IE46686B1 - N2-arylsulfonyl-l-argininamides and the pharmaceutically acceptable salts thereof - Google Patents

Description

This invention relates to N -arylsulfonyl-L-argininamides and the pharmaceutically and veterinarily acceptable salts thereof, examples of which are found to possess especial value in view of their outstanding antithrombotic properties and low toxicities. | i In the past, there have been many attempt's to obtain new and improved agents for the treatment of thrombosis.

The N -(p-tolysulfonyl)-L-arginine esters have been found to be one type of agent which can be used and these have been found to be effective in dissolving blood clots, ί (U.S.

Pateht No. 3,622,615, issued November 23, 1971). One family of compounds which have been found to be particularly useful as highly specific inhibitors of thrombin for the control of thrombosis Is the N -dansyl-L-arginine ester or amide.

(Our pending U.S. Application Serial No. 496,939, filed August, 13, 1974, now U.S. Patent No. 3,978,045) However, there is a continuing need for a highly specific inhibitor of thrombin for the:control of thrombosis, which exhibits lower toxicity. j v The present invention provides an N2-aryls'ulfonylL-argininamide of the formula (I): HN, h2n? C - Ng - CH-CH·,' I I 2 H H2CHCOR (I) Jn2so.

X Ar 4663S wherein R is (CH2)nc°OR2 wherein Rx is C2 to C1Q alkyl, C3 to C1Q alkenyl, C3 to C1Q alkynyl, C2 to C1Q alkoxyalkyl, C2 to C1Q alkylthioalkyl, C2 to alkylsulfinylalkyl, to C1Q hydroxyalkyl, C3 to C1Q alkoxycarbonylalkyl, C3 to C1Q alkylcarbonylalkyl, to C1Q haloalkyl, C? to C15 aralkyl, Cg to C15 ot-carboxyaralkyl, C3 to Clo cycloalkyl, C4 to C1Q cycloalkylalkyl, furfuryl, tetrahydrofurfuryl, optionally substituted with one or more of C-^ to Cg alkyl and/or to Cg alkoxy, 3furylmethyl, tetrahydro-3-furylmethyl optionally substituted with one or more of to Cg alkyl and/or C^ to Cg alkoxy, tetrahydro-2 (3 or 4)-pyranylmethyl (i.e. tetrahydro-2pyranylmethyl, tetrahydro-3-pyranylmethyl, or tetrahydro15 4-pyranylmethyl) optionally substituted with one or more of C^ to Cg alkyl and/or C^ to Cg alkoxy, 1,4-dioxa-2-cyclohexylmethyl optionally substituted with one or more of C^ to Cg alkyl and/or* C^ to Cg alkoxy, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl optionally substituted with one or more of C^ to Cg alkyl and/or C^ to Cg alkoxy, or tetrahydro-3thenyl; R2 is hydrogen, C^ to C^Q alkyl, Cg to C^ aryl or C? to C^2 aralkyl; and n is 1, 2 or 3, i (2), wherein R3 is hydrogen, C.^ to ClQ alkyl, C3 to ClQ alkenyl, 25 C3 to C1Q alkynyl, C2 to C1Q alkoxyalkyl, C2 to C^Q alkylthioalkyl, C2 to C1Q alkylsulfinylalkyl, to C1Q hydroxyalkyl, C3 to C1Q alkoxycarbonylalkyl, C3 to C1Q alkylcarCH - (CH-)_COORc | 2 m 5 R, 6 6 3 6 bonylalkyl, to C1Q haloalkyl, Cy to Clg aralkyl, Cg to C15 «-carboxyaralkyl, Cg to C^Q cycloalkyl, to C1Q cycloalkylalkyl, furfuryl, tetrahydrofurfuryl optionally substituted with one or more of to Cg alkyl and/or Cj to Cg alkoxy, 3-furylmethyl, tetrahydro-3-furylmethy! optionally substituted with one or more of C^ to Cg alkyl and/or to Cg alkoxy, tetrahydro-2 (3 or 4)-pyranylmethy1 optionally substituted with one or more of to Cg alkyl and/or to Cg alkoxy, 1,4-dioxa-2-cyclohexylmethy1 optionally substituted with one or more of to Cg alkyl and/or to Cg alkoxy, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl optionally substituted with one or more of C^ to Cg alkyl and/or C^ to Cg alkoxy, or tetrahydro-3-thenyl; is C^ to C^Q alkyl, phenyl optionally substituted with one or more of C^ to Cg alkyl and/or C^ to Cg alkoxy, Cy to C12 aralkyl or ring substituted benzyl wherein said substituent is C^ to Cg alkyl or C-^ to Cg alkoxy; Rg is hydrogen, C^ to C1Q alkyl, Cg to C1Q aryl or C? to C12 aralkyl; and m is 0, or 2. (3) wherein Rg is -COORg wherein Rg is hydrogen, C-^ to C1Q alkyl, Cg to C^Q aryl or Cy to C12 aralkyl; each Ry independently is cx to C1Q alkyl, phenyl, to Cg alkoxy, C2 to Cg alkoxycarbonyl or carboxyl; p is 0 or an integer from 1 to 4; Rg is substituted at the the 2 or 3-position; and Ry, if present, is substituted at the 2, 3, 4, 5 or 6-position, (4) optionally substituted with one or more of 0χ to C5 alkyl and/ or C1-C5 alkoxy, wherein Rg is hydrogen, to C1Q alkyl, Cg to C1Q aryl or C? to C12 aralkyl; and r is 1, 2, 3 or 4, wherein R^Q is hydrogen, to alkyl, Cg to C10 aryl or Cy to C12 aralkyl; Z is oxygen, sulphur or sulfinyl; and q is 0 or 1, or COOR.. \ wherein is hydrogen, to alkyl, Cg to C^Q aryl or Cy to C^2 aralkyl; i is 0, 1 or 2; j is 0, 1 or 2; and the sum of i + j is 1 or 2; and Ar is phenyl or naphthyl, substituted with at least: one of sulfoamino, carbamoyl, Cg to C^Q Ν,Ν-dialkylcarbamoyl, C2 to Cg N-alkylcarbamoyl, amino, C^ to C^Q alkylamino, mercapto, C^ to C^o alkylthio, Cy to C^2 aralkyl, carboxyl, C/ to C^Q alkoxycarbonyl, C2 to C^Q carboxyalkyl, C^ to acylamino, C2 to C^Q alkylcarbonyl, C^ to C^q hydroxyalkyl, C^ to C^Q haloalkyl, C^ to C^Q hydroxyalkoxy, and/or phenyl (optionally substituted with one or more of hydroxy, and/or C-^ to Cg alkoxy); phenyl or naphthyl, substituted with at least one of halo, nitro, cyano, hydroxy, C1 to alkyl, C-^ to C1Q alkoxy and/or C2 to C2Q dialkylamino, and at least one of sulfoamino, carbamoyl, Cg to C^Q Ν,Ν-dialkylcarbamoyl, C2 to 6 6 8 6 Cg N-alkylcarbamoyl, amino, Cj to CjQ alkylamino, mercapto, C1 to C1O alkYlthl°' c7 to ci2 aralkyl, carboxyl, C2 to CjQ alkoxycarbonyl, C2 to Cj0 carboxyalkyl, Cj to CjQ acylamino, C2 to C10 alkylcarbonyl, ci to cio hydroxyalkyl, Cj to CjQ haloalkyl, Cj to CjQ hydroxyalkoxy, and/or phenyl (optionally substituted with one or more of hydroxy, and/or Cj to C5 alkoxy); oxanthrenyl or dibenzofuranyl substituted With at least one of halo, nitro, cyano, hydroxy, C2 to C2Q dialkylamino, sulfoamino, carbamoyl, Cg to CjQ Ν,Ν-dialkylcarbamoyl, C2 to Cg N-alkylcarbamoyl, amino, Cj to CjQ alkylamino, mercapto, Cj to Cjq alkylthio, C? to Cj2 aralkyl, carboxyl, C2 to CjQ alkoxycarbonyl, C2 to CjQ carboxyalkyl, Cj to CjQ acylamino, C2 to Cjq alkylcarbonyl, Cj to Cjq hydroxyalkyl,, Ci to CjQ haloalkyl, Cj to Cjq hydroxyalkoxy,, and/or phenyl 1 15 (optionally substituted with one or more of hydroxy and/or Cj to Cg alkoxy); oxanthrenyl or dibenzofuranyl substituted with at least one of Cj to CjQ alkyl and/or Cj to CjQ alkoxy, and at least one of halo, nitro, cyano, hydroxy, C2 to C2Q dialkylamino, sulfoamino, carbamoyl, Cg to CjQ N,N-dialkyl20 carbamoyl, C2 to Cg N-alkylcarbamoyl, amino, Cj to CjQ alkylamino, mercapto, Cj to CjQ alkylthio, C? to Cj2 aralkyl, carboxyl, C2 to Cjq alkoxycarbonyl, C2 to CjQ carboxyalkyl, Cj to Cjq acylamino, C2 to CjQ alkylcarbonyl, Cj to CjQ hydroxyalkyl, Cj to CjQ haloalkyl, Cj to CjQ hydroxyalkoxy, and/or phenyl (optionally substituted with one or more of / hydroxy and/or Cj to Cg alkoxy); tetrahydronaphthyl, 1,2ethylenedioxyphenyl, chromanyl, 2,3-ethylenedioxyna’phthyl or xanthenyl, substituted with at least one of halo, nitro, cyano, hydroxy, C2 to C2Q dialkylamino, sulfoamino, carbamoyl, Cg to CjQ Ν,Ν- dialkylcarbamoyl, C2 to Cg N-alkylcarbamoyl, amino, Cj to CjQ alkylamino, mercapto, Cj to CjQ alkylthio, c7 t0 C12 aralkyl, carboxyl, Cj to CjQ alkoxycarbonyl, Cj to c10 carboxyalkyl, Cj to CjQ acylamino, C2 to CjQ alkylcarbonyl, C1 to Cio hydroxyalkyl, Cj to CjQ haloalkyl, Cj to CjQ hydro35 xyalkoxy, oxo and/or phenyl (optionally substituted with one or more of hydroxy, and/or Cj to Cg alkoxy); tetrahydronaphthyl, 1,2-ethylenedioxyphenyl, chromanyl, 2,3-ethylenedioxy7 4-6 6 36 naphthyl or xarithenyl, substituted with at least one of to C1Q alkyl and/or C4 to C1Q alkoxy, and at least one of halo, nitro, cyano, hydroxy, C2 to C2Q dialkylamino, sulfoamino, carbamoyl, C3 to C-^θ Ν,Ν-dialkylcarbamonyl, C2 to Cg N-alkyl5 carbamoyl, amino, to C1Q alkylamino, mercapto, C4 to C10 alkylthio, C? to C12 aralkyl, carboxyl, C2 to C1Q alkoxycarbonyl, C2 to C40 carboxyalkyl, C^ to C-^θ acylamino, C2 to C1Q alkylcarbonyl, C4 to C1Q hydroxyalkyl, C^ to C1Q haloalkyl, C^ to C4Q hydroxyalkoxy, oxo, and/or phenyl, (optionally substituted with one or more of hydroxy and/or C^ to Cg alkoxy) naphthoquinonyl, anthryl, phenanthryl, pentalenyl, haptalenyl, azulenyl, biphenylenyl, asym-indacenyl, sym-indacenyl, acenaphthylenyl, phenylcarbonylphenyl, phenoxyphenyl, benzofuranyl, isobenzofuranyl, benzo (b) thienyl, isobenzothienyl, thian15 threnyl, dibenzothienyl, phenoxathiinyl, indolyl, lH-indazolyl, quinolyl, isoquinolyl, phthalazinyl, 1,8-naphthridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, or benzimidazolyl optionally substituted with one or more of halo, nitro, cyano, hydroxy, to C1Q alkyl, C^ to C1Q alkoxy, C2 to C2Q dialkylamino, sulfoamino, carbamoyl, Cg to C1Q Ν,Ν-dialkylcarbamoyl, C2 to Cg N-alkylcarbamoyl, amino, C^ to alkylamino, mercapto, C^ to C^o alkylthio, C? to Cj2 aralkyl, carboxyl, C2 to C|0 alkoxycarbonyl, C2 to C^o carboxyalkyl, C^ to C^q acyl25 amino, C2 to C1Q alkylcarbonyl, 0χ to C1Q hydroxyalkyl, C-^ to C1Q haloalkyl, C^ to C1Q hydroxyalkoxy, and/or phenyl (optionally substituted with one or more of hydroxy and/or C^ to Cg alkoxy); C? to C^2 aralkyl, Cg to Clg cycloalkylphenyl, C^Q to C18 cycloalkylalkylphenyl, Cg to Clg cycloalkyloxyphenyl, Cg to C16 cycloalkylthiophenyl, 9,10-dihydroanthryl,:.5,6,7,8tetrahydroanthryl, 9,10-dih ydrophenanthryl, 1,2,3,4,5,6,7,8octahydrophenanthryl, indenyl, indanyl, fluoroenyl, acenaphthenyl, phenylthiophenyl, isochromanyl, 2,3-dihydrobenzofuranyl, 1,3-dihydroisobenz ofiiranyl, thioxanthenyl, 2H-chro35 menyl, 3,4-dehydro-l-isochromanyl, 4H-chromenyl, indolinyl, isoindolinyl, 1,2,3,4-tetrahydroquinolyl or 1,2,3,4-tetrahydroisoquinolyl group optionally substituted with one or more of halo, nitro, cyano, hydroxy to C1Q alkyl, to C1Q alkoxy, C2 to C2Q dialkylamino, sulfoamino, carbamoyl, C3 to N,Ndialkylcarbamoyl, C2 to Cg N-alkylcarbamoyl, amino, to C1Q alkylamino, mercapto, to Ο^θ alkylthio, Cy to C^2 aralkyl, carboxyl, C2 to C^Q alkoxycarbonyl, C2 to carboxyalkyl, to C^Q acylamino, C2 to Ο^θ alkylcarbonyl, to C^Q hydroxyalkyl, to C^Q haloalkyl, C-^ to C^Q hydroxyalkoxy, oxo and/or phenyl (bptionally substituted with one or more of hydroxyl and/or to C5 alkoxy), or phenyl substituted with at least one of alkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkyl and alkoxycarbonylalkoxy, the said substituent containing 3 to 7 carbon atoms and 'the said substituted phenyl group be ing optionally substituted further with one or more of methyl, ethyl, methoxy, ethoxy, hydroxy nad/or halo. Also encompassed within this invention are pharmaceutically acceptable and veterinarily salts thereof.

This invention also relates to a method for inhibiting activity and suppressing activation of thrombin in vivo in mammals which comprises administering to a non-human mammal a veterinarily (antithrombotically) effective amount of an N arylsulfonyl-L-argininamide or the pharmaceutically acceptable salts thereof.

Exemplification of the groups R and Ar will now be provided. R may be R. (1) - N (CH2)ncOOR2 wherein is C2 to Ο^θ alkyl, such as ethyl, propyl, butyl, isobutyl, pentyl, hexyl, octyl, or decyl, alkenyl of 3 to 10 (preferably 3 to 6) carbon atoms, such as allyl, 2-butenyl, 3-butenyl, 3-butenyl or 2-pentenyl, alkynyl of 3 to 10 (preferably 3 to 6) carbon atoms, such as 2-propynyl, 2-butynyl, or 3-butynyl, alkoxyalkyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as methoxymethyl, ethoxymethyl, propoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-propoxyethyl, 2-meth9 46636 oxypropyl, 3-methoxypropyl, 3-ethoxypropyl, 3-propoxypropyl, 4-methoxybutyl, 4-ethoxybutyl, 4-butoxybutyl, or 5-butoxypentyl, alkylthioalkyl of 2 to 10 (preferably 2 to 6) carbon atoms such as methylthiomethyl, ethylthiomethyl, propylthiomethyl, 2-methylthioethyl, 2-ethylthioethyl, 2-propylthioethyl, 3-methylthiopropyl, 2-methylthiopropyl, 3-ethylthiopropyl, 3-propylthiopropyl, 4-methylthiobutyl, 4-ethylthiobutyl, 4-butylthiobutyl, or 5-butylthiopentyl, alkylsulfinylalkyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as methylsulfinylmethyl, ethylsulfinylmethyl, propylsulfinylmethyl, 2-methylsulfinylethyl, 2-ethylsulfinylethyl, 2-propyl sulfinylethyl, 3-methylsulfinylpropyl, or 3-ethylsulfinylpropyl, hydroxyalkyl of 1 to 10 (preferably 1 to 6) carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl 2-hydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, or. 5-hydroxy pentyl, alkoxycarbonylalkyl of 3 to 10 (preferably 3 to 8) carbon atoms, such as methoxycarbonylmethyl, 2-ethoxycarbonyl ethyl, 2-ethoxycarbonylpropyl, 3-methoxycarbonylpropyl, 1methoxycarbonylbutyl, 2-ethoxycarbonylbutyl or 4-methoxycarbony lbutyl, alkylcarbonylalkyl of 3 to 10 carbon atoms such as methylcarbonylethyl, haloalkyl of 1 to 10 (preferably 1 to 5) carbon atoms such as chloromethyl, 2-chloroethyl, 2-bromoethyl, 2-chloropropyl, 3-chloropropyl, 2-chlorobutyl or 4chlorobutyl, aralkyl of 7 to 15 (preferably 7 to 10) carbon atoms, such as benzyl, phenethyl, 3-phenylpropyl, 4-phanylbutyl, 5-phenyl hexyl, 1-phenylethyl or 2-phenylpropyl, α-carboxyaralkyl of 8 to 15 (preferably 8 to 12) carbon atoms such as a-carboxybenzyl or α-carboxyphenethyl, Cg to C1Q cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl cyclooctyl, cycloncnyl or cyclodecyl, to cycloalkylalkyl, such as cyclopropylmethyl, cyclopentylmethyl, cyclohexy lmethyl, 2-cyclohexylethyl or cyclooctylmethyl, furfuryl tetrahydrofurfuryl, optionally substituted with one or more C1 to C5 alkyl, such as methyl, ethyl, propyl or butyl and/or C1 t0 ^5 alkox7 groups, such as methoxy, ethoxy, propoxy, or butoxy, 3-furylmethyl, tetrahydro-3-furylmethyl, optionally substituted with one or more to Cg alkyl such as methyl, ethyl, propyl, or butyl, and/or to C5 alkoxy groups, such 6 6 3 6 ιΟ as methoxy, ethoxy, propoxy, or butoxy, tetrahydro-2(3 or 4)pyranylmethyl optionally substituted with one or more to C5 alkyl such as methyl, ethyl, propyl or butyl and/or C^ to Cg alkoxy groups, such as methoxy, ethoxy, propoxy of butoxy, l,4-dioxa-2-cyclohexylmethy1 optionally substituted .with one > or more C^ to Cg alkyl such2 is hydrogen, C^ to C1Q alkyl, such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl, or decyl, Cg to C1Q aryl, such as phenyl, m-tolyl, or [naphthyl and aralkyl of 7 to 12 (pre ferably 7 to 10) carborj atoms, such as benzyl, or phenethyl, and n is 1, 2 or 3, | (2) CH - (CH2)mCOORg wherein Rg is hydrogen, C^ to C^Q alkyl, such as methyl, ethyl, propyl, butyl, isobutyl, pentyl, hexyl, octyl, or decyl, alkenyl of 3 to 10 (preferably 3 to 6) carbon atoms, such as allyl, 2-butenyl, 3-butenyl or 2-pentenyl, alkynyl of 3 to 10 (preferably 3 to 6) carbcn atoms, such as 2-propynyl, 2butynyl to 3-butynyl, alkoxyalkyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as methoxymethyl, ethoxymethyl, propoxy25 methyl, 2-methoxyethyl, 2-ethoxyethyl, 2-propoxyethyl, 2methoxypropyl, 3-methoxypropyl, 3-ethoxypropyl, 3-pfopoxypropyl, 4-methoxybutyl, 4-ethoxybutyl, 4-butoxybutyi; to 5butoxypentyl, alkylthioalkyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as methylthiomethyl, ethylthiomethyl, propylthiomethyl, 2-methylthioethyl, ethylthioethyl, 2-propylI thioethyl, 3-methylthiopropyl, 2-methylthiopropyl, 3-ethylthioprqpyl, 3-propylthiopropyl, 4-methylthiobutyl, 4-ethylthiobutyl, 4-butylthiobutyl, or 5-butylthiopentyl, alkylsulfinylalkyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as methylsulfinylmethyl, ethylsulfinylmethyl, propylsulfinylmethyl, 2-methylsulfinylethyl, 2-ethylsulfinylethyl, 2-propylsulfinylethyl, 3-methylsulfinylpropyl, or 3-ethylsulfinylpropyl, hydroxyalkyl of 1 to 10 (preferably 1 to 6) carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, or 5-hydroxypentyl, alkoxycarbonylalkyl of 3 to 10 (preferably 3 to 8) carbon atoms, such as methoxycarbonylmethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylpropyl, 3-methoxycarbonylpropyl, 1methoxycarbonyIbutyl, 2-ethoxycarbonyIbutyl, or 4-methoxycar15 bonyIbutyl, alkylcarbonylalkyl of 3 to 10 carbon atoms such as methylcarbonylethyl, haloalkyl of 1 to 10 (preferably 1 to 5) carbon atoms such as chlorcmethyl, 2-chloroethyl, 2-bromoethyl, 2-chloropropyl, 3-chloropropyl, 2-chlorobutyl, or 4chlorobutyl, aralkyl of 7 to 15 (preferably 7 to 10) carbon atoms, such as benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 6-phenylhexyl, 1-phenylethyl or 2-phenylpropyl, acarboxyaralkyl of 8 to 15 (preferably 8 to 12) carbon atoms, such as α-carboxybenzyl or α-carboxyphenethyl Cg to cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclo25 hexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, C^ to C^Q cycloalkylalkyl, such as cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclohexylethyl, cyclooctylmethyl, furfuryl, tetrahydrofurfuryl optionally substituted with one or more to Cg alkyl such as methyl, ethyl, propyl, or butyl, and/or to Cg alkoxy groups, such as methoxy, ethoxy, propoxy, or butoxy, 3-furylmethyl, tetrahydfo-3-furylmethyl optionally substituted with one or more C^ to Cg alkyl such as methyl, ethyl, propyl, or butyl, and/or C^ to Cg'alkoxy groups, such as methoxy, ethoxy, propoxy, or butoxy, tetra35 hydro-2(3 or 4)pyranylmethyl optionally substituted with one or more C^ to Cg alkyl such as methyl, ethyl, propyl, or butyl and/or C^ to Cg alkoxy groups, such as methoxy, ethoxy, propoxy or butoxy, l,4-dioXa-2-cyclohexylmethyl optionally •ί if ο y e substituted with one or more Cj to Cg alkyl such as methyl, ethyl, propyl, or butyl, and/or Cj to Cg alkoxy groups, such as methoxy, ethoxy, propoxy or butoxy, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl optionally substituted with one or more Cj to Cg alkyl such as methyl, ethyl, propyl or butyl, and/ or Cj to Cg alkoxy group, such as methoxy, ethoxy, propoxy or butoxy, and tetrahydro-3-thenyl; R^ is alkyl of 1 to 10 (preferably 1 to 5) carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or pentyl, phenyl optionally substituted with one or more Cj to Cg alkyl, such as methyl, ethyl, propyl or butyl, and/or Cj to Cg alkoxy groups, such as methoxy, ethoxy, propoxy or butoxy, aralkyl of 7 to 12 (preferably 7 to 10) carbon atoms, such as benzyl, or phenethyl, and ring substituted benzyl wherein said substituent is alkyl of 1 to 5 (preferably 1 to 3) carbon atoms, such as methyl, ethyl, propyl or isopropyl, or alkoxy of 1 to 5 (preferably 1 to 3) carbon atoms, such as methoxy, ethoxy, propoxy or isopropoxy; Rg is hydrogen, Cj to CjQ alkyl, such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl, or decyl, Cg to CjQ aryl, such as phenyl, m-tolyl, or naphthyl, and aralkyl of 7 to 12 (preferably 7 to 10) carbon atoms, such as benzyl, or phenethyl; and m is 0 or 1 or 2 R, '6 (3) wherein Rg is -COORg wherein Rg is hydrogen, Cj to Cjq alkyl, such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl or decyl, Cg to CjQ aryl, such as phenyl, m-tolyl or naphthyl, and aralkyl of 7 to 12 (preferably 7 to 10) carbon atoms, such as benzyl, or phenethyl; each Ry independently is hydrogen, alkyl of 1 to 10 (preferably 1 to 6) carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, hexyl, octyl, or decyl, phenyl, to C5 alkoxy, such as methoxy, ethoxy, propoxy, or butoxy, C2 to Cg alkoxycarbonyl, such as methoxycarbonyl, or ethoxycarbonyl, or carboxy; p is 0 or an integer of 1 to 4; Rg is substituted at the 2 or 3-position; and R? if present, is·, substituted at the 2, 3, 4, 5 or 6-position optionally substituted with one or more to Cg alkyl, such as methyl, ethyl, propyl, or butyl, or to Cg alkoxy groups, such as methoxy, ethoxy, propoxy or butoxy wherein Rg is hydrogen, to C1Q alkyl, s uch as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl, or decyl, Cg to Ο^θ aryl, such as phenyl, m-tolyl or naphthyl and aralkyl of 7 to 12 (preferably 7 to 10) carbon atoms, such as benzyl or phenethyl and r is 1, 2, 3 or 4, (5) - Ν Z V<CH2>q wherein R^Q is hydrogen, C-^ to alkyl, such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl or decyl, Cg to Clo aryl, such as phenyl, m-tolyl or naphthyl and aralkyl of 7 to 12 (preferably 7 to 10) carbon atoms, such as benzyl or phenethyl; Z is oxygen, sulphur ot sulfinyl (-SQ-); q is 0 or 1, and (6) s.

COOR. ’ll (ch2) -N wherein Rjj is hydrogen, Cj to CjQ alkyl, such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl or decyl, Cg to Cjq aryl, such as phenyl, m-tolyl or naphthyl, and aralkyl of 7 to 12 (preferably 7 to 10) carbon atoms, such as benzyl or phenethyl, i is 0, 1 or 2; j is 0, 1 or 2; and the sum of i + j is 1 or 2; and Ar is phenyl or inaphthyl substituted with at least one of sulfoamino, carbamoyl, Ν,Νdialkylcarbamoyl of 3 to 10 (preferably 3 to 7) carbon atoms, such as N,N-dimethylcarbamoyl, or Ν,Ν-diethylcarbamoyl, Nalkylcarbamoyl of 2 to 6 (preferably 2 to 4) carbon atoms, such as N-methylcarbamoyl, or N-ethyloarbamoyl, amino, alkylamino of 1 to 10 . (preferably 1 to 5) carbon atoms, such as methylamino, ethylamino, propylamino or butylamino, mercapto, alkylthio of 1 to 10 (preferably 1 to 5) carbon atoms, such as methylthio, ethylthio, propylthio, or butylthio, aralkyl of 7 to 12 (preferably 7 to 10) carbon atoms, such as benzyl or phenethyl, carboxyl, alkoxycarbonyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as methoxycarbonyl or ethoxycarbonyl, carboxyalkyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as carboxymethyl, 2-carboxyethyl or 2carboxypropyl, acylamino such as alkylcarbonylamino of 1 to 10 (preferably 1 to 5) carbon atoms, such as acetylamino, or propionylamino, alkylcarbonyl of 2 to 10 (preferably 2 to 6) carbon atoms such as acetyl or propionyl, hydroxyalkyl of 1 to 10 ( preferably 1 to 5) carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, or 2-hydroxypropyl, haloalkyl of 1 to 10 (preferably 1 to 5) carbon atoms, such as chloromethyl, trifluoromethyl, bromomethyl, or 2-chloroethyl, hydroxyalkoxy of 1 to 10 (preferably 1 to 5) carbon 46636 atoms, such as hydroxymethoxy, or 2-hydroxyethoxy and phenyl optionally substituted with at least one hydroxy and/or to C5 alkoxy, such as methoxy, ethoxy, propoxy, or butoxy; phenyl or naphthyl, substituted with at least one of sulfoamino, carbamoyl, Ν,Ν-dialkylcarbamoyl of 3 to 10 (preferably 3 to 7) carbon atoms, such as N,N-dimethylcarbamoyl or Ν,Ν-diethyloarbamoyl, N-alkylcarbamoyl of 2 to 6 (preferably 2 to 4) carbon atoms, such as N-methylcarbamoyl or Nethylcarbamoyl, amino, alkylamino of 1 to 10 (preferably 1 to 5) carbon atoms, such as methylamino, ethylamino, propylamino, or butylamino, mercapto, alkylthio of 1 to 10 (preferably 1 to 5) carbon atoms, such as methylthio, ethylthio, propylthio, or butylthio aralkyl of 7 to 12 (preferably 7 to 10) carbon atoms, such as benzyl, or phenethyl, carboxyl, alkoxycarbonyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as metho.xyoarbonyl, or ethoxycarbonyl, carboxyalkyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as carboxymethyl, 2-carboXyethyl, or 2-carboxypropyl, acylamino such as alkylcarbonylamino of 1 to 10 (preferably 1 to 5) carbon atoms, such as acetylamino, or propionylamino, alkylcarbonyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as acetyl, or propionyl, hydroxyalkyl of 1 to 10 (preferably 1 to 5) carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, or 2-hydroxypropyl, haloalkyl of 1 to 10 (preferably 1 to 5) carbon atoms, such as chloromethyl, trifluoromethyl, bromomethyl, or 2-chloroethyl, hydroxyalkoxy of 1 to 10 (preferably 1 to 5) carbon atoms, such as hydroxymethoxy, or 2hydroxyethoxy, and/or phenyl optionally substituted with one or more of hydroxy and/or C1 to Cg alkoxy, such as methoxy, ethoxy, propoxy or butoxy and at least one of halo, nitro, cyano, hydroxy, alkyl of 1 to 10 (preferably 1 to 5) carbon atoms, suoh as methyl, ethyl, propyl, or butyl, alkoxy of 1 to 10 (preferably 1 to 5) carbon atoms, such as methoxy, ethoxy, propoxy or butoxy, dialkylamino of 2 to 20 (prefer35 ably 2 to 10) carbon atoms, such as dimethylamino, diethylamino, or dipropylamino; oxanthrenyl or dibenzofuranyl substituted with at least one of halo, nitro, cyano, hydroxy, dialkylamino of 2 to 20 (preferably 2 to 10) carbon atoms, I; such as dimethylamino, diethylamino, or dipropylamino, sulfoamino, carbamoyl, Ν,Ν-dialkylcarbamoyl of 3 to 10 (preferably 3 to 7) carbon atoms, such as N,N-dimethy1carbamoyl, or N,N-diethylcarbamoyl, N-alkylcarbamoyl.of 2 to 6 (preferably 2 to 4) carbon atoms, .such as N-methylcarbamoyl, or N-ethyloarbamoyl, amino, alkylamino of 1 to 10 (preferably 1 to 5) carbon atoms, such as methylamino, ethylamino, propylamiho, or butylamino, mercapto, alkylthio of 1 to 10 (preferably 1 to 5) carbon atoms, such as methyl10 thio, ethylthio, propylthio, or butylthio, aralkyl of 7 to 12 (preferably 7 .to 10) carbon atoms, such as benzyl, or phenethyl, carboxyl alkoxycarbonyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as methoxycarbonyl, or ethoxycarbonyl, carboxyalkyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as carboxymethyl, 2-carboxyethyl or ^-carboxypropyl, acylamino such as alkylcarbonylamino of 1 to 10 (preferably 1 to 5) carbon atoms, such as acetylamino, or propionylamino, alkylcarbonyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as acetyl, or propionyl, hydroxyalkyl of 1 to 10 (preferably 1 to 5) carbon atoms, such asihydroxymethyl, 2-hydroxyethyl, or 2-hydroxypropyl haloalkyl of 1 to 10 (preferably 1 to 5) carbon atoms, such as chloromethyl, trifluoromethyl, bromomethyl, or 2-chloroethyl, hydroxyalkoxy of 1 to 10 (preferably 1 to 5) carbon atoms, such as hydroxymethoxy, or 2-hydroxyethoxy, and phenyl optionally substituted with one or more of hydroxy and/or C^-to Cg alkoxy, such as methoxy, ethoxy, propoxy, or butoXy; oxanthrenyl or dibenzofuranyl substituted with at; least one of alkyl of 1 to 10 (preferably 1 to 5) carbon atoms, i; such as methyl, ethyl, propyl, or butyl, alkoxy of 1 to 10 (preferably 1 to 5) carbon atoms, such as methoxy, ethoxy, propoxy or butoxy, and at least one of halo, nitro, cyano, hydroxy, dialkylamino of 2 to 20 (preferably 2 to ?10) carbon atoms, such as dimethylamino, diethylamino/ or dippo35 pylamino, sulfoamino, carbamoyl, Ν,Ν-dialkylcarbamoyl of 3 to 10 (preferably 3 to 7) carbon atoms, such as N,N-dimethylcarbamoyl or N,N-diethylcarbamoyl, N-alkylcarbamoyl of 2 to 6 (preferably 2 to 4) carbon atoms, such as Ni ν 4G686 methylcarbamoyl or N-ethylcarbamoyl amino, alkylamino of 1 to 10 (preferably 1 to 5) carbon atoms, such as methylamino, ethylamino, propylamino, or butylamino, mercapto, alkylthio of 1 to 10 (preferably 1 to 5) carbon atoms, such as methylthio, ethylthio, propvlthio or butylthio, aralkyl of 7 to 12 (preferably 7 to 10) carbon atoms, such as benzyl, or phenethyl, carboxyl, alkoxycarbonyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as methoxycarbonyl, or ethoxycarbonyl, carboxyalkyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as carboxymethyl, 2-carboxyethyl, or 2carboxypropyl, acylamino such as alkylcarbonylamino of 1 to 10 (preferably 1 to 5) carbon atoms, such as acetylamino, or propionylamino, alkylcarbonyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as acetyl, or propionyl hydroxy15 alkyl of 1 to 10 (preferably 1 to 5) carbon atoms', such as s hydroxymethyl, 2-hydroxyethyl, or 2-hydroxypropyl·, haloalkyl of 1 to 10 (preferably 1 to 5) carbon atoms, such as chloromethyl, trifluoromethyl, bromomethyl, or 2-chloroethyl, hydroxyalkoxy of 1 to 10 (preferably 1 to 5) carbon atoms, such as hydroxymethoxy, or 2-hydroxyethoxy, and phenyl optionally substituted with one or more of hydroxy and/or to Cg alkoxy, such as methoxy, ethoxy, propoxy or butoxy; tetrahydronaphthyl, 1,2-ethylenedioxypheny1, chromanyl, 2,3-ethylenedioxynaphthyl or xanthenyl, substituted with at least one of halo nitro, cyano, hydroxy, dialkylamino of 2 to 20 (preferably 2 to 10) carbon atoms, such as dimethylamino, diethylamino, or dipropylamino, sulfoamino, carbamoyl, Ν,Ν-dialkylcarbamoyl of 3 to 10 (preferably 3 to 7) carbon atoms, such as Ν,Ν-dimethylcarbamoyl, or N,N-diethyl30 carbamoyl, N-alkylcarbamoyl of 2 to 6 (preferably 2 to 4) Carbon atoms, such as N-methylcarbamoyl, or N-ethylcarbamoyl, amino, alkylamino of 1 to 10 (preferably 1 to 5) carbon atoms, such as methylamino, ethylamino, propylamino, or butylamino, mercapto, alkylthio of 1 to 10 (preferably 1 to 5) carbon atoms, such as methylthio, ethylthio, propylthio, or butylthio aralkyl of 7 to 12 (preferably 7 to 10) carbon atoms, such as benzyl, or phenethyl, carboxyl, 6636 alkoxycarbonyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as methoxycarbonyl or ethoxycarbonyl, carboxyalkyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as carboxymethyl, 2-carboxyethyl, or 2-carboxypropyl, acylamino such as alkylcarbonylamino of 1 to 10 (preferably 1 to 5) carbon atoms, such as acetylamino, or propionylamino, alkylcarbonyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as acetyl, or propionyl, hydroxyalkyl of 1 to 10 (preferably 1 to 5) carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, or 2-hydroxypropyl, haloalkyl of 1 to 10 (preferably 1 to 5) carbon atoms, such as chloromethyl, trifluoromethyl, bromomethyl, or 2-chloroethyl, hydroxyalkoxy of 1 to 10 (preferably 1 to 5) carbon atoms, such as hydroxymethoxy, or 2-hydroxyethoxy, oxo and/or phenyl optionally substituted with one or'more of hydroxy and/or to Cg alkoxy, such as methoxy, ethoxy, propoxy, or butoxy; tetrahydronaphthyl, 1,2- ethylenedioxyphenyl, chromanyl, 2,3-ethylenedioxynaphthyl or xanthenyl substituted with at least one of alkyl of 1 to 10 (preferably 1 to 5) carbon atoms, such as methyl, ethyl, propyl or butyl, alkoxy of 1 to IQ (preferably 1 to 5) carbon atoms, such as methoxy, ethoxy, propoxy, or butoxy and at least one of halo, nitro, cyano, hydroxy, dialkylamino of 2 to 20 (preferably 2 to 10) carbon atoms, such as dimethylamino, diethylamino, or dipropylamino, sulfoamino, carbamoyl, Ν,Ν-dialkylcarbamoyl of 3 to 10 (preferably 3 to 7) carbon atoms, such as N,N-dimethylcarbamoyl, or Ν,Ν-diethylcarbamoyl, N-alkylcarbamoyl of 2 to 6 (preferably 2 to 4) carbon atoms, such as N-methylearbamoyl, or N-ethylcarbamoyl amino, alkylamino of 1 to 10 (preferably 1 to 5) carbon atoms, such as methylamino, ethylamino, propylamino, or butylamino, mercapto, alkylthio of 1 to 10 (preferably 1 to 5) carbon atoms, such as methylthio, ethylthio, propylthio or butylthio, aralkyl of 7 to 12 :(preferably 7 to 10) carbon atoms, such as benzyl or phenethyl, carboxyl, alkoxycarbony! of 2 to 10 (preferably 2 to 6) carbon atoms, such as methexycarbonyl, or ethoxycarbonyl, , carboxyalkyl of 2 to 10 (preferably 2 to 6) carbon atoms, 46636 such as carboxymethyi, 2-carboxyethyl, or 2-carboxypropyl, acylamino such as alkylcarbonylamino of 1 to 10 (preferably 1 to 5) carbon atoms such as acetylamino, or propionylamino, alkylcarbonyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as acetyl, or propionyl, hydroxyalkyl of 1 to (preferably,! to 5) carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, or 2-hydroxypropyl, haloalkyl of 1 to 10 (preferably 1 to :5) carbon atoms, such as chloromethyl, trifluoromethyl, brctncmethyl, or 2-chloroethyl, hvdroxyalk10 oxy of 1 to 10 (preferably 1 to 5) carbon atoms, such as hydroxymethoxy, or 2-hydroxyethoxy, oxo, and/or phenyl optionally substituted with one or more of hydroxy and/or C^ to Cg alkoxy, such as methoxy, ethoxy, propoxy or butoxy; naphthoquinonyl, anthryl, phenanthryl, pentalenyl, heptalenyl, azulenyl, biphenylenyl, asymmetrical-indacenyl, symmetricalindacenyl, acenaphthylenyl, phenylcarbonylphenyl, phenoxyphenyl, benzofuranyl, isobenzafuranyl, benzo (b) thienyl, isobenzothienyl, thianthrenyl, dibenzothienyl, phenoxathienyl, indolyl, ΙΗ-indazolyl, quinolyl, isoquinolyl, phthalazinyl, 1,8-naphthridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl or benzimidazolyl optionally substituted with one or more of halo, nitro, cyano, hydroxy, alkyl of 1 to 10 (preferably 1 to 5 ) carbon atoms, such as methyl, ethyl, propyl, or butyl, alkoxy of 1 to 10 (preferably 1 to 5) carbon atoms, such as methoxy, ethoxy, propoxy, or butoxy, dialkylamino of 2 to 20 (preferably 2 to 10) carbon atoms, such as dimethylamino, diethylamino or dipropylamino, sulfoamino, carbamoyl, Ν,Ν-dialkylcarbamoyl of 3 to (preferably 3 to 7) carbon atoms, such as N,N-dimethylcarbamoyl, or Ν,Ν-diethyIcarbamoyl, N-alkylcarbamoyl of 2 to 6 (preferably 2 to 4) carbon atoms, such as N-methy1carbamoyl, or N-ethylcarbamoyl, amino, alkylamino of 1 to 10 (preferably 1 to 5) darbon atoms, such as methylamino, ethylamino, propylamino, or butylamino, mercapto, alkylthio of 1 to 10 (preferably 1 to 5) carbon atoms, such as methylthio, ethylthio, .propylthio, or butylthio, aralkyl of 7 to 6 6 8 6 (preferably 7 to 10) carbon atoms, such as benzyl or phenethyl, carboxyl, alkoxycarbonyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as methoxycarbonyl, or ethoxycarbonyl, carboxyalkyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as carboxymethyl, 2-carboxyethyl, or 2-carboxypropyl, acylamino such as alkylcarbonylamino of 1 to 10 (preferably 1 to 5) carbon atoms, such as acetylamino, or propionylamino, alkylcarbonyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as acetyl or propionyl, hydroxyalkyl of 1 to 10 (preferably 1 to 5) carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, or 2-hydroxypropyl, haloalkyl of 1 to 10 (preferably 1 to 5) carbon atoms, such as chloromethyl, trifluoromethyl, bromomethyl or 2-chloroethyl, hydroxyalkoxy of 1 to 10 (preferably 1 to 5) carbon atoms, such as hydroxymethoxy, or 2-hydroxyethoxy, and/or phenyl optionally substituted with one or more of hydroxy and/or Cj to Cg alkoxy, such as methoxy, ethoxy, propoxy or butoxy; Cy to Cj2 aralkyl, Cg to Cjg cycloalkylphenyl, to Cjg cycloalkylalkylphenyl, Cg to Cjg cycloalkyloxyphenyl, Cg to Cjg cycloalkyIthiophenyl, 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-l-isochromanyl, 4Hchromenyl, indolinyl, isoindolinyl, 1,2,3,4-cetrahydroquinolyl or 1,2,3,4-tetrahydroisoquinolyl, optionally substituted with one or more of halo, nitro, cyano, hydroxy, alkyl of 1 to 10 (preferably 1 to 5) carbon atoms, such as methyl, ethyl, propyl, or butyl, alkoxy of 1 to 10 (preferably 1 to 5) carbon atoms, such as methoxy, ethoxy, propoxy, or butoxy, dialkylamino of 2 to 20 (preferably 2 to 10) carbon atoms, such as dimethylamino, diethylamino, or dipropylamino, sulfoamino, carbamoyl, Ν,Ν-dialkylcarbamoyl of 3 to 10 (preferably 3 to 7) carbon atoms, such as N,Ndimethylcarbamoyl, or Ν,Ν-diethylcarbamoyl, N-alkylcarbamoyl of 2 to 6 (preferably 2 to 4) carbon atoms, such as N-methylcarbamoyl, or N-ethylcarbamoyl, amino, alkylamino of 1 to 10 (preferably 1 to 5) carbon atoms, such as methylamino, ethylamino, propylamino, or butylamino, mercapto, alkylthio of 1 to 10 (preferably 1 to 5) carbon atoms, suoh as methylthio, ethylthio, propylthio, or butylthio, aralkyl of 7 to 12 (preferably 7 to 10) carbon atoms, such as benzyl, or phenethyl carboxyl, alkoxycarbonyl of 2 to 10 (preferably 2 to 6) carbon atoms, suoh as methoxycarbonyl, or ethoxycarbonyl, carboxyalkyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as carboxymethyl, 2-carboxyethyl, or 2carboxypropyl, acylamino such as alkylcarbonylamino of 1 to 10 (preferably 1 .to 5) carbon atoms, sucn as acetylamino, or propionylamino, alkylcarbonyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as acetyl, or propionyl, hydroxyalkyl of 1 to 10 (preferably 1 to 5) carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, or 2-hydroxypropyl, haloalkyl of 1 to 10 (preferably 1 to 5) carbon atoms, such as chloromethyl, trifluoromethyl, bromomethyl, or 2-chloroethyl, hydroxyalkoxy of 1 to 10 (preferably 1 to 5) carbon atoms, such as hydroxymethoxy, or 2-hydroxyethoxy, oxo, and/or phenyl optionally substituted with one or more of hydroxy and/or C£ to C5 alkoxy, such as methoxy, ethoxy, propoxy, or butoxy or phenyl substituted with at least one 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 of methyl, ethyl, methoxy, ethoxy, hydroxy and halo. Thus the Ar group may be, for example, 3-propyl-4methoxyphenyl, 3-tert-butyl-4-methoxyphenyl, 3-secrbutyl4-hydroxyphenyl, 3-propoxyphenyl, 3-methoxy-4-propoxyphenyl, 3-propoxy-4-methoxyphenyl, 2,4-dimethoxy-3-propoxyphenyl, 3-butoxyphenyl, 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-isopentyloxyphenyl, 3,5-dimethyl-4-pentyloxyphenyl, 2,4-dimethoxy22 #6G8S 3-pentyloxyphenyl, 2,4-dinethoxy-3-hexyloxyphenyl, 2,4 - dimethoxy -3--(3- bromopropoxy) phenyl, 2,4-dimethoxy-3-(2-methoxyethoxy) phenyl, 2,4-dimethoxy-3(2-ethoxyethoxy)phenyl, 3-methyl-4-(2-methoxyethoxy)phenyl, 3-methyl-4-(3-methoxypropoxy)phenyl, 3-valeryl-4-methoxyphenyl, or 2,4-dimethoxy-4-(3-methoxycarbonylpropoxy) phenyl.

Preferred R radicals are (1) (CH2)nc°OR2 wherein Rg is C2 to CgQ alkyl, Cg to CgQ alkenyl, C2 to Cg^ alkoxyalkyl, C2 to CgQ alkylthioalkyl, C2 to CgQ alkylsulfinylalkyl, Cy to Cgg aralkyl, Cg to CgQ cycloalkyl, C4 to CgQ cycloalkylalkyl, furfuryl, tetrahydrofurfuryl, tetrahydro-2 (3 or 4)pyranylmethyl or 1,4-dioxa-2-cyclohexylmethyl; Rg is hydrogen, Cg to CgQ alkyl, Cg to CgQ aryl or Cy to Cg2 aralkyl; and n is 1, 2 or 3, ^/R3 (2) - V CH- (CH-) COOR| b Ifl O R4 wherein Rg is hydrogen, Cg to CgQ alkyl, Cg to CgQ alkenyl, C2 to CgQ alkoxyalkyl, Cg to CgQ alkylthioalkyl, Cg to CgQ alkylsulfinylalkyl, Cy to Cgg aralkyl, Cg to CgQ cycloalkyl, C^ to CgQ cycloalkylalkyl, furfuryl, tetrahydrofurfuryl, tetrahydro-2(3 or 4)-pyranylmethyl or l,4-dioxa-2-cyclohexylmethyl; R^ is Cg to CgQ alkyl, phenyl optionally substituted with one or more of Cg to Cg alkyl and/or Cg to Cg alkoxy, Cy to Cg2 aralkyl or ring substituted benzyl wherein said substituent is Cg to Cg alkyl or Cg to Cg alkoxy; Rg is hydrogen, Cg to CgQ alkyl, Cg to CgQ aryl or Cy to Cg2 aralkyl; and m is 0, 1 or 2 ?6 (3) (R-), wherein Rg is -COORg wherein Rg is hydrogen, C^ to C1Q alkyl, Cg to C^Q aryl or Cy to C^2 aralkyl; each Ry independently is C^ to C^Q alkyl or phenyl; p is an 0 or an integer of from 1 to 4; Rg is substituted at (the 2 or 3-position; and Ry if present is substituted at-the 2, 3, 4, 5 or 6-position ; optionally substituted with at least one of. C^ to· C5 alkyl, 10 and/or C^ to Cg alkoxy wherein Rg is hydrogen, C^ to C^Q alkyl, Cg to C^Q alkyl, Cg to aryl or Cy to C^2 aralkyl and r is 1, 2, 3, or 4, (5) - N 2 ' Vcn')q wherein R1Q is hydrogen, C^ to C^ alkyl, Cg to C1Q aryl or C? to C12 aralkyl; Z is oxygen, sulphur or sulfinyl; and q is 0 or 1, and wherein R^ is hydrogen, to alkyl, Cg to Clo aryl 5 and Cy to C^2 aralkyl; i is 0, 1 or 2; j is 0, 1 or 2; and the sum of i + j is 1 or 2.

The most preferred R radicals are (1) (CH2)nCOOR2 wherein R^ is C2 to C1Q alkyl, C2 to Cg alkoxyalkyl, C2 10 to Cg alkylthioalkyl, Cy to C1Q aralkyl, C4 to C1Q cycloalkylalkyl, furfuryl or tetrahydrofurfuryl; R2 is hydrogen or C^ to alkyl; and n is 1, 2 or 3, (2) - N CH“ mC00R5 wherein R3 is hydrogen, C1 to C1Q alkyl, C2 to Cg alkoxy15 alkyl, C2 to Cg alkoxyalkyl, C2 to Cg alkylthioalkyl, Cy to C1Q aralkyl, C4 to C1Q cycloalkylalkyl, furfuryl or tetrahydrofurfuryl; R4 is 0χ to Cg alkyl; Rg is hydrogen or C-l to C1Q alkyl; and m is 0, 1 or 2 (3) - Ν wherein Rg is -COORg wherein Rg is hydrogen or to C^Q alkyl; each Ry independently is hydrogen or to Cg alkyl; p is 0 or an integer of from 1 to 4; Rg is substituted at the 2 or 3-position; and Ry if present is substituted at the 2, 3, 4, 5'or 6-position, (4) optionally substituted with one or more of C^ to Cg alkyl, and/or C^ to Cg alkoxy wherein Rg is hydrogen or to C^Q alkyl; and r is 1, 2, 3 or 4, (5) - Ν Z wherein R1Q is hydrogen or C.^ to C1Q alkyl; Z is oxygen, sulfur or sulfinyl; and q is 0 or 1, and (6) 6 6 3 6 wherein is hydrogen or C-^ to C'lo alkyl; i is 0, 1 or 2; j is 0, 1 or 2; and the sum of i + j is 1 or 2.

Preferred Ar radicals include phenyl o-naphthyl substituted with at least one of sulfoamino, carbamoyl, Cg to C1Q Ν,Ν-dialkylcarbamoyl, C2 to Cg N-alkylcarbamoyl, amino, to C^Q alkylamino, mercapto, to alkylthio, Cy to C12 aralkyl, carboxyl, C2 to C^Q alkoxycarbonyl, C2 to carboxyalkyl, Cj to C^q acylamino, C2 to C-^θ alkylcarbonyl, C·^ to C^Q hydroxyalkyl, to C^q haloalkyl, C^ to C^o hydroxyalkoxy,, and/or phenyl optionally substituted with one or more of hydroxy and/or to Cg alkoxy; phenyl or naphthyl substituted with at least one of halo, nitro, cyano, hydroxy, C^ to C1Q alkyl, C^ to C1Q alkoxy and/or C2 to C2Q dialkylamino, and at least one of sulfoamino, carb15 amoyl, Cg to C^Q Ν,Ν-dialkylcarbamoyl, C2 to Cg N-alkylcarbamoyl, amino, C^ to C^q alkylamino, mercapto, C^ to C^Q alkylthio, Cy to C^2 aralkyl, carboxyl, C2 to C1f) alkoxycarbonyl, C2 to C1o carboxyalkyl, to C1Q acylamino, C2 to C10 alkylcarbonyl, C-j. to C10 hydraxyalkyl, c^' to C1Q haloalkyl, C^ to C^Q hydroxy alkoxy and/or phehyl (optionally substituted with one or more of hydroxy and/or C-^ to Cg alkoxy); oxanthrenyl or dibenzofuranyl substituted with at least one of halo, nitro, cyano, hydroxy, C2 to C2Q dialkylamino, C2 to Cg N-alkylcarbamoyl, C^ to C^Q alkylamino, mercapto, C^ to C1Q alkylthio., C2 to C^Q alkoxyoarbonyl, C^ to C^Q- hydroxyalkyl, Cj to C1Q haloalkyl and/or C^ to Clo hydroxyalkoxy; oxanthrenyl or dibenzofuranyl substituted with at least one of C·^ to C^q alkyl and/or C^ to C^q alkoxy, and at least one of halo, nitro, cyano, hydroxy, C2 to C20 dialkylamino, C2 to Cg N-alkylcarbamoyl, C^ to C1Q alkylamino, mercapto, C.^ to C^q alkylthio, C2 to C^Q alkoxycarbonyl, C^ to C1Q hydroxyalkyl, C^ to C1Q haloalkyl and/or to C1Q hydroxyalkoxy; tetrahydronaphthyl, 1,2-ethylenedioxyphenyl, chromanyl, 2,3ethylenedioxynaphthyl or xanthenyl substituted with at least one of halo, nitro, cyano, hydroxy, C2 to C2Q dialkylamino, C2 t0 c6 N“alkylcarbamoyl, to C^Q alkylamino, mercapto, t* ** — C^ to C1Q alkylthio, C2 to C1Q alkoxycarbonyl, C-^ to Chydroxyalkyl, to C1Q haloalkyl, C1 to C1Q hydroxyalkoxy, and/or oxo; tetrahydronaphthyl, 1,2-ethylenedioxyphenyl, chromanyl, 2,35 ethylenedioxynaphthyl or xanthenyl substituted with at least one of to alkyl and to C1Q alkoxy, and at least one of halo, nitro, cyano, hydroxy, C2 to C2Q dialkylamino, C2 to Cg N-alkylcarbamoyl, to alkylamino, mercapto, ci to Cio aikyithi°' C2 to cxo alkoxycark°nyi, to c^q hydroxylalkyl, C^ to C1Q haloalkyl, to C1Q hydroxyalkoxy, and/or oxo; anthryl, phenanthryl, biphenylenyl, sym-indacenyl, phenylcarbonylphenyl, phenoxyphenyl, benzofuranyl, benzo (b) thienyl, thianthrenyl, dibenzothienyl, phenoxathiinyl, quin15 olyl, isoquirtolyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, aoridinyl, phenazinyl, phenothiazinyl or phenoxazinyl optionally substituted with one or more of halo, nitro, cyano, hydroxy, C·^ to C^Q alkyl, to C1Q alkoxy, C2 to C2Q dialkylamino and/or to C^Q hydroxyalkoxy; Cy to C^2 aralkyl, Cg to C^g cycloalkylphenyl, C^Q to C^g cycloalkvlalkylphenyl, Cg to C^g cycloalkyloxyphenyl, 9,10dihydroanthryl, 5,6,7,8-tetrahydroanthryl, 9,10-dihydrophenanthryl, 1,2,3,4,5,6,7,8-octahydrophenanthryl, indenyl, indanyl, fluorenyl, acenaphthenyl, phenylthiophenyl, 2,325 dihydrobenzofuranyl, thioxanthenyl, 2H-chromenyl or 1,2,3, 4-tetrahydroquinolyl optionally substituted with one or more of halo, nitro, cyano, hydroxy, to alkyl, C^ to ClQ alkoxy, C2 to C2Q dialkylamino, C2 to Cg N-alkylcarbamoyl, to C^o hydroxyalkoxy, and/or oxo; or phenyl substituted with at least one alkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkyl and/or alkoxycarbonylalkoxy, the said substituent containing 3 to 7 carbon atoms and the said substituted phenyl group being optionally substituted further with one or more of methyl, ethyl, methoxy, ethoxy, hydroxy and/or halo. 6 6 3 ϋ More specifically preferred Ar radicals include phenyl or naphthyl, substituted with at least one of amino, Cj to C1Q alkylamino, Cj to CjQ alkylthio, C? to C12 aralkyl, Cg to C1Q alkoxycarbonyl, Cj to CjQ acylamino, Cg to CjQ alkylcarbonyl, Cj to CjQ hydroxyalkyl, Cj to CjQ hydroxyalkoxy and/or phenyl; phenyl or naphthyl substituted with at least one of amino, Cj to C1Q alkylamino, Cj to CjQ alkylthio, Cy to Cjg aralkyl, Cg to alkoxycarbonyl, Cj to CjQ acylamino, C9 to C10 alkylcarbonyl, Cj to Cjq hydroxyalkyl, Cj to C10 hydroxyalkoxy and/or phenyl, and at least one of halo, hydroxy, Cj to C1Q alkyl, Cj to Cj0 alkoxy and/or Cg to CgQ dialkylamino; dibenzofuranyl substituted with at least one halogen atom; dibenzofuranyl substituted with at least one of Cj to CjQ alkyl and/or Cj to CjQ alkoxy, and at least one halogen atom; tetrahydronaphthyl, 1,2-ethylenedioxyphenyl, chromanyl, 2,3ethylenedioxynaphthyl or xanthenyl, substituted with at least one halogen atom; tetrahydronaphthyl, 1,2-ethylenedioxyphenyl, chromanyl, 2,3ethylenedioxynaphthyl or xanthenyl, substituted with at least one of Cj to Cjq alkyl and Cj to Cjq alkoxy, and at least one halogen atom; anthryl, phenanthryl, binhenylenyl, phenoxyphenyl, benzofuranyl, benzo (b) thienyl, dibenzothienyl, phenoxanthiinyl, quinolyl, isoquinolyl, quinoxalinyl, acridinyl or_phenazinyl, optionally substituted with one or more of halo, hydroxy, Cj to Cjq alkyl, Cj to CjQ alkoxy and Cj to CjQ hydroxyalkoxy; Cy to Cj2 aralkyl, Cg to Cjg cycloalkylphenyl, fluorenyl, thioxanthenyl, 2H-chromenyl, or 1,2,3,4-tetrahydroquinolyl, optionally substituted with one or more of Cj to CjQ alkyl, Cj to Cjq alkoxy and/or oxo; or phenyl substituted with at least one of alkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkyl and/or alkoxycarbonylalkoxy, the said substituent containing I to 7 carbon atoms, and the said substituted phenyl group being opt.lonally .substituted further with one or more of methyl, ethyl, methoxy, ethoxy, hydroxy and/or halo.

The most preferred Ar radicals are phenyl or naphthyl, substituted with at least one of amino, Cj to CjQ alkylamino, C? to aralkyl, Cj to CjQ acylamino, Cj to CjQ hydroxyalkyl, and/or Cj to CjQ hydroxyalkoxy; phenyl or nap’hthy'l, substituted with at least one of amino, Cj to Cj0 alkylamino, Cy to Cj2 aralkyl, Cj to CjQ acylamino, Cj to Cjq hydroxyalkyl and/or Cj to CjQ hydroxyalkoxy and at least one of halo, hydroxy, Cj to CjQ alkyl and/or Cj to CjQ alkoxy; biphenylenyl, phenoxyphenyl, dibenzothienyl, phenoxathiinyl, quinolyl, or quinoxalinyl optionally substituted with one or more of hydroxy and/or Cj to CjQ alkyl; Cy to Cj2 aralkyl, Cg to Cjg cycloalkylphenyl, fluorenyl, or 2H-chromenyl group optionally substituted with one or more of Cj to CjQ alkyl, Cj to CjQ alkoxy and/or oxo; or phenyl substituted with at least one of alkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkyl and/or alkoxyoarbonylalkoxy, the said substituent containing 3 to 7 carbon atoms, and the said substituted phenyl group being optionally substituted further with one or more of methyl, ethyl, methoxy, ethoxy, hydroxy and/or halo.

Typical compounds of this invention include; 1-/N -(quinoline-8-sulfonyl)-L-arginyX7-4-methyl-2-piperidinecarboxylic acid 1-/N -(3-methylquinoline~8-sulfonyl)-L-arginyl7-4-methyl-2“ piperldinecarboxylic acid 1-/¾ - (3-ethylquinoline-8-sulfonyl)-L-arginyl7~4-methyl-2piperidinecarboxylic acid 6 6 3 6 1-/K -(3-sec-butoxybenzene-l-sulfonyl)-L-arginyl7-4-methyl2-piperidinecarboxylic acid 1-/Ϊ3 -(3,5-dimethyl-4-isopropoxybenzene-l-sulfonyl)-Larginyl/-4-methyl-2-piperidinecarboxylic acid 1-/N -(2,4-dimethoxy-3-butoxybenzene-l-sulfonyl)-L-arginyl7~ 4-methyl-2-piperidinecarboxylic acid 1-/N - (3-isopropoxybenzene-l-sulfonyl)-L-arginyl7-4-methyl2-piperidinecarboxylic acid N -(2-phenoxathiinylsulfonyl)-L-arginyl-N-tetrahydrofurfuryl10 glycine N - (2-fluoroenesulfonyl)-L-arcinyl-N-(2-methoxyethyl)glycine 1-ZP -(4-methoxy-3-cyclohexylbenzene-l-sulfonyl)-L-arginyl7“ 4-methyl-2-piperidinecarboxylic acid The pharmaceutically acceptable salts of the above 15 compounds are of course also included within the scope of this invention. For the preparation of the compounds of this invention, various methods can be employed depending upon the particular starting materials and/or intermediates involved. Successful preparation of these compounds is poss20 ible by way of several synthetic routes which are outlined below. (a) Condensation of an L-arginiamide with an arylsulfonyl halide This process may be illustrated as follows: 6 6 8 6 ΗΝ. Η2Ν Ν - CH2CH2CH2CHCOOH (II) ΝΗΗΝ C --· Ν - CH2CH2CH2CHCOOH (III) ΗΝ I R ΗΝ R' ' ' + RH (IV) ΗΝ, ΗΝ I R C - Ν - CH2CH2CH2CHCOR R ΗΝ (V) ΗΝ X.

C - Ν - CH2CH2 CH2CHCOR (VI) η2ν NH+ ArSO2X (VII) HN, H2N N - CH2CH2CH2CHCOR (I) H HNSOAr 46633 In the.above formulae, R and Ar are as defined herein above; X is halogen; R ' is a protective group for the ct-amino group, such as benzyloxycarbonyl or tertbutoxycarbonyl; R' and R'' are hydrogen or protective groups for the guanidino group, such as nitro, tosyl, trityl, or oxycarbonyl; and at least one of R' and R'1 is a protective group for the guanidino group.

The N2-arylsulfonyl-L-argininamide (I) is prepared by the condensation of an L-argininamide (VI) with a substantially equimolar amount of an arylsulfonyl halide (VII), preferably a chloride.

The condensation reaction is preferably effected in a suitable reaction-inert solvent in the presence of an excess of a base, such as an organic base (triethylamine, pyridine) or a solution of an inorganic base (sodium hydroxide, potassium carbonate) , at a temperature of 0°C to the boiling temperature of the solvent for a period of 10 minutes to 15 hours.

The preferred solvents for the condensation include benzene-diethyl ether, die thyl ether-water and dioxanewater .

After the reaction is complete, the formed salt is extracted with water, and the solvent is removed by such standard means as evaporation under reduced pressure to 2 give the N -arylsulfonyl-L-araininamide (I), which can be purified by trituration or recrystallization from a suitable solvent, such as diethyl ether-tetrahydrofuran, diethyl ether-methanol arid water-methanol, or may be chromatographed on silica gel.

The L-argininamides (VI) starting materials required for the condensation reaction can be prepared by protecting the guanidino and α-amino groups of L-arginine (II) via nitration, acetylation, formylation, phthaloylation, trifluoroacetylation, p-methoxybenzyloxycarbonylation, benzoylation, benzyloxycarbonylation, tert-butoxycarbonylation or 46636 tritylation and then condensing the formed N--substitutedN -substituted-L-arginine (III) with a corresponding amino acid derivative (IV) by such a conventional process as the acid chloride method, azide method, mixed anhydride method, activated ester method or carbodiimide method, and thereafter selectively removing the protective groups from the C 9 formed N -substituted-N -substituted-L-argininamide (V).

The amino acid derivatives (IV) which are the starting materc* J ials for the preparation of the N -substituted-N -substituted 10 -L-argininamides (V) are represented by the following formulae: H-N (CH2)nC0°R2 (VIII) H-N (IX) CH- (CH2) mCOOR5 H-N (X) C00Ro H· V(CH2)r (XI) COORjq X-\ COOR. .(ch2).

H-N Z V(CH-2)q (XII) H-N (ch2).. jj (XIII) 46636 In the above formulae, R^, R2, Rg, R^, Rg, Rg, Ry, R9, R1q, Ri;l, Z., n, m, r, q, i, and j are as defined herein above.

The amino acid derivatives of the above formula (VIII) or (IX) can be prepared by the condensation of a haloacetate, 3-halopropionate or 4-halobutyrate with an appropriate amine having the formula R^NH2 or RgNH2. (See, J. Org. Chem., 25 728-732 (1960)).

The condensation reaction maybe carried out without a solvent or in a solvent, such as benzene or diethyl ether, in the presence of an organic base, such as triethylamine or pyridine, at a temperature of 0°C to 80°C e.g. for a period of 10 minutes to 20 hours. After the reaction is complete, the formed amino acid derivative is separated by such conventional means as extraction 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 tertbutyl ester derivatives are preferred, because they are easily converted to other ester derivatives by aoidolysis in the presence of a corresponding alcohol employing an inorganic acid (HCl, H2SC>4, etc.) or an organic acid (toluenesulfonic aoid,’trifluoroacetic acid, etc.). In accordance with the process emoloyed for preparing 2-piperidinecarboxylic acid derivatives (X), the following scheme is illustrative: i (XVII) (XVIII) 46636 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 -5°C to 0°C. The resultant product (XV) is isolated by extraction with a solvent, e.g,, diethyl ether, and then treated with potassium hydroxide in a lower (Cj to CjQ) alkanol solvent to give the 1,2-dehydropiperidine (XVI). The . action of cyanogenating agents, e.g., hydrogen cyanide or sodium cyanide converts the 1,2-dehydropiperidines (XVI) to the corresponding 2-cyano analogs (XVII). Hydrolysis of the 2-cyanopiperidines (XVII) to yield the 2-piperidinecarboxylic acids (XVIII) is effected by treatment of the 2-cyanopiperidines (XVII) with an inorganic acid, such as hydrochloric acid or sulfuric acid.

The arylsulfonyl halides (VII) which are the starting materials for the preparation of the N -arylsulfonyl-Largininamides (I) may be prepared by halogenating the requisite arylsulfonic acids or their salts, e.g., sodium salts, by conventional methods well known to those skilled in the art.

Halogenation may be carried out without a solvent or in a suitable solvent e.g., halogenated hydrocarbons or DMF in the presence of a halogenating agent, e.g., phosphorous oxychloride, thionyl chloride, phosphorous trichlor25 ide, phosphorous tribromide or phosphorous pentachloride, at a temperature of -10°C to 200°C for a period of 5 minutes to 5 hours. After the reaction is complete, the reaction product is poured into ice water and then extracted with a solvent such as diethyl ether benzene, ethyl acetate, or chloroform.

The arylsulfonyl halide can be purified by recrystallization from a suitable solvent such as hexane, or benzene.

G G (b) Removal of the N -substituent from an N-substituted2 N -arylsulfonyl-L-argininamide.

This process may be illustrated as follows: HN HN I R HN HN 1.

HN HN I.

HN /1-6 63 6 N - CH2CH2CH2CHCOR HN R' ' ' (V).

C - N - CH2CH2CH2CHCOR (XIX) ArSO2X (VII) NfL· C-N - CH2CH2CH2CHCOR HN|O2 Ar (XX) LM X CH2CH2CH2CHCOR (I) H2N HNSO„ Ar In the above formulae, R, Ar, X, R', R'' and R'’' are as defined herein above.

The N -arylsulfonyl-L-argininamide (I)may be prepared by removing the NG-substituent from an NG-substituted2 N -arylsulfonyl-L-,argininamide (XX) by means of aeidolysis or hydrogenolysis. 4.6 6 3 6 The acidolysis may be effected by contacting the G 2 N -substituted-N -arylsulfonyl-L-arginiamide (XX) and an excess of an acid such as hydrogen fluoride, hydrogen chloride, hydrogen bromid e or trifluoroacetic acid, without a solvent or in a solvent, such as an ether (tetrahydrofuran, dioxane), an alcohol (methanol, ethanol) or acetic acid 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 24 hours. The products are isolated by evaporation of the solvent and the excess acid, or by trituration with a suitable solvent followed by filtration and drying.

Because of the use of the excess acid, the products 2 are generally the acid addition salts of the N -arylsul15 fonyl-L-argininamides (I), which can be easily converted to a free amide by neutralization.

The removal of the nitro group and the oxycarbonyl group, e.g., benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, is readily accomplished by the hydrogenolysis.

At the same time, the benzyl ester moiety which can be included in the R group is converted to the carboxyl group by the hydrogenolysis.

The hydrogenolysis is effected in a reaction-inert solvent, e.g., methanol, ethanol, tetrahydrofuran or dioxane, in the presence of a hydrogen-activating catalyst, e.g., Raney nickel, palladium, or platinum, in a hydrogen atmosphere at a temperature of 0°C to the boiling(temperature of the solvent, and preferably 10°C to 80°C for a period of 2 hours to 120 hours.

The hydrogen pressure is not critical, and atmospheric pressure is sufficient.

The N -arylsulfonyl-L-argininamides (I) are isolated by filtration of the catalyst followed by evaporation of the solvent.

The N -arylsulfonyl-L-argininamides may be purified 4663G in the same manner as described above.

G 2 The N -substituted-N -arylsulfonyl-L-argininamides (XX) starting materials may be prepared by condensing an NG-substituted-N3-substituted L-arginine (III) (generally G 2 the N -substituent is nitro or acyl, and the N -substituent is a protective group for the amino group, such as benzyloxycarbonyl, tert-butoxycarbonyl, or the like) and a corresponding amino acid derivative (IV), selectively removing G 2 only the N -substituent of an N -substituted-N -substituted L-argininamide (V) by means of catalytic hydrogenolysis or p acidolysis, and then condensing the thus obtained N -substituted-L-argininamide ( XIX) with an arylsulfonyl halide (VII), preferably a chloride in the presence of a base in a solvent. These reaction conditions are as described above in the condensation of an L-argininamide with an arylsulfonyl halide, and the removal of the N -substituent from an C* 9 N -substituted-N -arylsulfonyl-L-argininamide. (c) Condensation of an N -arylsulfonyl-L-arginyl halide with an amino acid derivative This process may be illustrated as follows: HN H2n/Z CH2CH2CH2CHCOOH nh2 + ArSO2X (XX) (VII) HN H2N Ar V H I N - CH0CH-CH-CHCOOH 2 2 J HNSO, (XXI)39 HN. η2ν CH2CH2CH2CHCOX HNSOI2 Ar + RH (XXII) (IV)-> H2N N - CH-CH-CH-CHCOR 2 2 2 1 HNSO„ L (I) In. the above formulae, R, Ar and X are as defined herein above.

The N -arylsulfonyl-L-argininamide (I) may be pre2 pared by the condensation of an N -arylsulfonyl-L-arginyl halide (XXII), preferably a chloride with at least an equimolar amount of an amino acid derivative (IV).

The condensation reaction may be carried out without ι 10 an added solvent in the presence of a base. However, satisfactory results will be obtained with the use of a solvent such as basic solvents (dimethylformamide, dimethylacetamide, etc.) or haiogenated solvents (chloroform, dichloromethane, etc.).

The amount of the solvent to be used is not critical and may vary from 5 to 100 times the weight of the N -arylsulfonyl-L-arginyl halide (XXII).

Preferred condensation reaction temperatures are in the range of from -10°C to 80°C and preferably from 20°C to 50°C. The reaction time is not critical, but varies with the amino acid derivative (IV) employed. In general, a period of from 5 minutes to 10 hours is operable. 46636 The obtained N -arylsulfonyl-L-argininanu.de may be isolated and purified in the same manner as described above.

The N - arylsulfonyl-L-arginyl halide (XXII) starting materials required for the condensation reaction may be prepared by reacting an N -arylsulfonyl-L-arginine(XXI) with at least an equimolar amount of a halogenating agent such as thionyl chloride, phosphorous oxychloride, phosphorus trichloride, phosphorous pentachloride or phosphorus tribromide. The halogenation may be carried out with or without an added solvent.

The preferred solvents are chlorinated hydrocarbons such as chloroform and dichloromethane, and ethers such as tetrahydrofuran and dioxane.

The amount of the solvent to be used is liot critical 2 and may vary from 5 to 100 times the weight of the N arylsulfonyl-L-arginine (XXI).

Preferred reaction temperature is in the range of -10°C to room temperature . The reaction time is not 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 2 starting materials for the preparation of the N -arylsulfonyl-L-arginyl halides (XXII) may be prepared by:the condensation of L-arginine ( II) with a substantially equimolar amount of arylsulfonyl halides (VII), by a 'method similar to that described in the condensation of an Largininamide with an arylsulfonyl halide.

It is well recognized in the art that an ester 2 derivative of the N -aryl siifonyl-L-arginlnamide (I) wherein R2, Rg, Rg, Rg, Rjq or Rjj is alkyl, aralkyl or aryl may be prepared from a carboxylic acid derivative of the N2arylsulfonyl-L-argininamide wherein R2, Rg, Rg, Rg, Rjq or R11 is hydrogen, by the conventional esterification 46636 methods well known to those skilled in the art. It is also well recognized in the art that the carboxylic acid derivative can be prepared from the ester derivative by the conventional hydrolysis or aoidolysis methods. The condit5 ions under which esterification, hydrolysis or aoidolysis would be carried out will be each apparent to those skilled in the art. . n • a t*. : The N -arylsulfonyl-L-argininamide (I) of tryis invention forms acid addition salts with any of a variety of inorganic. and organic acids. Some of the N -arylsulfonylL-argininamides containing a free carboxyl group, wherein R2, R5, Rg, Rg, R1q or Ri;l is hydrogen, forms salts with ?any of a variety of inorganic and organic bases. > ; · The product of the reactions described above /can be I isolated in the free form or in the form of salts i In ί ; addition, the- product can be obtained as pharmaceutically acceptable acid addition salts by reacting one of the free bases with an aoid, such as hydrochloric, hydrobrOmio, hydroiodic, nitric, sulfuric, phosphoric, acetic,(citric, maleic, succinic, lactic, tartaric, gluconic, benzoic, methanesulfonic’, ethanesulfonic, benzenesulfonic, or ptoluenesulfonic acid. In a similar manner, the product may be obtained as a pharmaceutically acceptable salt by reacting one of the free carboxylic acids with a base, such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, triethylamine, procaine,dibenzylamine, l-ephenamirie, N,N'dibenzylethylenediamine, or N-ethylpiperidine.

Likewise, treatment of the salts with a bajse or aoid results in a regeneration of the free amide.

As stated above, the N -arylsulfonyl-L-argininamides, and the salts thereof of this invention are characterized by their highly specific inhibitory activity in mammals against thrombin as well as by their substantial lack of toxicity, and therefore these compounds are useful' in the determination of thrombin in blood as diagnostic reagents, and/or for the medical control or prevention of thrombosis.

The compounds of this invention are also useful as an inhibitor of platelet aggregation.

The antithrombotic activity of the N -arylsulfonylL-argininamide of this invention was compared with that of a known antithrombotic agent, N -(p-tolylsulfonyl)-Larginine methyl ester, by determining the fibrinogen coagulation time. The measurement of the fibrinogen coagulation time was conducted as follows: An 0.8 ml aliquot of a fibrinogen solution, which had been prepared by dissolving 150 mg of bovine fibrinogen (Cohn fraction I) supplied by Armour Inc. in 40 ml of a borate saline buffer (pH 7.4), was mixed with 0.1 ml of a borate saline buffer, pH 7.4, (control) or a sample solution in the same buffer, and 0.1 ml of a thrombin solution (5 units/ml) supplied by Mochida Pharmaceutical Co., Ltd. was added to the solutions in an ice bath.

Immediately after mixing, the reaction mixture was transferred from‘the ice bath to a bath maintained at 25° C. Coagulation times were taken as the period between the time of transference to the 25°C bath and the time of the first appearance of fibrin threads. In the cases where no drug samples were added, the coagulation time was 50-55 seconds. The experimental results are summarized in Table 1. The term concentration required to prolong the coagulation time by a factor of two is the concentration of an active ingredient required to prolong the normal coagulation time 50-55 seconds to 100-110 seconds. ‘ The concentration required to prolong the coagulation time by a factor of two for the known antithrombotic agent, N - (p-tolylsulfonyl)-L-arginine methyl ester, was Ι,ΙΟΟμιη. The inhibitors are shown in Table 1 by indicating R and Ar in the formula (I) and the addition moiety.

When a solution containing an N2-arylsulfonyl-Largininamide of this invention was administered intravenously into animal bodies, the high antithrombotic activity in the circulating blood was maintained for from one to three hours. The halflife for decay of the anti-thrombotic compounds of this invention in circulating blood was shown to be approximately 60 minutes; the physiological condit5 ions of the host animals (rats, rabbit, dog and chimpanzee) were well maintained. The experimental decrease of fibrinogen in animals caused by infusion of thrombin was satisfactorily controlled by simultaneous infusion of the compounds of this invention.

The acute toxicity values (LDj-θ) determined by intravenous administration of substances of formula (I) in mice (male, 20 g) range from about 150 to 600 milligrams per kilogram of body weight. : Representative LDgQ values for the compounds of this invention are shown in the following Table, i Compound HNx C - NH - (CH~),CHC0R s' 3 | H2N HNSOgAr LD5o (mg/kg) Ar R JL OCH, 3 ^CH3 och.ch; z '''•CH OCHg 3 -N VcH, w ’ 173 Λ’ O(CH2)3CH3 ^ch3 -N \-CH, : 170 -N / CH, 250 - 300 9 LD5o values for N -dansyl-N-butyl-L-argininamide and N dansyl-N-methyl-N-butyl-L-argininamide are less than lo milligrams per kilogram, respectively.

The therapeutic agents in this invention may be administered to mammals, including humans, alone or in combination with pharmaceutically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmaceutical practice. The compound may be 6686 Ρ Ι&» presented in many unit dosage forms. For example, the compounds may bp injected parenterally, that is, intramuscularly, intravenously or subcutaneously. For parenteral administration', the compounds may be used in the form of sterile solutions containing other solutes, for example, sufficient saline or glucose to make the solution isotonic. The compounds may be administered orally in the form of tablets, capsules, troches or granules containing suitable excipients such as starch, lactose, and white sugar. The compounds may be administered sublingually in the form of troches or lozenges in which each active ingredient is mixed with sugar or corn syrups, flavoring agents and dyes, and then dehydrated sufficiently to make the mixture suitable for pressing into solid form. The compounds may be administered 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.

In addition, the dosage will vary with the particular patient under treatment.

When the composition is administered orally, a larger quantity of the active agent will be required to produce the same effect as caused with a smaller quantity given parenterally.

The therapeutic dosage is generally 10-50’ mg/kg of active ingredient parenterally, 10-500 mg/kg orally per day.

Having generally described the invention,'a more complete understanding can be obtained by reference to certain specific examples, which are included for purposes of illustration only and are not intended to be limiting unless otherwise 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, a 6 6 8 6 the invention includes such compositions in unit dose form.

The invention will now be illustrated by means of Examples in which parts and percentages are by weight.

EXAMPLE 1 (A) To a well stirred solution of 83.6 g. of L-arginine in 800 ml of 10% potassium carbonate solution was added 112.7 g of 2-dibenzothiophenesulfonyl chloride in 800 ml of benzene. The reaction mixture was stirred at 60°C for 5 hours, during which time the product precipitated. After one hour at room temperature, the precipitate was filtered and washed successively with benzene and water to give 127 g (76 percent) of N -(2-dibenzothienylsulfonyl)-Larginine.

(B) fonyl)-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. ι (C) ine tert-butyl ester: ' To a stirred solution of 2.67 g of N-butylglycine tert-butyl ester in 20 ml of chloroform was care- chloride obtained above. The reaction mixture was allowed to stand at room temperature for one hour.

At the end of this period, the reaction mixture was washed twice with 20 ml of saturated 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 collecteql by filtration and reprecipitated from ethanol-diethyl ether to give 3.1 g (49 percent) of N -(2-dibenzothienylsulfonyl)-L-arginyl-N-butylglycine tert-butyl ester.

I.R. (KBr): 3350, 1740, 1625 cm1 Analysis - Calcd. for C28H39°5N5S2*!2H2SO3 (Percent): C, 53.31; H, 6.39; N, 11.10 Found (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 ml of chloroform was added 50 ml of 15% HCl-ethyl acetate. The reaction mixture was stirred for 5 hours at room temperature. At the end of' this period, the reaction mixture was evaporated to dryness. The residue was washed several times with dry diethyl ether and chromatographed on 80 ml of Daiaion SK 102 ion exchange resin (200-300 (Japanese Industrial Standard) mesh, H+ form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with water and eluted with 3% ammonium hydroxide solution. ; i The fraction eluted from 3% ammonium hydroxide solution was evaporated to dryness to give 0.9 g (53 1 percent) of N - (2-dibenzothienylsulfonyl)rL-arginylN-butylglycine as an amorphous solid, I.R. (KBr): 3350, 1640, 1270 cm-1 Analysis-Calcd. for C24H3iN5°5S2 (percent): C, 53.78; H, 5.97; N, 12.96 DAIAION is a Registered Trade Mark. 46636 EXAMPLE 2 (A) N - (2-dibenzothienylsulfonyl)-L-arginy 1-N-(2-methoxyethyl)glycine ethyl ester To a stirred solution of 2.42 g of N-(2-methoxyethyl) glycine ethyl ester and 4.0 ml of triethylamine in 50 ml of chloroform, which was cooled in an ice-salt bath, was added in portions 7.0 g of N -(2dibenzothienylsulfonyl)-L-arginyl chloride obtained above. The reaction mixture was stirred overnight at room temperature. At the end of this period, 50 ml of chloroform was added and the chloroform solution was washed twice with 25 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo. The oily residue was washed with diethyl ether to give 5.5 g of powdery N -(2-dibenzothienylsulfonyl)-L-arginyl-N(2-methoxyethyl)glycine ethyl ester.

Analysis calcd. for CgjjHggOgNgSg^HgSOg (percent): C, 50.49; H, 4.07; N, 11.78 Found (percent): C, 50.22;. H, 4.18; N, 11.51 (Β) N -(2-dibenzothienylsulfonyl)-L-arginy1-N-(2-methoxyethyl) glycine: A solution of 5.5 g of N - (2-dibenzothienylsulfonyl)L-arginyl-N-(2-methoxyethyl)glycine ethyl ester in 15 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 ml of Daiaion SK 102 ion exchange resin (200-300 (Japanese Industrial Standard) mesh, H+ form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with ethanol-water (1 : 4) and eluted with ethanol -water-NH4OH (10 : 9 : 1), The main fraction was evaporated to dryness and washed with diethyl ether to give 3.05 g (62 pero cent) of N -(2-dibenzothienylsulfonyl)-L-argmyl-N(2-methoxyethyl) glycine as an amorphous solid. I.R. (KBr): 3400, 1630, 1280 cm-1 Analysis-Calcd. for C23H2gOgN5S2 (percent): C, 51.57; H, 5.46; N, 13.08 Found (percent): C, 51.35; H, 5.63; N, 12.86 EXAMPLE 3 G 2 (A) N -nitro-N -(tert-butoxycarbonyl)-L-argiriyl-N-butyl -glycine benzyl ester. = G 2 To a stirred solution of 28.4 g of N -nitro-N (tert-butoxycarbonyl)-L-arginine in 450 ml of dry tetrahydrofuran were added in turn 12.4 ml of triethylamine and 12.4 ml of isobutyl chloroformate while keeping the temperature at -5°C. After 15 minutes, to this were added 35.0 g of N-butylglycine benzyl ester p-toluenesulfonate, 12.4 ml of triethylamine and dry tetrahydrofuran, and then the mixture was stirred for 15 minutes at -5°C. At the end pf this period, the reaction.mixture was warmed to room temperature. The solvent was evaporated and the residue taken in 400 ml qf ethyl acetate, and washed successively with 200 ml of water, 100 ml of 5% sodium bicarbonate solution, 100 ml of.10% citric acid solution and 200 ml of water. The ethyl acetate solution was dried over anhydrous 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 x 6 cm) of 500 g of silica gel packed in chloroform.

The product was eluted first with chloroform, and then 3% methanol-chloroform. The fraction eluted from 3% methanol-chloroform was evaporated to dry35 ness to give 26.0 g (56 percent) of NG-nitro-N24 663G (tert-butoxycarbonyl)-L-arginyl-N-butylglycine benzyl ester in the form of a syrup.

I.R. (KBr): 3300, 1740, 1690 cm-1 (B) NG-nitro-L-arginyl-N-butylglycine benzyl ester hydrochloride: C 2 To a stirred solution of 26.0 g of N -nitro-N -(tertbutoxycarbonyl) -L-arginyl-N-butylglycine benzyl ester in 50 ml of ethyl acetate was added 30 :;>1 of 10% dry HCl-ethyl acetate at 0°C. After 3 hours, to this solution was added 200 ml of dry diethyl ether to precipitate a .viscous oily product.

This was filtered and washed with dry diethyl ether ri to give 20.8 g of N’-nitro-L-arginyl-N-butylglycine benzyl ester hydrochloride as an amorphous solid.

C 9 (C) N -nitro-N -(3-cyclohexyl-4-methoxyphenylsulfonyl)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 dioxane were added in turn 1.26 g of sodium bicarbonate, and 2.2 g of 3-cyclohexyl-4-.methoxyphenylsulfonyl chloride at 5°C, and stirring 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 with 10 ml of IN hydrochloric acid solution, 20 ml of water, ml of 5% sodium bicarbonate and 10 ml of water.

The ethyl acetate solution was dried over 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% methanol-chloroform. The fraction eluted from 3% methanol-chloroform was evaporated to give 2.6 g (77 percent) of NG-nitro-N2-(3-cyclo4 ϋ ΰ 3 6 hexyl-4-methoxyphenylsulfonyl)-L-arginyl-N-butylglycine benzyl ester in the form of an amorphous solid.

I.R. (KBr): 3300, 2920, 1740, 1640, 1250 cm Analysis-Calod. for C32H46°8N6S (percent): C, 56.95; H, 6.87 ; N, 12.46 Found (percent): C, 56,49; H, 6.63; N, 12.38 (D) N -(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginylN-butylglycine G 2 To a solution of 3.00 g of N -nitro-N -(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 diethyl ether and chromatographed on 80 ml of Daiaion SK 102 ion exchange resin (200-300 mesh, H+ form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with water, and eluted with 3% ammonium hydroxide solution.

The fraction eluted from 3% ammonium hydroxide solu25 tion was evaporated to dryness to give 1.5 g (72%) of N -(3-cyolohexyl-4-methoxyphenylsulfonyl)-Larginyl-N-butylglyoine as an amorphous solid.

I.R. (KBr): 3350, 2920, 1630, 1250 cm1 Analysis-Calcd. for C25H4iN6°5Si (percent): C, 55.63; H, 7.66; N, 12.98 Found (percent): C, 55.32; H, 7.39; N, 12.84 i t’ 6 J J EXAMPLE 4 C 2 (A) Ethyl 1-/Π -nitro-N -(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl7“4-methyl-2-piperidinecarboxylate. To a well stirred solution of 2.05 g of ethyl 1-(N -nitro-L-arginyl)-4-methyl-2-piperidinecarboxylate hydrochloride ana 1.26 g of NaHCOg 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 overnight at room temperature. At the end of this period, the reaction mixture was evaporated to dryness. The residue was taken· up in 50 ml of ethyl acetate, and the ethyl acetate solution was washed consecutively with 10% citric acid, saturated NaCl, saturated NaHCOg and saturated NaCl solutions. The ethyl acetate solution was evaporated and 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 2 g of ethyl 1-/N -nitro-N -(3-cyclohexyl-4-ntethoxybenzenesulfonyl)-L-arginyl7~4-methyl-2-piperidinecarboxylate.

I.R. (KBr): 3400, 1735, 1635, 1250 (cm-1) (B) Ethyl 1-ZN -(3-cyclohexyl-4-methoxyphenylsulfonyl)L-arginyl7-4-methyl-2-piperidinecarboxylate acetate. To a solution of 2.6 g of ethyl l-/NG-nitro-N^-(3cyolohexyl-4-methoxyphenylsulfonyl)-L-arginy1/-4methyl-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 shaken 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 <ξ6 3 θ g of ethyl 1.-/N -(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl7-4-methyl-2-piperidinecarboxylate acetate. /-2 (C) 1-£N -(3-cyclohexyl-4-methoxyphenylsulfonyl)-L5 arginyl7-4-methyl-2-piperidinecarboxylic acid A solution of 2.4 g of ethyl 1-/N - (3-cyclohexyl-4methoxyphenylsulfonyl)-L-arginyl7“4-methyl-2-piperidinecarboxylate acetate in 10 ml of ethanol and 10 ml of N NaOH solution was stirred overnight at room temperature. Then, the reaction mixture was concentrated and dissolved in 10 ml of water. The solution was neutralized with 2N HCl solution to give a white gummy precipitate which was dissolved in 150 ml of chloroform. The chloroform solution was washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated in vacuo to give 1.52 g of 1-/N -(3-cyclohexyl-4-methoxyphenylsul~ fonyl)-L-arginyl7-4-methyl-2-piperidineoarboxylic acid as an amorphous solid.

I.R. (KBr): 3350, 2920, 1S20, 1250 cm_1 Analysis-Calcd. for C26H4l°6N5S (percent): C, 56.60; H, 7.49; N, 12.70 Found (percent): C, 56.51; H, 7.53; N, 12.68 Various other N -arylsulfonyl-L-argininamides or acid addition salts thereof were synthesized in accordance with the procedures of the above examples, and the test results are summarized in Table 1. 6 G 8 6 /«* o O o o r> o o o o o u CO ko co Oi in rp kD 00 co rp rt — «X) rH kO Ok Ol kD rH kD CO r* «ι- k. fe fe ·» *. *. » * *-* 1 e rH H rH N rH rH H H H rH • M u k. k. a >* o o o o o o o o O o o o • LD p* ϋ kO in co CJ co o co o co w CO Ol ςρ Ol co kD *P m *tf kD *tf kD «, k. fe fe fe fe *> fe * * <* co rH CO H CO H co H co rH co rH to 00 CO 05 •«tf CO rP rp 00 co kO •H rd o p* [> CO ch 00 co •sp rH co rH CO (0 Φ z >i-P cn (N CM N N OJ r* Γ* 05 co -tf cn rH fl rH rH rH rH rH rH rH rH rH rH rH rH C 3 T) fl O G in kD 05 kD 05 rH 05 kD CO rH G N 00 kO kD CO kD P- P* P- 05 05 rH fO 0 a fl u a kD ko kO k£> r·* r— kD k0 in in m m 4-> c ·· ·· Φ h H Ol 05 Ol Ch co Ol 0* rp in p* 05 05 Ε g φ 00 m o kO kD co in oi 05 kD co P* a a? u • • • • » * * • rH ft O CO co Γ*· kO in m Ch. 05 kD 'D O O wart uo m tn m in in 'tf tf •«tf in m iH φ » (0 ft Φ ?KrH ο -H Λ fl U -P ft 0 ftp TABLE 1 ι ι ~ ftHJ It/)·· φ (0 C 0 ifi X 0 Μ Μ Ο M Φ M Z ft fl .rl Oj U rd φ C M O-H •H £ Φ-Ρ Φ I X3 f0 e Ο «Ρ Η ·Η M 3 J ft &5 c ψ) σ1 sag o fl φ o o o o Ψ4 Or*. >Λ 0 *-* fl +J 0 p >1 fl ? O Ol ΓΩ U U4JH □ wH fi UH 4-> +» •η | fl β Ή >t Ό 0 O +j β Φ I K Ol c o □ ω S I O0 Nl a a u Ol as u CM a u ι a a As co a u o N a cj N a \· u N a u co a u Ol a u a Ol o a o u u Ν N a a °X zu a ι N ffi P. έ CO - a a g CO a u o □ a o o sz~& a p e M 0) W — '-H I V) •rt Ό ω Φ >ι·Ρ rd ftf (β r-1 fi fi TJ «og rt (0 o ftf CJ fc +J fi ·· ·· QJ H M g 0) 0) 0) Qi5 rd Οι O J ro rd CM in oo in ω io O O Ο rd m cn 00 Γin in rd rrt O r- σ» CM CO co O o o\ CM ΟΟ in CM H ro <* CM in O O in cm CO Ό Γ0 I-i r-l r- in Γ- co O rd O O in in CO rd . oo CM CM rd rd m ro Η O io in io co (continued) ι qj ω Ql QJ >ird 0 -ri ffl ftf id Pk ϋ Q:M I I ~ Qiffl 1 W * · QJ ftf fi O W X 0 rt rt O rt QJ Μ Z Oi rtf *rt Qi ϋ i H s· one) in « E _ o +) η -nt « _ w 3 +i n S I Ό +J 0) C fi M φ O -rl O -rl 3 „ _ _ fi +> &< fi rt fi o rt α» ο ο ο ο >,ιη O H M 4J Η Ο Ή Λ Ο σι rd oi ο ffl Μ ? CM O ω I □ *—z CM 1 ffl □ CM w a CM ffl u a a h Z CM ffl ffl ffl I ffl •rt I T3 fi ‘rt >1 Ό Ο O ffl ffl ffl g Q) cm ro ffl O rtf* w g QJ · itf Η O W Qtffl ro ffl · CJ CM ffl CJ ffl CM O ffl O CM ffl cj \/ ro ffl u o CM ffl □ CM ffl υ ffl o o u CM ffl u ro ffl υ CM ffl υ CM ffl u CM ffl o ffl o o a CM ffl CJ \z z I ffl a o CM ffl CJ CM ffl CJ in ffl CM υ o o CJ CM ffl CJ \z z I O rd ro l: ffl Is CJ 5 O s-ffl CM ,-O ffl lo CJ CJ CM CM g Z z J 6 6 3 6 TABLE 1 (continued) / p oa ω •Η T) ω iP «—I nj (0 r-l β PTJ rd 0 β H 3 H fd 0 id u fa -p β ·* ·· OPP 6 0 0 0 O. 5 rl ¢/ 0 Η O hl o ko O O Lf) 10 CM 'tf in O CM o O n O O »tf CM CM rH r4 o n kD o in CM CO o CO rd O kD r—I CM H in -tf in σ» TABLE 1 (continued) Ο ω CM 0 Sh ο ·η Λ id P P fo ϋ fop I I fop ι ω · Φ td β o w x · Ρ Ρ Ο Ρ 0 W O fo fd ή fo ϋ *-* a y< 1 Tl 0 P 0 ofc P 0 ι xi ni e E e c L 0 Ρ Η -H P P- 0 0 •d n a +i O'- υ ·Η d fo tj\ Φ fd p β Ρ tr c a c 0 0 o fd CD 0 0 0 0 >1 ni S U M M 4J H ϋ ·Η Λ M-l P in H ι •H >1 0 L g Κ Ol o o u w B I u-s Oil a a u Ol a UN w □ I A Β oi a a Ol a u a Ol o u Ol a u a Ol o u Ol Ol a a u u V » M icm ad aa o υ σ & g (U Sri O a QtS o Ol H oi CM CM 6 6 3 6 TABLE 1 ( continued) 4663» fc W ω •η τι U) φ >+J r—l (tf flj r-l £ £ Ό (tf 0 C rt fi rt (tf o (tf U fe 4-) £ ·· ·· Φ fc fc g Φ Φ 0) CU 5 rt aO W D fil in in O o o O o 61 kD CM kD rt rt rt kD rt kD rt kD kD Γ* Z—» *» κ κ *. K rt 1 rt rt rt rt I—I rt rt s 0 o o m in o o o O o o o M3 r- CO · m sp o kD o rt «Φ sp rt rt rt rt sp rt sp kD * * *. * κ η rt ro rt rt rt rt rt rt rt l c p* co CM r* to rt CO rt o Z *r in m kD 61 rt rt σ» in sp 04 CM rn rt rt rt rt 61 '61 CM rt rt rt rt rt rt rt rt rt I—1 kD rt tn rt O cm O CO CM kD ffi tn kD sp tn rt in rt o 04 rt in in kD M3 M3 kD in in m in kD in rt co CO 00 in in co u *P in CM o rt O r- O kD co rti rt 03 00 σι σ» rt CM rt rt in in in m in in in in tn tn TABLE 1 (continued) rt φ ω ω a φ >1 rt 0 rt fe (tf fc P a o afc I I ap o d fi fc fc o a φ ·η I W · O W X · fc GJ W O ao^z I Ό P · Φ £ fi fc φ O rt Ο rt fi £ P tf 0 (tf Φ Φ Ρ Φ I fe (tf g O-PH'rl fc fife a O' cn £ (tf £ 0 0 0 0 Ή ° g fc fi 0 *-» (tf P 0 0 >1 (tf S rt o M3 ό ι—I d ufcfcpHOrtfemp +1 ‘rl I Ί3 G Ή >1 Ό 0 0 +> Sj-rl g QJ fc go υ ω W ι CHS Nl ffi ffi u N ffi u N ffi u I ffi a //\ a N ffi g φ · (tf rt 0 w az fc c wo (OJ I cO rt rt O rt 6 6 3 6 fi w W o o oj σι LO OJ O OJ LO o οo Ol LO o co cn «—I I _ o lo oi o Kj« r—! o co cn O LO -Φ (continued) TB •fi Ό ω qj >i.p fi rtf rtf <-i C rtf 0 fi H 3 H to 0 rtf O Cm +J fi ·· ·· Q) fi fi £ QJ 0 QJ Λ ? «fi Oj O W ffl ffl LO CO co O P* OJ OJ co co co o CD LO LO LO If) OJ I qj ω 0« GJ £>i i—1 Ο *fi 43 id fi -fi ffl 0 CU fi fi QJ TJ O a I I Qj4J 4 fi ffl f0 I W · xo ω a · fi qj ω o CUO'-Z I TJ QJ «fi G) fi QJ I 42 fd ε fi fi fi O fi ffi Ή 4) O -fi fi 3 fi O -H 3 ffl σι Cn βψι tJ1 fi ro fi O (0 QJ Ο Ο Ο O m ° s’ fi 3. θ'rtf 4J ϋ 0 ί>ι «ο > in U fi fi fi ffi U ·Η Α Ή +J •H >i O fi ε qj ffl o o u rn ffl a fi *c I Di OJ O O ο ω ffl ι cj-z Oil ffl ffl u OJ ffl U OJ ffl U I ffl ffl u n\ ffl OJ ffl ffl cn ffl U zffl fi in cn ffl ffl oj u cn W Ui λΐΛ| <3 O' B I I ε si · MHO co az n cn ϋ I u ft ω •Η Π3 ω ο >i«P Η Πί nJ r4 C 3Ό nJ ϋ β t“i 9 A nJ O rt U ft 4J β ·· ·· QJ Μ M £ QJ QJ QJ ft ? H CU O WPJ1 1 I 0 0 0 0 O O 0 0 0 O 0 CN ffl CN in CN in CN 00 cn cn CN CN ffl H ffl co ffl H ffl ffl ffl r—1 ffl * * fc. CN K », fc. fc. ri H H H H H H H rfi rfi rfi 'e K r-i \l »« *. u 0 O O 0' 0 0 ffl O O ffl 0 σ co CO 00 co in co Γ*· ffl O 00 CO 00 m cn cn cn cn cn ffl tr ffl ffl ffl * * ·. ·. *. κ fc. fc. * co rfi cn rfi m rfi ffl r-1 ffl r-i ffl rfi ffl ri ffl m H CN rd tT tj* ffl O) m ffl ffl in ffl ffl CN CN CN CN «—i CN cn CN ffl ffl ffl ffl ffl ffl ffl ffl ffl ffl ffl r* rfi ri pH «fi r- lfi H rfi r—1 rfi r-i rfi M σ» σ» CN r— ffl l—J ffl O ffl CO ffl cn cn cn *3* ffl CO ffl ffl CN tfi rfi 0 ffl ffl lo ffl ffl ffl ffl ffl ffl ffl ffl ffl tr 0 tr CF) CO ffl co ffl ffl C ffl u r* co CO in 4* ffl Ϊ-* O CO 0 co tr tr tT tT m ffl ffl ffl ffl CN 0 ffl in m in m in ffl ffl ffl ffl ffl ffl qj m ft GJ (continued) >ιΗ Ο ’H Χί nJ M X> ft 0 ft fi ft-P QJ β It/)·*-* _ fi O W X · fi fi Ο fi QJ H 0 ft nJ -fi ft ϋ ~ S τ3 ω -Ρ ω α> ι Λ rt g g{ fi Ο 4-> Η -H -rl Μ β 4J _ fi β ft Cn O β 4J σ · β rt β rt QJ O 0 0 0 ip *-* rt ° >t.rt § u |4 14 44 Η Ο -Η n m 44 ι •rl I t β -d >1 a o o 4J <·Η B i) fi 0) Ό s ft rf Oi N oo o w a ι 02 Nl a a o N a u N a o a z ι u Λ Ζ N a a Po a Ί 5 o u CN CN m tc u u V I cn ffi o CN w u CN ffi □ W u CN ffl ε qj · rt H 0 CO ftJS cn CO O ti* ffl <31 H ti* 6 6 3 6 Ll CQ W J'W ♦rl TJ ω ω >ι -υ ι—I nJ nJ r-1 fi fi Ό Ιΰ ϋ C r-l β r-l «J 0 fi O Cm +J β ·· ·· Φ Li Li 6 φ Φ ai a? h a o M ffi ffi ο ω am O ro i—l r-l O ro oo in in CTi O CN o oo ro in TJ* CN CN Ό nJ O Λ Ο Ο O vo O m ro vo ffi CN ffi r^J ni o Ll XI OOm mom ro vo ffi CN CN no nJ o Ll fi OOm oo CN *0 o Ll fi o o o m ffi vo ro vo ffi CN O TABLE 1 (continued) Ή ,β nJ Li -μ a u aL Li Φ no ft &,4j ι tn ·♦-> Φ m β o w x · Ll Ll O Ll Φ H 0 CL fi ffi ft □ Z J ro φ ψ) Φ +j Φ 1 X2 nJ £ fi β M 0 4J ffi -H Φ Ο ffi Ll fi +> ϋ H Q ft O' Cn fi ffi CT β nJ fi O nJ Φ Ο Ο Ο O M-i °*e Ll ft o *nJ ffi ϋ 2 >i fi 5 U Ll Ll ffi ffi 0 ffi Λ M-J ffi •rl kN O ffi e φ Ll *? Cd CN O O U W ffi 1 OZ CNl ffi ffi o CN ffi O CN ffi u H 8 CN CN ffi ffi o u V CO ffi □ O CN ffi o CN ffi u ffi o o o CN ffi □ ffi z /Λ a CM a g 0) . ra η o ω aa aP & -d> (T.

W -«p u I fi I ffi z O in O U σ v OJ P tf tf TJ nj o ρ fi · ο O m in cm in cn ko H mhh Τί Ό fd fd 0 0 P P fifi Ο O in Ο O in cn ko r-i ft rl r-l fd nd OOm OOm fllDrl ».*.·» m η H fd ·ϋ td fd o o P P fifi oom ιο H in m ko h rd Ti id fd 0 O P P fifi OOm OO o ^0 •tf CM ω •H T3 w 0 fd rd c! dd aog H fl 0 fd u fo P β ·· ·· P P g 0 0 0 fo 5 H fo O H tf tH rH in ω cn CM •tf o in rH CM co r* cm cm Η H cm σ» co > σ\ co cn cm kO kO m m TABLE 1 (continued) »H ω 0. 0 >1 •H 0 Ή Λ L jj fo 0 & M P o fo I fop I W · *-* 0 cd fi 0 w H · Ρ Ρ ο P 0 M p fo id Ή fo ϋ —1 tf ι Ti P 0 fi β P 0 Ο -H ϋ Ή fi fi P W P 0 I Λ (0 6 Ο Ρ Η ·Η P fiP fo Cn tn fi rd fi td 0 ο ο ο o ip nt 0“ «JJ 0 0 >1« Ϊ h M +> Η Ο Ή Λ Ή JJ i •H >i O JJ g Μ ΐ tf CM o o o w tf 1 OZ CM I tf tf o CM tf o CM tf u t W tf t o //\ B CM a a » o CM w U CM w o O ω fotf rH m tf O cn tf tf CJ—u CM tf □ o. •tf m cn a I cn W o CM tf o CM w O CM tf u \/ tf I tf o o o CM K u a CM m cn m 6 6 8 6 (continued) 46636 ν fi ffl w ffl H ω ♦η tj w GJ >ifi H (0 (0 rfi β 3Ό rdOg rfi (tf 0 rtf U ffl fi β ·· ·· GJ fi fi S OJ GJ GJ Oi 5 rfi & O ffl Ο hi O oj in ro cn «η LO rfi OO Ό· Pin O oo ro rfi LO rfi rfi OJ rfi sp O in σ» O O in TJ rtf o fi fi o o o o m lo fO L© rfi Sp rfi O OJ O O Ol LD CO rfi rfi O LO Ρ» P~ (continued) •fi Φ ffl w Pi GJ >1 rfi 0 -fi 43 nJ fi +> Ph o Pi fi I I Difi GJ Φ β fi fi O ffl <0 *fi I w · O w H fi GJ ffl ffl O'-* Ifi O “ M +1 ..... 0 0 β0)ΟΟΟΟ>ιΜ3 fit M +J Η U -J fi Jt JJ I Ό jj 1 O O4J •fi ε gj I CJ o a ω ca ι u—B N I Κ ffi U CJ ffi □ CJ ffi CJ as ύ. ffl Ol ffl fi Ci ffl a ffl o o u OJ I \/ ffl I . fp ffl ffl o-o Γ0 ffl u o Ol ffl ffl a o o οι O ro ffl ffl ffl ’· CWJ V I ro ffl U O Ol ffl o oj ffl o ffl o o o OJ ffl u OJ ffl u \Z z I ro ffl u OJ OJ ffl O LO L0 ro ffl U ro oi ffl υ g Φ . ro rfi 0 ffl Oafi in LO CO LO ro LO I G G 3 6 rt ffl Ό ftf O rt β Ο O in O cm in ΓΟ 0 rrt CO r-) irt TJ ftf o rt Λ Ο O in in cm in CO iO rrt O in co ro irt in in CM O in rrt o in cm O m co in rrt rd O m m in ω •rt Ό ui Φ >iffl rd fl ftf rd fi fi Rtf ftf 0 fi rd fi rrt ftf 0 ftf O fe 4j fi ·· Φ rt rt g 0) Φ Φ ft fc rrt ft O ω ο ffl CO rrt rt* rirt rt* CO in co CM in io r- rTABLE 1 (continued) •rt Φ w W Οι Φ >1 rd 0 Ή Λ rt rt -P Or ϋ Qi rt I I ft-P ι ω · Φ rt c O « · rt rt o rt Φ W O ft rt -rt p4 o — z I Ό Φ ffl Φ ffl Φ I xj rt g fi fi rt 0 ffl ffl ffl Φ 0 ffl rt fi ffl ϋ ffl fi ft Cn Cn fi ffl cr c rt fi o fl φ o o o o Ud o — rt ffl □ o >1 rt $ co O co r—l OrtrtfflrdUfflJbfflffl ο n g P4 O U ffl . u—z CM | ffl ffl O CM ffl U CM ffl ϋ I ffl z I X \ CN Β S O ffl I O 1 u CM CM ffl ffl u u \/ ? ffl U rt e 9°’ CM CM O ffl o ffl o \/ co ffl O . ffl CM O ffl , O U ί u CM ffl CM ffl co ffl o CO CM ffl □ 0Ί <0 o ΓU ί U Xs I ro ffi U rt* CM ffl U -Fit ro ffl O CM ffl U CM ffl □ ro ro = ffl cou ffl CM U ffl \O \ffl 'u tt ✓ ® co rffl co fflUffl ux'p O ro -0-8 46636 μ cfl rt Ό οι qj ChP rt (tf (tf rt £ fi Ό (tf 0 £ rt fi rt (tf 0 (tf o a P c ·· ·· QJ fc fc g QJ QJ a> a £ rt a o W D rt (continued) in o n o o in o o o O rt ko rt kD rt SP CM rt CM in 1 kD rt kD rt kD rt kD kD kD rt rt 1 rt rt rt rt rt rt rt rt rt rt ε te te te te 0 o o o o in in o o o o in in * O ko o kD p- in rt in St kD sp St CM sp CM rt CM rt rt rt rt rt CM te te te » te te > ·. ·» te te rt rt rt rt rt rt rt rt rt rt rt ι—1 a rt rt CM kD rt in rt co r> rt rt co cn cn rt rt cn rt in SP CM rt cn P> CM CM rt rt CM rt rt rt cn rt CM CM rt rt rt rt rt rt rt rt rt rt rt rt id in CO ω kD rt CM o cn CO kO kD ffi CM o st Sp CM rt 00 cn O o CM in C Ρ» P* P- P* P- kD kD p- P* P- Γ- rt kD rt rt in rt rt in kD rt rt CM rt co cn CM cn p* cn rt st CM rt υ rt rt sp sp rt CM co co CM CM rt rt m m m m in LO sp sp m m in in Φ ω alrt O rt fe (tf fc P a o a fc f 1 ap ι oi · —* QJ (0 £ O 01 X · fc fc O fc QJ Μ O a (ti rt a ο z | ro φ ρ QJ P Q) I fe (tf E £ £ fc 0 P rt rt QJ 0 rt fc fi P o rt fi a tn σ» CPO1 £ (ΰ C 0 (tf QJ 0 0 0 0 P (tf P 0 >1 (tf £ UfcfcPrtOrtfePP firt >, OOP rt g QJ fc I CM o —rr ffi a □ ω ffi I α—z CM I ffi ffi u u CM ffi U I ffi z I u //\ Z CM ffi ffi CM ffi U, C\i O a '8 ι » o o o u (Ν IN ffi ffi u o \/ a ι ffi u η *7m ffi □ fc σι ffi U O tN ffi u CN ffi λ/’ a I rt ffi υ g o υ CN ffi u rt ffi u o CM ffi u CM ffi U o m ffi £ « cis I . rt ffi u o CM ffi U CM rt ffi ffi u u o rt ffi U O rt CM rt ffi ffi U O O ε qj « (tf rt o w a £ O co > P* (continued) « U V μ ca « ω ffi rfi w Φ >iffi ffi (0 (β ffi e fi fi o c ffi ρ ffi .fi o fi O tt ffi fi ·· ·· Φ Ll Ll ε φ φ φ λ £ ffi ft o W O tt o o 1 Ip co co Ip VD vo ffi k. fc. ffi ffi ffi fc. fc. o o O o in in CN Γ- co ffi *tf CN k. k. *. co ffi CO ffi vo oo Γ- ffi o o CN CN CN CO CO ffi ffi ffi ffi co in Γ* CN O ffi o O vo in co (continued) r- r’tf -tp CM if) o o O m O - co Γ- m vo co vo ffi to ffi vo fc. t» fc. ffi ffi ffi ffi ffi i ». k. O o o o o ,o ffi cn CN vo in vo ”tf CN CN co ffi κ κ U. k. Ik co ffi CO ffi CO ffi o σι n CN co ro o σν o 00 vo CN ffi CN ffi ffi »—l ffi ffi ffi ffi ffi H Γ- co Γ- vo ffi Γ- vo Γ- CD vo co t k « in. « r- r- r- * Γ- r- in co • in «ςρ rr- in in r- in VD O O in in m in in m m in in tn o o co cn vo O O O in co VO Γιο V£> VO CN © ffi oo ’tf VO *tf ffi φ ω w ftfi ffi 0 ffi Xi fi Ll 4J tt 0 ft Ll ffi tt i i μ ft-P ffl Φ fi rt! M H Em pm ra I T3 Φ ffi Φ ffi Φ I eC fi ε fi fi Μ O ffi ffi ffi Φ O ffi Ll fi ffi ϋ ffi fi ft Cn tP α ffi cn fi fi fi O fi Φ O O 0 o y-t Ll ft O fi ffi 0 0 Ch fi £ (jHHffiffiOffiXrffiffi I ffi ffi I Ό fi ffi >1 Ό O O ffi < ffi S Φ Li rfi I CN O o w tt I u—is CN I w w o CN ffi u CN ffi υ tt έ Λ CN* ffi ffi CO ffi U co ’cn ffi u Li ffi I U O 0^5 n m a a u u η ω CM CM a a υ υ ΓΟΟ co ffi u co co CN ffi ffi o o co O ffi O CD •CN ffi o λ / ί 2 ffi U A§ <2ΛΟ co ΟΊ 4 6 6 S 6 (continued) 46636 /1 (continued) I.R.(KBr) Η 1 ε 3,370/ 1,635 1,580, 1,090 3,350, 1,620 1,455, 1,090 3,350, 1,620 1,455, 1,090 3,350, 1,625 1,460, 1,090 3,400, 1,630 1,455, 1090 3,400, 1,620 1,080 Elemental analysis Upper: Calculated Lower: Found 2 ffl lfi ffl ffl «fi rfi lfi «fi ffl tj* ffl ffl rfi rfi rfi rfi ffl ffl cn O .fi CN rfi rfi CO O ffl Γ- rfi rfi rfi rfi lfi o CN ffl CN CN rfi rfi O N? O CN rfi rfi rfi rfi ffl Ο ifi co r» vo ffl O ffl CO > ffl ffl ι—1 CN tt* ti* r·* r* OO Cl ffl ffl [*· r- in σι oo r· ffl ffl CN in O Cl ffl in ο ro σ) rn fi* in ffl in in ffl rfi ffl CN ffl in in in Ο H ffl ti* ffl ffl in in ffl ffl o in σι cn ffl 0 O in in CO ffl CN fi* lo in fi* fi* I ! •η ω ω ω ft φ £-|ifi 0 ’fi v CU 0 P, 14 ' t 1 1 0,44 I ω ..-. Φ ιβ β ο ω χ · L h 0 Μ «ΙΗ 0 cu ra a ο, o — 2 ffl = tr ti* ΐ t fi* fi* ι a o+> ® o — 44 (D 1 43 rt S ε fi fi (4 0 44 r-l a W fi. (DO a 14 fi 44 0 — oafio,bi&i rt 44 fi 44 0* fi rt C 00 OOOOOOMS a h 14 4J a o a λ n +) co O in. fi ΐ « Ν Ο Ο U Μ a ι υ—2 Ν ι a a υ Ν a Ο Ν a υ I a 2 Λ Ζ cn ffi ffl ύ •fi 1 Ό β ·Η >ι Ό 0 04J - . 1 ι 1 1 ffl tt il 1 ffl ffl 01 1 = = « tn o - O L y cn tu \ O CN* CN ffl ffl ffl 9« 1 σ CN O w υ Q CN n a a o U\2X 1 ffl ffl ffl tt o in CN a ffl CJ a U 1 Ο O ffl tt ffl tt υ · o CN ffl u ffl CN Sg: O o ffl CN ffl CJ CN tt 0 ffl CN tt ffl u υ O O ffl . . ffl $-8 fi s = tt* CN tt fflU tt'-' U I o° cn -1- Ε Φ · (8 rfi 0 ω ft β Cl Cl o o rfi rfi O rfi CN O rfi ffl o rfi fi* o rfi ¢1 ϋ 6 3 5 ρ CQ tf ιη ιη •τ o co o o cn kO in CM o kD O m cm in kO rH O OO cn O tn (continued) ω •η ό W ο >ιΡ rH 0 0 rH fi 3T3 0 0 fi H fi rH 0 0 0 tf fo P fi ·· ·· P P £ a Φ a &S rH fo 0 ω tf tf ι ω fo 0 Sri Ο H J3 0 Ρ P fo O fo P I ! fop in · — 0 0 fi 0 W K · P P 0 P 0 W 0 fo 0 -η fo υ ζ Ό 0 .. P 0 ·Η •ri fi P 0 I Λ fl E 0 P rH -H P fi P fo tf tf fi P tf fi 0 fi 0 0 0 0 0 0 0 Ip — O'0 P O 0 S 0 > tf PP+JrH 0-ΗΛΜΗΡ P •Η I Ό fi’H >i Ό 0 0 P < ή ε ο Ο CM co co •tf d in kO cn O cn rH vo oo rH cn co CM O «Η o I tf cio tf o tf tf P ΐ CM o W O O CM K tf CM tf tf tf o o tf CM tf tf y u w a ι tf—is CM I tf tf υ CM W tf CM tf o tf 2 I υ ω tf tf CM κ α ο CM tf α m cm « tf S 8 . 0.

\ CM tf I tf tf tf CM cn su O cn tf m m tf K tf tf V tf CM tf tf CM tf tf cn tf tf CO CM K tf tf tf \/ tf tf o -d g a . WHO m a c in o io O r o iH σ cn m K tf tf tf V a u o -d O H H CO o . ί J Μ ft ϋ) •Η Ό ω φ >+» «Η fl fl Η C fl Ο β Η G rH fl Ο fl CJ ft -μ β ·· ·· Φ Μ SH g Φ Φ Φ ft £ rH ft Ο MDP] Φ fl ft Φ >trH Ο ·Η XJ fl M 4J ft 0 ft M I ft+> 1 fl . Φ fl β O W X · Μ Ρ Ο M 0 W O ft fl -r! ft U S3 l TJ jj φ β β In φ Ο -Η ϋ Ή G Φ-Ρ Φ I fi fl g 4J rH ·Η μ β -μ . . . ft cn tP β 4J Ο1 β fl β 0 fl Φ Ο 0 Ο Ο ιμ ο ~ μΙ ο fl 4-> α ο >ι fl 5 U Μ M+»rH ϋ ·Η £1 UH Π-> ι +) •r| | Ό β -rl N Ό 0 0 4J riJ-H g(l) Ο Ν kD Ο ιη co m ιη ι-Η Ο co co o O rH O CO co tn in Ο co rH Ο ιη t—ι ο co rH Ο Ο co ιη kD Η Ο CO co CM > CO rH co o Ο co Ο ιβ CO rH Ο co ο.

CM η Ο οο co rH rH ri* rH O co o CM o co co CM rH co co rH rH rp co co m co o oo co rp rP in in CM d μ ι CM O □ w a ι u—a CM I a a u CM a u CM a □ I a a Λ Z (N a a f-1 r'i a a o u V a u o CO ι a a V ω a a o u o co co a' m a CO CM a u υ o a u CM CM a u u CM CM a u rp rH g φ . fl rH o W ft β rH rH rH in rH H kD rH rH CO rH rH β 6 S G in in rd o M* O O’ o co ro O Lf) rd o CO o in O co ro O O CM 0 O O m co (continued) w •rt Ό ω φ >i-P rd fl (0 rd fi fi Ό rt o c rd fi rd fl 0 rt CJ tl +> fi ♦· Φ rt rt ε φ φ φ as r-l ft 0 HPd •rd >trd Φ W ft Q 0 -rt XS rt rt +) ft o ft rt I I ft+J IW·*-» Φ fl fi o w x · rt rt o rt Φ ffl o ft α ·η ft □ Z Φ +) Φ XJ fl S fi rt 0 4J H *r| Ud O-> rt «Ρ □ o .rd rt fi X> ϋ -rd fi ft cn tn fidJtn fi fl fi -0rt00000>irtS Urtrt-PrdD’rd^MdX) •rd 4J S Φ “ST σι CM CM rd CO Γ» rd Γω co CM 'gg ~(g00 co CO P* σ σι ro m d\ CO O r0 m cm in O rd in rt rfj I ffl c o O u ω ffl 1 u—z CM 1 ffl ffl υ CM ffl u CM ffl υ ι ffl z I υ z (N a rt ro ffl a ro ro cm ffl ffl~ • a cm ffl a ® —* ro c CJ O ffl ffl r rd rd CO rd rd fO ffl a tn a a u u o ro CO ffl a CJ o co S—K CM CM CO ffl m a ffl U ffi CJ CJ CJ — O O o o O> rd rd CM CM rd o CM rd Ε Ο . h 0 tn ifi 6 68 6 /0 fit ffi « O LO rfi O LO rfi o o rfi O rfi LO O LO rfi I o co ro o co ro O CO ro b co ro O in co O OQ ro (continued) W •fi TJ υ) Φ >ι·μ H fl fl rfi β 3 TJ fl ϋ β rfi β rfi fl O fl U ffl •P β ·· »· Φ fi fi £ Φ Φ , Φ a£ rfi Pl O W O ffl >rfi o-fi 43 fl fi -P ffl O fflfi i I ο,-μ j ω Φ fl β 0 W X · fi fi O fi Φ ffl o o, fl.fi p, ϋ £ TJ Φ 4J Φ Φ ι ffl fl S β fi O +> rfi -fi O -rl fi 3 +» _ -fi 3 a cn Co β -P CH β fl β 0 fl Φ 0 0 O 0 m — fl +J ϋ 0 >1 fl 5 Ofifi+)rfiO«fi43Mfi+J I P •rt I Ό fl -H >i MO 04) rt! Tt g (U fi ·< I CM O u w ffl I U—3 rfi I ffl ffl U ffi ffl u CM ffl u ffl Z ύ.

// M rt! H cj ffi g Φ * ra rfi 0 ω a β in LO LO rfi LO LO CM CM σ> o in in • • • CM CM rfi CM CM CM rfi rfi rfi rfi rfi rfi tn ro LO CO tn r* rfi CM tn rfi in C LO in r* ffi ά σι σι ffi ffi U U \z ffi □ tn tx ffi ffi u u ° °ffi° in tn ffi ffi ct σι n u ffi y o u o ro CM rfi tn CM rfi LO CM rfi o o O CM CM LO LO LO rfi *» rfi rfi rfis r> o o o ϋ tn in OQ sp rfi co CO κ *. w ·. - ro rfi ro rfi d\ . l£> Trr ΪΠ— LO r» CM o • « • ro ro CM CM rfi rfi rfi rfi L0 CM (fi rfi LO SP in CM σι, σι ffi jffi □ tU in ffl CM cb txO σι σι ffi ffi 8 8 \z (ffi u to CM ffl u CM CM ro ffl ffl U U *- ro □ O ffl // sp CM rfi CM rfi 4^636 ρ CQ tf if) in rH co ro in m •H o co ro O co ro o o cm in in O in co (continued) ω •H tj to 0 >ip H 0 0 r-l C fi TJ 0 O fi H fi rH 0 0 0 tf fo P C ·· ·· Ρ P g 0 0 0 fo > rH fo O fo □ fo H 0 CO to foty >1 rH 0 -H tf 0 P P fo ϋ fop I I fop 0 0 P P fo 0 ι ω · tn X · P 0 fo O foO-2 1 Ό 0 P 0 0 P 0 ι a « e ε fi fi P 0 P rH H P zi 0 0 Ρ iJ 3+1 Γ) *-* 0 •H 3 fo Cn Ok 0 P c P m sue ϋ 0 n 0 0 OOOO t»i 3 ? u P PPH ϋ H tf MH P P •rH Tf fi TJ o < ·Η ro CM co H co 10 O r—1 10 o σ\ 10 ro CM o σ co ro co CO •tf co in tn in in in in in CM co ro «Η rH O co co tf CM P < I CM O /-py W CM CM tf w I 7-2 tf s§ 'imSm a a I CO co tf tf tf tf tf co tf . tf—2 CM J tf tf tf CM tf tf CM tf tf I W 2 //\ co CO tf w \zu a u o ΠΊ a u n r-~1 CM CO tf tf tf tf CM O co tf 8 ro tf tf co CM CO tf W tf tf O O CO -©-8 O PO tf tf ό rH PO rH •4* co E 0 · rH o W fo fi ro co H CM CO r—I ffl tt rfi I (continued) (A •fi Ό W Φ >i+> r-i rt rt H β rt ϋ β η β η rt ο rt ϋ ft •Ρ β ·· ·· φ μ μ g φ φ φ ft £ rfi ft ο ffl ρ ffl Φ ω ft Φ >i CU -p IW·.—* Φ rt β O oi X · μ μ ο μ φ ffl o ft rt ·η ft □ a I nJ Φ «μ Φ •Ρ φ ι χ* rt g β β μ Ο -μ Η -fi Φ Ο ή μ β -μ ϋ ·Η β ft Cn σι β -Ρ σ β rt β ο rt φ ο ο ο ο (p *1 Ο — rt -P □ o !>i rt 5 Ομμ+ΐΗϋ-ΗΛ^.μ I 4J •fi I nJ β -fi >i Ό 0 0 +J < -fi g Φ μ I CN Ο υ W ffl I 0—ζ CN I ffl ffl ο CN ffl υ CN ffl U I ffl ffl I ffl CN ffl Ε Φ · rt rfi 0 ω ft β o o o o o in CN in CN fi* lfi kO rfi kO lfi. fc. »» fe fe lfi lfi lfi lfi lfi ‘ fe fe fe fe fe o o o o in CO fi* CO in co cn cn m cn cn », «, »» * ·« rfi cn rfi cn lfi <31 CN 01 CN in r- cn CN cn cn CN cn cn rn cn lfi lfi lfi rfi rfi 00 CO lfi CO o m fi· fi* fi* in ,, , • • Γ* r- Γ* Γ* kO cn o cn m co Oi co pfe in fi* fi* fi* fi* in in in in in in ffl & cn ffl ά cn s CN «—» CN ffl m u ffl ~ u o m ffl cn ffl □ CN CN cn ffl ffl 0 0 a ' 0 cn ffl cn in — ffl CN CN ffl 0 0 O m cn •rfi kO cn rfi 0N cn 6686 The compounds shown in Table 2 below are prepared in the same manner. In this table, the prior art reference cited in the second column discloses a method of preparation for the compound listed in the second column. 6 0 8 6 TABLE 6 6 3 6 (continued.) } 6 6 8 6 (continued) CM ffi ffi o c o O X_M P o Z 0 cn ffi fi z—» Ό CM 0 ffi fc υ ffi ffi z ffi w ffi CM U o z ffi ffi O ω fc cn fc o P o 0) fc Q> fe P CM O W P rt (tf 0) 6 ϋ 8 ϋ EXAMPLE 2 (continued) 46636 (continued) 6 6 3 6 (continued) (continued) 6 6 8 6 EXAMPLE 2 (continued) 466S6 (continued) 46636 (continued) 46636 EXAMPLE 2 (continued) is (ϊ 8 6 EXAMPLE 2 (continued) EXAMPLE 5 Tablets suitable for oral administration Tablets containing the ingredients indicated below may be prepared by conventional techniques.

Ingredient Amount per tablet (mg) 2 N -(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl-N-butylglycine 250 Lactose 140: Corn starch j 351 Talcum 20 Magnesium stearate 5 i Total 450 mg EXAMPLE 6 i Capsules for oral administration | Capsules of the below were made up by throughly mixing together batches of the ingredients and filling hard gelatin capsules with the mixture. =10 --------- ' ' ......... ' '1- Ingredient. Amount per capsule (mg) 2 N -(3-cyclohexyl-4-methoxyphenyl- fonyl)-L-arginyl-N-butylglycine 250 [ Lactose 250 Total 500 mg EXAMPLE 7 Sterile solution for infusion The following ingredients are dissolved in water for intravenous perfusion and the resulting solution is then sterilized.

Ingredients Amount (g) 2 N -(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl-N-butylglycine 25 Buffer system As desired Glucose 25 Distilled water 500 PREPARATION A Arylsulfonyl chlorides (A) Sodium 3-butoxy-2,4-dimethoxybenzene sulfonate To a well stirred solution of 50.8 g of 2-butoxy-l,3-dimetoxybenzene in 160 ml of carbon tetrachloride was added dropwise 16.1 ml of chlorosulfonic acid at a temperature of O to ,,4 6 6 86 4°C. 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 result5 ing agueous layer was extracted with ether and then neutralized with 2N NaOH solution to precipitate white crystals which were filtered and dried to give 64.3 g (85.1%) of sodium 3butoxy-2,4-dimethoxybenzenesulfonate.

(B) 3-butoxy-2,4-dimethoxybenzenesulfonyl chloride To a stirred suspension of 60.0 g of dry, powdery sodium 3butoxy-2,4-dimethoxybenzenesulfonate in 150 ml of dry dimethyl formamide was added dropwise 69 ml of thionyl chloride over a period of 20 minutes at room temperature.

The reaction mixture was stirred for 15 minutes and poured gradually into 1,000 ml of ice water and stirred vigorously. After 1 hour, the agueous layer was decanted and the residual oil was extracted with 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%) of 3-butoxy-2,4-dimethoxybenzenesulfonyl chloride (Bp 154-5° C/l mm Hg) Analysis - Calcd. for C^H^gClOgS (peroent) : C, 46.68; H, 5.56 Found (percent); C, 46.71; H, 5.60 The following arylsulfqnyl chlorides not previously reported in the chemical literature were synthesized by the 1 t aforementioned preeedure. J ! j I -i β e s 6 TABLE 3 NO. Ar - SO2C1 I Boiling point Ar (melting point) A 165-166°C/1O mmHg 1 u ' 0(ch2)2ch3 (57.5 - 58.5°C) Λ 112-115°C/1 mmHg 2 0 O(CH2)3CH3 (33 - 35°C) Λ j:h3 'OCHgCHgCH^ CHg 3 □ 127-129°C/O.5 mmHg 4 ό 148-15O°C/1 mmHg o(ch2)4ch3 Λ o(ch2)3ch3 143-145°C/1 mmHg 5 υ (48 - 51°C) A 6 VCH2CH2CH3 (41 - 2°C) och3 4,6686 TABLE 3 (continued) No. Ar - SO2C1 1 Boiling point (melting point) Ar 1 Tl CH3 ' 139-140°C/l mmHg 7 '1 A CH0CH3 CH2CH3 Λ 1 CH, 8 1 1 129.5-132°C/l mmHg < C - CH, OCH CH, 3 3 CH, r 3 9 V - O(CH2)3CH3 145-148°C/1 mmHg <5h3 ^CH3 10 ι 1 151.5-153.5°C/1.5 mmHg V k 0(ch2)4ch3 ch3 CH, f* 3 11 V c O(CH2)3CH3 155-156°C/2 mmHg CH, 12 (44 - 45°C) k0CH2CH20CH3 6 6 8 6 TABLE 3 (continued) NO. Ar - SO2C1 Boiling point 1 Ar (melting point) 1 13 CH Ώ OCH2CH2CH2OCH3 187°C/1 mmHg 14 fl°CH3 OCH2CH2CH2Br OCH3 198-2OO°C/2 mmHg 15 hf3 0 (CH2) 3CO2CH3 och3 21O-22O°C/1 mmHg 16 OCH, fl ^/^0(¾) 2ch3 och3 16O-162°C/2 mmHg 17 pi^V0CH3 och3 154-155°C/1 mmHg 18 . |^\-°CH3 LJ-OfCH^CHs och3 17O-172°C/2 mmHg TABLE 3 (cpntinued) No. . Ar - SO2C1 -......... ' ' ........... ' t Boiling point Ar (melting point) 190CH3 L·! o(ch2)5ch3 och3 183-185°C31 mmHg 20 Ap L 1pch2ch2och3 OCH, / -5 ί 1 (46 - 47°) 21 -/Y1 lxlO2>3CH3 131°C/1 mmHg 22 r Ay ° ^2)2¾ (65 - 66°C) proportions of isomer unknown 23 ^γ0(0Η2)3εΗ3 %Λ)(ΰΗ2)3(:Η3 (30 - 32°C) 24 (CH.,),CH, 0 °(ch2)3ch3 2O8-21O°C/1 mmHg 6 8 6 TABLE 3 (continued) NO. Ar - S02Cl — Boiling point (melting point) Ar 25 zXvZKCHjgCHg V O(CH2)3CH3 178-179°C/2 mmHg 26 ό C0(CH2)2CH3 och3 Oily substance 27 Ar0CH3 0CH2CH20CH2CH3 och3 165-168°C/1 mmHg 28 Λ ^xACH\ Y CH-CH- oco2c2h5 Oily substance 29 ό \Zoc2h5 109-110°C/l.5 mmHg 30 Λ /C”3 OCH . CH3 111-116°C/1 mmHg s TABLE 3 (continued) No. Ar - SOjCl — Boiling point (melting point) Ar 31 Oily substance 32 A \^/AoCH2CH\ ch3 Oily substance - 33 ό O(CH2)4CH3 148-15O°C/1 mmHg’' 34 V^VCH3 OC2H5 152-153°C/2 mmHg , 5 ( 1 35 t^Y*3 xAolC^ljCHj 133-134°C/1 mmHg, 36 fY\c„3 CH3 142-143°C/1 mmHg 46636 100 Table 3 (continued) NO. Ar - SO2C1 Boiling point Ar 37 XX°C2H5 lH3 121-122°C/1 mmHg 38 ΤΎ“3 O(CH2)2CH3 ch3 133-135°C/1 mmHg 39 A-C ch3 136-139°C/1 mmHg 40 WCl/CH3 XCH3 (95 - 6°C) 41 prj X*CH3 7—< CH xCH3 _// Λ-0-(0Η9)90Η- \=uZ ch^ch3 ch'ch3 (101 - 103°C) 42 (CH2)2CH3 XXo(ch2)2ch3 142-144°C/1 mmHg 101 TABLE 3 (continued) 46636

Claims (20)

(I) : HN, C - N - CH2CH2CH2CHCOR (I) HNSO Ar wherein R is (1) - N (CH2).£q00R2 wherein Rj is C2_C1O a-LkY1' C3-C10 alkenY)-' C3-Cio alkYnY1' C2_C1O alkoxYalkY1r C2-C10 alkYlthioalkyl' C2-C1O alkY·*-sulfinylalkyl, Cj-CjQ hydroxyalkyl, C3~C10 alkoxycarbonyl10 alkyl, C3~Cj0 alkylcarbonylalkyl, Cj-Cjq haloalkyl, C7~Cj5 aralkyl, Cg-Cjg α-carboxyaralkyl, C3-Cjo cycloalkyl, c4“Cjq cycloalkylalkyl, furfuryl, tetrahydrofurfuryl optionally substituted with one or more of Cj-Cg alkyl and/or Cj-Cg alkoxy, 3-furylmethyl, tetrahydro-3-furylmethyl optionally

1. ,2,3,4-tetrahydroquinolyl, or 1,2,3,4-tetrahydroisoquinolyl, the optional substitution being by one or more of halo, nitro, cyano, hydroxy, Cy to Cy Q alkyl, Cy to Cy Q alkoxy, C 2 to C 20 dialkylamino, sulfoamino, carbamoyl, Cy to Cy Q N,N-di10 alkylcarbamoyl, amino,Cy to Cy Q alkylamino, mercapto, Cy to Cy Q alkylthio, C 7 to Cy 2 aralkyl, carboxyl, C 2 to Cy Q alkoxycarbonyl, C 2 to Cy Q carboxyalkyl, Cy to Cy Q acylamino, C 2 to Cy Q alkylcarbonyl, Cy to Cy Q hydroxyalkyl, Cy to Cy Q haloalkyl, oxo, and/or phenyl (optionally substituted with one or 1,2,3,4,5,6,7,8-octahydrophenanthryl, indenyl, indanyl, fluorenyl, acenaphthenyl, phenylthiophenyl, isochromanyl, 2,3dihydrobenzofuranyl', 1,3-dihydroisobenzofuranyl, thioxanthenyl, 2H-chromenyl, 3,4-dehydro-l-isochromanyl, 4H-chromenyl, indolinyl, isoindolinyl, 1,2,3,4-tetrahydroquinolyl or 1,2,3, 4-tetrahydroisoquinolyl, the optional substitution being by one or more of halo, nitro, cyano, hydroxy, Cg to Cg Q alkyl, Cg to Cg Q alkoxy, C 2 to C-,θ dialkylamino, sulfoamino, carbamoyl, Cg to Cg Q Ν,Ν-dialkylcarbamoyl, amino, Cg to Cg Q alkylamino, mercapto, Cg to Cg Q alkylthio, Cy to Cg 2 aralkyl, carboxyl, C 2 to CgQ alkoxycarbonyl, C 2 to CgQ carboxyalkyl·, Cg to Cg Q acylamino, C 2 to Cg Q alkylcarbonyl, Cg to Cg Q hydroxyalkyl, Cg to Cg Q haloalkyl, oxo, and/or phenyl (optionally substituted with one or more of hydroxy and/or Cg to Cg alkoxy). 2. 29. A process as claimed in any one of claims 23 to G 2 28 wherein the N -substituted-N -arylsulfonyl-L-argininamide or the N -arylsulfonyl-L-arginyl halide has been produced by a process including the step of reacting an L-argininamide with an arylsulfonyl halide. 30. A process as claimed in claim 29 wherein, the. arylsulfonyl halide is one hereinbefore identified by its formula in Table 3. 31. A process as claimed in claim 29 or claim 30. wherein the arylsulfonyl chloride has been prepared by halogenating an arylsulfonate or arylsulfonic acid. 32. A process as claimed in claim 31 wherein ..the ... arylsulfonyl chloride has been produced substantially as ... hereinbefore described in Preparation A or Preparation B, or substantially as described in either of these preparations modified by any entry of Table 3. (2) (CHg^COORg wherein Rg is hydrogen, Cj. to C lQ alkyl, Cg to C 1Q alkenyl, Cg to C lo alkynyl, C 2 to C 1Q alkoxyalkyl, C 2 to C 1Q alkylthioalkyl, C 2 to C 1Q alkylsulfinylalkyl, C^ to C 1Q hydroxy5 alkyl, Cg to C 1Q alkoxycarbonylalkyl, C^ to C 1Q haloalkyl, Cy to C 15 aralkyl, C g to C 15 α-carhoxyaralkyl, Cg to C 1Q cycloalkyl or C & to C^ Q cycloalkylalkyl; R^ is Cj to Cg alkyl, phenyl, Cy to C 12 aralkyl or ring substituted benzyl wherein said substituent is C^ to Cg alkyl and/or C^ to Cg 2 ; r optionally substituted as defined in claim 1, wherein R g and r are as defined in claim 1; Ar is phenyl, substituted with one or more of sulfoamino, (2) CH - (CH 2 ) m COORg

2. A compound as claimed in claim 1 wherein said R 35 is (2) - Ν. \ CH - (CH 2 ) m COOR 5 wherein Rg is hydrogen, Cg-C^ alkyl, Cg-C^ 0 alkenyl, CgC^ Q alkynyl, c 2 _C 10 alkoxyalkyl, C2-C^o alkylthioalkyl, C2~ C^Q alkylsulfinylalkyl, C^-C^q hydroxyalkyl, C 3 -C io alkoxycarbonylalkyl, C 3 -C 1Q alkylcarbonylalkyl, C^-C^ Q haloalkyl, C 7 -C 15 ara3>k y 1 ' C 8 -C 15 a-car 5oxyaralky1, θ3~ε 10 cycloalkyl, C^-C^q cycloalkylalkyl, furfuryl, tetrahydrofurfuryl optionally substituted with one or more C^-Cg alkyl and/or C^-Cg alkoxy groups, 3-furylmethyl, tetrahydro-3-furylmethy1 optio nally substituted with one or more of C 1 _Cg alkyl and/or C l -C 5 alkox Y tetrahydro-2-pyranylmethyl tetrahydro-3-pyranyl methyl or tetrahydro-4-pyranylmethyl optionally substituted with one or more of C^-Cg alkyl and/or C^-Cg alkoxy, 1,4dioxa-2-cyclohexylmethyl optionally substituted with one or more of C^-Cg alkyl and/or C^-Cg alkoxy, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl optionally substituted with one or more of C^-Cg alkyl and/or C^-Cg alkoxy or tetrahydro-3-thenyl; R 4 is C ]_“C 1O alkyl, phenyl (optionally substituted with one or more of C^-Cg alkyl and/or Cg-Cg alkoxy) Cy-C^ 2 aralkyl or ring substituted benzyl wherein said substituent is C^-C alkyl or Cj-Cg alkoxy; Rg is hydrogen, Cg-C.^ alkyl, C g -C 10 aryl or Cy-C 12 aralkyl; and m is Ο, 1 or 2. 3.4- tetrahydroisoquinolyl, the optional substitution being 3.4- dehydro-l-isochromanyl, 2H-chromenyl, 4H-chromenyl, 35 indolinyl, isoindolinyl, 1,2,3,4-tetrahydroquinolyl or 1,2,

3. A compound as claimed in claim 2 wherein said R is . 46636 (1) \ (CH 2 ) n COOR 2 wherein Rj is C 2 to Cj Q alkyl, C 2 to C g alkoxyalkyl, C 2 to C g alkylthioalkyl, Cy to Cj Q aralkyl, to Cj Q cycloalkylalkyl·, furfuryl or tetrahydrofurfuryl? R 2 is hydrogen or Cj 3,4-tetrahydroisoquinolyl, the optional substitution being by one or more of halo, nitro, cyano, hydroxy, Cg-Cg 0 alkyl, 20 G l -C io a lk°xy, C2~C2O dialkylamino, sulfoamino, carbamoyl, C3-Clo Ν,Ν-dialkylcarbamoyl, C2~Cg N-alkylcarbamoyl, amino, Cg-CgQ alkylamino, mercapto, c ^ -c 10 alkylthio, Cg-Cg 2 aralkyl, carboxyl, C 2 -Cg Q alkoxycarbonyl, C 2 ~Cg 0 carboxyalkyl, C g -C j_ o acylamino, C 2 -Cg Q alkylcarbonyl, Cg-Cg Q hydroxyalkyl, Cg-Cg Q 25 haloalkyl, Cg-Cg Q hydroxyalkoxy, oxo, and/or phenyl (optionally substituted with one or more of hydroxyl and/or Cg-Cg alkoxy); j or phenyl substituted with at least one of alkyl, plkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbopylalkyl 30 or alkoxycarbonylalkoxygfoup, the or each such substituent group containing 3Λΰν carbon atoms and the said substituted phenyl being optionally substituted further with one or more of halo, methyl, ethyl, methoxy, ethoxy, and/or hydroxy. f (3) - N 104 wherein R g is -COORg wherein Rg is hydrogen, C^-C^ Q alkyl, C g -C^ 0 aryl or C 7 - C·]^ aralkyl; each Ry independently is C^C^ o alkyl, phenyl, C^-Cg alkoxy, C 2 -C g alkoxycarbonyl or carboxyl; p is 0 or an integer of from 1 to 4; R g is 4. 6 6 3 6 1 31 33. A compound of the Formula (I) as defined in claim 1, or a pharmaceutically or veterinarily acceptable salt thereof when prepared by a process as claimed in any one of claims 23 to 32. 4 6 6 8 6 Bn 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 in claim 1, and, if desired salifying the reaction product obtained above. - - . _ 27. A process as claimed in claim 26 wherein the N arylsulfonyl-L-arginyl halide is contacted with at.-least--an . . equimolar amount of the amino acid derivative-at a temperature of from -10°C to +80°C. 28. A process as claimed in claim 23 or claim 26 substantially as hereinbefore described in any one of specific Examples 1 to 3 or substantially as described in any of. . Examples 1 to 3 as modified by any entry of Table 1 or Table 4-methyl-2-piperidinecarboxylic acid. 4 6 6 8 6 123 4-methyl-2-piperidinecarboxylic acid. 4-tetrahydroisoquinolyl, the optional substitution being by one or more of halo, nitro, cyano, hydroxy, Cg to Cg Q alkyl, Cg to Cg Q alkoxy, C 2 to C 2Q dialkylamino, sulfoamino, carbamoyl, Cg to Cg Q Ν,Ν-dialkylcarbamoyl, amino, Cg to Cg Q alkylamino, mercapto, Cg to Cg Q alkylthio, Cg to Cg 2 aralkyl, carboxyl, C 2 to CgQ alkoxycarbonyl, C 2 to Cg Q carboxyalkyl, Cg to CgQ acylamino, C 2 to CgQ alkylcarbonyl, Cg to CgQ hydroxyalkyl, Cg to Cg Q haloalkyl, oxo and/or phenyl (optionally substituted with one or more of hydroxy and/or Cg to Cg alkoxy)j optionally substituted naphthoquinonyl, anthryl, phenanthryl, pentalenyl, heptalenyl, azulenyl, biphenylenyl, asymmetrical or symmetrical-indacenyl, acenaphthylenyl, phenylcarbonylphenyl, phenoxyphenyl, henzofuranyl, isobenzofuranyl, benzo(b)thienyl, isobenzothienyl, thianthrenyl, dibenzothienyl, phenoxathiinyl, indolyl, IH-indazolyl, quinolyl, isoquinolyl, phthalazinyl, 1,8-naphth yridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl or benzimidazolyl, the optional substitution being by one or more of halo, nitro cyano, hydroxy, Cg to Cg Q alkyl, Cg to Cg Q alkoxy C 2 to C 20 dialkylamino, sulfoamino, carbamoyl, Cg to Cg Q Ν,Νdialkylcarbamoyl, amino, Cg to Cg Q alkylamino, mercapto, Cg to Cg Q alkylthio, Cg to Cg 2 aralkyl, carboxyl, C 2 to Cg Q alkoxycarbonyl, C 2 to Cg Q carboxyalkyl, Cg to Cg Q acylamino, C 2 to Cg Q alkylcarbonyl, Cg to Cg Q hydroxyalkyl, Cg to Cg Q haloalkyl, and/or phenyl (optionally substituted with one or more of hydroxy and/or Cg to Cg alkoxy). 4 6 6 8 6 i!20 by one or more of halo, nitro, cyano, hydroxy, Cg to Cg Q alkyl, Cg to Cg Q alkoxy, C 2 to C 2Q dialkylamino, sulfoamino, carbamoyl, Cg to Cg Q Ν,Ν-dialkylcarbamoyl, amino, Cg to Cg Q alkylamino, mercapto, Cg to Cg Q alkylthio, Cg to Cg 2 aralkyl, carboxyl, C 2 to Cg Q alkoxycarbonyl, C 2 to Cg Q carboxyalkyl, Cg to Cg Q acylamino, C 2 to Cg Q alkylcarbonyl, Cg to Cg Q hydroxyalkyl, Cg to Cg Q haloalkyl, oxo, and/or phenyl (optionally substituted with one or more of hydroxy and/or Cg to Cg alkoxy); optionally substituted naphthoquinonyl, anthryl, phenanthryl, pentalenyl, heptalenyl, azulenyl, biphenylenyl, asymmetrical or symmetrical-indacenyl, acenaphthylenyl, phenylcarbonylphenyl, phenoxyphenyl, henzofuranyl, isobenzofuranyl, benzo(b)thienyl, isobenzothienyl, thianthrenyl, dibenzothienyl, phenoxathiinyl, indolyl, lH-indazolyl, quinolyl, isoquinolyl, phthalazinyl, 1,8-naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxyzinyl or benzimidazolyl, the optional substitution being by one or more of halo, nitro, cyano, hydroxy, Cg to Cg Q alkyl, Cg to Cg Q alkoxy, C 2 to Cg 0 dialkylamino, sulfoamino, carbamoyl, Cg to Cg Q Ν,Ν-dialkylcarbamoyl, amino, Cg to Cg Q alkylamino, mercapto, Cg to Cg Q alkylthio, Cg to Cg 2 aralkyl, carboxyl, C 2 to Cg Q alkoxycarbonyl, C 2 to Cg Q carboxyalkyl, Cg to Cg Q acylamino, C 2 to Cg Q alkylcarbonyl, Cg to CgQ hydroxyalkyl, Cg to CgQ haloalkyl, and/or phenyl (optionally substituted with one or more of hydroxy and/or Cg to Cg alkoxy). 4.5.6.7.8- octahydrophenanthryl, indenyl, indanyl, fluorenyl acenaphthenyl, phenylthiophenyl, isochromanyl, 2,3-dihydrobenzofuranyl , 1,3-dihydroisobenzofuranyl,thioxanthenyl,

4. An N -arylsulf onyl-L-argininamide having the 20 formula (I) wherein R is (1) - N\^ (CH 2 )n C °OR 2 wherein Rj is C 2 to Cj Q alkyl, Cg to Cj Q alkenyl, C g to Cj Q alkynyl, C 2 to C 10 alkoxyalkyl, C 2 to Cj Q alkylthioalkyl, C 2 to Cjq alkylsulfinylalkyl, Cj to Cj Q hydroxyalkyl, C 3 to 25 Cjq alkoxycarbonylalkyl, Cj to Cj Q haloalkyl, C? to Cj g aralkyl, Cg to Cj 5 α-carboxyaralkyl, C 3 to Cj Q cycloalkyl or C 4 to Cjq cycloalkylalkyl; R 2 and n are as defined in claim 1, or (2) - Ν H4 ^6636 CH - ( CH 2 ) m COOR 5 wherein Rg is hydrogen, C^ to Ο^θ alkyl, Cg to Ο^θ alkenyl, Cg to C 1Q alkynyl, C 2 to C lo alkoxyalkyl, C 2 to C 1Q alkylthioalkyl, C 2 to alkylsulfinylalkyl, to C 1Q hydroxyalkyl, Cg to C 1Q alkoxycarbonylalkyl, 0 χ to C 1Q haloalkyl, Cy to C^g aralkyl, Cg to C^g α-carboxyaralkyl, Cg to C^ Q cycloalkyl or C 4 to C 1Q cycloalkylalkyl; R 4 is C^ to Cg alkyl, phenyl, Cy to C 12 aralkyl or ring substituted benzyl wherein said substituent is C^ to Cg alkyl and/or C^ to Cg alkoxy; Rg and m are as defined in claim 1; Ar is phenyl or naphthyl, substituted with at least one of sulfoamino, carbamoyl, Cg to C 1Q Ν,Ν-dialkylcarbamoyl, amino, C^ to C^q alkylamino, mercapto, C^ to C^ Q alkylthio, Cy to C^ 2 aralkyl, carboxyl, C 2 to C^ Q alkoxycarbonyl, C 2 to C^^ carboxyalkyl, C^ to C^ Q acylamino, C 2 to C^ Q alkylcarbonyl, Cj. to C 1Q hydroxyalkyl, C x to C 1Q haloalkyl, and/or phenyl (optionally substituted with one or more of hydroxy and/or Cj. to Cg alkoxy; phenyl or naphthyl, substituted with at least one of sulfoamino, carbamoyl, Cg to Cj.q Ν,Ν-dialkylcarbamoyl, amino, Cj. to Cj. Q alkylamino, mercapto, C x to alkylthio, Cy to Cj. 2 aralkyl, carboxyl, C 2 to Cj. Q alkoxycarbonyl, C 2 to C 1Q carboxyalkyl, Cj. to C 1O acylamino, C 2 to C^q alkylcarbonyl, C 1 t0 C 1O hydroxyalkyl, to C 1Q haloalkyl, and/or phenyl (optionally substituted with one or more of hydroxy, and/or to Cg alkoxy) and at least one of halo, nitro, cyano, hydroxy, to C 1Q alkyl, to C 1Q alkoxy or C 2 to C 2Q dialkylamino; 46 6 8 6 oxanthrenyl or dibenzofuranyl substituted with at least one of halo, nitro, cyano, hydroxy, C 2 to C 2Q dialkylamino, sulfoamino, carbamoyl, C 3 to C 10 Ν,Ν-dialkylcarbamoyl, amino, Ci to Cy Q alkylamino, mercapto, Cy to Cy Q alkylthio, Cy to 4-tetrahydroquinolyl, the optional substitution being by one or more of Cg to C 10 alkyl, Cg to Cg Q alkoxy and/or oxo; or phenyl substituted with at least one of alkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkyl and/or alkoxycarbonylalkoxy,the or each such substituent containing 3 to 7 carbon atoms and the said substituted phenyl being optionally substituted further with one or more of halo, methyl, ethyl, methoxy, ethoxy and/or hydroxy. 4 6 6 8 6 / R 1 (1) (CH 2 ) n COOR 2 wherein R^ is C 2 to C^ Q alkyl, Cg to C 1Q alkenyl, C 2 to C 1Q alkoxyalkyl, C 2 to C^ Q alkylthioalkyl, C 2 to C 1Q alkylsulf inylalkyl, Cy to C^g aralkyl, Cg to cycloalkyl, C t , 5. 34. A pharmaceutical or veterinary formulation comprising a compound as claimed in any one of claims 1 to 22 or claim 33. a pharmaceutical or veterinary composition comprising a compound as claimed in any one of claims 1 to 22 or 5 protective group, by means of aeidolysis or hydrogenolysis, and if desired, neutralising or salifying the reaction product obtained above. 24. A process as claimed in claim 23 wherein said G 2 aeidolysis is effected by contacting.the N -substituted-N 10 arylsulfonyl-L-argininamide with an excess of an acid at a temperature of -10°C to 100°C. 25. A process as claimed in claim 23 wherein said hydrogenolysis is effected in a reaction-inert solvent in the presence of a hydrogen-activating catalyst in a hydrogen 5.6.7.8- octahydrophenanthryl, indenyl, indanyl, fluoroenyl. 127 acenaphthenyl, phenylthiophenyl, isochromanyl, 2,3-dihydrobenzofuranyl, 1,3,-dihydroisobenzofuranyl, thioxanthenyl, 2H-chromenyl, 3,4-dehydro-l-isochromanyl, 4H-chromenyl, indolinyl, isoindolinyl, 1,2,3,4-tetrahydroquinolyl or 1,2,3, 5.6.7.8- tetrahydroanthryl, 9,10-dihydronhenanthryl, 1,2,3,4, 5 carbamoyl, Cg to Cg Q Ν,Ν-dialkylcarbamoyl, amino, Cg to Cg Q alkylamino, mercapto, Cg to Cg Q alkylthio, Cy to Cg 2 aralkyl, carboxyl, C 2 to Cg Q alkoxycarbonyl, C 2 to Cg Q carboxyalkyl, Cg to Cg Q acylamino, Cg to Cg Q alkylcarbonyl, Cg to C 1O hydroxyalkyl, Cg to Ao haloalkyl, and/or phenyl (optionally 5.6.7.8- tetrahydronaphthyl substituted with at least one of halo, nitro, cyano, hydroxy, sulfoamino, carbamoyl, C 3 to C 10 N^-diaWlcarbamoyl, amino, Cj to Cj Q alkylamino, mercapto, Cj to Cj Q alkylthio, Cy to Cj 2 aralkyl, carboxyl, 25 C 2 to Cjq alkoxycarbonyl, C 2 to Cj Q carboxyalkyl, Cj to Cj Q acylamino, C 2 to C 10 alkylcarbonyl, Cj to Cj Q hydroxyalkyl, Cj to Cjq haloalkyl or phenyl (optionally substituted with one or more of hydroxy and/or Cj to Cg alkoxy); optionally substituted C ? to Cj 2 aralkyl, 9,10-dihydro30 anthryl, tetrahydroanthryl, 8,10-dihydrophenanthryl, 1,2,3, 5 and/or C 2 to C 2Q dialkylamino and at least one of sulfoamino, carbamoyl, C 3 to Cj Q Ν,Ν-dialkylcarbamoyl, amino, Cj to Cj 0 alkylamino, mercapto, Cj to Cj Q alkylthio, Cy to Cjq aralkyl, carboxyl, C 2 to Cj Q alkoxycarbonyl, C 2 to Cj Q carboxyalkyl, Cj to Cj Q acylamino, C 2 to Cj Q alkylcarbonyl, 5,6,7,8-tetrahydronaphthyl substituted with at least one of halo, nitro, cyano, hydroxy, sulfoamino, carbamoyl, Cg to Cg 0 Ν,Ν-dialkylcarbamoyl, amino, Cg to Cg Q alkylamino, mercapto, Cg to CgQ alkylthio, Cy to C 12 aralkyl, carboxyl, C 2 to Cg Q alkoxycarbonyl, C 2 to CgQ carboxyalkyl, Cg to Cg Q acylamino, C 2 to CgQ alkylcarbonyl, Cg to Cg Q hydroxyalkyl, Cg-Cg^haloalkyloxo, and/or phenyl (optionally substituted with one or more of hydroxy and/or Cg to Cg alkoxy) ,· optionally substituted naphthoquinonyl, anthryl, phenanthryl, pentalenyl, heptalenyl, azulenyl, biphenylenyl, assymmetrical or symmetrical-indacenyl, acenaphthylenyl, phenylcarbonylphenyl, phenoxyphenyl, benzofuranyl, isobenzofuranyl, benzo(b)thienyl, isobenzothienyl, thianthrenyl, dibenzothienyl, phenoxathiinyl, indolyl, ΙΗ-indazolyl, quinolyl, isoquinolyl, phthalazinyl, 1,8-naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, acrindyl, phenazinyl,' phenothiazinyl, phenoxazinyl or benzimidazolyl, the optional substitution being by one or more of halo, nitro, cyano, hydroxy, Cg to CgQ alkyl, Cg to Cg Q alkoxy, C 2 to C 2Q dialkylamino, sulfoamino, carbamoyl, Cg to Cg Q Ν,Ν-dialkylcarbamoyl, amino, Cg to Cg 0 alkylamino, mercapto, Cg to Cg Q alkylthio, C ? to Cg 2 aralkyl, carboxyl, C 2 to Cg Q alkoxycarbonyl, C 2 to Cg Q carboxyalkyl, Cg to Cg Q acylamino, C 2 to Cg Q alkylcarbonyl, Cg to CgQ hydroxyalkyl, Cg to Cg Q haloalkyl, and/or phenyl (optionally substituted with one or more of hydroxy and/or Cg to Cg alkoxy). o 5 where Rj q is hydrogen, Cj to Cj Q alkyl, C g to Cj Q aryl, or Cy to Cj 2 aralkyl, Z and q are as defined in claim 1 or COOR.

5. An N -arylsulfonyl-L-argininamide having the formula (I) as defined in claim 1, wherein R is (1) - N (CH 2 ) 2 COOR 2 wherein Rg is furfuryl, 3-furylmethyl, tetrahydrofurfuryl or tetrahydro-3-furylmethyl; R 2 and n are as defined m claim 1 (2) ‘3 R, R •4 46&3G 117 where R 3 is furfuryl, 3-furylmethyl, tetrahydrofurfuryl or tetrahydro-3-furylmethyl; R 4 , Rg and m are as defined in claim 1 (3) 5 C 12 aralkyl, carboxyl, C 2 to Cy Q alkoxycarbonyl, C 2 to Cy Q carboxyalkyl, Cy to Cy Q acylamino, C 2 to Cy Q alkylcarbonyl, Ci to Cy Q hydroxyalkyl, Cy to Cy Q haloalkyl, and/or phenyl (optionally substituted with one or more of hydroxy and/or Cy to Cg alkoxy). 5 optionally substituted biphenylenyl, phenoxyphenyl, dibenzothienyl, phenoxathiinyl, quinolyl, or quinoxalinyl, the optional substitution being by one or more of hydroxy and/or Cj to Cj Q alkyl; optionally substituted C^ to Cj 2 aralkyl, C c to Cj g cycloal 5 wherein Rg Q is hydrogen or Cg to Cg Q alkyl; Z and g are as defined in claim 1 and wherein Rgg is hydrogen or Cg to Cg Q alkyl; i and j are as defined in claim 1; and Ar is phenyl or naphthyl, sub10 stituted with at least one of amino, Cg to Cg Q alkylamino, Cy to Cg 2 aralkyl, Cg to Cg Q acylamino, Cg to Cg Q hydroxyalkyl, and/or Cg to Cg Q hydroxyalkoxy; phenyl or naphthyl, substituted with at least one of amino, 113 Cj to Cj 0 alkylamino, C ? to Cj 2 aralkyl, Cj to C 1O acylamino, Cj to Cjq hydroxyalkyl and/or Cj to Cj Q hydroxyalkoxy and at least one of halo, hydroxy Cj to Cj Q alkyl or Cj to Cj Q alkoxy; 5 to Cj 0 alkyl? and n is as defined in claim 1 (2) CH (CH 2 ) m COOR 5 wherein R 3 is Cj to Cj Q alkyl, C 2 to C g alkoxyalkyl, C 2 to C g alkylthioalkyl, Cy to Cj Q aralkyl, C^ to Cj Q cycloalkylalkyl, furfuryl or tetrahydrofurfuryl; R^ is Cj to C g alkyl; 5 optionally substituted as defined in claim 1 wherein Rg and r are as defined in claim 1 COOR (5) \ch,) 2 7 q wherein R^ Q , Z and q are as defined in claim 1; or COOR. Wi (6) 5 to C^ o cycloalkylalkyl, furfuryl, tetrahydrofurfuryl, tetrahydrc-2-pyranylmethyl tetrahydro-3-pyranyl methyl, tetrahydro4-pyranylmethyl or l,4-dioxa-2-cyclohexylmethyl; R 2 and n are as defined in claim 1; 5.6.7.8- octahydrophenanthryl, indenyl, indanyl, f^uorenyl, £ 5 acenaphthenyl, phenylthiophenyl, isochromanyl, 2,3-dihydro15 benzofuranyl, 1,3-dihydroisobenzofuranyl, thioxanthenyl, 2Hchromenyl, 3,4-dehydro-l-isochromanyl, 4H-chromenyl, indolinyl, isoindolinyl, 1,2,3,4-tetrahydroquinolyl or 1,2, 5.6.7.8- tetrahydroanthryl, 9,10-dihydrophenanthryl, 1,2,3,4, 5 of sulfoamino, carbamoyl, C 3 -C^ Q N,N-dialkylcarbamoyl, C 2 -Cg N-alkylcarbamoyl, amino, c i“ c 10 alkylamino, mercapto, alkylthio, C ? -C 12 aralkyl, carboxyl, ε 2Ύ 0 carboxyalkyl, C,-C lo acylamino, C 2 ~C 10 alkylcarbonyl, hydroxyalkyl, haloalkyl, Ύ ε 10 hydroxyalkoxy, and/or phenyl 5 substituted into the ring at the 2 or 3-position; and the Ry group or groups if present are substituted into the ring at the 2, 3, 4, 5 or 6-position, COORg (4) optionally substituted with one or more of C^-Cg alkyl and/

6. An N -arylsulfonyl-L-argininamide having the formula (X) as defined in claim 1, wherein R is R, Ϊ6 (3) - N 46 6 θ ® 119 wherein R g , Ry and p are as defined in claim 1, R g and Ry are substituted as defined in claim 1; and Ar is naphthyl substituted with at least one of halo, nitro, cyano, hydroxy, Cj to Cj Q alkyl, Cj to Cg alkoxy

7. An N -arylsulfonyl-L-argininamide having the formula (I) as defined in claim 1, wherein R is (CH 2 ) n c OOR 2 wherein Rg is Cg to Cg Q alkylcarbonylalkyl, 2-thenyl, 3121 thenyl, or an optionally substituted tetrahydrofurfuryl or tetrahydro-3-furylmethyl group wherein the optional substitution is by one or more of Cj to Cg alkyl and/or Cj to Cg alkoxy, or tetrahydro-2-thenyl, tetrahydro-3-thenyl, tetra5 hydro-2-pyranylmethyl tetrahydro-3-pyranylmethyl, tetrahydro4-pyranylmethyl or l,4-dioxa-2-cyclohexylmethyl optionally substituted with one or more of Cj to Cg alkyl and/or Cj to Cg alkoxy; R 2 and n are as defined in claim 1, (2) CH - (CH 2 ) m COORg R, m are as defined in claim 1 and either R- is

8. An N -arylsulfonyl-L-argininamide having the formula (I) as defined in claim 1, wherein R is (1) R. (CH 2 ) n COOR 2

9. · An N -arylsulfonyl-L-argininamide as claimed in claim 1 wherein R is as defined in claim 1 and Ar is phenyl substituted with at least one of alkyl, or alkoxy, the number of the carbon atoms of each substituent which is attached to 20 the phenyl being 3 to 7 and the said phenyl being optionally substituted further with one or more of methyl, ethyl, methoxy, ethoxy, hydroxy and/or halo. IQ. An N -arylsulfonyl-L-argininamide having the formula (I) as defined in claim 1, wherein R is are substituted as defined in claim 1, and Ar is naphthyl substituted with at least one of halo, nitro, cyano, hydroxy, Cy to Cy Q alkyl or C 2 to C 2Q dialkyl25 ** 6 6 8 6 126 amino and at least one of sulfoamino, carbamoyl, Cg to Cj Q Ν,Νdialky lcarbamoyl, amino, Cj to Cj Q alkylamino, mercapto, Cj to C lo alkylthio, C ? to Cj Q aralkyl, carboxyl, C 2 to Cj Q alkoxycarbonyl, C 2 to Cj Q carboxyalkyl, Cj to C 10 acylamino, C 2 to C lo alkylcarbonyl, Cj to Cj Q hydroxyalkyl, Cj to Cj Q haloalkyl, and/or phenyl (optionally substituted with one or more of hydroxy and/or Cj to Cg alkoxy); naphthyl substituted with at least one Cj to C- alkoxy and at least one of sulfoamino, carbamoyl, C 3 to Cjq Ν,Ν-dialkylcarbamoyl, amino, C^ to Cj Q alkylamino, mercapto, Cj to Cj Q alkylthio, Cy to Cj 2 aralkyl, carboxyl, C 2 to Cj Q alkoxycarbonyl, C 2 to Cjq carboxyalkyl, Cj to Cj Q acylamino, C 2 to Cjq alkylcarbonyl, Cj to Cj Q hydroxyalkyl, Cj to Cj Q haloalkyl, and/or phenyl (optionally substituted with one or more of hydroxy and/or Cj to Cg alkoxy); phenyl or naphthyl substituted with at least one of sulfoamino, carbamoyl, C 3 to Cj Q Ν,Ν-dialkylcarbamoyl, amino, Cj to Cjq alkylamino, mercaoto, Cj to Cj Q alkylthio, Cy to Cj 2 aralkyl, carboxyl, C 2 to Cj Q alkoxycarbonyl, C 2 to Cjq carboxyalkyl, Cj to Cjq acylamino, C 2 to Cj Q alkylcarbonyl, Cj Cjq hydroxyaIky1, Cj to Cj Q haloalkyl, and/or phenyl (optionally substituted with one or more of hydroxy and/or C. to C c t JL D alkoxy); tetrahydronaphthyl substituted with at least one of halo, nitro, cyano, hydroxy, sulfoamino, carbamoyl, C 3 to Cj Q Ν,Νdialkylcarbamoyl, amino, Cj to Cj Q alkylamino, mercapto, Cj to Cjq alkylthio, Cy to Cj 2 aralkyl, carboxyl, C 2 to Cj Q alkoxycarbonyl, C 2 to Cj Q carboxyalkyl, Cj to Cj Q acylamino, C 2 to Cj 0 alkylcarbonyl, Cj to Cj Q hydroxyalkyl, Cj to Cj Q haloalkyl, or phenyl (optionally substituted with one or more of hydroxy and/or Cj to Cg alkoxy); optionally substituted C g to Cj g cycloalkylphenyl, Cj Q to Cj g cycloalkylalkylphenyl, C g to Cj g cycloalkoxyphenyl, C g to Cj g cycloalkyIthiophenyl, C ? to Cj 2 aralkyl, 9,10-dihydroanthryl,

10. Claim 33 and a pharmaceutically or veterinarily acceptable carrier thereof. 36. A formulation or composition as claimed in claim 34 or 35 in unit dosage form. 37. A formulation or composition as claimed in claim 10 alkoxy; Rg and m are as defined in claim 1. Ar is a phenyl or naphthyl, substituted with at least one of sulfoamino, carbamoyl, Cg to C 1Q Ν,Ν-dialkylcarbamoyl, amino, Cj. to C^ o alkylamino, mercapto, C^ to C^ Q alkylthio, Cy to C 12 aralkyl, carboxyl, Cg to C 1Q alkoxycarbonyl, Cg to C 1Q 10 substituted with one or more of hydroxy and/or Cg to Cg alkoxy). 10 wherein Rg and Cg to Cj 0 alkylcarbonylalkyl, 2-thenyl, 3-thenyl, tetrahydro3-thenyl or optionally substituted tetrahydrofurfuryl or tetrahydro-3-furylmethyl wherein the optional substitution is by one or more of Cj to Cg alkyl and/or Cj to Cg alkoxy, 10 Cj to Cjq hydroxyalkyl, Cj to Cj Q haloalkyl and/or phenyl (optionally substituted with one or more of hydroxy and/or Cj to Cg alkoxy); naphthyl substituted with at least one of sulfoamino, carbamoyl, C 3 to Cj Q Ν,Ν-dialkylcarbamoyl, amino, Cj to Cj Q 10 hydroxy, nitro, cyano, Cj to Cj Q alkyl, Cj to Cj Q alkoxy or C 2 to C 2Q dialkylamino, and at least one sulfoamino, carbamoyl, C 3 to Cj Q Ν,Ν-dialkylcarbamoyl, amino, Cj to Cj Q alkylamino, mercapto, Cj to Cj Q alkylthio, Cy to Cj 2 aralkyl, carboxyl, C 2 to Cj Q alkoxycarbonyl, C 2 to Pj Q 10 tetrahydronaphthyl, 1,2-ethylenedioxyphenyl, chromanyl, 2,3ethylenedioxynaphthyl or xanthenyl, substituted with at least one of halo, nitro, cyano, hydroxy, C 2 to C 2Q dialkylamino, sulfoamino, carbamoyl, Cg to Cy Q Ν,Ν-dialkylcarbamoyl, amino, Cy to Cy Q alkylamino, mercapto, Cy to Cy Q alkylthib, C? to 10 kylphenyl, fluorenyl, or 2H-chromenyl, the optional substitution being by one or more of Cj to Cj Q alkyl, Cj to Cjq alkoxy and/or oxo; or phenyl substituted with at least one of alkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkyl 10 R g is hydrogen or Cj to Cj Q alkyl; and m is as defined in claim 1 (3) - N (R 7 } p wherein R g is -COORg wherein R g is hydrogen or Cj to Cj Q alkyl? each Ry independently is Cj to C g alkyl; p is as 10 wherein R-q/ i and j are as defined in claim 1; and Ar is phenyl or naphthyl substituted with at least one of amino, C 1 t0 C 10 alk Y lamino ' Cx to C1Q alkylthio, C? to C12 aralkyl, C 2 t0 C io alkox Ycarbonyl, 0χ to C 1Q acylamino, C 2 to 0 1θ alkylcarbonyl, to C 1Q hydroxyalkyl, to C 1Q hydroxy15 alkoxy and phenyl; 110 ♦«C86 phenyl or naphthyl substituted with at least one of amino, C 1 to C 10 alk Y lalnino ' c i to c io alkylthioz c 7 to Cg 2 aralkyl, C 2 to C 1Q alkoxycarbonyl, Cg to Cg Q acylamino C 2 to C 10 alkylcarbonyl, Cg to CgQ hydroxyalkyl, Cg to C 10 hydroxyalkoxy and/or phenyl and at least one of halo, hydroxy, Cg to Clo alkyl, Cg to Cg Q alkoxy and/or C 2 to C 2Q dialkylamino ; dibenzofuranyl substituted with at least one halogen atom; dibenzofuranyl substituted with at least one of Cg to Cg Q alkyl or Cg to CgQ alkoxy and at least one halogen atom; tetrahydronaphthyl, 1,2-ethylenedioxyphenyl, chromanyl, 2,3ethylenedioxynaphthyl or xanthenyl, substituted with at least one halogen atom; tetrahydronaphthyl, 1,2-ethylenedioxyphenyl chromanyl, 2,3ethylenedioxynaphthyl or xanthenyl, substituted with at least one of Cg to Cg Q alkyl or Cg to Cg Q alkoxy and at least one halogen atom; optionally substituted anthryl, phenanthryl, biphenylenyl, phenoxyphenyl, henzofuranyl, benzo (b) thienyl, dibenzothienyl, phenoxathiinyl, quinolyl, isoquinolyl, quinoxalinyl, aoridinyl or phenazinyl, the optional substitution being by one or more of halo, hydroxy, Cg to Cg Q alkyl, Cg to Cg Q alkoxy and/or Cg to Cg Q hydroxyalkoxy; optionally substituted Cg to Cg 2 aralkyl, C g to Cg g cycloalky lphenyl, fluorenyl, thioxanthenyl, 2H-chromenyl or 1,2,3, 10 wherein Rg is hydrogen, C^ to C lo alkyl, Cg to C lo alkenyl, C 2 to C lo alkoxyalkyl, Cg to C 1Q alkylthioalkyl, Cg to C 1Q alkylsulfinylalkyl, Cy to C 15 aralkyl, Cg to 0 χ cycloalkyl, C^ to cycloalkylalkyl, furfuryl, tetrahydrofurfuryl, tetrahydro-2-pyranylmethyl, tetrahydro-3-pyranylmethyl 10 (optionally substituted with one or more of hydroxy and/or C^-Cg alkoxy); phenyl or naphthyl, substituted with at least one of halo, nitro, cyano, hydroxy, C ^ _C ]_O alkyl, C^-C^Q alkox y or C 2 -C 2O dialkylamino, and with at least one of sulfoamino, carba15 moyl, C 3 -C io Ν,Ν-dialkylcarbamoyl, C 2 ~Cg N-alkylcarbamoyl, amino, alkylamino, mercapto, c x c 10 alkylthio ' C 7 -C 12 aralkyl, carboxyl, C 2 ~C^ 0 alkoxycarbonyl, C 2 -C^ Q alkoxycarbonyl, C 2 ~C 10 carboxyalkyl, C^-Ο^θ acylamino, C 2 ~C 10 alkylcarbonyl, c ^~ c ^0 hydroxyalkyl, C ]_~C1O haloalkyl, C l“ C 10 20 hydroxyalkoxy, or phenyl (optionally substituted with one or more of hydroxy and/or C^-Cg alkoxy); oxanthrenyl or dibenzofuranyl substituted with at least one of halo, nitro, cyano, hydroxy, C 2 -C 2Q dialkylamino, sulfoamino, carbamoyl, C 3 -C jo Ν,Ν-dialkylcarbamoyl, C2~Cg N25 alkylcarbamoyl, amino, Cj-C.^ alkylamino, mercapto, c i -c x0 alkylthio, C 7 ~C^ 2 aralkyl, carboxyl, C 2 ~C^ 0 alkoxycarbonyl, Cj-C^q carboxyalkyl, c ].~ c ^q acylamino, C 2 ~C^ 0 alkylcarbonyl, C-^-C^q hydroxyalkyl, C^-C 1Q haloalkyl, C^-C^ Q hydroxyalkoxy, or phenyl (optionally substituted with one or more of 30 hydroxy and/or C^-Cg alkoxy); oxanthrenyl or dibenzofuranyl substituted with at least one of c j_- c 10 alkyl and/or alkoxy and with at least one of halo, nitro, cyano, hydroxy, c 2“ C 2O aislkylamino, sulfoamino, carbamoyl, Cg-C^ : Ν,Νdialkylcarbamoyl , C2~Cg N-alkylcarbamoyl, amino, C ]_“ C 1O 35 alkylamino, mercapto, C ]_ _C 1O alkylthio, C 7 -C 12 aralkyl, * 6 G y G carboxyl, C 2 -Cj 0 3 1 ^ 0 ^ 031150 ^ 1 r C 2 -C 10 carfaox y alk y 1 > c i“ C lo acylamino, C 2 -C lo alkylcarbonyl, Cj-Cjq hydroxyalkyl, Cj-Cjq haloalkyl, Cj-Cjq hydroxyalkoxy, and/or phenyl (optionally substituced with one or more of hydroxy and/or Cj-Cg alkoxy).; tetrahydronaphthyl, 1,2-ethylenedioxyphenyl, chromanyl, 2,3ethylenedioxynaphthyl or xantheyl, substituted with at least one of halo, nitro, cyano, hydroxy, C 2 -C 2O dialk y lamino ' sulfoamino, carbamoyl, C^-Cjq Ν,Ν-dialkylcarbamoyl, C 2 ~C g N-alkylcarbamoyl, amino, Cj-Cj 0 alkylamino, mercapto, Cj-Cj q alkylthio, C„-C 12 aralkyl, carboxyl, C 2 ~Cjq alkoxycarbonyl, C 2 -C io carbox y alk v 1 ’ c i -c io ac y lamin °' c 2 -c io aik y lcarl:ion y 1 ' Cj-Cjq hydroxyalkyl, Cj-Cj q haloalkyl, Cj-Cj 0 hydroxyalkoxy, oxo, and/or phenyl (optionally substituted with one or more of hydroxy and/or Cj-Cg alkoxy); tetrahydronaphthyl, 1,2-ethylenedioxyphenyl, chromanyl, 2,3ethylenedioxynaphthyl or xanthenyl group substituted with at least one of Cj-Cj Q alkyl and/or Cj-Cj q alkoxy, and with at least one of halo, nitro, cyano, hydroxy, C 2 -C 2Q dialkylamino, sulfoamirio, carbamoyl, Cg-Cj 0 Ν,Ν-dialkylcarbamoyl, C 2 -C g N-alkylcarbamoyl, amino, Cj-Cj 0 alkylamino, mercapto, C l _C lO alk y lthio ' C 7 -C 12 aralk y!' carboxyl, G 2“ C 10 alkox y carbonyl, C2-Cj0 carboxyalkyl, Cj-Cjq acylamino, C2-Clo alkylcarbonyl, Cj-C10 hydroxyalkyl, C l- C 10 haloalkyl, Cj-CjQ hydroxyalkoxy, oxo, and/or phenyl (optionally substituted with one or more of hydroxy and/or Cj-Cg alkoxy; optionally substituted naphthoquinonyl, anthryl, phenanthryl, pentalenyl, heptalenyl, azulenyl, biphenylenyl, asymmetrical indacenyl, symmetrical 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, the optional substitution being by one or more of halo, nitro, cyano, hydroxy, Cj-Cj q 107 alkyl, Cg-Cg Q alkoxy, C 2 -C 2o dialkylamino, sulfoamino, carbamoyl, C3-Clo Ν,Ν-dialkylcarbamoyl, C2~Cg N-alkylcarbamoyl, amino, Cg-CgQ alkylamino, mercapto, Cg-Cg^ alkylthio, Cy-Cg2 aralkyl, carboxyl, C2-CgQ alkoxycarbonyl, C 2 -c g0 carboxyalkyl, 5 C l- C 10 ac Y lamin °/ C 2 -C 10 a l k Y lc arbonyl, C l“ C lO h Y^ r ? x Y alkyl, Cg-Cg Q haloalkyl, Cg-Cg Q hydroxyalkoxy, and/or phenyl (optionally substituted with one or more of hydroxy jand/or Cg-Cg. alkoxy) ; ; ; i optionally substituted Cy-Cg 2 ara lkyl/ C 9 -C 16 cycloalky110 phenyl, c g 0 _c g3 cycloalkylalkylphenyl, Cg-Cgg cycloalkyloxyphenyl, Cg-Cgg cycloalkylthiophenyl, 9,10-dihydroanthryl, 10 or Cj-Cg alkoxy, wherein R g is hydrogen, C^-C·^ alkyl, C g -C 10 aryl or C 7“C 12 aralkyl; and r is 1, 2, 3 or 4, (5) - Ν Z V < CIJ 2> g wherein R 1Q is hydrogen, Cj-C^ alkyl, C g -C 1Q aryl or Cy-C 12 aralkyl; Z is oxygen, sulphur or sulfinyl; and q is 0 or

11. 1-/N -(quinoline-8-sulfonyl)-L-arginy17-4methyl-2-piperidinecarboxylic acid. '11 (4) CH2 )S .(CH. wherein Rjj, i and j are as defined in claim 1; and Ar is naphthyl, substituted with at least one qf halo,

12. 1-/N -(3-methylquinoline-8-sulfonyl)-L-arginy17“

13. 1-/ft 2 -(3-ethylquinoline-8-sulfonyl)-L-arginy17~

14. 1-/N -(3-sec-butoxybenzene-l-sulfonyl)-Larginyl7“4-methyl-2-piperidinecarboxylic acid. 15. 36 in the form of a tablet, capsule, powder packet, lozenge or troche. 38. An injectable formulation or an orally administrable formulation comprising a liquid and a compound as claimed in any one of claims 1 to 24 or claim 35. 15 atmosphere at a temperature of from 0°C to the boiling temperature of the solvent. 26. A process for producing an N -arylsulfonyl-Largininamide having the formula (I) as defined in claim 1, or a pharmaceutically or veterinarily acceptable salt there20 of, wherein R and Ar are as defined in claim 1, which process 2 comprises reacting an N -arylsulfonyl-L-arginyl halide having the formula: HN X C-N - CHgCHgCHgljlHCOX H 2 N η hnso 2 Ar

15. 1-/H -(3,5-dimethyl-4-isopropoxybenzene-lsulfonyl)-L-arginy ]7-4-methyl-2-piperidinecarboxylic acid. 15 more of hydroxyl and/or Cy to Cg alkoxy). i 15 carboxyalkyl, C^ to C^ Q acylamino, Cg to C 1Q alkylcarbonyl, Cj. to C 1Q hydroxyalkyl, Cj^ to C 1Q haloalkyl and/or phenyl (optionally substituted with one or more of hydroxy and/or C 1 C 5 alkox y>' phenyl or naphthyl, substituted with at least one of sulfo20 amino, carbamoyl, Cg to C^ Q Ν,Ν-dialkylcarbamoyl, amino, Cj. to Cj. Q alkylamino, mercapto, Cj. to C^ Q alkylthio, Cy to C^ 2 aralkyl, carboxyl, Cg to Cj. Q alkoxycarbonyl, Cg to C^ Q carboxyalkyl, Cj. to Cj. Q acylamino, Cg to C 1Q alkylcarbonyl, Cj. to C 1Q hydroxyalkyl, Cj. to C 1Q haloalkyl and phenyl 25 (optionally substituted with one or more of hydroxy, and/or Cj. to Cg alkoxy), and at least one of halo, nitro, cyano, hydroxy, Cj. to C i0 alkyl, Cj. to C^ Q alkoxy and/or Cg to C 2Q dialkylamino; oxanthrenyl or dibenzofuranyl substituted with at least one 30 of halo, nitro, cyano, hydroxy, Cg to C 2Q dialkylamino, sulfoamino, carbamoyl, Cg to C 1Q Ν,Ν-dialkylcarbamoyl, amino, 46636 Cg to CgQ alkylamino, mercapto, Cg to Cg Q alkylthio, C ? to Cg 2 aralkyl, carboxyl, Cg to Cg Q alkoxycarbonyl, Cg to Cg Q carboxyalkyl, Cg to Cg Q acylamino, Cg to Cg Q alkylcarbonyl, Cg to Cg 0 hydroxyalkyl, Cg to Cg Q haloalkyl, and/or phenyl (optionally substituted with one or more of hydroxy and/or Cg to C 5 alkoxy); tetrahydronaphthyl, 1,2-ethylenedioxyphenyl, chromanyl, 2,3ethylenedioxynaphthyl or xanthenyl substituted With at least one of halo, nitro, cyano, hydroxy, C 2 to C 2 q dialkylamino, sulfoamino, carbamoyl, Cg to Cg Q Ν,Ν-dialkylcarbamoyl, amino, Cg to CgQ alkylamino, mercapto, Cg to Cg Q alkylthio, C? to Cg 2 aralkyl, carboxyl, C 2 to Cg Q alkoxycarbonyl, C 2 to Cg Q carboxyalky1, Cg to Cg Q acylamino, C 2 to Cg Q alkylcarbonyl, Cg to CgQ hydroxyalkyl, Cg to Cg Q haloalkyl, oxo, and/or phenyl (optionally substituted with one or more of hydroxy and/or Cg to Cg alkoxy); optionally substituted naphthoquinonyl, anthryl, phenanthryl, pentalenyl, heptalenyl, azulenyl, biphenylenyl, asymmetrical or symmetrical-indacenyl, acenaphthylenyl, phenylcarbonylphenyl, phenoxyphenyl, benzofuranyl, isobenzofuranyl, benzo(b)thienyl, isobenzothienyl, thianthrenyl, dibenzothienyl, phenoxathiinyl, indolyl, ΙΗ-indazolyl, quinolyl, isoquinolyl, phthalazinyl, 1,8-naphthridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, Carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, or benzimidazolyl, the optional substitution being by one or more of«halo, nitro, cyano, hydroxy, Cg to CgQ alkyl, Cg to Cg Q alkoxy, Cg to C 2Q dialkylamino, sulfoamino, carbamoyl, Cg to Cg Q Ν,Ν-dialkylcarbamoyl, amino, Cg t0 C 10 alkylamino, mercapto, Cg to Cg Q alkylthio, C? to Cg 2 aralkyl, carboxyl, Cg to Cg Q alkoxycarbonyl, Cg to Cg Q carboxyalkyl, Cg to CgQ acylamino, Cg to Cg Q alkylcarbonyl, Cg to Cg 0 hydroxyalkyl, Cg to Cg Q haloalkyl, and/or phenyl (optionally substituted with one or more of hydroxy and/or Cg to Cg alkoxy); C g to Cg 6 cycloalky lphenyl, Cg Q to Cg g cycloalkylalky lphenyl, C 9 t0 C 16 c y° loa lkyloxyphenyl, C g to Cg g cycloalkylthiophenyl, 9,10-dihydroanthryl, 5,6,7,8-tetrahydroanthryl, 9,10125 46636 dihydrophenanthryl, 1,2,3,4,5,6,7,8-octahydrophenanthry1, indenyl, indanyl, fluorenyl, acenaphthenyl, phenylthiophenyl, isoohromanyl, 2,3-dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, thioxanthenyl, 2H-chromenyl, 3,4-dehydro5 1-isochromanyl, 4H-chromenyl, indolinyl, isoindolinyl, 15 wherein Rg is C 2 to Cg Q alkyl, Cg to Cg Q alkenyl, Cg to Cg Q alkynyl, C 2 to Cg Q alkoxyalkyl, C 2 to Cg Q alkylthioalkyl, C 2 to Cg Q alkylsulfinylalkyl, Cg to Cg Q hydroxyalkyl,Cg to Cg Q alkoxycarbonylalkyl, Cg to Cg Q haloalkyl, Cy to Cgg aralkyl, Cg to Cgg α-carboxyaralkyl, Cg to Cg Q cycloalkyl or 20 C 4 to Cg 0 cycloalkylalkyl; Rg and n are as defined in claim 1 i2? 15 tetrahydro-2-thenyl, tetrahydro-2(3 or 4)-pyranylmethyl or l,4-dioxa-2-cyclohexylmethyl optionally substituted with one or more of Cj to Cg alkyl and/or Cj to Cg alkoxy; and R^ is Cj to Cj 0 alkyl, and/or phenyl (optionally substituted with one or more of Cj to Cg alkyl or Cj to Cg alkoxy); Cy to 20 Cj 2 aralkyl or ring substituted benzyl wherein said' substituent is Cj to Cg. alkyl or Cj to Cg alkoxy; or Rg is furfuryl, 3-furylmethyl and R^ is phenyl (optionally substituted with one or more Cj to Cg alkyl or Cj to Cg alkoxy) C ? to Cj 2 aralkyl or ring substituted benzyl wherein said substituent 25 is Cj to Cg alkyl or Cj to Cg alkoxy 122 COOR, '9 (3) 15 alkylamino, mercapto, Cj to Cj Q alkylthio, Cy to Cj 2 aralkyl, carboxyl, C 2 to Cj Q alkoxycarbonyl, C 2 to Cj Q carboxyalkyl, Cj to Cjq acylamino, C 2 to Cj Q alkylcarbonyl, Cj to Cjq hydroxyalkyl, Cj to Cjq haloalkyl, and/or phenyl (optionally substituted with one or more of hydroxy and/or 20 Cj to Cg alkoxy),· 15 carboxyalkyl, Cj to Cj Q acylamino, C 2 to Cj Q alkylcarbonyl, Cj to Cjq hydroxyalkyl, Cj to Cj Q haloalkyl or phenyl (optionally substituted with one or more of hydroxy and/or Cj to Cg alkoxy); naphthyl substituted with at least one of sulfoamino, carbamoyl, C 3 to Cj Q Ν,Ν-dialkylcarbamoyl, 20 amino, Cj to Cj Q alkylamino, mercapto, Cj to Cj Q alkylthio, C 7 to C 12 aralkyl, carboxyl, C 2 to Cj Q alkoxycarbonyl, C 2 t0 C 1O carboxyalkyl, Cj to Cj 0 acylamino, C 2 to Cj Q alkylcarbonyl, Cj to Cj 0 hydroxyalkyl, Cj to Cj Q haloalkyl and/ or phenyl (optionally substituted with one or more of hydroxy and/or Cg to Cg alkoxy); 15 Cy to Cy 2 aralkyl, carboxyl, C 2 to Cy Q alkoxycarbonyl, C 2 to Cy Q oarboxyalkyl, Cy to Cy Q acylamino, C 2 to Cy Q alkylcarbonyl, Cy to Cy Q hydroxyalkyl, Cy to Cy Q haloalkyl, oxo, and/or phenyl (optionally substituted with one or more of hydroxy and/or Cy to C 4 alkoxy;) 20 optionally substituted naphthoquinonyl, anthryl, phenanthryl, pentalenyl, heptalenyl, azulenyl, biphenylenyl, asynmetricalindacenyl; symmetrical-indaoenyl, acenaphthylenyl, phenyloarbonylphenyl, phenoxyphenyl, benzofuranyl, isobenzofuranyl, ben2o(b)thienyl, isobenzothienyl, thianthrenyl, dibenzo25 thienyl, phenoxathiinyl, indolyl, ΙΗ-indazolyl, quinolyl. Isoquinolyl, phthalazinyl, 1,8-naphthridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, oarbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl or benzimidazolyl, th'e optional substitution being by one or more of halo, nitro, cyano, 30 hydroxy, Cy to Cy Q alkyl, Cy to Cy Q alkoxy, C 2 to C 20 dialkylamino, sulfoamino, carbamoyl, C 3 to Cy Q N,N-dialkyloarbamoyl, amino, Cy to Cy Q alkylamino, mercapto, Gy to Cy Q alkylthio, C ? to Cy 2 aralkyl, carboxy, C 2 to Cy Q alkoxycarbonyl, C 2 to Cy Q carboxyalkyl, Cy to Cy Q acylamino, C 2 to 35 c io alkylcarbonyl, Cy to Cy Q hydroxyalkyl, Cy to haloalkyl, and/or phenyl (optionally substituted with one or more of 4663 hydroxy and/or Cg to Cg alkoxy)? optionally substituted 9,10-dihydroanthryl, 5,6,7,8-tetrahydroanthryl, C ? to Cg 2 aralkyl, 9,10-dihydrophenanthryl, 15 and/or alkoxycarbonylalkoxy, the or each such substituent containing 3 to 7 carbon atoms and the said substituted phenyl being optionally substituted further with one or more of halo, methyl, ethyl, methoxy, ethoxy and/or hydroxy. 15 defined in claim 1; R g and R? are substituted as defined in claim 1 COOR, (4) - optionally substituted as defined in claim 1, wherein R g is hydrogen or Cg to Cg Q alkyl; and r is as defined in claim 1 15 tetrahydro-4-pyranylmethyl or l,4-dioxa-2~cyclohexylmentyl; R 4 , Rg and m are as defined in claim 1 (3) (R 7>p 109 466 86 wherein Rg is as defined in claim 1; each Ry independently is C-^ to C 1Q alkyl or phenyl; p is as defined in claim 1 Rg and Ry are substituted as defined in claim 1 COORg 15 1, or COOR '11 (6) - N. 105 wherein R^ is hydrogen, C ]_~C^ O alkyl, Cg-Cj-θ aryl or CyC 12 aralkyl; i is Ο, 1 or 2; j is Ο, 1 or 2; and the sum of i + j is 1 or 2; and Ar is phenyl or naphthyl, substituted with at least one 15 substituted with one or more of Cj-Cg alkyl and/or Cj-Cg alkoxy, tetrahydro-2-pyranylmethyl tetrahydro-3-pyranylmethyl or tetrahydro-4-pyranylmethyl optionally substituted with one or more of Cj-Cg alkyl and/or Cj-Cg alkoxy, 1,4dloxa-2-cyclohexylmethyl optionally substituted with one or 20 more of Cj-Cg alkyl and/or Cj-Cg alkoxy, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl optionally substituted with one or more of Cj-Cg alkyl and/or Cj-Cg alkoxy, or tetrahydro-3-thenyl; R 2 is hydrogen, Cj-C 10 alkyl, C g -C 1Q aryl or C 7 ~C 12 aralkyl; and n is 1, 2 or 3, 103 R.

16. 1-/ΓΤ -(2,4-dimethoxy-3-butoxybensene-l-3ulfonyl)L-arginylJ , -4-methyl-2-piperidinecarboxylic acid.

17. - (3-isopropoxybenzene-l-sulfonyl)-L-arginy£7 -4-methyl-2-piperidinecarboxylic acid.

18. N - (2-phenoxathiinylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine.

19. N -(2-£luorenesulfonyl)-L-arginyl-N-(2-methoxyethyl) glycine. 20. 1-/R -(4-methoxy-3-cyclohexylbenzene-l-sulfonyl) -L-arginyl7-4-methyl-2-piperidinecarboxylic acid. 21. A compound as claimed in claim 1 and identified by name of formula in any one of the specific Examples or in any entry in Table 1 or Table 2. 22. A pharmaceutically acceptable or veterinarily acceptable salt of a compound as claimed in any preceding claim. 23. A process for producing an N -arylsulfonyl-Largininamide having the formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof, wherein R and Ar are as defined in claim 1, which process comprises removing the or each N^-substituent from an N^-substituted-N 2 -arylsulfonyl-L-argininamide having the formula: 129 CHgCHgCHgCHCOR HN ' I R' R'' HNSOg Ar wherein R and Ar are as defined herein above; R' and R' 1 are independently hydrogen or a protective group for the guanidino group, at least one of R' and R'' being such a

20. 39. A pharmaceutical composition substantially as hereinbefore described in any one of Examples 5 to 7.