SU1181539A3 - Method of producing n -aryl-sulfonyl-l-argininamide or salts thereof - Google Patents

Abstract

The arginamides correspond to the formula: <IMAGE> in which Ar represents various aromatic groups and R represents one of the following groups: <IMAGE> The detailed definition of the Ar groups and the symbols in the R groups is found in Claim 1. The compounds and their acid addition salts are prepared from L-arginine by a three-step process. They have a specific inhibitory action against thrombin and can be used, preferably in the form of pharmaceutical preparations, for the treatment and for the prophylaxis of thromboses.

Description

alkoxyalkyl,

-WITH

Cho

akylthioalkyl Cj-C,, alkylsulfinylalkyl,, hydro:. -alkyl C-C, alkoxycarbonylalkyl,, alkylcarbonylalkyl, haloalkyl C, aralkyl € 7-C., o carboxyaralkyl C, -Cjr cycloalkyl C.-C, cycloalkyl, cycloalkyl C.-C, cycloalkyl furfuryl, tetrahydrofurfuryl, substituted if necessary with at least one alkyl, alkoxy group. or their mixtures, 3-furylmethyl, tetrahydro-3-furyl etyl, substituted, if necessary, with at least one alkyl C.-C, alkoxy group C, -Cj or mixtures thereof, tetrahydro2- (3 or 4) -pyranylmetyr, substituted in if necessary, at least one alkyl.,

alkoxy group or their mixtures, 1, diox-2-cyclohexenylmethyl, substituted if necessary with at least one, alkyl, alkoxy group C.-C-or their mixtures, 2-thienyl, 3-thienyl, tetrahydro-2-tenyl, substituted if necessary at least one C.-C alkyl, alkoxy or mixtures thereof, and tetrahydro-3-tenyl;

. - alkyl, phenyl, optionally substituted with at least one alkyl, alkoxy group or mixtures thereof, aralkyl or ring substituted benzyl, whose substituent is alkyl. or alkoxy group,

J- is hydrogen, alkyl, aryl aralkyl C-rQw; .- .-, ha - integer O, 1 or 2;

Kb

-)GROUP -

where R. is the group COOR., in which

RJ is hydrogen, alkyl, aryl Cj-C and aralkyl C; C "i /

each R group is, independently of others, hydrogen, alkyl, phenyl, alkoxy C, -Cy, alkoxycarbonyl Gj-C. or carboxy; p is an integer of 1-4;

Rf is substituted in position 2 or 3;

R may be substituted in the position 2,3,4,5 or 6 .;

COORg

T. rPi / PPA

V

(SNG

optionally substituted with one alkyl, alkoxy: a group C.j-Cj or mixtures thereof, where RJ is hydrogen, alkyl,

aryl aralkyl C. g - an integer of 1,2,3 or 4.

d sroNu

) z-GROUP

(CH2) q

where is hydrogen, alkyl, aryl

  aralkyl ,,. Z - OXY-, thio- and sulphinyl; .

q is an integer of O or 1,

COORii.

 - (CH2) i

(

de R is hydrogen, alkyl C;, - C, arylCj-C and aralkyl t

i is an integer O, 1 or 2;

j is an integer O, 1 or 2; sum i + j-integer 1 or 2; Ar is a phenyl or naphthyl group, any of which is substituted by at least one substituent selected from the group comprising sulfoamino, carbamoyl N, N-dialkylcarbamoyl Ci-C. , Nalkylcarbamoyl, amino, alknlamino, mercapto, alkylthio, aralkyl, carboxyl, alkoxycarbonyl, carboxyalkyl Cj-C,, acylamino C, -C ,, 0 alkylcar | bonyl, hydroxyalkyl Cd-C ;, haloalkyl. hydroxyalkoxy and phenyl substituted, if necessary, with at least one hydroxyl group, alkoxy group, or mixtures thereof; a phenyl or naphthyl group, any of which is substituted by at least one substituent selected from the group including halogen, nitro cyano, hydroxy, alkyl alkoxy (and dialkylamino Cj-Cj, and at least one substituent selected from the group including sulfoamino, carbamoyl, N | lJ-dialkylcarbamoyl C.-S., N-alkylcarbamoyl, amino, alkylamino C, -C, mercapto, alkylthio C, aralkyl, carboxyl, alkoxycarbonyl Cj.-C, carboxyalkyl, - acylamino C, alkylcarbonyl, hydroxy alkyl, haloalkyl , hydroxyalkoxy and phenyl, substituted if necessary m minimum by one hydroxyl group, alkoxy group, or by mixtures; an oxanthrenyl or dibenzofuranyl group substituted by at least one substituent selected from the group consisting of halogen, nitro, cyano, hydroxy, dialkylamino, sulfonamino, cardmoyl, NjN-dialkylcarbamoyl-ary, N-N, N-N, N-N, N-N, N-N, N-N, N-N, N-N, N-N Cj, amino, alkylamino mercapto, alkylthio, aralkyl, carboxyl, alkoxycarbonyl carboxyalkyl Cj-C ,,, acylamino, alkylcarbonyl, p, hydroxyalkyl Cf-C, haloalkyl, hydroxyalkoxy and phenyl, optionally substituted with at least one hydroxy noy group, alkoxy group C.-Cj, or mixtures thereof; an oxanthrenyl or dibenzofuranyl group substituted by at least one substituent selected from the group consisting of alknl C, Cde and alkoxy, and

at least one substituent selected from the group consisting of halogen, nitro, cyano, hydroxy, dialkylamino, sulfamino, carbamoyl, K, M-dialkylcarbamoyl Cj-C, N-alkylcarbamoyl, amino, alkylamino, mercapto, alkylthio C, -Cjj, aralkyl C, , carboxyl, alkoxycarbonyl, carboxyalkyl C, -C, acylamino, alkylcarbonyl, hydroxyalkyl, haloalkyl C-C, hydroxyalkoxyphenyl, optionally substituted with at least one hydroxyl group, alkoxy group, or mixtures thereof; tetrahydrnaphthyl,. 1,2-ethylenedioxyphenyl, chromanyl, 2,3-ethyl.-dioxynaphthyl or xanthenyl group, any of which is substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, dialkylamino, sulfoamino, carbamoyl, N, N-dialkylcarbamoyl Cj-C p, N-alkylcarbamoyl, amino, alkylamino, mercapto, alkylthyl, aralkyl, carboxyl, alkoxycarbonyl. , carboxyalkyl, acylamino C-C d, alkylcarbonyl, hydroxyalkyl, jj, haloalkyl, hydroxyalkoxyl, oxog, and phenyl, substituted, if necessary, with at least one hydroxyl group, alkoxy group, or mixtures thereof; a tetrahydronaphthyl 1,2-methylnrydioxyphenyl, chromanyl 2,3-ethylenedioxynaphthyl or xanthenyl group, any of which is substituted by at least one substituent selected from the group including alkyl C and alkoxy C, -C, p, and minimum

one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, dialkylamino, sulfamino, carbamoyl, N N-dialkylcarbamoyl, N-alkylcarbamoyl CjC, amino, alkydamino, mercapto, alkylthio, aralkyl Cjj-C. , carboxyl, alkoxycarbonyl Cj-C, carboxyalkyl, acylamino, alkylcarbonyl. hydroxyalkyl, haloalkyl, hydroxyalkoxy, p, oxo- and phenyl, optionally substituted with at least one hydroxyl group, alkoxy group C, (- Cr, their mixtures; naphthoquinonyl, anthryl, phenanthryl, pentalenyl, heptalenyl, azulelenyl biphenylenyl, a, s -an cerated, s-indacenyl, acenaphthylenyl, phenylcarbonyl, phenoxyphenyl, benzofuranyl, isobenzofuranyl, benzo (b) thiene, iso-benzothienyl, ti-adrenyl, benzothiylphenol, benzofuranil , quinazolinyl, cinnolinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl or benziimidazolil, any of which is unsubstituted or substituted with one or more groups selected from the set consisting of halogen, nitro, cyano, hydroxy, alkyl, alkoxy, Cj,, dialkilamyno, sulfoamino, carbamoyl, N |, N-dialkylcarbamoyl, N-alkylcarbamoyl CJ-GJ, amino, alkylamino C .; ,, hydroxy1

alkoxy, and phenyl substituted, if necessary, with at least one hydroxyl group, alkoxy group, or mixtures thereof; aralkyl, cycloalkylphenyl Cd-C; , cycloalkylphenyl CHI -choalkyloxyfenyl C, -Cj, cycloalkylthiophenyl, 9, 10-dihydroanthryl, 5,6,7,8 tetrahydroanthryl, 9,10-dihydrofenanthryl, 1,2,3,4,5, 6,7,8-octahydrofenanthryl , indenyl, indanyl, flyuorenil, acenaphthenyl, phenylthiophenyl, -izohromanil, 2,3digidrobenzofuranil, 1,3digidroizobenzofuranil, thioxanthenes, 2H-chromenyl, S, 4-dehydro-1-isochromanyl, AN-chromenyl, indolinyl, isoindolinyl, 1,2, 3,4-tetrahydrochynolyl or 1,2,3, 4-tetrahydroisoquinolyl, any of which is unsubstituted or substituted by one or more groups selected from the combination comprising halogen, nitro, cyano, hydroxyl, alkyl, alkoxy, dialkylamino Cj-Cjg, sulfoamino, carbamoyl, NIN-dialkylcarbamoyl, N-alkylcarbamoyl, amino, alkylamino. , mercapto ,. alkylthio C, aralkyl, carboxyl, alkoxycarbonyl C., carboxyalkyl acylamino C .;, alkylcarbonyl, hydroxyalkyl, haloalkyl, hydroxyalkoxy C, -C, oxo and phenyl substituted, if necessary, with at least one hydroxyl group, alkoxy group, or mixtures thereof; or a phenyl group substituted by at least one substituent selected from the group consisting of alkyl, alkoxy, haloxy, alkoxyalknl, and coxyalkoxy, alkoxycarbonylalkyl and alkrxycarbonyl alc citn-, and the indicated substituent has 3-7 carbon atoms, and the substituted phenyl alkyne is citn-, and the substituted substituent has 3-7 carbon atoms, and the substituted phenyl alkyne is citn-, and the indicated substituent has 3-7 carbon atoms, and the substituted phenylcityl- citn- is, and the substituted phenylcityl- citn- is if necessary, additionally substituted with at least one substituent selected from the group comprising methyl, ethyl, methoxy, ethoxyl, hydroxyl and halo,

its salts, characterized by the fact that H-arylsulfonyl-b-arlhalide of the general formula

to-sn2SNgSN2Snsoh

I

HNSO

n Ar

where Ar has the indicated meanings;

X is halogen,

reacted with an amino acid derivative having the general formula

RH,

where R has the specified value, followed, if necessary, by hydrolysis of the obtained product and its allocation in the free form of sludge as a salt.

2. The POP.1 method, characterized in that the N-arylsulfonyl-b-arginyl halide is reacted with a minimum with an equimolar amount of the amino acid derivative at a temperature of from -10 to.

Priority by featured;

RI

-N (1}

TROUPE

01.19.77 at

2) 0

-HI

10.03,77 at ches21psoon2

(CH2) mCOOR5 GROUP; -

/ Ri

06.06.77 priK - N

sn- (sn21psoonz;

R2

 / COOR j (CH2) p .. t - (SNg), 07.07.77 with R- -N.

SNG

j (CH2lpY - (CHalq

one

This invention relates to methods for producing new H-arylsulfonyl-harginine anamides and their salts that are effective in inhibiting and suppressing thrombosis and mammals.

A known method for producing esters of (p-tolylsulfonyl) -arginine of the formula

mn about

and and

) s-sn-s-is

H-S02- / VcH3

where R is methyl, isopropyl, sec-butyl and 2-isopropoxyethyl, which is obtained by esterification of (p-toluenesulfonyl) -L-arginine amide. These esters have thrombolytic activity.

The aim of the invention is to increase the range of agents that have thrombolytic activity with improved properties.

The goal is achieved, based on a known reaction, a preferred method for producing N-aryl sulfonyl-b-arginine amide-arginine form of the formula C-N-CH2 CH2 CH2-CHCOR HHNSO -At where R is selected from. groups including - (CI2COOB2 V where R is alkyl and l 9 siglspl C-alkenyl; we are alkyne, alkoxyalkyl, alkylthioalkyl Cj-C, alkyl, alkyl, alkyl, oxyalkyl, alkoxycarbonylalkyl, alkylcarbonyl-Cj, oxyalkyl, alkoxycarbonylalkyl, alkylcarbonylalkyl, oxyl, oxyalkyl, alkoxycarbonylalkyl, alkylcarbonylalkyl, hydroxyalkyl, oxyalkyl, alkoxycarbonylalkyl, alkylcarbonylalkyl, oxyl, oxyalkyl, alkoxycarbonylalkyl, alkylcarbonylalkyl, hydroxyalkyl, oxyalkyl, alkoxycarbonylalkyl, alkylcarboxylic alkyl pboxy aralkyl Cg-C, cycloalkyl, cycloalkylalkyl. d, furfuryl, tetrahydrofupfuryl, substituted if necessary with at least one alkyl, alkoxy group or their mixtures, 3-furylmethyl, tetrahydro-3-furylmethyl, substituted if necessary, is necessary. one alkyl .., alkoxy C C, or mixtures thereof, tetragons po2 (3 or 4) -pyranylmethyl, substituted if necessary with at least one alkyl C.-Cj, alkoxy group C, -C or their mixtures, 1,4 diox-2-cyclohexylmethyl, substituted if necessary with at least one alkyl y, alkoxy group C .-C, or their mixtures, 2-nie, nyl, 3-tenyl, tetrahydro-2tenyl, optionally substituted with at least one alkyl, alkoxy group C -Cj or their mixtures and tetrahydro-3-tenyl; hydrogen, alkyl, aryl C / -C. and aralkyl is an integer of 1, 2, or 3j CH- (CH2) mCOOR5 B hydrogen, alkyl, alkenyl, alkynyl Cj-Cje alkoxy alkyl, C, alkylthioalkyl, alkylsulfinyl alkyl Cj-Ci, j, hydroxyalkyl C-C ijj, alkoxycarbonyl, Cj-Ci, j, hydroxyalkyl C-C ijj, alkoxycarbonyl, Cj-Ci, j, hydroxyalkyl C-C ijj, alkoxycarbonyl, Cj-Ci, j, hydroxyalkyl C-C ijj, alkoxycarbonyl Cj-Ci, j, hydroxyalkyl C-C ijj, alkoxycarbonyl Cj-Ci, j, hydroxyalkyl C-C ijj, alkoxycarbonyl Cj-Ci, j, hydroxyalkyl C-C ijj, alkoxycarbonyl Cj-Ci, j; .-C, haloalkyl, aralkyl. , 0 -carboxyaralkyl C. , cycloalkyl cycloalkylalkyl furfuryl, tetrahydrofurfuryl, substituted if necessary with at least one alkyl, alkoxy group C., Su — or their mixtures, 3-furylmethyl, tetrahydro-3 furylmethyl, substituted if necessary with at least one alkyl, alkoxy or mixtures thereof, tetrahydro-2 (3 or 4) -pyranylmethyl, substituted if necessary with at least one alkyl, alkoxy group. or mixtures thereof. diox-2-cyclohexylmethyl, substituted if necessary with at least one alkyl, alkoxy group C; - C or their mixtures, 2thienyl, 3-thienyl, tetrahydro-2-tenyl, substituted if necessary with at least one alkyl C:, - C, alkoxy or mixtures thereof, and tetrahydro-3-phenyl; alkyl C,, phenyl, substituted if necessary with at least one alkyl, alkoxy group or mixtures thereof, aralkyl C — C; or ring-substituted benzyl, whose substituent is alkyl. or alkoxy C;, - Cj .; hydrogen, alkyl, aryl, and aralkyl, 2 is an integer of O, 1, or 2; O-group is a COOR group, in which RJJ is hydrogen, alkyl aryl and aralkyl C.C. Caldcha group R, regardless of the residue, is hydrogen, alkyl alkoxy group, alkoxycarbonyl Cj-Cj or carboxy group; p is an integer from 1 to 4; Rg is substituted in position 2 or 3, R., it can be substituted for 2,3,4,5 or 6. COORg NQ (СНг) -group, if necessary, substituted r-G + alcock with at least one alkyl 1 Lu, group C; -Cj or mixtures thereof, where Rg is hydrogen, alkyl aralkyl C is an integer of 1, 2, 3 or 4 COORto h / -group (CH2) (1 where R, o is alkyl hydrogen, and aralkyl OXI-, thio- and sulfinT lg pa; q is an integer O or 1; COOHi is (CH2) v MCHi) j where R is hydrogen, alkyl, a and aralkyl C, -C, 12 i is an integer O, 1 or 2; j is an integer O, 1 or 2; the sum i + j is an integer 1 or 2; Ar - phenyl or naphthyl. a group, any of which is bounded by at least one substituent selected from grams including sulfoamino, bamoyl, N, N-dialkylcarbyl, N-alkylcarbamo, amino, alkylamino, mercapto, alkylthy, aralkyl, C boyl, alkoxycarbonyl C C., carboxyalkyl So -C acylamino C ;, alkylalkyl C, -C, p, hydroxyalkyl, haloalkyl, hydroxyalkoxy and phenyl, optionally substituted with at least one hydroxyl group, alkoxy, or mixtures thereof; a phenyl or naphthyl group, any of which is substituted by at least one substituent selected from the group comprising halo, nitro, cyano, hydroxyl, alkyl, C alkoxy, p and dialkylamino, and at least one substituent selected from the group including sulfoamino, carbamoyl, S, K-dialkylcarbamoyl Cj, N-alkylcarbamoyl, am to, alkylamino, mercap-. , alkylthio aralkyl carboxyl, al-. coxycarbonyl carboxyalkyl C2-Cj (,, acylamino d, alkylcarbonyl, hydroxylalkyl, haloalkyl, hydroxyalkoxy, and phenyl substituted, if necessary, with at least one hydroxyl group, alkoxy group C, -C or mixtures thereof; oxantrenyl or dibenzofuranyl group substituted by mini- one by one substituent selected from the group including halo, nitro, cyano, hydroxy, dialkylamino Cj-Cjj sulfonamino, carbamoyl, N, N-dialkylcarbamoyl, N-alkylcarbamoyl Cj-C, amino, alkylamino C, mercapto, alkylthio C, -C., aralkyl, carboxyl, alko sikarbonil,, carboxyalkyl acylamino C) alkylcarbonyl, hydroxyalkyl, haloalkyl, hydroxyalkoxy, p, and phenyl, optionally substituted by at least one hydroxyl group, an alkoxy group C j-Cj-, or mixtures thereof; an oxanthrenyl or dibenzofuranyl group substituted by at least one substituent selected from the group including alkyl. and alkoxy, and at least a substituent selected from a group including halogen, nitro, cyano, hydroxy, dialkylamino sulfoamino, carbamoyl, NJ N-dialkylcarbamoyl, N-alkylcarbamoyl, amnno, alkylamino, mercapto, alkylthio, aralkyl S. -C, carboxyl, alkoxycarbonyl CA-C. , carboxyalkyl Cj-C d, acylamino, alkylcarbonyl, Reed roxyalkyl, haloalkyl, hydrox alkoxy, and phenyl, where necessary, if necessary, with at least one hydroxyl group, alkoxy group C-C, or mixtures thereof; tetrahydronaphthyl, 1,2-ethylenedioxyphenyl, chromanyl, 2,3-ethylenedioxynaftyl or xanthenyl groups, each of which is substituted by at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, dialkylamino, sulfamoamino, carbamoyl, M | Y- di alkylcarbamoyl, Nalkylcarbamoyl, amino, alkylamino, mercapto, alkylthio, aralkyl C-, carboxyl, alkoxycarbonyl, carboxyalkyl., acylamino C, -C, alkylcarbonyl, hydroxyalkyl C, haloalkyl C.-C, hydroxyalkoxyl.,. phenyl substituted as necessary and at least one hydroxyl group, an alkoxy group, or mixtures thereof; a tetrahydronaphthyl 1,2-ethylenedioxyphenyl, chromanyl, 2,3-ethylenedioxynaphthyl or xanthenyl group, any of which is substituted by at least one substituent, selected from the group including alkyl C — C and alkoxy C, and at least one substituent selected from the group including halo, nitro, cyano, hydroxy, dialkylamino Cj-C, | j, sulfoamino, carbamoyl, N N-dialkylcarbamoyl (,, N-alkylcarbamoyl, amino, alkylamino, mercapto, alkylthio, aralkyl C G, carboxyl, alkoxycarbonyl 2 10 carboxyalkylC, Cip, acylamino C, -C, alkylcarbonyl C, .- C, hydroxyalkyl, haloalkyl, hydroxyalkoxy C;, C, oxo- and phenyl, substituted if necessary with at least one hydroxyl group, alkoxy group C., - C5-, or their mixtures, naphthoquinonyl, anthryl, phenanthryl, pentalenyl, heptalenyl, azulene, biphenyle, a, s , 8-naphthridinyl, quinoxalinyl, quinazolinyl, zincno linil, carbazolyl, acridinyl, phenazylin, phenothiazinyl, phenoxazinyl, or benzimimidazolyl, any of which is unsubstituted with one or more groups selected from the group including halo, niro, cyano, hydroxy, alkyl C., alkoxy, dialkylamino C2-C2c sulfoamino , carbamoyl, N, N-dialkylcarbamoyl C jC d, N-alkylcarbamoyl C 1-e J, amine, alkylamino;, - (; mercapto, alkylthio, S., aralkyl, carboxyl, alkoxycarbonyl, p, carboxyalkyl, acylamino, alkylcarbonyl C,, hydroxy.ilkyl with —C. haloalkyl C; -C. hydroxyalkoxy. and phenyl substituted, if necessary, with at least one hydroxyl group, alkoxy group, or mixtures thereof; aralkyl C -, - C „, cycloalkylphenyl, cycloalkylphenyl C cycloalkyloxyphenyl CdC,, cycloalkylthiophenyl Cj-C, 9,10-dihydroanthryl, 5,6,7,8-tetrahydroanthryl, 9,10-dihydrophenanthryl, 1,2,3,4 , 5,6,7,8-octagydrofenanthryl, indenyl, ivdanyl, fluorenyl, acenaphenyl, phenylthiophenyl, isochrome yl, 2,3-dihydrbunzofuranyl, 1,3-dihydro isobenzofuranyl, thioxantenyl, 2H-chromenyl, 3,4 dehydro-1-isochroman, , 4H-chromenyl, indolinyl, isoindolinyl 1,2,3,4-tetrahydroquinolyl or 1,2,3,4-tetrahydroisoquinolyl, any of which is unsubstituted or substituted by one or more groups PAMI selected from the set consisting of halogen, nitro, cyano, hydroxyl, alkyl, alkoxy C.i-Cie, dialkylamino sulfoamino, carbamoyl, N N-dialkylcarbamoyl, N-alkylcarbamoyl, C 2 f 4, amino, alkylamino. mercapto, alkylthio, aoalkyl, carboxyl, alkoxycarbonyl, carboxyalkyl, acylamino, alkylcarbonyl CjC. , hydroxyalkyl C,,. haloalkyl. , hydroxyalkoxy, phenyl, substituted, if necessary, by at least one hydroxyl group, alkoxy group, or their mixtures I181S-39 or its combination. The aryl-sulfo method of the formula 25 30 where Ag i X - gal is introduced in mine mine 35 where R ime followed by hydrolysis of 40 by dividing e yide of the salt of N -Aryl nid prep with a minimum of 45 to the derivative of Pryhenylsul K; 50 83.6 g of L solution 112.7 g of 2 chloride in a -55 mixture during the precipitation of one precipitate in mi; or fopggy.ipgroup, substituted by at least one member selected from the H: I group, including alkyl, alkoxy, haloxy.p., a.pcoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkyl and alkoxycarboxy; Alkoxy, and said substituent has 3-7 carbon atoms. if necessary, the substituted phenyl group is additionally substituted by at least one substituent selected from the group comprising methyl, ethyl, methoxy, ethoxy, hydroxyl and halo, leu. lies in the fact that Nnyl-b-arginylhalogenide 1-cH cH ai cHcox iANSO, the indicated values; Ogen, interaction with proizvodisloty formul k. The specified value, if necessary, of the obtained product and obtained in free form or in sulphryl-b-arginyl-halogen reaction is equivalently equivalent to the amount of amino acid at a rate of 10 to 80 ° C. er 1. (2-Dibsnzofonil) -g-arginine. dibenzothiophenesulfonyl 800 ml of benzene is added to a stirred solution of rginine in 800 ml of 10% potassium arbonate. The reaction is stirred at 60c for 5 h, the research of which proceeds from the product. After a, at room temperature, it is filtered and washed successively with benzene and water to obtain 127 g (76%) of NZ- (2-AH-benzothienylsulfonyl) -L-draginine. (2-Dib nzothienylsulfonyl) -argynyl chloride. A suspension of 4.21 g of No- (2-dibenzoti nylsulfonyl) -b-arginine in 20 ml of thionyl chloride is stirred for 2 hours at room temperature. Adding cold dry DIETSCH1THEETTER leads to a precipitate which is collected by filtration and washed several times with dry diethyl ether to give No.- (2-dibenzothienium sulfonyl) -b-arginsh1Chloride. (2-Dibenzothienylsulfonyl) -Largynyl-K-butylglycine tert-butyl ether. A previously prepared (2-dibenzothienylsulfonyl) -L-arginyl chloride was carefully added to a stirred solution of 2.67 g of L-butylglycine-t-butyl-ether 9 in 20 ml of chloroform. The reaction mixture is left for one hour at room temperature. At the end of this interval, the reaction mixture is washed twice with 20 ml of saturated sodium chloride solution and evaporated to a dry residue. The residue is triturated with a small amount of diethyl ether to obtain an amorphous solid. It is collected by filtration and transplanted from ethanol / ethyl ether to obtain 3.1 g (49%) of (2-dibenzothienylsulfonyl) -L-β-vinyl-N-butylglycine t-butyl ether. IR spectrum (KVg): 3350, 1740, 1625 cm. Calculated,%: C 53.21, - H 6.39; N 11.10. C vNoOg G ,. t / 2H, 80s Found;%: C 53.21; H 6.46; N 10.89. } 2 (2-dibenzothienylsulfrnyl) -bar ginil-N-b util glycine. To a solution of 2.00 g of tert-butyl ether (2-dibenzothienylsulfonyl) -b-arginyl-H-butylglycine in 20 ml of chloroform was added 50 ml of 15% HCl-ethyl acetate. The reaction mixture is stirred for 5 at room temperature. At the end of this period, the reaction mixture is evaporated to a dry residue. The residue is washed several times with dry ethyl ether and subjected to chromatographic separation into 80 ml of Daiaion ® SK 102 ion exchange resin (particle size 200-300 mesh (0.053-0.074 mm), type H, manufactured by Mitsubishi Kemilk Industries Limited), filled in water , washed with water, eluting with 3% ammonium hydroxide solution. The fraction eluted from a 3% ammonium hydroxide solution was evaporated to a dry residue to give O, 9 g (53%) of No.- (2-dibenzothienylsulfonyl) L-arginyl-N-butylglycine as an amorphous solid. IR spectrum (KVg): 3350, 1640, 1270 cm Calculated,%: C 54.01; H 5.86; N 23.12. C ,, H ,, Found,%: C 53.78; H 5.97; N 12.96. Example 2. Ethyl ester No. - (2-dibenzothienylsulfonyl) -L-agyl-N- (2-methoxyethyl) -glycine. To a stirred solution of 2.42 g of (2-methoxyethyl) glycine ethyl ester and 4.0 ml of triethylamine in 50 ml of chloroform, which is cooled in an ice-salt bath, is added in portions of 7.0 g of the previously obtained No.- (2- dibenzothienylsulfonyl) -L-agyl chloride. The reaction mixture is stirred overnight at room temperature. At the end of this period, 50 ml of chloroform is added and the chloroform solution is washed twice with 25 ml of the sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo. The oily residue was washed with ethyl ether to obtain 5.5 g of powdered ethyl No.- (2-dibenzothienylsulfonyl) -b-arginyl-H- (2-methoxyethyl) -glycine. Calculated,%: C, 50.49; H 4.07; N 11.78. C2, p821 / 2; Found: C 50.22; H 4.18, N 11.51. (2-Dibenzothienylsulfonyl) -arginyl-N- (2-methoxyethyl) -glycine. A solution of .5.5 g of N (2-dibenzothienylsulfonyl) -b-arginyl-N- (2-methoxyethyl) glycine ethyl ether in 15 ml of methanol and 15 ml of 2N. NaOH solution is heated to 40 ° C and held at this temperature for 10 hours. At the end of this period, the reaction mixture is concentrated and chromatographed on 200 ml of Daiaion IOZ ion exchange resin (particle size 200-300 mesh (0.053-0.074 mm), type H, manufactured by Mitsubishi Kemilk Industries Limited), packed in water with an ethanol-water mixture (1: 4), eluted with an ethanol-water mixture NHjOH (10: 9: 1). The main fraction was evaporated to dryness and washed with ethyl ether to give 3.05 g (62%) (2-dibenzothieylsulfonyl) -b-arginyl-H- (2-methoxyethyl) -glycine as an amorphous solid. IR spectrum (KVg): 3400, 1630, 1280 cmH Calculated,%: C 51.57; H 5.46; N 13.08. .NjS, Found,%: C 51.35; H 5.63; N 12.86. Using the above procedures and methods, they synthesize a set of other K-arylsulfonyl-b-arginine amides or their salts by addition of acid. The test results of these compounds are summarized in table. 1. Presented in table. 2 compounds obtained in a similar way. The thrombolytic activity of N arylsulfonyl-b-arginine amines obtained according to the proposed method is compared with the same indicator for the known thrombolytic agent, methyl ester n- (p-tolylsulfonyl) -b-arginine, by determining the coagulation time of fibrinogen. Measurement of coagulation time of fibrinogen is carried out in the following way: 0.8 ml portions of fibrinogen solution, which is obtained by dissolving 150 mg of bovine fibrinogen (fraction I according to Cohn) supplied by Armour's company in 40 ml of borate buffer solution (pH 7, 4), mixed with O, 1 ml of borate go. Buffer solution (pH 7.4). Immediately after mixing, the reaction mixture is transferred from the ice bath to a bath maintained at 3914 at 25 ° C. The coagulation time is calculated as the period between the moment of transfer to the 25 ° C bath and the appearance of fibrin filaments for the first time. In cases where drug samples are not added, the coagulation time is 50-55 seconds. Experimental results are shown in Table. 1, where the concentration required to prolong the coagulation time by a factor of two corresponds to the concentration of the active ingredient required to extend the normal period of coagulation from 50-55 to 100-110 s. The concentration required to lengthen the coagulation time by half, for the known thrombolytic agent, methyl ester (n-Tolylsulfonyl) -1-arginine, is 1100. The inhibitors are presented in Table. 1 with the indication of R and Ar of the compound of formula I. If the solution containing n-arylsulfonyl-1.-Arginine amide, obtained according to the proposed method, is administered intravenously into the animal's body, high antithrombotic activity in the circulating blood is maintained for 1-3 h. The half-life of antithrombotic compounds obtained according to the proposed method is iv60 min in circulating blood; The physiological condition of the experimental animals (rats, rabbits, dogs and chimpanzees) remains good. An experimental decrease in the fibrinogen content in animals caused by the injection of thrombin is satisfactorily suppressed by the simultaneous injection of the proposed compounds. The magnitude of the lethal dose, which causes the death of half of the animals (LDjc) and a certain intravenous administration of a substance of formula I (male, 20 g), is 150-600 mg per kg of body weight. On the other hand, the LDjo values for known thrombolytic agents are less than 10 mg / kg. Thus, the proposed method allows to obtain new compounds with high thrombolytic activity and low toxicity.

about

tn r1l tS vO

with cho

°° is

L o

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Claims (3)

METHOD FOR PRODUCING N ² -ARILSULFONIL-b-ARGININAMIDE OR ITS SALTS. Method for the preparation of L ² -arylsulfonyl-L-argininamide of the general formula HbL _tm> C-X-CH _r CH ₂ CH ₂ -SNSOK 4 Η. HNS0 ₂ -Ar wherein R is selected from the group consisting of (a) wherein - alkyl, C ₂ -C ₁₀ alkenyl, Cj -C ₁₀ alkynyl C ₃ -C _1c, alkoxyalkyl, C ₂ -C ₁₀ alkylthioalkyl C _r ~ _{1 °} C alkylsulfinylalkyl C ₂ -C _1e . hydroxyalkyl C ^ -C ^, alkoxycarbonylalkyl C ₃ -C ^ _o , alkyl carbonylalkyl Cj-C _1o , haloalkyl C ₁ -C ^ _o , aralkyl C ₇ ~ C ₁₅ , d-carboxy aralkyl C _in -C ₁₅ , cycloalkyl C ₃ -C _ie , cycloalkylalkyl Cf ~ C ₁₀ , furfuryl, tetrahydrofurfuryl, optionally substituted with at least one C ₇ ~ C _$ alkyl, C ^ -C ^ alkoxy group or mixtures thereof, 3-furylmethyl, tetrahydro-3-furylmethyl, substituted if need least one alkyl C; -. Cg, alkoxy C ^ -C ^, or mixtures thereof, tetrahydro-2 (3 or 4) -piranilmetil, optionally substituted by at least one-g These alkyl C ₁ -C ₅ alk ksigruppoy _C1 ^, or mixtures thereof, 1,4-dioxa-2-cyclohexylmethyl, optionally substituted by at least one alkyl-C $ Su, alkoxy C _l -C $ or mixtures thereof, 2-thienyl, 3-thenyl, tetrahydro 2-tenyl, optionally substituted with at least one C ^ -Cy alkyl, C ^ -Cy alkoxy or mixtures thereof, and tetrahydro-3-tenyl; Rj is hydrogen, alkyl C ₁ -C _<e , aryl C ^ -C _1o and aralkyl C ₇ -C _i2 ; η is an integer of 1, 2 or 3; (b) to where From is hydrogen, alkyl C _l -C ₁₀ , al • phenyl Cj-Cjo, alkynyl C _e SU _i) 1181539 -C _z0 , alkoxyalkyl C ^ -C ^, alkyl Thioalkyl Cy-C ^, alkyl- ^: sulfinylalkyl C2-C1b> hydroxyalkyl C 7 ~ C 10, alkoxycarbonyl alkyl ^c i ~ ^c -t ·, alkylcarbonylalkyl C3-C _< ^b , haloalkyl C, -Cy, aralkyl C ₇ -C _{1 £} , οί-carboxyaralkyl Cg-C ^, cycloalkyl Cg-C _f , cycloalkylalkyl Cd-C ₁₀ , furfuryl, tetrahydrofurfuryl, optionally substituted with at least one C ^ alkyl -Cj, C ₇ -Ci alkoxy or mixtures thereof, 3-furylmethyl, tetrahydro-3-furylketyl, optionally substituted with at least one alkyl C.J-Su, alkoxy C, -Su or mixtures thereof, tetrahydro 2- (3 or 4) -pyranylmethyl, optionally substituted with at least one C _i -C _J. Alkyl, alkoxy group With y-Su or mixtures thereof, 1,4-dioxa-2-cyclohexylmethyl, optionally substituted with at least one C ^ -Cy alkyl, C ^ -Su alkoxy or mixtures thereof, 2thienyl, 3-thienyl, tetrahydro-2-tenyl, optionally substituted with at least one Su-Su alkyl, Su-Su alkoxy or mixtures thereof, and tetrahydro-3-tenyl; Ry is C ₄ -C _{1fl alkyl} , phenyl substituted if necessary with at least one C ^ -Cy alkyl, C ^ -Cy alkoxy group or mixtures thereof, C ₇ -C ₁₂ aralkyl or benzyl substituted in the ring, the substituent of which is C-alkyl Cy or alkoxy group C _t —C ^; Rg - hydrogen, alkyl SC-C ^, aryl. ^С С “ ^с <о” ^and aralkyl ”* - - ·> ha - integer 0,1 or 2; GROUP »group COORj, in which Rg is hydrogen, alkyl Su-C _1c , aryl C jC _w and aralkyl C-yί. each group R ^, independently of the others] hydrogen, alkyl C ^ -C, ^, phenyl, C.-Cy alkoxy, alkoxycarbonyl, C ₂ -C or carboxy; p is an integer of 1-4; R _{c is} substituted at position 2 or 3; R ^ may be substituted in position 2,3,4,5 or 6; Coorg - GROUP> Csn _d ) d, if necessary, substituted with at least one C ^ -C _y alkyl, C ₃ -Cy alkoxy group or mixtures thereof, where Ry is hydrogen, alkyl Cy-C _fe , aryl Su-Su ₀ and aralkyl CjC ^ J G is an integer of 1,2,3 or 4. ^(e) COORio -GROUP 'HcH ₂ ) q where Κ _ή0 is hydrogen, alkyl C ₁ -C ₇₀ , aryl ^C 4 ^_C u ^and aralkyl C _? -C _p ; Ζ - hydroxy, thio and sulfinyl troupe; q is an integer 0 or 1, (e) SOOII. · _ HsNgN where R _t1 is hydrogen, alkyl C, -C ₁₀ , aryl. · C _{ -C _<0 and aralkyl C _? -Su ₂ ; i is an integer of 0, 1 or 2; j is an integer of 0, 1 or 2; the sum i + j is an integer of 1 or 2; Ag is a phenyl or naphthyl group, any of which is substituted by at least one substituent selected from the group consisting of sulfoamino, carbamoyl Ν, Ν-dialkyl carbamoyl Cj-C _1e , Nalkylcarbamoyl C ^ -Cg, amino, alkylamino Su-Su ₀ , mercapto , alkylthio C ^ -C ^, aralkyl C ₇ -C ^, carboxyl ,, alkoxycarbonyl Cy-C _1b , carboxyalkyl Cj-Cy, acylamino C ₄ -C, alkylcarbonyl C- _4- C | _o , hydroxyalkyl C ₅ -C} _# , haloalkyl Cc-C ^, hydroxyalkoxy C} -C _1b and phenyl substituted, if necessary, with at least one hydroxyl group, alkoxy group Gj-Su, or mixtures thereof; a phenyl or naphthyl group, any of which is substituted by at least one substituent selected from the group consisting of halogen, nitro, cyano, hydroxy, alkyl C ^ -C ^, alkoxy C _L- C _2e and dialkylamino C ₂ -C _go , and at least one a substituent selected from the group consisting of sulfoamino, carbamoyl, Li | 11-dialkylcarbamoyl C ₃ -C ₁₀ , N-alkylcarbamoyl C ₂ -C ^, amino, alkylamino C ₁ -C ^ _o , mercapto, alkylthio C ₄ -C _i0 , aralkyl C ₇ -C _p , carboxyl, alkoxycarbonyl C _2. -C _2a , carboxyalkyl C ₂ -C _1o , acylamino C, -C ₁₀ , alkylcarbonyl C ₂ ~ C _1o , hydroxyalkyl C ^ -C ^, haloalkyl C ^ - C ^, guide roxyalkoxy C ₁ -C ₁₀ and phenyl, optionally substituted with at least one hydroxyl group, an alkoxy group C ^ -Cy, or mixtures of mixtures; an oxantrenyl or dibenzofuranyl group substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, dialkylamino C ₂ C _{2 ()} , sulfonamino, carbamoyl, N) N-dialkylcarbamoyl Cj-C _<0 , N-alkylcarbamoyl C ₂ ~ C _fi , amino, alkylamino С ₁ ~ С _1о , mercapto, alkylthio С _and -С _{1 (>} , aralkyl С ^ -С ^, carboxyl, alkoxycarbonyl С ₂ ~ С ₁₀ , carboxyalkyl ^with 2 ^с »acylamino C _i -C _{| e,} alkylcarbonyl _{C2 <0} hydroxyalkyl, C _f -C ₁₀ haloalkyl, C ₂ C _i0, C ₁ -C hydroxyalkoxy _{1 °} and phenyl optionally substituted by at least one hydroxyl Rupp, alkoxy C ^ - Cy · or their mixtures;. oksantrenilnaya or dibenzofuranilnaya group substituted by at least one substituent selected from the group consisting of alkyl C -C _{lv h} alkoxy and C ₁ -C _1e, and at least one substituent selected from group consisting of halogen, nitro, cyano, hydroxy, C ₂ -C dialkipamino _2O, sulfoamino, carbamoyl, Ν, Ν-dialkylcarbamoyl -Cj ₀ C _3, N-alkylcarbamoyl group C _r to C _6, amino, C ^ alkylamino, -C ^ , mercapto, alkylthio _{(-C those} aralkyl C ₇ ~ C _12, carboxyl, alkoxycarbonyl, C ₂ ~ C _<0, carboxyalkyl, C ₂ ~ C ₁₉ acylamino C _T C _<a, alkilkarbo yl C ₂ 0 _ίβ, hydroxyalkyl, C ^ -C, ^ C _i -C haloalkyl, hydroxyalkoxy-C ^ Cy and phenyl optionally substituted by at least one .gidroksilnoy group, alkoxy C ₁ -Su or mixtures thereof; tetrahydronaphthyl,. 1,2-ethylenedioxyphenyl, chromanyl, 2,3-ethylenedioxy-naphthyl or xanthenyl group, any of which is substituted by at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, dialkylamino C ₂ C ₂ о, sulfoamino, carbamoyl, Ν, N-dialkylcarbamoyl C ₃ -C , N-alkylcarbamoyl C ₂ ~ C ^, amino, alkylamino C ₁ -C _1b , mercapto, alkyltyl aralkyl C ₇ -C _{? 2} , carboxyl, alkoxycarbonyl. C ₂ -C _{1 {>} , carboxyalkyl C ₂ ~ C _1е , acylamino C-C _{ί 0} , alkyl _carbonyl C ₂ -C _f0 , hydroxyalkyl C ₇ -C _il? , haloalkyl Su-C ₁₀ , hydroxyalkoxyl, oxot and phenyl, optionally substituted with at least one hydroxyl group, alkoxy group C ^ -C ^, or mixtures thereof; tetrahydronaphthyl 1,2-ethipendioxyphenyl, chromanyl 2,3-ethylenedioxy-naphthyl or xanthenyl group, any of which is substituted by at least one substituent selected from the group consisting of alkyl C-C ₁₀ and alkoxy Οη-Ο, ρ, and at least one substituent selected from the group consisting of halo, nitro ,. cyano, hydroxy, dialkylamino C ₂ -C _2o , sulfoamino, carbamoyl, N ^ N-dialkylcarbamoyl Cj-C ^ _e , N-alkylcarbamoyl Cj-C ^, amino, alkylamino C ^ -C ^, mercapto, alkylthio С ^ -C _<s , aralkyl (C-C ^ ₂ , carboxyl, alkoxycarbonyl C ₂ ~ C _fe , carboxyalkyl C ₂ tC ^ ₀ , acylamino C ₁₀ , alkylcarbonyl C ₂ ~ C _1o »hydroxyalkyl C, -C _{1 #} , haloalkyl C _4- С _1е , hydroxyalkoxy С ^ —С ₁₀ , oxo- and phenyl, optionally substituted with at least one hydroxyl group, alkoxy-group С ^ -С ^, hjjh mixtures thereof; naphthoquinonyl, antryl, phenanthryl, pentalenyl, heptalenyl, azulenyl, biphenylenyl , a, s-indacenyl, s-indacenyl, acenaphthylenyl, phenylcarbonylphenyl, phenoxyphenyl, benzofuranyl, isobenzofuranyl, benzo (b) thienyl, isobenzothienyl, thanthrenyl, benzothienyl, phenoxathiinyl, indolyl, 1H-indazylyl, quinol, quinol naphthridinyl, quinoxaline, quinazolinyl, cinnolinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl or benzimimidazolyl, any of which is unsubstituted or substituted by one or more groups selected from the group consisting of halo, nitro, cyano, hydroxy, alkyl C ^ -C ^ ,, alkoxy C ^ -C ^ "dialkylamino C _r -C _2c, sulfoamino, carbamoyl, N _h N-dialkylcarbamoyl _{1 °} C ~ -C, N-alkylcarbamoyl C ₂ -C _s, amino, alkylamino, C-s, mercapto, 'ah-, keel thio C ₃ -Ο _ίο / aralkyl (CA ₁₂ . , carboxyl, alkoxycarbonyl C ₅ -C _1c , carboxyalkyl C ^ -C ^ acylamino C ₄ -C _1c , alkylcarbonyl C ₂ C _1o , hydroxyalkyl C „-C _w , haloalkyl C, -C _TV , hydroxyalkoxy C _x -C _1c and phenyl, optionally substituted with at least one hydroxyl group, an alkoxy group C ₁ “C _J, or mixtures thereof; aralkyl C ₇ -C ^, cycloalkylphenyl, cyclo- 'alkiphenyl C ₁₀ -C _7g , cycloalkyloxyphenyl C _? -C _f /, cycloalkylthiophenyl Cd-C ^, 9, 10-dihydroantryl, 5,6,7,8 tetrahydroantryl, 9,10-dihydrophenanthryl, 1,2,3,4,5, 6,7,8-oct'hydrophenanthryl, indenyl, indanyl, fpuorenyl, acenaphthenyl, phenylthiophenyl, isochromanyl, 2,3-dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, thioxanthenyl, 2H-chromenyl, 3 ·, 4-dehydro-1-isochromanil, 4H- chromenyl, indolinyl, isoindolinyl, 1,2,3,4-tetrahydroquinolyl or 1,2,3,4-tetrahydroisoquinolyl, any of which is unsubstituted or substituted by one or more groups selected from the group consisting of halogen. nitro, cyano, hydroxyl, alkyl, C ^ -C ^ _o, ^ alkoxy, C ^ -C _in, dialkylamino, C ₂ ~ C _2O, sulfoamino, carbamoyl, N | N-dialkylcarbamoyl C ₃ -C _1e, N-alkylcarbamoyl C ₂ - C ^, amino, alkylamino. C ₄ ~ C ₁₀ , mercapto ,, alkylthio C ₁ ~ C ₁₀ , aralkyl carboxyl, alkoxycarbonyl C _? -C _ie , carboxyalkyl C ₄ -C _<0 , acylamino Ci “C ₁₀ , alkylcarbonyl CjC _4c , hydroxyalkyl C _p -C ₁₀ , haloalkyl hydroxyalkoxyl C, | -C _<th , oxo and phenyl, optionally substituted at least one hydroxyl group, an alkoxy group C ^ -C ^, or mixtures thereof; or a phenyl group substituted with at least one substituent selected from the group consisting of alkyl, alkoxyl, halooxyl, alkoxyalkyl, aersoxyalkoxyl, alkoxycarbonylalkyl and alkoxycarbonylalkoxyl, wherein the indicated substituent has 3-7 carbon atoms, and said substituted phenyl group is optionally further substituted with at least one substituent selected from the group consisting of methyl, ethyl, methoxy, ethoxyl, hydroxyl and halogen, or its salts, characterized in that Y-arylsulfonyl L-arginyl halide of the general formula Prize Priority 01/19/77 at 03/10/77 at ponak:. Ri R GROUP ; (R ₂ ) n / Ri r-_ ^ (CH ₂ l _h COOR, HN ** cn-ch ₂ ch ₂ ch ₂ chcox η ₂ ν ^ζ · C _Og Ag or CH- (CH ₂ ) _m COOR ₅ = GROUP; · Where Ar has the indicated meanings; X-halogen is introduced into the reaction with an amino acid derivative having the general formula RH, where R has the indicated meaning, followed by, if necessary, hydrolysis of the obtained product and isolation in free form or in the form of a salt. 2. The method of pop. 1, characterized in that the No.-arylsulfonyl-L-arginyl halide is introduced into the reaction with a minimum of an equimolar amount of an amino acid derivative at a temperature of from -10 to 80 ° C. Λ 06.06.77 at ft — ^x ch- (CH ₂ Wor ₃ ; Ig / COORifX ^ <CH _g ) p '^ (CH _g ) _h 07/07/77 at R- —N (Ig) η ^ (CH Yx / X “ ^M '- (CH _g ) _h