IE44360B1 - N2-arylsulfonyl-l-argininamides and the pharmaceutically acceptabel salts thereof - Google Patents

Description

This invention relates to N -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof.

In the past, there have been many attempts to obtain new and improved agents for the treatment of thrombosis. The N -(p-tolylsulfonyl)-L-arginine esters have beer, found to be one type of agent which can be used and these have been found to be effective in dissolving blood clots. (U.S. Patent No. 3,622,615, issued November 23, 1971) One family of compounds which have been found to be par10 ticularly useful as highly specific inhibitors of thrombin 2 for the control of thrombosis is the N -dansyl-L-arginine ester or amine. (Oujj U.S. application Serial No. 496,939, filed August 13, 1974) However, there is a continuing need for a highly specific inhibitor on thrombin for the control of thrombosis, which exhibits lower toxicity.

It has been discovered that N -arylsulfonyl-L- argininamides exhibit antithrombotic activity and even lower toxicity levels at the same relative potencies, as compared 'With the 2 N -dansyl-L-argimne ester or amide.

In Patent Specification No. 331/79 . divided out of the present application, we describe and claim an N^-arylsulphonyl-L-argininamide having the formula HN - JJ - CH?Cil0(3IL,CJlCOR H2N H flN30o (I) I ά Ar wherein R is \ (CH2)nCOOR2 wherein R^ is C2“C10 alkyl, C3-Clo alkenyl, C3C10 alkynyl, C2-C10 alkoxyalkyl, C2~C10 carboxyalkyl, C3~C10 alkoxycarbonylalkyl, C^-C^q aralkyl, C3~C^0 cycloalkyi or C4-C^o cycloalkylalkyl; R2 is hydrogen or Cj-C^q alkyl; and n is 1, 2 or 3. (2) - N / \ CH - (CH2)mCOOR5 wherein R3 is hydrogen, C^C^ alkyl, C3~C10 alkenylf alkynyl, C2-Clo alkoxyalkyl, C2C1O carboxyalkyl, C3-C1Q alkoxy10 carbonylalkyl, C7~C^0 aralkyl, C3-C2o cycloalkyi or C^-C^q cycloalkylalkyl; R^ is C-^-C·^ alkyl; Rg is hydrogen or ci-ciq alkyl; and m is 0, 1 or 2. (3) wherein Rg is -COORg wherein Rg is C^-Cg alkyl; each R^ independently is hydrogen, C^-C^ allcyl or C^-Cg alkoxy; p is an integer of 1 to 5; R. is substituted into the piperidine ring at the 0 or 3-position; and each R? independently is substituted into the piperidine ring at the 2,3,4,5 or 6-position, C00R9x^\ (4) -NJ optionally substituted with one or more C^-Cg alkyl or C^-Cg 4 3 β ο alkoxy groups, wherein Rg is C^-Cg alkyl; and r is 1,2,3 or 4, COOR. . wherein 1, or SI z \ z Hcb2i4 is C^-Cg alkyl; z is oxy or thio; and g is 0 ox (5) - N COOR. (6)Wi, \(ch2).. wherein R11 is C^-Cg alkyl; I is 0, 1 or 2; j is 0, 1 or 2; and the sum i+j is 1 or 2; and Ar is 5,6,7,8-tetrahydronaphthyl, naphthyl, 1 or 2-naphthyl substituted with one substituent which is halogen, nitro,, cyano, hydroxy, C.j-C10 alkyl, dialkylamino, containing not more than 20 carbon atoms, C^-C^ alkoxy.

The present invention provides, subject to the disclaimer which follows, a compound of the formula I, or a pharmaceutically acceptable salt thereof, wherein R is (CH-) COOR„ 2 n 2 wherein is C2~C^q alkyl, C^-C^q alkenyl, alkynyl, C2“ciQ alkoxyalkyl, C2~C^q alkylthioalkyl, C2~C^0 alkylsulfinylC3“C^O alkoxycarbonylalkyl, Cg-C.^ alkylcarbonylalkyl, C^-Ο^θ haloalkyl, -7-^5 aralkyl, Cg-C15 X-carboxyaralkyl, C3~C1O cycloalkyl, C4~C10 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl optionally substituted with · le or more C^-Cg alkyl and/or C^-Cg alkoxy groups, 3-furyImethyl, tetrahydro-3-furylmethyl optionally substituted with one or more C^-Cg alkyl or C^-Cg alkoxy groups, tetrahydro2(3 or 4)-pyranyImethyl optionally substituted with one or more Cl-C5 alkY1 and/or C^-Cg alkoxy groups, l,4-dioxa-2-cyclohexylmethyl optionally substituted with one or more C^-Cg alkyl and/or cl-c5 alkoxy groups, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl, optionally substituted with one or more C^-Cg alkyl or C^-Cg alkoxy groups, or tetrahydro-3-thenyl; R2 is hydrogen, C-^-C^ alkyl, Cg-C1Q aryl, C7-C^2 aralkyl or 5-indanyl; and n is 1, 2 or p 3, (2) _N/ 3 wherein Rg is hydrogen, alkyl, CH-(CH2)mCOOR5 C3-C10 alkenyl, Cg-C^ alkynyl, C2-C^oalkoxyalkyl, C2~C^0 alkylthioalkyl, C2-C1Q alkylsulfinylalkyl, C^“C1O hydroxyalkyl, Cj-C^q earboxyalkyl, C3“cj_0 alkoxycarbonylalkyl, Cg-C1Q alkylearIxnylaljcyl haloalkyl, C7-C15 aralkyl, Cg-C15 o(-carboxyaralkyl, C3-C^q cycoalkyl, C4-C^Q cycloalkylalkyl, furfuryl, tetrahydrofurfuryl optionally substituted with one or more C^-Cg alkyl or Cl”C5 alkoxy cJrouPs» 3-furyImethyl, tetrahydro-3-furylmethyl, . optionally substituted with one or more C^-Cg alkyl or C^-Cg alkoxy groups, tetrahydro-2 (3 or 4)-pyranylmethyl optionally substituted with one or more C-^-Cg alkyl and/or C-^-Cg alkoxy groups, l,4-dioxa-2-cyclohexylmethyl optionally substituted with one or more C-^-Cg alkyl and/or C^-Cg alkoxy groups,2-thenyl, 3-thenyl, tetrahydro-2-thenyl optionally substitured with one or more C^-Cg alkyl or C^-Cg alkoxy groups, or tetrahydro-3-thenyl; is C^-C^q alkyl, carboxy, C2~C^0 alkoxycarbonyl, phenyl optionally substituted with one or more C^-Cg alkyl or C^-Cg alkoxy groups, C?-C12 aralkyl or ring substituted benzyl wherein said substituent is C\-Cg alkyl or C^-Cg alkoxy; Rg is hydrogen, C^-C.^ alkyl, Cg-C^ aryl, C?-C12 aralkyl or 5-indanyl; and m is 0, 1 or 2, F& (3) wherein Rg is -C00Rg wherein Rg is hydrogen, X’p Cjj-C-,θ alkyl, Cg-Ο^θ aryl, Cy-C12aralkyl or 5-indanyl; each R? independently is hydrogen, °l-C10 alkyl, phenyl C-j-C^ alkoxy or carboxy; p is an integer of 1 to 5» Rg is substituted into the piperidine zizg at the 2 or 3-position; and eaoh Ry independently is substituted. into the piperidine ring at the 2, 3, 4, 5 or 6-position COORg optionally substituted with one or more C-^-Cg groups, wherein Rg is hydrogen, Ο^-Ο^θ alkyl, aralkyl or 5-indanyl; and r is 1, 2, 3, or 4, (4) -N 1 CH 2) r alkyl or C^-Cg alkoxy , a3 TOR1O C6C10 aryl, C?-C12 (5) -N \(C32 wherein R-^θ is hydrogen, C^-C^q alkyl, cgcyQ aryl> C7~C12 aralky4 or 5-indanyl; Z is oxy, thio or sulfinyl; and ς is or 1, or 6. 4360 COOR^ (6)-N^^ wherein R^ is hydrogen, C.,-C10 alkyl Cg-C10 aryl, C-j-C^g aralkyl or 5-indanyl; i is 0, 1 or 2; j is 0 1 or 2; and the sum i+j is 1 or 2; and Ar is naphthyl, 5,6,7,8-tetrahydronaphthyl optionally substituted with one or more C^Cg alkyl or C^-Cg alkoxy groups, naphthyl substituted with at least one substituent which is halo nitro, cyano, hydroxy, C^-C^q alkyl, C^-C^q alkoxy or C2-C2Q dialkylamino, phenyl, phenyl substituted with at least one substituent which is halo, nitro, cyano, hydroxy, alkyl, C^-C10 alkoxy, C2-C20 dlalkylamino C7-C12 aralky1, or optionally substituted with one or more C^Cg alkyl or C^Cg alkoxy groups, wherein R12 iS hydrogen, alkyl or alkoxy; with the provisos that: when R is:- (1) - N<^ ^^(CH2)nCOOR2 wherein R1 is C2-C1O alkyl, C3-C1Q alkenyl, C3-C10 alkynyl, C2-C1O alkoxyalkyl, C2-C1Q carboxyalkyl, C3~C1Q alkoxycarbonylalkyl, C7-C10 aralkyl, C3-C1Q cycloaikyl or C4-C1Q cycloalkylalkyl; R2 is not hydrogen or C^-Ο^θ alkyl; 443G0 when R is:(2) - N 'CH - (CH,) COORI Z Itt □ wherein R3is hydrogen, C-^-C^g alkyl, C^-C.^ alkenyl, C3cq0 alkynyl.- O^-C^g alkoxyalkyl, Cg-C^g earboxyalkyl, Cg-C^g alkoxycarbonylalkyl, C^-C^o aralkyl, C3-C1Q cycloalkyl or C^-C^g cylo5 alkylalkyl; and R^ is C^-C^g alkyl; Rg is not hydrogen or G]_~c^q alkyl when R is :(3) Wherein Rg is -COORg wherein each R? independently is hydrogen, C^-C^o alkyl or C^-Cg alkoxy; p is an integer of 1 to 5; Rg is substituted into the piperidine ring at the 2 or 3-position; and R? is substituted into the piperidine ring at the 2,3,4,5 or 5position; Rg is not C^ to Cg alkyl; COOR, When R iss(4) ''-(CH, optionally substituted with one or more C^-Cg alkyl or C^-Cg alkoxy groups, Rg is not C^-Cg alkyl; COOR.

When R is:(5) - N * ^CH2>q wherein Z is oxy or thio; R^g is not C^-Cg alkyl; r- . 443G0 and when R is:- COORn Mch2 (6) -n( \(ch2 R^ is not -Cg alkyl; if, in the case of any of the provisos above, Ar is 5,6,7,8-tetrahydronaphthyl, naphthyl, 1-naphthyl substituted with one substituent which is halogen, nitro, cyano, hydroxy, Cl“C10 alkyl, C2_C20 dialkylamin0> or ci_c!io alkoxy or 2-naplrthyl substituted with one substituent'whioh is halogen, nitro, cyano, hydroxy, alkyl, θ2“θ20 dialkylamino or Gj-C^q * This invention also relates to a method for inhibiting activity and suppressing activation of thrombin in vivo, which comprises introducing into a living hody a pharmaceutically effective amount of an N2-arylsulfonyl-I-argininamide or the pharmaceutically acceptable salt thereof.

As stated above, in the formula:- ... - .

HN% ' C - if - CH„CH_CHoCHC0R (l) x J · 2 2 2| V 7 H HNSO„ · I Λ Ar Wherein R is selected from.'the group consisting of /R1 (l) - K. wherein IL is selected from the group X(CH2)nC00R21 10 consisting of θ2“®10 su°h as ethyl, propyl, butyl, . isobutyl, pentyl, hexyl, octyl, decyl or the like, alkenyl of 3-10 (preferably 3—6) carbon atoms, such as allyl, 2butenyl, 3-butenyl, 2-pentenyl or the like, alkynyl of 3-10 (preferably 3-6) carbon atoms, such as 2-propynyl, 215 butynyl, ^-butynyl or the like, alkoxyalkyl of 2-10 (preferably 2-6) carbon atoms, such as aiethoxymethyl, ethoxymethyl, propoxymethyl, 2-methoxyethyl, 2-efhoxyethyl, 2-propoxyethyl, 2-methoxypropyl, 3-methoxypropyl, 3— · ethoxypropyl, 3-propoxypropyl, 4-methoxybutyl, 4-ethoxybutyl, 4-butoxybutyl, 5-butoxypentyl or the like, alkylthio alkyl of 2—10 (preferably 2-6) carbon atoms, such as methyl thiomethyl, ethylthiomethyl, propylthiomethyl, 2-methylthioethyl, 4 3 G Ο 2-ethylthioethyl, 2-propylthioethyl, 3-methylthiopropyl, 2- methylthiopropyl, 3-etliyl thiopropyl, 3-propylthiopropyl, 4- methylthiobutyl, 4-ethylthiobutyl, 4-butylthiobutyl, - butylthiopentyl or the like, alkylsulfinylalkyl cf 2-10 (preferably 2-6) carbon atoms, such as methylsulfinylmethyl, ethylsulfib ylmethyl, propylsulfinylmethyl, 2-methylsulfinylethyl, 2-ethylsulfinylethyl, 2-propylsulfinylethyl, 3methylsulfinylpropyl, 3-ethylsulfinylpropyl or the like, hydroxyalkyl of 1-10 (preferably 1-6) carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2hydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, 5“hydroxypentyl or the like, carboxyalkyl of 2-10 (preferably 2-7) carbon atoms, such as carboxymethyl, 2-carboxyethyl, 2carboxypropyl, 3-carboxypropyl, 1-carboxybutyl, 2-carboxy15 butyl, 4-carboxybutyl or the like, alkoxycarbonylalkyl of 3- 10 (preferably 3-8) carbon atoms, such as methoxycarbonyImethyl, 2-ethoxycarbonylethyl, 2-ethoxycarbonylpropyl, 3-methoxycarbonylpropyl, 1-methoxycarbonylbutyl, 2-ethoxycarbonylbutyl, 4-methoxycarbonylbutyl or the like, alkyl carbonylalkyl of 3 to 10 carbon atoms such as methylcarbonylethyl, haloalkyl of 1-10 (preferably 1-5) carbon atoms such as chloromethyl, 2-chloroethyl, 2-bromoethyl, 2-chloropropyl, 3-chloropropyl, 2-chlorobutyl, 4-chlorobutyl or the like, aralkyl of 7-15 (preferably 7-10) carbon atoms, such as benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 6-phenyl hexyl, 1-phenylethyl, 2-phenylpropyl or the like,«i-carboxyaralkyl 11. 43 GO of 8-15 (preferably 8-12) carbon atoms, such as ^-carboxybenzyl, °(-carboxyphenethyl or the like, Cg-C^ cycloalkyl, such as cyclopropyl, cyclobutyl, eyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, C^-Ο^θ cycloalkylalkyl, such as cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclohexylethyl, cyclooctylmethyl or the like, furfuryl, tetrahydrofurfuryl, optionally substitured with one or more alkyl or C-^-Cg alkoxy groups, 3-furylmethyl, tetrahydro-3-furylmethyl, optionally substituted with one or more C^-Cg alkyl or Cl-C5 “^oxy gr°ups, tetrahydro-2(3 or 4)-pyranylmethyl optionally substituted vzith one or more C^-Cg alkyl and/or C^-Cg alkoxy croups, l,4-dioxa-2-cyclohexylmethyl optionally substituted with one or more cl-c5 alkY·1· aud/or C^-Cg alkoxy groups, 2-thenyl, 3-thenyl tetrahydro-2-thenyl, optionally substituted vzith one or more C-^-Cg alkyl or C^-Cg alkoxy groups and tetrahydro-3-thenylj Rg is selected from the group consisting of hydrogen, C^-C^q alkyl, such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl, decyl or the like, Cg-C^ aryl, such as phenyl, m-tolyl, naphthyl or the like, aralkyl of 7-12 (preferably 7-10) carbon atoms, such as benzyl phenethyl or the like, or 5-indanyl; and n is an integer of 1, 2 of Jf (2) - n/ j wherein R„ is selected from the yHCH2>mCOOR5 group consisting of hydrogen, C1-C1O alkyl, such as methyl, ethyl, propyl, butyl, isobutyl, pentyl, hexyl, octyl, decyl 'or the like, alkenyl of 3-10 (preferably 3-6) carbon atoms, such as allyl, 2-butenyl, 3-butenyl, 2-pentehyl or the like, alkynyl of 3-10 (preferably 3-6) carbon atoms, such as 2-propynyl, 2-butynyl, 3-butynyl or tho like, alkoxyalkyl of 2-10 (preferably 2-6) carbon atoms, such as 12. 4 3 C Ο methoxymethyl, ethoxymethyl, propoxymethyl, 2-methoxyethyl, 2- ethoxyethyl, 2-propoxyethyl, 2-methoxypropyl, 3-methoxypropyl, 3-ethoxypropyl, 3-propoxypropyl, 4-methoxybutyl, 4-ethoxybutyl, 4-butoxybutyl, 5-butoxypentyl or the like, alkylthioalkyl of 2-10 (preferably 2-6) carbon atoms, such as methyl thiomethyl, othylthiomethyl, propylthiomethyl, 2methylthioethyl, 2-ethylthioethyl, 2-propylthioethyl, 3methylthiopropyl, 2-methylthiopropyl, 3-ethylthiopropyl, 3- propylthiopropyl, 4-methylthiobutyl, 4-ethylthiobutyl, lO 4-butylthiobutyl,’ 5-butylthiopentyl_or the like, alkylsulfinylalkyl of 2-10 (preferably 2-6) carbon atoms, such as methylsulfinylmethyl, ethylsulfinylmethyl, propylsulfinylmethyl,2-methylsulfinylethyl, 2-ethylsulfinylethyl, 2- propylsulfinylethyl, 3-methylsulfinylpropyl, 3-ethyl15 sulfinylpropyl or the like, hydroxyalkyl of 1-10 (preferably 1- 6) carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, 3- hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl, 3hydroxybutyl, 5“bydroxypentyl or the like, carboxyalkyl of 2- 10 (preferably 2-7) carbon atoms, such as carboxymethyl, 2-carboxyethyl, 2-carboxypropyl, 3-carboxypropyl, 1carboxybutyl, 2-carboxybutyl, 4-carboxybutyl or the like, alkoxycarbonylalkyl of 3-10 (preferably 3-8) carbon atoms, such as methoxycarbonylmethyl, 2-methoxycarbonylethyl, 2ethoxycarbonylpropyl, 3-methoxycarbonylpropyl, 1-methoxy25 carbonyl bu t yl , 2-ethoxyearboiiylbutyl, 4-methoxyearbonyJbiityl 13.

I 44300 or ths like, alkyl carbonylalkyl of 3 to 10 carbon atoms such as methylcarbonylethyl, haloalkyl of 1-10 (preferably 1-5) carbon atoms such as chloromethyl, 2-chloroethyl, 2-bromoethyl, 2-ohloropropyl, 3-chloropropyl, 2-chiorobutyl, 4-chlorobutyl or the like, aralkyl of 7-15 (preferably 7-10) carbon atoms, such as benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 6-phenylhexyl, 1-phenylethyl, 2-phenylpropyl or the like, Λ -carboxyaralkyl of 8-15 (preferably 8-12) carbon atoms, such as d -carboxybenzyl, (X -carboxypbenethyl or the like, C3-Cl0 cycloalkyl, such as cyclopropyl, cyelobutyl, cyclopentyl, eyclohexyl, cycloheptyl, cyclooctyl, oyclononyl or cyclodecyl, cycloalkylalkyl, such as cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclohexylethyl, cyclooctylmethyl or the like, furfuryl, tetrahydrofurfuryl optionally substituted with one or more C-^-Cg alkyl or •Cj_-Cg alkoxy groups, 3-furylraethyl, tetrahydro-3-furylmethyl optionally substitured with one or more C^-Cg alkyl or C-^-Cg alkoxy groups, tetrahydro-2 (3 or 5)-pyranylmethyl optionally substituted with one or more -Cg alkyl and/or C^-Cg alkoxy groups, l,4-dioxa-2-cyclohexylmethyl optionally substituted with one or more C-^-Cg alkyl and/or C^-Cg alkoxy groups, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl optionally substituted, with one or more C^-Cg alkyl or C^-Cg alkoxy groups, and tetrahydro-3-thenyl; R4 is selected from the group consisting of alkyl of 1-10 (preferably 1-5) carbon atoms, such as methyl, ethj.1, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl or the like, carboxy, alkoxycarbonyl of 2-10 (preferably 2-5) carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or the like, phenyl optionally substituted with one or more C^-Cg alkyl or c^-Cg alkoxy groups, aralkyl of 7-12 (preferably 7-10) carbon atoms, such as benzyl phenethyl or the like, and ring substituted benzyl wherein said substituent is alkyl of 1-5 (preferably 1-3) carbon atoms, such as methyl, ethyl, propyl or isopropyl, or 14. alkoxy of 1-5 (preferably 1-3) carbon atoms, such as methoxy, ·». ethoxy, propoxy or isopropoxy; is selected from the group consisting of hydrogen, Ο^-Ο^θ alkyl, such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl, decyl or the like, Cg-C10ary1’ sucl1 as phenyl, m-tolyl, naphthyl or the like, aralkyl of 7“12 (preferably 7“1θ) carbon atoms, such as benzyl, phenethyl or the like, and 5-indanyl; and m is an Λ integer of 0, 1 or 2, (3) -N ) wherein Rg is -COORg wherein Rg is selected from the group consisting of hydrogen, ^“θιο alkyI ’ suck as methyl, ethyl, propyl, butyl, tertbutyl, hexyl, octyl, decyl or. the like, Cg-Ο^θ aryl> such as phenyl, m-tolyl, naphthyl or the like, aralkyl of 7“12 (preferably 7-10) carbon atoms, such as benzyl, phenethyl or the like, and 5-indanyl; each R? independently is hydrogen, alkyl of 1-10 (preferably 1-6) carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, hexyl, octyl, decyl or the like, phenyl Cj-Cg alkoxy or carboxy; p is an integer of 1 to 5; Rg is substituted at the 2 or 3-position; and R? can be substituted at the 2, 3, 4, 5 or 6-position, COORg optionally substituted with one or more C^-Cg alkyl or C^-Cg 25 alkoxy groups, wherein Rg is selected from the group consisting of hydrogen, alkyl, such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl,octyl, decyl or the like, Cg-C1Q aryl, such as phenyl, m-tolyl, naphthyl or the like, aralkyl of 7-12 (preferably 7-10) carbon atoms, such as benzyl, phenethyl or the like, and 5-indanyl; and r is an integer of 1, 2, 3 ox· A, COOR10 (5) -Ν 2 wherein R1Q is selected from the group consisting of hydrogen, ^θΙΟ alkyl, such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl, decyl or the like, Cg-C1Q aryl, such as phenyl^m-tolyl, naphthyl or the like, aralkyl of 7—12 (preferably 7“10) carbon atoms, such as benzyl, phenethyl or the like, and 5-indanyl; 2 is selected from the group consisting of oxy (-0-), thio (-S—) and sulfinyl (-SO-); q is an integerof 0 or 1, and COORjχ wherein R^ is selected from the group consisting of hydrogen, C^-Ο^θ alkyl, such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl, decyl or the like, Ο^-Ο^θ aryl, such as phenyl, m-tolyl, naphthyl or the like, aralkyl of 7-12 (preferably 7-1°) carbon atoms, such as benzyl,“phenethyl or the like, and 5-indanyl; i is an (6) -tr /(¾ )j lfi integer of Ο, 1 or 2; j is an integer of Ο, 1 or 2; and the sum of i+j is an integer of 1 or 2; and' Ar is selected from the group consisting of naphthyl, such as 1-naphthyl and 2-naphthyl, 5,6,7, 8-tetrahydronaphthyl, such as 5,6,7,8-tetrahydro-l-naphthyl optionally substituted with one or more C^-Cg alkyl or C^-Cg alkoxy groups and 5,6,7,8-tetrahydro-2-naphthyl, naphthyl substituted with at least one substituent selected from the group consisting of halo, such as fluoro, chloro, bromo and iodo, nitro, cyano, hydroxy, alkyl of 1-10 (preferably 1-5) carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or the like, alkoxy of 1-10 (preferably 1-5) carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy or the like, and dialkylamino of 2-20 (preferably 2-10) carbon atoms, such as dimethylamino, diethylamino, N-methyl-N-ethylamino or the like, phenyl, phenyl substituted with at least one substituent selected from the group consisting of halo, such as fluoro, chloro, bromo and iodo, nitro, cyano, hydroxy, alkyl of 1-10 (preferably 1-5) carbon 2q atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or the like, alkoxy of 1-10 (preferably 1-5) carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy or the like, and dialkylamino of 2-20 (preferably 2-10) carbon atoms, such as dimethylamino, diethylamino, N-methyl-N-ethylamino or the like, aralkyl of 7“12 (preferably '7-10) oarbon atoms, Ϊ7. 44300 optionally substituted with one or more C^-Cg alkyl or Cj“Cg alkoxy groups wherein R^ 4s hydrogen, alkyl of 1-10 (preferably 1-5) carbon atoms, such, as methyl, ethyl, propyl t or the like, or alkoxy of 1-10 (preferably 1-5) carbon atoms, suoh as methoxy, ethoxy, propoxy or the like. (Subject to the above proviso). Suitable illustrations of in the above formula (I) are c2~CjL0 alkyl> such as propyl, butyl, isobutyl, pentyl, hexyl and octyl, Cg-Cg alkenyl such as allyl, C^-Cg alkynyl, such as 2-propynyl, C^-Cg alkoxyalkyl, such as 2-methoxyethyl, 2-methoxypropyl, 2-ethoxyethyl and 3-methoxypropyl, C^-Cg alkyl thio alkyl, such as 2-ethylthioethyl and 2-methyl thioethyl, C2-Cg alkylsulfinylalkyl, such as 2-methylsulfinylethyl, C^-Cg hydroxyalkyl, suoh as 2-hydrcxyethyl and 3-bydroxybutyl, Cg-Cy carboxyalkyl, such as 1-carboxybutyl, Ο^-Οθ alkoxycarbonylalkyl, such as 2-ethoxycarbonylethyl, C^-Ο^θ aralkyl, such as 18. 4436ο benzyl and phenethyl, Cg-C^o di -curboxyaralkyl, such as carboxyphenethyl, Cq-Cjq cycloalkyl, such as cyclopropyl, cyclohexyl and cycloheptyl, C^-Ο^θ cycloalkylalkyl, such as cyclohexylmethyl, furfuryl, tetrahydrofurfuryl, 3-furylmethyl, tetrahydro-3-furylmethyl, 2-thenyl, 3-thenyl, tetrahydro-2thenyl and tetrahydro-3-thenyl.

Suitable illustrations of R^ in the above formula (l) are hydrogen, alkyl, such as methyl, propyl, butyl, isobutyl, pentyl, hexyl and octyl, C^-Cg alkenyl, such as allyl, Cj-Cg alkynyl, such as 2-propynyl, Cg-Cg alkoxyalkyl, such as 2-methoxyethyl, 2-methoxypropyl, 2-ethoxyethyl and 3-methoxypropyl, θ2~θβ alkylthioalkyl, such as 2-ethylthioethyl and 2-methylthioethyl, C^-Cg alkylsulfinylalkyl, such as 2-methylsulfinylethyl, C^-C^ hydroxyalkyl, such as 2hydroxyethyl and 3-hydroxybutyl, C^-C? carboxyalkyl, such as 1-carboxybutyl, C^-Cg alkoxycarbonylalkyl, such as 2ethoxycarbonylethyl, aralkyl, such as benzyl and phenethyl, Cg-C^ (A -carboxynralky] , such as -carboxyphenethyl, C3-Ci0 cycloalkyl, such as cyclopropyl, cyclohexyl and cycloheptyl, cycloalkylalkyl, such as cyclohexylmethyl, furfuryl, tetrahydrofurfuryl, 3-furylmethyl, tetrahydro-3-furylmothyl, 2-thenyl, 3-thenyl, tetrahydro-2thenyl and tetrahydro-3-thenyl.

Suitable illustrations of R^ in the above formula (i) are Cl“C5 alkyl, such as methyl and propyl, carboxy, ¢2-% 19. alkoxycarhonyl, sucll as ethoxycarbonyl, C^-C^Q aralkyl, such as benzyl, and ring substituted benzyl wherein said substituent is C^-C^ alkoxy, such as 4-methoxybenzyl. Suitable illustrations of R? are hydrogen, alkyl, such as methyl, ethyl, propyl and isopropyl, phenyl and carboxy, and the suitable position of R? is 1, 4 or 6.

COOH Suitable -Ν Z groups are 3-carboxy-4-morpholino, Voh/ 3-carboxy-4-thiomorpholino, l-oxo-3-carboxy-4-thiomorpholino and 4-carboxy-3“thiazolidinyl.

COOH Suitable -EK I J groups are 2-earboxy-l,2,3,4tetrahydro-l-quinolyl, 3-carboxy-l,2,3,4-tetrahydro-2isoquinolyl, l-carboxy-1,2,3,4-tetrahydro-2-isoquinolyl, 2-oarboxy-l-indolinyl 'and l-carboxy-2-isoindolinyl. Suitable illustrations of Rg, riq mti Rn are hydrogen, Ο^^-Ο^θ alkyl, such as methyl, ethyl, tert-butyl and octyl, Gg-Ο^θ aryl, such as phenyl and m-tolyl, C^-C^q aralkyl, such as benzyl, and 5-indanyl.

. Suitable illustrations of Ar in the above formula (1) are naphthyl, such, as 1-naphthyl ani,2-naphthyl, 5,6,7,8tetrahydronaphthyl, such as 5,6,7,8-tetrahydro-l-naphthyl and 5,6,7,8-tetrahyd.ro-2-naphthyl, naphthyl substituted with at least one substituent selected from the group consisting of halo, such as chloro and bromo, hydroxy, C^-C^ alkyl, such as methyl, ethyl and isopropyl, C^-Cr alkoxy, such as methoxy and ethoxy, Snd dialkylamine, auch as dimethylamino and diethylamino, phenyl, phenyl substituted with at least one substituent selected from the group consisting of halo, such as chloro, alicyl, such as methyl, ethyl, and isopropyl and alkoxy, such as methoxy, Ο^-Ο^θ aralkyl, such as phenethyl, · The pi'ef erred Ar groups are 1-naphthyl, 2-naphthyl, 5,6,7,8tetrahydro-l-naphthyl, 5,6,7,8-tetrahydro-2-naphthyl, 5~ chloro-1 -naphthyl, 6-chloro-2-naphthyl, 6-Dromo-l-naphthyl, -hydroxy-l-naphthyl, 7-hydroxy-2-naphthyl, o-methyl-220 naphthyl, 6-methyl-1-naphthyl, 7-methyl-1-naphthyl, 7-methyl2-naphthyl, 6-ethyl-2-naphthyl, 6,7-dimethyl-1-naphthyl, 21.

V, 6,7“dimethyl-2-naphthyl, 6-isopropyl-2-naphthyl, 5-methoxy1-naphthyl, 6-methoxy-2-naphthyl, 7“®sthoxy-2-naphthyl, 4,6-dimethoxy-2-naphtliyl, 6,7“dimethoxy-2-naphthyl, 6,7diethoxy—2-naphthyl, jj-dimethylamino-l-naphthyl, 5dimethylamino-2-naphthyl, 5-diethylaniino-l-naphthyl, 6dinje thyl amino-1 -naphthyl, 6-dimethylamino-2-naphthyl, 1:chlorophenyl, 2,4,5-trichlorophenyl?p-tolyl, anisyl, 3,4dimethoxyph.eny.1, 3,4,5“trimethoxyphenyl, 'Ί > Illustrative of suitable N, -arylsulfonyl-L-argininamxdes of • sufficient activity are the following·: COMPOUND NUMBER:1 N2-(2-naphthylsulfonyl)-Ii-arginyl-N-butylglycine benzyl ester 2 N -(0,7-dimethoxy-2-naphthylsulfonyl)-Ii-arginyl-N(2-methoxyethyl)glycine benzyl ester p N -(6,7-dimethoxy-2-naphthylsulfonyl)-I-arginyl-N(2-methoxyethyl)glycine 3-methylphenyl ester p N -(6,7-dime thoxy-2-naphthylsulfonyl)-I-arginyl-N20 (2-methoxyethyl)glycine 5-indanyl ester N2-(6,7-dimethyl-l-naphthylstu.fonyl)-l-arginyl-N-(2me thoxyethyl)glycine 22. Ρ Ν-(6,7-3imethoxy-2-naphthylsulfonyl)-L-arginyl~N-(2ethylthioethy1)glycine N2-(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(2methylthioethyl)glycine 8 N2-(7-methoxy-2-naphthylsulfonyl)-I-arginyl-ff-(2methylsuli‘inylethyl)glyeine 1^-(6,-7 -dimethoxy-2~naphthylsul:fonyl)“L-arginyl-H(2-hydroxyethyl)glyc ine N2-{6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N10 (3-hydroxybutyl)glycine N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(acarhoxyphene thyl)glyc ine N2 -(7-methy1-2-napnthylsulfonyl)-I-arginyl-N-furfurylglycine 13 N^-(7-inethy1-2-naphthylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine N2-(7-methoxy-2-naphthylsulfonyl)-L-arginyl-Nfurfurylglycine N2- (7-methoxy-2-nanhthylsulfonyl)-L-arginyl-N20 furfurylglycine tert-butyl ester N2-(7-aethoxy-2-naphthylsulfonyl)-L-arginyl-Ntetrahydrofurfurylglycine 23. Ν -(5-dimethylamino-1-naph.Chylsuifonyl)-L-arginyl~Nt etrahydrofurfurylglycine Λ • 18 N-(5-chloro-l-naph.thylsulfonyl)-L~arginyl~Ntetrahydrofurfurylglycine 19 N '-(l-naphthylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine N -(6,’/-dimethyl-1-naphthylsulfonyl)-L-arginyl-Nt et rahydro f ur f u rylglycine N -(5,6,7,8-tetrahydro-l-naphtliylsu.1.fonyl)-L-arginyl10 N-tetrahydrofurfurylglycihe N -(6,7“dimethoxy-2-naphthylsulfonyl)-L-arginyl-N- tetraliydrofurfurylglycine N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-Nbutylaspartic acid. 24 N2-(6,7-dimethoxy-2-naphthylsulfonyl)-Ii-arginyl-I!Tbutylaspartic acid diethyl ester N2-(6,7-dime thoxy-2-naphthylsulfonyl)-L-arginy1-Nhenzylaspartic acid Ii -(6,7-dimethoxy-2-naphthylsulfonyl)-l-arginyl-IiF20 henzylaspartic acid diethyl ester N2-(6,7-dimethoxy-2-naphthylsulfonyl)-1-arginy1-II-methylO-phenylalanine 24. 44300 N2-(6,7-dime thoxy-2-naphthylsulfonyl)-L-arginyl -N-me thyl-(4-methoxyphenyl)alanine l-(N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginylJ -2piperidinecarboxylic acid l-[N2~(6-methoxy-2-naphthylsulfoxiyl )-L-arginy lJ--2piperidinecarboxylic acid 1-(n2-(6,7-dimethoxy-2-naphthylsulfonyl )- b· arginyXJ -4mefch.yl-2-piperidinecarboxylic acid l-|N2-(7-methoxy~2-naphthylsulfonyl)-b-ai’ginyij-4~!iiethyl--2 piperidinecarboxylic acid l-[N2-( 5-methoxy-l-naphthylBiilfonyl )-b-arginyl] -4-methyl-2 p.i peridi nccarboxyi i c; aci tl 1“CN -(^,6-dimotboxy-2-naph.thylsuli,onyl)-L-arginylJ -4methyl -2 -pipe ri dine carboxyli c acid 1-|N —( 6,7-di ethoxy-2-naphthylsulfonyl) -b-arginylj -4methyl-2-piperidinecarboxylic acid 1-(N -(6,7-4imethoxy~2-naphthylsul£onyl)-L-arginyl| diethyl-2-piperidinecarboxylic acid l-(N2-(7-methoxy-2-naphthylsulfonyl) -L-arginylJ -4~ethyl-220 piperidinecarboxylic acid l“(N2-(6,7-dimethoxy~2-naphthylsulfonyl)-L-arginylJ -4propyl~2-piperidinecarboxyl±c acid . 43 6 0 ρ 1-{ϊϊ “(6,7-diinethoxy-2-naphth.ylsulf onyl) -L-arginyl^ -4isopropyl-2-pipei'idinecarboxylic acid ·> 1-£ν*·-(6,7-dimethoxy-2-naphthylsulfonyl}-L-’arginylJf-6— methyl-2-piperidineoarboX5*lic acid Λ 1-{N -(7-methoxy-2-naphthylsulfonyl)-L-arginyl) -2-mathyl-2 pipexidineearboxylic acid 1—Jn -^6,7-dimethoxy-2-naphthylsulfonyl)-L-arginylJ-3— pipexidinecarboxylic acid l-jN2-(7-methoxy-2-naphthylsulfonyl)-L-arginyl)-3piperidineoarboxylic acid l-(N2-(7-methoxy-2-naphthylsulfonyl)-L-argin.yl)-2, 6piperidinedicarboxylic acid l-{N2“(6,7-diniethoxy-2-napb.thylsulfonyl)-L-arginylJ -4phenyl-2-pip eridinecarboxyli c acid l-(N2-(l-naphthylsulfonyl)-L~arginyl) -4-methyl-2piperidinecarboxylic acid p 1—/Er —(2-naphthylsulfonyl)-l-afginyl7-4-isopropyl-2piperidinecarboxylic acid l-βϊ2-(5.6,7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl74-methyl-2-piperidinecarboxylic acid 26. 4 3 C Ο l-£N2-(6-chloro-2-naphthylsulfonyl)-L-arginyl^j-4-isopropyl 2-piperidinecarboxylic acid l-[N2-(5-dimethylamin.o-l-niaphthyl3ulfonyl)-L~arg;inyl] - '· 2-piperidinecarboxylic acid 51 i-jjt'!’“(7-niethyl“2-naphthylsulfonyl)-L-arginylJ-4“meth,yl-2piperidinecarboxylic acid 1- In2 -(7 -ma thyl-2 -naphthyl sul fonyl) -L-arginyl) -4-ethyl 2-piperidinecarboxylic acid « 1- [N2“(7-inetb.yl-2-maphthylsulfonyl )-L-arginyl3~4-isopropyl yg 2-piperidinecarboxylic acid 1 “(N2-(6“methyl-2-n.aphthylsulfonyl)-L-arginyl3“4-isopropyl 2-piperidinecarboxylie acid 1—JN ~(7-methyl-2-naphthylsulfonyl)-L-arginyl)-2hoxa tne thyl en ei min e c a rb oxyli c acid. 56 4-jN2-(7-methoxy-2-naphthylsulfonyl)-L-arginyl3-5thiomoipholinecarboxylic acid 4-jN -(7-methoxy-2-naphthylsulfonyl)-L-arginyl]-3earboxythiomorpholine 1-oxide 27. - [Ν2 - ( 6,7 -di me thoxy-2 -naphthylsul fonyl) -L-arginyl J -3 morpholinecarboxylic acid 4-[N2-(7-niethoxy-2-naphthylsulfonyl)-L-arginylJ-3— morpholinecarboxylic acid 3- [N2-(7-methoxy-2-naphthylsulfonyl)-L-arginylJ -4thiazolidinecarboxylic acid ' Λ 2-jN-(6,7-dimethoxy-2-naphthylsulf onyl)-L-arginylJ 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 2— (N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginylJ isoindoline—1-carboxylic acid g * N -(4-chlorophenylsulfonyl)-L-arginyl-N-butylglyeine N -(2,4,5-trichlorophenylsulfonyl)-L-arginyl-N-butylglycine N^-tosyl-L-arginyl-N-butyIglycine .

N -(4-methoxyphenylsulfonyl) -L-arginyl-N-b enzylglycin c ο · N “(3,4-dimothoxyphenylsulfonyl)-L-arginyl“N-(2-niethoxyethy.1.) glycine O N -( 3,4, fj-txi me thoxyphenylsulf onyl) -L-arginyl -N-( 2 methoxyethyl)glycine N^-phonethylsulfonyl-L-arginyl-N-furfurylglycine ο l-/Er-(2-dibe...zuf uranyl )-I-arginyl7-2-piperidinecarboxy lie acid 28.

V Of the compounds of thio invention, it will be understood that the following compounds are most preferred due to their high level, of antithrombotic activity and low level of toxicity.

N—(7“methoxy-2-naphthylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine -(7-methyl-2-naphthylsulfonylJ-L-arginyl-N-tetrahydrofurfurylglyeine o N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N10 tetrahydrofurfurylglyoine 1-[n1 2-(6,7-di mothoxy-2-naphthylsulfonyl)-L-arginyl}-4methyl-2-piperidinecarboxylie acid 1- Qi2-(7-methOxy-2-naphthylsulfonyl)-L-arginyl)-4methyl-2-piperidinecarboxylie acid l-jN^-(7-methoxy-2-naphthylsulfonyl)-L-arginyl^-4-ethyl2- piperidinecarboxylic acid The pharmaceutically acceptable salts of the above compounds are of course also included within the scope of this invention, Aa one skilled in the art can readily appreciate, the carbon atom of the N^-nrylsulfonyx-Lyargininamides, to which tho carboxyl group or the ester thereof is attached can be an asymmetric carbon atom ax.iuwing for the oxistenoo 29. of two optically active isomers, the D- anil L-diastereoisomens, as well as tho racemate, DL-mixture.

In accordance) with findings concerning the antithrombotic activity of such, compounds possessing an asymmetric carbon atom, the compounds of the present invention having the D-configuration are more active than those of tho Lconfiguration and are the preferred compounds, although the L- and DL-forms of the instant compounds are also considered within the purview of the present invention.

The above compounds are intended only to illustrate the variety of structures which can be used in the process of this invention, and the above listing is not to be construed - as limiting the scope of the invention.

For tho 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 possible by way of several synthetic routes which are outlined below. (a) Condensation of an L-argininamide with an arylsulfonyl halide This process may be illustrated as follows: HN^.

C - N - CH0ClLCHoCHC00H (ll) -> HpN'' I d “I H Nflg .

HN ¢. c - if - ch„ch_ch_chcooh (iii) HN < .( - Λ *( I R HN R' I R' + RH (IV) -> JC - N - CH„CH_CH„CHCOR (V) -> HN I I I R HN R' I R< HNx C - N - CH„CH„CH„CHC0R (Vl) H„NX I 2 2 2, * H NH2 + ArSOgX (VII) -} - Ν τ CH„CH„CH„CHCOR (i) H?NX I 2 2 2| · Λ H IINSO, I 2 Ar In the above formulas, R and Ar are as defined herein above; X is halogen; R1 is a protective grotto for the -amino group, such as benzyloxycarbonyl or tertbutoxvcarbonyl ; R' and R are selected from the group consisting of hydrogen and protective groups for the guanidino group, such as nitro, tosyl, trityl, 31. 43 θ θ oxycarbonyl and the like; and at least one of R> and R is a protective group for the guanidino group.

The N -arylsulfonyl-L-argin'inamide (i) is prepared by the condensation of an L-argininamide (Vi) with a substantially equimolar amount of an arylsulfonyl halide (yil), preferably a chloride.

The condensation reaction is generally effected in a suitable reaction-inert solvent in the presence of an oxcess of a base, such as an organic base (triethyl10 amine, 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, diethyl 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 2 pressure to give tho N -arylsulfonyl-L-argininamide (I), which can be purified by trituration or recrystallization 1‘rom a suitable solvent, such as diethyl ethertetrahydrofuran, diothyl ether-methanol und watermethanol, or may bo chromatographed on silica gel.

Tho L-argininamidos (VI) stai'ting materials required 32. ΙΟ 443C0 for the condensation reaction can be prepared byprotecting the guanidino and (Λ -amino groups of Larginine (ll) via nitration, acetylation, formylation, phthaloylation, trifluoroacetylation, p-methoxybenzyloxycarbonylation, benzoylation, benzyloxycarbonylation, tert-butoxycarbonylation or tritylation and then condensing the formed N -substituted-Ν substituted-L-arginine (ϋ) with a corresponding amino acid derivative (TV) by such a conventional process as the acid chloride method, azide method, mixed anhydride method, activated ester method or carbodiimide method, and thereafter.selectively xx removing the protective groups from the formed N substituted^ -substitutod-L-argininamide (V).

The amino acid derivatives (IV) which are the atarting materials for the preparation of the N-substituted— Λ N -substituted-L-argininawides (v) are represented by the following formulas! R., H-N^ 1 (vnr) (CH2)nC00R2 Ά H-N > \-|V «7 · (X) (ix) (XI) COOR. Λλ H-N Ζ (XII) COORn >(CH2) i-NZ <ch2)1 (xm) In the above formulas, R^, R£, R3, R^, R^, Rg, R?, r?, R10’ Rll’ Z’ n, m, r, q, i, and j are as defined herein above .· The amino acid derivatives of the above formula (VHt) or (IX) can be prepared by the condensation of a haloacetate, 3-halopropionate or 4-halobutyrate with an appropriate amine having the formula R-jNHg or R3NH2. (See, J. Org. Chem., 21 728-732 (i960)).

The condensation reaction is generally carried out without a solvent or in a solvent, such as benzene or ether, in the presence of an organic base, such as triethylamine or pyridine, at a temperature of 0°C to 80°C 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 aoid tert-butyl ester derivatives are preferred, because they are easily converted to other ester derivatives by acidolysis in 54. the presence of a corresponding alcohol employing an inorganic acid (HC1, H2SO4' etc·' or an organic acid (toluenesulfonic acid, trifluoroacetic acid, etc.).

In accordance with the process employed for preparing 2-piperidinecarboxylic acid derivatives (X), the following scheme is illustrative: i J Cl (XIV) (XV) (xvi) r7 r%*7 CN (H ) SZcOoH I 2 H (XVII) (XVIII) In the first reaction of the aforemetnioned 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 alkanol solvent to give the 1,2-dehydropiperidine (XVI). The action of cyanogenating agents, e.g., hydrogen cyanide or sodium cyanide converts the 1,220 dehydropiperidines (XVI) to the corresponding 2-eyano 43GO analogs (XVII). Hydrolysis of the 2-cyanopiperidines (XVII) to yield the 2-piperidinecarboxylie acids (XVUI) is effected by treatment of the 2-cyanopiperidines (XVII) with an inorganic acid, such as hydrochloric acid or sulfuric acid.

'The arylsulfonyl halides (Vll) which are the starting o materials for the preparation of the N -arylsulfonylL-argininamides (i) can 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.

In practice, halogenation is 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 trichloride, phosphorous tribromide or phosphorous pentachloride, at a temperature of -1O°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 ether, benzene, ethyl acetate, chloroform or the like.

The arylsulfonyl halide can be purified by recrystallization from a suitable solvent such as hexane, benzene or.the like, •36. 44300 (to) Removal of the N-substituent from an N -substituted2 N -arylsulfonyl-L-argininamide This process may be illustrated as follows: ^C-N-CHoCHnCHnCHCOR (V) ~ HNX I 2 2 2| I R” HN R* I R' HN^ .C-N-CH„CHoCH„CHC0R HN I 2 2 Zl I R NH_ R* 2 (XIX) ArS°2X (VIX) V HN _C~N-CH9CHQCH9CHCOR (XX) HN I 2 2 2| I R HNSO, R' I Ar HN^ h2n N-CH„CH„CH_CHCOR I Z Z Z| H HNS0o * Ar (I) 44300 In the above formulas, R, Ar, X, R', R and Rn* are as defined herein above.

The N -arylsulfonyl-L-argininamide (l) is prepared, by G G removing the N -substituent from an N -substitutedp N -arylsulfonyl-L-argininamide (XX) by means of aoidolysis or hydrogenolysis .

The aoidolysis is generally effected by contacting G 2 the N -suhstitufced-N -arylsulfonyl-L-argininamide (XX) and an excess of an acid such as hydrogen fluoride, hydrogen chloride, hydrogen bromide 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, and 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 tho use of the excess acid, the products 2 are generally tlie acid addition salts of tho N arylsulfonyl-L-argininamides (i), which can be easily converted to a free amide by neutralization.

The removal of tho nitro group and the oxycarbonyl group, e.g., benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, is readily accomplished by tho hydrogenolysis, 38. 44300 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 for a period of 2 hours to 120 hours.

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

The N2-arylsulfonyl-L-argininamides (i) are isolated by filtration of the catalyst followed by evaporation of the solvent.

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

The N -substituted-N -arylsulfonyl-L-argininamides (XX) starting materials can be prepared by condensing an Gr 2 N -substituted-N -substituted L-arginine (itt) (generally Cr 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 aoid derivative (IV) j 2 selectively removing only the N -substituent of an 59.

N&-substituted-N2—substituted L-argininamide (V) by mea of catalytic hydrogenolysis or acidolysis, and then Q. condensing the thus obtained N -substituted-L~ argininainide (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 Λ arylsulfonyl halide, and the removal of the N G 2 substituent from an N -substituted-N -arylsulfonyl-Largininamide. (c) Condensation of an N -arylsulfonyl-L--arginyl halide with iin amino acid derivative This process may be illustrated as follows: HN; 'C-N-CH-CH-CH-CHCOOH (ll) H-N^ 2 2 2| · NH20 UN h2n+ ArSOgX (VII) ,C-N-CH2CHgCHgCHCOOH HNS0o ι Ar (XXI) 40. c -n-chocii9 cii2 chc ox (XXII) HNSO, + RH (IV) -> II C-N-CH-CILCIRCIICOR H2NX 4 <Ί (I) HNS02 In the above formulas, R, Ar and X are as defined herein above . halide (XXII), preferably a chloride with at least an equimolar amount of an amino acid derivative (IV)· The condensation reaction can be carried out without an added solvent in the presence of a base. However, satisfactory results will be obtained with the use of a solvent such as basic solvents (dimethylformamide, dimethylacetamide, etc.) or halogenated solvents (chloroform, dichloromethane, etc.).

The amount of the solvent to be used is not critical and may vary from about 5 to 100 times the weight of tho N^-arylsulfonyl-I,-arginyl halide (XXII). 44300 Preferred condensation x'eactiou temperatures are in ·%» the range of from -10°C to room temperature. 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.

The obtained N -arylsulfonyl-L-argininamide can 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 can 2 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 can 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.

Tho amount of the solvent to be used is not critical and may vary from about 5 4° 100 times the weight of the N“-arylsulfonyl-L-arginine (XXI).

Preferred reaction temperature are in the range of -10°C to room temperature. The reaction time is not critical, but vari.es with the halogenating agent and reaction temperature. Xn 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 5 arylsulfonyl-L-arginyl halides (xxil) can be prepared by the condensation of L-arginine (II) with a substantially equimolar amount of arylsulfonyl halides (VXX), by a method similar to that described in the condensation of an L-argininand.de with an arylsulfonyl halide. (d) Guanidylation of an N -arylsulfonyl-L-ornitfainamide or an acid addition salt thereof This process may be illustrated as follows! k2n-ch2ch2ch2chcor (XXXX) -} HNSO„ I 2 Ar H HN^ I .C-N—CH„CH„CH„CHCOR (l) k2n- 22 2| HNSO, I 2 Ar In the above formulas, R and Ar are as defined herein above.

The* N -arylsulfonyl-L-argininamide (I) is prepared by guanidylating an N -arylsulfonyl-L-omithinamide (XXHE) with, an ordinary guanidylating agent such as an O-alkylisourea, S-alkylisothiourea, l-guanyl-3,5dimethylpyrazole or carbodiimide. The preferred ' guanidylating agents are the O-alkylisourea and the S-alkylisothiourea.

The guanidylation of the N -arylsulfonyl-L-omithinamide (XXHE) with the O-alkylisourea or S-alkylisothiourea is generally effected in a solvent in the presence of a base at a temperature of from 0°C to the boiling temperature of the-solvent for a period of from 30 minutes to 5θ hours.

Examples of the preferred bases are triethylamine, pyridine, sodium hydroxide and sodium methoxide.' The base is used in an amount of 0,01 to 0.1 equivalent to the N -arylsulf onyl-L-omithinamide.

Examples of the preferred solvents are water, waterothanol and water-dioxane. 2.

After the reaction is complete, the N -arylsulfonyl-L20 argininamide (l) is isolated by evaporation of the solvent followed by removal of the excess base and the formed salt by a water wash· It is well recognized in the art that an ester derivap tive of the N -arylsulf onyl-L-argininamide (i) wherein S^, Ηθ, R^, R1q or RX1 is alkyl, aralkyl, aryl or 44.

“Indanyl, can be prepared from a carboxylic acid 2 derivative of the N -arylsulfonyl-L-argininamide wherein Rg, Ry( Rg, Rg, R1Q or is hydrogen, by the conventional esterification 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 acidolysis methods. The conditions under which esterification, hydrolysis or acidolysis would be carried out will be each apparent to those skilled in the art.

The N -arylsulfonyl-L-argininamide (l) of this invention forms acid addition salts with any of a variety of inorganic and organic acids . Some of the l^-arylsulfonyl-L-argininamides containing a free carboxyl group, wherein Rg, R^, Rg, R^, R^g or R^j is hydrogen, forms salts with any of a variety of inorganic and organic bases .

The product of the reactions described above can be isolated in the free form or in the form of salts. In addition, the product can be obtained as pharmaceutically acceptable acid addition salts by reacting one of the free bases with an acid, suoh as hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, citric, maleic, succinic, lactic, tartaric, gluconic, benzoic, methanesulfonic, 443θθ ethanesulfonic, benzenesulfonic, p-toluenesulfonic aoid or the like. In a similar manner, the product can be obtained as pharmaceutically acceptable salts by reacting one of the free carboxylic acids with a base, such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, triethylamine, procaine, dibenzyl amine, 1-ephenamine,' N ,N ’-dibenzylethylene diamine, N-ethylpiperidine or the like.

Likewise, treatment of the salts with a base or acid results in a regeneration of the free amide.

As stated above, the N -arylsulfonyl-L-argininamides, and the salts thereof of this invention are characterized by their highly specific inhibitory activity 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 -arylsulfOftyl-L20 argininamide of this invention was compared with that of Q a known anti thrombotic agent, N -(p-tolylsulfonyl)-Larginine methyl cater, 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 46. prepared by dissolving 150 tng of bovine fibrinogen (Cohn fraction I) supplied by Armour Inc. in 40 ml of a borate saline buffei- (pH 7 ·Μ» was mixed with 0.1 ml of a borate Saline buffer, pH 7·4> (control) or a sample solution in the same buffer, and O.l ml of a thrombin solution (5 units/ ml) supplied by Moehida 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 5θ~55 seconds. The experimental results are summarized in Table 1. The term concentration required £0 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 100-310 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 1,10(^(. m.

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 N -naphthylsulfonyl-Largininamide of this invention was administered intravenously 47. 44300 into animal bodies, the high antithrombotic activity in the circulating blood was maintained for from one to three hours Tho halflife for decay of the anti-thrombotic compounds of this invention in circulating blood was shown to be appro5 ximately 60 minutes; the physiological conditions of the host animals (rat, 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 (ΐ,Ώ^θ) determined by intraperitoneal administration of substances of formula (i) in mice (male, 20 g) range from about 1,000 to 10,000 milligrams per kilogram of body weight, Representative LD^q values for the compounds of this invention are shown in the following Table. 48.

Compound — LD50 (mg/kg) N2-(6,7-diroethoxy-2-naphthylsulfonyl)-Larginyl-N-tetrahydrot’uri'urylglycine 620 1-/ΪΙ2-(6,7-dimethoxy-2-naphthylsulfonyl)-Iarginyl7-2-piperidinecarboxylic acid 1,500 Π >6-dimethoxy-2-naphbhylsulfonyl·)- Ii-arginyi/-4-inethyl-2-piperidinecarboxylic acid 670-1,000 2 1-/5 -(l-naphthylsulfonyl)-Ir-arginyl7-4methyl-2-piperidinecarboxylic acid 700-1,000 p 1-/5'-(5-dimethy3.amino-l-naphthylsulfonyl)I-arginyl7-2-piperidinecarboxylic acid 700-1,000 4-/52-(7-methoxy-2-naphthylsulfonyl) -Larginyl7-3-inorpholinecarboxylic acid > 1,000 p 2-/5 -(6,7-dimethoxy-2-naphthylsulfonyl)-Larginyl7-l,2,3,4-tetrahydroisoquinoline-3carboxylic acid > 1,000 2-/52-(6,7-dimethoxy-2-naphthylsulfonyl)-Larginyl7-l-isoindolinecarboxylic acid > 1,000 On the other hand, IU^q oalu.es for N -dansyl-N-butyl-1argininamide and N^-dansyl-N-methyl-N-butyl-L-argininamide are 75 and 70 milligrams per kilogram, respectively. 49.

The therapeutic agents of this invention may be administered alone or in combination with pharmaceutically acceptable carriers, tho proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmaceutical practice.

For example, the compounds may be 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, or granules containing suitable excipients such as starch, lactose, white sugar and the like.

The compounds may be administered sublingually in the form of troches or lozenges in which each active ingredient is mixed with sugar or corn syrups, flavoring agents and dyes, and then dehydrated sufficiently to make the mixture suitable for pressing into solid form. Tlie 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, 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 ean 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, the invention includes such compositions in unit dose form. 51.

EXAMPLE 1 (A) N -(5-methoxy-l-naphthylsulfonyl)-L-arginine: To a well stirred solution of l-arginine in 800 ml of 10?ί potassium carbonate solution was added. 114,7 g of 5-methoxynaphthalenesulfonyl 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 a 76 percent yield of -N -(5-methoxy-l-naphthylsulf onyl) -L-arginine .

(B) ΪΙ2-(5-methoxyll-naphthylsulfonyl)-L-arginyl chloride: A suspension of lY (5-methoxy-l-naphthylsulfonyl)-Larginine 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 3^-(5Hnethoxy-l-naphthylsulfonyl)-Larginyl chloride. (θ) N2-(5-methoxy-l-naphthylsulfonyl)-L-arginyl-N-(2-methylthioethyl)glycine tert-butyl ester: To a stirred solution of N'-(2-methylthioethyl)glycine tert-butyl ester in 20 ml of chloroform was carefully added N -(5-methoxy-l-naphthylsulfonyl)-L-arginyl chloride obtained above. The reaction mixture was allowed to stand at room temperature for one hour. At the end of 52. 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 water to give a crystalline material. This was collected hy filtration and reerystallized from ethanol-ethyl ether to give an 82 percent yield of ^-(S-methoxy-l-naphthylsulfonyl)L-arginy1-N-(2-methylthioethyl)glycine tert-butyl ester.

(D) N2-(5-methoxy-l-naphthylsulfonyl)-I-arginyl-N-(2-methylthioethyl) glycine: To a solution of N2-(5-methoxy-l-naphthylsulfonyl)-I-arginyl-N(2-methylthioethyl)glycine tert-butyl ester in 20 ml of chloroform was added 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 DaiaionCDsK 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 solution was evaporated to dryness to give a 79 percent yield of N2-(5-methoxy-l-naphthylsulfonyl)-L-arginy1-N-(2-methylthioethyl)glycine as an amorphous solid.

The following compounds are prepared in a similar manner: 55. 4300 Λ Ν -(5~methoxy-l-naphthylsulfonyl)-L-arginyl-N-(2methylthioethyl)glycine tert-butyl ester N -(5-methoxy-l-naphthylsulfonyl) -L-arginyl-N-(2methylthioethyl)-^-alanine N -(6,7-die thoxy-2-naphthylsulf onyl )-L-arginyl-N(2-meth.yl thioethyl )glycine N -(6-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(2methylthioethyl)glycine N2-(6,7-dimethoxy-2-naphthylsulfonyl)-N-(2— methylthioethyl) -N-( 3“carboxypropyl)-L-argininamide N -(6,7“dimethoxy-2-naphthylsulfonyl)-lT-(3methylthiopropyl)glycine N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2ethylthioethyl)-^» -alanine N -( 6,7-dimethoxy-2-naphthylsulfonyl) -L-arginyl-Nbenzylglycine benzyl ester N -(5-nitro-1-naphthylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine N -(7-hydroxy-2-naphthylsulfonyl)-L-arginyl-Ν'te t rahydro furfurylglycine 54. Ν -(5-eyano-l-naphthylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine ο N -(6,7- N^-(7-mothyl -2-naphthylsul fonyl. )-L-argi nyl -Ntetrahydrofurfuryl -^> -alanine p N -(6,7-flimQthoxy-2-naphthylsulfonyl )-L-arginyl-Nt o t rnhyd ro fu rf 11 ryl al ani no N -(7-methoxy-2-naphthylsulfonyl)-N-(3-earboxypropyl)10 N-1 e t rahyd ro furfuryl-1,-argininami de N -(6,7 “dirtle thoxy-2-uaphtliylsulfonyl) -L-arginyl-N(3-furylmethyl)glycine 1^-(6,7 -dimethoxy-2-naphthylsulfonyl)-l-arginyl-N-(tetrahydro 3-furylmethyl)glycine IT2—(6,7-dime thoxy-2-naphthy lsulf onyl) -I-arginyl-lf(2-thenyl) gly c ine N -(7-methoxy-2-naphthylsulfonyl)-1-arginyl-N-(3-thenyl) glycine N -(6,7-dimethoxy-2-naphthylsulfonyl)-l-arginyl-N20 (tetrahydro-2-thenyl)glycine 5544360 Ν -(7-methoxy-2-naphthylsulfonyl)-1-arginyl-N-)Tetrahydro-3thenyl)glycine Ng-(7-methoxy-2-naphthylsulfonyl)--1-arginyl-N-(4-methoxyfuryl) gly cine Ng-(7-methyl-2-naphthylsulfonyl)-I-arginyl-N-(5-methy1furfuryl)glycine Ng-(6,7-dimethoxy-2-naphthylsulfonyl)-1-arginyl-N(1,4-diacylohexylmethyl)glycine 1-(Ng-(6,7-dimethoxy-2-naphthylsulfonyl)-l-arginyl) -r410 methoxypiperidine-2-carboxylic acid. 1— (Ng —(6,7-dimethoxy-2-naphthylsulfonyl)-l-arginyl)-5methylhexamethyleneimine-2-carboxylic acid 1-(Ng-(3,7-dimethyl-2-dibenzofluranyl)-l-arginyl)-4.4dimethyl-2-piperidine carboxylic acid.

Ng-(3-methoxy-5.6,7,8-tetrahydro-2-naphthylsulfonyl)-larginyl-N-(tetrahydro-2-pyranylmethyl)glycine EXAMPLE 2 (A) N -(6-raethoxy-2-naphthylsulfonyl)-l-arginyl chloride: A suspension of 2.5 g of N^-(6-methoxy-2-naphthylsulfonyl)-1'20 arginine ir 20 ml of thionyl chloride was stirred for 2 hours at room temperature. Addition of cold dry ethyl ether resulted in a precipitate which was collected by filtration and washed several times with dry ethyl ether to give N -(6-methoxy-2-naphthylsulfonyl)-l-arginyl chloride. 56. 1-/T.P-(5-methoxy-l-naphthylsulfonyl)-l-arginyl/-4“. ethyl-2-piperidine carboxylic acid s 1-/&2-(6-methoxy-2-naphthylsulfony1)-L-arginyl/-4ethyl-2-piperidineoarboxylic acid ο 1-ZS -(4.,6-dimethoxy-2-naphthylsulfonyl)-I-arginyl7-4ethyl-2-piperidineearboxylic acid 1-/S2-(5-ethoxy-l-naphthylsulfonyl)-l-arginyl7-4“e bhyl?-piperidinecarboxylic acid 1—/Ti2-(7-ethoxy-2-naphthylsulfonyl)-I-arginyl7-410 ethyl-2-piperidinecarboxylic acid ο 1—/IT -(6,7-diethoxy-2-naphthylsulfonyl)-l-arginyl7-4ethyl-2-piperidinecarboxylic acid 1—/Ti2-(7-methoxy-2-naphthylsulfonyl)-l-arginyl7-4tert-butyl-2-piperidinecarboxy? ° acid Phenyl l-^Ii2-(7-methoxy-2-naphthylsaifonyl)-Ii-arginyl74-ethyl-2-piperidinecarboxylate 59. 443θ° Λ Benzyl 1-(Ν -(7-methoxy-2-naphtliylsulfonyl)-L-arginyl] 4-ethyl-2 -pip eri dine carboxylate p Benzyl 1-jJJ -(6,7-dimethoxy-2-naphthylsulfonyl)-Larginy-l] -4 -me thyl -2 -pip eri dine carboxyla t e 1-(N -(5-nitro'-l-naphthylsulfonyl)-L-arginylJ-4methyl-2-piperidinecarboxylic acid 1-[n2-(7-hydroxy-2-naphthylsulfonyl)-L-arginylJ -4ethyl-2-piperidinecarboxylic acid 1-(N -(5-cyano-l-naphthylsulfonyl)-L-arginylJ -4-mcthyl 10 2-piperidinecarboxylic acid 1-[N2-(7-methyl-2-naphthylsulfonyl)-L-arginylJ -4ethyl-2-piperidinecarboxylic acid p * 1-Qs -(5-dimethylamino-l-naphthyls ulfonyl)-L-arginylJ4-ethyl-2-piperidinecarboxylic acid l-pt2-(2-naphthylsulfonyl)-L-arginylJ -4-ethyl-2piperidinecarboxylic acid l-[N2-(5,6,7,8-tetrahydro-2-naphthylsulfonyl)-Largiuyl] -4-e thyl-2-pi pei’i dine carboxyl I c acid 60. 1-£n -(5-d.i.jnethylatnlno-l-naphthylsulfonyl) -L-arginyl] 4-methyl-2-piperidinecarboxylic acid 1-(N -(7-methyl-2-naphthylsulfonyl)-L-arginyl]-6methyl-2-piperidine carboxyli c aci d 1-pi2 -(7 -me thyl-2 -naphthylsulfonyl) -L-arginyl] -4-t ertbutyl-2-piperidine carboxyli c acid 1- (1^-( 5~ni trc -1-naphthylsulf onyl) -L-arginyl] indo line2- carboxylic acid Λ 2- jN -(5-cyano-l-naphthylsulfonyl)-L-arginyl] isoindoline10 1-carboxylic acid 4-(N2-(7-methyl-2-naphthylsulfonyl)-L-arginyl] thiomorpholine~3~carboxylic acid 4-(N^-(6,7-dimethyl-2-naphthylsulfonyl)-L-arginyl] morpholine-3-carboxylic acid 4-{N2-( 5,6,7,8-tetrahydro-2-r.aphthylsulfonyl) -Larginyl] -3-carboxythiomo rpholino 1-oxide 4_Ql2-(7-me thyl -2 -naphthylsulf onyl) -L-arginyl] mo rpholine3- carboxylic acid 4- {n -(7-chloro-2-naphthylsulfonyl)-L-arginyl] morpholine20 3-carboxylie acid 61. 4^30° • 4-fN2-(7-hydroxy-2-naphthylsulfonyl)-L-arginyl] morpholine-3-carboxylic acid l 4-(N2-(5~nitro-l-naphthylsulfonyl)-L-arginyl] thiomorpholine-3-carboxylic acid 4-[N2-(5-cyano-l-naphthylsulfonyl)-L-arginyl]thiomorpholin.e-3-carboxyiic acid 4-[N -(5-methoxy-l-naph.thylsulf‘onyl) -L-arginyl] morpholine-3-carboxylic acid 4-}¾2-(5-ethoxy-l-naphthylsulfonyl)-L-arginyl] morpholineyj-carboxylic acid 4-(N2-( 5-dimethylamino-l-naphthylsulfonyl) -L-arginyl} thiomorpholine-3-earboxylic acid 3-£)^-( l-naphthylsulfonyl) -L-arginyl] thiazolidine-4carboxylic acid 2-Ql2-(7-methoxy-2-naphthylsulfonyl)-L-arginyl] 1,2,3,4-tetrahydroisoquinoline-l-carboxylic acid 2-{N2-(7-raethoxy-2-naphthylsulfonyl) -L-arginyl] isoindoline-l-carboxylic acid 62. 443θθ ml of methanol and 10 ml of 2N-Na0H solution was warmed to 60°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 mesh, j.

H form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with ethanol-water (l:4) and eluted with ethanol-water-NH^OH (10:p:l).

The main fraction was evaporated to dryness and washed p with ethyl ether to give 2.0 g of 1-(N ~(6-methoxy-2naphthylsul fonyl) -L-arginyl) -2-piperidinecarboxylic acid aa an amorphous solid.

I.R. (KBr): 3,200 (broad), 1,620, 1,150 cm-1 Analysis - Calcd. for C23^31°6N5S (percent): C, 54.64; H, 6.18; N, 13.85 Pound (percent): C, 56.88; H, 6.31; N, 13.83 The following compounds are prepared in a similar manner: N2-(7-methoxy-2-n&phthylsulfonyl)-L-arginyl-N-(2methylthioethyl) glycine N-(4.6-dimetboxy-2-naphthylsuli'onyl)-L-arginyl-N(2-methylthioethyl)glycine 58.

(B) Ethyl 1- llf2-(6-niethoxy-2-naphthylsulfonyl)-L-arginylJ2-piperidinecarboxylate: To a stirred solution of 2.2 g of ethyl 2-piperidinecarboxylate and 4.1 ml of triethylamine in 50 ml of chlorofo,rm, which was cooled in an ice-salt bath, was added in portions N -(6-methoxy-2-naphthylsulfonyl)-Larginyl chloride obtained above. The reaction mixture was stirred overnight at room temperature. At 'the end of this period, 500 ml of chloroform was added and the chloroform solution was washed twice with 50 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo . The oil.y residue was washed with ethyl ether to give p 2.9 g of powdery ethyl 1-(N -(6-methoxy-2~naphthylsulfonyl)-L-arginylJ-2-piperidinecarboxylate.

For analysis of the product, a portion of the product was converted to the flavianate, M.P. 192-3°C.

I.R. (KBr): 3,210, 1,747, 1,638 cm-1 Analysis - Calcd. for C^Hg^OgN^S -Ο^θΗ^Ο^Ν^ (percent): C, 49.58; II, 4.87; Ν, 11.56 Found (percent): C, .49-24 H, 4.70; N, 11.85 (c) l-Qi2-(6-methoxy-2-naphthylsulfonyl)-L-arginylJ-2piperidinecarboxylic acid: A solution of 2.8 g of ethyl l-(N''-(6-methoxy-2naphthylsulfonyl)-L-arginylJ-2-piperidinecarboxylate in 57. 2-/52-(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl/1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 2-/52-(5-methoxy-l-naphthylsulfonyl)-L-arginyl/isoindoline-l-carbozylic acid 2-/52-(5-ethoxy-l-naphthylsulfonyl)-L-arginyl7-l,2,3,4tetrahydroisoquinoline-3-carboxylic acid EXAMPLE 3 (A) NG-nitro-2-/l-arginyl7-l,2,3» 4-tetrahydroi3oauinolinc-3carboxylic acid ethyl esterί To a stirred solution of 28.3 g of N&-nitro-2-If2-(tertbutoxycarbonyl )-L-arginine in 450 ml of dry tetrahydrofuran were added in turn triethylamine and isobutyl chloroformate while keeping the temperature at -5°C. After 15 minutes, to this was added l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid ethyl ester, and the mixture was stirred for 15 minutes at -5°C. At the end of this period, the reaction mixture was warmed to room temperature. The solvent was evaporated and the residue taken up in 400 ml of ethyl acetate, and washed successively with 200 ml of water, 100 ml of 5% sodium bicarbonate eolution, 100 ml of 10% citric acid solution and 200 ml of water. The ethyl acetate solution was dried over anhydrous eodium 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 6cm) of 500 g of silica gel packed in chloroform. The product was eluted first with chloroform, and then 3% methanolchloroform. The fraction eluted from 3% methanol-chloroform 63. was evaporated to dryness to give a 63 percent yield of N&-nitro-2-£t-arginyl/'-l,2,3,4-tetrahydroisoquinoline-3carboxylic acid ethyl ester in the form of a syrup.

(B) li^-nitro-2-/l-arginy1/-1,2,3,4-tetrahydroisoquinoline-3carboxylic acid ethyl ester hydrochloride: To a stirred solution of N -nitro-2-^K -tert-hutoxycarbonyl)l-arginyl/-l,2,3» 4-tetrahydroisoquinoline-3-carboxylic acid ethyl ester in 50 ml of ethyl acetate was added 80 ml of 10$ dry HCl-ethyl acetate at 0°C. After 3 hours, to this solution was added 200 ml of dry ethyl ether to precipitate a viscous oily product.

This was filtered and washed with dry ethyl ether to give NG-nitro-2-/s2-(tert-butoxycarbonyl)-I-arginyl/-l»2,3,4— tetrahydroisoquinoline-3-carboxylic acid ethyl ester as an amorphous solid. (0) NG-nitro-2-/S2-(7-mothyl-2-naphthylsulfonyl)-L-arginyl/l,2,3»4-tetrahydroisoquinoline-3-carboxylic acid ethyl ester: To a stirred solution of N-nitro-2-/l-arginy1/-1,2,3,420 tetrahydroisoquinoline-3-carboxylic acid ethyl ester hydrochloride in 20 ml of water and 20 ml of dioxane were added in turn 2.5 g of sodium bicarbonate, and 7-methyl-2naphthalenesulfonyl chloride in 30 ml of dioxane 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 40 ml of chloroform, and washed 64. 44300 with 10 ml of IN hydrochloric acid solution and 20 ml of water.

The chloroform 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 an 87 percent yield of N^-nitro-2-/5f2-(7-methyl-2-naphthylsulf'onyl)-Ii10 arginyl/-l,2,3,4-tetrahydroisoquinoline~3-carboxyliG acid ethyl ester in the form of an amorphous solid.

I.R. (KBr): 3,240, 1,740 1,630 cnf1 p (D) 2-/S -(7-methyl-2-naphthylsulfonyl)“L-argir.yl7-l,2,3,4“ tetrahydroisoquinoline-3-carboxylic acid ethyl ester: A To a solution ef N -nitro-2-/5(2-(7“methyl-2-naphthylsuli‘onyl)I-arginyl7-l,2,3,4-tetrahydroisoquinoline~3-carboxylic acid ethyl ester in 50 ml of ethanol and 0.5 ml of acetic acid was added 0.5 g of palladium-black and then the mixture was shaken in a hydrogen atmosphere for 100 hours at room temperature. At the end of this period, the ethanol solution was filtered to remove the catalyst and evaporated to give an oily product. Reprecipitation with ethanol-ethyl ether gave a 91# yield of 2-/5(2-(7-methyl-2-naphthylsuli'onyl)-I~ arginyl7-l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid ethyl ester.

(B) 2-/S2-(7-methyl-2-naphthylsulfonyl)-L-arginy 3/-1,2,3,4tetrahydroisoquinoline-3-carboxylic acid: A solution of 2-/5( -(7-methyl-2-naphthylsulfonyl)-l-arginyl/l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid ethyl ester 65. in 5 “I of ethanol and 7 ml of 1IT sodium hydroxide solution was stirred for 30 hours at room temperature. At the end of this period, the solution was concentrated to 5 ml, chromatographed on 80 ml of Daiaion SK 102 ion exchange resin (200 - 300 mesh, H+ form manufactured hy Mitsubishi Chemical Industries Limited) packed in water, washed with water, and eluted with 3/» ammonium hydroxide solution. The fraction eluted from 3$ ammonium hydroxide solution was evaporated to dryness, and the residue was purified by reprecipitation with ethanol-ethyl ether to give a 72 percent yield of 2-^if2-(7-methyl-2-naphthylsulfonyl)-L-arginyl7l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid as an amorphous solid.

The following compounds are prepared in a similar manner: 2-{N2-(7~methyl-2-naphthylsulfonyl)-L-arginyl) isoindolino-1-carboxylic acid - (Ν' -(6,7 -di me thyl -2 -naph thyl s ul fonyl) -L-arginyl) isoindoline-l-carboxylic acid 2-(Ν2-( 2 -nap hthylsulfonyl)-L-arginyl)isoindolino-120 carboxylic acid 2-(N2-(5,i5,7,8-tetrahydro-2-naphthylsulfonyl)-Larginyl) -1,2,3,4-tetrahydroisoquinoline~3-carboxylic acid 2-(n2-(5,6,7,8-tetrahydro-l-naphthylsulfonyl)-L25 arginyl) lsoJntlo line-!-carboxylic acid 66. 2-^Ν'-( 5-chloro-l-naphl.hylsulfoHyl )-J,-argi]iylJ! »2,3,4-t etrahydroi Boquinolii»<'-3-cat’hoxy He aci d ·*. 1-£n -(5-liydroxy-J-napht.hylsulfonyl )-L-arginyJ~| 1,2,3,4-totraliytlroquinoline-2-carboxyl i c acid 2-^N2-(5-dimethylamino-l-naphthylsulfonyl)-L-arginyl] isoindoline-l-carboxylic acid 2-(^^-(1-naphthylsulfonyl)-L-argjnylJ-l,2,3,4tetrahydroisoquinoline-3-carboxylic acid S-W2 4 (A) N2 -(6,7-dimethyl-l-naphthylsuIfor.yl)-l-arginyl-N(2-methcxyethyl)glycine: Λ p N -nitro-N -(6,7-dimethyl-l-naphthylsulfonyl)-L- arginyl-N(2-methoxyethyl)glycine benzyl eater was prepared by the procedure described in Example 3. Γ* o To a solution of N -nitro-N -(6,7-dimethyl-l-naphthylsulfonyl)-I>-arginyl-N-(2-methoxyethyl)glycine benzyl ester in 50 ml of ethanol and 0.5 ml of acetic acid was added 0.5 g of palladium-black and then the mixture was shaken in a hydrogen atmosphere for 100 hours at room temperature. At the end of this period, the ethanol solution was filtered to remove the catalyst and evaporated to dryness. The residue was washed several times with dry ethyl ether and chromatographed on 80 ml of Daiaion C&J SK 102 ion exchange resin (200 - 300 mesh, H+ form, manufactured hy Mitsubishi Chemical Industries 67.

' Limited) packed in water, washed with water, and eluted with 3% ammonium hydroxide solution. The fraction eluted from 3% ammonium hydroxide solution was evaporated to dryness to give 3^-(6,7-dimethyl-l-napnthylsulfonyl)-L arginyl-N-(2-methoxyethyl)glycine as an amorphous solid.

I.R. (KBr): 3,350 1,640 cm-1 Analysis - Calcd. (percent): C, 54.42; H, 6.55; N, 13.80 Found (percent): 0, 54.28; H, 6.32; N, 13.59 EXAMPLE! 5 (A) N2-(6,7-dimetlioxy-2-naphthylsulfonyl)-L-arginyl-EF(2-methoxyethyl)glycyl chloride hydrochloride: A suspension of 2.00 of g of H -(6,7-dimethoxy-2-naphthyl sulfonyl)-L-arginyl-3!r-(2-methoxyethyl)glycine in 2- ml of thionyl chloride was stirred for 2 hours at room temperature. Addition of cold dry ethyl ether resulted in a precipitate which was collected by filtration and 2 washed several times with dry ethyl ether to give N (6,7-dimethoxy-2-napnthylsulfonyl)-L-arginyl-N-(220 methoxyethyl)glycyl chloride hydrochloride. 68. ρ (Β) Ν -(6,7-dime thoxy-2 -naphthyl sul fonyl )-L-arginyl -N-( 2raethoxyethyl)glycine m-tolyl ester hydrochloride: A mixture of 2.00 g of m-cresol and N -(6,7-dimethoxy2-naphthylsulfonyl)-L-arginyl-N~(2-methoxyethyl)glycyl chloride hydrochloride obtained above was heated at 90°C for 50 minutes. At the end of this period, the reaction mixture was cooled, washed several times with dry ethyl ether, and then dissolved in 10 ml of dry ethyl alcohol. Addition of cold dry ethyl ether resulted in a precipitate which was washed several times with dry ethyl ether to give 2.12 g (86 percent) of N -(6,7“dimethoxy-2-naphthylsulfonyl)-L-arginyl-N(2-methoxyethyl)glyclne m-tolyl ester hydrochloride in the form of a powder.

I.R. (KBr): 3,250, 3,100, 1,740, 1,640 cm1.

The following compounds are prepared in a similar manner 2 N -(6,7~dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2ethylthioethyl)glyoine phenyl ester ο N -(6,7-flimnthoxy-2-naphthylsulfonyl )-b-arginyl-N-(220 ethylthioetliyl)glycii.v benzyl ester N -(6,7“dimethoxy-2-naphthylsulfonyl)-L-arginyl“Nbenzy.l gly cine phonyl estor 69.

N -(6,7-dimethoxy-2-naphthylsqlfonyl)-L-arginyl-Nfurfurylglycine benzyl ester N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N— tetrahydrofurfurylglycine phenyl ester Phenyl 1- (N2-(7-methyl-2-naphthylsulfonyl)-L-arginylJ4-ethyl-2-piperidinecarboxylate Benzyl 1-]n2-( 7-me thyl-2-naphthylsulf onyl)-L-arginyl] 4-ethyl-2-piperidinecarboxylate Benzyl 1- [^-(6 -chloro-2-naphthylsulfonyl) -L-arginyl^] 4-methyl-2-pip eri dine carb oxylat e Various other N -arylsulfonyl-L-argininamides οχsalts thereof were synthesized in accordance with the procedure of the above examples, and the test results are summarized in Table 1, • 70.

V TABLE 1 (Sheet 1) Compound Sample So. H HN% | JC-N-CH,CHqCH9CHCOR h2nx 2 “ 2| H-N-S02-Ar (I) Ar R Addition moiety Ϊ OX3 -<CH2CH2SCH3 'CH2C02H - 2 AX °°H3 .CH„CH„SC9H < 2 2 2 5 xCH2CO2C(CH3)3 l/2H2S03 3 It .CH„CH„SC„H_ 2 2 2 5xCH2CO2H - 4 yYY°CH3 COoH -t> - 5 DX, COoH -o - 6 to:; COgK -0-°¾ - <· 7 OX3 C°2H O°“3 - 443G0 TABLE 1 (Sheet 1 cont.) Concentration required to prolong the coagulation · time by a factor of two (/M) Preparation process (Ex. No.) m.p. (°C) Elementary analysis Upper: Calculated ($ Lower: Found (%) I.R. (KBr) (cm1) C H N 1 1 . ir 50.25 50.45 5.95 6.01 13.32 13.15 3,350 1,620 1,380 1,150 1 tt 50.43 50.57 6.65 6.58 ΙΟ.5Ο 10.71 3,350 1,745 1,650 1,360 5 1 171-2 50.60 50.51 6.19 6.30 12.29 12 .40 3,400 1,635 1,260 1,160 5 2 powder 53.82 53.66 6.21 5.96 13.08 12.81 3,350 1,625 1,155 3 2 powder 54.64 56.88 6.18 6.31 13.85 13.83 3,200 (broad) 1,620 1,150 0.4 2 t! 54.63 54.50 6.42 6,09 12.74 12.81 3,370 1,625 1,158 0.15 2 powder 55.47 55.49 6.4o 6.33 13.98 13.51 3,250 (broad) 1,625 TABLE 1 (Sheet 2) Sample No. Compound HN% ? C-N-CILCH„CH„CHCOR (l) h2n' 1 H-N-SOg-Ar Ar R Addition moiety 8 och3 co2h -nQ-CH, • 9 PX3 OCH-} -(/3 - 10 θ02”5 oc2H5 co2h . ->0-CH3 - 110CH3 OCH3 co2ii - 12 OX”3 C02H - 13 ^Y^-och3 co2h -N^-CH2CH2CH3 - 14 . tl — .........................——............. co2h -0-CH(CH3)2 - 4436° TABLE 1 (Sheet 2 cont.) Concentration requi rod to prolong tho coagulation time by a factor of two M) Preparation process (Ex. No.) m.p . (°C) Elementary analysis Upper: Calculated ($ Lower: Found ($ I.R. (KBr) (cm-1) C H N 2 powder 55.47 55.31 6.40 6.68 13.48 13.21 3,350 1,620 1,150 0.35 2 powder 54.63 54.55 6.42 6.42 12.74 12.58 3,350 (broad) 1,620 1,150 2 powder 56.13 56.11 6.80 6.85 12.12 11.95 3,300 (broad) 1,610 1,255 2 powder 55.40 55.71 6.62 6.48 12.43 12.53 3,360 1,620 1,150 2 powder 56.26 56.41 6.61 6.48 13.12 13.27 3,360 1,620 1,158 0.5 2 If 56.13 56.ll 6.80 6.81 12.12 II.96 3,400 1,620 • 2 It 56.13 56.21 6.80 6'.81 12.12 12.03 3,400 1,620 1,150 TABLE 1 (Sheet 3) Sample No. Compound HN h2nx H 1 :-n-ch2ch2ch2chcor H-N-S02-Ar (I) Ar R Addition moiety 15 'ifV<:^0CH3 och3 co2h -/ CH3 - 16 OX”3 CHg CO„H -Ό - 17 °°η3 Ό - 18 ΌΟ _/5O9H -o - 19 TO05 ''•CHgCOgH 20 II ^CH2C02H - 443®° TABLE 1 (Sheet 3 cont,) Concentration required to prolong the coagulation time by a factor of the (/1 M) Preparation, process (Ex. Xo.) m.p . (PO Elementary analysis Upper: Calculated I.R. (KBr) (cm-1) Lower: Found <$ C H N 2 II 54.63 54.54 6.42 6.40 12 .74 12.68 3,350 1,620 1,150 2 II 54.63 54.59 6.42 6.38 12.74 12.68 3,250 1,620 l,l60 2 powder 53.82 53.68 6.21 6.08 13.08 12.85 3,370 1,635 1,255 1,155 2 II 54.64 54.58 6.18 6.09 13.85 13.93 3,370 l,64o 1,260 1,155 0.25 1 11 55.47 55.75 6.40 6.19 13.48 13.26 3,350 (broad) 1,630 1,380 0.2 5 It 55.05 55.28 7.12 7.00 13.38 13.12 3,200 (broad) 1,635 1,380 TABLE 1 (Sheet 4) Sample No. Compound H | ;C-N-CH.CH„CH„CH30R (l) H„NX 2 2 2, H-N-SOg-Ar Ar R Addition moiety 21 OTS ^CH -Q •-N xCH2C02E - 22 tf _n/CH2-U XCH2CO2C(CII3)3 - 23 ft -n' * ^CHgCOgH - 24 tt _n^ot2-U * xch2co2c(ch3)3 25 0? n(ch3)2 ch2^ -Ν κ CW CH3C02H 26 0? Clw/CH2-Q -Nv nCH2C02K - 27 to i—1 /CH < J -N. 4 0CW - TABLE 1 (Sheet 4 cont.) Concentration required to prolong the coagulation time by a factor or two 0.M) Preparation process' (Ex. No.) m.p . (°C) Elementary analysis Upper: Calculated ($ Lower: Found $ I.R. (KBr) (cm“A) C H JJ 0.2 1 powder 54.22 53-98 5.50 5*55 13.18 13.24 3,320 (broad) 1,630 1,380 1 (1 57 -22 57.23 • 6.35 6.36 11.92 12.08 3,400 (broad) 1,740 1,620 0.15 1 tt 1 53.82 53.78 6.21 6.19 13.08 12.86 3,360 (broad) .1,625 1,380 1 tt 56.83 •56.95 6.98 6.83 11.84 11.98 3,400 (broad) 1,735 1,630 5 tt 53.28 53.13 6.02 6.82 13.81 13.71 3,320 (broad) 1,630 1,140 5 tt 51.15 50.86 5.60 5.66 12.97 12.87 3,320 (broad) 1,630 1,380 . 5 tt 54.64 53.36 6.18 6.00 13.85 13.58 3,350 (broad) 1,640 1,390 TABLE 1 (Sheet 5) Sample No. Compound H | (I) h2nx C-N-CH2CH2CH2CHC0R Η-Ν-302-Αγ Ar i R Addition moiety 28 OX;xCH2C02H - 29 00 _n/CH2U XCH2CO2H - 30 ZCH2ζΡ -n; zxch2co2h - 31 wxch -ζ?1 -νΓ XCH2CO2C(CH3)3 - 32 TO03 C0_H -£>“3 - 33 n co2h •O^S(CH3}2 - TABLE 1 (Sheet 5 cont.) Concentration required to prolong the coagulation time by a factoi of two Qvm) Preparation process (Ex. No.) m»p« (°C) Elementary analysis Upper: Calculated Lower: Pound (£) I.R. (KBr) (cm'1) C H N 5 powder 56.27 55.9S 6.61 6.78 13.12 13.24 3,350 (broad) 1,630 1,380 1,140 5 ft 54.21 54.36 6.92 6.93 13.74 13.76 3,300 (broad) 1,625 1,380 l,l60 1, 2 II 53.08 52.86 6.24 6.33 12.38 12.41 3,300 (broad) 1,640 1,160 1 II 56.02 55.83 6.97 6.88 11.27 11.28 3,400 (broad) 1,745 1,620 0.2 3 tl 57.23 56.89 6.61 6.50 13.91 13.70 3,390 (broad) 1,625 0.1 2 11 58.73 58.52 7.01 6.77 13.17 13.00 3,380 (broad) 1,620 TABLE 1 (Sheet 6) Sample No. h2nx Compound H 1 ;-n-ch2ch2ch2ce:or H-N-£ 0,,-Ar (I) * Ar R Addition moiety 34 co.. C02H -n^-ch(ch3)2 - 35 ¢0 ' co2h TO - 36 co COgH ^Qch(ch3)2 - 37 00 βίί3ΝχΌΗ3 co2h -t> M 38 CO COgH .Q^Hj - 39 co„ co2h -^2)-ch(ch3)2 - 40r TO00’ co2h 41 It co2h -0° - 443θθ TABLE 1 (Sheet 6 cont.) Concentration required tc prolong the coagulation time by a factor of two (AM> ✓ Preparation process (Ex. No.) m.p o (°C) Elementary analysis Upper: Calculated ($ Lower: Pound $ I.R.(KBr) (cm-1) C H N 3 ft 58.73 58.81 7.02 7.03 13.17 13.17 3,300 (broad) 1,615 1,380 1 3 If 56,42 56.38 6.38 6..52 14.31 14.53 3,350 (broad) 1,620 1,160 0.5 3 tt 58.00 57.83 6,82 6.77 13.53 13.63 3,350 (broad) 1,620 1,160 0.35 3 powder 55.58 55.62 6.61 6.81 16.21 16.03 3,350 (broad) 1,620 1,140 3 tf 55-96 56.12 7.15 7.28 14.19 14.07 3,350 (broad) 1,620 1,150 3 tt 5^.38 54 .08 6.21 5.91 12.69 •12.39 3,300 (broad) 1,625 , 2 tt 50.46 50.61 5.58 5.63 13.38 13.40 3.380 1,620 1.380 1,155 2 3 tt 52.06 52.31 5.76 5.81 13.80 13.51 3,320 1,620 1,390 1,155 TABLE 1 (Sheet 7)- 443G0 Sample No. HN^ H2NX Compound H 1 C-N-CH2CH2CH2CEC or H-N-SOg-Ar (I) Ar R Addition moiety 42 DOT COgH -h» v_/ - 43 ΟΟ,,Η Ό - 44 OT3 COgH - 45 OX33 ,,„„co - 46 tt Sco - 47 tt <0 co2h - 48 tt CH2CH2C00C2H5 CHgCOOH - 443 6 0 TABLE 1 (Sheet 7 cont.) C on een t ra t i ori required to prolong the ' coagulation time by a factor of two Pi' epara tion proCi^a (Ex. No.) m.p. (°C) Elementary analysis Upper: Gal dilated $ Lower: Pound I.R. (KBr) (cm-1) C H N - 2 powder 48.96 4-9.13 5.42 5.38 12.98 12.75 3,350 1,620 1,380 1,150 5 2 H 51.38. 51.45 5.81 5.86 13.03 13.12 3,350 1,630 1,255 1,150 2 tr - ./- 49.50 49 »31 5,34 5.40 13.75 13.68 3,350 3,200 1,622 2 V 58,27 58.45 5»9O 6.03 II.72 11.53 3,350 1,740 1,640 1,260 1,160 2 2 tt 57.62“ 57.68 5.70 5-55 12.00 11.73 3,300 (broad) 1,620 1,250 1,150 1.5 3 tt .. 56,93 57.12 5.49 5.43 12.30 12.14 3,360 1,625 1,200 1,150 6.5. . 1 - * If 54.63 54.28 6.42 6.31 12.74 12.53 3,350(broad) 1,740 TABLE 1 (Sheet 8) Compound Sample No. HN^. η2ν/£ H 1 j-n-ch2ch2ch2ce;or H-N-=02-Ar (I) Ar R Addition moiety 49 yYYoch3 ’ XJXXoCH3 /CH2-Q _N \=y ^chch2cooh COONH/j 50 n CHCH„C00C.H. 1 2 2 5 C00CnHK 5 l/2H2S03 51 OX3 COONa 0 COONa - 52 γ=γγ00Η3 _n/CH2CH20CH3 xch9cqqch9-^\ - 53 1»xch9ch5och. CH-COO-Ll^ CH3 HCl 54 ttxCHoCHo0CH. * * j \h2coq-^2^ HCl 443 6 0 > TABLE 1 (Sheet 8 cont.) Concentration required to prolong the coagulation time by a factor of two (A>0 . Preparation process (Ex. No.) m.p. (°C) Elementary analysis Upper: Calculated (£) Lower: Pound $ - I.R. (KBr) (cm-1) C H. N 2. powder 53.86 54.16 5.92 5.62 13.00 12.70 3,100 (broad) 1,620 2 IJ 54.53 54.23 6.10 5.80 9.64 9.34 1,720 ' 1,630 (broad) 2 - Π 48.55 48.31 4.93 4.64 11.80 11.53 3,300 (broad) 1,620 - 2 tl 57.22 56.98 6.24 6.18 11.12 11.31 3,300 3,150 1,740 1,650 20 6 II 54.09. 53.83 6.05 5.97 10.51 10.36 3,250 3,100 1,740 1,640 30 6 »F 55-53 55.37 6.12 6.01 10.12 10.01 3,350 3,150 1,740 1,650 χ44360 TABLE 1 (Sheet 9) Sample No. Compound HN^ f j-n-ch2ch2ch2ce:or H-N-SOg-Ar (I) Ar R Addition moiety 55 ΟΧΗ’ -N SO dooH - 56 tt •0 COOH - 57 ΖΖΥ °°η3 ^Λ<Ζοοη3 COOH - 58 tt COOH .<^-0 xch_coonh7/ A 4 59 nXCH -Nxchch2-£3 COOH - 60 t0”! ^CH3 XCHCH2-^^-OCH3 COOH - 43 60 TABLE 1 (Sheet 9 cont.) Concentration required to prolong the coagulation time by a Preparation process (Ex. No.) m.p · (°C) Elementary analysis Upper: Calculated ($ I.R. (KBr) (cm-1) Lower: Found factor of (,41 M) two C H N 4.5 2 . powder 48.96 49.13 5.42 5.36 12.98 13.01 3,350 1,620 1,380 2.5 2 It 54.64 54.63 6.42 6.56 12 .74 13,01 3,360 2,940 1,620 1,380 12 2 II 59.89 59.65 4.52 4.63 11,64 11,81 3,360 1,620 1,255 1,150 ? 2 « 53,85 53.61 5.93 5.76 13.00 12.84 3,320 1,610 2 2 II 57.42 57.37 6.C2 5.86 H.96 11,74 3,300 (broad) 1,600 2 II 57.41 57.33 6.03 5.94 11,96 11.73 3,300 1,610 V» · 443G0 TABLE 1 (Sheet 10) Sample No. Compound h2nx H 1 C-N-CHgCHgCHgCHCOR H-N-SOg-Ar (I) Ar R Addition moiety 61 ΌΤ -CHa COONa - 62 OX; OH 1 -CH-CH-CH-CH- CHgCOOH - 63 n -CH_CH„CH?CH„ XCHCH-COOH 1 2 COONH4 - 64 ttXCH2CH2CH2CH3N'xCHCH2C00C2H5 ioOCgHj l/2H2S03 65 -CHa ·0Ηο-^\ CHgCOOH - 66 %A^0CH3 (») COOH 2H20 67 tt -0 w COOH 1/20,0 . 443θθ TABLE 1 (Sheet 10 cont.) Concentration required to prolong the coagulation time by a factor of two (/•M) Preparation process .(Ex. No .) m.p. (°c) Elementary analysis Upper: Calculated ($ Lower: Pound . I.R, (KBr) (cm1) C H N 2 .5 2 powder 53.98 53.74 5.38 5.33 11.66 11.74 3,350 1,630 2 11 52.07 51.95 6.37 6,27 12.65 12.84 3,350 (broad) 1,620 2 tt 50.97 6.58 13.72 3,200 (broad) 50.67 6.61 13.39 1,610 (broad) 2 ft 52.01 51.77 6.69 6.50 10.11 10.00 1,725 1,620 1 tt 52.15 52.03 6.88 6.73 14.48 14.68 3,355 1,630 1,380 1,305 2 2 195-198 50.42 50.48 6.54 6.16 12.25 12.31 3,320 1,620 15 . 2 229-233 52.94 -52.73 6.30 6.15 12.87 12.93 3,350 1,620 --90 ν· 443G0 TABLE 1 (Sheet 11) Sample Mo. HN^ Compound H 1 3-N-CHaCH2CH2CEC0R H-N-SOg-Ar (1) Ar R Addition ' moiety 66 OT00’ ' ^CH2CH2SOCH- -X. * z JXCHgCOOH 4* 69 .ox: ,CH_CH„03 -n5 4 * 'CHgCOOH - 70 <°»O 'CHgCOOH - 71 ..OCH, -£^-°CH3 ^O^HgOC^ XCHgCOOH - 72 , ,-OCH-^2^-OCHq ^OCHj ch2ch2ch2ch, XCHgCHgCOOH • 73 H .CH2CH2OCH, xCHgCOOH - 4 3 60 TABLE 1 (Sheet’ll cont.) Concentration required to prolong the coagulation time by a factor of two //um) Preparation process (Ex. No.) m.p (°C) Elementary analysis Upper: Calculated Lower: Found (<£) I.R. (KBr) (cm-·1) C H N 6.5 1 powder 48.78 48.54 5-77 5»76 12.93 13.15 3,320 1,620 1,390 1 It 50.27 50.11 5.95 5.87 13.33 13.34 3,390 1,630 1,260 1,160 - 5 tt 53.76 53.66 5.95 5-83 14.25 14.19 3,400 3,200 1,635 | 5 powder 46.62 46.53 6.38 6.21 14.31 14.43 3,350 3,150 1,630 - 5 49.71 49.S4 7.02 7.26 13.18 13.36 3,250 (broad) 3,150 1,630 5 *» 46.24 46.31 6.40 6.53 13.48 13.41 3,320 3,150 1,630 TABLE 1 (Sheet 12) Sample No. Compound HN^ H2n/ H I C-N-CHjjCHgCHgCHCOR H-N-SOg-Ar (I)' Ar R Addition moiety 74 O3 ^CH,CH9CH5CH„ -N' 2 2 > XCHgCOOH HCl 75 z-<C1 -0“ Cl /CHgCHgCHgCHj “ ^0Η2002Η 76 £3C2h5 COgH - 77 .CO2H - 78 •o-xCH2CH2CH2CH3 ^CHjjCOjjH - 79 ΖΗΓ003 •Q-ooij “och3 Ov, COgH - 4 3 6 0 TABLE 1 (Sheet 12 cont.) C on c en t ra ti on required to prolong tho coagul tion time by a factor of two (/ M) Preparation process (Ex. No.) a.p. A°C) Elementary analysis Upper: Calculated Lower: Pound ($ I.R, (KBr) (em1) C H N 1 »1 4“ -74 47.53 6.75 6.51 14 .65 14.41 3,340 3,180 1,640 5 powder 40.71 4o.6o 4.95 4.78 13.19 13.03 3,360 3,150 1,620 3 powder 55.59 55.54 6.29 6.14 12.47 12.35 3,350 3,150 1,625 1 3 II 57.43 57.26 6.13 6.04 12.88 12.71 3,350 3,130 1,615 i 5 II 46 .80 46.61 6.1 I. 6.05 15.16 15.23 3.375 3,150 1 630 3 It 50.82 50.71 6.86 6.69 12.89 12.57 3.360 3,120 1,629 4430 . APPENDIX There are now described in greater detail preparation of materials of the kind, used in the foregoing examples.

PREPARATION A ··’ - ’/« Arylsulfonyl chlorides (A) Sodium 6,7-dimethoxy-2-naphthalenesulfonate To a well stirred solution of 70,8 g of sodium 6,7“ dihydroxy-2-naphthalenesulfonate and 77.2 g of sodium hydroxide in 450 ml of water was added dropwise 230 ml of dimethyl sulfate at 60°Q over a period of one hour, during which time the product precipitated. To this reaction mixture was added in portions 38.8 g of sodium hydroxide, and stirring was continued for one hour.

After one hour at room temperature, the precipitate was filtered, washed with ethanol and dried to give 50 g of ' sodium 6,7-dimethoxy-£-naphthnlenesulfonate.

(B) 6,7-dimethoxy-2maphthalenesulfonyl chloride To a stirred suspension of 50 g of finely divided sodium 6,7-dimethoxy-2-naphthalenesulfonate in 100 ml of dimethyl formamide was added dropwise 62.2 ml of thionyl chloride at room temperature. After 30-minutes, the reaction ' mixture was poured into H of ice water, and the precipitate filtorod and then dissolved into 250 mi ot* benzene.

. The benzene solution was repeatedly washed with water and dried over anhydrous sodium sulfate. The solvent was 25 evaporatod to dryness in vacuo, and the residue was 43°° recrystallized from benzene-n-hexane (l : l) to give 32 g of 6,7“dimethoxy-2-naphthalenesulfonyl chloride, M.P. 127.5 - 129.5°C Analysis - Calcd, for C^gH^^O^SCl (porcent): C, 5θ·26; H, 3.87; Cl, 12.37 Found (percent): C, 50.45; II, 4.00; Cl, 12.33 Tho following arylsulfonyl chlorides not previously reported in the chemical literature were synthesized by the aforementioned procedure which is essentially that as described in Ε. H. Rodd, Chemistry of Cai'bon Compounds Elsevier Publishing Company, 1954, Vol HE, P. 441-469· No. Arylsulfonyl Chloride M.P. (°C) 101025tx OCgH,. r* oc2h5 118 - 119.5 201025X 0CII3 0CH3 136.5 - 138.5 3 137 - 139 PREPARATION B Amino acid derivatives (A) N-butylglycine tert-butyl ester To 36.5 g of butylamine was added with stirring 15·Ο5 β ot tert-butyl chloroacetate over a period of 30 minutes, while maintaining the temperature at 3O-7O°C. The reaction mixture was held at 70°C for an additional one hour. At the end of this period, the excess butyl amino was evaporated in vacuo, and the residue was taken up in kO ml of 2N NaOH solution and 50 ml of benzene, transferred into a separatory funnel and well shaken. The benzene solution was separated, washed with water, dried over anhydrous sodium sulfate and filtered. After evaporation of benzene, the residue was distilled under reduced pressure to give 17.Ο g (90.9 percent) of N-butylglyeine· tert-butyl ester, B.P. 76°0/k mmHg.

The following amino acid tert-butyl esters not previously reported in the chemical literature were synthoaized by the uforementionod procedure whi.ch is essentially that as taught by A. J. Speziale et al., J. Org. Chem. 25 731 (I960).

No Amino Acid Derivative B.P. 1XCH2CO2-t-C2)H9 95°C/20 mmHg 2 -CH-CH(OH-)- CH2C02‘t’C4H9 65°O/ 5 mmHg 3 (ch2)4ch HN^ * - J \cH2C02-t-C4H9 89- 90°C/2.5 mmHg 4 (CH ) CH HNf J \cH2CO2-t-G4H9 83- 5°C/1.5 mmHg 5 -(0¾) CHΗΝς 2 1 J ^CH2CO2-t-C2tH9 125-13O°C/4 mmHg 6 -CH-CH-OCHHN< 2 -* XCH2CO2-t-C2tH9 61- 2°C/2 mniHg 7 -CH-CH-OCHHN< J ^CH2CH2C02-t-C4H9 94°C/ 3 mmHg 8 >CH-CH„0CHHNf j \cH2CH2CH2C02-t-C2|H9 60- 3°C/3 mmHg 9 -OH-CH^CH-OCIIHN< * ~ d \CH2C02-t-C4H9 95- 7°C/5 mmHg 10 -CK9CU20Cn2ClI3 ΗΝ'ζ - ·· - . ^CH2CU2CO2-t-O2(H9 102°C/Jl mmHg NO. Amino Acid Derivative B.P. 11 CH2CO2-t-C4H9 166°C/1O mmHg 12 ,CH„CH,.3CH„CII„ HN1. X 4 J ‘ XCH2C02-t-C4H9 106- 9°C/1.5 mmHg 13xch2ch2sch, ηνΓ jXCH2C02-t-C4H9 97°C/ 2.5 mmHg 14 Λ hn' ^CH2CH2CH2C02-t-C4H9 101°C/ 5 mmHg 15 HN^ XCH2CO2-t-C/(H9 101°C/ 5 mmHg 16 <0 'CHgCHgCOg-t-C^Hj 105°C/ 4 mmHg 17 xO HN^f ^CHgCOg-t-Cj/Iy 129-13O°C/8' mmHg 18 /CH2O HN< ^CH2CO2-t-C;|H9 145°C/15 mmHg 19 ^CHjjCHgCOg-t-C^ 156°c/10 mmHg No. Amino Acid Derivative B.P. 20 .(CH ) CH hn< j ^CIICO2-t-C4H9 ch3 93°C/26 mmHg 21 ^(CHkCH HNf JXCHCO2-t-C4H9 ’ ch3 110°C/27 mmHg 22x(ch2)4ch3 Ηΐίζ' 4 -* XCHC02-t-C4H9 ch3. 124°C/26 mmHg 23 .CHpCH-OCHq HN. JXCHCO2-t-C4H9 ch3 88- 9θ°C/6 mmHg 24xch?-Q Ht< ~ XCHCO2-t~C4H9 ch3 116- 8°C/2 mmHg 25XCHC0„-t-C.Ho I 2 4 9 cn3 167°C/16 mmHg 26 ΗΝχΌ XCHC02-t-C4H9 gh3 125°C/16 mmHg )00 NO. Amino Acid Derivative B.P. 27 <^-o CHCOg-t-C^ ch3 141°C/15 mmHg 28 CHg ^CH2CHaC02Lt-04H9 89°C/ 3 mmHg 29XCH2CO2-tH54H9 111°C/ 1 mmHg 30 ''ΟΗ^Ο,-Ι^ 91- 2°C/1 mmHg 31 ^0^¾0¾¾¾ SCH2CO2-t-C4H9 115°C/ 2 mmHg 32 OH m/CH2ch2chch3 HEK xCH2CO2-t-C4H9 82- 84°C/2 mmHg 33 ^CHjjCHgSOCHj “SHgCOg-t^ 150°C/ 0.5 maHg 34 ^/0¾0¾011XCH2CO2-t-C4H9 ' 95- 6°C/2 mmHg 35 ^CH„CsCH BNf ' xCH2CO2-t-C4H9 ιοί i V. .-. (β) Ν-(2-methoxyethyl)glycine ethyl ester To a stirred solution of I65.2 g of 2-methoxyethyl amine and 202.4 g of triethylamine in 1 ί of benzene was added ΛΤ dropwise a solution of 334.0 g of ethyl bromoacetate in 5 200 ml of benzene in one hour at room temperature. At the end of this period, the mixture was heated at reflux for 2 hours to complete the reaction. Upon chilling, the triethylamine hydrobromide was removed by filtration and washed with benzene. After removal of the solvent, the product was distilled in vacuo to yield 242.8 g (75-3 percent) of N-(2-methoxyethylJglycine ethyl ester, B.P. 73-5°C/4 mmHg.

The following amino acid ethyl esters not previously reported in the chemical literature were synthesized by the aforementioned procedure which is essentially that as taught by A. J. Speziale et al., J. Org. Chem., 25 731 (i960). , No, Amino Acid Ethyl Ester M.P, i°C) or B.P. (°C/mmHg) 1 (CH ) CH ch2co2c2h5 57- 8°C/3 mmHg 2inJ/CIl2CH20CH3 XcH2CH2G02C2H5 63- 4°C/3 mmHg ί 02 No. Amino Acid Ethyl Eater* M.P. (°C) or B.P. (°C/mmIlg) 3XCH -[^J HNf CH2C02C2H5 91- 3°C/2 mnHg 4ΧΟΗ0Η2ΟΟ2Ο2Η5 · HCl c°2c2h5 101-2°C 5 co2c2H5hn/ch2ch2ch2ch3Xch2co2c2h5 113- 6°C/3 mnHg 6 CO2C2H5 \ch2co2c2H5 116- 7°C/1 mmHg 7 00113 XCH-CHCHHN< J \ch2co2c2h5 78-80°C/2 mmHg 8 ^CHC02C2H, . HCl iH2C02C2«5 63-4°C (0) N-(2-aethoxyethyl)glycine benzyl ester P-tolueneaulfonate To a solution of 55.8 g of N-(2-methoxyethyl)glycine tert-butyl ester in 200 ml of benzene was added 63.8 g of benzyl alcohol and 72.9 g of p-toluenesulfonie acid monohydrate· The mixture was heated at reflux for 10 103 V 443θ° hours with the continuous removal of water through a -¼ Dean-Stark water trap. At the end Of this period, the solution was concentrated in vacuo, and to the residue was added 300 ml of dry ethyl ether. After 2 hours at room temperature, the formed precipitate was filtered, washed with dry ethyl ether and then recrystallized from ethyl acetate to yield 99.2 g (85 percent) of N-(2methoxyethyl)glycine benzyl ester p-toluenesulfonate, , I M.P. 95-6°C.

The following amino acid benzyl ester p-toluenesulfonate not previously’reported in the chemical literature were synthesized by tbe aforementioned procedure.

No. Amino Acid Benzyl Ester p-TolueneSulfonate M.P. (°C) 1 (CH2) CH„ όη2οο2οη2-0 97 “ 9 . 2 ^(ο«,)3οη, οιι2Μ2οιι2-θ 122 - 4 3 CII2CH(Cn3)2Χ°Η20020Η2-θ 94 - 5 4 (CH ) OIL HN\ x'CH2CH2C02CH2-/_V 66 - 8 104 V No. Amino Acid Benzyl Ester p-Toluenesulfonate M.P. (°C) 5 ,μΧ<™2>Λ xcb2oo2ch2^ 101 - 2 6m/0”rO xoh2oo2oh2-0 l4o - 3 7XraW0S0H2-O 154 - 6 8 ZCH2CH2~O ^ch2co2ch2-Q 133 - 5 9 hnCH2C02CH2-O 133 - 5 10xch2co2ch2-Q 133 - 8 1.1<(ο»2)2βη ™002°2-Ο C1I3 103 - 6 12 ^(Cll)CU . >IN\ xchco2ch2-Q CH3 92-4 105 44300 No. Amino Acid Benzyl Ester p-Toluenesulfonate M.P. (°C) 13 /CH2O XfHC02CH2-Q> CH3 123 - 6 .14xcs2ch2-Q X™co2ch2-Q. CH3 119 - 123 15 /CH2-Q Λ-u \ch2co2ch2-Q 130 - 1 PREPARATION C 2-Piperidinecarboxylic acids and esters thereof (A) 4-methyl-2-piperidinecarbonitrile 5 To 500 g of 10# sodium hypochlorite solution, cooled in an ice bath, there was added dropwise a solution of 33.6 g (0.21 mole) of 4-methylpiperidine aeetate in 10 ml of water over a period of 1 hour. At the end of this period, the reaction product was extracted twice with 500 ml of ethyl ether and dried over anhydrous sodium sulfate. After evaporation of ethyl ether, the 106 443G0 • ,..·..,'·, residue was added dropwise to a solution of 11.8 g (0.21 mole) of potassium hydroxide in hDQmls -of 96» ethanol uxder reflux.

. Refluxing was continued for an additional 10 minutes.

Sthanol was evaporated, and the residue was dissolved · into 50 ml of 2N sodium hydroxide solution and then. extracted with ether. · The ether layer was dried over anhydrous sodium sulfate and then ether evaporated. The residue was added to an· ice-cooled solution of 27 g (l mole) of hydrogen cyanide and 25 ml of concentrated hydrochloric acid in 300 ml of water. The solution was stirred at a teiqperature of 10 to 20°C for k hours and thereafter made basic by the addition of solid sodium hydroxide. The reaction product • was extracted with ether, dried over anhydrous sodium sulfate and then distilled under reduced pressure to give g (6656) of 4-methyl-2-piperidinecarbonitrile,. B.P· 96-97oC/10 mmHg.

The following 2-piperidinecarbonitriles not previously reported in the chemical literature were synthesized, by * the aforementioned procedure which is essentially that as taught by Grundon et al., J. Chem* Soc·, 19$3, 3898, Grundon et al., J. Chem. Soo., 1964. 2448, R. Bonftett et al., J. Chem. Soc., 14W. 2092 and H. Bohrae ct al., Ber., 1813 (aw). 107. 44300 I Η No. r7 B.P. 1 4-CiI2CH3 105-106°C/9 mmHg. 2 4-ch2ch2ch3 ll6°C/8 mmHg. 3XCH 4-ch/ jXCH3 104°C/4 mmHg. 4 2-CH3 (B) 4-Methyl-2-piperidinecarboxylic acid hydrochloride A solution of 16 g of 4-methyl-2-piperidinecarbonitrile in 250 ml of 6n hydrochloric acid was refluxed for 6 . hours. After evaporation of the solvent, the residue was recrystallized from water to give 13 g of 4-methyl-2piperidinecarboxylic acid hydrochloride.

(C) Ethyl 4-methyl-2-piperidinecarboxylate Xq A solution of 13 g (0,072 mole) of 4-methyl-2-piperidinecarboxylic acid hydrochloride and 50 ml of thionyl chloride in 300 ml of ethanol was refluxed for 4 hours. At the end of this period, the solvent was evaporated under reduced pressure, and the. residue was extracted with a solution of chlo’roform and saturated potassium carbonate solution. 108.

V The chloroform layer was dried over anhydrous sodium sulfate and then chloroform was evaporated. Distillation of the residue gave 7 .4 g (60$) of ethyl 4-methyl-2piporidineoarboxylato, B.P. 76~77°C/3 mmHg, (D) Benzyl 4-methyl-2-piperidinecarboxylate p-toluenesulfonate A solution of 20 g (0,112 mole) of 4-methyl-2-piperidine* carboxylic acid hydrochloride, 24 g (0.224 mole) of benzyl alcohol and 25,6 g (0,134 mole) of p-toluenesulfonic acid monohydrate in 100 ml of benzene was refluxed for 5 hours with the continuous removal of water through a Dean-Stark water trap. At the end of this period, the solvent was distilled off, and the residue was washed with ether-nhoxane and recrystallized to give 10 g (22$) of benzyl 4-methyl-2-piperidinocarboxylate p-toluenesulfonate, M.P. 16O-163°C.

The following 2-piperidinecarboxylates not previously reported in the chemical literature were synthesized by the aforementioned procedure. 109 44300 Or”7 H y No. *7 Addition moiety B.P. 1 4-ch2ch3 - - 82-4°c/3.5 mmHg 2 4-CH2CH2CH3 HCl 3 /CH4-CIlf J 'ch3 - 95-6°C/2 mmHg 4 2-CH3 - 57°C/3 mmHg Morpholine-3-earboxylie acid hydrochloride was prepared by the procedure described above, and has a melting point of 200-2°C.

The following starting materials for the preparation of p the N -arylsulfonyl-L-argininamides were prepared by the procedures described in the following literatures : Compound Literature C02H o J. Org. Chem., 29 2203 (1964) co2h HN^%° J. Org. Chem., 2£ 2203 (1964) 110 Compound Literature co2h J. Am. Chem. Soc., 22 200 (1937) CO,H 0 Zh. Obshch. Khim., 2 2245 (1973). CX, Ber., 44 2034 (19H) Q-co/” °r(L) H Ber., §2. 927 (1932) The methyl or ethyl ester of the aforementioned compounds were prepared by a conventional esterification procedure. Ethyl thiomorpholine-3-carboxylate has a boiling point of 108°C/4 mmHg.

Diethyl piperidine-2,6-dicarboxylate hydrochloride was prepared by the conventional esterification of piperidine2, 6-di carboxylic acid and has a melting point of 184-6°C . Isoindoline-l-carboxylic acid was prepared by a procedure similar to that for the preparation of isoquinoline-3carboxylic acid described in Ber., 44 2034 (1911), Ethyl isoindo.lino-l-cart)oxyl ato hydrochloride was prepared hy 43 6 0 the conventional esterification of isoindoline-1carboxylic acid and has a melting point of 139-140.5°C.' In so far as the present invention relates to a method of inhibiting the activity and suppressing the activation of thrombin in vivo, no claim is made herein to any such method when used for the prevention or cure of disease in human beings.

Furthermore no claim is imide herein to p N -arylsulfonyl-l-argininamide of the formula (I): HN.

HgN’ c - n - ch2ch2ch2chcor (I) wherein R is (1) XR1 HNSOAr (OH2)nCOOR2 wherein R^ is θ2“θ10 alkyl- G3-°10 alkenyl, C^- C10 alkynyl, G2-G10 alkoxyalkyl, C2C10 alkylthioalkyl, θ2“°10 alkylsulfinylalkyl, C^-C^q hyflroxyalkyl, C^-C^q alkoxycarbonylalkyl, alkylcarbonylalkyl, O^'^IO haloalkyl, aralkyl, Cg-C^ α-carboxyaralkyl, Cj-C^q cycloalkyl, C^-O^q cycloalkylalkyl, furfuryl, tetrahydrofurfuryl optionally substituted with one or more alkyl and/or alkoxy group, 3-furylaethyl, tetrahydro-3-furyImethyl optionally substituted with one or more alkyl and/or alkoxy group, tetrahydro2(3 or 4)-pyranylmethyl optionally substituted with one or more C^-C^ alkyl and/or alkoxy group, l,4-dioxa-2cyclohexylmethyl optionally substituted with one or more C^-Cg alkyl and/or (¾¾ alkoxy group, 2-thenyl, 112 44360 '1 3-thenyl, tetrahydro-2-thenyl optionally substituted, with one or more C^-C^ alkyl and/or alkoxy group and/or tetrahydro-3-thenyl; Rg ^-8 hydrogen, Cl“C10 alkyl, °6-C10 I aryl or C7-°12 aralkylj and n is 1, 2 or 3, ZK3 (2) - N XCH - (CHg)mC00R5 *4 wherein R^ is hydrogen, ^“^lO al^ylj alkenyl, alkynyl, 02~θ10 alkoxyall£y;i-, °2_C10 alkylthioalkyl, Og-^IO alkylsulfinylalkyl, C^-C^q hydroxyalkyl, 0^-C10 alkoxycarbonylalkyl, Cj-C^q alkylcarbonylalkyl, Cj-C·^ haloalkyl, Ογ-Ο^ aralkyl, Οθ-Ο·^ α-carboxyaralkyl, Cj-C^q cycloalkyl, G^-Ο^θ eycloalkylalkyl, furfuryl, tetrahydrofurfuryl optionally substituted with one or more 0-^-0^ alkyl and/or C^-C^ alkoxy group, 3-furylmethyl, tetrahydro-3-furylmethyl optionally substituted with one or more C^-Cg alkyl and/or Cj-Cg alkoxy group, tstrahydro-2(3 or 4)-pyranylmethyl optionally substituted with one or more 0^-65 alkyl and/or C^-Cg alkoxy group, l,4-dioxa-2-cyclohexylmethyl optionally substituted with one or more C^-C^ a^l£y1 and/or C^-C^ alkoxy group, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl optionally substituted with one or more 0^-0^ alkyl and/or C^-C^ alkoxy group, or tetrahydro-3-thenyl} R^ is C1-C10’ alkyl, phenyl optionally substituted with one or more C^-Cg and/or C^-O^ alkoxy group, °7“C12 aralkyl and/or ring substituted benzyl wherein said substituent is O^-Cg alkyl or C^-C^ alkoxyf 113 443 θθ R5 is hydrogen, G-j-C.^ alkyl, Cg-C10 aryl and/or Cy-C12 aralkyl; and m is 0, 1 or 2 wherein Rg is -COORg wherein Rg is hydrogen, a^y^-« C6“C10 aryl 01‘ C7-°i2 aralky·1·’ each Sy independently is hydrogen, 0-^-0^ alkyl, phenyl, 0^-0^ alkoxy, 02-0g alkoxycarbonyl or carboxy; p is an integer of 1 to 4; Rg ia substituted into the ring at the 2 or 3-position; and Ry is substituted into the ring at the 2, 3, 4, 5 or 6-position, (4) COORg optionally substituted with one or more C-j-Cg alkyl and/or °1”θ5 alkoxy group, wherein Rg is hydrogen, C^-C^q alkyl, θ6“°ιο aryl or Cy-C12 aralkyl; and r is an integer of 1 to 4, wherein R10 is hydrogen, C-j-C-^q alkyl, Cg-C10 aryl or 8y-C12 aralkyl; Z is thiCOr' sulfinyl? and q is 0 or 1, or 114 ( (6) C0°Rii \(ch2) wherein R^ is hydrogen, Ο^-Ο^θ alkyl, Cg-C^O aryl or °7”°12 5 aralkyl; i ie 0, 1 or 2} j is 0, 1 or 2; and the sum of i+j ie 1 or 2; and Ar is a phenyl group substituted with one or more alkyl or alkoxy substituents, the number of the carbon atoms of each substituent which is attached to the phenyl group being 3 to 7 and the said phenyl group being optionally substituted further with one or more methyl, ethyl, methoxy, ethoxy, hydroxyl and/or halo substituents.

Claims (15)

CLAIMS (SUBJECT TO THE FOREGOING DISCLAIMER): C-N-CH.CH.CH-CHCOR h2n H (I) HNS0o I 2 Ar or a pharmaceutically acceptable salt thereof, wherein R is (CH2)nC0°R2 wherein R^ is C2_c|o alkyl, C3_c^q alkenyl, Cg-C·^ alkynyl, C2~C10 alkoxyalkyl, c2-?]_q alkylthioalkyl, C2^C^Q alkylsulfinylalkyl, C^-C^q hydroxyalkyl, C2-C1Q carboxyalkyl, C3-C^o alkoxycarbonylalkyl, Cg-C10 alkylcarbonyalkyl, Cj-C^q haloalkyl, C7-C15 aralkyl, Cg-C15 ot-carboxyaralkyl, C3-C^o cycloalkyl, C4-C1Q cycloalkylalkyl, furfuryl, tetrahyd'rofurfuryl optionally substituted with one or more Cj_-Cg alkyl and/or C^-Cg alkoxy groups, 3-furylmethyl, tetrahydro- 3- fury lmethyl optionally substituted with one or more C^-Cg alkyl or C^-Cg alkoxy groups^, tetrahydro-2 (3 or 4)-pyranylmethyl optionally substituted with one or more C^-Cg alkyl and for C^-Cg alkoxy groups, l,4-dioxa-2-cyclohexylmethyl optionally substituted with one or more C^-Cg alkyl and/or C^-Cg alkoxy groups, 2-thenyl,

1. ) ~n' 1 - coor 2 wherein Rj ie Cg-C 10 alkyl, Cg-Cg alkenyl, Cg-Cg alkynyl, « Cg-Cg alkoxyalkyl, Cg-Cg alkylthioalkyl, Cg-Cg alkylsulfinylalkyl, C^-Cg hydroxyalkyl, Cg-C? carboxyalkyl, Cg-Cg lo alkoxycarbonylalkyl, C ? -C 10 aralkyl, Οθ-Cjg x.-carboxyaralkyl, Cg-CiQ cycloalkyl, C 4 -C 1Q cycloalkylalkyl, furfuryl, tetrahydrofurfuryl, 3-fury lmethyl, tetrahydro-3-furylmethyl,

2. 2 2j \ HNSO11 Ar 130 OS a pharmaceutically acceptable salt thereof, wherein Ar ia naphthyl, 5,6,7,8-tetrahydronaphthyl or naphthyl substituted with at least one substituent which is halo, nitro, cyano, hydroxy, Cj-C^ alkyl, Cj-Cjg alkoxy or C 2 -C 2O dialkylamino; / 2 2 2 | \ H,N (CH,) -COOR, 126 443G0 or a pharmaceutically acceptable salt thereof, wherein Ar is a C 1 -C 5 alkoxy substituted haphthyl group; R 1 is C 2 -C 10 alkyl or Cj-C^jj alkoxyalkyl; R 2 is hydrogen or C^-C^q alkyl; and n is 1, 2 or 3. 2) 2-thenyl, 3-thenyl, tetrahydro-2-thenyl or tetrahydro-3thenyli 123 2· λ compound as claimed in claim 1 wherein R is R, S 1 (1) —N wherein R, is C--C,-alkyl, ^(CH 2 ) COORg 1 2 10 Cg-Cg Cg-Cg alkynyl, C 2 -C g alkoxyalkyl, C 2 ~Cg alkylthioalkyl, Cg-Cg alkylsulfInylalkyl, C-^-Cg hydroxyalkyl, Crj-C^ carboxyalkyl, Cg-Cg alkoxycarbonylalkyl, C^-Cg haloalkyl, C^-C^q aralkyl, Cg-C^ 2 Z·-carboxyaralkyl, C 3 -C 10 cycloalkyl, C 4 -C 10 eycloalkylalkyl, furfuryl, tetrahydrofurfuryl, 3-furylmethyl, tetrahydro-3-furylmethyl, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl or tetrahydro-3thenyl; R 2 is hydrogen, C^-C^g alkyl, Cg-C^g aryl, C^-Ο^θ aralkyl or 5-indanyl? Z R 3 CH-(CH-) COORI «in □ Ra wherein Rg is hydrogen, C^-C^g alkyl, Cg-Cg alkenyl, Cg-Cg alkynyl, Cg-Cg alkoxyalkyl, C 2 -Cg alkylthioalkyl, C 2 ~Cg alkylsulfinylalkyl, C^Cg hydroxyalkyl, Cg-C^ carboxyalkyl, Cg-Cg alkoxycarbonylalkyl, Cj-Cg haloalkyl, C 7 -C 1Q aralkyl, Cg-C^g oi-carboxyaralkyl, C 3 _C 10 oyoloalkyl, C 4-C^ o eycloalkylalkyl, furfuryl, tetrahydrofurfuryl, 3-furylmethyl, tetrahydro-3-furylmethyl, 2thenyl, 3-thenyl, tetrahydro-2-thenyl or tetrahydro-3theynl? R 4 is C^-Cg alkyl, carboxy, Cg-Cg alkoxycarbonyl, phenyl, C 7 C 10 aralkyl or ring substituted benzyl wherein said substituent is tf.-c- alkyl or C -c, alkoxy? Rg is X Ul 443®° hydrogen, c x -C £q alkyl, C g -C l0 aryl, C ? -C lo aralkyl or

3. -furylmethyl; R 4 is hydrogen or C^Cg alkyl; Rg is hydrogen, C,j-C 10 alkyl, C 7 ~C 12 aralkyl or C g -C^ Q aryl; and n is 0, 1 or 2 18. An N -alkoxynaphthalenesulfonyl-L-argininamide having the formula: h 2 n· / or a pharmaceutically acceptable salt thereof, wherein Ar is naphthyl substituted with at least one C^-Cg alkoxy; R 7 is hydrogen or alkyl; R g is - COORg wherein R g is C^-C^ Q alkyl, C g -C 1Q aryl or C 7 ~C 12 aralkyl; R ? can be substituted 15 at the 2,3,4,5 or 6 -position; and R g is substituted at the 2 or 3 -position. 19. An N-naphthalenesulfonyl-L-argininamide having the formula: HN - ι :-N-CH 2 CH 2 CH 2 CHCONf ) H 2 Nz/ HNSO, Ar 129 443 GO or a pharmaceutically acceptable salt thereof, wherein Ar is naphthyl, 5,6,7,8-tetrahydronaphthyl or naphthyl substituted with at least one substituent which is halo, nitro, cyano, hydroxy, Cg-Cgθ alkyl or C 2 _C 20 dialkylamino; R 7 is hydrogen 3-carboxy-4-thiomorpholino, l-oxo-3-carboxy-4-thiomorpholino or 4-carboxy-3-thiazolidinyl; 124 or (5} a group of the formula which is 2-carboxy-l,2,3,4-tetrahydro-l-quinolyl, 3-carboxy1,2,3,4-tetrahydro-2-isoquinolyl, 1-carboxy-l,2,3,4-tetrahydro2-isoguinolyl, 2-carboxy-l-indolinyl or l-carboxy-2-isoindolinyl; R 2 « R 5 and ¾ in th ® above formulae being hydrogen, alkyl, Cg-C 1Q aryl, C 7 -C 10 aralkyl or 5-indanyl; __ ___ 3) wherein R? is hydrogen, Cg-Cg alkyl phenyl or carboxy, ahd R ? is substituted into the piperidine X5 ring at the 2, 4 or 6 position; 3-position; and R 7 is substituted into the piperidine ring at the 2, 3, 4, 5 or 6-position, 117 44300 optionally substituted with one or more C^-Cg alkyl and/or C^-Cg alkoxy groups wherein R g is hydrogen, C ]_ -C ^ o alkyl, C g -C 10 aryl, C 7 -C 12 aralkyl or 5-indanyl; and r is 1, 2, 3 or 4, wherein R 1Q is hydrogen, C^-Ο^θ alkyl, C g -C 10 aryl, C 7 ~C 12 aralkyl or 5-indanyl; Z is oxy, thio or sulfinyl; and q is 0 or 1, or COOR,·, wherein R^ is hydrogen, C-j-C^q alkyl, C g -C 10 aryl, C 7 ~C 12 aralkyl 3-thenyl, tetrahydro-2-thenyl optionally substituted with one or more C^-Cg alkyl or C^-Cg alkoxy groups or tetrahydro-3-thenyl; R 2 is hydrogen, C^-C.^ alkyl, C g -C 10 aryl, C 7 ~C 12 aralkyl or 4. ,6-dimethoxy-2-naphthyl, 6,7-dimethoxy-2-naphthyl or 6,7diethoxy-2-naphthyl; R^ is benzyl, phenethyl or 3-pheny1-propyl; 15 and R 2 is hydrogen, methyl, ethyl, tert-butyl, phenyl or benzyl.

4. A compound as claimed in claim 1 which ie N 2 -{7methoxy-2-naphthylsulfonyl)-L-arginyl-N-tetrahydrofurfury1glyoine. 4) a group of the formula COOH Z which is 3-carboxy-4-morpholino, 4 43 θ θ / Ν \ CH_(CiI,) — COOR, I Ζ Π 9 *4 wherein Rg is hydrogen, C^-C^ o alkyl, Cg-Cg alkenyl, Cg-Cg alkynyl, C 2 -C g alkoxyalkyl, C 2 ~Cg alkylthioalkyl, C 2 -C g alkylsulfinylalkyl, C^-Cg hydroxyalkyl, Cg^C? 5. The proviso of claim 1 is satisfied. 30. A process as claimed in claim 29 wherein R and Ar are as defined in claim 2. 31· λ process for producing a compound as claimed in claim 1 which process comprises guanidylating an M^-aryl-L-ornithinamide 5 is hydrogen, Cj-C^ alkyl, Cg-C 10 aryl or C 7 “C 12 j ia 0, 1 or 2? i is 0, 1 or 2; and i + j is 1 or 2. 22. A compound as claimed in any preceding claim having D-configuration in the carbon atom to which the carboxylic group is attached. 5 or Cg-Cg θ alkyl; R g is -COOR g wherein Rg is hydrogen, Cg-Cg θ alkyl, C g -Cgθ aryl and C 7 -Cg 2 aralkyl; R ? can be substituted at the 2,3,4,5 or 6 -position; and R g is substituted at the 2 or 3 -position. 20. An N -naphthalenesulfonyl-L-argininamide having the formula: COORio ι ^C-N-CH_CH-CH„CHCO-N HNSOI 2 Ar or a pharmaceutically acceptable salt thereof, wherein Ar is naphthyl, 5,6,7,8-tetrahydronaphthyl or naphthyl substituted with at least one substituent which is halo, nitro, cyano, hydroxy, Cg-Cg Q alkyl, Cg-Cg Q alkoxy or C 2 -C 20 dialkylamino; Rgθ is hydrogen, Cg-Cgθ alkyl, C g -Cg 0 aryl or C 7 ~Cg 2 aralkyl; Z is oxy, thio or sulfinyl; and 9 is 0 or 1. 21. formula: An N -naphthalenesulfonyl-L-argininamide having the HN X I COOR C-N-CH.CH-CH-CHCON: 5 Rg is furfuryl, 3-furylmethyl, tetrahydrofurfuryl or tetrahydro 5-methoxy-1-naphthyl, 6-methoxy-2-naphthyl, 7-methoxy-2-naphthyl,

5. A compound as claimed in claim 1 which is,N 2 -(7methyl-2-naphthyleulfonyl)-L-arginyl-N.-tetrahydrofurfurylglycine 5 carboxyalkyl, Cg-Cg alkoxycarbonylalkyl, C^-C·^ aralkyl, C 8“ C 12 ^“cahboxyaralkyl, Cg-C 10 cycloalkyl, C 4 _c j_q cycloalkylalkyl, furfuryl, tetrahydrofurfuryl, 3furylmethyl, tetrahydro-3-furylraethyl, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl or tetrahydro-3-thenyl; and R^ is 5 3. A compound as claimed in claim 2 wherein R ie x /R l 5-indanyl; R? is hydrogen, COORo (4) \ci^)r C l C lO alky1 ' C 6 _C 1O ary1 ' COORjq (5 >- N z . a lkyl, C g -C^Q aryl, C g -C 10 aryl, Ο ? -Ο 1Ο aralkyl or Οη-Cg alkyl, phenyl or Carboxy; wherein R g is hydrogen, C 7 -C lo aralkyl or 5-indanyl? wherein R^ is hydrogen, C 7 -C lo aralkyl or 5-indanyl? or COOR^i (6) wherein R 11 is hydrogen, Cl’C^O alk y 1 » C 6“ C 10 ary1 ' C 7 -C 10 or S-indanyl? and Ar is naphthyl, 5,6,7,8-tetrahydronaphthyl, naphthy.l substituted with at least one substituent which is halo, nitro, cyano, hydroxy, C^-Cg alkyl, C^-Cg alkoxy or C 2 -C 1Q 15 dialkylamino, phenyl, phenyl substituted with at least one substituent which is halo, nitro, cyano, hydroxy,.C^-Cg alkyl, C^-Cg alkoxy Or C 2 -C lo dialkylamino, C 7 -C 10 aralkyl, 122 ίΟΟ -co - -coo · or is hydrogen, Cj-C 5 alkyl or C^-Cg alkoxy. 5-indanyl; wherein R g is -COORg wherein R g ie hydrogen, C^-C^ alkyl, 5 or 6-position; Rg is not Cg -Cg alkyl) when R iss(4) COOR g optionally substituted with one or more Cg-Cg alkyl or Cg-Cg alkoxy groups, Rg is not Cg-Cg alkyl) 119. ««»·* COOR 10 . Ζ”\ when R is:- · (5) - N J. wherein 2 is oxy or thioj R-^θ is not C^-Cg alkyl; and when R is:(6) - N coon 1JL )i\j< S> \(CU 2 )j R^ is not C^-Cg alkyl; if, in the case of any of the provisos above, Ar is 5,6,7,8-tetrahydronaphthyl, naphthyl, 1-naphthyl substituted with one substituent which is halogen, nitro, cyano, hydroxy, C^-C^q alkyl, C2°20 dialkylamino, or C^-C 10 alkoxy or 2-naphthyl substituted with one substituent which is halogen, nitro, cyano, hydroxy, Cj-C^q alkyl, ^2^20 dialkylamino or alkoxy, wherein II and R 1 are each independently Ci-Cio alkyl, 5-indanyl; and n is 1, 2 or 3, (2) -N wherein Rg is hydrogen, alkyl, Cg-Ο^θ alkenyl, 0 3 “0 10 116 alkynyl, C 2 -c iq alkoxyalkyl, C 2 ~C 10 alkylthioalkyl, C 2 ~C 2 0 alkylsulfinylalkyl, C^-C·^ hydroxyalkyl, C 2 -C 10 car k ox y a lkyl» C 3 _C 1O a lkoxycarbonyalkyl, Cg-C^Q alkylί carbonylalkyl, Cj-C^q haloalkyl, C^-C^g aralkyl, Cg-C.^ a-car5 boxyaralkyl, Cg-C 10 cycloalkyl, C 4 -C 1Q cycloalkylalkyl, furfuryl, tetrahydrofurfuryl optionally substituted with one or more C^-Cg alkyl or C^-Cg alkoxy groups, 3-furylmethyl, tetrahydro-3-furylmethyl, optionally substituted with one or more Cj-Cg alkyl or C^-Cg alkoxy groups, tetrahydro-2 (3 or 4)-pyranylmethyl optionally

6. A compound ae claimed in claim 1 whioh ie N 2 -(6,7dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-tetrahydro£urfurylglycine.

7. A compound ae claimed in claim 1 which ie 1-{n 2 -(6,7dimathoxy~2-naphthylsulfonyl)-L-arginyl]-4«aathyl-2piperidinecarboxylic acid.

8. A compound ae olaimed in claim 1 which le 1-Jn 2 - (?* methoxy-2-naphthylaulfonyl)-b-arginyf} -4-methyl-2-piperdine* carboxylic aoid. 125 443G0

9. A compound as claimed in claim 1 which is 1 -[N -(7methoxy-2-naphthylsulfonyl)-L-arginyl]-4-ethyl-2-piperidinecarboxylic acid. 10. Having the formula: NgNOHgCHgCHgCHCCR hnso 2 Ar wherein R and Ar are as defined in claim 1 with a guanidylating agent, R and Ar being such that the provieo of claim 1 is satisfied. 15 32. A process as claimed in claim 31 wherein R and Ar are as defined in claim 2, and the guanidylating agent is an O-alkyliaourea, S-alkylisothiourea or l-guanyl-3,5-dimethylpyrazole or . a carbodiimide. 33. A procees as claimed in cny one of claims 25, 27, 29 or 20 32, and substantially as described in any one of Examples 1 to 5 with reference to any one of the compounds produced in those Examples. 135 34. A process as claimed in claim i.S and substantially as described with reference to any one of Sample Nos 1 to of Table 1. 35, A method of inhibiting activity and suppressing activa 5 tion of thrombin in vivo, which method comprises introducing into a living body a pharmaceutically effective amount of a compound as claimed in any one of claims 1 to 24. 36. A compound as claimed in claim 1 when produced by a process claimed in any one of claims 25 to 34. io 37. A pharmaceutical formulation comprising as active . ingredient a compound as claimed in any one of claims 1 tc 24 or claim 36. 58. A unit dose of a pharmaceutical formulation as claimed in claim 37. I 10 23. A compound as claimed in claim 1 which is any one of compounds Nos. 1 to 70 as hereinbefore designated. 24. A compound as'claimed in claim 1 which is any one of the compounds hereinbefore described· in Table 1. 25. A process for producing a compound as claimed 15 in claim 1 which process comprises reacting an L-arginamide having the formula: HN / HjN wherein R is as>. defined in claim 1 with an arylsulfonyl halide having tha formula ArSOgX wherein Ax* is as defined in oleim 1 and X is halogen, R and Ar being such that the proviso of claim 1 is satisfied. 131 N - CHjCHgCHjCHCOR NH. 26. A process as claimed in claim 25 wherein R and Ar are as defined in claim 2. 27. A process for producing a compound as claimed in ft claim 1 which process comprises removing the N -substituent G 2 from an N -substituted-N -arylsulfonyl-L-argininamide having the formula: HN. HN· ’C-N-CH,CH,CH,CHCOR | i ί i ( R HNSOI 2 Ar wherein R and Ar are as defined in claim 1; R' and R are hydrogen or protective groups for the guanidino group, and at least one of R' and R is a protective group for the guanidino group, R and Ar being such that the proviso of claim ί is satisfied. 28. A process as claimed in claim 27 wherein R and Ar are as defined in claim 2; and R' and R” are hydrogen, nitro, 15 acyl, tosyl, trityl or oxycarbonyl. 29. A process for producing a compound as claimed in 5 claim 1 which process comprises reacting an N -arylsulfonylL-arginyl halide having the formula: HN H 2 N CH 2 CH 2 CH 2 CHCOX HNSOAr 132 wherein Ar is as defined in claim 1 and X is halogen, with an amino aeid derivative having the formula: RH wherein R is as defined in claim 1, R and Ar being such that 10 C 7 -C^ 2 aralkyl; and n is 1, 2 or 3.

10. An N -alkoxynaphthalenesulfonyl-L-argin.inamide having the formula: H HN. z Ri -CH 2 CH 2 CH 2 CHCON<^ HNSO 2 ^^2^-° 00 ¾ III h 2 nAT or a pharmaceutically acceptable salt thereof, wherein Ar is naphthyl substituted with at least one C^-Cg alkoxy; R^ is Cy-C^g aralkyl; R 2 is hydrogen, C^-C^ Q alkyl, Cg-C 1Q aryl or 10 Cg-Cg alkyi, carboxy, Cg-Cg alkoxycarbonyl, C^-C^q aralkyl or ring substituted benzyl wherein said substituent is Cg-Cg alkoxy; . COORg 10 or 5-indanyl; i is 0, 1 or 2; j is 0, 1 or 2; and the sum i + j is 1 or 2; and Ar is naphthyl, 5,6,7,8-tetrahydronaphthyl optionally substituted with one or more Cj-Cg alkyl or C^-Cg alkoxy groups, naphthyl substituted with at least one substituent which is halo, 15 nitro, cyanOjhydroxy, alkyl, C^-C^Q alkoxy or C2~ C 2O dialkylamino, phenyl, phenyl substituted With at least one substituent which is halo, nitro, cyano, hydroxy, alkyl, c j_“ c 10 alkoxy optionally substituted with one or more C^-Cg alkyl or Cj-Cg alkoxy groups wherein R^ 2 is hydrogen, C ]_ -C ^ o alkyl or C^-Ο^θ alkoxy, with the provisos that; when R iss118 X (CH 2 ) n COOR 2 wherein Rg is C 2 -Cg 0 alkyl, C 3 -C lo alkenyl, C 3 -C lo alkynyl, C 2 -C io alltox y alk y 1 » C 2 -C io carbox y alk y 1 f c 3 -c 10 alkox y carbon yi _ alkyl, C 7 -Cg 0 aralkyl, C 3 -C g o cycloalkyl or C 4 -C 1Q eycloalkyl5 alkyl; R 2 is not hydrogen or Cg-C^alky!) when R is:(2) —N / R 3 X( ? H -< CH 2>in COOR 5 wherein R 3 is hydrogen, Cg-Cg Q alkyl, C 3 ~Cg 0 alkenyl, C 3 ~Cg 0 alkynyl, C 2“^10 & Ι^ οχ Υ 3 Ι^γΙ. ^2^10 carbox Y a lkyI, Cg-Cgg alkoxyoarbonylalkyl, C7-CgQ aralkyl, C3-Cg0 cycloalkyl or C4-Clo cycloalkylalkyl; and R4 is c j”C10 alkyl; Rg is not hydrogen or Cg-C 10 alkyl’when R is: - < R 7>p wherein Rg is -COORg wherein each R 7 independently is hydrogen, 0·]“0 10 alkyl or Cg-Cg alkoxy; p is an integer of 1 to 5; Rg is substituted into the piperidine ring at the 2 or 3-position; and R 7 is substituted into the piperidine ring at the 2, 3, 4, 10 substituted with one or more C^-Cg alkyl and or C^-Cg alkoxy groups, l,4-dioxa-2-eyclohexylmethyl optionally substituted with one or more c j_“ c g alkyl and or C^-Cg alkoxy groups, 2-thenyl, 3thenyl, tetrahydro-2-thenyl optionally substituted with one or more C^-Cg alkyl or C^-Cg alkoxy groupe or tetrahydro-3-thenyl; 15 R^ is 0 χ -0 10 alkyl, carboxy, Cj-C^q alkoxycarbonyl, phenyl optionally substituted with one or more C^-Cg alkyl or C^-Cg alkoxy groups, C 7 ~C 12 aralkyl or ring substituted benzyl wherein said substituent is C^-Cg alkyl or C^-Cg alkoxy; Rg is hydrogen, C^-C^ alkyl, C g -C 1Q aryl, C 7 ~C 12 aralkyl or 5-indanyl; and m is 20 Ο, 1 or 2, Rf (3) <*7>p wherein R g is -COORg wherein R g is hydrogen, 0χ-0 10 alkyl, c g“C 10 aryl, C 7 -C 12 aralkyl or 5-indanyl; each R ? independently is hydrogen, C^-C^ alkyl, phenyl C^-Cg alkoxy or carboxy; p is an Integer 25 of 1 to 5; R g is substituted into the piperidine ring at the 2 or

11. A compound as claimed in claim 10 wherein Ar is

12. An N -alkoxynaphthalenesulfonyl-L-argininamide having the formula: H \ I Z R 1 ^C-N-CH,CH,CH,CHCOH<

13. An N -alkoxynaphthalenesulfonyl-L-argininamide having the formula: H R / 1 HN; h 2 n \ I ^C-NS CH 2 CH 2 CH 2 CHCOK HNSO'< CH 2>n‘ COOR 2 Ar or a pharmaceutically acceptable salt thereof, wherein Ar is naphthyl substituted with at least one C^-Cg alkoxy; R^ is C 2” C 10 r 2 is hydrogen, C,j-C 10 alkyl, C g -C 10 aryl or C 7 -C^ 2 aralkyl; and n is 1, 2 or 3.

14. An N -alkoxynaphthalenesulfonyl-L-argininamide having the formula: ,C-N-CH 2 CH 2 CH 2 CHCON< HNSO•(CH 2 ) n -COOR 2 Ar wherein Ar is naphthyl substituted with at least one C^Cg alkoxy; R 1 is Cg-C^ 0 cycloalkyl or C^-C^q cycloalkylalkyl; R 2 is hydrogen, C^-C^q alkyl, Cg-C^Q aryl or C 7 ~C^ 2 aralkyl; and n is 1, 2 or 3. 15. An N -naphthalenesulfonyl-L-argininamide having 20 the formula: 127 44300 “V * ' to 1 ’ ^p-N-CHgCHgCHgCHCONQ H 2 n/ hL, X(CH 2>n-C00R 2 I 2 Ar or a pharmaceutically acceptable salt thereof, wherein Ar is naphthyl, 5,6,7,8-tetrahydronaphthyl or naphthyl substituted with at least one substituent which is halo, hydroxy, C.j-C 10 alkyl or Cg-Cgg dialkylamino; R 1 is Cg-C 10 alkyl, Cg-C^g alkoxyalkyl, C 2 -c 10 alkylthioalkyl, C 7 ~C 15 aralkyl, Cg-C^ cyclo-alkyl or C^-C^g eycloalkylalkyl; Rg is hydrogen, C^-C^g alkyl, C ? -C 12 aralkyl or Cg-C 1 g aryl; and n is 1, 2 or 3. 16. An N -alkoxynaphthalenesulfonyl-L-argininamide having the formula: HN; H 2 nZ 2 2 2 | \ HNSOg CHCOORAr or a pharmaceutically acceptable salt thereof, wherein Ar is naphthyl substituted with at least one C^Cg alkoxy; Rg is C 2 -C 10 ® 1 ^ 1 ' C 2 _C 10 alkoxyalkyl, Cg-C 1Q alkylthioalkyl, Cy-C^g aralkyl, Cg-C^g cycloalkyl or C^-C^g eycloalkylalkyl; R 4 is C^-Cg alkyl; and Rg is hydrogen, C^-C^ alkyl, Cy-C^g aralkyl or Cg-C^g aryl. 17. An N -naphthalenesulfonyl-L-argininamide having the formula: H X ί ^C-N-C _ -CHgCHgCHgCHCON-ς R-N·^ -J— ^'ΓΗCH-(CHg) n COORg Ar HNSO_ 128 or a pharmaceutically acceptable salt thereof, wherein Ar is naphthyl, 5,6,7,8-tetrahydronaphthyl or naphthyl substituted with at least one substituent which is halo, hydroxy, nitro, cyano, C^-C^ o alkyl, C^-C^q alkoxy or C 2 -C 20 dialkylamino;

15. 39« A unit dose as claimed.in claim 38 which is a tablet, capsule, troche,or lozenge.