CA1131621A - N.sup.2-arylsulfonyl-l-argininamides and the pharmaceutically acceptable salts thereof - Google Patents

N.sup.2-arylsulfonyl-l-argininamides and the pharmaceutically acceptable salts thereof

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Publication number
CA1131621A
CA1131621A CA293,199A CA293199A CA1131621A CA 1131621 A CA1131621 A CA 1131621A CA 293199 A CA293199 A CA 293199A CA 1131621 A CA1131621 A CA 1131621A
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Prior art keywords
group
alkyl
alkoxy
substituted
aralkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
CA293,199A
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French (fr)
Inventor
Shosuke Okamoto
Ryoji Kikumoto
Yoshikuni Tamao
Kazuo Ohkubo
Tohru Tezuka
Shinji Tonomura
Akiko Hijikata
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Mitsubishi Kasei Corp
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Mitsubishi Kasei Corp
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Publication date
Priority claimed from US05/760,672 external-priority patent/US4093712A/en
Priority claimed from US05/760,676 external-priority patent/US4097472A/en
Priority claimed from US05/760,668 external-priority patent/US4073913A/en
Priority claimed from US05/760,929 external-priority patent/US4101653A/en
Priority claimed from US05/760,745 external-priority patent/US4066773A/en
Priority claimed from US05/776,195 external-priority patent/US4097591A/en
Priority claimed from JP6650877A external-priority patent/JPS6010028B2/en
Priority claimed from US05/804,331 external-priority patent/US4140681A/en
Priority claimed from US05/804,368 external-priority patent/US4131673A/en
Application filed by Mitsubishi Kasei Corp filed Critical Mitsubishi Kasei Corp
Priority to US05/938,711 priority Critical patent/US4201863A/en
Priority to US06/041,419 priority patent/US4258192A/en
Priority to UA2814248A priority patent/UA8371A1/en
Publication of CA1131621A publication Critical patent/CA1131621A/en
Application granted granted Critical
Expired legal-status Critical Current

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    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
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    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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    • C07D211/16—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with acylated ring nitrogen atom
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    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
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    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
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    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

ABSTRACT OF THE DISCLOSURE

N2-arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof have been found to be effective as pharmaceutical agents for the inhibition and suppression of thrombosis in mammals.

Description

B~CKC;ROUND 0~` THE :c~ i rIo~

ield__f the In~ention rhis invention relates to t~e discovery of cer~a.in new and U9 eful ~ -arylsulfon~l-L-argininclnlides and the pharmaceu~i-cally acceptable salts thereof, ~hich are of especial value in view of their outstanding antithronlbotic properties and low to~YicitieS, Desc~i~tion of the Prior ~rt In the past, there have been many attempts to obtain ne~v and improved agents for the treatment of thrombosis. The N -(p-tolysulfonyl)-L-arginine esters have been found to be one type of agent ~hich can be used and these have been found to be effective in dissolvin.g blood clots. (U. ~. Patent No.
3,622,61~, issued November 23, 1971). One family of com pounds ~-hich have been found to be particularly useful as highly specific inhibitors of thrombin for t~e control of thrombosis is t-he N -dansyl-L-arginine ester or amide. (Our U.S. patent No. 3,978,045). However, there is a continuing need for a highly specific inhlbitor of thrombin for the control of thrombosis, which exhibits lower toxicity.

~ -.' ,
2~l ~ L~RY 0~ -rH~ I~ E~'TI0~;

It ~.as no~ been discovered chat N~-arylsulfonyl-L-ar"in-inamides e.~hibit antithronlbotic acti~ity clnd even lo~er to.~icity levels at the same relative potencies, as compared with the N2-clansyl-L-arginine ester or amide.

The invention pertains broadl~ bo an ~l -arylsulfonyl-L-argininamide of the formula:

/C - ~ - C~l2C~2CH2CHCOR (I) ~2~ ~ ~N~02 ~ r and the pharmaceutically acceptable salts thereof wherein R is selected from the~group consisting of (1) - N \
(CH2 )ncooR2 wherein Rl is selected from the group consisting of C2-Clo alkyl, C3-Clo alkenyl, C3-Clo alkynyl, C2-C10 alkoxYalkyl, C2-Clo alkylthioalhyl, C2-Clo alkylsulfinylalkyl, Cl-C10 hydroxyalkyl, C3-C10 alkoxycarbonylalkyl, C3-C10 alkyl-carbonylalkyl, Cl-Clo ~aloalkyl, C7-C15 aralky~, C~-C15 ~ -carboxyaralkyl, C3-Clo cycloalkyl, C4-Clo cycloalkylalkyl, furfuryl, tetrahydrofurfuryl optionally substituted with at least one Cl-Cs alkyl, Cl-Cs alkoYy or mixture3 thereof~

~ -2 , - - ~

.. . ., .. _ _ .. ~ . , . .. _ . _ . _ _ .
:: :
.

':
.

~.~3~i2~
3-furylme-th.yl, te-trahydro-3-fllrylmethyl op-tionally substituted with at least one Cl-C5 alkyl, Cl-C5 alkoxy or mix-tures there-of, tetrahydro-2 (3 or 4)-pyranylmethyl optionally subs-tituted wi-th at leas-t one Cl-C5 alkyl, Cl-C5 alkoxy or mixtures there-o*, 1,4-dioxa-2-cyclohexylmethyl optionally substituted with at least one Cl-C5 alkyl, Cl-C5 alkoxy or mixtures thereof~ ;
2-thenyl~ 3-thenyl, tetrahydro-2--thenyl op-tionally substi-tuted with at least one Cl-C5 alkyl, Cl-C5 alkoxy or mixtures thereof, and tetrahydro-3-thenyl; R2 is selected from the group consisting of hydrogen, Cl-Clo alkyl, C6-Clo aryl and C7-C12 aralkyl; and n is an integer of 1, 2 or 3, CH ~ (C~2)mCR5 wherein R3 is selected from the group consisting of hycrogen, Cl-Clo alkyl, C3-Clo alkenyl, C3-Clo alkynyl, C2-Clo ~lkoxyalkyl, C2-Clo alkylthioalkyl, C2-Glo alkylsulfi.nylalkyl, Cl-C10 hydroxyalkyl, C3-Clo alkoxycarbonylalkyl, C3-C10 alkyl-carbonylalkylj Cl-Clo haloalkyl, C7-C15 aralkYl~.C8-C15 ~ -carboxyaralkyl, C3-Clo cycloalkyl, C4-Clo cycloalkylalkyl, furfuryl, tetrahydrofurfuryl optionally substituted with at lea8t one Cl-C5 alkyl, Cl-Cs alkoxy or mixtures thereof~ 3-furylmethyl, tetrahydro-3-furylmet~yl optionally substituted ~ -3-~ ' ~31~Z~

Witil at least one Cl-C5 all;yl, Cl-C~ alko.Yv or mixtures tllereof, tetrahy-lro-2(3 or '~)-pyrallylmethyl optionally substituted Wit~l at least one Cl-C~ all~yl, Cl-C5 alkoY~
or mixtures thereof, l,4-dioxa-2-cyclollexylmethyl op~ionally substitutecl with at least one Cl-C~ all;yl, Cl-C~ alkoxy or mixtures tllereof`, 2-t~lenyl~ 3-thenyl, tetrahydro-2-thenyl optionally subjtitu-ted with at least one Cl-C~ alkyl, Cl-Cs alkoxy or mi~tures thereof t and tetrahydro-3-thenyl; R4 is selected from the group consls-ting of Cl-Clo alkyl, phenyl lQ optionally substituted with at least one Cl-Cs alkyl, Cl-Cs alkoxy or mix-tures thereof, C7-C12 aralkyl and ring substi-tuted benzyl wherein said substituent is Cl-Cs alkyl or Cl-C~
alkoxy; R5 is selected from the group consisting of hydrogen, Cl C10 all~ C6-C10 arYl and C7-C12 aralkyl; and m is an integer of 0, l or 2 (3) - N ~
(R7)p wherein R6 is -COORg wherein R8 is selected from the group consisting of hydrogen, Cl-Clo alkyl, C6-Clo aryl and C7-C12 aralkyl; each R7 independently is hydrogen, Cl-Clo alkyl, phenyl, Cl-C5 alkoxy, C2-C6 alkoxycarbonyl or carboxy; p is an integer of 1 to 4; R6 is substituted at the 2 or 3-position;

~ -4-' ~ , .
,~

~3~

and R7 can be substituted at the 2, 3, 4, 5 or 6-position, COOR-~
(4) -\~C~I2~ .

option~lly substituted ~ith a-t least one Cl-C5 alkyl, Cl-C5 alko~y or mi~tures -thereof, wherein R9 is selected from the group consisting of hydrogen, Cl-Clo alhyl, C6-Clo aryl and C7-C12 aralkyl; and r is an integer of 1, 2, 3 or 4, ~
(5) - l~ /Z
`-(CH2) q wherein Rlo is selected from the group consisting of hydrogen, Cl Clo alkyl, C6-C10 aryl and C7-C12 aralkyl; Z is selected from the group consisting of o~y, thio and sulfinyl; and q is an integer of O or 1, and COOR~, ~ (Cl12)i \ (C}l2)j ~

wherein Rll is selected from the group consisting of hydrogen, Cl-Clo alkyl, C~-Clo aryl and C7-C12 aralkyl; i is an integer l~ -5-~L33~;2~ . -of 0, l or 2; j i.s an intc~cr o-~ 0, 1 or 2; arli tlle sum of i -~ j is an inte~cr Or 1 or 2; and Ar is a pllenyl or naplltl~yl ~rollp, cllher sll~;t::it-ltccl ~itll ~ at least orle s-lbsti-tuent selccte~ rrom tlle group consisting of sul~oamino, carballloy], C3-Clo N,N-cliallcy:lcarbamoyl, C2-C6 N-alkylcarl~allloyl, amiJlo, Cl-Clo all;ylamino, merca~,to, Cl-ClO alkylthio, C7-C12 arall;yl, carboxy, C2-Clo alkoxy-carbonyl, C2-Clo carboxyalkyl~ C~-Clo acylamino, C2-Clo alkylcarbony~, Cl-C10 hydroxyalkyl, Cl-Clo haloalkyl, Cl-ClG
hydroxyalkoxy and phenyl optionally substitute~ wi-th at least one hydroxy, Cl-Cs allcoxy, or mi.xtures -thereor;

a phenyl or naphthyl group, either substitutecl with at least one sub~-tituellt selected from the group consisting ~ of halo, nitro, cyano, hydroxy, Cl-Clo all;yl., Cl-Clo all;ocy and C?-C20 diallcyla~nino, and at least one substi-tuellt selected from the group consistillg of sulfoamino, carbarnoyl, C3-Clo N,N-dialkylcarbanloyl, C2-C6 N-alky]carbamoyl, amino, Cl-Cio alkylamino, mercapto, Cl-Clo alkylthio, C7-Cl2 aralkyl, carboxy, C2-Clo alkoxycarborlyl, C2-Clo carboxyalkyl, Cl-C~o acylamino, C~-ClO alkylcarbonyl, Cl-ClO hydroxyallyl, Cl-Clo haloalkyl, Cl-C10 hyd.roxyall;oxy alld ~henyl optionally substitutecl ~ith at loast one hydroxy, Cl-Cs alkoxy, or mixtures thereof;

' ~ ..

an oxanthrenvl or diben~.of`uranyl group substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C2-C20 dialkylamino, sulfo-amillo, carbatlloyl, C3-Clo ~',N-diall;y:Lcarbamoyl, C2-C6 N-allcylcarbamoyl, amino, Cl-Clo all;y:Lami.rlo, mercapto~ Cl-Clo alkylthio, C7-C12 aralkyl, carboxyl, C2-Clo all;oxycarbonyl, C2-Clo carboxyalkyl, Cl-Clo acylamino, C2-Clo alkylcarbonyl, Cl-C10 hydro.Yyalkyl~ Cl-Clo haloalkyl, Cl-Clo hydroxyalkoYy, and phenyl optionally substituted with at least one hydroxy, Cl-Cs alkoYy, or mixtures thereof;

an oxanthrenyl or dibenzofuranyl group subs-tituted with a-t least one substituent selected from the group consisting of Cl-Clo alkyl and Cl-C10 alkoxy, and at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C2-C20 dialkylamino, sulfoamino, carbamoyl, C3-Clo N,N-dialkylcarbamoyl, C2-C6 ~-alkylcarbamoyl, amino, Cl-Clo alkylamino, mercapto, Cl-Clo alkylthio, C7-C12 aralkyl, carboxyl, C2-Clo alko~Yycarbonyl, C2-Clo carboYyalkyl, Cl-Clo acylamino, C2-Clo alkylcarbonyl, Cl-Clo hydroxyalkyl, Cl-Clo haloalkyl, Cl-Clo h~droxyalkoxy and phenyl optionally substi-tuted with at least one hydroxy, Cl-Cs alkoYy, or mixtures thereof;

~ 7 .

z~

a tetra~lydrollap~ltllyl, 1,2-ethylenedio~yphenyl, chromanyl, 2~3-ethylenedio.~vnaphthyl or xanthen~-l group, anv substituted with at least one substituent selectecl from the group con-SiSting of halo, nitro, cyano, hy-lro.~v, C2-C~o dialkylamino, sulfoamino, carbamoyl, C3-Clo N,N-clialkylcarbamonyl, C2-C6 ~-alkylcarbamoy:l, amino, Cl-CLo alkylamino, mercapto, Cl-Clo alkylthio, C7-C~2 aralkyl, carboxyl, C2-C10 alko.~ycarbonyl, C2-Clo carboxyalkyl, Cl-Clo acylamino, C2-Clo alkylcarbonyl, Cl-Clo hydro~yalkyl, Cl~Clo haloalkyl, Cl-Clo hydro~yalkoxy, oxo and phenyl optionally substituted ~ith at least one hydroxy, Cl-C~ alko~y, or mi~tures thereof;

a tetrahydronaphthyl, 1,2-ethylenedioxyphenyl, chromanyl, 2,3-ethylenedioxynaphthyl or xanthenyl group, any substituted with at least one substituent sel.ected from the group con-sisting of.Cl-Clo alkyl and Cl-Clo alkoxy, and at least one substituent selected from the group consisting of halo, nitro, cyano, hydro~y, C2-C20 dialkylamino, sulfoamino, carbamoyl, C3-C10 N,N-dialkylcarbamonyl, C2-C6 N-alkylcarbamoyl, amino, Cl-Clo alkylamino, mercapto, Cl-Clo alkylthio, C7-C12 aralkyl, carboxyl, C2-Clo alkoxycarbonyl, C2-Clo carboxyalkyl, Cl-Clo acylamino, C2-Clo alkylcarbonyl, Cl-Clo hydroxyalkyl, Cl-Clo haloalkyl, Cl-Clo hydroxyalkoxy, oxo and phenyl optionally substituted with at least one hydroxy, Cl-C5 alkoxy, or mixtures thereof;

a naphthoquinoll~l, anthryl, phenarlthryl, pentalenyl, heptalenyl, azulenyl, biphenylenyl, as-ind~cen;~l, a-indaeenyl~
aeenaphthylenyl, phenylcarbonylphellyl, phenox~phe~
benzo~urally:l, isobetlzotllranyl, benzo (b) ~hien-rl, i~obenzo-thienyl, thiculthrerly:L, d:iberlzothierlyl, phenoc.ltt~ yl, indolyl, l~l-inclazoly1, quino]yl, isoquinolyl, phthalazinyl, 1,8-naphthridinyl, quino~alinyl, quinazolinyl, cinnolinyl, carbazolyl1 acriclinyl, phenazinyl, phenothiazinyl, phenoxazinyl or benzimidazolyl group any of which is unsubstituted or substituted with one or more groups selected from the group eonsisting of halo, nitro, cyano, hydro.cy, Cl-Clo alkyl, Cl-Clo alkoxy, C2-C20 dialkylamino, sulfoamino, carbamoyl C3-Clo ~,~-dialkylcarbamoyl, C2-C6 ~-alkylearbcamoyl, amino, Cl-Clo a]kylamino, mercapto, Cl-Clo alkylthio, C7-C12 aralkyl, earbo.xyl, C2-Clo alkoxycarbonyl, C2-C10 carbo.cyalkyl, Cl-C~0 aeylamino, C2-Clo alkylcarbonyl, Cl-Clo hydro:cyalkyl, Cl-Clo haloalkyl, Cl-Clo hydroxyalko~y and phenyl optionally sub-stituted ~ith at least one hydroxy, Cl-C5 alkocy, or mi~tures thereo~;

a C7-Cl2 aralkyl, Cg-C16 cycloalkylphenyl, Clo-Cl~ cyclo-alkylalkylphenyl, Cg-C16 eyeloalkylo.cyphenyl, Cg-C16 cyclo-alkylthiophenyl, 9,10-dihydroanthryl, 5,6,7,8-tetrahydro-anthryl, 9,10-dihydrophenanthryl, 1,2,3,1~,5,6,7,8-octahydro-phenanthryl, indenyl, indanyl, fluorenyl, acenaph-thenyl, 9 _ ~.lp ~

~ 3~3~
phenyltllio~>nen~ ., isochromarl51, '',~-~lihyrlroi-j-?n~,o.'~l~an~I, 1,3-di~ly~roisobell~ofl,lr.ln~l,, thioxanttlenyl, ~fl-chronnenyl, 3,4-dehvdro-1-i,ochronlanyi, 4H-cilromenyl, incloliny-l, iso-indolinyl, 1,~,3,'i-tetrallydroquinolyl or 1,',3,'l-tetrahydro-isoquinol~-l group an~ o~ t~.iliCh is wlsubstitutecl or substituted ~ith one or more gro~lps selectecl from ttle group con3isting of halo, nitro, cyallo, h~clro~y, Cl-Clo all~l, Cl-CIo all~oYy, C2-C~o cli.alky,lan~ o, s~ oanlino, carbamo~-l, C3~10 ~N~-dialkylcarbamoyl, C~-C6 .~-alkvlcarbamoyl, amino, Cl-Clo al~ylamino, mercapto, Cl-Clo all;ylthio, C7-CI2 aralkyl, carbo~yl, C2-Clo allco~Yycarbonyl, C2-Clo carbo.Yyalkyl, Cl-Clo acylamino, C2-Clo all~ylcarbonyl, Cl-Clo hvdroYyalkyl, Cl-Clo haloal~yl, Cl-Clo hydroYyalko~y, o~o and phenyl optionally substi-tuted with a-t least one hydro.Yyl, Cl-C~ al~oYy, or miYtures thereof;
or a phenyl group 3ubstituted with at least one sub~tituent selected from the group consisting of all~yl, all~oYy, halo-alko.Yy, alko.Yyalkyl, alko.Yyalkoxy, alkoYycarbonylalkyl and alko~Yycarbonylalko.Yy, the said substituent containing 3 to 7 earbon atoms and the said substituted phenyl group being optionally substituted further with at least one substituent selected from the group eonsisting of methyl, ethyl, metho.~y, etho~y, hydro~y and halo.
The preparation of the N -arylsulfonyl-L-argininamides of Formula (I) is taken f~om the group of processes comprising:
(a) reacting a compound of the formula:
HN

wherein R is as defined above with an arylsulfonyl halide compound;

~', ~ . ... . . .. . . ... . . . . .
-: ' .

: . , ,, ~

~3~
(b) removing the NG-substitllent from an N~-substituted-N2-arylsulfonyl-L-argininamide having the formula:

HN ~
C - N - CH2C~I2CH2CHCOR
HN - l l R" HNS02 R' I
Ar wherein R and Ar are as defined herein above; R' and R"
are selected from the group consisting of hydrogen and protective groups for the guanidino group, and at least one of R' and R" is a protective group for the guanidino group, by means of acidolysis or hydrogenolysis, and, if desired, hydrolyzing the reaction product obtained above;

or (c) reacting an N2-arylsulfonyl-L-arginyl halide having the formula:

. HN ~
~ C - N - CH~CH2CH2CHCOX
H HNSO2Ar wherein Ar is as defined herein above and X is halogen, with an amino acid having the formula:

RH

wherein ~ is as defined herein above, and, if desired, hydrolyzing the reaction product obtained above.

6Z~
When a pharmaceutically (antithrombotically) effective amount of the N -arylsulfonyl-L-argininamide or the pharma-ceutically acceptable salts -thereof is administered -to a mammal, activity of or activiation oE -thrombin is inhibited or suppressed .

DE'r.~:Ll,l~r) I~LiCRTP'r'[O~' or.~ i'llr? PRI:,,F`l;`RRl;D E`lll()D,[`lr``;l`~

This in~enti.oll rrlates to a group o~` ~r~-arylsulronyl-L-arginillar~-ides of the ~ornr~lla (.C):

/ C - ~ - Cl-l2Cll~CII~C~-ICOR (I) ~-12~ 1 1 O .
~r wherein R is selected from the group consisting of ~ Rl (1) \ (cll2)ncooR2 wherein ~1 ia selected from the group consiating of C2-Clo alkyl, such as ethyl, propyl, butyl, isobutyl, pentylJ he.~yl, octyl, decyl or the like, alk~nyl of 3-10 (preferabl~- 3-6) , ~

-:
,~ .
' .

1~3~

carbon atoms, such as a~lyl, '-bucenyl, 3-butenyl, 2-pentenyl or the l:ike, alky-nyl of 3-10 (pre~erably 3-6) carbon atoms, 3~1Ch as 2-propyrlyl~ 2-butyrlyl, 3-but~l~l or the like, alko.Yy-alky:L of 2-10 ~prefera~lly 2-6) carbon atoms, such as metl~.o.cymethyl, ethoxymethyl, propoxymetllyl, 2-metho~cyethyl 2-etho.Yyethyl, 2-propo.Yye-thyl, 2-me-thoxypropyl ~ 3-methoxypropyl, 3-ethoxypropyl, 3-propoxypropyl, 4-methoxybutyl, 4-ethoxybutyl, 4-butoxybu-tyl, 5-butoxypentyl or the like, alkylthioalkyl of 2-10 (preferably 2-6) 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 or the like, alkylsulfinylalkyl of 2-10 (preferably 2-6) carbon atoms, such as methylsulfinylmethyl, ethylsulfinylmethyl, propylsulfinylmethyl, 2-methylsul~inyl-ethyl, 2-ethylsulfinylethyl, 2-propylsulfinylethyl~ 3-methylsulfinylpropyl, 3-ethylsulfinylpropyl or the like, hydroxyalkyl of 1-10 (preferably 1-6) carbon atoms, such as hydroeymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-propyl, 4-hydroxybutyl, 3-hydroxybutyl, 5-hydroxypentyl or the like, alko~ycarbonylalkyl of 3-10 (preferably 3-8) carbon ato~s, such as methoxycarbonylmethyl, 2-ethoxycarbonylethyl, 113~6'~1 2--ethoxvcarbon~lpIopyl, 3-metho.Yycarbonylpropyl, l-methoxy-carbon~lbutyl, ~-etho~ycclr~onyl.buty]., ~-methoxycarbonylbutyl or the l.ike, alkylcarbonylal.kyl of 3 to 10 carbon atoms such as metllylcclrbonylethyl or the like, haloalkyl of 1-10 (pre~erably 1-5) carbon atoms such as chloromethyl, 2-chloroethyl, 2-bromoethyl, 2-chloropropyl, 3-chloropropyl, 2-chlorobutyl, 4-chlorobutyl or the like, aralkyl of 7-1;
(preferably 7-10) carbon atoms, such as benzyl, pheneth;-l, 3-phenylpropyl, 4-phenylbutyl, 6-phenylhexyl, l-phenylethyl, 2-phenylpropyl or the like, d -carbo~yaralkyl of 8-15 (preferably 8-12) carbon atoms, such as ~ -carboxybenzyl, -carboxyphenethyl or the like, C3-C10 cycloalkyl, such as cyclopropyl7 cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, C4-Clo cycloalkylalkyl, sUch as cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclohexylethyl, cyclooctylmethyl or the like, furfuryl, tetrahydrofurfuryl, optionally subs.tituted with one or more Cl-Cs alkyl, such as methyl, ethyl, propyl, butyl, or the like, and/or Cl-Cs alkoxy groups, Such as methoxv, ethoxy, propoxy, butoxy or the like, 3-furylmethyl, tetrahy~ro-3-furylmethyl, optionally substituted with one or more Cl-Cs alkyl such as methyl, ethyl, propyl, butyl or the like, and/
or Cl-C5 alkoxy groups, such as methoxy, ethoxy, propoxy, butoxy or the like, tetrahydro-2(3 or 4)-pyranylmethyl ~ - 14 -~3~

optionally sllbstituted ~ith one or more Cl-C~ alkyl sllch as meth~l, eth~l, propyl, but~l or the like, an~,or Cl-C~
alko~ groups, such as metho.~y, ethoYy, propo.cy, buto~y or th0 l:il;e, :L,4-clio.~a-2-cyclohe.~vlnlethy] optlonall~ substitllted ~ith one or lnore Cl-C~ alkyl such as methyl, ethyl, propyl, butyl or the lil;e, and~or Cl-C5 alko.Yy groups, such as met~locy, ethoxy, propo~y, butoYy or the like, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl, optionally substituted ~Yith one or more Cl-C5 alkyl such as methyl, ethyl, propyl, butyl or the like, and/or Cl-C5 alkoxy groups such as metho.cy, ethoYy, propoxy, butoxy or the like and tetrahydro-3-thenyl; R2 is selected from the group consisting of hydrogen, Cl-Clo alkyl, such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl, decyl or the like, C6-Clo aryl, such as phenyl, m-tolyl, naphthyl or the lilce and aralkyl of 7-12 (preferably 7-10) carbon atoms, such as benzyl, phenethyl or the like, and n is an integer of l, 2 or 3, ICH - (CH2)mC00R5 wherein R3 is selected from the group consisting of hydrogen, Cl-Clo alkyl, 9uch as methyl, ethyl, propyl, butyl, isobutyl, pentyl, hexyl, octyl, decyl or the like, alkenyl of 3-10 ~ 15 -.. ~,~

~3~

(p:refer~bly 3-6) carbon atoms, SUCtl a~ ~llyl, 2-bu~en~-lt 3-butenyl, 2-pentenyl or tlle like, alk~lyl of 3-10 (preferabl~
3-6) carbon atoms, ~uch as 2-propynyl, '-but~y~, 3-but~nyl or the like, all~o~al~yl of 2-10 (pre~erably 2-6) carbon > atoms, such as metlloxymethyl, etllo.~ymethyl, propo.Y~methyl, 2-metho~yethyl~ 2-etho~yethyl, 2-propoxyethyl, 2-metho~y-prop~l, 3-methoY~propyl, 3~ethoxypropyl, 3-propo.Yypropyl, 4-methoxybutyl, 4-ethoxybutyl, 4-butoxybutyl, 5-butoxypentyl or the li.ke, alkylthioalkyl of 2-10 (preferably 2-6) carbon atoms, such as methylthiomethyl, ethylthiomethyl, prspylthio-methyl, 2-methylthioe-thyl, 2-ethylthioethyl, 2-propylthioethyl, 3-methylthiopropyl, 2-methylthiopropyl, 3-ethylthiopropyl, 3-propylthiopropyl, 4-methylthiobutyl, 4-ethylthiobutyl, 4-butylthiobutyl, 5-butylthiopentyl or the like, alkyl-sulfinylalkyl of 2-10 (preferably 2-6) carbon atoms) such as methylsulfinylmethyl, ethyls~llfinylmethyl, propylsulfinyl-methyl, 2-methylsulfinylethyl, 2-ethylsulfinylethyl~ 2-propylsulfinyl~thyl, 3-methylsulfinylpropyl, 3-ethylqulfinyl-propyl or the like, hydroxyalkyl of 1-10 (preferably 1-6) carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, 5-hydroxypentyl or the like, alkoxycarbonylalkyl of 3-10 (preferably 3-~) carbon atoms, such as methoxycarbonylmethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylpropyl, 3 methoxy-2; carbonylpropyl, l-methoxycarbonylbutyl, 2-ethoxycarbonylbutyl, ~"'''' .

Z

4-metho~ycar.bonylbutyl or the like, alkylcarbony].alkyl of 3 to 10 carbon atoms such as methylcarbonylethyl or the like, haloalkyl of 1-10 (preferably 1-5) carbon atoms such as chloromethyl, 2-chloroethy:LI 2-bromoethyl, 2-chloropropyl~
3-chloropropyl, 2~chlorobutyl, 4-chlorobutyl or the like, aral.ky.L of 7-15 (pre.~erably 7-:L0) carbon atoms, such as ben~yl, phenethyl, 3-pheny.l.propyl, l~-phenylbutyl, 6-phenyl-hexyl, l-phenylethyl, 2-phenylpropyl or the like, ~ -carboxy-aralkyl of 8-15 (preferably 8-12) carbon atoms, such as ~ -carboxybenzyl, ~ -carboxyphenethyl or the like C3-Clo cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, C4-C~o cycloalkyl.a:Lkyl, such as cyclopropylmethyl, cyclo-pentylmethyl, cyclohexylmethyl, 2-cyclohexylethyl, cyclo-1.5 octylmethyl or the like, furfuryl, tetrahydrofurfuryl optionally substituted with one or more Cl-Cs alkyl ~such as methyl, ethyl, propyl~ butyl or the like, and/or Cl-C5 alkoxy groups, such as methoxy, ethoxy, propoxy, butoxy or the like 3-furylmethyl, tetrahydro-3-furylmethyl optionally substituted with one or more Cl-Cs alkyl such as methyl, ethyl, propyl, butyl or the like, and/or Cl-C5 alkoxy groups, such as methoxy, ethoxy, propoxy, butoxy or the like, tetrahydro-2(3 or 4)-pyranylmethyl optionally substituted with one or ~ore Cl-Cs alkyl such as methyl~ ethyl, propyl, butyl or the like, ;~
~ ,~

~L~3~

and~or Cl~C5 alko.~y group3, such a3 metho.~y, ethoxy, propo.Yy, butoxy or the like, 1,4-dioxa-2-cyclohexylmethyl optionally sub3titutecl~ith one or more Cl-Cs alkyl such as methyl, ethyl, propyl, butyl or the like and/or Cl-Cs alkoxy groups, such as metho~y, ethoxy, propoxy, butoxy or the like, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl optionally substituted with one or more C~-C5 alkyl such as methyl, ethyl, propyl, butyl or the like, and/or Cl-C5 alkoxy groups, such as methoxy, ethoxy, propoxy, butoxy or the like, and tetrahydro-3-thenyl; R4 is selected from ~he group consisting of alkyl of 1-10 (preferably 1-5) carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl or the like, phenyl optionally substituted ~ith one or more Cl-Cs alkyl, such as methyl, ethyl, propyl, butyl or the like, and/or Cl-C5 alkoxy groups, such as methoxy, ethoxy, propoxy, butoxy or the like, aralkyl of 7-12 (preferably 7-10) carbon atoms, such as benzyl, phenethyl or the like, and ring substituted benzyl wherein said substituent is alkyl of 1-5 (preferably 1-3) carbon atoms, such as methyl, ethyl, propyl or isopropyl, or alkoxy of 1-5 (preferably 1-3) carbon atoms, such as methoxy, ethoxy, propoxy or isopropoxy, R5 is ~elected from the group consist-ing of hydrogen, Cl-Clo alkyl, such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl, decyl or the like, C6-Clo ~ryl, such as phenyl, m-tolyl, naphthyl or the like, and ;

.. ..

~3~Z~

aralkyl of` 7-12 (preferably 7-10) carbon atoms, such as benzyl, phcneth~l or the like; and m is an integer of 0, 1 or 2, /+\
(3) ~
(R7)p wherein R6 is -COOR8 ~herein R8 i3 selected from the group consisting of hydrogen, Cl-Clo alkyl, such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl, decyl or the like, C6-Clo aryl, sUch as phenyl, m-tolyl, naphthyl or the like, and aralkyl oP 7-12 (preferably 7-10) carbon atoms, such as ben~yl, phenethyl or the like; each R7 independently is hydrogen, alkyl of 1-10 (preferably 1-6) carbon atoms, such as methyl~ ethyl, propyl, isopropyl, butyl, hexyl, octyl, decyl or the like, phenyl, Cl-C5 alkoxy, such as methoxy, ethoxy~ propoxy, butoxy or the like, C2-C6 alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl or the like, or carboxy; p is an integer of 1 to 4; R6 is substituted at the 2 or 3-position; and R7 can be substituted at the 2, 3, 4, 5 or 6-position.

COORg ~, (4) - N
\ (CH,2)r :

z~

optivnally substituted ~ith one or more Cl~ ~ alkyl, 3uch a3 meth~l~ ethyl, propyl, butyl or the like, or Cl-C~ alko.ey group~, such as methoxy, ethoxy, propo~y, butoxy or the like whereirl R9 is ~elected from the grroup consi3tillg of hydrogen, .? Cl-Clo alkyl, 9-1Ch a3 methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl, decyl or the like, C6-Clo aryl, such as phenyl, m-tolyl, naphthyl or the like and aralkyl of 7-12 (preferably 7-10) carbon atoms, such as benzyl, phenethyl or the like;
and r is an integer of 1, 2, 3 or 4, COORlo (5) - N Z
~(CH2 )q wherein Rlo i3 selected from the group consisting of hydrogen, Cl-Clo alkyl, such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl, decyl or the like, C6-Clo aryl, such as phenyl, m-tolyl, naphthyl or the like, and aralkyl of 7-12 (preferably 7-10) carbon atoms, such as ben~yl, phenethyl or the like;
: Z is selected from the group consisting of oxy (-O-), thio {-S-) and sulfinyl(~S0 ); q i3 an integer of O or 1, and COOR
~(C~2 )i\¢~

O
~.' ~ ' , ~L~L3~

~herein Rll is selected from the group consisting of hydrogen, Cl-Clo alkyl, such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl, ~ecyl or the li!;e, C6-Clo aryl, such as phenyl, m-tolyl, naphthyl or the li~e, allCI araLkyl of ~-12 (preferably 7-10) carbotl atom~, sucll as benzyl, phenethyl or the lil~e; i is an integer of 0, l o:r 2; j is an integer of 0, 1 or 2; and the sum of i + j is an lnteger of 1 or 2;
and Ar is a phenyl or naphtilyl group, either sub3tituted with at least one substituent selected from the group con3isting of sulfoamino, carbamoyl, N,N-dialkvlcarbamoyl of 3-10 (preferably 3-7) carbon atoms, such as N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl or the like, N-alkylcarbamoyl of 2-6 (preferably 2-4) carbon atom~, such as N-methylcarbamoyl, N-ethylcarbamoyl or the like, amino, al~ylamino of 1-10 (preferably 1-5) carbon atoms, such as methylamino, ethylamino, propylamino, butylamino or the like, mercapto, alkylthio of 1-10 (preferably 1-5) carbon atoms, such a3 methylthio~
ethylthio, propylthio, butylthio or the like, aralkyl of 7-12 (preferably 7-10) carbon atoms, such as benzyl, phenethyl or the like, carboxyl, alkoxycarbonyl of 2-10 (preferably 2-6) carbon atoms, such as methoxycarbonyl, ethoxycarbonyl or the like, carboxyalkyl of 2-lO (preferably 2-6) carbon atoms, such as carboxymethyl, 2-carboxyethyl 7 2-carboxypropyl or the like, acylamino such as alkylcarbonylamino of l-10 (preferably 1131~

1-5) carbon atoms, such as acetylamino, propionylamino or the like, alkylcarbonyl of 2-10 (preferably 2-6) carbon atoms, such as acetyl, propi.onyl or -the like 7 hydro.Yyalkyl of 1-10 (preferably 1-~) carbon atoms, such as hydro.Yymethyl, 2-hydro~yethyl~ 2-h~-ck~o.Yypropyl or the llke, llaloalkyl of 1-10 (preferably 1-5) carbon atoms, such as chloromethyl, trifluoromethyl, bromomethyl, 2-chloroethyl or the like, hydroxyalkoxy of 1-10 (preferably 1-5) carbon atoms, such as hydro~YymethoYy, Z-hydro~YyethoYy or the like, and phenyl optionally substituted t~ith at least one hydroxy and/or Cl-C~
alkoxy, such as methoYy, etho.Yy, propoYy, buto.~y or the like;
a phenyl or naphthyl group, either substituted l~ith at least one substituent selected from the group consisting of sulfo-amino, carbamoyl, N,N-dialkylcarbamoyl of 3-10 (preferably 3~7) carbon atoms, such as N,N-dimethylcarbamoyl, N,N~diethyl-carbamoyl or the like, N-alkylcarbamoyl of 2-6 (preferably 2-4) carbon atoms~ such as N-me-thylcarbamoyl, N-ethylcarbamoyl or the like, amino, alkylamino of 1-10 (preferably 1-5) carbon atoms, such as methylamino, ethylamino, propylamino, butylamino or the like, mercapto, alkylthio of 1-10 (preferably 1-5) carbon atoms, such as methylthio, ethylthio, propylthio, butylthio or the like, aralkyl of 7-12 (preferably 7-10) carbon atoms, such as ben~yl, phenethyl or the like, carbo.Yyl, alkoxycarbonyl of 2~10 (preferably 2-6) carbon atoms, such as ~ - 22 -': ' . ~ . :

~3~
methoxycarbonyl, ethoxycarbonyl or -che like, carbo.cyalkyl of 2-10 (preferab]y 2-6) carbon atoms, such as carbo.~ymethyl, 2-carbo.~yethyl, -carbo~ypropyl or the like, acylamino such as a:Lkylcarbonylamino oP 1-1() (preferably 1-~) carbon atoms, such aj acetylamino, propionylamino or the like, alkylcarbonyl of 2-lO (preferably 2-6) carbon atoms, such as acetyl, propionyl or the like, hydroxyalkyl of 1-10 (preferably 1-~) carbon atoms, such as hydroxymethyl, 2-hydro~yethyl, 2-hydro.~ypropyl or the like, haloalkyl of l-lO (preferably 1-5) carbon atoms, such as chloromethyl, trifluoromethyl, bromo-methyl, 2-chloroethyl or the like, hydro~yalkoxy of 1-10 (preferably l-j) carbon atoms, such as hydroxymethoxy, 2-hydroxyethoxy or the like, and phenyl optionally substituted with at least one hydroxy and/or Cl-C~ alkoxy, such as methoxy, ethoxy, propo~y, butoxy or the like, and at least one substituent selected from the group consist-ing of halo, nitro, cyano, hydroxy, alkyl of l-lO (preferably 1-5) carbon atoms, such as methyl, ethyl, propyl, butyl or the like, alkoxy of 1-10 (preferably 1-5) carbon atoms, Such as methoxy, ethoxy, propoxy, butoxy or the like, dialkylamino of 2-20 (preferably 2-10) carbon atoms, such as dimethylamino~
dlethylamino, dipropylamino or the like; an o.~anthrenyl or dibenzofuranyl group substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, ~`al -23 -~ ., - . ' ' ' ' . :
' ~L33 ~

hydroxy, diallcylamino of 2-20 (preferably 2~10) carbon atoms, such as dimethylamino, diethylamino, cliprop~lamino or the like, sulfoamino, carbamoyl, ~,~-dialkylcarbamoyl of 3-10 (preferably 3-7) carbon atoms, such as ~ dimethylcarbamoyl, N,~-cliethylca~bamoyl or the lilce, ~-alkylcarbamoyl of 2-6 (preferably 2-4) carbon atoms, such as N-methylcarbamoyl, N-ethylcarbamoyl or the li~e, amino, alkylamino of 1-10 (preferably 1-5) carbon atoms, such as methylamino, ethylamino, propylamino, bu-tylamino or the like, mercapto, alkylthio of 1-10 (preferably 1-5) carbon atoms, such as methylthio, ethylthio, propylthio, butylthio or the like, aralkyl of 7-12 (preferably 7-10) carbon atoms, such as benzyl, phenethyl or the like, carbo.xyl, alkoxycarbonyl of 2-10 (preferably 2-6) carbon atoms, such as methoxycarbonyl, ethoxycarbonyl or the likep carboxyalkyl of 2-10 (preferably 2-6) carbon atoms, such as carboYymethyl, 2-carboxyethyl, 2-carboxypropyl or the like, acylamino such as alkylcarbonylamino of 1-10 (preferably 1-5) carbon atoms, such as acetylamino, propionylamino or the like, alkylcarbonyl of 2-10 (preferably 2-6) carbon atoms, such as acetyl, propionyl or the like, hydroxyalkyl of 1-10 (preferably 1-5) carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl or the like, haloalkyl of 1-10 (preferably 1-;) carbon atoms, such as chloromethylp trifluoro-methyl, bromomethyl, 2-chloroethyl or the like, hydroxyalkoxy ~ - 24 ~

1~3~62~

of 1-10 (preferably 1-~) carbon atoms, such as hydro.Yymethoxy, 2-hydroxyethoYy or the like, and phenyl optionally substi-tuted with at least one hydro.Yy and/or Cl-C5 all~o.Yy, such as methoYy, e-tho.Yy, propoY~, butoYy or the lilce; an o.Yanthrenyl or dibenzofuranyl gro~lp substitutecl~ith at least one substi-tuent selected from the group consisting of alkyl of 1-10 (preferably 1-5) carbon atoms, such as methyl, ethyl, propyl, butyl or the like, alkoxy of 1-10 (preferably 1-~) carbon atoms, such as methoxy, ethoxy, propoxy, butoxy or the like, and at least one substituent selected from the group consist-ing of halo, nitro, cyano, hydroYy, dialkylamino of 2-20 (preferably 2-10) carbon atoms, such as dimethylamino, diethylamino, dipropylamino or the like, sulfoamino, carbamoyl, N,N-dialkylcarbamoyl of 3-10 (preferably 3-7) carbon atoms, such as N,N-dimethylcarbamoyl, N,N-diethylcarbamayl or the like, N-alkylcarbamoyl of 2-6 (preferably 2-4) carbon atoms, such as N-methylcarbamoyl, N-ethylcarbamoyl or the like, amino, alkylamino of 1-10 (preferably 1-5) carbon atoms, such as methylamino, ethylamino, propylamino, butylamino or ~; ~0 the like, mercapto, alkylthio of l-10 (preferably 1-5) carbon atoms, such as methylthio,~;ethylthio, propylthio, butyl~thio or the like, aralkyl of 7-12 (preferably 7-10) carbon atoms, such as benzyl, phenethyl or the like, carboxyl, alkoxy-c~arbonyl of 2-10 (preferably 2-63 carbon atoms, such as .
~ ' ï ~ 25 -.;, . , ~ : .

.
. ~ . .
, , :
., . . . ~ , . .
.

:. - ' : ~

6Z~

methoxycarbonyl, etho~ycarbonyl or the like, carboxyalkyl of 2-10 (preferably 2-6) carbon atoms, sllch as carboxymethyl, 2-carbo~yethyl, 2-carboxvpropyl or the like, acylamino such as alkylcarbonylamino of 1-10 (preferably 1-~) carbGn atoms, such as acetylamino, propionylamino or the like, alkylcarbonyl of 2-10 (preferably 2-6) carbon atoms, such as ace-tyl, propionyl or the like, hydroxyalkyl of 1-10 (preferably 1-5) carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl or the like, haloalkyl of 1-10 (preferably 1-5) carbon atoms, such as chloromethyl, trifluoromethyl, bromo-methyl, 2-chloroethyl or the like, hydro~yalkoxy of 1-10 (preferably 1-5) carbon atoms, such as hydroxymethoxy, 2-hydroxyethoxy or -the like, and phenyl optionally substituted with at least one hydroxy and/or Cl-C5 alkoxy, suoh as methoxy, ethoxy, propoxy, butoxy or the like; a tetrahydronaphthyl, 1,2-ethylenedioxyphenyl, chromanyl, 2,3-ethylenedioxynaphthyl or xanthenyl group, any substituted with at least one sub-stituent selected from the group consistin~ of halo, nitro, cyano, hydroxy, dialkylamino of 2-20 (preferably 2-10) carbon atoms, such as dimethylamino, diethyl.amino, dipropylamino or the like, sulfoamino, carbamoyl, N,N-dialkylcarbamoyl of 3-10 (preferably 3-7) carbon atoms, such as N,N-dimethyl-carbamoyl, N,N-diethylcarbamoyl or the like, N-alkylcarbamoyl ; of 2-6 (preferably 2-4) carbon atoms, such as N-methylcarbamoyl, ~: .

.:,' ':

~: . ~ ~~` . :
.

.

;Zl ~-ethylcarbamoyl or the like, amino, alkylamino of 1-10 (preferably 1-5) carbon atoms, such as methylaminot ethyl-amino, propylamino, butylamino or the like, mercapto, alkylthi.o of 1-10 (preferably 1-5) carbon atoms, such as methylthio, ethylthio, propylthio, butylthio or the like, aralkyl of 7 12 (preferably 7-10) carbon atoms, such as ben~yl, phenethyl or the like, carboxyl, alko~ycarbonyl of 2-10 (preferably 2-6) carbon atoms, such as methoxycarbonyl, ethoxycarbonyl or the like, carboxyalkyl of 2-10 (preferably 2-6) carbon atoms, such as carboxymethyl, 2-carboxyethyl, 2-carboxypropyl or the like, acylamino such as alkylcarbonyl-amino of 1-10 (preferably 1-5) carbon atoms, such as acetyl-amino, propionylamino or the like, alkylcarbonyl of 2-10 (preferably 2-6) carbon atoms, such as acetyl, propionyl or the like, hydroxyalkyl of 1-10 (preferably 1-5) carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl or the like, haloalkyl of 1-10 (preferably 1-5) carbon atoms, such as chloromethyl, trifluoromethyl, bromomethyl, 2-chloroethyl or the like, hydroxyalkoxy of 1-10 (preferably 1-5) carbon atoms, such as hydroxymethoxy, 2-hydroxyethoxy or the like, oxo and p~enyl optionally substituted with at least one hydroxy and/or Cl-C5 allcoxy, such as methoxy, ethoxy, propoxy, : : ~ butoxy or the like; a tetrahydronaphthyl, 1,2-ethylenedioxy-phenyl, chro~manyl, 2,3-ethylenedioxynaphthyl or xanthenyl ~ J 27 -., ,~ ., . .

.

' ': , : : : ~ :

group, any substituted with at least one substituent selected from the group consisting of alkyl of 1-lO (preferably 1-5) carbon atoms, such as meth~-l, ethyl, propyl, butyl or the like, alkoxy of l-lO ipreferably 1-~) carbon atoms, such as g methoxy, etllo.~y, propoxy, butoxy or the like, and at least one substituent selected from the group consi5t-ing of halo, nitro, cyano, hydroxy, dialkylamino of 2-20 (preferably 2-10) carbon atoms, such as dimethylamino, diethylamino, dipropylamino or the like, sulfoamino, carbamoyl, N,N-dialkylcarbamoyl of 3-lO (preferably 3-7) carbon atoms, such as N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl or the like, N-alkylcarbamoyl of 2-6 (preferably 2-4) carbon atoms, sUch as N~methylcarbamoyl, N-ethylcarbamoyl or the like, amino, alkylamino of 1-10 (preferably 1-5) carbon atoms, such as methylamino, ethylamino, propylamino, butylamino or the like, mercapto, alkylthio of 1-10 (preferably 1-5) carbon atoms, such as methylthio, ethylthio, propylthio, butylthio or the like, aralkyl of 7-12 (preferably 7-lO) carbon atoms, such as benzyl~ phenethyl or the like, carboxyl, alkoxy-carbonyl of 2-10 (preferably 2-6) carbon atoms, such as methoxycarbonyl, ethoxycarbonyl or the like, carboxyalkyl of 2-10 (preferably 2-6) carbon atoms, such as carboxymethyl, :
2-carboxyethyl, 2-carboxypropyl or the like, acylamino such as alkylcarbonylamino of l-lO (pFeferably 1-5) carbon atoms, ~ ' ~ àl -2.8-:' , . ~ . ' ' . : .
. : `" ' ::
' ' ` ' ' such as acetylamino, proplonylamino or the like, alkylcar-bonyl of 2-lO (preferably 2-6) carbon atoms, such as acetyl, propionyl or the like, hydroxyalkyl of l-10 (prererably 1-5) carbon atoms~ such as hydroxymethyl, 2-llydroxvethyl~ 2-hydroxypropyl or the like, haloalkyl of 1-10 (preferably 1-5) earbon atoms, such as chloromethyl, trifluoromethyl, bromomethyl, 2-chloroethyl or the like, hydroxyalkoxy of 1-10 (prefsrably 1-5) carbon atoms, such as hydroxymethoYy, 2-hydroxyethoxy or the like, oxo, and phenyl optionally substituted with at least one hydroxy and/or Cl-Cs alkoxy, such as methoxy, ethoxy, propoxy, butoxy or the like;
a naphthoquinonyl, anthryl, phenanthryl, pentalenyl, heptalenyl, azulenyl, biphenylenyl, as-indacenyl, S-indacenyl, aeenaphthylenyl, phenylcarbonylphenyl, phenoxyphenyl, benzo-furanyl, isobenzofuranyl, benzo (b) thienyl, isobenzothienyl, thianthrenyl, dibenzothienyl, phenoxathiinyl, lndolyl, lH-indazolyl? quinolyl, isoquinolyl, phthalazinyl, 1,8-naphthridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl or benzimidazolyl group any of whieh is unsubstituted or substituted with one or more groups selected ~rom the group consisting of halo, nitro, cyano, hydroxy, alkyl of 1-10 - (preferably l-5) carbon atoms, such as methyl, ethyl, propyl, ; butyl or the like, alkoxy of l-10 (preferably 1-5) carbon ~ ~ .
.

~ 29 --,,r ,s . . ~ - , .
. - . - ~: : - . .
, .

, ~

~ '~
~1;316~

atoms, such as methoxy, ethoxy, propo~y, buto.Yy or the like, dialkylamino of 2-20 (preferably 2-lO) carbon atoms, such as dimethylarnino, cliethyl~lino, dipropylamino or the like, sulfoa~ino, carbamoyl, ~,N-dialkylcarbamoyl of 3-10 (prefer-ably 3-7) c~rbon atoms, such as N,.~-climethylcarbamoyl, N,N-diethylcarbamoyl or-the like, ~-alkylcarbamoyl of 2-6 (preferably 2-4) carbon atoms, such as ~-methylcarbamoyl, ~-ethylcarbamoyl or the like, amino, alkylamino of 1-lO
(preferably 1-5) carbon atoms, such as methylamino, ethylamino, 10 propylamino, butylamino or the like, mercapto, alkylthio of l-lO (preferably 1-5) carbon atoms, such as methylthio, `:
ethylthio, propylthio, butylthio or the like, aralkyl of 7-12 (preferably 7-10) carbon atoms, such as benzyl, phenethyl or .
the like, carboxyl, alkoxycarbonyl of 2-10 (preferably 2-6) 15 carbon atoms, such as metho~ycarbonyl, ethoxycarbonyl or the like, carboxyalkyl of 2-10 (preferably 2-6) carbon atoms, uoh as carboxymethyl, 2-carboxyethyl, 2-carboxyproPyl or the like, acylamino such as alkylcarbonylamino of 1-10 (prefer-ably 1-5) carbon atoms, such as acetylamino, propionylamino 20 or the like, alkylcarbonyl of 2-lO (preferably 2-6) carbon ~ atoms, such as acetyl, proplonyl or the like, hydroxyalkyl : of 1-10 (preferably 1-5) carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl or the like, haloalkyl of 10 (preferably 1-5) oarbon atoms, such as chlo~omethyl, .
~ 30 ~

~'. . ~ ` . .

. . . ~
~ .

z~

trifluoromethyl, bromomethyl, 2-chloroethyl or the like, hydroxyall;oxy of 1-10 (preferably 1-5) carbon a-toms, such as hydro~ymetho~y, 2-hydro~yetho~y or the like, and phenyl optionally substituted with at least one hydro.Yy and~or Cl~C5 alko.Yy, iuch as methoxy, etho~y, propoxy, butoYy or the like; a C7-C12 aralkyl, Cg-C16 cycloalkylphenyl, Clo-Clg cycloalkylalkylphenyl, C9-C16 cycloalkylo.Yyphenyl, Cg-Cl6 cycloalkylthiophenyl, 9,10-dihydroanthryl, 5,6,7,8-tetrahydro-anthryl, 9,10-dihydrophenanthryl, 1,2,3,4,5,6,7,8-octahydro-phenanthryl~ indenyl, indanyl, fluorenyl, acenaphthenyl, phenylthiophenyl, isochromanyl, 2,3-dihyd.robenzofuranyl, 1,3-dihydroisobenzofuranyl, thioxanthenyl, 2EI-chromenyl, 3,4-dehydro-1-isochromanyl, 4H-chromenyl, indolinyl, isoindolinyl, 1,2,3,4-tetrahydroquinolyl or 1,2,3,4-tetra-hydroisoquinolyl group any of which is unsubstituted or substituted with one or more groups selected from the group consisting of halo, nitro, cyano, hydroxy, alkyl of 1-10 (preferably 1-5) carbon atoms, such as methyl, ethyl, propyl, butyl or the like, alkoxy of 1-10 (preferably 1-5) carbon atoms, such as methoxy, ethoxy, propoxy, butoxy or the like, dialkylamino of 2-20 (preferably 2-10) carbon atomsj such as dimethylamino, diethylamino, dipropylamino or the like, sulfoamino, carbamoyl, N,N-dialkylcarbamoyl of 3-10 (prefer-ably 3-7) carbon atoms, such as N,N-dimethylcarbamoyl, ~,., (,, ',. ' : :'. . :
, ' : - ' ~

1~3~2~

diethylcarbamoyl or the like, ~-alkylcarbamoyl of 2-6 (preferably 2-4) carbon atoms, such as ~-methylcarbamoyl, ~-ethvlcarbamoyl or the lil~e, amino, alkylamino of 1-10 (preferably 1-5) carbon atoms, such as methylamino, ethyl-amino, propylamino, butylamino or the like, mercapto, alkylthio of 1-10 (preferably 1-5) carbon atoms, such as methylthio, ethylthio, propylthio, butylthio or the like, aralkyl of 7-12 (preferably 7-10) carbon atoms, such as benzyl, phenethyl or the like, carboxyl, alkoxycarbonyl of 2-10 (preferably 2-6) carbon atoms, such as methoxycarbonyl, ethoxycarbonyl or the like, carboxyalkyl of 2-10 (preferably 2-6) carbon atoms, such as carboxymethyl, 2-carboxyethyl, 2-carboxypropyl or the like, acylamino such as alkylcarbonyl-amino of 1-10 (preferably 1-5) carbon atoms, such as acetyl-amino, propionylamino or the like, alkylcarbon.yl of 2-10 (preferably 2-6) carbon atoms, such as acetyl, propionyl or the like, hydroxyalkyl of l-10 (preferably 1-5) carbon atoms, ~; such as hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl or the like, haloalkyl of l-10 (preferably 1-5) carbon atoms, such as chlorornethyl, trifluoromethyl, bromomethyl, 2-chloroethyl or the like,~hydroxyalkoxy of 1-10 (preferably 1-5) carbon atoms, such as hydroxymethoxy, 2-hydroxyethoxy or the like, oxo, and phenyl optionally substituted with at least one hydroxy and/or Cl-Cs alkoxy, such as methoxy, ethoxy, ,' ' ~

1:~L3~

propoxy, buto~y or the like;
or a phenyl group substituted ~ith at least one substituent selectecl f`rom the group consisting of alkyl, alkoxy, halo-alkoxy, all;oxy~ll{yl, all;oxyalko.~y, alkoxyc~rbonylalkyl and alkoxycarbonylalko.Yy, the s~icl substituent containin~ 3 to 7 carbon atoms, and the ~aid substituted phenyl group being optionally substituted further ~ith at least one substituent selected ~rom the group consisting o~ methyl, ethyl, methoxy, ethoxy, hydroxy and halo, such as 3-propyl-4-metho.Yyphenyl~
3-tert-butyl-4-methoxyphenyl, 3-sec-butyl-4-hydrax~phenyl, 3-propoxyphenyl, 3-methoxy-4-propoxyphenyl, 3-propoxy-4-methox~phenyl, 2,4-dimethoxy-3-propoxyphenyl, 3-bu-toxyphenyl, 2-butoxyphenyl, 2,5-dibutoxyphenyl, 3,4-dibutoxyphenyl, 2,4-dibutoxyphenyl, 3-methyl-4-butoxyphenyl, 3,5-dimethyl-4-butoxyphenyl, 2,4-dimethoxy-3-butoxyphenyl, 2,4-dichloro-3-butoxyphenyl, 3-pentyloxyphenyl, 3-isopen-tyloxyphenyl, 3~5-dimethyl-4-pentyloxyphenyl, 2~4:-dlme-thoxy-3-pentyloxy-phenyl, 2,4-dimethoxy-3-hexyloxyphenyl, 2,4-dime-thoxy-3-(3-bromopropoxy)phenyl, 2,4-dimethoxy-3-(2-methoxyethoxy) ~ 20 phenyl, 2,4-dimethoxy-3-(2-ethoxyethoxy)phenyl, 3-methyl-4-;~ (2-methoxyethoxy)phenyl, 3-methyl-4-(3-methoxypropoxy)phenyl, 3-valeryl 4-methoxyphenyl, 2,4~dimethoxy-4-(3-me-thoxycarbonyl-propoxy)phenyl and the like.

:a~J ' .. , , . . ~ , -:, ' ~', ' , : ' A preferred El:radical is selected from thc group consis-ting of (1) - N ~
\ (C1~12 )nCOOR2 where:in Rl i5 selectecl from the group consisti.ng of C2-Clo alkyl, C3-Clo alkenyl, C2-Clo alkoxyalkyl, C2-Clo alkyl-thio-alkyl, C2-Clo alkylsulfinylallcyl, C7-Cls aralkyl, C3-Clo cycloalkyl, CL~-Clo cycloalkylalkyl, furfuryl, tetrahydro-furfuryl, te-trahydro-2(3 or 4)-pyranylmethyl and 1,4-dioxa-2-cyclohexylmethyl; R2 is selected from the group consisting of hydrogen, Cl-Clo alkyl, C6-Clo aryl and C7-cl2 aralkyl;
and n is an integer of 1, 2 or 3, (2) - N\ H (C~l ) COOR

~ R~

wherein R3 is selected from the group consisting of hydrogen, Cl-Clo alkyl, C3-Clo alkenyl, C2-Clo alkoxyalkyl, C2-Clo alkyl-thioalkyl, C2-Gio alkylsulfinylalkyl, C7-Cls aralkyl, C3-C10 cycloalkyl, C4-C10 cycloalkylalkyl, furfuryl~ tetrahydro-furfuryl, tetrahydro-2(3 or 4)-pyranylmethyl and 1~4-dioxa-2-cyclohexylmethyl; R4 is selected from the group consisting of Cl-C10 alkyl, phenyl optionally substituted with at least : one Cl-C5 alkyl, Cl-C5 alkoxy or mixtures thereof, C7-C12 ~ - 34 _ .

, ~31b;~1 aralkyl and ring substituted benzyl ~rherein said substituen-t is Cl-C5 alhvl or Cl-C5 alkoxy; R5 is selected from the group consisting of hydrogen, Cl-Clo al~yl, C6-C]o ar~-l and C7-C12 aralkyl; and m is an integer of 0, l or 2 ~6 (3) - ~

(R7)p wherein R6 is -COOR8 wherein R~ is selected from the group consisting of` hydrogen, Cl~Clo alkyl, C6-clo aryl and C7-C12 aralkyl; each R7 independently is hydrogen, Cl-Clo alkyl or phenyl; p is an integer of 1 to 4; R6 is substituted at the 2 or 3-position; and R7 can be substi-tuted at the 2, 3, 4, 5 or 6-position, COORo ~ \
(4) -N J

-optionally substituted with at least one Cl-C5 alkyl, Cl-C5 alkoxy or mixtures thereof, wherein R9 is selected from the group consisting of hydrogen, Cl-Clo alkyl, C6-C10 aryl and C7-C12 aralkyl; and r is an integer of 1, 2, 3 or 4, ~ ' ' ~ ~ ~5 .~,,.-~, ,~

, ~' ' ' ' ' ., ,. ~

COORlo \ (CE12)q wherein Rlo is selected from the group consisting of hydrogen, Cl-Clo alkyl, C6-Clo aryl and C7-C12 aralkyl; Z is selected from the group consisting of oxy, thio and sulfinyl; and q is an integer of O or 1, and .
:` COOI~
~ 2) ~

wherein Rll is selected from the group consisting of hydrogen, .
Cl-Clo alkyl, C6-Clo aryl and C7-C12 aralkyl; i is an integer of 0, l or 2; j is an integer of 0, 1 or 2; and the sum of i + j is an integer of 1 or 2 . ~ :
The most preferred R radical is selected from the group consisting of ~: / RI
~; (1) N \(C~2)nCOR2 , . :
:
Zo wherein Rl is selected from~the~group consisting of C2-ClO
alkyl, C2-C6 alkoxyalkyl, C2-C6 alkylthioalkyl, C7-CIo aralkyl, C4-Clo cycloalkylalkyl, furfuryl and tetrahydrofurfuryl; R2 is -: :
- :
':; .
::
~: :
:~ - 36 -., . . - - .

:~

hydrogen or Cl-Clo alkyl; and n is an .integer of 1, 2 or 3, ~ R3 (2) - N
IC~I-(CI-I2 )mCOOR5 I~4 wherein R3 is selected from the group collsisting of hydrogen, Cl-Clo allcyl, C2-C6 alkoxyalkyl, C2-C6 allcyl-thioalkyl, C7-Clo aralkyl, CL~-Clo cycloalkylalkyl, furfuryl and tetrahydro-furfuryl; R4 is Cl-C5 alkyl; Rs ls hydrogen or Cl-Clo alkyl;
and m is an integer of 0, 1 or 2 (3) - N ~

(R7)p wherein R6 is -COORg whe.rein R8 is hydrogen or Cl-C10 alkyl;
.each R7 independently is hydrogen or Cl-C6 alkyl; p is an integer of 1 to 4; R6 is substituted at the 2 or 3-position;
and R7 can be substituted at the 2, 3, 4, 5 or 6-positlon, : COORg (4) - ~
20 ~ ~(CH2)) optionally substituted with at least one Cl-Cs alkyl, Cl-Cs , '. ~. ' ' ' ' :. :
6,~

alkoxy or mi.Ytures thereof, wherein Rg i3 hyclrogen or Cl-Clo alkyl; and r is an integer of 1, 2, 3 or 4, C 00 Rl o (5) - l~ ~ z ~(C~2~q wherein Rlo is hydrogen or Cl-Clo alkyl; Z is selected from the group consisting of oxy, thio and sulfinyl; and q is an integer of 0 or 1, and C O (~
\(rl;2 ) J ~

wherein Rll is hydrogen or Cl-Clo alkyl; i is an integer of 0, l or 2; j is an integer of 0, 1 or 2; and the sum of i + j is an lnteger of l or 2.

A suitable Ar radical i5 a phenyl or naphthyl group, either substituted with at least one substituent selected from the ~: group consisting of sulfoaminoJ carbamoyl, C3-Clo N,N-:
: dialkylcarbamonyl, C2-C6 N-alkylcarbamoyl, amino, Cl-Clo alkylamino, mercapto, Cl-Clo alkylthio, C7-C12 aralkyl, carboxy, C2-C10 alkoxycarbonyl, C2-C10 carboYyalkyl, Cl-Clo acylamino, C2-Clo alkylcarbonyl, Cl-Clo hydroxyalkyl, Cl-C10 ~':

' - 38 -.

,';. ' ,:

\~ ~

~9.3~

haloalkyl, Cl-Clo hyclroxyalkoxy and phenyl optionally sub-stituted with at leas-t one hydroxy, CL-Cs allcoxy, or mixtures thereof;

a pheny:L or naphthyl group, either subs-t:ituted ~i-th at least one substi-tuent selected from the group consisting of halo, nitro, cyano, hydroxy, Cl-Clo alkyl, Cl-Clo alkoxy and C2-C20 dialkylamino, and at least one substituent selected from the group consis-ting of sulfoamino, carbamoyl, C3-Clo N,N-dialkylcarbamoyl, C2-C6 N-alkylcarbamoyl, amino, ~
1~ Cl-Clo alkylamino, mercapto, Cl-Clo alkylthio, C7-C12 aralkyl, -carboxy, C2-Clo alkoxycarbonyl, C2-Clo carboxyalkyl, Cl-Clo acylamino, C2-CLo alkylcarbonyl, Cl-Clo hydroxyalkyl, Cl-Clo haloalkyl, Cl-Cld hydroxyalkoxy and phenyl optionally substituted with at least one hydroxy, Cl-Cs alkoxy, or 15~ mixtures thereof;

an oxan-threnyl or dibenzofuranyl group substituted with at ; least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C2-c20 dialkylamino, C2-C6 N-alkylcarbamoyl, Cl-Clo alkylamino, mercapto, Cl-Clo alkyl-- thio, C2-Clo alkoxycarbonyl, Cl~Clo hydroxyalkyl, Cl-Clo haloalkyl and Cl-Clo hydroxyalkoxy;

an oxanthrenyl or dibenzofuranyl group substituted with at ~~ ~
least one substltuent selected from the group conslsting ~::
~ .
.

- 39 ~
, ,, , . . . ~

.: ' , ' . ' . ~ :

1~ 3~2~

of Cl-C10 alkyl and Cl-C10 alkoYy, and at least one substi-tuent selected from the group consisting of ha:Lo, nitro~
cyano, hydroxy, C2~C20 dialkylamino, C2-C6 N-alkylcarbamoyl, Cl-Clo all;ylamino, mercapto, Cl-Clo alkylthio, C2-Clo alkoxy-carbonyl, Cl-Clo hydroYyallcyl, Cl-Clo haloalkyl and Cl-Clo hydroxyalkoxy;

a tetrahydronaphthyl, 1,2-ethylenedio.Yyphenyl, chromanyl, 2~3-ethylenedloxynaphthyl or xanthenyl group, any substitu-ted with at least one substituent selected from the group consist-ing o~ halo, nitro, cyano, hydroxy, C2-C20 dialkyIamino, C2-C6 N-al~ylcarbamoyl, Cl-C10 alkylamino, mercapto, Cl-C10 alkylthio, C2-Clo alkoxycarbonyl, Cl-Clo hydroxyalkyl, Cl-Clo haloalkyl, Cl-Clo hydroxyalkoxy, and oxo;

a tetrahydronaphthyl, l,2-ethylenedioxyphenyl, chromanyl, 2,3-ethylenedioxynaph-thyl or xanthenyl group, any substituted with at least one substituent selected from the group consist-ing of Cl-Clo alkyl and Cl-Clo alkoxy, and at least one substituent selected from the group consisting o~ halo, ni-tro, cyano, hydroxy, C2-C20 dialkylamino, C2-C6 N-alkylcarbamoyl, Cl-Clo alkyla~no, mercapto, Cl-Clo alkylthlo~ C2-Clo alkoxy-carbonyl, Cl-Clo hydroxyalkyl, Cl-Clo haloalkyl, Cl-Clo hydroxyalkoxyj and oxo;
, ~ 40 -~' :

~ '`
1~3~

an antllryl, phenanthryl, biphenylenyl, S-indacenyl, phenyl-carbonylphenyl, phenoxyphenyl, benzofuranyl, benzo (b) thienyl, thianthrenyl, ~ibenzothienyl, p~eno~athiinyl, quinolyl, isoquinolyl, quinoxalinyl, q-linazolinyl~ cinnolinyl, carbazolyl~ acriclinyl, phenazinyl, phenothiazinyl or pheno-xazinyl group any of which is unsubstituted or substituted with one or more groups selected from the group consisting of halo, nitro, cyano, hydroxy, Cl-Clo alkyl, Cl-Clo alkoxy~
C2-C20 dialkylamino and Cl-Clo hydroxyalkoxy;

a C7-C12 aralkyl, Cg-C16 cycloalkylphenyl, Clo-Clg cyclo-alkylalkylphenyl, Cg-Cl6 cycloalkyloxyphenyl, 9,10-dihydro-anthryl, 5,6,7,8-tetrahydroanthryl, 9,10-dihydrophenanthryl, 1~2,3,4~5,6,7,8-octahydrophenanthryl, indenyl, indanyl, fluorenyl, acenaphthenyl, phenylthiophenyl, 2,3-dihydrobenzo-furanyl, thioxanthenyl, 2H-chromenyl or 1j2,3,4--tetrahydro-quinolyl group any of which is unsubstituted or sub3tituted with one or more groups selected from the group consisting of halo, nitro, cyano, hydroxy, Cl-Clo alkyl, Cl-Clo alkoxy, C2-C20 dialkylamino, C2-C6 ~-alkylcarbamoyl, Cl-Clo hydroxy-alkoxy, and oxo;

or a phenyl group substituted with at least one substituent selected from the group consisting of alkyl, akoxy, halo-alkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkyl and .

~' ::~ ~ ' ,i : :
-~31~i2~

alkoxycarbonylall;oxy, the said substituent containing 3 to 7 carbon atoms and the said substituted phenyl group being optionally substituted further wi-th at least one substituent selected from the group consisting of methyl, ethyl, methoYy, etho~y, hydro.~y and halo.

preferred Ar radical is a phenyl or naphthyl group, either substitu-ted ~ith at least one substituen-t selected from the group consisting of amino, Cl-Clo alkylamino, Cl-Clo alkyl-thio, C7-Cl2 aralkyl, C2-ClO alkoxycarbonyl, Cl-Clo acylamino, C2-ClO alkylcarbonyl, Cl-Clo hydroYyalkyl, Cl-Clo hydroxy-alkoYy and phenyl;

a phenyl or naphthyl group, either substituted ~ith at least one substituent selected from the group consisting of amino, Cl-Clo alkylamino, Cl-Clo alkylthio, C7-C12 aralkyl, C2-Clo alkXYCarbnYl, Cl-C10 acylamino, C2-C10 alkylcarbonyl, Cl~Clo hydroxyalkyl, Cl-Clo hydroxyalkoxy and phenyl, and at least one substituent selected from the group consisting of halo, hydroxy, Cl-Clo alkyl, Cl-Clo alkoxy and C2-C20 dialkylamillo;
:
a dibenzofuranyl group substituted with at least one sub-stituent selected from the group consisting of halo;

.

~ ~ - 42 ~
, ~ , ~13~;Z~

a dibenzofuranyl group substituted with a-t leas-t one sub-stituerLt selected from the group consisti~lg of Cl-Clo alkyl and Cl-Clo alkoxy, and~a-t least one substituent selected from the g:roup consisting o~ halo;

a te-trahydronaE~h-thyl, :L,2-e-thylenedioxyphenyl, chromanyl, 2,3-ethylenedioxynaphthyl or xanthenyl group, any substitu-ted with at least one substituent selected from the group consist-ing of halo;

a tetrahydronaph-thyl, l,2-ethylenedioxyphenyl, chromanyl, 2~3-ethylenedioxynaphthyl or xanthenyl group, any substi-tuted ~ith at least one substi-tuent selected from the group consist-ing of Cl-Clo alkyl and Cl-Clo alkoxy, and a-t least one sub-stituent selected from the g.roup consisting of halo;

an anthryl, phenanthryl, biphenylenyl, phenoxyphenyl, benzofuranyl, benzo (b) thienyl, dibenzothienyl, phenoxathiinyl, quinolyl~ isoquinolyl, qulnoxalinyl~ acridinyl or phenazinyl, group any of which is unsubstituted or Substituted with one or more groups selected from the group consisting of halo, hydroxy, Cl-Clo alkyl, Cl-Clo alkoxy and Cl-C10 hydroxyalkoxy;

a C7-C12 aralkyl, Cg-C16 cyc:Loalkylphenyl, fluorenyl, thioxanthenyl, 2H-chromenyl, or 1,2,3,4--tetrahydroquinolyl group any o~ which is unsubstituted or subs-tituted with one ,. ~ ,~ .

, . .. .... . . .
: ' .

' .

~3~

or more groupj selected from the group consisting of Cl-Clo alkyl, Cl-Clo alko.cy and oxo;

or a phenyl group substituted ~ith at least one substituent selected from t~le group consisting of all;yl, alkoxy, halo-alko~y, allcocyalkyl, alkoxyalkocy, alko.Yycarbonylalkyl and alkoxycarbonylallcoxy, the said substituent containing 3 to 7 carbon atoms, and the said substituted phenyl group being optionally substituted further with at least one substituent selected from the group consisting of methyl, ethyl, methoxy, ethoxy, hydroxy and halo.

The most preferred ~r radical is a phenyl or naphthyl group, either substituted with at least one substituent 3 elected from the group consisting of amino, Cl-Clo alkylamino, C7-C12 aralkyl, Cl-Clo acylamino, Cl-Clo hydroxyalkyl, and Cl-Clo hydroxyalkoxy;

a phenyl or naphthyl group, either substituted with at least one substituent selected from the group consisting of amino, Cl-C10 alkylamino, C7-C12 aralkyl, Cl-C10 acylamino, Cl-Clo hydroxyalkyl and Cl-Clo hydroxyalkoxy and at least one sub-stituent selected from the group consisting of halo, hydroxy, Cl-Clo alkyl and Cl-Clo alkoxy;

.

~ - 44 -~,.

:' `' ~

~3~

a biphenylenyl, pheno.~yphenyl, dibenzothienyl, pherlo.Yathiinyl, quinolyl, or quino.Yalinyl group any of which is unsubstituted or substituted ~ith one or more groups selected f`rom the group consistillg o~ hydro.~y and Cl-Clo alkyl;

a C7-C12 aralkyl, Cg-C16 cycloallcylphenyl, fluorenyl, or 2H-chromenyl group any of which is unsubstituted or substi-tuted with one or more groups selected from the group consist-ing of Cl-C10 alkyl, Cl-C10 alkoxy and oxo;

or a phenyl group substituted with at least one substituent selected frorn the group consisting of alkyl, alkoxy, halo-alkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkyl and alkoxycarbonylalkoxy, the said substituent containing 3 to 7 carbon atoms, and the said substituted phenyl group being optionally substituted further with at least one substituent selected from the group consisting of methyl, ethyl, methoxy, ethoxy, hydroxy and halo.

Typical compounds of this invention include:
l-lN2-(quinoline-8-sulfonyl)-L-arglnyl~-4-methyl-2-piperidine-carboxylic acid l-~N -(3-methylquinoline-8-sulfonyl)-L-arginyl~-4-methyl-2-piperidinecarboxylic acid :

~ ~ - 45 -' ,,d ~ ~

" ': . ' ~ ,' , ' . .
, ' .

~13~6~

l-~N -(3-ethylquinoline-8-sulfonyl)-L-arginyl~-4-methyl-2-piperidinacarboxylic acid l-tN2-(3-sec-butoxyberlzene-1-sulfonyl)-L-arginyl~-4-methyl-2-piperidinecarboxylic acid l-~N -(3,5~dimethyl-4-isopropoxybenzene-1-sulfonyl~-4-methyl-2-piperidinecarboxylic acid l-~N2-(2J4-dimetho.yy-3-butoxybenzene-l-sulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylic acid l-~N2-(3-isopropoxybenzene-1-sulfonyl)-L-arginyl)-4-methyl-2-piperidinecarboxylic acid N -(2-pheno~yathilnyl3uLfonyl)-L-arginyl-N-tetrahydrofurfur glycine N -(2-fluorenesulfonyl)-L-arginyl-N-(2-me-tho~yethyl)glyclne N t-4-methoxy-3-cyclohexylbenzene-l-sulfonyl)-L-arginyl) 4-methyl-2-piperidinecarboxylic acid The pharmaceutically acceptable salts of the above compounds are of course also included wlthin the scope of this invention.

For the preparation of the compounds of this lnvention, various methods can be employed depending upon the particular ~ .
~ ~ - 46 -. : .... , _ . _ , :.

': ' .~ , , ~ , ~, .

~L131Ç;2~L

starting materials and/or intermediates in-olved. Successful preparation of -these compounds is possible by way of several synthetic routes ~ihicll are ou-tlined belo~

(a) Condensation of an L-argininamide ~iith an arylsulfonyl halide This proces~ may be illustrated as follows:

H~
~C -- N - CH2CH2CH2CIICOOH (II) 1 0 ' EIN ~
~c - l~r -- CH2CH2CH2CHCOOH (m) R " E~N
R' I
R"' + RH (IV) EIN
,C -- N -- CH2CH2CH2CHCOR (V) R " HN
R' I
R"' 2~0 HN~
H2N ~ ICH2CH2CH2CHCOR ( VI ) : H NH2 ~ ArS02~ ~ ( VII ) :
~ - 47 ~
i - : --, . . . .
, . - . ~ .
. : , .

, , 1~3~;2~

H~ ~
C - N - CH2CH2CH2CHCOR (I) ~r In the above formulas, ~ anc1~r are as defined herein above; Y is halogen; R"'is a protective group for the ~ -amino group, such as benzyloxycarbonyl or tert-buto~ycarbonyl; R' and R" are selected from the group consisting of hydrogen and protective groups for the guanldino group, such as nitro, tosyl, trityl, oxycarbonyl and the li~e; and at leas-t one of R' and R" is a protec-tive group for the gua~nidino group.
The N2-arylsulfonyl-L-argininamide (I) is prepared by the condensation of an L-argininamide (VI) ~ith a sub-~15 stantially equimolar amount~of an arylsulfonyl halide (VII), preferably a chl~oride.~
:
~ The condensation r0action is~;generally effected in a ~: ~
suitable reaction-inert solvent in the presence of an excess of a base, such~as an organlc base (trlethylamlne, 2~0 pyridlne) or a solutlon of~an 1norganic base ~(sodlum hydroxlde, potassium carbonate), at a temperature of 0C
:
to the boiling temperature o~ the solvent for a period ~ of lO minutes to lg hours~

`~'.--, ~ - 48 -: . ,, , ~ : , . . .

,: .
,~
. : , ~ , ~3~%~

The preferred solvents for the condensation include benzene-diethyl ether, diethyl ether-~ater and dio.~ane-~ater.
~fter tlle reaction :i~ complete, the formed salt is e.~tracted ~ith ~ater, and the solvent is removed by such standard means as evaporation ~mder reduced pressure to give the N -arylsulfonyl-L-argininamide (I), ~hich can be purified by trituration or recrystalliza-tion from a suitable solvent, such as diethyl ether-tetrahydrofuran, diethyl ether-methanol and water-methanol, or may be chromatographed on 3i.1i ca gel.
The L-argininamides (VI) star-ting materials required for the condensation reaction can be prepared by protecting the guanidino and ~ -amino groups of L-arginine (II) via nitration, acetylation, formylation, phthaloylation, trifluoroacetylation, p-methoxybenzylo~ycarbonylation, benzoylation, benzyloxycarbonylation, tert-buto~y-carbonylation or tritylation and then condensing the formed N -sub3tituted-N -substituted-L-arginine (m) with a corresponding amino acid~ derivative (IV) by 3uch a - conventional process as~the acid ohloride method, azide method, mixed anhydride method, activated ester method or carbodiimide method, and thereafter selectively removing the protective groups from the formed , ~L3~2~

-substituted-~2-sub3titutecl-L-argininamicle (V).
The an~no acid derivati.ves (IV) which are the starting material3 for the preparation Or the ~G-~ubstituted-~ -s~lbstitutecl-L-arginillamides (~') are repre3ented by the follo~ing formulas:

H ~ / 1 (V~I) \ (I~) \ (CEl2)ncooR2 C~l-(CE12)mC

~ R6 CO~, H-N ~ (~) H-N

COORlo COORll ~ 15 ~C (CH2)J ~ ( xm ) : : : H2)q In the above formulas, Rl, R2, R3~ R4~ RS, R6, R7~ Rg, RloJ Rll, Z, n, m, r, q, i, and j are as defined herein above The amino acid derivatives of the above formula (vm) or (IX) can be prepared by the concdensation of a halo-acetate, 3-halop-oplo~ate or 4-halobutyrate with an ,' .

~ 5 ~
~,, .

.

., : ' :~ , :

;. .

~33~

appropriate amine having the formula Rl~H2 or R3~-~I2.
(See, J. Org. Chem., 2r, 723-732 (1960)).
The condensation reaction i9 generally carried ou-t with-out a sol~ent or :in a solvent, 3UCtl as benzene or ether, ; in the preserIce of an organic base, such as triethylamine or pyricline, at a temperature of O C to ~0 C for a period of 10 minutes to 20 hours. After the reaction is com-ple-te, the formecl amino acid derivative is separated by such conventional means as e~traction with a suitable solvent or evaporation of the reaction solvent and thereafter purified by distillation under reduced pressure.
Among the amino acid derivatives, amino acid tert-butyl ester derivatives are preferred, because they are easily converted to other ester derivatives by acidolysis in the presence of a corresponding alcohol employing an inorganic acid (~ICl, ~I2S04, e-tc.) or an organic acid ; (toluenesulfonic acid, -trifluoroacetic acid, etc.).
In accordance with the process employed for preparing ; 20 2-piperidinecarbo~ylio acid derivatives (~), the follow-ing scheme is illustrative:

.
.

~ .

'~

R7 NaOC ~ ~ ~ R7 ____7 ~ R7 ~I Cl (.YIV) (YV) (~VI) R7 ~l20 ~ ~ R7 N CN (H+) ~ C02H
H H
( XVl C) ( ~Y V:~ ) In -the first reaction of the aforementioned scheme, an appropriately substituted piperidine (.XIV) is contacted with an aqueous sodium hypochlorite solution at a temperature of -5C to 0C. The resultant product (YV) is isolated by extraction with a solvent, e.g., diethyl ether, and then treated ~ith potassium hydro~ide in a lower alkanol solvent to give the 1,2-dehydropiperidine (XVI). The action of cyanogenating agents~ e.g., hydrogen cyanide or sodium cyanide converts the 1J2 :: :
dehydropiperidines (XVI) to the corresponding 2~-cyano analogs (XVII). Hydrolysis o~ the 2-cyanopiperi~dines (XVII) to yield the 2-piperidine;carboxylic acids (XVII) ~ , :
is effected by treatment of the 2-oyanopiperldines (XVII) with an inorganic acid, such as hydrochloric acid or :
sulfuric acid ~ ' ~: .
: ' ~ , .
~ - 52 -': ~ : ': ' :

- - ' 1~3~

The arylsulforLyl halides (~ rhich are the starting materials for the preparation of the ~ -arylsulfonyl-L~argininamides (I) can be prepared by halogenating the recluisite arylsulfonic acids or their salts, e.g., sodium salts, by conventional method~ trell known to those sl;illed in the art In practice, halogenation is carried out without a solvent or in a suitable solvent e.g., halogenated hydrocarbons or D~ in the presence of a halogenating agent, e.g., phosphorous o~ychloride, thionyl chloride, phosphorous trichloride, phosphorous tribromide or phosphorous pentachloride, a-t a temperature of -10 C
to 200C for a period of 5 minutes to 5 hours. ~f-ter the reaction is complete, the reaction product is poured into ice water and then e~tracted with a solvent such as ether, benzene, ethyl acetate, chloroform or the like.
The arylsul~onyl halide can be purified by recrystalli-zation from a suitable solvent such as hexane, benzene ~; 20 or the like.

(b) Removal of the N -substituent from an NG-substituted-N -arylsulfonyl-L-argininamlde This process may be illustrated as follows:

:

~ 53 -- . . , ' ~:
,, ~'. .
, .

C - N -- CH2CH2CH2CHCOR ( V) IEl" HN
R' I
R"' ~LN~ Ar~O~.~ (VII) /C - N - CH2CH2CH2CHCOR (~YI~) ~ 3 l~lN I I
I R" ~H2 R

HN ~
~C - N -- CH2CH2CH2CHCOR (X.Y) HN

R' R" H~102 Ar HN~
~ C - N - CH2CH2CH2CHCOR (I) :` L5 H2N / H HNS02 Ar In the above formulas, R, Ar, Y, R', R"~and R"' are as defined herein above. ~ -The N2-arylsulfonyl-L-argininamide (I) is prepared by removing the NG-substituent from an NG-substltuted-N -arylsulfonyl-L-argininamide (XY) by means of acidolysis : or hydrogenolysis.

~ 54 ~
~a --.
.. -. . .
.
. .
-.. , .

~13~6~

The acidolysis is generally effected by contacting theNG-substituted-~2-arylsulfonyl-L-argininamide (~Y) and an excess of an acid such as hydrogen f`luoride, h~-drogen chloricle, hydrogen bromicle or tritluoroacetic acid, witho-lt a solvent or in a solvent, such as an ether (tetrahydrofuran, clio~ane), an alcohol (methanol, ethanol) or acetic acld at a temperature of -10 C to 100 C, preferably 10 C to 60 C and more preferably at room temperature for a period of 30 minutes to ~4 hours.
The products are isolated by evaporation of the solvent and the e~cess acid, or by -trituration with a suitable solvent followed by filtration and drying.
Because o~ the use of the e.Ycess acid, the products are generally the acid addition salts of the ~ -arylsulfonyl-L-argininamides (I), which can be easily converted to a free amide by neutralization.
The removal of the nitro group and the o~Yycarbonyl group, e.g., benzyloxycarbonyl, p-ni-trobenzyloxycarbonyl, ls readily accomplished by the hydrogenolysis.
At the same time, the ben~yl ester moiety whioh can be included in the R group is converted to the carbo.Yyl group by the hydrogenolysis.
The hydrogenolysis is effected in a reaction-inert solvent, e.g., methanol, ethanol, tetrahydrofuran or q ~ 5~
j - -,~ , .
.

.
.

~ -~!3~6~23l dio.Yane~ in the presellce of a hydrogen-acti~-ating catalyst, e.g., Raney nichel, palladium, or platinum, in a hydrogen atmosphere at a temperature of 0C to the boiling temperature of the solverlt, and preferably 10 C
to ~0C ~or a period of 2 hours to 120 ~lours, The hydrogen pressure is not critical, and atmospheric pressure is sufficient.
The N -arylsulfonyl-L-argininamides (I) are i~olated by filtration of the catalyst followed by evaporation of the solvent The N2-arylsulfonyl-L-argininamides can be purified in the same manner as described above.
The NG-substituted-N -arylsulfonyl-L-argininamides (X~) starting materials can be prepared by condensing an N -substituted-~ -substituted L-arginine (m) (generally the NG-substituent is nitro or acyl, and the ~ -sub-stituent is a protective group for the amino group, such as benzyloxycarbonyl, tert-buto~ycarbonyl, or the like) and a corresponding amino acid derivative (IV), selec-tively removing only the N -substituent of an NG-3ub-stituted-N2-substi-tuted L-argininamide (V) by means of catalytic hydrogenolysis or acidolysis, and then condensing the thus obtained NG-substitu-ted-L-argininamide (XIX) with an arylsulfonyl halide (VII), preferably a :
~` .
~ - 56 -: . , , : .: ~, - . . .. : ' :
. . .
. .

~` ~

chloride in tlle presence of a ba~e in a Sol~-ent~ These reaction conditions are as described abo~e in the con-densation of an L~argininamlcle ~-~ith an arylsulfonyl halidc, and the renlo~-al of the N -sub3titllent from an 3 N -~ubstitutecl-N -aryl~ulfonyl-L-arg~ inamide, (c) Condensation of an N -arylsulfonyl-L-arginyl halide with an amino acid deri~ati~e This process may be illustrated as follows:

HN ~ I
C - N - CH2CH2CH2CHCOOEI(II) -H2N ~

+ ArS02Y (VII) -HN
~15 ~C - N - CH2CH2CH2CHCOOEI(~YI) --~
~HNS02 Ar HN ~ H
H2N ~ CH2CH2CH2CHCOY (~YII) Ar + RH(IV) ~ .

~'~
- :

~.~ - 57 ~
,~

' ' ~- .

~L~
~C - N - CH2CE12CI{2CHCOR (I) ~2 ~r In the above form~llas, R, .~r and ~ are as defined herein above.
The N -arylsulfonyl-L-argininamide (I) is prepared by the condensation of an N -arylsulfonyl-L-arginyl halide (~II), preferably a chloride with at least an equimolar amount of an amino acid derivative (IV).
The condensation reaction can be carried out without an added solvent in the presence of a base. However, satisfactory results will be obtained with -the use of a solvent such as basic solven-ts (dimethylformamide, dimethylacetamide, etc.) or halogenated solvents (chloroform, dichloromethane, etc.) The amount of the solvent to be used is not critical and may vary from about 5 to lO0 times the weight of the N2-arylsu1fonyl-L-arginyl halide (~XII).
~20 Preferred condensa-tion reaction temperatures are in the range of from -lO C to 80 C and preferably from 20 C to to 50C. The reaction time is not critical, but varles ; with the amino acid derivative (IV) employed. In general, ; a period of from 5 minutes to 10 hours is operable.
.

~ ~ 5~ ~
.

, ' ': ~. . -~3~;2~

The obtained N -arylsulfonyl-I,-argin:inamide c~l be iso:Lated and purified in the same manner as described above.
The N -arylsulfonyl-L-arginyl ha:Lide (XXII) starting materials required for the conclensa-tion reaction can be prepared by reacting an N -arylsulfonyl-L-arginine (XXI) ~ith a-t leas-t an equimolar amount o-f a halogenating agen-t such as th;onyl chloride, phosphorous oxychloride, phosphorus trichloride, phosphorous pentachloride or phosphorus tribromide. The halogenation can be carried ou-t with or without an added solven-t.
The pre~erred solvents are chlorinated hydrocarbons such as chloro-form,and dichloromethane, and ethers such as tetrahydrofuran and dioxane.
The amount of the solven-t to be used is not crit:ica:l and may vary from about 5 to 100 times the weight of the N2-arylsulfonyl-L-arginine (XXI).
Preferred reaction temperature is in the range of -1~0 C
to room temperature. The reaction time is no-t critical, but varies with the halogenating agent and reaction temperature. In general, a period of 15 minutes to 5 hours is operable.
The N -arylsulfonyl-L-arginines (XXI) which are the :^ , 59 ~

. ., ,~. . . ~ . ~

' :
I

~ '~
~3~2~l starting materials for the preparation of the ~~-arylsulfonyl-L-argiIlyl halides (Y~II) can be prepared by the condensation of L-arginine (II) with a sub-stantially equimolar amount of arylsulrollyl halides 5 (VII), bv a method slmilar to that clescribed in the condensation of an L-argininamicde with an arylsulfonyl halide.
It is well recogni~ed in the art that an ester derivative of the N -arylsulfonyl-L-argininamide (I) wherein R2, R5 10 R8, Rg, Rlo or Rll is allcyl, aralkyl or aryl can be prepared from a carbocylic acid derivative of the ~ -arylsulfonyl-L-argininamide wherein R2, R5, Rg, Rg, Rlo or Rll is hydrogen, by the conventional esterification methods well known to those skilled in the art. It is 15 also well recognized in the art that -the carbocylic acid derivative can be prepared from the ester deri~-ati~-e by the conventional hydrolysis or acidolysis methods. The conditions under which esterification, hydrolysis or acidolysis would be carried out will be each apparent to 20 those skilled in the art.
: "

~, .... .

. -., - .
, . .

. . ,~
.. . . ..
. :
.

1~3~2~

The N -arylsulfonyl-L-argininanlide (I) of this invention forms acid addition salts with any of a varie-ty of inor~anic and organic acids. Some of the N -arylsulfonyl-L-argininamides containing a free carboxyl group, where.in ~2, R5, Rg, Rg, Rlo or Rll is hydrogen, forms saL-ts with any of` a variety of inorganic ancl organic bases.
The product of the reactions desc:ribed above can be isolated in the free form or in the form of salts. In addition, the product can be obtained as pharmaceutically acceptable acid addition salts by reacting one of the free bases with an acid, such as hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, ci-tric, maleic, succinic, lactic, tartaric, gluconic, benzoic, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic acid or the likc. In a similar manner, the product can be obtained as pharmaceutical:Ly acceptable salts by reac-ting one of the free carboxylic acids wlth a base, such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, triethylamine~
procaine, dibenzylamine, l-ephenamine, N,N'-dibenzylethylene-~20~ diamine, N-ethylpiperidin~ or the lil~e.
; Likewise, treatment of the salts with a base or acid results in a regeneration of -the free amide.
As stated above, the N -arylsulfonyl-L-arginiIlamides, and the salts thereof of this lnventlon are characterized by :
j, ~ .............. ..
: ' ' ~ ~ -" .
~- ~ - 61 --~ . . . .

~J~3~Z~

their highly specific inhibitory activity in mammals against thrombin as well as by their substantial lack of to.Yicity, and therefore these compounds are useful in the determination of thrombin in blood as diagnostic reagents, and/or for the medical control or preventioII of thrombosis.
The compounds of this invention are also useful as an inhibitor of platelet aggregation.
The antithrombotic activity of the N -arylsulfonyl-L-argininamide of this invention was compared with tha-t of a known antithrombo-tic agent, N -(p-tolylsulfonyl)-L-arginine methyl ester, by determining the fibrinogen coagu- -lation time. The measurement of the fibrinogen coagulation time was conducted as follo~s:
~ An 0.8 ml aliquot of a fibrinogen solution, which had been prepared by dissolving 1~0 mg of bovine fibrinogen (Cohn fraction I) supplied by ~rmour Inc. in 40 ml of a borate saline buffer (p~ 7.4), ~as mixed with 0.1 ml of a boraté
saline buffer, pH 7.4, (control) or a sample solution in ~ the sanle buffer, and 0.1 ml of a thrombin solution (5 units/
; 20 ml) supplied by Mochida Pharmaceutical Co., Ltd. was added to the solutions in an ice bath. ~
- Immediately after mixing, the reaction mi~ture was trans-ferred from the ice bath to a bath maintained at 25 C.
Coagulation times were taken as the period between the time ' , ~ ~ - 62 --, .,, ~ . _ _., __ ,, :
' ~ ' , ~3~

of transference to the 25C bat~l ancl the time of -t~le first appearance of f`ibrin threacls. In the cases where no drug samples were addecl, the coagulation time was 50-55 seconds~
The experimen-tal results are summarized in Table l. The term "eoneentration required to prolong the coagulation time by a faetor Or two" is the eoncentration of an active ingredient requlred to prolong the normal coagulation time 50-55 seconds to lO0-:ll0 seconds.
The concentration required to prolong the coagulation time by a factor of two for the known antithrombo-tLc agent, N -(p-tolylsulfonyl)-L~arginine methyl ester, was l,lOO~Lm.
The inhibitors are shown in Table l by indicating R and Ar n the formula (I~ and the addition moiety.
When a solution contain:Lng an N -arylsulfonyl-L-argininamide of this invention was administered intravenously into animal bodies, the high antithrombotlc activity in the oircula-ting blood was maintained for from one to three hours.
The halflife for decay of the antl-thrombotic compo~nds of this invent1on in circulating blood was shown to be appro-~20 ximately 60 minutes; -the physiological conditions of the host animals (rats, rabbit, dog and chlmpanzee) were~well maintained. The experimental decrease of fibrinogen~l~
animals caused by :Lnfusion of thrombin was satisfaetorily ~ controlled by simul-taneous infusion of the compounds of : :
~ ~ - 63 -s ~

~ ' ,~
.

^;

this in~rentiorl.
The acute to~icity values (LD50) determlned by intravenou3 adm:inistration of substances of formula (I) in mice (male, 20 g) range from about 1~0 to 600 milligrams per kilogram of body ~eight.
Representative LDso values for -the compounds of this inven-tion are sho~rn in the follo~ing Table.

Compound H2~ ~ NH (CH~j3CHCoR LDgo (mg/kg) Ar ~NS~r _ ~ OCH2CII~ CH3 -1~ ~ CH3 173 _ .~ O(CH2)3CH3 -1~\ 3 CH3 170 ~ -N ~ C~l3 250 - 300 ~ - 64 -'' .

_ _ . . . _ , . . . _, , .
. . .

:

~3~

Compo~nd ~C - N~ - (CH2)3C~ICOR LD50 (mg/kg) llNS02Ar Ar R

~ ~ 270 ¦ ~ ,C H5 COO}I

~ N \ ~ ~ 260 On the other hand~ LDso values for N ~dansyl-N~butyl~L~
argininamide and N2~dansyl-N-methyl-N-bu-tyl-L~argininamide are less than lO milligrams per kllogram~ respectively.

The therapeutic agents in this invention may be adminis-tered to mammals, including humans, alone or in combination ~i-th pharmaceutically accep-table carriers, the proportion of ~hich is determined by -the solubility and chemical nature ~ of the compound, chosen route of administra-tion and standard :;

~ .
~ 65 ~

- - . . . . _ :'~
'-'~ ' ~3~

pharmaceutical practice.
For e.~ample, the compounds may be injected parenterally, that is, intramuscularly, intravenously or subcu-taneously.
For parenteral administrat:ion, the compounds may be used in the form of sterile solutions containing other Solutes~ ~or e~ample, sufficient saline or glucose to make the solution isotonic. The compounds may be administered orally in the form of -tablets, capsules, or granules containing suitable e~cipients such as starch, lactose, white sugar and -the like.
The compounds may be administered sublingually in the form of troches or lozenges in which each active ingredient is mi~ed with sugar or corn syrups, flavoring agents and dyes, and then dehydrated sufficiently to make the mi~ture suitable for pressing into solid form. The compounds may be ad-ministered orally in the form of solutions which may contain coloring and flavoring agents. Physicians will determine the dosage of the present therapeutic agents which will be most suitable for humans, and dosages vary with the mode of administration and the particular compound chosen. ln addition, the dosage will vary with the particular patient under treatment.
When the composition i5 administered orally, a larger quantity of the active agent wlll be required to produce the same eff-ct as caused with a smaller quan~ity gi~en parenterally.

~ :

. . , : :' .. , . , : -~' , ' ' . , . : -' ' .

~l~L3~%~

The therapeutic dosage is generally 10-50 mg/kg of active ingredient parenterally, 10-500 mg~kg orally per day.
Having generally describecl the invetltion, a more complete ~mderstanding can be obtained by referetlce to certain specific e~amples, ~ihich are :includecl ~or purpoSes of illustration only and are not intended -to be limiting unless other~ise specified.
It is to be understood that the present invention incLudes pharmaceutical compositions containing a compound of the invention as an active ingredient. Such compositions may be in the forms described above. In particuLar, the invention includes such compositions in unit dose form.

~ - 67 -,, . . ~

.

FY ~ ~lP L E

(A) N -(2-dibenzothienylsulfonyl)-L-arginine:
To a ~ell stirred sol~stion of 83.6 g of L-arginine in 800 ml of 10~ pota~sium carbcnate solutiorl was added 112.7 g of 2-dibenzothiophenesulfonyl chloride in 800 ml of benzene. The reaction mi~ture was stirred at 60C for 5 hours, during which time the product precipitated. After one hour at room temperature, the precipitate was filtered and washed successively wi-th benzene and water to give 127 g (76 percent) of ~2-(2-dibenzothienylsulfonyl)-L-arginine.

; (B) N -(2-dibenzothienylsulfonyl)-L-arginyl chloride:
A suspension of 4.21 g of N -(2-dibenzothienylsulfonyl)-L-arginine in 20 ml of thionyl chloride was stirred for 2 hours at room temperature. Addition of cold dry diethyl ether resulted in a precipitate which was collected by filtration and washed several times with dry diethyl ether to give N -(2-dibenzothienylsulfonyl)-L-arginyl chloride.

(C) N -(2-dibenzothienylsulfonyl)-L-arginyl-N-butylglycine tert-butyl ester:
~; ~ To a stirred solu-tion of 2.67 g of N-butylglycine .

.
.
. . .
~ . ~
'~ -' ' . ~

~L~3~6Zl tert-butyl ester in 20 ml of` chloroform ~ras carefully added N -(2-dibenzothienylsulfonyl)-L-arginyl chloride obtained above. The reaction mi~cture ~a~ allo~ed to stand at room temperature f`or one hour.
At the end of` this period, t~le reaction mi.~;ture ~as washed -twice ~ith 20 ml of satura-ted sodium chloride solution and evaporated to dryness.
The residue was triturated with a small amount of - diethyl ether to give an amorphous solid. This was collected by filtration and reprecipitated from ethanol-ethyl ether to give 3.1 g (49 percent) of N --(2-dibenzothienylsulfonyl)-L-arginyl-N-but,vlglycine tert-butyl ester.
I.R. (KBr): 3350, 1740, 1625 cm 1 ~nalysis - Calcd. for C281~l395N5$2 ~H2S3 (P
C, 53.31; H, 6.39; N, 11.10 ~ound (percent):
C, 53.21; H, 6.46; N, 10.89 (D) N -(2-dibenzothienylsulfonyl)-L-arginyl-N-butylglycine:
To a solution of 2.00 g of N -(2-dibenzothienylsulfonyl)--L-arginyl-N-butylglycine tert-butyl ester in 20 ml of chloroform was added 50 ml of l5a~0 HCl-ethyl aoetate.
The reaction mi~cture was stlrred for 5 hours at room temperature. At the end of this period, the reaction :

;~ :

J
:: .
: . -- .---- . . ., _ .
,~ . . : .

, ~L~3~

mi~ture was evaporated to dryness. The residue was washed several times with dry diethyl ether and chromatographed on 80 ml of Daiaion ~ SK 102 ion e~change resin (200-300 mesh, ~[ form, manufactured by ~litsubishi Chemical Industries Limited) pacl;ed in water, ~ashed with water and eluted with 3,~ ammonium hydro~ide solution.
The fraction eluted from 3~p ammonium hydro~ide solution was evaporated to dryness to give 0.9 g (53 percent) of N -(2-dibenzothienylsulfonyl)-L-arginyl-~-butyl-glycine as an amorphous solid, I R. (KBr):
3350, 1640, 1270 cm 1 .~nalysis-Calcd- for C24H31~505S2 (percent) C, 54.01; H, 5.86; N, 13.12 Found (percent):
l; C, 53-78; H, 5.97; N, 12.96 E~A~LE 2 (A) N -(2-dibenzothienylsulfonyl)-L-arginyl-N-(2-methoxy-: ~ :
ethyl)glycine ethyl ester ~
To a stirred solution of 2.42 g of ~-(2-metho~ye-thyl) glycine ethyl ester and 4.0 ml of triethylamine ln 50 ml of chloroform, which was cooled in an ice-salt : . .

- ~ .: .
. - ., , : . -.

: ' - ' ,: , , , ' '` : ' ~3~%1 bath, ~as added in portions 7.0 g of N -(2-di~enzothienyl-sulfonyl)-L-arginyl chloride obtained abo~e. rhe re-action mi~ture t~as stirred overnight at room temperature.
,~t the encl of t~Lis periocl, 50 ml of chloroform was added and the chloroforlll solution t~as t~aslled t~ice ~ith 2~ ml of saturatecl sodium chloride solution~ clried over anhydrous soclium sulfate and evaporated in vacuo. The oily residue ~as t~ashed with ethyl ether to give 5.5 g of powdery N -(2-dibenzothienylsulfollyl)-L-arginyl-N-(2-methoYyethyl)glycine ethyl ester Analysis calcd- for C2sH2306~5S2~ 2 H2S3 (P
C, 50.49; H, 4.07; N, 11.78 Found (percent):
C, 50.22; H, 4.18; N, 11.51 (B) N -(2-dibenzothienylsulfony])-L-arginyl-N-(2-methoYy-ethyl)glycine:
A soIution of 5.5 g of N2-(2-dibenzothienylsulfonYl)-L-arginyl-N-(2-methoxyethyl)glycine e-thyl ester in 1~ ml of methanol and 15 ml of 2N-NaOH solution was warmed to 40 C and held at that temperature for 10 hours. At the end of this period, the reaction mixture was concentrated and chromatographed on 200 mI of Daiaion ~ SK 102 ion exchange resin (200 300 mesh, H formJ manufactured by Mitsubishi Chemical Industries Limited) packed n water, ~ ~ ' ~ .

~ 71 -.
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washecl witll ethano1~ ater (1: 4) and eluted t~ith ethano1-water-N[l40~L (10: 9: 1 ), The main fraction was evaporated to dr~es, and washed ~ith ethyl ether to give 3.05 g (6~ percent) o~ N _ (2-clibenzo l;llien~,-lsu1fotlyl )-L-argillyl-~i-(2-methoY~:ethyl ) glycine QS an amorpho~ls solid. I.R. (KBr): 3400, 1630, 1280 cm 1 r~nalysis-calcd- for C23~I296N5~2 (percent) C, 51.57; H, 5.46; N, 13.08 F`ound (percent~:
C, 51 .35; H, 5 .63; N, 12 .86 - .

E~ lP kE 3 (A) N -nitro-N -( tert-buto.Yycarbony1 ) -L-arginy1-N-bu tyl-glycine be~lzyl ester To a stirred solution of 28.4 g of ~ -nitro-~ -(tert-buto~cycarbonyl)-L-arginine in 450 ml of dry tetrahydro- - -furan were added in turn 12 .4 ml of` triethylamine and 12.4 ml of isobutyl chloroformate while keeping -the ~temperature at -5C. After 15 minutes, t~o this were added 35.0 g of N-buty1glyclne benzyl ester p-toluenesulfonate, l2.4 ml of trlethylamine and~ dry tetrahydrofuran, and then the mi.Yture was stirred for 15 minutes at -5 C. At the end of` this period, the :

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reaction mi.Yture was warmed to room temperatllre. The solvent was evaporated and the residue taken in 400 ml of ethyl acetate, and washed successively with 200 ml of water, 100 ml of 5~ao sodi.um blcarbonace solution, 100 ml of lOao citric acid solution ancl 200 ml of water.
The ethyl acetate solution was dried over an~lydrous sodium sulfate. Upon evaporation of the solvent, the residue was dissolved in 20 ml of chloroform, and the solution was applied to a column (80 cm ~ 6 cnl) of 500 g of silica gel packed in chloroform.
The product was eluted first with chloroform, and then 3~p methanol-chloroform. The fraction eluted from 3~p methanol-chloroform was evaporated to dryness to give 26,0 g (~6 percent) of NG-nitro-N -(tert-buto.Yycarbonyl)-L-arginyl-N-butylglycine benzyl ester in the form of a syrup.
I.R. (KBr): 3300, 1740, 1690 cm 1 (B) N -nitro-L-arginyl-N-butylglycine benzyl ester hydro-chloride:
Z0 To a stirred solution of 26.0 g of NG-nitro-N -(tert-~ buto~ycarbonyl)-L-arginyl-N-butylglycine benzyl ester in ; ~ 50 ml of ethyl acetate was added 80 ml of lO~o dry HCl-; ethyl acetate at 0 C. After 3 hours, to this solution ' ~

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~3~621 ~ias added 200 ml of dry ethyl ether to precipitate a Visco~ls oily procluct.
This ~as filtered and washed ~ith dry ethvl ether to glve 20.8 g of ~G-nitro-L-arginyl-~-butylglycine benzyl ester hydrochloride as an amorphous solid.

(C) NG-nitro-N -(3-cyclohe.eyl-4-methoYyphenylsulfonyl)-L-arginyl-N-butylglycine benzyl ester:
To a stirred solution of 2.33 g of N -nitro-L-arginyl-N-butylglycine benzyl ester hydrochloride in 10 ml of water and 40 ml of dio.~ane were addecl in turn 1.26 g of sodium bicarbonate~ and 2.2 g of 3-cyclohe.Yyl-4-metho.Yyphenylsulfonyl ohloride at 5C, and stirrlng was continued for 3 hours at room temperature. At the end of this period, the solvent was evaporated and the residue dissolved in 100 ml of ethyl acetate, and washed successively ~ith 10 ml of lN hydrochloric acid solution, 20 mI of water, 2~0 ml of~5~0 sodium bicarbonate and lO ml of water. ~ ~
The ethyl acetate solution was dried o~er anhydrous ::: : :
sodium sulfate Upon evaporation of the solvent, the residue was chromatographed on 50 g of silica gel packed in chloroform, washed with chloroform and; eluted with 3~0 methanol-chloroform, The fraction eluted from , ~ ~ 3 - 74 _ :

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3do methanol-chloroform ~as evaporatecl to give 2.6 g (77 percent) of NG-nitro-N -(3-cycloheYyl-~-methoxy-phenylsulfonyl)-L-arginyl-~ butylglycine benzyl ester in the f`orm oî an amorphous 301icl.
I.R. (ICBr): 3300, 2920, 1740, 1640, 1250 cm 1 ~ nalysis-calcd~ for~ C32H4608N6S (percent):
C, 56.95; H, 6.87; N~ 12.46 Found (percent):
C, j6.49; EI, 6.63; N, 12.38 (D) N -(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl-N-butylglycine To a solution of 3.00 g of ~ -nitro-~ -(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl-N-butylglycine benzyl ester in 50 ml of ethanol, 10 ml of acetic acid and 10 ml of water was added 0.5 g of palladium-black and then the mixture was shaken in a hydrogen atmosphere for 50 hours at room temperature. At -the end of this period, the ethanol solution was filtered to remove the catalyst and evaporated to dryness. The residue was washed several times with dry ethyl e-ther and chromato-graphed on 80 ml of Daiaion (~) -SK 102 ion e.Ychange resin (200--300mesh, H+ form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with water, and eluted with 3do ammonium hydroxide solution.

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The fraction eluted from 3/a~ ammonium hydroxide solution was evaporated to dryness to give 1.5 g (72$) o f N2-(3-cyclohexyl-4-metho~phenylsulfonyl)-L-arginyl _~r_ butylglycine as an amorpholli sol:id.
I.R. (I~Br): 3350, 2920~ 1630~ 1250 cm Analysis-CalcCl. for C2~l4lN65Sl (percent) C, 55.63; H, 7.66; N, 12.98 ~ound (percent): C, 55.32; H, 7.39; N, 12.84 E~A~LE 4 (A) Ethyl l-~N -nitro-N -(3-cyclohe~yl-4-methoxyphenyl-sulfonyl)-L-arginyl~-4-methyl-2-piperidinecarboxylate To a well stirred solution of 2 05 g of ethyl l-(N -nitro-L-arginyl)-4~methyl-2-piperidiIIecarbo~ylate hydrochloride and 1.26 g of NaHC03 in 10 ml of water and 40 ml of dioxane, was added in portions 2.2 g of ~ 3-cyclohexyl-4-methoxybenzenesulfonyl chloride, while ; maintaining the temperature at 0 C. The reaction~ ~ mixture was stirred o~ernight at room temperature. At ; ; the end of this period, the reaction mi.xture was evapo-rated to dryness. The residue was taken up in 50 ml of ethyl acetate, and~the ethyl acetate solution was washed .

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consecutively with lO~o citric acid, saturated ~aCl, saturated ~aHC03 and saturated ~aCl solutions. The ethyl acetate solution was evaporated ancl the residue was chromatographed on silica gel packed in chloroform, and eluted from chloroform containing 3~ methanol. The main fraction was evaporated to dryness to give 2.6 g of ethyl l-[NG-nitro-~ -(3-cyclohexyl-4-metho.Yybenzene-sulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate~
I.R. (~Br): 3400, 1735, 1635, 1250 (cm 1) (B) Ethyl l-~N -(3-cyclohe~yl-4-methoxyphenylsulfonyl)-L-arginyl~~4-methyl-2-piperidinecarbo~ylate acetate To a solution of 2.6 g of ethyl l-~NG-nitro-~T -(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl~-4-methyl-2-piperidinecarboxylate in 40 ml of ethanol, 10 ml of water and 20 ml of acetic acid, was added 0.5 g of palladium black and then the mixture was sha~en in a hydrogen atmosphere for 15 hours at room temperature.
The solution was filtered to remove the catalyst and evaporated to give an oily product.
Reprecipitation with ethanol-diethyl ether gave 2.4 g of ethyl l-l~ -(3-cyclohexyl-4-methoxyphenylsulfoIIyl)-L-arginyl~-4-methyl-2-p~peridinecarboxylate acetate.

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( C ) 1- ~N - ( 3-cyclohe.Yyl -4 -metho.Yyphenylsulfonyl~-L--arginyl~--4-methyl~2-piperidineearbo.~cylic acid A solution of 2.4 g of ethyl 1- lN -( 3-cyclohe.~;yl-4-metho.;yphenylsulfonyl)-L-arginyl~ -4-methyl -2-piperidine-earbo.Y~late acetate in 10 ml of` ethallol arld 10 ml of N-NaO~I solution was stirred overnight at room tempera-ture. Then, the reaetion miYture ~as eoneentrated ancl dissolved in 10 ml of water. The solution was neutralized with 2N-HCl solution to glve a white gummy precipitate whieh was dissolved in 150 ml of chloroform. The ehloro-form solution was washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated in vaeuo to give 1 .52 g of l-[N -(3-cyelohe~cyl-4-metho~cy-phenylsulfony1)-L-arginyl~--4-methyl--2-piperidinecarbo~cylic aeid as an amorphous solid.
I.R. (KBr): 3350, 2920, 1620, 1250 em 1 Analysis-calcd- for C26H416N5S (percent):
C, 56.6Q; H, 7.49; N, 12.70 Found (percent):
C, 56.51; H, 7.53; N, 12.68 Various other N -arylsulf`onyl-L-arg1n1namides or aeid .
addition salts thereof were synthesized in aceordance with the proeedures of the above e.Yamp1es, and the test results are summarized in Table 1.
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E~A~lPLE 5 Tablet9 sui-table for oral administration Tablets containing the ingredients indicated belo~ may be prepared by conventlonal techniques~

_ _ _ r~mo~nt per tablet Ingredient (m~) .. ~
N2-(3-cycloheYyl-4-metho,Y~phenylsulfonyl)- 250 L-arginyl-N-butylglycine Lactose 140 Corn starch 35 ralcum 20 ~lagnesium stearate 5 ____ _ _ ._ Total 450 mg E,~LE 6 Capsules for oral administration Capsules of the belo~ ere made up by thoroughly mi.Ying together batches of the ingredients and filling hard gelatin capsules with the mi.~ture.

. _ ~ . . .. _ . Amount per capsule Ingredlent (mg) _ ... . ____ . _ ~
N2-(3 cycloheYyl-4-metho~yphenylsulfonyl)- 250 L-arginyl-N-butylglycine Lactose ` 250 ~ __ _ ~ ~.
Total 5O mg --. . ... .. , . _. __ .

~ -~ 112 -~, . . .. . _ _ ___ , . .. _ . _ . ... ..~ ~ , , . , :

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:: , 1~L31~

E~ PLE 7 Sterile ~olution for infusion rhe follo-~ing ingredients are dissolve-,l i,n ~ater for intravenous perfusion and the resultirlg solutioll is then sterilized, Ingredients ¦Amount (g) N2-(3-cycl.ohe.Yyl-4-methoxyphenylsulfonyl)- _ _ __ _ L-arginyl-~-butylglycine Buffer system As desired Glucose 2~

Distilled water ~00 _ _ PREP~R~TION A

Arylsulfonyl chlorides (A) Sodium 3-butoxy-2,4-dimethoxybenzene sulfonate , To a well stirred solution of ;O.S g of-2-buto.~y-1,3-dimethoxybenzene in 160 ml of carbon tetrachloride was added dropwise 16.1 ml of chlorosulfonic acid at a temperature of O to 4C. The reaction mixture was stirred for one hour at room temperature, poured into crushed ice and then diluted to 300 ml,with water.
Upon evaporation of carbon tetrachloride, the resulting aqueous .

~ ` - 113 -, -~3L3~2~

layer was e.Ytracted with ether and then neutralized with 2~ aO~I solution to precipitate white crystals which were filtered and clried to give 64.3 g (85.1~) of soclium 3-buto.Yy-2~4-dimetho:cybe~lzellesulforlate .

(B) 3-buto .Yy-2, 4 -dinle tho.~ybenzenesul~onyl chlorlcle To a stirred suspension of 60.0 g of dry, powdery sodium 3-buto.~y-2,4-dimetho~yben~enesulfonate in 150 ml of dry dimethylformamide was added dropwide 69 ml of thionyl chloride over a period of 20 minutes at room temperature.
The reaction mi.~ture was stirred for 15 minutes and poured gradually inta 1,000 ml of ice water and stirred vigorously.
After 1 hour, the aqueous layer was decantecl and -the residual oil was e.~tracted wi-th benzene, washed with water, dried over anhydrous sodium sulfate, distilled to remove the solvent and then distilled in vacuo to give 47.5 g (80.1,~o) of 3-buto.cy-2,4-dimetho~ybenzenesulfonyl chloride (Bp 154-5C/l mm Hg) Analysis - Calcd. for C12H15C15S (Percent):
C, 46.68; H, 5.56 ~ound (percent): C, 46.71; H, 5.60 The following arylsulfonyl chlorides not previously reported in the chemical literature were synthesized by the afore-mentioned procedure.
, , .

~ - 114 -. ~

1~L3~621 -- 'Ar - ~02C~ Boiling point No . I Ar ¦ (melting point ) 1 ~ 165-166C/10 mmHg o(c~2)2CH3 (57 ~5 - 58.5 C) 2 ~ 112-115C/l mmHg : ~ O(CK2)3C~l3 (33 - 35 C) '~` C~3 3 OCH2CH2CH\ 127-129 C/0.5 mm~Ig _ _ I

4 ~ 148-150 C/l mn~Ig : (CH2 )L~CH3 :
; ~

~ (CH2 ) 3C~3 (48 7l~ ) .;~ ; - ~ ' '~ :

6 [~CH2CH~CH3 ( 41 -- 2 C ) ~ :' ~ ~j - 115 -~3~6~

-~r - ~O~Cl. Boiling point No. ~r (melting point) C \Cff2cH3 139-l~lO C/1 ml~l8
8 ~ CH3 129.5-132 C/l mmHg oCH3CH3 L ` ~ 2) rll~ 14g-l48c/l mm~lg 10 ~ (CH2)-'~CH3 151.5-153.5 C/].. 5 mmHg :; ' : _ .
: 11 ~ CH3 155-1~6 C/2 ~mHg L~2~:~2U~ (44 - 4gc) ,.
~ f - 116 -- ' ,, '~' ' , 1~L3~6;~

.,~r - S02Cl l~oiling point ~o . ___( mel ting point ) .... _ 13 ~ Cl-l3 187 C /1 m~lg OC~12C~{2CE-I2CE~3 ,.. _ __ 14 ~ OCH3 198-200 C/2 mmHg OCH 3 - ---¦

~ OCH3 210-220C/1 mmHg -: OCH 3 .- .

16 ~ 0(CH2 )2CH3 160-162 C/2 mmHg . ~

~ ~ 17 [~ (CH2 )3Cl~I3 154-1g5 ~ /1 mmHg : ; OCH3 ~

1, 0~ /2 mmHg Y. ~., .

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Ar -- S02ClBoiling point ~o. Ar (melting point) 19 ~ ()(C}12 ) 5C113183-18~C/l mmHg OCI{

~ OCH2CI-120C~13 ( 46 ~ 47 C ) 21 ~ $t C~2)3CH3 ~ 131 C/l mmHe O(CH2 )2CH3 22 ~ OCH3 (65 - 66~C ) : ' _ _ ,, O ( CH2 ) 3CH 3 2 3 ~ O ( CH2 ) 3CH 3 ( 3 0 - 32 C ) . ~ O ( CHz ) 3CH 3 24 ~ 208-210 C/l mmHg O ( C H2 ) 3CH 3 :

~, - 118 - .

:

.. . .

' .. . .
, ' : .' ' '~ , -;~-o. i~r ~ ~02Cl ~ Boiling point ~r (mel ting point ) O ( CE12 ) 3C H 3 2 g /~ ~9 C, 2 mmtLg .O ( CEI2 ) 3C~l 3 _ 26 ~cO(cH2 )2CH3 Oily sub3tance .

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Z ~ .\ Oily substance 29 ~\ OC2HS 109-110C/1 .5 mmHg ~, ~ 116~ /I mmHg ,~
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.~r - ~02Cl Boiling point `lo. ~r (meltin~ point) 31 (~ CH3 Oily ~bs tance OCHCH ~CH3 __ . .

32 ~ C H2 C~ O l l y s u b s t an c e 2-153C/2 mmHg ~` Ls ~; 133-1340C/lmmg L~ 2-143C/l mmIg .

.. _ . ... , , _ . , _ _ _ _ _ .. . _ _ _ _ _ ~ ....

~,' '" . ' . ' ' ' , , ~3162~

j .~r ~ `~2Cl ¦Boiling point ~o. I ~r ¦(m~lting point) ~7 ~ OC l-l5 121-122C ,;l mmilg _ 38 ~ 2 )2CH ~ l33-l35 C jl mm~lg _ c~ 3 CH

39 -$0 H / 3 136-139 C/l rnmHg . .

~t;

41 ~ \ CH3 ( lO] - 103 C j :
~, (CH2 )2CH3 42 ~(CH2)2cH3 142 144 C~l mmHg .
;~ ' ~ l - 121 -',~`~, ' : '`

': :
:

,: ;

3~L~21 ~r - SO2Cl Boiling point ~r ( mel ting poin t ) ... ... _ __ __ : ~~ 1~ ~ tl~ ; lg8-~6o C/l mm~le OCH 3 _ -~ ~

f ~ 2C/l mm~6 47 ~ ~;~C}I3 158--159 C/l: mrrlHg _ OCH3 3 ~

~ ' ~ - 122 -_.... . . __ . _ .:
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Having no~i fully described the invention, it ~ill be apparent to one of ordinary skill in the ~rt that many changes and modifications can be made thereto ~ithout departin~ from the spirit of the in~ention as set fortll ~lerein.

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Claims (50)

the embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows 1 A process for preparing an N2-arylsulfonyl-L-argininamide of formula:

(I) and the pharmaceutically acceptable salts thereof wherein R is selected from the group consisting of (1) - wherein R1 is selected from the group consisting of C2-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C2-C10 alkoxyalkyl, C2-C10 alkylthioalkyl, C2-C10 alkylsulfinyl-alkyl, C1-C10 hydroxyalkyl, C3-C10 alkoxycarbonylalkyl, C3-C10 alkylcarbonylalkyl, C1-C10 haloalkyl, C7-C15 aralkyl, C8-C15 .alpha.-carboxyaralkyl, C3-C10 cycloalkyl, C4-C10 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl optionally substituted with at least one C1-C15 alkyl, C1-C5 alkoxy or mixtures thereof, 3-furylmethyl, tetrahydro-3-furylmethyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, tetrahydro-2(3 or 4)-pyranylmethyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, 1,4-dioxa-2-cyclohexylmethyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, and tetrahydro-3-thenyl; R2 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl and n is an integer of 1, 2 or 3, (2) - wherein R3 is selected from the group consisting of hydrogen, C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C2-C10 alkoxyalkyl, C2-C10 alkylthioalkyl, C2-C10 alkylsulfinylalkyl, C1-C10 hydroxyalkyl, C3-C10 alkoxycarbonylalkyl, C3-C10 alkylcarbonylalkyl, C1-C10 haloalkyl, C7-C15 aralkyl, C8-C15 .alpha. -carboxyaralkyl, C3-C10 cycloalkyl, C4-C10 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, 3-furylmethyl, tetrahydro-3-furylmethyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, tetrahydro-2(3 or 4)-pyranylmethyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, 1,4-dioxa-2-cyclohexyl-methyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, and tetrahydro-3-thenyl; R4 is selected from the group consisting of C1-C10 alkyl, phenyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, C7-C12 aralkyl and ring substituted benzyl wherein said substituent is C1-C5 alkyl or C1-C5 alkoxy; R5 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl;
and m is an integer of 0, 1 or 2 (3) - wherein R6 is -COOR8 wherein R8 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; each R7 independently is hydrogen, C1-C10 alkyl; phenyl, C1-C5 alkoxy, C2-C6 alkoxycarbonyl or carboxy; p is an integer of 1 to 4; R6 is substituted at the 2 or 3-position; and R7 can be substituted at the 2, 3, 4, 5 or 6-position, (4) - optionally substituted with at lesat one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, wherein R9 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; and r is an integer of 1, 2, 3 or 4, (5) - ;:

wherein R10 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; Z

is selected from the group consisting of oxy, thio and sulfinyl; and q is an integer of 0 or 1, and (6) wherein R11 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; i is an integer of 0, 1 or 2; j is an integer of 0, 1 or 2;
and the sum of i + j is an integer of 1 or 2; and Ar is a phenyl or naphthyl group, either substituted with at least one substituent selected from the group consisting of sulfoamino, carbamoyl, C3-C10 N,N-dialkylcarbamoyl C2-C6 N-alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxy, C2-C10 alkoxycarbonyl, C2-C10 carboxyalkyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy and phenyl optionally substituted with at least one hydroxy, C1-C5 alkoxy, or mixtures thereof;
a phenyl ornaphthyl group, either substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy and C2-C20 dialkylamino, and at least one substituent selected from the group consisting of sulfoamino, carbamoyl, C3-C10 N,N-dialkylcarbamoyl, C2-C6 N-alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxy, C2-C10 alkoxy-carbonyl, C2-C10 carboxyalkyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkaxy and phenyl optionally substituted with at least one hydroxy, C1-C5 alkoxy, or mixtures thereof;
an oxanthrenyl or dibenzofuranyl group substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C2-C20 dialkylamino, sulfoamino, carbamoyl, C3-C10 N,N-dialkylcarbamoyl, C2-C6 N-alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxyl, C2-C10 alkoxycarbonyl, C2-C10 carboxyalkyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy, and phenyl optionally substituted with at least one hydroxy, C1-C15 alkoxy, or mixtures thereof;
an oxanthrenyl or dibenzofuranyl group substituted with at least ane substituent selected from the group consisting of C1-C10 alkyl and C1-C10 alkoxy, and at least one substituent selected from the g:roup consisting of halo, nitro, cyano, hydroxy, C2-C20 dialkylamino, sulfoamino, carbamoyl, C3-C10 N,N-dialkylcarbamoyl, C2-C6 N-alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxyl, C2-C10 alkoxy-carbonyl, C2-C10 carboxyalkyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy and phenyl optionally substituted with at least one hydroxy, C1-C5 alkoxy, or mixtures thereof;
a tetrahydronaphthyl, 1,2-ethylenedioxyphenyl, chromanyl, 2,3-ethylenedioxyanphthyl or xanthenyl group any substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C2-C20 dialkylamino, sulfoamino, carbamoyl, C3-C10 N,N-dialkylcarbamoyl, C2-C6 N-alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxyl, C2-C10 alkoxycarbonyl, C2-C10 carboxyalkyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxy-alkyl, C1-C10 haloalkyl, C1-C10 hydroxylalkoxy, oxo and phenyl optionally substituted with at least one hydroxy, C1-C5 alkoxy, or mixtures thereof;
a tetrahydronaphthyl, 1,2-ethylenedioxyphenyl, chromanyl, 2,3-ethylenedioxynaphthyl or xanthenyl group, any substituted with at least one substituent selected from the group consisting of C1-Clo alkyl and C1-C10 alkoxy, and at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C2-C20 dialkylamlno, sulfoamino, carbamoyl, C3-C10 N,N-dialkylcarbamoyl, C2-C6 N-alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxyl, C2-C10 alkoxycarbonyl, C2-C10 carboxyalkyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy, oxo and phenyl optionally substituted with at least one hydroxy, C1-C5 alkoxy, or mixtures thereof;
a naphthoquinonyl, anthryl, phenanthryl, pentalenyl, heptalenyl, azulenyl, biphenylenyl, as-indacenyl, S-indacenyl, acenaphthylenyl, phenylcarbonylphenyl, phenoxyphenyl, benzofuranyl, isobenzofuranyl, benzo (b) thienyl, isobenzothienyl, thianthrenyl, dibenzothienyl, phenoxathiinyl, indolyl, lH-indazolyl, quinolyl, isoquinolyl, phthalazinyl, 1,8-naphthridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl or benzimidazolyl group any of which is unsubstituted or substituted with one or more groups selected from the group consisting of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy, C2-C20 dialkylamino, sulfoamino, carbamoyl, C3-C10 N,N-dialkylcarbamoyl, C2-C6 N-alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxyl, C2-C10 alkoxycarbonyl, C2-C10 carboxyalkyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy and phenyl optionally substituted with at least one hydroxy, C1-C5 alkoxy, or mixtures thereof;
a C7-C12 aralkyl, C9-C16 cycloalkylphenyl, C19-C18 cycloalkylalkylphenyl, C9-C16 cycloalkyloxyphenyl, C9-Cl6 cycloalkylthiophenyl, 9,10-dihydroanthryl, 5,6,7,8-tetrahydroanthryl, 9,10-dihydrophenanthryl,
1 2,3,4,5,6,7,8-octahydrophenanthryl, indenyl, indanyl, fluorenyl, acenaphthenyl, phenylthiophenyl, isochromanyl, 2,3-dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, thioxanthenyl, 2H-chromenyl, 3,4-dehydro-1-isochromanyl, 4H-chromenyl, indolinyl, isoindolinyl, 1,2,3,4-tetrahydroquinolyl or 1,2,3,4-tetrahydroisoquinolyl group any of which is unsubstituted or substituted with one or more groups selected from the group consisting of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy, C2-C20 dialkylamino, sulfoamino, carbamoyl, C3-C10 N,N-dialkylcarbamoyl, C2-C6 N-alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxyl,C2-C10 alkoxycarbonyl, C2-C10 carboxyalkyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy, oxo and phenyl optionally substituted with at least one hydroxyl, C1-C5 alkoxy, or mixtures thereof; or a phenyl group substituted with at least one substituent selected from the group consisting of alkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkyl and alkoxycarbonylalkoxy, the said substituent containing 3 to 7 carbon atoms and the said substituted phenyl group being optionally substituted further with at least one substituent selected from the group consisting of methyl, ethyl, methoxy, ethoxy, hydroxy and halo, comprising:
reacting a compound of the formula:

wherein R is as defined above with an arylsulfonyl halide compound.
2. An N2 arylsulfonyl-L-argininamide of the formula (I) and the pharmaceutically acceptable salts thereof, wherein R and Ar are as defined in claim 1, whenever prepared by the process of claim 1 or the obvious chemical equivalent thereof.
3. A process for preparing an N2 arylsulfonyl L-argininamide of formula (I):

(I) and the pharmaceutically acceptable salts thereof wherein R is selected from the group consisting of (1) - wherein R1 is selected from the group consisting of C2-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C2-C10 alkoxy-alkyl, C2-C10 alkylthioalkyl, C2-C10 alkylsulfinylalkyl, C1-C10 hydroxyalkyl, C3-C10 alkoxycarbonylalkyl, C3-C10 alkylcarbonylalkyl, C1-C10 haloalkyl, C7-C15 aralkyl, C8-C15 .alpha. -carboxyaralkyl, C3-C10 cycloalkyl, C4-C10 cyclo-alkylalkyl, furfuryl, tetrahydrofurfuryl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, 3-furylmethyl, tetrahydro-3-furylmethyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, tetrahydro-2(3 or 4)-pyranylmethyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, 1,4-dioxa-2-cyclohexylmethyl opt1onally substituted with at least one Cl-C5 alkyl, Cl-C5 alkoxy or mixtures thereof, 2-thenyl, 3-thenyl, tetrahydro Z-thenyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, and tetrahydro-3-thenyl;
R2 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; and n is an integer of 1, 2 or 3, (2) - wherein R3 is selected from the group consisting of hydrogen, C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C2-C10 alkoxyalkyl, C2-C10 alkylthioalkyl, C2-C10 alkylsulfinylalkyl, C1-C10 hydroxyalkyl, C3-C10 alkoxycarbonylalkyl, C3-C10 alkylcarbonylalkyl, C1-C10 haloalkyl, C7-C15 aralkyl, C8-C15 .alpha. -carboxyaralkyl, C3-C10 cycloalkyl, C4-C10 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl optionally substituted with at least one 11-C5 alkyl, C1-C5 alkoxy or mixtures thereof, 3-furylmethyl, tetrahydro-3-furylmethyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, tetrahydro-2(3 or 4)-pyranylmethyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, 1 4-dioxa-2-cyclohexyl-methyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl optionally subtituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, and tetrahydro-3-thenyl; R4 is selected from the group consisting of C1-C10 alkyl, phenyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, C7-C12 aralkyl and ring substituted benzyl wherein said substituent is C1-C5 alkyl or C1-C5 alkoxy; R5 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl;
and m is an integer of 0, 1 or 2 (3) wherein R6 is -COOR8 wherein R8 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; each R7 independently is hydrogen, C1-C10 alkyl; phenyl, C1-C5 alkoxy, C2-C6 alkoxycarbonyl or carboxy; p is an integer of 1 to 4; R6 is substituted at the 2 or 3-position; and R7 can be substituted at the 2, 3, 4, 5 or 6-position, (4) optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, wherein R9 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; and r is an integer of 1, 2, 3 or 4, (5) - wherein R10 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; Z
is selected from the group consisting of oxy, thio and sulfinyl; and q is an integer of O or 1, and (6) wherein R11 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; i is an integer of 0, 1 or 2; j is an integer of 0, 1 or 2;
and the sum of i + j is an integer af 1 or 2; and Ar is a phenyl or naphthyl group, either substituted with at least one substituent selected from the group consisting of sulfoamino, carbamoyl, C3-C10 N,N-dialkylcarbamoyl, C2-C6 N-alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxy C2-C10 alkoxy-carbonyl, C2-C10 carboxylalkyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy and phenyl optionally substituted with at least one hydroxy, C1-C5 alkoxy, or mixtures thereof;
a phenyl or naphthyl group, either substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy and C2-C20 dialkylamino, and at least one substituent selected from the group consisting of sulfoamino, carbomoyl, C3-C10 N,N-dialkylcarbamoyl, C2-C6 N-alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxy, C2-C10 alkoxy-carbonyl, C2-C10 carboxyalkyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy and-phenyl optionally substituted with at least one hydroxy, C1-C5 alkoxy, or mixtures thereof;
an oxanthrenyl or dibenzofuranyl group substituted:
with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C1-C20 dialkylamino, C2-C6 N-alkylcarbamoyl, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C2-C10 alkoxycarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl and C1-C10 hydroxyalkoxy;
an oxanthrenyl or dibenzofuranyl group substituted with at least one substituent selected from the group consisting of C1-C10 alkyl and C1-C10 alkoxy, and at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C2-C20 dialkylamino, C2-C6 N-alkylcarbamoyl, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C2-C10 alkoxycarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl and C1-C10 hydroxyalkoxy;
a tetrahydronaphthyl, 1,2-ethylenedioxyphenyl, chromanyl, 2,3-ethylenedioxynaphthyl or xanthenyl group, any substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C2-C20 dialkylamino, C2-C6 N-alkylcarbamoyl, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C2-C10 alkoxycarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy, and oxo; a tetrahydronaphthyl 1,2-ethylenedioxyphenyl, chromanyl, 2,3-ethylenedioxynaphthyl or xanthenyl group, any substituted with at least one substituent selected from the group consisting of C1-C10 alkyl and C1-C10 alkoxy, and at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C2-C20 dialkylamino C2-C6 N-alkylcarbamoyl, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C2-C10 alkoxycarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy, and oxo;
an anthryl, phenanthryl, biphenylenyl, S-indacenyl, phenylcarbonylphenyl, phenoxyphenyl, benzofuranyl, benzo (b) thienyl, thianthrenyl, dibenzothienyl, phenoxathiinyl, quinolyl, lsoquinolyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl group any of which is unsubstituted or substituted with one or more groups selected from the group consisting of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy, C2-C20 dialkylamino and C1-C10 hydroxyalkoxy;
a C7-C12 aralkyl, C9-C16 cycloalkylphenyl, C10-C18 cycloalkylalkylphenyl, C9-C16 cycloalkyloxyphenyl, 9,10-dihydroanthryl, 5,6,7,8-tetrahydroanthryl, 9,10-dihydrophenanthryl, 1,2,3,4,5,6,7,8-octahydrophenanthryl, indenyl, indanyl, fluorenyl, acenaphthenyl, phenylthio-phenyl, 2,3-dihydrobenzofuranyl, thioxanthenyl, 2H-chromenyl or 1,2,3,4-tetrahydroquinolyl group any of which is unsubstituted or substituted with one or more groups selected from the group consisting of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy, C2-C20 dialkylamino, C2-C6 N-alkylcarbamoyl, C1-C10 hydroxyalkoxy, and oxo;
or a phenyl group substituted with at least one substituent selected from the group consisting of alkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkyl and alkoxycarbonylalkoxy, the said substituent containing 3 to 7 carbon atoms and the said substituted phenyl group being optionally substituted further with at least one substituent selected from the group consisting of methyl, ethyl, methoxy, ethoxy, hydroxy and halo, comprising reacting a compound of the formula:

wherein R is as defined above with an arylsulfonyl halide compound.
4. An N2 arylsulfonyl-L-argininamide compound of the formula (I) and the pharmaceutically acceptable salts thereof wherein R and Ar are as defined 1n claim 3, whenever prepared by the process of claim 3 or an obvious chemical equivalent thereof.
5. A process for preparing an N2 arylsulfonyl-L
argininamide of formula (I):

(I) and the pharmaceutically acceptable salts thereof wherein said R is selected from the group consisting of (1) - wherein R1 is selected from the group consisting of C2-C10 alkyl, C3-C10 alkenyl, C2-C10 alkoxyalkyl, C2-C10 alkylthioalkyl, C2-C10 alkylsulfinylalkyl, C7-C15 aralkyl, C3-C10 cycloalkyl, C4-C10 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl, tetrahydro-2(3 or 4)-pyranylmethyl and 1,4-diqxa-2-cyclohexylmethyl; R2 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; and n is an integer of 1, 2 or 3, (2) - wherein R3 is selected from the group consisting of hydrogen, C1-C10 alkyl, C3-C10 alkenyl, C2-C10 alkoxy-alkyl, C2-C10 alkylthioalkyl, C2-C10 alkylsulfinylalkyl, C7-C15 aralykl, C3-C10 cycloalkyl, C4-C10 cycloalkyl-alkyl, furfuryl, tetrahydrofurfuryl, tetrahydro-2(3 or 4)-pyranylmethyl and 1,4-dioxa-2-cyclohexylmethyl; R4 is selected from the group consisting of C1-C10 alkyl, phenyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, C7-C12 aralkyl and ring substituted benzyl wherein said substituent is C1-C5 alkyl or C1-C5 alkoxy; R5 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; and m is an integer of O, 1 or 2 (3) wherein R6 is -COOR8 wherein R8 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; each R7 independently is hydrogen, C1-C10 alkyl or phenyl; p is an integer of 1 to 4; R6 is substituted at the 2 or 3-position; and R7 can be substituted at the 2, 3, 4, 5 or 6-position, (4) optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, wherein R9 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl: and r is an integer of 1, 2, 3 or 4, (5) - wherein R10 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; Z
is selected from the group consisting of oxy, thio and sulfinyl; and q is an integer of O or 1, and (6) wherein R11 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 arallkyl;
i is an integer of 0, 1 or 2; j is an integer of 0, 1 or 2; and the sum of i + j is an integer of 1 or 2; and said Ar is a phenyl or naphthyl group, either substituted with at least one substituent selected from the group consisting of amino, C1-C10 alkylamino, C1-C10 alkylthio, C7-C12 aralkyl, C2-C10 alkoxycarbonyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 hydroxyalkoxy and phenyl; and wherein said Ar is;
a phenyl or naphthyl group, either substituted with at least one substituent selected from the group consisting of amino, C1-C10 alkylamino, C1-C10 alkylthio, C7-C12 aralkyl, C2-C10 alkoxycarbonyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 hydroxylalkoxy and phenyl, and at least one substituent selected from the group consisting of halo, hydroxy, C1-C10 alkyl, C1-C10 alkoxy and C2-C20 dialkylamino;
a dibenzofuranyl group substituted with at least one substituent selected from the group consisting of halo;
a dibenzofuranyl group substituted with at least one substituent selected from the group consisting of C1-C10 alkyl and C1-C10 alkoxy, and at least one substituent selected from the group consisting of halo;
a tetrahydronaphthyl, 1,2-ethylenedioxyphenyl, chromanyl, 2,3-ethylenedioxynaphthyl or xanthenyl group, any substituted with at least one substituent selected from the group consisting of halo;
a tetrahydronaphthyl, 1,2-ethylenedioxyphenyl, chromanyl, 2,3-ethy1enedioxynaphthyl or xanthenyl group, any substituted with at least one substituent selected from the group consisting of C1-C10 alkyl and C1-C10 alkoxy, and at least one substituent selected from the group consisting of halo;
an anthryl, phenanthryl, biphenylenyl, phenoxyphenyl, benzofuranyl, benzo (b) thienyl, dibenzothienyl, phenoxathiinyl, quinolyl, isoquinolyl, quinoxalinyl, acridinyl or phenazinyl group any of which is unsubstituted or substituted with one or more groups selected from the group consisting of halo, hydroxy, C1-C10 alkyl, C1-C10 alkoxy and C1-C10 hydroxyalkoxy;
a C7-C12 aralkyl, C9-C16 cycloalkylphenyl, fluorenyl, thioxanthenyl, 2H-chromenyl, or 1,2,3,4-tetrahydroquinolyl group any of which is unsubstituted or substituted with one or more groups selected from the group consisting of C1-C10 alkyl, C1-C10 alkoxy and oxo;
or a phenyl group substituted with at least one substituent selected from the group consisting of alkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkyl and alkoxycarbonylalkoxy, the said substituent containing 3 to 7 carbon atoms and the said substituted phenyl group being optionally substituted further with at least one substituent selected from the group consisting of methyl, ethyl, methoxy, ethoxy, hydroxy and halo; comprising: reacting a compound of the formula:

wherein R is as defined above with an arylsulfonyl halide compound.
6. An N2 arylsulfonyl-L-argininamide of the formula (I) and the pharmaceutically acceptable salts thereof, wherein R and Ar are as defined in claim 5, whenever prepared by the process of claim 5 or an obvious chemical equivalent thereof.
7. A process for preparing an N2 arylsulfonyl-L-argininamide of formula (I):

and the pharmaceutically acceptable salts thereof wherein R is selected from the group consisting of:

(1) - wherein R1 is selected from the group consisting of C2-C10 alkyl,C2-C6 alkoxyalkyl, C2-C6 alkylthioalkyl, C7-C10 aralkyl C4-C10 cycloalkylalkyl, furfuryl and tetrahydrofurfuryl; R2 is hydrogen or C1-C10 alkyl; and n is an integer of 1, 2 or 3, (2) wherein R3 is selected from the group consisting of hydrogen, C1-C10 alkyl, C2-C6 alkoxyalkyl, C2-C6 alkylthioalkyl, C7-C10 aralkyl, C4-C10 cycloalkylakl, furfuryl and tetrahydrofurfuryl; R4 is C1-C5 alkyl; R5 is hydrogen or C1-C10 alkyl; and m is an integer of 0, 1 or (3) wherein R6 is -COOR8 wherein R8 is hydrogen or C1-C10 alkyl; each R7 independently is hydrogen or C1-C6 alkyl;
p is an integer of 1 to 4 R6 is substituted at the 2 or 3-position; and R7 can be substituted at the 2, 3, 4, 5 or 6-position, (4) optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, wherein R9 is hydrogen or C1-C10 alkyl; and r is an integer of 1, 2, 3 or 4, (5) wherein R10 is hydrogen or C1-C10 alkyl; Z is selected from the group consisting of oxy, thio and sulfinyl; and q is an integer of 0 or 1, and (6) -wherein R11 is hydrogen or C1-C10 alkyl; i is an integer of 0, 1 or 2; j is an integer of 0, 1 or 2; and the sum of i + j is an integer of 1 or 2; and said Ar is a phenyl or naphthyl group, either substituted with at least one substituent selected from the group consisting of amino, C1-C10 alkylamino, C7-C12 aralkyl, C1-C10 acylamino, C1-C10 hydroxyalkyl, and Cl-C10 hydroxyalkoxy;
a phenyl or naphthyl group, either substituted with at least one substituent selected from the group consisting of amino, C1-C10 alkylamino, C7-C12 aralkyl, C1-C10 acylamino, C1-C10 hydroxyalkyl and C1-C10 hydroxyalkoxy and at least one substituent selected from the group consisting of halo, hydroxy, C1-C10 alkyl and C1-C10 alkoxy;
a biphenylenyl, phenoxyphenyl, dibenzothienyl, phenoxathiinyl, quinolyl, or quinoxalinyl group any of which is unsubstituted or substituted with one or more groups selected from the group consisting of hydroxy and C1-C10 alkyl;
a C7-C12 aralkyl, C9-Cl6 cycloalkylphenyl, fluorenyl, or 2H-chromenyl group any of which is unsubstituted or substituted with one or more groups selected from the group consisting of C1-C10 alkyl, C1-C10 alkoxy and oxo;
or a phenyl group substituted with at least one substituent selected from the group consisting of alkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkyl and alkoxycarbonylalkoxy, the said substituent containing 3 to 7 carbon atoms and the said substituted phenyl group being optionally substituted further with at least one substituent selected from the group consisting of methyl, ethyl, methoxy, ethoxy, hydroxy and halo, comprising:
reacting a compound of the formula:

wherein R is as defined above with an arylsulfonyl halide compound.
8. An N2 arylsulfonyl-L-argininamide of the formula (I) and the pharmaceutically acceptable salts thereof, wherein R and Ar are as defined in claim 7, whenever prepared by the process of claim 7 or an obvious chemical equivalent thereof.
9. A processing for preparing an N2 arylsulfonyl-L-argininamide of formula (I):

(I) and the pharmaceutically acceptable salts thereof, wherein R is selected from the group consisting of ( 1 ) wherein R1 is selected from the group consisting of C2-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C2-C10 alkoxyalkyl, C2-C10 alkylthioalkyl, C2-C10 alkylsulfinyl-alkyl, C1-C10 hydroxyalkyl, C3-C10 alkoxycarbonylalkyl, C3-C10 alkylcarbonylalkyl, C1-C10 haloalkyl, C7-C15 aralkyl, C8-C15.alpha. -carboxyaralkyl, C3-C10 cycloalkyl, C4-C10 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, 3-furylmethyl, tetrahydro-3-furylmethyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, tetrahydro-2(3 or 4)-pyranylmethyl optionally substituted witll at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, 1,4-dioxa-2-cyclohexylmethyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, and tetrahydro-3-thenyl; R2 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl;
and n is an integer of 1, 2 or 3, (2) wherein R3 is selected from the group consisting of hydrogen, C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C2-C10 alkoxyalkyl, C2-C10 alkylthioalkyl, C2-C10 alkylsulfinylalkyl; C1-C10 hydroxyalkyl, C3-C10 alkoxycarbonylalkyl, C3-C10 alkylcarbonylalkyl, C1-C10 haloalkyl, C7-C15 aralkyl, C8-C15.alpha.-carboxyaralkyl, C3-C10 cycloalkyl, C4-C10 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, 3-furylmethyl, tetrahydro-3-furylmethyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, tetrahydro-2(3 or 4)-pyranylmethyl optionally substituted with at least one Cl-C5 alkyl, C1-C5 alkoxy or mixtures thereof, 1,4-dioxa-2-cyclohexyl-methyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl optionally substituted with at least on C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, and tetrahydro-3-thenyl; R4 is selected from the group consisting of C1-C10 alkyl, phenyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, C7-C12 aralkyl and ring substituted benzyl wherein said substituent is C1-C5 alkyl or C1-C5 alkoxy; R5 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl;
and m is an integer of 0, 1 or 2 ( 3 ) wherein R6 is -COOR8 wherein R8 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; each R7 independently is hydrogen, C1-C10 alkyl; phenyl, C1-C5 alkoxy, C2-C6 alkoxycarbonyl or carboxy; p is an integer of 1 to 4; R6 is substituted at the 2 or 3-position; and R7 can be substituted at the 2, 3, 4, 5 or 6-position, (4) optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, wherein R9 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; and r is an integer of 1, 2, 3 or 4, (5) wherein R10 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; Z

is selected from the group consisting of oxy, thio and sulfinyl; and q is an integer of 0 or 1, and (6) wherein R11 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl, i `
is an integer of 0, 1 or 2; j is an integer of 0, 1 or 2;
and the sum of i + j is an integer of 1 or 2 and Ar is a phenyl or naphthyl group, either substituted with at least one substituent selected from the group consisting of sulfoamino, carbamoyl, C3-C10 N,N-dialkylcarbamoyl, C2-C6 N-alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxy, C2-C10 alkoxycarbonyl, C2-C10 carboxyalkyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy and phenyl optionally substituted with at least one hydroxy, C1-C5 alkoxy, or mixtures thereof;
a phenyl or naphthyl group, either substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy and C2-C20 dialkylamino, and at least one substituent selected from the group consisting of sulfo-amino, carbamoyl, C3-C10 N,N-dialkylcarbamoyl, C2-C6 N-alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxy, C2-C10 alkoxy-carbonyl, C2-C10 carboxyalkyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C-10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy and phenyl optionally substituted with at least one hydroxy, C1-C5 alkoxy, or mixtures thereof;
an oxanthrenyl or dibenzofuranyl group substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C2-C20 dialkylamino, sulfoamino, carbamoyl, C3-C10 N,N-dialkylcarbamoyl, C2-C6 N-alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxyl, C2-C10 alkoxycarbonyl, C2-C10 carboxyalkyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy, and phenyl optionally substituted with at least one hydroxy, C1-C5 alkoxy, or mixtures thereof;
an oxanthrenyl or dibenzofuranyl group substituted with at least one substituent selected from the group consisting of C1-C10 alkyl and C1-C10 a1koxy, least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C2-C20 dialkylamino, sulfoamino, carbamoyl, C3-C10 N,N-dialkylcarbamoyl, C2-C6 N-alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxyl, C2-C10 alkoxy-carbonyl, C2-C10 carboxyalkyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy and phenyl optionally substituted with at least one hydroxy, C1-C5 alkoxy, or mixtures thereof, a tetrahydronaphthyl, 1,2-ethylenedioxyphenyl, chromanyl, 2,3-ethylenedioxynaphthyl or xanthenyl group, any substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C2-C20 dialkylamino, sulfoamino, carbamoyl, C3-C10 N,N-dialkylcarbamoyl, C2-C6 N-alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxyl, C2-C10 alkoxycarbonyl, C2-C10 carboxyalkyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy, oxo and phenyl optionally substituted with at least one hydroxy, C1-C5 alkoxy, or mixtures thereof;
a tetrahydronaphthyl, 1,2 ethylenedioxyphenyl, chromanyl, 2,3-ethylenedioxynaphthyl or xanthenyl group, any substituted with at least one substituent selected from the group consisting of C1-C10 alkyl and C1-C10 alkoxy, and at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C2-C20 dialkylamino, sulfoamino, carbamoyl, C3-C10 N,N-dialkylcarbamoyl, C2-C6 N-alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxyl, C2-C10 alkoxycarbonyl, C2-C10 carboxyalkyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy, oxo and phenyl optionally substituted with at least one hydroxy, C1-C5 alkoxy, or mixtures thereof;
a naphthoquinonyl, anthryl, phenanthryl, pentalenyl, heptalenyl, azulenyl, biphenylenyl, as-indacenyl, S-indacenyl, acenaphthylenyl, phenylcarbonylphenyl, phenoxyphenyl, benzofuranyll isobenzofuranyl, benzo (b) thienyl, isobenzothienyl, thianthrenyl, dibenzothienyl, phenoxathiinyl, indolyl, 1H-indazolyl, quinolyl, isoquinolyl, phthalazinyl, 1,8-naphthridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl or benzimidazolyl group any of which is unsubstituted or substituted with one or more groups selected from the group consisting of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy, C2-C20 dialkylamino, sulfoamino, carbamoyl, C3-C10 N,N-dialkylcarbamoyl, C2-C6 N-alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxyl, C2-C10 alkoxycarbonyl, C2-C10 carboxyalkyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy and phenyl optionally substituted with at least one hydroxy, C1-C5 alkoxy, or mixtures thereof;
a C7-C12 aralkyl, C9-C16 cycloalkylphenyl, C10-C18 cycloalkylalkylphenyl, C9-C16 cycloalkyloxyphenyl, C9-C16 cycloalkylthiophenyl, 9,10-dihydroanthryl, 5,6,7,8-tetrahydroanthryl, 9,10-dihydrophenanthryl, 1,2,3,4,5,6,7,8-octahydrophenanthryl, indenyl, indanyl, fluorenyl, acenaphthenyl, phenylthiophenyl, isochromanyl, 2,3-dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, thioxanthenyl, 2H-chromenyl, 3,4-dehydro-1-isochromanyl, 4H-chromenyl, indolinyl, isoindolinyl, 1,2,3,4-tetrahydroquinolyl or 1,2,3,4-tetrahydroisoquinolyl group any of which is unsubstituted or substituted with one or more groups selected from the group consisting of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy, C2-C20 dialkylamino, sulfoamino, carbamoyl, C3-C10 N,N-dialkylcarbamoyl, C2-C6 alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxyl, C2-C10 alkoxycarbonyl, C2-C10 carboxyalkyl, C1-C10 acylamlno, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy, oxo and phenyl optionally substituted with at least one hydroxyl, C1-C5 alkoxy, or mixtures thereof;
or a phenyl group substituted with at least one substituent selected from the group consisting of alkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkyl and alkoxycarbonylalkoxy, the said substituent containing 3 to 7 carbon atoms and the said substituted phenyl group being optionally substituted further with at least one substituent selected from the group consisting of methyl, ethyl, methoxy, ethoxy, hydroxy and halo, comprising:

removing the NG-substituent from an NG-substituted-N2-arylsulfonyl-L-argininamide having the formula:

wherein R and Ar are as defined herein above; R' and R"
are selected from the group consisting of hydrogen and protective groups for the guanidino group, and at least one of R' and R" is a protective group for the guanidino group, by means of acidolysis or hydrogenolysis, and, if desired, hydrolyzing the reaction product obtained above.
10. An N2 arylsulfonyl-L-argininamide of the formula (I) and the pharmaceutically acceptable salts thereof wherein R and Ar are as defined in claim 9, whenever prepared by the process of claim 9 or an obvious chemical equivalent thereof.
11. The process of preparing an N2 arylsulfonyl-L-argininamide of the formula (I) and the pharmaceutically acceptable salts thereof wherein R and Ar are as defined in claim 9, in accordance with the process of claim 9 wherein said acidolysis is effected by contacting the NG-substituted-N2-arylsulfonyl-L-argininamide and an excess of an acid at a temperature of -10°C to 100°C.
12. An N2 arylsulfonyl-L-argininami.de of the formula (I) and the pharmaceutically acceptable salts thereof wherein R and Ar are as defined in claim 11, whenever prepared by the process of claim 11 or an obvious chemical equivalent thereof.
13. The process of preparing an N2 arylsulfonyl-L-argininamide of the formula (I) and the pharmaceutically acceptable salts thereof wherein R and Ar are as defined in claim 9, in accordance with the process of claim 9 wherein said hydrogenolysis is effected in a reaction-inert solvent in the presence of a hydrogen-activating catalyst in a hydrogen atmosphere at a temperature of 0°C to the boiling temperature of the solvent.
14. An N2 arylsulfonyl-L-argininamide of the formula (I) and the pharmaceutically acceptable salts thereof wherein R and Ar are as defined in claim 13, whenever prepared by the process of claim 13 or an obvious chemical equivalent thereof.
15. A process for preparing an N2 arylsulfonyl-L-argininamide oE formula (I):

( I ) and the pharmaceutically acceptable salts thereof, wherein R is selected from the group consisting of (1) wherein R1 is selected from the group consisting of C2-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C2-C10 alkoxyalkyl, C2-C10 alkylthioalkyl, C2-C10 alkylsulfinylalkyl, C1-C10 hydroxyalkyl, C3-C10 alkoxycarbonylalkyl, C3-C10 alkylcarbonylalkyl, C1-C10 haloalkyl, C7-C15 aralkyl, C8-C15.alpha. -carboxyaralkyl, C3-C10 cycloalkyl, C4-C10 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, 3-furylmethyl, tetrahydro-3-furylmethyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, tetrahydro-2(3 or 4)-pyranylmethyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, 1,4-dioxa-2-cyclohexylmethyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl optionally substituted with at least one C1-C5 alkyl,C1-C5 alkoxy or mixtures thereof, and tetrahydro-3-thenyl; R2 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; and n is an integer of 1, 2 or 3, (2) wherein R3 is selected from the group consisting of hydrogen, C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl C2-C10 alkoxyalkyl, C2-C10 alkylthioalkyl, C2-C10 alkylsulfinylalkyl, C1-C10 hydroxyalkyl, C3-C10 alkoxycarbonylalkyl, C3-C10 alkylcarbonylalkyl, C1-C10 haloalkyl, C7-C15 aralkyl, C8-C15.alpha.-carboxyaralkyl, C3-C10 cycloalkyl, C4-C10 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, 3-furylmethyl, tetrahydro 3-furylmethyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, tetrahydro-2(3 or 4)-pyranylmethyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, 1,4-dioxa-2-cyclohexylmethyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl optionally substituted with at least one C1-C50 alkyl, Cl-C5 alkoxy or mixtures thereof, and tetrahydro-3-thenyl; R4 is selected from the group consisting of C1-C10 alkyl, phenyl optionally substituted with at least on C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, C7-C12 aralkyl and ring substituted benzyl wherein said substituent is C1-C5 alkyl or C1-C5 alkoxy; R5 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl;
and m is an integer of 0, 1 or 2 (3) wherein R6 is -COOR8 wherein R8 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; each R7 independently is hydrogen, C1-C10 alkyl; phenyl, C1-C5 alkoxy, C2-C6 alkoxycarbonyl or carboxy; p is an integer of 1 to 4; R6 is substituted at the 2 or 3-position; and R7 can be substituted at the 2, 3, 4, 5 or 6-position, (4) optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, wherein R9 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; and r is an integer of 1, 2, 3 or 4, (5) wherein R10 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; Z
is selected from the group consisting of oxy, thio, and sulfinyl; and q is an integer of 0 or 1, and (6) wherein R11 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; i is an integer of 0, 1 or 2; j is an integer of 0, 1 or 2;
and the sum of i + j is an integer of 1 or 2; and wherein Ar is a phenyl or naphthyl.
group, either substituted with at least one substituent selected from the group consisting of sulfoamino, carbamoyl, C3-C10 N,N-dialkylcarbamoyl, C2-C6 N-alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxy, C2-C10 alkoxycarbonyl, C2-C10 carboxyalkyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy and phenyl optionally substituted with at least one hydroxy, C1-C5 alkoxy, or mixtures thereof;
a phenyl or naphthyl group, either substituted with as least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy and C2-C20 dialkylamino, and at least one substituent selected from the group consisting of sulfoamino, carbamoyl, C3-C10 N,N-dialkylcarbamoyl, C2-C6 N-alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxy, C2-C10 alkoxycarbonyl, C2-C10 carboxyalkyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyallcoxy and phenyl optionally substituted with at least one hydroxy, C1-C5 alkoxy, or mixtures thereof;
an oxanthrenyl or dibenzofuranyl group substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C2-C20 dialkylamino, C2-C6 N-alkylcarbamoyl, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C2-C10 alkoxycarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl and C1-C10 hydroxyalkoxy;
an oxanthrenyl or dibenzofuranyl group substituted ith at least one substituent selected from the group consisting of C1-C10 alkyl and C1-C10 alkoxy, and at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C2-C20 dialkylamino, C2-C6 N-alkylcarbamoyl, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C2-C10 alkoxycarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl and C1-C10 hydroxyalkoxy;
a tetrahydronaphthyl, 1,2-ethylenedioxyphenyl, chromanyl, 2,3-ethylenedioxynaphthyl or xanthenyl group, any substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C2-C20 dialkylamino, C2-C6 N-alkylcarbamoyl, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C2-C10 alkoxycarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy, and oxo;
a tetrahydronaphthyl 1,2-ethylenedioxyphenyl, chromanyl, 2,3-ethylenedioxynaphthyl or xanthenyl group, any substltuted with at least one substituent selected from the group consisting of C1-C10 alkyl and C1-C10 alkoxy, and at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C2-C20 dialkylamino, C2-C6 N-alkylcarbamoyl, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C2-C10 alkoxycarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy, and oxo;
an anthryl, phenanthryl, biphenylenyl, S-indacenyl, phenylcarbonylphenyl, phenoxyphenyl, benzofuranyl, benzo (b) thienyl, thianthrenyl, dibenzothienyl, phenoxathiinyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbozolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl group any of which is unsubstituted or substituted with one or more groups selected from the group consisting of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy, C2-C20 dialkylamino and C1-C10 hydroxyalkoxy;
a C7-C12 aralkyl, C9-C16 cycloalkylphenyl, C10-C18 cycloalkylalkylphenyl, C9-C16 cycloalkyloxyphenyl, 9,10-dihydroanthryl, 5,6,7,8-tetrahydroanthryl, 9,10-dihydro-phenanthryl, 1,2,3,4,5,6,7,8-octahydrophenanthryl, indenyl, indanyl, fluorenyl, acenaphthenyl, phenylthio-phenyl, 2,3-dihydrobenzofuranyl, thioxanthenyl, 2H-chromenyl or 1,2,3,4-tetrahydroquinolyl group any of which is unsubstituted or substituted with one or more groups selected from the group consisting of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy, C2-C20 dialkylamino, C2-C6 N-alkylcarbamoyl, C1-C10 hydroxyalkoxy, and oxo;
or a phenyl group substituted with at least one substituent selected from the group consisting of alkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkyl and alkoxycarbonylalkoxy, the said substituent containing 3 to 7 carbon atoms and the said substituted phenyl group being optionally substituted further with at least one substituent selected from the group consisting of methyl ethyl, methoxy, ethoxy, hydroxy and halo, comprising:
removing the NG-substituent from an NG-substituted-N2-arylsulfonyl-L-argininamide having the formula:

wherein R and Ar are as defined herein above; R' and R"
are selected from the group consisting of hydrogen and protective groups for the guanidino group, and at least one of R' and R" is a protective group for the guanidino group, by means of acidolysis of hydrogenolysis, and, if desired, hydrolyzing the reaction product obtained above.
16. An N2 arylsulfonyl-L-argininamide of the formula (I) and the pharmaceutically acceptable salts thereof wherein R and Ar are as defined in claim 15, whenever prepared by the process of claim 15 or an obvious chemical equivalent thereof.
17. The process of preparing an N2 arylsulfonyl-L-argininamide of the formula (I) and the pharmaceutically acceptable salts thereof wherein R and Ar are as defined in claim 15, in accordance with the process of claim 15, wherein said acidolysis is effected by contacting the NG-substituted-N2-arylsulfonyl-L-argininamide and an excess of an acid at a temperature of -10°C to 100°C.
18. An N2 arylsulfonyl-L-argininamide of the formula (I) and the pharmaceutically acceptable salts thereof wherein R and Ar are as defined in claim 17, whenever prepared by the process of claim 17 or an obvious chemical equivalent thereof.
19. The process of preparing of N2 arylsulfonyl-L-argininamide of the formula (I) and the pharmaceutically acceptable salts thereof wherein R and Ar are as defined in claim 15, in accordance with the process of claim 15 wherein said hydrogenolysis is effected in a reaction-inert solvent in the presence of hydrogen-activating catalyst in a hydrogen atmosphere at a temperature of 0°C to the boiling temperature of the solvent.
20. An N2 arylsulfonyl-L-argininamide of the formula (I) and the pharmaceutically acceptable salts thereof wherein R and Ar are as defined in claim 19, whenever prepared by the process of claim 19 or an obvious chemical equivalent thereof.
21. A process for preparing an N2 arylsulfonyl-L-argininamide of formula (I):

(I) and the pharmaceutically acceptable salts thereof, wherein said R is selected from the group consisting of (1) wherein R1 is selected from the group consisting of C2-C10 alkyl, C3-C10 alkenyl, C2-C10 alkoxyalkyl, C2-C10 alkylthioalkyl, C2-C10 alkylsulfinylalkyl, C7-C15 aralkyl, C3-C10 cycloalkyl, C4-C10 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl, tetrahydro-2(3 or 4)-pyranylmethyl and 1,4-dioxa-2-cyclohexylmethyl; R2 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; and n is an integer of 1, 2 or 3, (2) wherein R3 is selected from the group consisting of hydrogen, C1-C10 alkyl, C3-C10 alkenyl, C2-C10 alkoxyalkyl, C2-C10 alkylthioalkyl, C2-C10 alkylsulfinylalkyl, C7-C15 aralkyl, C3-C10 cycloalkyl, C4-C10 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl, tetrahydro-2(3 or 4)-pyranylmethyl and 1,4-dioxa-2-cyclohexylmethyl; R4 is selected from the group consisting of C1-C10 alkyl, phenyl optionally substituted with at least on C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, C7-C12 aralkyl and ring substituted benzyl wherein said substituent is C1-C5 alkyl or C1-C5 alkoxy;

R5 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; and m is an integer of 0, 1 or 2 (3) wherein R6 is -COOR8 wherein R8 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; each R7 independently is hydrogen, C1-C10 alkyl or phenyl; p is an integer of 1 to 4; R6 is substituted at the 2 or 3-position; and R7 can be substituted at the 2, 3, 4, 5, or 6-position, (4) optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, wherein R9 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; and r is an integer of 1, 2, 3 or 4, (5) wherein R10 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; Z
is selected from the group consisting of oxy, thio and sulfinyl; and q is an integer of 0 or 1, and (6) wherein R11 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; i is an integer of 0, 1 or 2; j is an integer of 0, 1 or 2;
and the sum of i + j is an integer of 1 or 2; and said Ar is a phenyl naphthyl group, either substituted with at least one substituent selected from the group consisting of amino, C1-C10 alkylamino, C1-C10 alkylthio, C7-C12 aralkyl, C2-C10 alkoxycarbonyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 hydroxyalkoxy and phenyl; and wherein said Ar is;

a tetrahydronaphthyl, 1,2-ethylenedioxyphenyl, chromanyl, 2,3-ethylenedioxynaphthyl or xanthenyl group, any substituted with at least one substituent selected from the group consisting of C1-C10 alkyl and C1-C10 alkoxy, and at least one substituent selected from the group consisting of halo;
an anthryl, phenanthryl, biphenylenyl, phenoxyphenyl benzofuranyl, benzo (b) thienyl, dibenzothienyl, phenoxathiinyl, quinolyl, isoquinolyl, quinoxalinyl, acridinyl or phenazinyl group any of which is unsubstituted or substituted with one or more group selected from the group consisting of halo, hydroxy, C1-C10 alkyl, C1-C10 alkoxy and C1-C10 hydroxyalkoxy;
a C7-C12 aralkyl, C9-C16 cycloalkylphenyl,fluorenyl, thioxanthenyl, 2H-chromenyl, or 1,2,3,4-tetrahydroquinolyl group any of which is unsubstituted or substituted with one or more groups selected from the group consisting of C1-C10 alkyl, C1-C10 alkoxy and oxo;
or a phenyl group substituted with at least one substituent selected from the group consisting of alkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkyl and alkoxycarbonylalkoxy, the said substituent containing 3 to 7 carbon atoms and the said substituted phenyl group being optionally substituted further with at least one substituent selected from the group consisting of methyl, ethyl, methoxy, ethoxy, hydroxy and halo, comprising:

removing the NG-substituent from an NG-substituted-N2-arylsulfonyl-L-argininamide having the formula:

wherein R and Ar are as defined herein above; R' and R"
are selected from the group consisting of hydrogen and protective groups for the guanidino group, and at least one of R' and R" is a protective group for the guanidino group, by means of acidolysis of hydrogenolysis, and, if desired, hydrolyzing the reaction product obtained above.
22. An N2 arylsulfonyl-L-argininamide of the formula (I) and the pharmaceutically acceptable salts thereof wherein R and Ar are as defined in claim 21, whenever prepared by the process of claim 21 or an obvious chemical equivalent thereof.
23. The process of preparing an N2 arylsulfonyl-L-argininamide of the formula (I) and the pharmaceutically acceptable salts thereof wherein R and Ar are as defined in claim 21, in accordance with the process of claim 21, wherein said acidolysis is effected by contacting the NG-substituted-N2-arylsulfonyl-L-argininamide and an excess of an acid at a temperature of -10°C to 100°C.
24. An N2 arylsulfonyl-L-argininamide of the formula (I) and the pharmaceutically acceptable salts thereof wherein R and Ar are as defined in claim 23, whenever prepared by the process of claim 23 or an obvious chemical equivalent thereof.
25. The process of preparing an N2 arylsulfonyl-L
argininamide of the formula (I) an the pharmaceutically acceptable salts thereof wherein R and Ar are as defined in claim 21, in accordance with the process of claim 21 wherein said hydrogenolysis is effected in a reaction-inert solvent in the presence of a hydrogen-activating catalyst in a hydrogen atmosphere at a temperature of 0°C to the boiling temperature of the solvent.
26. An N2 arylsulfonyl-L-argininamide of the formula (I) and the pharmaceutically acceptable salts thereof wherein R and Ar are as defined in Claim 25, whenever prepared by the process of Claim 25 or an obvious chemical equivalent thereof.
27. A process for preparing an N2 arylsulfonyl-L-argininamide of formula (I):

(I) and the pharmaceutically acceptable salts thereof, wherein said R is selected from the group consisting of (1) wherein R1 is selected from the group consisting of C2-C10 alkyl, C2-C6 alkoxyalkyl, C2-C6 alkylthioalkyl, C7-C10 aralkyl, C4-C10 cycloalkylalkyl, furfuryl and tetrahydrofurfuryl; R2 is hydrogen of C1-C10 alkyl; and n is an integer of 1, 2 or 3, (2) wherein R3 is selected from the group consisting of hydrogen, C1-C10 alkyl, C2-C6 alkoxyalkyl, C2-C6 alkylthioalkyl, C7-C10 aralkyl, C4-C10 cycloalkylalkyl, furfuryl and tetrahydrofurfuryl; R4 is C1-C5 alkyl; R5 is hydrogen or C1-C10 alkyl; and m is an integer of 0, 1 or (3) wherein R6 is -COOR8 wherein R8 is hydrogen or C1-C10 alkyl; each R7 independently is hydrogen or C1-C6 alkyl;
p is an integer of 1 to 4; R6 is substituted at the 2 or 3-position; and R7 can be substituted at the 2, 3, 4, 5 or 6-position, (4) optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, wherein R9 is hydrogen or C1-C10 alkyl; and r is an integer of 1, 2, 3 or 4, (5) wherein R10 is hydrogen or C1-C10 alkyl: Z is selected from the group consisting of oxy, thio and sulfinyl; and q is an integer of 0 or 1, and (6) wherein R11 is hydrogen or C1-C10 alkyl; i is an integer of 0, 1 or 2; j is an integer of 0, 1 or 2; and the sum of i + j is an integer of 1 or 2; and said Ar is a phenyl or naphthyl group, either substituted with at least one substituent selected from the group consisting of amino, C1-C10 alkylamino, C7-C12 aralkyl, C1-C10 acylamino, C1-C10 hydroxyalkyl, and C1-C10 hydroxyalkoxy; and wherein said Ar is a phenyl or naphthyl group, either substituted with at least one substituent selected from the group consisting of amino, C1-C10 alkylamino, C7-C12 aralkyl, C1-C10 acylamino, C1-C10 hydroxyalkyl and C1-C10 hydroxyalkoxy and at least one substituent selected from the group consisting of halo, hydroxy, C1-C10 alkyl and C1-C10 alkoxy;
a biphenylenyl, phenoxyphenyl, dibenzothienyl, phenoxathiinyl, quinolyl, or quinoxalinyl group any of which is unsubstituted or substituted with one or more groups selected from the group consisting of hydroxy and C1-C10 alkyl;
a C7-C12 aralkyl, C9-C16 cycloalkylphenyl, fluorenyl, or 2H-chromenyl group any of which is unsub-stituted or substituted with one or more groups selected from the group consisting of C1-C10 alkyl, C1-C10 alkoxy and oxo;
or a phenyl group substituted with at least one substituent selected from the group consisting of alkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkyl and alkoxycarbonylalkoxy, the said substituent containing 3 to 7 carbon atoms and the said substituted phenyl group being optionally substituted further with at least one substituent selected from the group consisting of methyl, ethyl, methoxy, ethoxy, hydroxy and halo, comprising:
removing the NG-substituent from an NG-substituted-N2-arylsulfonyl-L-argininamide having the formula:

wherein R and Ar are as defined herein above; R' and R"
are selected from the group consisting of hydrogen and protective groups for the guanidino group, and at least one of R' and R" is a protective group for the guanidino group, by means of acidolysis or hydrogenolysis, and, if desired, hydrolyzing the reaction product obtained above.
28. An N2 arylsulfonyl-L-argininamide of the formula (I) and the pharmaceutically acceptable salts thereof wherein R and Ar are as defined in Claim 27, whenever prepared by the process of Claim 27 or an obvious chemical equivalent thereof.
29. The process of preparing an N2 arylsulfonyl-L-argininamide of the formula (I) and the pharmaceutically acceptable salts thereof wherein R and Ar are defined in Claim 27, in accordance with the process of Claim 27, wherein said acidolysis is effected by contacting the NG-substituted -N2-arylsulfonyl-L-argininamide and an excess of an acid at a temperature of -10°C to 100°C.
30. An N2 arylsulfonyl-L-argininamide of the formula (I) and the pharmaceutically acceptable salts thereof wherein R and Ar are as defined in Claim 29, whenever prepared by the process of Claim 29 or an obvious chemical equivalent thereof.
31. The process of preparing an N2 arylsulfonyl-L-argininamide of the formula (I) and the pharmaceutically acceptable salts thereof wherein R and Ar are as defined in Claim 27, in accordance with the process of Claim 27, wherein said hydrogenolysis is effected in a reaction-inert solvent in the presence of a hydrogen-activating catalyst in a hydrogen atmosphere at a temperature of 0°C to the boiling temperature of the solvent.
32. An N2 arylsulfonyl-L-argininamide of the formula (I) and the pharmaceutically acceptable salts thereof wherein R and Ar are as defined in Claim 31, whenever prepared by the process of Claim 31 or an obvious chemical equivalent thereof.
33. A process for preparing an N2 arylsulfonyl-L-argininamide of formula (I):
(I) and the pharmaceutically acceptable salts thereof, wherein R is selected from the group consisting of (1) wherein R1 is selected from the group consisting of C2-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C2-C10 alkoxy-alkyl, C2-C10 alkylthioalkyl, C2-C10 alkylsulfinylalkyl, C1-C10 hydroxyalkyl, C3-C10 alkoxycarbonylalkyl, C3-C10 alkylcarbonylalkyl, C1-C10 haloalkyl, C7-C15 aralkyl, C8-C15.alpha.-carboxyaralkyl, C3-C10 cycloalkyl, C4-C10 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, 3-furylmethyl tetrahydro-3 furylmethyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, tetrahydro-2(3 or 4)-pyranylmethyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, 1,4-dioxa-2-cyclohexylmethyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, and tetrahydro-3-thenyl; R2 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; and n is an integer of 1, 2 or 3, (2) wherein R3 is selected from the group consisting of hydrogen, C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C2-C10 alkoxyalkyl, C2-C10 alkylthioalkyl, C2-C10 alkylsulfinylalkyl, C1-C10 hydroxyalkyl, C3-C10 alkoxycarbonylalkyl, C3-C10 alkylcarbonyalkyl, C1-C10 haloalkyl, C7-C15 aralkyl, C8-C15 .alpha.-carboxyaralkyl, C3-C10 cycloalkyl, C4-C10 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, 3-furylmethyl, tetrahydro-3-furylmethyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, tetrahydro-2(3 or 4)-pyranylmethyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, 1,4-dioxa-2-cyclohexylmethyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, and tetrahydro-3-thenyl; R4 is selected from the group consisting of C1-C10 alkyl, phenyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, C7-C12 aralkyl and ring substituted benzyl wherein said substituent is C1-C5 alkyl or C1-C5 alkoxy; R5 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl;
and m is an integer of 0, 1 or 2 (3) wherein R6 is -COOR8 wherein R8 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; each R7 independently is hydrogen, C1-C10 alkyl; phenyl, C1-C5 alkoxy, C2-C6 alkoxycarbonyl or carboxy; p is an integer of 1 to 4; R6 is substituted at the 2 or 3-position; and R7 can be substituted at the 2, 3, 4, 5 or 6-position, (4) optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, wherein R9 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; and r is an integer of 1, 2, 3 or 4, (5) wherein R10 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; Z
is selected from the group consisting of oxy, thio and sulfinyl; and q is an integer of 0 or 1, and (6) wherein R11 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; i is an integer of 0, 1 or 2; j is an integer of 0, 1 or 2;
and the sum of i + j is an integer of 1 or 2; and Ar is a phenyl or naphthyl group, either substituted with at least one substituent selected from the group consisting of sulfoamino, carbamoyl, C3-C10 N,N-dialkyl-carbamoyl, C2-C6 N-alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxy, C2-C10 alkoxycarbonyl, C2-C10 carboxyalkyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy and phenyl optionally substituted with at least one hydroxy, C1-C5 alkoxy, or mixtures thereof;
a phenyl or naphthyl group, either substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy and C2-C20 dialkylamino, and at least one substituent selected from the group consisting of sulfoamino, carbamoyl, C3-C10 N,N-dialkylcarbamoyl, C2-C6 N-alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxy, C2-C10 alkoxycarbonyl, C2-C10 carboxyalkyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy and phenyl optionally substituted with at least one hydroxy, C1-C5 alkoxy, or mixtures thereof;
an oxanthrenyl or dibenzofuranyl group substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C2-C20 dialkylamino, sulfoamino, carbamoyl, C3-C10 N,N-dialkylcarbamoyl, C2-C6 N-alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxyl, C2-C10 alkoxycarbonyl, C2-C10 carboxyalkyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy, and phenyl optionally substituted with at least one hydroxy, C1-C5 alkoxy, or mixtures thereof;
an oxanthrenyl or dibenzofuranyl group substituted with at least one substituent selected from the group consisting of C1-C10 alkyl and C1-C10 alkoxy, and at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C2-C20 dialkylamino, sulfoamino, carbamoyl, C3-C10 N,N-dialkylcarbamoyl, C2-C6 N-alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxyl, C2-C10 alkoxycarbonyl, C2-C10 carboxyalkyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy and phenyl optionally substituted with at least one hydroxy, C1-C5 alkoxy, or mixtures thereof;
a tetrahydronaphthyl, 1,2-ethylenedioxyphenyl, chromanyl, 2,3-ethylenedioxynaphthyl or xanthenyl group, and substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C2-C20 dialkylamino, sulfoamino, carbamoyl, C3-C10 N,N-dialkylcarbamoyl, C2-C6 alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxyl, C2-C10 alkoxycarbonyl, C2-C10 carboxyalkyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy, oxo and phenyl optionally substituted with at least one hydroxy, C1-C5 alkoxy, or mixtures thereof;
a tetrahydronaphthyl, 1,2-ethylenedioxyphenyl, chromanyl, 2,3-ethylenedioxynaphthyl or xanthenyl group, and substituted with at least one substituent selected from the group consisting of C1-C10 alkyl and C1-C10 alkoxy, and at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C2-C20 dialkylamino, sulfoamino, carbamoyl, C3-C10 N,N-dialkylcarbamoyl, C2-C6 N-alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxyl, C2-C10 alkoxycarbonyl, C2-C10 carboxyalkyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy, oxo and phenyl optionally substituted with at least one hydroxy, C1-C5 alkoxy, or mixtures thereof;
a naphthoquinonyl, anthryl, phenanthryl, pentalenyl, heptalenyl, azulenyl, biphenylenyl, as-indacenyl, S-indacenyl, acenaphthylenyl, phenylcarbonylphenyl, phenoxyphenyl, benzofuranyl, isobenzofuranyl, benzo (b) thienyl, isobenzothienyl, thianthrenyl, dibenzothienyl, phenoxathiinyl, indolyl, 1H-indazolyl, quinolyl, isoquinolyl, phthalazinyl, 1,8-naphthridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl or benzimidazolyl group any of which is unsubstituted or substituted with one or more groups selected from the group consisting of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy, C2-C20 dialkylamino, sulfoamino, carbamoyl, C3-C10 N,N-dialkylcarbamoyl, C2-C6 N-alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxyl, C2-C10 alkoxycarbonyl, C2-C10 carboxyalkyl, C1-C10 acylamino, C2-C10 alkylcarbonyl) C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy and phenyl optionally substituted with at least one hydroxy, C1-C5 alkoxy, or mixtures thereof;
a C7-C12 aralkyl, C9-C16 cycloalkylphenyl, C10-C18 cycloalkylalkylphenyl, C9-C16 cycloalkyloxyphenyl, C9-C16 cycloalkylthiophenyl, 9,10-dihydroanthryl, 5,6,7,8-tetrahydroanthryl, 9,10-dihydrophenanthryl, 1,2,3,4,5,6,7,8-octahydrophenanthryl, indenyl, indanyl, fluorenyl, acenaphthenyl, phenylthiophenyl, isochromanyl, 2,3-dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, thioxanthenyl, 2H-chromenyl, 3,4-dehydro-1-isochromanyl, 4H-chromenyl, indolinyl, isoindolinyl, 1,2,3,4-tetrahydroquinolyl or 1,2,3,4-tetrahydroisoquinolyl group any of which is unsubstituted or substituted with one or more groups selected from the group consisting of halo, nitro cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy, C2-C20 dialkylamino, sulfoamino, carbamoyl, C3-C10 N,N-dialkylcarbamoyl, C2-C6 N-alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxyl, C2-C10 alkoxycarbonyl, C2-C10 carboxyalkyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy, oxo and phenyl optionally substituted with at least one hydroxyl, C1-C5 alkoxy, or mixtures thereof;
or a phenyl group substituted with at least one substituent selected from the group consisting of alkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkyl and alkoxycarbonylalkoxy, the said substituent containing 3 to 7 carbon atoms and the said substituted phenyl group being optionally substituted further with at least one substituent selected from the group consisting of methyl, ethyl, methoxy, ethoxy, hydroxy and halo, comprising:
reacting an N2-arylsulfonyl-L-arginyl halide having the formula:
wherein Ar is as defined herein above and X is halogen, with an amino acid having the formula:

RH

wherein R is as defined herein above, and, if desired, hydrolyzing the reaction product obtained above.
34. An N2 arylsulfonyl-L-argininamide of the formula (I) and the pharmaceutically acceptable salts thereof wherein R and Ar are as defined in claim 33, whenever prepared by the process of claim 33 or an obvious chemical equivalent thereof.
35. The process of preparing an N2 arylsulfonyl-L-argininamide of the formula (I) and the pharmaceutically acceptable salts thereof, wherein R and Ar are as defined in claim 33, in accordance with claim 33, wherein the N2-arylsulfonyl-L-arginyl halide is reacted with at least an equimolar amount of the amino acid derivative at a temperature of from -10°C to +80°C.
36. An N2 arylsulfonyl-L-argininamide of the formula (I) and the pharmaceutically acceptable salts thereof wherein R and Ar are as defined in claim 35 whenever prepared by the process of claim 35 or an obvious chemical equivalent thereof.
37. A process for preparing an N2 arylsulfonyl-L-argininamide of formula (I):
(I) and the pharmaceutically acceptable salts thereof, wherein R is selected from the group consisting of (1) wherein R1 is selected from the group consisting of C2-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C2-C10 alkoxyalkyl, C2-C10 alkylthioalkyl, C2-C10 alkylsulfinylalkyl, C1-C10 hydroxyalkyl, C3-C10 alkoxycarbonylalkyl, C3-C10 alkylcarbonylalkyl, C1-C10 haloalkyl, C7-C15 aralkyl, C8-C15?-carboxyaralkyl, C3-C10 cycloalkyl, C4-C10 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, 3-furylmethyl, tetrahydro-3-furylmethyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, tetrahydro-2(3 or 4)-pyranylmethyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, 1,4-dioxa-2-cyclohexylmethyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, and tetrahydro-3-thenyl; R2 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; an n is an integer of 1, 2 or 3, (2) wherein R3 is selected from the group consisting of hydrogen, C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C2-C10 alkoxyalkyl, C2-C10 alkylthioalkyl, C2-C10 alkylsulfinylalkyl, C1-C10 hydroxyalkyl, C3-C10 alkoxycarbonylalkyl, C3-C10 alkylcarbonylalkyl, C1-C10 haloalkyl, C7-C15 aralkyl, C8-C15?carboxyaralkyl, C3-C10 cycloalkyl, C4-C10 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, 3-furylmethyl, tetrahydro-3-furylmethyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, tetrahydro-2(3 or 4)-pyranylmethyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, 1,4-dioxa-2 cyclohexyl-methyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, and tetrahydro-3-thenyl; R4 is selected from the group consisting of C1-C10 alkyl, phenyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, C7-C12 aralkyl and ring substituted benzyl wherein said substituent is C1-C5 alkyl or C1-C5 alkoxy; R5 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl;

and m is an integer of 0, 1 or 2 (3) wherein R6 is -COOR8 wherein R8 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; each R7 independently is hydrogen, C1-C10 alkyl; phenyl, C1-C5 alkoxy, C2-C6 alkoxycarbonyl or carboxy; p is an integer of 1 to 4; R6 is substituted at the 2 or 3-position; and R7 can be substituted at the 2, 3, 4, 5 or 6-position, (4) optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, wherein R9 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; and r is an integer of 1, 2, 3 or 4, (5) wherein R10 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; Z
is selected from the group consisting of oxy, thio and sulfinyl; and q is an integer of 0 or 1, and (6) wherein R11 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; i is an integer of 0, 1 or 2; j is an integer of 0, 1 or 2;
and the sum of i + j is an integer of 1 or 2; and wherein said Ar is a phenyl or naphthyl group, either substituted with at least one substituent selected from the group consisting of sulfoamino, carbamoyl, C3-C10 N,N-dialkylcarbamoyl, C2-C6 N-alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxy, C2-C10 alkoxycarbonyl, C2-C10 carboxyalkyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy and phenyl optionally substituted with at least one hydroxy, C1-C5 alkoxy, or mixtures thereof;
a phenyl or naphthyl group, either substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy and C2-C20 dialkylamino, and at least one substituent selected from the group consisting of sulfoamino, carbamoyl, C3-C10 N,N-dialkylcarbamoyl, C2-C6 N-alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxy, C2-C10 alkoxy-carbonyl, C2-C10 carboxyalkyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy and phenyl optionally substituted with at least one hydroxy, C1-C5 alkoxy, or mixtures thereof;
an oxanthrenyl or dibenzofuranyl group substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C2-C20 dialkylamino, C2-C6 N-alkylcarbamoyl, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C2-C10 alkoxycarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl and C1-C10 hydroxyalkoxy;
an oxanthrenyl or dibenzofuranyl group substituted with at least one substituent selected from the group consisting of C1-C10 alkyl and C1-C10 alkoxy, and at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C2-C20 dialkylamino, C2-C6 N-alkylcarbamoyl, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C2-C10 alkoxycarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl and C1-C10 hydroxyalkoxy;
a tetrahydronaphthyl, 1,2-ethylenedioxyphenyl, chromanyl, 2,3-ethylenedioxynaphthyl or xanthenyl group, and substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C2-C20 dialkylamino, C2-C6 N-alkylcarbamoyl, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C2-C10 alkoxycarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy, and oxo;
a tetrahydronaphthyl, 1,2-ethylenedioxyphenyl, chromanyl 2,3-ethylenedioxynaphthyl or xanthenyl group, and substituted with at least one substituent selected from the group consisting of C1-C10 alkyl and C1-C10 alkoxy, and at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C2-C20 dialkylamino, C2-C6 N-alkylcarbamoyl, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C2-C10 alkoxycarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy, and oxo ;
an anthryl, phenanthryl, biphenylenyl, S-indacenyl, phenylcarbonylphenyl, phenoxphenyl, benzofuranyl, benzo (b) thienyl, thianthrenyl, dibenzothienyl, phenoxathiinyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl group any of which is unsubstituted or substituted with one or more groups selected from the group consisting of halo, nitro, cyano, hydroxy. C1-C10 alkyl, C1-C10 alkoxy, C2-C20 dialkylamino and C1-C10 hydroxyalkoxy;
a C7-C12 aralkyl, C9-C16 cycloalkylphenyl, C10-C18 cycloalkylalkylphenyl, C9-C16 cycloalkyloxyphenyl, 9,10-dihydroanthryl, 5,6,7,8-tetrahydroanthryl, 9,10-dihydrophenanthryl, 1,2,3,4,5,6,7,8-octahydrophenanthryl, indenyl, indanyl, fluorenyl, acenaphthenyl, phenylthio-phenyl, 2,3-dihydrobenzofuranyl, thioxanthenyl, 2H-chromenyl or 1,2,3,4-tetrahydroquinolyl group any of which is unsubstituted or substituted with one or more groups selected from the group consisting of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy, C2-C20 dialkylamino, C2-C6 N-alkylcarbamoyl, C1-C10 hydroxyalkoxy, and oxo;
or a phenyl group substituted with at least one substituent selected from the group consisting of alkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkyl and alkoxycarbonylalkoxy, the said substituent containing 3 to 7 carbon atoms and the said substituted phenyl group being optionally substituted further with at least one substituent selected from the group consisting of methyl, ethyl, methoxy, ethoxy, hydroxy and halo, comprising:
reacting an N2-arylsulfonyl-L-arginyl halide having the formula:

wherein Ar is as defined herein above and X is halogen, with an amino acid derivative having the formula:

RH

wherein R is as defined herein above, and, if desired, hydrolyzing the reaction product obtained above.
38. An N2 arylsulfonyl-L-argininamide of the formula (I) and the pharmaceutically acceptable salts thereof wherein R and Ar are as defined in claim 37, whenever prepared by the process ox claim 37 or an obvious chemical equivalent thereof.
39. The process of preparing an N2 arylsulfonyl-L-argininamide of the formula (I) and the pharmaceutically acceptable salts thereof, wherein R and Ar are as defined in claim 37, in accordance with claim 37, wherein the N2-arylsulfonyl-L-arginyl halide is reacted with at least an equimolar amount of the amino acid derivative at a temperature of from -10°C to +80°C.
40. An N2 arylsulfonyl-L-argininamide of the formula (I) and the pharmaceutically acceptable salts thereof wherein R and Ar are as defined in claim 39, whenever prepared by the process of claim 39 or an obvious chemical equivalent thereof.
41. A process for preparing an N2-arylsulfonyl-L-argininamide of the formula (I):

(I) and the pharmaceutically acceptable salts thereof, wherein said R is selected from the group consisting of (1) wherein R1 is selected from the group consisting of C2-C10 alkyl, C3-C10 alkenyl, C2-C10 alkoxyalkyl, C2-C10 alkylthioalkyl, C2-C10 alkylsulfinylalkyl, C7-C15 aralkyl, C3-C10 cycloalkyl, C4-C10 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl, tetrahydro-2(3 or 4)-pyranylmethyl and 1,4-dioxa-2-cyclohexylmethyl; R2 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; and n is an integer of 1, 2 or 3, (2) wherein R3 is selected from the group consisting of hydrogen, C1-C10 alkyl, C3-C10 alkenyl, C2-C10 alkoxyalkyl, C2-C10 alkylthioalkyl, C2-C10 alkylsulfinylalkyl, C7-C15 aralkyl, C3-C10 cycloalkyl, C4-C10 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl, tetrahydro-2(3 or 4)-pyranylmethyl and 1,4-dioxa-2-cyclohexylmethyl; R4 is selected from the group consisting of C1-C10 alkyl, phenyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, C7-C12 aralkyl and ring substituted benzyl wherein said substituent is C1-C5 alkyl or C1-C5 alkoxy, R5 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; and m is an integer of 0, 1 or 2 (3) wherein R6 is -COOR8 wherein R8 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; each R7 independently is hydrogen, C1-C10 alkyl or phenyl; p is an integer of 1 to 4: R6 is substituted at the 2 or 3- position; and R7 can be substituted at the 2, 3, 4, 5 or 6-position, (4) optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, wherein R9 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; and r is an integer of 1, 2, 3 or 4, (5) wherein R10 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; Z
is selected from the group consisting of oxy, thio and sulfinyl; and q is an integer of 0 or 1, and (6) wherein R11 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; i is an integer of 0, 1 or 2; j is an integer of 0, 1 or 2;
and the sum of i + j is an integer of 1 or 2; and wherein said Ar is:
a phenyl or naphthyl group, either substituted with at least one substituent selected from the group consisting of amino, C1-C10 alkylamino, C1-C10 alkylthio, C7-C12 aralkyl, C2-C10 alkoxycarbonyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 hydroxyalkoxy and phenyl, and at least one substituent selected from the group consisting of halo, hydroxy, C1-C10 alkyl, C1-C10 alkoxy and C2-C20 dialkylamino;
a dibenzofuranyl group substituted with at least one substituent selected from the group consisting of halo;
a dibenzofuranyl group substituted with at least one substituent selected from the group consisting of C1-C10 alkyl and C1-C10 alkoxy, and at least one substituent selected from the group consisting of halo;
a tetrahydronaphthyl, 1,2-ethylenedioxyphenyl, chromanyl, 2,3-ethylenedioxynaphthyl or xanthenyl group, and substituted with at least one substituent selected from the group consisting of halo;
a tetrahydronaphthyl, 1,2-ethylenedioxyphenyl, chromanyl, 2,3-ethylenedioxynaphthyl or xanthenyl group, and substituted with at least one substituent selected from the group consisting of C1-C10 alkyl and C1-C10 alkoxy and at least one substituent selected from the group consisting of halo;
an anthryl, phenanthryl, biphenylenyl, phenoxyphenyl, benzofuranyl, benzo (b) thienyl, dibenzothienyl, phenoxathiinyl, quinolyl, isoquinolyl, quinoxalinyl, acridinyl or phenazinyl group any of which is unsubstituted or substituted with one or more groups selected from the group consisting of halo, hydroxy, C1-C10 alkyl, C1-C10 alkoxy and C1-C10 hydroxyalkoxy; a C7-C12 aralkyl, C9-C16 cycloalkylphenyl, fluorenyl thioxanthenyl, 2H-chromenyl, or 1,2,3,4-tetrahydroquinolyl group any of which is unsubstituted or substituted with one or more groups selected from the group consisting of C1-C10 alkyl, C1-C10 alkoxy and oxo;
or a phenyl group substituted with at least one substituent selected from the group consisting of alkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkyl and alkoxycarbonylalkoxy, the said substituent containing 3 to 7 carbon atoms and the said unsubstituted phenyl group being optionally substituted further with at least one substituent selected from the group consisting of methyl, ethyl, methoxy, ethoxy, hydroxy and halo, comprising:
reacting an N2-arylsulfonyl-L-argininamide of the formula:

wherein Ar is as defined above and X is halogen, with an amino acid derivative having the formula:

RH

wherein R is as defined herein above, and, if desired, hydrolyzing the reaction product obtained above.
42. An N2 arylsulfonyl-L-argininamide of the formula (I) and the pharmaceutically acceptable salts thereof wherein R and Ar are as defined in claim 41, whenever prepared by the process of claim 41 or an obvious chemical equivalent thereof.
43. The process of preparing an N2 arylsulfonyl-L-argininamide of the formula (I) and the pharmaceutically acceptable salts thereof, wherein R and Ar are as defined in claim 41, in accordance with claim 41, wherein the N2-arylsulfonyl-L-arginyl halide is reacted with at least an equimolar amount of the amino acid derivative at a temperature of from -10° to +80°C.
44. An N2 arylsulfonyl-L-argininamide of the formula (I) and the pharmaceutically acceptable salts thereof wherein R and Ar are as defined in claim 43, whenever prepared by the process of claim 43 or an obvious chemical equivalent thereof.
45. A process of preparing an N2arylsulfonyl-L-argininamide of the formula (I):

(I) and the pharmaceutically acceptable salts thereof, wherein said R is selected from the group consisting of:

(1) wherein R1 is selected from the group consisting of C2-C10 alkyl, C2-C6 alkoxyalkyl, C2-C6 alkylthioalkyl, C7-C10 aralkyl, C4-C10 cycloalkylalkyl, furfuryl and tetrahydrofurfuryl; R2 is hydrogen or C1-C10 alkyl; and n is an integer of 1, 2 or 3, (2) wherein R3 is selected from the group consisting of hydrogen, C1-C10 alkyl, C2-C6 alkoxyalkyl, C2-C6 alkylthioalkyl, C7-C10 aralkyl, C4-C10 cycloalkylalkyl, furfuryl and tetrahydrofurfuryl; R4 is C1-C5 alkyl; R5 is hydrogen or C1-C10 alkyl; and m is an integer of 0, 1 or (3) wherein R6 is -COOR8 and R8 is hydrogen or C1-C10 alkyl;
each R7 independently is hydrogen or C1-C6 alkyl; p is an integer of 1 or 4; R6 is substituted at the 2 or 3-position; and R7 can be substituted at the 2, 3, 4, 5 or 6-position, (4) optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof wherein R9 is hydrogen or C1-C10 alkyl; and r is an integer of 1, 2, 3 or 4, (5) wherein R10 is hydrogen or C1-C10 alkyl; Z is selected from the group consisting of oxy, thio and sulfinyl; and q is an integer of 0 or 1, and (6) wherein R11 is hydrogen or C1-C10 alkyl; i is an integer of 0, 1 or 2; j is an integer of 0, 1 or 2; and the sum of i + j is an integer of 1 or 2; and said Ar is a phenyl or naphthyl group, either substituted with at least one substituent selected from the group consisting of amino, C1-C10 alkylamino, C7-C12 aralkyl, C1-C10 acylamino, C1-C10 hydroxyalkyl, and C1-C10 hydroxyalkoxy and wherein;
said Ar is a phenyl or naphthyl group, either substituted with at least one substituent selected from the group consisting of amino, C1-C10 alkylamino, C7-C12 aralkyl, C1-C10 acylamino, C1-C10 hydroxyalkyl and C1-C10 hydroxyalkoxy and at least one substituent selected from the group consisting of halo, hydroxy, C1-C10 alkyl and C1-C10 alkoxy;
a biphenylenyl, phenoxyphenyl, dibenzothienyl, phenoxathiinyl, quinolyl, or quinoxalinyl group any of which is unsubstituted or substituted with one or more groups selected from the group consisting of hydroxy and C1-C10 alkyl;
a C7-C12 aralkyl, C9-C16 cycloalkylphenyl, fluorenyl, or 2H-chromenyl group any of which is unsubstituted or substituted with one or more groups selected from the group consisting of C1-C10 alkyl, C1-C10 alkoxy and oxo;
or a phenyl group substituted with at least one substituent selected from the group consisting of alkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonalkyl and alkoxycarbonylalkoxy, the said substituent containing 3 to 7 carbon atoms and the said substituted phenyl group being optionally substituted further with at least one substituent selected from the group consisting of methyl, ethyl, methoxy, ethoxy, hydroxy and halo, comprising:
reacting an N2-arylsulfonyl-L-arginyl halide having the formula:

wherein Ar is as defined above and X is halogen, with an amino acid derivative having the formula:

RH

wherein R is as defined herein above, and, if desired, hydrolyzing the reaction product obtained above.
46. An N2 arylsulfonyl-L-argininamide of the formula (I) and the pharmaceutically acceptable salts thereof wherein R and Ar are as defined in claim 45, whenever prepared by the process of claim 45 or an obvious chemical equivalent thereof.
47. The process of preparing an N2 arylsulfonyl-L-argininamide of the formula (I) and the pharmaceutically acceptable salts thereof, wherein R and Ar are as defined in claim 45, in accordance with claim 45, wherein the N2-arylsulfonyl-L-arginyl halide is reacted with at least an equimolar amount of the amino acid derivative at a temperature of from -10°C to +80°C.
48. An N2 arylsulfonyl-L-argininamide of the formula (I) and the pharmaceutically acceptable salts thereof wherein R and Ar are as defined in claim 47, whenever prepared by the process of claim 47 or an obvious chemical equivalent thereof.
49. A process for preparing an N2-arylsulfonyl-L-argininamide of the formula:

(I) and the pharmaceutically acceptable salts thereof wherein R is selected from the group consisting of (1) wherein R1 is selected from the group consisting of C2-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C2-C10 alkoxyalkyl, C2-C10 alkylthioalkyl, C2-C10 alkylsulfinylalkyl, Cl-C10 hydroxyalkyl, C3-C10 alkoxycarbonylalkyl, C3-C10 alkylcarbonylalkyl, Cl-C10 haloalkyl, C7-C15 aralkyl, C8-C15.alpha. -carboxyaralkyl, C3-C10 cycloalkyl, C4-C10 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof,C3-furylmethyl, tetrahydro-3-furylmethyl optionally substituted with at least one Cl-C5 alkyl, Cl-C5 alkoxy or mixtures thereof, tetrahydro-2(3 or 4)-pyranylmethyl optionally substituted with at least one Cl-C5 alkyl, Cl-C5 alkoxy or mixtures thereof, 1,4-dioxa-2-cyclohexylmethyl optional.ly substituted with at least open C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, and tetrahydro-3-thenyl; R2 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; and n is an integer of 1, 2 or 3, (2) wherein R3 is selected from the group consisting of hydrogen, C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C2-C10 alkoxyalkyl, C2-C10 alkylthioalkyl, C2-C10 alkylsulfinylalkyl, C1-C10 hydroxyalkyl, C3-C10 alkoxycarbonylalkyl, C3-C10 alkylcarbonylalkyi, C1-C10 haloalkyl, C7-C15 aralkyl, C8-C15,.alpha.-carboxyaralkyl, C3-C10 cycloalkyl, C4-C10 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, 3-furylmethyl; tetrahydro-3-furylmethyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, tetrahydro-2(3 or 4)-pyranylmethyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, 1,4 dioxa-2-cyclohexylmethyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, and tetrahydro-3-thenyl; R4 is selected from the group consisting of C1-C10 alkyl, phenyl optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, C7-C12 aralkyl and ring substituted benzyl wherein said substituent is C1-C5 alkyl or C1-C5 alkoxy; R5 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12; aralkyl;
and m is an integer of 0, 1 or 2 (3) wherein R6 is -COOR8 wherein R8 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; each R7 independently is hydrogen, C1-C10 alkyl; phenyl, C1-C5 alkoxy, C2-C6 alkoxycarbonyl or carboxy; p is an integer of 1 to 4; R6 is substituted at the 2 or 3-position; and R7 can be substituted at the 2, 3, 4, 5 or 6-position, (4) optionally substituted with at least one C1-C5 alkyl, C1-C5 alkoxy or mixtures thereof, wherein R9 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; and r is an integer of 1, 2, 3 or 4, (5) wherein R10 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; Z
is selected from the group consisting of oxy, thio and sulfinyl; and q is an integer of 0 or 1, and (6) wherein R11 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl and C7-C12 aralkyl; i is an integer of 0, 1 or 2; j is an integer of 0, 1 or 2;
and the sum of i + j is an integer of 1 or 2; and Ar is a phenyl or naphthyl group, either substituted with at least one substituent selected from the group consisting of sulfoamino, carbamoyl, C3-C10 N,N-dialkylcarbamoyl, C2-C6 N-alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxy, C2-C10 alkoxycarbonyl, C2-C10 carboxyalkyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy and phenyl optionally substituted with at least one hydroxy, C1-C5 alkoxy, or mixtures thereof;
a phenyl or naphthyl group, either substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy and C2-C20 dialkylamino, and at least one substituent selected from the group consisting of sulfoamino, carbamoyl, C3-C10 N,N-dialkylcarbamoyl, C2-C6 N-alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxy, acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy and phenyl optionally substituted with at least one hydroxy, C1-C5 alkoxy, or mixtures thereof;
an oxanthrenyl or dibenzofuranyl group substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C2-C20 dialkylamino, sulfoamino, carbamoyl, C3-C10 N,N-dialkylcarbamoyl, C2-C6 N-alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxyl, C2-C10 alkoxycarbonyl, C2-C10 carboxyalkyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy, and phenyl optionally substituted with at least one hydroxy, C1-C5 alkoxy, or mixtures thereof;
an oxanthrenyl or dibenzofuranyl group substituted with at least one substituent selected from the group consisting of C1-C10 alkyl and C1-C10 alkoxy, and at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C2-C20 dialkylamino, sulfoamino, carbamoyl, C3-C10 N,N-dialkylcarbamoyl, C2-C6 N-alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxyl, C2-C10 alkoxy-carbonyl, C2-C10 carboxyalkyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy and phenyl optionally substituted with at least one hydroxy, C1-C5 alkoxy, or mixtures thereof;
a tetrahydronaphthyl, 1,2-ethylenedioxyphenyl, chromanyl, 2,3-ethylenedioxynaphthyl or xanthenyl group, and substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C2-C20 dialkylamino, sulfoamino; carbamoyl, C3-C10 N,N-dialkylcarbamoyl, C2-C6 N-alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxyl, C2-C10 alkoxy-carbonyl, C2-C10 carboxyalkyl, C1-C10 acylamino, C2-C10 alkylcar-bonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy, oxo and phenyl optionally substituted with at least one hydroxy, C1-C5 alkoxy, or mixtures thereof;
a tetrahydronaphthyl, 1,2-ethylenedioxyphenyl, chromanyl, 2,3-ethylenedioxynaphthyl or xanthenyl group, and substituted with at least one substituent selected from the group consisting of C1-C10 alkyl and C1-C10 alkoxy, and at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C2-C20 dialkylamlno, sulfoamino, carbamoyl, C3-C10 N,N-dialkylcarbamonyl, C2-C6 N-alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxyl, C2-C10 alkoxycarbonyl, C2-C10 carboxyalkyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxy-alkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy, oxo and phenyl op-tionally substituted with at least one hydroxy, C1-C5 alkoxy, or mixtures thereof;

a naphthoquinonyl, anthryl, phenanthryl, pentalenyl, heptalenyl, azulenyl, biphenylenyl, as-indacenyl, S-indacenyl, acenaphthylenyl, phenylcarbonylphenyl, phenyoxyphenyl, benzofuranyl, isobenzofuranyl, benzo (b) thienyl, isobenzothienyl, thianthrenyl, dibenzothienyl, phenoxanthiinyl, indolyl, 1H-indazolyl, quinolyl, isoquinolyl, phthalazinyl, 1,8-naphthridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, or benzimidazolyl group any of which is unsubstituted or substituted with one or more groups selected from the group consisting of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy, C2-C20 dialkylamino, sulfoamino, carbamoyl, C3-C10 N,N-dialkylcarbamoyl, C2-C6 N-alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxyl, C2-C10 alkoxycarbonyl, C2-C10 carboxyalkyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy and phenyl optionally substituted with at least one hydroxy, C1-C5 alkoxy, or mixtures thereof;
a C7-C12 aralkyl, C9-C16 cycloalkylphenyl, C10-C18 cycloalkylalkylphenyl, C9-C16 cycloalkyloxyphenyl, C9-C16 cycloalkylthiophenyl, 9,10-dihydroanthryl, 5,6,7,8-tetrahydroanthryl, 9,10-dihydrophenanthryl, 1,2,3,4,5,6,7,8-octahydrophenanthryl, indenyl, indanyl, fluorenyl, acenaphthenyl, phenylthiophenyl, isochromanyl, 2,3-dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, thioxanthenyl, 2H-chromenyl, 3,4-dehydro-1-isochromanyl, 4H-chromenyl, indolinyl, isoindolinyl, 1,2,3,4-tetrahydroquinolyl or 1,2,3,4-tetrahydroisoquinolyl group any of which is unsubstituted or substituted with one or more groups selected from the group consisting of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy, C2-C20 dialkylamino, sulfoamino, carbamoyl, C3-C10 N,N-dialkylcarbamoyl, C2-C6 N-alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxyl, C2-C10 alkoxycarbonyl, C2-C10 carboxyalkyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy, oxo and phenyl optionally substituted with at least one hydroxyl, C1-C5 alkoxy, or mixtures thereof;
or a phenyl group substituted with at least one substituent selected from the group consisting of alkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxy-carbonyalkyl and alkoxycarbonylalkoxy, the said substituent containing 3 to 7 carbon atoms and the said substituted phenyl group being optionally substituted further with at least one substituent selected from the group consisting of methyl, ethyl, methoxy, ethoxy, hydroxy and halo, taken from the group of processes comprising:
(a) reacting a compound of the formula:

wherein R is as defined above with an arylsulfonyl halide compound;
(b) removing the NG-substituent from an NG-substituted-N2-arylsulfonyl-L-argininamide having the formula:

wherein X and Ar are as defined herein above; R' and R"
are selected from the group consisting of hydrogen and protective groups for the guanidino group, and at least one of R' and R" is a protective group for the guanidino group, by means of acidolysis or hydrogenolysis, and, if desired, hydrolyzing the reaction product obtained above;

or (c) reacting an N2-arylsulfonyl-L-arginyl halide having the formula:

wherein Ar is as defined herein above and X is halogen, with an amino acid having the formula:

RH

wherein R is as defined herein above, and, if desired, hydrolyzing the reaction product obtained above.
50. An N2 arylsulfonyl-L-argininamide of the formula (I) and the pharmaceutically acceptable salts thereof, wherein R and Ar are defined in claim 49, whenever prepared by a process according to claim 49 or the obvious chemical equivalent thereof.
CA293,199A 1974-11-08 1977-12-16 N.sup.2-arylsulfonyl-l-argininamides and the pharmaceutically acceptable salts thereof Expired CA1131621A (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US05/938,711 US4201863A (en) 1974-11-08 1978-08-31 N2 -Arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof
US06/041,419 US4258192A (en) 1977-12-16 1979-05-22 N2 -Arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof
UA2814248A UA8371A1 (en) 1974-11-08 1979-08-30 Process for the preparation of n2-arylsulfonyl-l-argininamides

Applications Claiming Priority (18)

Application Number Priority Date Filing Date Title
US05/760,672 US4093712A (en) 1974-11-08 1977-01-19 N2 -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof
US760,672 1977-01-19
US05/760,745 US4066773A (en) 1974-11-08 1977-01-19 N2 -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof
US760,745 1977-01-19
US05/760,929 US4101653A (en) 1974-11-08 1977-01-19 N2 -arylsulfonyl-argininamides and the pharmaceutically acceptable salts thereof
US760,929 1977-01-19
US760,668 1977-01-19
US05/760,668 US4073913A (en) 1974-11-08 1977-01-19 N2 -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof
US760,676 1977-01-19
US05/760,676 US4097472A (en) 1974-11-08 1977-01-19 N2 -arylsulfonyl-l-argininamides and the pharmaceutically acceptable salts thereof
US05/776,195 US4097591A (en) 1974-11-08 1977-03-10 N2 -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof
JP6650877A JPS6010028B2 (en) 1977-06-06 1977-06-06 N↑2-arylsulfonyl-L-argininamides and pharmaceutically acceptable salts thereof
US66508/77 1977-06-06
US804,331 1977-06-07
US804,368 1977-06-07
US05/804,331 US4140681A (en) 1974-11-08 1977-06-07 N2 -Arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof
US05/804,368 US4131673A (en) 1974-11-08 1977-06-07 N2 -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof
US776,195 1985-09-16

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
LT4368B (en) 1994-12-22 1998-08-25 Biochem Pharma Inc. Low molecular weight bicyclic thrombin inhibitors
US6057314A (en) * 1995-12-21 2000-05-02 Biochem Pharma Inc. Low molecular weight bicyclic thrombin inhibitors
CN111961114A (en) * 2020-08-03 2020-11-20 扬州中宝药业股份有限公司 Argatroban intermediate and preparation method and application thereof

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5533499A (en) * 1978-08-31 1980-03-08 Mitsubishi Chem Ind Ltd N2-arylsulfonyl-l-arginineamide and its pharmaceutically acceptable salt
IE48623B1 (en) * 1978-08-31 1985-03-20 Mitsubishi Chem Ind Alpha-(n-arylsulfonyl-l-argininamides,processes for their preparation and pharmaceutical compositions containing these substances
GB9209032D0 (en) * 1992-04-25 1992-06-10 Ciba Geigy Ag New peptide derivatives
FR2761065B1 (en) * 1997-03-20 2000-03-03 Synthelabo N- (ARGINYL) BENZENESULFONAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION

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US3978045A (en) * 1973-08-13 1976-08-31 Mitsubishi Chemical Industries Ltd. N2 -dansyl-L-arginine derivatives, and the pharmaceutically acceptable acid addition salts thereof

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
LT4368B (en) 1994-12-22 1998-08-25 Biochem Pharma Inc. Low molecular weight bicyclic thrombin inhibitors
US6057314A (en) * 1995-12-21 2000-05-02 Biochem Pharma Inc. Low molecular weight bicyclic thrombin inhibitors
CN111961114A (en) * 2020-08-03 2020-11-20 扬州中宝药业股份有限公司 Argatroban intermediate and preparation method and application thereof

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IL53685A0 (en) 1978-03-10
DE2801478C2 (en) 1991-01-31
DK150521C (en) 1987-10-19
NL187746B (en) 1991-08-01
DE2801478A1 (en) 1978-07-20
SE7800512L (en) 1978-07-20
NO158681B (en) 1988-07-11
UA8370A1 (en) 1996-03-29
DD137352A5 (en) 1979-08-29
FI780073A (en) 1978-07-20
FI72316B (en) 1987-01-30
IT1126229B (en) 1986-05-14
NL187746C (en) 1992-01-02
NO158681C (en) 1988-10-19
DK150521B (en) 1987-03-16
GB1596971A (en) 1981-09-03
SE452624B (en) 1987-12-07
PH15913A (en) 1983-04-22
FI72316C (en) 1987-05-11
NZ186198A (en) 1980-12-19
IL53685A (en) 1985-12-31
DK26378A (en) 1978-07-20
NO780191L (en) 1978-07-20
SU1181539A3 (en) 1985-09-23
GR60787B (en) 1978-08-28
NL7800448A (en) 1978-07-21
CH648293A5 (en) 1985-03-15
CH633773A5 (en) 1982-12-31

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