CS228113B2 - Production of n2-arylsulphonyl-l-argininamides and their salts - Google Patents
Production of n2-arylsulphonyl-l-argininamides and their salts Download PDFInfo
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OKAMOTO SHOSUKE, ΚΟΒΕ, KIKUMOTO RYOJI, MACHIDA,OKAMOTO SHOSUKE, ΚΟΒΕ, KIKUMOTO RYOJI, MACHIDA,
TAMAO YOSHIKUNI, YOKOHAMA, OHKUBO KAZUO, MICHADA, TEZUKA TOHRU, YOKOHAMA, TONOMURA SHINJI, TOKIO,TAMAO YOSHIKUNI, YOKOHAMA, OHKUBO KAZU, MICHADA, TEZUKA TOHRU, YOKOHAMA, TONOMURA SHINJI, TOKIO,
HIJIKATA AKIKO, ΚΟΒΕ (Japonsko)HIJIKATA AKIKO, ΚΟΒΕ (Japan)
1. MITSUBISHI CHEMICAL INDUSTRIES LIMITED, TOKIO (Japonsko)1. MITSUBISHI CHEMICAL INDUSTRIES LIMITED, TOKIO (Japan)
2. OKAMOTO SHOSUKE, ΚΟΒΕ (Japonsko) (54) Způsob výroby N2-arylsulfonyl-L-argininamidů a jejich solí2. OKAMOTO SHOSUKE, ΚΟΒΕ (Japan) (54) Method for producing N 2 -arylsulfonyl-L-argininamides and their salts
Vynález se týká způsobu výroby N2-arylsulfonyl-L-arginihamidů a jejich solí s netoxickými kyselinami, které je možno použít jako prostředků proti trombóze vzhledem k jejich velmi nízké toxicitě.The present invention relates to a process for the preparation of N 2 -arylsulfonyl-L-arginine amides and their non-toxic acid salts which can be used as anti-thrombosis agents due to their very low toxicity.
Je známa celá řada obdobných sloučenin, které mají význam při léčbě trombózy, například N2- (p-tolylsulfonyl) -L-argininové estery jsou látkami, které účinným způsobem rozpouštějí krevní sraženiny, jak bylo popsáno v US patentu č. 3 622 615.A variety of similar compounds are known to be useful in the treatment of thrombosis, for example, N 2 - (p-tolylsulfonyl) -L-arginine esters are agents that effectively dissolve blood clots, as described in US Patent No. 3,622,615.
Zvláštní skupinou sloučenin, které jsou vysoce specifickými inhibitory trombinu a jsou proto vhodné k zábraně trombózy, jsou estery nebo amidy N2-dansyl-L-argininu.A special class of compounds which are highly specific thrombin inhibitors and are therefore suitable for the prevention of thrombosis are the esters or amides of N 2 -dansyl-L-arginine.
Přesto je zapotřebí většího množství vysoce specifických inhibitorů trombinu, zejména takových, které mají nízkou toxicitu.However, a greater number of highly specific thrombin inhibitors are needed, especially those having low toxicity.
Nyní bylo zjištěno, že N2-arylsulfonyl-L-argininamidy mají antitrombotickou účinnost i velmi nízkou toxicitu při téže relativní účinnosti jako N2-dansyl-L-argininové estery nebo amidy. Tyto sloučeniny je možno vyjádřit obecným vzorcem IIt has now been found that N 2 -arylsulfonyl-L-arginine amides have both antithrombotic activity and very low toxicity at the same relative activity as N 2 -dansyl-L-arginine esters or amides. These compounds can be represented by formula (I)
HN \HN \
C—N—CH2CH2CH2CHCÓR /1 I ,C — N — CH2CH2CH2CHCOR / 1 I,
HžN H HNSO2HNN H HNSO2
Ar (I) kdeAr (I) where
R znamenáR is
1.1.
R1 /R 1 /
—N \—N \
(CH2)nCOOR2 kde(CH 2 ) n COOR 2 where
Ri znamená alkyl o 2 až 10 atomech uhlíku, alkenyl o 3 až 10 atomech uhlíku, alkinyl o 3 až 10 atomech uhlíku, alkoxyalkyl o 2 až 10 atomech uhlíku, alkylthio228113 alkyl o 2 až 10 atomech uhlíku, alkylsulfinylalkyl o 2 až 10 atomech uhlíku, hydroxyalkyl o 1 až 10 atomech uhlíku, karboxyalkyl o 2 až 10 atomech uhlíku, alkoxykarbonylalkyl o 3 až 10 atomech uhlíku, alkylkarbonylalkyl o 3 až 10 atomech uhlíku, halogenalkyl o 1 až 10 atomech uhlíku, aralkyl o 7 až 15 atomech uhlíku, a-karboxyaralkyl o 8 až 15 atomech uhlíku, cykloalkyl o 3 až 10 atomech uhlíku, cykloalkylalkyl o 4 až 10 atomech uhlíku, furfuryl, tetrahydrofurfuryl, popřípadě substituovaný alespoň ]edním alkylovým zbytkem o 1 až 5 atomech uhlíku a/nebo alkoxylovým zbytkem o 1 až 5 atomech uhlíku, 3-furylmethyl, tetrahydro-3-furylmethyl, popřípadě substituovaný alespoň jedním alkylovým zbytkem o 1 až 5 atomech uhlíku a/nebo alkoxylovým zbytkem o 1 až 5 atomech uhlíku, tetrahydro-2-(3- nebo -4-)pyranylmethyl, popřípadě substituovaný alespoň jedním alkylovým zbytkem o 1 až 5 atomech uhlíku a/ /nebo alkoxylovým zbytkem o 1 až 5 atomech uhlíku, l,4-dioxa-2-cyklohexylmethyl, popřípadě substituovaný alespoň jedním alkylovým zbytkem o 1 až 5 atomech uhlíku a/nebo alkoxylovým zbytkem o 1 až 5 atomech uhlíku, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl, popřípadě substituovaný alespoň jedním alkylovým zbytkem o 1 až 5 atomech uhlíku a/nebo alkoxylovým zbytkem o 1 až 5 atomech uhlíku, a tetrahydro-3-thenyl, popřípadě substituovaný alespoň jedním alkylovým zbytkem o 1 až 5 atomech uhlíku a/nebo alkoxylovým zbytkem o 1 až 5 atomech uhlíku,R1 is alkyl of 2 to 10 carbon atoms, alkenyl of 3 to 10 carbon atoms, alkynyl of 3 to 10 carbon atoms, alkoxyalkyl of 2 to 10 carbon atoms, alkylthio228113 alkyl of 2 to 10 carbon atoms, alkylsulfinylalkyl of 2 to 10 carbon atoms , C 1 -C 10 hydroxyalkyl, C 2 -C 10 carboxyalkyl, C 3 -C 10 alkoxycarbonylalkyl, C 3 -C 10 alkylcarbonylalkyl, C 1 -C 10 haloalkyl, C 7 -C 15 aralkyl, and -carboxyaralkyl of 8 to 15 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, cycloalkylalkyl of 4 to 10 carbon atoms, furfuryl, tetrahydrofurfuryl, optionally substituted with at least 1 to 5 carbon atoms and / or 1 to 5 alkoxy radicals 5-carbon atoms, 3-furylmethyl, tetrahydro-3-furylmethyl, optionally substituted with at least one alkyl radical of 1 to 5 carbon atoms and / or alkoxy radical of 1 to 5 carbon atoms, trahydro-2- (3- or -4-) pyranylmethyl, optionally substituted with at least one C 1 -C 5 alkyl and / or C 1 -C 5 alkoxy, 1,4-dioxa-2-cyclohexylmethyl, optionally substituted with at least one C 1 -C 5 alkyl radical and / or C 1 -C 5 alkoxy radical, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl, optionally substituted with at least one C 1 -C 5 alkyl radical, and / or (C 1 -C 5) alkoxy and tetrahydro-3-thenyl, optionally substituted with at least one C 1 -C 5 alkyl and / or C 1 -C 5 alkoxy radical,
Rž znamená atom vodíku, alkyl o 1 až 10 atomech uhlíku, aryl o 6 až 10 atomech uhlíku, aralkyl o 7 až 12 atomech uhlíku a 5-indanyl a n znamená celé číslo 1, 2 nebo 3,R @ 2 is hydrogen, alkyl of 1 to 10 carbon atoms, aryl of 6 to 10 carbon atoms, aralkyl of 7 to 12 carbon atoms and 5-indanyl and n is an integer of 1, 2 or 3,
2.2.
R3 R 3
Z —N \Z —N \
CH—(CH2]mCOOR5 R, kdeCH - (CH 2 ) m COOR 5 R where
Rs znamená atom vodíku, alkyl o 1 až 10 atomech uhlíku, alkenyl o 3 až 10 atomech uhlíku, alkinyl o 3 až 10 atomech uhlíku, alkoxyalkyl o 2 až 10 atomech uhlíku, alkylthioalkyl o 2 až 10 atomech uhlíku, alkylsulfinylalkyl o 2 až 10 atomech uhlíku, hydroxyalkyl o 1 až 10 atomech uhlíku, karboxyalkyl o 2 až 10 atomech uhlíku, alkoxykarbonylalkyl o 3 až 10 atomech uhlíku, alkylkarbonylalkyl o 3 až 10 atomech uhlíku, halogenalkyl o 1 až 10 atomech uhlíku, aralkyl o 7 až 15 atomech uhlíku, ω-karboxyaralkyl o 8 až 15 atomech uhlíku, cykloalkyl o 3 až 10 atomech uhlíku, cykloalkylalkyl o 4 až 10 atomech uhlíku, furfuryl, tetrahydrofurfuryl, popřípadě substituovaný alespoň jedním alkylovým zbytkem o 1 až 5 atomech uhlíku a/nebo alkoxylovým zbytkem o 1 až 5 atomech uhlíku, 3-furylmethyl, tetrahydro-3-furylmethyl, popřípadě substituovaný alespoň jedním alkylovým zbytkem o 1 až 5 atomech uhlíku a/nebo alkoxylovým zbytkem o 1 až 5 atomech uhlíku, tetrahydro-2-(3- nebo -4-)pyranylmethyl, popřípadě substituovaný alespoň jedním alkylovým zbytkem o 1 až 5 atomech uhlíku a/nebo alkoxylovým zbytkem o 1 až 5 atomech uhlíku, l,4-dioxa-2-cyklohexylmethyl, popřípadě substituovaný alespoň jedním alkylovým zbytkem o 1 až 5 atomech uhlíku a/nebo alkoxylovým zbytkem o l až 5 atomech uhlíku, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl, popřípadě substituovaný alespoň jedním alkylovým zbytkem o 1 až 5 atomech uhlíku a/nebo alkoxylovým zbytkem o 1 až 5 atomech uhlíku a tetrahydro-3-thenyl, popřípadě substituovaný alespoň jedním alkylovým zbytkem o 1 až 5 atomech uhlíku a/nebo alkoxylovým zbytkem o 1 až 5 atomech uhlíku,R 5 is hydrogen, alkyl of 1 to 10 carbon atoms, alkenyl of 3 to 10 carbon atoms, alkynyl of 3 to 10 carbon atoms, alkoxyalkyl of 2 to 10 carbon atoms, alkylthioalkyl of 2 to 10 carbon atoms, alkylsulfinylalkyl of 2 to 10 carbon atoms, hydroxyalkyl of 1 to 10 carbon atoms, carboxyalkyl of 2 to 10 carbon atoms, alkoxycarbonylalkyl of 3 to 10 carbon atoms, alkylcarbonylalkyl of 3 to 10 carbon atoms, haloalkyl of 1 to 10 carbon atoms, aralkyl of 7 to 15 carbon atoms , ω-carboxyaralkyl of 8 to 15 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, cycloalkylalkyl of 4 to 10 carbon atoms, furfuryl, tetrahydrofurfuryl, optionally substituted by at least one alkyl radical of 1 to 5 carbon atoms and / or alkoxy radical of 1 up to 5 carbon atoms, 3-furylmethyl, tetrahydro-3-furylmethyl, optionally substituted with at least one alkyl radical of 1 to 5 carbon atoms and / or alkoxy radical of 1 to 5 carbon atoms tetrahydro-2- (3- or -4-) pyranylmethyl, optionally substituted with at least one C 1 -C 5 alkyl radical and / or C 1 -C 5 alkoxy radical, 1,4-dioxa-2-cyclohexylmethyl, optionally substituted with at least one C 1 -C 5 alkyl and / or C 1 -C 5 alkoxy, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl, optionally substituted with at least one C 1 -C 5 alkyl radical, and / or (C 1 -C 5) alkoxy and tetrahydro-3-thenyl, optionally substituted with at least one C 1 -C 5 alkyl and / or C 1 -C 5 alkoxy radical,
R< znamená alkyl o 1 až 10 atomech uhlíku, karboxyl, alkoxykarbonyl o 2 až 10 atomech uhlíku, fenyl, popřípadě substituovaný alespoň jedním alkylovým zbytkem o 1 až 5 atomech uhlíku a/nebo alkoxylovým zbytkem o 1 až 5 atomech uhlíku, aralkyl o 7 až 12 atomech uhlíku a na jádře substituovaný benzyl, kde substituentem je alkyl o 1 až 5 atomech uhlíku nebo alkoxyl o 1 až 5 atomech uhlíku,R @ 1 represents alkyl of 1 to 10 carbon atoms, carboxyl, alkoxycarbonyl of 2 to 10 carbon atoms, phenyl, optionally substituted with at least one alkyl radical of 1 to 5 carbon atoms and / or alkoxy radical of 1 to 5 carbon atoms, aralkyl of 7 up to 12 carbon atoms and benzyl substituted on the nucleus, wherein the substituent is an alkyl of 1 to 5 carbon atoms or an alkoxy of 1 to 5 carbon atoms,
Rs znamená atom vodíku, alkyl o 1 až 10 atomech uhlíku, aryl o 6 až 10 atomech) uhlíku, aralkyl o 7 až 12 atomech uhlíku nebo 5-indanyl a m znamená celé číslo 0, 1 nebo 2,R5 is hydrogen, alkyl of 1 to 10 carbon atoms, aryl of 6 to 10 carbon atoms, aralkyl of 7 to 12 carbon atoms or 5-indanyl and m is an integer of 0, 1 or 2,
3.3.
kdewhere
Re znamená skupinu —COORe, kde Rs znamená atom vodíku, alkyl o 1 až 10 atomech uhlíku, aryl o 6 až 10 atomech uhlíku, aralkyl o 7 až 12 atomech uhlíku a 5-indanyl,R 6 is -COOR 6 wherein R 5 is hydrogen, alkyl of 1 to 10 carbon atoms, aryl of 6 to 10 carbon atoms, aralkyl of 7 to 12 carbon atoms, and 5-indanyl,
R7 znamená atom vodíku, alkyl o 1 až 10 atomech uhlíku, fenyl, alkoxyskupinu o 1 až 5 atomech uhlíku nebo karboxyskupinu, p je celé číslo 1 až 5,R 7 is hydrogen, C 1 -C 10 alkyl, phenyl, C 1 -C 5 alkoxy or carboxy, p is an integer of 1 to 5,
Re je substituován v poloze 2 nebo 3,Re is substituted in the 2 or 3 position,
R7 může být substituován v poloze 2, 3, 4, 5 nebo 6,R 7 may be substituted at the 2, 3, 4, 5 or 6 position,
4.4.
COOR* uhlíku, fenyl, popřípadě substituovaný alespoň jedním substituentem ze skupiny atom halogenu, nitroskupina, kyanoskupina, hydroxyskupina, alkyl o 1 až 10 atomech uhlíku, alkoxyl o 1 až 10 atomech uhlíku a dialkylaminoskupina o 2 až 20 atomech uhlíku, dále může Ar znamenat aralkyl o 7 až 12 atomech uhlíku, nebo skupiny přičemž tato skupina je popřípadě substituována alespoň jedním alkylovým zbytkem o 1 až 5 atomech uhlíku a/nebo alkoxylovým zbytkem o 1 až 5 atomech uhlíku, kdeCOOR * carbon, phenyl, optionally substituted with at least one of halogen, nitro, cyano, hydroxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, and C 2 -C 20 dialkylamino; (C až-Calkyl) aralkyl group or group, which group is optionally substituted by at least one C 5-C / alkyl group and / or C alko-Cyl alkoxy group wherein:
Rg znamená atom vodíku, alkyl o 1 až 10 atomech uhlíku, aryl o 6 až 10 atomech uhlíku, aralkyl o 7 až 12 atomech uhlíku aR 8 is hydrogen, alkyl of 1 to 10 carbon atoms, aryl of 6 to 10 carbon atoms, aralkyl of 7 to 12 carbon atoms, and
5-indanyl a r znamená celé číslo 1, 2, 3 nebo 4,5-indanyl and r is an integer of 1, 2, 3 or 4,
5.5.
-N Z W (City kde-N Z W (City where
Rio znamená atom vodíku, alkyl o 1 až 10 atomech uhlíku, aryl o 6 až 10 atomech uhlíku, aralkyl o 7 až 12 atomech uhlíku a 5-indanyl,R 10 is hydrogen, alkyl of 1 to 10 carbon atoms, aryl of 6 to 10 carbon atoms, aralkyl of 7 to 12 carbon atoms, and 5-indanyl,
Z znamená oxyskupinu, thioskupinu nebo sulflnylovou skupinu a q znamená celé číslo 0 nebo 1,Z represents an oxy group, a thio group or a sulfinyl group and q represents an integer of 0 or 1,
6.6.
kdewhere
Ru znamená atom vodíku, alkyl o 1 až 10 atomech uhlíku, aryl o 6 až 10 atomech uhlíku, aralkyl o 7 až 12 atomech uhlíku a 5-indanyl, i znamená celé číslo 0, 1 nebo 2, j znamená celé číslo 0, 1 nebo 2, součet i + j je roven 1 nebo 2 a Ar znamená neiftyl, 5,6,7,8-tetrahydronaftyl, popřípadě substituovaný alespoň jedním alkylovým zbytkem o 1 až 5 atomech uhlíku a/nebo alkoxylovým zbytkem o 1 až 5 atomech uhlíku, naftyl, popřípadě substituovaný alespoň jedním substituentem ze skupiny atom halogenu, nitroskupina, kyanoskupina, hydroxyl, alkyl o 1 až 10 atomech! uhlíku, alkoxyl o 1 až 10 atomech uhlíku, dialkylaminoskupína o 2 až 20 atomechR 1 is hydrogen, C 1 -C 10 alkyl, C 6 -C 10 aryl, C 7 -C 12 aralkyl and 5-indanyl; i is an integer of 0, 1 or 2, j is an integer of 0, 1 or 2, the sum of i + j is 1 or 2 and Ar is neiftyl, 5,6,7,8-tetrahydronaphthyl, optionally substituted with at least one C 1 -C 5 alkyl radical and / or C 1 -C 5 alkoxy radical , naphthyl, optionally substituted with at least one of halogen, nitro, cyano, hydroxyl, alkyl of 1 to 10 atoms; C 1 -C 10 alkoxy, C 2 -C 20 dialkylamino
popřípadě substituovaný alespoň jedním alkylovým zbytkem o 1 až 5 atomech uhlíku a/nebo alkoxylovým zbytkem o 1 až 5 atomech uhlíku, kdeoptionally substituted with at least one C 1 -C 5 alkyl and / or C 1 -C 5 alkoxy radical, wherein:
R12 znamená atom vodíku, alkyl o 1 až 10 atomech uhlíku nebo alkoxyl o 1 až 10 atomech uhlíku.R 12 represents a hydrogen atom, an alkyl of 1 to 10 carbon atoms or an alkoxy of 1 to 10 carbon atoms.
Stejně účinné jsou i z farmaceutického hlediska přijatelné soli uvedených sloučenin. Tyto látky jsou vhodné k inhibici účinnosti a aktivace trombinu in vivo. Tohoto účinku se dosáhne tím způsobem, že se aplikuje účinná dávka sloučeniny obecného vzorce I nebo její soli.The pharmaceutically acceptable salts of the compounds are equally effective. These agents are useful for inhibiting the activity and activation of thrombin in vivo. This effect is achieved by administering an effective dose of a compound of formula I or a salt thereof.
Vynález se tedy týká způsobu výroby N2-arylsulfonyl-L-argininamidu obecného vzorceIThe invention therefore relates to a process for the preparation of N 2 -arylsulfonyl-L-argininamide of the formula I
HN' \HN '\
e_N—CH2CH2CH2CHCOR /ZZ I Ie_N — CH2CH2CH2CHCOR / ZZ11
(CH2)nCOOR2 kde(CH 2 ) n COOR 2 where
Ri znamená alkyl o 2 až 10 atomech uhlíku, ethyl, propyl, butyl, isobutyl, pentyl,. hexyl, oktyl, decyl, apod., alkenyl o 3 až 10 (s výhodou 3 až 6) atomech uhlíku, jako allyl, 2-butenyl, 3-butenyl, 2-pentenyl apod., alkinyl o 3 až 10 (s výhodou 3 až 6) atomech uhlíku, jako 2-propinyl, 2-butinyl, 3-butinyl ap., alkoxyalkyl o 2 až 10 atomech uhlíku (s výhodou 2 až 6 atomech uhlíku), jako methoxymethyl, ethoxymethyl, propoxymethyl, 2-methoxyethyl, 2-ethoxyethyl,R1 is alkyl of 2 to 10 carbon atoms, ethyl, propyl, butyl, isobutyl, pentyl, and the like. hexyl, octyl, decyl, and the like, alkenyl of 3 to 10 (preferably 3 to 6) carbon atoms such as allyl, 2-butenyl, 3-butenyl, 2-pentenyl and the like, alkynyl of 3 to 10 (preferably 3 to 6) carbon atoms such as 2-propynyl, 2-butynyl, 3-butynyl and the like, alkoxyalkyl of 2 to 10 carbon atoms (preferably 2 to 6 carbon atoms) such as methoxymethyl, ethoxymethyl, propoxymethyl, 2-methoxyethyl, -ethoxyethyl,
2- propoxyethyl, 2-methoxypropyl, 3-methoxypropyl, 3-ethoxypropyl, 3-propoxypropyl, 4-methoxybutyl, 4-ethoxybutyl, 4-butoxybutyl, 5-butoxypentyl apod., alkylthioalkyl o 2 až 10 (s výhodou 2 až 6) atomech uhlíku, jako methylthiomethyl, ethylthiomethyl, propylthiomethyl, '2-methylthioethyl, 2-ethylthioethyl, 2-propylthioethyl,2-propoxyethyl, 2-methoxypropyl, 3-methoxypropyl, 3-ethoxypropyl, 3-propoxypropyl, 4-methoxybutyl, 4-ethoxybutyl, 4-butoxybutyl, 5-butoxypentyl and the like, alkylthioalkyl of 2 to 10 (preferably 2 to 6) carbon atoms such as methylthiomethyl, ethylthiomethyl, propylthiomethyl, 2-methylthioethyl, 2-ethylthioethyl, 2-propylthioethyl,
3- methylthiopropyl, 2-methylthlopropyl, 3-ethylthiopropyl, 3-propylthlopropyl, 4-methylthiobutyl, 4-ethylthiobutyl, 4-butylthiobutyl, 5-butylthiopentyl apod., alkylsulfinylalkyl o 2 až 10 (s výhodou 2 až 6) atomech uhlíku, jako methylsulfinylmethyl, ethylsulfinylmethyl, propylsulfinylmethyl, 2-methylsulfinylethyl, 2-ethylsulfinylethyl,3-methylthiopropyl, 2-methylthlopropyl, 3-ethylthiopropyl, 3-propylthlopropyl, 4-methylthiobutyl, 4-ethylthiobutyl, 4-butylthiobutyl, 5-butylthiopentyl and the like, alkylsulfinylalkyl of 2 to 10 (preferably 2 to 6) carbon atoms such as methylsulfinylmethyl, ethylsulfinylmethyl, propylsulfinylmethyl, 2-methylsulfinylethyl, 2-ethylsulfinylethyl,
2- propylsulflnylethyl, 3-methylsulfinylpropyl, 3-ethylsulfinylpropyl apod., hydroxyalkyl o 1 až 10 (s výhodou 1 až 6 ) atomech uhlíku, jako hydroxymethyl, 2-hydroxyethyl,2-propylsulfinyl ethyl, 3-methylsulfinylpropyl, 3-ethylsulfinylpropyl and the like, hydroxyalkyl of 1 to 10 (preferably 1 to 6) carbon atoms such as hydroxymethyl, 2-hydroxyethyl,
3- hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, 5-hydroxypentyl apod., karboxyalkyl o 2 až 10 (s výhodou 2 až 7) atomech uhlíku, jako karboxymethyl, 2-karboxyethyl, 2-karboxypropyl, 3-karboxypropyl, 1-karboxybutyl, 2-karboxybutyl,3-hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, 5-hydroxypentyl and the like, carboxyalkyl of 2 to 10 (preferably 2 to 7) carbon atoms such as carboxymethyl, 2-carboxyethyl, 2-carboxypropyl, 3- carboxypropyl, 1-carboxybutyl, 2-carboxybutyl,
4- karboxybutyl apod., alkoxykarbonylalkyl o 3 až 10 (s výhodou 3 až 8) atomech uhlíku, jako methoxykarbonylmethyl, 2-ethoxykarbonylethyl, 2-ethoxykarbonylpropyl, 3-methoxykarbonylpropyl, 1-methoxykarbonylbutyl, 2-ethoxykarbonylbutyl, 4-methoxykarbonylbutyl, alkylkarbonylalkyl o 3 až 10 atomech uhlíku, například methylkarbonylmethyl apod., halogenalkyl o 1 až 10 (s výhodou 1 až 5) atoňiech uhlíku, jako chlormethyl, 2-chlorethyl, 2-bromethyl, 2-chlorpropyl, 3-chlorpropyl, 2-chlorbutyl,4-carboxybutyl and the like, alkoxycarbonylalkyl of 3 to 10 (preferably 3 to 8) carbon atoms, such as methoxycarbonylmethyl, 2-ethoxycarbonylethyl, 2-ethoxycarbonylpropyl, 3-methoxycarbonylpropyl, 1-methoxycarbonylbutyl, 2-ethoxycarbonylbutyl, 4-methoxycarbonylbutyl, 4-methoxycarbonylbutyl 3 to 10 carbon atoms, for example methylcarbonylmethyl and the like, haloalkyl of 1 to 10 (preferably 1 to 5) carbon atoms such as chloromethyl, 2-chloroethyl, 2-bromoethyl, 2-chloropropyl, 3-chloropropyl, 2-chlorobutyl,
4-chlorbutyl apod., aralkyl o 7 až 15 (s výhodou 7 až 10) atomech uhlíku, jako benzyl, fenethyl, 3-fenylpropyl, 4-fenylbutyl, 6-fenylhexyl, 1-fenylethyl, 2-fenylpropyl ap., ai-karboxyaralkyl o 8 až 15 (s výhodou 8 až 12) atomech uhlíku, jako a-karboxybenzyl, α-karboxyfenethyl apod., cykloalkyl o 3 až 10 atomech uhlíku, jako cyklopropyl, cyklobutyl, cyklopentyl, cyklohexyl, cykloheptyl, cyklooktyl, cyklononyl nebo cyklodecyl, cykloalkylalkyl o 4 až 10 atomech uhlíku, jako cyklopropylmethyl, cyklopentylmethyl, cyklohexylmethyl, 2-cyklohexylethyl, cyklooktylmethyl apod., furfuryl, tetrahydrofurfuryl, popřípadě substituovaný alespoň jedním alkylovým zbytkem o 1 až 5 atomech uhlíku a/nebo alkoxylovým zbytkem o 1 až 5 atomech uhlíku, 3-furylmethyl, tetrahydro-3-furylmethyl, popřípadě substituovaný alespoň jedním alkylovým zbytkem o 1 až 5 atomech uhlíku a/nebo alkoxylovým zbytkem o 1 až 5 atomech uhlíku, tetrahydro-2-(3- nebo -4-)pyranylmethyl, popřípadě substituovaný alespoň jedním alkylovým zbytkem o 1 až 5 atomech uhlíku a/nebo alkoxylovým zbytkem o 1 až 5 atomech uhlíku, l,4-dioxa-2-cyklohexylmethyl, popřípadě substituovaný alespoň jedním alkylovým zbytkem o 1 až 5 atomech uhlíku a/nebo alkoxylovým zbytkem o 1 až 5 atomy uhlíku, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl, popřípadě substituovaný alespoň jedním alkylovým zbytkem o 1 až 5 atomech uhlíku a/nebo alkoxylovým zbytkem o 1 až 5 atomech uhlíku, a tetrahydro-3-thenyl, popřípadě substituovaný alespoň jedním alkylovým zbytkem o 1 až 5 atomech uhlíku a/nebo alkoxylovým zbytkem o 1 až 5 atomech uhlíku, nebo substituovaný pyranyl, Rz znamená atom vodíku, alkyl o 1 až 10 atomech uhlíku, jako methyl, ethyl, propyl, butyl, terc.butyl, hexyl, aryl o 6 až 10 atomech uhlíku, jako fenyl, m-tolyl, naftyl apod., aralkyl o 7 až 12 (s výhodou 7 až 10) atomech uhlíku, jako benzyl, fenethyl apod. a 5-indanyl a n znamená celé číslo 1, 2 nebo 3,4-chlorobutyl and the like, aralkyl of 7 to 15 (preferably 7 to 10) carbon atoms such as benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 6-phenylhexyl, 1-phenylethyl, 2-phenylpropyl and the like; carboxyaralkyl of 8 to 15 (preferably 8 to 12) carbon atoms such as α-carboxybenzyl, α-carboxyphenethyl and the like, cycloalkyl of 3 to 10 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl , C 4 -C 10 cycloalkylalkyl such as cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclohexylethyl, cyclooctylmethyl and the like, furfuryl, tetrahydrofurfuryl, optionally substituted with at least one C 1 -C 5 alkyl radical and / or C 1 -C 5 alkoxy radical carbon, 3-furylmethyl, tetrahydro-3-furylmethyl, optionally substituted with at least one C 1 -C 5 alkyl and / or C 1 -C 5 alkoxy, tetrahydro-2- (3- or -4-) pyranylmethyl, eventually substituted with at least one C 1 -C 5 alkyl and / or C 1 -C 5 alkoxy, 1,4-dioxa-2-cyclohexylmethyl, optionally substituted with at least one C 1 -C 5 alkyl and / or alkoxy C 1 -C 5 radical, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl, optionally substituted with at least one C 1 -C 5 alkyl radical and / or C 1 -C 5 alkoxy radical, and tetrahydro-3 -thenyl, optionally substituted with at least one C 1 -C 5 alkyl radical and / or C 1 -C 5 alkoxy radical, or substituted with pyranyl, R 2 represents hydrogen, C 1 -C 10 alkyl such as methyl, ethyl, propyl , butyl, tert-butyl, hexyl, aryl of 6 to 10 carbon atoms such as phenyl, m-tolyl, naphthyl and the like, aralkyl of 7 to 12 (preferably 7 to 10) carbon atoms such as benzyl, phenethyl and the like, and 5-indanyl and n are an integer of 1, 2 or 3,
2. skupinu2nd group
R3 R 3
ZOF
-N \-N \
CH— (CH2)mCOOR5 CH (CH 2 ) m COOR 5
Rš kdeRš kde
Rs znamená atom vodíku, alkyl o 1 až 10 atomech uhlíku, jako methyl, ethyl, propyl, butyl, isobutyl, pentyl, hexyl, oktyl, decyl apod., alkenyl o 3 až 10 (s výhodou 3 až 6) atomech uhlíku, jako allyl, 2-butenyl, 3-butenyl, 2-pentenyl apod., alkinyl o 3 až (s výhodou 3 až 6) atomech uhlíku, jako 2-propinyl, 2-butinyl, 3-butinyl apod., alkoxyalkyl o 2 až 10 atomech uhlíku (s výhodou 2 až 6 atomech uhlíku), jako methoxymethyl, ethoxymethyl, propoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-propoxyethyl, 2-methoxypropyl, 3-methoxypropyl,R 5 represents a hydrogen atom, an alkyl of 1 to 10 carbon atoms such as methyl, ethyl, propyl, butyl, isobutyl, pentyl, hexyl, octyl, decyl and the like; alkenyl of 3 to 10 (preferably 3 to 6) carbon atoms such as allyl, 2-butenyl, 3-butenyl, 2-pentenyl and the like, alkynyl of 3 to (preferably 3 to 6) carbon atoms such as 2-propynyl, 2-butynyl, 3-butynyl and the like, alkoxyalkyl of 2 to 10 carbon atoms (preferably 2 to 6 carbon atoms) such as methoxymethyl, ethoxymethyl, propoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-propoxyethyl, 2-methoxypropyl, 3-methoxypropyl,
3- ethoxypropyl, 3-propoxypropyl, 4-methoxybutyl, 4-ethoxybutyl, 4-butoxybutyl, 5-butoxypentyl apod., alkylthioalkyl o 2 až 10 atomech uhlíku (s výhodou 2 až 6 atomech uhlíku), jako methylthiomethyl, ethylthiomethyl, propylthiomethyl, 2-methylthioethyl, 2-ethylthioethyl, 2-propylthioethyl, 3-methylt:hiopropyl, 2-methylthiopropyl, 3-ethylthiopropyl, 3-propylthiopropyl,3-ethoxypropyl, 3-propoxypropyl, 4-methoxybutyl, 4-ethoxybutyl, 4-butoxybutyl, 5-butoxypentyl and the like, alkylthioalkyl of 2 to 10 carbon atoms (preferably 2 to 6 carbon atoms) such as methylthiomethyl, ethylthiomethyl, propylthiomethyl, 2-methylthioethyl, 2-ethylthioethyl, 2-propylthioethyl, 3-methylthiopropyl, 2-methylthiopropyl, 3-ethylthiopropyl, 3-propylthiopropyl,
4- methylthiobutyl, 4-ethylthiobutyl, 4-butylthiobutyl, 5-butylthiopentyl apod., alkylsulfinylalkyl o 2 až 10 (s výhodou 2 až 6) atomech uhlíku, jako methylsulfinylmethyl, ethylsulfinylmethyl, propylsulfinylmethyl, 2-methylsulfinylethyl, 2-ethylsulfinylethyl, 2-propylsulfinylethyl, 3-methylsulfinylpropyl, 3-ethylsulíinylpropyl apod., hydroxyalkyl o 1 až 10 (s výhodou 1 až 6) atomech uhlíku, jako hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, 5-hydroxypentyl apod., karboxyalkyl o 2 až 10 (s výhodou 2 až 7) atomech uhlíku, jako karboxymethyl, 2-karboxyethyl, 2-karboxypropyl, 3-karboxypropyl, 1-karboxybutyl, 2-karboxybutyl, 4-karboxybutyl apod., alkoxykarbonylalkyl o 3 až 10 (s výhodou 3 až 8) atomech uhlíku, jako methoxykarbonylmethyl, 2-methoxykarbonylethyl, 2-ethoxykarbonylpropyl, 3-methoxykarbonylpropyl, l-methoxyk:arbonylbutyl, 2-ethoxykarbonylbutyl, 4-méthoxykarbonylbutyl apod., alkylkarbonylalkyl o 3 až 10 atomech uhlíku, například methylkarbonylmethyl apod., halogenalkyl o 1 až 10 (s výhodou 1 až 5) atomech uhlíku, jako chlormethyl, 2-chlorethyl, 2-bromethyl, 2-chlorpropyl, 3-chlor. propyl, 2-chlorbutyl, 4-chiorbutyl apod., aralkyl o 7 až 15 (s výhodou 7 až 10) atomech uhlíku, jako benzyl, fenethyl, 3-fenylpropyl, 4-fenylbutyl, 6-fenylhexyl, 1-fenylethyl, 2-fenylpropyl apod., a-karboxyaralkyl o 8 až 15 (s výhodou 8 až 12) atomech uhlíku, jako α-karboxybenzyl, a-karboxyfenethyl apod., cykloalkyl o 3 až 10 atomech uhlíku, jako cyklopropyl, cyklobutyl, cyklopentyl, cyklohexyl, cykloheptyl, cyklooktyl, cyklononyl nebo cyklodecyl, cykloalkylalkyl o 4 až 10 atomech uhlíku, jako cyklopropylmethyl, cyklopentylmethyl, cyklohexylmethyl, 2-cyklohexylethyl, cyklooktylmethyl apod., furfuryl, tetrahydrofurfuryl, popřípadě substituovaný alespoň jedním alkylovým zbytkem o 1 až 5 atomech uhlíku a/nebo alkoxylovým zbytkem o 1 až 5 atomech uhlíku, 3-furylmethyl, tetrahydro-3-furylmethyl, popřípadě substituovaný alespoň jedním alkylovým zbytkem o 1 až 5 atomech uhlíku a/nebo alkoxylovým zbytkem o 1 až 5 atomech uhlíku, tetrahydro-2104-methylthiobutyl, 4-ethylthiobutyl, 4-butylthiobutyl, 5-butylthiopentyl and the like, alkylsulfinylalkyl of 2 to 10 (preferably 2 to 6) carbon atoms such as methylsulfinylmethyl, ethylsulfinylmethyl, propylsulfinylmethyl, 2-methylsulfinylethyl, 2-ethylsulfinylethyl, 2- propylsulfinylethyl, 3-methylsulfinylpropyl, 3-ethylsulfinylpropyl and the like, hydroxyalkyl of 1 to 10 (preferably 1 to 6) carbon atoms such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, 5-hydroxypentyl and the like, carboxyalkyl of 2 to 10 (preferably 2 to 7) carbon atoms such as carboxymethyl, 2-carboxyethyl, 2-carboxypropyl, 3-carboxypropyl, 1-carboxybutyl, 2-carboxybutyl, 4-carboxybutyl and the like, alkoxycarbonylalkyl of 3 to 10 (preferably 3 to 8) carbon atoms such as methoxycarbonylmethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylpropyl, 3-methoxycarbonylpropyl, 1-methoxycarbonylbutyl, 2-ethoxycarbonylbutyl, 4-methoxybutyl, 4-methoxybutyl, 4-methoxybutyl, 4-methoxybutyl; 10 atoms carbon atoms such as methylcarbonylmethyl and the like, haloalkyl of 1 to 10 (preferably 1 to 5) carbon atoms such as chloromethyl, 2-chloroethyl, 2-bromoethyl, 2-chloropropyl, 3-chloro. propyl, 2-chlorobutyl, 4-chlorobutyl and the like, aralkyl of 7 to 15 (preferably 7 to 10) carbon atoms such as benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 6-phenylhexyl, 1-phenylethyl, 2- phenylpropyl and the like, α-carboxyaralkyl of 8 to 15 (preferably 8 to 12) carbon atoms such as α-carboxybenzyl, α-carboxyphenethyl and the like, cycloalkyl of 3 to 10 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl , cyclooctyl, cyclononyl or cyclodecyl, cycloalkylalkyl of 4 to 10 carbon atoms, such as cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclohexylethyl, cyclooctylmethyl and the like, furfuryl, tetrahydrofurfuryl, optionally substituted with at least one alkyl radical of 1 to 5 carbon atoms and / or alkoxy C 1 -C 5 radical, 3-furylmethyl, tetrahydro-3-furylmethyl optionally substituted by at least one C 1 -C 5 alkyl radical and / or C 1 -C 5 alkoxy radical, tetrahydro-210
-(3- nebo -4-jpyranylmethyl, popřípadě substituovaný alespoň jedním alkylovým zbytkem o 1 až 5 atomech uhlíku a/nebo alkoxylovým zbytkem o 1 až 5 atomech uhlíku, l,4-dioxa-2-cyklohexylmethyl, popřípadě substituovaný alespoň jedním alkylovým zbytkem o 1 až 5 atomech uhlíku a/nebo alkoxylovým zbytkem o 1 až 5 atomech uhlíku, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl, popřípadě substituovaný alespoň jedním alkylovým zbytkem o 1 až 5 atomech uhlíku a/nebo alkoxylovým zbytkem o 1 až 5 atomech uhlíku a tetrahydro-3-thenýl, popřípadě substituovaný alespoň jedním alkylovým zbytkem o 1 až 5 atomech uhlíku a/ /nebo alkoxylovým zbytkem o 1 až 5 atomech uhlíku, Rí znamená alkyl o 1 až 10 (s výhodou 1 až 5) atomech uhlíku, jako methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sek.butyl, pentyl apod., karboxyskupinu, alkoxykarbonyl o 2 až 10 (s výhodou 2 až 5) atomech uhlíku, jako methoxykarbonyl, ethoxykarbonyl, propoxykarbonyl apod., fenyl, popřípadě substituovaný alespoň jedním alkylovým zbytkem o 1 až 5 atomech uhlíku a/nebo alkoxylovým zbytkem o 1 až 5 atomech uhlíku, aralkyl o 7 až 12 (s výhodou 7 až 10) atomech uhlíku, jako benzyl, fenethyl apod., a na jádře substituovaný benzyl, kde substituentem je alkyl o 1 až 5 (s výhodou 1 až 3) atomech uhlíku, jako methyl, ethyl, propyl nebo isopropyl nebo alkoxyl o 1 až 5 (s výhodou 1 až 3] atomech uhlíku, jako methoxyl, ethoxyl, propoxyl nebo isopropoxyl, Rs znamená atom vodíku, alkyl o 1 až 10 atomech uhlíku, jako methyl, ethyl, propyl, butyl, terc.butyl, hexyl, oktyl, decyl apod., aryl o 6 až 10 atomech uhlíku, jako fenyl, m-tolyl, naftyl apod., aralkyl o 7 až 12 (s výhodou 7 až 10) atomech uhlíku, jako benzyl, fenethyl apod., a 5-indanyl a m znamená celé číslo 0, 1 nebo 2,- (3- or -4-pyranylmethyl) optionally substituted with at least one C 1 -C 5 alkyl and / or C 1 -C 5 alkoxy, 1,4-dioxa-2-cyclohexylmethyl optionally substituted with at least one alkyl radical C 1 -C 5 and / or C 1 -C 5 alkoxy, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl, optionally substituted with at least one C 1 -C 5 alkyl and / or alkoxy radical; C1-C5 and tetrahydro-3-thenyl optionally substituted by at least one C1-C5 alkyl and / or C1-C5 alkoxy radical, R1 is C1-C10 alkyl (preferably 1-5) carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl and the like, carboxy, alkoxycarbonyl of 2 to 10 (preferably 2 to 5) carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and the like; , phenyl optionally substituted with at least one C 1 -C 5 alkyl radical and / or C 1 -C 5 alkoxy radical, aralkyl C 7-12 (preferably 7 to 10) carbon atoms such as benzyl, phenethyl and the like, and on the nucleus substituted benzyl, wherein the substituent is alkyl of 1 to 5 (preferably 1 to 3) carbon atoms such as methyl, ethyl, propyl or isopropyl, or alkoxy of 1 to 5 (preferably 1 to 3) carbon atoms such as methoxy, ethoxy, propoxy or isopropoxy, R 5 represents a hydrogen atom, an alkyl of 1 to 10 carbon atoms, such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl, decyl and the like, aryl of 6 to 10 carbon atoms such as phenyl, m -olyl, naphthyl and the like, aralkyl of 7 to 12 (preferably 7 to 10) carbon atoms such as benzyl, phenethyl and the like, and 5-indanyl and m is an integer of 0, 1 or 2,
3.3.
(Rj)p kde ' R6 je —COORe, kde Rs znamená atom vodíku, alkyl o 1 až 10 atomech uhlíku, jako methyl, ethyl, propyl, butyl, terc.butyl, hexyl, oktyl, decyl apod., aryl o 6 až 10 atomech uhlíku, jako fenyl, m-tolyl, naftyl a podobně, aralkyl o 7 až 12 (s výhodou 7 až 10) atomech uhlíku, jako benzyl, fenethyl apod. a 5-indanyl, (R7)D je atom vodíku, alkyl o 1 áž 10 (s výhodou 1 až 6] atomech uhlíku, jako methyl, ethyl, propyl, isopropyl, butyl, hexyl, oktyl, decyl apod., fenyl, alkoxyl o 1 až 5 atomech uhlíku nebo karboxyl, p je celé číslo 1 až 5, Re je substituován v poloze 2 nebo 3 a Rz je popřípadě substituován v poloze 2, 3, 4, 5 nebo 6,(R j) p wherein R 6 is -COOR e, wherein R 5 is hydrogen, C 1 -C 10 alkyl such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl, decyl and the like, aryl of 6 to 6 10 carbon atoms such as phenyl, m-tolyl, naphthyl and the like, aralkyl of 7 to 12 (preferably 7 to 10) carbon atoms such as benzyl, phenethyl and the like, and 5-indanyl, (R 7) D is hydrogen, alkyl of 1 to 10 (preferably 1 to 6) carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, hexyl, octyl, decyl and the like, phenyl, C 1 -C 5 alkoxy or carboxyl, p is an integer of 1 to 5, R 6 is substituted at the 2 or 3 position and R 2 is optionally substituted at the 2, 3, 4, 5 or 6 position,
4.4.
COORs popřípadě substituovaný alespoň jedním alkylovým zbytkem o 1 až 5 atomech Uhlíku a/nebo alkoxylovým zbytkem o 1 až 5 atomech uhlíku, kde R9 znamená atom vodíku, alkyl o 1 až 10 atomech uhlíku, jako methyl, ethyl, propyl, butyl, terc.butyl, hexyl, oktyl, decyl apod., aryl o 6 až 10 atomech uhlíku, jako fenyl, m-tolyl, naftyl a podobně, aralkyl o 7 až 12 (s výhodou 7 až 10] atomech uhlíku, jako benzyl, fenethyl apod. a 5-indanyl a r znamená celé číslo 1, 2, 3 nebo 4,COOR 5 optionally substituted with at least one C 1 -C 5 alkyl radical and / or C 1 -C 5 alkoxy radical wherein R 9 is hydrogen, C 1 -C 10 alkyl such as methyl, ethyl, propyl, butyl, tert. butyl, hexyl, octyl, decyl and the like; aryl of 6 to 10 carbon atoms such as phenyl, m-tolyl, naphthyl and the like; aralkyl of 7 to 12 (preferably 7 to 10) carbon atoms such as benzyl, phenethyl and the like. and 5-indanyl ar is an integer of 1, 2, 3 or 4,
5. '5. '
COOR1CU COOR 1CU
-N Z (CH^ kde-NZ (CH 2 where
R10 znamená atom vodíku, alkyl o 1 až 10 atomech uhlíku, jako methyl, ethyl, propyl, butyl, terc.butyl, hexyl, Oktyl, decyl a podobně, aryl o 6 až 10 atomech uhlíku, jako fenyl, m-tolyl, naftyl apod., aralkyl o 7 až 12 (s výhodou 7 až 10) atomech uhlíku, jako benzyl, fenethyl apod. a 5-indanyl, Z znamená oxyskupinu (—O—·), thioskuplnu (—S—·) a sulfinylovou skupinu (—SO—), q je celé číslo 0 nebo 1 aR 10 represents a hydrogen atom, an alkyl of 1 to 10 carbon atoms such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl, decyl and the like, aryl of 6 to 10 carbon atoms such as phenyl, m-tolyl, naphthyl and the like, aralkyl of 7 to 12 (preferably 7 to 10) carbon atoms such as benzyl, phenethyl and the like, and 5-indanyl, Z is oxy (-O-), thioscycline (-S-), and sulfinyl ( —SO—), q is an integer of 0 or 1 and
6.6.
COORn kdeCOORn where
R11 znamená atom vodíku, alkyl o 1 až 10 atomech uhlíku, jako methyl, ethyl, propyl, butyl, terc.butyl, hexyl, oktyl, decyl apod., aryl o 6 až 10 atomech uhlíku, jako fenyl, m-tolyl, naftyl apod., aralkyl o 7 až 12 (s výhodou 7 až 10) atomech uhlíku, jako benzyl, fenethyl apod. a 5-indanyl, i znamená celé číslo 0, 1 nebo 2, j je celé číslo 0, 1 nebo 2 a součet i + j je roven 1 nebo 2, a Ar znamená naftyl, jako 1-naftyl a 2-naftyl, 5,6,7,8-tetrahydronaftyl, popřípadě substituovaný alespoň jedním alkylovým zbytkem o 1 až 5 atomech uhlíku a/nebo alkoxylovým zbytkem o 1 až 5 atomech uhlíku, jako 5,6,7,8-tetrahydro-l-naftyl a 5,6,7,8-tetrahydro-2-naftyl, naftyl, substituovaný alespoň jedním substituentem ze skupiny atom halogenu, jako fluoru, chloru, bromu a jodu, nitroskupinou, kyanoskupinou, hydroxyskupinou, alkylem o 1 až 10 (s výhodou 1 až 5) atomech uhlíku, jako je methyl, ethyl, propyl, isopropyl, butyl, isobutyl apod., alkoxylem o 1 až 10 {s výhodou 1 až 5) atomech uhlíku, jako je methoxyl, ethoxyl, propoxyl, isopropoxyl, butoxyl, sek.butoxyl, terc.butoxyl, pentyloxyl apod. a dialkylaminoskupinou o 2 až 20 (s výhodou 2 až 10) atomech uhlíku, jako je dimethylaminoskupina, diethylamlnoskupina, N-methyl-N-ethylaminoskupina, apod., fenyl, fenyl substituovaný alespoň jedním substituentem ze skupiny atom halogenu, jako fluoru, chloru, bromu a jodu, nitroskupinu, kyanoskupinu, hydroxyskupinu, alkyl o 1 až 10 (s výhodou 1 až 5) atomech uhlíku, jako methyl, ethyl, propyl, isopropyl, butyl, isobutyl apod., alkoxyl o 1 až 10 (s výhodou 1 až 5) atomech uhlíku, jako methoxyl, ethoxyl, propoxyl, isopropoxyl, butoxyl, sek.butoxyl, terc.butoxyl, pentyloxyl apod., a dialkylaminoskupina o 2 až 20 (s výhodou 2 až 10) atomech uhlíku, jako dimethylaminoskupina, diethylaminoskupina, N-methyl-N-ethylaminoskupina apod., aralkyl o 7 až 12 (s výhodou 7 až 10) atomech uhlíku, jako benzyl, fenethyl apod.,R11 represents hydrogen, alkyl of 1 to 10 carbon atoms such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl, decyl and the like, aryl of 6 to 10 carbon atoms such as phenyl, m-tolyl, naphthyl and the like, aralkyl of 7 to 12 (preferably 7 to 10) carbon atoms such as benzyl, phenethyl and the like and 5-indanyl, i is an integer of 0, 1 or 2, j is an integer of 0, 1 or 2 and the sum i + j is 1 or 2, and Ar is naphthyl, such as 1-naphthyl and 2-naphthyl, 5,6,7,8-tetrahydronaphthyl, optionally substituted with at least one C 1 -C 5 alkyl radical and / or an alkoxy radical of 1 to 5 carbon atoms, such as 5,6,7,8-tetrahydro-1-naphthyl and 5,6,7,8-tetrahydro-2-naphthyl, naphthyl, substituted with at least one substituent from the group halogen, such as fluorine, chlorine, bromine and iodine, nitro, cyano, hydroxy, alkyl of 1 to 10 (preferably 1 to 5) carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and the like, alkoxy of 1 to 10 {s you suitable for 1 to 5) carbon atoms such as methoxy, ethoxy, propoxyl, isopropoxyl, butoxyl, sec-butoxy, tert-butoxyl, pentyloxy and the like and a dialkylamino group of 2 to 20 (preferably 2 to 10) carbon atoms such as dimethylamino , diethylamino, N-methyl-N-ethylamino, and the like, phenyl, phenyl substituted with at least one of halogen, such as fluorine, chlorine, bromine and iodine, nitro, cyano, hydroxy, alkyl of 1 to 10 (preferably 1 up to 5) carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and the like, alkoxy of 1 to 10 (preferably 1 to 5) carbon atoms such as methoxy, ethoxy, propoxyl, isopropoxyl, butoxyl, sec-butoxyl , t-butoxy, pentyloxy and the like, and a dialkylamino group of 2 to 20 (preferably 2 to 10) carbon atoms such as dimethylamino, diethylamino, N-methyl-N-ethylamino and the like, aralkyl of 7 to 12 (preferably 7 to 12) 10) carbon atoms such as benzyl, phenethyl and the like,
popřípadě substituovaný alespoň jedním alkylovým zbytkem o 1 až 5 atomech uhlíku a/nebo alkoxylovým zbytkem o 1 až 5 atomech uhlíku, kde Riz je atom vodíku, alkyl o 1 až 10 (s výhodou 1 až 5) atomech uhlíku, jako methyl, ethyl, propyl apod., nebo alkoxyl o 1 až 10 (s výhodou 1 až 5) atomech uhlíku, jako methoxyl, ethoxyl, propoxyl apod.optionally substituted with at least one C 1 -C 5 alkyl radical and / or C 1 -C 5 alkoxy radical wherein R 8 is hydrogen, C 1 -C 10 alkyl (preferably 1 to 5), such as methyl, ethyl, propyl and the like, or alkoxy of 1 to 10 (preferably 1 to 5) carbon atoms such as methoxy, ethoxy, propoxyl and the like.
Vhodným významem Ri ve vzorci I je alkyl o 2 až 10 atomech uhlíku, jako propyl, butyl, isobutyl, pentyl, hexyl a oktyl, alkenyl o 3 až 6 atomech uhlíku, jako allyl, alkinyl o 3 až 6 atomech uhlíku jako 2-propinyl, alkoxyalkyl o 2 až 6 atomech uhlíku, jako 2-methoxyethyl, 2-methoxypropyl, 2-ethoxyethyl a 3-methoxypropyl, alkylthioalkyl o 2 až 6 atomech uhlíku, jako je 2-ethylthioethyl a 2-methylthioethyl, alkylsulfinylalkyl o 2 až 6 atomech uhlíku, jako 2-methylsulfinylethyl, hydroxyalkyl o 1 až atomech uhlíku, jako 2-hydroxyethyl a 3-hydroxybutyl, karboxyalkyl o 2 až atomech uhlíku, jako 1-karboxybutyl, alkoxykarbonylalkyl o 3 až 8 atomech uhlíku, jako 2-ethoxykarbonylethyl, aralkyl o 7 až 10 atomech uhlíku, jako benzyl a fenethyl, α-karboxyaralkyl o 8 až 12 atomech uhlíku, jako «-karboxyfenethyl, cykloalkyl o 3 až 10 atomech uhlíku, jako cykopropyl, cyklohexyl a cykloheptyl, cykloalkylalkyl o 4 až 10 atomech uhlíku, jako cyklohexylmethyl, furfuryl, tetrahydrofurfuryl, 3-furylmethyl, tetrahydro-3-furylmethyl, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl a tetrahydro-3 thenyl.A suitable meaning of R 1 in formula I is an alkyl of 2 to 10 carbon atoms such as propyl, butyl, isobutyl, pentyl, hexyl and octyl, alkenyl of 3 to 6 carbon atoms such as allyl, alkynyl of 3 to 6 carbon atoms such as 2-propynyl , (2-6C) alkoxyalkyl such as 2-methoxyethyl, 2-methoxypropyl, 2-ethoxyethyl and 3-methoxypropyl, (2-6C) alkylthioalkyl such as 2-ethylthioethyl and 2-methylthioethyl, (2-6C) alkylsulfinylalkyl; carbon such as 2-methylsulfinylethyl, hydroxyalkyl of 1 to carbon atoms such as 2-hydroxyethyl and 3-hydroxybutyl, carboxyalkyl of 2 to carbon atoms such as 1-carboxybutyl, alkoxycarbonylalkyl of 3 to 8 carbon atoms such as 2-ethoxycarbonylethyl, aralkyl o From 7 to 10 carbon atoms, such as benzyl and phenethyl, α-carboxyaralkyl of 8 to 12 carbon atoms, such as n-carboxyphenethyl, cycloalkyl of 3 to 10 carbon atoms, such as cyclopropyl, cyclohexyl and cycloheptyl, cycloalkylalkyl of 4 to 10 carbon atoms, such as cyclohexylmethyl, furfuryl, tetrah hydrofurfuryl, 3-furylmethyl, tetrahydro-3-furylmethyl, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl and tetrahydro-3-thenyl.
Výhodným významem R3 ve vzorci I je atom vodíku, alkyl o 1 až 10 atomech uhlíku, jako methyl, propyl, butyl, isobutyl, pentyl, hexyl a oktyl, alkenyl o 3 až 6 atomech uhlíku, jako allyl, alkinyl o 3 až 6 atomech uhlíku, jako 2-propinyl, alkoxyalkyl o 2 až 6 atomech uhlíku, jako 2-methoxyethyl, 2-methoxypropyl, 2-ethoxyethyl a 3-methoxypropyl, alkylthioalkyl o 2 až 6 atomech uhlíku, jako' 2-ethylthioethyl a 2-methylthioethyl, alkylsulfinylalkyl o 2 až 6 atomech uhlíku, jako 2-methylsu'finvlethyl, hydroxyalkyl o 1 až 6 atomech uhlíku, jako 2-hydroxyethyl a 3-hydroxybutyl, karboxyalkyl o 2 až 7 atomech uhlíku, jako 1-karboxybutyl, alkoxykarbonylalkyl o 3 až 6 atomech uhlíku, jako 2-ethoxykarbonylethyl, aralkyl o 7 až 10 atomech uhlíku, jako benzyl a fenethyl, «-karboxyaralkyl o 8 až 12 atomech uhlíku, jako a-karboxyfenethyl, cykloalkyl o 3 až 10 atomech uhlíku, jako cyklopropyl, cyklohexyl a cykloheptyl, cykloalkylalkyl o 4 až 10 atomech uhlíku, jako cyklohexylmethyl, furfuryl, tetrahydrofurfuryl, 3-furylmethyl, tetrahydro-3-furylmethyl, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl a tetrahydro-3-thenyl.Preferred R 3 in formula I is hydrogen, alkyl of 1 to 10 carbon atoms such as methyl, propyl, butyl, isobutyl, pentyl, hexyl and octyl, alkenyl of 3 to 6 carbon atoms such as allyl, alkynyl of 3 to 6 atoms carbon such as 2-propynyl, (2-6C) alkoxyalkyl such as 2-methoxyethyl, 2-methoxypropyl, 2-ethoxyethyl and 3-methoxypropyl, (2-6C) alkylthioalkyl such as 2-ethylthioethyl and 2-methylthioethyl, alkylsulfinylalkyl of 2 to 6 carbon atoms such as 2-methylsulfinyl ethyl, hydroxyalkyl of 1 to 6 carbon atoms such as 2-hydroxyethyl and 3-hydroxybutyl, carboxyalkyl of 2 to 7 carbon atoms such as 1-carboxybutyl, alkoxycarbonylalkyl of 3 to 6 carbon atoms such as 2-ethoxycarbonylethyl, aralkyl of 7 to 10 carbon atoms such as benzyl and phenethyl, N-carboxyaralkyl of 8 to 12 carbon atoms such as α-carboxyphenethyl, cycloalkyl of 3 to 10 carbon atoms such as cyclopropyl, cyclohexyl and cycloheptyl C 4 -C 10 cycloalkylalkyl, such as cyclo xylmethyl, furfuryl, tetrahydrofurfuryl, 3-furylmethyl, tetrahydro-3-furylmethyl, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl and tetrahydro-3-thenyl.
Vhodným významem R4 ve vzorci I je alkyl o 1 až 5 atomech uhlíku, jako methyl, a propyl, karboxyl, alkoxykarbonyl o 2 až 5 atomech uhlíku, jako ethoxykarbonyl, aralkyl o 7 až 10 atomech uhlíku, jako benzyl a na jádře substituovaný benzyl, kde substituentem je alkoxyl o 1 až 3 atomech uhlíku, jako 4-methoxybenzyl.A suitable value for R4 in formula I is alkyl of 1 to 5 carbon atoms such as methyl, and propyl, carboxyl, alkoxycarbonyl of 2 to 5 carbon atoms such as ethoxycarbonyl, aralkyl of 7 to 10 carbon atoms such as benzyl and benzyl substituted on the nucleus, wherein the substituent is C 1 -C 3 alkoxy, such as 4-methoxybenzyl.
Vhodným významem R7 je atom vodíku, alkyl o 1 až 6 atomech uhlíku, jako methyl, ethyl, propyl a isopropyl, fenyl a karboxyl a vhodnou polohou R7 je 2, 4 nebo 6.A suitable value for R 7 is hydrogen, alkyl of 1 to 6 carbon atoms, such as methyl, ethyl, propyl and isopropyl, phenyl and carboxyl, and a suitable position for R 7 is 2, 4 or 6.
Vhodnými skupinamiSuitable groups
COOH ^dHz^ jsou 3-karboxy-4-morfollnový zbytek, 3-karboxy-4-thiomorfolinový zbytek, 1-oxo-3-karboxy-4-thiomorfolinový zbytek a 4-karboxy-3-thiazolidinyl.COOH dH ^ Z ^ is 3-carboxy-4-morfollnový radical, 3-carboxy-4-thiomorpholine, 1-oxo-3-carboxy-4-thiomorpholino and 4-carboxy-3-thiazolidinyl.
Vhodnými skupinamiSuitable groups
H00 3 jsou 2-karboxy-l,2,3,4-tetrahydro-l-chinolyl, 3-karboxy-l,2,3,4-tetrahydro-2-isochinolyl, l-karboxy-l,2,3,4-tetrahydro-2-isochinolyl, 2-karboxy-l-indollnyl a l-karboxy-2-isoindolinyl.H 3 O are 2-carboxy-1,2,3,4-tetrahydro-1-quinolyl, 3-carboxy-1,2,3,4-tetrahydro-2-isoquinolyl, 1-carboxy-1,2,3,4 -tetrahydro-2-isoquinolyl, 2-carboxy-1-indolinyl and 1-carboxy-2-isoindolinyl.
Vhodným významem Rz, Rs, Re, R9, R10 a R11 je atom vodíku, alkyl o 1 až 10 atomech uhlíku, jako methyl, ethyl, terc.butyl, a oktyl, aryl o 6 až 10 atomech uhlíku, jako fenyl a m-tolyl, aralkyl o 7 až 10 atomech uhlíku, jako benzyl a 5-indanyl.Suitable meanings of R 2, R 5, R 6, R 9, R 10 and R 11 are hydrogen, alkyl of 1 to 10 carbon atoms such as methyl, ethyl, tert-butyl, and octyl, aryl of 6 to 10 carbon atoms such as phenyl and m- tolyl, C7 -C10 aralkyl such as benzyl and 5-indanyl.
Vhodným významem Ar ve vzorci I je naftyl, jako 1-naftyl a 2-naftyl, 5,6,7,8-tetrahydronaftyl, jako 5,6,7,8-tetrahydro-l-naftyl a 5,6,7,8-tetrahydro-2-naftyl, naftyl, substituovaný alespoň jedním substituentem ze skupiny atom halogenu, jako chloru a bromu, hydroxyskupina, alkyl o 1 až 5 atomech uhlíku, jako methyl, ethyl, a isopropyl, alkoxyl o 1 až 5 atomech uhlíku, jako methoxyl a ethoxyl, dialkylaminoskupina o 2 až 10 atomech uhlíku, jako dimethylaminoskupina a diethylaminoskupina, fenyl, fenyl substituovaný alespoň jedním substituentem ze skupiny atom halogenu, jako chloru, alkyl o 1 až 5 atomech uhlíku, jako methyl, ethyl a isopropyl a alkoxyl o 1 až 5 atomech uhlíku, jako methoxyl, aralkyl o 7 až 10 atomech uhlíku, jako fenethyl,A suitable meaning of Ar in formula I is naphthyl, such as 1-naphthyl and 2-naphthyl, 5,6,7,8-tetrahydronaphthyl, such as 5,6,7,8-tetrahydro-1-naphthyl and 5,6,7,8 -tetrahydro-2-naphthyl, naphthyl substituted with at least one substituent selected from the group consisting of halogen atom such as chlorine and bromine, hydroxy, alkyl of 1 to 5 carbon atoms such as methyl, ethyl, and isopropyl, alkoxy of 1 to 5 carbon atoms such as methoxy and ethoxy, C 2 -C 10 dialkylamino, such as dimethylamino and diethylamino, phenyl, phenyl substituted with at least one substituent selected from halogen, such as chlorine, C 1 -C 5 alkyl such as methyl, ethyl and isopropyl, and C 1 alkoxy up to 5 carbon atoms, such as methoxy, aralkyl of 7 to 10 carbon atoms, such as phenethyl,
Výhodnými skupinami Ar jsou 1-naftyl, 2-naftyl, 5,6,7,8-tetrahydro-l-naftyl, 5,6,7,8-tetrahydro-2-naftyl, 5-chlor-l-naftyl, 6-chlor-2-naftyl, 6-brom-l-naftyl, 5-hydroxy-1-naftyl, 7-hydroxy-2-naftyl, 6-methyl-2-naftyl, 6-methyl-l-naftyl, 7-methyl-l-naftyl, 7-methyl-2-naftyl, 6-ethyl-2-naftyl, 6,7-dimethyl-l-naftyl, 6,7-dimethyl-2-naftyl, 6-isopropyl-2-naftyl-5-methoxy-l-naftyl, 6-methoxy-2-naftyl, 7-methoxy-2-naftyl, 4,6-dimethoxy-2-naftyl, 5-dimethylamino-l-naftyl,Preferred Ar groups are 1-naphthyl, 2-naphthyl, 5,6,7,8-tetrahydro-1-naphthyl, 5,6,7,8-tetrahydro-2-naphthyl, 5-chloro-1-naphthyl, 6- chloro-2-naphthyl, 6-bromo-1-naphthyl, 5-hydroxy-1-naphthyl, 7-hydroxy-2-naphthyl, 6-methyl-2-naphthyl, 6-methyl-1-naphthyl, 7-methyl- 1-naphthyl, 7-methyl-2-naphthyl, 6-ethyl-2-naphthyl, 6,7-dimethyl-1-naphthyl, 6,7-dimethyl-2-naphthyl, 6-isopropyl-2-naphthyl-5- methoxy-1-naphthyl, 6-methoxy-2-naphthyl, 7-methoxy-2-naphthyl, 4,6-dimethoxy-2-naphthyl, 5-dimethylamino-1-naphthyl,
5-dimethylamino-2-naftyl, 5-diethylamino-l-naftyl, 6-dimethylamino-l-naftyl, 6-dimethylamino-2-naftyl, 4-chlorfenyl, 2,4,5-trichlorfenyl, p-tolyl, anisyl, 3,4-dimethoxyfenyl, 3,4,5-trimethoxyfenyl,5-dimethylamino-2-naphthyl, 5-diethylamino-1-naphthyl, 6-dimethylamino-1-naphthyl, 6-dimethylamino-2-naphthyl, 4-chlorophenyl, 2,4,5-trichlorophenyl, p-tolyl, anisyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl,
Příkladem N2-arylsuIfonyl-L-argininamidů s dostatečnou účinností jsou tyto látky:Examples of N 2 -arylsulfonyl-L-argininamides having sufficient activity are:
N2- (6,7-dimethoxy-2-naftylsulf onyl) -L-arginyl-N-propylglycin,N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-propylglycine,
N2-( 6,7-dimethoxy-2-naf tylsulf onyl )-L-arginyl-N-propylglycin ve formě terc.butylesteru,N 2 - (6,7-dimethoxy-2-naphthylsulphonyl) -L-arginyl-N-propylglycine as tert-butyl ester,
N2- (6,7-dimethoxy-2-naftylsulf onyl ] -L-arginyl-N-butylglycin, terc.butylester N2- (6,7-dimethoxy-2-nafty 1sulfonyl)-L-arginyl-N-butylglycin,N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-butylglycine, tert-butyl ester N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-butylglycine ,
N2-( 6,7-dimethoxy-2-naftylsulf onyl )-L-arginyl-N-isobutylglycin,N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-isobutylglycine,
N2- (8,7-dimethoxy-2-naftylsulf onyl) -L-arginyl-N-pentylglycin,N 2- (8,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-pentylglycine,
N2-( 6,7-dimethoxy-2-naftylsulf onyl )-L-arginyl-N-hexylglycin,N 2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-hexylglycine,
N2- (6,7-dimethoxy-2-naf tylsulf onyl} -L-arglnyl-N -oktylglycin,N 2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-octylglycine,
N2- (4,6-dimethoxy-2-naftylsulf onyl) -L-arginyl-N-butylglycin,N 2 - (4,6-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-butylglycine,
N2- (6,7-diethoxy-2-naf tylsulf onyl) -L-arginyl-N-butylglycin,N 2- (6,7-diethoxy-2-naphthylsulfonyl) -L-arginyl-N-butylglycine,
N2- (6-methoxy-2-naf tylsulf onyl) -L-arginyl-N-butylglycln,N 2 - (6-methoxy-2-naphthylsulfonyl) -L-arginyl-N-butylglycine,
N2- (5-methoxy-l-naf tylsulf onyl) -L-arginyl-N-butylglycin,N 2- (5-methoxy-1-naphthylsulfonyl) -L-arginyl-N-butylglycine,
N2- (7-methoxy-2-naf tylsulf onyl) -L-arginyl-N-propylglycín,N 2 - (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N-propylglycine,
N2- (7-methoxy-2-naf tylsulf onyl) -L-ařginyl-N-butylglycin,N 2 - (7-methoxy-2-naphthylsulfonyl) -L-amininyl-N-butylglycine,
N2-(7-methb,.y-2-naftylsulfonyl)-L-arginyl-N-pentylglycin,N 2 - (7-Methyl-2-naphthylsulfonyl) -L-arginyl-N-pentylglycine,
N2- (2-naftylsulf onyl )-L-arginyl-N-butylglycin, ethylester N2- (2-naftylsulf onyl) -L-arginyl-N-butylglycinu, benzylester N2- (2-naftylsulf onyl) -L-arginyl -N-butylglycinu,N 2 - (2-naphthylsulfonyl) -L-arginyl-N-butylglycine, N 2 - (2-naphthylsulfonyl) -L-arginyl-N-butylglycine ethyl ester, N 2 - (2-naphthylsulfonyl) -L- arginyl -N-butylglycine,
N2- (2-naftylsulf onyl) -L-arginyl-N^butyl-;/J-alanin,N- 2- (2-naphthylsulfonyl) -L-arginyl-N-butyl- N-alanine,
N2- (5,6,7,8-tetrahydro-l-naftylsulf onyl) -L-arginyl-N-butylglycin,N 2 - (5,6,7,8-tetrahydro-1-naphthylsulphonyl) -L-arginyl-N-butylglycine,
N2- (5,6,7,8-tetrahydro-2-naftylsulf onyl) -L-arginyl-N-pentylglycin,N 2 - (5,6,7,8-tetrahydro-2-naphthylsulfonyl) -L-arginyl-N-pentylglycine,
N2- (5,6,7,8-tetrahydro-2-naftylsulf onyl ] -L-arginyl-N-butyl-jS-alanin,N 2- (5,6,7,8-tetrahydro-2-naphthylsulfonyl) -L-arginyl-N-butyl-5S-alanine,
N2- (6-brom-l-nafťylsulf onyl) -L-arginyl-N-butylglycin,N 2- (6-bromo-1-naphthylsulfonyl) -L-arginyl-N-butylglycine,
N2- (6-methyl-2-naftylsulfonyl )-L-arginyl-N-pentylglycin,N 2 - (6-methyl-2-naphthylsulfonyl) -L-arginyl-N-pentylglycine,
N2- (7-methyl-2-naftylsulf onyl )-L-arginyl-N-butylglycin,N 2 - (7-methyl-2-naphthylsulfonyl) -L-arginyl-N-butylglycine,
N2- (5-dimethylamino-l-naf tylsulf onyl) -L-arglnyl-N-butylglycin,N 2 - (5-dimethylamino-1-naphthylsulphonyl) -L-arginyl-N-butylglycine,
N2- (6,7-dimethoxy-2maf tylsulf onyl) -L-arginyl-N-allylglycin,N 2 - (6,7-dimethoxy-2-maphthylsulfonyl) -L-arginyl-N-allylglycine,
N2- (6,7-dimethoxy-2-naftylsulf onyl) -L-arginyl-N- (2-propinyl Jglycin,N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-propynyl) glycine,
N2- (6,7-dimethoxy-2-naf tylsulf onyl) -L-arginyl-N- (2-methoxyeťhyl Jglycin, ethylester N2- (6,7-dlmethoxy-2-naf tylsulf onyl) -L-arginyl-N- (2-methoxyethyl) glycinu, oktylester N2-(6,7-dimethoxy-2-naftylsulf onyl ] -L-arginyl-N- (2-methoxyethyl) glycinu,N- 2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine, ethyl 2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl -N- (2-methoxyethyl) glycine, N 2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine octyl ester,
N2- (6,7-dimethoxy-2-naf tylsulf onyl) -L-arginyl-N- (2-methoxyethyl) glycinu ve formě benzylesteru,N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine as the benzyl ester,
3-methylfenylester N2- (6,7-dimethoxy-2-naf tylsulf ony]) -L-arginyl-N- (2-methoxyethyl) glycinu,N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine 3-methylphenyl ester,
5-indanylester N;2-( 6,7-dimethoxy-2-naftylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycinu,N ; 2- (6,7-Dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine 5-indanyl ester,
N2-(6,7-dimethůxy-2-naftylsulfonyl)-L-arginyl-N-(2-methoxyethyl)-jS-alanin, ethylester N2-(6,7-dimethoxy-2-haftylsulfonyl) L-arginyl-N- (2-methoxyethyl) -β-alaninu,N 2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) -1S-alanine, N 2 - (6,7-dimethoxy-2-haphtylsulfonyl) -L-arginyl- N- (2-methoxyethyl) -β-alanine,
N2- (6,7-dlméthoxy-2-naftylsulf onyl) -N- (2-měthóxýethyl) -N- (3-karboxypropyl) -L-arginihamidN 2- (6,7-Dimethoxy-2-naphthylsulfonyl) -N- (2-methoxyethyl) -N- (3-carboxypropyl) -L-arginine amide
N2- (6,7-diniéthoxy-2-naftylsulf onyl) -N- (2-méthúxyethyl) -N- (3-terc.butoxykarbonylpropyl) -L-argininamid,N 2- (6,7-diethoxy-2-naphthylsulphonyl) -N- (2-methoxyethyl) -N- (3-tert-butoxycarbonylpropyl) -L-argininamide,
N2-(6,7-dimethoxy-2-naftylsulfonyl)-N-(3-methoxypropyl Jglycin,N 2- (6,7-dimethoxy-2-naphthylsulfonyl) -N- (3-methoxypropyl) glycine,
N2-( 6,7rdimethoxy-2-naf tylsulf onyl )-L-arginyl-N-( 2-ethoxyethyl) -/3-alanin,N 2 - (6,7-dimethoxy-2-naphthylsulphonyl) -L-arginyl-N- (2-ethoxyethyl) - β-alanine,
N2- (6,7-dlmethoxy-2-naftylsulfonyr)-L-arginyl-N- (2-methoxypropyl Jglycin,N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxypropyl) glycine,
N2- (6,7-diethoxy-2-naftylsulf onyl )-L-arginyl-N- (2-methoxyethyl) glycin,N 2- (6,7-diethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine,
N2- (4,6-dimethoxy-2-naf tylsulf onyl) -L-arginyl-N- (2-methoxyethyl) glycin,N 2- (4,6-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine,
N2- (4,6-dimethoxy-2-naftylsulf onyl) -L-arginyl-N- (2-methoxyethyl) glycin ve formě ethylesteru,N 2 - (4,6-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine as the ethyl ester,
N2- (6-methoxy-2-naftylsulfonyl) -L-arginyl-N- (2-methoxyethyl Jglycin,N 2 - (6-methoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine,
N2- (5-methoxy-i-naf tylsulf onyl) -L-arginyl-N-(2-methoxyethyl) glycin,N 2 - (5-methoxy-1-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine,
N2- (7-methoxy-2-nafty lsulf onyl) -L-arginyl-N- (2-methoxyethyl) glycin, ethylester N2- (7-methoxy-2-naf tylsulf onyl) -L-arginyl-N- (2-methoxyethyl) glycinu,N- 2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine, ethyl 2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine,
N2- (5-methoxy-l-naftylsulfonyl )-L-arginyl-N- (2-methoxyethyl) %-alanin,N- 2- (5-methoxy-1-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) -alanine,
N2- (1-naf ty lsulf onyl) -L-arginyl-N- (2-methoxyethyl) glycin,N 2 - (1-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine,
N2- (5,6,7,8-tetrahydro-l-naf ty lsulf onyl) -L-arginyl-N- (2-methoxyethyl) glycin,N 2- (5,6,7,8-tetrahydro-1-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine,
N2- (5-chlor-l-naf tylsulf onyl) -L-arginyl-N- (2-methoxyethyl) glyúin,N 2 - (5-chloro-1-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine,
N2- (6-chlor-2-naf tylsulf onyl) -L-arginyl -N- (2-methoxyethyl) glycin,N 2- (6-chloro-2-naphthylsulfonyl) -L-arginyl -N- (2-methoxyethyl) glycine,
N2- (7-methyl-2-naftylsulf onyl) -L-arginyl-N- (2-methóxyethyl Jglycin,N 2 - (7-methyl-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine,
N2- (7-methyl-l-naf tylsulf onyl) -L-arginyl-N-(2-methoxyethyl Jglycin,N 2 - (7-methyl-1-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine,
N2- (6,7-dimethyl-l-naf tylsulf onyl) -L-arginyl-N-{ 2-methoxyethyl Jglycin,N 2- (6,7-dimethyl-1-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine,
N2- (5-dimethylamino-l-naf tylsulfonyl )-L-arginyl-N- (2-methoxyethyl Jglycin,N 2- (5-dimethylamino-1-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine,
N2- (7-hydroxy-2-naf tylsulfonyl)-L-arginyl-N- (2-methoxyethyl Jglycin,N 2 - (7-hydroxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine,
N2- (6,7-dimethoxy-2-naf tylsulf onyl) -L-arginyl-N- (2-ethylthloethyl) glycin,N 2- (6,7-dimethoxy-2-naphthylsulphonyl) -L-arginyl-N- (2-ethylthloethyl) glycine,
N2- (7-methoxy-2-naftylsulf onyl) -L-arginyl-N- (2-měthylthióethyljglycin,N 2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methylthioethyl) glycine,
N2- (7-methoxy-2-naf tylsulf onyl) -L-arginyl -N- (2-methylsulfinylethyl Jglycin,N 2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl -N- (2-methylsulfinylethyl) glycine,
N2- (6,7-dimethoxy-2-naf tylsulf onyl )-L-arginyl-N- (2-hydroxyethyl) glycin,N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-hydroxyethyl) glycine,
N2- (6,7-dimethoxy-2-naf tylsulf onyl )-L-arginyl-N- (3-hydroxybutyl Jglycin,N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (3-hydroxybutyl) glycine,
N2- (6,7-dimethoxy-2-naf tylsulf onyl) -L-arginyl-N- (1-karboxybutyl) glycin,N 2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (1-carboxybutyl) glycine,
N2- (6,7-dimethoxy-2-naftylsulf onyl) -L-arginyl-N- (2-ethoxykarbonylethyl) glycin,N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-ethoxycarbonylethyl) glycine,
N2- (6,7-dimethoxy-2-naf tylsulf onyl )-L-arginyl-N-benzylglycin, terc.butylester N2- (6,7-dimethoxy-2-naf tylsulf onyl) -L-arginyl-N-benzylglycinu,N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-benzylglycine, tert-butyl ester N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N -benzylglycine,
N2- (6,7-dimethoxy-2-naf tylsulf onyl) -L-arglny 1-N-f enethylglyc in,N 2 - (6,7-dimethoxy-2-naphthylsulphonyl) -L-arginyl 1-N-phenylethylglycine,
N2- (6,7-dimethoxy-2-naftylsulfonyl ] -L-arginyl-N-benzyl-i/í-alanin, terc.butylester N2-(6,7-dimethoxy-2-naftylsulf onyl) -L-arginyl-N-benzyl-(í-alaninu,N 2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-benzyl-1H-alanine, tert-butyl ester N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L- arginyl-N-benzyl- (1-alanine),
N2- (6,7-dimethoxy-2-naftylsulf onyl )-L-ar ginyl-N -f enethyl-jS-alanin,N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arinyl-N-phenyl-5S-alanine,
N2- (4,6-dimethoxy-2-naftylsulfonyl )-L-arginyl-N-benzylglycin,N 2- (4,6-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-benzylglycine,
N2- (7-methoxy-2-naftylsulfonyl) -L-arginyl-N-fenylethylglycin,N 2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N-phenylethylglycine,
N2- (7-methoxy-2-naf tylsulf onyl) -L-arglnyl-N-benzyl-jS-alanin,N 2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N-benzyl-5S-alanine,
N2- (6-methoxy-2-nafty lsulf onyl) -N-benzyl-N- (3-karboxypropyl) -L-argininamid,N 2- (6-methoxy-2-naphthylsulfonyl) -N-benzyl-N- (3-carboxypropyl) -L-argininamide,
N2- (6-methoxy-2-naftylsulfonyl) -N-benzyl-N- (3-terc.butoxykarbonylpropyl J -L-argininamid,N 2- (6-methoxy-2-naphthylsulfonyl) -N-benzyl-N- (3-tert-butoxycarbonylpropyl) -L-argininamide,
N2- (5-methoxy-l-naf tylsulf onyl} -L-arglnyl-N-benzylglycin,N 2- (5-methoxy-1-naphthylsulfonyl) -L-arginyl-N-benzylglycine,
N2- (2-naftylsulf onyl) -L-arginyl-N-benzyl-jS-alanin,N 2- (2-naphthylsulfonyl) -L-arginyl-N-benzyl-5S-alanine,
N2- (2-naftylsulf onyl) -L-arginyl-N-benzylglycin, iW .N 2 - (2-naphthylsulfonyl) -L-arginyl-N-benzylglycine, iW.
N2-( 5,6,7,8-tetrahydro-l-naftylsulfonyl )-L-arginyl-N-fenethylglycin,N 2 - (5,6,7,8-tetrahydro-1-naphthylsulfonyl) -L-arginyl-N-phenethylglycine,
N2- (5,6,7,8-tetrahydro-2-naftylsulfonyl) -L-arginyl-N-benzylglycin,N 2 - (5,6,7,8-tetrahydro-2-naphthylsulfonyl) -L-arginyl-N-benzylglycine,
N2- (5,6,7,8-tetr ahydr o-2-naf ty lsulf onyl) -L· -arginyl-N-benzyl-jS-alanin,N 2 - (5,6,7,8-tetrahydro-2-naphthylsulfonyl) -L-argininyl-N-benzyl-5S-alanine,
N2- (7-methyl-2-naf tylsulfonyl) -L-arginyi-N-fenethylglyCln,N 2- (7-methyl-2-naphthylsulfonyl) -L-arginyl-N-phenethylglycine,
N2- (6,7-dimethoxy-2-naftylsulfonyl )-L-arginyl-N-(ai-karboxyfenethyl)glycin,N 2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (α-carboxyphenethyl) glycine,
N2- (6,7-dimethoxy-2-naftylsulfonyl }-L-arginyl-N-cyklohexylmethylglycin, terc.butylester N2-(6,7-dimethoxy-2-naftylsulfonyl ) -L-arginyl-N-cyklohexylmethylglycinu,N 2 - (6,7-dimethoxy-2-naphthylsulfonyl} -L-arginyl-N-cyklohexylmethylglycin, of N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-cyklohexylmethylglycinu,
N2- (6,7-dimethoxy-2-nafty lsulf onyl) -L-arginyl-N-cykloheptylglycin,N 2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-cycloheptylglycine,
N2- (4,6-dimethoxy-2-nafty lsulf onyl ] -L-arginyl-N-cyklohexylglycin,N 2- (4,6-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-cyclohexylglycine,
N2- (7-methoxy-2-naf tylsulf onyl) -L-arginyl-N-cyklohexylglycin,N 2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N-cyclohexylglycine,
N2- (6-methoxy-2-naftylsulfonyl) -L-arginyl-N-cyklohexylmethylglycin,N 2- (6-methoxy-2-naphthylsulfonyl) -L-arginyl-N-cyclohexylmethylglycine,
N2- (5-methoxy-l-naf tylsulf onyl) -L-arginyl-N-cyklohexylmethyl-fS-alanin, terc.butylester N2-( 5-methoxy-l-naf tylsulfonyl ) -L-arginyl-N-cyklohexylmethyl-jS-alaninu,N- 2- (5-methoxy-1-naphthylsulfonyl) -L-arginyl-N-cyclohexylmethyl-5S-alanine, tert-butyl ester N- 2- (5-methoxy-1-naphthylsulfonyl) -L-arginyl-N- cyclohexylmethyl-5S-alanine,
N2- (6,7-dimethoxy-2-naf tylsulfonyl) -L-arginyl-N-cyklohexylglycin,N 2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-cyclohexylglycine,
N2- (6,7-dimethoxy-2-naf tylsulf onyl) -L-arginyl-N-cyklohexyl-^-alanin, terc.butylester N2- (6,7-dimethoxy-2-naftylsulf onyl ) -L-arginyl-N-cyklohexy-/3-alaninu,N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-cyclohexyl-4-alanine, tert-butyl ester N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L- arginyl-N-cyclohexyl-3-alanine,
N2- (6,7-dimethoxy-2-naf tylsulf onyl) -N -cyklopropyl-N- (3-karboxypropyl) -L-argininamid,N 2- (6,7-dimethoxy-2-naphthylsulfonyl) -N-cyclopropyl-N- (3-carboxypropyl) -L-argininamide,
N2-(1-naftylsulf onyl)-L-arginyl-N-cyklohexylglycin,N 2 - (1-naphthylsulfonyl) -L-arginyl-N-cyclohexylglycine,
N2-( 5,6,7,8-tetrahydro-l-naf ty lsulf onyl)-L-arginyl-N-cyklohexylglycin,N 2- (5,6,7,8-tetrahydro-1-naphthylsulfonyl) -L-arginyl-N-cyclohexylglycine,
N2-(5,6,7,8-tetrahydro-2-naf tylsulf onyl)-Lar ginyl-N -cyklohexylmethylglycin,N 2- (5,6,7,8-tetrahydro-2-naphthylsulfonyl) -Larginyl-N-cyclohexylmethylglycine,
N2- (7-methyl-2-naf tylsulf onyl) -L-arginyl-N-cyklohexylmethylglyein,N 2 - (7-methyl-2-naphthylsulfonyl) -L-arginyl-N-cyclohexylmethylglycine,
N2- (7-methyl-2-naf tylsulf onyl) -L-arginyl-N-furfurylglycin,N 2- (7-methyl-2-naphthylsulfonyl) -L-arginyl-N-furfurylglycine,
N2- (7-methyl-2-naf tylsulfonyl) -L-arginyl-N-tetrahydrofurfurylglycin,N 2- (7-methyl-2-naphthylsulfonyl) -L-arginyl-N-tetrahydrofurfurylglycine,
N2- (7-methoxy-2-naf tylsulf onyl) -L-arginyl-N-furfurylglycin, terc.butylester N2-{ 7-methoxy-2-naftylsulfonyl ) -L-arginyl-N-furfurylglycinu,N 2 - (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N-furfurylglycine, N 2 - (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N-furfurylglycine tert-butyl ester,
N2- (7-methoxy-2-naf tylsulf onyl) -L-arginyl-N-tetrahydrofurfurylglyciťi,N 2 - (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N-tetrahydrofurfuryl glycine,
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N2-(5-chlor-l-naftylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycin,N 2- (5-chloro-1-naphthylsulfonyl) -L-arginyl-N-tetrahydrofurfurylglycine,
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N2- (6,7-dimethyl-l-naftylsulf onyl) -L-arginyl-N-tetrahydrofurfuryíglycin,N 2 - (6,7-dimethyl-1-naphthylsulfonyl) -L-arginyl-N-tetrahydrofurfurylglycine,
N2- (5,6,7,8-tetrahydro-l-naf tylsulf onyl) -L-arginyl-N-tetrahydrofurfurylglycin,N 2 - (5,6,7,8-tetrahydro-1-naphthylsulfonyl) -L-arginyl-N-tetrahydrofurfurylglycine,
N2- (6,7-dimethoxy -2-naftylsulf onyl) -L-arginyl-N-tetrahydrofurfurylglycin,N 2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-tetrahydrofurfurylglycine,
N2- (6,7-dimethoxy-2-naftylsulf onyl) -L-arginyl-N-butylalanin, terc.butylester N2- (6,7-dimethoxy-2-naftylsulf onyl) -L-arginyl-N-butylalaninu,N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-butylalanine, tert-butyl ester N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-butylalanine ,
N2- (6,7-dimethoxy-2-naftylsulf onyl) -L-arginyl-N-pentylalanin,N 2 - (6,7-dimethoxy-2-naphthylsulphonyl) -L-arginyl-N-pentylalanine,
N2- (6,7-dimethoxy-2-nafty lsulf onyl) -L-arginyl-N-benzylalanin,N 2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-benzylalanine,
N2- (6,7-dimethoxy-2-naf tylsulf onyl) -L-arginyl-N-fenethylalanin,N 2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-phenethylalanine,
N2- (6,7-dimethoxy~2-naftylsulfonyl )-L-arginyl-N-cyklohexylalanin,N 2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-cyclohexylalanine,
N2- (4,6-dimethoxy-2-naf tylsulf onyl) -L-arginyl-N-cyklohexylmethylalanin,N 2- (4,6-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-cyclohexylmethylalanine,
N2- (7-methoxy-2-naftylsulfonyl) -L-arglnyl-N-propylalanin,N 2- (7-methoxy-2-naphthylsulphonyl) -L-arginyl-N-propylalanine,
N2- (6,7-dimethoxy- 2-naftylsulf onyl )-L-arginyl-N- (2-methoxyethyl) alanin,N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) alanine,
N2- (6,7-dimethoxy- 2-naf ty lsulf onyl) -L-arginylnorvalin, kyselina N2-(6,7-dimethoxy-2-naftylsulfonyl)-L-arginyl-N-butylaspar agová, diethylester kyseliny N2-(6,7-dimethoxy-2-naftylsulf onyl) - L-arginyl-N-butylasparagové, , kyselina N2- (6,7-dimethoxy-2-naftylsulfonyl)-1-arginyl-N-benzylasparagová, diethylester kyseliny N2-(6,7-dimethoxy-2-naftylsulf onyl) - L-arginyl-N-benzylasparagové,N 2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginylnorvaline, N 2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-butylaparamic acid, N diethyl ester 2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-butylasparagic acid, N - 2- (6,7-dimethoxy-2-naphthylsulfonyl) -1-arginyl-N-benzylasparagic acid, diethyl ester N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) - L-arginyl-N-benzylaparagine,
N2- (6,7-dimethoxy-2-naf tylsulf onyl) -L-arginyl-N-methyl-j3-fenylalanin,N 2- (6,7-dimethoxy-2-naphthylsulphonyl) -L-arginyl-N-methyl-β-phenylalanine,
N2- (6,7-dimethoxy-2-nafty lsulf onyl) -L-arginyl-N-methyl-f/ϊ- (4-methoxyfenyl }alanin, kyselina 1- [ N2- (6,7-dimethoxy-2-naftyIsulf onyl) -L-arginyl ] -2-piperidinkarboxylová, ethyl-1- [ N2- (6,7-dixnethoxy-2-naf tylsulf onyl) -L-arginyl ] -2-piperidinkarboxylát, kyselina 1- [ N2- (6-methoxy-2-naf tylsulf onyl} -L-arginyl ] -2-piperidinkarboxylová, kyselina 1- [ N2- (6,7-dimethoxy-2-naftylsulf onyl) -L-arginyl ] -4-methyl-2-piperidinkarboxylová kyselina 1- [ N2- (7-methoxy-2-naftylsulfonyl) -L-arginyl ] -4-methyl-2-piperidinkarboxylová, kyselina 1- [ N2- (5-methoxy-l-naftylsulf onyl) -L-arginyl ] -4-methyl-2-piperidinkarboxylová, ethyl-l-[ N2- (5-methoxy-l-naftylsulfonyl) -L-arginyl ] -4-methyl-2-piperidinkarboxylát, kyselina 1- [ N2- (4,6-dimethoxy-2-naftylsulf onyl) -L-arginyl ] -4-methyl-2-piperidinkarboxylová, kyselina 1- [ N2- (6,7-díethoxy-2-naftylsulf onyl) -L-arginyl ] -4-methyl-2-piperidinkarboxylová, kyselina 1- [ N2- (6,7-dimethoxy-2-naf tylsulf onyl) -L-arginyl ] -4-ethyl-2-piperidinkarboxylová, kyselina 1- [ N2- (7-methoxy-2-naftylsulf onyl) -L-arginyl ] -4-ethyl-2-piperidinkarboxylová, kyselina 1- [ N2- (6,7-dimethoxy-2-naftylsulf ony 1) -L-arginyl ] -4-propyl-2-piperidinkarboxylová, kyselina 1- [ N2- (6,7-dimethoxy-2-naftylsulf onyl) -L-arginyl ] -4-isopropyl-2-piperidinkarboxylová, kyselina 1- [ N2- (6,7-dimethoxy-2-naftylsulf onyl) -L-arginyl ] -6-methyl-2-piperidlnkarboxylová, kysebna 1- [ N2- (7-methoxy-2-naftylsulf onyl) -L-arginyl ] -2-methyl-2-piperidinkarboxylová, kyselina 1- [ N2- (6,7-dimethoxy-2-naftylsulf onyl) -L-arginyl ] -3-piper idinkarboxylová, methyl-1- [ N2- (6,7-dimethoxy-2-naftylsulf onyl) -L-arginyl ] -3-piperidinkarboxylát, kyselina 1- [ N2- (7-methoxy-2-naftylsulf ony 1) -L-arginyl ] -3-piper idinkarboxylová, kyselina 1- [ N2- (7-methoxy-2-naftylsulf onyl) -L-arginyl ] -2,6-piperidinkarboxylová, kyselina 1- [ N2- (6,7-dimethoxy-2-naf ty 1sulf onyl) -L-arginyl ] -4-f enyl-2-piperidinkarboxylová, kyselina 1- [ N2- (1-naftylsulf onyl) -L-arginyl] -4-methyl-2-piperidinkarboxylová, ethyl-1- [ N2- (Imaf tylsulf onyl) -L-arginyl ] -4-methyl-2-piperidinkarboxylát, kyselina 1- [ N2- (2-naftylsulf onyl }-L-arginy 1 ] -4-isopr opyl-2-piper idinkarboxylová, ethyl-1-[ N2- (2-naftylsulfonyl) -L-arginyl ]-d-isopropyl^-piperidinkarboxylát, kyselina 1- [ N2- (5j6,7,8-tetrahydro-2-naf ty lsulf onyl ] -L-arginyl ] -4-methy 1-2-piperidinkarboxylová, ethyl-1- [ N2- (5,6,7,8-tetrahydro-2-naftylsulf onyl) -L-arginyl ] -4-methyl-2-piperidinkarboxylát, kyselina 1- [ N2- (6-chlor-2-naf tylsulf onyl) -L-arginyl]-4-isopropyl-2-piperidinkarboxylová, kyselina 1- [ N2- (5-dimethylamino-l-naftylsulf onyl) -L-arginyl ] -2-piperidinkarboxylová, kyselina 1- [ N2- (7-methyl-2-naftylsulf ony 1 ] -L-arginyl ] -4-methyl-2-piperidinkarboxylová, kyselina 1- [ N2- (7-methyl-2-naf ty 1sulf onyl) -L-arginyl ] -4-ethyl-2-piperidinkarboxylová, kyselina 1- [ N2- (7-methyl-2-naftylsulf onyl ] -L-arginyl ] -4-isopropyl-2-piperidinkarboxylová, ethyl-1- [ N2- (7-methyl-2-naftylsulfonyl)-L-arginyl ] -4-isopropyl-2-piperidinkarboxylát, kyselina 1- [ N2- (6-methyl-2-naf tylsulf ony 1 ] -L-arglnyl ] -4-isopr opy 1-2-piperidinkarboxylová, kyselina 1- [ N2- (7-methyl-2-naftylsulf onyl) -L-arginyl ] -2-hexamethyleninlinkarboxylová, kyselina 4- [ N2- (7-methoxy-2-naf tylsulf onyl) -L-arginyl ] -3-thiomorfolinkarboxylová,N- 2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-methyl-N - (4-methoxyphenyl) alanine, 1- [N 2 - (6,7-dimethoxy- 2-naphthylsulfonyl) -L-arginyl] -2-piperidinecarboxylic acid, ethyl 1- [N 2- (6,7-dixethoxy-2-naphthylsulfonyl) -L-arginyl] -2-piperidinecarboxylate, 1- [acid] N 2- (6-methoxy-2-naphthylsulfonyl) -L-arginyl] -2-piperidinecarboxylic acid 1- [N 2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl] -4 methyl-2-piperidinecarboxylic acid 1- [N 2 - (7-methoxy-2-naphthylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid 1- [N 2 - (5-methoxy-1- naphthylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid, ethyl 1- [N 2- (5-methoxy-1-naphthylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylate, acid 1 - [N 2 - (4,6-dimethoxy-2-naphthylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid 1- [N 2 - (6,7-diethoxy-2-naphthylsulfonyl)] -L-arginyl] -4-methyl-2-piperidinecarboxylic acid 1- [N 2 - (6,7-dimethoxy-2-naphthyl) Ylsulfonyl) -L-arginyl] -4-ethyl-2-piperidinecarboxylic acid 1- [N 2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl] -4-ethyl-2-piperidinecarboxylic acid 1 - [N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl] -4-propyl-2-piperidinecarboxylic acid 1- [N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) 1-L-arginyl] -4-isopropyl-2-piperidinecarboxylic acid 1- [N 2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl] -6-methyl-2-piperidinecarboxylic acid, acid 1 - [N 2 - (7-methoxy-2-naphthylsulfonyl) -L-arginyl] -2-methyl-2-piperidinecarboxylic acid 1- [N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L -arginyl] -3-piperidinecarboxylic acid methyl 1- [N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl] -3-piperidinecarboxylate 1- [N 2 - (7-methoxy) 2-naphthylsulfonyl) -L-arginyl] -3-piperidinecarboxylic acid 1- [N 2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl] -2,6-piperidinecarboxylic acid 1- [N 2- (6,7-Dimethoxy-2-naphthylsulfonyl) -L-arginyl] - 4-phenyl-2-piperidinecarboxylic acid 1- [N 2 - (1-naphthylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid ethyl-1- [N 2 - (Imaphthylsulfonyl) - L-arginyl] -4-methyl-2-piperidinecarboxylate, 1- [N 2- (2-naphthylsulfonyl) -L-arginyl] -4-isopropyl-2-piperidinecarboxylic acid, ethyl 1- [N 2 - (2-naphthylsulfonyl) -L-arginyl] -d-isopropyl-4-piperidinecarboxylate 1- [N 2 - (5,6,7,8-tetrahydro-2-naphthylsulfonyl) -L-arginyl] -4- Methyl 1-2-piperidinecarboxylic acid, ethyl 1- [N 2 - (5,6,7,8-tetrahydro-2-naphthylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylate, 1- [N 2- (6-chloro-2-naphthylsulfonyl) -L-arginyl] -4-isopropyl-2-piperidinecarboxylic acid 1- [N 2- (5-dimethylamino-1-naphthylsulfonyl) -L-arginyl] - 2-piperidinecarboxylic acid 1- [N 2 - (7-methyl-2-naphthylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid 1- [N 2 - (7-methyl-2- naphthylsulfonyl) -L-arginyl] -4-ethyl-2-piperidinecarboxylic acid 1- [ N 2 - (7-methyl-2-naphthylsulfonyl) -L-arginyl] -4-isopropyl-2-piperidinecarboxylic acid, ethyl-1- [N 2 - (7-methyl-2-naphthylsulfonyl) -L-arginyl] - 4-Isopropyl-2-piperidinecarboxylate, 1- [N 2 - (6-methyl-2-naphthylsulfonyl) -L-arginyl] -4-isopropyl-2-piperidinecarboxylic acid, 1- [N 2 - (7-methyl-2-naphthylsulfonyl) -L-arginyl] -2-hexamethylenine-linkarboxylic acid 4- [N 2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl] -3-thiomorpholinecarboxylic acid,
4- [ N2- (7-methoxy-2-naftylsulfonyl) -L-arginyl ] -3-karboxythiomorf olin-1-oxid, kyselina 4- [ N2- (6,7-dimethoxy-2-nafty 1sulf onyl)-L-arginyl ] -3-morf olinkarboxylová, kyselina 4-[N2-(7-methoxy-2-naftylsulf onyl) -L-arginyl ] -3-morf olinkarboxylová, kyselina 3- [ N2- (7-methoxy-2-naftylsulf onyl ] -L-arginyl] -4-thiazolidinkarboxylová, kyselina 2- [ N2- (6,7-dimethoxy-2-nafty 1sulfonyl) -L-arginyl] -1,2,3,4-tetrahydroisochinolin-3-karboxylová, kyselina 2- [ N2- (6,7-dimethoxy-2-naftylsulf onyl) -L-arginyl ] isoindolin-1-karboxy.lová,4- [N 2 - (7-methoxy-2-naphthylsulfonyl) -L-arginyl] -3-carboxythiomorpholin-1-oxide, 4- [N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) acid] -L-arginyl] -3-morpholinecarboxylic acid 4- [N 2 - (7-methoxy-2-naphthylsulphonyl) -L-arginyl] -3-morpholinecarboxylic acid 3- [N 2 - (7-methoxy) -2-naphthylsulfonyl] -L-arginyl] -4-thiazolidinecarboxylic acid 2- [N 2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl] -1,2,3,4-tetrahydroisoquinoline -3-carboxylic acid 2- [N 2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl] isoindoline-1-carboxylic acid,
N2- (4-chlorf eny lsulf onyl) -L-arginyl-N-butylglycin,N 2- (4-chlorophenylsulfonyl) -L-arginyl-N-butylglycine,
N2- (2,4,5-trichlorfenylsulfonyl) -L-arginyl-N-butylglycin,N 2- (2,4,5-trichlorophenylsulfonyl) -L-arginyl-N-butylglycine,
N2-tosyl-L-arginyl-N-butylglycin,N 2 -tosyl-L-arginyl-N-butylglycine
N2- (4-methoxyf enylsulf onyl) -L-arginyl-N-benzylglycin,N 2- (4-methoxyphenylsulfonyl) -L-arginyl-N-benzylglycine,
N2- (3,4-dimethoxyf enylsulf onyl) -L-arginyl-N-( 2-methoxyethyl] glycin,N 2- (3,4-dimethoxyphenylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine,
N2- (3,4,5-trimethoxyf enylsulf ony 1 ] -L-arginyl-N- (2-methoxyethyl) gly cin,N 2- (3,4,5-trimethoxyphenylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine,
N2-fenethylsulfonyl-L-arginyl-N-furfurylglycin,N 2 -phenethylsulfonyl-L-arginyl-N-furfurylglycine
N2- (l,4-benzodioxan-6-sulf onyl) -L-arginyl-N- (2-methoxyethyl) glycin,N 2 - (1,4-benzodioxan-6-sulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine,
N2- (6,7-ethy lendioxy-2-naf tylsulf onyl) -L-arginyl-N- (2-methoxyethyl ] glycin, kyselina 1- [ N2- (2-dibenzof uranyl ] -L-arginyl ]-2-piperidinkarboxylová.N 2- (6,7-ethylenedioxy-2-naphthylsulphonyl) -L-arginyl-N- (2-methoxyethyl] glycine, 1- [N 2 - (2-dibenzofuranyl) -L-arginyl] - 2-piperidinecarboxylic acid.
Ze sloučenin podle vynálezu jsou vzhle dem ke své vysoké antitrombotické účinnos ti a nízké toxicitě zvláště výhodné tyto látkyOf the compounds of the invention, these compounds are particularly preferred because of their high antithrombotic activity and low toxicity
N2- (6,7-dimethoxy-2-naftylsulf onyl) -L-arginyl-N-butylglycin,N 2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-butylglycine,
N2- (7-methoxy-2-naftylsulf ony 1 ] -L-arginyl-N-butylglycin,N 2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N-butylglycine,
N2- (6,7-dimethoxy-2-nafty lsulf onyl ] -L-arginyI-N-( 2-methoxyethyl j glycin, ethylester N2- (6,7-dimethoxy-2-naftylsulf onyl ] -L-arginyl-N- (2-methoxyethyljglycinu,N- 2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine, ethyl 2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl -N- (2-methoxyethyl) glycine,
N2- (4,6-dimethoxy-2-naf · y Isulf onyl) -L-arginyl-N- (2-methoxyethyl j glycin,N 2- (4,6-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine,
N2- (7-methoxy-2-naftylsulf onyl} -L-arginyl-N-( 2-methoxyethyl jglycin,N 2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine,
N2-(5,6,7,8-tetrahydro-l-nafty Isulf onyl)'.-L-arginyl-N-(2-methoxyethyl jglycin,N 2 - (5,6,7,8-tetrahydro-1-naphthylsulfonyl) -1-arginyl-N- (2-methoxyethyl) glycine,
N2-(7-in/úhoxy-2-naftyTsulfonyl)-L-arg'inyl-N-tet>'ahydrofurfurýlglycin,N 2 - (7-inoxy-2-naphthylsulfonyl) -L-arginyl-N-tetrafluorofurylglycine,
N2- (7-methyl-2-naftylsulfonyl) -L-arginyl-N-tetrahydrofurfurylglycin,N 2- (7-methyl-2-naphthylsulfonyl) -L-arginyl-N-tetrahydrofurfurylglycine,
N2- (6,7-dimethoxy-2-naftylsulf onyl) -L-arginyl-N-tetrahydrofurfurylglycin, kyselma l-[N2-(6,7-dimethoxy-2-naftylsulfonyl )-L-arginyl]-4-methyl-2-plperidinkarboxylová, kyselina l-[N2-(7-methoxy-2-naftylšulfonyl)-L-arginyl j-4-methyl-2-piperidinkarboxylová a kyselina 1- [ N2- (7-methoxy-2-naf tylsulf onyl ] -L-arginyl ] -4-ethyl-2-piperidinkarboxylová.N- 2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-tetrahydrofurfurylglycine, acid 1- [N 2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl] -4- methyl-2-plperidinecarboxylic acid 1- [N 2 - (7-methoxy-2-naphthylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid and 1- [N 2 - (7-methoxy-2- naphthylsulfonyl] -L-arginyl] -4-ethyl-2-piperidinecarboxylic acid.
Vynález se rovněž týká způsobu výroby farmaceuticky přijatelných solí těchto sloučenin.The invention also relates to a process for the preparation of pharmaceutically acceptable salts of these compounds.
Jě zřejmé, že uhlíkový atom těchto látek, na nějž se váže karboxylová skupina nebo esterová skupina, může být asymetrický, takže vznikají opticky aktivní isomery, a to D- á L-diastereoisomery a jejich racemická směs.It will be appreciated that the carbon atom of the compounds to which the carboxyl group or the ester group is attached may be asymmetric, so that the optically active isomers are formed, namely the D- and L-diastereoisomers and the racemic mixture thereof.
Pokud jde o účinnost těchto sloučenin, jsou sloučeniny v konfiguraci D účinnější něž Sloučeniny v konfiguraci L a racemáty, přestože i tyto formy mají určitou antitrombotíčkou účinnost. Svrchu uvedené sloučeniny byly uvédeny pouze proto, aby byla zřejmá různost struktury sloučenin podle vynálezu.Compounds in the D configuration are more potent with respect to the efficacy of these compounds than the L compounds and the racemates, although these forms also have some antithrombotic activity. The above compounds have only been mentioned in order to show the structural differences of the compounds according to the invention.
Nové deriváty L-argininu lze získat tak, že se použije výchozích látek, v nichž Ar má svrchu uvedený význam a R znamená skupinu obecného vzorce C°°R»The novel derivatives of L-arginine can be obtained by use of starting materials in which Ar is as hereinbefore defined and R represents a group of formula C R °° »
- r'V;- r'V;
~N^ ( CRl2}j kde~ N ^ ( CR 12 } j where
Ru, i a j mají svrchu uvedený význam.Ru, i and j are as defined above.
Ar má svrchu uvedený význam aAr is as defined above and
X znamená atom halogenu, s derivátem aminokyseliny obecného vzorce . RHX represents a halogen atom, with an amino acid derivative of the general formula. RH
kdewhere
R má svrchu uvedený význam, načež se popřípadě reakční směs hydrolyzuje.R is as defined above, whereupon the reaction mixture is optionally hydrolyzed.
Sloučeniny obecného vzorce I tvoří adiční soli s celou řadou anorganických i organických kyselin. Rada těchto látek, obsahujících volnou karboxylovou skupinu, v nichž svrchu uvedené substituenty znamenají atom vodíku, tvoří soli s velkým množstvím anorganických i organických zásad.The compounds of formula I form addition salts with a variety of inorganic and organic acids. Many of these free carboxyl groups in which the above substituents are hydrogen form salts with a large amount of inorganic and organic bases.
Reakční produkty je možno izolovat ve volné formě nebo ve formě jejich solí. Mimoto je možno tyto látky získat ve formě farmaceuticky přijatelných adičních solí tak, že se volné látky uvedou v reakci s kyselinou, například chlorovodíkovou, bromovodíkovou, jodovodíkovou, dusičnou, sírovou, fosforečnou, octovou, citrónovou, maleinovóu, jantarovou, mléčnou, vinnou, glukonovou, benzoovou, methansulfonovou, ethansulfonovou, benzensulfonovou, p-toluensulfonovou apod. Obdobně je možno výsledný produkt získat ve formě farmaceuticky přijatelné soli tak, že se některé z volných karboxylových kyselin uvedou v reakci se zásadou, například hydroxidem sodným, hydroxidem draselným, hydroxidem amonným, triethylaminem, prokainem, dibenzylaminem, N,N‘-dibenzylethylendiaminem, N-ethylpiperidinem apod.The reaction products may be isolated in the free form or in the form of their salts. In addition, they can be obtained in the form of pharmaceutically acceptable addition salts by reacting the free substances with an acid such as hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, citric, maleic, succinic, lactic, tartaric, gluconic , benzoic, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic and the like. Similarly, the resulting product can be obtained in the form of a pharmaceutically acceptable salt by reacting some of the free carboxylic acids with a base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, triethylamine, procaine, dibenzylamine, N, N'-dibenzylethylenediamine, N-ethylpiperidine and the like.
V případě, že se působí na sůl zásadou nebo kyselinou, je možno získat zpět volné amidy.If the salt is treated with a base or an acid, the free amides can be recovered.
Jak již bylo svrchu uvedeno, mají sloučeniny obecného vzorce I a jejich soli vysokou specifickou inhibiční účinnost proti trombinu a současně malou toxicitu, takže je možno je použít jako diagnostické látky pro stanovení trombinu v krvi a/nebo k zábraně a prevenci trombózy.As mentioned above, the compounds of the formula I and their salts have a high specific thrombin inhibitory activity and at the same time a low toxicity, so that they can be used as diagnostic agents for the determination of thrombin in blood and / or for preventing and preventing thrombosis.
Sloučeniny podle vynálezu je rovněž možno použít jako inhibitory shlukování krevních destiček.The compounds of the invention may also be used as platelet aggregation inhibitors.
Antitrombotická účinnost N2-arylsulfonyl-L-argininamidu podle vynálezu byla srovnávána s účinností známé antitrombotické látky, methylesterů N2-(p-tolylsulfonylj-L-árgininu stanovením doby srážlivosti, ovlivňované fibrinogenem. Toto stanovení bylo prováděno tímto způsobem:The antithrombotic activity of N 2 -arylsulfonyl-L-argininamide according to the invention was compared with that of the known antithrombotic substance, N 2 - (p-tolylsulfonyl) -L-arginine methyl esters by determining the clotting time influenced by fibrinogen.
0,8 ml roztoku fibrinogenu, který byl připraven rozpuštěním 150 mg hovězího fibrinogenu (Cóhnova frakce I) ve 40 ml boritanového pufru o pH 7,4 se smísí s 0,1 ml boritanového pufru o pH 7,4 v případě kontrolního roztoku nebo se vzorkem v témže pufru, načež se k oběma roztokům v ledové lázni přidá 0,1 ml roztoku trombinu o koncentraci 5 jednotek/ml.0.8 ml of the fibrinogen solution prepared by dissolving 150 mg of bovine fibrinogen (Cohn Fraction I) in 40 ml of borate buffer pH 7.4 is mixed with 0.1 ml of borate buffer pH 7.4 in the case of a control solution or sample in the same buffer, and 0.1 ml of 5 units / ml thrombin solution is added to both solutions in the ice bath.
Okamžitě po promísení se reakční směs přenese z ledové lázně do lázně o teplotě 25 °C. Doba koagulace se měří jako doba od přenesení do lázně o teplotě 25 CC do prvního'objevení fibrinových látek. V případě, že nebyla přidána žádná účinná látka, bylo to228113 to období 50 až 55 sekund. Experimentální výsledky jsou uvedeny v tabulce I. Pod pojmem „koncentrace“, Jíž je zapotřebí k dvojnásobnému prodloužení koagulace, znamená koncentraci účinné látky; která .prodlouží dobu koagulace z 50 až 55 sekund na 100 až 110 sekund.Immediately after mixing, the reaction mixture was transferred from an ice bath to a 25 ° C bath. The coagulation time is measured as the time from transfer to a 25 ° C bath until the first appearance of fibrin substances. If no drug was added, this was a period of 50 to 55 seconds. The experimental results are given in Table I. The term "concentration", which is required to double the coagulation twice, means the concentration of the active substance; which increases the coagulation time from 50 to 55 seconds to 100 to 110 seconds.
Tato doba koagulace se dosáhne;.pči použití známého antitromboticlíého činidla, tj. methylesteru N2-(p-tolylstílfonyl:)^Líargininu v množství 1100 μπιοΚ Inhibitory podle vynálezu jsou v tomto směru srovnány v tabulce I při uvedení substituentů R a Ar a adiční skupiny.This coagulation time is achieved using the known antithrombotic agent, i.e., N 2 - (p-tolylstilphonyl) methyl ester. L-arginine in an amount of 1100 μπιοΚ The inhibitors of the invention are compared in this respect in Table I with the substituents R and Ar and addition groups.
V případě, že se roztok sloučeniny; podle vynálezu podá nitrožilně, udrží se vysoká antitrombotická účinnost v oběhu 1 až 3 hodiny. Biologický poločas; antttrombotícké sloučeniny podle vynálezu v krevním oběhu je přibližně 60 minut. Přitom se ^neprojevilo porušení jiných fyziologických pochodů u pokusných zvířat, například krysy.králíka, psa a šimpanze. Pokusný pokles fibrinogenu u zvířat, způsobený Infúzí trombinu, bylo možno uspokojivým způsobem vyrovnat současnou infúzí sloučenin podle >vynálezu.In case the solution of the compound; according to the invention administered intravenously, maintaining high antithrombotic activity in the circulation for 1 to 3 hours. Half-life; The anti-thrombotic compounds of the invention in the bloodstream are approximately 60 minutes. There was no violation of other physiological processes in experimental animals such as rat, dog, and chimpanzee. The experimental decrease in fibrinogen in animals caused by the infusion of thrombin was satisfactorily compensated by the simultaneous infusion of the compounds of the invention.
Hodnoty LDso pro sloučeniny podle vynálezu jsou uvedeny v tabulce:The LD 50 values for the compounds of the invention are shown in the table:
Sloučenina LDso (mg/kg)Compound LD 50 (mg / kg)
N2- (7-methyl-2-naf tylsulf onylj-L-arginyl-N-butylglycin > 1500N 2 - (7-methyl-2-naphthylsulfonyl) -L-arginyl-N-butylglycine> 1500
N2-(6,7-dimethoxy-2-naftylsulfonylj-L-arginyl-N-(2-methoxyethyl jglycin 1900—2400N 2 - (6,7-dimethoxy-2-naphthylsulphonyl) -L-arginyl-N- (2-methoxyethyl) glycine 1900-2400
N2- (6,7-dimethoxy-2-naf tylsulf onyl) -L-arginyl-N-(2-ethoxyethyl j-á-alanin 680—1000N 2 - (6,7-dimethoxy-2-naphthylsulphonyl) -L-arginyl-N- (2-ethoxyethyl) -α-alanine 680-1000
N2-(4,6-dimethoxy-2-naftylsulfonyl)-L-arginyl-N-(2-methoxy ethyl Jglycin 860—1000N- 2- (4,6-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxy ethyl) glycine 860-1000
N2- (7-methoxy-2-naf tylsulf onyl) -L-arginy 1-N- (2-methoxyethyl Jglycin 2000N 2 - (7-methoxy-2-naphthylsulfonyl) -L-arginy 1-N- (2-methoxyethyl) glycine 2000
N2- (5,6,7,8-tetrahydro-l-naf tylsulf onyl)-L-arginyl-N- (2-methoxyethyl jglycin >1500N- 2- (5,6,7,8-tetrahydro-1-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine> 1500
N2- (6,7-dimethy 1-1-naftylsulf onyl-L-arginyl-N-(2-methoxyethyljglycin >1500N 2 - (6,7-Dimethyl-1-naphthylsulfonyl-L-arginyl-N- (2-methoxyethyl) glycine> 1500
N2- (6,7-dimethoxy-2-naftyJsulfonyl)-L-arginyl-N-(2-ethylthioethyl Jglycin > 1000N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-ethylthioethyl) glycine> 1000
N2- (6,7-dimethoxy-2-naftylsulf onyl) -L-arginyl-N-benzylglycin >1000 saN 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-benzylglycine> 1000 s
Sloučenina LDso (mg/kg)Compound LD 50 (mg / kg)
N2- (4,6-dimethoxy-2-naftylsulfonyl j-L-arginyl-N-benzylglycin > 1000N 2 - (4,6-dimethoxy-2-naphthylsulfonyl) -1-arginyl-N-benzylglycine> 1000
N2- (5-methoxy-l-naf tylsulf onyl ) - L-arginy 1-N -benzylglycin > 1000N 2 - (5-methoxy-1-naphthylsulfonyl) - L-arginy 1-N-benzylglycine> 1000
N2-(6,7-dimethoxy-2-naf tylsulf onyl ) -L-arginyl-N-fenethyíglycih > 1500N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-phenethylglycine> 1500
N2- (6,7-dimethoxy-2-naf ty 1 sulf ony 1) -L-arginyl-N-cyklohexylglycin >1500N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-cyclohexylglycine> 1500
N2- (6,7-dlmethoxy-2-naf tylsulf onyl )-L-arginyl-N-cyklohexylmethylglycin > 1500N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-cyclohexylmethylglycine> 1500
N2- (7-methyl-2-naf tylsulfonyl ]-L-arginyl-N-tetrahydrofurfurylglycin 600N 2- (7-methyl-2-naphthylsulfonyl) -L-arginyl-N-tetrahydrofurfurylglycine 600
N2- (6,7-idimethOixy-2-naf tylsulfonylj-L-arginyl-N-tetrahydrofurfurylglycin 620N 2 - (6,7-idimethoxyl-2-naphthylsulfonyl) -L-arginyl-N-tetrahydrofurfurylglycine 620
N2- (6,7’dímethoxy-2-naf tylsulf onyl ) -L-arginyl-N -buty lalanin > 1500N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-butylanine> 1500
N2-(4,6-dimethoxy-2-naftylsulfonyl)-L-arginy 1-N-cyklohexylmethylalanin > 1500 kyselina 1- [ N2-(6,7-dimethoxy-2-naf ty l9ulfonyl j-L-arginyí }-2-piperidinkarboxylová 1500 ethyl-l-[N2-(7-methoxy-2-naftylsulfonyl)-L-arginy 1]-4-methyl-2-piperidinkarboxylát 670—1000 l-[ N2- (4,6-dimethoxy-2-naftyl, sulfonyl J -L-arginyl ] -4-methyl-2-piperidinkarboxylová kyselina 670—1000 kyselina l-[N2-(l-naftylsulfonyl)-L-arginyl]-4-methyl-2-piperidinkarboxylová 700—1000 kyselina 1- [ N2- (5-dimethylamino-l-naftylsulfonyl)-L-arginyl ] -2-pipéridinkarboxylová 700—1000 kyselina 4-[N2-(7-methoxy-2*B4ÍtyÍSuU onyl) -L-arginy 1} -3-morfolinokarboxylová >1000 kyselina ž-ífiN^f^dtmethoxy-2-naf tylsulf onyl) -L-arglnyl ] -1,2,3,4-tetrahydroisochinoIin-3-karboxylová > 1000N 2 - (4,6-dimethoxy-2-naphthylsulfonyl) -L-arginy 1-N-cyclohexylmethylalanine> 1500 1- [N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -1-arginyl} -2 -piperidinecarboxylic acid 1500 ethyl 1- [N 2 - (7-methoxy-2-naphthylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylate 670-1000 1- [N 2 - (4,6-dimethoxy- 2-naphthyl, sulfonyl-1-L-arginyl] -4-methyl-2-piperidinecarboxylic acid 670-1000 1- [N 2 - (1-naphthylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid 700- 1000 1- [N 2 - (5-dimethylamino-1-naphthylsulfonyl) -L-arginyl] -2-piperidinecarboxylic acid 700-1000 4- [N 2 - (7-methoxy-2-Biphenylsulfonyl) -L-arginic acid 1} -3-morpholinocarboxylic acid> 1000 (N - [(4-dimethoxy-2-naphthylsulfonyl) -L-arginyl] -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid> 1000
Sloučenina LD50 (mg/kg) kyselina 2-[N2-(6,7-dimethoxy-2-naf tylsulf onyl) -L-arginyl ] -1-isoindolinkarboxylová > 1000Compound LD50 (mg / kg) 2- [N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl] -1-isoindolinecarboxylic acid> 1000
Akutní toxicita byla stanovena intraperitoneálním podáním sloučenin obecného vzorce I myším samcům o hmotnosti 20 g v rozmezí 1000 až 10 000 mg/kg tělesné hmotnosti.Acute toxicity was determined by intraperitoneal administration of compounds of Formula I to male mice weighing 20 g in the range of 1000 to 10,000 mg / kg body weight.
Na druhé straně jsou hodnoty LD50 pro N2-dansyl-N-butyl-L-argininamid a N2-dansyl-N-methyl-N-butyl-L-argininamid 75 a 70 mg/kg.On the other hand, the LD 50 values for the N 2 -dansyl-N-butyl-L-argininamide, and N 2 -dansyl-N-methyl-N-butyl-L-argininamide 75 and 70 mg / kg.
Sloučeniny podle vynálezu je možno podávat jako takové nebo spolu s farmaceuticky přijatelnými nosiči, jejichž podíl závisí na rozpustnosti a chemické povaze účinné látky, cestě podání a dalších faktorů. Sloučeniny podle vynálezu je možno podávat nitrosvalově, nitrožilně nebo podkožně ve formě sterilních roztoků s obsahem dalších složek, například chloridu sodného nebo glukózy k dosažení isotonicity roztoku. Při perorálním podání je možno použít tablety, kapsle nebo granule s obsahem škrobu, laktózy, sacharózy apod. Subllmguální aplikace je možná zejména při smíšení účinné látky s cukrem nebo kukuřičným sirupem, chuťovými látkami a barvivý s následnou dehydrací a lisováním. Při perorálním podání roztoků obsahují tyto roztoky obvykle chuťové látky a barviva. Vhodnou dávku a cestu podání stanoví lékař. Při perorálním podání je obvykle možno podat větší množství nebo účinnější sloučeninu k dosažení téhož účinku jako při parenterálním podání. Účinná dávka je obvykle 10 až 50 mg/kg parenterálně nebo 10 až 500 mg/kg perorálně. Vhodné lékové formy a dávky jsou uvedeny zejména v příkladech provedení.The compounds of the invention may be administered as such or together with pharmaceutically acceptable carriers depending on the solubility and chemical nature of the active ingredient, the route of administration and other factors. The compounds of the invention may be administered intramuscularly, intravenously or subcutaneously in the form of sterile solutions containing other ingredients, for example sodium chloride or glucose, to achieve isotonicity of the solution. For oral administration, tablets, capsules or granules containing starch, lactose, sucrose and the like may be used. Sublingual administration is particularly possible when the active ingredient is mixed with sugar or corn syrup, flavorings and colorants, followed by dehydration and compression. When administered orally, these solutions usually contain flavoring and coloring agents. The appropriate dose and route of administration will be determined by the physician. For oral administration, it is usually possible to administer a greater amount or more effective compound to achieve the same effect as parenteral administration. The effective dose is usually 10 to 50 mg / kg parenterally or 10 to 500 mg / kg orally. Suitable dosage forms and dosages are particularly indicated in the Examples.
Vynález bude osvětlen dále v příkladech.The invention will be illustrated in the examples below.
Příklad 1Example 1
A. N2- (6,7-dimethoxy-2-naftylsulfonyl) -L-argininA. N 2- (6,7-Dimethoxy-2-naphthylsulfonyl) -L-arginine
K roztoku 83,6 g L-argininu v 800 ml 10% uhličitanu draselného se za energického míchání přidá 114,7 g 6,7-dimethoxynaftalensulfonylchloridu v 800 ml benzenu. Reakční směs se míchá při . teplotě 60 °C 5 hodin, po této době se vzniklá sraženina po hodině stání při teplotě místnosti odfiltruje a postupně promývá benzenem a vodou, čímž se ve výtěžku 76 % získá 129 g N2-(6,7-dimethoxy-2-naf tylsulf onyl) -L-argininu o teplotě tání 252 až 255 °C.To a solution of 83.6 g of L-arginine in 800 ml of 10% potassium carbonate was added 114.7 g of 6,7-dimethoxynaphthalenesulfonyl chloride in 800 ml of benzene with vigorous stirring. The reaction mixture was stirred at RT. at 60 ° C for 5 hours, after which time the precipitate after one hour at room temperature the filtered and washed successively with benzene and water to give in 76% yield gave 129 g of N 2 - (6,7-dimethoxy-2-naphthylsulfonyl onyl) -L-arginine, m.p. 252-255 ° C.
Β. N2-(6,7-dimethoxy-2-naftylsulfonyl)-L-arginylchloridΒ. N 2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl chloride
Suspenze 2,00 g N2-(6,7-dimethoxy-2-naftylsulfonyl)-L-argininu ve 200 ml thionylchloridu se míchá 2 hodiny při teplotě místnosti. Přidáním chladného bezvodého diethyletheru vzniká sraženina, která se oddělí filtrací a několikrát se promyje bezvodým diethyletherem, čímž se získá N2-(6,7-dimethoxy-2-naf tylsulf onyl) -L-arginylchlorid.A suspension of 2.00 g of N 2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginine in 200 ml of thionyl chloride was stirred at room temperature for 2 hours. Addition of cold anhydrous diethyl ether gives a precipitate which is collected by filtration and washed several times with anhydrous diethyl ether to give N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl chloride.
C. Terc.butylester N2-(6,7-dimethoxy-2-naf tylsulf onyl) -L-arginyl-N-butylglycinuC. tert-Butyl N @ 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-butylglycine
K míchanému roztoku 2,64 g N-butylglycinu ve formě terc.butylesteru ve 20 ml chloroformu se opatrně přidá svrchu získaný N2- (6,7-dimethoxy-2-naftylsulf onyl) -L-arginylchlorid. Reakční směs se nechá stát při teplotě místnosti hodinu a pak se dvakrát promyje 20 ml nasyceného roztoku chloridu sodného, načež se odpaří do sucha.To a stirred solution of 2.64 g of N-butylglycine tert-butyl ester in 20 mL of chloroform was carefully added the above-obtained N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl chloride. The reaction mixture was allowed to stand at room temperature for one hour and then washed twice with 20 ml of saturated sodium chloride solution and then evaporated to dryness.
Odparek se rozetře s malým množstvím vody na krystalický materiál, který se oddělí filtrací a nechá se překrystalovat ze směsi ethanolu a ethyletheru, čímž se ve výtěžku 82 % získá 2,28 g terc.butylesteru N2- (6,7-dimethoxy-2-naftylsulfonyl )-L-arginyl-N-butylglycinu o teplotě tání 164 až 166° Celsia.The residue was triturated with a small amount of water to give a crystalline material which was collected by filtration and recrystallized from ethanol / ethyl ether to give 2.28 g of N 2 - (6,7-dimethoxy-2) tert -butyl ester in 82% yield. 164 DEG-166 DEG C. (naphthylsulfonyl) -L-arginyl-N-butylglycine.
Spektrum v infračerveném světle v KBr má maxima při 3390, 3165, 1735, 1370 cm-1. Analýza pro G28H43O7N5S . V2 H2SO3: vypočteno:The infrared spectrum in KBr has peaks at 3390, 3165, 1735, 1370 cm -1 . Analysis for G28H43O7N5S. V2 H2SO3: calculated:
52,98 % C, 7,00 % H, 11,04 % N, nalezeno ·% H, 7.00%, N 11.04%, found ·
52,69 θ/ο C, 6,98 % H, 10,86 % N.H, 6.98; N, 10.86.
D. N2- (6,7-dimethoxy-2-naf tylsulf onyl) -L-arginyl-N-butylglycinD. N 2- (6,7-Dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-butylglycine
K roztoku 2,00 g N2-(6,7-dimethoxy-2-naftylsulfonyl)-L-arginyl-N-butylglycinu ve formě terc.butylesteru ve 20 ml chloroformu se přidá 50 ml 15% kyseliny chlorovodíkové v ethylacetátu. Reakční směs se míchá 5 hodin při teplotě místnosti. Na konci této doby se reakční směs odpaří do sucha, odparek se několikrát promyje bezvodým diethyletherem a pak se chromatografuje na 80 ml aniontoměničové pryskyřice o průměru zrn 200 až 300 mesh (Daiaion(R) SK 102 v H+ formě) ve vodě, sloupec se propláchne vodou a pak se vymývá 3% roztokem hydroxidu amonného.To a solution of 2.00 g of N 2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-butylglycine as tert-butyl ester in 20 ml of chloroform was added 50 ml of 15% hydrochloric acid in ethyl acetate. The reaction mixture was stirred at room temperature for 5 hours. At the end of this time, the reaction mixture was evaporated to dryness, the residue was washed several times with anhydrous diethyl ether and then chromatographed on 80 ml of 200-300 mesh anion-exchange resin (Daiaion (R) SK 102 in H + form) in water. Rinse with water and then elute with 3% ammonium hydroxide solution.
Takto získané frakce se odpaří do sucha, čímž se ve formě amorfní pevné látky získá ve výtěžku 79 % 1,43 g N2-(6,7-dimethoxy-2-naf tylsulf onyl) -L-arginyl-N-butylglycinu.The fractions thus obtained were evaporated to dryness to give 1.43 g of N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-butylglycine as an amorphous solid in 79% yield.
Spektrum v infračerveném světle v KBr má maxima při 3360, 3140, 1622 cm-1. Analýza pro C24H35N5O7S:The infrared spectrum in KBr has peaks at 3360, 3140, 1622 cm -1 . Analysis for C24H35N5O7S:
vypočteno:calculated:
53,62 % C, 6,56 % H, 13,03 % N, ηα1θ7ΟΠΠ'% C, 53.62;% H, 6.56;% N, 13.03%.
53,48 % C, 6,43 % Η, 12,98 % Ν.53.48%, 6.43% Η, 12.98% Ν.
Odpovídajícím způsobem je možno získat tyto sloučeniny:Accordingly, the following compounds can be obtained:
N2- (7-methyl-2-naftylsulf onyl) -L-arginyl-N-butyl-(3-alanin,N 2 - (7-methyl-2-naphthylsulfonyl) -L-arginyl-N-butyl- (3-alanine),
N2- (7-methyl-2-naf tylsulf onyl) -N- (2-methoxyethyl) -N- (3-karboxypropyl) -L-argininamid,N 2- (7-methyl-2-naphthylsulfonyl) -N- (2-methoxyethyl) -N- (3-carboxypropyl) -L-argininamide,
N2- (5-methoxy-l-naf tylsulf onyl) -L-arginyl-N- (2-methylthioethyl Jglycin,N 2 - (5-methoxy-1-naphthylsulfonyl) -L-arginyl-N- (2-methylthioethyl) glycine,
N2- (5-methoxy-l-naf tylsulf onyl) -L-arginyl-N- (2-methylthioethyl Jglycin ve formě terc.butylesteru,N 2- (5-methoxy-1-naphthylsulfonyl) -L-arginyl-N- (2-methylthioethyl) glycine as the tert-butyl ester,
N2- (5-methoxy-l-naftylsulf onyl ] -L-arginyl-N- (2-methylthioethyl )-/J-alanin,N- 2- (5-methoxy-1-naphthylsulfonyl) -L-arginyl-N- (2-methylthioethyl) - N-alanine,
N2- (6,7-diethoxy-2-naftylsulf onyl) -L-arginyl-N- (2-methylthioethyl jglycin,N 2 - (6,7-diethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methylthioethyl) glycine,
N2- (6-methoxy-2-naf tylsulf onyl) -L-arginyl-N- (2-methylthioethyl Jglycin,N 2 - (6-methoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methylthioethyl) glycine,
N2- (6,7-dimethoxy-2-naftylsulf onyl) -N- (2-methylthioethyl J -N- (3-karboxypropyl j -L-argininamid,N 2- (6,7-dimethoxy-2-naphthylsulfonyl) -N- (2-methylthioethyl) -N- (3-carboxypropyl) -L-argininamide,
N2- (6,7-dimethoxy-2-naftylsulfonyl )-N- (3-methylthiopropyl Jglycin,N 2- (6,7-dimethoxy-2-naphthylsulfonyl) -N- (3-methylthiopropyl) glycine,
N2-(6,7-dimethoxy-2-naftylsulfonyl)-L-arginyl-N- (2-ethylthioethyl) -/?-alanin, benzylester N2- (6,7-dlmethoxy-2-naftylsulfonyl) -L-arginyl-N-benzylglycinu,N- 2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-ethylthioethyl) -N-alanine benzyl ester N 2- (6,7-dimethoxy-2-naphthylsulfonyl) -L- arginyl-N-benzylglycine,
N2- (6,7-dimethoxy-2-naftylsulfonyl-N-benzyl-N- {3-terc.butoxykarbonylpropyl) -L-argininamid,N 2- (6,7-dimethoxy-2-naphthylsulfonyl-N-benzyl-N- (3-tert-butoxycarbonylpropyl) -L-argininamide),
N2- (6,7-diethoxy-2-naf tylsulf onyl) -L-arglnyl-N-cyklohexylglycln, kyselina 4-N-[ N2-(6,7-dimethoxy-2-naftylsulf onyl J -L-arginyl ] -N-cyklohexylaminomáselná,N 2 - (6,7-diethoxy-2-naphthylsulfonyl) -L-arginyl-N-cyclohexylglycine, 4-N- [N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl ] -N-cyclohexylaminobutyric,
N2- (4,6-dimethoxy-2-naf tylsulfonyl) -L-arginyl-N-fenethyl-/3-alanin,N- 2- (4,6-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-phenethyl- [3-alanine],
N2- (6-methoxy-2-naftylsulfonyl )-L-arginyl-N- (3-fenylpropyl) glycln,N 2- (6-methoxy-2-naphthylsulfonyl) -L-arginyl-N- (3-phenylpropyl) glycine,
N2- (5-methoxy-l-naf tylsulf onyl) -L-arglnyl-N-benzyl-/3-alanin,N 2 - (5-methoxy-1-naphthylsulfonyl) -L-arginyl-N-benzyl- β-alanine,
N2- (3-nltro-l-naf tylsulf onyl J -L-arginyl-N-tetrahydrofurfurylglycin,N 2 - (3-nitro-1-naphthylsulfonyl) -L-arginyl-N-tetrahydrofurfurylglycine,
N2- (7-hydroxy-2-naftylsulfonyl J-L-argínyl-N-tetrahydrofurfurylglycin,N 2 - (7-hydroxy-2-naphthylsulfonyl) -1-arginyl-N-tetrahydrofurfurylglycine,
N2- (5-kyano-l-naf tylsulf onyl) -L-argínyi-N-tetrahydrofurfurylglycin,N 2- (5-cyano-1-naphthylsulfonyl) -L-arginyl-N-tetrahydrofurfurylglycine,
N2- (6,7-dimethoxy-2-naf tylsulf onyl J-L-arginyl-N-tetrahydrofurfuryl-/í-alanln,N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -1-arginyl-N-tetrahydrofurfuryl-1-alanine,
N2- (7-methyl-2-naf tylsulf onyl) -L-arginyl-N-tetrahydrofurfuryl-jS-alanin,N 2- (7-methyl-2-naphthylsulfonyl) -L-arginyl-N-tetrahydrofurfuryl-5-alanine,
N2- (6,7-dlmethoxy-2-naf tylsulf onyl) -L-arginyl-N-tetrahydrofurfurylalanin,N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-tetrahydrofurfurylalanine,
N2- (7-methoxy-2-naf tylsulf onyl) -N- (3-karbo xypropyl J -N-tetrahydrof urfuryl-L-argininamid,N 2- (7-methoxy-2-naphthylsulfonyl) -N- (3-carboxypropyl) -N-tetrahydrofurfuryl-L-argininamide,
N2- (7-methoxy-2-naf tylsulf onyl) -L-arginyl-N-butylalanln,N 2 - (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N-butylalanine,
N2-( 7-methoxy-2-naf tylsulf onyl ·)-L-arginyl-N-pentylalanin,N 2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N-pentylalanine,
N2- (6,7-dimethoxy-2-naftylsulf onyl) -L-arginy 1- N-Isobuty lalanín,N 2 - (6,7-dimethoxy-2-naphthylsulphonyl) -L-argin-1-N-isobutyl lalanine,
N2- {7-raethoxy-2-naf tylsulf ony 1) -L-arginyl-N-benzylalanin,N 2 - (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N-benzylalanine,
N2-{5-methoxy-l-naf tylsulf onyl)-L-arginyl-N-butylalanin,N 2- (5-methoxy-1-naphthylsulfonyl) -L-arginyl-N-butylalanine,
N2- (6,7-dimethoxy-2-naf tylsulf onyl) -L-arglnyl-N- (3-fenylpropyl) alanin,N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (3-phenylpropyl) alanine,
N2- (5-methoxy-l-naf tylsulfonyl) -L-arginyl-N-benzylalanin,N 2- (5-methoxy-1-naphthylsulfonyl) -L-arginyl-N-benzylalanine,
N2- (7-methoxy-2-naf tylsulf onyl)-L-arginyl-N-cyklohexylalanin,N 2- (7-methoxy-2-naphthylsulphonyl) -L-arginyl-N-cyclohexylalanine,
N2- (6,7-dimethoxy-2-naftylsulfonyl) -L-arginyl-N-cyklohexylmethylalanln,N 2- (6,7-dimethoxy-2-naphthylsulphonyl) -L-arginyl-N-cyclohexylmethylalanine,
N2- (6,7-dimethoxy-2-naf tylsulf onyl) -L-arginyl-N-butylbutyrin,N 2 - (6,7-dimethoxy-2-naphthylsulphonyl) -L-arginyl-N-butylbutyrine,
N2- (6,7-dimethoxy-2-naftylsulfonyl) -L-arglnyl-N- (3-f urylmethyl) glycin,N 2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (3-furylmethyl) glycine,
N2-{ 6,7-dimethoxy-2-naftylsulf onyl J -L-arginyl-N-{ tetrahydro-3-f urylmethyl }· glycin,N 2 - {6,7-dimethoxy-2-naphthylsulphonyl-L-arginyl-N- {tetrahydro-3-furylmethyl} glycine,
N2- (6,7-dimethoxy-2-naftylsulf onyl J-L-arginyl-N- (2-thenyl Jglycin,N 2 - (6,7-dimethoxy-2-naphthylsulphonyl) L-arginyl-N- (2-thenyl) glycine,
N2-(6,7-dimethoxy-2-naf tylsulf onyl J-L-arginyl-N- (2-acetylethyl) glycln,N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) L-arginyl-N- (2-acetylethyl) glycine,
N2- (7-methoxy-2-naftylsulfonyl) -L-arginyl-N- (4-methoxyf urf uryl) glycin,N 2 - (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N- (4-methoxyfuryl) glycine,
N2- (7-methyl-2-naf tylsulf onyl) -L-arginyl-N- (5-methylf urf uryl Jglycin,N 2- (7-methyl-2-naphthylsulphonyl) -L-arginyl-N- (5-methylfurfuryl) glycine,
N2- (6,7-dimethoxy-2-naftylsulf onyl) -L-arginyl-N- (1,4-díoxacyklohexylmethyl) glycin,N 2- (6,7-dimethoxy-2-naphthylsulphonyl) -L-arginyl-N- (1,4-dioxacyclohexylmethyl) glycine,
1- [ N2- (6,7-dimethoxy-2-naf tylsulf onyl) -L-arginyl ]-4-methoxypiperidin-2-karboxylová kyselina, kyselina 1- [ N2- (6,7 dlmethoxy-2-naf tylsulf onyl) -L-arginyl ] -3-methylhexamethylenimin-2-karboxylová, kyselina 1- [ N2- (3,7-dimethyl-2-dibenzofuranylj -L-arginyl] -4,4-dimethyl-2-piperidinkarboxylová,1- [N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl] -4-methoxypiperidine-2-carboxylic acid 1- [N 2 - (6,7-dimethoxy-2-naphthyl) Tylsulfonyl) -L-arginyl] -3-methylhexamethylenimine-2-carboxylic acid, 1- [N 2- (3,7-dimethyl-2-dibenzofuranyl) -L-arginyl] -4,4-dimethyl-2-piperidinecarboxylic acid,
N2- (3-methoxy-3,6,7,8-tetrahydro-2-naftylsulf onyl) -L-arginyl-N- (tetrahydro-2-pyranylmethyl)glycin,N 2 - (3-methoxy-3,6,7,8-tetrahydro-2-naphthylsulfonyl) -L-arginyl-N- (tetrahydro-2-pyranylmethyl) glycine,
N2- (7-methoxy-2-naf tylsulf onyl) -L-arginyl-N- (3-thenylj glycin,N 2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N- (3-thenyl) glycine,
N2- (6,7-dimethoxy-2-naftylsulf onylj -L-arginyl-N(tetrahydro-2-thenyl) glycin,N 2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N (tetrahydro-2-thenyl) glycine,
N2- (7-methoxy-2-naftylsulf onylj -L-arginyl-N- (tetrahydro-3-thenyl) glycin.N 2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N- (tetrahydro-3-thenyl) glycine.
P ř í k 1 a d 2Example 1 a d 2
A. N2- (6-methoxy-2-naf tylsulf onyl) -L-arginylchloridA. N 2- (6-Methoxy-2-naphthylsulfonyl) -L-arginyl chloride
Suspenze 2,5 g N2-(6-methoxy-2-naftylsulfonyl )-L-argininu ve 20 ml thionylchloridu se míchá 2 hodiny při teplotě místnosti. Po přidání bezvodého chladného diethyletheru vznikne sraženina, která se promyje na filtru několikrát bezvodým ethyletherem, čímž se získá N2-(6-methoxy-2-naftylsulfonylj-L-argiňylchlorid.A suspension of 2.5 g of N 2 - (6-methoxy-2-naphthylsulfonyl) -L-arginine in 20 ml of thionyl chloride was stirred at room temperature for 2 hours. Addition of anhydrous cold diethyl ether gave a precipitate which was washed on the filter several times with anhydrous ethyl ether to give N 2 - (6-methoxy-2-naphthylsulfonyl) -1-arginyl chloride.
B. Ethyl-1- [ N2- [ 6-methoxy-2-naftylsulfonyl)-L-arginyl ] -2-piperidinkarboxylátB. Ethyl 1- [N 2 - [6-methoxy-2-naphthylsulfonyl) -L-arginyl] -2-piperidinecarboxylate
K míchanému roztoku 2,2 g ethyl-2-piperidinkarboxylátu a 4,1 ml triethylaminu v 50 ml chloroformu se za chlazení na ledové lázni se solí po částech přidá svrchu získaný N2-6-methoxy-2-naftylsulf onyl) -L-arginylchlorid. Reakční směs se míchá přes noc při teplotě místnosti, pak se přidá 500 ml chloroformu a chloroformový roztok se dvakrát promyje 50 ml nasyceného roztoku chloridu sodného, vysuší se bezvodým síranem sodným a odpaří ve vakuu. Olejovitý zbytek se promyje ethyletherem, čímž se získá 2,9 g práškovitého ethyl-1-[N2-(6-methoxy-2-naftylsulf onyl j -L-arginyl ] -2-piperidinkarboxylátu.To a stirred solution of 2.2 g of ethyl 2-piperidinecarboxylate and 4.1 ml of triethylamine in 50 ml of chloroform was added portionwise the above-obtained N 2 -6-methoxy-2-naphthylsulfonyl) -L- with cooling in an ice bath. arginylchloride. The reaction mixture is stirred overnight at room temperature, then 500 ml of chloroform are added and the chloroform solution is washed twice with 50 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo. The oily residue was washed with ethyl ether to give 2.9 g of powdery ethyl 1- [N 2 - (6-methoxy-2-naphthylsulphonyl) -1-arginyl] -2-piperidinecarboxylate.
Pro analytické účely se část tohoto produktu převede na flavinát o teplotě tání 192 až 193 °C.For analytical purposes, a portion of this product is converted to a flavinate of m.p. 192-193 ° C.
Spektrum v infračerveném světle v KBr má maxima při 3210, 1747, 1638 cm-1.The infrared spectrum in KBr has maxima at 3210, 1747, 1638 cm -1 .
Analýza pro C25H36O6N5S . CioHsOsNžS: vypočteno:Analysis for C25H36O6N5S. C 10 H 15 O 5 N 2 S: calculated:
49,58 % C, 4,87 % H, 11,56 % N, nalezeno:% C, 49.58;% H, 4.87;% N, 11.56.
49,24 0/0 c, 4,70 % H, 11,85 % N.49.24 0/0 C, 4.70% H, 11.85% N.
C. 1- [ N2- (6-methoxy-2-naftylsulf onyl j -L-arginyl]-2-piperidinkarboxylová kyselinaC. 1- [N 2 - (6-Methoxy-2-naphthylsulfonyl) -L-arginyl] -2-piperidinecarboxylic acid
Roztok 1,8 g ethyl-1-[N2-6-methoxy-2-naf tylsulfonyl) -L-arginyl ] -2-piperidinkarboxylátu v 15 ml methanolu a v 10 ml roztoku hydroxidu sodného o koncentraci 2 N se zahřívá na 60 °C a na této teplotě se udržuje 10 hodin. Pak se reakční směs zahustí a chromatografuje na 200 ml iontoměničové pryskyřice o průměru zrn 200 až 300 mesh (Daision(R) SK 102 v H+ formě] ve vodě, sloupec se promývá směsí ethanolu a vody v poměru 1:4a pak směsí ethanolu, vody a hydroxidu amonného v poměru 10 : : 9 : 1. Hlavní frakce se odpaří do sucha a promyje se ethyletherem, čímž se ve formě amorfní pevné látky získá 2,0 g kyseliny 1-[ N2- (6-methoxy-2-naftylsulf onyl) -L-arginyl ] -2-piperidinkarboxylové.A solution of 1.8 g of ethyl 1- [N 2 -6-methoxy-2-naphthylsulfonyl) -L-arginyl] -2-piperidinecarboxylate in 15 ml of methanol and 10 ml of 2 N sodium hydroxide solution is heated to 60 ° C. ° C and held at this temperature for 10 hours. The reaction mixture is concentrated and chromatographed on 200 ml of 200-300 mesh ion exchange resin (Daision (R) SK 102 in H + form) in water, washing the column with ethanol / water 1: 4 and then ethanol / water. The main fraction was evaporated to dryness and washed with ethyl ether to give 2.0 g of 1- [N 2 - (6-methoxy-2-naphthylsulfulfate) as an amorphous solid. onyl) -L-arginyl] -2-piperidinecarboxylic acid.
Spektrum v infračerveném světle v KBr má maxima při 3200, 1620, 1150 cm“1. Analýza pro C23H31O6N5S:The KBr infrared spectrum has peaks at 3200, 1620, 1150 cm -1 . Analysis for C23H31O6N5S:
vypočteno:calculated:
54,64 % C, 6,18 % H, 13,85 °/o N, nalezeno:% C, 54.64;% H, 6.18%;
56,88 % C, 6,31 % H, 13,83 % N.% H, 6.31;% N, 13.83.
Odpovídajícím způsobem je možno získat tyto sloučeniny:Accordingly, the following compounds can be obtained:
N2- (6-chlor-2-naftylsulf onyl-L-arginyl-N-butylglycin,N 2- (6-chloro-2-naphthylsulfonyl-L-arginyl-N-butylglycine),
Ni2- (7-methyl-2-naf tylsulf onyl) -L-arginyl -N- (2-ethoxyethyl J glycin,N i2 - (7-methyl-2-naphthylsulfonyl) -L-arginyl-N- (2-ethoxyethyl J glycine,
N2- (7-methoxy-2-naftylsulf onyl) -L-arginyl-N- (2-methylthioethyl) glycin,N 2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methylthioethyl) glycine,
N2- (4,6-dimethoxy-2-naf tylsulf onyl j -L-arginyl-N- (2-methylthioethyl) glycin,N 2 - (4,6-dimethoxy-2-naphthylsulphonyl) -L-arginyl-N- (2-methylthioethyl) glycine,
N2- (4,6*dimethoxy-2-naftylsulf onyl j -L-arginyl-N-fenethyl-já-alanin,N 2 - (4,6 * dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-phenethyl-1-alanine,
N2- (6,7-dimethoxy-2-naf tylsulf onyl j -N-benzyl-N- (3-karboxypropyl) -L-argininamid,N 2 - (6,7-dimethoxy-2-naphthylsulphonyl) -N-benzyl-N- (3-carboxypropyl) -L-argininamide,
N2- (7-methoxy-2-naf tylsulf onyl) -L-arginyl-N-cyklohexylnorleucin,N 2- (7-methoxy-2-naphthylsulphonyl) -L-arginyl-N-cyclohexylnorleucine,
N2- (7-methoxy-2-naf tylsulf onyl) -L-arginyl-N-butylisoleucin,N 2- (7-methoxy-2-naphthylsulphonyl) -L-arginyl-N-butylisoleucine,
3β3β
Ν2- (7-methoxy-2-naf tylsulf onyl) -L-arginyl-N-pentylbutyrin,Ν 2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N-pentylbutyrine,
N2- (6,7-dimethoxy-2-naftylsulfonyl) -L-arginyl-N-butylalanin,N 2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-butylalanine,
N2- (6,7-dlmethoxy-2-naf tylsulf onyl )-L-arginyl-N-cykloheptylalanin,N 2- (6,7-dimethoxy-2-naphthylsulphonyl) -L-arginyl-N-cycloheptylalanine,
N2- (7-methoxy-2-naf tylsulfonyl) -L-arglnyl-N- (2-methoxyethyl) alanin,N 2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) alanine,
N2- (6,7-dimethoxy-2-nafty lsulf onyl) -L-arginyl-N- (2-ethoxyethyl) alanin,N 2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-ethoxyethyl) alanine,
N2- (7-methoxy-2-naftylsulf onyl) -L-arginyl-N-cyklohexyl-,/S-alanin,N 2 - (7-methoxy-2-naphthylsulphonyl) -L-arginyl-N-cyclohexyl-, S-alanine,
N2- (7-methoxy-2-naf tylsulf onyl) -L-arglnyl-N- (2-methoxyethyl) norvalin,N 2 - (7-methoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) norvaline,
N2- (6,7dimethoxy-2-naf tylsulf onyl )-L-arginyl-N-benzylleucln, kyselina 1- [ N2- (5-methoxy-l-naftylsulfonyl ] -L-arginyl ] -4-ethyl-2-piperidinkarboxylová, kyselina 1- [ N2- (6-methoxy-2-naftylsulfonyl) -L-arginyl ] -4-ethyl-2-piperidinkarboxylová, kyselina 1- [ N2- (4,6-dimethoxy-2-naftylsulfonyl )-L-arginyl ] -4-ethyl-2-piperidinkarboxylová, kyselina 1- [ N2- (5-ethoxy-l-naftylsulf onyl) -L-arginyl ] -4-ethyl-2-piperidinkarboxylová, kyselina 1- [ N2- (7-ethoxy-2-naf tylsulf onyl) -L-arginyl ] -4-ethyl-2-piperidinkarboxylová, kyselina 1- [ N2- (6,7-diethoxy-2-naf tylsulfonyl ) -L-arginyl ] -4-ethyl-2-plperidinkarboxylová, kyselina 1- [ N2- (7-methoxy-2~naftylsulfonyl) -L-arginyl ] -4-ter c.butyl-2-piperidinkarboxylová, f enyl-1- [ N2- (7-methoxy-2-naftylsulfonyl) -L-arginyl ] -4-ethyl-2-piperidinkarboxylát, benzyl-1- [ N2- (7-methoxy-2-naftylsulf onyl) -L-arginyl ] -4-ethyl-2-piper idinkarboxylát, benzyl-1- [ N2- (6,7-dimethoxy-2-naftylsulf onyl) -L-arginyl ] -4-methyl-2-piperidinkarboxylát, kyselina 1- [ N2- (5-nitro-l-naftylsulf onyl) -L-arginyl ] -4-methyl-2-plperidinkarboxylová, kyselina 1- [ N2- (7-hydroxy-2-naf tylsulf onyl) -L-arginyl ] -4-ethyl-2-plperidlnkarboxylová, kyselina 1- [ N2- (5-kyano-l-naftylsulfonyl) -L-arginyl ] -4-methyl-2-plperidinkarboxylová, kyselina 1- [ N2- (7-methyl-2-naf tylsulf onyl) -L-arginyl ] -4-ethyl-2-piperidlnkarboxylová, kyselina 1- [ N2- (5-dimethylamino-l-naftylsulf onyl) -L-arginyl ] -4-ethyl-2-piperidinkarboxylová, kyselina 1- [ N2- (2-iniaf,tylsulf onyl) -L-arginyl ] -4-ethyl-2-plperidinkarboxylová, kyselina 1- [ N2- (5,8,7,8-tetrahydro-2-nafity lsulf omyl j -L-arginyl ] -4-ethyl-2-pipeiridlinkarboxylová, kyselina 1- [ N2- (5-dimethylamino-l-nafitylsulfony 1) -L-arginyl ] -4-methy 1-2-piperidinkarboxylová, kyselina 1- [ N2- (7-meithyl-2-naf tylsulf onyl ) -L-arginyl ] -6-methyl-2-piperidinkarboxylová, k yselina 1- [ N2- (7-meithy 1-2-inaf ty 1sulf onyl)-L-ariginyl ]-4Merc.buityl-2-pipertdlnkairboxylov6, kyselina l-[N2-(5-nltno-l-n»ftylsulf onyl ) -L-arginyl ] -indolin-2-karboxylová, kyselina 2-[N2-(5-kyano-l-naftylsulfonyl) -L-arginyl ] isoindolln-1-karboixylavá, kyselina 1- (N2- (7-meithyl-2-inaf tylsulf onyl ) -L-arginyl Jithiomúrf olin-3-karboxyiová, kyselina 4-[ Ns- (6,7-dim»thyl-2-naftylsulfonyl) -L-arginyl ] morf olin-3-karboixylová,N 2- (6,7-Dimethoxy-2-naphthylsulfonyl) -L-arginyl-N-benzylleucine, 1- [N 2- (5-methoxy-1-naphthylsulfonyl) -L-arginyl] -4-ethyl-2 -piperidinecarboxylic acid 1- [N 2 - (6-methoxy-2-naphthylsulfonyl) -L-arginyl] -4-ethyl-2-piperidinecarboxylic acid 1- [N 2 - (4,6-dimethoxy-2-naphthylsulfonyl) 1-L-arginyl] -4-ethyl-2-piperidinecarboxylic acid 1- [N 2- (5-ethoxy-1-naphthylsulfonyl) -L-arginyl] -4-ethyl-2-piperidinecarboxylic acid 1- [ N- 2- (7-ethoxy-2-naphthylsulfonyl) -L-arginyl] -4-ethyl-2-piperidinecarboxylic acid 1- [N 2- (6,7-diethoxy-2-naphthylsulfonyl) -L- arginyl] -4-ethyl-2-plperidinecarboxylic acid, 1- [N 2- (7-methoxy-2-naphthylsulfonyl) -L-arginyl] -4-tert-butyl-2-piperidinecarboxylic acid, phenyl-1- [ N 2 - (7-methoxy-2-naphthylsulfonyl) -L-arginyl] -4-ethyl-2-piperidinecarboxylate, benzyl 1- [N 2 - (7-methoxy-2-naphthylsulfonyl) -L-arginyl] - 4-ethyl-2-piperidinecarboxylate, benzyl 1- [N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L-a 4-Methyl-2-piperidinecarboxylate, 1- [N 2 - (5-nitro-1-naphthylsulfonyl) -L-arginyl] -4-methyl-2-plperidinecarboxylic acid, 1- [N 2 - ( 7-hydroxy-2-naphthylsulfonyl) -L-arginyl] -4-ethyl-2-plperidinecarboxylic acid 1- [N 2- (5-cyano-1-naphthylsulfonyl) -L-arginyl] -4-methyl- 2-Plperidinecarboxylic acid 1- [N 2 - (7-methyl-2-naphthylsulfonyl) -L-arginyl] -4-ethyl-2-piperidinecarboxylic acid 1- [N 2 - (5-dimethylamino-1- naphthylsulfonyl) -L-arginyl] -4-ethyl-2-piperidinecarboxylic acid 1- [N 2- (2-iniaphylsulfonyl) -L-arginyl] -4-ethyl-2-plperidinecarboxylic acid 1- [ N 2 - (5,8,7,8-tetrahydro-2-naphthylsulfonyl) -L-arginyl] -4-ethyl-2-piperidinecarboxylic acid 1- [N 2 - (5-dimethylamino-1-naphthylsulfones) 1-L-arginyl] -4-methyl-2-piperidinecarboxylic acid 1- [N 2 - (7-methyl-2-naphthylsulphonyl) -L-arginyl] -6-methyl-2-piperidinecarboxylic acid 1- [N 2 - (7-Meithy-2-inaphthylsulfonyl) -L-arig 1- [N 2- (5-nitro-1-phthylsulfonyl) -L-arginyl] -indoline-2-carboxylic acid, 2- [N 2 - (5- cyano-1-naphthylsulfonyl) -L-arginyl] isoindoline-1-carboxylic acid, 1- (N 2 - (7-meithyl-2-inaphthylsulfonyl) -L-arginyl Jithiourofoline-3-carboxylic acid, 4 - [ with N - (6,7-dim »methyl-2-naphthylsulfonyl) -L-arginyl] morpholin-3-karboixylová,
4- [ N2- (5,6,7,8-teitrahydro-2-naftylsultonyl) -L-arginyl ] -3-karboxythiomorfolin-l-oxid, kyselina 4- [ N2- (7-meithyl-2-naftylsulf onyl) -L-arginyl ] morf olin-3-kfflrboxylová, kyselina 4- (Kf2- (7-chlor-2-naftylsulfonyl ) -L-argiiny 1 ] morf olin-3-k.arboxylová, kyselina 4- [ N2- (7-hydroxy-2-nafty 1sulfonyl) -L-arginyl ] mor f olin-3-kiarboxylová, kyselina 4- [ N2- (5-nitro-2-naftylsulfonyl ) -L-arginyl ] thiomorf olln-3-karboxylové, kyselina 4-[ N2- (5-kyano-l-na.ftylsulíonyl) -L-arginyl jthiomorfolin-3-karboxylová, kyselina 4- f N2- (5-mef hoxy-l-nafty 1sulf onyl) -L-arginyl ] morf olin-3-karbQxyl'Ová, ethyl-4- [ N2- (4,6-dimethoxy-2-naftylsulf onyl) -L-arginyl ] morf olin-3-karboxylát, kyselina 4- i N2- (5-ethoxy-l-naftylsulf onyl] -L-arginyl ] morf olin-3-karboxylová, kyselina 4- [ N2-15-dimethyliamino-l-nafitylsulif onyl) -L-airginyl jthlomo'rfolin-3-karboxylová, kyselina 3- [ N2- (1-naf.tylsuif omyl) -L-arginyl]thia0Olidiini-4-karboxylová, kyselina 2-[N:2-(7-methoxy-2-na£tylsulfomyl)-L-arginyl]-1,2,3,4-tetrahydroisochinolin-l-karboxylová, kyselina 2-[ N2- (7-meťhoxy-2-nafltylisuifony 1] -L-arginyl ] isoindolin-1-karboxylová, kyselina 2- [ N2- (4,6-dimeíhoxy-2-naf tylsulfonyl) -L-arginyl ] -1,2,3,4-tetrahydroisochiinjolini-3-karboxylová, kyselina 2-[ N2-15-metboxy-l-naftylsu liony 1) -L-arginyl ] isoindolin-1-karboxylová a kyselina 2- [ N2- (5-ethoxy-l-naftylsulf onyl-L-arginyl ] -1,2,3,4-tetrahydroisochinioliin-3-karboxylová.4- [N 2 - (5,6,7,8-tetrahydro-2-naphthylsulphonyl) -L-arginyl] -3-carboxythiomorpholine-1-oxide, 4- [N 2 - (7-meithyl-2-naphthylsulfonyl) -acid onyl) -L-arginyl] morpholin-3-carboxylic acid 4- (Kf 2- (7-chloro-2-naphthylsulfonyl) -L-argininyl) morpholin-3-carboxylic acid 4- [N 2- (7-hydroxy-2-naphthylsulfonyl) -L-arginyl] morpholin-3-carboxylic acid 4- [N 2- (5-nitro-2-naphthylsulfonyl) -L-arginyl] thiomorpholinyl-3 -carboxylic acid, 4- [N 2 - (5-cyano-1-naphthylsulphonyl) -L-arginyl] thiomorpholine-3-carboxylic acid, 4- [N 2 - (5-methoxy-1-naphthylsulfonyl)] -L-arginyl] morpholine-3-carbonyl-ethyl-4- [N 2- (4,6-dimethoxy-2-naphthylsulfonyl) -L-arginyl] morpholine-3-carboxylate, 4- N 2- (5-ethoxy-1-naphthylsulfonyl) -L-arginyl] morpholine-3-carboxylic acid 4- [N 2 -15-dimethyliamino-1-naphthylsulphonyl) -L-airginyl-thiomorpholin-3 -carboxylic acid, 3- [N 2 - (1-naphthylsulfonyl) -L-arginyl] thiazolidinyl-4-carboxylic acid 2- [N : 2- (7-methoxy-2-naphthylsulfomyl) -L-arginyl] -1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid seline, 2- [N 2 - (7-methoxy) -2-naphthylisulfonyl 1-L-arginyl] isoindoline-1-carboxylic acid 2- [N 2 - (4,6-dimethoxy-2-naphthylsulfonyl) -L-arginyl] -1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid, 2- [N 2 -15-methoxy-1-naphthylsulfonyl) -L-arginyl] isoindoline-1-carboxylic acid, and 2- [N 2 - (5-ethoxy-1-naphthylsulfonyl) -L-arginyl] -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.
Příklad 3Example 3
A. N2- (6,7-dimethoxy-2-inaftyl<sulfonyl ] -L-arginyl-N- (2-methoxyethyl] glycylchloridhydrochloridA. N 2- (6,7-Dimethoxy-2-inaphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycyl chloride hydrochloride
Suspenze 2,00 g N2- (6,7-dimethoxy-2-naftylsulf onyl) -L-arginyl-N- (2-methoxyethyl) glycinu ve 20 ml thionylchioridu se míchá 2 hodiny při teplotě místnosti. Přidáním chladného bezvodého ethyletheru vznikne sraženina, která se oddělí filtrací a několikrát se promyje bezvodým ethyletherem, čímiž se získá N2-(6,7-dimethoxy-2-naftylsulf onyl) -L-arginyl-N- (2-methoxyethyl) glycylchioridhydrochlorid.A suspension of 2.00 g of N 2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine in 20 ml of thionyl chloride was stirred at room temperature for 2 hours. Addition of cold anhydrous ethyl ether gave a precipitate which was collected by filtration and washed several times with anhydrous ethyl ether to give N 2- (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycylchloride hydrochloride.
B. Hydrochlorid m-iolylesteru N2-(6,7-dimeithioxy-2-niaftylsulf onyl) -L-arglnyl-N- (2-methoxyethyl ] glycinuB. N 2 - (6,7-Dimethylthioxy-2-naphthylsulphonyl) -L-arginyl-N- (2-methoxyethyl) glycine m-iolylester hydrochloride
Srqěs 2,00 g m-kresolu a N2-(6,7-dimethoxy-2-naftylsulfonyl)-L-arginyl-N- [ 2-methoxýethyl ] glycylchlocidhydrochloridu, získaného svrchu uvedeným způsobem sa zahřívá na 90 QC 50 mimt. Na konci této doby se reakční směs zchladí, několikrát se promyje bezvodým ethyletherem a pak se rozpustí v 10 ml bezvodého ethylalkoholu. Po přidání chladného bezvodého ethyletheru vznikne sraženina, která se několikrát promyje bezvodým ethyletherem, čímž se ve výtěžku 86 % ve formě prášku získáSrqěs 2.00 g of m-cresol and N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- [2-methoxyethyl] glycylchlocidhydrochloridu obtained as described above was heated to 90? C 50 mimt. At the end of this time, the reaction mixture was cooled, washed several times with anhydrous ethyl ether and then dissolved in 10 ml of anhydrous ethyl alcohol. Addition of cold anhydrous ethyl ether gave a precipitate which was washed several times with anhydrous ethyl ether to give a powder (86% yield).
2,12 ' g N2-(6,7-dimethoxy-2-nafítylsulfonyl)-L-arginyl-N- (2-methoxyethyl) glycinu ve formě hydrochloridu m-tolylesteru.2.12 g of N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-methoxyethyl) glycine as the m-tolyl ester hydrochloride.
Spektrum v infračerveném světle v KBr má maxima při 3250, 3100, 1740, 1640 cm-1.The infrared spectrum in KBr has maxima at 3250, 3100, 1740, 1640 cm -1 .
Odpovídajícím způsobem je možno vyrobit tyto sloučeniny:The following compounds can be prepared accordingly:
N2- (6,7-dimethoxy-2-naftylsulfonyl) -L-arginyl-N- (2-ethylthioethyl) glycin ve formě fenylesiteru, benzylester N2- (6,7-dimetboxy-2-ouftylsulf onyl) -L-arginyl-N- (2-ethyithioethyl] glycinu, fenyleslter N2- (6,7-dimethoxy-2-naftylsulfonyl) -L-íarginyl-N-benzylglycimu, benzylester N2- (6,7-dimethoxy-2-naftylsu,lf onyl ] -L-airginyl-N-f urfurylglycinu, feuylesler N2- (6,7-dimethoxy-2-nafitylf enylsulfonyl) -L-arginyl-N-tetrahydrofuirfurylglycin, f enyl-1- [ N2- (7-meithyl-2-maftylsulf onyl ] -L-arginyl ] -4-ethyl-2-piper; dinkarboxylát, benzyl-1- [ N2- (7-met hyl-2-naftylsulf onyl) -L-arginyl ] -4-ethyl-2-píperidinkarboxylát, benzyl-1- [ N2- (6-chlor-2-uafty 1sulfoinyl) -L-arginyl ] -4-methyl-2-piperidinkarboxylát a ethyl-4- [ N2- f7-meíthyl-2-methylsulf onyl) -Liarginyl ] mcrf olin-3-karboxylát.N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-N- (2-ethylthioethyl) glycine as the phenyl ester, N 2 - (6,7-dimethoxy-2-ouftylsulfonyl) -L- arginyl-N- (2-ethyithioethyl] glycine fenyleslter N 2 - (6,7-dimethoxy-2-naphthylsulfonyl) -L-íarginyl benzylglycimu N-benzyl N 2 - (6,7-dimethoxy-2-naftylsu, 1-Onyl] -L-airginyl-Nf urfurylglycine, N 2- (6,7-dimethoxy-2-naphthylphenylsulfonyl) -L-arginyl-N-tetrahydrofuranofurylglycine, phenyl-1- [N 2 - (7-meithyl- 2-onyl maftylsulf] -L-arginyl] -4-ethyl-2-piperidinyl; pyridinecarboxylate benzyl-1- [N 2 - (7-met hyl-2-naftylsulf) -L-arginyl] -4-ethyl- 2-piperidinecarboxylate, benzyl 1- [N 2 - (6-chloro-2-uphthylsulfoinyl) -L-arginyl] -4-methyl-2-piperidinecarboxylate and ethyl 4- [N 2 - (7-methyl-2-) methylsulfonyl) -Liarginyl] methyl-3-carboxylate.
Způsobem podle předchozích příkladů byly získány další N2-arylsulfonyl-L-argininamidy nebo jejich adiční Soli. Výsledky jsou uvedeny dále v tabulce I:Further N 2 -arylsulfonyl-L-arginine amides or addition salts thereof were obtained by the method of the previous examples. The results are shown in Table I below:
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Příklad 4Example 4
Tablety pro perorální podáníTablets for oral administration
Běžným způsobem je možno připravit tablety do složek, uvedených v tabulce:Tablets can be prepared in conventional manner by the ingredients listed in the table:
MnožstvíAmount
Složka na 1 tabletu (mg)Ingredient per 1 tablet (mg)
Příprava APreparation
Ar ylsulf onylchloridyAr ylsulfonyl chlorides
A. 6,7-dimethoxy-2-naftalensulfonát sodnýA. Sodium 6,7-dimethoxy-2-naphthalenesulfonate
K energicky míchanému roztoku 70,8 gTo an vigorously stirred solution of 70.8 g
6,7-dihydroxy-2-naftalensulfonátu sodného aSodium 6,7-dihydroxy-2-naphthalenesulfonate a
77,2 g ; hydroxidu sodného ve 450 ml vody se po kapkách přidá 230 ml dimethylsulfátu při teplotě 60 °C v průběhu 1 hodiny, přičemž současně dochází ke srážení produktu. K reakční směsi se po částech přidá77.2 g ; Sodium hydroxide in 450 ml of water was added dropwise with 230 ml of dimethyl sulfate at 60 ° C over 1 hour, at the same time the product precipitated. The reaction mixture was added portionwise
38,8 g hydroxidu sodného a směs se dále hodinu míchá při teplotě místnosti. Po této době se sraženina odfiltruje, promyje se ethanolem a vysuší, čímž se získá 50 g 6,7-dimethoxy-2-naftalensulfonátu sodného.38.8 g of sodium hydroxide and the mixture was further stirred at room temperature for 1 hour. After this time, the precipitate was filtered off, washed with ethanol and dried, yielding 50 g of sodium 6,7-dimethoxy-2-naphthalenesulfonate.
B. 6,7-dimethoxy-2-naftalensulfonylchloridB. 6,7-Dimethoxy-2-naphthalenesulfonyl chloride
K míchané suspenzi 50 g jemně rozptýleného 6,7-dimethoxy-2-naftalensulfonátu sodného ve 100 ml dimethylformamldu se po kapkách přidá 62,2 ml thionylchloridu při teplotě místnosti. Po 30 minutách se reakční směs vlije do i litru vody s ledovou drtí a vzniklá sraženina se oddělí filtrací a rozpustí ve 250 ml benzenu. Benzenový roztok se několikrát promyje vodou a pak se vysuší bezvodým síranem sodným. Rozpouštědlo se odpaří dosucha ve vakuu a odparek se nechá překrystalovat ze směsi benzenu a n-hexanu v poměru 1:1, čímž se získá 32 g 6,7-dimethoxy-2-naftalensulfonylchloridu o teplotě tání 127,5 až 129,5 °C.To a stirred suspension of 50 g of finely divided sodium 6,7-dimethoxy-2-naphthalenesulfonate in 100 ml of dimethylformamide was added dropwise 62.2 ml of thionyl chloride at room temperature. After 30 minutes, the reaction mixture was poured into 1 liter of crushed water and the resulting precipitate was collected by filtration and dissolved in 250 ml of benzene. The benzene solution was washed several times with water and then dried over anhydrous sodium sulfate. The solvent was evaporated to dryness in vacuo and the residue was recrystallized from benzene / n-hexane (1: 1) to give 32 g of 6,7-dimethoxy-2-naphthalenesulfonyl chloride, m.p. 127.5-129.5 ° C. .
Analýza pro C12H11O4SCI:Analysis for C12H11O4SCI:
vypočteno:calculated:
50,26 % C, 3,87 % H, 12,37 % Cl, nalezeno:% C, 50.26;% H, 3.87;% Cl, 12.37.
50,45 % C, 4,00 % H, 12,33 % Cl.% C, 50.45;% H, 4.00;
V následující, tabulce jsou uvedeny v literatuře dosud nepopsané arylsulfonylchloridy, které jsou získány způsobem, který je v podstatě totožný se způsobem podle publikace Ε. H. Rood, „Chemistry of Carbon Compounds“, Elsevier Publishing Company, 1954, sv. III, str. 441 až 469:The following table lists the arylsulfonyl chlorides not previously described in the literature, which are obtained by a process which is essentially identical to that of publication Ε. H. Rood, " Chemistry of Carbon Compounds ", Elsevier Publishing Company, 1954, Vol. III, pp. 441 to 469:
Teplota tání (°C)Melting point (° C)
ČísloNumber
ArylsulfonylchloridArylsulfonyl chloride
Příprava BPreparation
Deriváty aminokyselinAmino acid derivatives
A. Terc.butylester N-butylglycinuA. N-Butylglycine tert-butyl ester
Ke 36,5 g butylaminu se přidá za stálého míchání 15,05 g terc.butylchloracetátu v průběhu 30 minut, přičemž se teplota směsi udržuje v rozmezí 30 až 70 °C. Pak se další hodinu směs zahřívá na 70 °C. Na konci této doby se přebytek butylaminu odpaří ve vakuu a odparek se smísí se 40 ml roztoku hydroxidu sodného o koncentraci 2 N a 50 mililitrech benzenu, načež se přenese do dělicí nálevky, benzen se oddělí, promyje vodou, vysuší bezvodým síranem sodným a zfiltruje. Po odpaření benzenového podílu se odparek destiluje za sníženého tlaku, čímž se ve výtěžku 90,9 % získá 17,0 g terc.butylesteru N-butylglycinu o teplotě varu 76 CC při tlaku 533,3 Pa.To 36.5 g of butylamine is added, with stirring, 15.05 g of tert-butyl chloroacetate over a period of 30 minutes, maintaining the temperature of the mixture between 30 and 70 ° C. The mixture was then heated at 70 ° C for an additional hour. At the end of this time, the excess butylamine was removed in vacuo and the residue was treated with 40 ml of 2 N sodium hydroxide solution and 50 ml of benzene, transferred to a separatory funnel, separated, washed with water, dried over anhydrous sodium sulfate and filtered. After evaporation of the benzene fraction, the residue is distilled under reduced pressure to give 17.0 g of N-butylglycine tert-butyl ester of boiling point 76 DEG C. (0.5 mm Hg) at 90.9% yield.
Obdobným způsobem byly získány následující terc.butylestery aminokyselin, které dosud nebyly popsány v literatuře. Postup je v podstatě shodný se způsobem podle publikace A. J. Speciále et al., J. Org. Chem. 23, 731(1960):In a similar manner, the following tert-butyl amino acid esters were obtained, which have not been described in the literature. The procedure is essentially the same as that of A. J. Special et al., J. Org. Chem. 23, 731 (1960).
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číslo Derivát aminokyselinyamino acid derivative
Teplota varu °C/PaBoiling point ° C / Pa
Číslo Derivát aminokyseliny Teplota varu °C/Pa yCH2CHz—θNumber Amino acid derivative Boiling point ° C / P aCH 2 CH from - no
Teplota varu °C/PaBoiling point ° C / Pa
Číslo Derivát aminokyselinyNumber Amino acid derivative
CH2CH2OHCH2CH2OH
ZOF
HN 95 až 96/266,6 \HN 95 to 96 / 266.6 \
CH2CO2-t-C4H9CH2CO2-t-C4H9
CH2C = CH ZCH 2 C = CH 2
HN \HN \
CtoCOz-t-CáHg ...........CtoCO2-t-CaHg ...........
Claims (12)
Applications Claiming Priority (12)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US05/638,985 US4055636A (en) | 1974-11-08 | 1975-12-09 | N2 -alkoxynaphthalenesulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof |
| US05/646,522 US4018915A (en) | 1976-01-05 | 1976-01-05 | N2 -alkoxynaphthalenesulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof |
| US05/649,219 US4018913A (en) | 1976-01-14 | 1976-01-14 | N2 -alkoxynaphthalenesulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof |
| US05/653,217 US4055651A (en) | 1974-11-08 | 1976-01-28 | N2 -alkoxynaphthalenesulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof |
| US05/656,014 US4041156A (en) | 1974-11-08 | 1976-02-06 | N2 -alkoxynaphthalenesulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof |
| US05/656,870 US4046876A (en) | 1974-11-08 | 1976-02-10 | N2 -alkoxynaphthalenesulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof |
| US05/669,743 US4070457A (en) | 1974-11-08 | 1976-03-24 | N2 -naphthalenesulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof |
| US05/707,536 US4036955A (en) | 1976-07-22 | 1976-07-22 | N2 -naphthalenesulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof |
| US05/713,486 US4073914A (en) | 1974-11-08 | 1976-08-11 | N2 -naphthalenesulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof |
| US05/723,474 US4096255A (en) | 1974-11-08 | 1976-09-14 | N2 -naphthalenesulfonyl-L-argininamides, and pharmaceutical salts, compositions and methods |
| US05/728,051 US4104392A (en) | 1974-11-08 | 1976-09-30 | N2 -naphthalenesulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof, and antithrombotic compositions and methods employing them |
| CS768025A CS228103B2 (en) | 1975-12-09 | 1976-12-08 | Production of n-2-arylsulphonyl-l-arginiamides and their salts |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CS228113B2 true CS228113B2 (en) | 1984-04-16 |
Family
ID=27582904
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS76902A CS228113B2 (en) | 1975-12-09 | 1979-02-09 | Production of n2-arylsulphonyl-l-argininamides and their salts |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS228113B2 (en) |
-
1979
- 1979-02-09 CS CS76902A patent/CS228113B2/en unknown
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