CA1137469A - N.sup.2-arylsulfonyl-l-argininamides and the pharmaceutically acceptable salts thereof - Google Patents
N.sup.2-arylsulfonyl-l-argininamides and the pharmaceutically acceptable salts thereofInfo
- Publication number
- CA1137469A CA1137469A CA000376574A CA376574A CA1137469A CA 1137469 A CA1137469 A CA 1137469A CA 000376574 A CA000376574 A CA 000376574A CA 376574 A CA376574 A CA 376574A CA 1137469 A CA1137469 A CA 1137469A
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- group
- arginyl
- aralkyl
- naphthylsulfonyl
- 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
Links
Landscapes
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
N2-arylsulfonyl-L-argininamides of the formula
N2-arylsulfonyl-L-argininamides of the formula
Description
1-1374ti9 PHARMACEUTICALLY ACCEPTABI,E SALTS THEREOF
This application is a division of Canadian Serial No. 266,501, filed November 24, 1976.
BACKGROUND OF THE INVENTION
Field of the Invention This invention relates to the discovery of certain new and useful N2-arylsulfonyl-L-argininamides and the pharma-ceutically acceptable salts thereof, which are of especial value in view of their outstanding antithrombotic properties and low toxicities.
Description of the Prior Art In the past, there have been many attempts to obtain new and improved agents for the treatment of thrombosis. The N2-(p-tolylsuIfonyl)-L-arginine esters have been found to be one type of agent which can be used and these have been found to be effective in dissolving blood clots. (U. S.
Patent No. 3,622,615, issued November 23, 1971).
One family of compounds which have been found to be par-ticularly useful as highly specific inhibitors of thrombin for the control of thrombosis is the N2-dansyl-L-arginine ester or amide. (The applicant's U.S. Patent No. 3,978,045).
However, there is a continuing need for a highly specific inhibitor on thrombin for the control of thrombosis, which exhibits lower toxicity.
.,., ~
~ - 2 -1137~
SU~ IAIIY O~ T1~13 INVI~,NT:ION
It has no-~/ I)ce~l ~liscov~reci that N -arylsu] rony1 ar~inillamides exhibi~ alltithrom~otic activity and everl lower toxicity lcvels at the same relative potencies, as compared witll tlle N -clansyl-L-ar6ini1~e ester or amide, The compoun~s Or thi.s invention can ~e re~resented by the formula (I):
llN ;~, }I N ~ I C~2C}~2CH21C~ICOR (I) ]I }INS02 Ar wherein R is selected from the group COllSiS ting of -10 (1) - N ~ wherein R1 is selected from the group ( C~2 )nC00~2 g 2 C10 alkyl~ C3-Clo alkenyl, C3-C alkynyl C2-C10 alkoxya~]~yl, C2-C10 alkylthioalkyl, C2-ClO alkyl-Sulfinylall~yl~ CL-C10 I~y(lroxyallcy]~ c2_cl0 C~lhoxyall~yl~
C3-C10 alkoxycarbonylalkyl, C3-C10 alkylcarbonylalkyl, Cl-Clo haloalkyl, C7-C1s aralkyl, Cg-Cls ~-carboxyaralkyl, C3-Clo cycloalkyl, C4-Clo cycloalkylalkyl, furfuryl, tetrahydrofurfuryl, optionally substituted with at least one Cl-Cs alkyl and/or Cl-Cs alkoxy,3-furylmçthyl, tetrahydro-3-furylmethyl, optionally substituted with at least one Cl-Cs alkyl and/or Cl-Cs alkoxy tetrahydro-~2(3 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 at least one Cl-Cs alkyl and/or Cl-Cs 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 113'~9 grour) consistin~r of` l~y~lrog~ C1O al.ky~., CG-Cl~ aryl, C7-C12 aralkyl all(i 5-indallyl; a~ n is ~n int~g~r of` ~, 2 or 3~ (2) - N\ '3 wllerei~ 3 is sel.ecte(l from (C~12 )mC~5 the group collsis tirlg of lly~lrogen, Cl -C10 a].lcyl, C3-C10 3 10 .Llcyllyl., C2-C10 alko~cyal~cyl, C2-C alkyl-tJ~ioalkyl, C2-C10 al.kylsulfinyl.alkyl, Cl-C10 hyclroxyalkyl, C2-C10 carboxyalkyl, C3-C10 alkoxycarbonylalkyl, C3-C10 alkylcarbonylalkyl, Cl-C10 haloalkyl, C7-C15 aralkyl, C8-C15 ~-carboxyaralkyl, C3-C10 cycloalkyl, C4 C10 cy y furfuryl, tetrahydrofurfuryl, optionally substituted with at least one Cl-C5 alkyl and/or Cl-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 alkQxy, 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; R4 is selected from the group consisti~
of Cl-C10 alkyl, carboxy, C2-C10 alkoxycarbonyl, phenyl, optionally substituted with at least one Cl-C5 alkyl and/or Cl-C5 alkoxy C7-C12 aralkyl and ring substituted benzyl wherein said substituent is C1-C5 alkyl or Cl-C5 alkoxy; R5 is selected from the group consisting of hydrogen, Cl-CI0 alkyl, C6-C10 aryl, C7-C12 aralkyl and 5-indanyl; and m is an integer of 0, 1 or 2, R,6 (3) - ~ wherein R6 is -COOR8 wherein R8 is selected (R7)p 1-~3 7~
from the group consisting of hydrogen, Cl-Clo alkyl, C6-C1o aryl, C7-C12 aralkyl and 5-indanyli (R7)p is hydrogen, Cl-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 substituted at the 2, 3, 4, 5 or 6-position, COOR~ ~ .
(4) -~ ~ which is optionally substituted with at least one Cl-C5 alkyl and/or Cl-C5 alkoxy, wherein Rg is selected from the group consisting of hydrogen, Cl-C1o alkyl, C6-Clo aryl, C7-C12 arallcyl. ~n(l COOI~10 5-indanyl; all(:l r is arl intc!ger of 1, 2, 3 or 1l, (5) -N ;~ erein ~10 is \'((~1'2 )(I
selectecl fronl tlle group conSistirlg o~` llyclrogell, C~ 10 al.lcyl, C6-ClO aryl, C7-C~2 arallcyl and 5--indanyl; Z is sel.ected from the group consi.s ting of oxy, tlLio an(l slll (`i.nyl; alld q :is COOIll 1 an integer oi' O or 1., a~ld (6) -N\ ~ ~ ?irl ~11 is se,lected f`rom tlle g,roup consis ting of lly(irogell, Cl-ClO
6 ClO ~ryl ~ C7-C12 arallcyl ancl 5-in(lally 1; i i s illteger ol' O, 1. or 2; j i.s an integer of` O, 1. or 2; alld thc Sun) of i+j is all integer of 1 or 2; an(l Ar is selectecl from t}le group collS.iSting Or naplltllyl~ 5,6,7,8-tctrally(lrorlapiltllyl, optionally substituted with at least one Cl-C5 alkyl and/or Cl-C5 alkoxy - 1~37~f~{t n~ tl~yl slJbsti.tuto(l witll at least one sut>~tituetlt selecte from the groll~ consisting of halo~ nitro, cyano, hydroxy, Cl-C10 alkyl, Cl-C1O alkoxy an(l C2-C20 ~iallcylamino, phenyl, phenyl su~stitutecl Wit~l at least one substitllent selectetl from the group con~isting of halo, nitro, cy~lo, hydroxy, C1-Clo alkyl, C]-C10 alkoxy and C2-C20 ~ialky~-~mirlo, C7-C12 yl,and~
and ~ } 1~12 which are optionally substituted with at least LO one Cl-Cs alkyl and/or Cl-C5 alkoxy, wherein R12 is hydrogen, Cl-C10 alkyl or Cl-C10 alkoxy.
Also encompass~(l witllin tllis invelltioJI aro l~harnlaceutically accepta~le scllts thcreof.
This invention also relates to a nlet]lo(l f`or inhil)i.ting activity an~l sl~ppre~slJl~ activation or tllr(~ml)i.n in vi.vo, '. WhiCIl Comr~ri~e~ i~lt;rO~Cin~ illtO a livi~lg l)~)(ly a })harma-ce~ltica~y Orrcc~ivc amo~lnt ol` all N2-ur~lxlllrol~y:l-1-arginiJIan~ le or thc ~ armaccutically acccp~ )lo salt thcrcol`.
This invention is also a process for producing an N -arylsulfonyl-~O L-argininamide having the formuIa (I):
HN
/C - Nl -CH2CH2CH2cHcoR (I) Ar B
li;~'7~
or the pharmaceutically acceptable salt thereof "~ erelrl R lS SeleCTSea from the group consisting of / Rl (1) -N wherein Rl is selected frorl the group (CH2)nCR2 9 f C2 C10 alkyl, C3-C10 alkenyl, C3-Clo alkynyl, C -C
alkoxyalkyl., C2-C1O alkylthioalkyl, C2-C1O alkylsulfinylalkyl, C3-Clo alkylcarbonylalkyl, Cl-C1O hydroxyalkyl, C2-C1O carboxyalkyl, C3-Clo alkoxycarbonylalkyl, Cl-ClO haloalkyl, C7-C15 aralkyl, C~-C15 ~-carboxyaralkyl, C3-Clo cycloalkyl, C4-Clo cycloalkylalkyl, furfuryl, tetrahydrofurfuryl, 3-furylmethyl~ tetrahydro-3-furylllletllyl, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl, and tetrahydro-3-thenyl; R2 iS selected from the group consisting of hydrogen, Cl-ClO alkyl, C6-C1O aryl, C7-C12 aralkyl and 5-indanyl; and n is an integer of 1, 2 or 3,
This application is a division of Canadian Serial No. 266,501, filed November 24, 1976.
BACKGROUND OF THE INVENTION
Field of the Invention This invention relates to the discovery of certain new and useful N2-arylsulfonyl-L-argininamides and the pharma-ceutically acceptable salts thereof, which are of especial value in view of their outstanding antithrombotic properties and low toxicities.
Description of the Prior Art In the past, there have been many attempts to obtain new and improved agents for the treatment of thrombosis. The N2-(p-tolylsuIfonyl)-L-arginine esters have been found to be one type of agent which can be used and these have been found to be effective in dissolving blood clots. (U. S.
Patent No. 3,622,615, issued November 23, 1971).
One family of compounds which have been found to be par-ticularly useful as highly specific inhibitors of thrombin for the control of thrombosis is the N2-dansyl-L-arginine ester or amide. (The applicant's U.S. Patent No. 3,978,045).
However, there is a continuing need for a highly specific inhibitor on thrombin for the control of thrombosis, which exhibits lower toxicity.
.,., ~
~ - 2 -1137~
SU~ IAIIY O~ T1~13 INVI~,NT:ION
It has no-~/ I)ce~l ~liscov~reci that N -arylsu] rony1 ar~inillamides exhibi~ alltithrom~otic activity and everl lower toxicity lcvels at the same relative potencies, as compared witll tlle N -clansyl-L-ar6ini1~e ester or amide, The compoun~s Or thi.s invention can ~e re~resented by the formula (I):
llN ;~, }I N ~ I C~2C}~2CH21C~ICOR (I) ]I }INS02 Ar wherein R is selected from the group COllSiS ting of -10 (1) - N ~ wherein R1 is selected from the group ( C~2 )nC00~2 g 2 C10 alkyl~ C3-Clo alkenyl, C3-C alkynyl C2-C10 alkoxya~]~yl, C2-C10 alkylthioalkyl, C2-ClO alkyl-Sulfinylall~yl~ CL-C10 I~y(lroxyallcy]~ c2_cl0 C~lhoxyall~yl~
C3-C10 alkoxycarbonylalkyl, C3-C10 alkylcarbonylalkyl, Cl-Clo haloalkyl, C7-C1s aralkyl, Cg-Cls ~-carboxyaralkyl, C3-Clo cycloalkyl, C4-Clo cycloalkylalkyl, furfuryl, tetrahydrofurfuryl, optionally substituted with at least one Cl-Cs alkyl and/or Cl-Cs alkoxy,3-furylmçthyl, tetrahydro-3-furylmethyl, optionally substituted with at least one Cl-Cs alkyl and/or Cl-Cs alkoxy tetrahydro-~2(3 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 at least one Cl-Cs alkyl and/or Cl-Cs 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 113'~9 grour) consistin~r of` l~y~lrog~ C1O al.ky~., CG-Cl~ aryl, C7-C12 aralkyl all(i 5-indallyl; a~ n is ~n int~g~r of` ~, 2 or 3~ (2) - N\ '3 wllerei~ 3 is sel.ecte(l from (C~12 )mC~5 the group collsis tirlg of lly~lrogen, Cl -C10 a].lcyl, C3-C10 3 10 .Llcyllyl., C2-C10 alko~cyal~cyl, C2-C alkyl-tJ~ioalkyl, C2-C10 al.kylsulfinyl.alkyl, Cl-C10 hyclroxyalkyl, C2-C10 carboxyalkyl, C3-C10 alkoxycarbonylalkyl, C3-C10 alkylcarbonylalkyl, Cl-C10 haloalkyl, C7-C15 aralkyl, C8-C15 ~-carboxyaralkyl, C3-C10 cycloalkyl, C4 C10 cy y furfuryl, tetrahydrofurfuryl, optionally substituted with at least one Cl-C5 alkyl and/or Cl-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 alkQxy, 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; R4 is selected from the group consisti~
of Cl-C10 alkyl, carboxy, C2-C10 alkoxycarbonyl, phenyl, optionally substituted with at least one Cl-C5 alkyl and/or Cl-C5 alkoxy C7-C12 aralkyl and ring substituted benzyl wherein said substituent is C1-C5 alkyl or Cl-C5 alkoxy; R5 is selected from the group consisting of hydrogen, Cl-CI0 alkyl, C6-C10 aryl, C7-C12 aralkyl and 5-indanyl; and m is an integer of 0, 1 or 2, R,6 (3) - ~ wherein R6 is -COOR8 wherein R8 is selected (R7)p 1-~3 7~
from the group consisting of hydrogen, Cl-Clo alkyl, C6-C1o aryl, C7-C12 aralkyl and 5-indanyli (R7)p is hydrogen, Cl-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 substituted at the 2, 3, 4, 5 or 6-position, COOR~ ~ .
(4) -~ ~ which is optionally substituted with at least one Cl-C5 alkyl and/or Cl-C5 alkoxy, wherein Rg is selected from the group consisting of hydrogen, Cl-C1o alkyl, C6-Clo aryl, C7-C12 arallcyl. ~n(l COOI~10 5-indanyl; all(:l r is arl intc!ger of 1, 2, 3 or 1l, (5) -N ;~ erein ~10 is \'((~1'2 )(I
selectecl fronl tlle group conSistirlg o~` llyclrogell, C~ 10 al.lcyl, C6-ClO aryl, C7-C~2 arallcyl and 5--indanyl; Z is sel.ected from the group consi.s ting of oxy, tlLio an(l slll (`i.nyl; alld q :is COOIll 1 an integer oi' O or 1., a~ld (6) -N\ ~ ~ ?irl ~11 is se,lected f`rom tlle g,roup consis ting of lly(irogell, Cl-ClO
6 ClO ~ryl ~ C7-C12 arallcyl ancl 5-in(lally 1; i i s illteger ol' O, 1. or 2; j i.s an integer of` O, 1. or 2; alld thc Sun) of i+j is all integer of 1 or 2; an(l Ar is selectecl from t}le group collS.iSting Or naplltllyl~ 5,6,7,8-tctrally(lrorlapiltllyl, optionally substituted with at least one Cl-C5 alkyl and/or Cl-C5 alkoxy - 1~37~f~{t n~ tl~yl slJbsti.tuto(l witll at least one sut>~tituetlt selecte from the groll~ consisting of halo~ nitro, cyano, hydroxy, Cl-C10 alkyl, Cl-C1O alkoxy an(l C2-C20 ~iallcylamino, phenyl, phenyl su~stitutecl Wit~l at least one substitllent selectetl from the group con~isting of halo, nitro, cy~lo, hydroxy, C1-Clo alkyl, C]-C10 alkoxy and C2-C20 ~ialky~-~mirlo, C7-C12 yl,and~
and ~ } 1~12 which are optionally substituted with at least LO one Cl-Cs alkyl and/or Cl-C5 alkoxy, wherein R12 is hydrogen, Cl-C10 alkyl or Cl-C10 alkoxy.
Also encompass~(l witllin tllis invelltioJI aro l~harnlaceutically accepta~le scllts thcreof.
This invention also relates to a nlet]lo(l f`or inhil)i.ting activity an~l sl~ppre~slJl~ activation or tllr(~ml)i.n in vi.vo, '. WhiCIl Comr~ri~e~ i~lt;rO~Cin~ illtO a livi~lg l)~)(ly a })harma-ce~ltica~y Orrcc~ivc amo~lnt ol` all N2-ur~lxlllrol~y:l-1-arginiJIan~ le or thc ~ armaccutically acccp~ )lo salt thcrcol`.
This invention is also a process for producing an N -arylsulfonyl-~O L-argininamide having the formuIa (I):
HN
/C - Nl -CH2CH2CH2cHcoR (I) Ar B
li;~'7~
or the pharmaceutically acceptable salt thereof "~ erelrl R lS SeleCTSea from the group consisting of / Rl (1) -N wherein Rl is selected frorl the group (CH2)nCR2 9 f C2 C10 alkyl, C3-C10 alkenyl, C3-Clo alkynyl, C -C
alkoxyalkyl., C2-C1O alkylthioalkyl, C2-C1O alkylsulfinylalkyl, C3-Clo alkylcarbonylalkyl, Cl-C1O hydroxyalkyl, C2-C1O carboxyalkyl, C3-Clo alkoxycarbonylalkyl, Cl-ClO haloalkyl, C7-C15 aralkyl, C~-C15 ~-carboxyaralkyl, C3-Clo cycloalkyl, C4-Clo cycloalkylalkyl, furfuryl, tetrahydrofurfuryl, 3-furylmethyl~ tetrahydro-3-furylllletllyl, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl, and tetrahydro-3-thenyl; R2 iS selected from the group consisting of hydrogen, Cl-ClO alkyl, C6-C1O aryl, C7-C12 aralkyl and 5-indanyl; and n is an integer of 1, 2 or 3,
(2) -N wnerein R3 is selected fronl the group CH-(c~2),ncOo!~s ::
- 6a -B
1137~
sistill~J of hy(b-oge~ Cl() alkyl~ C3-Cln alk~r~ C3 C10 y y C2-C10 alkoxyalkyl, C~-Cl(~ alkylLhioalkyl, C2-Cl() alkylsulrinylalkyl, Cl-C10 hyclroxv,31kyl, Cl~-C10 carl)ox~alhyl, C~-Cl(~ ali:t)xycarbonylalkyl.
C3-C10 alkylcarbonvlalkyl, Cl-ClO haloaliyl, (:7-C15 .nr.llkyl, C~-Cl~, cl-carboxyaralkyl, C3-(:1r) cy(loalkyl, (~-Cl() cyclo.lliylalkyl, rurFuryl, tetrahydrofurfuryl, 3-fu)ylllletllyl, tetrallydr()-3-furyllllethyl~ 2-thenyl.
- 6a -B
1137~
sistill~J of hy(b-oge~ Cl() alkyl~ C3-Cln alk~r~ C3 C10 y y C2-C10 alkoxyalkyl, C~-Cl(~ alkylLhioalkyl, C2-Cl() alkylsulrinylalkyl, Cl-C10 hyclroxv,31kyl, Cl~-C10 carl)ox~alhyl, C~-Cl(~ ali:t)xycarbonylalkyl.
C3-C10 alkylcarbonvlalkyl, Cl-ClO haloaliyl, (:7-C15 .nr.llkyl, C~-Cl~, cl-carboxyaralkyl, C3-(:1r) cy(loalkyl, (~-Cl() cyclo.lliylalkyl, rurFuryl, tetrahydrofurfuryl, 3-fu)ylllletllyl, tetrallydr()-3-furyllllethyl~ 2-thenyl.
3-thellyl, tetrahydlo-2-tllellyl, and tetrdhydro-3-lhellyl; R4 is selected from the group consistillg of Cl-C10 ali;yl, carl)oxy, C2-C1O alkoxycarbonyl, phenyl C7-C12 aralkyl and rillg substituted berlzyl wllerein said substituent is Cl-C5 alkyl or Cl-C5 alkoxy; R5 is selecteci frnm the grou;) Collsistillg of llydrogen, Cl-C10 alkyl, C6-C10 aryl, C7-C12 aralkyl and 5-indallyl;
and m is an inteyer of 0, 1 or 2, ~ .
~ (3) -N ~ ~1heleill R6 is -COOR8 wllereili R~ is selected from t the group consisting of hydrogen~ Cl-C10 alkyl, C6-C10 aryl, C7-C12 aralkyl and 5-indanyl; R7 is hydrogen, Cl-ClO alkyl, l~henyl Cl-C5 alkoxy or carboxy; R6 is substitutecl at the 2 or 3-position; and R7 can be substituted at the 2, 3, 4, 5 or 6-position, C~
~ (CIi2)~ wherein Rg is selected from the group con-sisting of hydrogen, Cl-C10 a!kyl, C6-(10 aryl, C7-C12 a~-alkyl and - 6b -B
5-indanyl; an~l r i~ arl inte~er o~ 1, 2, 3 or ~.
COORln >-~
(5) -N 7 whereill Rl() is selectrcl fronl the group consisting ~( C112 ) (1 of hydrogen, Cl-C1O a1kyl, C6-C1O aryl, C7-C12 aralkyl and 5-inddnyl;
Z is selectecl frolll the group consisting of oxy, thio and sulfinyl; and q is an integer of O or 1, and COOKl 1 ~(C1~2);~
(CH2)J ~ wherein ~11 iS selected from the group consisting of hydrogell, Cl-ClO alkyl, C6-C10 aryl, C7-C12 a~^alkyl 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 fronl the group consistincl of.naphthyl, 5,6,7,8-tetrahydronaphthyl, naphthyl substituted with at least one substituent selectecl from the group conslsting of llalo, nitro, cyano, hydroxy, Cl-CIO alkyl, Cl-C10 alkoxy and C~-C20 dialkylamino, phenyl, phenyl substituted with at least one substituent selected froln the group consisting of halo, nitro, cyano, hydroxy, Cl-C10 alkyl, Cl-ClO alkoxy and C2-C20 dialkylalnino, C7-Clc aralkyl, -1 ~ ' ~~ X o ~
B - 6c -and ~ } R12 wherein R12 is hydrogen, Cl-C10 alkyl or Cl-C10 alkoxy, which comprises: reacting an L-argininamide having the formula:
HN ~
,_,,C - N - CH2CH2CH2CHCOR
NH~
wherein R is defined herein above with an arylsulfonyl halide having the for~ula: ArS02X, wherein Ar is as defined herein above and X is halogen.
- 6d -ti9 DETAILED DESC~IPTION OF T~IE PREFERRED EMBODI~ENTS
This invention relates to a group of N -arylsulfonyl-L-argininamides of the formula (I):
HN ~
H N~ 1 2cH2cH2lcHcoR (I) Ar wherein R is selected from the group consi~ting of (1) - N \ 1 wherein Rl is selected from the group ( CH2 )nCR2 consi9ting of 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-butenyl, 2-pentenyl or the like, alkynyl of 3-10 (preferably 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 methoxymethyl, ~ ~ :
ethoxymethyl, propoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-propoxyethyl~ 2-methoxypropyl~ 3-methoxypropyl, 3-ethoxypropyl, 3-propoxypropyl, 4-methoxybutyl, 4-ethoxybutyl,
and m is an inteyer of 0, 1 or 2, ~ .
~ (3) -N ~ ~1heleill R6 is -COOR8 wllereili R~ is selected from t the group consisting of hydrogen~ Cl-C10 alkyl, C6-C10 aryl, C7-C12 aralkyl and 5-indanyl; R7 is hydrogen, Cl-ClO alkyl, l~henyl Cl-C5 alkoxy or carboxy; R6 is substitutecl at the 2 or 3-position; and R7 can be substituted at the 2, 3, 4, 5 or 6-position, C~
~ (CIi2)~ wherein Rg is selected from the group con-sisting of hydrogen, Cl-C10 a!kyl, C6-(10 aryl, C7-C12 a~-alkyl and - 6b -B
5-indanyl; an~l r i~ arl inte~er o~ 1, 2, 3 or ~.
COORln >-~
(5) -N 7 whereill Rl() is selectrcl fronl the group consisting ~( C112 ) (1 of hydrogen, Cl-C1O a1kyl, C6-C1O aryl, C7-C12 aralkyl and 5-inddnyl;
Z is selectecl frolll the group consisting of oxy, thio and sulfinyl; and q is an integer of O or 1, and COOKl 1 ~(C1~2);~
(CH2)J ~ wherein ~11 iS selected from the group consisting of hydrogell, Cl-ClO alkyl, C6-C10 aryl, C7-C12 a~^alkyl 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 fronl the group consistincl of.naphthyl, 5,6,7,8-tetrahydronaphthyl, naphthyl substituted with at least one substituent selectecl from the group conslsting of llalo, nitro, cyano, hydroxy, Cl-CIO alkyl, Cl-C10 alkoxy and C~-C20 dialkylamino, phenyl, phenyl substituted with at least one substituent selected froln the group consisting of halo, nitro, cyano, hydroxy, Cl-C10 alkyl, Cl-ClO alkoxy and C2-C20 dialkylalnino, C7-Clc aralkyl, -1 ~ ' ~~ X o ~
B - 6c -and ~ } R12 wherein R12 is hydrogen, Cl-C10 alkyl or Cl-C10 alkoxy, which comprises: reacting an L-argininamide having the formula:
HN ~
,_,,C - N - CH2CH2CH2CHCOR
NH~
wherein R is defined herein above with an arylsulfonyl halide having the for~ula: ArS02X, wherein Ar is as defined herein above and X is halogen.
- 6d -ti9 DETAILED DESC~IPTION OF T~IE PREFERRED EMBODI~ENTS
This invention relates to a group of N -arylsulfonyl-L-argininamides of the formula (I):
HN ~
H N~ 1 2cH2cH2lcHcoR (I) Ar wherein R is selected from the group consi~ting of (1) - N \ 1 wherein Rl is selected from the group ( CH2 )nCR2 consi9ting of 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-butenyl, 2-pentenyl or the like, alkynyl of 3-10 (preferably 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 methoxymethyl, ~ ~ :
ethoxymethyl, propoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-propoxyethyl~ 2-methoxypropyl~ 3-methoxypropyl, 3-ethoxypropyl, 3-propoxypropyl, 4-methoxybutyl, 4-ethoxybutyl,
4-butoxybutyl, 5-butoxypentyl or the like, alkylthioalkyl of 2-10 (preferably 2-6) carbon atoms, such as methylthiomethyl, ethylthiomethyl, propylthiomethyl, 2-methylthioethyl, 1-1374~9 2-ethylthi.oetllyl, 2-1)roi)ylthioet~lyl, 3-metllylthiopropyl, 2-methylthioprol)yl, 3-ethylthiopropyl, 3-propyltlliopropyl~
~-metlly]tll:iol~lltyl~ /I-etllylthioI~utyl, Il--btltyltlliobutyl~
~-metlly]tll:iol~lltyl~ /I-etllylthioI~utyl, Il--btltyltlliobutyl~
5-butyltllio~entyl or the like, allcy:lsulf`inylall~yl of 2-10 (pre~erably 2-6) carbon atoms, such as methylsulfinylmethyl, ethylsulfinylmethy.l, propylsulfinylmet}lyl, 2-methylsulfinyl-ethyl, 2-etllylsul~inylethyl~ 2-propylslllfinylethyl, 3-methylslllriJIy]l)ropyl~ 3-ethy]sulfi.nylprolyl or the lil~e, hy(1roxyalkyl Or I -l.O (preferal)ly 1-6) carboll atoms, such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl~ 3-hydroxybutyl, 5-hydroxy-pentyl or the llke, carboxyalkyl of 2-10 (preferably 2-7) carbon atoms, such as carboxymethyl, 2-carboxyethyl, 2-carboxypropyl, 3-carboxypropyl, l-carboxybutyl~ 2-carboxy-buty:L, 4-carboxybuty:L or the like, alkoxycarbonylalkyl of 3-10 (preferahly 3-8) carbon atoms, sllch as methoxycarbonyl-metllyl, 2-ethoxycarl~ollyletllyl, 2-etl~oxycarborlylpropyl, 3-metlloxycarl)oJIyll)rol)yl~ l-metlloxycarbolly.ll)lltyl, 2-etlloxy-c~r1~onylb-ltyl., /I-nletlloxycarl)ollylblltyl or tlle lilce, alkylcarbonylalkyl of 3-10 carbon atoms, such as methylcarbony-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 th~
like, aralkyl of 7-15 (preferably 7-10) carbon atoms, such as benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 6-phenylhexyl, l-phenylethyl, 2 phenylpropyl or the like, -carboxyaralkyl of 8-15 li~'7~C~
(preferably 8-12) carbon atoms, such as ~ -carboxybenzyl, ~ -carboxyphenethyl or the like, C3-C10 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohept~
cyclooctyl, cyclononyl or cyclodecyl, C4-C10 cycloalkylalkyl, S such as cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl 2-cyclohexylethyl, cyclooctylmethyl or the like, furfuryl, tetrahydrofurfuryl, optiorally substituted with at least one Cl-C5 alkyl and/or Cl-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-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, 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 n is an interger of 1, 2 or 3, ~R3 (2) - N wherein R3 is selected from the ICH (CH2)mcOoR5 group consisting of hydrogen, Cl-C10 alkyl, such as methyl, ethyl, propyl, butyl, isobutyl, pentyl, hexyl, octyl, decyl or the like, alkenyl of 3-10 (preferably 3-6) carbon atoms, such as allyl, 2-butenyl, 3-butenyl, 2-pentenyl or the like, alkynyl of 3-10 (preferably 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 ~137~
methoxymcthyl1el,lloxymcthyl, I)ropoxymetllyl., 2-methoxyethyl, 2-et;lloxyetlly] ~ 2-1)rol)oxyetl~yl~ 2-methoxypropyl, 3-methoxy-proL)yl~ 3-etlloxyl)lollyl., 3-propoxypropy~ -methoxyl)lltyl~
4-etlloxyblltyl, ~-hlltoxybutyl, 5-butoxypel-1tyl or the like, alkylthioalliyl oL` 2-:1~ (preferably 2-6) carboll atoms, such ~s methyltllio~ ly:l~ e~hylthiomethyl~ prol)ylthionletllyl, 2-methylt~ioetllyl, 2-ethyltllioethyl, 2-propylthioethyl, 3-metllyltlLioprol)yl, 2-methylthiopropyl, 3-etllylthiopropyl, 3-proF)ylthiopl-opyl, Il-mctllyltlliob~lty], I~-ethy]thiob-ltyl, 4-butylthiobutyl, 5-butylthiopentyl or the like, alkyl-sulfinylalkyl of 2-10 (preferably 2-6) carbon atoms, such as methylsulfirlylnnethyl, ethylsulfinylmethyl, propyl-sulfinylmethyl$,2-methylsulfinylethyl, 2-etllylsulfinylethyl, 2-propylsulfinyletllyl, 3-methylsulfinylpropyl, 3-ethyl-sulfinylpropyl or the like, hydroxyalkyl of 1-10 (preferably 1-6) carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropy], 2-1ly~roxypropyl, 4-hy(lroxyl)lltyl, 3-lly(lroxyl-lll;yl, r~-llydroxypclltyl or tllC l~ c, carl)oxyalliyl of 2-1~ (I)rel`cr;ll)ly .>-7) c.lrl)oll atom~, s~lcll 1~ C;l.l'bOXylll('t1l 2-c1rboxyctllyl~ 2-(:1rl)oxyl)rol)y]~ 3-c1rl)oxyp]~ol)y1~ 1-carl~oxyl)lltyl~ '-carl)oxyl)utyl~ 11-carboxyl)lltyl or tllc like, a.ll;oxycarl)o~lylalky,l ol` '3-:1() (})rcf`cral)ly '3-~3) C1r-)011 atoms, such as mett~oxycarl)olly.lmetlly.l, 2-metlloxyc1rl~ollyletllyl~ 2-ethoxycarbollylprol~yl, 3-mettloxycarbol~yll)rol)yl~ l-metlloxy-Cl ~`I)OIl y I l)ll l.y 1, >--(` tIIOXYC1I`I)OIIY J 1)ll l, y l, 11--lll(` tll() XyC1 r~l)olly.l1)1ltyI
I ~) _ li;~t~ 9 or the like, alkylcarbonylalkyl of 3-10 carbon atoms, such as methylcarbonylethyl or the like, haloalkyl of 1-10 (preferably 1-5) carbon atoms such as chloromethyl, 2-chloroethyl, 2-bromoethy 2-chloropropyl, 3-chloropropyl, 2-chlorobutyl, 4-chlorobutyl or the like, aralkyl of 7-15 (preferably 7-10) carbon atoms, such as benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 6-phenylhexy~
l-phenylethyl, 2-phenylpropyl or the like, G~ -carboxyaralkyl of 8-15 ~preferably 8-12) carbon atoms, such as G~ -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 Cl-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-2-thenyl 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 of alkyl of 1-10 (preferably l-S) 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 atom~
such as benzyl phenethyl or the like, and ring substituted benzyl wherein said substituent is alkyl of 1-5 (preferably 1-3) carbon atoms, such as methyl, ethyl, propyl or isopropyl, or 1:~3'7~ 3 alkoxy of 1-5 (preferably 1-3) carbon atoms, such as methoxy, ethoxy, propoxy or isopropoxy; R5 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 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 ~t~6 integer of 0, 1 or 2, (3) -N ~ wherein R6 is -COOR8 (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 or 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 substitutecl at the 2, 3, 4, 5 or 6-position, COOR ~
(4) - ~ ¦ which is optionally substituted with at ~ CH2 rr least one Cl-C5 alkyl and/or Cl-C5 alkoxy, wherein Rg is selected from the group 11~'74~i,9 collsisting of lly(lrogcll~ C~-C10 alkyl, sucl~ as methyl, ethyl, propyl, bllt;yl~ ~ert~ ttyl~ hexyl~ octyl, decyl or the lilce, C~~C10 uryl, SIICII as phellyl ~ m-tolyl, naplltllyl. or the like, arulky:L of` 7-L2 (prcf`crab:l.y 7-10) carboll UtomS~ sllch as bellzyl, phenetllyl or the like, and 5-indanyl; ~n(i r is all integer of 1, 2, 3 or ll, coor~ O
~ .
(5) -N ~ wllcre:irl Rlo is selected from Ihe group ~C112)(1 consisting of hydrogell, 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-indarlyl; Z is selected from the group consisting of oxy (-O-), thio (-S-) and sulfinyl (-SO-); q is an integer of O or 1, and C~
~(CII2) ~ whereill ~ll is selectcd ~rom the grollp COllsi.Stil)g Or lly(lro~cll, cl-clO al];yl, sucll us metllyl, ethyl, I)rol)yl, blltyl, telt-l?~ltyl, llcxyl., octyl, decyl ~r tlle like, C6-C10 aryl, SllCh aS phellyl, m-tolyl, naplltllyl or the like, aralkyl of 7-12 (preferably 7-10) carbon atoms, such as berlzyl, ~tlelle~tlyl or the like, arl(l 5-irld.lllyl.; i is an ~ 13 -integer of 0, l or 2; j is an integer of 0, 1 or 2; and the sum of i-tj is an integer of 1 or 2; an~ Ar is seleeted from the group eonsisting o~ naphthyl, sueh as l-naphth~l and 2-naphthyl, 5,6,7,8-tetrahydronaphthyl, optionally su~stituted with at least one Cl-C5 alkyl and/or Cl-C5 alkoxy ~uch as 5,6,7,8-tetrahyclro-l-naphthyl and 5,6,7,8-tetrahydro-2-llaphthy1, naplltllyl substituted Wittl at least one substituent selectetl fronl the grollp eonsisting of ha:lo, such as fluoro, chloro, ~)romo arl(l iodo, ni-tro, cyano, hydroxy, allcyl of 1-10 (preferabl.y 1.-5) carbon atoms, SUCIl as methyl, ethyl, propyl, isopropyl, butyl, isobu-tyl or the lilce, alkoxy of l-lO (preferably 1-5) earbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy or the lilce~ and dialkylamino of 2-20 (preferably 2-lO) carbc)ll atoms, such as dimethylamillo, dietllylamino, N-methyl-N-ethylamino or the ].i]ce, phenyl, phenyl substituted ~ith at least one substituent seleeted from the group eon-SiSting Or halo, sueh as fluoro, ehloro, bromo and iodo, nitro, eyano, hyclroxy, alkyl o.f l-10 (preferably 1-5) carbon atoms, such as methy:l., ethyl, propyl, isopropy]., butyl, isol)llty.L or th(3 lilcc3, allcoxy of 1-1.0 (preferal)ly 1-5) carbon atoms, such as methoxy, ethoxy,propoxy, isopropoxy, butoxy, see-butoxy, tert-butoxy, pentyloxy or the lilce, and dialkylamino of 2-20 (preferably 2-10) earbon atoms, sueh as dimethylamino, cliethylamino, N-methyl-N-ethylamino or the like, aralkyl of 7-12 (preferably 7-lO) earbon atoms, 1`~3~J~g such as bcnzyl, phenethyl or the like, and ~ ) , ~ ' ~0~
~ ~ ~ and ~ } R12 which are optionally substitllted with at least one Cl-C5 alkyl and/o~ Cl-C5 alkoxy, wherein R12 is h~dToqen, 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, 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-methoxypropylJ 2-ethoxyethyl and 3-methoxypropyl, C2-C6 alkylthioalkyl, such as 2-ethylthioethyl and 2-methylthioethyl, C2-C6 alkylsulfinylalkyl, such a9 2-methylsulfinylethyl~
Cl-C6 hydroxyalkyl, such as 2-hydroxyethyl and 3-hydroxyb.utyl, C2-C7 carboxyalkyl, such as l-carboxybutyl, C3-C8 alkoxycarbonyl-alkyl, such as 2-ethoxycarbonylethyl~ C7-C10 aralkyl, such a9 betlzyl al(J pher~etllyl~ C8-C12 .~1 -ca:rboxyaralkyl, such as ~ -carboxyphenetllyl, C3-Cl~ cycloalky:L, SllCh as cyclopropyl, cyclohexyl and cycloheptyl, Cl-C10 cycl.oalky~allcyl, such as cyclohexylmetlly:l, t`lm ruryl, tetrallydrorurrllryl~ 3-furylmethyl, tetrahydro-3-fulylmetllyl~ 2--thenyl, 3-thenyl, tetrahydro-2-tllollyl all(l tetrallyclro-3-thenyl.
~uitabl.e i.Llustrlt;iorls of R3 in the above I`ormula (I) are hy(lrogerl, Cl-CI() allyl.~ sucll as methyl, propyl, butyl, isobutyl, pentyl, iloxyl and oc-tyl., C3-C6 al]cenyl, such as allyl~ C3-C6 allcynyl, sueh as 2-propynyl, C2-C6 allcoxyalkyl, such as 2-methoxyetllyl~ 2-methoxypropyl, 2-ethoxyethyl dlld 3-methoxypropyl, C2-C6 alkylthioalkyl, sucll as 2-ethylthio-ethyl and 2-metllylthioethyl, C2-C6 allcylsulfinylalkyl, such as 2-methylsulfinylethyl~ Cl-C6 hydroxyal]{yl, sucll as 2-hydroxyethyl and 3-hydroxybutyl, C2-C7 carboxyalkyl, such as l-earboxyblltyl, C3-C8 alkoxycarbonylallcyl, such as 2-ethoxycarL)onylctllyl, C7-C10 arallcyl, sucll as l)ellzyl alld l)llell~tllyl~ C8-C12 ~ -carboxy~ra]ky~, sllcll as ~ -carl)oxy-pholletllyl, C3-CI~ cyc:loa~l;yl, sucll as cyc]o~ o~yl, cyclohexyl all(l cycloll(!l~lyl, (Il-Cl~ cye.loa.LI;ylallcy:l, sllcll as cyclolloxyl-metllyl, f`urf`uryl, tetrahy(lrofurt'uryl, 3-l'urylmetllyl, tetrahy(lro-3--rllrylm(3tllyl, 2--thetlyl, 3-thc!llyl, tetrahydro-2--thellyl an(l tetrully(lro-3-thenyl.
~ui-table il:LIlstratiolls Or ~1l in the above fornlula (I) are C1-C5 allyl, sllch as metllyl and propyl, e.lrl)oxy, C2-C5 ti9 alkoxycarbonyl, such as ethoxycarbonyl~ C7-C10 aralkyl, such as benzyl, and ring substituted benzyl wherein said substituent is Cl-C3 alkoxy, ~uch a~ 4-methoxybenzyl.
Suitable illu~trations of R7 are hydrogen, Cl-C6 alkyl, such as methyl, ethyl, propyl and isopropyl, phenyl and carboxy, and the suitable position of R7 is ~J 4 or 6.
COOH
)~ , Suitable -N Z groups are 3-carboxy-4-morpholino, \-(CH2)/
3-carboxy-4-thiomorpholino~ 1-oxo-3-carboxy-4-thiomorpholino and 4-earboxy-3-thiazolidinyl.
COOH
Suitable -N ~ ~ groups are 2-carboxy-1~2~3~4-tetrahydro-l-quinolyl, 3-earboxy-1,2,3,4-tetrallydro-2-isoquinolyl, l-carboxy-1,2,3,4-tetrahydro-2-isoquinolyl, 2~earboxy-1-indolinyl and 1-earboxy-2-isoindolinyl.
Suitable illustrations of R2, R5, R8, Rg, Rlo and Rll are hydrogen, Cl-C10 alkyl, sueh as methyl~ ethyl, tert-butyl and oetyl, C6-C10 aryl, such as phenyl and m-tolyl, C7-ClO
aralkyl, such as benzyl, and 5-indanyl.
Sui~able illustrations o~ Ar in th~ above formula (I) are naphthyl, such as l-naph-thyl and 2-naphthyl~ 5,6,7,8-tetrahydronaphthyl, such as 5,6,7,8-tetrahydro-1-naphthyl and s,6,7,8-tetrahydro-2-naphthyl, naphthyl substituted with at least one substituent selected 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 methoxy and ethoxy, and C2-C10 dialkylamino, such as dimethylamino and diethylamino, phenyl, phenyl substituted with at least one substituent selected from the ~roup consisting of halo, such as chloro, Cl-C5 alkyl, such as methyl, ethyl and isopropyl and Cl-C5 alkoxy, such as methoxy, C7-C10 aralkyl, such as phenethyl, ~ ) such 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-naphthyl, 5-chloro-l-naphthyl, 6-chloro-2-naphthyl, 6-bromo-1-naphthyl, 5-hydroxy-1-naphthyl, 7-hydroxy-2-naphthyl, 6-methyl-2-naphthyl, 6-methyl-1-naphthyl, 7-methyl-1-naphthyl, 7-methyl-2-naphthyl, 6-ethyl-2-naphthyl, 6,7-dimethyl-1-naphthyl, ~ 18 -1~3~ i9 f"7-dimetllyl-2-l-al)lltllyl, 6-isopropy:L--2-llaphtllyl, 5--methoxy-.I-naphthyl ~ fi-mc tlloxy-2-napllthy.l, 7-methoxy-2-rlclplltltyl ~ ' ,6-dimetlloxy-2-1laE~ hyJ, 6,7-dimetlloxy-2--1aplltllyl, G,7-(lictlloxy-2-rlclplltl~yl, 5-di.mctlly~anurlo-1-llal)lltllyl~ 5-dimethylamillo-2-rlapllthyl~ 5-diethylamino-1-naptlthyl, 6-dimettlyla~ illo-L-Ilal~ tllyl, 6-climethylami.llo-Z-naptlt}ly.L ~
chlorol)hcllyl., 2,1~,5-trichlorophenyl~p-to1y], anisyl, 3,4-dimettloxyllhelly~, 3,/~,5-trimetl-loxypllerlyl, ~
~ ) and (~3 Illustrative of suitable N -arylsulforlyl-L-argininamides of sufficient activity are the fol.lowing:
NZ-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-propylglycirle N -(fi,7-~limctllo~y-2-1laplltlly1sll]follyl)-~,-argi~lyl-N-propylglycille t;crt-blltyl cster N --(fi,7-~ tllo~y--,"--ll<ll>lltlly:L~ rolly~ rillyl--N--hllty:lg1ycille N -(6,7-dinletlloxy-2-lla~ LIlylsulronyl)-L-argillyl-N~
bllty:lg]ycillc tert-l~lltyl ester _ 19 _ ~3'7~69 N -(6,7-(linletl~c)xy~ aplltllyls-l:Lrorlyl)-l,-<ltgillyl.-N-i obutyl~,lycillc N -(6,7-(limcttloxy-2-tlap}lthy:Lsulfollyl)-L-artri.nyl-N-pentylglycine N -(6,7-~1i.mcthoxy-2-llaplltllylsulfollyl)-L-argirlyl-N-hexy]gly CillC
N -(6,7-dimetlloxy-2-llaphthy:Lsulfonyl)-L-argirlyl-N-o c ~:yl~lycill c N -(4,6-~imetlloxy-2-naphthylsulfonyl)-I,-arginyl-N-butylg]ycinc N -(6,7-~lietlloxy-2-rlaphtllylsulfonyl)-L-argillyl-N-buty]glycille N -(6-methoxy-2-llapllthylsulfonyl)-L-arginyl-N-butylglycine N2-(5-methoxy-1-naphthylsulfonyl)-L-arginyl-N-butylglycine N -(7-methoxy-2-naph-thylsulfonyl)-L-argillyl-N-propylglycine N -(7-methoxy-2-naphtllylsulfollyl)-L-argirlyl-N-butylglycine N -(7-methoxy-2-llaplltllylSulfollyl)-L-argillyl-N-pentylglycine N -(2-naphthylsulfollyl)-L-arginyl-N-butylglycine N -(Z-nal)lltllyl~ ronyl)-l,-argillyl-N-b~ltylglycine ethyl cster ~() _ 1~3'~9 N -(2-naphthylsulfony].)-L-arginyl-N-butylglycine ben~yl ester N -(2-naphthylsulfonyl)-L-arginyl-N-butyl-~ ~alanine N -(5,6,7,8-tetrahydro-1-naphthylsulfonyl)-L-arginyl-N-butylglycine N -(5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl-N-pentylglycine N -(5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl-N-butyl-~ -alanine N -t6-bromo-1-naphthylsulfonyl)-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-propynyl)glycine N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arglnyl-N-(2-methoxyethyl)glycine 1~37~69 N --( (), 7--( l i ~ ( ) Y y ~ y l ~ O J ~ f, i l l y ~--N--IIIC l,llO~y(~t:llyl )~, I )'(`.i 11'~! (?tllyl C~ l,C:I`
N ((-,7--~ ncl.lloxy-.'-lla7)lllllyl~ill1 fo]lyl )--1,--a~gil-ly~--N-(2-mctlloxyetllyl )~1 yc.irle o ctyl es ter N -(6,7-(1inlcl llox:y-2-1lal)lltllylsulron~ -arginyl-N-(2-mel;lloxyetlly:L)glycirle t)cn~yl ester N -(6,7-d:i mel;llo,Yy-;'-ll~lL)ILl;hylsu:l rOIly~ )-I,-a~gillyl.-N-(2-mctl~oxycl;llyl)gLyc:ille '3-methy:lpllellyl e.ster N -(6, 7-(lime thoxy-2-l1aplltllylsul ronyl ) -I,-arginyl-N--(2-methoxyetllyl)glyc~ e 5-indanyl ester N --(G ,7-dimethoxy-2-1laphtl-lylsulfonyl )-L,-arginyl-N-(2-methoxyetllyl)-~,--alanine ~:
N -(6~7-dimetho:;y-2-naplltllylsul ronyl )-L-arginyl-N-(2-metlloxyel,l~yl)- ~, -alulli.ne etllyl estel N --(G,7--d.illlcl,llo.Y~ tllyls~ `olly.l )--N-(2--nlctlloxyctlly:l )--N--('~--c~rl~oxyl~rol~yl )--l,--arg:i7l:ill.lm.i.(lc N --(G,7--(limclLIoxy--;'--n~ l;llylsllll`olly1.)--N--( '-metlloxyc?tllyl)--N -( '3-terl~ tOXyc;ll l~ony:l pro~yl ) -L-arp;.i ll:i llanli(le N -(6,7-dimctlloxy-,-rla~ tllylslllrollyl)-N-(3-nlel:lloxy-2() prol~yl )g,l yc:i ue 1~37~
N -(6,7-~lirnethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-ethoxyethyl)-~ -alanine N -(6,7-dimethoxy-2-naphthylsul~onyl)-L-arginyl-N-(2-methoxypropyl)glycine N2-(6~7-diethoxy-2-naphthylsul~onyl)-L-arginyl-N-(2-methoxyethyl)glycine N2-(4,6-dimethoxy-2-naphthylsul~onyl)-L-arginyl-N-(2-methoxyethyl)glycine N -(4,6-dimethoxy-2-naphthylsulfonyl)-L-argillyl-N-(2-methoxyethyl)glycine ethyl e~ter N -(6-methoxy-2-naphthyl9ul~onyl)-L-arginyl-N-(2-methoxyethyl)glycine N -(5-methoxy-1-naphthylsul~onyl)-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 N -(5-methoxy-1-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)-~ -alanine tii9 N ~ naphthylslllfonyl)-L-arginyl-N-(2-methoxyethyl)glycine N -(5,6,7,8-tetrahydro-1-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine N -(5-chloro-1-naphthylsulfonyl)-L-arginyl-N-(2-methoxy-ethyl)glycine N -(6-chloro-2-naphthyl~ulfonyl)-L-arginyl-N-(2-methoxy-ethy~)glycine N -(7-methyl-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxy-ethyl)glycine N -(7-methyl-1-naphthylsulfonyl)-L-arginyl-~-methoxy-ethyl)glycine N -(6,7-dimethyl-1-naphthylsulfonyl)-L-arginyl-N- (2-methoxyethyl)glycine N -(5-dimethylamino-1-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine N -(7-hydroxy-2-naphthylsulfonyl)-L-arginyl-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 -- 24 _ {j9 N -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methylsulfinylethyl)glycine N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-hydroxyethyl)glycine N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(3-hydroxybutyl)glycine N -(6,7-dimethoxy-2-naphthyl~ulfonyl)-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-naphthylsulfonyl)-L-arginyl-N-benzylglycine tert-butyl ester N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-phenethylglycine N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-benzyl-~ -alanine N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-benzyl- ~ -alanine tert-butyl ester - 2~ -113~ 9 N -(f~7~ metlloxy-2-lla~lt~lyls~ `orlyl)-L-~r~i.nyl-N-pllCll~tlly~ lllillC
N _(11 ,f)-~lin~ctlloyy-2-~ ltlly~ o~ly~ r~i.llyl-N
benzylg],ycine N -(7-methoxy-2-J-Ia~ tl-lylsulronyl)-L-argirlyl-N-phenetlly:l glycinc N -(7-metl~oYy-2-llar)ll~llylsu].forlyl)-L-arginyl-N-l~ellzy].-~ -alani.ne N -(6-mctl-loxy-2-naplltllylsulronyl.)-N-ben~yl-N-(3-c rboxypropy].)-l,-argininamicle N -(6-methoxy-2-rlapllthylsulfonyl)-N-benzyl-N-(3-tert-butoxycarbonylpropy].)-l,-argininamide N -(5-methoxy-1-naplltllylsulforlyl)-L-argillyl.-N-benzylglycine N -(2-naphtllylslllronyl)-L-arginyl-N-benzyl-~ -a]anine N -(2-nap~ y.ls~l.lt`oJIy.l.)-L-arc,illy].-N-l)cll~ylglycillc N -(5,6,7,8-tetrahydro-1-naphthylsulfonyl)-L-arginyl-N-phenethylglycille N -(5,6,7,8-tetrahyclro-2-naphthylsulfollyl)-L-argillyl.-N-benzylglyci.rlc li;~'7'~9 N -(5~GJ7~-tCtraIIY(IrO-2-rIaP}It1IY19U1~OIIY1)-L-arginY1-N
b (~Jl ~ Y~ Lrl i rl N -(7--mCtl~Y1--2~ PI~tIlY15I11fOnY1)--L-arg:ilIYI.-N-PIIenetlIY1 g I y Cill e N -( 6 ~7-di.methOXY-2-llal)I1thY1 SU1 fnIIY1 ) _L-LIrgj.rIY1-N-(~ -carhoxyphellethyl. )glycine N -(6 ,7-(1ime tl~oxy-2-naphthylsulfonyl )-I,-arginyl-N-cyclohexylmet}lylglycine N --(6,7--dimethoxy-2--napllthylsulfonyl)--L--argi.nyl--N-cyclohexylmetllylglycille tert-butyl es ter N -(6~7-dimethOXY-2-naPhthY15U1fOnY1)-L-arginY1-N-cycloheptylglycille N -( 4, G-di methoxy-2-napht}lylslll fonyl ) -L-arginyl -N-cyc ] o hoxyl ~.1 y C:i ll e N -(7-met}IOXY-2-11aPIItIIY15U1rOrIY1 )-L-argirIY] -N-CYC1OheXY1-f~ yc~
N --((;--mel.lloxy--~-nu~ l,lly~ .LJ`ollyl )--L--urt,illyl--N--cyclollexyL--motllylglycillo N --( r~--nlelNIOI;Y--I--II;~ .IIYI .`;111 I`OIIY I )--I,--;.11~g.j.11Y I--N--CYC.I OlleXYI.
~ ~374f~9 N -(5-metlloxy-l-nclplltllylsulf`ollyl)-I,-arginy:L-N-cyclohexyllllell~yL-¦~ -a.~allirle tert-L~utyl ester N -(fi~7-d.i.nl(?tlloxy-.~ al)lltllylsul.l`ollyl)-l,-.lr~illy:l-N-cyclo}l~xylgl.ycil-~
N -(6,7-(1illletl~oxy~2-1lapllthyl.sulfonyl)-l,-argi.llyl-N-cyclo}lexy.L-~ -a.lall:i.rle N -(6,7-dimetllo~y-2--lap]lthylslllfonyl)-L-argillyl-N-cyclohexyl-~ -ala~ e tert-butyl ester N-cyclopropyl-N-(3-carboxypropyl)-N -(6,7-cl;.methoxy-2-naphthyl.sulf`onyl)-L-argininamide N -(l-naphthylslllfollyl)-L-arginyl-N-cyclohexylglycine N -(5,6,7,8-tetrahydro-1-naphthylsulronyl)-L-arginyl-N-cyclohexylg:Lycine N -(5,6,7~8-tctrallydro-2-naplltllylsulfonyl)-1,-arginyl-N-; 15 cyclohexyLmethylglycine N -(7-meLIIyl-'-~ llyl.Sulf`onyl)-L-argilly:l-N-cyc~ollexyl-mc t llyl gly c:irl c N -(7-methyl-2-1laphthylsulfonyl)-L-arginyl-N-furfurylglycine N -(7-methyl-2-naphthylsulfonyl)-L-arginyl-N-tetrahydro-furfurylglycine 1:~374f~9 N -(7-1ncl;]loxy-~ tltllylstllfollyl)-L-arginy].-N--furf`llrylglyc~
N -(7-metlloxy-'-na~ tl~ylsulfolly:l)-L-argilly:L-N-f rfurylglycille tert-l~utyl ester N -(7-metlloxy-2-llaplltllylsulfonyl)-L-argi]lyl-N-totrahydro~ rrllrylglycirlc N -(5-(~inl(3tl1ylal1l:il1o-l-llapllt~lylsulfonyl)-L-~r~i~lyl-N
tetrahydro ru r fll rylglycille N -(5-chloro-1-naphthylsulfonyl)-L-arginyl-N-tetrahydrofurfllrylglycine N -(l-naplltllylsul rOI-yl ) -L-arginyl-N-tetrally(lrofurfur g]ycine N -(6,7-dimethyl-1-naphthylsulforlyl)-L-arginyl-N-tetrallyclrofurfurylglycine N -(5,G,7,8-tetrally(lro-1-naplltllylsulfollyl.)-L-argillyl-N-tetrally(irorllrf`lll yl.gl ycitle N --(G ,7-d.i nlc~ ~11oxy-2-llu~ tlly~ su:ll`ollyl )--L--argillyl -N--tctr~ y(lrol`llr.l`-lrylg,I.yci.llc N -(6,7-dinlctllo~y-,'-1lal)lltlly]sull`o~lyl.)-L-al~ginyl.-N-l~ yl~ -llli 11(3 - 2~ -N -(G~7-(1:ime~lloxy-2-1laa~lltilylslllf`ol-lyl)~L,-arg~ yl--N--L~utylala~ e I ert;-hlltyl ester N --(6~7--~1imcl;lloxy-2--1lal)lltllylsu1.rolly].)~ ar~ yl--N--pelltyla].arline N --(6,7-~limethoxy-"-llaphtalylsul.fonyl)--L-argirlyl-N-bcrl~.yl alanine ,, N ~-( 6 ~7-di metlloxy-2-]nlr)llthylslllfonyl ) -L-arginy.l.-N-phene thyla.lallille N -( 6, 7-dimethoxy-2-1lapllthylsulf:`onyl ) -L-arginyl -N--cyclohexyla].alli]le N -(4 ,6-dimethoxy-2-naphthylsulfonyl )-L-arginyl-N-cycl ohexyl metllylal anine N -( 7-methoxy-2-naphthylsulfonyl )-L-arginyl-N-propylalanine N --(6,7--~limothoxy-2-1lclpllt}lylg-llrollyl)--1~--arginyl-~(2-metllo~y-ethyl )aLallinc N --(fi,7--(I~ lel.llo~y--.!-u;ll)lll llylsu~ ~`ony.l )--l,--al~gillyl.llorvalillc N -(6,7-~1i.motl~oxy-2-1laphthylsulfonyl.)-L-arginyl-N-butylaspartic acid N -(6,7-(limeLlloYy-2-llal)lltlly:LsulLfollyl)-L-nrgillyl-N-l~utylasp<lrtic uci.(l (liethyl ec~ ter - 3~ --g N -(6,7-dimethoxy-2-~lap}lthylsulfollyl)-l,-argillyl-N-b nzylaspart::ic acid N -(6,7-dimetlloxy-2-rlaptltllyl.slllf`ollyl)-L-arg.illyl-N-benzylaspartic acid dlethyl ester N -(6,7-di.methoxy-2-lla~lltllyls-ll.follyl)-L-argilly].-N-metlly:l-~ -plleny~ alanl]l (~
N -(6,7-dimetl-1oxy-2-napllthylsulfollyl)-L-arg:inyl-N-methyl--(4-metlloxyphenyl)alanine l-[N2-(6,7-dimethoxy-2-1laphthylsulfonyl)-L-arginyl~-2-piperidirlecarboxyli c acid Ethyl l-~N -(6,7-di.methoxy-2-rlapllthylSIllforlyl)-L-argirlyl~-2-pi~eridineearboxylate l-[N -(6-methoxy-2-naphthylsulfonyl)-L-arginyl~-2-piperidineearboxylie aeid l-[N -(6,7-dimethoxy-2-napllthylsulforlyl)-L-arginyl~
methyl-2-piperidineearboxylic aeid 1--tN --(7--mctlloxy--2--naplltllylslllfonyl )--I,-arginyl~--4--methyl-2--piperidineearboxylie aeid l-tN -(5-methoxy-1-naphthylsulfonyl)-L-argillyl~-4-methyl-2-pi~eri(lillec.lrl~oxy.lie aeid : .
1:~3';'~
Ethyl l-~N -(5-methoxy-1-naphthylsulfonyl)-L-arginyl~
methyl-2-piperidinecarboxylate l-~N -(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl~-4-methyl-2-piperidinecarboxylic acid l-~N -(6,7-diethoxy-2-naphthylsulfonyl)-L-arginyl~-4-methyl-2-piperidinecarboxylic acid l-tN2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl~ -4-ethyl-2-piperidinecarboxylic acid l-~N2-(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 l-tN -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl~-6-methyl-2-piperidinecarboxylic acid l-tN -(7-methoxy-2-naphthylsulfonyl)-L-arginyl~-2-methyl-2-piperidinecarboxylic acid l-[N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl~-3-piperidinecarboxylic acid Methyl l-~N -(6,7-dimethoxy-2-napllthylsulfonyl)-L-arginyl~ -3-piperidinecar~oxylate l-tN -(7-methoxy-2-naphthylsulfony:L)-L-arginyl~-3-piperidinecarboxylic acid l-[N -(7-methoxy-2-naphthylsulfonyl)-L-arginyl~-2, 6-piperidinedlcarboxylic acid l-tN2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl~-4-phenyl-2-piperidinecarboxylic acid l-~N2-(1-naphthylsulfonyl)-L-arginyl~-4-methyl-2-piperidinecarboxylic acid Ethyl l-~N -(l-naphthylsulfonyl)-L-arginyl~ -4-methyl-2-piperidinecarboxylate l-[N -(2-naphthylsul~onyl)-L-arginyl~-4-isopropyl-2-piperidinecarboxylic acid Ethyl l-[N2-(2-naphthylsulfonyl)-L-arginyl~-4-isOPropyl-2-piperidinecarboxylate l-[N -(5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl3-- 4-methyl-2-piperidinecarboxylic acid Ethyl l-[N -(5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl~-4-methyl-2-piperidinecarboxylate ~ 33 -~:~37~t~9 l-[N -(6-chloro-2-naphthylsulfonyl)-L-arginyl~-4-isopropyl-2-piperidinecarboxylic acid l-[N -(5-dimethylamino-1-naphthylsulfonyl)-L-arginyl~-2-piperidinecarboxylic acid l-[N -(7-methyl-2-naphthylsulfonyl)-L-arginyl~-4-methyl-2-piperidinecarboxylic acid l-~N -(7-methyl-2-naphthylsulfonyl)-L-arginyl~-4-ethyl-2-piperidinecarboxylic acid l-rN -(7-methyl-2-naphthylsulfonyl)-L-arginyl~-4-isopropyl-2-piperidinecarboxylic acid Ethyl l-[N -(7-methyl-2-naphthyl~ulfonyl)-L-arginyl~-4-isopropyl-2-piperidinecarboxylate l-[N2-(6-methyl-2-naphthylsulfonyl)-L-arginyl~-4-isopropyl-2-piperidinecarboxylic acid 1 - [N -(7-methyl-2-naphthylsulfonyl)-L-arginyl~-2-hexamethyleneiminecarboxylic acid 4~ CN - ( 7-methoxy-2-naphthylsulfonyl)-L-arginyl~-3-thiomorpholinecarboxylic acid 4-~N -(7-methoxy-2-naphthylsulfonyl)-L-arginyl~ -3-carboxythiomorpholine l-oxide 1-13~9 4-~N -(6,7-dimethoxy-2-naphthylSulfonyl)-L-arginyl~-3-morpholinecarboxylic aci~
4-[N -(7~methoxy-2-naphthylsulfonyl)-L-arginyl~-3-morpholinecarboxylic acid 3 - [N -(7-methoxy-2-naphthylsulfonyl)-L-arginyl~-4-thia olidinecarboxylic acid 2-rN -(6~7-dimethoxy-2-naphthylsulfonyl)-L-arginyl~-1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid 2-~N2-(6~7-dimethoxy-2-naphthylsulfonyl)-L-arginyl~
i oindoline-l-carboxylic acid N -(4-chlorophenylsulfonyl)-L-arginyl-N-butylglycine N -(2~4,5-trichlorophenylsulfonyl)-L-arginyl-N-butylglycine N2-tosyl-L-arginyl-N-butylglycine N -(4-methoxyphenylsulfonyl)-L-arginyl-N-benzylglycine N -( 3,4-dimethoxyphenylsulfonyl)-L-arginyl-N-(2-methoxyethyl) glycine N -(3,4,5-trimethoxyphenylSulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine N -phenethylsulfonyl-L-arginyl-N-furfurylglycine <~
N ~ -t)en~o-li oxall -G-sulfonyl)-L-argirlyl-N-(2-methoxyethyl) g] ycine N~--(f ,7--c~ y l e~e(li oxy--2--naplltlly:l sul rOlly:l )--I,--argi llyl -N--(2-mctlLoxyetllyl )gl ycine l-~N -(2-cl:ibell~c)r~lrarlyl)-L--arginyl~ -2-piperi c~inecarbo~Yylic ac:i(l Of ttle compoullcls c~r this invention, it ~ill be l~lclerstood that the fo.Llowirlg compounds are most preferred clue to their high level Or antittlrombotic activity ancl lo~ level of toxicity.
N -(6,7-climethoxy-2-naphthylsulfonyl)-L-arginyl-N-butyLglycine N2-(7-methoxy-2-napllthylsulrorlyl)-L-arginyl-N-butylglycine N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoYyetlly~)f,rlycirle N -(6,7-<limet}loYy-2-rlapllthylsulronyl)-L-argi,nyl-N-(2-methoxyethyl)glyci,rle ethyl ester N -(l~,G-~li,motlloxy-2-lllplltllylsu]follyl)-L-~rf~ yl-N
(2-metlloxyetllyl)f,rlycille N -(7-methoxy-2-napllthylsulfonyl)-L-arginy~-N-(2-methoxyetllyl )glycine 1:~37~9 N -(5tfi~7~-tc~r~lly(lro~ aph~llylsulrorly~ -arginy~-N
( 2-me t~loxye tllyl )e~ yci.le N -(7-metlloxy-2-]lcll)lltlly1.sll1rollyl)-l,-argirlyl-N-tetrallydro-furrurylglycillo N -(7-metIIY:L-2-~ )1It~Y1SII1rOIIY1)-L-argiIIY~-N-tetra}IYdrO-L`ur.rurylgl ycillc N -(6~7-(IinIetIIOXY-2-IIIPIIt}IY1SU1fOnY1)-L-argiIIY1-N-totra11y(1roI`Ilrr~lry.lgLycille 1-~N -(6,7-dimethoxy-2-naphthyls-llfoslyl)-L-arginyl~-4-methyl-2-piperidinecarboxylie acid 1- CN -( 7-metlloxy-2-llaphtllylsulrollyl)-L-argin methyl-2-piperidinecarboxylie acid l.-tN -(7-methoxy-2-naphthyl.sulfonyl)-L-arginyl~ -ethyl-2-piperidinecarl)oxyl.ic aeid 'I`he pllarm~collt:ica1:ly acceptal.)l.e sa.l.ts o:f the above compounds are of cours-? a:lso inelll(l(?d within t11e seope of this illV('lltiOII, As one skilled in the art ean readily appreeiate, tlle carbon atom of the N -arylsulfonyl-L-argininamides, to whicll the carl)oxyl. gro~ or tlle ester tl~oreo~` is attaehed call 1)e an asymmo1;ric carhosl atom allowi.llg ror the exi.stence i;~3~ i9 ol` t~ro o~ticnlly active isomers, the n- alld l,-diastereoisomers, as wcl 1. as l:he raccnlat(?, I)l,-mixture .
In accordallce ~i tll f'i.n(lings conccrnir-g tl~(! alltitllrombotic act;iv.i ty o r s.,cl, compoun(ls possessillg un asymltletl lc carborl atom, the compoullds of the present inventioll having the D-conrigllra t ioll ar c more active than thoS(! of the L--conl`ig~lral;ioll ull(l arc tho prer(!rrc(l compollll(ls, a]tllough the 1,- an(l I)l,-l'ornl.s of ~lle :instant compollll(ls ar(! also considerecl wi thill tll(? purview Or the present inverltiorl .
Thc above compourl(1s are intende(l only to illustrate the variety of structures which can be used in the process of this invention, an(l tlle above listing is not to be construed as limiting the :3cope of tlle invcntion.
}?or the preparatiorl of the compowlds Or thls invention, various methods can be employed depending UpOII the particu-lar starting materials and/or intermediates involved.
Successful preparal ion of theSe compounds is possible by way of` severa1 syllthetic routc!s which are outlilled below.
(a) Con(lensatiorl of' an L-ar~inirlami(lc witll an ary].su]follyl ~ 11-1 1 .i.ll(!
TlLiS pI'OCCSS mily bc! i,llus trated as fol~ ows:
C -- N -- Cll2C112C112 jcllcOOll (11 ) Il NH2 ~ 38 --IIN ~
~C --N -- C112C112C112Cl~COOll ( t;) R" IIN
~' I
R "' + RTI (IV) >
IIN
~C - N - Cll2c~l2cll2cllcoR (V) >
R" IIN
1~' 1 IIN ~
C -- N -- CH2cE~2cll2cHcoR ( VI ) + ArS02X ( VII ) ~N ~ :
~C -- N -- C}12C112Cll2cllcOR ( I ) I~NS2 Ar ~n Lllc abovc l`ornllllas ~ 1~ arl~l Ar are as ~lerino(l llcrein above; X is lla~ogen; R"~ is a protective group for :-the ~ -am:ino group, such as benzyloxycarbonyl or tert- ;
l~utoxycarbollyl; R~ and R" are selccted from tlle group con~istillfr Or llydrofren an(l protoctivo grollps ror thc gllatli(lill() grollp~ ~ucll as nitro, tosyl, trityl, 1~37~9 oxycarbollyi all(l the like; ancl at lcast one Or R~ and ~" is a protc-ctive group for the guanidlno group.
rhc N~-arylsulrotlyl-L-argillinamicle (I) is prepared by tllc con(lellsatiotl of an L-ar~inillami(le (VI) with a sul~stalltially eqllimo1ar amount of an ary1sulfony1 hali(lc (V:II), prcferably a ch10ride.
Tllc con(lcllsatioll reaction is genera]ly efrected in a suita~)l.e react:ioll-iJIert soLvent in the presence of an excess Or a ~ase, s~lch as an orgallic l~ase (triethyl-amine, pyridine) or a solution of an inorganic base (sodillm hydroxi(le, potassium carbonate), at a tempera-ture of` ~C to the boiling temperature of the solvent for a period of 10 minutes to 15 hours.
The preferred solvents for tlle condellsation include benzene-clietllyl ether, diethyl ether-water and dioxane-water.
~fter the reaction is complete, tlle rorme(l salt is extracted with water, and the so1vent is removed by such stanclard mealls as evaporation under redllcecl 2~ ~rossnro Io ~,ivc lllo N2-arylsu1L`ollyl-l-argillinamide (~.), wllicll call bo ~uriricll ~y trituratioll or recrystalli-ZtltiOII rrom a sllital~le solvellt~ sllcll as ~ie-thyl ether-tctr~llydrol`llrall~ di.otllyl ethor-mctllt~lol ancl water-lllCtllallO.l ~ OI' Illtly bo CllrOmtlLOgraplle(l Oll silica gcl.
I`l~o l-arci~illanu(los (Vl.) startirl~ nul~olia:Ls rcquirctl 1:~3~ 9 for the condensation reaction can be prepared by protecting the guanidino and ~ -amino group9 of L-arginine (II) via nitration, acetylation, formylation, phthaloylation, trifluoroacetylation, p-methoxy-benzyloxycarbonylation, benzoylation, benzyloxy-carbonylation, tert-butoxycarbonylation or tritylation and then condensing the formed NG-substituted-~2-substituted-L-arginine (m) with a corresponding amino acid derivative (IV) by such a conventional proceqs 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 NG-substituted-N -substituted-L-argininamide (V).
The amino acid derivatives (IV) which are the starting materialq for the preparation of the NG-substituted-N2-9ubstituted-L-argininamide9 (V) are represented by the following formulas:
H-N~ 1 ( vm ) H-N~ 3 (IX) (CH2)nCR2 1 ('CH2)mCR5 I COORg R7 (X) ~ (XI) ~3~i9 COORlo COORll CH~ (XII) \ (CH2)~ ~ ( xm ) In the above ~ormulas, Rl, R2, R3, R4, R5, R6, R7, Rg, Rlo, Rll, Z, n, m, r, q, i, and ~ are as defined 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-halobutyrate with an appropriate amine having the formula RlNH2 or R3NH2. (See, J. Org. Chem., 2~ 728-732 (1960)).
The condensation reaction is generally carried out without a solvent or in a Solvent, such a~ benzene or ether, in the presence of an organic base, such as triethylamine or pyridine, at a temperature of O C to 80C for a period of 10 minutes to 20 hours. A~ter the reaction iB complete, the formed amino acid derivative is separated by such conventional mean~ as extraction with a suitable solvent or evaporation of the reaction solvent and thereafter purified by distillation under reduced pressure.
Among the amino acid derivative~ amino acid tert-butyl ester derivatives are preferred, because they are easily converted to other ester derivatives by acidolysis in 1:~374~
the presence of` a corresponding alcohol employing an inorganic acid (HCl, H2S04, etc.) or an organi~ acid (toluenesulfonic acid, trifluoroacetic acid, etc.).
In accordance with the proce9s employed for preparing ~ 2-piperidinecarboxylic acid derivatives (X), the following scheme is illustrative:
NaOCl ~ R KOH~ ~ R7 _HCN>
H Cl (XIV) (XV) (XVI) R7 H20 > ~ R7 N CN (H~) N C02H
H
(XVII) (xvm) In the firat reaction of the aforementioned scheme, an appropriately substituted piperidine (XIV) is contacted with an aqueous sodium hypochlorite solution at a temperature of -5C to 0C. The reRultant product (XV) is isolated by extraction with a solvent, e g., diethyl ether~ and then treated with pota9sium hydroxide in a lower alkanol solvent to give the 1,2-dehydropiperidine (XVI). The action of cyanogenating agents, e.g., hydrogen cyanide or sodium cyanide converts the 1,2-dehydropiperidines (XVI) to the corresponding 2-cyano ~ 43 -~3~4~9' analogs (XVII). Hydrolysis of the 2-cyanopiperidines (XVII) to yield the 2-piperidinecarboxylic acids xvm) is effected by treatment of the 2-cyanopiperidineS
(XVII) with an inorganic acid, such as hydrochloric acid or sulfuric acid.
The arylsulfonyl halides (VII) which are the starting materials for the preparation of the N2-arylsulfonyl-L-arglninamides (I) can be prepared by halogenating the requisite arylsulfonic acids or their salt~ e.g., sodium salt~, by conventional methods well known to those skilled in the art.
In practice, halogenation is carried out without a solvent or in a quitable qolvent e.g., halogenated hydrocarbons or DMF in the presence of a halogenating agent, e.g., phosphorous oxychloride, thionyl chloride, phosphorous trichloride, pho9phorous tribromide or phosphorous pentachloride, at a temperature of -10C
to 200C for a period of 5 minutes to 5 hours. After the reaction is complete, the reaction product is poured into ice water and then extracted with a solvent such as ether, benzene, ethyl acetate, chloroform or the like.
The arylsulfonyl halide can be purified by recrystalli-zation from a suitable solvent such as hexane, benzene or the llke.
~i37~9 (b) Removal of the NG-su'Dstituent from an NG-substituted--N -arylsulfonyl-L-argininamide This process may be illustratecl as follows:
HN
H2cH2cH2cHcoR (V) ,~
R " HN
R~ I
R"~
HN ~C-I -cH2cH2cH2cHcoR (XIX) ArSO2X (VII) R ~ 2 HN ~, C--N--CH2 CH2 CH2 CHC OR ( XX ) R~ HNSO2 R~ I
Ar C-N-CH2CH2CH2CHCOR ( I ) Ar 45 . s ' ' ~ ~374~9 ln the above ~ormulas~ 1~, Ar, X, R', R" and ~"~ are as clefi.nccl hereirl above Tlle N -ary1slll.l`ollyl-L-argininami(le (1) i.s prepared by renlov~ g tl~e N(~-substituent f`rom an N(-substituted-N -arylsulfonyl-I-argininamide (XX) by means of aciclol.ysis or ~Iyclrogellolysis.
I`he aciciol.ysi s is generally effecl;ed by contacting tlle N~-substituted-N -arylsulfonyl-L-argininamide (XX) and an excess of an aeid 9UCI~ as llydrogen fluoride~ ~Iyclrogen chloride, hydrogell l)romide or tri.fl.uoroacetic acid, without a solvent or in a solvent, SUCII QS an etller ( tetrahydrofurall, dioxane), an alcohol (metllat~ol, etllanol) or acetic acid at a temperature of -10C to 100C, and preferably at room temperature for a period of 30 minutes to 24 hours.
The products are isolated by evaporation of the solvent and the excess acid, or by trituration with a suitable so.lv(?llt rol.l.owed l)y filtration ancl dryi.ll~.
IICCaUSC 0~` tllC IlSe 0.~ C! CXCOSY ;IC~ tllc PIO(IIICI:S
are g(`ll(`lUI IY l,lIC aCi~l a(~ OII ~:al.l,S 0~` tllc N--arylsulrollyl-L-argininami(les (I), whicll can be easily convcrt(!(l lo a E`ree amicle by ne~ltr;l:l.izal;ioll.
The removal Or the nitro group aud tlle oxycarbonyl group, e.g., benzyloxycarbonyl, p-nitrobellzyloxy-carbollyl, i.s rea~lily accompl.i41le(l l~y tlle llydrogenolysis.
~ ~6 --li3746i9 At the same time, the benzyl e~ter moiety which can be included in the R group is converted to the carboxyl group by the hydrogenolysis.
~he hydrogenolysis i8 effected in a reaction-inert solvent~ e.g., methanol, ethanol, tetrahydrofuran or dioxane, in the presence of a hydrogen-activating catalyst, e.g., Raney nickel, palladium, or platinum, in a hydrogen atmosphere at a temperature of 0C to the boiling temperature of the solvent for a period of 2 hours to 120 hours.
The hydrogen pressure is not critical, and atmospheric pressure is sufficient The N -arylsulfonyl-L-argininamides (I) are isolated by filtration of the catalyst followed by evaporation of the solvent The N -arylsulfonyl-L-argininamides can be purified in the same mànner as described above.
The NG-substituted-N2-arylsulfonyl-L-argininamides (XX) starting materials can be prepared by condensing an NG-substituted-N2-substituted L-arginine (m) (generally the NG-sub9tituent is nitro or acyl, and the N2-substituent is a protective group for the amino group, such as benzyloxycarbonyl, tert-butoxycarbonyl, or the like) and a corresponding amino acid derivative (IV)~
selectively removing only the N -substituent of an li3~469 -snbstit~1te(l-N -substituted 1,-arginiJ1amide (V) by means of cata1ytic hydrogenolysis or ac.i.dolysis, and tllen co11(1c11si11~ thc th1ls obtai11ed N -stll)slitl1t~d-l,-al~ lli(lc (~ ) witll all arylstllt`o1lyl lla.l.ido (Vll), preferably a chloride in the presence of a base in a so~verlt. T11cse reaction conditions are as c1escribed abovc i11 tlle con(lc1lsation Or an l,-argilli11amide with an aryls11~`o1ly] l~a~ide, and the removal oI` the NG-substitllont f`rom an NG-subst.ituted-N --arylsulronyl--L--argin:inamide.
(c) Condensati.o1l of an N -arylsulfonyl-I,-arginyl halide with an amino acid derivative This process may be illustratecl as follows:
1~ ~
~C-N-C~12CH2CH2CHCOO~I (II) N}12 + Ar~02X (VII) Il IIN ~
1I N ~C N Cl"C112C~121CIIC0011 (XXI) >
l~r li37~9 IIN ~
,c-N-clt2c~t2cH2c~lcox (XX~I) ~NS02 ~r -~ Rll(IV) ->
ll IIN ~
Il N ~ 2 2 2ll~COR(I) IINI:;02 Ar In the above formulas, R, Ar and X are as defined herein above.
The N -arylsu]fonyl-L-arginirlamide (I) is prepared by - the condensation of an N -arylsulfonyl-L-arginyl halide (XXII), preferably a chloride witll at least an equimolar amount of an amino acid derivative (IV).
The condellsation reaction can be carried out without an added solvent in the presence of a base. However, satisfactory results will be obtainect with the use of a ~olvollt SllCIl ~14 I)asic solve~lts (~limi~tllylformamide~
dimethylacetamide, etc.) or halogenated solvents (chloroform, dichloromethane, etc.).
The amolult of the solvent to be used is not critical and may vary from abollt 5 -to 100 times l;l~e weigllt of t;~lo N -arylslllrollyl-l-ar~irlyl hali(te (XXI]) .
1~3~4~9 I'reftrretl con(lellsatioTI rcactiol~ tem~eratures are in the range of rrom -10C to room temperature. The reaction time is not critical, but varies with the amino acid dcrivative (IV) employed. In general, a period Or from 5 minutes to 10 hours is operable.
The obtaiJIed N -arylsulfonyl-L-argininamicle can be isolated a~ld lurifit~d in the same manller as described abovo.
The N -arylsull`ollyl-L-ar6rinyl halide (XXII) starting matcrials re(luired for the con(lensation reaction can be prepared by reacting an N -arylsulronyl-L-arginine (XXI) with at least an equimolar amount of a halo-genating agent such as thionyl chloride, phosphorous oxycllloride, phosphorus trichloride, phosphorous pentacllloride or phosphorus tribromidc. The halogena-tion can be carried out with or withollt an added solvent.
The preferred solvents are chlorillate(l hydrocarbons such as chloroform ~Id dichloron)ethalle, an~l etllcrs such as tetrahydrol`llran and diox~ule.
: 2~ t~llo~ . t>l` t.ll~ lvt~llt lo l)~ t~ lot clitic~l nll~ nlay vary l`rom a~out 5 to 1()0 times tlle weight of tllc N -aryl~ult`ollyl-L-argilline (XX~).
l'roferrc(l rcactioll temperature arc in tllc ratlge Or -10 C to room teml~erature. The reaction time is not critical, l~ut varies with the ha1Ogellatillg agent and 1~37~i9 reaction temperature. In general, a period of 15 minutes to 5 hours is operable, The N -arylsulfonyl-L-arginine~ (XXI) which are the starting materials for the preparation of the N -arylsulfonyl-L-arginyl halides (XXII) can be prepared by the condensation of L-arginine (II) with a sub-stantially equimolar amount of arylsulfonyl halides (VII), by a method similar to that described in the condensation of an L-argininamide with an arylsulfonyl halide.
(d) Guanidylation of an N -arylsulfonyl-L-ornithinamide or an acid addition salt thereof This process may be illustrated as follows:
H2N--c~2cH2cH2cHcoR (~cm) --->
HN I o2 Ar HN ~
H N ~ CH2cH2cH2lcHcoR (I) Ar In the above formulas~ R and Ar are as defined herein above.
The N -arylsulfonyl-L-argininamide (I) is prepared by li374~9 guanidylating an N -arylsulfonyl-L-ornithinanude (XXlI) with ~1 ordinary guanidylating agent such as an 0-alkylisourea, S-alkylisothiourea, l-guanyl-3,5-dimethylpyrazole or carbodiimide. The preferred guanidylating agents are the 0-alkylisourea and the S-alkylisothiourea.
The guanidylation of the N -arylsulfonyl-L-ornithinamide (xxm) with the 0-alkylisourea or S-alkylisothiourea is generally effected 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 50 hou~s.
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.
Examples of the preferred solvents are water, water-ethanol and water-dioxane, After the reaction is complete, the N -arylsulfonyl-L-argininamide (I) is isolated by evaporation of the solvent followed by removal of the excess base and the formed salt by a water wash.
It i9 well recognized in the art that an ester deriva-tive of the N -arylsulfonyl-L-argininamide (I) wherein R2, R5~ R8, Rg, Rlo or Rll i9 alkyl, aralkyl, aryl or li374~;9 5-indanyl, can be prepared from a carboxylic acid derivative of the N -arylsulfonyl-L-argininamide 2~ R5~ R8, Rg, Rlo or Rll is hydrogen by the conventional esterification methods well known to those skilled in the art. It is also well recognized in the art that the carboxylic acid derivative can be prepared from the ester derivative by the conventional hydrolysis or acidoly~is methods. The conditions under which e~terification, hydrolysis or acidolysis would be carried out will be each apparent to those skilled in the art.
The N -arylsulfonyl-L-argininamide (I) of this invention forms acid addition salts with any of a variety of inorganic and organic acids. Some of the N -arylsulfonyl-L-argininamides containing a free carboxyl group, 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 of salts. In addition, the product can be obtained as pharmaceutically acceptablc acid addition salt4 by reacting one of the free bases with an acid, such as hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric~ phosphoric, acetic~ citric, maleic, succinic, lactic, tartaric, gluconic, benzoic, methanesulfonic, ~ 53 -1~37469 o ~ l i c, ~ o l ~ I ( l l (? .~ U I [ () l l i. C ~I C i. ( l o r ;llC .1 i 1~(?~ 1 11 <I Y:i IlI.i I ~I r III-IIIIIC? 1`~ 1~ll(? ~) 1'()(1ll (` 1, Cllll l)C OL) t LillCC
LS ~ 11'111ilC(~II I i (`11 1 I y ~1(`(`(?1) t:~LL) I (? YCI I L.Y 1)~ IIC l.:i ll~r OIIC! 0 r tlle I)ot.lsY.il.llll ll)~ o~ l(?, i~rllrllo~ llll lly~ o~ ly~.clnli.llc, roca~ le, (I:il)~ Ianl.il)(?, .I.-e~ c]l Lm.il~ N,N '-(I:il)c?n:~,y:l.etlly1el1e-clial~ le, N-ctllyll)il)c~t~:i.(l:inc 01~ tllc .lil;e.
elriY C? ~ t r(?~ 111(?11 1; O r L 11(~ s.ll. L s ~i t ll ~- 1.) LY (? O r aci(l resul ts ill ~1 r('g(?llel'al..i()ll ol' L:IIC? rt'(!(` allli.(l(`.
1 0 l~ s s t a t -? ( l . I L ) -) V (?, ~ N --.~ y l. Y I I .I r O l l y ~ r ~ a llLi ( l c? y ~
the sall;s- tll(?l~eof c)l` thi~; illVO]ltiOII are cllar-lctc?ri~e(l l~y their ~ ,llly ~l~cc:i.ri.c i.n~ i.tory act:i.v~ y a~.linsl; throml)ir as well as ~ lC.i. L' Slll)S t.lll tial. lacli o L` L o~;:i ci. ty~ all(l Lllcr(?~`ol~e t~ ;(? collll~o~ e lls(~ lL :ill ~ (I(?ternlirlatioll .
Or t11roml~:ill :il~ l).lood as clia~,]lostic re.~ e]lts, an(l/or ror the mediccLl COII trol o L` prC?Vell tion Or tllrOllll)OSis, Tlle com~)o~lllclY o r` tl~:i.Y i.nvclltloll are al.Yo USC?rll1 as arl illllil):i tO1~ ol' l)l.atel et ~lg~rc?~atioll ~
Tlle a]l ti throml~o L i c ac l;i.vi ty O r L hc N -arylsulfonyl-L-~o arg:i.llillanli.(l(~ ` Llli~; .i.llV(?lll,i.OII \~/aY COIIII)al'('(l w.i.tll tllat ol~
a kllowll allt:il:lllollll)c)L,:i.c aC~ellt, N -(p-l;o.lylsll:l I`olly].)-L--argiJli.]le mCI:II~'I c~ite:l~ del.c.rlllilli]~,~,r tl~c ~ :i]lo~,e]l coa~u-latioll time. Tlle mecl~jllremellt Or tlle l`.il)rino~ell coa~,,rulatio tinle waY colldllcte(l aY l`ollows:
~rl ~.8 nll ali(l~loL ol` a l`.il)r.i.no~;c]l solllL.i.oll, wlli(llll.l-l L)ee - 5~ -~:~3~
prcpared by disso1ving 150 mg of bovine fibrinogen (Cohn fraction I) sllpplied hy Armour Inc. in 40 ml of a borate saline buffer (pH 7.~), was mixed with 0.1 ml of a borate saline buffer, pH 7.4, (control) or a sample solution in the same buffer, and 0.1 ml of a -thrombin solution (5 units/
ml) supplied by Mochida Pharmaceutical Co., Ltd. was added to the solutions in an ice bath.
Immediately after mixing9 the reaction mixture was trans-ferred from the ice bat-h to a bath maintained at 25 C.
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 concentration of an active ingredient required to prolong the normal coagulation time 50-55 seconds to 100-110 seconds, The concentration required to prolong the coagulation time by a factor of two for the known antithrombotic agent, N -(p-tolylsulfonyl)-L-arginine methyl ester, was l,lOO~m.
The inhibitors are shown in Table 1 by indicating R and Ar in the formula (I) and the addition moiety.
When a solution con-taining an N -arylsulfonyl-L-argininamide of this invention was administered intravenously ~ 55 ~
~i3';'4~9 into LlnirllaL l)odie:;, I;llc lligll alltitllronll)otic activi.ty in tlle C:irCll lati.ll~ oO(I was mai.l~t.liJIo(l f`or from ol)e t;o tllree IlOUrS .
'I`]~ a1r.~ r~-r ~leeaY ol` 1,1l0 ~Irlti-tllrOnll~OI;~;C COm~)O~II1(l$ Or tll;S j~V(`IILj.()ll jll (~;~C~I.Iat~ 100(1 W;1S :;IIOWII 1,0 1~0 a~pro--ximately 60 minutos; the physiologi cal condi. tions of the host allima:ls trat, ral)l)it~ (log allcl cllimpan~ee) were well maintaille(l. ~rhe exl~erime~ltal decrease Or r:ibrinogeJl in aninla.l.s causo(l l)y illl`l.lsiorl of tllrombirl was satisfactori.ly controllecl l~y s:imultalleolls inf`usion of tlle compounds of thi s inven ti on .
Tlle acute to~cici ty values (I,D50) determined by intraperito--neal. admini.stlatioll of substa~lces of formula (I) in mice (male, 20 g) rallge rrom about l,000 to l0,000 milligrams per kilogram of body weight.
Represelltative LD50 values for tl~e compolm~ls of this inven-tiOlI are sllown :in the roll.owing Tabl e .
..._.
(~ ) o l ~ I, D ~ o ( nlg/l; g ) N --( 7--mO t lly I -2~ )Jl l,lly I ~;ul l'ollyl )--1,-- >
arg:irlyl-N-lllll.yltrlyo:illo 1,500 2 ~ . ...... ..
N -(6,7-(1imotlloxy-2-1laplltllylsulI'ollyl )-L-arginyl-N-(2-metllo~:yethyl)glycirle 1,~00-2,400 2 '' ------ . .... _ N --(6 ,7-(limethoxy-2-rlapllthylsulf'onyl )--L--arginyl--N--(2--ethoxyethyl )--~--alanine 660-1, 000 .. .. _ ........... ...... _ .. _.
~ . .
C o mpo ull d ~D50 ( mg/kg ) 2 __ N --(/1 ,6-diltl~tl~oYy--,?--n~plltllylsu] ronyL )--1,--. l l '~ N--(, '--111 ( ! 1, ~ l l y ~ c .i 1 l ~ 6 6 0--1, 0 0 0 _ N ~-(7-me tlloxy-2 naplltllylsulforlyl )-L- 2, 000 arginyl--N-( 2 -me thoxye tllyl )glyci.ne . . . ,.
N~-(5~6~7~ ;etr~llly~iro-l-naplltllylsulfolly:l )- ~ r I,-argillyl -N-(, -metlloxyetlly:L )g] yc:i ne 1, ~00 2 ~ __ N --( 6, 7 -di me l:llyl -:1--nzlphl;l-lylsul ronyl )--L-- >
iar6:irlyl -N-( 2-me tlloxycthy]. )glyc:ine 1, 500 . ._ N -( 6, 7--d :i mc! tho xy-2 -napllthyl suL fonyl ) -1,-arg:inyl-N-(2-etllyl thioethyl )glyc.ine >1~ ()00 .
N -(6,7-dimethoxy-2-naE)httlylsulfonyl)~L- >1 000 arginyl-N-bell~yl.glycille ~
~ . _ N2-(4,6--limettloxy-2-rlapllthylstllronyl )-L,-argilly:L-N-l)ell~yl~;lyc~ e 1,000 _ _ . __ . ___ N -(5-methoxy-1-1lill)lltllylsulrollyl )-L-- ~1 000 arginyl-N-t)erl~ylglycine ~
. . _ . ._ ._ . . .
.~ N -(6,7-climetlloxy-2-tlapllthylsulfonyl)-L-arginyl-N-phenethy:l glycine ~1, 500 ~- 2 --~- ~ - --- _ _ N --(6 ,7--dimet;lloxy-2--llaphthylsulfonyl )-L-arg:i.tlyl-N-cyc lollexyl gl ycine ~1, 500 . _ . __ _ .__ .~
N -( 6, 7 -di me thoxy-2 -naphthylsul fonyl ) -L-arginyl-N--cycl ollexy~metllylgl.ycine ~1, 500 _ . .
N -(7-nletllyl -2-rlal)lltlly.l sll].rorly:L )-L- 600 argi.rly:l.--N-tet:rally(ll orllrrltryLglyci-lle . _ ~ 57 ~
li3~ 9 ..
~ompollrlcl ~ 50 (mg/lcg) . .. _._ ___ N -(~),7-dimctlloxy-,'-l1a~ tllyls~ `ony])-l,- ~2 ~llf,i~ l-- N--~(`t l~ `of~ rllryl ~r~ ~Cill(~
._ ._ ._ N -(G~7-(1imetlloxy-2-naptlttlylsulf`onyl)-L- > 1 roo arginyl-N-butyla]<llline "
_ . .
N -(4,~ imetlloxy-2-1lclpllthy:Lsulfonyl)-l,- > ~,5~0 argilly1-N-cyclollrxy.lmetlly]cllallin(?
l-~N~-(f)~7-~limetlloxy-2-rlapllttlylsu]fc)llyl)-l~- 1 500 arginyl~-2-pil)cri(lillecarbo.Yylic acicl , ... .. .
Ethyl l.l- N -(7-metlloxy-2-rlaphttlylsulforlyl)- 670-1 000 L-arginyl~ -nletl~yl-2-piperidirlecarboxy~ate l-[N2-(4~6-climetlloxy-2-naphthylsulfonyl)-L-arginyl~-4-nlethy]-2-piperidinecarboxyli.c 670-1,000 acid ~ __ .
]-[N -(l-napllthy:lslllt`onyl)-L-arginyl)-4- 700-1,000 metl~y.l-2-~)ipol-idillecarboxylic acid . . . _ ... . __ ]-- CN -( 5-dimetllylamillo-1-naptltllylsulfo~lyl)-L-arginyl~-2-pil)e]iAirlecarboxy.]ic acid 700-1,000 _ 11- [N - ( 7-motlloxy-~ aplll:hylsuL ronyl ) -L- ~ 1,~00 alginy.l~-'3-nlolpllolillocarl)oxy.lic aci(l .. _ _ I
2-¦N--(~ nI(~I;IIO~;Y-2-~ )IItIIY~ Y-I-)-I~-arg:illyl~-1,2,~ ol.lally(lloiso(~ inolillc-~- ~ 1,000 C ;l 1 ~ " (~ j ( 1 , _ .
2- LN -( ~j ~ 7--(IinI~ t~ Y-2-IIa})IItIIY1SII11 OI~Y I- )-IJ- ~ ::
ar~rillyl~ isoin(lt,lillccurl~o.~ylic acid ~ 1,00() On the other hall(l, 1,D5~ values ror N -dallsyl-N-b~ltyl-L-arginil~amide and N -d~lsyl-N-methyl-N-buty:l-L-argirlinamide aI'e 75 and 7~ mill.i~,ram~ per ki.logranl~ rcspective]y.
1~374~9 Tlle therapelltic agellts Or tllis inventioll muy be admilliYtered alolle or in conll)illaLioll wi LII pllarmcleeutlcul Iy uecc!ptclble carriers, tlle l)ro~)or~ion Or whieh is determine(l by tlle so lul~i ] i ty arl(l el~elll:i ca I n.ltllrc! Or the eompollllcl~ ellosen routeof administration and standard pharmaeeuti eal praetiee .
F`or exampl e, the compounds may be in jeeted parenterally, that is, intramllsclllurly, intravenously or sul~eutaneously.
F`or parenteral ac1nlinistration, the eompourl(ls may be used in the form Or sterile solutions eontailling other solutes, for exampl(?, suff`icierlt saline or g]ueose t;o malce the solution isotonic. L`he eoml)ollllds may be administerecl oral]y in the form of` tablets, capsules, or granules eontaillirlg suitable eXCipi.elltS SUCIl as starch~ laetose, white sugar and the like.
Tlle compoun(ls mly be aclmillistereci sub~itlgllu11y in the form f troehes or lozetlges in whieh eaeh aetive ingreclient is mixed wi th sugar or eorn syrups, f`lavoring agents and dyes ~
and tllell delly<irate(i su~`riei ently to make the mixture suitable ror pressillg into so]i d form. The eompoullcis may be aci-ministered ora] ly ill the form Or solutions W}liCh may eontain eolorin~ un(l rlavorillg agetlts. l'hysiciulls will cletermine the dosage of the present therapeutie agents whieh will be most suitab:Le, and dosages vary with tlle mocie of administra-- -tion and the particular compourld chosen. In acldition, the dosage will vary wi tll the particular patient under treatment .
When the composition is administered oral]y, a larger quantity ~ 59 -1137~9 of` l l~e clCt.iVe a~''CIIt will be re~ ired to pro~ ce tlle same er`recl; as canse(l wi.tll a small(?r llualltity gi.verl parenterally.
lle tller~r)ellt:ic dosage :is genera.11y 10-50 mg/lcg of acti.ve ingrc(licllt pal ellter.l l Iy, 10-5()0 mg/l<g ora.l..l.y per day .
Having generally described the invent;ion, a more complete unders tanding can bC! obtai.ned by reii`erence to certain specific exampleS, wlli cll are :inc1~l(led fot~ purposes of i.lltls tration on~y ~n(l are not inten(le~i to be l.imi.ti.ngr l.llll.e::;S ot]~erwise sp e ci. ~'i ed .
~ ~0 _ 1~37~9 EXA~IPLE
(A) N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginine:
To a well stirred solution of 83.6 g of L-arginine in 800 ml of 10~ potassium carbonate solution was added 114.7 g of 6,7-dimethoxy-2-naphthalenesulfonyl cnloride in 800 ml of benzene. The reaction mixture was stirred at 60 C for 5 hours, during which time the product precipi-tated. After one hour at room temperature, the precipi-tate was filtered and washed ~uccessively with benzene and water to give 129 g (76 percent) of N2-(6,7-dimethoxy-2-naphthylsu~fonyl)-L-arginine, M.P. 252-5 C.
(B) N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl chloride;
A suspension of 2.00 g of N -(6,7-dimethoxy-2-naphthyl-sulfonyl)-L-arginine in 20 ml of thionyl chloride was stirred for 2 hours at room temperature. 4ddition of cold dry diethyl ether resulted in a precipitate which was collected by filtration and washed several times with dry diethyl ether to give N2-(6,7-dimethoxy-2-n phthylsulfonyl)-L-arginyl chloride.
(C) N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyliN-butylglycine tert-butyl ester:
To a stirre~ solution of 2.6/~ g of N-butylglycine tert-butyl ester in 20 ml of c~oroform was carefully 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 solutlon and evaporated to drynes~.
The residue was triturated with a small amount of water to give a crystalline material. This was collected by filtration and recrystallized from ethanol-ethyl ether to give 2.28 g (82 percent) of N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylglycine tert-butyl ester, M.P. 164-166C, I.R. (KBr): 3,390, 3,165, 1,735, 1,370 cm 1.
Analysi9 - Calcd. for C28H4307N5S-~H2S3 (perc C, 52.98; H, 7.00; N, 11.04 Found (percent): C, 52.69;
H~ 6.98; N, 10.86 (D) N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylglycine:
To a solution of 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 of 15%
HCl-ethyl acetate. The reaction mixture was stirred 37~tjg for 5 llours at room temperature. At tlle end of this peri.od, tlle relcti.on mixture wclS evaporate(i to dryness.
The residllc was w.lslled several times wi. th dry diethyl ctller an(l cllromatographed on 80 ml. ot` I)aiaion (~) SK 102 ion exchallfre resin (200-300 mesh, ~I form, manufactured hy Mi tsllbi.slli. Cllcmical Industries Limited) paclced in water, wa.;lle(l ~/i th ~/ater an(:l e.lu ted wi th 3% ammonium hy(lro~c:i d e so] u tion.
Thc f`rlctior~ ted from 3% ammoni~lm hy(lroxi(le solution was evaporate-l to dryness to give 1.l~3 g (79 percent) o f N -( 6, 7-dime thoxy-2 -naph thylsul fonyl ) -L-arginyl-N-butylglyci.ne as an amorphous solid, I .R . (KE3r): 3, 360, 3,140, I.,622 cm 1 Ana.LysiS - Calcd. for C2~ l35N507S (percent) C, 53.62, H, 6.56; N, 13.03 F`oulld (percent):
C, 53.48; H, 6.43; N, 12.98 The following compounds are prepared in a sirnilar manll( r:
N -(7-m~ thyl -2-n1phtllylsulronyl ) -L -ar~,inyl--N-butyl--g -alal~ c N2--(7--mctlly.l--2-napllthyl.Sul~onYl)-N-(2~ el.llo~;yctllyl)-N-(3-carboxypropyl )-L-argininamide N -( 5-methoxy-1-naphthylsulfonyl. )-I -arginyl-N-(2-methyl thioethyl )glyclne 1~ 37~9 N -(5-methoxy-1-naphthylsulfonyl)~L-arginyl-N-(2-methylthioethyl)glycine tert-butyl ester N -(5-methoxy-1-naphthylsulfonyl)-L-arginyl-N-(2-methylthioethyl)-~ -alanine N -(6,7-diethoxy-2-naphthylsulfonyl)-L-arginyl-N-( -methylthioethyl)glycine N -(6-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methylthioethyl)glycine N -(6,7-dimethoxy-2-naphthylsulfonyl)-N-(2-methylthioethyl)-N-(3-carboxypropyl)-L-argininamide N -(6,7-dimethoxy-2-naphthylSulfonyl)-N-(3-methylthiopropyl)glycine N -(6,7-dimethoxy-2-naphthylsul~onyl)-L-arginyl-N-(2-ethylthioethyl)-~ -alanine 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 ~i3~ i9 Il-N{ N -(f)~7-(1imcllloxy-2-rla~ thylSulrollyl)-L-arginyl) -N-cyclolloxy~an)inobutyric acid N -(/I,6-llimctlloxy-2-rlaplltllylslllPolly~ ,-ar~ yl-N-phelle tllyl~ lanille N -(6-methoxy-2-rlaphthylsulfonyl)-L-argiJIyl-N-(3-pllcllylpropy:l)glycine N -(5-mot;l~oxy-~-napllthylslllrolly.l.)-l,-argi.lly~.-N-~crl~yl-~ -alalline N2-(5-nitro-1-naphthylsulfonyl)-L-arginyl-N-tetrahydro-furfurylglyci.lle N -(7-11ydroxy-2-naphthylsulfonyl)-L-arginyl-N-tetrally(~rorurrllry]glycille N -(5-cyano-1-naph1;hylsulfonyl)-L-arginyl-N-tetrahydro-. furfllrylgl.ycille N -(6,7-dinletlloxy-2-naphtllylsulfonyl.)-1,-arginyl-N-tetrahydrorurfuryl-~ -alanine N2-(7-methyl.-2-rlaphtllylsulfonyl)-L-argillyl-N-tetrahydrof-lrfuryl-t -alanine N -(6,7-dimethoxy-2-naphthylSulfonyl)-L-arginyl-N-t~trahy(lrorllrrllrylalanine - ~5 -1~37~69 N -(7-metl-1oxy-2-slapllthylsulforlyl)-N-(3-carboxypropyl)-N-tetrally~lrorllrfuryl~ arginillami(le N -(7-methoxy-2-naphtllylsulfonyl)~ arginyl-N-butylalanille N -(7-methoxy-2-napllthylsulfonyl)-L-argi.nyl-N-pentylalanin~
N2-(5-methoxy-1-1lapllthylsulfonyl)-L-argirlyl-N-butylalanine N -(6,7-(1:inletlloxy-2-nal)hthylslllfollyl)-L-argirlyl~N-isoblltylalallille N -(7-methoxy-2-rlaphthylsulfonyl)-L-arginyl-N-benzylalanin N -(6,7-dimethoxy-2-naphthylsulfollyl)-L-arginyl-N-(3-phenylpropyl)alanine N -(5-methoxy-1-naphthylsul~onyl)-L-arginyl-N-benzylalanin-N -(7-methoxy-2-naphthylsulfonyl)-L-argirlyl-N-cyclo-hexylalanille N?-((j~7-~ llel;lloxy-2-~ tlly~ lrolly~ -argillyl-N-cyclohc.~y:llllctllylalanillc N -(6,7-climetlloxy-2-rlaplltllylslllt`ony.])-l,-.lrgillyl-N-bu tylbu tyrinc N -(6,7-climetlloxy-2-rla~hthyJslllfoJlyl)-l,-ar~ yl-N- :
( ~--r" l yl m~ yl )~rl yc i 11C`
N ~ 7-(1imc~lloxy-2-naphthylSulror-y]. )-L-arginyl-N--( tel,r;llly(llo-3-1`1~rylmetllyi )g:lycine N -(6,7~ in)etlloxy-2-~ p~lthylslllrolly~ arginy]-N--( 2--t ~ l y l ) ~r .l y c ~
N -(7-methoxy-2-napllthylslllrollyl )-I,-arginyl-N-( 3-t~lellyl )glycille N -( 6 ,7-dime thoxy-2-rlapllthylsulforlyl )-L-arginyl-N--( tetrahy(lIo-2-thenyl )glycine N -(7-methoxy-2-naphthylsu.l fonyl )-L-argirlyl-N-( tetrahydro-3-thenyl )glycine --N2-(6,7-dimethoxy-2-naphthaylsulfonyl)-L-arginyl-N-(2-acetylethyl)glyc N2-(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(4-methoxyfurfuryl)glyci N2-(7-methyl-2-naphthylsulfonyl)-L-arginyl-N-(5-methylfurfuryl)glycine N2-(6,7,-dinlethoxy-2-naphthylsulfonyl)-L-arginyl-N-(l,4-dioxacyclohexylmethyl)glycine l-[N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L- arginyl]-4-methoxypiperidin 2-carboxylic acid l-[N2-(6,7,-dimethoxy-2-naphthylsulfonyl)-L-arginyl]-5-methylhexamethyleneinline-2-carboxylic acid l-[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 .
(A) N -(6-methoxy-2-naphthylsulfonyl)-L-arginyl chloride .
A suspension of` 2 .5 g of N -(6-methoxy-2-napllthylsulfonyl )-1,--arginine i n 20 m~ of tllionyl chl.oride was s tirred for 2 hollrs at room temperature . Add1 tion of cold dry ethyl et~er reslllted i.n a precipitate whicll was collected by fil-tratioll and washed several times wi th dry ethyl ether to gi ve N -( 6-me thoxy-2 -naphthylsul follyl ) -L-arginyl chlo ri d e, ~3~i9 (~) Ethy]. 1-[~ -(6-nlethoxy-2-1lat~hthylsulfollyl)-L-argirlyl~-2-piper.i.dillecclrboxylate ~o a stirred solutioll of 2.2 g of otllyl 2-piperidine-carl)oxylate an~ .l ml of trietllylamille in 50 ml of chloroform~ which was cooled in an ice-salt bath, was actded .in port:iolls N2-(6-methoxy-2-naplltllylslllf`ollyl)-L-arginyl chlor:i-le ot~taine(l above. Th( rcacl:.i.ol-l mixture was stirred overlli~rll~ at room tempera-ture. At the en(l o~ this perioct, 500 ml of chlorororm was ad(le(l and ttle chloroform solution was ~ashed twice with 50 ml of saturated sodium chloride solution, dried over anhy~trous sodium sulfate and evaporated in vacuo.
Tlle oily residue ~as washed with ethyl ether to give 2.9 g of powdery ethyl l-~N -(6-methoxy-2-rlaphthyl-sulfonyl)-L-arginylJ-2-piperidinecarboxylate.
For analysis of the product, a portion of the product was converted to the flavianate, M.P. 192-3C.
I.R. (K~r): 3,210, l~747, 1,638 cm l Allalysis - C~lc~l. for C25H356N5S Cl~ll6 8 2 C, 49.58; 1[, l1.87; N, 11.56 Foul-l(l (percent): C, 49.24;
Il, 4.7~; N, 1.1.85 (C) l-tN -(6-methoxy-2-napllthylsulfonyl)-L-arginyl~-2-r~ r~ rl)o xyl i c ~ ci ~l A solllt:ioJI ol` 2.~ ~ Or otl~yJ. l-~N -(~)-motllo~y-2- ~:
~laplltlly.Lsll.LL`olly:l)-L-argillyl~-2-piperidi.llecarl)oxylate in 1~3~9 15 ml Or rnethanol and 10 ml of 2N-NaOH solution was warmed to 60 C and held at that temperature for 10 hours. At the end of -this period, the reaction mixture was concentrated and chromatographed on 200 ml of Daiaion ~ SK 102 ion exchange resin (200 - 300 mesll, H form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with ethanol-water (1:4) and eluted with ethanol-water-NH40H (10:9:1).
The main fraction was evaporated to dryness and washed with ethyl ether to give 2.0 g of l-~N -(6-methoxy-2-naphthylsulfonyl)-L-arginyl~-2-piperidinecarboxylic acid as an amorphous solid.
I.R. (KBr): 3,200 (broad), 1,620, 1,150 cm Analysis - Calcd. for C23H3106NsS (percent) C, 54.64; H, 6.18; N, 13.85 Found (percent):
C, 56.88; H, 6.31; N, 13.83 The following compounds are prepared in a similar manner:
N -(6-chloro-2-naphthylsulfonyl)-L-arginyl-N-butylglycine N -(7-methyl-2-naphthylsulfonyl)-L-arginyl-N-(2-ethoxyethyl)glyclne N -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methylthioethyl)glycine li3~ 9 N ~ 6-(linle~ll<)xy-2-naplltllylsulfollyl)-l,-argillyl-N-(2-rllctlly:l, tllio(.~ yl )~].ycil-o N'---( ~1, (i -(I i Illl` ~hox y--,'--n;~ lly 1~ 1 1 ouy 1 )--1,--a I'C~ y I--N--phene-tllyl - ~ -a I anine N -(6,7-dimetl-1oxy-2-rlap}lthylsulrollyl)-N-benzyl-N-(3-carl)oxypropyl. )-I,-argininamide N2-(7-methoxy-2-naphthylsulronyl)-L-arginyl-N-cyclohoxylllorleucirle N -(7-methoxy-2-naphthylsulronyl)-L-arginyl-N-butylisolellcille N -(7-methoxy-2-naphthylsulronyl)-L-arginyl-N-pentylbutyrine N2-(6,7-diethoxy-2-l1aphthylsulronyl)-L-arginyl-N-butylalanille N - ( 6,7-dimethoxy-2-naphthylsulfonyl)-L-arginy].-N-cycloheptyl alanille N -(7-metboxy-2-naphthylsulronyl)-L-arginyl-N-(2-methoxyetllyl )alanine N -(6,7-dimethoxy-2-naph-thylsulfonyl)-L-arginyl-N-(2-ct:hoxyetllyl)alanine N -(7-methoxy-2-rlaphthylsulf`onyl)-L-arginyl-N-cyc]ohexyl-~ -a~anine N ~ y--"--~ 1 hy I .';11 1 l`o t l y l. )--1,--~ g i l l y l--N--(2--methoxyethyl)norvaline N ~(6,7-dimetlloxy-2-1laphthyls~ orlyl)-l,-arginyl-N-ben~ylleucille l-~NZ-(5-metlloxy-l-naphtllylsulfonyl)-L-arginyl~-4-ethyl-2-pipericlinecarboxylic acid ; l-[N2-(6-methoxy-2-naphthylsulfonyl)-1,-arginyl~-4-ethyl-2-piperi(iinecarboxylic acid l-CN -(ll,6-cli.methoxy-2-naphthylsulfonyl)-L-arglnyl~
- ethyl-2-piperidinecarboxylic acid l-[N2-(5-ethoxy-1-naphthylsulfonyl)-1,-arginyl~-4-ethyl-2-piperidinecarboxylic acid :L-[N -(7-ethoxy-2-naphthylsulfollyl)-l,-argillyl~
ethyl-2-pi.peri(linecarboxylic acid l-CN2-(6,7-diethoxy-2-llaphthylsulfollyl)-L-arginyl~-4-ethyl-2-piperidi.llecarboxylic acid l-~N2-(7-metlloxy-2-naplltllylsulfonyl )-I,-argi.tlyl~-ll-I;ert~ ltyl-2-l)iperi.~1:inecarhoxylic aci(l ~:~37~69 l'helly]. l-~N -(7-methoxy-2-naphthylsul.forlyl)-L-arginyl~ -4-ethyl-2-E)il)eridinecarl)oxylate 13e~ .y.] 1-[N~-(7-motlloxy-2-1lapl~tllyl.~ rollyl)-L-z~rgil-yl~ -4-ethyl -2-pi.peridirlecarboxylate Ben~y] l.-[N -(fi,7-(li.methoxy-2-naplltllylsulfonyl)-L-argilly.l~ -methyl-2-piperidillecarboxylate l-[N -(5-nitro-1-l1ar~ht}lylsul rorlyl ) -L-arginyl~
mcthy.l.-2-pipori.(lirlocarboxylic acid l-~N -(7-llyclroxy-2-naphthylsulfolly].)-L-arginyl~-4-ethyl-2-piperiAinecarboxylic acid l-[N -(5-cyano-1-rlaphthylsulfonyl)-L-arginyl~ -methyl-2-piperidinecarboxylic acid l-~N -(7-methyl-2-naphthylsulfonyl)-L-arginyl) -4-ethyl-2-piperidinecarboxylic acid 1-~N~-(5-dinlotllylalllillo-1-l1aphthylsulrollyl)-L-arginy]~-1y l -~ )i r) (~ c cL~ )o xy l :i c ~ Ci (l ';
l-~N -(2-nupll~llylsull`ollyl)-L-argilly]J -ll-etllyl-2-pil)eri(lillocari)oxyl:ic aci~
l-~N -(5,fi~7,~ tl~lly(lro-2-l-lar)~ yl~ `c)~lyl)-r,-ar~i]ly.l~-ll-etllyl-2-1)ipcridirlccarl,oxylic acid 1~7~9 l-[N -(5-dimethylamino-1-naphthylsulfonyl)-L-arginyl~-4-methyl-2-piperidinecarboxylie acid l-~N -(7-methyl-2-naphthylsulfonyl)-L-arginyl~-6-methyl-2-piperidineearboxylic aeid l-tN -(7-methyl-2-naphthylsulfonyl)-L-arginyl~-4-tert-butyl-2-piperidineearboxylie aeid l-~N2-(5-nitro-1-naphthylsulfonyl)-L-arginyl~indoline-2-earboxylie acid 2- ~N -( 5-eyano-1-naphthylsulfonyl)-L-arginyl~isoindoline-l-carboxylic acid 4-[N -(7-methyl-2-naphthylsulfonyl)-L-arginyl]thio-morpholine-3-earboxylie aeid 4-[N -(6,7-dimethyl-2-naphthylsulfonyl)-L-arginyl~
morpholine-3-earboxylic aeid 4-~N -(5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl~-3-earboxythiomorpholine l-oxide 4-~N -(7-methyl-2-naphthylsulfonyl)-L-arginyl~morpholine-3-carboxylie aeid 4-~N -(7-ehloro-2-naphthylsulfonyl)-L-arglnyl~morpholine-3-earboxylic aeid ~ 73 -1~L3~9 4-~N2-(7-hydroxy-2-naphthylsul~onyl)-L-arginyl~
morpholine-3-carboxylic acid 4-~N ~(5-nitro-1-naphthylsulfonyl)-L-arginyl~thio-morpholine-3-carboxylic acid 4-tN -(5-cyano-1-naphthylsulfonyl)-L-arginyl~thio-morpholine-3-carboxylic acid 4-~N -(5-methoxy-1-naphthylsulfonyl)-L-arginyl~
morpholine-3-carboxylic acid Ethyl 4-rN -(4,6-dimethoxy-2-naphthyl~ulfonyl)-L-arginyl~ morpholine-3-carboxylate 4- ~N2-(5-ethoxy-1-naphthylsul~onyl)-L-arginyl~
morpholine-3-carboxylic acid 4-rN2-( 5-dimethylamino-1-naphthylsulfonyl)-L-arginyl~ ~
thiomorpholine-3-carboxylic acid :
3-tN -(l-naphthylsulfonyl)-L-arginyl~thiazolidine-4-carboxylia acid 2-~N2-(7-methoxy-2-naphthylsulfonyl)-L-arginyll-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid 2-[N2-(7-methoxy-2-naphthylsulfonyl)-L-arginyl~
isoindoline-l-carboxylic acid 1~3~4~9 2-~N2-(~1~G-(limel,~loxy-2-1lal)hthylSulrollyl )-L-arginyl~-1,2,3,~1-tetrally(lto:iso(~ lolirle-3-carhoxylic acid '--~N --( r~--n~ y--l ~ > 1~ y l ~ l rO I ~ y l )--1 --1 1 ~ri ~ I y.l.
isoin(loli.lle-l-carboxylic acid 2-[N2-(5-ethoxy-.1-naphtllylsulronyl)-1 -arginyl~-l ,2, 3,4-tetrahydroisoquinoline-3-carboxylic acid EXA~PLE 3 (A) NG-nitro-N -( tert-butoxycarbonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester:
To a stirrecl solu-tion of 28.3 g of NG-nitro-N -(tert-butoxycarbollyl. )-I-arginine in 450 ml Or dry tetrahydrofuran were addo(l i.n turl-l 12 ,ll ml of triethylamine and 12 .4 ml Or isobutyl. chlorof ormate while keeping the temperature 1t -5 C. After 15 minutes, to this was added 111.2 g of N-(2-mct;hoxy(?tllyl)glycine ethyl oster, alld the mixture wa~ s tirro(l 1`0r 15 minutes at -5 C . ~\t the end of this el.i.o(l, tll(? r olct:iOII mixtur(? was WUI m(?(! to r oom tempera-llllc. I`h( :;olvellt wa~ cvll)0rut(3(l alld tllo resi(ll~e talce ul) in /10() ml ol` ethyl acetate, and wuslle(l succesSively with 200 m.]. of water, 100 ml of 5% sodillm bicarl-onatc ~;ollll;ioll, 1()() ml ol` .1()% c:i l;rlc uci(l :;olllt:i.nll ulld 200 ml of wul or. Tl~o otllyl acctatc soluti.ol~ wus dr:i.o(l ovor ~ 75 ---~37~6~
anhydrolJs sodj.llm sulfate. Upon evar)oration of the .solveIlt~ tlIc I~e.si(Iue was disso:I.ve(l i.I~ 20 ml of ch.l.oro-fo ~t, and thc XO]UtiOII was applied to a colu~ (80 cm x 6 cm) Or 500 g Or silica gel packe(I in chloroform.
The procIuct was e].uted first with chloro~`orm, ~Id then 3~ nletha~IoJ.-chlorororm. The fraction eluted from 3%
methaIlol-c}llolororm was evaporate(I to dryness to give 25.8 g (63 ~ercent) o:f NG-nitro-N -(tert-butoxycarbonyl)-L-arginyJ.-N-(2-nIetIloxyethyl.)glycine ethyl ester in the .form Or a sy~
]:.R. (IC~r): 3,300, 1,740, 1,690 cm (B) N -nitro-L-arginyl-N-(2-methoxyetIIy.l)glycine ethyl ester hydrocIIloride:
To a stirred solution of 29.8 g of NG-nitro-N2-(tert-butoxycarbonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester in 50 ml of ethyl acetate was added 80 ml of 10~ dry }ICl-ethyl acetate at 0C. After 3 hourS, to this solutioI-l was added 200 ml of dry ethyl ether to precipitate a viscous oily product.
This was fi.ltercd and washed with dry ethyl ether to give 24.1 g of N -nitro-L-arginyl-N-(2-methoxyethyl) glycine ethyl ester hydrochloride as an amorphous solid.
(C) N -llitro-N -(6,7-dimethoxy-2-naplIthylsuJronyl)-L-arginyl-: N-(2-methoxyethyl)glycine ethyl ester:
_ ~fi _ ~37~
To a stirred solution of 4.0 g of NG-nitro-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester hydrochloride in 20 ml of water and 20 ml of dioxane were added in turn 2.5 g of sodium bicarbonate, and 3.5 g of 6,7-dimethoxy-; 2-naphthalenesulfonyl chloride in 30 ml of dioxane at 5C, and stirring wa~ continued for 3 hours at room temperature. At the end of this period, the solvent wa~ evaporated and the residue dissolved in 40 ml of chloroform, and washed with 10 ml of lN hydrochloric acid solution and 20 ml of water.
The chloroform solution was dried over anhydrouA sodium sulfate. Upon evaporation of the solvent, the residue was chromatographed on 50 g of silica gel packed in chloroform, washed with chloroform and eluted with 3%
methanol-chloroform. The fraction eluted from 3%
methanol-chloroform was evaporated to give 5.3 g (87 percent) of N -nitro-N -(6,7-dimethoxy-2-naphthyl-sulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester in tl form of an amorphous solid.
3 I.R. (K~r): 3,240, 1,740, 1,630 cm 1 (D) N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester:
To a ~olution of 3.00 g of N -nitro-N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine ~ 77 ~
1~374f~i9 olllyl (~ r~o nll o~ o~ 1ll(l ().5 ml Or acotic .i.~l W~ .5 F of`~ n~ ucl~ atl~l t~l~rl t}le mixtllrc ~as ~llal;en ill a hy(lrogen atmospllere for .1.00 llolll~ .It loo~ tll~. A~ (l Or-tlli~ ~eriocl, the ethanol so.Lution was filtered to remove the catalyst and evaporated to give an oily product. Ilepreci.pitation with ethano.l.-ethy1 ether gave 2.53 g (91~o) of N -(6,7-dimetlloxy-2-1laplltllylsulfonyl )-L-arginyl-N-(2-methoxyethyl) g1ycine ethy.l. ester.
~or ana1ysi.s o.f the product, a portion Or the product was converted to the flavianate; M.P. 185 C, I.R. (KBr):
3,375, 3,200, 1,740 cm 1.
A~la1ysis - Calcd. for C25~l37N58S C10l6 2 8 C, 47.67; ~l, 4.92; N, 11.12 Found (percent):
C, 47.6ll; ll, 4.81; N, 11.12 (E) N2-(6,7-dimethoxy-2-naphthy1Su1fony1)-L-argilly1-N-(2-methoxyethyl )~rl ycine:
A solutioll of 2.5 g of N -(6,7-dimethoxy-2-l1aphthy1-Slll l`ollyl )-l,-a]~giny.l -N-(2-mel;hoxyotllyl. )~l.ycillc ethyl esl:er in ~ ml. of eth~lo1 alld 7 ml. ol`.lN ~odium hydroxide SO lutiOll was stirrcd for 30 hours at room temperature.
At ~he en(l of` tllis period, the so1utioll was concentrated to 5 ml, chroma~ogra~lled on ~0 nll o~` ~aiaion ~ ~K 102 ion exchull~e re~ill (200 - 300 mesh~ ll i`orm manufacturo~
1~37~S~
by Mi~su~)islli Cl~emical Il~d-lstries Limited) packed in water, wasl~e(l with water, and elute(l with 3% ammonium hydroxi(le SOlUtioll, Tlle rraction elllte(l from 3%
allllllollillm llydro~;:i(le solllt,ioll was evapor-ll,ed '~,o (Iryness, ancl the rcsid~le ~as puriried by reprecipitation with ethanol-etl)yl ctller to give 1 32 g (72 percent) of N -(6,7-(1imetlloxy-2-naphthylsulfollyl)-L-argillyl-N-(2-methoYyetllyl)glycille as an amorphous solid.
I.ll. (KL3r): 3,380, 3,180, 1,630 cm 1 ~na]ysis - Calcd. for C23lI33N508S (percent): C, 51.20;
Il, 6.17; N, IZ.98 Found (percent): C, 50.93;
~, 6.02; N, 12.63 The following compounds are prepared in a similar marner:
N -(5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl-N-(2-ethoxyethyl)glycine N -(5,6,7,8-tetrahydro-2-naphthylsul~ollyl)-L-arginyl-N-(2-methoxyetllyl)glycille N -(7-ethyl-2-naphthylsulfonyl)-L-argillyl-N-(2-methoxyethyl)glycine N -(5-methoxy-1-naphthylsulfonyl)-L-arginyl-N-cyclollexylglycine ~ 79 -1~37469 N -(7-metlloxy-2-1lapllthylsulronyl)-L-argiJIyl-N- ~ :
(3-cyclol~exyl)~ opyIglycine 2-~N -(7-nletllyl-2-naplltllylslllfollyl)-1,-arginyl~-1,2,3,4-tetrahydroisoquinoline-3-carboxylic ac.id 2-tN2-(7-nlethyl-2-naphthylsulrollyl)-L-arginyl~
isoincloline-l-carboxylic acid 2-tN2-(6~7-dinlcthyl-2-napllthylsulforlyl)-L-argillyl~
isoi.nclol,ille-]-carboxylic acid 2-~N -(2-naphthylsulfonyl)-L-arginyl~i,soindoline-l-carboxylic acid 2-~N -(5,6,7,8-tetrahydro-2-napllthylsulfollyl)-L-arginyl~-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 2-~N2-(5,6,7,8-tetrahydro-1-naphtllylsulfonyl)-L-urgillyl~i,soilldo.lillc-l-carl)oxy]ic uci-l ~ CN -(5-(IIIOrO-I-~ IYI~IILrOIIYI)-I-;Irf~;IIY1~-3,~ ;llly(tloiso~ llolillc--3--c~t~l~oxylic ~ci(l l-CN ~-( 5-1~y~lJoxy-,l-nal~lltlly.lsu:lrollyl)-l,-urginy.l3 -1~2~3,11-tctrallydroc]llirlo:linc-2-carl)o~y:lic aci(l li3~4ti,9 2-~rN -(5-dimotllylaniino~ aplltllylstl~follyl)-L-ar~inyl~
iso~ (101.ine-.l-carl)oxylic aci(l 2-~N2-(l-l~ tllylslll rOny~ -arginy~ 2~3 tetrahydroisoquinoline-3-carboxylic acid EXAMplL 1l (A) L-arginyl-N-(2-methoxyethyl)glycine ethyl ester hydrochloricle:
To a solutiorl of l~ o g of NG-nitro-l-arginyl-N-(2-me-tlloxyethyl)glycine ethyl ester hydrochloride in 50 ml of ethanol was added 0.5 g of palladium-black and then the mixture was shaken in a llydrogen atmosphere for 150 hours at room temperature. At the end of this period, tlle ethanol solution was filtered to remove the catalyst and evaporated to give an oily product.
Reprecipitatioll witll ethanol-etllyl ether gave 3.0 g (81%) of L-argirlyl-N-(2-metlloxyetllyl)~lycille ethyl o~t~r llydrochlor~itle in tlle form Or a ~owder.
(~) N -(4,6-(iin1otlloxy-2-nclplltllylSulforlyl)-~-arginyl-N-(2-methoxyethyl)glycine ethyl ester:
To a well stirred solution of 2.00 g o r L-arginyl-N-(2-metlloxyetllyl)glycirle etllyl estor hy(lrocll]oride and 1.95 ~ of K2C03 in 20 ml. of water and ]0 ml of dioxane - 8l -1~3~ 9 was adlie~l drnl)~/ise a solutioll of 2.17 g of 4,6-climetlloxy-2-JIa~ thalerlesll~forlyl chloricle iJI 30 ml Or dioxalle over a period Or 30 m:i~lutes wlli]e mair~taining tlle te~ )e~ rc llt 0C. Thc reuctioll nuxture ~/as stirred for an ad(,litiOnal 5 hours at room temperature.
At the ell(l of` tllis period, tlle solvent was evaporated alld the reYi,(llle talcer~ ) in 50 ml of chloroform.
'rhe chlorororm sollltion was filtere(l to remove the insollll~le material alld clried over anhydro-ls soclium sul~`atc. A(ldil;ioll of 150 ml of etllyl ether to the chloroform solution resulted in a precipitate which was separated by decantation and purified by reprecipitation with ethanol--ethyl ether to give 2.31 g (72 percent) of N -(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethy])glycine ethyl ester.
For analysis of the product, a portion of the product was converted to the flavianate; M.['. 225-227 C, 1.1~. (KJlr): '3,375, 3,200, 1,742 cm 1. -.
,~ Analys;,s -- Calcd. for C25ll37N 08S-C ll~
N208S (percent): C, 47.67; H, 4.92; N, 11.12 Found (percent): C, 47.62; Il, 4.84; N, ll.i8 (B) N -(4,6-(lillletlloxy-2-rlaplltllylsulfo~ly1)-l,-argillyl-N-(2-nl(~tllox~cl,lly~ r~ ycil~
~ ~3~7~9~
N - (4 ,6-dime~IIo~y-2-naphtIlylslllrorlyl)-L-arginyl-N-(2-methoxyetIlyl)g.IyciIle was ol~tai~led in the form of an amorp}Ious sol:id in a m.~lner similar to that described ~an~ 3 (r,) I.R. (ICIJr): 3, 360, 3,180, 1J610 cm 1, EXAMI'L~ 5 (A) N2-(6,7-dimethoxy-2-naphthylsùlfonyl)-L-arginyl-N-phenetIIylglyci.lle:
N -nitro-N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-phenethylglycine b.enzyl ester was prepared by the procedure described ln Lxample 3, and has a melting point of 133-5 C.
To a SOlUtiOII of 3.00 g of NG-nitro-N -(6,7-dimethoxy-2-naphthylsl.llfonyl)-L-arginyl-N-pherIethylglycine benzyl ester in 50 ml of ethanol and 0.5 ml. Or aCetiC acid was added 0.5 g of` palladium-black and thcn the mixture was shakerI in ~ ~Iydrogen atmosphere for 100 hours at room tompetal~ o~ At tlIc on(I of this l)or:io~I, I;IIc ethanol ~.
50 Lll tion w.~s l`i.LI;orc(I to rcmove thc cata:Iyst and evaporate(i to dryness. The residue was washed several times with dry ctlIyl other and chromatograplled on 80 ml.
of ~aiai.on ~ ~K 102 ion exchange resi.n (200 - 300 mesh, H form, manufactured by M.i.tsu~)ishi Chemica]. Industrios 1~37~69 Limi. ted) pac1cc(l in water, waslled wi. th water, and elutecl wi th ~% ammoni um hyclrclxi(le solnltioll . rhe fraction clutcd l`rom 1~ nmnlonillm hy(lloxi(lc SO.llltiOII was evapo-rute(l I;o dryllcs:; to give 1..7l g (7()"~0) Or N -(6,7-dime thoxy-2 -naphthylsul fonyl ) -L-arginyl-N-phenethyl -glycille as all amorpllolls solicl I .R. (K}3r): 3, ~360, 3,200, 1, 590 cm 1 Alla:Lysj.s - Cal.cd. for C28ll35N507S (percellt) C, 57.42;
H, 6.02; N, 11.97 Fowld (percent): C, 57.09;
Il, 6.06; N, 11.7ll (A) N -( 6 ,7-dimetlloxy-2-naplltllylslll. follyl ) -L-1rgirlyl-N-(2-methoxyetllyl)glycyl chloride hydrochloride:
A suspensiorl of 2 .00 g of N -(6,7-dimethoxy-2-naphthyl-sulfonyl )-L-arginyl-N-(2-methoxyethyl )glycine in 20 ml of thionyl chloride was stirred for 2 hours at room temperature. A(iAition of co].d dry ethyl ether resulted in a precil)itnt;e which was collectecl ~)y fi.ltration and wasllc<l sevl?ru.L ti.mcs with clry ethyl cther to give N -( 6, 7 -dimethoxy-2-naphthylsulfoslyl )-L-argi n yl -N -( 2 -methoxyetllyl )glycyl clllori(lc hydroch:lo ride .
_ ~ _ 1~3'74~j9 n) N -(6,7-d:inIot,lloxy-2-~lal)IltllyIsul~oIlyI.)-L,-arginyl-N-(2-met}IoxyelI~y.L)g:I.yciJle m-tolyl ester IIycIrochlori(Ie:
A mixtIlre oL` 2.00 g of m-cresol and N -(6,7-dimettloxy-2-1la~ tllyls~l1f`ollyl)-L--arginyl-N-(2-nlotlloxyetllyl)glycyl chloride hydrochl.oride obtainecl above was heated at 90 C ror 50 min~Ites. ~t the en~t of this period, the reacl;ion n~i~tnrc was cool.ed, WaSlleCI several times with dry 0t;IIYl Cttlel', arId t:heIl clissolve-I i.n 1.0 ml o~ dry e l: lly~. 1 1 CO 110 1. Addi.tioll of` cold dry etIIy:I etIIcr resultcd in a precipitate which was washed several times with (lry ethyl ether to give 2.12 g (86 percent) of N -(6,7-dimetIloxy-2-naphttlylsulfonyl)-L-arginyl-N-(2~metIIoxyethyl)glyciTle m-tolyl ester hydrochloride in the form of a powcier.
I.R. (KBr): 3,250, 3,100, 1,740, 1,640 cm The f`ol.Lowi.ng compoI.mds are prepared in a similar manner:
N -(6,7-dimethoxy-2-naphthy1sulfonyl)-L-arginyl-N-(2-etllyltII.ioetlly~)g.Lycille phenyl ester N -(f~7-(l.imotIIoxy-2-l~ lltIly:Islllf`onyI)-~ rg,:iTlyI-N-(2-oI:IIy.II;Il:iootIlyI)~,lyc:ille benzyl est,or N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-ben~yl.g.lycine pIIenyl. ester - 85 ~
li3~4~9 N ~-( G, 7-(l i nle tllc)xy-2-na~)ll I; llyl~;ul t`olly~ I.,-arginyl-N-r,l ~ r~ I yci ]I ~ zy l o~
, N -( ( J 7 -/I ~ Y-- --I 1~ Y ~ I OII Y I ) -I--;I L ~ Y I--N--totrally(llol`-lrl:`ury.l.~rl.yc.ille pllellyl. oYter ,, l~lenyl l- (N -(7-metlly:L-2-llapl~LIIylsulrorlyl )-L-arginylJ---otllyl-2-pi.l)e~ illecarhoxylal:e 13ellzyl 1- [N -(7-metllyl-2-rlaphtllyls;lllronyl)-L-arginyl~--Il-e thyl-2-pi~eri(liillecarboxylate Benæyl 1- ¦N -(~-CII1OrO-2--l1aPI1thYLSU1rOrIY1 )-L--argiIIY1~--Il--nnethyl-2-piperi(linec~rboxyl.~Ltc 1~ thyl ~ N - ( 7 -mo t llyl -2 -llaph t llyl slll L`ollyl ) -L-arbrinyl mo rpllo lille -3 -c arl~o ~cyla t e Varioll~ otller N -arylYul f`otlyl-I,-arg:irlillllnli~les or s.ll Is tlloreol` wero sylltllcsi.æe-l in accorclallce witll tlle proco~lllre oL` tlle al)ovo exanlpl.es, all(l tlle l;est re~lllts are ~ulllnlari~e(l in Tal).lo .L.
~ 86 --1:~3'~i9 _ ___ L
r _ O O O O O .~ O O ~1 C ~ O O O O O r- O O O O
E o ~o ~ a, t r~ _ . - c ~--r~ r~ r~ o cr~ r- ~ r~ ~ 0 r~
a _ t~ ~ ~r~ ~ _ r~ r~ _ ~ _ r~ ~ r~ ~ ~, _ _ <~ ~_o~ ~ ~ co _- ~0 r~ ~1 _s o~ O ~o . -- ;~. r~ro :~1 c~ O o~ O ~o O _ O cO r~ v~
, .~ ~_ ~_ _ _ r~ ~1 _ ~ r r~ _ O N rl .S ~ ~_ .. . . ~ ::1 C IA Ir~ O ~ 1~ 1~
_ . . ._ _ __ _ _ O ' O I ~ V I ~ ~E `O '~0 1~ `O `O `O
E o O _ r O ,~ O .~ X ~o r~ r~ o~ ~ r~ c I ~ I NN N r~ r N N r r N N t t . ~-- rL~ ~O L ~ ~ L, . r L~ O r 3 7 O : :
,.
r c, i~. _ _ _~ _~ _~ _~ _~
L _. , _ r .7 ~ .~ ,. ~ _ r~
~o $o _~cr, O N u~
, 1 . or or o ~ E l ~ l S l ~ l . ~ _ l .
.
L r r~ r~
~a o or~r~ L~ r~ T ~ r~ ~ T ~ t~
O L~ 3:N r~N Nr~ Nr~ N Lj L~ ~ Lj L)-- t N
E~ N ~N ON L~ N ~ _ O N N N N r N
O N O :1: L O V _ L~ :~: r L~ C~ _ L~
L, \ / \ / \ / \ / \ / \ / \./
Ul _ f ~. ~, l l ~ ~
r L ~ ~
,.
4~j~
~ ~ r-~ _, 0 GO t'~ t O O N O O 0 0 r~ 0 t~--I t~ t~ O O O t~ O t r~ _ ~ ~;; t~ t'~; t'~ ;; ~; t'~; t'~ t~;; t'~ t~ -~ t'~ t'~ _l __ I _ ____ . ...
. _ " ~. _ _ rl rl t~ ~O O _~ 7 t~ N N N N
t~ ___ I .__ _ __ :~ ,r~ rl ,~ rl t~ rl t~ _, ~ t t~ O O~ -~
~O t~ t~ t~ I~ t~ I~ t~ \O ~O _t --t E ~o t, __ ~0 -t r~ tJ~ (~ ~ _ ~to ~l :1 t~ ~ ;O
o 1~ ~ Ir u~ 7 -t O O ¦ u~ ~ ~ t~ t~
. ~ l t rl O ~ n _~ 4 O~ 4 t~ 4 ~ _~ _~ ~ -- __ a o 00~0_3 _ ' .~ ~ ~ C ~. J U~
o~.4'-~, _ O C: r _ ~ N r _ t~ r~ t o t~ N N t~
E :t: 3: r N _N E~ t.) r ~N t~ ~N O ~ r N
~D _ f , f ~ ~ Z ~
h :1 _ ._ E ~, 0 O _ N t.~ ~l 1~374~i9 ~ u ~0C~ ~500~
_ __ __ ~ ~; _ ~o Ir 7 0 J O Ir, rl ,r~ 0 ~o ~ ~7 ~
,. ~ ~. _ ~ _ _ ~1 _ O I rl _ rl N
~ ~ ,~ _- 'D r ~r .7 ~ 1~ r~ rl \0 u~ 7 L r _ ~O O ~O O ~O O O 1~ ~O ~O O ~O ~O ~O
_ , . O N O r. O ~1 _7 ~1 O r~ ~0 .7 0~ u~
1.1 G ~ 1.1 U 'r irA N ~I N lNA --A~ ~\ ~ U~ A
E -- : : : : ~ :
n^
.. ~o r~ ~ _~ _~ _~ _~ _l C~ o~ ' C
d 7 ~ ~ O. L ,~ Ir ~
~ o E o-- N N ~ 7 ~~LO-'-O l ~ I
. _ _ ~
O O ~ r ,,~ _ r/ r O C r ~:
~,rl i 0: rl N C N N ~N N ~N -r ~N oN N N
O ~N ~N N N N rl N N ~N N N N T C
:~ \/ \/ \/ \/ \/ \/ \/
S_Y _ =r~r~ ~ l ~ Z ~. ~. ' L~ ~ _ ; ~ ~
~ 89 --4~9 ~ ~ A _~ O C~ O I O ~`I C~ O C~ C~ ~ O O ~ ~_~
ts _ r~t~ l ~; (~t~; r~; t~; ~t~.l t~; ., . 7. t N CO t . O o~ -- ~N ---- _t ~
_ v ~; _ _, O I N _ _ ___ _l _ N ~1 O O
~' C :~ . . -' O I - .1~ .t O 0. t` O tJ~ ~O. ~ 0 ~0 1~ t~ ~O ~O ~ ~ ~O ~ t` t` ~O ~O ~O `V' C . .. _ ._ Cl0. 3 ~ t~ t` N t'~ t N ~o Ul t~ t~ t7~ t` t~ OL ~ .~ N N _t ~t ~ t N N N N N N
~IJ - ~ _ ~ ~0 ~ _ ,0~ _ .
Q _~ ~ t --~ --I --' --I
~vC~ .__ 8 2 c ~- z . . . . __ _ __ _ N ~
a 0^ ;8 ~ ~ O~ ~ o . _ ._ _ L ~ t~ ~
tS oN _ ~ ~ ~ C'~ ~ t _ _~ t~ o t~ ~ ~ _ _ t~ _ 0~ o :~N I =:~: _N N N N t N t^. N TN oN N N
~ N ~ ~ ~ / \ ~ \
1-:~ _ g~_~ :~: ~: ~j. ~ ~,D~, :;, ~374~i~
_ ,.
~^ ooo ool~o oo~l oooo oo~ ootOto ooo
like, aralkyl of 7-15 (preferably 7-10) carbon atoms, such as benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 6-phenylhexyl, l-phenylethyl, 2 phenylpropyl or the like, -carboxyaralkyl of 8-15 li~'7~C~
(preferably 8-12) carbon atoms, such as ~ -carboxybenzyl, ~ -carboxyphenethyl or the like, C3-C10 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohept~
cyclooctyl, cyclononyl or cyclodecyl, C4-C10 cycloalkylalkyl, S such as cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl 2-cyclohexylethyl, cyclooctylmethyl or the like, furfuryl, tetrahydrofurfuryl, optiorally substituted with at least one Cl-C5 alkyl and/or Cl-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-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, 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 n is an interger of 1, 2 or 3, ~R3 (2) - N wherein R3 is selected from the ICH (CH2)mcOoR5 group consisting of hydrogen, Cl-C10 alkyl, such as methyl, ethyl, propyl, butyl, isobutyl, pentyl, hexyl, octyl, decyl or the like, alkenyl of 3-10 (preferably 3-6) carbon atoms, such as allyl, 2-butenyl, 3-butenyl, 2-pentenyl or the like, alkynyl of 3-10 (preferably 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 ~137~
methoxymcthyl1el,lloxymcthyl, I)ropoxymetllyl., 2-methoxyethyl, 2-et;lloxyetlly] ~ 2-1)rol)oxyetl~yl~ 2-methoxypropyl, 3-methoxy-proL)yl~ 3-etlloxyl)lollyl., 3-propoxypropy~ -methoxyl)lltyl~
4-etlloxyblltyl, ~-hlltoxybutyl, 5-butoxypel-1tyl or the like, alkylthioalliyl oL` 2-:1~ (preferably 2-6) carboll atoms, such ~s methyltllio~ ly:l~ e~hylthiomethyl~ prol)ylthionletllyl, 2-methylt~ioetllyl, 2-ethyltllioethyl, 2-propylthioethyl, 3-metllyltlLioprol)yl, 2-methylthiopropyl, 3-etllylthiopropyl, 3-proF)ylthiopl-opyl, Il-mctllyltlliob~lty], I~-ethy]thiob-ltyl, 4-butylthiobutyl, 5-butylthiopentyl or the like, alkyl-sulfinylalkyl of 2-10 (preferably 2-6) carbon atoms, such as methylsulfirlylnnethyl, ethylsulfinylmethyl, propyl-sulfinylmethyl$,2-methylsulfinylethyl, 2-etllylsulfinylethyl, 2-propylsulfinyletllyl, 3-methylsulfinylpropyl, 3-ethyl-sulfinylpropyl or the like, hydroxyalkyl of 1-10 (preferably 1-6) carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropy], 2-1ly~roxypropyl, 4-hy(lroxyl)lltyl, 3-lly(lroxyl-lll;yl, r~-llydroxypclltyl or tllC l~ c, carl)oxyalliyl of 2-1~ (I)rel`cr;ll)ly .>-7) c.lrl)oll atom~, s~lcll 1~ C;l.l'bOXylll('t1l 2-c1rboxyctllyl~ 2-(:1rl)oxyl)rol)y]~ 3-c1rl)oxyp]~ol)y1~ 1-carl~oxyl)lltyl~ '-carl)oxyl)utyl~ 11-carboxyl)lltyl or tllc like, a.ll;oxycarl)o~lylalky,l ol` '3-:1() (})rcf`cral)ly '3-~3) C1r-)011 atoms, such as mett~oxycarl)olly.lmetlly.l, 2-metlloxyc1rl~ollyletllyl~ 2-ethoxycarbollylprol~yl, 3-mettloxycarbol~yll)rol)yl~ l-metlloxy-Cl ~`I)OIl y I l)ll l.y 1, >--(` tIIOXYC1I`I)OIIY J 1)ll l, y l, 11--lll(` tll() XyC1 r~l)olly.l1)1ltyI
I ~) _ li;~t~ 9 or the like, alkylcarbonylalkyl of 3-10 carbon atoms, such as methylcarbonylethyl or the like, haloalkyl of 1-10 (preferably 1-5) carbon atoms such as chloromethyl, 2-chloroethyl, 2-bromoethy 2-chloropropyl, 3-chloropropyl, 2-chlorobutyl, 4-chlorobutyl or the like, aralkyl of 7-15 (preferably 7-10) carbon atoms, such as benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 6-phenylhexy~
l-phenylethyl, 2-phenylpropyl or the like, G~ -carboxyaralkyl of 8-15 ~preferably 8-12) carbon atoms, such as G~ -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 Cl-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-2-thenyl 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 of alkyl of 1-10 (preferably l-S) 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 atom~
such as benzyl phenethyl or the like, and ring substituted benzyl wherein said substituent is alkyl of 1-5 (preferably 1-3) carbon atoms, such as methyl, ethyl, propyl or isopropyl, or 1:~3'7~ 3 alkoxy of 1-5 (preferably 1-3) carbon atoms, such as methoxy, ethoxy, propoxy or isopropoxy; R5 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 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 ~t~6 integer of 0, 1 or 2, (3) -N ~ wherein R6 is -COOR8 (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 or 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 substitutecl at the 2, 3, 4, 5 or 6-position, COOR ~
(4) - ~ ¦ which is optionally substituted with at ~ CH2 rr least one Cl-C5 alkyl and/or Cl-C5 alkoxy, wherein Rg is selected from the group 11~'74~i,9 collsisting of lly(lrogcll~ C~-C10 alkyl, sucl~ as methyl, ethyl, propyl, bllt;yl~ ~ert~ ttyl~ hexyl~ octyl, decyl or the lilce, C~~C10 uryl, SIICII as phellyl ~ m-tolyl, naplltllyl. or the like, arulky:L of` 7-L2 (prcf`crab:l.y 7-10) carboll UtomS~ sllch as bellzyl, phenetllyl or the like, and 5-indanyl; ~n(i r is all integer of 1, 2, 3 or ll, coor~ O
~ .
(5) -N ~ wllcre:irl Rlo is selected from Ihe group ~C112)(1 consisting of hydrogell, 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-indarlyl; Z is selected from the group consisting of oxy (-O-), thio (-S-) and sulfinyl (-SO-); q is an integer of O or 1, and C~
~(CII2) ~ whereill ~ll is selectcd ~rom the grollp COllsi.Stil)g Or lly(lro~cll, cl-clO al];yl, sucll us metllyl, ethyl, I)rol)yl, blltyl, telt-l?~ltyl, llcxyl., octyl, decyl ~r tlle like, C6-C10 aryl, SllCh aS phellyl, m-tolyl, naplltllyl or the like, aralkyl of 7-12 (preferably 7-10) carbon atoms, such as berlzyl, ~tlelle~tlyl or the like, arl(l 5-irld.lllyl.; i is an ~ 13 -integer of 0, l or 2; j is an integer of 0, 1 or 2; and the sum of i-tj is an integer of 1 or 2; an~ Ar is seleeted from the group eonsisting o~ naphthyl, sueh as l-naphth~l and 2-naphthyl, 5,6,7,8-tetrahydronaphthyl, optionally su~stituted with at least one Cl-C5 alkyl and/or Cl-C5 alkoxy ~uch as 5,6,7,8-tetrahyclro-l-naphthyl and 5,6,7,8-tetrahydro-2-llaphthy1, naplltllyl substituted Wittl at least one substituent selectetl fronl the grollp eonsisting of ha:lo, such as fluoro, chloro, ~)romo arl(l iodo, ni-tro, cyano, hydroxy, allcyl of 1-10 (preferabl.y 1.-5) carbon atoms, SUCIl as methyl, ethyl, propyl, isopropyl, butyl, isobu-tyl or the lilce, alkoxy of l-lO (preferably 1-5) earbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy or the lilce~ and dialkylamino of 2-20 (preferably 2-lO) carbc)ll atoms, such as dimethylamillo, dietllylamino, N-methyl-N-ethylamino or the ].i]ce, phenyl, phenyl substituted ~ith at least one substituent seleeted from the group eon-SiSting Or halo, sueh as fluoro, ehloro, bromo and iodo, nitro, eyano, hyclroxy, alkyl o.f l-10 (preferably 1-5) carbon atoms, such as methy:l., ethyl, propyl, isopropy]., butyl, isol)llty.L or th(3 lilcc3, allcoxy of 1-1.0 (preferal)ly 1-5) carbon atoms, such as methoxy, ethoxy,propoxy, isopropoxy, butoxy, see-butoxy, tert-butoxy, pentyloxy or the lilce, and dialkylamino of 2-20 (preferably 2-10) earbon atoms, sueh as dimethylamino, cliethylamino, N-methyl-N-ethylamino or the like, aralkyl of 7-12 (preferably 7-lO) earbon atoms, 1`~3~J~g such as bcnzyl, phenethyl or the like, and ~ ) , ~ ' ~0~
~ ~ ~ and ~ } R12 which are optionally substitllted with at least one Cl-C5 alkyl and/o~ Cl-C5 alkoxy, wherein R12 is h~dToqen, 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, 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-methoxypropylJ 2-ethoxyethyl and 3-methoxypropyl, C2-C6 alkylthioalkyl, such as 2-ethylthioethyl and 2-methylthioethyl, C2-C6 alkylsulfinylalkyl, such a9 2-methylsulfinylethyl~
Cl-C6 hydroxyalkyl, such as 2-hydroxyethyl and 3-hydroxyb.utyl, C2-C7 carboxyalkyl, such as l-carboxybutyl, C3-C8 alkoxycarbonyl-alkyl, such as 2-ethoxycarbonylethyl~ C7-C10 aralkyl, such a9 betlzyl al(J pher~etllyl~ C8-C12 .~1 -ca:rboxyaralkyl, such as ~ -carboxyphenetllyl, C3-Cl~ cycloalky:L, SllCh as cyclopropyl, cyclohexyl and cycloheptyl, Cl-C10 cycl.oalky~allcyl, such as cyclohexylmetlly:l, t`lm ruryl, tetrallydrorurrllryl~ 3-furylmethyl, tetrahydro-3-fulylmetllyl~ 2--thenyl, 3-thenyl, tetrahydro-2-tllollyl all(l tetrallyclro-3-thenyl.
~uitabl.e i.Llustrlt;iorls of R3 in the above I`ormula (I) are hy(lrogerl, Cl-CI() allyl.~ sucll as methyl, propyl, butyl, isobutyl, pentyl, iloxyl and oc-tyl., C3-C6 al]cenyl, such as allyl~ C3-C6 allcynyl, sueh as 2-propynyl, C2-C6 allcoxyalkyl, such as 2-methoxyetllyl~ 2-methoxypropyl, 2-ethoxyethyl dlld 3-methoxypropyl, C2-C6 alkylthioalkyl, sucll as 2-ethylthio-ethyl and 2-metllylthioethyl, C2-C6 allcylsulfinylalkyl, such as 2-methylsulfinylethyl~ Cl-C6 hydroxyal]{yl, sucll as 2-hydroxyethyl and 3-hydroxybutyl, C2-C7 carboxyalkyl, such as l-earboxyblltyl, C3-C8 alkoxycarbonylallcyl, such as 2-ethoxycarL)onylctllyl, C7-C10 arallcyl, sucll as l)ellzyl alld l)llell~tllyl~ C8-C12 ~ -carboxy~ra]ky~, sllcll as ~ -carl)oxy-pholletllyl, C3-CI~ cyc:loa~l;yl, sucll as cyc]o~ o~yl, cyclohexyl all(l cycloll(!l~lyl, (Il-Cl~ cye.loa.LI;ylallcy:l, sllcll as cyclolloxyl-metllyl, f`urf`uryl, tetrahy(lrofurt'uryl, 3-l'urylmetllyl, tetrahy(lro-3--rllrylm(3tllyl, 2--thetlyl, 3-thc!llyl, tetrahydro-2--thellyl an(l tetrully(lro-3-thenyl.
~ui-table il:LIlstratiolls Or ~1l in the above fornlula (I) are C1-C5 allyl, sllch as metllyl and propyl, e.lrl)oxy, C2-C5 ti9 alkoxycarbonyl, such as ethoxycarbonyl~ C7-C10 aralkyl, such as benzyl, and ring substituted benzyl wherein said substituent is Cl-C3 alkoxy, ~uch a~ 4-methoxybenzyl.
Suitable illu~trations of R7 are hydrogen, Cl-C6 alkyl, such as methyl, ethyl, propyl and isopropyl, phenyl and carboxy, and the suitable position of R7 is ~J 4 or 6.
COOH
)~ , Suitable -N Z groups are 3-carboxy-4-morpholino, \-(CH2)/
3-carboxy-4-thiomorpholino~ 1-oxo-3-carboxy-4-thiomorpholino and 4-earboxy-3-thiazolidinyl.
COOH
Suitable -N ~ ~ groups are 2-carboxy-1~2~3~4-tetrahydro-l-quinolyl, 3-earboxy-1,2,3,4-tetrallydro-2-isoquinolyl, l-carboxy-1,2,3,4-tetrahydro-2-isoquinolyl, 2~earboxy-1-indolinyl and 1-earboxy-2-isoindolinyl.
Suitable illustrations of R2, R5, R8, Rg, Rlo and Rll are hydrogen, Cl-C10 alkyl, sueh as methyl~ ethyl, tert-butyl and oetyl, C6-C10 aryl, such as phenyl and m-tolyl, C7-ClO
aralkyl, such as benzyl, and 5-indanyl.
Sui~able illustrations o~ Ar in th~ above formula (I) are naphthyl, such as l-naph-thyl and 2-naphthyl~ 5,6,7,8-tetrahydronaphthyl, such as 5,6,7,8-tetrahydro-1-naphthyl and s,6,7,8-tetrahydro-2-naphthyl, naphthyl substituted with at least one substituent selected 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 methoxy and ethoxy, and C2-C10 dialkylamino, such as dimethylamino and diethylamino, phenyl, phenyl substituted with at least one substituent selected from the ~roup consisting of halo, such as chloro, Cl-C5 alkyl, such as methyl, ethyl and isopropyl and Cl-C5 alkoxy, such as methoxy, C7-C10 aralkyl, such as phenethyl, ~ ) such 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-naphthyl, 5-chloro-l-naphthyl, 6-chloro-2-naphthyl, 6-bromo-1-naphthyl, 5-hydroxy-1-naphthyl, 7-hydroxy-2-naphthyl, 6-methyl-2-naphthyl, 6-methyl-1-naphthyl, 7-methyl-1-naphthyl, 7-methyl-2-naphthyl, 6-ethyl-2-naphthyl, 6,7-dimethyl-1-naphthyl, ~ 18 -1~3~ i9 f"7-dimetllyl-2-l-al)lltllyl, 6-isopropy:L--2-llaphtllyl, 5--methoxy-.I-naphthyl ~ fi-mc tlloxy-2-napllthy.l, 7-methoxy-2-rlclplltltyl ~ ' ,6-dimetlloxy-2-1laE~ hyJ, 6,7-dimetlloxy-2--1aplltllyl, G,7-(lictlloxy-2-rlclplltl~yl, 5-di.mctlly~anurlo-1-llal)lltllyl~ 5-dimethylamillo-2-rlapllthyl~ 5-diethylamino-1-naptlthyl, 6-dimettlyla~ illo-L-Ilal~ tllyl, 6-climethylami.llo-Z-naptlt}ly.L ~
chlorol)hcllyl., 2,1~,5-trichlorophenyl~p-to1y], anisyl, 3,4-dimettloxyllhelly~, 3,/~,5-trimetl-loxypllerlyl, ~
~ ) and (~3 Illustrative of suitable N -arylsulforlyl-L-argininamides of sufficient activity are the fol.lowing:
NZ-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-propylglycirle N -(fi,7-~limctllo~y-2-1laplltlly1sll]follyl)-~,-argi~lyl-N-propylglycille t;crt-blltyl cster N --(fi,7-~ tllo~y--,"--ll<ll>lltlly:L~ rolly~ rillyl--N--hllty:lg1ycille N -(6,7-dinletlloxy-2-lla~ LIlylsulronyl)-L-argillyl-N~
bllty:lg]ycillc tert-l~lltyl ester _ 19 _ ~3'7~69 N -(6,7-(linletl~c)xy~ aplltllyls-l:Lrorlyl)-l,-<ltgillyl.-N-i obutyl~,lycillc N -(6,7-(limcttloxy-2-tlap}lthy:Lsulfollyl)-L-artri.nyl-N-pentylglycine N -(6,7-~1i.mcthoxy-2-llaplltllylsulfollyl)-L-argirlyl-N-hexy]gly CillC
N -(6,7-dimetlloxy-2-llaphthy:Lsulfonyl)-L-argirlyl-N-o c ~:yl~lycill c N -(4,6-~imetlloxy-2-naphthylsulfonyl)-I,-arginyl-N-butylg]ycinc N -(6,7-~lietlloxy-2-rlaphtllylsulfonyl)-L-argillyl-N-buty]glycille N -(6-methoxy-2-llapllthylsulfonyl)-L-arginyl-N-butylglycine N2-(5-methoxy-1-naphthylsulfonyl)-L-arginyl-N-butylglycine N -(7-methoxy-2-naph-thylsulfonyl)-L-argillyl-N-propylglycine N -(7-methoxy-2-naphtllylsulfollyl)-L-argirlyl-N-butylglycine N -(7-methoxy-2-llaplltllylSulfollyl)-L-argillyl-N-pentylglycine N -(2-naphthylsulfollyl)-L-arginyl-N-butylglycine N -(Z-nal)lltllyl~ ronyl)-l,-argillyl-N-b~ltylglycine ethyl cster ~() _ 1~3'~9 N -(2-naphthylsulfony].)-L-arginyl-N-butylglycine ben~yl ester N -(2-naphthylsulfonyl)-L-arginyl-N-butyl-~ ~alanine N -(5,6,7,8-tetrahydro-1-naphthylsulfonyl)-L-arginyl-N-butylglycine N -(5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl-N-pentylglycine N -(5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl-N-butyl-~ -alanine N -t6-bromo-1-naphthylsulfonyl)-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-propynyl)glycine N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arglnyl-N-(2-methoxyethyl)glycine 1~37~69 N --( (), 7--( l i ~ ( ) Y y ~ y l ~ O J ~ f, i l l y ~--N--IIIC l,llO~y(~t:llyl )~, I )'(`.i 11'~! (?tllyl C~ l,C:I`
N ((-,7--~ ncl.lloxy-.'-lla7)lllllyl~ill1 fo]lyl )--1,--a~gil-ly~--N-(2-mctlloxyetllyl )~1 yc.irle o ctyl es ter N -(6,7-(1inlcl llox:y-2-1lal)lltllylsulron~ -arginyl-N-(2-mel;lloxyetlly:L)glycirle t)cn~yl ester N -(6,7-d:i mel;llo,Yy-;'-ll~lL)ILl;hylsu:l rOIly~ )-I,-a~gillyl.-N-(2-mctl~oxycl;llyl)gLyc:ille '3-methy:lpllellyl e.ster N -(6, 7-(lime thoxy-2-l1aplltllylsul ronyl ) -I,-arginyl-N--(2-methoxyetllyl)glyc~ e 5-indanyl ester N --(G ,7-dimethoxy-2-1laphtl-lylsulfonyl )-L,-arginyl-N-(2-methoxyetllyl)-~,--alanine ~:
N -(6~7-dimetho:;y-2-naplltllylsul ronyl )-L-arginyl-N-(2-metlloxyel,l~yl)- ~, -alulli.ne etllyl estel N --(G,7--d.illlcl,llo.Y~ tllyls~ `olly.l )--N-(2--nlctlloxyctlly:l )--N--('~--c~rl~oxyl~rol~yl )--l,--arg:i7l:ill.lm.i.(lc N --(G,7--(limclLIoxy--;'--n~ l;llylsllll`olly1.)--N--( '-metlloxyc?tllyl)--N -( '3-terl~ tOXyc;ll l~ony:l pro~yl ) -L-arp;.i ll:i llanli(le N -(6,7-dimctlloxy-,-rla~ tllylslllrollyl)-N-(3-nlel:lloxy-2() prol~yl )g,l yc:i ue 1~37~
N -(6,7-~lirnethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-ethoxyethyl)-~ -alanine N -(6,7-dimethoxy-2-naphthylsul~onyl)-L-arginyl-N-(2-methoxypropyl)glycine N2-(6~7-diethoxy-2-naphthylsul~onyl)-L-arginyl-N-(2-methoxyethyl)glycine N2-(4,6-dimethoxy-2-naphthylsul~onyl)-L-arginyl-N-(2-methoxyethyl)glycine N -(4,6-dimethoxy-2-naphthylsulfonyl)-L-argillyl-N-(2-methoxyethyl)glycine ethyl e~ter N -(6-methoxy-2-naphthyl9ul~onyl)-L-arginyl-N-(2-methoxyethyl)glycine N -(5-methoxy-1-naphthylsul~onyl)-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 N -(5-methoxy-1-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)-~ -alanine tii9 N ~ naphthylslllfonyl)-L-arginyl-N-(2-methoxyethyl)glycine N -(5,6,7,8-tetrahydro-1-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine N -(5-chloro-1-naphthylsulfonyl)-L-arginyl-N-(2-methoxy-ethyl)glycine N -(6-chloro-2-naphthyl~ulfonyl)-L-arginyl-N-(2-methoxy-ethy~)glycine N -(7-methyl-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxy-ethyl)glycine N -(7-methyl-1-naphthylsulfonyl)-L-arginyl-~-methoxy-ethyl)glycine N -(6,7-dimethyl-1-naphthylsulfonyl)-L-arginyl-N- (2-methoxyethyl)glycine N -(5-dimethylamino-1-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine N -(7-hydroxy-2-naphthylsulfonyl)-L-arginyl-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 -- 24 _ {j9 N -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methylsulfinylethyl)glycine N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-hydroxyethyl)glycine N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(3-hydroxybutyl)glycine N -(6,7-dimethoxy-2-naphthyl~ulfonyl)-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-naphthylsulfonyl)-L-arginyl-N-benzylglycine tert-butyl ester N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-phenethylglycine N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-benzyl-~ -alanine N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-benzyl- ~ -alanine tert-butyl ester - 2~ -113~ 9 N -(f~7~ metlloxy-2-lla~lt~lyls~ `orlyl)-L-~r~i.nyl-N-pllCll~tlly~ lllillC
N _(11 ,f)-~lin~ctlloyy-2-~ ltlly~ o~ly~ r~i.llyl-N
benzylg],ycine N -(7-methoxy-2-J-Ia~ tl-lylsulronyl)-L-argirlyl-N-phenetlly:l glycinc N -(7-metl~oYy-2-llar)ll~llylsu].forlyl)-L-arginyl-N-l~ellzy].-~ -alani.ne N -(6-mctl-loxy-2-naplltllylsulronyl.)-N-ben~yl-N-(3-c rboxypropy].)-l,-argininamicle N -(6-methoxy-2-rlapllthylsulfonyl)-N-benzyl-N-(3-tert-butoxycarbonylpropy].)-l,-argininamide N -(5-methoxy-1-naplltllylsulforlyl)-L-argillyl.-N-benzylglycine N -(2-naphtllylslllronyl)-L-arginyl-N-benzyl-~ -a]anine N -(2-nap~ y.ls~l.lt`oJIy.l.)-L-arc,illy].-N-l)cll~ylglycillc N -(5,6,7,8-tetrahydro-1-naphthylsulfonyl)-L-arginyl-N-phenethylglycille N -(5,6,7,8-tetrahyclro-2-naphthylsulfollyl)-L-argillyl.-N-benzylglyci.rlc li;~'7'~9 N -(5~GJ7~-tCtraIIY(IrO-2-rIaP}It1IY19U1~OIIY1)-L-arginY1-N
b (~Jl ~ Y~ Lrl i rl N -(7--mCtl~Y1--2~ PI~tIlY15I11fOnY1)--L-arg:ilIYI.-N-PIIenetlIY1 g I y Cill e N -( 6 ~7-di.methOXY-2-llal)I1thY1 SU1 fnIIY1 ) _L-LIrgj.rIY1-N-(~ -carhoxyphellethyl. )glycine N -(6 ,7-(1ime tl~oxy-2-naphthylsulfonyl )-I,-arginyl-N-cyclohexylmet}lylglycine N --(6,7--dimethoxy-2--napllthylsulfonyl)--L--argi.nyl--N-cyclohexylmetllylglycille tert-butyl es ter N -(6~7-dimethOXY-2-naPhthY15U1fOnY1)-L-arginY1-N-cycloheptylglycille N -( 4, G-di methoxy-2-napht}lylslll fonyl ) -L-arginyl -N-cyc ] o hoxyl ~.1 y C:i ll e N -(7-met}IOXY-2-11aPIItIIY15U1rOrIY1 )-L-argirIY] -N-CYC1OheXY1-f~ yc~
N --((;--mel.lloxy--~-nu~ l,lly~ .LJ`ollyl )--L--urt,illyl--N--cyclollexyL--motllylglycillo N --( r~--nlelNIOI;Y--I--II;~ .IIYI .`;111 I`OIIY I )--I,--;.11~g.j.11Y I--N--CYC.I OlleXYI.
~ ~374f~9 N -(5-metlloxy-l-nclplltllylsulf`ollyl)-I,-arginy:L-N-cyclohexyllllell~yL-¦~ -a.~allirle tert-L~utyl ester N -(fi~7-d.i.nl(?tlloxy-.~ al)lltllylsul.l`ollyl)-l,-.lr~illy:l-N-cyclo}l~xylgl.ycil-~
N -(6,7-(1illletl~oxy~2-1lapllthyl.sulfonyl)-l,-argi.llyl-N-cyclo}lexy.L-~ -a.lall:i.rle N -(6,7-dimetllo~y-2--lap]lthylslllfonyl)-L-argillyl-N-cyclohexyl-~ -ala~ e tert-butyl ester N-cyclopropyl-N-(3-carboxypropyl)-N -(6,7-cl;.methoxy-2-naphthyl.sulf`onyl)-L-argininamide N -(l-naphthylslllfollyl)-L-arginyl-N-cyclohexylglycine N -(5,6,7,8-tetrahydro-1-naphthylsulronyl)-L-arginyl-N-cyclohexylg:Lycine N -(5,6,7~8-tctrallydro-2-naplltllylsulfonyl)-1,-arginyl-N-; 15 cyclohexyLmethylglycine N -(7-meLIIyl-'-~ llyl.Sulf`onyl)-L-argilly:l-N-cyc~ollexyl-mc t llyl gly c:irl c N -(7-methyl-2-1laphthylsulfonyl)-L-arginyl-N-furfurylglycine N -(7-methyl-2-naphthylsulfonyl)-L-arginyl-N-tetrahydro-furfurylglycine 1:~374f~9 N -(7-1ncl;]loxy-~ tltllylstllfollyl)-L-arginy].-N--furf`llrylglyc~
N -(7-metlloxy-'-na~ tl~ylsulfolly:l)-L-argilly:L-N-f rfurylglycille tert-l~utyl ester N -(7-metlloxy-2-llaplltllylsulfonyl)-L-argi]lyl-N-totrahydro~ rrllrylglycirlc N -(5-(~inl(3tl1ylal1l:il1o-l-llapllt~lylsulfonyl)-L-~r~i~lyl-N
tetrahydro ru r fll rylglycille N -(5-chloro-1-naphthylsulfonyl)-L-arginyl-N-tetrahydrofurfllrylglycine N -(l-naplltllylsul rOI-yl ) -L-arginyl-N-tetrally(lrofurfur g]ycine N -(6,7-dimethyl-1-naphthylsulforlyl)-L-arginyl-N-tetrallyclrofurfurylglycine N -(5,G,7,8-tetrally(lro-1-naplltllylsulfollyl.)-L-argillyl-N-tetrally(irorllrf`lll yl.gl ycitle N --(G ,7-d.i nlc~ ~11oxy-2-llu~ tlly~ su:ll`ollyl )--L--argillyl -N--tctr~ y(lrol`llr.l`-lrylg,I.yci.llc N -(6,7-dinlctllo~y-,'-1lal)lltlly]sull`o~lyl.)-L-al~ginyl.-N-l~ yl~ -llli 11(3 - 2~ -N -(G~7-(1:ime~lloxy-2-1laa~lltilylslllf`ol-lyl)~L,-arg~ yl--N--L~utylala~ e I ert;-hlltyl ester N --(6~7--~1imcl;lloxy-2--1lal)lltllylsu1.rolly].)~ ar~ yl--N--pelltyla].arline N --(6,7-~limethoxy-"-llaphtalylsul.fonyl)--L-argirlyl-N-bcrl~.yl alanine ,, N ~-( 6 ~7-di metlloxy-2-]nlr)llthylslllfonyl ) -L-arginy.l.-N-phene thyla.lallille N -( 6, 7-dimethoxy-2-1lapllthylsulf:`onyl ) -L-arginyl -N--cyclohexyla].alli]le N -(4 ,6-dimethoxy-2-naphthylsulfonyl )-L-arginyl-N-cycl ohexyl metllylal anine N -( 7-methoxy-2-naphthylsulfonyl )-L-arginyl-N-propylalanine N --(6,7--~limothoxy-2-1lclpllt}lylg-llrollyl)--1~--arginyl-~(2-metllo~y-ethyl )aLallinc N --(fi,7--(I~ lel.llo~y--.!-u;ll)lll llylsu~ ~`ony.l )--l,--al~gillyl.llorvalillc N -(6,7-~1i.motl~oxy-2-1laphthylsulfonyl.)-L-arginyl-N-butylaspartic acid N -(6,7-(limeLlloYy-2-llal)lltlly:LsulLfollyl)-L-nrgillyl-N-l~utylasp<lrtic uci.(l (liethyl ec~ ter - 3~ --g N -(6,7-dimethoxy-2-~lap}lthylsulfollyl)-l,-argillyl-N-b nzylaspart::ic acid N -(6,7-dimetlloxy-2-rlaptltllyl.slllf`ollyl)-L-arg.illyl-N-benzylaspartic acid dlethyl ester N -(6,7-di.methoxy-2-lla~lltllyls-ll.follyl)-L-argilly].-N-metlly:l-~ -plleny~ alanl]l (~
N -(6,7-dimetl-1oxy-2-napllthylsulfollyl)-L-arg:inyl-N-methyl--(4-metlloxyphenyl)alanine l-[N2-(6,7-dimethoxy-2-1laphthylsulfonyl)-L-arginyl~-2-piperidirlecarboxyli c acid Ethyl l-~N -(6,7-di.methoxy-2-rlapllthylSIllforlyl)-L-argirlyl~-2-pi~eridineearboxylate l-[N -(6-methoxy-2-naphthylsulfonyl)-L-arginyl~-2-piperidineearboxylie aeid l-[N -(6,7-dimethoxy-2-napllthylsulforlyl)-L-arginyl~
methyl-2-piperidineearboxylic aeid 1--tN --(7--mctlloxy--2--naplltllylslllfonyl )--I,-arginyl~--4--methyl-2--piperidineearboxylie aeid l-tN -(5-methoxy-1-naphthylsulfonyl)-L-argillyl~-4-methyl-2-pi~eri(lillec.lrl~oxy.lie aeid : .
1:~3';'~
Ethyl l-~N -(5-methoxy-1-naphthylsulfonyl)-L-arginyl~
methyl-2-piperidinecarboxylate l-~N -(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl~-4-methyl-2-piperidinecarboxylic acid l-~N -(6,7-diethoxy-2-naphthylsulfonyl)-L-arginyl~-4-methyl-2-piperidinecarboxylic acid l-tN2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl~ -4-ethyl-2-piperidinecarboxylic acid l-~N2-(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 l-tN -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl~-6-methyl-2-piperidinecarboxylic acid l-tN -(7-methoxy-2-naphthylsulfonyl)-L-arginyl~-2-methyl-2-piperidinecarboxylic acid l-[N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl~-3-piperidinecarboxylic acid Methyl l-~N -(6,7-dimethoxy-2-napllthylsulfonyl)-L-arginyl~ -3-piperidinecar~oxylate l-tN -(7-methoxy-2-naphthylsulfony:L)-L-arginyl~-3-piperidinecarboxylic acid l-[N -(7-methoxy-2-naphthylsulfonyl)-L-arginyl~-2, 6-piperidinedlcarboxylic acid l-tN2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl~-4-phenyl-2-piperidinecarboxylic acid l-~N2-(1-naphthylsulfonyl)-L-arginyl~-4-methyl-2-piperidinecarboxylic acid Ethyl l-~N -(l-naphthylsulfonyl)-L-arginyl~ -4-methyl-2-piperidinecarboxylate l-[N -(2-naphthylsul~onyl)-L-arginyl~-4-isopropyl-2-piperidinecarboxylic acid Ethyl l-[N2-(2-naphthylsulfonyl)-L-arginyl~-4-isOPropyl-2-piperidinecarboxylate l-[N -(5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl3-- 4-methyl-2-piperidinecarboxylic acid Ethyl l-[N -(5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl~-4-methyl-2-piperidinecarboxylate ~ 33 -~:~37~t~9 l-[N -(6-chloro-2-naphthylsulfonyl)-L-arginyl~-4-isopropyl-2-piperidinecarboxylic acid l-[N -(5-dimethylamino-1-naphthylsulfonyl)-L-arginyl~-2-piperidinecarboxylic acid l-[N -(7-methyl-2-naphthylsulfonyl)-L-arginyl~-4-methyl-2-piperidinecarboxylic acid l-~N -(7-methyl-2-naphthylsulfonyl)-L-arginyl~-4-ethyl-2-piperidinecarboxylic acid l-rN -(7-methyl-2-naphthylsulfonyl)-L-arginyl~-4-isopropyl-2-piperidinecarboxylic acid Ethyl l-[N -(7-methyl-2-naphthyl~ulfonyl)-L-arginyl~-4-isopropyl-2-piperidinecarboxylate l-[N2-(6-methyl-2-naphthylsulfonyl)-L-arginyl~-4-isopropyl-2-piperidinecarboxylic acid 1 - [N -(7-methyl-2-naphthylsulfonyl)-L-arginyl~-2-hexamethyleneiminecarboxylic acid 4~ CN - ( 7-methoxy-2-naphthylsulfonyl)-L-arginyl~-3-thiomorpholinecarboxylic acid 4-~N -(7-methoxy-2-naphthylsulfonyl)-L-arginyl~ -3-carboxythiomorpholine l-oxide 1-13~9 4-~N -(6,7-dimethoxy-2-naphthylSulfonyl)-L-arginyl~-3-morpholinecarboxylic aci~
4-[N -(7~methoxy-2-naphthylsulfonyl)-L-arginyl~-3-morpholinecarboxylic acid 3 - [N -(7-methoxy-2-naphthylsulfonyl)-L-arginyl~-4-thia olidinecarboxylic acid 2-rN -(6~7-dimethoxy-2-naphthylsulfonyl)-L-arginyl~-1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid 2-~N2-(6~7-dimethoxy-2-naphthylsulfonyl)-L-arginyl~
i oindoline-l-carboxylic acid N -(4-chlorophenylsulfonyl)-L-arginyl-N-butylglycine N -(2~4,5-trichlorophenylsulfonyl)-L-arginyl-N-butylglycine N2-tosyl-L-arginyl-N-butylglycine N -(4-methoxyphenylsulfonyl)-L-arginyl-N-benzylglycine N -( 3,4-dimethoxyphenylsulfonyl)-L-arginyl-N-(2-methoxyethyl) glycine N -(3,4,5-trimethoxyphenylSulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine N -phenethylsulfonyl-L-arginyl-N-furfurylglycine <~
N ~ -t)en~o-li oxall -G-sulfonyl)-L-argirlyl-N-(2-methoxyethyl) g] ycine N~--(f ,7--c~ y l e~e(li oxy--2--naplltlly:l sul rOlly:l )--I,--argi llyl -N--(2-mctlLoxyetllyl )gl ycine l-~N -(2-cl:ibell~c)r~lrarlyl)-L--arginyl~ -2-piperi c~inecarbo~Yylic ac:i(l Of ttle compoullcls c~r this invention, it ~ill be l~lclerstood that the fo.Llowirlg compounds are most preferred clue to their high level Or antittlrombotic activity ancl lo~ level of toxicity.
N -(6,7-climethoxy-2-naphthylsulfonyl)-L-arginyl-N-butyLglycine N2-(7-methoxy-2-napllthylsulrorlyl)-L-arginyl-N-butylglycine N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoYyetlly~)f,rlycirle N -(6,7-<limet}loYy-2-rlapllthylsulronyl)-L-argi,nyl-N-(2-methoxyethyl)glyci,rle ethyl ester N -(l~,G-~li,motlloxy-2-lllplltllylsu]follyl)-L-~rf~ yl-N
(2-metlloxyetllyl)f,rlycille N -(7-methoxy-2-napllthylsulfonyl)-L-arginy~-N-(2-methoxyetllyl )glycine 1:~37~9 N -(5tfi~7~-tc~r~lly(lro~ aph~llylsulrorly~ -arginy~-N
( 2-me t~loxye tllyl )e~ yci.le N -(7-metlloxy-2-]lcll)lltlly1.sll1rollyl)-l,-argirlyl-N-tetrallydro-furrurylglycillo N -(7-metIIY:L-2-~ )1It~Y1SII1rOIIY1)-L-argiIIY~-N-tetra}IYdrO-L`ur.rurylgl ycillc N -(6~7-(IinIetIIOXY-2-IIIPIIt}IY1SU1fOnY1)-L-argiIIY1-N-totra11y(1roI`Ilrr~lry.lgLycille 1-~N -(6,7-dimethoxy-2-naphthyls-llfoslyl)-L-arginyl~-4-methyl-2-piperidinecarboxylie acid 1- CN -( 7-metlloxy-2-llaphtllylsulrollyl)-L-argin methyl-2-piperidinecarboxylie acid l.-tN -(7-methoxy-2-naphthyl.sulfonyl)-L-arginyl~ -ethyl-2-piperidinecarl)oxyl.ic aeid 'I`he pllarm~collt:ica1:ly acceptal.)l.e sa.l.ts o:f the above compounds are of cours-? a:lso inelll(l(?d within t11e seope of this illV('lltiOII, As one skilled in the art ean readily appreeiate, tlle carbon atom of the N -arylsulfonyl-L-argininamides, to whicll the carl)oxyl. gro~ or tlle ester tl~oreo~` is attaehed call 1)e an asymmo1;ric carhosl atom allowi.llg ror the exi.stence i;~3~ i9 ol` t~ro o~ticnlly active isomers, the n- alld l,-diastereoisomers, as wcl 1. as l:he raccnlat(?, I)l,-mixture .
In accordallce ~i tll f'i.n(lings conccrnir-g tl~(! alltitllrombotic act;iv.i ty o r s.,cl, compoun(ls possessillg un asymltletl lc carborl atom, the compoullds of the present inventioll having the D-conrigllra t ioll ar c more active than thoS(! of the L--conl`ig~lral;ioll ull(l arc tho prer(!rrc(l compollll(ls, a]tllough the 1,- an(l I)l,-l'ornl.s of ~lle :instant compollll(ls ar(! also considerecl wi thill tll(? purview Or the present inverltiorl .
Thc above compourl(1s are intende(l only to illustrate the variety of structures which can be used in the process of this invention, an(l tlle above listing is not to be construed as limiting the :3cope of tlle invcntion.
}?or the preparatiorl of the compowlds Or thls invention, various methods can be employed depending UpOII the particu-lar starting materials and/or intermediates involved.
Successful preparal ion of theSe compounds is possible by way of` severa1 syllthetic routc!s which are outlilled below.
(a) Con(lensatiorl of' an L-ar~inirlami(lc witll an ary].su]follyl ~ 11-1 1 .i.ll(!
TlLiS pI'OCCSS mily bc! i,llus trated as fol~ ows:
C -- N -- Cll2C112C112 jcllcOOll (11 ) Il NH2 ~ 38 --IIN ~
~C --N -- C112C112C112Cl~COOll ( t;) R" IIN
~' I
R "' + RTI (IV) >
IIN
~C - N - Cll2c~l2cll2cllcoR (V) >
R" IIN
1~' 1 IIN ~
C -- N -- CH2cE~2cll2cHcoR ( VI ) + ArS02X ( VII ) ~N ~ :
~C -- N -- C}12C112Cll2cllcOR ( I ) I~NS2 Ar ~n Lllc abovc l`ornllllas ~ 1~ arl~l Ar are as ~lerino(l llcrein above; X is lla~ogen; R"~ is a protective group for :-the ~ -am:ino group, such as benzyloxycarbonyl or tert- ;
l~utoxycarbollyl; R~ and R" are selccted from tlle group con~istillfr Or llydrofren an(l protoctivo grollps ror thc gllatli(lill() grollp~ ~ucll as nitro, tosyl, trityl, 1~37~9 oxycarbollyi all(l the like; ancl at lcast one Or R~ and ~" is a protc-ctive group for the guanidlno group.
rhc N~-arylsulrotlyl-L-argillinamicle (I) is prepared by tllc con(lellsatiotl of an L-ar~inillami(le (VI) with a sul~stalltially eqllimo1ar amount of an ary1sulfony1 hali(lc (V:II), prcferably a ch10ride.
Tllc con(lcllsatioll reaction is genera]ly efrected in a suita~)l.e react:ioll-iJIert soLvent in the presence of an excess Or a ~ase, s~lch as an orgallic l~ase (triethyl-amine, pyridine) or a solution of an inorganic base (sodillm hydroxi(le, potassium carbonate), at a tempera-ture of` ~C to the boiling temperature of the solvent for a period of 10 minutes to 15 hours.
The preferred solvents for tlle condellsation include benzene-clietllyl ether, diethyl ether-water and dioxane-water.
~fter the reaction is complete, tlle rorme(l salt is extracted with water, and the so1vent is removed by such stanclard mealls as evaporation under redllcecl 2~ ~rossnro Io ~,ivc lllo N2-arylsu1L`ollyl-l-argillinamide (~.), wllicll call bo ~uriricll ~y trituratioll or recrystalli-ZtltiOII rrom a sllital~le solvellt~ sllcll as ~ie-thyl ether-tctr~llydrol`llrall~ di.otllyl ethor-mctllt~lol ancl water-lllCtllallO.l ~ OI' Illtly bo CllrOmtlLOgraplle(l Oll silica gcl.
I`l~o l-arci~illanu(los (Vl.) startirl~ nul~olia:Ls rcquirctl 1:~3~ 9 for the condensation reaction can be prepared by protecting the guanidino and ~ -amino group9 of L-arginine (II) via nitration, acetylation, formylation, phthaloylation, trifluoroacetylation, p-methoxy-benzyloxycarbonylation, benzoylation, benzyloxy-carbonylation, tert-butoxycarbonylation or tritylation and then condensing the formed NG-substituted-~2-substituted-L-arginine (m) with a corresponding amino acid derivative (IV) by such a conventional proceqs 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 NG-substituted-N -substituted-L-argininamide (V).
The amino acid derivatives (IV) which are the starting materialq for the preparation of the NG-substituted-N2-9ubstituted-L-argininamide9 (V) are represented by the following formulas:
H-N~ 1 ( vm ) H-N~ 3 (IX) (CH2)nCR2 1 ('CH2)mCR5 I COORg R7 (X) ~ (XI) ~3~i9 COORlo COORll CH~ (XII) \ (CH2)~ ~ ( xm ) In the above ~ormulas, Rl, R2, R3, R4, R5, R6, R7, Rg, Rlo, Rll, Z, n, m, r, q, i, and ~ are as defined 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-halobutyrate with an appropriate amine having the formula RlNH2 or R3NH2. (See, J. Org. Chem., 2~ 728-732 (1960)).
The condensation reaction is generally carried out without a solvent or in a Solvent, such a~ benzene or ether, in the presence of an organic base, such as triethylamine or pyridine, at a temperature of O C to 80C for a period of 10 minutes to 20 hours. A~ter the reaction iB complete, the formed amino acid derivative is separated by such conventional mean~ as extraction with a suitable solvent or evaporation of the reaction solvent and thereafter purified by distillation under reduced pressure.
Among the amino acid derivative~ amino acid tert-butyl ester derivatives are preferred, because they are easily converted to other ester derivatives by acidolysis in 1:~374~
the presence of` a corresponding alcohol employing an inorganic acid (HCl, H2S04, etc.) or an organi~ acid (toluenesulfonic acid, trifluoroacetic acid, etc.).
In accordance with the proce9s employed for preparing ~ 2-piperidinecarboxylic acid derivatives (X), the following scheme is illustrative:
NaOCl ~ R KOH~ ~ R7 _HCN>
H Cl (XIV) (XV) (XVI) R7 H20 > ~ R7 N CN (H~) N C02H
H
(XVII) (xvm) In the firat reaction of the aforementioned scheme, an appropriately substituted piperidine (XIV) is contacted with an aqueous sodium hypochlorite solution at a temperature of -5C to 0C. The reRultant product (XV) is isolated by extraction with a solvent, e g., diethyl ether~ and then treated with pota9sium hydroxide in a lower alkanol solvent to give the 1,2-dehydropiperidine (XVI). The action of cyanogenating agents, e.g., hydrogen cyanide or sodium cyanide converts the 1,2-dehydropiperidines (XVI) to the corresponding 2-cyano ~ 43 -~3~4~9' analogs (XVII). Hydrolysis of the 2-cyanopiperidines (XVII) to yield the 2-piperidinecarboxylic acids xvm) is effected by treatment of the 2-cyanopiperidineS
(XVII) with an inorganic acid, such as hydrochloric acid or sulfuric acid.
The arylsulfonyl halides (VII) which are the starting materials for the preparation of the N2-arylsulfonyl-L-arglninamides (I) can be prepared by halogenating the requisite arylsulfonic acids or their salt~ e.g., sodium salt~, by conventional methods well known to those skilled in the art.
In practice, halogenation is carried out without a solvent or in a quitable qolvent e.g., halogenated hydrocarbons or DMF in the presence of a halogenating agent, e.g., phosphorous oxychloride, thionyl chloride, phosphorous trichloride, pho9phorous tribromide or phosphorous pentachloride, at a temperature of -10C
to 200C for a period of 5 minutes to 5 hours. After the reaction is complete, the reaction product is poured into ice water and then extracted with a solvent such as ether, benzene, ethyl acetate, chloroform or the like.
The arylsulfonyl halide can be purified by recrystalli-zation from a suitable solvent such as hexane, benzene or the llke.
~i37~9 (b) Removal of the NG-su'Dstituent from an NG-substituted--N -arylsulfonyl-L-argininamide This process may be illustratecl as follows:
HN
H2cH2cH2cHcoR (V) ,~
R " HN
R~ I
R"~
HN ~C-I -cH2cH2cH2cHcoR (XIX) ArSO2X (VII) R ~ 2 HN ~, C--N--CH2 CH2 CH2 CHC OR ( XX ) R~ HNSO2 R~ I
Ar C-N-CH2CH2CH2CHCOR ( I ) Ar 45 . s ' ' ~ ~374~9 ln the above ~ormulas~ 1~, Ar, X, R', R" and ~"~ are as clefi.nccl hereirl above Tlle N -ary1slll.l`ollyl-L-argininami(le (1) i.s prepared by renlov~ g tl~e N(~-substituent f`rom an N(-substituted-N -arylsulfonyl-I-argininamide (XX) by means of aciclol.ysis or ~Iyclrogellolysis.
I`he aciciol.ysi s is generally effecl;ed by contacting tlle N~-substituted-N -arylsulfonyl-L-argininamide (XX) and an excess of an aeid 9UCI~ as llydrogen fluoride~ ~Iyclrogen chloride, hydrogell l)romide or tri.fl.uoroacetic acid, without a solvent or in a solvent, SUCII QS an etller ( tetrahydrofurall, dioxane), an alcohol (metllat~ol, etllanol) or acetic acid at a temperature of -10C to 100C, and preferably at room temperature for a period of 30 minutes to 24 hours.
The products are isolated by evaporation of the solvent and the excess acid, or by trituration with a suitable so.lv(?llt rol.l.owed l)y filtration ancl dryi.ll~.
IICCaUSC 0~` tllC IlSe 0.~ C! CXCOSY ;IC~ tllc PIO(IIICI:S
are g(`ll(`lUI IY l,lIC aCi~l a(~ OII ~:al.l,S 0~` tllc N--arylsulrollyl-L-argininami(les (I), whicll can be easily convcrt(!(l lo a E`ree amicle by ne~ltr;l:l.izal;ioll.
The removal Or the nitro group aud tlle oxycarbonyl group, e.g., benzyloxycarbonyl, p-nitrobellzyloxy-carbollyl, i.s rea~lily accompl.i41le(l l~y tlle llydrogenolysis.
~ ~6 --li3746i9 At the same time, the benzyl e~ter moiety which can be included in the R group is converted to the carboxyl group by the hydrogenolysis.
~he hydrogenolysis i8 effected in a reaction-inert solvent~ e.g., methanol, ethanol, tetrahydrofuran or dioxane, in the presence of a hydrogen-activating catalyst, e.g., Raney nickel, palladium, or platinum, in a hydrogen atmosphere at a temperature of 0C to the boiling temperature of the solvent for a period of 2 hours to 120 hours.
The hydrogen pressure is not critical, and atmospheric pressure is sufficient The N -arylsulfonyl-L-argininamides (I) are isolated by filtration of the catalyst followed by evaporation of the solvent The N -arylsulfonyl-L-argininamides can be purified in the same mànner as described above.
The NG-substituted-N2-arylsulfonyl-L-argininamides (XX) starting materials can be prepared by condensing an NG-substituted-N2-substituted L-arginine (m) (generally the NG-sub9tituent is nitro or acyl, and the N2-substituent is a protective group for the amino group, such as benzyloxycarbonyl, tert-butoxycarbonyl, or the like) and a corresponding amino acid derivative (IV)~
selectively removing only the N -substituent of an li3~469 -snbstit~1te(l-N -substituted 1,-arginiJ1amide (V) by means of cata1ytic hydrogenolysis or ac.i.dolysis, and tllen co11(1c11si11~ thc th1ls obtai11ed N -stll)slitl1t~d-l,-al~ lli(lc (~ ) witll all arylstllt`o1lyl lla.l.ido (Vll), preferably a chloride in the presence of a base in a so~verlt. T11cse reaction conditions are as c1escribed abovc i11 tlle con(lc1lsation Or an l,-argilli11amide with an aryls11~`o1ly] l~a~ide, and the removal oI` the NG-substitllont f`rom an NG-subst.ituted-N --arylsulronyl--L--argin:inamide.
(c) Condensati.o1l of an N -arylsulfonyl-I,-arginyl halide with an amino acid derivative This process may be illustratecl as follows:
1~ ~
~C-N-C~12CH2CH2CHCOO~I (II) N}12 + Ar~02X (VII) Il IIN ~
1I N ~C N Cl"C112C~121CIIC0011 (XXI) >
l~r li37~9 IIN ~
,c-N-clt2c~t2cH2c~lcox (XX~I) ~NS02 ~r -~ Rll(IV) ->
ll IIN ~
Il N ~ 2 2 2ll~COR(I) IINI:;02 Ar In the above formulas, R, Ar and X are as defined herein above.
The N -arylsu]fonyl-L-arginirlamide (I) is prepared by - the condensation of an N -arylsulfonyl-L-arginyl halide (XXII), preferably a chloride witll at least an equimolar amount of an amino acid derivative (IV).
The condellsation reaction can be carried out without an added solvent in the presence of a base. However, satisfactory results will be obtainect with the use of a ~olvollt SllCIl ~14 I)asic solve~lts (~limi~tllylformamide~
dimethylacetamide, etc.) or halogenated solvents (chloroform, dichloromethane, etc.).
The amolult of the solvent to be used is not critical and may vary from abollt 5 -to 100 times l;l~e weigllt of t;~lo N -arylslllrollyl-l-ar~irlyl hali(te (XXI]) .
1~3~4~9 I'reftrretl con(lellsatioTI rcactiol~ tem~eratures are in the range of rrom -10C to room temperature. The reaction time is not critical, but varies with the amino acid dcrivative (IV) employed. In general, a period Or from 5 minutes to 10 hours is operable.
The obtaiJIed N -arylsulfonyl-L-argininamicle can be isolated a~ld lurifit~d in the same manller as described abovo.
The N -arylsull`ollyl-L-ar6rinyl halide (XXII) starting matcrials re(luired for the con(lensation reaction can be prepared by reacting an N -arylsulronyl-L-arginine (XXI) with at least an equimolar amount of a halo-genating agent such as thionyl chloride, phosphorous oxycllloride, phosphorus trichloride, phosphorous pentacllloride or phosphorus tribromidc. The halogena-tion can be carried out with or withollt an added solvent.
The preferred solvents are chlorillate(l hydrocarbons such as chloroform ~Id dichloron)ethalle, an~l etllcrs such as tetrahydrol`llran and diox~ule.
: 2~ t~llo~ . t>l` t.ll~ lvt~llt lo l)~ t~ lot clitic~l nll~ nlay vary l`rom a~out 5 to 1()0 times tlle weight of tllc N -aryl~ult`ollyl-L-argilline (XX~).
l'roferrc(l rcactioll temperature arc in tllc ratlge Or -10 C to room teml~erature. The reaction time is not critical, l~ut varies with the ha1Ogellatillg agent and 1~37~i9 reaction temperature. In general, a period of 15 minutes to 5 hours is operable, The N -arylsulfonyl-L-arginine~ (XXI) which are the starting materials for the preparation of the N -arylsulfonyl-L-arginyl halides (XXII) can be prepared by the condensation of L-arginine (II) with a sub-stantially equimolar amount of arylsulfonyl halides (VII), by a method similar to that described in the condensation of an L-argininamide with an arylsulfonyl halide.
(d) Guanidylation of an N -arylsulfonyl-L-ornithinamide or an acid addition salt thereof This process may be illustrated as follows:
H2N--c~2cH2cH2cHcoR (~cm) --->
HN I o2 Ar HN ~
H N ~ CH2cH2cH2lcHcoR (I) Ar In the above formulas~ R and Ar are as defined herein above.
The N -arylsulfonyl-L-argininamide (I) is prepared by li374~9 guanidylating an N -arylsulfonyl-L-ornithinanude (XXlI) with ~1 ordinary guanidylating agent such as an 0-alkylisourea, S-alkylisothiourea, l-guanyl-3,5-dimethylpyrazole or carbodiimide. The preferred guanidylating agents are the 0-alkylisourea and the S-alkylisothiourea.
The guanidylation of the N -arylsulfonyl-L-ornithinamide (xxm) with the 0-alkylisourea or S-alkylisothiourea is generally effected 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 50 hou~s.
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.
Examples of the preferred solvents are water, water-ethanol and water-dioxane, After the reaction is complete, the N -arylsulfonyl-L-argininamide (I) is isolated by evaporation of the solvent followed by removal of the excess base and the formed salt by a water wash.
It i9 well recognized in the art that an ester deriva-tive of the N -arylsulfonyl-L-argininamide (I) wherein R2, R5~ R8, Rg, Rlo or Rll i9 alkyl, aralkyl, aryl or li374~;9 5-indanyl, can be prepared from a carboxylic acid derivative of the N -arylsulfonyl-L-argininamide 2~ R5~ R8, Rg, Rlo or Rll is hydrogen by the conventional esterification methods well known to those skilled in the art. It is also well recognized in the art that the carboxylic acid derivative can be prepared from the ester derivative by the conventional hydrolysis or acidoly~is methods. The conditions under which e~terification, hydrolysis or acidolysis would be carried out will be each apparent to those skilled in the art.
The N -arylsulfonyl-L-argininamide (I) of this invention forms acid addition salts with any of a variety of inorganic and organic acids. Some of the N -arylsulfonyl-L-argininamides containing a free carboxyl group, 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 of salts. In addition, the product can be obtained as pharmaceutically acceptablc acid addition salt4 by reacting one of the free bases with an acid, such as hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric~ phosphoric, acetic~ citric, maleic, succinic, lactic, tartaric, gluconic, benzoic, methanesulfonic, ~ 53 -1~37469 o ~ l i c, ~ o l ~ I ( l l (? .~ U I [ () l l i. C ~I C i. ( l o r ;llC .1 i 1~(?~ 1 11 <I Y:i IlI.i I ~I r III-IIIIIC? 1`~ 1~ll(? ~) 1'()(1ll (` 1, Cllll l)C OL) t LillCC
LS ~ 11'111ilC(~II I i (`11 1 I y ~1(`(`(?1) t:~LL) I (? YCI I L.Y 1)~ IIC l.:i ll~r OIIC! 0 r tlle I)ot.lsY.il.llll ll)~ o~ l(?, i~rllrllo~ llll lly~ o~ ly~.clnli.llc, roca~ le, (I:il)~ Ianl.il)(?, .I.-e~ c]l Lm.il~ N,N '-(I:il)c?n:~,y:l.etlly1el1e-clial~ le, N-ctllyll)il)c~t~:i.(l:inc 01~ tllc .lil;e.
elriY C? ~ t r(?~ 111(?11 1; O r L 11(~ s.ll. L s ~i t ll ~- 1.) LY (? O r aci(l resul ts ill ~1 r('g(?llel'al..i()ll ol' L:IIC? rt'(!(` allli.(l(`.
1 0 l~ s s t a t -? ( l . I L ) -) V (?, ~ N --.~ y l. Y I I .I r O l l y ~ r ~ a llLi ( l c? y ~
the sall;s- tll(?l~eof c)l` thi~; illVO]ltiOII are cllar-lctc?ri~e(l l~y their ~ ,llly ~l~cc:i.ri.c i.n~ i.tory act:i.v~ y a~.linsl; throml)ir as well as ~ lC.i. L' Slll)S t.lll tial. lacli o L` L o~;:i ci. ty~ all(l Lllcr(?~`ol~e t~ ;(? collll~o~ e lls(~ lL :ill ~ (I(?ternlirlatioll .
Or t11roml~:ill :il~ l).lood as clia~,]lostic re.~ e]lts, an(l/or ror the mediccLl COII trol o L` prC?Vell tion Or tllrOllll)OSis, Tlle com~)o~lllclY o r` tl~:i.Y i.nvclltloll are al.Yo USC?rll1 as arl illllil):i tO1~ ol' l)l.atel et ~lg~rc?~atioll ~
Tlle a]l ti throml~o L i c ac l;i.vi ty O r L hc N -arylsulfonyl-L-~o arg:i.llillanli.(l(~ ` Llli~; .i.llV(?lll,i.OII \~/aY COIIII)al'('(l w.i.tll tllat ol~
a kllowll allt:il:lllollll)c)L,:i.c aC~ellt, N -(p-l;o.lylsll:l I`olly].)-L--argiJli.]le mCI:II~'I c~ite:l~ del.c.rlllilli]~,~,r tl~c ~ :i]lo~,e]l coa~u-latioll time. Tlle mecl~jllremellt Or tlle l`.il)rino~ell coa~,,rulatio tinle waY colldllcte(l aY l`ollows:
~rl ~.8 nll ali(l~loL ol` a l`.il)r.i.no~;c]l solllL.i.oll, wlli(llll.l-l L)ee - 5~ -~:~3~
prcpared by disso1ving 150 mg of bovine fibrinogen (Cohn fraction I) sllpplied hy Armour Inc. in 40 ml of a borate saline buffer (pH 7.~), was mixed with 0.1 ml of a borate saline buffer, pH 7.4, (control) or a sample solution in the same buffer, and 0.1 ml of a -thrombin solution (5 units/
ml) supplied by Mochida Pharmaceutical Co., Ltd. was added to the solutions in an ice bath.
Immediately after mixing9 the reaction mixture was trans-ferred from the ice bat-h to a bath maintained at 25 C.
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 concentration of an active ingredient required to prolong the normal coagulation time 50-55 seconds to 100-110 seconds, The concentration required to prolong the coagulation time by a factor of two for the known antithrombotic agent, N -(p-tolylsulfonyl)-L-arginine methyl ester, was l,lOO~m.
The inhibitors are shown in Table 1 by indicating R and Ar in the formula (I) and the addition moiety.
When a solution con-taining an N -arylsulfonyl-L-argininamide of this invention was administered intravenously ~ 55 ~
~i3';'4~9 into LlnirllaL l)odie:;, I;llc lligll alltitllronll)otic activi.ty in tlle C:irCll lati.ll~ oO(I was mai.l~t.liJIo(l f`or from ol)e t;o tllree IlOUrS .
'I`]~ a1r.~ r~-r ~leeaY ol` 1,1l0 ~Irlti-tllrOnll~OI;~;C COm~)O~II1(l$ Or tll;S j~V(`IILj.()ll jll (~;~C~I.Iat~ 100(1 W;1S :;IIOWII 1,0 1~0 a~pro--ximately 60 minutos; the physiologi cal condi. tions of the host allima:ls trat, ral)l)it~ (log allcl cllimpan~ee) were well maintaille(l. ~rhe exl~erime~ltal decrease Or r:ibrinogeJl in aninla.l.s causo(l l)y illl`l.lsiorl of tllrombirl was satisfactori.ly controllecl l~y s:imultalleolls inf`usion of tlle compounds of thi s inven ti on .
Tlle acute to~cici ty values (I,D50) determined by intraperito--neal. admini.stlatioll of substa~lces of formula (I) in mice (male, 20 g) rallge rrom about l,000 to l0,000 milligrams per kilogram of body weight.
Represelltative LD50 values for tl~e compolm~ls of this inven-tiOlI are sllown :in the roll.owing Tabl e .
..._.
(~ ) o l ~ I, D ~ o ( nlg/l; g ) N --( 7--mO t lly I -2~ )Jl l,lly I ~;ul l'ollyl )--1,-- >
arg:irlyl-N-lllll.yltrlyo:illo 1,500 2 ~ . ...... ..
N -(6,7-(1imotlloxy-2-1laplltllylsulI'ollyl )-L-arginyl-N-(2-metllo~:yethyl)glycirle 1,~00-2,400 2 '' ------ . .... _ N --(6 ,7-(limethoxy-2-rlapllthylsulf'onyl )--L--arginyl--N--(2--ethoxyethyl )--~--alanine 660-1, 000 .. .. _ ........... ...... _ .. _.
~ . .
C o mpo ull d ~D50 ( mg/kg ) 2 __ N --(/1 ,6-diltl~tl~oYy--,?--n~plltllylsu] ronyL )--1,--. l l '~ N--(, '--111 ( ! 1, ~ l l y ~ c .i 1 l ~ 6 6 0--1, 0 0 0 _ N ~-(7-me tlloxy-2 naplltllylsulforlyl )-L- 2, 000 arginyl--N-( 2 -me thoxye tllyl )glyci.ne . . . ,.
N~-(5~6~7~ ;etr~llly~iro-l-naplltllylsulfolly:l )- ~ r I,-argillyl -N-(, -metlloxyetlly:L )g] yc:i ne 1, ~00 2 ~ __ N --( 6, 7 -di me l:llyl -:1--nzlphl;l-lylsul ronyl )--L-- >
iar6:irlyl -N-( 2-me tlloxycthy]. )glyc:ine 1, 500 . ._ N -( 6, 7--d :i mc! tho xy-2 -napllthyl suL fonyl ) -1,-arg:inyl-N-(2-etllyl thioethyl )glyc.ine >1~ ()00 .
N -(6,7-dimethoxy-2-naE)httlylsulfonyl)~L- >1 000 arginyl-N-bell~yl.glycille ~
~ . _ N2-(4,6--limettloxy-2-rlapllthylstllronyl )-L,-argilly:L-N-l)ell~yl~;lyc~ e 1,000 _ _ . __ . ___ N -(5-methoxy-1-1lill)lltllylsulrollyl )-L-- ~1 000 arginyl-N-t)erl~ylglycine ~
. . _ . ._ ._ . . .
.~ N -(6,7-climetlloxy-2-tlapllthylsulfonyl)-L-arginyl-N-phenethy:l glycine ~1, 500 ~- 2 --~- ~ - --- _ _ N --(6 ,7--dimet;lloxy-2--llaphthylsulfonyl )-L-arg:i.tlyl-N-cyc lollexyl gl ycine ~1, 500 . _ . __ _ .__ .~
N -( 6, 7 -di me thoxy-2 -naphthylsul fonyl ) -L-arginyl-N--cycl ollexy~metllylgl.ycine ~1, 500 _ . .
N -(7-nletllyl -2-rlal)lltlly.l sll].rorly:L )-L- 600 argi.rly:l.--N-tet:rally(ll orllrrltryLglyci-lle . _ ~ 57 ~
li3~ 9 ..
~ompollrlcl ~ 50 (mg/lcg) . .. _._ ___ N -(~),7-dimctlloxy-,'-l1a~ tllyls~ `ony])-l,- ~2 ~llf,i~ l-- N--~(`t l~ `of~ rllryl ~r~ ~Cill(~
._ ._ ._ N -(G~7-(1imetlloxy-2-naptlttlylsulf`onyl)-L- > 1 roo arginyl-N-butyla]<llline "
_ . .
N -(4,~ imetlloxy-2-1lclpllthy:Lsulfonyl)-l,- > ~,5~0 argilly1-N-cyclollrxy.lmetlly]cllallin(?
l-~N~-(f)~7-~limetlloxy-2-rlapllttlylsu]fc)llyl)-l~- 1 500 arginyl~-2-pil)cri(lillecarbo.Yylic acicl , ... .. .
Ethyl l.l- N -(7-metlloxy-2-rlaphttlylsulforlyl)- 670-1 000 L-arginyl~ -nletl~yl-2-piperidirlecarboxy~ate l-[N2-(4~6-climetlloxy-2-naphthylsulfonyl)-L-arginyl~-4-nlethy]-2-piperidinecarboxyli.c 670-1,000 acid ~ __ .
]-[N -(l-napllthy:lslllt`onyl)-L-arginyl)-4- 700-1,000 metl~y.l-2-~)ipol-idillecarboxylic acid . . . _ ... . __ ]-- CN -( 5-dimetllylamillo-1-naptltllylsulfo~lyl)-L-arginyl~-2-pil)e]iAirlecarboxy.]ic acid 700-1,000 _ 11- [N - ( 7-motlloxy-~ aplll:hylsuL ronyl ) -L- ~ 1,~00 alginy.l~-'3-nlolpllolillocarl)oxy.lic aci(l .. _ _ I
2-¦N--(~ nI(~I;IIO~;Y-2-~ )IItIIY~ Y-I-)-I~-arg:illyl~-1,2,~ ol.lally(lloiso(~ inolillc-~- ~ 1,000 C ;l 1 ~ " (~ j ( 1 , _ .
2- LN -( ~j ~ 7--(IinI~ t~ Y-2-IIa})IItIIY1SII11 OI~Y I- )-IJ- ~ ::
ar~rillyl~ isoin(lt,lillccurl~o.~ylic acid ~ 1,00() On the other hall(l, 1,D5~ values ror N -dallsyl-N-b~ltyl-L-arginil~amide and N -d~lsyl-N-methyl-N-buty:l-L-argirlinamide aI'e 75 and 7~ mill.i~,ram~ per ki.logranl~ rcspective]y.
1~374~9 Tlle therapelltic agellts Or tllis inventioll muy be admilliYtered alolle or in conll)illaLioll wi LII pllarmcleeutlcul Iy uecc!ptclble carriers, tlle l)ro~)or~ion Or whieh is determine(l by tlle so lul~i ] i ty arl(l el~elll:i ca I n.ltllrc! Or the eompollllcl~ ellosen routeof administration and standard pharmaeeuti eal praetiee .
F`or exampl e, the compounds may be in jeeted parenterally, that is, intramllsclllurly, intravenously or sul~eutaneously.
F`or parenteral ac1nlinistration, the eompourl(ls may be used in the form Or sterile solutions eontailling other solutes, for exampl(?, suff`icierlt saline or g]ueose t;o malce the solution isotonic. L`he eoml)ollllds may be administerecl oral]y in the form of` tablets, capsules, or granules eontaillirlg suitable eXCipi.elltS SUCIl as starch~ laetose, white sugar and the like.
Tlle compoun(ls mly be aclmillistereci sub~itlgllu11y in the form f troehes or lozetlges in whieh eaeh aetive ingreclient is mixed wi th sugar or eorn syrups, f`lavoring agents and dyes ~
and tllell delly<irate(i su~`riei ently to make the mixture suitable ror pressillg into so]i d form. The eompoullcis may be aci-ministered ora] ly ill the form Or solutions W}liCh may eontain eolorin~ un(l rlavorillg agetlts. l'hysiciulls will cletermine the dosage of the present therapeutie agents whieh will be most suitab:Le, and dosages vary with tlle mocie of administra-- -tion and the particular compourld chosen. In acldition, the dosage will vary wi tll the particular patient under treatment .
When the composition is administered oral]y, a larger quantity ~ 59 -1137~9 of` l l~e clCt.iVe a~''CIIt will be re~ ired to pro~ ce tlle same er`recl; as canse(l wi.tll a small(?r llualltity gi.verl parenterally.
lle tller~r)ellt:ic dosage :is genera.11y 10-50 mg/lcg of acti.ve ingrc(licllt pal ellter.l l Iy, 10-5()0 mg/l<g ora.l..l.y per day .
Having generally described the invent;ion, a more complete unders tanding can bC! obtai.ned by reii`erence to certain specific exampleS, wlli cll are :inc1~l(led fot~ purposes of i.lltls tration on~y ~n(l are not inten(le~i to be l.imi.ti.ngr l.llll.e::;S ot]~erwise sp e ci. ~'i ed .
~ ~0 _ 1~37~9 EXA~IPLE
(A) N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginine:
To a well stirred solution of 83.6 g of L-arginine in 800 ml of 10~ potassium carbonate solution was added 114.7 g of 6,7-dimethoxy-2-naphthalenesulfonyl cnloride in 800 ml of benzene. The reaction mixture was stirred at 60 C for 5 hours, during which time the product precipi-tated. After one hour at room temperature, the precipi-tate was filtered and washed ~uccessively with benzene and water to give 129 g (76 percent) of N2-(6,7-dimethoxy-2-naphthylsu~fonyl)-L-arginine, M.P. 252-5 C.
(B) N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl chloride;
A suspension of 2.00 g of N -(6,7-dimethoxy-2-naphthyl-sulfonyl)-L-arginine in 20 ml of thionyl chloride was stirred for 2 hours at room temperature. 4ddition of cold dry diethyl ether resulted in a precipitate which was collected by filtration and washed several times with dry diethyl ether to give N2-(6,7-dimethoxy-2-n phthylsulfonyl)-L-arginyl chloride.
(C) N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyliN-butylglycine tert-butyl ester:
To a stirre~ solution of 2.6/~ g of N-butylglycine tert-butyl ester in 20 ml of c~oroform was carefully 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 solutlon and evaporated to drynes~.
The residue was triturated with a small amount of water to give a crystalline material. This was collected by filtration and recrystallized from ethanol-ethyl ether to give 2.28 g (82 percent) of N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylglycine tert-butyl ester, M.P. 164-166C, I.R. (KBr): 3,390, 3,165, 1,735, 1,370 cm 1.
Analysi9 - Calcd. for C28H4307N5S-~H2S3 (perc C, 52.98; H, 7.00; N, 11.04 Found (percent): C, 52.69;
H~ 6.98; N, 10.86 (D) N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylglycine:
To a solution of 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 of 15%
HCl-ethyl acetate. The reaction mixture was stirred 37~tjg for 5 llours at room temperature. At tlle end of this peri.od, tlle relcti.on mixture wclS evaporate(i to dryness.
The residllc was w.lslled several times wi. th dry diethyl ctller an(l cllromatographed on 80 ml. ot` I)aiaion (~) SK 102 ion exchallfre resin (200-300 mesh, ~I form, manufactured hy Mi tsllbi.slli. Cllcmical Industries Limited) paclced in water, wa.;lle(l ~/i th ~/ater an(:l e.lu ted wi th 3% ammonium hy(lro~c:i d e so] u tion.
Thc f`rlctior~ ted from 3% ammoni~lm hy(lroxi(le solution was evaporate-l to dryness to give 1.l~3 g (79 percent) o f N -( 6, 7-dime thoxy-2 -naph thylsul fonyl ) -L-arginyl-N-butylglyci.ne as an amorphous solid, I .R . (KE3r): 3, 360, 3,140, I.,622 cm 1 Ana.LysiS - Calcd. for C2~ l35N507S (percent) C, 53.62, H, 6.56; N, 13.03 F`oulld (percent):
C, 53.48; H, 6.43; N, 12.98 The following compounds are prepared in a sirnilar manll( r:
N -(7-m~ thyl -2-n1phtllylsulronyl ) -L -ar~,inyl--N-butyl--g -alal~ c N2--(7--mctlly.l--2-napllthyl.Sul~onYl)-N-(2~ el.llo~;yctllyl)-N-(3-carboxypropyl )-L-argininamide N -( 5-methoxy-1-naphthylsulfonyl. )-I -arginyl-N-(2-methyl thioethyl )glyclne 1~ 37~9 N -(5-methoxy-1-naphthylsulfonyl)~L-arginyl-N-(2-methylthioethyl)glycine tert-butyl ester N -(5-methoxy-1-naphthylsulfonyl)-L-arginyl-N-(2-methylthioethyl)-~ -alanine N -(6,7-diethoxy-2-naphthylsulfonyl)-L-arginyl-N-( -methylthioethyl)glycine N -(6-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methylthioethyl)glycine N -(6,7-dimethoxy-2-naphthylsulfonyl)-N-(2-methylthioethyl)-N-(3-carboxypropyl)-L-argininamide N -(6,7-dimethoxy-2-naphthylSulfonyl)-N-(3-methylthiopropyl)glycine N -(6,7-dimethoxy-2-naphthylsul~onyl)-L-arginyl-N-(2-ethylthioethyl)-~ -alanine 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 ~i3~ i9 Il-N{ N -(f)~7-(1imcllloxy-2-rla~ thylSulrollyl)-L-arginyl) -N-cyclolloxy~an)inobutyric acid N -(/I,6-llimctlloxy-2-rlaplltllylslllPolly~ ,-ar~ yl-N-phelle tllyl~ lanille N -(6-methoxy-2-rlaphthylsulfonyl)-L-argiJIyl-N-(3-pllcllylpropy:l)glycine N -(5-mot;l~oxy-~-napllthylslllrolly.l.)-l,-argi.lly~.-N-~crl~yl-~ -alalline N2-(5-nitro-1-naphthylsulfonyl)-L-arginyl-N-tetrahydro-furfurylglyci.lle N -(7-11ydroxy-2-naphthylsulfonyl)-L-arginyl-N-tetrally(~rorurrllry]glycille N -(5-cyano-1-naph1;hylsulfonyl)-L-arginyl-N-tetrahydro-. furfllrylgl.ycille N -(6,7-dinletlloxy-2-naphtllylsulfonyl.)-1,-arginyl-N-tetrahydrorurfuryl-~ -alanine N2-(7-methyl.-2-rlaphtllylsulfonyl)-L-argillyl-N-tetrahydrof-lrfuryl-t -alanine N -(6,7-dimethoxy-2-naphthylSulfonyl)-L-arginyl-N-t~trahy(lrorllrrllrylalanine - ~5 -1~37~69 N -(7-metl-1oxy-2-slapllthylsulforlyl)-N-(3-carboxypropyl)-N-tetrally~lrorllrfuryl~ arginillami(le N -(7-methoxy-2-naphtllylsulfonyl)~ arginyl-N-butylalanille N -(7-methoxy-2-napllthylsulfonyl)-L-argi.nyl-N-pentylalanin~
N2-(5-methoxy-1-1lapllthylsulfonyl)-L-argirlyl-N-butylalanine N -(6,7-(1:inletlloxy-2-nal)hthylslllfollyl)-L-argirlyl~N-isoblltylalallille N -(7-methoxy-2-rlaphthylsulfonyl)-L-arginyl-N-benzylalanin N -(6,7-dimethoxy-2-naphthylsulfollyl)-L-arginyl-N-(3-phenylpropyl)alanine N -(5-methoxy-1-naphthylsul~onyl)-L-arginyl-N-benzylalanin-N -(7-methoxy-2-naphthylsulfonyl)-L-argirlyl-N-cyclo-hexylalanille N?-((j~7-~ llel;lloxy-2-~ tlly~ lrolly~ -argillyl-N-cyclohc.~y:llllctllylalanillc N -(6,7-climetlloxy-2-rlaplltllylslllt`ony.])-l,-.lrgillyl-N-bu tylbu tyrinc N -(6,7-climetlloxy-2-rla~hthyJslllfoJlyl)-l,-ar~ yl-N- :
( ~--r" l yl m~ yl )~rl yc i 11C`
N ~ 7-(1imc~lloxy-2-naphthylSulror-y]. )-L-arginyl-N--( tel,r;llly(llo-3-1`1~rylmetllyi )g:lycine N -(6,7~ in)etlloxy-2-~ p~lthylslllrolly~ arginy]-N--( 2--t ~ l y l ) ~r .l y c ~
N -(7-methoxy-2-napllthylslllrollyl )-I,-arginyl-N-( 3-t~lellyl )glycille N -( 6 ,7-dime thoxy-2-rlapllthylsulforlyl )-L-arginyl-N--( tetrahy(lIo-2-thenyl )glycine N -(7-methoxy-2-naphthylsu.l fonyl )-L-argirlyl-N-( tetrahydro-3-thenyl )glycine --N2-(6,7-dimethoxy-2-naphthaylsulfonyl)-L-arginyl-N-(2-acetylethyl)glyc N2-(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(4-methoxyfurfuryl)glyci N2-(7-methyl-2-naphthylsulfonyl)-L-arginyl-N-(5-methylfurfuryl)glycine N2-(6,7,-dinlethoxy-2-naphthylsulfonyl)-L-arginyl-N-(l,4-dioxacyclohexylmethyl)glycine l-[N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L- arginyl]-4-methoxypiperidin 2-carboxylic acid l-[N2-(6,7,-dimethoxy-2-naphthylsulfonyl)-L-arginyl]-5-methylhexamethyleneinline-2-carboxylic acid l-[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 .
(A) N -(6-methoxy-2-naphthylsulfonyl)-L-arginyl chloride .
A suspension of` 2 .5 g of N -(6-methoxy-2-napllthylsulfonyl )-1,--arginine i n 20 m~ of tllionyl chl.oride was s tirred for 2 hollrs at room temperature . Add1 tion of cold dry ethyl et~er reslllted i.n a precipitate whicll was collected by fil-tratioll and washed several times wi th dry ethyl ether to gi ve N -( 6-me thoxy-2 -naphthylsul follyl ) -L-arginyl chlo ri d e, ~3~i9 (~) Ethy]. 1-[~ -(6-nlethoxy-2-1lat~hthylsulfollyl)-L-argirlyl~-2-piper.i.dillecclrboxylate ~o a stirred solutioll of 2.2 g of otllyl 2-piperidine-carl)oxylate an~ .l ml of trietllylamille in 50 ml of chloroform~ which was cooled in an ice-salt bath, was actded .in port:iolls N2-(6-methoxy-2-naplltllylslllf`ollyl)-L-arginyl chlor:i-le ot~taine(l above. Th( rcacl:.i.ol-l mixture was stirred overlli~rll~ at room tempera-ture. At the en(l o~ this perioct, 500 ml of chlorororm was ad(le(l and ttle chloroform solution was ~ashed twice with 50 ml of saturated sodium chloride solution, dried over anhy~trous sodium sulfate and evaporated in vacuo.
Tlle oily residue ~as washed with ethyl ether to give 2.9 g of powdery ethyl l-~N -(6-methoxy-2-rlaphthyl-sulfonyl)-L-arginylJ-2-piperidinecarboxylate.
For analysis of the product, a portion of the product was converted to the flavianate, M.P. 192-3C.
I.R. (K~r): 3,210, l~747, 1,638 cm l Allalysis - C~lc~l. for C25H356N5S Cl~ll6 8 2 C, 49.58; 1[, l1.87; N, 11.56 Foul-l(l (percent): C, 49.24;
Il, 4.7~; N, 1.1.85 (C) l-tN -(6-methoxy-2-napllthylsulfonyl)-L-arginyl~-2-r~ r~ rl)o xyl i c ~ ci ~l A solllt:ioJI ol` 2.~ ~ Or otl~yJ. l-~N -(~)-motllo~y-2- ~:
~laplltlly.Lsll.LL`olly:l)-L-argillyl~-2-piperidi.llecarl)oxylate in 1~3~9 15 ml Or rnethanol and 10 ml of 2N-NaOH solution was warmed to 60 C and held at that temperature for 10 hours. At the end of -this period, the reaction mixture was concentrated and chromatographed on 200 ml of Daiaion ~ SK 102 ion exchange resin (200 - 300 mesll, H form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with ethanol-water (1:4) and eluted with ethanol-water-NH40H (10:9:1).
The main fraction was evaporated to dryness and washed with ethyl ether to give 2.0 g of l-~N -(6-methoxy-2-naphthylsulfonyl)-L-arginyl~-2-piperidinecarboxylic acid as an amorphous solid.
I.R. (KBr): 3,200 (broad), 1,620, 1,150 cm Analysis - Calcd. for C23H3106NsS (percent) C, 54.64; H, 6.18; N, 13.85 Found (percent):
C, 56.88; H, 6.31; N, 13.83 The following compounds are prepared in a similar manner:
N -(6-chloro-2-naphthylsulfonyl)-L-arginyl-N-butylglycine N -(7-methyl-2-naphthylsulfonyl)-L-arginyl-N-(2-ethoxyethyl)glyclne N -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methylthioethyl)glycine li3~ 9 N ~ 6-(linle~ll<)xy-2-naplltllylsulfollyl)-l,-argillyl-N-(2-rllctlly:l, tllio(.~ yl )~].ycil-o N'---( ~1, (i -(I i Illl` ~hox y--,'--n;~ lly 1~ 1 1 ouy 1 )--1,--a I'C~ y I--N--phene-tllyl - ~ -a I anine N -(6,7-dimetl-1oxy-2-rlap}lthylsulrollyl)-N-benzyl-N-(3-carl)oxypropyl. )-I,-argininamide N2-(7-methoxy-2-naphthylsulronyl)-L-arginyl-N-cyclohoxylllorleucirle N -(7-methoxy-2-naphthylsulronyl)-L-arginyl-N-butylisolellcille N -(7-methoxy-2-naphthylsulronyl)-L-arginyl-N-pentylbutyrine N2-(6,7-diethoxy-2-l1aphthylsulronyl)-L-arginyl-N-butylalanille N - ( 6,7-dimethoxy-2-naphthylsulfonyl)-L-arginy].-N-cycloheptyl alanille N -(7-metboxy-2-naphthylsulronyl)-L-arginyl-N-(2-methoxyetllyl )alanine N -(6,7-dimethoxy-2-naph-thylsulfonyl)-L-arginyl-N-(2-ct:hoxyetllyl)alanine N -(7-methoxy-2-rlaphthylsulf`onyl)-L-arginyl-N-cyc]ohexyl-~ -a~anine N ~ y--"--~ 1 hy I .';11 1 l`o t l y l. )--1,--~ g i l l y l--N--(2--methoxyethyl)norvaline N ~(6,7-dimetlloxy-2-1laphthyls~ orlyl)-l,-arginyl-N-ben~ylleucille l-~NZ-(5-metlloxy-l-naphtllylsulfonyl)-L-arginyl~-4-ethyl-2-pipericlinecarboxylic acid ; l-[N2-(6-methoxy-2-naphthylsulfonyl)-1,-arginyl~-4-ethyl-2-piperi(iinecarboxylic acid l-CN -(ll,6-cli.methoxy-2-naphthylsulfonyl)-L-arglnyl~
- ethyl-2-piperidinecarboxylic acid l-[N2-(5-ethoxy-1-naphthylsulfonyl)-1,-arginyl~-4-ethyl-2-piperidinecarboxylic acid :L-[N -(7-ethoxy-2-naphthylsulfollyl)-l,-argillyl~
ethyl-2-pi.peri(linecarboxylic acid l-CN2-(6,7-diethoxy-2-llaphthylsulfollyl)-L-arginyl~-4-ethyl-2-piperidi.llecarboxylic acid l-~N2-(7-metlloxy-2-naplltllylsulfonyl )-I,-argi.tlyl~-ll-I;ert~ ltyl-2-l)iperi.~1:inecarhoxylic aci(l ~:~37~69 l'helly]. l-~N -(7-methoxy-2-naphthylsul.forlyl)-L-arginyl~ -4-ethyl-2-E)il)eridinecarl)oxylate 13e~ .y.] 1-[N~-(7-motlloxy-2-1lapl~tllyl.~ rollyl)-L-z~rgil-yl~ -4-ethyl -2-pi.peridirlecarboxylate Ben~y] l.-[N -(fi,7-(li.methoxy-2-naplltllylsulfonyl)-L-argilly.l~ -methyl-2-piperidillecarboxylate l-[N -(5-nitro-1-l1ar~ht}lylsul rorlyl ) -L-arginyl~
mcthy.l.-2-pipori.(lirlocarboxylic acid l-~N -(7-llyclroxy-2-naphthylsulfolly].)-L-arginyl~-4-ethyl-2-piperiAinecarboxylic acid l-[N -(5-cyano-1-rlaphthylsulfonyl)-L-arginyl~ -methyl-2-piperidinecarboxylic acid l-~N -(7-methyl-2-naphthylsulfonyl)-L-arginyl) -4-ethyl-2-piperidinecarboxylic acid 1-~N~-(5-dinlotllylalllillo-1-l1aphthylsulrollyl)-L-arginy]~-1y l -~ )i r) (~ c cL~ )o xy l :i c ~ Ci (l ';
l-~N -(2-nupll~llylsull`ollyl)-L-argilly]J -ll-etllyl-2-pil)eri(lillocari)oxyl:ic aci~
l-~N -(5,fi~7,~ tl~lly(lro-2-l-lar)~ yl~ `c)~lyl)-r,-ar~i]ly.l~-ll-etllyl-2-1)ipcridirlccarl,oxylic acid 1~7~9 l-[N -(5-dimethylamino-1-naphthylsulfonyl)-L-arginyl~-4-methyl-2-piperidinecarboxylie acid l-~N -(7-methyl-2-naphthylsulfonyl)-L-arginyl~-6-methyl-2-piperidineearboxylic aeid l-tN -(7-methyl-2-naphthylsulfonyl)-L-arginyl~-4-tert-butyl-2-piperidineearboxylie aeid l-~N2-(5-nitro-1-naphthylsulfonyl)-L-arginyl~indoline-2-earboxylie acid 2- ~N -( 5-eyano-1-naphthylsulfonyl)-L-arginyl~isoindoline-l-carboxylic acid 4-[N -(7-methyl-2-naphthylsulfonyl)-L-arginyl]thio-morpholine-3-earboxylie aeid 4-[N -(6,7-dimethyl-2-naphthylsulfonyl)-L-arginyl~
morpholine-3-earboxylic aeid 4-~N -(5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl~-3-earboxythiomorpholine l-oxide 4-~N -(7-methyl-2-naphthylsulfonyl)-L-arginyl~morpholine-3-carboxylie aeid 4-~N -(7-ehloro-2-naphthylsulfonyl)-L-arglnyl~morpholine-3-earboxylic aeid ~ 73 -1~L3~9 4-~N2-(7-hydroxy-2-naphthylsul~onyl)-L-arginyl~
morpholine-3-carboxylic acid 4-~N ~(5-nitro-1-naphthylsulfonyl)-L-arginyl~thio-morpholine-3-carboxylic acid 4-tN -(5-cyano-1-naphthylsulfonyl)-L-arginyl~thio-morpholine-3-carboxylic acid 4-~N -(5-methoxy-1-naphthylsulfonyl)-L-arginyl~
morpholine-3-carboxylic acid Ethyl 4-rN -(4,6-dimethoxy-2-naphthyl~ulfonyl)-L-arginyl~ morpholine-3-carboxylate 4- ~N2-(5-ethoxy-1-naphthylsul~onyl)-L-arginyl~
morpholine-3-carboxylic acid 4-rN2-( 5-dimethylamino-1-naphthylsulfonyl)-L-arginyl~ ~
thiomorpholine-3-carboxylic acid :
3-tN -(l-naphthylsulfonyl)-L-arginyl~thiazolidine-4-carboxylia acid 2-~N2-(7-methoxy-2-naphthylsulfonyl)-L-arginyll-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid 2-[N2-(7-methoxy-2-naphthylsulfonyl)-L-arginyl~
isoindoline-l-carboxylic acid 1~3~4~9 2-~N2-(~1~G-(limel,~loxy-2-1lal)hthylSulrollyl )-L-arginyl~-1,2,3,~1-tetrally(lto:iso(~ lolirle-3-carhoxylic acid '--~N --( r~--n~ y--l ~ > 1~ y l ~ l rO I ~ y l )--1 --1 1 ~ri ~ I y.l.
isoin(loli.lle-l-carboxylic acid 2-[N2-(5-ethoxy-.1-naphtllylsulronyl)-1 -arginyl~-l ,2, 3,4-tetrahydroisoquinoline-3-carboxylic acid EXA~PLE 3 (A) NG-nitro-N -( tert-butoxycarbonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester:
To a stirrecl solu-tion of 28.3 g of NG-nitro-N -(tert-butoxycarbollyl. )-I-arginine in 450 ml Or dry tetrahydrofuran were addo(l i.n turl-l 12 ,ll ml of triethylamine and 12 .4 ml Or isobutyl. chlorof ormate while keeping the temperature 1t -5 C. After 15 minutes, to this was added 111.2 g of N-(2-mct;hoxy(?tllyl)glycine ethyl oster, alld the mixture wa~ s tirro(l 1`0r 15 minutes at -5 C . ~\t the end of this el.i.o(l, tll(? r olct:iOII mixtur(? was WUI m(?(! to r oom tempera-llllc. I`h( :;olvellt wa~ cvll)0rut(3(l alld tllo resi(ll~e talce ul) in /10() ml ol` ethyl acetate, and wuslle(l succesSively with 200 m.]. of water, 100 ml of 5% sodillm bicarl-onatc ~;ollll;ioll, 1()() ml ol` .1()% c:i l;rlc uci(l :;olllt:i.nll ulld 200 ml of wul or. Tl~o otllyl acctatc soluti.ol~ wus dr:i.o(l ovor ~ 75 ---~37~6~
anhydrolJs sodj.llm sulfate. Upon evar)oration of the .solveIlt~ tlIc I~e.si(Iue was disso:I.ve(l i.I~ 20 ml of ch.l.oro-fo ~t, and thc XO]UtiOII was applied to a colu~ (80 cm x 6 cm) Or 500 g Or silica gel packe(I in chloroform.
The procIuct was e].uted first with chloro~`orm, ~Id then 3~ nletha~IoJ.-chlorororm. The fraction eluted from 3%
methaIlol-c}llolororm was evaporate(I to dryness to give 25.8 g (63 ~ercent) o:f NG-nitro-N -(tert-butoxycarbonyl)-L-arginyJ.-N-(2-nIetIloxyethyl.)glycine ethyl ester in the .form Or a sy~
]:.R. (IC~r): 3,300, 1,740, 1,690 cm (B) N -nitro-L-arginyl-N-(2-methoxyetIIy.l)glycine ethyl ester hydrocIIloride:
To a stirred solution of 29.8 g of NG-nitro-N2-(tert-butoxycarbonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester in 50 ml of ethyl acetate was added 80 ml of 10~ dry }ICl-ethyl acetate at 0C. After 3 hourS, to this solutioI-l was added 200 ml of dry ethyl ether to precipitate a viscous oily product.
This was fi.ltercd and washed with dry ethyl ether to give 24.1 g of N -nitro-L-arginyl-N-(2-methoxyethyl) glycine ethyl ester hydrochloride as an amorphous solid.
(C) N -llitro-N -(6,7-dimethoxy-2-naplIthylsuJronyl)-L-arginyl-: N-(2-methoxyethyl)glycine ethyl ester:
_ ~fi _ ~37~
To a stirred solution of 4.0 g of NG-nitro-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester hydrochloride in 20 ml of water and 20 ml of dioxane were added in turn 2.5 g of sodium bicarbonate, and 3.5 g of 6,7-dimethoxy-; 2-naphthalenesulfonyl chloride in 30 ml of dioxane at 5C, and stirring wa~ continued for 3 hours at room temperature. At the end of this period, the solvent wa~ evaporated and the residue dissolved in 40 ml of chloroform, and washed with 10 ml of lN hydrochloric acid solution and 20 ml of water.
The chloroform solution was dried over anhydrouA sodium sulfate. Upon evaporation of the solvent, the residue was chromatographed on 50 g of silica gel packed in chloroform, washed with chloroform and eluted with 3%
methanol-chloroform. The fraction eluted from 3%
methanol-chloroform was evaporated to give 5.3 g (87 percent) of N -nitro-N -(6,7-dimethoxy-2-naphthyl-sulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester in tl form of an amorphous solid.
3 I.R. (K~r): 3,240, 1,740, 1,630 cm 1 (D) N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester:
To a ~olution of 3.00 g of N -nitro-N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine ~ 77 ~
1~374f~i9 olllyl (~ r~o nll o~ o~ 1ll(l ().5 ml Or acotic .i.~l W~ .5 F of`~ n~ ucl~ atl~l t~l~rl t}le mixtllrc ~as ~llal;en ill a hy(lrogen atmospllere for .1.00 llolll~ .It loo~ tll~. A~ (l Or-tlli~ ~eriocl, the ethanol so.Lution was filtered to remove the catalyst and evaporated to give an oily product. Ilepreci.pitation with ethano.l.-ethy1 ether gave 2.53 g (91~o) of N -(6,7-dimetlloxy-2-1laplltllylsulfonyl )-L-arginyl-N-(2-methoxyethyl) g1ycine ethy.l. ester.
~or ana1ysi.s o.f the product, a portion Or the product was converted to the flavianate; M.P. 185 C, I.R. (KBr):
3,375, 3,200, 1,740 cm 1.
A~la1ysis - Calcd. for C25~l37N58S C10l6 2 8 C, 47.67; ~l, 4.92; N, 11.12 Found (percent):
C, 47.6ll; ll, 4.81; N, 11.12 (E) N2-(6,7-dimethoxy-2-naphthy1Su1fony1)-L-argilly1-N-(2-methoxyethyl )~rl ycine:
A solutioll of 2.5 g of N -(6,7-dimethoxy-2-l1aphthy1-Slll l`ollyl )-l,-a]~giny.l -N-(2-mel;hoxyotllyl. )~l.ycillc ethyl esl:er in ~ ml. of eth~lo1 alld 7 ml. ol`.lN ~odium hydroxide SO lutiOll was stirrcd for 30 hours at room temperature.
At ~he en(l of` tllis period, the so1utioll was concentrated to 5 ml, chroma~ogra~lled on ~0 nll o~` ~aiaion ~ ~K 102 ion exchull~e re~ill (200 - 300 mesh~ ll i`orm manufacturo~
1~37~S~
by Mi~su~)islli Cl~emical Il~d-lstries Limited) packed in water, wasl~e(l with water, and elute(l with 3% ammonium hydroxi(le SOlUtioll, Tlle rraction elllte(l from 3%
allllllollillm llydro~;:i(le solllt,ioll was evapor-ll,ed '~,o (Iryness, ancl the rcsid~le ~as puriried by reprecipitation with ethanol-etl)yl ctller to give 1 32 g (72 percent) of N -(6,7-(1imetlloxy-2-naphthylsulfollyl)-L-argillyl-N-(2-methoYyetllyl)glycille as an amorphous solid.
I.ll. (KL3r): 3,380, 3,180, 1,630 cm 1 ~na]ysis - Calcd. for C23lI33N508S (percent): C, 51.20;
Il, 6.17; N, IZ.98 Found (percent): C, 50.93;
~, 6.02; N, 12.63 The following compounds are prepared in a similar marner:
N -(5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl-N-(2-ethoxyethyl)glycine N -(5,6,7,8-tetrahydro-2-naphthylsul~ollyl)-L-arginyl-N-(2-methoxyetllyl)glycille N -(7-ethyl-2-naphthylsulfonyl)-L-argillyl-N-(2-methoxyethyl)glycine N -(5-methoxy-1-naphthylsulfonyl)-L-arginyl-N-cyclollexylglycine ~ 79 -1~37469 N -(7-metlloxy-2-1lapllthylsulronyl)-L-argiJIyl-N- ~ :
(3-cyclol~exyl)~ opyIglycine 2-~N -(7-nletllyl-2-naplltllylslllfollyl)-1,-arginyl~-1,2,3,4-tetrahydroisoquinoline-3-carboxylic ac.id 2-tN2-(7-nlethyl-2-naphthylsulrollyl)-L-arginyl~
isoincloline-l-carboxylic acid 2-tN2-(6~7-dinlcthyl-2-napllthylsulforlyl)-L-argillyl~
isoi.nclol,ille-]-carboxylic acid 2-~N -(2-naphthylsulfonyl)-L-arginyl~i,soindoline-l-carboxylic acid 2-~N -(5,6,7,8-tetrahydro-2-napllthylsulfollyl)-L-arginyl~-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 2-~N2-(5,6,7,8-tetrahydro-1-naphtllylsulfonyl)-L-urgillyl~i,soilldo.lillc-l-carl)oxy]ic uci-l ~ CN -(5-(IIIOrO-I-~ IYI~IILrOIIYI)-I-;Irf~;IIY1~-3,~ ;llly(tloiso~ llolillc--3--c~t~l~oxylic ~ci(l l-CN ~-( 5-1~y~lJoxy-,l-nal~lltlly.lsu:lrollyl)-l,-urginy.l3 -1~2~3,11-tctrallydroc]llirlo:linc-2-carl)o~y:lic aci(l li3~4ti,9 2-~rN -(5-dimotllylaniino~ aplltllylstl~follyl)-L-ar~inyl~
iso~ (101.ine-.l-carl)oxylic aci(l 2-~N2-(l-l~ tllylslll rOny~ -arginy~ 2~3 tetrahydroisoquinoline-3-carboxylic acid EXAMplL 1l (A) L-arginyl-N-(2-methoxyethyl)glycine ethyl ester hydrochloricle:
To a solutiorl of l~ o g of NG-nitro-l-arginyl-N-(2-me-tlloxyethyl)glycine ethyl ester hydrochloride in 50 ml of ethanol was added 0.5 g of palladium-black and then the mixture was shaken in a llydrogen atmosphere for 150 hours at room temperature. At the end of this period, tlle ethanol solution was filtered to remove the catalyst and evaporated to give an oily product.
Reprecipitatioll witll ethanol-etllyl ether gave 3.0 g (81%) of L-argirlyl-N-(2-metlloxyetllyl)~lycille ethyl o~t~r llydrochlor~itle in tlle form Or a ~owder.
(~) N -(4,6-(iin1otlloxy-2-nclplltllylSulforlyl)-~-arginyl-N-(2-methoxyethyl)glycine ethyl ester:
To a well stirred solution of 2.00 g o r L-arginyl-N-(2-metlloxyetllyl)glycirle etllyl estor hy(lrocll]oride and 1.95 ~ of K2C03 in 20 ml. of water and ]0 ml of dioxane - 8l -1~3~ 9 was adlie~l drnl)~/ise a solutioll of 2.17 g of 4,6-climetlloxy-2-JIa~ thalerlesll~forlyl chloricle iJI 30 ml Or dioxalle over a period Or 30 m:i~lutes wlli]e mair~taining tlle te~ )e~ rc llt 0C. Thc reuctioll nuxture ~/as stirred for an ad(,litiOnal 5 hours at room temperature.
At the ell(l of` tllis period, tlle solvent was evaporated alld the reYi,(llle talcer~ ) in 50 ml of chloroform.
'rhe chlorororm sollltion was filtere(l to remove the insollll~le material alld clried over anhydro-ls soclium sul~`atc. A(ldil;ioll of 150 ml of etllyl ether to the chloroform solution resulted in a precipitate which was separated by decantation and purified by reprecipitation with ethanol--ethyl ether to give 2.31 g (72 percent) of N -(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethy])glycine ethyl ester.
For analysis of the product, a portion of the product was converted to the flavianate; M.['. 225-227 C, 1.1~. (KJlr): '3,375, 3,200, 1,742 cm 1. -.
,~ Analys;,s -- Calcd. for C25ll37N 08S-C ll~
N208S (percent): C, 47.67; H, 4.92; N, 11.12 Found (percent): C, 47.62; Il, 4.84; N, ll.i8 (B) N -(4,6-(lillletlloxy-2-rlaplltllylsulfo~ly1)-l,-argillyl-N-(2-nl(~tllox~cl,lly~ r~ ycil~
~ ~3~7~9~
N - (4 ,6-dime~IIo~y-2-naphtIlylslllrorlyl)-L-arginyl-N-(2-methoxyetIlyl)g.IyciIle was ol~tai~led in the form of an amorp}Ious sol:id in a m.~lner similar to that described ~an~ 3 (r,) I.R. (ICIJr): 3, 360, 3,180, 1J610 cm 1, EXAMI'L~ 5 (A) N2-(6,7-dimethoxy-2-naphthylsùlfonyl)-L-arginyl-N-phenetIIylglyci.lle:
N -nitro-N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-phenethylglycine b.enzyl ester was prepared by the procedure described ln Lxample 3, and has a melting point of 133-5 C.
To a SOlUtiOII of 3.00 g of NG-nitro-N -(6,7-dimethoxy-2-naphthylsl.llfonyl)-L-arginyl-N-pherIethylglycine benzyl ester in 50 ml of ethanol and 0.5 ml. Or aCetiC acid was added 0.5 g of` palladium-black and thcn the mixture was shakerI in ~ ~Iydrogen atmosphere for 100 hours at room tompetal~ o~ At tlIc on(I of this l)or:io~I, I;IIc ethanol ~.
50 Lll tion w.~s l`i.LI;orc(I to rcmove thc cata:Iyst and evaporate(i to dryness. The residue was washed several times with dry ctlIyl other and chromatograplled on 80 ml.
of ~aiai.on ~ ~K 102 ion exchange resi.n (200 - 300 mesh, H form, manufactured by M.i.tsu~)ishi Chemica]. Industrios 1~37~69 Limi. ted) pac1cc(l in water, waslled wi. th water, and elutecl wi th ~% ammoni um hyclrclxi(le solnltioll . rhe fraction clutcd l`rom 1~ nmnlonillm hy(lloxi(lc SO.llltiOII was evapo-rute(l I;o dryllcs:; to give 1..7l g (7()"~0) Or N -(6,7-dime thoxy-2 -naphthylsul fonyl ) -L-arginyl-N-phenethyl -glycille as all amorpllolls solicl I .R. (K}3r): 3, ~360, 3,200, 1, 590 cm 1 Alla:Lysj.s - Cal.cd. for C28ll35N507S (percellt) C, 57.42;
H, 6.02; N, 11.97 Fowld (percent): C, 57.09;
Il, 6.06; N, 11.7ll (A) N -( 6 ,7-dimetlloxy-2-naplltllylslll. follyl ) -L-1rgirlyl-N-(2-methoxyetllyl)glycyl chloride hydrochloride:
A suspensiorl of 2 .00 g of N -(6,7-dimethoxy-2-naphthyl-sulfonyl )-L-arginyl-N-(2-methoxyethyl )glycine in 20 ml of thionyl chloride was stirred for 2 hours at room temperature. A(iAition of co].d dry ethyl ether resulted in a precil)itnt;e which was collectecl ~)y fi.ltration and wasllc<l sevl?ru.L ti.mcs with clry ethyl cther to give N -( 6, 7 -dimethoxy-2-naphthylsulfoslyl )-L-argi n yl -N -( 2 -methoxyetllyl )glycyl clllori(lc hydroch:lo ride .
_ ~ _ 1~3'74~j9 n) N -(6,7-d:inIot,lloxy-2-~lal)IltllyIsul~oIlyI.)-L,-arginyl-N-(2-met}IoxyelI~y.L)g:I.yciJle m-tolyl ester IIycIrochlori(Ie:
A mixtIlre oL` 2.00 g of m-cresol and N -(6,7-dimettloxy-2-1la~ tllyls~l1f`ollyl)-L--arginyl-N-(2-nlotlloxyetllyl)glycyl chloride hydrochl.oride obtainecl above was heated at 90 C ror 50 min~Ites. ~t the en~t of this period, the reacl;ion n~i~tnrc was cool.ed, WaSlleCI several times with dry 0t;IIYl Cttlel', arId t:heIl clissolve-I i.n 1.0 ml o~ dry e l: lly~. 1 1 CO 110 1. Addi.tioll of` cold dry etIIy:I etIIcr resultcd in a precipitate which was washed several times with (lry ethyl ether to give 2.12 g (86 percent) of N -(6,7-dimetIloxy-2-naphttlylsulfonyl)-L-arginyl-N-(2~metIIoxyethyl)glyciTle m-tolyl ester hydrochloride in the form of a powcier.
I.R. (KBr): 3,250, 3,100, 1,740, 1,640 cm The f`ol.Lowi.ng compoI.mds are prepared in a similar manner:
N -(6,7-dimethoxy-2-naphthy1sulfonyl)-L-arginyl-N-(2-etllyltII.ioetlly~)g.Lycille phenyl ester N -(f~7-(l.imotIIoxy-2-l~ lltIly:Islllf`onyI)-~ rg,:iTlyI-N-(2-oI:IIy.II;Il:iootIlyI)~,lyc:ille benzyl est,or N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-ben~yl.g.lycine pIIenyl. ester - 85 ~
li3~4~9 N ~-( G, 7-(l i nle tllc)xy-2-na~)ll I; llyl~;ul t`olly~ I.,-arginyl-N-r,l ~ r~ I yci ]I ~ zy l o~
, N -( ( J 7 -/I ~ Y-- --I 1~ Y ~ I OII Y I ) -I--;I L ~ Y I--N--totrally(llol`-lrl:`ury.l.~rl.yc.ille pllellyl. oYter ,, l~lenyl l- (N -(7-metlly:L-2-llapl~LIIylsulrorlyl )-L-arginylJ---otllyl-2-pi.l)e~ illecarhoxylal:e 13ellzyl 1- [N -(7-metllyl-2-rlaphtllyls;lllronyl)-L-arginyl~--Il-e thyl-2-pi~eri(liillecarboxylate Benæyl 1- ¦N -(~-CII1OrO-2--l1aPI1thYLSU1rOrIY1 )-L--argiIIY1~--Il--nnethyl-2-piperi(linec~rboxyl.~Ltc 1~ thyl ~ N - ( 7 -mo t llyl -2 -llaph t llyl slll L`ollyl ) -L-arbrinyl mo rpllo lille -3 -c arl~o ~cyla t e Varioll~ otller N -arylYul f`otlyl-I,-arg:irlillllnli~les or s.ll Is tlloreol` wero sylltllcsi.æe-l in accorclallce witll tlle proco~lllre oL` tlle al)ovo exanlpl.es, all(l tlle l;est re~lllts are ~ulllnlari~e(l in Tal).lo .L.
~ 86 --1:~3'~i9 _ ___ L
r _ O O O O O .~ O O ~1 C ~ O O O O O r- O O O O
E o ~o ~ a, t r~ _ . - c ~--r~ r~ r~ o cr~ r- ~ r~ ~ 0 r~
a _ t~ ~ ~r~ ~ _ r~ r~ _ ~ _ r~ ~ r~ ~ ~, _ _ <~ ~_o~ ~ ~ co _- ~0 r~ ~1 _s o~ O ~o . -- ;~. r~ro :~1 c~ O o~ O ~o O _ O cO r~ v~
, .~ ~_ ~_ _ _ r~ ~1 _ ~ r r~ _ O N rl .S ~ ~_ .. . . ~ ::1 C IA Ir~ O ~ 1~ 1~
_ . . ._ _ __ _ _ O ' O I ~ V I ~ ~E `O '~0 1~ `O `O `O
E o O _ r O ,~ O .~ X ~o r~ r~ o~ ~ r~ c I ~ I NN N r~ r N N r r N N t t . ~-- rL~ ~O L ~ ~ L, . r L~ O r 3 7 O : :
,.
r c, i~. _ _ _~ _~ _~ _~ _~
L _. , _ r .7 ~ .~ ,. ~ _ r~
~o $o _~cr, O N u~
, 1 . or or o ~ E l ~ l S l ~ l . ~ _ l .
.
L r r~ r~
~a o or~r~ L~ r~ T ~ r~ ~ T ~ t~
O L~ 3:N r~N Nr~ Nr~ N Lj L~ ~ Lj L)-- t N
E~ N ~N ON L~ N ~ _ O N N N N r N
O N O :1: L O V _ L~ :~: r L~ C~ _ L~
L, \ / \ / \ / \ / \ / \ / \./
Ul _ f ~. ~, l l ~ ~
r L ~ ~
,.
4~j~
~ ~ r-~ _, 0 GO t'~ t O O N O O 0 0 r~ 0 t~--I t~ t~ O O O t~ O t r~ _ ~ ~;; t~ t'~; t'~ ;; ~; t'~; t'~ t~;; t'~ t~ -~ t'~ t'~ _l __ I _ ____ . ...
. _ " ~. _ _ rl rl t~ ~O O _~ 7 t~ N N N N
t~ ___ I .__ _ __ :~ ,r~ rl ,~ rl t~ rl t~ _, ~ t t~ O O~ -~
~O t~ t~ t~ I~ t~ I~ t~ \O ~O _t --t E ~o t, __ ~0 -t r~ tJ~ (~ ~ _ ~to ~l :1 t~ ~ ;O
o 1~ ~ Ir u~ 7 -t O O ¦ u~ ~ ~ t~ t~
. ~ l t rl O ~ n _~ 4 O~ 4 t~ 4 ~ _~ _~ ~ -- __ a o 00~0_3 _ ' .~ ~ ~ C ~. J U~
o~.4'-~, _ O C: r _ ~ N r _ t~ r~ t o t~ N N t~
E :t: 3: r N _N E~ t.) r ~N t~ ~N O ~ r N
~D _ f , f ~ ~ Z ~
h :1 _ ._ E ~, 0 O _ N t.~ ~l 1~374~i9 ~ u ~0C~ ~500~
_ __ __ ~ ~; _ ~o Ir 7 0 J O Ir, rl ,r~ 0 ~o ~ ~7 ~
,. ~ ~. _ ~ _ _ ~1 _ O I rl _ rl N
~ ~ ,~ _- 'D r ~r .7 ~ 1~ r~ rl \0 u~ 7 L r _ ~O O ~O O ~O O O 1~ ~O ~O O ~O ~O ~O
_ , . O N O r. O ~1 _7 ~1 O r~ ~0 .7 0~ u~
1.1 G ~ 1.1 U 'r irA N ~I N lNA --A~ ~\ ~ U~ A
E -- : : : : ~ :
n^
.. ~o r~ ~ _~ _~ _~ _~ _l C~ o~ ' C
d 7 ~ ~ O. L ,~ Ir ~
~ o E o-- N N ~ 7 ~~LO-'-O l ~ I
. _ _ ~
O O ~ r ,,~ _ r/ r O C r ~:
~,rl i 0: rl N C N N ~N N ~N -r ~N oN N N
O ~N ~N N N N rl N N ~N N N N T C
:~ \/ \/ \/ \/ \/ \/ \/
S_Y _ =r~r~ ~ l ~ Z ~. ~. ' L~ ~ _ ; ~ ~
~ 89 --4~9 ~ ~ A _~ O C~ O I O ~`I C~ O C~ C~ ~ O O ~ ~_~
ts _ r~t~ l ~; (~t~; r~; t~; ~t~.l t~; ., . 7. t N CO t . O o~ -- ~N ---- _t ~
_ v ~; _ _, O I N _ _ ___ _l _ N ~1 O O
~' C :~ . . -' O I - .1~ .t O 0. t` O tJ~ ~O. ~ 0 ~0 1~ t~ ~O ~O ~ ~ ~O ~ t` t` ~O ~O ~O `V' C . .. _ ._ Cl0. 3 ~ t~ t` N t'~ t N ~o Ul t~ t~ t7~ t` t~ OL ~ .~ N N _t ~t ~ t N N N N N N
~IJ - ~ _ ~ ~0 ~ _ ,0~ _ .
Q _~ ~ t --~ --I --' --I
~vC~ .__ 8 2 c ~- z . . . . __ _ __ _ N ~
a 0^ ;8 ~ ~ O~ ~ o . _ ._ _ L ~ t~ ~
tS oN _ ~ ~ ~ C'~ ~ t _ _~ t~ o t~ ~ ~ _ _ t~ _ 0~ o :~N I =:~: _N N N N t N t^. N TN oN N N
~ N ~ ~ ~ / \ ~ \
1-:~ _ g~_~ :~: ~: ~j. ~ ~,D~, :;, ~374~i~
_ ,.
~^ ooo ool~o oo~l oooo oo~ ootOto ooo
6 o u~ rl r~ r~ ~ ~ O ~ O _J r~ ~ r~ ~o to t ~ ~O r~o N
~:_ r~~ ; ~ ~ ~ ~ ~
_ ___ ., ~ t _, ~ to ,~ ~ .s I_ to t r~ ~ o 1 d ~ ;~. N rl O O fl ~ ~ t~ N ~j . , U ~' r O~ t~ O _~ ,~ O O ~ _~ O u~ ~O ~
d O _ O ~O `O ~0 1~ ~0 O ~0 ~O ~0 `O ~0 E o O . . ~o u~ s N . . ~0 -~ _~ ~ tr ~ u~ ~s .~ ~ u~ ~ r~ u~ u~ ~
. .~ . ~
o o : : : : : :
C
~ O ;~; ~ _~ _~ _l ,~ _l ~
C ~ ~O
O O C ~
b O tD tl r` ' O
C C ~ o L ~
C~LOvU _ _ C, l N l N I N I
~: E ,~ ~ _~
'~ ' _ _ ~ , r~ r~ r~ ~ ~ ~ ' ~ O O _r~ C --_~r~ ~ ~ ~ ~ -O 1.> -- :~, J: O ~ ~ N O ~ N O _ N N O S
oD. ~) =N O N O N o ~N O N N O O N N
~N ~.) ~~ :1: ~ ~ ~ .~ C ~ ~: ._ c 'r \Z/ \'/ \Z~ \ ~ r \z ~\ _ iC N N N _ O
~t ~ : ~ : , : : ~3 ~ ' _ ^ _ I _ ~- l~oo l~oo oooo ooo oooo o o oooo _ ~ ,~ O -7 r~ _1 `O r~ O r r~ r~ o r~ _I r~ O r~ ~o r~--I r~ ~ Or r~ r;r;; r;r~; r~ r~ r;r~;; r; ; r;r;;;
---- - ~ - ---~ ~ ~ - r~ r~ 7 ~ r~ o rJ~ r~ o r~ r`l r ~. D _ _ a~ _J _ _ r~ r~ _ _~ r~ r~ _~ _I~ rJ ~ _ ~ _1 _1 _< ,_1 _ ~ _1 _ _~ _ _1 _ a ~ ~ _ v~ O .~ ~ .~ ~O I-- - O O ~o ~ --~ O
I rJ ~ :r: r~ r~ r~ 01 r ~o~r~ r'~ O _ I ~ ~0 --~ O
r r~ h. ---7 '7 ~ ~~ ~ ~ ~` r` `O r~ r~
rU L. r r~ r~ r r~~ O rD r~ r~\ r r~, O N r`J r~ ~
`l _J ~7 r~ r U~ ~r~ 7 ~7 . ~ _ O r r~-- rD ~r~
E r~ -' ~ : ~--_ b. ~ u d r~ '~ r ~ _~ _~ _~ _~ _~ _~
~ ';, r.~
r o r rD r,~ ~ ~` O ~ U~
r rD r O ~' r _.
_ ~a~z ~ u ~ ~ n _ I ~
b :~
O O _ ~, Y N oN _ o r~ ~ _ O _ o ~, O~ ~ o E :C 0 7 :r: ~ 7' 7~ ~1 O _ ~ \ / \ / \ / \ / \ / \/ \/
:: T ~ F ~ ~ 1 1 ~ L ~
1 ~ 3'7469 _ CO~
. _ u~ O O t` 0 3 1~ 11~ Oo N CO O -t C` O O CO O 3 ~o O O cO~
E ~ N ~oC'~ N 1~ C'~ ~1 N ~0 ~ N r~ ~-\ 1-1 _ ~V ~ N 1~ C ~ r~ _l 1 U ~; r~;;_; c~;;; r~~; ~ ;; __;
. ~ _ ..
~; ~ ~ -t t, CO ~` CO C) (--I O ~1 8 .t -t . ~ l i ~~ r~ _ j r~ ~ j _~ O' O
-i _ .__ _ ~ __ ~ - r ~ ~ ~O C'~ ~ O CO c~\ O ccl '~ r~ I
C C~ _ ~O`v ~O ~O 0~0 . ~0~0 0~0 0~0 O D. 3 C.) ~0 1~ (` O ~ CO ~0 1~ 1~ _. N O CO ~0--I ~ J _ _~ _ _t 3n ~ N N N N 1 _ C_ E _ 3 : : : : : CO _ .~u)~
Vu -I -~ -I -I -I -I -' b _ O O CJ ~ 3 _ avS,od~ I~
- !J O O ~ N
o b 1~, 0 nl __ _ _ ._ ~ .
O oC`I ~ ~ ~ c~~ _ _~
3 ~ :c: -- c~~ ~ c~ c~ o ~ o E _1: O S O O C~~ O C-~ N O C~ . ~N _. ~ b~ O
O N N N N NN O N O N N N N N N
C~ S 5: ~ C~ ~CS~ ~ ~ ~ CS~ C~ C,~
N Z \ ~ \ / \ ~ \ ~\ / \ ~
-;F _ : ' ~ N ,_, c,l L ~ ~ L t;
cn 1~3'7~i9 .~, oo~ ~o~ o~ ~o oo~ o-~o t O _1 ~ 0 N ~o O N ~~ t~ t-- ~0 O t~ 0 -~ t~
r~ rO
t~~ r~ t~ t~~ t~ ~ t~ t~ _~ t~~ t~ _l t~ t~ _ t~ ;
.. __ _ __ ~_ __ ~ ~ N t~ ^! ~. ~ r! ~v ~ ~
1 ~ ~, r t I O O ~_ O O ~ O O
a ~ ,: N O t~ Ir~ N O r~ _t to O O _ t ~ O
t~ ~t~. Ir~ I~ ~ r.~ ~O ~O I~ ~.~\ `O ~O I~ u~ ~O \O
e . . _ ~ ~ 0 _, r~ 0~ 0 r~ N t~ 1~ ~ 0 E ~ t~ ~ t~ .7 t~ ~o ~ _, t~ ~o ~7 o N -1 O tr~
-1 O. ~ ~0 ~0 N r~ tr~ t~ r~ N r~ tu~ tA t~ 0 t _ I _ . ~ t~ t,~ . t 0 ~ o t~^ b E _ . t~ ~ tl~tl t 3 11~_ o, -CV~- r1 _~ _~ ____ ~
aO'~ ~ _~ _~ ~ ~ _~ _~
b. b t~
: Ql O
O O _ t J ~
'~ tt~ ~J L O ~ N O t.~ O
C ~ D E t~ ~ ,~ ,,~
r ~
~1 V O V~
.~ .
~, .~ .
tr N 7 ~) oN U ~ r~ ~N oN N oN ~) oN ~N N
~? xN 7 N ~Nr~ N N NN r~ ~N _N N N N N
:~N _ \ / \ ~ \ / \ / \ / \ / \ /
S O O
~ ~ _ : `_ _ : _ . ~ _ _l _ O
~ iS ~ _~ N 1-l :t v~ ~O
V) __ ~_ _ 9~ _ ~3~74t~{~
. ~ n ~ ~D O e O 7 O O O O O O ~O O O ~ O _7 O O O
_ ~ ~ _~ ~ ,. r~ _~ r~ ~ -~
." $ 7 r~ u~ _7 r~ ~ r~ rl 1~ .7 ~O .7 O~ t , ,~'a _ o Or~; rl O rl N ::1 O rj rj O O
r :J a 3: r~ rJ 0 1~r~ rl o~ u~ r~ ~0 O V~ r~
L a ~ u~ 7 u~ u~ L~ u~~O ~O u~ ~ ~O u~ u~ u~
E ~ o _ 0 ~ 0 ~O ~O 7 _7 ~ r~ _~ ~ l _~ r o O r; rl ~0 ~0 ~ ~ ~ o~ r~ _; 0 0 ~ I _ u~ 1~ ~ r~ u~ r~ u~ u~ ~ ~ It~ u~
E ~o _ a ~ ~, ~ a I u ,0 ~^ ~ _~
a o ~ ~
s ~ a L O ~ a o ~o o o c o a .. , v _ _ . .
., a ~ a~u~ a/~o~ a~
_ ~ _ :'~ : ' O O r ~ _ U ~ r o 1.~ a ~ oN~D oN ~) N ~D r~ ~D 3N ~ oN N N
S . IN N ~N ~N N N N N SN N ~N N ~N N
\~ \~ ~/ \:Z/ \~/ \,~/ \z~
/~\ _ ~ 3N 1 t'~ r~
~ ~O) _ . C ~r .: ~ :- : : ~ .' ~ _ ~ 1~ r~ l 0~ O _l 1~1 1~
~O ~O ~O ~O
_ 95 _ i9 _ L _ O ~ ~ ~ ~ ~ ~ ~ ~ ~ _ _ ____ ~ ~ _ _ A I ~ _ _, ,_ _~
b a ~ o _ A .~ .,~ ~ A _ ~ _ G~ o __ E ~ ~ ~ I N ~3 _t N t r r~ ~ O ~
~, n J o ~ o o o ~ ~ o o o o o o _ _, .n~ b, _~
.n O r~ _~ ,~ --1 _~ _~ ri b _ _ O O
~' b ~ a D 0 7: O rl _, 0 3 -~ ~D E o--` rl o c o a .1 ~ . _ ._ _ o o ~ ~ c ~ , r~ N ~ rl C ~N ~N ~N rN C ~ N N N N C ~ O .~.
:1: \7j/ ~\7r/ \71/ \ i \ / r
~:_ r~~ ; ~ ~ ~ ~ ~
_ ___ ., ~ t _, ~ to ,~ ~ .s I_ to t r~ ~ o 1 d ~ ;~. N rl O O fl ~ ~ t~ N ~j . , U ~' r O~ t~ O _~ ,~ O O ~ _~ O u~ ~O ~
d O _ O ~O `O ~0 1~ ~0 O ~0 ~O ~0 `O ~0 E o O . . ~o u~ s N . . ~0 -~ _~ ~ tr ~ u~ ~s .~ ~ u~ ~ r~ u~ u~ ~
. .~ . ~
o o : : : : : :
C
~ O ;~; ~ _~ _~ _l ,~ _l ~
C ~ ~O
O O C ~
b O tD tl r` ' O
C C ~ o L ~
C~LOvU _ _ C, l N l N I N I
~: E ,~ ~ _~
'~ ' _ _ ~ , r~ r~ r~ ~ ~ ~ ' ~ O O _r~ C --_~r~ ~ ~ ~ ~ -O 1.> -- :~, J: O ~ ~ N O ~ N O _ N N O S
oD. ~) =N O N O N o ~N O N N O O N N
~N ~.) ~~ :1: ~ ~ ~ .~ C ~ ~: ._ c 'r \Z/ \'/ \Z~ \ ~ r \z ~\ _ iC N N N _ O
~t ~ : ~ : , : : ~3 ~ ' _ ^ _ I _ ~- l~oo l~oo oooo ooo oooo o o oooo _ ~ ,~ O -7 r~ _1 `O r~ O r r~ r~ o r~ _I r~ O r~ ~o r~--I r~ ~ Or r~ r;r;; r;r~; r~ r~ r;r~;; r; ; r;r;;;
---- - ~ - ---~ ~ ~ - r~ r~ 7 ~ r~ o rJ~ r~ o r~ r`l r ~. D _ _ a~ _J _ _ r~ r~ _ _~ r~ r~ _~ _I~ rJ ~ _ ~ _1 _1 _< ,_1 _ ~ _1 _ _~ _ _1 _ a ~ ~ _ v~ O .~ ~ .~ ~O I-- - O O ~o ~ --~ O
I rJ ~ :r: r~ r~ r~ 01 r ~o~r~ r'~ O _ I ~ ~0 --~ O
r r~ h. ---7 '7 ~ ~~ ~ ~ ~` r` `O r~ r~
rU L. r r~ r~ r r~~ O rD r~ r~\ r r~, O N r`J r~ ~
`l _J ~7 r~ r U~ ~r~ 7 ~7 . ~ _ O r r~-- rD ~r~
E r~ -' ~ : ~--_ b. ~ u d r~ '~ r ~ _~ _~ _~ _~ _~ _~
~ ';, r.~
r o r rD r,~ ~ ~` O ~ U~
r rD r O ~' r _.
_ ~a~z ~ u ~ ~ n _ I ~
b :~
O O _ ~, Y N oN _ o r~ ~ _ O _ o ~, O~ ~ o E :C 0 7 :r: ~ 7' 7~ ~1 O _ ~ \ / \ / \ / \ / \ / \/ \/
:: T ~ F ~ ~ 1 1 ~ L ~
1 ~ 3'7469 _ CO~
. _ u~ O O t` 0 3 1~ 11~ Oo N CO O -t C` O O CO O 3 ~o O O cO~
E ~ N ~oC'~ N 1~ C'~ ~1 N ~0 ~ N r~ ~-\ 1-1 _ ~V ~ N 1~ C ~ r~ _l 1 U ~; r~;;_; c~;;; r~~; ~ ;; __;
. ~ _ ..
~; ~ ~ -t t, CO ~` CO C) (--I O ~1 8 .t -t . ~ l i ~~ r~ _ j r~ ~ j _~ O' O
-i _ .__ _ ~ __ ~ - r ~ ~ ~O C'~ ~ O CO c~\ O ccl '~ r~ I
C C~ _ ~O`v ~O ~O 0~0 . ~0~0 0~0 0~0 O D. 3 C.) ~0 1~ (` O ~ CO ~0 1~ 1~ _. N O CO ~0--I ~ J _ _~ _ _t 3n ~ N N N N 1 _ C_ E _ 3 : : : : : CO _ .~u)~
Vu -I -~ -I -I -I -I -' b _ O O CJ ~ 3 _ avS,od~ I~
- !J O O ~ N
o b 1~, 0 nl __ _ _ ._ ~ .
O oC`I ~ ~ ~ c~~ _ _~
3 ~ :c: -- c~~ ~ c~ c~ o ~ o E _1: O S O O C~~ O C-~ N O C~ . ~N _. ~ b~ O
O N N N N NN O N O N N N N N N
C~ S 5: ~ C~ ~CS~ ~ ~ ~ CS~ C~ C,~
N Z \ ~ \ / \ ~ \ ~\ / \ ~
-;F _ : ' ~ N ,_, c,l L ~ ~ L t;
cn 1~3'7~i9 .~, oo~ ~o~ o~ ~o oo~ o-~o t O _1 ~ 0 N ~o O N ~~ t~ t-- ~0 O t~ 0 -~ t~
r~ rO
t~~ r~ t~ t~~ t~ ~ t~ t~ _~ t~~ t~ _l t~ t~ _ t~ ;
.. __ _ __ ~_ __ ~ ~ N t~ ^! ~. ~ r! ~v ~ ~
1 ~ ~, r t I O O ~_ O O ~ O O
a ~ ,: N O t~ Ir~ N O r~ _t to O O _ t ~ O
t~ ~t~. Ir~ I~ ~ r.~ ~O ~O I~ ~.~\ `O ~O I~ u~ ~O \O
e . . _ ~ ~ 0 _, r~ 0~ 0 r~ N t~ 1~ ~ 0 E ~ t~ ~ t~ .7 t~ ~o ~ _, t~ ~o ~7 o N -1 O tr~
-1 O. ~ ~0 ~0 N r~ tr~ t~ r~ N r~ tu~ tA t~ 0 t _ I _ . ~ t~ t,~ . t 0 ~ o t~^ b E _ . t~ ~ tl~tl t 3 11~_ o, -CV~- r1 _~ _~ ____ ~
aO'~ ~ _~ _~ ~ ~ _~ _~
b. b t~
: Ql O
O O _ t J ~
'~ tt~ ~J L O ~ N O t.~ O
C ~ D E t~ ~ ,~ ,,~
r ~
~1 V O V~
.~ .
~, .~ .
tr N 7 ~) oN U ~ r~ ~N oN N oN ~) oN ~N N
~? xN 7 N ~Nr~ N N NN r~ ~N _N N N N N
:~N _ \ / \ ~ \ / \ / \ / \ / \ /
S O O
~ ~ _ : `_ _ : _ . ~ _ _l _ O
~ iS ~ _~ N 1-l :t v~ ~O
V) __ ~_ _ 9~ _ ~3~74t~{~
. ~ n ~ ~D O e O 7 O O O O O O ~O O O ~ O _7 O O O
_ ~ ~ _~ ~ ,. r~ _~ r~ ~ -~
." $ 7 r~ u~ _7 r~ ~ r~ rl 1~ .7 ~O .7 O~ t , ,~'a _ o Or~; rl O rl N ::1 O rj rj O O
r :J a 3: r~ rJ 0 1~r~ rl o~ u~ r~ ~0 O V~ r~
L a ~ u~ 7 u~ u~ L~ u~~O ~O u~ ~ ~O u~ u~ u~
E ~ o _ 0 ~ 0 ~O ~O 7 _7 ~ r~ _~ ~ l _~ r o O r; rl ~0 ~0 ~ ~ ~ o~ r~ _; 0 0 ~ I _ u~ 1~ ~ r~ u~ r~ u~ u~ ~ ~ It~ u~
E ~o _ a ~ ~, ~ a I u ,0 ~^ ~ _~
a o ~ ~
s ~ a L O ~ a o ~o o o c o a .. , v _ _ . .
., a ~ a~u~ a/~o~ a~
_ ~ _ :'~ : ' O O r ~ _ U ~ r o 1.~ a ~ oN~D oN ~) N ~D r~ ~D 3N ~ oN N N
S . IN N ~N ~N N N N N SN N ~N N ~N N
\~ \~ ~/ \:Z/ \~/ \,~/ \z~
/~\ _ ~ 3N 1 t'~ r~
~ ~O) _ . C ~r .: ~ :- : : ~ .' ~ _ ~ 1~ r~ l 0~ O _l 1~1 1~
~O ~O ~O ~O
_ 95 _ i9 _ L _ O ~ ~ ~ ~ ~ ~ ~ ~ ~ _ _ ____ ~ ~ _ _ A I ~ _ _, ,_ _~
b a ~ o _ A .~ .,~ ~ A _ ~ _ G~ o __ E ~ ~ ~ I N ~3 _t N t r r~ ~ O ~
~, n J o ~ o o o ~ ~ o o o o o o _ _, .n~ b, _~
.n O r~ _~ ,~ --1 _~ _~ ri b _ _ O O
~' b ~ a D 0 7: O rl _, 0 3 -~ ~D E o--` rl o c o a .1 ~ . _ ._ _ o o ~ ~ c ~ , r~ N ~ rl C ~N ~N ~N rN C ~ N N N N C ~ O .~.
:1: \7j/ ~\7r/ \71/ \ i \ / r
-7, _ ~i N r~ -- :~ ~
, i, i ~L s ~
1~3746'9 ._ ~ O .~ ~ ~ C ~ ~ D - ~ ~ ^ ,-~ ~ A O ^ .A
~t ~, r~ 1~ r~ ô O r~ l~ r~ ~ ~ ô o~ r~ _ __ r _ __ ~ ~ .~_1 ~ ~ ~ _~ ~__ . -- _ _ A 1 _ _ A ~ _ _, A .~ C A _ _ .,,~ . :~ ~,~ ;1. _~ _~ 01, `~ ~-- i= ~ ~i~ ~i ~ ~ ~ ~ ~ _ ~ rl ~1 ~ O _-- _ C~o~,EO~ ~ _ 1~ o o -~ ~ ~ o~
_ __ U,)~ ~ ~'~''-.
~ l _ e ~ _r~ A _~ ~ --~
11~ ~
1 ~ ~ ~ ~ ~3 ~ ~0 ~ , i ~ n _ r ~
g7 li374~9 ~ ', o~-o o~-~ ooo o.,~A oo~ o~ ooc, .~ o~ .~,~ o~ .~ ~ ~o~
_ . d a ~; _ _ _ _ _ r~ ~ O ~ _ _ O _ ~ _ a o ~ _ o ~ o ~o ~ r~ 1~ _ D IC N _ 9 4 . _ ~ -- 51 ~ ~ ~A O ~ ~ ~ D ~ ~ ~
1~1 ~ ~ ~0 ~ ~1 ~
a o ~ ~ ~ ~ ~
~L ~^ L L~ ~
;.
~, ,,, ,.
1~3'7469 o .A ~ o ~ ~ ~ ~ r o o ~ o ~ o o o o o o _ r~-_ r~__, ~rl-l-~ r~ _~ ~`N-l r~__, r~_,_, I _ _ _ .
,~3 ~. ~ r rl ~ ~ r~l ~o ~o rl r~ r .t ro _ _ _ O _, _ _ _ ~1 _ _ _ rl N ~1 h ~1 . $ _ a , _ -O _ _ 0 , O ra ro ~ _ ro ro r~ O
1~ 1~ ~C ~o t~ r' ~o o I~ r~~C ~O o\o _ , . r~ 0 `O --I O ~0 r~ _~ O 1~ r~ _, r~ _r E ~ 1r~ U~ ~ ~ ~ - - ~ ~ .1 ~ ~o o~
.1 '4 .~ ::> O O ~O r,~ r~ ~O ~O r~ ~ ~O ~O _-r -r D _ O V . . ~ _ _ , '.1 ,~ o _ ~' C' C 1" N N N N N N N
C - ., 0,,00~3 ~.~ ~rJ ~'~0 ~- l ' .' IJ ~ O rJ .rl .~ .
_ ._ .~ ~N
e 1 ~ oN l , l l l l ~^ _ :~
14 N _ N N
O O .~ I~ r~ _ _ _ ~ r~ ~~ N N ,~ ~N ~ _ , O U $~ ~ N~ ~) ~ ~S~ O ~:~
~ 7N _ ,.~ ~ ~ n '' ~: ~ : ~ : ~, : ~ ., r~ _ . ..
4 ' v~ ~o r~ ra o~ O _~
Ez, rt~ co ro ro ro rr. rJ~
_ 99 _ ~13 746~
_ ~ _ _ _ . _ ,, .~_t t O O O~ O O O O ro `~ O .~ ~ ~ O O O ~ 'r~ rl r e .~ o .r r~ ~r~ N ~O -~ r'~ r~ `~J ~ r`~ ~ I ~ r ! ~ r ,~, r~
r_ _ r~_~ ~ ~ r~ r~_ ~ r~ r~ r~r~_~
-- 1~ _ _ ~ rr 0 r~ -~ 7 0 `v 0 O rô ~ t O
~. o ~. rj ~; ~; ~ _~ ~' ~ r~ ~ ;J :~
~ ~ __~ _~_ _~ _ _.
_, --I 'J: O _ 0 0 2 ~ r~ ~ N G _. O
1~ - _ `O ~O ~O ~O ~O ~O _7 _7 ~O ~O O ~O
_ . . r~ r~ rtl rr~ O O ~. rl~ O ~ 0 `O ~ _- O~
_L r~ `O 7 .~ a ~ _ 7 ~ .. _ _o : :~o r~ :~o ~
~ I _.
~"
L u N NN N N N _~
~ _ .vCo~Cv ~, ~ O ~ ~
,: ~ __ ~~0,~- O' ~ ' ~
~r ~1b~
N o â G O G O O
~S ~ ~9 _ ~ : ~ ~
:' . ~ ~ ~ _ ~ ~
_ ,~ 2; N 2 O~ o0 ~374~9 â ~ rl ~ â
_ r _ r~ r _~ ; r~ ~; r~ ; r ~; r~ ;
n ~ ~, rl _~ .- ~ rl _ O ~ r~ r - ~ r~ ~
, ~ _ _. _ _ _ ~ ~ o r~ r~
~ rJ _ _._ _ ~ _ a ~ r - o v ~ ~ O _ ,~ r~ I~ .t ~o t r~ _ ~ ~.... I'~ ~ `V ~:! I~ 'O ~' . ~O
E o O r~ O .t ,_ ~ rJ , ~1 -t rl ~ o o ~
~ 3 ~ o ~ ,o ~o _ ~ .,~ ,~ .''~ '.i o `~
_ _ ~ _ ___ E~ o Cl ru ~J ~o~^ o 01 ~ L -O^
_ n 9 ~ ~ ~ ~ ~ ~ ~
ô~
ooo-~
.,__o a o ~. ~ a ._ o~ o~ __ o~ . ' 2 l o ~N l - ~3, o l - _~ o l ~_1 r~ ~: r~
_ _ r~ ~ _ r r~
_ 11 ~)O C~O (~O Oj ~ 0~ 0~
~,"~ _ g~ ~ ~ .
.t ~ ~ . ~
_ E ,C ` n 1~37q~9 ~ ~ o~ ~ o 7~~ o~L ~
~ - ~ O t-` ~ t~ t'` O r~ rl i .t O t~
t~ ~;~ ; r~ ~ ~; ~ ; ~ ~, ~ ~ _ ~
A -- 7 `O rl ___ rl ~ ____ 0 0 -t _ ___ ~ _ ~_ . O O ~ O O ~I N O O ~ O ~
" a ~ _ _ _ ____ ___ _ ___ _.__ a -- ~ r ~o t-~ 0 N 1~ t~ O ~ IOA t N ~O O ~O
a ta ~ v~ ~ ~o ~o ~ ~ r~ t~ ,~ ~ ~D ~ .r~ ~
C - .. _ _ ._ _ .
E o cl t ~ o rl ~ t ~ t~ 1~ t O J ~ v~ t I
C 3 O N ~ 1~ t~ N N t~ t~ ~ -t u~ ~
_ O^ U-~_ _ tl^ 0~
~o~ lV 'O 1.~, ~ lV ~ lV .
O_ LZ~
.
. v ~ o a 3 - 1~ ~l E o~
cv~`U~~u _ _ oN oN N O
. " V '~oN l _~3,oN l _ ~3oN l o~t~N
rl ~n~ o o Ont - - ~ ~
tS N ~ _ ~ _ E r S ~: (~ oN ~ oN [~ oN O _ oN OrN _N
o t s s sN sN sN sN sN sN O sN ~`I s ~I N
S t~ ~ ~ O t~ \ ~ t.) O \ / Y/ ~</
S-7. _ 7t. 7 7 7. ;~ 7. ~' S S t~ :1: S .
t ~ : ~tS : .~ : :
. ~ _~ ~
_~ _ m o ~ t~ t~ o 3 N
~ 102 --li3~74~
_ r~ D O a ~ -- 8 "
~ Oo O O r, 8 7 8 ~ o 8 r~ o ~ rJ r.~ -7 1-1 No rl o r N 1` 7 un r~ 7 u~ r~
_ r~ ~ r~ ; ¦ r~ r~ _ r~ ; . _ . ____ _ r~ r~ _~
.~ ~ rl O _ ~1 7 - O ,~ t r~ r~ 7 ~O ~
. ~ O i'. . N r; 1 _ ~1 ~J O O N rl O O
a a _ 1 1 --~ ~
r t. ,J~ _ r7! ~ 0 r i~ 1~ r~ ~ ~ ~ r to L a _ ~ ~0 ~0 . __ un ~ ~o ~ ~r\ T
E ~ c~ O _~ ~ r~ o ~ ~o t. 1~ r~ ~o r~, O, 1~ u~
_~ ~, O~ ,0 t t O~ O ~t t ,,~ ~ Nr\ N~
_ __ . I~^ L ~ - r~ -r~ r _ -~ U r _~ r _l E-- o _ ~o-- O ~t O al _.......... . . __ _ a U . ~ _l _l ,~ _l _~ ,~
r v o J ' -- O 1. ~ NO
__ _ .. _ . 01 oN oN
V l l ~ oN l T _~0 l ~ ?C
_ mr~ r ~nr _ _ _ Or/_~ r~ r r O oN :1~ r~ r~ r~ ~ r ~ _ ~ ~ ~ Q ~ D ~ r u_ D o r~ rl oN ~ u U _ D = ~ . . __ . _ . .
b O O : :
r~ _ ~ . _ E r~ ~t _l . . ~ ~ ,~
1~3~4~i9 ~ ~ ,~ .,,~
r _ O O 0 3 0 O O O O O O O 1~ O O .:) O
r o ~ r~ _ r~ _ ~o ~ ~ rr~ rl O ~ t r~ _~
n -- :. C~ O --I rl ~ t , -~ _ r~ C~ r~
. _ _ r~ __ _ _ ____ rl r~ O O _ _ _ _ _ ~: rOr~ r~ rl r~ _ - r;) ~o 1~ O ~ ~ O
L ~ ~ _ ~ ~r I~ ~ ~ ~ _~a o ~ ~
L L - r~v~ r~ rD tu~ 3 ~t r~ 7 ~ .t N
~ ~ L~ u~ v~ r r~ r~ r~ .~ _ ~O v~ r~ rl O ~.0 . ~ _ L ~ L r ., ~ ô L
E _ ~ : I ~ .~ _ o o V o .
n 34C~ .. 1 _1 _1 _~ _~ ~ _~
~ ' -- C rJ _ O ~ ^ o, N 1~ 1 ~ L L o ~' O
. _ ___ O" O'l C ~ W l c~3oN l 3~9 r ~n ~ ~n _ _ .
U ~ ~ D ~ ~ ~ ~ C 1 U---~
~5 _ ~r~ . ... _ ~
L O ~ : : : : ~r~ r~ ~ ~ . .
. ~ . ~0 O _ __ ._ ...
E ;z o r~NN N N N N
1~374~9 _ _ __ __ __ _ _ ~
~ _ C O O "~ -~ N'O r~ ~ .~ ~ O o O
r ~ ~ ; ~:~ ~ ~ _~ ~ ~ ~ ~
n ~ ---- ~ 2 ~~-- -- ~_ _ - .s ~ ~, 0 0 ~ _ __ ___ __ ____ ____ _ __ _.__ __ a :~ ~ O r~ ~ N r C~ ~ N ~ ~ ~ 'O ~ -S ~
., ~ :~ ~ u~ .~. `O `O `0~0 1~ 1~ ~` ~) `O O `O
~ .~ .~ ~c! ~ r~ r_ O JJ ~0 ~ r~ N _. N N O
~ ~ J ~ ~ ~ -2 -2 N ~ -2 s ~ ~ A ~ I) _ .~ ~ r~ O O
~J _1 U O : N N O 3 _ -- r. o ~ _l ~ u~ ~ .r~ ~n ., v ~ o d v ~ O O ~ I r~ N ,~ r~
O ~. C., U d _ O _ __ _ ~ --_ _ ~. r~
O ~ _ ~ ~ ~ ~ _ ~ _ ~ D ~~ ~ _~ oN ~ U _N _N _N _ .) \/ \/ \/ \/ \/ \/ \/
=n i, ~ ;~ :~; 1. I. ''F
?N - - ---E Z N N ~1 . O ~ _~
4ti9 ~, T~r T~:`IL`
'b _ :'. r~ r~ 1 r-t\ O _ ~ r~ r! ~ C~
r ~ ~ _ r~ _~ - _t r~~ r'~ ~ r~ r~~ r r'~ r~
~ ~ . ~c ~, '1 ~ "~ ~ ~o _ ~ ~ ~ ,~
E rJ O r~ ~ ~ r~ r~D U~ _t r~ Ir\ ~ r~ r~ ~ t r 3 D _ O ~ : O ~ 0 0 _ L
~ t~ t l~j l i3~ 9 o ~ ~ ~ ~ ~ a o c o ~ ~ o ~ ,~ r-~ ~ o '~a o O o O o~ O ~1 t n $~ _ rn ~ m m ~ o __ _ r~
~ _ :i' o ~ ~ ~O N ~ _ c, ~ O _. ~ ~ o ,.:1 . :~ r` . ~ ~ .t .- _- r'~ rl ~1 ~ ~t t . a ':P _ ~ I ~ ~ _ _ a ~ ~ r I o ~o o ~o ~o ~o ~o ~o r ~o o .... _ E o o ~ o _ ~ _ o 1~ .t O~ r~-l O 0 o ~ r~ I~ o ~n n r ~ ~O ~ r~ rl~ i r~
_ O L ,C~-E _ 3 N r~, : : : _ o _ . ~ ~ ~ U~ In n ~n ~r~ Ir~ rn _-' I
00~10,~'5 L C r., r~ O O ~.
O -7 ~ ...
.0:~
~ E l l l l l l l ~^
_ ... _ ,_~ ~ ~ Y D ~ Y o o~ D~
_N \ ~ \ / \ / \ ~ \ / \ /
~r~\ _ = ~1 r~r~` r~'`
; ~ L ~ , 741j9 _ ___ ---------r- --m ~ o ~ o E _ _ ~_ o ~ ~ o o ~ ~ U~ _ ~ U~ ~ o ~ r~ _ r~ _~ _ ~ _ ~ ~ ___ ~ ~ ;~ o~ 0 o ~ V\ ~ _ C~ 0 1~ ~ ~ O O
_. ~. r~ r^ r~ r~ ; ~ - r~ ~ ~ o ~o o __ __ ._ __ . _ . ___ _ ~ _. ~o c~ _~ "~ r~ C ~ ~ ~ r~ ~o o ct~
c ~ --~ ~ ~ ~o o ~o ~o ~o ~o ~o ~o O ~o E C O C~ N ~ ~ C C 1~'\ ~ CO rl 0 o o ~o _~
r ~, O _ ~ ~ ~ ~ ~O ~ I_~ .~ _ v~
~ ~ L ~ ~ cl E _ O : : l rl _ :
C,~~'~-~-C O ' 1~ ~ U~ U~ ~ ~
_ O ._ __ __ L O t~ d 1~ ~0 ~.
C ~ O _, O L ~ rl O
~_; ~ ~ ~t ~o~<~ ~ '; "
L ~ ~ : ~ ~ ~_\/ :
.~ ~ ~ ~ ~
I ~0 _ 0 ~ ._ _ -- -_ .. _ _ _ r~ ~ ...... _ _~ ~ 1~l r~
~ _r~ rlrl - ~ _ _ 1~ 0 ~o r~ r a a ~_ __ ~ r~ rl _ _ _____ ~ r r a ~ _5: O ~C~ r~ C~ rl r~ _ ~ a ~t, ~ rl 0.
L a O_ _~r~ ~ ~O O O \2 O ~ ~O o r~ r~
E O o C~ r~ ~ rl r~ 0 r~ r~ ~0 r~ ~ u~ 0 ~ V . . . . . . . . . . . . . .
~ ~ _ :~1 ~ ~ ~ _ .
L ~ __ _~ .~ ., r L ,~ l ~O ~O Ir\ _~ Ir~
~ ~' C a ~ .. ._ . . __ I . _ ,i ~. r~
~0 ~ , r~ r~ _ ~ _ . _ E _ ". r V V_ t V ~t V ~ r~ ~ ~ ~0 ~
V ~ _N rl S S~ _N y _N y _N _ I _r~ _N ~1 S V V V V ~: V _ 1: V V V V V
S~ _ \5/ \~,/ \,/ \~/ \~,/ \~/ \j/ .
_ ~t 0~ ~ : _ : ~ :
V/Z _ _1 ~ r_ ~0 ~.~ ~0 1~37469 ~ ~ 2 o r O ~
r _ ~ ~ ~ ~ ~) ~ ,A ~ ~ u~ ~ o o o ~ ~ ~ ~ o o ~ ~ ~ ,~ .0 .~ r~ o r^,~o ~~ ~ ~ ~o rJ` r~ _ _ . ~ ~ _ r~ ~ _ ~ _ _, ~ ~ _. _ r _ _ ~ _ ~ v ~ _ 7 1 ~ __ ~r a ~ ~ ~ I ~ r~ r~ _ o~ ~ ~ rl rl o ~o 4 o b ;~ ,0 ~ `O `4 `O `O ~ `O ~a ~ `O `O
~ .... _ - -- ---~ . --- -E o o r~ N r~ rl r'~ N a a ~ ~ r~ u~ ~a. .-r ~o ~o~ _ _"~r~ . r~ ~ ~S v~r`
r ` . _ _ __ : .
_ r o -1 ~ _1 _1 v~ ~r~ u~
cl' -~"~o~-N ~ 1,~
o ~ _ _ r _ ~ ~o t ~ ~ ~ w 1i37~69 ___ _ â _~ o~ _ _ E _ ~ D D _ D D
_ r~ ~ r~ ~ O 1 o~ ~o O O O C 1~ ~ ~ r~ r~ - r~
~ ____ r~ _ ~ _ r~ _ _ ~ r~ ~ ~ r~ -n ~ . _ ~ I .^ ~ J, _ r~ ~ ~ O - ~ I~ :~
.'~ _ :~. _ ~I 1, ~ r~ _ r~ ~! ~ r~ x .~ _, _ o ~ ~ ~ r~ r~ _ rl _ _ ~ ~ ~ ~ r~ r~
~ ~ ~ __. _.____.__ ._, _ _ . _ _ ___ a - _ _ ~0 ~ r~ r~ rl r~ C~ ~o _ _ x _ O r`.
.. .. _ _____.___ .____--¦ o ~o _ ~o ~ o ~ r~ o rc J O ~ I r~ r~ r~ ' 0 ~o O ro r~ r . 0 r. r . u~
r ~ J ~ ¦____ _- _7 ~ rl ~O 1~ r~ ~o ~o _ 1.
E~o~ r~. : : : : : : . ~, ._~ r ~ _ .
L u -~ ~ r~ _~ r~ r~ r~
r~ _~
~ O 1 '' r.~~Eo :~ r~l O
o ~. u~ ~
~ ' ~u l l l l .1 8~ 1~
~ _ ._ U _~ r~ \ / \ / _ _~ ~ u ~ J~) ~,~7~ _ :C-Y~. ~j: :~: ~ Z
~\ _ ~ NrJ ~ r~ r~ r~ .
~ ~ ~ ~ : .~ : :
~ _ ~ Z .1 o _, ~. n 1~i37469 __ . _ _ ~ ~ a ¢ U _ r~ ~ _ ~ r~ O O O O O O o O O c~ O O O
_ _ . ,_ - - ~ 1- ~ - - ~ ~-;; ~;;; ~
,~ r ~ ~ X r~ _~ ~ rl _~ r~ r~ r/ r~ r~ v~ ~
_ ,. __ ,.____, __ __ _~ _ _ _~ _1 L d ~,= I~ r~ rl r~ r~ r~ ,rl rl ~o ~C rl ~ r~ r~
C .. __ ___.__ - .__ ~____ _~ _ __ _ ~ r~. J r~ r~ r~. rc r~ r~ rl ro r~ O O rrl~ u~ ~~
_ ~ J _ ~r Ir co ro r~ u~ ~ ~ rl~ r~ V~ u~
C U L : : : : : :
, ~ ~ ~ ~ ~
.__ , ._ .' U _ o C .1 -- ~ _~ O
_ _ ._ _ _ _ 3 ~r n L _ ol,~ _ _r~ ~ ~ ~
N
~U~ _ ............... ___ ._ .
æ ~N r-~'~ U~
L
~ ~ ~ ~ .
O- _ . . ~ .
rn _ r~ ~ _~ :~ rD . _ l ~1 1-13746C~
~- ~ ~l ~ -- ---E _ o o o n: _ o ~ :~ ~ O O ~ o .A o ,~ o ~ o o o o o ~ o o o .n r~ .J :~ I' r~ .n ~ r~ ~, r~ o o r. ;- o . . ~ _ ~' r _ _, ~^ _ ~ r~ ~ ~ ~ _ r ~ r~ r~ _ ~, _, _ _ _ ___ ____ .__ ~_ n ';~; ;~ r~ ~ , - 7~ ~ ~ ~ _. q~ o ~> _ _1` C/ ~ , `~ _ __ ,, " " ,, ,~ " ,~ ,~ ,~ ,~ ,~ ., rJ a ~ _ .___ _ ___ '____.__ ___ ___ _ ~ r _ _ _ ~ ~ r~ ~ r~ J r,~ ~o rL' ~ ~ ~ o ~ r-~ .... _ _ . __ _~_ E ~ o 'n o o r~ 7 0 r~ o In ~o `O ~ o r~
o J ~ ' . 'n .n n .~ ~ _7 Ir\ In 'n 4~ rl r,.
. _ ~ . __ -I
E _ -J : : : : : :
_ __ r~ 0 1 c~ ~; r r r. r ~ rl r L _ ._........... _ _ O
O O o ~ ~
. o ~ a O O, ' ~ E ~ ~ O
~o.~, ~ ., ~
~ E l l r l l l l ~t ~
_ _ o ~ ~: _ _~ .,~
r--~ O f ~) r ,~ O ,~ O ,[~ I ,~n ~ Or~ S ~ ) ~i _N _ D ~ _ Vl ,~ _~ _~ .1 _~ "
1~7~9 .., O. .~.~0 0'l .., ~e 0.~.O a~-_ ~ _ _ _ _ _ ~ ~ ~ O 1 _ ~ _ _ _ r~ _ ll q ~^ - .1 u q. ., ~ o r~ o - - .
_ _ ,~ ~. , _ _ _ r ~ _ _ a r~ rl ^l_ _~
~ o ~. ___ ___ ~____ ~- ' ~ ~ ___ e .. .. _ __ E ~ 1.~ ~ ~~0 Ir~ . . N .~ ~0 ~0 tl~ _~ O N
e L ~ ~ ~ ~ ~ 01~ ~ ~ ,~ ~_ ~ O ~ ~.~ N N N N ~ ~
e o .
e.L'CO~É L-!`1~ ~1 _1 U~
e o ~ , o u ~ oN f ~ -- ~) o ~ ~ ,~ ~ a _rl D
S-~. _ 0~ O
~
S N O __ S S--t ~ o~ ~ ~ ~ 1 ~3'74~ii9 ~ r r r ~ ~
_ . ~ ~ _~ T .-- O ' -- _ _ _ _ ~ ~
_ ~ ~ _~ ~ _ -.... -'__ ~ ~ 3 3 ~ _ 1: ~. 'O ~ '~J r~ - ,~1 ~ ., ~ ~ ~:` ~1 _ I~_ ___ O '~ _~ __ . _ `~ `~ 'O .,'~ `O ~O
L L~,) ~O `O t`~ ~ .~ ~ -- ~0 ~ 0 ~ r~ ,~ ~,~
c~ _ r~ .~7.~ ~ ,~r~ ,~\0 _-~\ u~
E _ o r : : = : :
1 ~ ~, L _ a N ~O ~D
~ O ~ ~ ~
~e C ;j ~
~u\ _ ~ ~'` ~' 0~ ... .
~, ~
1 ~ 374f~9 ~ ~o ~ ~00~0~ ~O 0~ D rV~
~;; ~r;-; r~;;; r~; r~; ,;; r~;
_ __ ._ __ ._ __ ~: ,0 _ j_ _ - _ - r O s . j_ _~ _ r,~ ~ ~~ ~ _ _ _ - _ r~ r ~ _ _ _ ~
J J ~ _ .___ __ .__ .~. _ _ :~ ~ ~ r~ r ~ ~ ~ ~ r~ _ ' _ _ _ ~ r r~
, L ~ ~ D ~ - - ~^ ~_ ~ ^ ~ _ Ir.
C .. .. ___ _ I _ ____ .. __ _ r L L D r~ D ~D r 'r _~ ~ to ~D ~~ _ r _0.9 U ~ V~ 0~0~ 07 . 1~ ~ .
O~ ~_ _ ., C N r~ r~ N rl rl rl -- OL ~
_ O . ___ .~ _ ~ o a 5 ~ a ~ o ,. u~ v~
C o ~ ._ L -J~ ; r~ r~ Ir; rJ
C ~ o V O _ . ~,, ::
., V l . l l l l ~ . ~
_ _ _ .__ .__ L .
~ ~ ~ $o ~u\
I
~i r _~ O Ll _ r L ~ : ~ : : :
_l i _ ' ., ~ .__ O _. . O N N I Nl ~ ~ I
`
--~ 16--1~37469 O , e ~ ~! _ ~ ~ .~ o ~ O c, _ r-~ _ ~ ~ r~ _ ~ r-~ ~ ~ ~ r~ r. ~ -A ~, ;'. 0 .- .r~ r ~ . _ r ~ ~ _ ~ r ~ r 3 ~ ~ _ r~ r I r I rl r~ r~ r ~ r~ !~ ~ r . L a o :1: co r r r r rl o . ~o o o ~ o E L b 0 _~ ~O O O 1~ r~ o r~ ~à O r~ o o _. r~ o _ ___ r r r J , r ~J o ~ rl _ ~ .-r E _ ~, : : : : _ _ a c ~. _ L r~ r ~/ ~ ~ r.~J r~ rl rr~
c ~ a 2 0 ~. 1~ Ir~
r ~ _ r E O ~ r l `v _~
o r~ b. O ~ ._ _ --J ~0 _ ~ D ~ D
~ _ __ ___ _ r~ :c ~ n ~ .4 1~ :
113'~ 9 o o ~ ~ o ~ ~ o o o o o o ~ ~ ~ o o ~ o ~ I
O ~ cO ~ u~ rl r~ ~ ~ ~ ~ ~ O~
z ~_ z ~ ~ ~ ~r ~ ~ ~ ~ ~ ~ ~ ~ ~ ~:r _ _ _l r~ ~ _l ~ ~ ~ ~ _~ _ a~ --~ ~ ~ = ~ ~ 0~ ~ ~O ~ ~ r~ ~O
tJ 3 ~ 4~ u~ ~o ~o .D ~o ~ ~ù v~ u~ u~ ~ ~ u~
~ ~3 C~ OCI ~ ~ O~ ~:0 O~ eo ~ ~ _ ~D ~C>
1~ ~ ~1 ~0 ~ 00 .rl~
Eli b : ~1 r7 3 : :
00_ 3~ X u~ ~ ~ _ ~
0~,~C03 ~OoOg~ O~ ~`I U~ Ul O O,~, _~ ~ l l _~
. _ ;,~r~ ~ ~ ~
--llô-- -1:~3'~4~i9 . _ _ .
_ _ ~
E O O O L O; ~ O 1:) O rA ~1 ~ 3 0 0 ~-1 .''`. IA . ~ r~ r! ~ ~ - ) r ~) ~ _I ~ tr) _~
r~ r _ ~ ~ ~ r ~ r~ r~ _, ____ _ ___ _ ~ .
/: ^ ~ 0 'O "~ : IA _ r ~
~ r~ ~ _~ r~ r - ~:~ r -r ~1 - _~ c~
' _ ,~ , - r~ r~ r~ ~_ _ _, r ~ r~ ~J
_ ~ _ _ ~_ 1_ ~ 0 ,, u _ = r. ~!r ~ _r ~ 1~ IA 00 ; r IA 1'~
_ ~ o ~ ~ ~~ ~ ~o o ~ . ~r - r _ L _ J rl ~_-- . _r ~ ~ I~ ~
~ . ~ _ ~o o r r ~ r r r ~ i A _r t ___ . _ . L _ I _ . .
. ~ ~1 . . . _ L;O O _ _ _ _ ~ .
~ _ ~
~ E l l l ~ ~
_ ~ _ _ ~ O O _ rl O ~ rl :~: :~
E ~ _ ù:r~ _~ rJ N rl S rl N N N rl oN
g rl _ _ _ S S S ~ S S S 3 ~, ~ \/ \/ ~/ \/ ~/ \/ \/
s _ ~ . _ i i ,. l ~: f ~
,//\ , ~' ~N sr` s~r`r~ _r~ r~ S r~ ~ o O _l , ~ ~
v~
1 ~3'7~tj9 al _ O O ~ o o In ~o o o oo ~, u~ u~ ~ ~ ~ ~ r~ u~ ~ ~D ~ ~
h _ t~ _I ~D t~) .--l ~O ~ _I ~D t~) _I ~Ct ~ t'~ -(^ ~ ^ ~ \^r~l ~ (^
~ ~ ~ ~ ~ ~ ~ ~ ~
a ,~ ~ Nr.~ _I O _ 1~-1 ~ ~
(J ~ h ~D ~ ~D ~ ~D ~D ~
o L L _ ~ I~ I~ ~ ~D O O
~Oû O _ ~ _ 'no ~, ~ r~ ,~
,., _ -- O ~ "
j~ ^ _ ~
;` ~ '' ~8 ` ~
~ .t ~ "
L _ ~
_ E -- ~ ~ N ~ U S
n - o u ~)~oN ~oN D ~o . L~
~120-1~3~4~9 Tablets suitable for oral administration Tablets contain.ing the ingredients indicated below may be prepared by conventional techniques.
... .... ~ .. _ , Ingredient Amount per tablet . -- . . . . .. _ : N -(7-methoxy-2-naphthylsulfonyl)- 250 L-arginyl-N-(2-methoxyethyl)glycine Lactose 140 Corn starch 35 Talcum 20 Magnesium stearate 5 .
. Total 450 mg . ._ Capsules for oral administration Capsules of the below were made up by thoroughly mixing together batches of the ingredients and filling hard gelatin capsules with the mixture.
_. . . __ .._ _ .... _ Ingredient Amount per capsule N -(7-methoxy-2-naphthylsul~onyl)- 250 L-arginyl-N-(2-methoxyethyl)glycine Lactose 250 . ..... _.. _ . .
Total 500 mg ._ . _ _ .. . .
li374ti9 EXA~tl'_E 9 Sterilc solution ror inrllsion Tlle ~`ollowing ingl~o(l:iollts arc dissolvcd :in wator for intravellous perfusloll an~l the resul ting solution i9 then s terili zed .
. .. .. _.
lngredi ents Amoun t ( ~) ~, ------ __. _ N ~ -( 7 -mc 1,11oxy-2-llapll thylsul rOtly~ ) _ 2 5 L-argi nyl -N~ me tlloxyctllyl )~] ycinc Buffer sys-tem As desired Glucose 25 Distille<l water 500 ~:
- I "'! --1:~3~469 PREPARATION A
Arylsulfonyl chloricles (A) ~odium 6,7-dimetl~oxy-2-rlaphthaleneSUlfona-te To a well stirred solution o~ 70.8 g of sodium 6,7-clihydroxy-2-naplltll11enesulfonate anti 77.2 ~ of sodium hydro~ide in 450 ml of water was added dropwise 230 ml Or dimethyl sulfate at 60C over a period of one hour, durillg whicll timo the product precipitated. To this reaction mixture was added in portions 38.8 g of sodiùm hydroxide, and stirring was continued for one hour.
After one hour at room temperature, the precipitate was filtered, washetl with ethanol and dried to give 50 g of sodlum 6,7-dimethoxy-2-naphthalenesulfonate.
(B) 6,7-dimethoxy-2-naphthalenesulfonyl chloride To a stirred suspension of 50 g of finely divided sodium 6,7-dimethoxy-2-naphthalenesulfonate in 100 ml of dimethyl-forn~lmi~le was adt~ed dropwisc 62.2 m] of thionyl chloride at room l;cnls)oratllre. After 30 minutos, Lhe reaction mixture was pourc(l illtO 1 ~ of ice water~ and the precipi-tate ri~ torecl alld tllen dissolved into 250 ml of ben~ene.
Tlle ben~elle ~olution was repeatedly waslled with water and drit-(l ovor antlydrous so(lillnl sllll`ate I`bc so:Lvellt wat ovapor~Lotl l,o (Iryllo~ ill vacuo~ alld tlle rosi(luc W~IS
1:~374f~9 recrystallize(l from benzene-n-hexane (1 : l) to give 32 g of 6,7-dimethoxy-2-naphthalenesulfonyl chloride~
~I.P. 127.5 - 12'~.5C
All~lysis - Calc(l. ror Cl2llll0l~SCl. (porcoll~): C, 50.26;
H, 3.87; Cl, 12.37 Found (percent): C, 50.45;
H, 4.00; Cl, 12.33 The following arylsulfonyl chlorides not previously reportecl in the chemical literature were synthesi~ed by thc aroremelltiolled procedure which is essentially that as described i.n E. H. Rodd, "Chemistry Or Carbon CompoundS", Elsevier Publistung Company, 1954, Vol m, P. 441-469.
_ _ No. Arylsulfonyl Chloride M.P. (C) ~ .. _ C10 S ~f~ ~,OC2H5 I 2 ~ C2H5118 - 119.5 2 1 2 ~ ~ OC~I~l36.S - 133.5 _ . _ ~ (:lo~ ~ O) l~7 - 13 _ .
- ].2l~ -1 ~37~
PRE}'ARATION B
Amillo acicl derivatives (A) N-butylglycinc tert-butyl ester To 36.5 g of butylamine was added with stirring 15.05 g of tert-butyl clll.oroacetate over a period of 30 minutes, while mai.lltai~ lg the temperature at 30-70C. The reaction nLixtnre was held at 70 C for an additional one hollr. At the en(i of this period~ the cxcess butyl amine was evaporated in vacuo, and the residue was taken up in 40 ml of 2N NaOI~ solution and 50 ml of benzene, transferred into a separatory funnel and well shaken. The benzene solutioll was separated, washed with water, dried over anllydrolls sodi.llm sulfate and filtered. After evaporation of ben~elle, the residue was distilled under reduced pressuro to g:i.vc 17.0 g (90.9 percent) of N-butylglycine tcrt-~ tyl cs ter, 11.1' . 7GC/4 nmlllg .
'rhe 1'O~ lOWill~ alllillO uci(l tert-butyL cstcrs not ~reviously rel~orLc~ tllc chcmi.cul .Litcrutllrc wcrc sy~ltllesized by l;lIC Ul`Or-`nlOllLiO11(?(l prOCC~IlJre WlLi Cll .i:i c~selltially that as taught by A. J. Speziale et al., J. Org. Chem. 2~ 731 (1960).
1~3t74~
~ .
,, No . l~mi llo Aci(l I)crivative I~ .P .
_ _ . _ - ' 1 I IN \ ~ ' 3 9 5 C / 2 0 mml I g Cll,~CO,,-~-CIIl{~
_ -- --- -- _ ~ .
~C112CII(C113)2 2 IIN 6 5 C/ 5 mmllg _ \C112C02-t-C41~9 . __.
3 ~(Cll2)l~cll3 89~90 C/2.5 mmHg \C112C02-t-CI~ __ 4 IIN ~ ( C112 ) 5(~ 8 3-5C /1 . 5 mn~lg C 2C2 t C4Hg .
_ .- .~
~(CH2 )7C113 125-130 C/4 mmHg CH2C 2 ~ t -C~ H
_ . _ . .
6 ~CI12Ctl20C113 61- 2 C/2 mmHg \Cli2C02--t--CLIH9 ~
_ . .
7 HN~CH2CI12 0CI13 94 C/ 3 mmHg 2C112C2-t-C4~9 _ , ~ 2C 120CH3 o
, i, i ~L s ~
1~3746'9 ._ ~ O .~ ~ ~ C ~ ~ D - ~ ~ ^ ,-~ ~ A O ^ .A
~t ~, r~ 1~ r~ ô O r~ l~ r~ ~ ~ ô o~ r~ _ __ r _ __ ~ ~ .~_1 ~ ~ ~ _~ ~__ . -- _ _ A 1 _ _ A ~ _ _, A .~ C A _ _ .,,~ . :~ ~,~ ;1. _~ _~ 01, `~ ~-- i= ~ ~i~ ~i ~ ~ ~ ~ ~ _ ~ rl ~1 ~ O _-- _ C~o~,EO~ ~ _ 1~ o o -~ ~ ~ o~
_ __ U,)~ ~ ~'~''-.
~ l _ e ~ _r~ A _~ ~ --~
11~ ~
1 ~ ~ ~ ~ ~3 ~ ~0 ~ , i ~ n _ r ~
g7 li374~9 ~ ', o~-o o~-~ ooo o.,~A oo~ o~ ooc, .~ o~ .~,~ o~ .~ ~ ~o~
_ . d a ~; _ _ _ _ _ r~ ~ O ~ _ _ O _ ~ _ a o ~ _ o ~ o ~o ~ r~ 1~ _ D IC N _ 9 4 . _ ~ -- 51 ~ ~ ~A O ~ ~ ~ D ~ ~ ~
1~1 ~ ~ ~0 ~ ~1 ~
a o ~ ~ ~ ~ ~
~L ~^ L L~ ~
;.
~, ,,, ,.
1~3'7469 o .A ~ o ~ ~ ~ ~ r o o ~ o ~ o o o o o o _ r~-_ r~__, ~rl-l-~ r~ _~ ~`N-l r~__, r~_,_, I _ _ _ .
,~3 ~. ~ r rl ~ ~ r~l ~o ~o rl r~ r .t ro _ _ _ O _, _ _ _ ~1 _ _ _ rl N ~1 h ~1 . $ _ a , _ -O _ _ 0 , O ra ro ~ _ ro ro r~ O
1~ 1~ ~C ~o t~ r' ~o o I~ r~~C ~O o\o _ , . r~ 0 `O --I O ~0 r~ _~ O 1~ r~ _, r~ _r E ~ 1r~ U~ ~ ~ ~ - - ~ ~ .1 ~ ~o o~
.1 '4 .~ ::> O O ~O r,~ r~ ~O ~O r~ ~ ~O ~O _-r -r D _ O V . . ~ _ _ , '.1 ,~ o _ ~' C' C 1" N N N N N N N
C - ., 0,,00~3 ~.~ ~rJ ~'~0 ~- l ' .' IJ ~ O rJ .rl .~ .
_ ._ .~ ~N
e 1 ~ oN l , l l l l ~^ _ :~
14 N _ N N
O O .~ I~ r~ _ _ _ ~ r~ ~~ N N ,~ ~N ~ _ , O U $~ ~ N~ ~) ~ ~S~ O ~:~
~ 7N _ ,.~ ~ ~ n '' ~: ~ : ~ : ~, : ~ ., r~ _ . ..
4 ' v~ ~o r~ ra o~ O _~
Ez, rt~ co ro ro ro rr. rJ~
_ 99 _ ~13 746~
_ ~ _ _ _ . _ ,, .~_t t O O O~ O O O O ro `~ O .~ ~ ~ O O O ~ 'r~ rl r e .~ o .r r~ ~r~ N ~O -~ r'~ r~ `~J ~ r`~ ~ I ~ r ! ~ r ,~, r~
r_ _ r~_~ ~ ~ r~ r~_ ~ r~ r~ r~r~_~
-- 1~ _ _ ~ rr 0 r~ -~ 7 0 `v 0 O rô ~ t O
~. o ~. rj ~; ~; ~ _~ ~' ~ r~ ~ ;J :~
~ ~ __~ _~_ _~ _ _.
_, --I 'J: O _ 0 0 2 ~ r~ ~ N G _. O
1~ - _ `O ~O ~O ~O ~O ~O _7 _7 ~O ~O O ~O
_ . . r~ r~ rtl rr~ O O ~. rl~ O ~ 0 `O ~ _- O~
_L r~ `O 7 .~ a ~ _ 7 ~ .. _ _o : :~o r~ :~o ~
~ I _.
~"
L u N NN N N N _~
~ _ .vCo~Cv ~, ~ O ~ ~
,: ~ __ ~~0,~- O' ~ ' ~
~r ~1b~
N o â G O G O O
~S ~ ~9 _ ~ : ~ ~
:' . ~ ~ ~ _ ~ ~
_ ,~ 2; N 2 O~ o0 ~374~9 â ~ rl ~ â
_ r _ r~ r _~ ; r~ ~; r~ ; r ~; r~ ;
n ~ ~, rl _~ .- ~ rl _ O ~ r~ r - ~ r~ ~
, ~ _ _. _ _ _ ~ ~ o r~ r~
~ rJ _ _._ _ ~ _ a ~ r - o v ~ ~ O _ ,~ r~ I~ .t ~o t r~ _ ~ ~.... I'~ ~ `V ~:! I~ 'O ~' . ~O
E o O r~ O .t ,_ ~ rJ , ~1 -t rl ~ o o ~
~ 3 ~ o ~ ,o ~o _ ~ .,~ ,~ .''~ '.i o `~
_ _ ~ _ ___ E~ o Cl ru ~J ~o~^ o 01 ~ L -O^
_ n 9 ~ ~ ~ ~ ~ ~ ~
ô~
ooo-~
.,__o a o ~. ~ a ._ o~ o~ __ o~ . ' 2 l o ~N l - ~3, o l - _~ o l ~_1 r~ ~: r~
_ _ r~ ~ _ r r~
_ 11 ~)O C~O (~O Oj ~ 0~ 0~
~,"~ _ g~ ~ ~ .
.t ~ ~ . ~
_ E ,C ` n 1~37q~9 ~ ~ o~ ~ o 7~~ o~L ~
~ - ~ O t-` ~ t~ t'` O r~ rl i .t O t~
t~ ~;~ ; r~ ~ ~; ~ ; ~ ~, ~ ~ _ ~
A -- 7 `O rl ___ rl ~ ____ 0 0 -t _ ___ ~ _ ~_ . O O ~ O O ~I N O O ~ O ~
" a ~ _ _ _ ____ ___ _ ___ _.__ a -- ~ r ~o t-~ 0 N 1~ t~ O ~ IOA t N ~O O ~O
a ta ~ v~ ~ ~o ~o ~ ~ r~ t~ ,~ ~ ~D ~ .r~ ~
C - .. _ _ ._ _ .
E o cl t ~ o rl ~ t ~ t~ 1~ t O J ~ v~ t I
C 3 O N ~ 1~ t~ N N t~ t~ ~ -t u~ ~
_ O^ U-~_ _ tl^ 0~
~o~ lV 'O 1.~, ~ lV ~ lV .
O_ LZ~
.
. v ~ o a 3 - 1~ ~l E o~
cv~`U~~u _ _ oN oN N O
. " V '~oN l _~3,oN l _ ~3oN l o~t~N
rl ~n~ o o Ont - - ~ ~
tS N ~ _ ~ _ E r S ~: (~ oN ~ oN [~ oN O _ oN OrN _N
o t s s sN sN sN sN sN sN O sN ~`I s ~I N
S t~ ~ ~ O t~ \ ~ t.) O \ / Y/ ~</
S-7. _ 7t. 7 7 7. ;~ 7. ~' S S t~ :1: S .
t ~ : ~tS : .~ : :
. ~ _~ ~
_~ _ m o ~ t~ t~ o 3 N
~ 102 --li3~74~
_ r~ D O a ~ -- 8 "
~ Oo O O r, 8 7 8 ~ o 8 r~ o ~ rJ r.~ -7 1-1 No rl o r N 1` 7 un r~ 7 u~ r~
_ r~ ~ r~ ; ¦ r~ r~ _ r~ ; . _ . ____ _ r~ r~ _~
.~ ~ rl O _ ~1 7 - O ,~ t r~ r~ 7 ~O ~
. ~ O i'. . N r; 1 _ ~1 ~J O O N rl O O
a a _ 1 1 --~ ~
r t. ,J~ _ r7! ~ 0 r i~ 1~ r~ ~ ~ ~ r to L a _ ~ ~0 ~0 . __ un ~ ~o ~ ~r\ T
E ~ c~ O _~ ~ r~ o ~ ~o t. 1~ r~ ~o r~, O, 1~ u~
_~ ~, O~ ,0 t t O~ O ~t t ,,~ ~ Nr\ N~
_ __ . I~^ L ~ - r~ -r~ r _ -~ U r _~ r _l E-- o _ ~o-- O ~t O al _.......... . . __ _ a U . ~ _l _l ,~ _l _~ ,~
r v o J ' -- O 1. ~ NO
__ _ .. _ . 01 oN oN
V l l ~ oN l T _~0 l ~ ?C
_ mr~ r ~nr _ _ _ Or/_~ r~ r r O oN :1~ r~ r~ r~ ~ r ~ _ ~ ~ ~ Q ~ D ~ r u_ D o r~ rl oN ~ u U _ D = ~ . . __ . _ . .
b O O : :
r~ _ ~ . _ E r~ ~t _l . . ~ ~ ,~
1~3~4~i9 ~ ~ ,~ .,,~
r _ O O 0 3 0 O O O O O O O 1~ O O .:) O
r o ~ r~ _ r~ _ ~o ~ ~ rr~ rl O ~ t r~ _~
n -- :. C~ O --I rl ~ t , -~ _ r~ C~ r~
. _ _ r~ __ _ _ ____ rl r~ O O _ _ _ _ _ ~: rOr~ r~ rl r~ _ - r;) ~o 1~ O ~ ~ O
L ~ ~ _ ~ ~r I~ ~ ~ ~ _~a o ~ ~
L L - r~v~ r~ rD tu~ 3 ~t r~ 7 ~ .t N
~ ~ L~ u~ v~ r r~ r~ r~ .~ _ ~O v~ r~ rl O ~.0 . ~ _ L ~ L r ., ~ ô L
E _ ~ : I ~ .~ _ o o V o .
n 34C~ .. 1 _1 _1 _~ _~ ~ _~
~ ' -- C rJ _ O ~ ^ o, N 1~ 1 ~ L L o ~' O
. _ ___ O" O'l C ~ W l c~3oN l 3~9 r ~n ~ ~n _ _ .
U ~ ~ D ~ ~ ~ ~ C 1 U---~
~5 _ ~r~ . ... _ ~
L O ~ : : : : ~r~ r~ ~ ~ . .
. ~ . ~0 O _ __ ._ ...
E ;z o r~NN N N N N
1~374~9 _ _ __ __ __ _ _ ~
~ _ C O O "~ -~ N'O r~ ~ .~ ~ O o O
r ~ ~ ; ~:~ ~ ~ _~ ~ ~ ~ ~
n ~ ---- ~ 2 ~~-- -- ~_ _ - .s ~ ~, 0 0 ~ _ __ ___ __ ____ ____ _ __ _.__ __ a :~ ~ O r~ ~ N r C~ ~ N ~ ~ ~ 'O ~ -S ~
., ~ :~ ~ u~ .~. `O `O `0~0 1~ 1~ ~` ~) `O O `O
~ .~ .~ ~c! ~ r~ r_ O JJ ~0 ~ r~ N _. N N O
~ ~ J ~ ~ ~ -2 -2 N ~ -2 s ~ ~ A ~ I) _ .~ ~ r~ O O
~J _1 U O : N N O 3 _ -- r. o ~ _l ~ u~ ~ .r~ ~n ., v ~ o d v ~ O O ~ I r~ N ,~ r~
O ~. C., U d _ O _ __ _ ~ --_ _ ~. r~
O ~ _ ~ ~ ~ ~ _ ~ _ ~ D ~~ ~ _~ oN ~ U _N _N _N _ .) \/ \/ \/ \/ \/ \/ \/
=n i, ~ ;~ :~; 1. I. ''F
?N - - ---E Z N N ~1 . O ~ _~
4ti9 ~, T~r T~:`IL`
'b _ :'. r~ r~ 1 r-t\ O _ ~ r~ r! ~ C~
r ~ ~ _ r~ _~ - _t r~~ r'~ ~ r~ r~~ r r'~ r~
~ ~ . ~c ~, '1 ~ "~ ~ ~o _ ~ ~ ~ ,~
E rJ O r~ ~ ~ r~ r~D U~ _t r~ Ir\ ~ r~ r~ ~ t r 3 D _ O ~ : O ~ 0 0 _ L
~ t~ t l~j l i3~ 9 o ~ ~ ~ ~ ~ a o c o ~ ~ o ~ ,~ r-~ ~ o '~a o O o O o~ O ~1 t n $~ _ rn ~ m m ~ o __ _ r~
~ _ :i' o ~ ~ ~O N ~ _ c, ~ O _. ~ ~ o ,.:1 . :~ r` . ~ ~ .t .- _- r'~ rl ~1 ~ ~t t . a ':P _ ~ I ~ ~ _ _ a ~ ~ r I o ~o o ~o ~o ~o ~o ~o r ~o o .... _ E o o ~ o _ ~ _ o 1~ .t O~ r~-l O 0 o ~ r~ I~ o ~n n r ~ ~O ~ r~ rl~ i r~
_ O L ,C~-E _ 3 N r~, : : : _ o _ . ~ ~ ~ U~ In n ~n ~r~ Ir~ rn _-' I
00~10,~'5 L C r., r~ O O ~.
O -7 ~ ...
.0:~
~ E l l l l l l l ~^
_ ... _ ,_~ ~ ~ Y D ~ Y o o~ D~
_N \ ~ \ / \ / \ ~ \ / \ /
~r~\ _ = ~1 r~r~` r~'`
; ~ L ~ , 741j9 _ ___ ---------r- --m ~ o ~ o E _ _ ~_ o ~ ~ o o ~ ~ U~ _ ~ U~ ~ o ~ r~ _ r~ _~ _ ~ _ ~ ~ ___ ~ ~ ;~ o~ 0 o ~ V\ ~ _ C~ 0 1~ ~ ~ O O
_. ~. r~ r^ r~ r~ ; ~ - r~ ~ ~ o ~o o __ __ ._ __ . _ . ___ _ ~ _. ~o c~ _~ "~ r~ C ~ ~ ~ r~ ~o o ct~
c ~ --~ ~ ~ ~o o ~o ~o ~o ~o ~o ~o O ~o E C O C~ N ~ ~ C C 1~'\ ~ CO rl 0 o o ~o _~
r ~, O _ ~ ~ ~ ~ ~O ~ I_~ .~ _ v~
~ ~ L ~ ~ cl E _ O : : l rl _ :
C,~~'~-~-C O ' 1~ ~ U~ U~ ~ ~
_ O ._ __ __ L O t~ d 1~ ~0 ~.
C ~ O _, O L ~ rl O
~_; ~ ~ ~t ~o~<~ ~ '; "
L ~ ~ : ~ ~ ~_\/ :
.~ ~ ~ ~ ~
I ~0 _ 0 ~ ._ _ -- -_ .. _ _ _ r~ ~ ...... _ _~ ~ 1~l r~
~ _r~ rlrl - ~ _ _ 1~ 0 ~o r~ r a a ~_ __ ~ r~ rl _ _ _____ ~ r r a ~ _5: O ~C~ r~ C~ rl r~ _ ~ a ~t, ~ rl 0.
L a O_ _~r~ ~ ~O O O \2 O ~ ~O o r~ r~
E O o C~ r~ ~ rl r~ 0 r~ r~ ~0 r~ ~ u~ 0 ~ V . . . . . . . . . . . . . .
~ ~ _ :~1 ~ ~ ~ _ .
L ~ __ _~ .~ ., r L ,~ l ~O ~O Ir\ _~ Ir~
~ ~' C a ~ .. ._ . . __ I . _ ,i ~. r~
~0 ~ , r~ r~ _ ~ _ . _ E _ ". r V V_ t V ~t V ~ r~ ~ ~ ~0 ~
V ~ _N rl S S~ _N y _N y _N _ I _r~ _N ~1 S V V V V ~: V _ 1: V V V V V
S~ _ \5/ \~,/ \,/ \~/ \~,/ \~/ \j/ .
_ ~t 0~ ~ : _ : ~ :
V/Z _ _1 ~ r_ ~0 ~.~ ~0 1~37469 ~ ~ 2 o r O ~
r _ ~ ~ ~ ~ ~) ~ ,A ~ ~ u~ ~ o o o ~ ~ ~ ~ o o ~ ~ ~ ,~ .0 .~ r~ o r^,~o ~~ ~ ~ ~o rJ` r~ _ _ . ~ ~ _ r~ ~ _ ~ _ _, ~ ~ _. _ r _ _ ~ _ ~ v ~ _ 7 1 ~ __ ~r a ~ ~ ~ I ~ r~ r~ _ o~ ~ ~ rl rl o ~o 4 o b ;~ ,0 ~ `O `4 `O `O ~ `O ~a ~ `O `O
~ .... _ - -- ---~ . --- -E o o r~ N r~ rl r'~ N a a ~ ~ r~ u~ ~a. .-r ~o ~o~ _ _"~r~ . r~ ~ ~S v~r`
r ` . _ _ __ : .
_ r o -1 ~ _1 _1 v~ ~r~ u~
cl' -~"~o~-N ~ 1,~
o ~ _ _ r _ ~ ~o t ~ ~ ~ w 1i37~69 ___ _ â _~ o~ _ _ E _ ~ D D _ D D
_ r~ ~ r~ ~ O 1 o~ ~o O O O C 1~ ~ ~ r~ r~ - r~
~ ____ r~ _ ~ _ r~ _ _ ~ r~ ~ ~ r~ -n ~ . _ ~ I .^ ~ J, _ r~ ~ ~ O - ~ I~ :~
.'~ _ :~. _ ~I 1, ~ r~ _ r~ ~! ~ r~ x .~ _, _ o ~ ~ ~ r~ r~ _ rl _ _ ~ ~ ~ ~ r~ r~
~ ~ ~ __. _.____.__ ._, _ _ . _ _ ___ a - _ _ ~0 ~ r~ r~ rl r~ C~ ~o _ _ x _ O r`.
.. .. _ _____.___ .____--¦ o ~o _ ~o ~ o ~ r~ o rc J O ~ I r~ r~ r~ ' 0 ~o O ro r~ r . 0 r. r . u~
r ~ J ~ ¦____ _- _7 ~ rl ~O 1~ r~ ~o ~o _ 1.
E~o~ r~. : : : : : : . ~, ._~ r ~ _ .
L u -~ ~ r~ _~ r~ r~ r~
r~ _~
~ O 1 '' r.~~Eo :~ r~l O
o ~. u~ ~
~ ' ~u l l l l .1 8~ 1~
~ _ ._ U _~ r~ \ / \ / _ _~ ~ u ~ J~) ~,~7~ _ :C-Y~. ~j: :~: ~ Z
~\ _ ~ NrJ ~ r~ r~ r~ .
~ ~ ~ ~ : .~ : :
~ _ ~ Z .1 o _, ~. n 1~i37469 __ . _ _ ~ ~ a ¢ U _ r~ ~ _ ~ r~ O O O O O O o O O c~ O O O
_ _ . ,_ - - ~ 1- ~ - - ~ ~-;; ~;;; ~
,~ r ~ ~ X r~ _~ ~ rl _~ r~ r~ r/ r~ r~ v~ ~
_ ,. __ ,.____, __ __ _~ _ _ _~ _1 L d ~,= I~ r~ rl r~ r~ r~ ,rl rl ~o ~C rl ~ r~ r~
C .. __ ___.__ - .__ ~____ _~ _ __ _ ~ r~. J r~ r~ r~. rc r~ r~ rl ro r~ O O rrl~ u~ ~~
_ ~ J _ ~r Ir co ro r~ u~ ~ ~ rl~ r~ V~ u~
C U L : : : : : :
, ~ ~ ~ ~ ~
.__ , ._ .' U _ o C .1 -- ~ _~ O
_ _ ._ _ _ _ 3 ~r n L _ ol,~ _ _r~ ~ ~ ~
N
~U~ _ ............... ___ ._ .
æ ~N r-~'~ U~
L
~ ~ ~ ~ .
O- _ . . ~ .
rn _ r~ ~ _~ :~ rD . _ l ~1 1-13746C~
~- ~ ~l ~ -- ---E _ o o o n: _ o ~ :~ ~ O O ~ o .A o ,~ o ~ o o o o o ~ o o o .n r~ .J :~ I' r~ .n ~ r~ ~, r~ o o r. ;- o . . ~ _ ~' r _ _, ~^ _ ~ r~ ~ ~ ~ _ r ~ r~ r~ _ ~, _, _ _ _ ___ ____ .__ ~_ n ';~; ;~ r~ ~ , - 7~ ~ ~ ~ _. q~ o ~> _ _1` C/ ~ , `~ _ __ ,, " " ,, ,~ " ,~ ,~ ,~ ,~ ,~ ., rJ a ~ _ .___ _ ___ '____.__ ___ ___ _ ~ r _ _ _ ~ ~ r~ ~ r~ J r,~ ~o rL' ~ ~ ~ o ~ r-~ .... _ _ . __ _~_ E ~ o 'n o o r~ 7 0 r~ o In ~o `O ~ o r~
o J ~ ' . 'n .n n .~ ~ _7 Ir\ In 'n 4~ rl r,.
. _ ~ . __ -I
E _ -J : : : : : :
_ __ r~ 0 1 c~ ~; r r r. r ~ rl r L _ ._........... _ _ O
O O o ~ ~
. o ~ a O O, ' ~ E ~ ~ O
~o.~, ~ ., ~
~ E l l r l l l l ~t ~
_ _ o ~ ~: _ _~ .,~
r--~ O f ~) r ,~ O ,~ O ,[~ I ,~n ~ Or~ S ~ ) ~i _N _ D ~ _ Vl ,~ _~ _~ .1 _~ "
1~7~9 .., O. .~.~0 0'l .., ~e 0.~.O a~-_ ~ _ _ _ _ _ ~ ~ ~ O 1 _ ~ _ _ _ r~ _ ll q ~^ - .1 u q. ., ~ o r~ o - - .
_ _ ,~ ~. , _ _ _ r ~ _ _ a r~ rl ^l_ _~
~ o ~. ___ ___ ~____ ~- ' ~ ~ ___ e .. .. _ __ E ~ 1.~ ~ ~~0 Ir~ . . N .~ ~0 ~0 tl~ _~ O N
e L ~ ~ ~ ~ ~ 01~ ~ ~ ,~ ~_ ~ O ~ ~.~ N N N N ~ ~
e o .
e.L'CO~É L-!`1~ ~1 _1 U~
e o ~ , o u ~ oN f ~ -- ~) o ~ ~ ,~ ~ a _rl D
S-~. _ 0~ O
~
S N O __ S S--t ~ o~ ~ ~ ~ 1 ~3'74~ii9 ~ r r r ~ ~
_ . ~ ~ _~ T .-- O ' -- _ _ _ _ ~ ~
_ ~ ~ _~ ~ _ -.... -'__ ~ ~ 3 3 ~ _ 1: ~. 'O ~ '~J r~ - ,~1 ~ ., ~ ~ ~:` ~1 _ I~_ ___ O '~ _~ __ . _ `~ `~ 'O .,'~ `O ~O
L L~,) ~O `O t`~ ~ .~ ~ -- ~0 ~ 0 ~ r~ ,~ ~,~
c~ _ r~ .~7.~ ~ ,~r~ ,~\0 _-~\ u~
E _ o r : : = : :
1 ~ ~, L _ a N ~O ~D
~ O ~ ~ ~
~e C ;j ~
~u\ _ ~ ~'` ~' 0~ ... .
~, ~
1 ~ 374f~9 ~ ~o ~ ~00~0~ ~O 0~ D rV~
~;; ~r;-; r~;;; r~; r~; ,;; r~;
_ __ ._ __ ._ __ ~: ,0 _ j_ _ - _ - r O s . j_ _~ _ r,~ ~ ~~ ~ _ _ _ - _ r~ r ~ _ _ _ ~
J J ~ _ .___ __ .__ .~. _ _ :~ ~ ~ r~ r ~ ~ ~ ~ r~ _ ' _ _ _ ~ r r~
, L ~ ~ D ~ - - ~^ ~_ ~ ^ ~ _ Ir.
C .. .. ___ _ I _ ____ .. __ _ r L L D r~ D ~D r 'r _~ ~ to ~D ~~ _ r _0.9 U ~ V~ 0~0~ 07 . 1~ ~ .
O~ ~_ _ ., C N r~ r~ N rl rl rl -- OL ~
_ O . ___ .~ _ ~ o a 5 ~ a ~ o ,. u~ v~
C o ~ ._ L -J~ ; r~ r~ Ir; rJ
C ~ o V O _ . ~,, ::
., V l . l l l l ~ . ~
_ _ _ .__ .__ L .
~ ~ ~ $o ~u\
I
~i r _~ O Ll _ r L ~ : ~ : : :
_l i _ ' ., ~ .__ O _. . O N N I Nl ~ ~ I
`
--~ 16--1~37469 O , e ~ ~! _ ~ ~ .~ o ~ O c, _ r-~ _ ~ ~ r~ _ ~ r-~ ~ ~ ~ r~ r. ~ -A ~, ;'. 0 .- .r~ r ~ . _ r ~ ~ _ ~ r ~ r 3 ~ ~ _ r~ r I r I rl r~ r~ r ~ r~ !~ ~ r . L a o :1: co r r r r rl o . ~o o o ~ o E L b 0 _~ ~O O O 1~ r~ o r~ ~à O r~ o o _. r~ o _ ___ r r r J , r ~J o ~ rl _ ~ .-r E _ ~, : : : : _ _ a c ~. _ L r~ r ~/ ~ ~ r.~J r~ rl rr~
c ~ a 2 0 ~. 1~ Ir~
r ~ _ r E O ~ r l `v _~
o r~ b. O ~ ._ _ --J ~0 _ ~ D ~ D
~ _ __ ___ _ r~ :c ~ n ~ .4 1~ :
113'~ 9 o o ~ ~ o ~ ~ o o o o o o ~ ~ ~ o o ~ o ~ I
O ~ cO ~ u~ rl r~ ~ ~ ~ ~ ~ O~
z ~_ z ~ ~ ~ ~r ~ ~ ~ ~ ~ ~ ~ ~ ~ ~:r _ _ _l r~ ~ _l ~ ~ ~ ~ _~ _ a~ --~ ~ ~ = ~ ~ 0~ ~ ~O ~ ~ r~ ~O
tJ 3 ~ 4~ u~ ~o ~o .D ~o ~ ~ù v~ u~ u~ ~ ~ u~
~ ~3 C~ OCI ~ ~ O~ ~:0 O~ eo ~ ~ _ ~D ~C>
1~ ~ ~1 ~0 ~ 00 .rl~
Eli b : ~1 r7 3 : :
00_ 3~ X u~ ~ ~ _ ~
0~,~C03 ~OoOg~ O~ ~`I U~ Ul O O,~, _~ ~ l l _~
. _ ;,~r~ ~ ~ ~
--llô-- -1:~3'~4~i9 . _ _ .
_ _ ~
E O O O L O; ~ O 1:) O rA ~1 ~ 3 0 0 ~-1 .''`. IA . ~ r~ r! ~ ~ - ) r ~) ~ _I ~ tr) _~
r~ r _ ~ ~ ~ r ~ r~ r~ _, ____ _ ___ _ ~ .
/: ^ ~ 0 'O "~ : IA _ r ~
~ r~ ~ _~ r~ r - ~:~ r -r ~1 - _~ c~
' _ ,~ , - r~ r~ r~ ~_ _ _, r ~ r~ ~J
_ ~ _ _ ~_ 1_ ~ 0 ,, u _ = r. ~!r ~ _r ~ 1~ IA 00 ; r IA 1'~
_ ~ o ~ ~ ~~ ~ ~o o ~ . ~r - r _ L _ J rl ~_-- . _r ~ ~ I~ ~
~ . ~ _ ~o o r r ~ r r r ~ i A _r t ___ . _ . L _ I _ . .
. ~ ~1 . . . _ L;O O _ _ _ _ ~ .
~ _ ~
~ E l l l ~ ~
_ ~ _ _ ~ O O _ rl O ~ rl :~: :~
E ~ _ ù:r~ _~ rJ N rl S rl N N N rl oN
g rl _ _ _ S S S ~ S S S 3 ~, ~ \/ \/ ~/ \/ ~/ \/ \/
s _ ~ . _ i i ,. l ~: f ~
,//\ , ~' ~N sr` s~r`r~ _r~ r~ S r~ ~ o O _l , ~ ~
v~
1 ~3'7~tj9 al _ O O ~ o o In ~o o o oo ~, u~ u~ ~ ~ ~ ~ r~ u~ ~ ~D ~ ~
h _ t~ _I ~D t~) .--l ~O ~ _I ~D t~) _I ~Ct ~ t'~ -(^ ~ ^ ~ \^r~l ~ (^
~ ~ ~ ~ ~ ~ ~ ~ ~
a ,~ ~ Nr.~ _I O _ 1~-1 ~ ~
(J ~ h ~D ~ ~D ~ ~D ~D ~
o L L _ ~ I~ I~ ~ ~D O O
~Oû O _ ~ _ 'no ~, ~ r~ ,~
,., _ -- O ~ "
j~ ^ _ ~
;` ~ '' ~8 ` ~
~ .t ~ "
L _ ~
_ E -- ~ ~ N ~ U S
n - o u ~)~oN ~oN D ~o . L~
~120-1~3~4~9 Tablets suitable for oral administration Tablets contain.ing the ingredients indicated below may be prepared by conventional techniques.
... .... ~ .. _ , Ingredient Amount per tablet . -- . . . . .. _ : N -(7-methoxy-2-naphthylsulfonyl)- 250 L-arginyl-N-(2-methoxyethyl)glycine Lactose 140 Corn starch 35 Talcum 20 Magnesium stearate 5 .
. Total 450 mg . ._ Capsules for oral administration Capsules of the below were made up by thoroughly mixing together batches of the ingredients and filling hard gelatin capsules with the mixture.
_. . . __ .._ _ .... _ Ingredient Amount per capsule N -(7-methoxy-2-naphthylsul~onyl)- 250 L-arginyl-N-(2-methoxyethyl)glycine Lactose 250 . ..... _.. _ . .
Total 500 mg ._ . _ _ .. . .
li374ti9 EXA~tl'_E 9 Sterilc solution ror inrllsion Tlle ~`ollowing ingl~o(l:iollts arc dissolvcd :in wator for intravellous perfusloll an~l the resul ting solution i9 then s terili zed .
. .. .. _.
lngredi ents Amoun t ( ~) ~, ------ __. _ N ~ -( 7 -mc 1,11oxy-2-llapll thylsul rOtly~ ) _ 2 5 L-argi nyl -N~ me tlloxyctllyl )~] ycinc Buffer sys-tem As desired Glucose 25 Distille<l water 500 ~:
- I "'! --1:~3~469 PREPARATION A
Arylsulfonyl chloricles (A) ~odium 6,7-dimetl~oxy-2-rlaphthaleneSUlfona-te To a well stirred solution o~ 70.8 g of sodium 6,7-clihydroxy-2-naplltll11enesulfonate anti 77.2 ~ of sodium hydro~ide in 450 ml of water was added dropwise 230 ml Or dimethyl sulfate at 60C over a period of one hour, durillg whicll timo the product precipitated. To this reaction mixture was added in portions 38.8 g of sodiùm hydroxide, and stirring was continued for one hour.
After one hour at room temperature, the precipitate was filtered, washetl with ethanol and dried to give 50 g of sodlum 6,7-dimethoxy-2-naphthalenesulfonate.
(B) 6,7-dimethoxy-2-naphthalenesulfonyl chloride To a stirred suspension of 50 g of finely divided sodium 6,7-dimethoxy-2-naphthalenesulfonate in 100 ml of dimethyl-forn~lmi~le was adt~ed dropwisc 62.2 m] of thionyl chloride at room l;cnls)oratllre. After 30 minutos, Lhe reaction mixture was pourc(l illtO 1 ~ of ice water~ and the precipi-tate ri~ torecl alld tllen dissolved into 250 ml of ben~ene.
Tlle ben~elle ~olution was repeatedly waslled with water and drit-(l ovor antlydrous so(lillnl sllll`ate I`bc so:Lvellt wat ovapor~Lotl l,o (Iryllo~ ill vacuo~ alld tlle rosi(luc W~IS
1:~374f~9 recrystallize(l from benzene-n-hexane (1 : l) to give 32 g of 6,7-dimethoxy-2-naphthalenesulfonyl chloride~
~I.P. 127.5 - 12'~.5C
All~lysis - Calc(l. ror Cl2llll0l~SCl. (porcoll~): C, 50.26;
H, 3.87; Cl, 12.37 Found (percent): C, 50.45;
H, 4.00; Cl, 12.33 The following arylsulfonyl chlorides not previously reportecl in the chemical literature were synthesi~ed by thc aroremelltiolled procedure which is essentially that as described i.n E. H. Rodd, "Chemistry Or Carbon CompoundS", Elsevier Publistung Company, 1954, Vol m, P. 441-469.
_ _ No. Arylsulfonyl Chloride M.P. (C) ~ .. _ C10 S ~f~ ~,OC2H5 I 2 ~ C2H5118 - 119.5 2 1 2 ~ ~ OC~I~l36.S - 133.5 _ . _ ~ (:lo~ ~ O) l~7 - 13 _ .
- ].2l~ -1 ~37~
PRE}'ARATION B
Amillo acicl derivatives (A) N-butylglycinc tert-butyl ester To 36.5 g of butylamine was added with stirring 15.05 g of tert-butyl clll.oroacetate over a period of 30 minutes, while mai.lltai~ lg the temperature at 30-70C. The reaction nLixtnre was held at 70 C for an additional one hollr. At the en(i of this period~ the cxcess butyl amine was evaporated in vacuo, and the residue was taken up in 40 ml of 2N NaOI~ solution and 50 ml of benzene, transferred into a separatory funnel and well shaken. The benzene solutioll was separated, washed with water, dried over anllydrolls sodi.llm sulfate and filtered. After evaporation of ben~elle, the residue was distilled under reduced pressuro to g:i.vc 17.0 g (90.9 percent) of N-butylglycine tcrt-~ tyl cs ter, 11.1' . 7GC/4 nmlllg .
'rhe 1'O~ lOWill~ alllillO uci(l tert-butyL cstcrs not ~reviously rel~orLc~ tllc chcmi.cul .Litcrutllrc wcrc sy~ltllesized by l;lIC Ul`Or-`nlOllLiO11(?(l prOCC~IlJre WlLi Cll .i:i c~selltially that as taught by A. J. Speziale et al., J. Org. Chem. 2~ 731 (1960).
1~3t74~
~ .
,, No . l~mi llo Aci(l I)crivative I~ .P .
_ _ . _ - ' 1 I IN \ ~ ' 3 9 5 C / 2 0 mml I g Cll,~CO,,-~-CIIl{~
_ -- --- -- _ ~ .
~C112CII(C113)2 2 IIN 6 5 C/ 5 mmllg _ \C112C02-t-C41~9 . __.
3 ~(Cll2)l~cll3 89~90 C/2.5 mmHg \C112C02-t-CI~ __ 4 IIN ~ ( C112 ) 5(~ 8 3-5C /1 . 5 mn~lg C 2C2 t C4Hg .
_ .- .~
~(CH2 )7C113 125-130 C/4 mmHg CH2C 2 ~ t -C~ H
_ . _ . .
6 ~CI12Ctl20C113 61- 2 C/2 mmHg \Cli2C02--t--CLIH9 ~
_ . .
7 HN~CH2CI12 0CI13 94 C/ 3 mmHg 2C112C2-t-C4~9 _ , ~ 2C 120CH3 o
8 HN 60- 3 C /3 mn~lg \c~l2c~l2cll2co2-t-cLlli9 . . . . . _ I
9 I~N~CH2CII2CH20C~3 95~ 7C/5 mnlllg Cll2co2-t-c4~l9 _ . . _ . __ . _ HN~ 2C1120C112C113 102 C/ 4 mmHg \CII~(~II,,('0~-1,-CIllll~
. .
~ t26 -1~374~
_ . _ No. Amino Aci(l l)erivative I~.l'.
-- - .
11 HN/ 2C 12 ~3) 166C/l O mmHg (~112C02~ C1~119 __ _ _ _ /cll2cll2scll2cll3 o 12 HN \ 1 o6 - 9 C /1 . 5 mmHg C~12C02 - t-C1~1~9 _ . _ ...... . . _ ._ .
/C112c1l2~;cll 13 I-IN\ 3 97 C/ 2 .5 mn~g C112C02 - t--CL~1~9 _ 1ll llN 101 C/ 5mn~g ~ CH2cH2cll2c02 t C4 9 _ _ _. I
15HN~0 101 C / 5 mmHg \ Cll2C02 - t -C4~1 .
_ ._ .
16l~N--0 105 C/ 4 mm}lg 2 2C2 t CI~H9 _._ : 17 HN~0 129-130 C/8mmHg (~lI"C02-t-C~ .
. .. . ..... _ .
I 8 / C 11~ - ~ l 4 5 C / l 5 mn il g 2-1;-( 111~) _ . ._ _ :19 IlN\ ~ O ~ 5G C/l 0 mmHg , ._ Cll2cll2(:o2-~-c4ll9 1 , __ _ 1~3~ 9 N o . /~n~ o Ac- (I I)c ri v~ t i ve ~
IlJ ~ C/:~G lmlHt 2]. Cl CO -I -C~ I l U C/27 mmHg _ _ __ _ 22 ~( C112 )11CI~3 1211C/26 mmHg C~13 _ . ____ ~ 2C 20CH3 23 \CtlC02--t-CI tl9 88-- 90 C/6 mml~g ¦ \rllC; ~-t-C//H9 116- 8 C /- mmH
. - . .
2 5 l 1 2 4 ~ 167 C / I G mml~
HN ~O .
26 1CHC~)2 t C4Hg 12 ~ C/-~ mmHg - 12B _ 1~37~9 _ .
No. Am~no Acid Derivative B.P.
... _ . . ..__ ~ CH2--0 27 ~ CHCO2-t-C4H 141 C/15 mmHg _ _ ..
28 2 2CO2 t C4Hg 89 C/ 3 mmHg _ . _ .. __ _ . -~
29 ~ CH2- ~ 111C/ 1 mmHg CH2co2-t_c4H .
_ _ _ _ _ ~
~ CH2CO2-t-C4Hg 91- 2 C/l mmHg .__ __ _ . _ _, : 31 ~ CH2cH2co2c2Hs 115 C/ 2 mmHg CH2CO2-t-C4H
- OH --- __ 32 HN ~ CH2CH2CHCH3 82- 84 C/2 mmHg 2CO2 t C4Hg . . _ ._ .. --- -- ... _ ,,_ . ~ CH2CH SOCH
33 HN 2 3 150 C/ 0.5 mmHg _ .__ ._ _ . . - .
34 ~ CH2CH20H 95- 6 C/2 mmHg CH2CO2-t-C4H
. . .. . _ HN ~ 2C_CH
CH2CO -t-C4H .
. _ - __ . __ _ ~_ _ - 129 _ 1~37469 (1~) N-(2-metlloxyetllyl.)~,rlyci,n(? etllyl e~ster I`o a stirred solutiorl Or ~65.2 ~ or 2-m(tlloxyethylamine alld 202.1l t of` ~riotl~ylamillo iJl I Q Or her~zerle was a-klecl ( I 1`0 J~ W i. ::~ 0 El ::; O I I I l. i OJ I 0 1 3 3 11 . O g O ~ O 1, 1 l y 1 ~) ro n10 El C O 1, El t O i l l 200 ml of bellzelle in one hour at room temperature. At the end Or tll:is period, the mixture was heated at reflux for 2 hours to complete the reaction. Upon cl~lling~ -the triethylar~ le hydrobromide was removed by filtration and WaShe(l Wi th bell~ene. ~rter removal of the solvent, the product was distilled in vacuo to yield 242.8 g (75.3 percent) Or N-(2-methoxyethyl)glycine ethyl ester, B.P. 73-5 C/l~ mmHg.
The following ElmillO acid ethyl esters not previously reportecl in the chemical literaturo were synthesized by the aroremerltioned procedure whicll is essentially that as taugllt by A. J. Spe~iale et al., J. Org. Chem., 2~`
7~1 (1'360)-:o, Amillo Ao.i d J~,lhy.l I~`sl;e r ~ 1~1.1'. (( (,) o r ll.l'.
.. _ ._ _ .~
1 ~ ((II~))(II~ 57- 8C/3 mn~fg Cll2(:()2c2ll5 . _ . _ Cll,,CI~, OCII, 2 l~ \ ~ ~ ~ 63- ll C/3 mmllg ~
Cll2cll2co2c2ll~5 - _ -11374~
- - - -M.l'. ( C) or B.P.
No. ~nlillo ~ci(l l3tllyl ~tor ( (,/mmllg) _ IlN/~ ~ . _ ,H 2( ' 02 C 21-1 5 ~ ( ` /2 mn~ g C~ L0l-2C
_ ~C02C2115 ~Ctl~C112(,}12CI-13 113- 6 C/3 mmHg \ C112C02C2115 _ _ 6 C12C211 ~ 116- 7C/l mmHg \C112C02C2115 . __ .
7 /CH2CIIC}I3 78-80C/2 mm~g \C112C02C2115 . - -.
/(C112)~C113 8 CIIC"C2ll5 . HCl63-4 C
_ C112C02C2~15 (C) N-(2-metlloxyetllyl)glycine ben~yl ester P-tolueneSulfonate To a solution Or 55.8 g of N-(2-methoxyethyl)glycine tert-butyl ester in 200 ml of benzene was added 63.8 g of benzyl alcollol and 72.9 g of p-toluellesulfonic acid monohydrate. Tlle mixture waR lleated at rorlux for 10 - 13l- -i~3746:~
hours with the continuous removal of water through a Dean-Stark water trap. At the end of this period, the sollltioll was concelltrated in vacuo, and to the residue was ad(le(l 3~0 ml of dry ethyl etl~er. Arter 2 hours at room temperature, the formed precipitate was filtered, washed with (lry ethyl ether and then recrystallized from ethyl acetate to yield 99.2 g (85 percent) of N-(2-methoxyethyl)glycille benzyl ester p-tol~lenesulforlate, M-l'. 95-6C.
The followillg amiJIo acid benzyl ester p-toluenesulfonate not previously reported in the chemical literature were syntllesize(l by the arorementioned procedure.
.
No. Amino Acid Benzyl Ester M P. ( C) _ p-Toluenesul~onate 1~ CH2C02CH2- ~ 97 ~ 9 _ .. . _._ 2 \ C 11 Z C 2 C~2--@~ 1 .? .? -- ll _ .
¦ \~`H"COzCHz~
4 ~((~z)3 113 66 -- 8 -- I 3 ."
~37469 No Amillo l~ci(l I3c~nr~yl l~ter M 1' (C) . 1 ) -'1`0 l ~lCII C:;ll I ~`orlc~ t e _ . .~
r) (CH )~CH,~ I ()I -- 2 G ~ cH2--~ 14 o -- 3 . _ . _. _ . _ 7 \ ~H2C~l2c2cH2~ 1 5ll -- 6 8 / C H 2 CH2--~ 13 3 _ 5 9 C112C02C~12 ~~) 13 3 -- 5 ~ ~ CH2--O
lo \CH2c2c~2~ 133 -- 8 _ . _ __ ..
\ CHC 02 CH2 ~ ¦ I ( ) '3 _ _ ._ __ _ . _ __ .
~_~~
- l33 -~37469 . . . _ _ .
No Amino Acid Benzyl Ester M P ( C
. p-Toluene~ulfonate . .
_ 13 3 123 - 6 ¦
_ _ _ 14 ~ CHC02CH2~ ~ 119 - 123 _ _, ...
CH2C02CH2 ~ 13 0 .
PREPARATION C
2-Piperidinecarboxylic acid~ and esters thereof (A) 4-methyl-2-piperidinecarbonitrile To 500 g of 10% sodium hypochlorite solution cooled in an ice bath, there was added dropwise a solution of 33.6 g (0.21 mole) of 4-methylpiperidine acetate in lO ml of water over a period of l hour. At the end of this period, the reaction product was extracted twice with 500 ml of ethyl ether and dried over anhydrous sodium sul~ate. After evaporation of ethyl ether, the residue was added dropwise to a solution of 11.8 g (0.21 100 ml of mole) of potassium hydroxide in~96~ ethanol under reflux.
Pefluxing was continued for ~n additional 10 minutes.
Ethanol was evaporated, and the residue was dissolved into 50 ml of` 2~ sodium hydroxide solution and then extracted with ether.
The ether layer was dried over anhydrous sodium sulfate and then ether evaporated. The residue was added to an ice-cooled solution of 27 g (1 mole) of hydrogen cyanide and 25 ml of concentrated hydrochloric acid in 300 ml of water, The solution was stirred at a temperature of 10 to 20C 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 to give 17 g (66%) of 4-methyl-2-piperidinecarbonitrile, B.P.
96-97C/10 mmHg.
The following 2-piperidinecarbonitriles not previously reported in the chemical literature were synthesized by the aforementioned procedure which is essentially that as taught by Grundon et al., J. Chem. Soc., 1963, 3898, Grundon et al., J. Chem. Soc., _964, 2448, R. Bonnett et al., J. Chem. Soc., 19~9, 2092 and H. Bohme et al., Ber., 92 1613 (1959).
113~4~9 N CN
H
N o 7 _ ., l I Cl2CH3105-106C/9 mmllg.
_ . _ _ . . _ . 24-CI12CI12C1l3116 C/8 mml{g.
Cll,3 . 3 < Cll 104C/Il mmllg.
_ _ _.
ll 2-C113 _ -. _ . .~
(B) 4-Methyl-2-piperidinecarboxylic acid hyclrochloride A solution of 16 g of 4-methyl-2-piperidinecarbonitrile in 250 mL Or 6N llydrocllloric acid was refluxed rOr 6 hours. Arter evaporatioll of` the solvcllt, the residue was recrysta:Lli~ed from water to give 13 g Or 4-methyl-2-piperid~ ecarboxylic acid Jlydrochloricle.
~C) I~`l;lly'l ~-mc~tllyl-,'-l):iJ)ori.dillecarl)oxylal;c A so~ Lioll ol` 13 g (().072 mo.le) ol` ll-moLlly~--2~pipcricli.l-1e-car~oxy].ic aci(i llydroclllori(le alld 50 nll ol` tlliol~yl chlo~i(le in 300 nll of etllallol waX refluxed l`or ll llollrs. At the elld of thi~ period, the solvent was evaporateci uncler reduced pressllrc, ancl the re~idue was extracted Witll a solution Or chloroform and saturated potassium car~onate solution, - ~36 -1~37~
The ch.lorofoln~ yer was driecl over anhyclrous sodium sulJ`ate all(l t:llen c~l.loroform wa~ cvaporat:o(l. Di.stillation of tlle rcsidlle glVC 7 1~ g (60~) of etllyl 1l-nletl~yl-2-pipericl:inecarl)oxyl.lte, B.'. 7~-77 C/3 mmllg.
(D) Benzyl 4-metllyl-2-pipericlirlecarboxylate p-toluenesulfonate A solution of` 20 g (0.1.12 mole) of 4-methyl-2-piperidine-carboxyl.lc acid llyclrochloride~ 24 g to.224 mole) of benzyl alcohol und 25.6 e~ (0.134 mole) Or p-toluenesulfonic acid monohydrate i.n L00 ml. oÇ berlzene was refl.uxed for 5 hourS
with the continuous removal of water through a Dean-Stark water trap. At the end of this period, the solvent was distil].eA of`r, and the resi.due was was}led with ether-n-hexane and recrystallized to give 10 g (22%) of ~enzy 4-methyl-2-piperidinecarboxylate p-toluenesulfonate, M.P. 160-163 C.
The following 2-piperidinecarboxylates not previously reportecl in the chemical literature were synthesized by the aroremelltiolleA procedure.
- I~7 -1~37469 __ .__ No. ~ Addition B.P.
._ . _._ _ .. _ 1 CH2CH3 _82-4C/3.5 mmHg _ ._ ... __ _ _ ., 2 2CH2CH3 HCl - ~CH3 . -3 \CH _95-6 C/2 mmHg _. . _ 4 2-CH3 l 57 C/3 mmHg Morpholine-3-carboxylic acid hydrochloride was prepared by the procedure described above, and has a melting point of 200-2C.
The following starting material9 for the preparation of the N -aryl9ulfonyl-L-argininamides were prepared by the procedures des-cribed in the following literatures:
_ Compound Literature _ ... .
HN ~ J. Org. Chem., 2~ 2203 (1964) . _ _ .
HN ~ O J. Org. Chem., ~2 2203 ~1964) ~ ~ -Compo~ (l Literatllre . ._ ('O~,lt IIN ~ J. Am. Chem. Soc., 5(~ 200 (1937) _ .. . . .. _ COz~
IIN~ ~h. Ob!ihCh. lChim., 2 2245 (1973) _. _ . . .__._ __._ ~ C021~ Ber., 44 20311 (1911) _A _.......... . . ~
C0 H(D) or(L)¦~er-, ~ 927 (1932) Tl~e methyl or ethyl ester of` the aforementioned compounds were prepared by a cbnventlonal esterification procedure.
Ethyl thiomorplloline-3-carboxylate has a boiling point of 108C/4 mmllg.
Diethyl piperidine-2,6-dicarboxylate hydrochloride was prepared by the conventional esterification of piperidine-2,6-dicarboxylic acid and has a melting point of 184-6C.
lsoindolille-l-car~oxylic acid was prepared by a procedure similar to that for ~he preparation of isoquinoline-3-carboxylic acid described in Ber., 44 2034 (1911) . Ethyl isoindoline-l-carhoxylate hydrochloride wa~ prepare~l by -- I 1') -- , 1~37~6i9 the convent:iollal esterification of isoindoline-l-cnrboxylic acicl arld has a melting point of 139-140.5 C.
Ilnvillg now flll]y described the invellt;ion, it will be npl)arcllt to OIIC of ordillnry skill in tlle nrt tllat many changes and modifications can be made thereto without dcpartillg from t,lle~ spirit of thc invelltion as set forth lle rei n .
. .
~ t26 -1~374~
_ . _ No. Amino Aci(l l)erivative I~.l'.
-- - .
11 HN/ 2C 12 ~3) 166C/l O mmHg (~112C02~ C1~119 __ _ _ _ /cll2cll2scll2cll3 o 12 HN \ 1 o6 - 9 C /1 . 5 mmHg C~12C02 - t-C1~1~9 _ . _ ...... . . _ ._ .
/C112c1l2~;cll 13 I-IN\ 3 97 C/ 2 .5 mn~g C112C02 - t--CL~1~9 _ 1ll llN 101 C/ 5mn~g ~ CH2cH2cll2c02 t C4 9 _ _ _. I
15HN~0 101 C / 5 mmHg \ Cll2C02 - t -C4~1 .
_ ._ .
16l~N--0 105 C/ 4 mm}lg 2 2C2 t CI~H9 _._ : 17 HN~0 129-130 C/8mmHg (~lI"C02-t-C~ .
. .. . ..... _ .
I 8 / C 11~ - ~ l 4 5 C / l 5 mn il g 2-1;-( 111~) _ . ._ _ :19 IlN\ ~ O ~ 5G C/l 0 mmHg , ._ Cll2cll2(:o2-~-c4ll9 1 , __ _ 1~3~ 9 N o . /~n~ o Ac- (I I)c ri v~ t i ve ~
IlJ ~ C/:~G lmlHt 2]. Cl CO -I -C~ I l U C/27 mmHg _ _ __ _ 22 ~( C112 )11CI~3 1211C/26 mmHg C~13 _ . ____ ~ 2C 20CH3 23 \CtlC02--t-CI tl9 88-- 90 C/6 mml~g ¦ \rllC; ~-t-C//H9 116- 8 C /- mmH
. - . .
2 5 l 1 2 4 ~ 167 C / I G mml~
HN ~O .
26 1CHC~)2 t C4Hg 12 ~ C/-~ mmHg - 12B _ 1~37~9 _ .
No. Am~no Acid Derivative B.P.
... _ . . ..__ ~ CH2--0 27 ~ CHCO2-t-C4H 141 C/15 mmHg _ _ ..
28 2 2CO2 t C4Hg 89 C/ 3 mmHg _ . _ .. __ _ . -~
29 ~ CH2- ~ 111C/ 1 mmHg CH2co2-t_c4H .
_ _ _ _ _ ~
~ CH2CO2-t-C4Hg 91- 2 C/l mmHg .__ __ _ . _ _, : 31 ~ CH2cH2co2c2Hs 115 C/ 2 mmHg CH2CO2-t-C4H
- OH --- __ 32 HN ~ CH2CH2CHCH3 82- 84 C/2 mmHg 2CO2 t C4Hg . . _ ._ .. --- -- ... _ ,,_ . ~ CH2CH SOCH
33 HN 2 3 150 C/ 0.5 mmHg _ .__ ._ _ . . - .
34 ~ CH2CH20H 95- 6 C/2 mmHg CH2CO2-t-C4H
. . .. . _ HN ~ 2C_CH
CH2CO -t-C4H .
. _ - __ . __ _ ~_ _ - 129 _ 1~37469 (1~) N-(2-metlloxyetllyl.)~,rlyci,n(? etllyl e~ster I`o a stirred solutiorl Or ~65.2 ~ or 2-m(tlloxyethylamine alld 202.1l t of` ~riotl~ylamillo iJl I Q Or her~zerle was a-klecl ( I 1`0 J~ W i. ::~ 0 El ::; O I I I l. i OJ I 0 1 3 3 11 . O g O ~ O 1, 1 l y 1 ~) ro n10 El C O 1, El t O i l l 200 ml of bellzelle in one hour at room temperature. At the end Or tll:is period, the mixture was heated at reflux for 2 hours to complete the reaction. Upon cl~lling~ -the triethylar~ le hydrobromide was removed by filtration and WaShe(l Wi th bell~ene. ~rter removal of the solvent, the product was distilled in vacuo to yield 242.8 g (75.3 percent) Or N-(2-methoxyethyl)glycine ethyl ester, B.P. 73-5 C/l~ mmHg.
The following ElmillO acid ethyl esters not previously reportecl in the chemical literaturo were synthesized by the aroremerltioned procedure whicll is essentially that as taugllt by A. J. Spe~iale et al., J. Org. Chem., 2~`
7~1 (1'360)-:o, Amillo Ao.i d J~,lhy.l I~`sl;e r ~ 1~1.1'. (( (,) o r ll.l'.
.. _ ._ _ .~
1 ~ ((II~))(II~ 57- 8C/3 mn~fg Cll2(:()2c2ll5 . _ . _ Cll,,CI~, OCII, 2 l~ \ ~ ~ ~ 63- ll C/3 mmllg ~
Cll2cll2co2c2ll~5 - _ -11374~
- - - -M.l'. ( C) or B.P.
No. ~nlillo ~ci(l l3tllyl ~tor ( (,/mmllg) _ IlN/~ ~ . _ ,H 2( ' 02 C 21-1 5 ~ ( ` /2 mn~ g C~ L0l-2C
_ ~C02C2115 ~Ctl~C112(,}12CI-13 113- 6 C/3 mmHg \ C112C02C2115 _ _ 6 C12C211 ~ 116- 7C/l mmHg \C112C02C2115 . __ .
7 /CH2CIIC}I3 78-80C/2 mm~g \C112C02C2115 . - -.
/(C112)~C113 8 CIIC"C2ll5 . HCl63-4 C
_ C112C02C2~15 (C) N-(2-metlloxyetllyl)glycine ben~yl ester P-tolueneSulfonate To a solution Or 55.8 g of N-(2-methoxyethyl)glycine tert-butyl ester in 200 ml of benzene was added 63.8 g of benzyl alcollol and 72.9 g of p-toluellesulfonic acid monohydrate. Tlle mixture waR lleated at rorlux for 10 - 13l- -i~3746:~
hours with the continuous removal of water through a Dean-Stark water trap. At the end of this period, the sollltioll was concelltrated in vacuo, and to the residue was ad(le(l 3~0 ml of dry ethyl etl~er. Arter 2 hours at room temperature, the formed precipitate was filtered, washed with (lry ethyl ether and then recrystallized from ethyl acetate to yield 99.2 g (85 percent) of N-(2-methoxyethyl)glycille benzyl ester p-tol~lenesulforlate, M-l'. 95-6C.
The followillg amiJIo acid benzyl ester p-toluenesulfonate not previously reported in the chemical literature were syntllesize(l by the arorementioned procedure.
.
No. Amino Acid Benzyl Ester M P. ( C) _ p-Toluenesul~onate 1~ CH2C02CH2- ~ 97 ~ 9 _ .. . _._ 2 \ C 11 Z C 2 C~2--@~ 1 .? .? -- ll _ .
¦ \~`H"COzCHz~
4 ~((~z)3 113 66 -- 8 -- I 3 ."
~37469 No Amillo l~ci(l I3c~nr~yl l~ter M 1' (C) . 1 ) -'1`0 l ~lCII C:;ll I ~`orlc~ t e _ . .~
r) (CH )~CH,~ I ()I -- 2 G ~ cH2--~ 14 o -- 3 . _ . _. _ . _ 7 \ ~H2C~l2c2cH2~ 1 5ll -- 6 8 / C H 2 CH2--~ 13 3 _ 5 9 C112C02C~12 ~~) 13 3 -- 5 ~ ~ CH2--O
lo \CH2c2c~2~ 133 -- 8 _ . _ __ ..
\ CHC 02 CH2 ~ ¦ I ( ) '3 _ _ ._ __ _ . _ __ .
~_~~
- l33 -~37469 . . . _ _ .
No Amino Acid Benzyl Ester M P ( C
. p-Toluene~ulfonate . .
_ 13 3 123 - 6 ¦
_ _ _ 14 ~ CHC02CH2~ ~ 119 - 123 _ _, ...
CH2C02CH2 ~ 13 0 .
PREPARATION C
2-Piperidinecarboxylic acid~ and esters thereof (A) 4-methyl-2-piperidinecarbonitrile To 500 g of 10% sodium hypochlorite solution cooled in an ice bath, there was added dropwise a solution of 33.6 g (0.21 mole) of 4-methylpiperidine acetate in lO ml of water over a period of l hour. At the end of this period, the reaction product was extracted twice with 500 ml of ethyl ether and dried over anhydrous sodium sul~ate. After evaporation of ethyl ether, the residue was added dropwise to a solution of 11.8 g (0.21 100 ml of mole) of potassium hydroxide in~96~ ethanol under reflux.
Pefluxing was continued for ~n additional 10 minutes.
Ethanol was evaporated, and the residue was dissolved into 50 ml of` 2~ sodium hydroxide solution and then extracted with ether.
The ether layer was dried over anhydrous sodium sulfate and then ether evaporated. The residue was added to an ice-cooled solution of 27 g (1 mole) of hydrogen cyanide and 25 ml of concentrated hydrochloric acid in 300 ml of water, The solution was stirred at a temperature of 10 to 20C 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 to give 17 g (66%) of 4-methyl-2-piperidinecarbonitrile, B.P.
96-97C/10 mmHg.
The following 2-piperidinecarbonitriles not previously reported in the chemical literature were synthesized by the aforementioned procedure which is essentially that as taught by Grundon et al., J. Chem. Soc., 1963, 3898, Grundon et al., J. Chem. Soc., _964, 2448, R. Bonnett et al., J. Chem. Soc., 19~9, 2092 and H. Bohme et al., Ber., 92 1613 (1959).
113~4~9 N CN
H
N o 7 _ ., l I Cl2CH3105-106C/9 mmllg.
_ . _ _ . . _ . 24-CI12CI12C1l3116 C/8 mml{g.
Cll,3 . 3 < Cll 104C/Il mmllg.
_ _ _.
ll 2-C113 _ -. _ . .~
(B) 4-Methyl-2-piperidinecarboxylic acid hyclrochloride A solution of 16 g of 4-methyl-2-piperidinecarbonitrile in 250 mL Or 6N llydrocllloric acid was refluxed rOr 6 hours. Arter evaporatioll of` the solvcllt, the residue was recrysta:Lli~ed from water to give 13 g Or 4-methyl-2-piperid~ ecarboxylic acid Jlydrochloricle.
~C) I~`l;lly'l ~-mc~tllyl-,'-l):iJ)ori.dillecarl)oxylal;c A so~ Lioll ol` 13 g (().072 mo.le) ol` ll-moLlly~--2~pipcricli.l-1e-car~oxy].ic aci(i llydroclllori(le alld 50 nll ol` tlliol~yl chlo~i(le in 300 nll of etllallol waX refluxed l`or ll llollrs. At the elld of thi~ period, the solvent was evaporateci uncler reduced pressllrc, ancl the re~idue was extracted Witll a solution Or chloroform and saturated potassium car~onate solution, - ~36 -1~37~
The ch.lorofoln~ yer was driecl over anhyclrous sodium sulJ`ate all(l t:llen c~l.loroform wa~ cvaporat:o(l. Di.stillation of tlle rcsidlle glVC 7 1~ g (60~) of etllyl 1l-nletl~yl-2-pipericl:inecarl)oxyl.lte, B.'. 7~-77 C/3 mmllg.
(D) Benzyl 4-metllyl-2-pipericlirlecarboxylate p-toluenesulfonate A solution of` 20 g (0.1.12 mole) of 4-methyl-2-piperidine-carboxyl.lc acid llyclrochloride~ 24 g to.224 mole) of benzyl alcohol und 25.6 e~ (0.134 mole) Or p-toluenesulfonic acid monohydrate i.n L00 ml. oÇ berlzene was refl.uxed for 5 hourS
with the continuous removal of water through a Dean-Stark water trap. At the end of this period, the solvent was distil].eA of`r, and the resi.due was was}led with ether-n-hexane and recrystallized to give 10 g (22%) of ~enzy 4-methyl-2-piperidinecarboxylate p-toluenesulfonate, M.P. 160-163 C.
The following 2-piperidinecarboxylates not previously reportecl in the chemical literature were synthesized by the aroremelltiolleA procedure.
- I~7 -1~37469 __ .__ No. ~ Addition B.P.
._ . _._ _ .. _ 1 CH2CH3 _82-4C/3.5 mmHg _ ._ ... __ _ _ ., 2 2CH2CH3 HCl - ~CH3 . -3 \CH _95-6 C/2 mmHg _. . _ 4 2-CH3 l 57 C/3 mmHg Morpholine-3-carboxylic acid hydrochloride was prepared by the procedure described above, and has a melting point of 200-2C.
The following starting material9 for the preparation of the N -aryl9ulfonyl-L-argininamides were prepared by the procedures des-cribed in the following literatures:
_ Compound Literature _ ... .
HN ~ J. Org. Chem., 2~ 2203 (1964) . _ _ .
HN ~ O J. Org. Chem., ~2 2203 ~1964) ~ ~ -Compo~ (l Literatllre . ._ ('O~,lt IIN ~ J. Am. Chem. Soc., 5(~ 200 (1937) _ .. . . .. _ COz~
IIN~ ~h. Ob!ihCh. lChim., 2 2245 (1973) _. _ . . .__._ __._ ~ C021~ Ber., 44 20311 (1911) _A _.......... . . ~
C0 H(D) or(L)¦~er-, ~ 927 (1932) Tl~e methyl or ethyl ester of` the aforementioned compounds were prepared by a cbnventlonal esterification procedure.
Ethyl thiomorplloline-3-carboxylate has a boiling point of 108C/4 mmllg.
Diethyl piperidine-2,6-dicarboxylate hydrochloride was prepared by the conventional esterification of piperidine-2,6-dicarboxylic acid and has a melting point of 184-6C.
lsoindolille-l-car~oxylic acid was prepared by a procedure similar to that for ~he preparation of isoquinoline-3-carboxylic acid described in Ber., 44 2034 (1911) . Ethyl isoindoline-l-carhoxylate hydrochloride wa~ prepare~l by -- I 1') -- , 1~37~6i9 the convent:iollal esterification of isoindoline-l-cnrboxylic acicl arld has a melting point of 139-140.5 C.
Ilnvillg now flll]y described the invellt;ion, it will be npl)arcllt to OIIC of ordillnry skill in tlle nrt tllat many changes and modifications can be made thereto without dcpartillg from t,lle~ spirit of thc invelltion as set forth lle rei n .
Claims (44)
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 R3is 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, 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 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 dialkylanlino, C7-C12 aralkyl, , , , , , and wherein R12 is hydrogen, C1-C10 alkyl or C1-C10 alkoxy, which comprises: reacting an L-argininamide having the formula:
wherein R is defined herein above with an arylsulfonyl halide having the formula: ArSO2X, wherein Ar is as defined herein above and X is halogen.
(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 R3is 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, 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 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 dialkylanlino, C7-C12 aralkyl, , , , , , and wherein R12 is hydrogen, C1-C10 alkyl or C1-C10 alkoxy, which comprises: reacting an L-argininamide having the formula:
wherein R is defined herein above with an arylsulfonyl halide having the formula: ArSO2X, wherein Ar is as defined herein above and X is halogen.
2. An N2-arylsulfonyl-L-argininamide and the pharma-ceutically 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 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 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.
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 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 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.
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.
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-argininamide 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.
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.
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-C10 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.
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-C10 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 alkoxycarbonylalkyl, 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, C1-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, 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; R4 is selected from the group consisting of C1-C5 alkyl, carboxy, C2-C5 alkoxycarbonyl, phenyl, C7-C10 aralkyl and ring substituted benzyl wherein said substituent is C1-C3 alkyl or 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 selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl, C7-C10 aralkyl and 5-indanyl; R7 is hydrogen, C1-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 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.
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 alkoxycarbonylalkyl, 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, C1-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, 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; R4 is selected from the group consisting of C1-C5 alkyl, carboxy, C2-C5 alkoxycarbonyl, phenyl, C7-C10 aralkyl and ring substituted benzyl wherein said substituent is C1-C3 alkyl or 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 selected from the group consisting of hydrogen, C1-C10 alkyl, C6-C10 aryl, C7-C10 aralkyl and 5-indanyl; R7 is hydrogen, C1-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 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 from 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-C10 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 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; 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-1-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 .
wherein R is selected from the group consisting of:
(1) wherein R1 is selected from 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-C10 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 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; 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-1-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-hydrofurfurylglycine.
36 N2-(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 N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-tetrahydro-
38. N2-(6,7-dimethoxy-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-arginyl]-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-arginy]]-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-[N2-(7-methoxy-2-naphthylsulfonyl)-1-arginyl]-4-ethyl-2-piper-idine carboxylic acid.
44. 1-[N2-(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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000376574A CA1137469A (en) | 1975-12-09 | 1981-04-29 | N.sup.2-arylsulfonyl-l-argininamides and the pharmaceutically acceptable salts thereof |
Applications Claiming Priority (25)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US638,985 | 1975-12-09 | ||
| US05/638,985 US4055636A (en) | 1974-11-08 | 1975-12-09 | N2 -alkoxynaphthalenesulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof |
| US05/646,522 US4018915A (en) | 1976-01-05 | 1976-01-05 | N2 -alkoxynaphthalenesulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof |
| US646,522 | 1976-01-05 | ||
| US05/649,219 US4018913A (en) | 1976-01-14 | 1976-01-14 | N2 -alkoxynaphthalenesulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof |
| US649,219 | 1976-01-14 | ||
| US05/653,217 US4055651A (en) | 1974-11-08 | 1976-01-28 | N2 -alkoxynaphthalenesulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof |
| US653,217 | 1976-01-28 | ||
| 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 |
| 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 |
| CA000376574A CA1137469A (en) | 1975-12-09 | 1981-04-29 | N.sup.2-arylsulfonyl-l-argininamides and the pharmaceutically acceptable salts thereof |
| US707,536 | 1991-05-30 | ||
| US723,474 | 1991-06-28 | ||
| US728,051 | 1991-07-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1137469A true CA1137469A (en) | 1982-12-14 |
Family
ID=27583924
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000376574A Expired CA1137469A (en) | 1975-12-09 | 1981-04-29 | N.sup.2-arylsulfonyl-l-argininamides and the pharmaceutically acceptable salts thereof |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1137469A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003026575A3 (en) * | 2001-09-24 | 2003-05-01 | Synaptic Pharma Corp | Molecules specific for npff receptors and uses thereof |
-
1981
- 1981-04-29 CA CA000376574A patent/CA1137469A/en not_active Expired
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003026575A3 (en) * | 2001-09-24 | 2003-05-01 | Synaptic Pharma Corp | Molecules specific for npff receptors and uses thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4046876A (en) | N2 -alkoxynaphthalenesulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof | |
| US4018915A (en) | N2 -alkoxynaphthalenesulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof | |
| US4018913A (en) | N2 -alkoxynaphthalenesulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof | |
| US4289772A (en) | 1-Piperidinophthalazines as cardiac stimulants | |
| US4070457A (en) | N2 -naphthalenesulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof | |
| CA1102316A (en) | N su2 xx-arylsulfonyl-l-argininamides and the pharmaceutically acceptable salts thereof | |
| CA2232116C (en) | Novel n-aryl piperidine compounds, process for their preparation and pharmaceutical compositions containing them | |
| US4041156A (en) | N2 -alkoxynaphthalenesulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof | |
| US4036955A (en) | N2 -naphthalenesulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof | |
| US4104392A (en) | N2 -naphthalenesulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof, and antithrombotic compositions and methods employing them | |
| US4055636A (en) | N2 -alkoxynaphthalenesulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof | |
| CA2433025A1 (en) | Substituted piperidines/piperazines as melanocortin receptor agonists | |
| PT1499589E (en) | De | |
| US4096255A (en) | N2 -naphthalenesulfonyl-L-argininamides, and pharmaceutical salts, compositions and methods | |
| JPH0641064A (en) | 2-oxoethyl derivative | |
| CA2431996A1 (en) | Melanocortin receptor agonists | |
| KR20070043998A (en) | Piperidine derivatives as histamine h3 receptor ligands | |
| IE48623B1 (en) | Alpha-(n-arylsulfonyl-l-argininamides,processes for their preparation and pharmaceutical compositions containing these substances | |
| Boegesoe et al. | Antihypertensive activity in a series of 1-piperazino-3-phenylindans with potent 5-HT2-antagonistic activity | |
| SU731897A3 (en) | Method of preparing n-(1,3,4-thiadiazol-2-yl)-benzamide derivatives | |
| HU221811B1 (en) | N-acylated piperidine derivatives, process for producing them, and pharmaceutical compositions containing them | |
| US4957927A (en) | (Diarylmethoxy alkyl)-1-pyrrolidines and piperidines having cardiovascular activity | |
| US4071621A (en) | N2 -alkoxynaphthalenesulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof | |
| US4069318A (en) | N2 -Alkoxynaphthalenesulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof | |
| CA1137469A (en) | N.sup.2-arylsulfonyl-l-argininamides and the pharmaceutically acceptable salts thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |