CA1102316A - N su2 xx-arylsulfonyl-l-argininamides and the pharmaceutically acceptable salts thereof - Google Patents

N su2 xx-arylsulfonyl-l-argininamides and the pharmaceutically acceptable salts thereof

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Publication number
CA1102316A
CA1102316A CA266,501A CA266501A CA1102316A CA 1102316 A CA1102316 A CA 1102316A CA 266501 A CA266501 A CA 266501A CA 1102316 A CA1102316 A CA 1102316A
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CA
Canada
Prior art keywords
alkyl
group
arginyl
aralkyl
hydrogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
CA266,501A
Other languages
French (fr)
Inventor
Shosuke Okamoto
Ryoji Kikumoto
Yoshikuni Tamao
Kazuo Ohkubo
Tohru Tezuka
Shinji Tonomura
Akiko Hijikata
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mitsubishi Kasei Corp
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Mitsubishi Kasei Corp
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Filing date
Publication date
Priority claimed from US05/638,985 external-priority patent/US4055636A/en
Priority claimed from US05/646,522 external-priority patent/US4018915A/en
Priority claimed from US05/649,219 external-priority patent/US4018913A/en
Priority claimed from US05/653,217 external-priority patent/US4055651A/en
Priority claimed from US05/656,014 external-priority patent/US4041156A/en
Priority claimed from US05/656,870 external-priority patent/US4046876A/en
Priority claimed from JP3062176A external-priority patent/JPS52113919A/en
Priority claimed from US05/669,743 external-priority patent/US4070457A/en
Priority claimed from US05/707,536 external-priority patent/US4036955A/en
Priority claimed from US05/713,486 external-priority patent/US4073914A/en
Priority claimed from US05/723,474 external-priority patent/US4096255A/en
Priority claimed from US05/728,051 external-priority patent/US4104392A/en
Application filed by Mitsubishi Kasei Corp filed Critical Mitsubishi Kasei Corp
Publication of CA1102316A publication Critical patent/CA1102316A/en
Application granted granted Critical
Expired legal-status Critical Current

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Abstract

ABSTRACT OF THE DISCLOSURE
N2-arylsulfonyl-L-argininamides of the formula

Description

N -AI~YLSUL.F(lNYL-L-l~ lNINAMInP,~ NI) Tll~;:
PII~RMl\CF:UTIC~LLY ACCI'PTI~BL~ S~LT~ TII~R~
I~A('~ ) Ol;~ 1`1ll~` ~ N ~ `N L`:l oN

r lt,- ~"~ "~
Tlli ~ i ll V I l l, i O I ~ i (. O t ll C (li ~ CO VC I')' O ~ ~ I l C\~
usoful N -1rylSUlrOllyl-L-11`~,rinill.1111i(lCg Illd l.llC ~)llal' ccutically accel~t.ll)le s.llts tl~eJ coL`, wll.icll ;ll e -~' c~:ln~
value in view Or tlleir outstanclill~,r alltitl~lonll~ol;ic l~ro~)eI~tie~;
alld low toxici ties .

l~escril~t;ioll o~` lllc l'~.ior Arl;

In .the l)lSt~ there llave beel~ mally .attcllll~ts l,o ollta~ CW
and iml)rovccl al,ellt~; for tllc trcatlllcllt ol` tlllollll)o~ llc N ~ I;oJ.ylsu1rolly1)-L-3r~inine e~ters 1l1VC l~(?CII roun(l to :
be one type Or a~,ellt wl-i cll C1~ e used cllld l,llCSC llaVC l)eCn found to be erfective in ~issolvill~ l~lootl clol,s. (u. ~;~

Patent No . 3,622 ,615, issued Noveml)er 23, 1971 ) One ~arnily Or coml)ounds ~llicll ~lave becll roull~l to l)e l-~r-ticularly u~;erul as lli~llly speciric inllil)itol~ Or tllroml)i for tl~e. colltrol ol` tllrolllL)osi.s is ~ c N~-dallsy.l~ e -ester or an~idc. (The applieant~s U.S. Patent No. 3,978/045.) llowevcr, tllcre i.s a COllti~lUi.ll~ IICCCI Lor 1 ~ .y ~ CCi~`iC
inllibi-tor o~l tllron)l)irl for tlle control Or l:llroml~o~ ;, wllicl exhibits lower toxicity.

-- ~ --Sl)~ Y Ol~ lNVl~N'l`lON

It llas now ~n (liscoverecl tllat N -ary.Ls-l]~onyl-l,-ar~irlillamid~s exhib:i~ alltitllronl~otic activi~y alld ev~n lower toxicity l~vels at the same relative potencies, as S compared witlL tlle N -cl~nsyl-L-argin~ sl;~r or anudc.
The compourl~s Or thi.s inverltion Call ~ r~ selltCd ~y t~lC
formula (I):

H N ~C I _ CII~C112CH2C~ICOR (I) Ar wherein R is selectecl from the group Co~l~isti~l~ of .10 (1) - N ~ wherein Rl 1s sel~ctecl ~ro~ the group ( C~2 )nC~2 g C2 C10 all~yl, C3-Clo 21]cenyl~ C3-C a1kynyl C2-C10 alkoxya~l~yl, C2-C10 alkyl~llioal]cy]~ C2-C10 alkyl-sulrinyl~lkyl, CL-Cl~ lly(lroxyallcy].~ C2-CI(~ c~llhoxyallcyl, C3-C10 alkoxycarbonylalkyl, C3-C10 alkyica.rbonylalkyl, Cl-C10 haloa1kyl, C7-Cls aralkyl, Cg-Cls ~-carboxyaralkyl, C3-C
cycloalkyl, C4-C1o cycloalkylalkyl, furfuryl, -tetrahydrofurfuryl, optionally substituted with at least one Cl Cs alkyl and/or Cl-Cs alkoxy 3-furylmethyl, tetrahydro-3-furylmethyl, optionally substituted wi-th at least one Cl-Cs alkyl and/or Cl-Cs alkoxy tetrahydro-2t3 or 4)-pyranylmethyl optionally substituted with at least one Cl-Cs alkyl and/or Cl~Cs alkoxy, 1,4-dioxa-2-cyclohexylmethyl optionally substituted with a-t least one :
Cl-Cs alky~ and/or Cl-C~ alkoxy, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl optionally substituted with at least one Cl-Cs alkyl and/or Cl-Cs alkoxy, and tetrahydro-3-thenyl;
R2 is selected from the group consisting of ~Iyclrog~n~ C~C10 .llky~ C~-Cl~ ary]., C7-C12 aral3~y:L cu-ld 5-:ind~lyl, ~ is c~ lt~g~r of` 1, 2 or 3, (2) - N ~ ~ leroill r~ ls ~ cte~l from Cll-(C112 ),1lCOOR5 ~ , the group COII~:iS t:illg of llydrogen, C~-ClO ~llcyl, C3-C10 alke]lyl J C3-Cl~ al3cy~lyl, C2-Clo ~lko~Yyallcyl, C2-Clo alkyl-thioalkyl, C2-ClO ~lkylsulfinyl~lkyl, Cl-ClO lly~roxyallcyl, C2-C10 carboxyalkyl, C3-C10 alkoxycarbonylalky]., C3-C10 alkylcarbonylalkyl, Cl-C10 haloalkyl, C7-C15 aralkyl, C8-C15 ~-carboxyaralkyl, C3-C10 cycloalkyl, C4-C10 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl, optionally substituted with at -;
least one Cl-C5 alkyl and/or Cl-C5 alkoxy 3-furylmethyl, tetrahydro-3-Eurylmethyl, optionally substituted with at least one Cl-C5 alkyl and/or Cl-C5 alkoxy tetrahydro-2(3 or 4)-pyranylmethyl optionally substituted with at least one Cl-C5 alkyl and/or Cl-C5 alkoxy, 1,4-dioxa-2-cyclohexylmethyl optionally substituted with at least one Cl-C5 alkyl and/or Cl-C5 alkoxy, 2-thenyl, 3-thenyl, tetrahydro-2--th~nyl optionally substituted with at least one Cl-C5 alkyl and/or Cl-C5 alkoxy and tetrahydro-3-thenyl; R4 is selected from the group consisting o Cl-C10 alkyl, carboxy, C2-C10 alkoxycarbonyl, phenyl, optionally substituted with at least one Cl-C5 alkyl and/or Cl-C5 alkoxy Cl-C~ aralkyl and ring substituted benzyl wherein said substituent is Cl-C5 alkyl or Cl-C5 alkoxy; R5 .--i5 selected from the group consistiny of hydrogen, Cl-C10 alkyl, C6-C10 aryl, C7-C12 aralkyl and 5-indanyl; and m is an integer of 0, 1 or 2, t3) - ~ wherein R6 is -COOR8 wherein R8 is selected (~7)p ~, _~_ from the group consisting o~ hydrogen, Cl-C10 alkyl, C6-C1o aryl, C7-Clz aralkyl and 5~indanyl; (R7)p is hydrogen, C~-C10 alkyl, phenyl Cl-C5 alkoxy or carboxy; p is an integer of 1 to 5; R6 is substituted at the 2 or 3-position; and R7 can be s~stituted at the 2, 3, 4~ 5 or 6-position, COOR ~

which is optionally substituted with at ~CH~ r :
least one Cl-Cs alkyl and/or Cl-C5 alkoxy, wherein Rg is selected from the group consisting of hydrogen, Cl-C10 alkyl, ~6-C10 aryl, C7-C~2 aralkyl an(l lO
5-indanyl; and r is an ~
integer of 1, 2, 3 or ll, (5) -N ~ wherein Rlo is \, (C112 ) q selected from the group consisting of hycirogen, Cl-ClO allcyl, C6-ClO aryl, C7-Cl2 aralkyl and 5-indanyl; Z is selected from the group consisting o~ oxy, t~lio ~ld Sulri,lyl; and q is an integer of O or ~ d (6) -N \ ~ ~ erein R

is selected from tlle group consisting Or hydro~ell, C1-ClO

alkyl, C6-ClO aryl~ C7-C12 aralkyl and 5~ (lanyl; i is an integer of O, l or 2; j is an integer of` O, l or 2; and the
2~0 sum of i+j is aJI i.nteger of l or 2; and Ar is selected from the group consistill~ Or napht~lyl, 5~6~7~8-tctrally(ironaphtllyl~
optionally substituted with at least one Cl-C5 alkyl and/or Cl-C5 alkoxy ~` 5 ,h.

naphthyl ~ubstituted with at least one substituent selectecl from the group consisting of halo, nitro, cyano, hydroxy, 10 Y Cl (~10 alkoxy al~d C2-C20 diallcylamino, phenyl phenyl substituted with at least one subs-tituent selected f`rom the group consisting of halo, nitro, cyano, hydroxy, Cl-C10 alkyl, Cl-C10 alkoxy and C2-CzO dialkylamino, C7-C12 aralkylfand ~ ) ~ ~ ~ 9 ~ ) and ~ } R12 which are optionally substituted with at least on Cl-C5 alkyl and/or Cl-C5 alkoxy, wherein R12 is hydrogent Cl-C10 alkyl or Cl-C10 alkox~r.
Also encompassed within this invention are pharmaceutically acceptable salt5 thereo~.
This invention also relates to a rnethod for inhibiting lS activity and suppressing activation o~ thromhin in vivo9 ~ic~ cs:.~9~e,~ rc~ucing into a liv~ng l~ocly a ~harma~
ceuticall.y crrective amoullt Or all N -arylslllrollyl-L-argininami-le or t~le pharmaccutically acceptalrle salt thercof.

,,~

~2~

DFTAILED DESCRIPTION OF THE PREFERRED_EMBODI~ENTS

T~is invention relates to a group of N -arylsul~onyl-L-argininamides of the ~ormula (I):

~IN
~ C - N - CH2CH~CH2CHCOR (~) ~ HNS02 Ar wherein R iB selected from the group consisting of (1) - N \ wherein Rl is selected from the group ( CH2 )nC OOR2 consisting o~ C2-C10 alkyl, such as 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-butenyl9 2-pentenyl or the like, al~ynyl of
3-10 (preferably 3-6) carbon atoms, such as 2-propynyl, 2-butynyl~ 3-hutynyl or the like~ alkoxyalkyl Or 2-10 (preferably 2-6) carbon atom~ 9 such as methoxymethyl, :
ethoxymethyl~ propoxymethyl, Z-methoxyethyl, Z-ethoxyethyl, 2-propoxyethyl, 2-methoxypropyl~ 3-methoxypropyl, 3 ethoxypropyl~ 3-propoxypropyl, 4-methoxybutyl, 4~ethoxybutyl~
4-butoxybutyl, 5-butoxypen-tyl or the like, alkyl.thioalkyl of 2-10 (preferably 2-6) carbon atoms, such as methylthiomethyl, ethylthiomethyl, propylthiomethyl, 2-methylthioethyl, ~ 7 , _ ,, , ___ _ ,_ _,,, _. _ _ _ _., _ __ .. . .. . .. .~_ .. _ .. _ .. _ _ .. -- -- .--.. --A_ - .-- . ----'' - ' - ' . '.

}2~

2-ethylthioethyl, 2-propylthioethyl, 3-methylthiopropyl, 2-methylthiopropyl, 3-ethylthiopropyl, 3-propylthiopropyl, 4-r~etllylt]llObU tyl 9 4-ethylthiobutyl, 4-b-ltylthiobwtyl,
5-butylthiopentyl or -the like, alkylsu.Lfinylallcyl of 2-10 (pre-~erably 2-6) carbon atoms, such as methylsul~inylmethyl, ethylsulfinylmethyl, propylsulfinylmethyl, 2-methylsulfinyl-ethyl, 2-ethylsulfinylethyl, 2-propylsulfinylethyl, 3-methylsulfirlylpropyl, 3-ethylsulfinylpropyl or the like, hydroxyalkyl of 1-10 (preferal~ly 1-6) carbon atoms, such as hydro~ymethyl, 2-hydroxyethyl~ 3-hydroxypropyl~ 2-hydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, 5-hydroxy-pentyl or the like, carboxyalkyl of 2-10 (preferably 2-7?
carbon atoms, such as carboxy~ethyl, 2-carboxyethyl~ 2~
carboxypropyl, 3-carboxypropyl, l-carboxybutyl~ 2-carboxy-butyl, 4-carboxybutyl or -the like, alkoxycarbonylalkyl of 3-10 (preferably 3-8) carbon atoms, such as methoxycarbonyl-~thyl, 2-ethoxycarbonylethyl, 2-ethoxycarbonylpropyl, 3-nlethoxyca~ oJ]y]propyl~ l-methoxycal~l)olly~h~ltyl~ 2-et~loxy-carl~onylb~ltyl, Il-met~loxycarbonylb~ltyl or tl~e lik~, . `-alkylcarbonylalkyl of 3-10 carbon atoms, such as methylcar~ony-lethyl or the like, 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 a~ benzyl, phenethyl, 3-phenylpropyl, 4-phenylbukyl, 6-phenylhexyl, l~phenylethyl, 2 phenylpropyl or the like, -carboxyaralkyl of 8-15 ,~ .

~preferably 8-12) carbon a-toms, such as ~ -carboxybenzyl, ~ -carboxyphenethyl or the like, C3-ClO cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl~ cyclononyl or cyclodecyl, C4--C10 cycloalkylalkyl, such as cyclopropylmethyl, cyclopentylmethy]., cyclohexylmethyl, 2-cyclohexylethyl, cyclooctylmethyl or the like, furfuryl, tetrahydrofurfuryl, optionally substituted with at least one Cl-C5 alkyl and/or Cl-C5 alkoxy 3-furylmethyl, tetrahydro~3-furylmethyl, optionally substituted ~ith at least one Cl-C5 alkyl and/or Cl-C5 alkoxy tetrahydro-2(3 or 4~-pyranylmethyl optionally substituted with at least one Cl-C5 alkyl and/or Cl-C5 alkoxy, 1,4-dioxa-2-cyclohexylmethyl optionally substituted with at least one Cl-C5 alkyl and/or Cl-C5 alkoxy, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl optionally substituted with at least one Cl-C5 alkyl and/or Cl-C5 alkoxy, and tetrahydro-3-thenyl; R2 is selected from the group consisting of hydrogen, Cl-C10 alkyl, such as methyl, ethyl, propyl, butyl, tert-butyl, he~yl, octyl, decyl or the like, C6-ClO
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 n is an interger o 1, 2 or 3, R

(2) - N ~ wherein R3 is selected from the CH-(cH2)mcooR5 group consisting of hydrogen, Cl-ClO alkyl, such as methyl, ~5 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-pentenyl or the like, alkynyl of 3-10 (preferab].y 3-6) carbon atoms, such as 2-propynyl, 2-butynyl, 3-butynyl or the like, alkoxyalkyl of 2-10 (preferably 2-6) carbon atoms, such as 3~

methoxyrnethyl1ethoxymethyl~ ~ropoxyrnethyl, 2-methoxyethyl~
2~ethoxyethyl~ 2-propoxyethyl~ 2-methoxypropyl~ 3-methoxy-propyl, 3-ethoxypropyl, 3-propoxypropyl, 4-methoxybutyl~
4-etlloxybutyl, ll-butoxybutyl, 5-bu-toxypentyl or the like~
alkylthioalkyl of 2-10 (preferably 2-6) carbon atoms, such as methyltlliomethyl, ethylthiomcthyl, propylthiomethyl, 2-methylthioethyl, 2-ethylthioethyl, 2-propylthioe-thyl, 3-methyltt~opropyl, 2-methylthiopropyl, 3~ethylthiopropyl, 3-propylthiopropyl, 4-methyltlliobutyl, 4-ethylthi.obutyl, 4-butylthiobutyl, 5-butylthiopentyl or the :Like, alkyl-sulfinylalkyl of 2-10 (preferably 2-6) carbon atoms, such as methylsulfinyimethyl, ethylsulfi~ylmethyl, propyl sulfinylmethyl~2-methylsul~inylethyl, 2-ethylsulfinylethyl, 2-propylsulfinylethyl, 3-methylsulfinylpropyl~ 3-ethyl-sulfinylpropyl or the like, hydroxy~lkyl of 1-10 (preferably 1-6) carbon atom~, such as hydroxymethyl 9 2-hydroxyethyl~
3-hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl, 3 hy~lroxyl>ll-tyl, r~-lly(lroxyl)ollty:l or t~llC 1.il;c, carl)oxy~l]iyl of 2-]0 (prercr-LI)Jy 2-7) call)oll atom~J ~uc1lL~ C1rl)0~ynl0tllyl, 2-rarboxyetllyl, 2-c~rboxyprol)yl, 3-carboxypropy]., l-car~oxyblltyJ., 2-calboxybutyJ~ ll-carboxyl)lltyl or the like, a:Llioxycarbo~lyl.lJ.]cy.L Or ~-10 (~rc~eral~.iy ~ car~o~l atom~, such a~ mettJoxycarbollyLnlethyl~ 2~nletl~oxycLrbollylethyl~ 2-ethoxycLrbolly.lpropyl, ~-meLIIoxycarbo~lyi~)rol)yl, l-methoxy ~5 C~ lyll)lllyl, -~ loxy~ll)ollyJl)u~y~ ! 1. Ilo ~yc~l l'l)OIly.l 1) ''~;, L~i or the like, a]kylcarbonylalkyl of 3-10 carbon atoms, such as rnethylcarbonylethyl or the like, 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 ].ike, aral]cyl of 7-15 (prefexably 7-10) carbon atoms, such as benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 6-phenylhexyl, l-phenylethyl, 2-phenylpropyl or the like, d~ -carboxyaralkyl of 8-15 (preferably 8-12) carbon atoms, such as c~ -carboxybenzyl, ~ -carboxyphenethyl or the like, C3-C10 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, C4-C10 cycloalkylalkyl, such as cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclohexylethyl, cyclooctylmethyl or the like, furfuryl, tetrahydrofurfuryl, optionally substituted with at least one Cl-C5 alkyl and/or C1-C5 alkoxy 3-furylmethyl, tetrahydro-3 furylmethyl, optionally substituted with at least one Cl-C5 alkyl and/or Cl-C5 alkoxy tetrahydro-2(3 or 4)-pyranylmethyl optionally substituted with at least one Cl-C5 alkyl and/or Cl-C5 alkoxy, 1,4-dioxa-2-cyclohexylmethyl optionally substituted with at least one Cl-C5 alkyl and/or Cl-C5 alkoxy, 2-thenyl, 3-thenyl, tetrahydro-Z-thenyl optionally substituted with at least one Cl-C5 alkyl and/or C1-C5 alkoxy, and tetrahydro~3-thenyl;
R~ is selected from the group consisting of alkyl of 1-10 ~preferably 1-5~ carbon atoms, such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl or the like, carboxy, alkoxycarbonyl of 2-10 ~preferably 2-5) carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or the like, phenyl, optionally substituted with at least one Cl-C5 alkyl and/or Cl-C5 alkoxy aralkyl of 7-12 (preferably 7-10) carbon atoms, such a~ 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 ,''~,' 11~323~L6 alkoxy of 1-5 (preferably 1-3) carbon atoms, such as methoxy, - e-thoxy, propoxy or isopropoxy; R5 is selected from the group con~.isting of hydrogen, Cl-C10 alkyl, such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl, decyl or the like, C6-C10 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 m is an ~6 integer of 0, 1 or 2, (3) -N ~ wherein R6 is -COORg (R7)p wherein R8 is selected from the group consisting of hydrogen, Cl-C10 alkyl, such as methyl,ethyl, propyl, butyl, tert butyl, hexyl, octyl, decyl or the like, C6~C10 aryl, such as phenyl, m-tolyl, naphthyl ox the like, aralkyl of 7-12 (preferably 7-10) carbon atoms, such as benzyl, phenethyl or the like, and 5-indanyl; (R7) is hydrogen, alkyl of 1-10 (preferably 1-6) carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, hexyl, octyl, decyl or the like, phenyl Cl-C5 alkoxy or carboxy; p is an integer of 1 to 5; R6 is substituted at the 2 or 3-position; and R7 can be substituted at the 2, 3, 4, 5 or 6-position, COOR ~
(4) - N ¦ which is optionally substituted with at ~ CH2~r least one Cl-C5 alkyl and/or Cl-C5 alkoxy, wherein Rg is selected from the group ..,,~

~23~

consisting of hyclrogen, Cl-C10 alkyl, such as methyl, ethyl, propyl, butyl, tert-butyl~ hexyl, octyl, decyl or -the li]ce, C6-C10 aryl, sllch as phenyl., m-tolyl9 naphthyl or the like, ara:lkyl Or 7--12 (preferably 7-10) carboll atoms~ such as benzyl, phenethyl or the like, and 5-indanyl.; and r is an integer Or 1, ~, 3 or 4, C~l O
\
(5) -N Z wherein Rlo is selected from the group (CH2)q consisting of hydrogen, Cl-C10 alkyl, such as methyl, e-thyl, propyl, butyl, tert-butyl, hexyl, octyl, decyl or the like, C~-C10 aryl, such as phenyl~m-tolyl, naphthyl or the like, aralkyl of 7-12 (preferably 7-10) carbon a-toms, such as benzyl, phenethyl or the like, and 5-indanyl; Z is selected from the group consisting of oxy (--O-), thio (~S-) and sulfinyl (-SO-); q is an integer of O or 1, and :

COORl 1 ~
( c l I z ) ~ w h e l ei n n ] ] i bi ~ e ] e c t e d f ro m tlle group COII~;iStill~ of llydrl)G'CJl, Cl--Clo ~ll~yl~ SllCIl a~ metllyl, ethyl, ~rol~yl, I)u-tyl, tcrt-l)lltyl., hexyl, octy~, dccyl clr tlle like, C6-C10 aryl, ~uch ~S phellyl, m-tolyl, naphthyl or the like, aralkyl of 7-12 (preferably 7-10) carbon atoms, such as berl~yl, pllcrl~ttlyl or the like, arlcl 5-irldallyl.; i is an '3 - ~

,, .

23~
lnteger of 0, 1 or 2; j is an integer of 0, 1 or 2; ancL the sum of i~ ls an inte~er of 1 or 2; an~ Ar is selected f~om the group consisting of naphthyl, such as l-naphkh~l and 2-naphthyl, 5,6,7,8-tetrahydronaphthyl, optionally suhstituted with at least one Cl-C5 alkyl and/or Cl--C5 alkoxy such as 5,6,7,8-tetr~ ydro-l~naphthyl and 5,6,7,8-tetrahy(lro-2-aphtllyl, nilphtllyl substituted witll at leasl one substituent selectecl L~ronl tlle group eonsi.stillg o~ ha:Lo, sucll as fluoro, chloro, brotl)o ancl iodo, nitro, eyano, hyclroxy~ allcyl of 1-10 (preferably 1-5) earbon atoms, SllCIl as met;hyl, ethyl, propyl, isopropyl, butyl, isobutyl or -tlle li.lse, alkoxy of 1-10 (preferably 1-5) carbon a-toms, such as methoxy, ethoxy, propoxy, isopropoxy, bu-toxy, sec-butoxy, tert-butoxy, pentyloxy or the like~ alld diallcylamillo oL` 2-20 (prererably 2-10) carbon atoms, such as dime-thylamillo, cliethylamino, N-methyl-N-ethylamino or the l.i.ke, phenyl, pllenyl subs-tituted ~ith at least one substituent selected rrom the group COIl-iStillg Or halo, such as rluoro, ch1oro, bromo an~ io~lo, ni.tro, cyarlo, hydroxy, allcyl o.f 1-~10 (p.referal)ly 1-5) carbon atoms, SllCh clS mel!;llyl., ethy1, propyl~ isol~ropy~ lltyl, iiobll~y.l. or l)lc Lik(, a:lkoxy ol` 1-:J() ¦~rel`eIably 1-5) carbon atoms, 9uch .l9 metlloxy, ethoxy,propoxy, isopropoxy, bu-toxy, sec-butoxy~ tert-b-ltoxy, pentyl.oxy or the .lil<e, arld dial.kylamino o.f 2-20 (prererably 2-lU) earl.)oll atollls, suel as dimethylam:ino~ ~liethylamirlo, N-metllyl.-N-etllylclllLirlo or the like, aral]cy:l of 7-12 (preferab1y 7-10) earbon atoms, ,, -- I 11 _ ~iuch aS bonzyl~ phenethyl or the like~and~

ô~ ~`0) ~ ~ _ ~ and ~ } R12 which are optionally substituted with at least one Cl-C5 alkyl and/or Cl-CS alkoxy, wherein R12 is hvdroqen, alkyl of 1-10 (preferably 1 5) carbon atoms, such as methyl, ethyl~ propyl or the like, or alkoxy of 1-10 (preferably 1-5) carbon atoms, such as methoxy, ethoxy, propoxy or the like.
Suitable illustrations of Rl in the above formula (I) are C2-C10 alkyl~ such as propyl 9 butyl, isobutyl, pentyl, hexyl and octyl, C3-C6 alkenyl such as allyl, C3-C6 alkynyl9 such as 2-propynyl, C2-C6 alkoxyalkyl 7 such as 2-~ethoxyethyl, Z~methoxypropyl, 2-ethoxyethyl and 3-metho~ypropyl, C2~C6 alkylthioa~kyl 9 such as Z-ethylthioethyl and 2-methylthioethyl, C2-C6 alkylslllfi~ylalkyl, 9uoh as 2-methylsulfinylethyl, Cl-C6 hydroxyalkyl~ such as 2 hydroxyethyl and 3-hyd~oxybutyl 9 Cz~C7 carboxyalkYl, such as l-carboxybutyl~ C3-C8 alkoxycarbonyl-alkyl, such as 2-ethoxycarbonylethyl~ C7-C10 aralkyl, such as -- 1.~ --.

~.'.''' 3:~

bell~yl and ph~nethyl, C8-C12 .~ -carboxyaralkyl, such as ~ -carboxyphene-tllyl, C3-C10 cycloalkyl, such as cycloprop-yl, cyclohexyl and cycloheptyl, Cl-Clo cycloalkylalkyl, such as cyclohexylmetllyl, :fur:~uryl, te-trahydrof`urfllryl, 3~furylmethyl, -tetrahydro-3-furylme-thyl~ 2-thenyl, 3--thenyl, te-trahyclro-2-thenyl and tetrahydro-3-thenyl.
Suitable illustrations of R3 in the above formula (I) are hydrogen, Cl-Clv alkyl, such as methyl9 propyl, butyl, isobutyl, pentyl, hexyl and octyl, C3-C6 alkenyl, such as allyl, C3-C6 alkynyl, such as 2-propynyl, C2-C6 alkoxyalkyl, such as 2-methoxyethyl, 2-methoxypropyl, 2-ethocyethyl dllcl 3-methoxypropyl, C2-C6 alkylthioalkyl, such as 2-ethylthio-ethyl and 2-methylthioethyl, C2-C6 alkylsulfinylalkyl, such as 2-methylsulfir.~ylethyl, Cl-C6 hyd:roxyalkyl, such as 2-hydroxyethyl and 3-hydroxybutyl, C2--C7 carboxyalkyl, such as l-carboxybutyl, C3-C8 alkoxycarbonylalkyl, sueh as 2-ethoxyc~rbonyletllyl~ C7-Clo aral]cyl~ Such as ~enzyl and l)hcllotllyl~ C~-C12 d~ -c~ o~;y~r~ y~., S~lCll US ;~( -CUl~l~OXy phcllet~lyl, C3-Cl O cycl.oa~ yl, SllCll a.s cyc l.ol-2~ u~ yc~ y.~ -Cl~ cyelo~:Lliyl.~.ll~y:l, sllcll ~ eyelol)~xy~.-methyl~ furfuryl., tetrahydrofurfuryl, 3-furylmethyl, tetrallydro-3~~urylmethyl, 2-thenyl, 3-therlyl, te-trahydro-2-thenyl ancl tetrallydro-3-thenyl.
~uitable illustratiolls of RJ~ in the above formula (I) are C~-c5 a.lky.l.~ sllcll us metllyl and propy~, carl)oxy, C2-C5 - l6 -~!

23~

allcoxycarbonyl, such as ethoxycarbonyl, C7-C10 aralkyl, such as benzyl~ and ring qubstituted benzyl wherein said su~stituent is Cl-C3 a:Lkoxy, such as 4-methoxybenzrl.
Suitable illustrations of R7 are hydrogen, Cl-C6 alkyl, such as methyl~ ethyl, propyl and isopropyl 9 phenyl and carboxy, and the suitable position of R7 i9 ~s 4 or 6.

COOH
)--\ .
Suitable -N \Z group~ are 3-carboxy-4 morpholino, \ (C~2)q 3-carboxy~4-thiomorpholino, 1-oxo-3-carboxy-4.-thio~orpholino and 4-carboxy-3-thiazolidinyl.

COOH
Suitable -N ~ ~ groups are 2-carboxy-1~2~3,4-tetrahydro-l-quinolyl, 3-carboxy-1,2,3,4-tetrallydro-2- -isoquinolyl, l~carboxy-1~2,3,4~tetrahydro 2-isoquinolyl, 2-carboxy l-indolinyl and 1-carboxy-2-isoindolinyl.
Sui.table illu9trations of R2, R~ R87 R9- Rlo and Rll are hydrogen, Cl-C10 alkyl, such as methyl~ ethyl, tert-butyl and octyl, C6-C10 aryl, such as phenyl and m-tolyl, C7 C10 ; aralkyl, such as benzyl, and 5-indanyl.

- 17 ~
~ .

2~

Sui-table il:lus-trations of ~r in the above formula (I) are naphthyl, such as l-naphthyl and 2-naphthyl~ 5,6,7,8-tetrahydsronaphthyl, such as 5,6,7,8~tetrahydro~1-naphthyl and 5,6,7,8-te-trahydro-2-naphthyl~ naph-thyl substituted ~ith at least one substituent ~e].ected from the group consisting of halo, such as chloro and bromo, hydroxy, Cl-C5 alkyl, such as methyl, ethyl and isopropyl, Cl-C5 alkoxy, such as methox-y and ethoxy, and C2-C10 dialkylamino, such as di~ethylanuno and diethylamino, phenyl, phenyl substituted wi.th at least one substituent selected from the group consisting o:~ halo, such as chloro, Cl-C5 alkyl, such as methyl, ethyl and isopropyl and Cl-C5 alkoxy, such as methXYs C7~C10 arallcyl~ ~uch as phenethyl, ~uch as ~ ) , ~ ~ , such as and . _ ~ , such as ~

The preferred Ar groups are l-naphthyl, 2-naphthyl, 5,6,7,8-tetrahydro-l-naphthyl~ 5,6,7,8-tetrahydro.-2-naph-thyl, 5-chloro-l-.naphthyl, 6~chloro-2-naphthyl, 6-bromo l-naphthyl, 5-hydroxy-1-naphthyl, 7-hydroxy-2-naphthyl, 6-methyl-2-naphthyl, 6~methyl-l~naphthyl, 7-methyl-1-naphthyl~ 7-me-thyl-2-naphthyl, 6-ethyl-2-naphthyl, 6,7-dimethyl-1-naphthyl, ~ 18 -c , , , ' , . . ' , G,7-dimethyl-2-rlapllthyl, 6-i sopropyl-2-naphtllyl, 5-methoxy-l-naphtllyl, 6-methoxy-2-naphthyl, 7-methoxy-2-napllthyl, /l,6-~limt?thoxy-2-rlclpll-tllyl., 6~7-dime-thoxy-2-llapllthyl~ ~77-ciit-~tlloxy-2~napllt~ly~, 5-dimethyla~irlo-1-rlaplltlly:L, 5-dimethylamino-2-naptlthyl, 5-di.ethylamino-1-napllthyl~ 6-dimettlylamillo-l-rlaphthyl, 6-dimethylamino-2-rlaphthyl, -4--chlorophenyl, 2,4,5-trichlorophenyl~p-tolyl, anisyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, ~ ) ~ ~ ancl ~ ~ .

Illustrative of suitable N -arylsul~onyl-L-argininamides of sufficient activity are the following:

N -(6,7-di~nethoxy-2-naphthylsulfonyl)-L-arginy.l-N-propyltglyciJIe :

N -(f~,7-(limt?tlloxy-2-llapl)tlly1sl1J.fonyl)-L-ar~illyl-N-propyJ.glycille t;ert-~utyl ester N -(G,7-tlimetlloxy-2-~1a~ tlly:L~llJrolly.l)-L-arg:i]lyl-N-.
~utyJglycint-~

N -(G,7-dimethoxy-2-naphtlly1sulronyl)-L-arginy1-N-butylglycine tert-~utyl ester _ ~9 _ ~.

. ' .

N -( 6, 7 -cli.me tllo~cy-2 -llaphtllylsu:L foJIyl ) -L--a.t g.i llyl -N-isobu tyl gl yc ine N -( 6, 7-(1imc thoxy~2--naT)htllylsul ronyl )--L-arg:i.rly L--N-p en tyl gl ycin e N -(6,7-dlmethoxy-2-l1aphthylsulf`ollyl)-l,-argi~lyl--N-hexyl gly cin e N -(6,7-dimethoxy-2-rlaphthylsulfonyl)-L-argi2lyl-N-o c-tylglyciJl~

N -(4 ~6-climetlloxy-2-rlaph-t~lsulfonyl ) -I,-arginyl-N-butylglycine N -(6,7-~1iethoxy-2-naphtllylsulfonyl )-L-argillyl-N-butylglycine N -( 6-methoxy-2-naphthylsul fonyl ) -I,-arginy:l.-N-butylglycine . . .
N -( 5-methoxy-1-naphthylsulfonyl )-L-arginyl-N-butylglycine N --( 7 methoxy-2--naph-tllylsul ~onyl )--L--arginyl--N-propylglycine N -(7-methoxy-2-JIaplltllylsulfonyl )--L--arginyl.-N--butyl.glycine N -(7-methoxy-2-naph-tllylsul :t'onyl ) -L-a:rginyl -N-pen tylglycine N --(2-naphthylsul:f'onyl )-L-arginyl--N-butylglycine N --(2 lla~ tlly:lslllrollyl~-l,--argillyl-N-blltyJglyciJlc ethyl cster .

_ ;~o _ r --i ..

L~i N ~(2-naphthylsulfonyl)-L~arginyl~N-butylglycine benzyl ester N -(2-naph-thylsulfonyl)-L-arginyl-N-butyl-~ -alanine N ~(5,6,7,8-tetrahydro-1-naphthylsulfonyl)-L-arginy.L-N-butylglycine N -(5,6,7,8-tetral~ydro-2-naphthylsulfonyl)-L-arginyl~N-pe~$ylglycine N2-(5,6~7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl N-: butyl-~ -alanine ~ 10 N -(6-bromo-1-~aphthylsulfonyl)-L-arginyl-N-butylglycine ; N -~6-methyl-2-naphthylsulfonyl)-L-arginyl-N-pentylglycine ;

N -(7-methyl-2-naphthylsulfonyl)-L-arginyl-N-butylglycine :

N -(5-dimethylamino-1-naphthylsulfonyl~-L-arginyl-N
butylglycine ~:

N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-allylglycine N2 (6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-prop~nyl)glyci~e N2-(6~7-dim0thoxy-2-naphthylsulfonyl)-L-arglnyl-N-(2-methoxyethyl)glycine ~:
.
,, . , 213~

N -(6~7-dinlc~lloxy-2-lla~ yl~ ollyl)-L-ar~illyl-N-(2-mctllo~yetlly~){,r:lycillc etllyl ester N (~,7-~ o~y "-ll~lltllylslllrOllyl)-l.,-<lr~ y].-N-(2-metlloxyetllyl)glycine oc-tyl ester N -(6,7-dimetlloxy-2-naphthyl~ulronyl)-L-arginyl-N-(2-methoxyethyl)glycine ben~yl ester N -(6,7-dimethoxy-2-naphthylsul~onyl)-L-ar~inyl-N-(2-methoxyethyl)glycine 3-methylphenyl ester N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine 5-indarlyl ester N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)-~-alanine N2-(6~7-dimethoxy-2-naphthyls~l~onyl)-L-arginyl-N-(2-methoxyèthyl)-~ -alanine ethyl ester N -(~,7-dillletllo~y-2-1l~lltllyl~ lrolly:l.)-N-(2~metlloxyethyl)-N~ -carlloxyl~rnl)y~ r~rill:irlam~ e N -(G~7-~inle-~lloxy-2-~ lylslllrollyl)-N-(2-nletlloxyet~lyl) N-(3-terl;-l~ul;o~ carl)onylpl~opyl)-L-ilrgi.llirl.lnli(le N -(6,7-dimethoxy-2-napllthylslllfonyl)-N~(3-metlloxy-pro~y~)fr]ycill~

N -(6,7-dimethoxy-2-naphthylsulfonyl)-1-argillyl-N-(2-ethoxyethyl)-~ -alanine N -(6,7-dimethoxy-2-llaphthylsulforlyl)-L-Qrginyl-N-(2-methoxypropyl)glycine N -~6,7-diethoxy-2-naphthylsulronyl)-L-arginyl-N-( -methoxyethyl)glycine N -~4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl~glycine N -(4,5-dimethoxy-2-naphthyl 9 ul fonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester N -(6-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxye-thyl)glycine N -(5-methoxy-1-naphthylsulfonyl~-L-arginyl-N-~2-methoxyethyl)glycine N -(7-methoxy-2-naphthylsulfonyl)-L~arginyl-N-(2- ;~
methoxyethyl)glycine .

N -(7-methoxy-2~naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester .

I N -(5-methoxy-1-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl~-~ -alanine .. . .

~ 1- ..

~23~

N ~ na.phthylsulfonyl)-L-arginyl ~-(2-methoxyethyl)glycine N -(5,6,7,8-tetrahydro-1-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine N -(5-chloro-1-naphthylsulfonyl)-L-arglnyl-N-(2-methoxy-ethyl)glYcine N -(6-chloro-2-naphthylsulfonyl~-L-arginyl-N~(2-methoxy-ethy~)glycine N -(7-methyl-2-naphthylsulfonyl~-L-arginyl-~(2-methoxy-ethyl)glycine N (7-methyl-l-naphthylsulfonyl)-L-arginYl-~-meth ethyl)glycine N -(6,7-dimethyl-1-naphthylsulfonyl)-L-arginyl-N- (2-;nethoxyeth.Yl)glycine N -(5-dimethylamino-l-naphthylsulfonYl)-L-arginyl-N-(2 cethoxyethyl)glycine N -(7-hydroxy-2-naphthylsulfonyl~ arglnyl-N-(2-methoxy-ethyl ) glycine N -~6,7-dimethoxy-2-naphthylsulfonyl~-L~arginyl-N (2-ethylthioethyl)glycine N -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(2- .
methylthioethyl)glycine ~.

.
- 2L~

N -(7-methoxy 2-naphthylsulfonyl)-L-arginyl-N-~2-methylsul~inylethyl~glycine N ~(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-hydroxyethyl~glycine N2-(6~7-dimethoxy-2-naphthylsulfonyl)~I-arginyl-N-(3-hydroxybutyl)glycine N -(6,7-dimetkoxy-2-naphthyl9ulfonyl)-L-arginyl-N-(l-carboxybutyl)glycine -N -(6,7-dimethoxy-2-naphthylSulfonyl)-L-arginyl-N-(2-ethoxycarbonylethyl)glycine N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-benzylglycine N -~6,7-dimethoxy-2-naphthylsul~onyl)-L-arginyl-N-benzylglycine tert-butyl ester N -(6,7-dimethoxy-2-naphthylsulfonyl)-L~arginyl-N-phenethylglycine N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-ar~inyl-N- ~;
benzyl-~ -alanine ; N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-benzyl- ~-alanine ter'-butyl ester .

3~

N -(6,7-dimethoxy-2-naphthylsulfonyl)-L~arginyl-N-phene tllyl~ alani,ne N _(11 ~G-dimet]lo.~cy-2-nap]lt}lylS-Il fonyl )-L-arginyl -N-benzylglycine N -(7-methoxy-2--naphthylsulfonyl)-L-arginyl-N-phenethylglycine N -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-ben~yl-~ -aLanine N -(6-methoxy-2-naphthylsulfonyl.)-N-benzyl-N-(3-carboxypropyl)-L-argininamide N -~6-methoxy-2-naphthylsulfonyl)-N-benzyl-N-(3-tert-butoxycarbonylpropyl)-L-argininamide N -(5-methoxy-1-naphthylsulfonyl~-L-arginyl-N-benzylglycine N -(2-naphthylsulfonyl)-L-arginyl-N-benzyl-~ -alanine N -(2-1lap~ y.l~ll1 r`OJIY.I. )-L - arginY1 - N-bCn~Y1g1YCiIIC

N -(5,6,7,8-tetrahydro-1 naphthylsulfonyl)-L-arginyl-N-phenetllylglycille N -(5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl-N-benzylglyc:i.nc ? 2,3 ~

N -(5,6,7,8-~tetrallydro-2-naph-thylsulfonyl)-L-arginyl~N-benzy~ alarline N2-~7-metllyl-2-na~hthylsulf`onyl )--L-arginyi.-N-pllellethyl--g] ycine N -(6,7-d:imethoxy-2-napht.hylSulfonyl)-L-argirlyl-N~
earl~oxyp}lenethyl)glycine N -(6,7-dimetlloxy-2-naphthylSulfonyl)-L-arginyl-N-eyclohexylmethylglyeine N - ( 6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-cyclohexylmethylglycine tert-butyl ester N -(6,7-dimethoxy-2-naphthylsul~onyl)-L-arginyl-N-eyeloheptylglycine N -(4~6-di.methoxy-2-naphthylsulfonyl) L~arginyl-N-eye~.ohexylglyeille N -(7-methoxy-2-llaphtllylsulfonyl)-L-argillyl-N-eyelohexyl-g~yei.~lo N -(~-nlo~ y-~ ly.lsu.LJ.`ollyl.)-L-argillyl-N-eyelollexyl-mol;llyl~lycill(3 N -( 5--mol,lloxy-l -lulpl~ I llyl .`;1l1. I`olly.l )-I,-arg.i lly I -N-cyc l ollexy:L--Ill~!l,lly~ o -- ~7 --"~

3~

N -(5-methoxy~ aphthylSUlfonyl~ L-arginyl-N-cy~lohexylmet}lyl-~ -alanine tert-l~utyl ester N ~ ,7-dimethoxy-2-llclplltllylsulf`onyl)-L-argi]ly:L-N-cyclohexylglycine N -(6,7 -di me thoxy-2-llaphthyl5ulfonyl)-L-arginyl-N-cyclohexyl-~ -alanine N -~6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-cyclohexyl -~ -alanine tert-butyl ester N-cyclopropyl~N-(3-carboxypropyl)-N -(6,7-dlmethoxy-2-naphthyl~ul~onyl)-L-argininamide N -(l-naphthylsulfonyl)-L-arginyl-N-cyclohexylglycine N -(5,6,7,8-tetrahydro-1-naphthylsulfonyl)-L-arginyl-N- -cyclohexylglycine N -(5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl-N-; 15 cyclohexylmethylglycine N2-(7-ne~ly]-2-llc~ tllylslllfollyl)-L-ar~inyl-N-cyc:lollexyl-motllylglycirlc N -(7-methyl-2-naphthylsulfonyl)-L-arginy~-N-furfllrylglycine N -(7-methyl-2-naph-thylsulfonyl)-L-arginyl-N-tetrahydro-furfurylglycine ~, ~2i,~

N -(7-methoxy-2-JIaphthylsulfonyl)-L-arginyl-N-furfury~.glycille N -(7-me-tllo~y-2-naplltllylS-Ilfonyl)-lJ-argiJlyl-N-f`urfurylglycirle tert-bu-tyl ester N -(7-methoxy-2-rlap}ltllylsul~onyl)-L-arginyl-N-tetrahy(lrorur.furylglycirle N -(5-dimetllylamino-].-rlaphthylsulf`onyl)-L-arginyl-N-tetrahydrofurf`llrylglycine N -(5-chloro-1-naphthylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine N -(l-naph-thylsul~onyl)-L-arginyl-N-tetrahydrof`urfuryl-glycine N -(6,7-dimethyl-1-naphthylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine N -(5,6~7~8-tetrally~ro-1-napllthylsulf'onyl)-L-arginyl-N--tetrahydrof`-lrt`uryJ glycine N -(6~7-di.nl(3Llll)xy-2-llal)lltlly-.SulL`ollyl)-L-argillyl-N-tctrallydrorurrurylglyci.lle N -(6,7-dimQ~IIoxy-2-llul)~ltlly.l.~ulrollyl)-L-~rgi]lyl-N-~ y~7~ o _ .
~' 2 b3 ~

N -(6,7-~imet~loxy-2-l1aplltllylslllfonyl)-L-argiJlyl-N-butyla~ine t~rt-butyl ester N -(6,7-dim~t~loxy-2-1laplltllylsulronyl)-L-clIginyl-N-pentylalarline N -(6,7-dimethoxy-2-naphthylsul~onyl) L-arginyl-N-b~n~ylalanine N -(6,7-dime-thoxy~2-naphthylsulfonyl)-L-arginyl-N-phenethylalanille N -(6,7-dimet;hoxy-2-naphthylsulfollyl)~L-arginyl-N-cyclohexylalanine :

N -(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-cyclohexylmethylalanine N -(7-methoxy-2-naphthylsulronyl)-L-arginyl-N-propylalanine N -(6,7-dimethoxy-2-1~apllthylsulfonyl)-L-arginyl-N-(2-metlloxy-etJIyl.)ala~ e N -(6~7-~ leilloxy-,-~ plll,lly:lsul~`o~ly:l)-l,-ar~r.il-y~ lorvalillo N -(6,7 dimetlloxy-2-naphthylsulronyl)-L-arginyl-N
butylaspartic acid N -(6,7-dinle~lloxy-2-naplltlly~sulfollyl)-l.,-arginyl-N-~utylaspartic aci.d diotllyl ester .

- 3~ --.,~,........... .

N -(6,7-dimetlloxy--2-rlaplltllylsulfollyl )-L-arginy:l-N-ben~y:laspartic aci(l N -( 6, 7-(1:i nletlloxy-2-rlap}lthylSulrollyl )-I,-ar~ yl-N-ben~;ylaspartlc acid diethyl ester N --(6,7-(limo~hoxy--2-napllthyls~l:l.rollyl)-L--arg:illy:l-N--n1ethyl ~ -pllenylalani3le N -(6 ,7-dimetl-loxy-2-l1aphthylsulrollyl )-L--argr:illyl~N-methyl-_( l~--me t~loxyphenyl ) alanine l-~N2-(6 ,7-dime thoxy~2-naphthylsulfonyl ) -L-arginyl~--2-piperidillecarboxylic aci.d Ethyl l - [N - ( 6, 7 -di me thoxy-2 -naph-i;hyl s u .l ro n y]. ) -L-argi n yl~ -2--piperidinecarboxylate 1- [N2-( 6-methoxy-2-naph thylsulfonyl )-L-arginyl~ -2 -piperidillecarboxylic acid 1- [N -( 6 ~ 7 -(lime l;hoxy-2-napllthy].su~ fonyl )-L-arginy Z.~ -4-metllyl-2-pil)~?ri(li.llecarboxylic acid 1- [N -(7-mcl,llo~y-2-nap]ltllylsulronyl )-I,-argilly~ -4 -methyl-2-piperidinecarboxylic acid 1- [N -( 5-me thoxy-l -naph-thylsul fonyl ) -L-arginyl~ -4 -methyl -2--2 0 . ~i. r~ ~ ri. ~ l o c .~ o xy.l i c ~I c i ~

~ l _ ..
I

~ .
.' 2~6 Ethyl 1~ (5-me-thoxy-1-naphthylsulfonyl)-L-arginyl~-4-methyl-2-piperidinecarboxylate l-~N -(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl~-4-methyl-2-piperldinecarboxylic acid l-~N -(6,7-diethoxy-2-naphthylsul~onyl)-L-arginyl~-4-methyl-2-piperidinecarboxylic acid l-~N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl~ -4-ethyl-2-piperidinecarboxylic acid l-rN -(7-methoxy-2-naphthylsulfonyl)-L-arginyl~-4-ethyl-2-piperidinecarboxylic acid l-rN -( 6~7-dimethoxy-2-naphthylsulfonyl)-L-arginyl~-4-propyl-2-piperidinecarboxylic acid l-~N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl~-4- ~-isopropyl-2-piperidinecarboxylic acid 1$ l-~N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-argi~yl3-6-methyl-2-piperidinecarboxylic acid l-~N -(7-methoxy-2-naphthylsul~onyl)-L-arginyl~-2-me.thyl-2-piperidinecarboxylic acid 1 [N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl~-3-piperidinecarboxylic acid , 3 ~ ,................ ... .
.
l 1'-' ~ 2~:~.6 ~lethyl 1- CN -( 6 7 7-di.methoxy-2-llaphthylsulfonyl)-L-arginy].~-3-piperidin~acarboxyla-te l-~N -(7-methoxy-2-naphthylsulfony.l)-L arginyl~-3 piperidinecarboxylic acid l~[N -(7-methoxy-2-naphthylsulfonyl)-L-arginrl~-2, 6-piperidinedlc~rboxylic acid l-[N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl~-4,-phenyl-2-piperidinecarboxylic acid l-~N ~ naphthylsulfonyl)-L-arginyl~-4-methyl-2-piperidinecarboxylic acid Ethyl l-~N -(l-naphthylsulfonyl)-L arginyl~-4,-methyl-2-piperidinecarboxylate N -(2-naphthylsulfonyl)-L-argirlyl~-4-isopropyl-2-piperidinecarboxylic acid Ethyl l-~N2-(2-naphthylsulfonyl)-L-arginyl~-4-isoPropyl 2~piperidinecarboxylate l-CN (5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl~-4-methyl-2-piperidinecarboxylic acid ! Ethyl l-[N -(5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl~-4-methyl-2-piperidinecarboxylate .. .. . . . . . ..... ... . .. .. .... . . .. . . . . ... . .. .... . . . .... . . .. ... . .. . . .
..

~23~6 l-[N -(6-chloro-2-naphthylsulfonyl)-L-arginyl~4-isopropyl-2-piperidinecarbo~ylic acid l-~N ~(5-dimethylamino-1 naphthylsulfonyl)-L-arginyl~-2-piperidinecarboxylic acid l-[N -(7~methyl-2-naphthyl sul fonyl)-L-arginyl~-4-me-thyl~2-piperidinecarboxylic acid l-~N -(7-methyl-2-~aphthylsulfonyl.)-L-arginyl~-4-ethyl-2-piperidillecarboxylic acid l-~N -(7-methyl-2 naphthylsulfonyl)-L-arginyl~~4 isopropyl-2-piperidinecarboxylic acid Ethyl l-~N -(7-methyl-2-naphthylsulfonyl)-L-arginyl~-4-isopropyl-2-piperidinecarboxylate l-tN -(6 methyl-2-naphthylsul~onyl~-L-arginyl~-4-isopropyl-2-piperidinecarboxylic acid l-[N -(7 methyl-2-naphthylsulfonyl)-L-arginyl~2-hexamethyleneiminecarboxylic acid 4-[N -(7-methoxy-2-naphthylsul~onyl)-L-arginyl~ -3 thiomorpholinecarboxylic acid ; 4 CN -(7-methoxy-2-naphthylsulfonyl)-L-arginyl~ -3-carboxythiomorpholine l-oxide ~. _ ... , . ,.. ... ,. ,.,, . . . ., . _ .. _,__ .. , l .
I

4-~N ~(6~7-~ime-thoxy~2~naphthylSu].fonyl)~L-arginyl~ 3-morpholinecarboxylic acid 4-[N -(7~methoxy~2-naphthylsul~onyl)-L~arginyl~-3-morpholinecarboxylic acid 3-[N -(7~methoxy-2-naphthylSulfonyl)-L-arginyl~-4-thiazolidinecarboxylic acid 2 - tN2 -(6,7-dimethoxy-2-~aphthylsulfonyl)-L-arginyl~-1 J 2,3~4-tetrahydroisoquinoline-3-carboxylic acid 2-~N2-(6,7-dimethoxy-2-naphthylsul~onyl)-L-arginyl~
isoindoline-l-carboxylic acid N -(4-chlorophenylsulfonyl)-L-arginyl-N-butylglycine N -(294,~-trichlorophenylsulfonyl)-L-arginyl-N-butylg7ycine N -tosyl-L-arginyl-N-butylglycine N -(4 methoxyphenylsulfonyl)-L-arginyl-N-benzylglycine N (3,4-dimethoxyphenylsul~onyl)-L-arginyl-N-(2-methoxyethyl) glycine N -(3r4,5-trimethoxyphenylsulfonyl)-L~arginyl-N-(2-methoxyethyl)glycine N -phenethylsulfonyl-L-arginyl-N-furfurylglycine ~ 35 ~
r~
~.
l l;

2~

N ~ -ben~odioxan-6-sulfonyl)-L-argirlyl-N-(2 me-thoxyethyl) glycine N --(fi,7--c~ll;y~ io~cy--2~ tlly~ ]rO~ly~ r~illyl--N--(2-me-thoxyetllyl)glycLne l-tN ~(2-dibenzorura~yl)-L-arginyl~-2-piperidillecarboxylic acid ~' Of the compounds of this invention, i-t will be ~Iderstood that the following compounds are most preferred due to their high level Or antitllrombotic activity ancl lo~ level of toxicity.

N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylglycine N -(7-methoxy-2-naphthylsul~onyl)-L-arginyl-N-butylglycine N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine N -~6,7-climethoxy-2-naphthylsulfonyl) L-arginyl-N-(2-methoxyethyl)glycine ethyl ester N -(ll,6-dinlctlloxy-2-l~apllthyls~llfonyl)-L-arginyl-N-( 2-methoxyetllyl )glycine N -(7-methoxy-2-naphthylsul~onyl)-L-arginyl-N-(2-me-thoxyetllyl)glycille ~;

-- ~6 --2 :
N -(5,6,7,8~tetrahydro~ aphthylsulronyl)-l-arginyl-N-~2-metho~yethyl)g.lycine N -(7-methoxy-2-l1apllt}ly].slllfollyl)-L-argiJlyl-N-tetrallydro-f` rf`urylglyci.ne N -(7-me~hyl-2-na~ tllyl.sulfollyl)-L-arg:inyl.-N-te-trahydro-furfurylg,lycine '' N -(6,7-climethoxy-2-naphthylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycille 1. rN -(6,7-dimethoxy-2--naphthylsul:fonyl)-L-arginyl~-4 methyl-2-piperidinecarboxylic acid l-~N -(7-metho~y-2-naphthylsu~fonyl~-L-arginyl~-4-methyl-2-piperidinecarboxylic acid l-~N (7-methoxy-2-naphthylsulfonyl)-L-arginyl~-4-ethyl-2-piperidinecarl~oxylic acid Tlle pllarmacelltical.ly acceptable sal.ts of the above compoundS
are of collrse a.lso incllldcd within tlle scope of this i ll ven ti on .
As one skilled in the art can readily appreciate, the carbon atom o r the N -arylsulfonyl-L-argininamides, to whicll the carl~oxy.l. group or tlle ester thorco~`is attached can l~c an a.symmctric car~on atom a:1.1Owi.n~ ~or the existence ~ 37 ~

3~;

of two optically active isomers, the D- and I-diastereoisomers, as we~l as the racemate, DL-mixture.
In accordance with rindings concerning tl)e a11tithrombotic activit;y Or such compollJ1ds poSSeSSi1lg an asymmetric carbon atom, the compounds of` the pres E3nt invention having -the D-config~1ra-tion are more active -than those Or the L-config~lratio~ d are thc preferrec1 compounds, although the I- and DL-forms of tlle inStal1t compounds are also considered within the purview Or tlle 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.
~or the preparation of the compounds Or this invention, various methods can be employed depending upon the parti cu-- -lar starting materials and/or intertnediates involved.
Successf`ul preparation of these compounds is possible by way of severa1 syntl~etic routes which are outlilled below.
(a) Conde11sation o~ an L-arginir1ami~lc with an ary:lsulfonyl 2 0 1~
This proccss may be illustra-ted as rOllOws ~IN
~ C -- N -- C 112 C112C l l~C}~
2 H NH2 ;~

~ 3~ --~. , l~G2~L6 HN ~
~C--N--CH2CH2CH2CHCOOH (II) I ~" E~N
R' I
R"' ~.

-~ RH (IV) HN
~C--N--Cl-12CH2CH2CHCOR (V) I R" E-~
R' I

HN ~
C - N - CH2CH2C~12CHCOR ~VI) ~ + ArS02X (VII) HN
~C - N - CH2CE~2CH2CHCOR (I) HNSo~
Ar ~' Ill tllo above l`ormlllas~ R ~Id Ar are a~ derillc~ herein above; X is llalogell; R"~ is a protective group for the ~ -am.ino group~ such as benzyloxycarbonyl or tert~
buto~ycarbonyl R' and R" are seleote(l from the group Collsistillg Or hy~rogen and protective grollps ror the gllani~lirlo group, such as nitro, tosyl, trityl, - 3~ - :

~2~

oxycarbonyl and the like; and at least one of R~ and R" ls a protecti~e group for the guanidino group.
The N -arylsulfonyl-L-argininamide (I) is prepared by thc condeJIsatioll of an L-argininanli(lo (VI) wi-th a sulostantially equimolar amount of an arylsulfonyl haliclc (VII), preferably a chloride.
~he condensatiorl reaction is generally e-~ected in a suitable reaction-inert solvent in tlle presence of an excess of a base, such as an organic base (triethyl- :
amine~ pyridine) or a solution of an inorganic base (sodium hydroxide, potassium carbonate)-, at a tempera- ~ :
ture 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 dioxane-water. ~ ~
After the reaction is complete, the formed salt is : --extracted Wit]l water, aDd the solvent is removed by such standard means as evaporation under re~uced ~)rc.~ rc I;o ~:ivc thc N -arylsll]rony1-J-argi~llnamide (]:), wlli.cl~ c~l ~e puriricd ~y trituratioll or recrysta~
~atioll L`rolll a sui-tal)le solvellt, ~ucll as diethyl ether-Lctrallytlrorllrall, dictllyl ethcr-rnetll~lol an(l watcr- ::
metll~loL, or nlay ~c cllromatograplle(l on silica gel.
l`llc L-ar~inillanu(lcs (Vl) startlrlg m.ltoria:ls require(l ~ ~0 -;2~

for the condensation reac-tion can be prepared by protecting -the guanidino and ~ amino groups of L-arginine (II) vi.a nitra-tion, acetyla-tion, formylation, phthaloylation, tri~luoroacetylation~ p-methoxy-benzyloxycarbonylation, benzoylation9 benzyloxy~
carbonylation~ tert-butoxycarbonylation or tritylation and then condensing the formed N -substituted-N -substituted-L-arginine (II) with a corresponding amino acid deriva-tive (IV) by such a conventional process as the acid chloride method, azide method, mixed anhydride method, activated ester method or carbodiimide method, and thereafter selectively removing the protective groups from the formed N -qubstituted-N -substituted-L-argininamide (V).
The amino acid derivatives (IV) which are the starting materials for the preparation of the NG-substituted-N -substituted-L-argininamides (V) are represented by the following formulas~

H-N ~ 1 (vm) H-N~ 3 (IX) (CH2)nCR2 ~ CH~(CH2)mCR,~ :

I R6 COORg H-N ~ (X) ~I~)r (XI) ~ 41 -.. , . .. . . . .. ... . . . , . .. ., .. ~ .. . . .. . ..
r .
. .
~, .

~ 23i~ ~
COO~lo COO~
CHz (XII) ~ CHz) ~ (XII) In the above formulas, Rl, X2, R3, R4, R59 R6, R7, Rg, RloJ Rll, Z, n, m, r, q, i, and j are as dofined herein above.
The amino acid derivatlves of the above formula (vm) or (IX) can be prepared by the condensation of a haloacetate, 3-halopropionate or 4-hal.obutyrate with an appropriate amine having the formula RlNH2 or R3NH2o (See, J. Org. Chem5~ 2~ 728-732 (1960)).
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 pyridineJ at a temperature of 0C to 80 C for a period of lO minutes to 20 hour9. 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 r~duced pressure.
Among the amino acid derivatives~ amino acid tert-butyl ; ester derivatives are preferred~ because they are easily converted to other ester derivatives by acidolysis in , , , , , , , , . . . ; .. ... . . ... ... .. ... . . .. . .
~ ..
., .

: ", ~ Q2~

the presence of a corresponding alcohol employing an inorganic acid (HCl, HzSO~, etc.) or ~n or~anic acid ~toluenesulfonic acid, trifluoroacetic acid, etc.).
In accordance w.ith the process employed for preparing 2-piperidinecarboxylic acid derivatives (X), the following scheme i9 illustrative:

Cl> ~ R ~ ~ 7 H Cl (~IV) (XY) (XVI) 7 2~ _~ ~ R7 N CN (H~) N C02H
H H
(XVII) (xvm) In the first reaction of the a~orementioned schemeJ 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., die-thyl ether~ and then treated with potassium hydroxide in a lower alkanol solvent to give the 1J2-dehydropiperidine (XVI). The action of cyanogenating agents~ e.g., hydrogen cyanide or sodium cyanide converts the 1,2-~0 dehydropiperidines (XVI) to the corresponding 2-cyano ~ ' - '~~

~, analogs (XVII). HydrolysiS of the 2-cyanopiperidines (XVII) to yield the 2-piperidinecarboxylic acids (XVII~ is effected by treatment of the 2-cyanopiperidines (XVII) with an inorganic acid, such as hydrochloric acid or sulfuric acid.
The arylsulfonyl halides (VII) which are the starting materials for the prepara-tion of the N2-aryls~tlfonyl-L-ar~ininamides (I) can be prepared by halogenatin~
the requisi-te 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 ouk without a ~olvent or in a suitable solvent e.g., halogenated ~ ~;
hydrocarbons or D~F in the presence of a halogenatin~
agent, e.g., phosphorous oxychloride, thionyl chloride, phosphorous trichloride, phosphorous tribromide or phosphorous pentachloride, at a temperature of -10 C
to 200C for a period 3f 5 minutes to 5 hours. After the reaction is complete9 the reaction produc~ is poured into ice water and then extracted with a solvent ~uch as ether, benzene, ethyl acetate, chloroform or the like.
The arylsulfonyl halide can be purified by recrystalli-zation from a ~uitable solvent such as hexane, benzene or -the like.

_ 44 -~, '' ~ . ` ,.

~ ~'~

(b) Remo~al of the N -substituent from an NG-substituted--N ~arylsulfonyl~L-argininamide This process may be illustrated as follows:

HN
~IN ~C IN CH2C~IZCH21HCOR (V) -I R" HN
F~l I
R"~

HN ~C-l-cH2cH2cH2cHcoR (XIX) _AlS02X (VII) I R~ NH2 R' HN ;~
fC-N-cH2cH2cH2cHcoR (XX) I R~' HNS02 :R' I
Ar H2cHcoR (I~
H ~SO2 Ar - 4~ - 9 , _., . . . . .. _ _ ._ _ _._ _, _ .. _.. _ ._ . . _ .. .. ...... . _ _.. _ .. ~_. ____ . _ _ ----f _ .
.' ,, .
"

~2~6 In the above formulas, R, Ar, X~ R'~ R" and R"~ are as definecl llerein above.
TI1e N -arYISU1rOIIY1-L-CIrgiIIinaIt1ide 1I) j.S prepared by removing tlle N -subs-tituent f`rom all N~-substituted-N -arylslllronyl-L-argininamide (XX) by means of aciclolysis or hydrogenolys:is.
Tile acidolysis is generally effected by contac-ting the N -substituted-N -arylsulfonyl-L-argininamide (XX) and an excess of an acid such as hydrogen fluoride, hydrogen chloride, hydrogell bromide or trifluoroacetic acid, without a solvent or in a solvent, such as an ether (tetrahydrofuran, dioxane~, an alcohol (meth~nol, ethanol) or acetic acid at a temperature of -10 C to 100 C, ~ld pr~erably at room temperature for a period of` 30 minutes to 24 hours.
The products are isolated by evaporation of the solvent and the excess acidj or by trituration with a suitable so~vellt ~ollowe(l l)y filtratioll an~ (lrying.
]lecalls(? Or tllC IlSe ol` I;l~o OXC(?:;~ ;ICi(1, tllC p.l'O~]IICtS
are ~,elleral~y tllc ~ci~ 3(l:itioll 9.-ltg oi` tllo N -arylsul~onyl-L-argininamides (I), which can be easily collverte(l to a ~ree an~de by ne~ttrali~ation.
The removal Or the nitro group ~Id tlle oxycarbonyl grou~, e.g., benzyloxycarbonyl, p-nitroben~yloxy-carl~ollyl, is rca~ily accomL~ ed by tlle hydrogellolysis.

~6 -~ .

f At the same time, the ben~yl ester moiety wh:Lch can be included in the R group i9 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 prasence of a hydrogen-activating oatalyst, e.g.~ Raney nickel, palladium, or platinum, in a hydrogen atmosphere at a temperature of 0C to the boiling temperature of the solvent for a period 10 of 2 hours to 120 hours.
The hydrogen pressure is not critical, and atmospheric pressure is sufficient, The N -arylsul~onyl-L-argininamides (I) are isolated by filtration of the catalyst followed by evaporation 15 of the solvent The N -arylsulfonyl-L-argininamides can be purified in the same ~anner as described above.
The NG-substituted-N2-arylsulfonyl-L-argininamides (XX) starting materials can be prepared by conden~ing an 20 NG-substituted-N -substituted L-arginine (DI) (generally the NG-substituent is nitro or acyl, and the N2-substituent is a protective group for the a~ino group 7 ! such as benzyloxycarbonyl, tert-butoxycarbonyl, or the like) and a corresponding amino acid derivative (IV)~
25 selectively removing only the N -subs-tituent of an ~ 47 -~. l ., -substituted-N2-substituted L~argininamide (V) by means of catalytic hydrogenolysis or acidolysis, and then colldcllsill~ tlle f;llus obtained NG-sl~bstitllted-L-Ul'~:illill.llll.idO (~lX) Willl ~1 arylsllli`ollyl lla.l.iclc (VIl), preferably a chloride in the presence of a base in a solvent. These reaction conditions are as described above i.n the conde]lsation of an L-argininamide with an arylsulfonyl ha].ide, and the remova~. of the NG-substituent from an NG-substituted-N -arylsulfonyl-L-argininamide, (c) Condensation of an N -arylsulfonyl-L-arginyl halide with an amino acid derivative This process may be illustrated as follows: -llN
}I N ~ N CH2CH2CH21CHCOOH (II) NH2 ~ , ~ ~rS02X (VII) ~C--N--cll2cll2c}l2cllcoo~l (XX~
~INSO
2 ~.
~r :~

~ 48 -C-N--C112C1~2CH2C~ICOX (x~
1~2N
}LN S 2 Ar -~ ~1 (IV) ll IIN ~
,C-N-cll2cH2c~l2cHcOR (I) Ar In the above formulas, R, Ar and X are as defined lO herein above.
The N -arylsulfonyl-L-argininamide (I~ is prepared by the condensation of an N -arylsulfonyl-L-arginyl halide (XXII), pre~erably a ch]oride with at least an equimolar amo~mt of an amino acid derivative (IV).
The condensation reaction can be carried out without an added solvent in the presence of a baseO However, satisfactory results will be obtained with the use of - a solverlt sllcll as basic solven1;s (dimethyl~ormamide~
dimethylacetamide, etc.) or halogenated solvents (chloroform, dichloromethane, etc.).
The amol~t of the solvent to be used is not critical and may vary from abollt 5 to 100 ti mes l;lle wei~llt Or tho N -aryls~ ol~y~ arginyl llalido (XXI])..

~ 9 .

'3~ :

Preferred condensatiorl reaction temperatures are in the range of from -10C to room temperature. The reaction time is not critical, but varies with the ~.
ami.no aci(l derivative (IV) employed. 131 general, a period of from 5 minutes to 10 hours is operable.
The obtained N -arylsulfonyl-L-argininamide can be isolated and puriried in the same manner as described above : The N -arylsuli`onyl-L-arginyl halide (XXII) star-ting materials required f`or the condensa-tion reaction can be prepared by reacting an N -arylsulfonyl.-L-arginine (XXI) with at least an equimolar amount of a halo-genating agent such as thionyl chloride, phosphorous oxychloride, phosphorus trichl.oride~ phosphorous pentachloride or phosphorus tribromide. The halogena-tion can be carried out wi.th or without an added solvent.
The preferred solvents are chlorinatecl hydrocarbons such as chlorororm and tlichloromethalle, and et~lers such as ~ :
tetrahydrof`uran an~l dioxane. ~.
2() 'I`l~e alllo~ , ol` tllo solvollt l;n l)o use~l is ~lol c.ritical ~ .
arl~ may vary ~`rom a~out 5 to 100 times tlle weight of ~:
the N~-arylslllrollyl-L-ar~ ine (XXI).
l'rcrerrc~ reactioll temperature are in ~lle rallge of -10 C to room temperature. The reaction time is not cri.tical, but -varies with the halogellating agent and .

... .

a~

reaction temperature. In ~eneral, a period of 15 mlnutes to 5 hours is operable.
The N ~arylsulfonyl-L-arginines (XXI) w~.ch are the s-tarting materials for the preparation of the N -arylsulfonyl L-arginyl halides (X~ can be prepared by -the condensation of L-arginine (Il) with a sub-stantially equimolar amount of arylsulfonyl halides (YII), by a method similar to that desc.ribed in the condensation of an L-argininamide with an arylsul~onyl halide.
(d) Guanidylation of an N -arylsulfonyl-L-ornithinamide or an acid addition salt thereof This process may be illustrated as follows:

H2N--CH2CH2CH2 ICHCOR (X~c) ~ , HN1~2 Ar HN ~
~c-N-cH2cH2cH2CHCOR (I) ~INS02 Ar In the above formulas, R and Ar are as defined herein above.
The N -arylsul~onyl-L-argininamide (I) is prepared by ; - 51 -,.
, , ',"

f ~ 3~

guanidylating an N -arylsul~onyl-L-ornithina~ide (XXII) with an ordinary guanidyla-ting agent such as an 0-alkylisourea, S-alkylisothiourea, l-guanyl-3,5-dimethylpyrazole or carbodiimide~ The pre~erred guanidylating agents are the 0-alkylisourea and the S-alkylisothiourea.
The guanidylation o~ the N -arylsulfonyl-L-ornithinamide (xxm~ with the 0-alkylisourea or S-alkyliso-thiourea is generally e~ected in a solvent in the presence of a base at a temperature of from 0C to the boiling temperature of the solvent for a period of from 30 minutes to ~0 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 -arylsulfonyl-L-ornithinamide.
E~amples of the preferred solvents are water, water~
ethanol and water-dioxane.
After the reaction is complete, the N -arylsulfonyl-L-argininam de (I) is isolated by evaporation o~ the solvent followed by removal of the excess base and the ~ormed salt by a water wash.
I It is well recogni~ed in the art that an cster deriva-tive o~ the N -arylsulfonyl-L-arginina~ide (I) wherein R2, R5~ R8, R9, Rlo or Rll is alkyl, aralkyl, aryl or _ 52 ~

...... ,. ,. . . _ _ , _ ,.
',, ,-5-indanyl, can be prepared from a carbo~ylic acid derivative of the N -arylsulfonyl-L-ar~ininamide wherein R2~ R5~ Rg~ Rg~ Rlo or Rll Y
the conven-tional 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 conven-tional hydrolysis or acidolysis methods. The conditions under which esterification, hydrvlysis or acidolysis would be carried out will be each apparent to those skilled in the ar-t.
The N -arylsulfonyl-L-argininamdde (I) of tlLis invention forms acid addition salts ~ith any of a variety of inorganic and organic acids. Some of the N -arylsulfonyl-L-argininamides containing a free carboxyl group9 wherein R2, R5, R8, Rg, Rlo or Rll 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 o~ salts. In addition, the product can be obtained as pharmaceutically acceptable acid addition salts by reacting one of the free bases with an acid, such as hydrochloric, hydrobrondc, hydroiodic, nitric, sulfuric, phosphoric, acetic, oitric; maleic, succinic, lactic, tartaric, gluconic, benzoic, methanesulfonic, _ . :, etha]leslilfollic, I)en:~ellesulfonic, p-t;oluenesulf`onic acid or thc 1i IC(:!. In a sinli.l.ar marlller, I;he prod-lct can be obtained as p]-larmacellticall.y accel~table salts by reacting one Or the rree carl~oYy.l.ic acid.s Wit]l a l)ase, sucll aS sodium llydroxide, potassium hy(lro~;:ide~ ammonium hydroxick3~ -triethylamille, procai ne, clihe~ yl~mi.ne, l-ephenamitle, N ,N ' -diben~ylethylene-diamine~ N-etllylpiperidirle or the like.
Likewise, treatment of` the salts with a base or a~id res~llts in a regenerat;ioll of the free amide.
As stated above, the N arylsulfonyl-L-argi~ amides, ~nd the salts thereof of this invention are charac-terized by their l ighly speclfic inllibitory acti~ity against thrombin as ~ell as by their substantial lack of t:oxicity9 and thcrerore these compounds are usel`l.ll in the determination of thrombin in blood as diagnostic reagents, andjor for the medical control or prevention of thrombosis.
The compounds of thi.s invention are also useful as an inhibitor oI` plate~.et aggregation.
The antithroml~otic ac-tivity of the N -arylsulfonyl-L-argini.narni(le of tlli.s irlverltion was compared wi th tl~al; of a ]cnown antithroml)otic agellt, N -(p-tolylsl.~l.rollyl)-L--arginille rnel;llyl ester, by determining tlle fi.brinogen coagu--lation time . The measuremen t of` the fibrinogen coagulation time was conducted as rOllOws: :
l~n 0.8 ml al.i(LIlot ol` a ~`iL)rirlogell SO~ ,iOll, WlliC~ ad been ~ 54 ~

~ . .

~'2~

prepared by dissolving 150 mg of bovine fibrinogen (Cohn fraction I) supplied by Armour Inc. in 40 ml of a bora-te saline bu~fer (pH 7.4), was mixed with 0.1 ml of a borate saline bu~fer, pH 7 4, (control) or a sample solution in -the same buffer~ and 0.1 ml of a thrombin solution (5 units/
ml) supplied by Mochida Pharmaceutical Co., Ltd. was added to the solutions in an ice bath.
Immediately after mixing9 the reaction mixture was trans-ferred from the ice bath to a bath maintained at 25C.
Coagulation times were taken as the period between the time of transference to the 25C bath and the time of the first appearance of fibrin threads. In the cases where no drug samples were added, the coagulation time was 50-55 seconds.
The experimental results are summarized in Table 1. The term "concentration required to prolong the coagulation time by a factor of two" is the concerltration of an active ingredient required to prolong the normal coagulation time 50~55 seconds to 100-110 seconds~
The concentration required to prolong the coagulation time by a ~actor of two for the known antithrombotic agent, N -~p-tolylsulfonyl)-L arginine methyl ester~ was 1~100~ 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 -arylsulfonyl-L-argininamide of this in~ention was administered intra~enously , .

~ 55 ~

~ .

~.~$~

illtO animal bo(lies7 the higll antithronIbotic ac~ivity in the CirCIllati llg bloO(I W-19 nlaintaillc(l ror ~`rom one to three hours.
rl1e IIalf:lifc ror ~Iccay of tlle antl-t]lrotlIl)otic conlpoul~cls Or ~ S i.IlvollL:ioJl i.n circulatillg l~loo~i W.IS s11owl~ ~o I~e a~pro-ximately 60 minutes; the physiological conditions of the host aninla:Ls ~rat, rabbit, ~log an~ chimpan~ee) were well maintained. The experimental decrease of fibrinogen in animals caused by in-rusion of thrombin was satisfac-torily controllecl by simultaneous inf`usion of the compounds of this invention. ~ :
The acute toxicity values (LD50) de-termined by intraperito-neal administration of sub5tances Or forrnula (I) in mice (male, 20 g) range from about 17000 to lO,000 milligrams per kilogram of body weight. ~ -Representative LD50 values for the conpol~lds o~ this inven~
tion are shown in the rollowing Table.

. ~ .
Co~ )o~ L~ 0 (mg/Iig) .... . . ... '; _ ~-(7~ y1~ lyl~ ollyl)-]~-~r~i nyl -N ~ I;y:l g1 yc:i n c ~ l, 500 _ ., _. _ .......... ._ .. . . _ .. ._ ___ N -(6,7-dimethoxy-2-1lapllthy~sulf`olly~)-L-arginyl-N-(2--methoxyethyl)glycine l,900-2,400 . ,, _ . _ .
N -(6,7-dimethoxy-2-naphthylsulf`onyl)-L-arginyl-N-(2-e-thoxyethyl)- ~-aI~lne 660-1~000 .~

- 56 - .

3 2~ 9 ~ _ Compou~d 1,D50 (mg/kg) 2 _ N ~ ,6-cli-netl-oxy-2-llaplltllylsulronyl)-],-~l~gi~ -N-(2-~llctllox~rctl~y-l)g~ ~cill~ 660-1,000 . .. ._ _ ..
N -(7-metlloxy-2-nal)hthylsulf`onyl)-L- 2 000 arginyl-N-(2-methoxyethyl)glycine t 2 - _ _ N -(5,6,7,8-tetrahy(iro-1-naphtllyl.slllfony:l)- > 1 L-arginyl-N-(2-met}loxyetllyl)glycine ~ ,500 2 ~ -- - .
N -(6,7-dimethyl-:1 naphthylsulfonyl)-L- ~1 00 arginyl-N-(2-methoY~yethyl)glycine ,5 _ . , ... ... _ . _ . _ . . . _ N -(6,7-dimethoxy-2-naphtllylsulfonyl)-L-arginyl-N-(2-ethylthioethyl)glycille >1~000 2 ~~~~--- --- ~
N -(6,7-dimethoxy-2-naphthylsulfonyl)~L- >1 000 arginyl-N-ben~ylglycine ~ 2 ~ - -: N -(4,Ç-dimethoxy-2-naphthylsulfonyl)-L- >1 000 argillyl.-N-Ie~zy:LglyCill(? ' _ , _. ~
N -(5-methoxy-1-naphtllylsulfonyl)--L- ~1,000 arginyl-N--ben~ylglycine , . ~
N -(6,7-dimethoxy-2-naph-thyls~lf~nyl)-L- .
arginyl-N-phenethylglycine ~19 500 2 -- ------_ _ .
N -(6,7-dimetlloxy-2-1laphthylsulfonyl)-L- >1 500 arginyl-N-cyclollexylglycinc J
2 - .
N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-cyc~ohexylmetllylglycine ~1,500 2 -- ~ _ .
N -(7-met~lyl-2-naplltllylslllronyl)-L- 600 arginy:l.-N-tetrallydrorllrrllrylglyci.lle :
_ ........... _ _ .~ :

~ ----C o mp ouncl _ _ ~ - ----N -( 6, 7 -di me tlloxy--2--lla~ thy~ sul fonyl )--L-- 62 0 argillyl -N-tctlallydror~lr~`ury]~]yci.lle _ ......... .. _._ ....... __ . ...
N - ( 6 , 7 -~1 i me t llo x y--2 -nap ht hyl s u l f on yl ) -L- > 1 00 arginyl-N-bu tylalanine . 5 . _ _ ____ _ N -(/~, 6-dimethoxy-2-naphthy:lsulf`onyl ) -L- > 1 500 argilly~ -N-eyc l ohexyl me thyla~ anine ~
__ . . _ ___ ._ l-[N2-(6 ,7-dimethoxy-2-naphthylsuli`onyl )-L- 1 00 arginyl~-2-piperidineearboxylie aeid .5 . ._ _ _ . _ _ _ _ .................... . .
E-thyl [1- N -(7-methoxy-2-naphthylsulfonyl )-L-arginyl~ -methyl-2-piperidinecarboxylate 670-1, 000 _ _ ~__ 7 ._._.___ . _._ 1- [N -(4, 6-climethoxy-2-naphthylsulf`onyl ~ -L-arginyl~-4-methy:l-2-piperidinecarboxylic 670--1,000 -:
acid ::
_. _ ~ _ . _ _ : .
l-[N -(l-napllthylsulfonyl)-L-argirlyl)-4- 700-1 000 methyJ-2-piperidinecarboxylic acid ~
.... _ ~
1- [N -( 5-dimethylamino--l-naphthylsul f`onyl ) -L-arginyl~-2-piperidineearboxy~ie aeid 700-1,000 ~ :
__ . _ . , . ~_ 4-[N -(7-methoxy-2 -naphthylsulronyl )-L- >
arginyl ~-3-mor~ o:l ineearboxylie aeid 1, OOC1 ...... _ _ _ __ .
2-~N -(~7-(~1imetlloxy-Z-naphtllyl~ lrollyl)-l,-ar~;i]lyl~-l, ','3,1~ o1;ral)y~1ro isO~ nOl itle--~-- ~ 1.,000 S~l t'l~O ~iy l ~ 1 (`.i (I
_ _ . . _ _ _ 2- ~N -( 6, 7-dime thoxy-2-naphtllylsul ï ony l )--L-ar~,rillyl~-l-isoi;~ o]itlecarboxy]ie acid ~] ,000 . ., , _ On the o tller han(l, I,D5~ vallles l~or N -dallsy~--N--butyl--L--arginiJIamide and N -darlsyl-N-mettlyl-N-butyl-L-argininatnide are 75 ~n~l 70 IlLi lli~rrams per kilo~ram~ respeel;ive~y.

~,.,,~, The therapeut:ic agents of this inven~ion may be admini.Ytered alone or in coml):inati.o1l with pharmaceutically acceptable carriers, the proportion Or which is determined by the so11lbility an(1 chenlicul l1atllre Or -the compoll1ld, cl1osen route of administration and standard pharmaceutical practice.
For example, the compounds may be injected parenterally, that is, intramuscularly, intravenously or subcutaneously, For parenteral admini.stration, the compounds may be used in the form of sterile solutions con-taining other solutes, for example, suff`icient saline or g~.ucose to make the solution :iso-tonic Tlle compounds may be adminis-tered orally in the form of tablets, capsules, or granules containing suitable excipients such as starch, lactose, white sugar and the like.
The compounds mly be admiriistered snbli.rlglla11.y i.n tl1e form f troches or l.ozenges in which each active ingredient is mixed with sugar or corn syrups~ ~lavoring agents and. dyes~
and then del1ydruted s11~ficiently to ma]ce the mixture suitable ror pressi~1g into soli.d form. The compo~ s may be ad-ministered ora].ly in the form Or solutions which may contain coloring al1(1 rl.uvorin~ a~ents. Physiciar1s will determine :~.
the dosage of the present therapeutic agents which will be most suitable, and dosages vary with the mode of administra-tion and the particular compound chosen. In additlon, the dosage wil.l vary with the particular patient under treatment.
When the compo~i-tion is admini.stered orally, a larger quantity ~ 5~ ~

,, of` the active agent will be required to procluce the same effect as caused with a smaller quantity gi,ven paren-terally.
The therape-ltic dosage is generally 1,0-50 mg~/kg of active i~lgrcclicllt palellteral.ly, 10-500 mg/kg ora].ly per (lay.
Having generally describecl the invention, a more,complete understanding can be obtainecl by reference to certain specific exampleS,which are included for purposes Or illustration .
only and are not intended to be limi.ting unless otherwise speci~ied.

:

~ - 60 -, ~, ~

EXA~LI3 (A) N --(6,7-dimethoxy-2-naph-thylsulfonyl)-L-arginine:
To a well stirred solution of 83.6 g of L-arginine in 800 ml of 10% potas,sium carbonate solution was added 114.7 g of 6,7-dimethox~r-2-naphthalenesulfonyl chloride in 800 ml of benzene~ The reaction mixture was s-tirred at 60 C for 5 hours, cluring which time the product precipi-tated. After one hour at room temperature, -the precipi-tate was filtered and washed successively with benzene and water to give 129 g (76 percent) of N2-(6~7-dimethoxy-2-naphthylsulfonyl)~ arginine, M.P. 252-5 C.

(B) N2 (6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl chloride~ .

A suspension o~ 2.00 g of N -(6,7-dimethoxy-2-naphthyl- '-sulfonyl)-L arginine in 20 ml o~ thionyl chloride was stirred for 2 hours at room temperature~ Addition of cold dry diethyl ether resulted in a precipitate which was collected by ~iltrati.on and washed several times with dry diethyl ether to give N2-(6,7-dimethoxy-2-20 1 naphthylsulfonyl)-L-arginyl chloride~

(C) N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylglycine tert-butyl ester:

~,~

To a s-tirred solution o~ 2.6l~ g of N-butylglycine tert-butyl ester in 20 ml of chloroform was care~ully added N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl chloride obtained above. The reaction mixture was allowed to stand at room temperature for one hour. At the end of this period, the reaction mixture was washed twice with 20 ml of saturated sodium chloride solution and evaporated to dryness.
The residue was triturated wi-th a ~mall amount of water to give a crystalline material. This was collected by ~iltration and recrystallized from ethanol-ethyl ether to give 2 28 g (82 percent) of N -(6,7-dimethoxy-2-naphthylsul~onyl)-L arginyl-N-butylglycine tert~butyl ester, M.P. 164-166 C, I.R~ (KBr). 3,390, 3,165, 1,735, 1,370 cm Analy5is ~ Calcd. for C28H4307N5S-2H2S03 (percen ) C, 52 98; H, 7.00; N, 11.04 ~ound (percent): C~ 52.69;
Hy 6~98, N, 10 86 (D) N -(6~7-dimethoxy-2-naphthylsulfonyl)-L-arginyl N-butyl~lycine:
To a sclution o~ 2~00 g of N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylglycine tert-butyl ester in 20 ml of chloroform was added 50 ml o~ 15~
HCl-ethyl acetate. The reaction mixture was stirred ~. . ,.,, ",. .. . ..... . .. . .
~a ~ ..
., .
, , ...
. ,, for 5 hours at room temperature. At tlle ellcl of this period, the reaction n~-ixt~lre was evaporated to dryrless.
The resi(llle was waslled several tlmes wi th clry diethyl ethet an(l chrolllatographed on 80 ml of l)aiaioll ~ SK 102 ion excha1lge resin (200-300 mestl, 1-l form, mcanufactured by Mi tsllbishi Chemical Industries Limi tecl) paclcecl in ~/ater, washed wi th water and eluted ~lith 3'10 ammo1lium hy(lro~ e 503UtiOII.
Tho t`ractio1l ellJte~l from 3% ammo~ lm hy(lroxi(le solution was evai~orated to dryness to give 1.1l3 g (79 percellt) o f N -( 6, 7-dime thoxy-2 -naph thylsul fonyl ) -L-arginyl-N
butylglycine as an amorphous solid, I.R. (IC13r): 3,360, 3,140~ 1,622 cm 1, Analysis - Calc~l. for C24~135N507S (p(~rcellt):
C, 53.62; ~1, 6.56; N, 13.03 l~ound (percent):
C, 53.48; 1-1, 6.43; N, i2.98 The followinfr compounds are prepare(l in a similar -ma~ cr:
N -(7-motllyl-2-nal)htllylslllro1lyJ )-l,~rf~;illy1-N-~utyl--~-2 0 a l a~ l o Nz-(7-m(~tllyl-2-rlar~llt~lyl~u:lrorly~ )-N-(2~ ;y~l;llyl)-N-(3 carboxypropyJ )-L-argininamide N -( 5-me-tlloxy-1-rlaphtllylsulf`ony:l ) -I -arg,inyl-N-( 2-me thyl thioe thyl )glycine :~:

~ .

; ~, .
~ I"' ~ I'''' 3~.~

N -(5-methoxy-1-naphthylsulf~nyl)-L-arginyl-N-(2-methylt:hioethyl)glycine tert-butyl ester N -(5-methoxy-1-naphthylsulfonyl)-1,-arginyl-N-(2-rnethylthioethyl)-~ -alanine N -(6,7-diethoxy-2-naphthylsul~onyl)-L-arginyl-N-(2-methylthioethyl)glycine N -(6-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methylthioethyl)glycine N -(6,7-dimethoxy-2-naphthylsulfonyl)-N-(2-methylthi.oethyl)-N-(3-carboxypropyl)-L-argininamide N -(6,7-dimethoxy-2-naphthylSul~onyl)-N-(3-methylthiopropyl)glycine N -(6,7~dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-ethylthioethyl)-~ -alanlne N -(6~7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N
benzylglycine benzyl ester N -(6,7-dimethoxy-2-naphthylsulfonyl)-N-benzyl-N-(3-tert-butoxycarbonylpropyl)-L-argininamide , N -(6,7-diethoxy-2-naphthylSulfonyl)-L-arginyl-N-cyclohexylglycine . - 6 .. . . . .... . . . . . .. . . . . . . . . . .. .. ... . ..
r ;,~
:

~23~

I~-N{ N (6,7-di.nletl~oxy-2-naphthylsulroJly]) L,-arginyl~ -N-cyclohexylaminobutyric acid N ~ 6-(l.imetlloxy-2-1laplltllylsulfolly:l)-l,-argillyl-N-pbenethyl-~ -alanine N -(6-mettloxy-2-naphthylsulfonyl)-L-argirlyl-N-(3~
pl~etlylpropy.l.)glycine N -(5-motlloxy-1-llaphthylsulfony~ L-ar~ yl-N-~ell~yl- ;~
~-alaniIle ' :~

N -(5-nitro-1-naphthylsulfonyl)-L-arginyl-N-tetrahydro-furfllry:Lglycine N -(7-hyclroxy-2-naphthylsulfonyl)-L-arginyl-N- .
teLral~y(trorurfllrylglycille N -(5-cyano-1-naphthylsulfonyl)-L-arginyl-N-tetrahydro . furfurylglycine N -(6,7-dimethoxy-2-naphthylSulfonyl)-l,-argirlyl-N-t c tratlytlrofurfuryI - ~ -alanine N -(7-metllyl-2-1lapll-t1lylsulfollyl)-l,-argillyl-N-tetrahycirofurfuryl-~--alanine N -(6,7-dimethoxy-2-naphthylsul~onyl)-L-arginyl-N-1;c~trahy(lrorllrfllry.1alanine ~ ~5 -_ , ..
'; '' ,' , N -(7-methoxy-2~llapllthylsulfonyl)-N-(3-carboxypropyl)~
N-tetrahyclrofuri~uryl-L-argininamide N -(7-methoxy-2-naphthylsulronyl)-1,-argirlyl~N-butyla].anine N ~(7-methoxy-2-naphthylsul:fonyl)-L-argi.nyl-N-pentylalanine N -(5-methoxy-1-naphtllylsulfonyl)-L-argrinyl-N~bu-tylalanine N -(697-dimethoxy-2-naphthyls~ onyl)-L-arginyl-N-isobuty.~alanine ~-N -(7-methoxy-2-naphthylsul~onyl)-L-arginyl-N-benzylalanine N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(3-phenylpropyl)alanine N -~5-methoxy-l-naphthylsulfonyl)-L-arginyl-N-benzylalanine N -(7-methoxy-2-naphthylsulronyl)-L-arginyl-N
hexylalanille N~-(G,7-(linlethoxy-2-1luplltllylsll:Lrol~yl)-L-arginyl-N-cyclo~lc~yJmotllylalanillc N ~(6,7-~imctlloxy-2-}1aphtllylsulfollyl)-~,-urgillyl-N-l~utylbutyrirle N -(6~7-~imethoxy-2-rlapllthylsll.L~oJly])-T~-arginyl-N
('~-f~ ylm~ yl )~rlycinc , N -(6,7-dimethoxy-2-naphthylSulfonyl)-L-arginyl-N-(tet~ahy~:ro-3-fllrylmethyl)glycin~ ' N -(6,7 di.methoxy-2-naphthylsulroTlyl)-l,-arginyl-N- , ',' (2-thenyl)glycine N ~(7-metho~y-2-naphthylsulforlyl)-L-arginyl-N-(3-thenyl)glycine N (6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(tetrahydro-2-thenyl)glycine N -(7~methoxy-2-naphthylsulfonyl)-L-arginyl-N-~tetrahydro-3-thenyl)glycine ' --N2-(6,7-dimethoxy-2-naphthaylsu1fonyl)-L-arginyl-N-(2-acetylethyl)glycine N2-(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(4-methoxyfurfuryl)glycine N2-(7-methyl-2-naphthylsulfonyl)-L-arginyl-N-(5-methylfurfuryl)glycine N2-(6,7,-~imethoxy-2-naphthylsulfonyl)-L-arginyl-N-(1,4-dioxacyclohexylmethyl)glycine l-[N2-t6,7-dimethoxy-2-na~hthylsulfonyl)-L-arginyl]-4-methoxypiperidine-2-carboxylic acid l-[N2-(6,7,-dimethoxy-2-naphthylsulfonyl)-L-arginyl~-5- "':
methylhexamethyleneimine-2-carboxylic acid 1-[N2-(3,7-dimethyl-2-dibenzofuranyl)-L-arginyl]-4,4-dimethyl-2-piperidinecarboxylic acid N2-(3-methoxy-5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl-N-(tetrahvdro-2-pyranylmethyl)glycine-~
EXAM~LE 2 : 25 (A) N -(6-me-thoxy-2-naphthylsulfonyl)-L-arginyl chloride, A suspension of 2.5 g of N2-(6-methoxy-2-naphthylsulfonyl~-L-arginine in 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 chlori,de, ~, -67-(B) Etllyl l-[N -(6-me-thoxy-2-naphthyl9ulronyl)-L-arginyl~-2-piperidinecarboxylate To a stirrecl solution of 2.2 g of etlly:L 2-piperidine-car~oxylate and ll.l ml o~ triethylami]le in 50 ml o:f chloroform, which wa9 cooled in an ice-salt bath, was added in portions N -(6-me-thoxy-2-naphthylsulfonyl)-L-arginyl chloride obtained above. The reaction mixture was stirred overnight at room tempera-ture. At the end of this period, 500 ml of` chloroform was actded and tlle chloroform solution was washed twice ~ith 50 ml o~ saturated sodium chloride solution~ dried over anhydrou5 sodium sulfate and e~aporated in vacuo.
The oily residue was washed with ethyl ether to glve 2.9 g o~ powdery ethyi l-~N -(6-methoxy-2-naphthyl-sulfonyl)-L-arginyl~-2-piperidinecarboxylate~
For analysis of the product, a portion of the product - was converted to the flavianate~ M.P. 192-3C. :.
I3r): 3,210, 1,747, 1,638 cm 1 alysi~ - Calcd- for C25H356N5S Cl~f68 2 C~ 49.58; ll, ll.87; N, 11.56 ~`ound (percent): C~ 49.24;
}-f, 4.7~; N, 11.85 (C) l-[N -(6-methoxy-2-llaphthylsulfonyl~-l-arginyl~-2-r~if)oridi3lecurl)0xylic aci(t ~ i.o~ ol 2.~ ~ ~r c~lly~ N~ o~y-2-nupll~lly:LslllLollyl)-L u3~iIIyl~-2-pi~eri(li.]lecarl)oxylate in .~ ~
6~ -,.;~' .

2~

l5 ml of me-thanol and 10 ml of 2N-NaoLl solut.ion was wa~led to 60C and held at tha-t temperature for lO
hours~ At the end of -thls period, -the reaction nuxture was concentratec1 and chromatographed 011 200 ml of Daiaion ~ SK 102 ion exchange resin (200 -- 300 mesll, H~ f`orm, manufactured by Mitsubishi ChemiCal Industries Limited) packed in water, washed wi-th ethanol-water (l:4) and eluted with ethanol-water-NlIL~OH (lO:9:l).
The main fraction was evaporated to dryness and washed with ethyl ether to gi.ve 2.0 g o~ N -(6-methoxy-2 napht:hylsulfonyl)-L-arg.inyl~-2-piperidinecarboxylic acid as an amorphous solid.
I.R. ~K~r): 3JZ00 (broad), 1~620~ 1J150 cm AnalySis - Calcd for C23H3106N5S (percent) C, 54.64; H, 6ol8; N, 13.85 Found (percent):
C~ 56~88; H, 6.31; N, 13~83 The following compounds are prepared ln a similar manner:
N -(6-chloro-2-naphthylsulfonyl)-L-arginyl N-butylglycine N -(7-methyl-2-naphthylsulfonyl)-L-arginyl~N-(2-ethoxyethyl)glycine .
N -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methylthioethyl)glycine 3~

N -(4,6-(limetlloxy 2-naphtllylslllfonyl)-L-arginyl-N-(2-methylthioethyl)glycine N2-(~17(;-(l:lm(~ oxy-,'-~ lll.llyl~ lt`olly.'l )-I,-argillyl-N--phene-thyl- ~ -alanine N -(6,7-~limethoxy-2-naphthylsulfonyl)-N-benzyl-N-(3-carboxypropyl ~--L-arginlnamide N -~7-methoxy-2-naphthylsulfonyl~-IJ-arginyl~N- :
cyclohexylnorleucine -N -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-butylisoleucine N ~(7-me-thoxy-2-naphthylsulfonyl)-L-arginyl-N-pentylbutyrine ' - :~

; N -(6,7-diethoxy-2-naphthylsulfonyl~-L-arginyl-N-butylalanine N -(6~7-dimethoxy-2-naphthyl~ulfonyl)-L-arginy].-N-cycloheptylalanine N -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)alanine N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N- :
(2-othoxy~tlly]~alanine _ 7o _ ~C ' N -(7 methoxy-2-naphthylsulfonyl)-L-arginyl-N-cyclohexyl-~7 -al anine N -(7-n~ xy-,?-t~ tllyl~ roIly~ -alfri3ly]-N-(2- ~ -methoxyethyl)norvaline N -(6,7-dimethoxy-2-naphthylsulforlyl)-I,-argiryl-N-ben~.ylleucine , l-~N -(5-~ethoxy-1-naphthylsulfonyl)-L-arginyl3-1l-: ethyl-2-piperidinecarboxylic acid l-[N -(6-methoxy-2-naphthylSulfonyl)~I,-arginylJ-4-ethyl-2-piperidinecarboxylic acid l-rN -(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl~-4-ethyl-2-piperidinecarboxylic ~acid l-[N -(5-ethoxy-1-naphthylsulfonyl)-L-arginyl~-4-ethyl-2-piperidinecarboxylic acid l~[N -(7-ethoxy-2-naphtllylsulfonyl)-L-arginyl)-4-e-thyl-2-piperi.dinecarboxylic acid l-CN -(6,7 diethoxy-2-naphthylsulfonyl)-L-arginyl~-4-ethyl-2~piperidi.Ilecarboxylic acid l~CN2-(7-metJloxy-2-naphthylsu~follyl)-l,-ar~ yl~-4-tort~ tyl-2-I)iperi.(l:i.necarhoxy:lic acid :~
.

Phenyl l-tN -(7-methoxy~2-naphthylsulfonyl)~L-arginylJ-4-ethyl-2-piperidinecarboxylate 131?ll:r.y~ N2-( 7-mctl~oxy-2-1lap~l tllyl~ `onyl ) ~L-arginyl~
4-ethyl-2-piperidinecarboxylate -~

Ben~y] l-[N -(6,7-dimethoxy-2-naplltllylsulfonyl)-L-arginyl~-4-methyl-2-piperidinecarboxylate l-~N -(5-nitro-1-naphthylsulfonyl)-L-arginyl~-4-methyl-2-piperidinecarboxylic acid l-tN -(7-hydroxy-2-naphthylSulfonyl)-L-arginyl~-4-ethyl-2-piperidinecarboxyllc acid l-[N -¦5-cyano-1-naphthylsulfonyl)-L-arginyl~-4-methyl-2-piperidinecarboxylic acid l-~N ~(7-methyl-2-naphthylSulfonyl)-L-arginyl3-4-ethyl-2-piperidinecarboxylic acid 1-tN2-(5--~imetllylamillo~l-naphthyls~llrollyl)-L-arginyl~-ll-ethyl-~ )o~ ccarboxy.i.ic aci<l l-~N -(2-nap~ltllylsulf`onyl)-L-arginyl~ -ethyl-2-pi~eri.dillccarboxylic aci~

L-~N -(5,~),7,~-Lotral~y(lro-2-na~ thyl~ lrollyl)-1,-ar~ yl~ etllyl-2-~iperidinecarl)oxylic acid :

-- 7~ --s~
.,~ ...... .

l-~N -(5-dimethylamino-1-na.ph-thylsul.fonyl)-L-arginylJ-4-fnethyl-2-piperidinecarboxylic acid l~~N -(7-methyl-2-naphthylsulfonyl)-L-arginyl~-6-methyl-2-piperidinecarboxylic acid l-CN -(7-methyl-2-naphthylsul~onyl~-L-arginyl~-4-tert-butyl~-2-piperidinecarboxylic acid 1-~N -( 5-nitro-1-naphthyl~ulfonyl)-L-arginylJindoline-2-carboxylic acid 2-~N2-(5-cyano-1-naphthylsulfonyl)-L-arginyl~isoindoline--l-carboxylic acid 4- [N -( 7-methyl-2-naphthylsul~onyl)-L arginyl~thio morpholine~3-carboxylic acid 4-~N -(6,7~dimethyl-2-naphthyl.sul~onyl)-L-arginyl~
morpholine-3-carboxylic acid 4-tN -(5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl~-3-carboxythiomorpholine l-oxide 4-~N -(7-methyl-2-naphthylsulfonyl)-L-arginyl~morpho7ine- :
3-carboxylic acid 4 ZN -(7-chloro-2-naphthylsulfonyl) L-arginyl~morpholine-3-carboxylic acid ~ 73 -~ . .
.
~" .

~ ~.,, ~, ~ ~

4~N -(7-hydroxy-2-naphthylsulfonyl)-L arginyl~
morpholine-3~carboxylic acid 4-~N -(5-nitro-1-naphthylsulfonyl)-L-arginyl~-thio-morpholine-3-carboxylic ac.id 4-~N -(5-cyano--1-naphthylsulfonyl)-L-arginyl~thio-morpholine-3-carboxylie acid ~ CN -( 5-methoxy-l-naphthyl3ulfonyl)-L-arginyl3 morpholine-3-carboxylic acid Ethyl 4~N -(4,6-dimethoxy-2-l~aphthyl~ul~onyl)-L-arginylJ morpholine-3-carboxylate 4-~N -(5 ethoxy-l-naphthylsulfonyl)-L-arginyl~
morpholine-3-earboxylie acid 4 - rN - ( 5-dimethylamino-1-naph1;hylsulfonyl)-L-arginyl~
thiomorpholine-3-carboxylie acid 3-~N2-(l-naphthyl9ul~onyl)-L-arginyl~t.hiazolidine-4-earboxylie aeid 2-~N -(7-methoxy~2-naphthylsulfonyl~-L-arginyl~ :
1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid ~ :~

2-tN2-~7-methoxy-2-naphthylsulfonyl)-L-arginyl~ :
isoindoline-l-earboxylic acid ?

2-[N2~ ,6~imet}loxy-2-napllthylSulf`ony]~)-L-ar~in 1,2,3,4~tetrally~Iro.iso~ inoline-3-carboxylic acid ?-~N~-(rj-n~ o~y~ ly~ rollyl)-]~ rilly:
isoi.ndo]ille-l-carbo~.ylic acid 2-~N -(5-etho~y-1-naphthylsulfonyl)-I-aIglnyl~-l,Z,3,ll-tetrahydroisoquinoline-3-carboxylic acid EXAMPLE

(A) NG-nitro-N -(ter-t-butoxycarbo~yl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester:
To a stirred solution of 28.3 g of N -nitro-N -(tert-butoxycarbonyl)~L-arginine in 450 ml of dry tetrahydrofuran were added i.n turn 12.4 ml of triethylamine and 12.4 ml of isobutyl chloroformate while keeping the temperature at -5 C. ~fter 15 minutes, to th.is was added 11~.2 g of . N-(Z-metlloxyetIIyl)glycine ethyl ester~ and the mixture was stirred Ior 15 minutes at -5C. At the end of this io-l, tlle l'eaCtiOIl miXtllre was warme~l to room tempera-~III`C. 'l`lle solvellt was cvalora~ed alld tllc resi(llIe taken up in lIOO mI Or ethyl acetate~ and washed successively with 200 ml of water, 100 ml of 5% sodillm bicar~onate .sol~ iol~, 1()() ml ot` 109~, c,:i l;ric aci(l sollll,:io~ d 200 ml.
of wal;cr. Tllc etllyl acctatc solllt.ioll was ~Iric(l ovcr ~ 7S -.

lla~2316 an}ly(lrolls sod:i11m sulfate. Upon ovaporati.ol1 of -the solven~;, the residue was disso:l.ved in 20 ml of chloro-form9 alld the .so1utio~ as app:I.ied to a co:lllnu-l (80 cm x 6 cnl) o t` 500 ~r o l` gilica ~ a(~lie(l ill clllorof The procltlct wa9 eluted firSt wi th chlorol'orm, a3ld the 3% mel;l1a~lo~.-ch:Loroform. The fracti.on e:lute(l from 3%
methanol-C]l.1o]:~oform was evaporated to dryness to give 25,8 g (63 perce11t) o.f NG-nitro-N -(tert-b1ltoY~ycarbonyl) L-arginyl-N-(2-n1ethoxyethyl )glycirle ethyl ester in the form Or a syr~lp, I.R. (ISBr)- 3,300, l,7L~o, 1,690 cm (~) N --ni tro-L-aIginyl-N--(2--methoxyetllyL )g.lycine ethyl ester h~dro chlo ri de:
To a stirred solution of 29.8 g of NG-nitro-N2-(tert-butoxycarbonyl)-L-arginyl-N-(2-methoxyethyl~glycine ethyl es ter in 50 ml of ethyl acetate was added 80 ml of 10% dry ~ICl-ethyl acetate at 0C. Af`ter 3 hours, to this so.l.utiorl was acklecl 200 m.l of dr~ ethyl ether to precipitate a viscous oily product.
This Wlls fi.ltered and w~shecl wi th dry etllyl ether to give 24.l g Or N -nitro--L-arginyl-N-(2-methoxyethyl) glycine et~1yl ester hydrochloride as a~1 amorphous solid.

(C) N -ni. tro-N -(6,7-dimet}loxy-2-rlaplltllylsul fonyl )-L-arginyl-N-(2-metlloxyel;hyJ )glycine el;hyl ester:

1~) _ , ... ... _.
,...
, '~ ,"'' .

~$~

To a stirred solu-tion of 4.0 g o~ N ~nitro-L-arginyl-N-(2-methoxy~-thyl)glycine ethyl ester hydrochloride in 20 ml of water and 20 ml of dioxane were added in turn 2.5 g of sodium bicarbona-tc7 and 3.5 g of 6,7-dimethoxy-2-naphthalenesul~onyl chloride in 30 ml of dioxane at ~C, and stirring was continued for 3 hours at room temperature. At the end of this period, the solvent was evaporated and the r~sidue dissolved in 40 ml oP
chloroform, and washed with 10 ml of lN hydrochloric acid solution and 20 ml of water.
The chloroform solution was dried over anhydrous sodium sul~ate D Upon evaporation of the solvent, the re~idue wa~ chromatographed on 50 g of silica gel packed in chloroform, wa3he~ with chloroform and eluted with 3%
S methanol-chloroform. The fraction eluted from 3%
methanol-chloroform was evaporated to give 5.3 g ~87 percent) of NG-nitro-N -(6,7-dimethoxy-2-naphthyl-sulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester in th~
form of an amorphous solid.
I.R. ~KBr): 3,Z40, 1,740, 1~630 cm 1 (D) N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester:
To a 901ution of 3.00 g of NG-nitro-N -(6,7 dimethoxy-2-naphthylsulfonyl)-I,-arginyl-N-(2-methoxyethyl)glycine ~ 77 ~

. . .. , .. . . . ......... ... ,.. , . .. ..... .. . .. , ., ., . . .. ~. . .. . .. ~ .. .....

.
.

2~

etlly] ost~r i.n 50 ml of etllarlol alld 0.5 ml Or acetic aci(l was aclcl~(l 0.5 g Or palla(tiurn-black ancl then the mi.xture w~ shalien in a llycirogen atmospllere ror 100 llo~lrs at l~oom tc~ml)cratllrc. At tlle ollcl Or tl~i4 period, the ethano] solution was fi.ltered to remove the catalyst and evaporated -to give an o.ily product. Reprecipitation with ethanol-ethyl ether gave 2 53 g (91%j of N -(6,7-dimethoxy-2-naphthyl5ulfonyl)--L-argi.nyl-N-(2-methoxyethyl) glycine ethyl ester.
~or analysis of the product~ a portion Or the product was converted to the flavianate; M.P. 185 C, I.R. (KBr):
3,375, 3,200, 1,71~0 cm 1.
Analysis - Calcd- for C25H37N58S ClOH6 2 8 (P
C, 47.67; H, 4~92; N~ 11.12 ~ound (percent)~
C, 47.64; H, 4.81; N, 11.12 (E) N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2 methoxyethyl)g~.ycine~
A soltltloll of 2.5 g of N -(6,7--dimethoxy-2-naphthyl-~111ro~lyl.)~L-ar~iny.l.-N-(2-me-thoxyotlly.l)gl.ycine etllyl esl;er i.ll 5 ml. Or etll.~nol alld 7 m~. o~ l.N ~odium hydroxide ~O lUtiOII was stirre(l ror 30 hours at room temperature.
At the encl of` tlliS ~eriod, the solution was concentrated to 5 ml, chromatograpllecl on 80 ml Or ~aiaion ~ ~K 102 ion excllan~e resill (200 - 300 melh, ll t`orm manu~acture~ :

~ 7~ -.~,` ' .

by Mi tsubishi Chemical Industries Limited) packed in water, washecl with water, and elutecl with 3% ammonium hyclroxide solution. The fraction e]uted from 3%
amnlo~ nl ~Iy~lro~;i dc solution was evaporat(3d to dryne~s, and the res:idue l~as purified by reprecipitation with ethanol-ethyl ether to give 1.32 g (72 percent) of N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-a~ginyl--N (2-methoxyethyl)glycine as an amorphous solid.
I.R. (KBr): 3,380, 3,180, 1,630 cm 1 10 Ana]ysis -- Calcd. for Cz3H33N508S (percent): C, 51.20;
H, 6.17; N, 12.98 Found (percent): C, 50.93;
H, 6.02; N, 12.63 The foilowing compounds are prepared ~n a similar manner:
N -(5,6,7,8--tetrahydro-2-naphthylsulfonyl)-L-arginyl- ~-N--(2--ethoxyethyl)glycine N --(5,6,7,8-tetrahydro-2 naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine N --(7--ethyl--2--naphthylsulfonyl)--L--arginyl--N--(2--metho2~yethyl)glycine N --(5-methoxy-1-naphthylsulf`onyl)-L-arginyl--N-cyclohexylglycine ~ 79 --~. , .

~z~

N -(7-me-thoxy-2-naphthylsulfonyl)-L-arginyl-N-(3-cyclollc~yl31~ropyl~1ycine 2-tN2-(7-nlethyl-2-llaphthylsulfonyl)-L-areinyl~-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 2-~N2-(7-~ethyl-2-nap~lthylsulfonyl)-L-argin isoindoline-l-carboxylic acid 2-tN~-(6~7-dimethyl-2-naphthylsulfonyl)~L-arginy~
isoindolirle-l-carboxyllc acid 2-~N -(2-naphthylsulfonyl)~L-arginylJisoindoline~
carboxylic acid 2-~N -(5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl~-1,2,3,4-tetrahydroisoquinolirle-3-carboxylic acid 2- ~-(5,6,7,8-tetrahydro-1-naphthylsulfonyl~-L-argilly1~:isoi.l~lo~ lc-1-cQrhoxyli.c aci~l 2-~N -(~-cl~10ro-l-rla~lltlly:lslll rO~Iy~ ~ar~ yl3-I,2,'3,~ ctr;ll)y(lroiSog~ lolinc-3-carl~oxylic acid .L-[N~-(5-l~y~lroxy-l-lla~lltlly.lsulrollyl)-1,-argillyl3 ~
].~2~3~1l-tt?~rally(lroqlli.rlolin~-2-carl)oxylic acid - 8~ -33~

2-~N -~5-climethylamino-1-naphthylsu]fonyl)-L-arginyl~
isoindo~ine-l-carl~oxylic acid 2-~N2-(l-nal~htllylsl~lforlyl)-L-arginyl~-lJ2~37ll-tetrahydroisoq~linoline-3-carboxylic acid EXAMPLE ~l (A) L-arginyl-N-(2-methoxyethyl)glyclne ethyl ester hyclrochl.oride:
To a so~.ution of 4.0 g of N -nitro-l,-arginyl-N-(2-methoxyethyl)glycine ethyl es-ter hydrochloride in 50 ml of ethanol was added 0.5 g of palladium-black and then the mixture was shaken in a hydrogen atmosphere for 150 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.
; 15 Reprecipitati.on with ethanol-etllyl ether gave 3.0 g (81%~ of L-arginyl-N-(2-metlloxyethyl)glycille ethyl e~ter llydrochl.oride in tlle form o~` a pow~er.

(B) N -(4,6-dimetlloxy-2~napllthylSulfonyl~-L,-arginyl-N-(2-metlloxyethyl)glyci.ne ethyl ester:
To a well stirred solu-tion of 2.00 g Or L arginyl-N-(2-methoxyethyl)glycine ethyl estor lly(lrochloride and 1,95 g of K2C03 in 20 ml of water and .10 ml of dioxane ''~
~ .

~ras added c1ropll/ise a solution of 2.17 g of 4~6-dimethoxy--2-naphtllaleneslllfonyl chloride in 30 ml of dioxane over a period of 30 minlltes wllile maintainillg llle t;e~ erlt(lr~ ut 0 C. Tlle reacl;ioll nuxture was ~' stirred for an additional 5 hours at room temperature.
At the end of t~liS period, the solvent was evaporated and the residue taken up in 50 ml of chlo'roform.
The chloro-form solution was filtered to remove the insolllble material and dried over anhydrous sodium slll`ate. ~ddi tiOIl of 150 ml of etllyl e-ther to tlle chloroform solution resulted in a precipitate whic'h was separated by decantation and purified by reprecipitation with ethanol--ethyl ether to glve 2.31 g (72 percent) of N -(4,6-dimethoxy-2-naphthylsu:Lfonyl)-L-arginyl~N--(2-methoxyethyl)glycine ethyl ester.
For analysis of the product, a portion of the product was converted to the flavianate; M.P. 225-227 C, I.R. (Kl~r): 3,375, 3,200, 1,742 cnl Analysis - Calc<l. for C251l37N508S C101 6 N208S (percent): C, 47.67; 'H, 4.92; N, 11.12 F`ound (percent): C, 47.62; 1l, 4.84; N, 11.18 (n) N --(4,6-dimetlloxy-2-naplltllylsulfolly~)-L--arginyl-N-(2-nletl~oxyollly] )~lycillc:

~' N -(4 ,~-dimethoxy-2-naphthylSulforlyl)-L-ar~inyl-N-(2-methoxyethyl)glycine was obt~ined in the ~orm of an amorpllous solid in a manner similar to that deseribed in Exanlpl~ 3 (E)-I~R. (KBr): 3,360, 3,180, 1,610 cm ~A) N2-(6,7-dimethoxy-2-naphthylSùlfonyl)-L-arginyl-N-phenethylglycille:
N -nitro-N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-- 10 arginyl-N-phenethylglycine b.enzyl ester was prepared by the procedure described in Example 3, and has a mel-ting point o~ 133-5C.
To a solution of 3.00 g Or N -nitro-N -(6,7-dimethoxy-2-naphthylsul~onyl~-L-arginyl-.N-phenethylglycine benzyl ester i.JI 50 ml of ethanol and 0.5 ml o~ acetic aeid was aclded 0.5 g Or palladinm-black and then t~le mixture was shakerl in a llydrogen atmosphere for 100 hours at room tempera!llro. ~t tlle encl o~ this pcli.o(l, I:lle ethanol ~ollltion wag f`ilterecl to remov~ the cata.lyst and evaporated to dryness. The residue was washed several times with dry cthyl ether and cl~romatograplle(l on 80 ml o~ I)ai.aion ~ SK 102 ion exchange resi.n (200 - 300 mesh, Il form, manufactured by M.i.tsubishi Chemieal Industrie.s - ~3 -, Li mited) packed jJI water, washed wi th water~ and eluted with 3~ ammonium hydroxide solution. The fraction e:Lutcd f`rom 3% ~mmonium hy(lroxi(le solution was evapo-ratecl l;o (IrY11eS9 to give 1.71 g (709~0) of N --~6,7--dimethoxy-2-naphthylsulfonyl)~l -arginyl-N-phenethyl-glycine as an amorphous solicl.
I.R. (KBr): 3,360, 3,200, 1,590 cm Analysis - Calcd. for C28H35N507S (percent): C, 57 ll2;
H7 6.02; N, 11.97 Found (percent) C, 57.09;
0 119 6.l)6; N, 11.74 (A) N -(6~7-dimethoxy-2-r~aphthylSulfionyl)-L-arginyl-N~(2-methoxyethyl)glycyl chloride hydrochloride:
A suspension of 2 00 g of N -(6,7-dimethoxy-2-naphthyl-sulfonyl)-L--arginyl-N-(2--me~thoxyethyl)glycinein 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 collectecl hy fi ltration and wasllc(l several timcs with dry ethyl ether to give N -(6~7--dimethoxy-2-naphthylsulf`onyl)-L-argillyl-N-(2--methoxyethyl)glycyl chloricle hydrochloride. ` ~' ~ 84 ~ :

(~) N -(6,7-d:Lmethoxy-2~napht}ly~sulfony])-L-argiJlyl-N-(2-met;hoxyetllyl)glycirle m-tolyl ester l~yclrochloride:
A mixtllre of 2.00 g of m-cresol and N ~(6,7-dimethoxy-2-nal~lltllyls-llrollyl)-L-argillyl-N-(2-nlotlloxye-tllyl)glycyl chloride hydrochloride obtained above was heated at 90C for 50 minu-tes. At the end o-f this period, -the reaction mixture was cooled, washed sever~l times with dry ethyl ether, and then dissolved in lO ml of dry e-thyl alcohol. ~ddition of cold dry etlly] 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-dirnethoxy-2-naphthylsulfonyl)~L-arginyl-N-(2-methoxyethyl)glycine m-tolyl ester hydrochloride in the form of a powder.
I.R. (KBr): 3,250, 3,100, 1,740, 1,640 crn 1 The following compounds are prepared in a ~imilar manner:
N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-etllyl~h:ioet~lyl)glycitle phenyl ester N -(~,7-dimetlloxy-2-n~plltllylslllf`ollyl)-1,-~r~jnyl-N-(2-etl)ylt;llioetlly:l)glycille be~zyl ester N -(6,7-dimethoxy-2-naph-thylsulfonyl)-L-arginyl-N-benzylglycine phenyl ester -- 8~ --~,~

N -(6,7 dimetho~y 2~napllthyls~l1f'ollyl)-L,-argillyl-N-furf`llry:lgrlyci.lle ~enzyl ester N -(~),7-~linlcl,llo~y~ plltllyl~ lrollyl)-l,-argilly.L-N-tetrallyclrofurfuryl~.l.ycille phenyl. ester Phellyl 1 ~N -(7-methyl-2-naphthylsulfonyl)-L-arginyl~-4-ethyl-2-piperidinecarhoxylate BenZY1 1- [N -(7-methyl-2-naphthylsulfonyl)-L-arginyl~ -~-ethyl-2-pipericl.inecarboxylate ~enzyl 1- LN -(6-chloro-2-llaphthylsulfonyl)-L-arginyl~-4-methyl-2-p~peridinecarboxy1.ate Ethyl l~-[N -(7-me-thyl-2-naphthylslllfollyl)-L-ar6inyl~ `
morpholllle-3-carbo~cylate :' Various other N -arylsulfonyl-L-argininamides or sa~ts thercof were syntheSizecl in accor~ance with tlle procedllre oL` tlle abOVQ exanlpl~s, ~ld tlle ~test re~ltb a~ ullmlari~ed in T~bl~ 1.

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E_A~LE 7 Tablets suitable ~or oral ad~inistration Tablets contain:ing the ingredients indicated below may be prepared by conventional techniques.

_ ...
.~ IngredientAmount per tablet ,,, ,~ , .
N -(7-methoxy-2-naphthylSulfonyl)- 250 L~arginyl-N-(2-methoxyeth-yl)glycine .

Lactose 140 Corn starch 35 Talcum 20 Magnesium stearate 5 _ ~ ~ ~ ~
_450 mg : ::

F,XAMPLE 8 Capsules for oral administration .- :
Caps~le5 of the below were made up by thoroughly mixin~
together batches of -the ingredients and filling hard gelatin capsule~ with the mixture.

~ _~
_ _ _ Ingredient (mg) i N -(7-methoxy-2-naphthylsulfonyl)- 250 L-arginyl-N-(2-methoxyeth~l)glycine .

Lactose 250 .
_ _ . - . __ .
: Total 500 mg ,:

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

EXA~U'I~E ?

Sterile Sol.UtiOIl for infusion r~l~ f~OllOwi,~f~ te~ t.~ r~ S~io:l~rc~cl ~ at~l l`or .~ intravellous perfusion an~l the resulting solutioll is then .~ s terili Y.ed .

~ . _..... .
lngredi en ~sAnlo~ln t ( ~r) . ._ ____ _...... _ __ N~-(7-metlloxy-2-l1aplltlly:Lsul ronyl )- 25 L--ar~rinyl-N-(2-1lle~l~oxyotl~yl)glycille Buffer sys tem As clesired Glucose 2 5 Dis tillecl l~ater 500 .
~;.

;
o ''' , ., . . ., , _.. .. . ~
7~
i.
1 .'', Z~

- - -A L~Y ~ f`olly l ci~ l o:r.i~les io(l:i~lnl G,7-rl.i.lllctlloxy-2-~ E)llt:lla:L(3l~c~ 1t`ol~al:c To a ~.~c:l:l gt;irre~l so:Lution of 70.8 gr of so(li.llm 6,7-di.llyrllo~;y~ i;11l1el~esu:lr`ol-late a~l~l 77.2 ~r of~ soclium lly~lro~ lr~ 50 nnl ol` ~Yal;e:r ~rag .l(l(lC(l rlrop~ i se 230 nll.
ol (linlct,llyI. su~ rat;c at 60C over a l)ori ocl of ol-le hour~
rill~ t~llLcll tilllO tlle l~rocl~lct proc~ ll:r(l, To tllis ~:
react:i.oll m-i~;tllre ~as ackle(l i.ll l)ortloJls ~3c3.~ ~ oL` so~ rn ~i l1ydro~ le, and stirring was conti.rltlecl f`or ol~e hollr. ~:
After olle llour at room temperaturo, tlle prec:ipitlte was rilterecl, t~rasllo(l wi.th etllallol and clriocl to ~i.ve 50 g Or ,~
socliun1 6J7-clinletlloxy-2-llapl~tllalelles~ `ol~atQ~

( B ) 6, 7 -(linle t;llo~cy-2-llal~htlI11ellesll:l f`on~ L cll:l o r:i(lc .
'rO a s tirre~I sus~-)ellsiol1 of 50 ~ of :fille.l y (liviclcrl so~lium ,, ~.
6,7-(limotllo.~y-2~ plltha:l.el-leslllrollato in 1,()() nll 0~` climetllyl~
rorrllanl.irle ~ ; a~l(l(?(1 (Iro~ r:isc 62., nll Or` 1;11iollyl cll:l.oricle ; r()()~ `1111)(.! r1 1,11 t`C . ~ ;c~ 1` 3() nl~ C3~C tioll :
Ill:i. ~c ~; l l r e ~ .i l l tO .l. ~ o ~` i c (~ < l l l (l 1; 11(3 l) rc! ci ~
tate l`:i I tcre(l a~l(l t;hl?ll ~Iissolv(3(l illtO 2so nlL Or l~ell~clle.
~rllc l.~ .C~o L~ oll ~ lg :~ tc~ Llll~
~I :r.i. ~ ( l o v ~ y( l t o l l s ~; o cl i l l rll ~ ; o .l. v cl l t ~ ly `~ ~

:
.

, .
~23 3L3L~2;~

rec:rysta~ .e(l from l)e~ elle-JI-llexalle (1: 1) to grive 32 g of 6~7-(Iimetl1oxy-2~napIltha1enesul[`o~Iyl cllloricle, ~I.I'. l27.5 -- :I2').5 C
ArIaIy.~; - C.lIc(I. I~ol CL2II~ lOI~.';C:I. (poIcol~ C, 5().26;
H, 3,87; Cl".2.37 Found (percent): C, 50.45;
~J ~.00; Cl, 12.33 The following ary1s~1fol1yl ciLlorides not previously reported ln tlle cllemical ].i terature were syntIlesi~ed by the a~orenIelltlolled procedure which is eYserltia:L1y -that as cIescr:ibed irl E. Il. I~od-l, "Chemistry Or Carbol1 Compourlds", Elsev:ier Publislung Company, 1954, Vol :[II, P, 4~ 469.
. - ............... ~ . .. .
,` No. Ary:lsulfollyl Chloride l`l.P. ( C) _ ... ~ .... .... _.. _~

~ 1 ~ ~lOz~ [ O~ 8 -- 119.S ~ :

~ ~: C.l 2~; ~
2 ~ OCII,31 3~ . 5 - ~I.38.5 .... _ .
15 ~ ~('I0,~

.
:

-- ] 211 --, . _- - ., . _ , . ... . . ..... . . _ _ . _ .. .... ... _ .. ~
. ' , ,.,~

r~~
31~

1'1~1~,l'AI~ ()N ll A ~ O a c :i ( l ( 10 r:i. va l; :i V

( /~ ) N ~ l t y .l ~; l y c i l l c l; e ~ u t y:L e ~: t e :r ~`o ~G.5 ~r 0l` hlll;yl.alni,lle was added w:il;h stirr:i.ncr :L5.05 g Or terl,-l)lll;y.1 cllloroQcetate ovc,~r a poriod o~' 30 mill~,lte.s, wll:i.le nn.~ l{r l;lle ten~,peratu.re i,lt 30-7(')C. 'I`lle rcclcl,ioll n~ tllre ~ras 11eJ.cl at 70C ~o t' a3l arl(:li.tio~la:L 03le was c~r,ll)c) r~l,od ~ VaC:I10, .l~ld tlle rcsi.clue was talccll up iJI
40 nl1, Or ,N NaOII so lutioll and 50 m.L ol' I)e3~i~.enr3, tr~n~1`erreci illtO a sel)aratory r~nllel alld ~rcl,.1 shalcell. The berl~ene so,i~ll;io~ ra.~ sr;~l:)a.ratecl~ wasllccl Wi tll ~r~.-tcr~ clrlcd over al~llyllr(>lls so(.l~ Lt'ate al~cl r:iLtcre(l. Al`tcr evul~oratio of l~en:~e~lc, tlle r e~si clue was ciisti.Ll.cd ullcler r e(.lucecl .
, r~ ~; 9 ~ I o ~ i v(~ 1 7 . 0 ~ ,) ( 3 . ~) I) c` r`c (' ll l, ) 0 ~' N -~ ,'C :i. l l C
tct l -l)lll.y~ ,t(~ .1'. 7~iC'/I~ 1Illlllll,. ~ ' '1`11(~ 1`oJ 10\~ O .l(,~ C~ ; llot ~ violl;ly .
t'C`~)O I`i.(`~l :i 11 1,ll(' Cll(`tlli C~l I .I.. i l.C`l`ill,ll J`(! W(`J`(J ~`:;yJI l,lI(',';i `~c(l l~y . ~ ~
tll-.~ al'orcnlc~ll;:iollc(l l)roco(l~lrc Wll,iCIl :is o~s~elltia:l:l.y l,llat .-~ ' .
a~; ta~l~,rl~t l.~y A . J . Spc,~,:i,a,le et al ., J . Org. Chenl. 2 r~ 7 (19t')0) .

- ~25 - .

I .

r~

- - -N o . ~ nl i l l o ~ i v~ t~ 13 .1~ .
_ _ __ _ _ :LI I N - ' .3 9 5 C/ 2 ( ) nllltl l g \(,~ o)~ c~ _ _ 2 IIN~ 2 ( 3)2 G5 C/ 5 mmllg \CII"CO,~ C11119 _ _ 3 /( (~1~2 )~ 11,3 8~ )O C/2 . 5 nlrrlllg \('II,,CO,~-t:-Cllll() _ _~ _ _I
1l I IN / ( 2 ) 5 3 8 3 - 5 ( ' /.1. . 5 mntl 1 g \(:~12C2 -t -c~l1l9 . .
_ _ _ _ .
~ ( C112 ) 7 C~ ~ 3 12 5--:l 3 0 C /~1 mn~l gr (,11 ? C ? ~ t--(, / 1-19 .
__. ~ __ . .
6 ~lN/Cl 2Cll~ C113 6:1- 2 C/2 mn~lg \(,II?CO~--t--C~1119 . . :
7 /(,11~C112()('113 9/1 C/ '3 nln~lg ~ . \(,112(~112C02-t-c1~ll9 _ , ...... : . ,
8 /~ ,C112()C11,3 60- 3 C/'3 nlnlllg (~112~ CII,_C02 ~ t-cll1l9 _ ~
/~ll )cll~ ,o~ll ~IIN\ '~ 3 ~r)_ 7(,/5 I)~ r ('II,CO~ ) ~_ ~_ _ Cll"CII ,OCII"(~II, o 10IIN/ ~ -3 1():' C/ ~I nlmllg . , .

- 1~6 -'' .

- - -No, Anli 1l(1 Ao:i (l l)(~liv~lt:.i vo 11.1' .
__ _ __ ~
:l l./ (, l I;, C l 1" -~ :I G G C / I O nln~l g (~112(~2 1;~ (,) _ .................... _ Cll,CII ~;CIl Cll, o 2 ~ IN/ '- 2 2 3 1 oG - ~ c ~ l. . 5 m~ ,r (~ t-('11ll(3 __ :L ' 3/ ( ' I I ~ C 112 ~ C 1~ ,3 ( ) ~7 (~ , r~ ;
('112CO"~ __ .
__ ,D _ _ ~

1ll IIN 1(.)1 C~ 5 mnJIg : -\'C112C112C112C02-t-C1113~
_ . _ . "
1 5 IIN~l J :1. OJ. C~ 5 Illl~ g _ \Cll,~C02~ 119 ',.~' ' . 1G ILN--O Lo5 C~ 11 nilnllg ;~
\ C112CI-l2c02 - t ~cl~ . _ ~ O ' . ___ . : ~

17 IIN~ 12~-:l 30 C/.'3 nmlllg . ('Il ,C(),,-~;-C~ ___ ___ . . ;~
I ~¢ I I N \ I / l r~ ~ ~ C ~ I r~ g ~`I1"('0" -~ ~ .. _ . (`11 -O
L'J IIN/ ~ 1 5G C/l() mrllllfr \ (' 112 (' 11~ --L -(~ _ ~ .~

-- l27 -. , , 3~6 _~ _ ~ ____ . _ ; ' O I I N ` ~ ' 3 o \(~ ~ /(~ ;

.. _ ~ _ I I N 2 ) 3 '~ n ~' I ( ,11(, 0, --I --(~ 11 I 1 0 (, /2 7 1~ , _ . _ IIN /( ( I 2 )~(,11,3 22 \(~1l(,o2_~ (3 .L21l 'C/2G r _ , . _ ~
IIN/ Cl12CI120(,113 2 3(~ ~X-90(,/6 ._ ~ . ~ _ __ , ~ (,112--- . 21~Cl13 1:16- 8C/2 mmllg .
~ __ _ 11 N ;- ;~ ~ . .
5\( ~ o ~ 11 . ~ '7(' /' I ~ "1"~
_ ~\ ._ ,~G (~ O?~I; ,~ ] ? 5 (,/: G 11mlllo :.

;
~' 3~

No. Amino Acid Deriv~tive ~
_ __ ............................ . . ~
~ CH2--~
27 ~CHCO -t C4H 141 C/~.5 mn~g . _ . ~
28 ~(CH2)3CH3 89 C/ 3 mmHg CEI2CH2C02--t--C4Hg :
_ _ _ . . _.,........ . _ . _ I , .
/ 2 (~ o . , 29 HN~ 111 C/ 1 mmHg CH2C02--t -C I~H9 I - .

3 O . ~ _ _ 91-- 2C /1 mmH
CH2C2--t--C4H
~ _ 31 CH2CH2C02C2H5 115 C/ 2 mmHg CH C O --t--C 4H
.. . ._ ,, ~,_ . ~ ,, OH
32 ~N~CH2CH2CHCH3 82-- 84 C/2 mn~g CH2C2 t C4Hg ~ __ . .~ . __ --~CH2cH2socH3 .
33 HN\ 150C/ 0.5mmHg CH2 ~ 2--t--C 4H .
. ,, ,,, __ _ ~.~ _ . _ , , ,... ~ .. _ 34 E~N~ 2 2 95-- 6 C/2 mn~Ig CH C02--t--C4H .
. ~ __ _ . . , . _ _ . 35 ~ CH2C -=CH
_ 2C 2 CI~EI

-- 129 _ . 3 ... ~ .... ,.................. .... ,........ , . ~;
,., .
'.~
. ., r~

r 0l` I.I`~ y.l.Lll~ lO ill I ,e ol` ~ 110 Wtl; a(~
ll~O~ OI~";~ 3~1 .() ~J' ol ('~ y.~ OlllO-lC(~Lc~
2()0 n11. 0r l)(~ llt! :i" olle IIOlI:t` at l~()olll t(?r~ t~lre. At tllc ClICI oJ` tl~ e-r:iocl, tlle nlixtu.r(~ waS ILe~cltec1 at rer~ x t`or ~ l1ol1r.~ to conl1~:1.ete tlle re.1ct:ioll~ Upoll clLil1:irlg, the l;l.ictl1yl allli llo hyclrob.~omid~ .IS l (~nlo~ c(l l~ i I t r~l t; i oll .1l~l ~,lS~ r:i 1;11 I)cll.~ . AL`t;e:L l.'C,`llIOVLI.I. Or tll~ so:lvt~llt~ tllo pro~lllct ~as clist.i.l I.ocl i.ll vacuo to y:ie:l(l ~ll2.8 g (75.3 perccllt) Or N-(2-nletlloxyet;lly:L)glyc:illc etlly:L cst-?r, - B.l~. 73--5 (Y/ll rlmlll~
l~c L`o:l:10~ lg ~1n1.illo aci.c1 otl~yl o~;l;c:r.~i llol, l)reviol1cily ~ -rel)ortcl1 :i ll. I;lle cllell1:ica:1. :I:i teratlll c ~iere ciy1lt]lc~ .ec1 l~y L5 tll(~ cl~ o~ l1 t:i o1l(a~-l Z~l oc~ :L~ca, ~l1icl1 i i e~ (?l1 ti.l:l:l y l,¦l~t as tall~ t l)y A. J. S1)o~:ia:Le cl. al ., J. ()rg. Cllc'lll.~ ~r~

7~1 ( I '~f;O) -,... . _ ( N o, A nl i l ~ o /~ c i ( I 1~`1 l l y 1 I~`s l c r ( ( ' ~ ;n l~ ) _~ ~_ ~ .
L IIN\ - ~ .) 57~ /.3 n~nl11g (~11,>~ ,;,11 r) .
._ , ~
2 / C11~ ()('11,3 G ~- 11~/~3 mrl~1g ('ll,,C'~I,)(~()~)C2ll,5 __ ~

.
,.

~ .
. . ~.

~23~

. ,' .
N o, ~\ IIN I I O ~ o i ( l l;~ y l. I~s t o l ( (, /nlllll l g ) ~ :
_ ~ ~
',~

'3 ~ (~11 ~'() (: 1-1 () 1 ~ /2 n~ :
~
~ _~_ . ~: .

1~ i I ,11 " (,1~,~ C 2115 1 IC 1 L () 1. ~2 C

CO~C,~115 .
,.__ ~ _ 1 (1'()2(`2~15 5ilN /CII~C,II~(,II;~C113 L 1.3-- G c/3 mnlllg , . _\ ('112(~0~,~C~115 . _ ' .' 6 C 11 -Cl 12 ~ l I o - 7 C /:l nlmll g .~ ~........... ~ .
, ~ . _ .:
7 1lN/(~ llcll3 78-8()~'C/~
(~1~12C02C2115 . .
----llN/(C112 ) ,3C113 ~ ! ;
8 ~ 1C~()"C21l5 . ]ICI. (i3-11 C
_ (,II"~,O"C"II ~ . . _ .' : ..

(C) N-(2-nlel,llo,~yotl~l )g,lyc:inc L)c~ .y:l. csl,o~ l)-t(~ ellcs1l:if`0llat:c To a solllt;:io]l oL` 55.8 g of` N-(2-moll~o,~cyot,llyl)gLycill(3 -tert-l)utyl estor ill 200 ml of l)ell:~el~(? W-IS acl(:le(l 63.8 ~
oL` hell~,y:l. alcoJIol. alld 72.9 g Or p-tolllellesu:Lrorli.c aci~l n~ollolly(l-~ to, ~rl~O nl.i.~l;uro Wil~i llcal;c(l .~1; rolNl.u~c ror 1,0 :.; , .
''' ' ,;' , -- 13 1 -- ~ .

~ ' .. ~ .

3~6 hollrs ~lritll tlle conti.nuous reniova:l of` l~aLer through a 3~ea~ ;tarlc water trap. At the end Or tllis pe:riod, tlle sol~ll ioll w~s concelltrated in vacuo, allcl to the residue was c~ erl 3()0 m.l ol` dry etllyl cLllor. Arl er 2 hours at room temperature, the formed precipitate l~ras filtered, washed wi Ih dry ethyl ether arld then recryY tallized from etllyl acetate Lo yield 99,2 g (85 percellt) of N-(2- :
methoYye-tlly:L)g.lycine be2lzyl ester p-(;o:llleneslllrorla-te~ -M.P . 95--6C.
The rOl loltrillg amlllo acid benzyl ester p-toluenesulfonate not previol~sl.y reported in -the chemica:L ].i terature were syntllesizc<l by tlle alorementioned procedl.lre. .

~ ~ _ No Amillo Acid Benzyl Eslter M ~' (~ ) . .............. . p-Toluenesul :~onate . . ~
_ . .......... _ 1~ CH2 C 2 CH2 ~ 97 -- 9 2~ ~ Cll~ ) lC13 3 1 "~

3llN~ - ( 3 ) ~ 9/1 _ 5 ,,,: (,112(~02C112 -~
: _ , u 1l \CI{ C112C02C112 ~

- I 3.' -r ., ,...

.

: ~

~ - - - --1\ 11 1 i I I ( I /~ ( ~ i ( I 1 J c I 1 ~ ~ I 1.~ .; 1; ( ~ I ~ 1 , N (~ . I ) -'I `( ~ 1 1 1 (~1 1 ~ .; I 1 1 1 0 ~ ~ ~ ) /(('11" )/1('11~3 ~ :
r~ \ C 1 1 2 (; 2 C 112 4~ I ( ) I ~ 2 _ _ _ _ .... .
~i ~IN~C 2 ~ . 1110 -- 3 \CII"C02C112~~
_ . . _. _ ~ 7 C~ CII, CO ~C 12~ ~ 511 -- G~ ~

(-,11, (,11 -(~ .
- 8 IIN/ 2 2 ~ 133 -- 5 ~ . \C112C02C112~
. I 0 --.: 9 ," 2 2 ~ 1 3 3 -- 5 ~ --- ~('112-0 ~ ~ ~ ., ] O , \ ~ I 3'3 - 8 r- (~112C 2('112 _ __ _ I I N ~- ~ 3 . ~ :
. I I \~ 2-~ 103 - (~
~.' . (~ ' ~ :
~ /(~ LI I ~

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

~Z~3~6 .
~muno Acid Benzyl Ester M.P (C) No. p-Toluenesulfonate _ _ ~ ' :
5 ~ CH~ ~ 130 - 1 .

PREPAR~TION C

2-Piperidinecarboxylic acids ~d esters thereoP
... . .
^ (A) 4-methyl-2-piperidinecarbonitrile To 500 g of 10% 90dium hypochlorite solution cooled in an ice bath, there was added dropwise a solution of 33.6 g (0 21 mole) o~ 4-methylpiperidine acetate 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 : - 134 -...
;,."~
, ~'' .

2~

resiclue was aclded dropwise to a solution Or lL.8 g (0,21 lO0 ml of mole) of potassium hydroxide in/ 96q/o e-tllanol urlder rc~lux.
~efluxing was con-tinued for an additional 10 minutes.
Ethanol was evapora-ted, and the residue was di~solved into 50 ml of` 2N sodium hydro~cide solution and then extracted with ether.
The ether layer was dried over anhydrous sodiurn sulfate - and then ether evaporated. The residue was added to an ice--cooled solution of 27 g (1 mole) of hydrogen cyanide and 25 ml of concentrated hydrochlor:ic acid in 300 ml of water. The solution was stirred at a temperature of 10 to 20 C for 4 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 I;o give 17 g (66%) of` 4-methyl-2-plperidinecarbonitrile, B.P.
96-97C/10 mmHg.
The following 2-piperidinecarbonitriles not previouSly reported in the chemical literature were synthesized b-$~
the aforementioned proceclure which is essentially that as taught by Grundon et al., J. Chem. Soc., 196~j 3898, Grundon et al~, J. Chem. Soc., ~ 2448, R. Bonnett et al., J. Chem. Soc., ~, 2092 and H. Bohme e-t al., Ber.~ 92 1613 (l959).

..
",' '.

- 135 ~

, ~ ' "

~' ~ ~23~1L6 r~7 1~ CN

N o . ~_ Ll . L' .

--(, 11 2 C l ~, ~ l. () S ~ r, 12 C 1 1 " (, 1 [ 3 :I :I. G c~ /~3 Il"~ r ~_ ~,<1~ ~
2-(,113 _.

(13) ~ letll~L-,'~ er~ ecar~)oxy1ic aci~ (lrocll:l.ori.~lc . ~ ;

/~ SOllltiC)II of :L~ ~ of l~-metllyl-2-r)ipc~r:icl~ c~lrl)ollitri:l.e il~ 25() nll Or (~N lly~ oclllolic aci(l WLIS rol`:Lllx~(l l`or O
hours, A[ tor ~vaporatioll oI~ the solvcllt, the resiclue w~s rocry.it~:l.]i~ecl lI~onl water to g.ive 13 g Or /~-methyl--2-ri~ lor~ o~ .i c aci~l lly(lrocllloL~:i( (C) 1~,1;1JyI 1~--r~ i l)(Jl~:i(liIIC`(`~ l)O)i.yIi,~
A .~ ( () . ()7,J nlo l e ) o ~ l C- ~:
c ~ o ~ y l :i (~ ( l l o c l l l o ~ (i 5 () lll l o ~ i o l l ~ :l c l l .L o l i ( l o ill ')()(~ Tlll ol' cLllallo:l w.~s rQL':luxo(l l`or ll llollrs. /~t t~
Or t~ oriocl? tl~(! so:l.vellt was e~rar)orato(l url(lc~r rcducecl ~ro~i.s~lre, all(l tll(! ro~ 3 wai extracto(l ~ri.l;ll a sol~ltiorl Or Clll.OrOf'Ol'lll clll(l S..I.tlll'al;Q(l pOI;asSillnl CalL'i)Oll'ltQ sO.l.lltiOn, "
.~, 'I`he cll:Loro:ro~ Layer was ciri.ecl over anllyclrolls sodium silll ato a~(l tllen chlororornl was evar~oral;od . Disti].].a(;ion Or tlle ros:i.(lllc ~;avc 7,11 g (Go~O) Or etlly~ mcl;}lyl-2-piperid:i.lloc.~ ylatc, 13.1'. 76-77C/3 mlllll,~.

(D) Benzyl ll-metllyl-2-pipericliIlecarboxy:Late p--toluQnesulfollate i~ solution oi` 20 g (0.112 mole) of ll-metlly~.-2-pi.peridine-carl)oxy:li.c acid llydrochloride, 211 g (0.22l~ nlole) of` benzyl alcollol al~d 25.6 g (().1.3l~ mole) Or p-l;oluerlesulfonic acid moJIolly(ira~e in :lO0 m.I. Or berlzl3rle was rc~rluxed for 5 hours wi th the continuous removal of water throllgll a Dean-Stark water trap. Al; tlle end of this period, tlle solvellt was clistille(l of ~, an(l tlle residue was wasllocl wi th etller-n-llexane and recrystal1ized to give 10 g ( '2%) of l~erlzy1 :~
4-methyl-2-piperidinecarboxylate p-tol.uenesul.fonate~
M.P. 160--163C .
The following 2-piperidinecarboxylates no t previously reportecl i.n tlle cllemical l:iterature were syllthesized by tlle arol~enlellt.ioIled p.rocedure.

I ~)7 _ . ~ ~
~ ..
~ . ~' .
,.......................................... ..

~23 . N C2C2~5 -r ~ _ No. ~ Addition B.P.
~ _ ......... ~
1 ~ CH2C~3 . 82-4 C/3.5 m~Hg __ ~ _ ___ 2 4-C~2CH2CH3 HCl ¦ 3 ~ 4 C~ 3 _95-6~C/2 mmHg ¦
_ . ~__ . - . . __ _ . .
4 2-C~3 . _ ~7~
, Morpholine-3-carboxylic acid hydrochloride was prepared by the procedure described above, and has a melting point of 200~2C, The following starting materials for the preparation of the N -arylsulfonyl-L-argininamides were prepared by the procedures described in the following literatures:

. _ ., , _ . ~ _ . Compound Litera-ture _~ .. .. . . ~ . . ~

HN ~ J. Org. Chem., 29 2203 (1964) ___ . _. ~ ~

J. Org. ~ "
, - 138 - :
, , . .. . . , .,, . ~ ~ r ~ - ~ ~:
...
~ ,..~
",''' ~ ~, ' .

3 ~i c o ~ o ~ I i ~; e r l l l l r c _ ~ _ . .
(~o~
IIN ~ ~ J Am. Cl~em. ~oc., r~') 2()0 (:L937) . . - . . _ _ _ ~

IIN ~ ~I Obsllcl~ llim.~ 2 22l~5 (1973) ._. ._.. . .. _ _ _ C02ll Ber , ~ 20311 (]9LI) ~ ; ) 0~ (L) Ber. ~ ~ 9Z7 ( L93~) Tlle methyl or ethyl ester of` the aforemen-tiorlecl compounds were prepared by a eonventional esterifiea-tisn proeedure.
Ethyl tiliomorplloline-3-earboxylate has a boiling point of 108C/4 mmllg.
Diethyl pipericline-2,6-diearboxylate llydroehloride was preparecl by the eonventiollal esterif`icat:ioll of piperi~ine-2,~-cliearbo~ylie aeicl and has a melting pO illt O~ 1811-6C .
lsoindoline-L-ear~oxylic acid was prepc-re(l by a proeeclure irni:lar to thaL- ~or the preparation of isoquinoline-3-carboxyLic acid described in Ber., 4ll 2034 (1911). Ethy:L
isoindoLille-]-c.lrboxylate hydrochlori(le wa5 prepare~ y ....

;,, 2~

the convcn t:i.ona:l es teri:fi cation of isoin(lolirle-l-carl)oxylic ~cid and has a melting pOillt of 139-1110.5 C.
Ilavin~ l~o~ l y clescribed the :inventioil~ i t will be al~l>al cllt to ollo Or Or(~ ary slcill ill tll~ ~rt tll~t m~lly changes alld moclifications can be macle thereto without del)artill~ :t`rom tlle spirit of thc invention a9 Set rorth ,~ ; herei]l.

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

t J, ~ ,"~''~ ' ';
' 1 l") _ , ,~

Claims (46)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:
1. A process for producing an N2-arylsulfonyl-L-argininamide having the formula (I):

(I) or the pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of (1) wherein R1 is selected from the group consisting of C2-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C2-C10 alkoxyalkyl, C2-C10 alkylthioalkyl, C2-C10 alkylsulfinylalkyl, C3-C10 alkylcarbonylalkyl, C1-C10 hydroxyalkyl, C2-C10 carboxyalkyl, C3-C10 alkoxycarbonylalkyl, C1-C10 haloalkyl, C7-C15 aralkyl, C8-C15 .alpha.-carboxyaralkyl, C3-C10 cycloalkyl, C4-C10 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl, 3-furylmethyl, tetrahydro-3-furylmethyl, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl, and tetrahydro-3-thenyl, R2 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl, C7-C12 aralkyl and 5-indanyl; and n is an integer of 1, 2 or 3, (2) wherein R3 is selected from the group consisting of hydrogen, C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C2-C10 alkoxyalkyl, C2-C10 alkylthioalkyl, C2-C10 alkylsulfinylalkyl, C1-C10 hydroxyalkyl, C2-C10 carboxyalkyl, C3-C10 alkoxycarbonylalkyl.
C3-C10 alkylcarbonylalkyl, C1-C10 haloalkyl, C7-C15 aralkyl, C8-C15 .alpha.-carboxyaralkyl, C3-C10 cycloalkyl, C4-C10 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl, 3-furylmethyl, tetrahydro-3-furylmethyl, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl, and tetrahydro-3-thenyl; R4 is selected from the group consisting of C1-C10 alkyl, carboxy, C2-C10 alkoxycarbonyl, phenyl C7-C12 aralkyl and ring substituted benzyl wherein said substituent is C1-C5 alkyl or C1-C5 alkoxyl R5 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl, C7-C12 aralkyl and 5-indanyl;
and m is an integer of 0, 1 or 2, (3) wherein R6 is -COOR8 wllerein R8 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl, C7-C12 aralkyl and 5-indanyl; R7 is hydrogen, C1-C10 alkyl, phenyl C1-C5 alkoxy or carboxy; R6 is substituted at the 2 or 3-position; and R7 can be substituted at the 2, 3, 4, 5 or 6-position, (4, wherein R9 is selected from the group con-sisting of hydrogen, C1-C10 alkyl, C6-C10 aryl, C7-C12 aralkyl and 5-indanyl; and r is an integer of 1, 2, 3 or 4, (5) wherein R10 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl, C7-C12 aralkyl and 5-indanyl;
Z is selected from the group consisting of oxy, thio and sulfinyl; and q is an integer of 0 or 1, and (6) wherein R11 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl, C7-C12 aralkyl and 5-indanyl; i is an integer of 0, 1 or 2; j is an integer of 0, 1 or 2;
and the sum of i + j is an integer of 1 or 2, and Ar is selected from the group consisting of naphthyl, 5,6,7,8-tetrahydronaphthyl, naphthyl substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy and C2-C20 dialkylamino, phenyl, phenyl substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy and C2-C20 dialkylamino, C7-C12 aralkyl, , , , , , and wherein R12 is hydrogen, C1-C10 alkyl or C1-C10 alkoxy,which comprises: removing the NG-substitutent from an NG-substituted-N2-arylsulfonyl-L-argininamide having the formula:

wherein R and Ar are as defined above; R' and R" are selected from the group consisting of hydrogen and protective groups for the guanidino group, and at least one of R' and R" is a protective group for the guanidino group.
2. An N2-arylsulfonyl-L-argininamide and the pharmaceutically acceptable salts thereof, whenever prepared by the process of claim 1.
3. The process of claim 1, wherein said N2-arylsulfonyl-L-argininamide has the formula:

wherein R1 is selected from the group consisting of C2-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C2-C10 alkoxyalkyl, C2-C10 alkylthioalkyl, C2-C10 alkylsulfinylalkyl, C1-C10 hydroxyalkyl, C2-C10 carboxylalkyl, C3-C10 alkoxycarbonylalkyl, C3-C10 alkylcarbonylalkyl, C1-C10 alkylsulfinylakyl, C7-C15 aralkyl, C8-C15 .alpha.-carboxyaralkyl, C3-C10 cycloalkyl, C4-C10 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl, 3-furylmethyl, tetrahydro-3-furylmethyl, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl and tetrahydro-3-thenyl; R2 is selected from the group con-sisting of hydrogen, C1-C10 alkyl, C6-C10 aryl, C7-C12 aralkyl and 5-indanyl; n is an integer of 1, 2 or 3; and Ar is selected from the group consisting of naphthyl, 5,6,7,8-tetrahydronaphthyl, naphthyl substituted with at least one substituent selected from the group con-sisting of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy and C2-C20 dialkylamino, phenyl, phenyl substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy, and C2-C20 dialkylamino, C7-C12 aralkyl, ,, , , and wherein R12 is hydrogen, C1-C10 alkyl or C1-C10 alkoxy.
4. An N2-arylsulfonyl-L-argininamide and the pharmaceutically acceptable salts thereof, whenever produced by the process of claim 3.
5. The process of claim 1, wherein said N2-arylsulfonyl-L-argininamide has the formula:

wherein R3 is selected from the group consisting of hydrogen, C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C2-C10 alkoxyalkyl, C2-C10 alkylthioalkyl, C2-C10 alkylsulfinylalkyl, C1-C10 hydroxyalkyl, C2-C10 carboxyalkyl, C3-C10 alkoxycarbonylalkyl, C3-C10 alkylcarbonylalkyl, C1-C10 haloalkyl, C7-C15 aralkyl, C8-C15 .alpha.-carboxyaralkyl, C3-C10 cycloalkyl, C4-C10 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl, optionally substituted with at least one C1-C5 alkyl and/or C1-C5 alkoxy 3-furylmethyl, tetrahydro-3-furylmethyl, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl and tetrahydro-3-thenyl; R4 is selected from the group consisting of C1-C10 alkyl, carboxy, C2-C10 alkoxycarbonyl, phenyl, C7-C12 aralkyl and ring substituted benzyl wherein said substituent is C1-C5 alkyl or C1-C5 alkoxy; R5 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl, C7-C12 aralkyl and 5-indanyl; m is an integer of 0, 1 or 2; and Ar is selected from the group consisting of naphthyl, 5,6,7,8-tetrahydronaphthyl, naphthyl substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy and C2-C20 dialkylamino, phenyl, phenyl substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy and C2-C20 dialkylamino, C7-C12 aralkyl, , , , and wherein R12 is hydrogen, C1-C10 alkyl or C1-C10 alkoxy.
6. An N2-arylsulfonyl-L-argininamide and the pharmaceutically acceptable salts thereof, whenever produced by the process of claim 5.
7. The process of claim 1, wherein said N2-arylsulfonyl-L-argininamide has the formula:

wherein R6 is -COOR8 wherein R8 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl, C7-C12 aralkyl and 5-indanyl;
R7 is hydrogen, C1-C10 alkyl, phenyl or carboxy; R6 is substituted at the 2 or 3-position; R7 can be substituted at the 2, 3, 4, 5 or 6-position; and Ar is selected from the group consisting of naphthyl, 5,6,7,8-tetrahydronaphthyl, naphthyl substituted with at least one sub-stituent selected from the group consisting of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy and C2-C20 dialkylamino, phenyl, phenyl substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy and C2-C20 dialkylamino, C7-C12 aralkyl, , , , and wherein R12 is hydrogen, C1-C10 alkyl or C1-C10 alkoxy.
8. An N2-arylsulfonyl-L-aryininamide and the pharmaceutically acceptable salts thereof, whenever produced by the process of claim 7.
9. The process of claim 1, wherein said N2-arylsulfonyl-L-argininamide has the formula:

wherein R9 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl, C7-C12 aralkyl and 5-indanyl; r is an integer of 1, 2, 3 or 4, and Ar is selected from the group consisting of naphthyl, 5, 6, 7, 8-tetrahydronaphthyl, naphthyl substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy and C2-C20 dialkylamino, phenyl, phenyl substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy and C2-C20 dialkylamino, C7-C12 aralkyl, ,, , , and wherein R12 is hydrogen, C1-C10 alkyl or C1-C10 alkoxy.
10. An N2-arylsulfonyl-L-argininamide and the pharmaceutically acceptable salts thereof, whenever produced by the process of claim 9.
11. The process of claim 1, wherein said N2-arylsulfonyl-L-argininamide has the formula:

wherein R10 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl, C7-C12 aralkyl and 5-indanyl; Z is selected from the group consisting of oxy, thio and sulfinyl; q is an integer of 0 or 1; and Ar is selected from the group consisting of naphthyl, 5,6,7,8-tetrahydronaphthyl, naphthyl substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy and C2-C20 dialkylamino, phenyl, phenyl substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy and C2-C20 dialkylamino, C7-C12 aralkyl, ,,, ,, and wherein R12 is hydrogen, C1-C10 alkyl or C1-C10 alkoxy.
12. An N2-arylsulfonyl-L-argininamide and the pharmaceutically acceptable salts thereof, when prepared by the process of claim 11.
13. The process of claim 1, wherein said N2-arylsulfonyl-L-argininamide has the formula:

wherein R11 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl, C7-C12 aralkyl and 5-indanyl; i is an integer of 0, 1 or 2; j is an integer of 0, 1 or 2; and the sum of i + j is an integer of 1 or 2; and Ar is selected from the group consisting of naphthyl, 5,6,7,8-tetrahydronaphthyl, naphthyl substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy and C2-C20 dialkylamino, phenyl, phenyl substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy and C2-C20 dialkylamino, C7-C12 aralkyl, ,, , , , and wherein R12 is hydrogen, C1-C10 alkyl or C1-C10 alkoxy.
14. An N2-arylsulfonyl-L-argininamide and the pharmaceutically acceptable salts thereof, when prepared by the process of claim 13.
15. The process of claim 1, wherein said N2-arylsulfonyl-L-argininamide has the formula:

wherein R is selected from the group consisting of (1) wherein R1 is selected from the group consisting of C2-C10 alkyl, C3-C5 alkenyl, C3-C6 alkynyl, C2-C6 alkoxy-alkyl, C2-C6 alkylthioalkyl, C2-C6 alkylsulfinylalkyl, C1-C6 hydroxy-alkyl, C2-C7 carboxyalkyl, C3-C8 alkoxycarbonylalkyl, C1-C5 haloalkyl, C7-C10 aralkyl, C8-C12 .alpha.-carboxyaralkyl, C3-C10 cycloalkyl, C4-C10 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl, 3-furylmethyl, tetrahydro-3-furylmethyl, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl and tetrahydro-3-thenyl; R2 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl, C7-C10 aralkyl and 5-indanyl; and n is an integer of 1, 2 or 3, (2) wherein R3 is selected from the group consisting of hydrogen, Cl-ClO alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C2-C6 alkoxyalkyl, C2-C6 alkylthioalkyl, C2-C6 alkylsulfinylalkyl, Cl-C6 hydroxyalkyl, C2-C7 carboxyalkyl, C3-C8 alkoxycarbonylalkyl, Cl-C5 haloalkyl, C7-Clo aralkyl, C8-C12 ~-carboxyaralkyl, C3-C10 cycloalkyl, C4-C10 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl, 3-furylmethyl, tetrahydro-3-furylmethyl, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl and tetrahydro-3-thenyl; R4 is selected from the group consisting of Cl-C5 alkyl, carboxy, C2-C5 alkoxycarbonyl, phenyl, C7-C10 aralkyl and ring substituted benzyl wherein said substituent is Cl-C3 alkyl or Cl-C3 alkoxy; R5 is selected from the group consisting of hydrogen, Cl-ClO alkyl, C6-C10 aryl, C7-Clo aralkyl and 5-indanyl; and m is an integer of 0, 1 or 2, `

(3) wherein R6 is -COOR8 wherein R8 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl, C7-C10 aralkyl and 5-indanyl; R7 is hydrogen, Cl-C6 alkyl, phenyl or carboxy;
R6 is substituted at the 2 or 3-position; and R7 can be substituted at the 2, 3, 4, 5 or 6-position, (4) wherein R9 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl, C7-C10 aralkyl and 5-indanyl; and r is an integer of 1, 2, 3 or 4, (5) wherein R10 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl, C7-C10 aralkyl and 5-indanyl; Z
is selected from the group consisting oF oxy, thio and sulfinyl; and q is an integer of 0 of 1, and (6) wherein R11 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl, C7-C10 aralkyl and 5-indanyl; i is an integer of 0, 1 or 2; j is an integer of 0, 1 or 2;
and the sum of i + j is an integer of 1 or 2; and Ar is selected from the group consisting of naphthyl, 5,6,7,8-tetrahydronaphthyl, naphthyl substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C1-C5 alkyl, C1-C5 alkoxy and C2-C10 dialkylamino, phenyl, phenyl substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C1-C5 alkyl, C1-C5 alkoxy and C2-C10 dialkylamino, C7-C10 aralkyl, ,,, ,, and wherein R12 is hydrogen, C1-C5 alkyl or C1-C5 alkoxy.
16. An N2-arylsulfonyl-L-argininamide and the pharmaceutically acceptable salts thereof, when prepared by the process of claim 15.
17. The process of claim 15, wherein said N2-arylsulfonyl-L-argininamide has the formula:
wherein R is selected from the group consisting of:

(1) , wherein R1 is selected fronl the group consisting of C2-C10 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C2-C6 alkoxyalkyl, C2-C6 alkylthioalkyl, C2-C6 alkylsulfinylalkyl, C1-C6 hydroxyalkyl, C2-C7 carboxyalkyl, C3-C8 alkoxycarbonylalkyl, C7-C10 aralkyl, C8-C12 .alpha.-carboxyaralkyl, C3-C10 cycloalkyl, C4-C10 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl, 3-furylmethyl, tetrahydro-3-furylmethyl, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl and tetrahydro-3-thenyl; R2 is hydrogen, C1-C10 alkyl, C6-C10 aryl, C7-C10 aralkyl or 5-indanyl, and n is an integer of 1, 2 or 3, (2) wherein R3 is selected from the group consisting of hydrogen, C1-C10 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C2-C6 alkoxyalkyl, C2-C6 alkylthioalkyl, C2-C6 alkylsulfinylalkyl, C1-C6 hydroxyalkyl, C2-C7 .alpha.-carboxyaralkyl, C3-C10 cycloalkyl, C4-C10 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl, 3-furylmethyl, tetrahydro-3-furylmethyl, 2 thenyl, 3-thenyl, tetrahydro-2-thenyl and tetrahydro-3-thenyl; R4 is selected from the group consisting of C1-C5 alkyl, carboxy, C2-C5 alkoxycarbonyl, C7-C10 aralkyl and ring substituted benzyl wherein said substituent is C1-C3 alkoxy; R5 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl, C7-C10 aralkyl and 5-indanyl; and m is an integer of 0, 1 or 2, (3) Wherein R6 is -COOR8 wherein R8 is hydrogen, C1-C10 alkyl, C6-C10 aryl, C7-C10 aralkyl or 5-indanyl; R6 is substituted at the 2- or 3-position; R7 is selected from the group consisting of hydrogen, C1-C6 alkyl, phenyl and carboxy, and the position of R7 is 2, 4 or 6, (4) 3-carboxy-4-morpholino, (5) 3-carboxy-4-thiomorpholino, (6) 1-oxo-3-carboxy-4-thiomorpholino, (7) 4-carboxy-3-thiazolidinyl, (8) 2-carboxy--1,2,3,4-tetrahydro-1-quinolyl, (9) 3-carboxy-1,2,3,4-tetrahydro-2--isoquinolyl, (10) 1-carboxy-1,2,3,4-tetrahydro-2-isoquinolyl, (11) 2-.
-carboxy-l-indolinyl and (12) 1-carboxy-2-isoindolinyl; and Ar is selected from the group consisting of naphthyl, 5,6,7,8-tetrahydronaphthyl, naphthyl substituted with at least one substituent selected from the group consisting of halo, hydroxy, C1-C5 alkyl, C1-C5 alkoxy and C2-C10 dialkylamino, phenyl, phenyl substituted with at least one substituent selected from the group consisting of halo, C1-C5 alkyl and C1-C5 alkoxy, C7-C10 aralkyl, , and .
18. An N2-arylsulfonyl-L-argininamide and the pharmaceutically acceptable salts thereof, whenever prepared by the process of claim 17.
19. The process of claim 1, wherein said N2-arylsulfonyl-L--argininamide is N2-(6,7-dimethoxy-2-naphthylsulFonyl)-L-arginyl-N--butylglycine.
20. N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylglycine and the pharmaceutically acceptable salts thereof, whenever produced by the process of claim 19.
21. The process of claim 1, wherein said N2-arylsulfonyl-L--argininamide is N2-(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-butyl-glycine.
22. N2-(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-butylglycine and the pharmaceutically acceptable salts thereof, whenever produced by the process of claim 21.
23. The process of claim 1, wherein said N2-arylsulfonyl-L--argininamide is N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N--(2-methoxyethyl)glycine.
24. N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl) glycine and the pharmaceutically acceptable salts, whenever produced by the process of claim 23.
25. The process of claim 1, wherein said N2-arylsulfonyl-L-argininamide is N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl) glycine ethyl ester.
26 N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxy-ethyl)glycine ethyl ester and the pharmaceutically acceptable salts thereof, whenever produced by the process of claim 25.
27. The process of claim 1, wherein said N2-arylsulfonyl-L-argin-inamide is N2-(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxy-ethyl)glycine.
28. N2-(4,6-dimethoxy 2-naphthysulfonyl)-L-arginyl-N-(2-methoxy-ethyl)glycine and the pharmaceutically acceptable salts thereof, whenever produced by the process of claim 27.
29. The process of claim 1, wherein said N2-arylsulfonyl-L-argin-inamide is N2-(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl) glycine.
30. N2-(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl) glycine and the pharmaceutically acceptable salts thereof, whenever produced by the process of claim 29.
31. The process of claim 1, wherein said N2-arylsulfonyl-L-argin-inamide is N2-(5,6,7,8-tetrahydro-1-naphthylsulfonyl)-L-arginyl-N-(2-methoxy-ethyl)glycine.
32. N2-(5,6,7,8-tetrahydro-1-naphthylsulfonyl)-L-arginyl-N--(2-methoxyethyl)glycine and the pharmaceutically acceptable salts thereof, whenever produced by the process of claim 31.
33. The process of claim 1, wherein said N2-arylsulfonyl-L-argininamide is N2-(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-tetra-hydrofurfurylglycine.
34. N2-(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-tetrahydro-furfurylglycine and the pharmaceutically acceptable salts thereof, when-ever produced by the process of claim 33.
35. The process of claim 1, wherein said N2-arylsulfonyl-L-argininamide is N2-(7-methyl-2-naphthylsulfonyl)-L-arginyl-N-tetra-
36. N2-(7-methyl-2-naphthylsulfonyl)-L-arginyl-N-tetrahydrofur-furylglycine and the pharmaceutically acceptable salts thereof, whenever produced by the process of claim 35.
37. The process of claim 1, wherein said N2-arylsulfonyl-L-arginin-amide is N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-tetrahydro-furfurylglycine.
38. N -(6,7-dinnethoxy-2-naphthylsulfonyl)-L-arginyl-N-tetrahydro-furfurylglycine and the pharmaceutically acceptable salts thereof, whenever produced by the process of claim 37.
39. The process of claim 1, wherein said N2-arylsulfonyl-L-arginin-amide is 1-[N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-argirlyl]-4-methyl-2--piperidine carboxylic acid.
40. 1-[N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl]-4-methyl-2--piperidinecarboxylic acid and the pharmaceutically acceptable salts thereof, whenever produced by the process of claim 39.
41. The process of claim 1, wherein said N2-arylsulfonyl-L-arginin-amide is 1-[N2-(7-methoxy-2-naphthylsulfonyl)-L-arginyl]-4-methyl-2-piper-idine carboxylic acid.
42. 1-[N2-(7-methoxy-2-naphthylsulfonyl)-L-arginyl]-4-methyl-2--piperidine carboxylic acid and the pharmaceutically acceptable salts thereof, whenever produced by the process of claim 41.
43. The process of claim 1, wherein said N2-arylsulfonyl-L-arginin-amide is 1-[N -(7-methoxy-2-naphthylsulforlyl)-L-arginyl]-4-ethyl-2-piper-idine carboxylic acid.
44. 1-[N -(7-methoxy-2-naphthylsulfonyl)-L-arginyl]-4-ethyl-2-piper-idine carboxylic acid and the pharmaceutically acceptable salts thereof, whenever produced by the process of claim 43.
45. A process for producing an N2-arylsulfonyl-D-argininamide having the formula (1):
(I) or the pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of (1) wherein R1 is selected from the group consisting of C2-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C2-C10 alkoxyalkyl, C2-C10 alkylthioalkyl, C2-C10 alkylsulfinylalkyl, C3-C10 alkylcarbonylalkyl, C1-C10 hydroxyalkyl, C2-C10 carboxyalkyl, C3-C10 alkoxycarbonylalkyl, C1-C10 haloalkyl, C7-C15 aralkyl, C8-C15 .alpha.-carboxyaralkyl, C3-C10 cycloalkyl, C4-C10 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl, 3-furylmethyl, tetrahydro-3-furylmethyl, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl, and tetrahydro-3-thenyl; R2 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl, C7-C12 aralkyl and 5-indanyl; and n is an integer of 1, 2 or 3, (2) wherein R3 is selected from the group consisting of hydrogen, C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C2-C10 alkoxyalkyl, C2-C10 alkylthioalkyl, C2-C10 alkylsulfinylalkyl, C1-C10 hydroxyalkyl, C2-C10 carboxyalkyl, C3-C10 alkoxycarbonylalkyl, C3-C10 alkylcarbonylalkyl, C1-C10 haloalkyl, C7-C15 aralkyl, C8-C15 .alpha.-carboxyaralkyl, C3-C10 cycloalkyl, C4-C10 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl, 3-furylmethyl, tetrahydro 3-furylmethyl, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl, and tetrahydro-3-thenyl; R4 is selected from the group consisting of C1-C10 alkyl, carboxy, C2-C10 alkoxycarbonyl, phenyl,C7-C12 aralkyl and ring substituted benzyl wherein said substituent is C1-C5 alkyl or C1-C5 alkoxy; R5 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl, C7-C12 aralkyl and 5-indanyl;
and m is an integer of 0, 1 or 2.

(3) wherein R6 is -COOR8 wherein R8 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl, C7-C12 aralkyl and 5-indanyl; R7 is hydrogen, C1-C10 alkyl, phenyl C1-C5 alkoxy or carboxy; R6 is substituted at the 2 or 3-position; and R7 can be substituted at the 2, 3, 4, 5, or 6 position, (4) wherein R9 is selected from the group con-sisting of hydrogen, C1-C10 alkyl, C6-C10 aryl, C7-C12 aralkyl and 5-indanyl; and r is an integer of 1, 2, 3 or 4, (5) wherein R10 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl, C7-C12 aralkyl and 5-indanyl;
Z is selected from the group consisting of oxy, thio and sulfinyl; and q is an integer of 0 or 1, and (6) wherein R11 is selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl, C7-C12 aralkyl and 5-indanyl; i is an integer of 0, 1 or 2; j is an integer of 0, 1 or 2;
and the sum of i + j is an integer of 1 or 2; and Ar is selected from the group consisting of naphthyl, 5,6,7,8-tetrahydronaphthyl, naphthyl substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy and C2-C20 dialkylamino, phenyl, phenyl substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy and C2-C20 dialkylamino, C7-C12 aralkyl, , , , , , , and wherein R12 is hydrogen, C1-C10 alkyl or C1-C10 alkoxy which comprises:
removing the NG-substituent from an NG-substituted-N2-arylsulfonyl-D--argininamide having the formula:

wherein R and Ar are as defined above; R' and R" are selected from the group consisting of hydrogen and protective groups for the guanidino group, and at least one of R' and R" is a protective group for the guanidino group.
46. An N2-arylsulfonyl-D-argininamide of the formula:

and the pharmaceutically acceptable salts thereof, whenever produced by the process of claim 45.
CA266,501A 1975-12-09 1976-11-24 N su2 xx-arylsulfonyl-l-argininamides and the pharmaceutically acceptable salts thereof Expired CA1102316A (en)

Applications Claiming Priority (24)

Application Number Priority Date Filing Date Title
US05/638,985 US4055636A (en) 1974-11-08 1975-12-09 N2 -alkoxynaphthalenesulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof
US638,985 1975-12-09
US646,522 1976-01-05
US05/646,522 US4018915A (en) 1976-01-05 1976-01-05 N2 -alkoxynaphthalenesulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof
US649,219 1976-01-14
US05/649,219 US4018913A (en) 1976-01-14 1976-01-14 N2 -alkoxynaphthalenesulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof
US653,217 1976-01-28
US05/653,217 US4055651A (en) 1974-11-08 1976-01-28 N2 -alkoxynaphthalenesulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof
US656,014 1976-02-06
US05/656,014 US4041156A (en) 1974-11-08 1976-02-06 N2 -alkoxynaphthalenesulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof
US05/656,870 US4046876A (en) 1974-11-08 1976-02-10 N2 -alkoxynaphthalenesulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof
US656,870 1976-02-10
JP30621-1976 1976-03-19
JP3062176A JPS52113919A (en) 1976-03-19 1976-03-19 Preparation of tertiary alkylester of n-substituted amino acid or thei r acid salts
US05/669,743 US4070457A (en) 1974-11-08 1976-03-24 N2 -naphthalenesulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof
US669,743 1976-03-24
US05/707,536 US4036955A (en) 1976-07-22 1976-07-22 N2 -naphthalenesulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof
US707,536 1976-07-22
US05/713,486 US4073914A (en) 1974-11-08 1976-08-11 N2 -naphthalenesulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof
US713,486 1976-08-11
US05/723,474 US4096255A (en) 1974-11-08 1976-09-14 N2 -naphthalenesulfonyl-L-argininamides, and pharmaceutical salts, compositions and methods
US05/728,051 US4104392A (en) 1974-11-08 1976-09-30 N2 -naphthalenesulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof, and antithrombotic compositions and methods employing them
US723,474 1991-06-28
US728,051 1991-07-15

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Families Citing this family (23)

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SE8203887D0 (en) * 1982-06-23 1982-06-23 Kabivitrum Ab NEW TROMBIN INHIBITIVE ASSOCIATIONS
CA2008116C (en) * 1989-02-23 2001-11-20 Thomas Weller Glycine derivatives
US6559127B1 (en) 1997-07-31 2003-05-06 Athena Neurosciences, Inc. Compounds which inhibit leukocyte adhesion mediated by VLA-4
US7030114B1 (en) 1997-07-31 2006-04-18 Elan Pharmaceuticals, Inc. Compounds which inhibit leukocyte adhesion mediated by VLA-4
US6291453B1 (en) 1997-07-31 2001-09-18 Athena Neurosciences, Inc. 4-amino-phenylalanine type compounds which inhibit leukocyte adhesion mediated by VLA-4
US6583139B1 (en) 1997-07-31 2003-06-24 Eugene D. Thorsett Compounds which inhibit leukocyte adhesion mediated by VLA-4
US6362341B1 (en) 1997-07-31 2002-03-26 Athena Neurosciences, Inc. Benzyl compounds which inhibit leukocyte adhesion mediated by VLA-4
US6939855B2 (en) 1997-07-31 2005-09-06 Elan Pharmaceuticals, Inc. Anti-inflammatory compositions and method
AR013384A1 (en) * 1997-07-31 2000-12-27 Athena Neurosciences Inc SUBSTITUTED TYPE OF PHENYLALANINE COMPOUNDS INHIBITING LEUKOCYTE ADHESION INTERMEDIATED BY VLA-4
US6423688B1 (en) 1997-07-31 2002-07-23 Athena Neurosciences, Inc. Dipeptide and related compounds which inhibit leukocyte adhesion mediated by VLA-4
US6489300B1 (en) 1997-07-31 2002-12-03 Eugene D. Thorsett Carbamyloxy compounds which inhibit leukocyte adhesion mediated by VLA-4
US6492421B1 (en) 1997-07-31 2002-12-10 Athena Neurosciences, Inc. Substituted phenylalanine type compounds which inhibit leukocyte adhesion mediated by VLA-4
CA2359115C (en) 1999-01-22 2011-06-21 Elan Pharmaceuticals, Inc. Acyl derivatives which treat vla-4 related disorders
AR035476A1 (en) 1999-01-22 2004-06-02 Elan Pharm Inc HETEROARILO AND HETEROCICLIC COMPOUNDS WITH FUSIONED RING, WHICH INHIBIT THE ADHESION OF LEUKOCYTES THROUGH VLA-4, PHARMACEUTICAL COMPOSITIONS, THE USE OF THE SAME FOR THE MANUFACTURE OF A MEDICINAL PRODUCT AND A BIOLOGICAL METHOD 4
US6436904B1 (en) 1999-01-25 2002-08-20 Elan Pharmaceuticals, Inc. Compounds which inhibit leukocyte adhesion mediated by VLA-4
CA2359114A1 (en) * 1999-01-25 2000-07-27 Elan Pharmaceuticals, Inc. Compounds which inhibit leukocyte adhesion mediated by vla-4
US6407066B1 (en) 1999-01-26 2002-06-18 Elan Pharmaceuticals, Inc. Pyroglutamic acid derivatives and related compounds which inhibit leukocyte adhesion mediated by VLA-4
TWI281470B (en) 2002-05-24 2007-05-21 Elan Pharm Inc Heterocyclic compounds which inhibit leukocyte adhesion mediated by alpha4 integrins
TW200307671A (en) 2002-05-24 2003-12-16 Elan Pharm Inc Heteroaryl compounds which inhibit leukocyte adhesion mediated by α 4 integrins
EP1940827B1 (en) 2005-09-29 2011-03-16 Elan Pharmaceuticals Inc. Carbamate compounds which inhibit leukocyte adhesion mediated by vla-4
DK1940826T3 (en) 2005-09-29 2011-04-18 Elan Pharm Inc Pyrimidinylamide compounds that inhibit leukocyte adhesion mediated through BLA-4
JP5135235B2 (en) 2006-02-27 2013-02-06 エラン ファーマシューティカルズ，インコーポレイテッド Pyrimidinylsulfonamide compounds that inhibit leukocyte adhesion mediated by VAL-4
WO2010126914A1 (en) 2009-04-27 2010-11-04 Elan Pharmaceuticals, Inc. Pyridinone antagonists of alpha-4 integrins

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