethylcarbamoyl] -2- (naphthalen-2-ylsulfonylamino) -propionyl] -amino] -acetic acid ethyl ester, (1: 1) epimer mixture, MS (ISP): 661.5 (M + H) +.

Priprava izhodnega materiala:Preparation of starting material:

a) Suspenziji 10.3 g t-butil-rac-[(4-amidino-2-morfolinil)metil]karbamat hemisulfita (Primer 7Bb) v 1030 ml metilenklorida dodamo 3.15 ml etil estra klormravljinčne kisline. Reakcijsko zmes ohladimo na 4 °C in dokapavamo 637.2 ml 0.1 N natrijevega luga. Nato mešamo pri 5 °C, zatem odločimo organsko fazo, jo izperemo z vodo, sušimo in uparimo. Izoliramo 10.5 g etil estra (RS)-[2-terc-butoksikarbonilaminometil)-morfolin-4-il]-imino-metilkarbaminske kisline,a) To a suspension of 10.3 g of t-butyl-rac - [(4-amidino-2-morpholinyl) methyl] carbamate hemisulfite (Example 7Bb) in 1030 ml of methylene chloride was added 3.15 ml of chloromic acid ethyl ester. The reaction mixture was cooled to 4 ° C and 637.2 ml of 0.1 N sodium hydroxide was added dropwise. It is then stirred at 5 ° C, then the organic phase is determined, washed with water, dried and evaporated. Isolate 10.5 g of ethyl (RS) - [2-tert-butoxycarbonylaminomethyl) -morpholin-4-yl] -imino-methylcarbamic acid ethyl ester,

MS (ISP); 331.4 (M + H) + .MS (ISP); 331.4 (M + H) < + >.

b) 8.9 g pri a) dobljenega materiala raztopimo v 50 ml ocetestra, dodamo 50 mlb) 8.9 g in a) of the material obtained is dissolved in 50 ml of acetic acid, 50 ml is added

4Μ solne kisline v ocetestru in mešamo pri sobni temperaturi. Po uparjenju nastale suspenzije dobimo 7.3 g etil ester hidroklorida (RS)-(2-aminometil-morfolin-4-il)imino-metilkarbaminske kisline, MS (ISP): 231.4 (M + H)⁺.4Μ hydrochloric acid in acetic acid and stirred at room temperature. Evaporation of the resulting suspension gave 7.3 g of ethyl hydrochloride (RS) - (2-aminomethyl-morpholin-4-yl) imino-methylcarbamic acid ethyl ester, MS (ISP): 231.4 (M + H) ⁺ .

Primer 51Example 51

Analogno Primeru 50 pripravimo iz ustreznih estrov naslednje spojine:The following compounds were prepared analogously to Example 50 from the corresponding esters:

a) iz t-butil estra (S)-N-ciklopropil-N-(2-tetrazol-5-il-etil)-3-naftalin-2ilsulfonilamino-sukcinamske kisline (Primer 36Ac) etil ester [2-[(S)-3-[ciklopropil-2-(tetrazol-5-il)-etil-karbamoil]-3-(naftalen-2ilsulfonilamino)-propionilaminometil]-morfolin-4-il]imino-metilkarbaminske kisline, (1:1) epimerna zmes, MS (ISP): 671.6 (M + H) + .a) From (S) -N-cyclopropyl-N- (2-tetrazol-5-yl-ethyl) -3-naphthalin-2ylsulfonylamino-succinic acid t-butyl ester (Example 36Ac) [2 - [(S) ethyl ester -3- [cyclopropyl-2- (tetrazol-5-yl) -ethyl-carbamoyl] -3- (naphthalen-2ylsulfonylamino) -propionylaminomethyl] -morpholin-4-yl] imino-methylcarbamic acid, (1: 1) epimeric mixture , MS (ISP): 671.6 (M + H) < + >.

b) iz etil estra N-[3-(t-butoksikarbonil)-N-(2-naftilsulfonil)-L-alanil]-N-ciklopropil-j3alanina (Primer 2.B)j)9) etil ester 3-[[(S)-3-[4-etoksikarbonilamino-imino-metil)morfolin-2-ilmetiIkarbamoil]2-(naftalen-2-ilsulfonilamino)-propionil]-ciklopropil]-amino]-propionske kisline ali tavtomer amino skupine, (1:1) epimerna zmes, MS (ISP): 673.5 (M - H)’.b) N- [3- (t-Butoxycarbonyl) -N- (2-naphthylsulfonyl) -L-alanyl] -N-cyclopropyl-3 -alanine ethyl ester (Example 2.B) j) 9) ethyl ester 3 - [[ (S) -3- [4-Ethoxycarbonylamino-imino-methyl) morpholin-2-ylmethylcarbamoyl] 2- (naphthalen-2-ylsulfonylamino) -propionyl] -cyclopropyl] -amino] -propionic acid or an amino group tautomer, (1: 1) epimer mixture, MS (ISP): 673.5 (M-H) '.

Primer 52Example 52

Analogno Primeru 48 dobimo iz t-butil estra (S)-N-ciklopropil-N-(2-tetrazol-5-iletil)-3-naftalin-2-ilsulfonilamino-sukcinamske kisline (Primer 36Ac) in naslednjih derivatov aminometil-piperidina ustrezne produkte:Analogous to Example 48 was obtained from (S) -N-cyclopropyl-N- (2-tetrazol-5-ylethyl) -3-naphthalin-2-ylsulfonylamino-succinic acid t-butyl ester (Example 36Ac) and the following aminomethyl-piperidine derivatives of the corresponding products:

a) iz etil ester hidroklorida (S)-(3-aminometil-piperidin-l-il)-imino-metilkarbaminske kisline (Primer 48d) etil ester [(S)-3-[(S)-3-[ciklopropil-2-(tetrazol-5-il)-etil-karbamoil]-3-(naftalen-2ilsulfonilamino)-propionilaminometil]-piperidin-l-il]-imino-metilkarbaminske kisline, MS (ISP): 669.6 (M + H) + .a) (S) - (3-Aminomethyl-piperidin-1-yl) -imino-methylcarbamic acid ethyl ester hydrochloride (Example 48d) [(S) -3 - [(S) -3- [cyclopropyl-2] ethyl ester - (tetrazol-5-yl) -ethyl-carbamoyl] -3- (naphthalen-2ylsulfonylamino) -propionylaminomethyl] -piperidin-1-yl] -imino-methylcarbamic acid, MS (ISP): 669.6 (M + H) +.

b) iz izobutil ester hidroklorida [(S)-(3-aminometil-piperidin-l-il]-iminometilkarbaminske kisline (1:1) (Primer 49) (S)-N(l)-ciklopropil-N(4)-[(S)-l-izobutoksikarbonilamino-imino-metil)-piperidin-3ilmetil]-2-(naftalen-2-ilsulfonilamino)-N(l)-[2-tetrazol-5-il)-etil]sukcinamid,b) [(S) - (3-Aminomethyl-piperidin-1-yl] -iminomethylcarbamic acid isobutyl ester hydrochloride (1: 1) (Example 49) (S) -N (1) -cyclopropyl-N (4) - [(S) -1-Isobutoxycarbonylamino-imino-methyl) -piperidin-3-ylmethyl] -2- (naphthalen-2-ylsulfonylamino) -N (1) - [2-tetrazol-5-yl) -ethyl] succinamide,

MS (ISP): 697.5 (M + H)+.MS (ISP): 697.5 (M + H) < + >.

Primer 53Example 53

Analogno Primeru 48 dobimo ob uporabi ustreznih arilsulfonil estrov namesto t-butil estra (S)-N-ciklopropil-N-etoksikarbonilm,etil-3-(naftalen-2-sulfonilamino)sukcinamske kisline naslednje produkte:Analogous to Example 48, the following products were obtained using the corresponding arylsulfonyl esters instead of (S) -N-cyclopropyl-N-ethoxycarbonyl, ethyl-3- (naphthalene-2-sulfonylamino) succinic acid t-butyl ester:

a) iz etil estra N-[3-(t-butoksikarbonil)-N-(2-naftilsulfonil)-L-alanil]-N-ciklopropil-/3alanina (Primer 2.B)j)9) etil ester 3-[[(S)-3-[(S)-l-(etoksikarbonilamino-imino-metil)-piperidin-3ilmetilkarbamoil]-2-(naftalen-2-ilsulfonilamino)-propionil]-ciklopropil-aminojpropionske kisline ali tavtomer amidino skupine, MS (ISP): 673.5 (M + H)+.a) N- [3- (t-Butoxycarbonyl) -N- (2-naphthylsulfonyl) -L-alanyl] -N-cyclopropyl- / 3 -alanine ethyl ester (Example 2.B) j) 9) ethyl ester 3- [ [(S) -3 - [(S) -1- (ethoxycarbonylamino-imino-methyl) -piperidin-3ylmethylcarbamoyl] -2- (naphthalen-2-ylsulfonylamino) -propionyl] -cyclopropyl-amino-propionic acid or tautomer of the amidino group, MS (ISP): 673.5 (M + H) < + >.

b) iz metil estra (S)-2-[2-terc-butoksikarbonil-l-[ciklopropil-(2-etoksikarboniletil)karbamoil]-etilsulfamoil]-benzojske kisline (Primer 38Bb) etil ester 3-[[(S)-3-[(S)-l-(etoksikarbonilamino-imino-metil)-piperidin-3ilmetilkarbamoil]-2-(2-metoksikarbonil-fenilsulfonilamino)-propionil]-ciklopropilaminoj-propionske kisline ali tavtomer amidino skupine, MS (ISP): 681.5 (M + H) +b) from (S) -2- [2-tert-butoxycarbonyl-1- [cyclopropyl- (2-ethoxycarbonylethyl) carbamoyl] -ethylsulfamoyl] -benzoic acid methyl ester (Example 38Bb) 3 - [[(S) - ethyl ester; 3 - [(S) -1- (ethoxycarbonylamino-imino-methyl) -piperidin-3-ylmethylcarbamoyl] -2- (2-methoxycarbonyl-phenylsulfonylamino) -propionyl] -cyclopropylamino-propionic acid or tautomer of the amidino group, MS (ISP): 681.5 (M + H) < + >.

Primer 54Example 54

Analogno Primeru 3, vendar ob uporabi ustreznih estrov, dobimo:Analogous to Example 3, but using the appropriate esters, we get:

54a) iz estra Primera 5 lb)54a) from Example 5 ester ester)

3-[[(S)-3-[4-(etoksikarbonilamino-imino-metil)morfolin-2-ilmetilkarbamoil]-2(naftalen-2-ilsulfonilamino)-propionil]-ciklopropil]-amino]-propionsko kislino ali tavtomer amidino skupine, (l:l)-epimerna zmes, MS (ISN): 645.2 (M - H)'.3 - [[(S) -3- [4- (ethoxycarbonylamino-imino-methyl) morpholin-2-ylmethylcarbamoyl] -2 (naphthalen-2-ylsulfonylamino) -propionyl] -cyclopropyl] -amino] -propionic acid or tautomer amidino groups, (l: 1) -Epimer mixture, MS (ISN): 645.2 (M-H) '.

54b) iz estra Primera 53b)54b) from the ester of Example 53b)

54b)l. 2-[(S)-l-[(2-karboksi-etil)-ciklopropil-karbamoil]-2-[(S)-l-(etoksikarbonilamino-imino-metil)-piperidin-3-ilmetilkarbamoil]-etilsulfamoil]-benzojsko kislino ali tavtomer amidino skupine, MS (ISP): 639.5 (M + H)+ in54b) l. 2 - [(S) -1 - [(2-carboxy-ethyl) -cyclopropyl-carbamoyl] -2 - [(S) -1- (ethoxycarbonylamino-imino-methyl) -piperidin-3-ylmethylcarbamoyl] -ethylsulfamoyl] - benzoic acid or tautomer of the amidino group, MS (ISP): 639.5 (M + H) + and

54b)2. 2-[(S)-l-[(2-etoksikarbonil-etil)-ciklopropil-karbamoil]-2-[(S)-l(etoksikarbonilamino-imino-metil)-piperidin-3-ilmetilkarbamoil]-etilsulfamoil]benzojsko kislino ali tavtomer amidino skupine, MS (ISP): 667.6 (M + H) + Primer 5554b) 2. 2 - [(S) -1 - [(2-ethoxycarbonyl-ethyl) -cyclopropyl-carbamoyl] -2 - [(S) -1 (ethoxycarbonylamino-imino-methyl) -piperidin-3-ylmethylcarbamoyl] -ethylsulfamoyl] -benzoic acid or tautomer of the amidino group, MS (ISP): 667.6 (M + H) + Example 55

Analogno Primeru 29 pripravimo prekoAnalogously to Example 29 we prepare via

a) ciklopropilamida benziloksikarbonilamino-ocetne kisline, MS(EI): 248 (M)a) Benzyloxycarbonylamino-acetic acid cyclopropylamide, MS (EI): 248 (M)

b) benzil ester hidroklorid 2-ciklopropilamino-etilkarbaminske kisline (1:1), MS(EI); 234(M)b) 2-cyclopropylamino-ethylcarbamic acid benzyl ester hydrochloride (1: 1), MS (EI); 234 (M)

c) t-butil ester hidroklorida (S)-3-[(S)-3-[(2-amino-etil)-ciklopropil-karbamoil]-3(naftalen-2-ilsulfonilamino)-propionilaminometil]-piperidin-l-karboksilne kisline (1:1)inc) (S) -3 - [(S) -3 - [(2-amino-ethyl) -cyclopropyl-carbamoyl] -3 (naphthalen-2-ylsulfonylamino) -propionylaminomethyl] -piperidine-1- carboxylic acids (1: 1) and

d) t-butil estra (S)-3-[(S)-3-[ciklopropil-(2-pirazin-2-ilkarbonilamino-etil)karbamoil]-3-(naftalen-2-ilsulfonilamino)-propionilaminometil]-piperidin-lkarboksilne kisline, MS (ISP): 708.8 (M + H).d) (S) -3 - [(S) -3- [cyclopropyl- (2-pyrazin-2-ylcarbonylamino-ethyl) carbamoyl] -3- (naphthalen-2-ylsulfonylamino) -propionylaminomethyl] -piperidine t-butyl ester -1 Carboxylic acids, MS (ISP): 708.8 (M + H).

(S)-N4-[(S)-l-(amino-imino-metiI)-piperidin-3-ilmetil]-N l-ciklopropil-2-(naftalen-2 ilsulfonilamino)-Nl-[2-(pirazin-2-ilkarbonil-amino)-etil] sukcinamid-acetat,(S) -N4 - [(S) -1- (amino-imino-methyl) -piperidin-3-ylmethyl] -N 1-cyclopropyl-2- (naphthalen-2-ylsulfonylamino) -N1- [2- (pyrazine- 2-ylcarbonyl-amino) -ethyl] succinamide-acetate,

MS (ISP): 650.7 (M + H).MS (ISP): 650.7 (M + H).

Priprava izhodnega materialaPreparation of starting material

a) K 24 g N-benziloksikarbonil-glicina in 8 ml ciklopropilamina v 240 ml metilenklorida, dodamo ob mešanju 23.1 g N-(3-dimetilaminopropil)-N’-etilkarbodiimid hidroklorida (EDC) in mešamo 4 ure pri sobni temperaturi. Zmes prevzamemo v etru in izperemo z IN solno kislino, z raztopino natrijevega hidrogen karbonata in vodo. Po sušenju in uparjenju etrne faze dobimo 23 g ciklopropilamida benziloksikarbonilamino-ocetne kisline.a) To 24 g of N-benzyloxycarbonyl-glycine and 8 ml of cyclopropylamine in 240 ml of methylene chloride, 23.1 g of N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (EDC) were added while stirring and stirred for 4 hours at room temperature. The mixture was taken up in ether and washed with 1N hydrochloric acid, sodium hydrogen carbonate solution and water. After drying and evaporating the ether phase, 23 g of benzyloxycarbonylamino-acetic acid cyclopropylamide are obtained.

b) K 23 g produkta iz a) v 250 ml tetrahidrofurana pri 10 do 23 °C dokapavamo 17.6 ml boran-dimetilsulfida. Zmes segrevamo ob refluksu, nato pa ohladimo na -10 °C. Ob hlajenju z ledom dokapavamo 75 ml 2N solne kisline in prevzamemo zmes pri sobni temperaturi v etru. Etrno fazo izperemo z vodo. Vodne faze ponovno naalkalimo z 90 ml 2N natrijevega luga in ekstrahiramo z etrom. Etrne faze izperemo z vodo, nato pa jih nakisamo (pH 2) z 2N solno kislino (v dioksanu) in jih uparimo. Ostanek naplavimo v etru in filtriramo. Dobimo lig benzil ester hidroklorida 2ciklopropilaminoetilkarbaminske kisline.b) 17.6 ml of boron-dimethyl sulfide are added dropwise to 23 g of the product from a) in 250 ml of tetrahydrofuran at 10 to 23 ° C. The mixture was heated at reflux and then cooled to -10 ° C. Under ice-cooling, 75 ml of 2N hydrochloric acid are added dropwise and the mixture is taken up at room temperature in ether. The ether phase is washed with water. The aqueous phases were re-basified with 90 ml of 2N sodium hydroxide solution and extracted with ether. The ether phases were washed with water, then acidified (pH 2) with 2N hydrochloric acid (in dioxane) and evaporated. The residue was taken up in ether and filtered. The 2-cyclopropylaminoethylcarbamic acid lig benzyl ester of hydrochloride is obtained.

c) Analogno Primeru 29b)c)d)e) dobimo t-butil ester hidroklorid (S)-3-[(S)-3-[(2amino-etil)-ciklopropil-karbamoil]-3-(naftalen-2-ilsulfonilamino)-propionilaminometil]-piperidin-l-karboksilne kislinec) Analogous to Example 29b) c) d) e) t-butyl ester hydrochloride (S) -3 - [(S) -3 - [(2 amino-ethyl) -cyclopropyl-carbamoyl] -3- (naphthalene-2- ilsulfonylamino) -propionylaminomethyl] -piperidine-1-carboxylic acid

d) K 400 mg amin hidroklorida iz c) in 0.11 ml Hunigove baze v 4 ml metilenklorida dodamo 94 mg pirazinkarboksilne kisline in 127 mg EDC. Zmes mešamo 20 ur pri sobni temperaturi in jo nato prevzamemo v ocetestru. Ocetestrno fazo izperemo z vodo. Po sušenju in uparjenju kromatografiramo surovi produkt preko kremeničnega gela z ocetestrom/metanolom (9:1). Dobimo 288 mg t-butil estra (S)-3-[(S)-3[ciklopropil-(2-pirazin-2-ilkarbonilamino-etil)-karbamoil]-3-(naftalen-2ilsulfonilamino)-propionil-aminometil]-piperidin-1 -karboksilne kisline.d) To 400 mg of amine hydrochloride from c) and 0.11 ml of Hunig's base in 4 ml of methylene chloride add 94 mg of pyrazinecarboxylic acid and 127 mg of EDC. The mixture was stirred for 20 hours at room temperature and then taken up in acetone. The acetic ester phase is washed with water. After drying and evaporation, the crude product is chromatographed over silica gel with acetone / methanol (9: 1). (S) -3 - [(S) -3 [cyclopropyl- (2-pyrazin-2-ylcarbonylamino-ethyl) -carbamoyl] -3- (naphthalen-2ylsulfonylamino) -propionyl-aminomethyl] - 288 mg are obtained - piperidine-1-carboxylic acids.

Primer 56Example 56

Analogno Primeru 55, le ob uporabi ustreznih kislin ali kislinskih derivatov namesto pri Primeru 55d) uporabljene pirazinkarboksilne kisline, namreč ob uporabi a) monometil ester klorida oksalne kisline, b) kompleksa SO3, N(CH3)3,Analogous to Example 55, only using the appropriate acids or acid derivatives instead of Example 55d) of the pyrazinecarboxylic acid used, namely using a) oxalic acid chloride ester, b) SO3, N (CH3) 3 complex,

c) benzilkloroformiata, d) klorocetne kisline, e) klorida fenoksiocetne kisline, f) fenilglioksilne kisline, g) pirogrozdove kisline, h) nikotinske kisline, i) N-oksida nikotinske kisline oz. j) 3,4-dihidroksifenilocetne kisline, dobimo naslednje spojine:c) benzyl chloroformate, d) chloroacetic acid, e) phenoxyacetic acid chloride, f) phenylglyloxylic acid, g) pyrogrotic acid, h) nicotinic acid, i) nicotinic acid N-oxide, respectively. j) 3,4-Dihydroxyphenylacetic acid, the following compounds are obtained:

a) metil ester acetat N-[2-[[(S)-3-[(S)-l-(amino-imino-metil)-piperidin-3-ilmetilkarbamoil]-2-(naftalen-2-ilsulfonilamino)-propionil]-ciklopropil-amino]-etil]oksamske kisline (1:1), MS (ISP): 630.5 (M + H)a) N- [2 - [[(S) -3 - [(S) -1- (amino-imino-methyl) -piperidin-3-ylmethylcarbamoyl] -2- (naphthalen-2-ylsulfonylamino) methyl ester - propionyl] -cyclopropyl-amino] -ethyl] oxamic acid (1: 1), MS (ISP): 630.5 (M + H)

b) 2-[[(S)-3-[(S)-l-(amino-imino-metil)-piperidin-3-ilmetilkarbamoil]-2-(naftalen-2ilsulfonilamino)-propionil]-ciklopropil-amino]-etil]-sulfaminsko kislino,b) 2 - [[(S) -3 - [(S) -1- (amino-imino-methyl) -piperidin-3-ylmethylcarbamoyl] -2- (naphthalen-2ylsulfonylamino) -propionyl] -cyclopropyl-amino] - ethyl] -sulfamic acid,

MS (ISP): 624.5 (M + H)MS (ISP): 624.5 (M + H)

c) benzil ester acetat 2-[[(S)-3-[(S)-l-(amino-imino-metil)-piperidin-3ilmetilkarbamoil]-2-(naftalen-2-ilsulfonilamino)-propionil]-ciklopropil-amino]-etil]karbaminke kisline (1:1), MS (ISP): 678.5 (M + H)c) Benzyl ester acetate 2 - [[(S) -3 - [(S) -1- (amino-imino-methyl) -piperidin-3-ylmethylcarbamoyl] -2- (naphthalen-2-ylsulfonylamino) -propionyl] -cyclopropyl- amino] -ethyl] carbamic acid (1: 1), MS (ISP): 678.5 (M + H)

d) (S)-N4-[(S)-l-(amino-imino-metil)-piperidin-3-ilmetil]-N l-(2-kloroacetilaminoetil)-Nl-ciklopropil-2-(naftalen2-ilsulfinilamino)-sukcinamid acetat (1:1),d) (S) -N4 - [(S) -1- (amino-imino-methyl) -piperidin-3-ylmethyl] -N 1- (2-chloroacetylaminoethyl) -Nl-cyclopropyl-2- (naphthalen2-ylsulfinylamino) -succinamide acetate (1: 1),

MS (ISP): 620.4 (M + H)MS (ISP): 620.3 (M + H)

e) (S)-N4-[(S)-l-(amino-imino-metil)-piperidin-3-ilmetil]-Nl-ciklopropil-2-(naftalen 2-ilsulfmilamino)-Nl-(2-fenoksiacetilamino-etil)-sukcinamid acetat (1:1),e) (S) -N4 - [(S) -1- (amino-imino-methyl) -piperidin-3-ylmethyl] -N1-cyclopropyl-2- (naphthalen 2-ylsulfinylamino) -Nl- (2-phenoxyacetylamino- ethyl) -succinamide acetate (1: 1),

MS (ISP): 678.6 (M + H)MS (ISP): 678.6 (M + H)

f) (S)-N4-[(S)-l-(amino-imino-metil)-piperidin-3-ilmetil]-Nl-ciklopropil-2-(naftalen2-ilsulfinilamino)-Nl-[2-(2-okso-2-fenil-acetilamino-etil]-sukcinamid acetat (1:2),f) (S) -N4 - [(S) -1- (amino-imino-methyl) -piperidin-3-ylmethyl] -N1-cyclopropyl-2- (naphthalen2-ylsulfinylamino) -Nl- [2- (2- oxo-2-phenyl-acetylamino-ethyl] -succinamide acetate (1: 2),

MS (ISP): 676.6 (M + H)MS (ISP): 676.6 (M + H)

g) (S)-N4-[(S)-l-(amino-imino-metil)-piperidin-3-ilmetil]-Nl-ciklopropil-2-(naftalen 2-ilsulfinilamino)-N l-[2-(2-okso-propionilamino)-etil]-sukcinamid acetat (1:1),g) (S) -N4 - [(S) -1- (amino-imino-methyl) -piperidin-3-ylmethyl] -N1-cyclopropyl-2- (naphthalen 2-ylsulfinylamino) -N 1- [2- ( 2-oxo-propionylamino) -ethyl] -succinamide acetate (1: 1),

MS (ISP): 614.6 (M + H)MS (ISP): 614.6 (M + H)

h) (S)-N4-[(S)-l-(amino-imino-metil)-piperidin-3-ilmetil]-Nl-ciklopropil-2-(naftalen 2-ilsulfmilamino)-Nl-[2-(piridin-3-ilkarbonilamino)-etil]-sukcinamid acetat (1:2),h) (S) -N4 - [(S) -1- (amino-imino-methyl) -piperidin-3-ylmethyl] -Nl-cyclopropyl-2- (naphthalen 2-ylsulfinylamino) -Nl- [2- (pyridine) -3-ylcarbonylamino) -ethyl] -succinamide acetate (1: 2),

MS (ISP); 649.1 (M + H)MS (ISP); 649.1 (M + H)

i) (S)-N4-[(S)-l-(amino-imino-metil)-piperidin-3-ilmetil]-Nl-ciklopropil-2-naftalen2-ilsulfonilamino-Nl-[2-(l-oksi-nikotinoilamino)-etil]-sukcinamid acetat (1:1),i) (S) -N4 - [(S) -1- (amino-imino-methyl) -piperidin-3-ylmethyl] -N1-cyclopropyl-2-naphthalen2-ylsulfonylamino-N1- [2- (1-oxy- nicotinoylamino) -ethyl] -succinamide acetate (1: 1),

MS (ISP): 666.5 (M + H)MS (ISP): 666.5 (M + H)

j) (S)-N4-[(S)-l-(amino-imino-metil)-piperidin-3-ilmetil]-Nl-ciklopropil-Nl-[2-(3,4dihidroksi-fenilacetilamino)-etil]-2-(naftalen-2-ilsulfinilamino)-sukcinamid acetat (1:1), MS (ISP): 694.6 (M + H).j) (S) -N4 - [(S) -1- (amino-imino-methyl) -piperidin-3-ylmethyl] -N1-cyclopropyl-N1- [2- (3,4-dihydroxy-phenylacetylamino) -ethyl] - 2- (Naphthalen-2-ylsulfinylamino) -succinamide acetate (1: 1), MS (ISP): 694.6 (M + H).

Primer 57Example 57

Analogno Primeru 3 dobimo iz estra Primera 56a) naslednjo kislino:Analogous to Example 3, the following acid is obtained from the ester of Example 56a):

N-[2-[[(S)-3-[(S)-l-(amino-imino-metil)-piperidin-3-ilmetilkarbamoil]-2-(naftalen-2ilsulfonilamino)-propionil]-ciklopropil-amino]-etil]-oksamsko kislino,N- [2 - [[(S) -3 - [(S) -1- (amino-imino-methyl) -piperidin-3-ylmethylcarbamoyl] -2- (naphthalen-2ylsulfonylamino) -propionyl] -cyclopropyl-amino] -ethyl] -oxamic acid,

MS (ISP): 616.5 (M + H).MS (ISP): 616.5 (M + H).

Primer 58Example 58

Analogno Primeroma 29 in 55, le ob uporabi metil ester hidroklorida [(S)-3-aminometil-piperidin-l-ilj-imino-metilkarbaminske kisline (1:2) namesto t-butil estra (S)-3-aminometil-l-piperidinkarboksilne kisline (Primer 29d), dobimo:Analogous to Examples 29 and 55, only using [(S) -3-aminomethyl-piperidin-1-yl-imino-methylcarbamic acid methyl ester hydrochloride (1: 2) instead of (S) -3-aminomethyl-1-t-butyl ester -piperidinecarboxylic acid (Example 29d), yields:

metil ester (S)-3-[(S)-3-[2-kloracetilamino-etil]-ciklopropil-karbamoil]-2-(naftalen-2ilsulfonilamino)-propionilaminometil]-piperidin-l-il]-imino-metilkarbaminske kisline, MS (ISP): 648.4 (M + H).(S) -3 - [(S) -3- [2-Chloroacetylamino-ethyl] -cyclopropyl-carbamoyl] -2- (naphthalen-2ylsulfonylamino) -propionylaminomethyl] -piperidin-1-yl] -imino-methylcarbamic acid methyl ester , MS (ISP): 648.4 (M + H).

Priprava izhodnega materiala:Preparation of starting material:

Analogno Primeru 48, vendar ob uporabi metil estra klormravljinčne kisline namesto etil estra klormravljinčne kislline (Primer 48c) dobimo metil ester hidroklorid [(S)-3-aminometil-piperidin-l-il]-imino-metilkarbaminske kisline (1:2),Analogous to Example 48, but using hydrochloric acid methyl ester instead of hydrochloric acid ethyl ester (Example 48c) gave the [(S) -3-aminomethyl-piperidin-1-yl] -imino-methylcarbamic acid methyl ester hydrochloride (1: 2).

MS (termo spray): 215 (M + H).MS (thermo spray): 215 (M + H).

Primer 59Example 59

Analogno Primeru 58 pripravimo naslednje spojine:The following compounds were prepared analogously to Example 58:

a) metil ester N-[2-[ciklopropil-[(S)-3-[(S)-l-(imino-metoksikarbonilamino-metil)piperidin-3-ilmetilkarbamoil]-2-(naftalen-2-ilsulfonilamino)-propionil]-amino]-etil]oksamske kisline, MS (ISP): 702.6 (M + H).a) N- [2- [cyclopropyl - [(S) -3 - [(S) -1- (imino-methoxycarbonylamino-methyl) piperidin-3-ylmethylcarbamoyl] -2- (naphthalen-2-ylsulfonylamino) methyl ester - propionyl] -amino] -ethyl] oxamic acid, MS (ISP): 702.6 (M + H).

b) benzil ester [2-[ciklopropil-[(S)-3-[(S)-l-(metoksikarbonilamino-imino-metil)piperidin-3-ilmetilkarbamoil]-2-(naftalen-2-ilsulfonilamino)-propionil]-amino]etilkarbaminske kisline, MS (ISP): 736.7 (M + H).b) [2- [cyclopropyl - [(S) -3 - [(S) -1- (methoxycarbonylamino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -2- (naphthalen-2-ylsulfonylamino) -propionyl] benzyl ester] -Amino] ethylcarbamic acid, MS (ISP): 736.7 (M + H).

c) metil ester [(S)-3-[(S)-3-[ciklopropil-(2-metilsulfonilamino-etil)-karbamoil]-3(naftalen-2-ilsulfonilamino)-propionilaminometil]-piperidin-l-iI]-iminometilkarbaminske kisline, MS (ISP): 680.5 (M + H).c) [(S) -3 - [(S) -3- [cyclopropyl- (2-methylsulfonylamino-ethyl) -carbamoyl] -3 (naphthalen-2-ylsulfonylamino) -propionylaminomethyl] -piperidin-1-yl] methyl ester] -iminomethylcarbamic acid, MS (ISP): 680.5 (M + H).

Primer 60Example 60

Analogno Primeru 29, le ob uporabi N-cikJopropilglicin-etil estra namesto 2-butilaminoetilazid-hidroklorida (v Primeru 29b), dobimo preko [[(S)-3-[(S)-l-terc-butoksikarbonil-piperidin-3-ilmetilkarbamoil]-2-(naftalen-2sulfonilaminoj-propionilj-ciklopropil-aminoj ocetne kisline in t-butil estra [(S)-3-[(S)-3-(ciklopropil-metoksikarbamoilmetil-karbamoil)-3(naftalen-2-sulfonilamino)-propionilaminometil]-piperidin-l-karboksilne kisline, (S)-N4-[(S)-l-(amino-imino-metiI)-piperidin-3-ilmetil]-Nl-ciklopropil-Nlmetoksikarbamoilmetil-2-(naftalen-2-sulfonilamino)-sukcinamid acetat (1:1),Analogous to Example 29, only using N-cyclopropylglycine-ethyl ester instead of 2-butylaminoethylethyl azide hydrochloride (in Example 29b) is obtained via [[(S) -3 - [(S) -1-tert-butoxycarbonyl-piperidine-3- ylmethylcarbamoyl] -2- (naphthalene-2-sulfonylamino-propionyl-cyclopropyl-amino acetic acid and t-butyl ester [(S) -3 - [(S) -3- (cyclopropyl-methoxycarbamoylmethyl-carbamoyl) -3 (naphthalene-2- sulfonylamino) -propionylaminomethyl] -piperidine-1-carboxylic acid, (S) -N4 - [(S) -1- (amino-imino-methyl) -piperidin-3-ylmethyl] -Nl-cyclopropyl-N-methoxycarbamoylmethyl-2- ( naphthalene-2-sulfonylamino) -succinamide acetate (1: 1),

MS (ISP): 588.6 (M + H).MS (ISP): 588.6 (M + H).

Priprava izhodnega materiala:Preparation of starting material:

500 mg [[(S)-3-[(S)-l-terc-butoksikarboniI-piperidin-3-ilmetilkarbamoil]-2-(naftalen 2-sulfonilamino)-propionil]-ciklopropil-amino] ocetne kisline umešamo skupaj z 71 mg O-metilhidroksilamin-hidroklorida, 0.28 ml N-metilmorfolina in 376 mg BOP v 10 ml metilenklorida, mešamo 20 ur pri sobni temperaturi. Zmes prevzamemo v ocetestru, izperemo z IN solno kislino in nato z vodo. Po sušenju in uparjenju očistimo produkt preko kremeničnega gela z ocetestrom/metanolom (9:1). Dobimo 282 mg t-butil estra [(S)-3-[(S)-3-(ciklopropil-metoksikarbamoilmetil-karbamoil)-3(naftalen-2-ilsulfonilamino)-propionilaminometil]-piperidin-l-karboksilne kisline, MS (ISP): 646.6 (M + H).500 mg of 71 mg of [[[(S) -3 - [(S) -1-tert-butoxycarbonyl-piperidin-3-ylmethylcarbamoyl] -2- (naphthalene 2-sulfonylamino) -propionyl] -cyclopropyl-amino] acetic acid mg of O-methylhydroxylamine hydrochloride, 0.28 ml of N-methylmorpholine and 376 mg of BOP in 10 ml of methylene chloride were stirred for 20 hours at room temperature. The mixture was taken up in acetone, washed with 1N hydrochloric acid and then with water. After drying and evaporation, the product was purified over silica gel with acetic acid / methanol (9: 1). 282 mg of [(S) -3 - [(S) -3- (cyclopropyl-methoxycarbamoylmethyl-carbamoyl) -3 (naphthalen-2-ylsulfonylamino) -propionylaminomethyl] -piperidine-1-carboxylic acid t-butyl ester, MS is obtained (MS ( ISP): 646.6 (M + H).

Primer 61Example 61

Analogno Primeroma 29 in 60 dobimo naslednje spojine:Analogously to Examples 29 and 60, the following compounds are obtained:

a) (S)-N4-[(S)-l-(amino-imino-metil)-piperidin-3-ilmetil]-Nl-benzil-oksikarbamoilmetil-Nl-ciklopropil-2-(naftalen-2-ilsulfinilamino)-sukcinamid acetat (1:1),a) (S) -N4 - [(S) -1- (amino-imino-methyl) -piperidin-3-ylmethyl] -N1-benzyl-oxycarbamoylmethyl-N1-cyclopropyl-2- (naphthalen-2-ylsulfinylamino) - succinamide acetate (1: 1),

MS (ISP): 664.5 (M + H)MS (ISP): 664.5 (M + H)

b) (S)-N4-[(S)-l-(amino-imino-metil)-piperidin-3-il-metil]-N 1-ciklopropil-N 1-metilsulfonilkarbamoilmetil-2-(naftalen-2-ilsulfinilamino)-sukcinamid acetat (1:1),b) (S) -N4 - [(S) -1- (amino-imino-methyl) -piperidin-3-yl-methyl] -N 1-cyclopropyl-N 1-methylsulfonylcarbamoylmethyl-2- (naphthalen-2-ylsulfinylamino ) -succinamide acetate (1: 1),

MS (ISP): 636.5 (M + H)MS (ISP): 636.5 (M + H)

c) (S)-N4-[(S)-l-(amino-imino-metil)-piperidin-3-ilmetil]-N 1 -ciklopropii-N 1 ciklopropilkarbamoilmetil-2-(naftalen-2-iIsulfinilamino)-sukcinamid acetat (1:1),c) (S) -N4 - [(S) -1- (amino-imino-methyl) -piperidin-3-ylmethyl] -N 1 -cyclopropyl-N 1 cyclopropylcarbamoylmethyl-2- (naphthalen-2-ylsulfinylamino) -succinamide acetate (1: 1),

MS (ISP): 598.6 (M + H)MS (ISP): 598.6 (M + H)

d) (S)-N4-[(S)-l-(amino-imino-metil)-piperidin-3-il-metil]-Nl-ciklopropil-2(naftalen-2-ilsulfinilamino)-Nl-(piridin-3-ilmetilkarbamoil-metil)-sukcinamid acetat (1:2), MS (ISP): 649.5 (M + H)d) (S) -N4 - [(S) -1- (amino-imino-methyl) -piperidin-3-yl-methyl] -Nl-cyclopropyl-2 (naphthalen-2-ylsulfinylamino) -Nl- (pyridine- 3-ylmethylcarbamoyl-methyl) -succinamide acetate (1: 2), MS (ISP): 649.5 (M + H)

e) (S)-N4-[(S)-l-(amino-imino-metil)-piperidin-3-il-metil]-N 1 -ciklopropil-Nl-[2-(3,4dihidroksi-fenil)etilkarbamoilmetil]-2-(naftalen-2-ilsulfonilamino)-sukcinamid acetat (1:2), MS (ISP): 694.5 (M + H)e) (S) -N4 - [(S) -1- (amino-imino-methyl) -piperidin-3-yl-methyl] -N 1 -cyclopropyl-N1- [2- (3,4-dihydroxy-phenyl) ethylcarbamoylmethyl ] -2- (Naphthalen-2-ylsulfonylamino) -succinamide acetate (1: 2), MS (ISP): 694.5 (M + H)

f) (S)-N4-[(S)-l-(amino-imino-metil)-piperidin-3-il]-Nl-ciklopropil-Nl-(2-hidroksietilkarbamoilmetil)-2-(naftalen-2-ilsulfinilamino)-sukcinamid acetat (1:1),f) (S) -N4 - [(S) -1- (amino-imino-methyl) -piperidin-3-yl] -N1-cyclopropyl-N1- (2-hydroxyethylcarbamoylmethyl) -2- (naphthalen-2-ylsulfinylamino) ) -succinamide acetate (1: 1),

MS (ISP): 602.2 (M + H).MS (ISP): 602.2 (M + H).

Primer 62Example 62

2.0 g (S)-N-(3-benziloksi-propil)-N-ciklopropil-3-naftalen-2-ilsulfonilaminosukcinamske kisline in 1.35 g metil ester hidroklorida [(S)-3-aminometil-piperidin-lil]-imino-metilkarbaminske kisline (1:2) (Primer 58) mešamo pri sobni temperaturi z 1.91 g BOP in 2.34 ml l,8-diazabiciklo(5.4.0)undec-7-ena (DBU) v 20 ml metilenklorida. Po uparjenju in kromatografiji preko kremeničnega gela z ocetestrom/metanolom (19:1) dobimo 2.35 g metil estra [(S)-3-[(S)-3-[(3-benziloksi-propil)67 ciklopropil-karbamoil]-3-(naftalen-2-ilsulfonilamino)-propionilaminometil]piperidin-l-il]-imino-rnetilkarbaminske kisline.2.0 g (S) -N- (3-benzyloxy-propyl) -N-cyclopropyl-3-naphthalen-2-ylsulfonylaminosuccinic acid and 1.35 g methyl ester hydrochloride [(S) -3-aminomethyl-piperidin-lyl] -imino- methylcarbamic acid (1: 2) (Example 58) was stirred at room temperature with 1.91 g of BOP and 2.34 ml of 1,8-diazabicyclo (5.4.0) undec-7-ene (DBU) in 20 ml of methylene chloride. Evaporation and chromatography over silica gel with acetone / methanol (19: 1) gave 2.35 g of methyl [(S) -3 - [(S) -3 - [(3-benzyloxy-propyl) 67 cyclopropyl-carbamoyl] -3 methyl ester - (Naphthalen-2-ylsulfonylamino) -propionylaminomethyl] piperidin-1-yl] -imino-phenylcarbamic acid.

Priprava izhodnega materiala:Preparation of starting material:

a) 8.58 g N-BOC-ciklopropilamina in 15 g O-benzil-3-brom-l-propanola v 90 ml dimetilformamida pri 0 do 5 °C dodamo 2.5 g natrijevega hidrida (55% v olju). Zmes mešamo 1 uro pri 0 do 5 °C in 3 ure pri sobni temperaturi, nakar dodamo pri 0 do °C vodno raztopino amonijevega klorida. Zmes porazdelimo v etru/vodi, etrne faze izperemo z vodo, nato sušimo in uparimo. Po kromatografiji preko kremničnega gela z etrom/heksanom (1:4) mešamo 11.5 g produkta s 120 ml 4.8M solne kisline v dioksanu. Po uparjenju kristaliziramo ostanek v etru, filtriramo kristale in jih izperemo z etrom. Dobimo 9.0 g (3-benziloksi-propil)-ciklopropil-amin hidroklorida, MS (ΕΙ): 206 (M + H).a) 8.58 g of N-BOC-cyclopropylamine and 15 g of O-benzyl-3-bromo-1-propanol in 90 ml of dimethylformamide at 0 to 5 ° C were added 2.5 g of sodium hydride (55% in oil). The mixture was stirred for 1 hour at 0 to 5 ° C and for 3 hours at room temperature, then an aqueous solution of ammonium chloride was added at 0 to ° C. The mixture was partitioned in ether / water, the ether phases were washed with water, then dried and evaporated. After chromatography on silica gel with ether / hexane (1: 4), 11.5 g of the product is mixed with 120 ml of 4.8M hydrochloric acid in dioxane. After evaporation, the residue is crystallized in ether, the crystals are filtered off and washed with ether. 9.0 g (3-benzyloxy-propyl) -cyclopropyl-amine hydrochloride are obtained, MS (E +): 206 (M + H).

b) 9.0 g produkta iz a) in 11.77 g 4-t-butil estra N-(2-naftilsulfonil)-L-asparaginske kisline (Primer 23a) mešamo skupaj s 14.4 g BOP in 15.9 ml Hunigove baze v 200 ml metilenklorida. Zmes prevzamemo v etru, etrno fazo izperemo z IN solno kislino in nato z vodo. Po sušenju in uparjenju etrne faze kromatografiramo ostanek preko kremeničnega gela z ocetestrom/heksanom (1:2). Dobimo 14.85 g t-butil estra (S)-N(3-benziloksi-propil)-N-ciklopropil-3-naftalen-2-iIsulfonilamino-sukcinamske kisline, MS (ISN): 565.8 (M - H).b) 9.0 g of the product from a) and 11.77 g of N- (2-naphthylsulfonyl) -L-aspartic acid 4-t-butyl ester (Example 23a) were mixed together with 14.4 g of BOP and 15.9 ml of Hunig's base in 200 ml of methylene chloride. The mixture was taken up in ether, the ether phase was washed with 1N hydrochloric acid and then with water. After drying and evaporation of the ether phase, the residue is chromatographed over silica gel with acetone / hexane (1: 2). 14.85 g of (S) -N (3-benzyloxy-propyl) -N-cyclopropyl-3-naphthalen-2-ylsulfonylamino-succinic acid t-butyl ester is obtained, MS (ISN): 565.8 (M-H).

c) 14.85 g Produkta iz b) raztopimo v 60 ml dioksana in tej raztopini dodamo 120 ml 4.8M solne kisline v dioksanu. Zmes mešamo pri sobni temperaturi, jo prevzamemo v etru in izperemo z vodo. Po sušenju in uparjenju etrne faze dobimo 12.87 g (S)-N(3-benziloksi-propil)-N-ciklopropil-3-naftalen-2-ilsulfonil-amino-sukcinamske kisline, MS (ISN): 509.2 (M - H).c) 14.85 g of the product from b) is dissolved in 60 ml of dioxane and 120 ml of 4.8M hydrochloric acid in dioxane are added to this solution. The mixture was stirred at room temperature, taken up in ether and washed with water. Drying and evaporation of the ether phase gave 12.87 g of (S) -N (3-benzyloxy-propyl) -N-cyclopropyl-3-naphthalen-2-ylsulfonyl-amino-succinic acid, MS (ISN): 509.2 (M - H) .

Primer 63Example 63

970 mg metil estra [(S)-3-[(S)-3-[(3-benziloksi-propil)-ciklopropil-karbamoil]-3(naftalen-2-ilsulfonilamino)-propionilaminometil]-piperidin-l-il]-imino-mefilkarbaminske kisline raztopimo v 5 ml metilenklorida in dodamo raztopini 5 ml 0.6M raztopine borovega tribromida v metilenkloridu. Po 1.5 urah mešanja pri sobni temperaturi dodamo zmesi 20 ml nasičene raztopine natrijevega hidrogen karbonata. Zmes porazdelimo med ocetestrom in vodo. Po sušenju in uparjenju očistimo surovi produkt preko kremeničnega gela z ocetestrom/metanolom 9:1. Dobimo 465 mg čistega metil estra [(S)-3-[(S)-3-[ciklopropil-(3-hidroksi-propil)karbamoil]-2-(naftalen-2-ilsulfonilamino)-propionilaminometil]-piperidin-l-il]imino-metilkarbaminske kisline, MS (ISP): 617.7 (M + H).970 mg methyl [(S) -3 - [(S) -3 - [(3-benzyloxy-propyl) -cyclopropyl-carbamoyl] -3 (naphthalen-2-ylsulfonylamino) -propionylaminomethyl] -piperidin-1-yl] methyl ester] -imino-methyl-carbamic acid is dissolved in 5 ml of methylene chloride and 5 ml of 0.6M solution of boron tribromide in methylene chloride are added to the solution. After stirring at room temperature for 1.5 hours, a mixture of 20 ml of saturated sodium hydrogen carbonate solution was added to the mixture. The mixture is partitioned between acetone and water. After drying and evaporation, the crude product is purified over a silica gel with 9: 1 acetone / methanol. 465 mg of pure [(S) -3 - [(S) -3- [cyclopropyl- (3-hydroxy-propyl) carbamoyl] -2- (naphthalen-2-ylsulfonylamino) -propionylaminomethyl] -piperidine-1- il] imino-methylcarbamic acids, MS (ISP): 617.7 (M + H).

Primer 64Example 64

274 mg metil estra [(S)-3-[(S)-3-[ciklopropil-(3-hidroksi-propil)karbamoil]-2(naftalen-2-ilsulfonilamino)-propionilaminometil]-piperidin-l-il]-imino-metilkarbaminske kisline (Primer 63), 1 ml IN metiljodida v tetrahidrofuranu, 2 ml IM raztopine DBU v tetrahidrofuranu in 2 ml metilenklorida, mešamo skupaj pri sobni temperaturi. Zmes uparimo in kromatografiramo ostanek preko kremeničnega gela z ocetestrom/metanolom 9:1. Dobimo 120 mg (S)-Nl-ciklopropil-N4-[(S)-l-(iminometoksikarbonilamino-metil)-piperidin-3-ilmetil]Nl-(3-metoksipropil)-2-(naftalen-2ilsulfonilamino)-sukcinamida, MS (ISO): 631.6 (M + H).274 mg methyl [(S) -3 - [(S) -3- [cyclopropyl- (3-hydroxy-propyl) carbamoyl] -2 (naphthalen-2-ylsulfonylamino) -propionylaminomethyl] -piperidin-1-yl] - imino-methylcarbamic acid (Example 63), 1 ml of IN methyliodide in tetrahydrofuran, 2 ml of IM DBU solution in tetrahydrofuran and 2 ml of methylene chloride were stirred together at room temperature. The mixture was evaporated and chromatographed the residue over silica gel with 9: 1 acetone / methanol. 120 mg of (S) -Nl-cyclopropyl-N4 - [(S) -1- (iminomethoxycarbonylamino-methyl) -piperidin-3-ylmethyl] N1- (3-methoxypropyl) -2- (naphthalen-2ylsulfonylamino) -succinamide is obtained. MS (ISO): 631.6 (M + H).

Primer 65Example 65

Analogno Primeru 29, vendar ob uporabi a) difenil ester klorida fosforove kisline oz. b) dietil ester klorida fosforove kisline namesto monoetil ester klorida oksalne kisline (Primer 29f), dobimoAnalogous to Example 29, but using a) the diphenyl ester of phosphoric acid or. b) phosphoric acid chloride diethyl ester instead of oxalic acid monoethyl chloride ester (Example 29f)

a) difenil ester acetat 2-[[(S)-3-[(S)-1 -(amino-imino-metil)-piperidin-3-ilmetilkarbamoil]-2-(naftalen-2-sulfonilamino)-propionil]-butilamino]-etilamidofosforove kisline (1:1), MS (ISP): 792.4 (M + H),a) Diphenyl ester acetate 2 - [[(S) -3 - [(S) -1- (amino-imino-methyl) -piperidin-3-ylmethylcarbamoyl] -2- (naphthalene-2-sulfonylamino) -propionyl] - butylamino] -ethylamidophosphoric acid (1: 1), MS (ISP): 792.4 (M + H),

b) (S)-N4-[(S)-l-(amino-imino-metil)-piperidin-3-ilmetil]-N 1 -butil-Nl-(2dietoksifosforilamino-etil)-2-(naftalen-2-sulfonilamino)-sukcinamid acetat (1:1),b) (S) -N4 - [(S) -1- (amino-imino-methyl) -piperidin-3-ylmethyl] -N 1-butyl-N1- (2diethoxyphosphorylamino-ethyl) -2- (naphthalen-2- sulfonylamino) -succinamide acetate (1: 1),

MS (ISP): 696.2 (M + H).MS (ISP): 696.2 (M + H).

Primer 66Example 66

Analogno Primeru 48, vendar ob uporabi di-t-butil-dikarbonata namesto etil estra klormravljinčne kisline (v Primeru 48c), dobimo preko t-butil estra (S)-(3-benziloksikarbonilaminometil-piperidin-l-il)-imino-metilkarbaminske kisline, MS (termo spray): 391 (M + H)+ in preko t-butil estra (S)-(3-aminometil-piperidin-l-il)-imino-metilkarbaminske kisline,Analogous to Example 48, but using di-t-butyl dicarbonate instead of hydrochloric acid ethyl ester (in Example 48c), the (S) - (3-benzyloxycarbonylaminomethyl-piperidin-1-yl) -imino-methylcarbamic acid t-butyl ester is obtained. acids, MS (thermo spray): 391 (M + H) + and via (S) - (3-aminomethyl-piperidin-1-yl) -imino-methylcarbamic acid t-butyl ester,

MS (ISP): 257.2 (M + H)+ etil ester [[(S)-3-[(S)-l-(terc-butoksikarbonilamino-imino-metil)-piperidin-3-ilmetilkarbamoil]-2-(naftalen-2-ilsulfonilamino)-propionil]-ciklopropil-amino]-ocetne kisline, MS (ISP); 687.5 (M + H)+·MS (ISP): 257.2 (M + H) + ethyl ester [[[(S) -3 - [(S) -1- (tert-butoxycarbonylamino-imino-methyl) -piperidin-3-ylmethylcarbamoyl] -2- (naphthalene) -2-Ylsulfonylamino) -propionyl] -cyclopropyl-amino] -acetic acid, MS (ISP); 687.5 (M + H) + ·

Primer 67Example 67

Analogno Primeru 1, vendar ob uporabi [(4-aminometil-piperidin-l-il)-iminometiljamin-dihidroklorida namesto (S)-l-amidino-3-(aminometil)piperidindihidroklorida, pripravimo etil ester hidroklorid (S)-3-[[3-[l-(amino-imino-metil)piperidin-4-ilmetilkarbamoil]-2-(naftalen-2-ilsulfonilamino)-propionil]-cikloheksilaminoj-ocetne kisline, MS (ISP): 629.6 (M + H) ⁺ .Analogous to Example 1, but using [(4-aminomethyl-piperidin-1-yl) -iminomethylamine-dihydrochloride instead of (S) -1-amidino-3- (aminomethyl) piperidinedihydrochloride, ethyl ester hydrochloride (S) -3- [ [3- [1- (amino-imino-methyl) piperidin-4-ylmethylcarbamoyl] -2- (naphthalen-2-ylsulfonylamino) -propionyl] -cyclohexylamino-acetic acid, MS (ISP): 629.6 (M + H) ⁺ .

Priprava izhodnega materiala:Preparation of starting material:

a) Raztopini 130 g 1,1-dimetil etil estra (4-piperidinilmetil)-karbaminske kisline v 1300 ml dimetilformamida dodamo 138 ml trietilamina in 61.8 g formamidinsulfinske kisline in mešamo pri sobni temperaturi čez noč. Izločeni material odfiltriramo, naplavimo v 500 ml etanola, ponovno filtriramo in sušimo. Dobimo 65.6 g t-butil ester hemisulfita l-(amino-imino-metil)-piperidin-4-ilmetilkarbaminske kisline,a) To a solution of 130 g of 1,1-dimethyl ethyl ester (4-piperidinylmethyl) -carbamic acid in 1300 ml of dimethylformamide was added 138 ml of triethylamine and 61.8 g of formamidinsulfinic acid and stirred at room temperature overnight. The recovered material was filtered off, washed with 500 ml of ethanol, filtered again and dried. 65.6 g of 1- (amino-imino-methyl) -piperidin-4-ylmethylcarbamic acid t-butyl ester is obtained,

MS (ISP); 257.4 (M + H) + .MS (ISP); 257.4 (M + H) < + >.

b) 65.6 g pri a) dobljenega materiala raztopimo v 656 ml IN solne kisline in mešamo 5 ur pri 50 °C. Topilo uparimo, ostanek naplavimo v 500 ml etanola, odnučamo in sušimo. Dobimo 48.5 g [(4-aminometil-piperidin-l-il)-imino-metil]-amin dihidroklorida, MS (ISP): 573.5 (M + H) ⁺ .b) Dissolve 65.6 g of the material obtained in 656 ml of 1N hydrochloric acid and stir for 5 hours at 50 ° C. The solvent was evaporated, the residue was taken up in 500 ml of ethanol, drained and dried. 48.5 g of [(4-aminomethyl-piperidin-1-yl) -imino-methyl] -amine dihydrochloride are obtained, MS (ISP): 573.5 (M + H) ⁺ .

Primer 68Example 68

Analogno Primeru 67 pripravimo iz ustreznih t-butil estrov naslednje produkte:The following products were prepared analogously to Example 67 from the corresponding t-butyl esters:

68a) etil ester trifluoracetat [[(S)-3-[l-(amino-imino-metil)-piperidin-4-ilmetilkarbamoil]-2-(naftalen-2-ilsulfonilamino)-propionil]ciklopropil-amino]-ocetne kisline, MS (ISP): 587.8 (M + H)+.68a) [[(S) -3- [1- (amino-imino-methyl) -piperidin-4-ylmethylcarbamoyl] -2- (naphthalen-2-ylsulfonylamino) -propionyl] cyclopropyl-amino] -acetic acid ethyl ester , MS (ISP): 587.8 (M + H) < + >.

68b) etil ester hidroklorid [[(S)-3-[l-(amino-imino-metil)-piperidin-4-ilmetilkarbamoil]-2-(naftalen-2-ilsulfonilamino)-propionil]benzil-amino]-ocetne kisline, MS (ISP): 637.4 (M + H)+.68b) [[(S) -3- [1- (amino-imino-methyl) -piperidin-4-ylmethylcarbamoyl] -2- (naphthalen-2-ylsulfonylamino) -propionyl] benzyl-amino] -acetic acid ethyl ester hydrochloride , MS (ISP): 637.4 (M + H) < + >.

68c) etil ester hidroklorid [[(S)-3-[l-(amino-imino-metil)-piperidin-4-ilmetilkarbamoil]-2-(naftalen-2-ilsulfonilamino)-propionil]cikloheksilmetil-amino]- ocetne kisline, MS (ISP): 643.6 (M + H) +.68c) [[(S) -3- [1- (amino-imino-methyl) -piperidin-4-ylmethylcarbamoyl] -2- (naphthalen-2-ylsulfonylamino) -propionyl] cyclohexylmethyl-amino] -acetic acid ethyl ester hydrochloride , MS (ISP): 643.6 (M + H) < + >.

68d) etil ester hidroklorid [[(S)-3-[l-(amino-imino-metil)-piperidin-4-ilmetilkarbamoil]-2-(naftalen-2-ilsulfonilamino)-propionil]-butil-amino]- ocetne kisline (1:1), MS (ISP): 603.4 (M + H) + .68d) [[((S) -3- [1- (amino-imino-methyl) -piperidin-4-ylmethylcarbamoyl] -2- (naphthalen-2-ylsulfonylamino) -propionyl] -butyl-amino) -acetic acid ethyl ester acids (1: 1), MS (ISP): 603.4 (M + H) < + >.

68e) etil ester hidroklorid (S)-3-[[3-[l-(amino-imino-metil)-piperidin-4-ilmetilkarbamoil]-2-(naftalen-2-ilsulfonilamino)-propionil]ciklopropil-amino]-propionske kisline, MS (ISP): 601.6 (M + H) + .68e) Ethyl ester hydrochloride (S) -3 - [[3- [1- (amino-imino-methyl) -piperidin-4-ylmethylcarbamoyl] -2- (naphthalen-2-ylsulfonylamino) -propionyl] cyclopropyl-amino] - propionic acids, MS (ISP): 601.6 (M + H) +.

68f) etil ester heksafluorofosfat (S)-3-[[3-[l-(amino-imino-metil)-piperidin-4ilmetilkarbamoil]-2-(naftalen-2-ilsulfonilamino)-propionil]-benzil-aminojpropionske kisline (1:1), MS (ISP): 651.6 (M + H) + .68f) Hexafluorophosphate (S) -3 - [[3- [1- (amino-imino-methyl) -piperidin-4-ylmethylcarbamoyl] -2- (naphthalen-2-ylsulfonylamino) -propionyl] -benzyl-amino-propionic acid ethyl ester (1 : 1), MS (ISP): 651.6 (M + H) < + >.

68g) etil ester heksafluorofosfat (S)-3-[[3-[l-(amino-imino-metil)-piperidin-4-ilmetil karbamoil]-2-(naftalen-2-ilsulfonilamino)-propionil]-cikloheksilmetil-amino]propionske kisline (1:1), MS (ISP): 657.5 (M + H) ⁺ .68g) Hexafluorophosphate (S) -3 - [[3- [1- (amino-imino-methyl) -piperidin-4-ylmethylcarbamoyl] -2- (naphthalen-2-ylsulfonylamino) -propionyl] -cyclohexylmethyl-amino ethyl ester ] propionic acids (1: 1), MS (ISP): 657.5 (M + H) ⁺ .

68h) (S)-N4-[l-(amino-imino-metil)-piperidin-4-ilmetil]-Nl-ciklopropil-2-(naftalen 2-ilsulfonilamino)-Nl-(3-okso-butil)-sukcinamid hidroklorid,68h) (S) -N4- [1- (amino-imino-methyl) -piperidin-4-ylmethyl] -N1-cyclopropyl-2- (naphthalen 2-ylsulfonylamino) -Nl- (3-oxo-butyl) -succinamide hydrochloride,

MS (ISP): 571.6 (M + H)+.MS (ISP): 571.6 (M + H) < + >.

Primer 69Example 69

Analogno Primeru 3 pripravimo iz estrov Primera 67 in 68 naslednje kisline:Analogously to Example 3, the following acids were prepared from the esters of Examples 67 and 68:

a) hidroklorid (S)-3-[[3-[l-(amino-imino-metil)-piperidin-4-ilmetilkarbamoil]-2(naftalen-2-ilsulfonilamino)-propionil]-cikloheksil-amino]-ocetne kisline,a) (S) -3 - [[3- [1- (amino-imino-methyl) -piperidin-4-ylmethylcarbamoyl] -2 (naphthalen-2-ylsulfonylamino) -propionyl] -cyclohexyl-amino] -acetic acid hydrochloride ,

MS (ISP): 601.6 (M + H) +MS (ISP): 601.6 (M + H) < + >.

b) (S)-[[3-[l-(amino-imino-metil)-piperidin-4-ilmetilkarbamoil]-2-(naftalen-2ilsulfonilamino)-propionil]-ciklopropil-amino]-ocetno kislino,b) (S) - [[3- [1- (amino-imino-methyl) -piperidin-4-ylmethylcarbamoyl] -2- (naphthalen-2ylsulfonylamino) -propionyl] -cyclopropyl-amino] -acetic acid,

MS (ISP); 559.6 (M + H)+MS (ISP); 559.6 (M + H) < + >.

c) [[(S)-3-[l-(amino-imino-metil)-piperidin-4-ilmetilkarbamoil]-2-(naftalen-2ilsulfonilamino)-propionil]-benzil-amino]-ocetno kislino,c) [[(S) -3- [1- (amino-imino-methyl) -piperidin-4-ylmethylcarbamoyl] -2- (naphthalen-2ylsulfonylamino) -propionyl] -benzyl-amino] -acetic acid,

MS (ISP); 609.5 (M + H)+MS (ISP); 609.5 (M + H) < + >.

d) (S)-[[3-[l-(amino-imino-metil)-piperidin-4-ilmetilkarbamoil]-2-(naftalen-2ilsulfonilamino)-propionil]-cikloheksilmetil-amino]-ocetno kislino,d) (S) - [[3- [1- (amino-imino-methyl) -piperidin-4-ylmethylcarbamoyl] -2- (naphthalen-2ylsulfonylamino) -propionyl] -cyclohexylmethyl-amino] -acetic acid,

MS (ISP): 615.5 (M + H)+MS (ISP): 615.5 (M + H) < + >.

e) (S)-[[3-[l-(amino-imino-metil)-piperidin-4-ilmetilkarbamoil]-2-(naftalen-2ilsulfonilamino)-propionil]-butil-amino]-ocetno kislino,e) (S) - [[3- [1- (amino-imino-methyl) -piperidin-4-ylmethylcarbamoyl] -2- (naphthalen-2ylsulfonylamino) -propionyl] -butyl-amino] -acetic acid,

MS (ISP): 575.5 (M + H)+MS (ISP): 575.5 (M + H) < + >.

f) hidroklorid (S)-3-[[3-[l-(amino-imino-metil)-piperidin-4-ilmetilkarbamoil]-2(naftalen-2-ilsulfonilamino)-propionil]-ciklopropil-amino]-propionske kisline, MS (ISP): 573.5 (M + H)+f) (S) -3 - [[3- [1- (amino-imino-methyl) -piperidin-4-ylmethylcarbamoyl] -2 (naphthalen-2-ylsulfonylamino) -propionyl] -cyclopropyl-amino] -propionic acid hydrochloride , MS (ISP): 573.5 (M + H) < + >.

g) (S)-3-[[3-[l-(amino-immo-metil)-piperidin-4-ilmetilkarbamoil]-2-(naftalen-2ilsulfonilamino)-propionil]-benzil-amino]-propionsko kislino,g) (S) -3 - [[3- [1- (amino-imino-methyl) -piperidin-4-ylmethylcarbamoyl] -2- (naphthalen-2ylsulfonylamino) -propionyl] -benzyl-amino] -propionic acid,

MS (ISP): 623.6 (M + H)+MS (ISP): 623.6 (M + H) < + >.

h) (S)-3-[[3-[l-(amino-imino-metil)-piperidin-4-ilmetilkarbamoil]-2-(naftalen-2ilsulfonilamino)-propionil]-cikloheksilmetil-amino]-propionsko kislino,h) (S) -3 - [[3- [1- (amino-imino-methyl) -piperidin-4-ylmethylcarbamoyl] -2- (naphthalen-2ylsulfonylamino) -propionyl] -cyclohexylmethyl-amino] -propionic acid,

MS (ISP): 629.5.MS (ISP): 629.5.

Primer 70Example 70

1.0 g N-[N4-[[(S)-l-amidino-3-piperidinil]metil]-N2-(2-naftil-sulfonil)-L-asparaginil] N-ciklopropilglicina (Primer 4a) raztopimo v 10 ml dimetilformamida, dodamo1.0 g of N- [N4 - [[(S) -1-amidino-3-piperidinyl] methyl] -N2- (2-naphthyl-sulfonyl) -L-asparaginyl] N-cyclopropylglycine (Example 4a) was dissolved in 10 ml of dimethylformamide , we add

0.2 ml morfolina, 0.8 g BOP in 1.1 ml 4-etilmorfoIina in mešamo čez noč pri sobni temperaturi. Reakcijski zmesi dodamo 20 ml IN solne kisline, uparimo in ostanek kromatografiramo z gradientom vode/acetonitrila na koloni RP-18. Dobimo 0.5 g (S)-N4-[(S)-l-(amino-imino-metil)-piperidin-3-ilmetil]-Nl-ciklopropil-Nl-morfolin4-ilkarbonilmetil-2-(naftalen-2-ilsulfonilamino)-sukcinamid-hidroklorida (1:1),0.2 ml of morpholine, 0.8 g of BOP and 1.1 ml of 4-ethylmorpholine and stirred at room temperature overnight. 20 ml of 1N hydrochloric acid were added to the reaction mixture, evaporated and the residue was chromatographed with a water / acetonitrile gradient on RP-18 column. 0.5 g (S) -N4 - [(S) -1- (amino-imino-methyl) -piperidin-3-ylmethyl] -Nl-cyclopropyl-N1-morpholin4-ylcarbonylmethyl-2- (naphthalen-2-ylsulfonylamino) is obtained - Succinamide hydrochloride (1: 1),

MS (ISP): 628.5 (M + H)+·MS (ISP): 628.5 (M + H) + ·

Primer 71Example 71

Raztopino 0.8 g benzil estra 2-[[(S)-3-[(S)-l-(amino-imino-metil)-piperidin-3ilmetilkarbamoil]-2-(naftalen-2-ilsulfonilamino)-propionilj-ciklopropil-aminojetilkarbaminske kisline (Primer 56c) v 20 ml metanola po dodatku 0.2 g paladija na oglju hidriramo 24 ur pri sobni temperaturi. Katalizator odfiltriramo, filtrat uparimo in ostanek sušimo. 0.57 g tako dobljenega materiala v 30 ml tetrahidrofurana dokapavamo pri 0 °C k raztopini 0.57 g 3.4-bis-(2-propeniloksi)-3-ciklobuten-1.2diona v 20 ml tetrahidrofurana in reakcijsko zmes mešamo 5 ur pri sobni temperaturi. Topilo uparimo in ostanek kromatografiramo na kremeničnem gelu z ocetestrom/acetonom/ocetno kislino/vodo (6:2:1:1). Produktne frakcije uparimo in dobimo po sušenju ostanka 0.6 g (S)-Nl-[2-[2-aliloksi-3,4-diokso-ciklobut-l-enilamino)-etil]-N4-[(S)-l-(amino-imino-metil)-piperidin-3-ilmetil]-Nl-ciklopropil-2(naftalen-2-ilsulfonilamino)-sukcinamid acetata (1:1), MS (ISP): 680.6 (M + H) ⁺ ·A solution of 0.8 g of 2 - [[(S) -3 - [(S) -1- (amino-imino-methyl) -piperidin-3-ylmethylcarbamoyl] -2- (naphthalen-2-ylsulfonylamino) -propionyl-cyclopropyl-aminoethylcarbamine benzyl ester of acid (Example 56c) in 20 ml of methanol after addition of 0.2 g of palladium on charcoal was hydrated for 24 hours at room temperature. The catalyst was filtered off, the filtrate was evaporated and the residue was dried. 0.57 g of the material thus obtained in 30 ml of tetrahydrofuran is added dropwise at 0 ° C to a solution of 0.57 g of 3,4-bis- (2-propenyloxy) -3-cyclobutene-1.2 dione in 20 ml of tetrahydrofuran and the reaction mixture is stirred for 5 hours at room temperature. The solvent was evaporated and the residue was chromatographed on silica gel with acetic acid / acetone / acetic acid / water (6: 2: 1: 1). The product fractions were evaporated and obtained after drying the residue 0.6 g (S) -N1- [2- [2-allyloxy-3,4-dioxo-cyclobut-1-enylamino) -ethyl] -N4 - [(S) -1- ( amino-imino-methyl) -piperidin-3-ylmethyl] -Nl-cyclopropyl-2 (naphthalen-2-ylsulfonylamino) -succinamide acetate (1: 1), MS (ISP): 680.6 (M + H) ⁺ ·

Primer 72Example 72

0.1 g pri Primeru 71 dobljenega materiala raztopimo v 10 ml acetonitrila ob dodatku 1 kapljice vode in tej raztopini dodamo 0.03 g paladijevega(II)-acetata in 0.08 ml trietilfosfita. Zatem dodamo 0.13 ml 2N natrijevega 2-etilkapronata v vodi in reakcijsko zmes mešamo 1.5 ur pri sobni temperaturi. Izločeni material odfiltriramo, izperemo z etrom/heksanom in filtrni ostanek sušimo. Izoliramo 0.090 g (S) N4-[(S)l-(amino-imino-metil)-piperidin-3-ilmetil]-Nl-ciklopropil-Nl-[2-(3,4-diokso-2hidroksi-ciklobut-l-enilamino)-etil]-2-(naftaIen-2-ilsulfonilamino)-sukcinamidacetata (1:1), MS (ISP); 640.5 (M + H) + ·0.1 g of Example 71 was dissolved in 10 ml of acetonitrile with the addition of 1 drop of water, and 0.03 g of palladium (II) -acetate and 0.08 ml of triethyl phosphite were added to this solution. Then 0.13 ml of 2N sodium 2-ethylcapronate in water is added and the reaction mixture is stirred for 1.5 hours at room temperature. The recovered material was filtered off, washed with ether / hexane and the filter residue dried. 0.090 g of (S) N4 - [(S) 1- (amino-imino-methyl) -piperidin-3-ylmethyl] -Nl-cyclopropyl-N1- [2- (3,4-dioxo-2-hydroxy-cyclobut-1) is isolated -enylamino) -ethyl] -2- (naphthalen-2-ylsulfonylamino) -succinamidacetate (1: 1), MS (ISP); 640.5 (M + H) + ·

Primer 73Example 73

Analogno Primeru 3 pripravimo naslednje kisline iz ustreznih estrov:Analogously to Example 3, the following acids were prepared from the corresponding esters:

a) Iz estra Primera 49 ciklopropil-[(S)-3-[(S)-l-(izobutoksikarbonilamino-iminometil)-piperidin-3-ilmetilkarbamoil]-2-(naftalen-2-ilsulfoniIamino)-propionil]aminoj-ocetno kislino ali tavtomer amidinske skupine, MS (ISP): 659.5 (M + H) ⁺ a) From the ester of Example 49 cyclopropyl - [(S) -3 - [(S) -1- (isobutoxycarbonylamino-iminomethyl) -piperidin-3-ylmethylcarbamoyl] -2- (naphthalen-2-ylsulfonylamino) -propionyl] amino-acetic acid or tautomer of the amidine group, MS (ISP): 659.5 (M + H) ⁺

b) Iz estra Primera 66 [[(S)-3-[(S)-l-(imino-terc-butoksikarbonilamino-metil)piperidin-3-ilmetilkarbamoil]-2-(naftalen-2-ilsulfonilamino)-propionil]-ciklopropil amino]-ocetno kislino ali tavtomer amidinske skupine, MS (ISP): 659.7 (M + H) +b) From Example 66 ester [[(S) -3 - [(S) -1- (imino-tert-butoxycarbonylamino-methyl) piperidin-3-ylmethylcarbamoyl] -2- (naphthalen-2-ylsulfonylamino) -propionyl] - cyclopropyl amino] -acetic acid or tautomer of the amidine group, MS (ISP): 659.7 (M + H) +

Spojino s formulo I, njen solvat ali njeno sol lahko na sam po sebi znan način uporabimo kot učinkovino za pripravo farmacevtskih preparatov, npr. tablet in kapsul z naslednjo sestavo:A compound of formula I, a solvate or a salt thereof, can be used in a manner known per se as an active ingredient for the preparation of pharmaceutical preparations, e.g. tablets and capsules having the following composition:

Primer A na tabletoExample A per tablet

Učinkovina The active ingredient 200 mg 200 mg Mikrokristalna celuloza Microcrystalline cellulose 155 mg 155 mg Koruzni škrob Corn starch 25 mg 25 mg Smukec Talc 25 mg 25 mg Hidroksipropilmetilceluloza Hydroxypropylmethylcellulose 20 me 20 me

425 mg425 mg

Primer BExample B

na kapsulo per capsule Učinkovina The active ingredient 100.0 mg 100.0 mg Koruzni škrob Corn starch 20.0 mg 20.0 mg Mlečni sladkor Milk sugar 95.0 mg 95.0 mg Smukec Talc 4.5 mg 4.5 mg Magnezijev stearat Magnesium stearate 0.5 me 220.0 mg 0.5 me 220.0 mg

F. HOFFMANOMA ROCHEF. HOFFMANOMA ROCHE

Claims (25)

PATENTNI ZAHTEVKIPATENT APPLICATIONS 1. Sulfonamidokarboksamidi s formuloSulfonamidocarboxamides of the formula OOh A' χ-A 'χ- IIII O v kateri pomenijoWhat they mean about X skupino s formulo χΐ ali X² :X group of formula χΐ or X ² : T CH₂ ali O,T CH ₂ or O, R¹, R², RH in R²! neodvisno drug od drugega H ali COO-nižji alkil,R ¹ , R ² , RH and R ² ! independently of one another H or COO-lower alkyl, Y H ali, če je X skupina X², ali če je X skupina χΐ, v kateri vsaj eden izmedYH or, if X is a group X ² , or if X is a group χΐ in which at least one of Rl in R² ni H, lahko stoji Y tudi za CH2COOH ali SO2-A’,R 1 and R ^{2 are} not H, Y may also stand for CH 2 COOOH or SO 2 -A ', A in A’ aril, heteroaril, heterociklil, alkil ali cikloalkil,A and A 'aryl, heteroaryl, heterocyclyl, alkyl or cycloalkyl, Q H, nižji alkil ali nižji alkil(OH, COOH ali COO-nižji alkil),Q H, lower alkyl or lower alkyl (OH, COOH or COO-lower alkyl), M skupino s formulo Ml, ali kadar je X skupina X², ali kadar je X skupinaM is a group of formula M1, or when X is an X ² group or when X is a group Xl in vsaj eden izmed Rl, R² in Q ni H, in/ali kadar je A alkil ali cikloalkil, tedaj je M lahko tudi skupina z eno izmed formul M² - M^ ch-ch₂1Xl and at least one of R, R ^2, and Q is not H and / or where A is alkyl or cycloalkyl, then M can also be a group of one of the formulas M ² - M ^ CH-CH ₂ 1 C=O 1C = O 1 N(R⁶) (M²) (M¹) c=oN (R ⁶ ) (M ² ) (M ¹ ) c = o N—< R³ N - <R ³ R⁴ R ⁴ R⁵ R ⁵ 1(,1 (, -CH₂CH(NH(CO)₁.₂R⁷)- (M³)-CH ₂ CH (NH (CO) _{1. 2} R ⁷ ) - (M ³ ) -CH₂CH(NHC(O)O-benzil)- (M⁴) =CH(CH₂)i.₂R⁷ (M5) =CHCH₂C(O)R⁸ (M6) =CHCH₂NH(CO)].₂R⁷ (M⁷) =CHCH₂NHC(O)O-benzil (M⁸)-CH ₂ CH (NHC (O) O-benzyl) - (M ⁴ ) = CH (CH ₂ ) i. ₂ R ⁷ (M ⁵ ) = CHCH ₂ C (O) R ⁸ (M ⁶ ) = CHCH ₂ NH (CO)]. ₂ R ⁷ (M ⁷ ) = CHCH ₂ NHC (O) O-benzyl (M ⁸ ) R³ H, nižji alkil ali alkenil, aril, heteroaril, cikloalkil ali (aril, heteroaril ali cikloalkil)-nižji alkil,R ^{3 is} H, lower alkyl or alkenyl, aryl, heteroaryl, cycloalkyl or (aryl, heteroaryl or cycloalkyl) lower alkyl, R⁴ H, nižji alkil, aril, cikloalkil, ali (aril ali cikloalkil)-nižji alkil,R ^{4 is} H, lower alkyl, aryl, cycloalkyl, or (aryl or cycloalkyl) lower alkyl, R⁵ H, nižji alkil ali v danem primeru preko nižjega alkilena vezan COOH, COOnižji alkil, nižji alkanoil, OH, nižji-alkanoiloksi, nižji-alkoksi, aril-nižji alkoksi, CONH₂, CONHCH₂CH₂OH, CONHOH, CONHOCH3,R ⁵ H, lower alkyl or optionally linked lower alkylene COOH, COO lower alkyl, lower alkanoyl, OH, lower-alkanoyloxy, lower-alkoxy, aryl-lower alkoxy, CONH ₂ , CONHCH ₂ CH ₂ OH, CONHOH, CONHOCH3, CONHO-benzil, CONHSO₂-nižji alkil, CONHCH₂CH₂-aril, CONH cikloalkil, CONHCH₂-heteroaril, NH₂, NHCOO-nižji alkil, NHCOO-nižji aralkil, NHSO3H, (NHSO₂ ali NHSO3)-nižji alkil, NH-nižji alkanoil, NHCOCOOH, NHCOCOO-nižji alkil, NH-cikloalkil, NH-(3,4-diokoso-2-hidroksi-ciklobut-l-enil), NH-[2-nižji-(alkoksi ali alkeniloksi)-3,4-dioksociklobut-l-enilj, NHCH₂-heteroaril, NHCOCO-(aril ali nižji alkil), NHCOCH₂Cl, NHCOCH₂O-aril, NHCOCH₂-aril, NHCO(aril ali heteroaril), NHPO3(R9,r10), heteroaril, ali v danem primeru z O ali S prekinjen in v danem primeru z do 2 substituentoma iz skupine nižji alkil, COOH, COO-nižji alkil, CH₂OH in CH₂O-benzil, obročno substituiran CON(CH₂)₄-9,CONHO-benzyl, CONHSO ₂ -lower alkyl, CONHCH ₂ CH ₂ -aryl, CONH cycloalkyl, CONHCH ₂ -heteroaryl, NH ₂ , NHCOO-lower alkyl, NHCOO-lower aralkyl, NHSO3H, (NHSO ₂ or NHSO3) -alkyl, NH-lower alkanoyl, NHCOCOOH, NHCOCOO-lower alkyl, NH-cycloalkyl, NH- (3,4-dioxo-2-hydroxy-cyclobut-1-enyl), NH- [2-lower- (alkoxy or alkenyloxy) -3 , 4-dioxocyclobut-1-enyl, NHCH ₂ -heteroaryl, NHCOCO- (aryl or lower alkyl), NHCOCH ₂ Cl, NHCOCH ₂ O-aryl, NHCOCH _2- aryl, NHCO (aryl or heteroaryl), NHPO3 (R9, r10 ), heteroaryl, or optionally terminated with O or S, and optionally with up to 2 substituents from the group lower alkyl, COOH, COO-lower alkyl, CH ₂ OH and CH ₂ O-benzyl, ring-substituted CON (CH ₂ ) ₄ -9, R^inRlO H, nižji-alkil ali fenil, pri čemer v primeru, da so Q, Rl, R2, R³ in R5 istočasno H, R⁴ ne sme biti fenil, N(R6) benzilamino ali v danem primeru z O ali S prekinjen in v danem primeru z do 2 substituentoma iz skupine nižji alkil, COOH, COO-nižji alkil, CH₂OH, CH₂O-benzil, obročno substituiran N(CH₂)4_9,R inRlO H, lower-alkyl or phenyl, whereby in the case that Q, R, R 2, R ³ and R 5 are simultaneously H, R ⁴ can not be phenyl, N (R6) benzylamino, or optionally with an O or S is interrupted and optionally with up to 2 substituents from the group lower alkyl, COOH, COO-lower alkyl, CH ₂ OH, CH ₂ O-benzyl, ring-substituted N (CH ₂ ) 4_9, R⁷ in R⁸ aril, heteroaril, cikloalkil ali heterociklil, aliR ⁷ and R ⁸ aryl, heteroaryl, cycloalkyl or heterocyclyl, or R⁸ v danem primeru z do 2 substituentoma iz skupine okso, COO-nižji alkil, (CH₂)o-lOH, (CH₂)o-lOCO-nižji alkil, CONH₂, CONH-nižji alkil aliR ⁸ optionally with up to 2 substituents from the group oxo, COO-lower alkyl, (CH ₂ ) o-10H, (CH ₂ ) o-lOCO-lower alkyl, CONH ₂ , CONH-lower alkyl, or CON(nižji-alkil)₂, substituiran N(CH₂)4_9, kot tudi njihovi hidrati ali solvati in njihove fiziološko prenesljive soli.CON (lower-alkyl) ₂ , substituted N (CH ₂ ) 4 - 9, as well as their hydrates or solvates and their physiologically tolerated salts. 2. Spojine po zahtevku 1, kjer soCompounds according to claim 1, wherein they are X skupino χΐ, v kateri je gvanidino skupina nezaščitena,X group χΐ in which the guanidino group is unprotected, Y H,Y H, A aril, heteroaril ali heterociklil,A is aryl, heteroaryl or heterocyclyl, Q ima zgornji pomen inQ has the above meaning and M pomeni bodisi skupino Ml, v kateri imata in R⁴ zgornji pomen, pri čemer v primeru, da sta Q, R^ in R$ iztočasno H, R⁴ ne sme biti H ali fenil, inM represents either the group Ml in which both R ^{4 have the} above meaning, where, if Q, R 4 and R 8 are simultaneously H, R ⁴ must not be H or phenyl, and R^ pomeni H, nižji alkil, ali v danem primeru preko nižjega alkilena vezanR4 represents H, lower alkyl, or optionally bonded via lower alkylene COOH, COO-nižji alkil, nižji alkanoil, OH, nižji alkanoiloksi, NH₂, NHCOOnižji alkil, NHSO3H, (NHSO₂ ali NHSO3)-nižji alkil, NH-nižji alkanoil, NHCOCOOH, NHCOCOO-nižji alkil ali NHPO₃(R^{8 9},R¹⁰), ali, če Q ni H, tedaj jeCOOH, COO-lower alkyl, lower alkanoyl, OH, lower alkanoyloxy, NH ₂ , NHCOO lower alkyl, NHSO3H, (NHSO ₂ or NHSO3) lower alkyl, NH-lower alkanoyl, NHCOCOOH, NHCOCOO-lower alkyl or NHPO ₃ (R ^{8 9} , R ¹⁰ ), or, if Q is not H, then it is M lahko tudi skupina M², v kateri je N(R6) v danem primeru s COOH ali COOnižjim alkilom substituiran N(CH₂)4_9·M may also be a group M ² in which N (R 6) optionally substituted with COOH or COO lower alkyl N (CH ₂ ) 4_9 · 3. Spojine po zahtevku 1, kjer Y pomeni H, X skupino χΐ in je M skupina Ml in je v primeru, da vsaj eden izmed Rl in R² (v χΐ) ni H in/ali če Q ni H in/ali če je A alkil ali cikloalkil, M lahko stoji tudi za skupino M².Compounds according to claim 1, wherein Y is H, X is a group χΐ and M is a group Ml and in case at least one of R1 and R ² (in χΐ) is not H and / or if Q is not H and / or A is alkyl or cycloalkyl, M may also stand for the group M ² . 4. Spojine po zahtevku 1, kjer Y pomeni H, X skupino X² in je M skupina Ml ali M².Compounds according to claim 1, wherein Y is H, X is group X ² and M is group M1 or M ² . 5. Spojine po zahtevku 1, kjer Y pomeni H, X skupino χΐ in je M skupina ali M^, pod pogojem, da vsaj eden izmed Rl in R² (v X1) ni H in/ali da Q ni H in/ali daje A alkil ali cikloalkil.5. Compounds according to claim 1, wherein Y is H, X is a group χΐ and M is a group, or M ^, provided that at least one of Rl and ^R2 (in X1) is not H and / or that Q is not H and / or A is alkyl or cycloalkyl. 6. Spojine po zahtevku 1, kjer Y pomeni H, X skupino χΐ in je M skupina ali M²’ pod pogojem, da vsaj eden izmed Rl in R² (v χΐ) ni H in/ali da Q ni H in/ali daje A alkil ali cikloalkil.Compounds according to claim 1, wherein Y is H, X is a group χΐ and M is a group or M ² 'provided that at least one of R1 and R ² (in χΐ) is not H and / or that Q is not H and / or A is alkyl or cycloalkyl. 7. Spojine po zahtevku 3, kjer Y in Q pomenita H, X skupino χΐ in je M skupina Ml in je v primeru, da vsaj eden izmed Rl in R² (v χΐ) ni H in/ali če je A alkil ali cikloalkil, tedaj M lahko stoji tudi za skupino M².Compounds according to claim 3, wherein Y and Q are H, X is a group χΐ and M is a group Ml and in case at least one of R1 and R ² (in χΐ) is not H and / or if A is alkyl or cycloalkyl , then M can also stand for group M ² . 8. Spojine po zahtevku 3, kjer Y pomeni H, Q pomeni nižji-alkil(OH, COOH aliCompounds according to claim 3, wherein Y is H, Q is lower-alkyl (OH, COOH or COO-nižji alkil), X skupino χΐ in M skupino Ml ali M².COO-lower alkyl), X group χΐ and M group Ml or M ² . 9. Spojine po zahtevku 1, kjer je A naftil, metilkinolil, metiltetrahidrokinolil, metil, piridil ali s t-butilom, CF3, fenilom, ciklopentilom, karboksi, metoksikarbonilom, etoksikarbonilom, OCF3, CN, CONH₂ ali tetrazolilom substituiran fenil.Compounds according to claim 1, wherein A is naphthyl, methylquinolyl, methyltetrahydroquinolyl, methyl, pyridyl or t-butyl, CF3, phenyl, cyclopentyl, carboxy, methoxycarbonyl, ethoxycarbonyl, OCF3, CN, CONH ₂ or tetrazolyl substituted phenyl. 10. Spojine po zahtevku 1, kjer Q pomeni H, CH3, CH₂COOH, CH₂CH₂OH ali CH₂COOC₂H₅.Compounds according to claim 1, wherein Q is H, CH 3, CH ₂ COOH, CH ₂ CH ₂ OH or CH ₂ COOC ₂ H ₅ . 11. Spojine po zahtevku 1, kjer X pomeni skupino χΐ, T je CH₂, eden izmed Rl in R^ je H in drugi H ali COO-(metil, etil, izobutil ali t-butil).Compounds according to claim 1, wherein X is a group χΐ, T is CH ₂ , one of R 1 and R 4 is H and the other is H or COO- (methyl, ethyl, isobutyl or t-butyl). 12. Spojine po zahtevku 1, kjer X pomeni skupino χΐ, T je O, eden izmed Rl in R^ je H in drugi H ali COOC₂H5·Compounds according to claim 1, wherein X is a group χΐ, T is O, one of R1 and R4 is H and the other is H or COOC ₂ H5 · 13. Spojine po zahtevku 1, kjer X pomeni skupino X^ in stojita Rl in R^l za H.13. Compounds according to claim 1, wherein X is a group X1 and R1 and R3 are H. 14. Spojine po zahtevku 1, kjer M pomeni skupino M^, R^ je H, CH3, propil, izopropil, butil, pentil, alil, ciklopropil, ciklopentil, cikloheksil, ciklopropil-metil, cikloheksilmetil, piridilmetil ali v danem primeru s klorom ali metoksi substituiran benzil in R^ stoji za H, izopropil, 2-butil, izobutil, fenil, benzil ali cikloheksil.14. Compounds according to claim 1, wherein M represents a group M ^, R ^ is H, CH 3, propyl, isopropyl, butyl, pentyl, allyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropyl-methyl, cyclohexylmethyl, pyridylmethyl or optionally chlorine or methoxy substituted benzyl and R4 stands for H, isopropyl, 2-butyl, isobutyl, phenyl, benzyl or cyclohexyl. 15. Spojine po zahtevku 1 ali 14, kjer je R^ skupina (CH₂)q.₂-R^ in R⁵⁰ H, OH, C(CH₃)₂OH, COCH3, OCOCH3, COO(H, CH3 ali C₂H₅), NHCOOCH3, NHCOCH3, tetrazolil, CONH₂, metiloksadiazolil, OCH3, benziloksi, morfolinokarbonil, CONHOCH3, CONHO-benzil, CONHSO₂CH3, CONHCH₂-piridil, CONH-ciklopropil, CONHCH₂CH₂-C₆H₃(OH)₂, CONHCH₂CH₂OH, NHCOCOOH, NHCOCOOCH3, NHCOCOOC₂H₅, NHSO3H, NHSO₂CH₃, NHCOO-benzil, NHCOCH₂C1, NHCOCH₂OC₆H₅, NHCOCOC₆H₅, NHCOCOCH3, NHCO-piridil, NHCO-piridil-N-oksid, NHCO-pirazinil, NHCOCH₂C₆H₃(OH)₂, NHPO(OC₆H₅)₂, NHPO(OC₂H₅)₂, NH-(3,4-diokso2-hidroksiciklobut- 1-enil) ali NH-(2-aliloksi-3,4-dioksociklobut- 1-enil).15. Compounds according to claim 1 or 14, wherein the R group is (CH ₂₎ q. ₂ -R ^ and R ⁵⁰ H, OH, C (CH ₃ ) ₂ OH, COCH3, OCOCH3, COO (H, CH3 or C ₂ H ₅ ), NHCOOCH3, NHCOCH3, tetrazolyl, CONH ₂ , methyloxadiazolyl, OCH3, benzyloxy, morpholinocarbonyl, CONHOCH3, CONHO-benzyl, CONHSO ₂ CH3, CONHCH ₂ -pyridyl, CONH-cyclopropyl, CONHCH ₂ CH ₂ -C ₆ H ₃ (OH) ₂ , CONHCH ₂ CH ₂ OH, NHCOCOOH, NHCOCOOCH3, NHCOCOOC ₂ H ₅ , NHSO3H, NHSO ₂ CH ₃ , NHCOOO-benzyl, NHCOCH ₂ C1, NHCOCH ₂ OC ₆ H ₅ , NHCOCOC ₆ H ₅ , NHCOCOCH3, NHCO-pyridyl, NHCO-pyridyl-N-oxide, NHCO-pyrazinyl, NHCOCH ₂ C ₆ H ₃ (OH) ₂ , NHPO (OC ₆ H ₅ ) ₂ , NHPO (OC ₂ H ₅ ) ₂ , NH- (3,4-dioxo-2-hydroxycyclobut-1-enyl) or NH- (2-allyloxy-3,4 -dioxocyclobut-1-enyl). 16. Spojine po zahtevku 1, kjer M pomeni skupino in je N(R^) heksametilenimino.16. Compounds according to claim 1, wherein M represents a group and N (R4) is hexamethylenimino. 17. Spojine po zahtevku 1 ali 2 iz skupine naslednjih:17. Compounds according to claim 1 or 2 from the group of the following: N-[N4-[[(S)-l-(amidino-3-piperidinil]metil]-N2-(2-naftilsulfonil)-L-asparaginil]-Nciklopropilglicin, (S)-[[3-[(S)-l-(amino-imino-metil)piperidin-3-ilmetilkarbamoil]-2-(naftalin-2sulfonilamino)propionil]ciklopropilamino]propionska kislina, [(S)-3-[(S)-l-(amino-imino-metil)piperidin-3-ilmetilkarbamoil]-2-(4-trrifluormetilfenilsulfonilamino)propionil]-ciklopropil-amino]ocetna kislina.N- [N4 - [[(S) -1- (amidino-3-piperidinyl] methyl] -N2- (2-naphthylsulfonyl) -L-asparaginyl] -Ncyclopropylglycine, (S) - [[3 - [(S) -1- (amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -2- (naphthalen-2-sulfonylamino) propionyl] cyclopropylamino] propionic acid, [(S) -3 - [(S) -1- (amino-imino- methyl) piperidin-3-ylmethylcarbamoyl] -2- (4-trifluoromethylphenylsulfonylamino) propionyl] -cyclopropyl-amino] acetic acid. 18. Spojine po zahtevku 1 ali 2 iz skupine naslednjih:Compounds according to claim 1 or 2 from the group of the following: (S)-N4-[(S)-l-(amino-imino-metil)piperidin-3-ilmetil]-Nl-karboksimetil-Nlciklopentil-2-(naftalin-2-sulfonilamino)sukcinamid, [(S)-3-[(S)-2-(amino-imino-metil)piperidin-3-ilmetilkarbamoil]-2-(naftalen-2sulfonilamino)propionil]-propil-aminoocetna kislina,(S) -N4 - [(S) -1- (amino-imino-methyl) piperidin-3-ylmethyl] -Nl-carboxymethyl-Ncyclopentyl-2- (naphthalene-2-sulfonylamino) succinamide, [(S) -3 - [(S) -2- (amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -2- (naphthalene-2-sulfonylamino) propionyl] -propyl-aminoacetic acid, N-[N4-[[(S)-l-(amidino-3-piperidinil]metil]-N2-(2-naftilsulfonil)-L-asparaginil]-N(o-klorbenzil)glicin, [2-[[(S)-3-[(S)-l-(amino-imino-metil)piperidin-3-ilmetilkarbamoil]-2-(naftalen-2sulfonilamino)propionil]-butil-amino]etil]oksamska kislina, (S)-N4-[(S)-l-(amino-imino-metil)piperidin-3-ilmetil]-Nl-butil-2-(naftalen-2sulfonilamino)-Nl-(2-sulfoamino-etil)-sukcinamid, [(S)-3-[(S)-l-(amino-imino-metil)piperidin-3-ilmetilkarbamoil]-2-(4-t-butilfenilsulfonilaminoj-propionil-ciklopropil-aminoj-ocetna kislina.N- [N4 - [[(S) -1- (amidino-3-piperidinyl] methyl] -N2- (2-naphthylsulfonyl) -L-asparaginyl] -N (o-chlorobenzyl) glycine, [2 - [[( S) -3 - [(S) -1- (amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -2- (naphthalene-2-sulfonylamino) propionyl] -butyl-amino] ethyl] oxamic acid, (S) -N4 - [(S) -1- (amino-imino-methyl) piperidin-3-ylmethyl] -Nl-butyl-2- (naphthalene-2sulfonylamino) -Nl- (2-sulfoamino-ethyl) -succinamide, [(S) -3 - [(S) -1- (amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -2- (4-t-butylphenylsulfonylamino-propionyl-cyclopropyl-amino-acetic acid. 19. Spojine po zahtevku 1 iz skupine naslednjih:19. Compounds according to claim 1 in the group of the following: 3-[[(S)-3-[(S)-l-(amino-imino-metil)piperidin-3-ilkarbamoil]-2-(4-karbamoilfenilsulfonilamino)-propionil]ciklopropil-amino]propionska kislina, (S)-N4-[(S)-l-(amino-imino-metil)piperidin-3-ilmetil]-Nl-ciklopropil]-2-(naftalen-2 ilsulfonilamino)-Nl-[2-(pirazin-2-ilkarbonil-amino)etil]-sukcinamid, (S)-N4-[(S)-l-(amino-imino-metil)piperidin-3-ilmetil]-Nl-ciklopropil]-N 1-(2-(3,4dihidroksi-fenil)-etilkarbamoilmetil]-2-(naftalen-2-ilsulfonilamino)-sukcinamid.3 - [[(S) -3 - [(S) -1- (amino-imino-methyl) piperidin-3-ylcarbamoyl] -2- (4-carbamoylphenylsulfonylamino) -propionyl] cyclopropyl-amino] propionic acid, (S ) -N4 - [(S) -1- (amino-imino-methyl) piperidin-3-ylmethyl] -Nl-cyclopropyl] -2- (naphthalen-2-ylsulfonylamino) -Nl- [2- (pyrazin-2-ylcarbonyl) -amino) ethyl] -succinamide, (S) -N4 - [(S) -1- (amino-imino-methyl) piperidin-3-ylmethyl] -Nl-cyclopropyl] -N 1- (2- (3,4-dihydroxy) -phenyl) -ethylcarbamoylmethyl] -2- (naphthalen-2-ylsulfonylamino) -succinamide. 20. Spojine po zahtevku 1 iz skupine naslednjih:20. Compounds according to claim 1 in the group of the following: 2- [(S)-2-[(S)-l-amino-imino-metil)piperidin-3-iImetilkarbamoil]-l-[ciklopropil-(2etoksikarbonil-etil)-karbamoil]-etilsulfamoil]-benzojska kislina,2- [(S) -2 - [(S) -1-amino-imino-methyl) piperidin-3-ylmethylcarbamoyl] -1- [cyclopropyl- (2ethoxycarbonyl-ethyl) -carbamoyl] -ethylsulfamoyl] -benzoic acid, 3- [[(S)-3-[(S)-l-amino-imino-metil)-piperidin-3-ilkarbamoil]-2-(4-cianofenilsulfonilamino)-propionil]-ciklopropil-amino]-propionska kislina, (S)-N(4)-[4-(amino-imino-metil)-morfolin-2-ilmetil]-N(l)-ciklopropil-N(l)-[2(tetrazol-5-il)-etil]-2-(naftalin-2-ilsulfonil)-sukcinamid.3 - [[(S) -3 - [(S) -1-amino-imino-methyl) -piperidin-3-ylcarbamoyl] -2- (4-cyanophenylsulfonylamino) -propionyl] -cyclopropyl-amino] -propionic acid, (S) -N (4) - [4- (amino-imino-methyl) -morpholin-2-ylmethyl] -N (1) -cyclopropyl-N (1) - [2 (tetrazol-5-yl) -ethyl ] -2- (Naphthalin-2-ylsulfonyl) -succinamide. etil ester [[(S)-3-[4-(amino-imino-metil)-morfolin-2-ilmetilkarbamoil]-2-(naftalin-2-ilsulfonil)-propionil]-ciklopropil-amino]-ocetne kisline, [[(S)-3-[4-(amino-imino-metil)-morfolin-2-ilmetilkarbamoil]-2-(naftalen-2-ilsulfonil)-propionil]-ciklopropil-amino]-ocetna kislina,[[(S) -3- [4- (amino-imino-methyl) -morpholin-2-ylmethylcarbamoyl] -2- (naphthalin-2-ylsulfonyl) -propionyl] -cyclopropyl-amino] -acetic acid ethyl ester, [ [(S) -3- [4- (amino-imino-methyl) -morpholin-2-ylmethylcarbamoyl] -2- (naphthalen-2-ylsulfonyl) -propionyl] -cyclopropyl-amino] -acetic acid, 2-[[(S)-3-[(S)-l-(ammo-imino-metil)-piperidin-3-ilmetiIkarbamoil]-2-[naftalen-2ilsulfonilamino)-propionil]ciklopropil-amino]-etil-sulfaminska kislina, (S)-N4-[(S)-l-(amino-imino-metil)piperidin-3-ilmetil]-Nl-2-(kloroacetilamino-etil)Nl-ciklopropil-2-(naftalen-2-ilsulfonilamino)-sukcinamid, (S)-N4-[(S)-l-(amino-imino-metil)-piperidin-3-ilmetil]-Nl-ciklopropil-2-(naftalen-2ilsulfonilamino)-Nl-(2-fenoksiacetilamino-etil)-sukcinamid, (S)-N4-[(S)-l-(amino-imino-metil)-piperidin-3-ilmetil]-Nl-ciklQpropil-2-(naftalen-2ilsulfonilamino)-Nl-[2-(2-okso-2-fenil-acetilamino)-etiI]-sukcinamid, (S)-N4-[(S)-l-(amino-immo-metil)-piperidin-3-ilmetil]-Nl-ciklopropil-2-(naftalen-2ilsulfonilamino)-Nl-[2-(2-okso-propionilamino)-etil]-sukcinamid, (S)-N4-[(S)-l-(amino-imino-metil)-piperidin-3-ilmetil]-Nl-ciklopropil-2-(naftalen-2ilsulfonilamino)-Nl-[2-piridin-3-ilkarbonilamino)-etil]-sukcinamid, (S)-N4-[(S)-l-(amino-imino-metil)-piperidin-3-ilmetil]-Nl-ciklopropil-2-naftalen-2ilsulfonilamino-Nl-[2-(l-oksi-nikotinoilamino)-etil]-sukcinamid.2 - [[(S) -3 - [(S) -1- (amino-imino-methyl) -piperidin-3-ylmethylcarbamoyl] -2- [naphthalen-2ylsulfonylamino) -propionyl] cyclopropyl-amino] -ethyl-sulfamine acid, (S) -N4 - [(S) -1- (amino-imino-methyl) piperidin-3-ylmethyl] -Nl-2- (chloroacetylamino-ethyl) N1-cyclopropyl-2- (naphthalen-2-ylsulfonylamino ) -succinamide, (S) -N4 - [(S) -1- (amino-imino-methyl) -piperidin-3-ylmethyl] -Nl-cyclopropyl-2- (naphthalen-2ylsulfonylamino) -Nl- (2-phenoxyacetylamino) -ethyl) -succinamide, (S) -N4 - [(S) -1- (amino-imino-methyl) -piperidin-3-ylmethyl] -Nl-cyclopropyl-2- (naphthalen-2ylsulfonylamino) -Nl- [2 - (2-oxo-2-phenyl-acetylamino) -ethyl] -succinamide, (S) -N4 - [(S) -1- (amino-imino-methyl) -piperidin-3-ylmethyl] -N1-cyclopropyl- 2- (Naphthalen-2ylsulfonylamino) -Nl- [2- (2-oxo-propionylamino) -ethyl] -succinamide, (S) -N4 - [(S) -1- (amino-imino-methyl) -piperidine-3 -ylmethyl] -Nl-cyclopropyl-2- (naphthalen-2ylsulfonylamino) -Nl- [2-pyridin-3-ylcarbonylamino) -ethyl] -succinamide, (S) -N4 - [(S) -1- (amino-imino) -methyl) -piperidin-3-ylmethyl] -Nl-cyclopropyl-2-naphthalen-2ylsulfonylamino-N1- [2- (1-oxy) otinoylamino) -ethyl] -succinamide. 21. Spojine po enem izmed zahtevkov 1 do 20 za uporabo pri pripravi zdravil, zlasti zaviralcev s trombinom izzvane agregacije ploščic in strjevanja fibrinogena v krvni plazmi.Compounds according to any one of claims 1 to 20 for use in the preparation of medicaments, in particular thrombin inhibitors-induced platelet aggregation and fibrinogen solidification in blood plasma. 22. Postopek za pripravo spojin po enem od zahtevkov 1 do 20, označen s tem, daA process for the preparation of compounds according to any one of claims 1 to 20, characterized in that a) kislino s formuloa) an acid of formula MM A^x N' COOH iA ^x N 'COOH i Y pretvorimo z aminom s formuloY is converted by an amine of the formula II q-nhch₂-x iii aii njegovo soljo ob intermediarni zaščiti funkcionalnih skupin, ki jih vsebujejo skupine A, Ύ m M (v II) in Q (v III), aiiII q-nhch ₂ -x iii aii its salt with the intermediate protection of the functional groups contained in groups A, Ύ m M (in II) and Q (in III), aii b) amin s formulob) an amine of formula QQ 0^/0 ¹ , /SC AM N X³ JV0 ^ / 0 ¹ , / SC AM NX ³ JV A^x N C ! !lA ^x NC! ! l Y O v kateri je skupina aii X^²:YO in which the group aii X ^ ² : pretvorimo z amidirnim sredstvom mis converted by the amidating agent m c) po želji funkcionalno pretvorimo reakcije sposobno skupino, ki se nahaja v skupini M ali Q spojine s formulo I, inc) optionally functionally converting the reaction-capable group contained in the group M or Q of a compound of formula I, and d) po želji prevedemo spojino s formulo I v njeno fiziološko prenesljivo sol aii sol spojine s formulo I v prosto kislino ali bazo.d) optionally converting a compound of formula I into its physiologically tolerable salt, or a salt of a compound of formula I into a free acid or base. 23. Farmacevtski preparat, označen s tem, da vsebuje spojino po enem izmed zahtevkov 1 do 20 kot učinkovino.A pharmaceutical composition comprising a compound according to any one of claims 1 to 20 as an active ingredient. 24. Uporaba spojine po enem od zahtevkov 1 do 20 za pripravo zdravil za zdravljenje ali profilakso bolezni, kijih povzroča s trombinom izzvana agregacija ploščic ali strjevanje fibrinogena v krvni plazmi.Use of a compound according to any one of claims 1 to 20 for the preparation of medicaments for the treatment or prophylaxis of diseases caused by platelet-induced platelet aggregation or clotting of fibrinogen in blood plasma. 25. Spojine s formulo III po zahtevku 22, kjer pomeni X skupino Xl in vsaj eden izmed Rl, R² in Q ni H, ali kjer je X skupina X², kot tudi spojine s formulo IV po zahtevku 22, kjer pomeni M skupino M^, ali če je X^ skupina Χ^², ali če je X^ skupina X^1 in istočasno Q ni H in/ali če je A alkil ali cikloalkil, tedaj M lahko stoji tudi za eno izmed skupin M² do M^.25. Compounds of formula III according to claim 22, wherein X is a group Xl and at least one of R, R ² and Q is not H or wherein X is a group X ^2, as well as a compound of formula IV according to claim 22, wherein M represents a group M ^, or if X ^ is a group Χ ^ ² , or if X ^ is a group X ^ 1 and at the same time Q is not H and / or if A is alkyl or cycloalkyl, then M may also stand for one of the groups M ² to M ^.