NZ182812A - N2-aryl(or aralkyl)sulphonyl-l-argininamides and pharmaceutical compositions - Google Patents

N2-aryl(or aralkyl)sulphonyl-l-argininamides and pharmaceutical compositions

Info

Publication number
NZ182812A
NZ182812A NZ182812A NZ18281276A NZ182812A NZ 182812 A NZ182812 A NZ 182812A NZ 182812 A NZ182812 A NZ 182812A NZ 18281276 A NZ18281276 A NZ 18281276A NZ 182812 A NZ182812 A NZ 182812A
Authority
NZ
New Zealand
Prior art keywords
alkyl
hydrogen
naphthyl
aralkyl
arginyl
Prior art date
Application number
NZ182812A
Inventor
S Okamoto
R Kikumoto
Y Tamao
K Ohkuba
T Tezuka
S Tonomura
A Hijikata
Original Assignee
Mitsubishi Chem Ind
S Okamoto
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from US05/638,985 external-priority patent/US4055636A/en
Priority claimed from US05/646,522 external-priority patent/US4018915A/en
Priority claimed from US05/649,219 external-priority patent/US4018913A/en
Priority claimed from US05/653,217 external-priority patent/US4055651A/en
Priority claimed from US05/656,014 external-priority patent/US4041156A/en
Priority claimed from US05/656,870 external-priority patent/US4046876A/en
Priority claimed from US05/669,743 external-priority patent/US4070457A/en
Priority claimed from US05/707,536 external-priority patent/US4036955A/en
Priority claimed from US05/713,486 external-priority patent/US4073914A/en
Priority claimed from US05/723,474 external-priority patent/US4096255A/en
Priority claimed from US05/728,051 external-priority patent/US4104392A/en
Priority to NZ187716A priority Critical patent/NZ187716A/en
Application filed by Mitsubishi Chem Ind, S Okamoto filed Critical Mitsubishi Chem Ind
Publication of NZ182812A publication Critical patent/NZ182812A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
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    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
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    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D277/06—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/12—1,4-Thiazines; Hydrogenated 1,4-thiazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
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    • C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/30—Oxygen atoms, e.g. delta-lactones
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    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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    • C07K5/06—Dipeptides
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

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  • Chemical & Material Sciences (AREA)
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  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Biochemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Hematology (AREA)
  • Diabetes (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Furan Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Indole Compounds (AREA)

Description

<div class="application article clearfix" id="description"> <p class="printTableText" lang="en">New Zealand Paient Spedficaiion for Paient Number 1 82812 <br><br> 18 2812 <br><br> i <br><br> Priority Date(s): hfclsTfFl; ,» &lt;? -z^.q Yfc&gt; <br><br> &lt; •7b;fr-i-7fc;/o ■* **•"*■ 7« |««-6-7fe, .f-f.-'fc.S? &lt;f Tfo <br><br> Complete Specification FHe-d: .h'&amp;.I'p <br><br> Clas^ »^b\ IIG-5 <br><br> V/IU09, 1 1 g 1 g 1 1 1 '• 1 1 1 1 « 1 s i, |i B 8^JT I, <br><br> Publication Date: .. I. T\ ... <br><br> P.O. Joi|rna!, Wo: ... 12£&gt;A <br><br> f <br><br> NEW ZEALAND <br><br> PATENTS ACT, 1953 <br><br> No.: <br><br> Date: <br><br> COMPLETE SPECIFICATION <br><br> j "N -ARYLSULFONYL-L-ARGININAMIDES AND THE PHARMACEUTICALLY <br><br> I <br><br> I ACCEPTABLE SALTS THEREOF" <br><br> */We, MITSUBISHI CHEMICAL INDUSTRIES LIMITED, a Japanese body corporate, of, 5-2, Maranouchi 2-chome, Chiyoda-ku, .Tokyo, Japan, and SHOSUKE OKAMOTO, a Japanese citizen, of, 15-18, Asahigaoka 3-chome, Tarumi-ku, Kobe-shi, Hyogo, Japan <br><br> V <br><br> hereby declare the invention for which P / we pray that a patent may be granted to pa»/us, and the method by which it is to be perfo to bje particularly described in and by the following atatemen <br><br> 1 - <br><br> (Followed by Page 1 <br><br> 182812 <br><br> 2 <br><br> This invention relates to N --arylsulfcnyl-L-argininamides and the pharmaceutically acceptable salts thereof. <br><br> In the past, there have been many attempts to obtain new and improved agents for the treatment of thrombosis. The <br><br> 2 <br><br> 5 .N " (p-tolyls/ulfonyl) -L-arginine esters have been found to i <br><br> be one type of agent which can be used and these have been found to be ,,effective in dissolving blood clots. (U.S. <br><br> Patent No. 3,622,615, issued November 23, 1971) <br><br> One family of compounds which have been found to be par- <br><br> 10 ticularly useful as highly specific inhibitors of thrombin <br><br> 2 <br><br> for the control of thrombosis is the N -dansy1-L-arginine ester or amide. <br><br> However, there is a continuing need for a highly specific 15 inhibitor dn thrombin for the control of thrombosis, which exhibits lower toxicity. <br><br> 2 <br><br> It has beer discovered that N -arylsulfony1-L- argininamides exhibit antithrombotic activity and even lower toxicity levels at' the same relative potencies, as compared with the 2 <br><br> 20 N -dansy1-L-arginine ester or amide. <br><br> In our specification No. 187 716, divided out of the present application, we describe and claim an JT-aryl-sulphonyl-L-arginiriamide having the formula <br><br> K.N <br><br> X0 - N - OH^CiL-.CIUCIlCOR <br><br> r I "" ! <br><br> H2N H HFG05 (I) <br><br> I <br><br> - M.Z. PATE:VT 1F-J-CE <br><br> t; r I FEB 1979 <br><br> Ar il received <br><br> - la <br><br> wnerein R -!?■ <br><br> 182812 <br><br> (1) -u <br><br> (6li2)nC00R2 <br><br> wherein R1 is C9-ClQ alley 1, C^-C 1Q alkenyl, aJtynyi <br><br> ^2~^10 al^0Xi/a-'-^&lt;T-'-5 ^2~^10 carD0X^a^-1lCy"'-' alkoxy_ <br><br> carbonyla-lkyl, aralkyl, ^3_^10 cycloal-k-yl or ^4~~^10. <br><br> cycloalkylalkyl; R2 is hydrogen or C-^C-^ alkyl; and n i <br><br> 1, 2 or 5 v <br><br> (2) - N <br><br> VCH - (CH2)mCOOR5 <br><br> K ■ <br><br> wherein R3 is hydrogen, .c1-c10 alkyl, C^-Cio alkenyl, c3-c10 alkynyl, c2~C.io alkoxyalkvl, c2-c.10 carboxyalkyl, c3-c10 alkoxycarbonylalkyl, C7-C10 aralkyl, C3-c10 cyclo alkyl or c;(-cjo cyoloalkylalkyl; is ci-cjo alkyl; Rr; ia hydrogen or C^-Ciq alkyl; and 111 is 0, 1 2, <br><br> (3) - N <br><br> wherein is -coorg wherein Rg iii Cj -c9 alkyl; each Ry indupcadently ia hydrogen, cj-cjq alkyl or C^-C^ alkoxy; j&gt; ia an in o f 1 to 5; R£ is subs ti luteal, into the pipcridinc r.in/j at tho 2 or 3~po s:i l;i on ; and .each R_ . independently if. 'uubutituttid into the piperidine ring at the 2, 3, 4, 5 or- b~poriti&lt;jn, <br><br> optionally substituted with one or more Ci-C 5 alkyl or ■c1-c5 alk'oxy groups, who rein Ii&lt;&gt; La CI-C9 alkyl; and r ia ,1, 2, 3 or '1, <br><br> N2L PAT&lt;EV'f <br><br> ;-lf£blct -2- <br><br> [.*( received <br><br> 18 2812 <br><br> (5) - <br><br> coonvo /-\ <br><br> N Z <br><br> \ / (CH2ii wherein r_lo is CJ/-C9 alkyl; Z is oxy or tUio; and q is 0 o r 1, o r <br><br> C00Rai <br><br> W ' N\ , . Jj /J <br><br> \(CU2) <br><br> I <br><br> 10 . <br><br> 15 <br><br> ■wherein Ru is C1-C9 alkyl; i is 0, 1 or 2; j is 0, 1 or 2; and the sum i+j is 1 or 2; ' <br><br> and Ar is 5,6,7,8-tetrahydronaphthyl, naphthyl, 1 or 2-naphthyl substituted with one crubstituent which is halogen, nitro, cyano, hydroxy, O1-C10 alkyl, dialkylarnino containing not more than 20 carbon atoms, or C1-C1Q" alkoxy, <br><br> naphthyl substituted by two C-^-C-^q alkoxy groups, which may be the same or different e.g. <br><br> OR" <br><br> wherein R" and R1" each independently are ci-cioalkyl'&gt; <br><br> 20 <br><br> a°~\ <br><br> wherein R 12 is C1~C5 <br><br> a-/ <br><br> - 3 - <br><br> 18 2812 <br><br> 2 <br><br> The present invention provides an N ■^*-yisulfonoyl-I-argininamide having the formula: <br><br> HN&lt; <br><br> c—N—CH2 CH2 CH2 CHCOR (I) <br><br> h2N^ I I <br><br> H HNSO <br><br> Ar <br><br> % <br><br> r? 182812 <br><br> or a pharmaceutically acceptable salt thereof, wherein R is <br><br> ^R1 <br><br> n'&gt;"(ch-) coor„ <br><br> ^ n ^ <br><br> wherein is C2~C'lo alkyl, C-;,-Clo alkenyl, C3~C10 alkynyl, <br><br> C2-Cio alkoxyalkyl, C2-Ci0 alkylthioalkyl/ C2~C10 alkylsulfinyl-5 alkyl, c^~c^o ^ydroxyalkyl, C2~C10 car"koxyalkyl' C3~Clo a-*-^oxy~ <br><br> carbonylalkyl, C3-C2q alkylcarbonylalky1, C-^-C^q haloalkyl, Cy-C^,-aralkyl, Cg-C25 ^~cark°xyaralkyl r G3~cio cycl°alkyl, C4-Ci0 cycloalkylalky1,furfuryl, tetrahydrofurfuryl optionally substituted with one or more alkyl and/or alkoxy groups, 10 3-furylmethyl, tetrahydro-3-furylmethyl optionally substituted with one or more C^-C^ alkyl or C-^-C^ alkoxy groups, tetrahydro-2(3 or 4)-pyranylmethyl optionally substituted with one or more C1-C5 alkyl and/or Ci-C5 alkoxy groups, 1,4-dioxa-2-cyclohexyl-methvl optionally substituted with one or more £-^""£5 alkyl and/or 15 (-l~(-5 alkoxy groups, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl, optionally substituted with one or more C^-C^ alkyl or C-^-C^ <br><br> alkoxy groups, or tetrahydro-3-thenyl; R2 is hydrogen, ci-cj_o alkyl, C5~C2o aryl&gt; C7~C12 aralkyl or 5-indanyl; and n is 1, 2 or 3, (2). _N/ 3 wherein is hydrogen, ci~c10 <br><br> 20 NCH-(CH2)mCOOR5 <br><br> R4 <br><br> C3^C10 alkenyl, C3~C^0 al^ynyl, C2~Cio alk°xyalkyl, C2~C10 alkylthioalkyl, C2~Cio alkylsulf inylalkyl, C^-C^Q hydroxyalkyl, C2-C10 carbOxyalkyl, C3~C10 alkoxycarbonylalky1, C3~C10 alkylcar- ■ bcnylalkyl ,C-^-C^0 haloalkyl, aralkyl, C8 C15 c^-carboxyaralkyl, <br><br> C3-C10 cycloalkyl, C^-C^q cycloalkylalkyl, furfuryl, tetrahydrofurfuryl optionally substituted with one or more C-^-C^ alkyl or C^^^^lk^x^^roups , 3-furylmethyl, tetrahydro-3-furylmethyl, <br><br> ' -t FEB 1979 <br><br> 25 <br><br> % <br><br> 182812 <br><br> optionally substituted with one or more Ci-C5 alkyl or alkoxy groups, tetrahydro-2(3 or 4)-pyranylmethyl optionally substituted with one or more alkyl and/or C^-C^ alkoxy groups, 1,4-dioxa-2-cyclohexylmethyl optionally substituted with <br><br> 5 one or more alkyl and/or alkoxy groups, 2-thenyl, <br><br> 3-thenyl, tetrahydro-2-thenyl optionally substitured with one or more alkyl or C-^-C^ alkoxy groups, or tetrahydro-3-thenyl; <br><br> is alkyl, carboxy, ^2~^10 alkoxycarbony 1' phenyl optionally substituted with one or more C^-C^ alkyl or C^-C^ <br><br> 10 alkoxy groups, aralkyl or ring substituted benzyl wherein said substituent is C^-C&lt;- alkyl or-C-^-C,- alkoxy; is hydrogen, <br><br> Cjl~Cj_q alkyl, C5~C10 arY^/ C7~C12 aral^Yl or 5-indanyl; and m is <br><br> 0, 1 or 2, *6 <br><br> (3) _N'/rns wherein Rg is -COORg wherein Rg is hydrogen, <br><br> V <br><br> (R7) <br><br> 7 p <br><br> C^_C^0 alkyl, C6-Cj_0 arYl/ Caralkyl or 5-indanyl; each R^ independently is hydrogen, phenyl, C^-C^ alkoxy or carboxy; p is an integer of 1 to 5, Rg is substituted into the piperidine ring at the 2 or 3-position; and each Ry independently is substituted into the piperidine ring at the 2, 3, 4,' 5 or 6-position COORg <br><br> (4) -V^ <br><br> (CI1 2) r optionally substituted with one or more C^-C^ alkyl or C]_-G5 alkoxy groups, wherein Rg is hydrogen, C-^-C^q alkyl, Cg-C^ aryl, C^-C-^2 • aralkyl or 5-indanyl; and r is 1, 2, 3, or 4, &lt;^P0Rlp <br><br> 25 <br><br> 15 <br><br> 20 <br><br> \ <br><br> (5) -N Z <br><br> wherein R^Q is hydrogen, ci~c]_0 alkyl, cg~cio arYl' <br><br> C-j-C, 0 aralkyl or 5-indanyl; Z is oxy, thio or sulfiriY^fa^nd q is 0 or 1, or <br><br> 6. « - S APR J979 <br><br> - 182812 <br><br> COORj,! <br><br> J-{caz) <br><br> (6) ""N\. ^ whersin is hydrogen, CyC^ alkyl, <br><br> ^ * 2.' j <br><br> ^6 ^10 ary"'-, C7 ^12 aralkyl or 5-indanyl; i is 0, 1 or 2; j is.O, 1 or 2; and the sum i + j is 1 or 2; <br><br> and Ar is naphthyl, 5,6,7,8-tetrahydronaphthyl optionally substituted with one or more alkyl or C^-C^ alkoxy groups, <br><br> naphthyl substituted with at least one substituent which is halo, nitro, cyano, hydroxy, alkyl, alkoxy or C2-C2q dialkylamino, phenyl, phenyl substituted with at least one . substituent which is halo, nitro, cyano, hydroxy, g^-c-^q alkyl, C3-C10 alkoxy, or C2~C2Q dialkylamino, C?-C12 aralky-l, or <br><br> 0 <br><br> o or <br><br> 'Pv, <br><br> each of &gt;/hich is optionally substituted with one or more alkyl or C-^-C,- alkoxy groups, wherein R-^?- is hydrogen, C-^-C^ <br><br> 10 <br><br> alkyl or Cj-C^g alkoxy; provided that <br><br> ^R-, <br><br> when R is:- <br><br> (1) - N <br><br> 1 <br><br> (CH2)riC00R2 <br><br> wherein R± is C^-C-,Q alkyl, C^-C1Q alkenyl, C^-C-^ alkynyl, <br><br> C2~C10 alko-xyalkyl&gt; C2~°10 carboxyalkyl, C^-C10 alkoxy-carbonylalkyl, C7-C10 aralkyl, C^-C^ cycloalkyl or C4-Cl0 <br><br> ,^_ay.cl.oalk-y.lalkyl; R? is not hydrogen or C-, -C-, n alkyl n.z. patent c.tice ^ 1 ±u <br><br> - 1 FEB 1979 <br><br> received <br><br> 7. <br><br> when R is:- (2) - N <br><br> E3 <br><br> CH - (0Ho) COORc i 2'm 5 <br><br> E4 <br><br> 182812 <br><br> wherein R3 is hydrogen, Cj.-ClO alkyl, C3-C10 alkenyl, C3-C10 allcynyl, C2-C10 alkoxyallcyl, C2-C10 carboxyalkyl, C3-C10 alkoxy carbonylalkyJ., C7-C10 aralkyl, C3-C10 cyclo — alkyl or C2f-Cio cycloalkylalkyl; and R4 is C-,-C-,alkyl; R^ is. not hydrogen or cx-ciq alkyl " 5 <br><br> Rs <br><br> ,, r when R is:- (3) - N <br><br> H <br><br> (&amp;?) <br><br> v 7 p wherein R£ is -COORg ; each R7 <br><br> independently is hydrogen, C^-C^o alkyl or C^—alkoxy; p is. an integer of 1 to 5&gt; R6 is substituted into the piporidine ring at the 2 or 3-position; and R7 is substituted into the p.iper.idine ring at the 2, 3&gt; 4, 5 or 6-position; Rg is not to alkyl _ • <br><br> when R is:- <br><br> \0H2)r optionally substituted with one or more Ci—C5 alkyl or C1-C5 alkoxy groups, R^ is not G-^-Cg alkyl <br><br> GOOR10 <br><br> when R is:- • (5) - N J* <br><br> w herein Z is oxy or thio; R-^q is not C^-Gg. alkyl <br><br> L <br><br> 8. <br><br> 182812 <br><br> and when R is:- <br><br> R <br><br> 11 <br><br> COORn <br><br> &gt;-(c,i2)xv^N ' <br><br> (fi) -&lt; J <br><br> is not C.j-Og alkyl; if Ar is 5,6,7,8-tetra- <br><br> hydronaphthyl, naphthyl, 1-naphthyl substituted with one substituent which is halogen, nitro, cyano, hydroxy, CI~C10 alkyl, ^2~^2Q dialkylamino, or al^o;x;y' 2-naphthyl substituted wi.th one substituent which is halogen, nitro, cyano, hydroxy, C^-C^q alkyl, ^2~G20 dialkylamino or Ci"^10 ' alkoxy, naphthyl._substituted by two C2_~ClO alkoxy groupswhich_ may be the same or different e.g. <br><br> wherein R" and R1" each indc- <br><br> OR'" <br><br> pendently are ^IkyrT' <br><br> ■OO <br><br> alkoxy; <br><br> ~^\-R"X2 wherein R]_2 ^1~^5 <br><br> ' 182812 <br><br> This invention alr.o relatcn to a method for inhibiting activity and suppressing activation of thrombin in vivo, which comprises introducing into a living body a. pharmaceutically effective amount of an -arylsul'fonyl-L-argininamide or <br><br> V • * <br><br> the pharmaceutically acceptable salt thereof. <br><br> As started above, in tha formula:- .. . <br><br> hn^ <br><br> C - N - CHoCHoCHoCHC0R (l) <br><br> H I 2 2 2\ <br><br> H HNS0o <br><br> I 2 <br><br> Ar wlierexfi R is selected from.'the group consisting' of* <br><br> /R1 <br><br> (l) — N. wherein R, is selected from the group <br><br> N(CH2)nC00R2 <br><br> consisting of ^2""^10 such, as ethyl, propyl, butyl, <br><br> isobutyl, pentyl, hexyl, octyl, decyl or the like, alkenyl of 3—10 (preferably 3-6) carbon atoms, such as allyl, 2 — <br><br> butenyl, 3—butenyl, 2-pentenyl or the like, allcynyl of 3—10 (preferably 3-6) carbon atoms, such as 2—propyxiyl, 2— butynyl, 3-butynyl or the like, alkoxyalkyl of 2—10 (preferably 2—6) carbon atoms, such as me thoxymethy.l, ethoxyiisthyl, propoxyraethyl, 2-me t ho xy ethyl, 2— ethoxyethyl} 2—propcxyethvl, 2-methoxypropyl, 3-methoxypropyl, 3— ethoxypropyl, 3—propoxypropyl, 4—methoxybutyl , h—ethoxybutyl, h—butoxybutyl, 5-butoxypentyl or the like, alkylthioalkyl of £-10 (preferably 2-6) carbon atoms, such as methyl thiomethyl, ethyl thio methyl, propyl thioinethyl, 2-methylthioethyl, <br><br> 10. <br><br> n.Z. PATENT OFFICE <br><br> 15 JAN 1979 <br><br> 1828,12 <br><br> 2-ethylthioethyl, 2-propylthioe thyl3-methylthiopropyl, <br><br> 2-methyl thiopropyl, 3-ethyl thiopropyl, 3-propylthiopropyl, <br><br> 4-methylthiobutyl, ^t-ethylthiobutyl, '4-butylthiobutyl, <br><br> 5-butylthiopentyl or the like, alkylsulfinylalkyl of 2-10 (preferably 2-6) carbon atoms, such as methylsulfinylmethyl, ethylsulfinylmethyl, propylsulfinylmethyl, 2-methyisulfinyl-ethyl, 2-ethylsulfinylethyl, 2-propylsulfinylethyl, 3-methylsulfinylpropyl, 3-ethylsulfinylpropyl or the like, hydroxyalkyl of 1—10 (preferably 1-6) carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, 5-hydroxy-pentyl or the like, carboxyalkyl of 2-10 (preferably 2-7) <br><br> carbon atoms, such as carboxymethyl, 2-carboxyethyl, 2— carboxypropyl, 3-carboxypropyl, 1-carboxybutyl, 2-carboxy— <br><br> butyl, h—carboxybutyl or the like, alkoxycarbonylalkyl of <br><br> 3-10 (preferably 3-8) carbon atoms, such as methoxycarbonyliriethyl, 2-ethoxycarbonylethyl, 2-ethoxycarbonylpropyl, 3-methoxycarbonyl-propyl, 1-methoxycarbonylbutyl, 2-ethoxycarbonylbutyl, 4-methoxy-carbonylbutyl or the like, alkyl carbonylalkyl of 3 to 10 carbon atoms such as methylcarbonylethyl, haloalkyl of 1-10 (preferably 1-5) carbon atoms such as chloromethyl, 2-chloroethyl, 2-bromo-ethyl, 2-chloropropyl, 3-chloropropyl, 2-chlorobutyl, 4-chloro-butyl or the like, aralkyl of 7-15 (preferably 7-10) carbon atoms, such as benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 6-phenyl-hexyl, i-phenylethyl, 2-phenylpropyl or the like,^-carboxyaralkyl n.z. PATENT OFFICE <br><br> 15 JAN 1979 <br><br> 11. <br><br> R£CE;V~D <br><br> 18 2812 <br><br> of 8-15 (preferably 8-12) carbon atoms, such as ^-carboxybenzyl, <br><br> cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl', cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, c4~c^q cycl°al^ylalkyl,' <br><br> such as cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclohexylethyl, cyclooctylmethyl or the like, furfuryl, tetrahydrofurfuryl, optionally substitured with one or more alkyl;and/or C-^-C^ alkoxy groups, 3-furylmethyl, tetrahydro-3-furyl-methyl, optionally substituted with one or more C-^-C^ alkyl or C1~C5 alkoxy groups, tetrahydro-2(3 or 4)-pyranylmethyl optionally substituted with one or more alkyl and/or alkoxy groups <br><br> 1,4-dioxa-2-cyclohexylmethyi optionally substituted with one or mor&lt; C1-C5 alkyl and/or alkoxy groups, 2-thenyl, 3-thenyl tetra- <br><br> hydro-2-tbenyl, optionally substituted with one or more alkyl or C^-C^ alkoxy groups and tetrahydro-3-thenyl; R2 is selected from the group consisting of hydrogen, alkyl, such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl, decy1. or the like, Cg-C^Q aryl, such as phenyl, m-tolyl, naphthyl or the like, aralkyl of 7-12 (preferably 7-10) carbon atoms, such as benzol phenethyl or the like, or 5-indanyl; and n is an integer of 1, 2 <br><br> ^-carboxyphenethyl or the like, ^"C^O cycloalkyl, such as wherein is selected from the <br><br> CH-(CH„) COOR 1 v 2 ' m m 5 <br><br> group consisting of hydrogen, Cj^.-C alkyl, such as methyl, ethyl, propyl, butyl, .isobutyl, pentyl, hexyl, octyl, <br><br> decyl "or the like, alkenyl of 3-10 (preferably 3-6) carbon atoms, such as allyl, 2-butenyl, 3-butenyl, 2-penten;1 the like,, alkynyl of 3-.10 (preferably 3-6) carbon at&lt; <br><br> such as 2-propynyJ , 2-butynyl, 3~butyriy1 or the like alkoxyalkyl of 2-JO (preferably 2-6) carbon atoms, si <br><br> 12. <br><br> methoxymethyl^ethoxymethyl, propoxymethyl, 2-methoxyethyl, <br><br> 2-ethoxyethyl, 2-propoxyethyl, 2-methoxypropyl, 3-methoxy— propyl, 3-ethoxypropyl, 3-propoxypropyl, k-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— methylthio ethyl , 2-ethylthio ethyl, 2-propylthio ethyl, 3 — methylthiopropyl, 2-methylthiopropy1, 3-ethylthiopropyl, <br><br> 3-propylthiopropyl, b—methylthiobutyl, ^-ethylthiobutyl, <br><br> 4-butylthiobutyl, 5-butylthiopentyl or the like, alkyl-sulfinylalkyl of 2-10 (preferably 2-6) carbon atoms, such as methylsulfinylmethyl, ethylsulfinylmethyl, propyl-sulfinylmethyl^2-methylsulfinylethyl, 2-ethylsulfinylethyl, <br><br> 2-propylsulfinylethyl, 3-methylsulfinylpropyl, 3-ethyl-sulfinylpropyl or the like, hydroxyallcyl of 1-10 (preferably <br><br> 1-6) carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, <br><br> 3-hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl, 3— hydroxybutyl, 5-hydroxypentyl or the like, carboxyalkyl of <br><br> 2-10 (preferably 2-j) carbon atoms, such aa carboxymethyl, 2-carboxyethyl, 2-carboxypropyl, 3-carboxypropyl, 1-carboxybutyl, 2-carboxybutyl, U—carboxybutyl or the like, alkoxycarbonylalkyl of 3~10 (preferably 3-8) carbon atoms, such as methoxycarbonylmethyl, 2-methoxycarbonylethyl, 2— ethoxycarbonylpropyl, 3-methoxycarbonylpropyl, 1-methoxy-carbonyJ bu ty 1 , 2 -o t hoxycarbonyJ.hu tyl , h -me t;ho xycarbonyJ bu tyl <br><br> 182812 <br><br> or the like, alkyl carbonyialkyl of 3 to 10 carbon atoms such as methylcarbonylethyl, haloalkyl of 1-10 (preferably 1-5) carbon atoms such as chlorornet tiyl , 2-chloroethyJ, 2 -bromoethyl, <br><br> 2 -chlo ropropyl , 3-chlorop ropyl , 2 — c 11 _1 o to bu ty.'L , 'l-ch] orobutyl 5 or the lake, aralkyl of 7-15 (preferably 7-10) carbon atoms, <br><br> such as benzyl, phenethyl, 3 —phenylp ropyl, —phenylbutyl, <br><br> 6-pheny l.hexyl , 1-phonylo thyl, 2 -phenylp ropy J or the like, (A —carboxyarulkyi of 8-15 (preferably 8-12) carbon atoms, <br><br> such as -carboxybenzyl, (X -carboxyphene thyl or the like, <br><br> 10 C3~C10 cycloalkyl, such as cyclopropyl, cyclobutyl, » <br><br> cyclopentyl, cyclohexyl, cycloheptyl, eye]ooctyl, cyclononyl or cyclodecyl, 0^—1cycloalkylalkyl, such as cyclopropyl— <br><br> methyl, cycJ opentylnie thyl, cyclohexylme t; hyl , 2-cyclohexyl-ethyl, cyclooctylniethyl or the like, furfuryl, tetrahyd.ro — ]_5 furfuryl optionally substituted with one or more C-^-C^ alkyl or ■C-^-C^ alkoxy groups, 3-furylmethyl, tetrahydro-3-furylmethyl optionally substitured with one or more C^-C^.alkyl or C^-C^ <br><br> alkoxy groups, tetrahydro-2(3 or 4)-pyranylmethyl optionally substituted with one or .more alkyl ahd/or C2~C5 alkoxy groups <br><br> 20 1,4-dioxa-2-cyclohexylmethyl optionally substituted with one or more alkyl and/or alkoxy groups, 2-thenyl, 3-thenyl, <br><br> tetrahydro-2-thenyl optionally substituted with one or more C-^-C^ alkyl or alkoxy groups, and tetrahydro-3-thenyl; is selected from the group consisting of alkyl of 1-10 (preferably 25 1-5) carbon atoms, such as methyl, ethyl, propyl, isopropyl, <br><br> butyl, isobutyl, sec-butyl, pentyl or the like, carboxy, alkoxy-t carbonyl of 2-10 (preferably 2-5) carbon atoms, such as methoxy- <br><br> .carbonyl, ethoxycarbor.yl, propoxycarbonvl or the like, phenyl <br><br> - '/V*' - - __ __ "* <br><br> t FEBW^^10113117 substituted with one or more C-^-Cg alkyl or alkoxy <br><br> —" groups, aralkyl of 7-12 (preferably 7-10) carbon atoms, such as <br><br> RECEIVED ^ <br><br> ""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 <br><br> 182812- <br><br> alkoxy of 1—5 (preferably 1—3) carbon atoms, such as methoxy, <br><br> ethoxy, propoxy or isopropoxy; R is selected from the group <br><br> 5 <br><br> consisting of hydrogen, Cj^-C alkyl, such as methyl., ethyl, <br><br> propyl, butyl, tert-butyl, hexyl, octyl, decyl or the like, c^-c^q aryl, such as phenyl, m-tolyl, naphthyl or the like, <br><br> aralkyl of 7~12 (preferably 7~10) carbon atoms, such as benzyl, phenethyl or the like, and 5~iudanyl; and m is an <br><br> A <br><br> integer of 0, 1 or 2, (3) -N \ wherein is -COORg <br><br> •VP / <br><br> wherein. Rg is selected from the group consisting of hydrogen, 10 ^1~^10 &gt; su°h as methyl, ethyl, propyl, butyl, tert- <br><br> butyl, hexyl, octyl, decyl or the like, c^-c^q ar^"^» su°b as phenyl, m-tolyl, naphthyl or the like, aralkyl of 7_12 (preferably 7_10) carbon atoms, such as benzyl, phenethyl - or the like, and 5-indanyl; each-R7 independently is hydrogen, <br><br> !5 alkyl of 1-10 (preferably 1-6) carbon atoms, such as methyl, ethyl, <br><br> propyl, isopropyl, butyl, hexyl, octyl, decyl or the like, phenyl^ C1~C5 alkoxy or carboxy; p is an integer of 1 to 5; Rg is sub- <br><br> Stituted at the 2 or 3-position; and R7 can be substituted at the <br><br> 2, 3, 4, 5 or 6-position, <br><br> 20 <br><br> CO OR 9 N.Z. PATENT OFFICE <br><br> 15 JAN 1979 ^ <br><br> (M-N I <br><br> ~-(cii2)r ^ <br><br> optionally substituted with one or more alkyl or C-^-C^ <br><br> 25' ' alkoxy groups, wherein Rg is selected from the group <br><br> ~ -15- <br><br> 18 281% <br><br> 1-0 <br><br> i consisting of hydrogen, C ~C Q alky}, such as methyl, ethyl, <br><br> propyl, butyl, tert-butyl, hexyl, octyl, decyl or the like, <br><br> Cg-C^Q aryl, such as phenyl, m-tolyl, naphthyl or the like, <br><br> aralkyl of J-12 (preferably 7_10) carbon atoms, such as benzyl, phenethyl or the like, and 5-indanyl; and r is an integer of 1, 2, 3 or k, <br><br> C00R10 <br><br> (5) -N *Z wherein R^q is selected from the group <br><br> V':/, <br><br> consisting of hydrogen, ^^""^lO &gt; such as methyl, ethyl, <br><br> propyl, butyl, tert-butyl, .hexyl, octyl, decyl or the like, c^-c^q 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; Z is selected from the group consisting of oxy (-0-), thio (—S—) and sulfinyl (-SO-); q is an integer of 0 or 1, and coori;l &gt;-(cn2)^&lt;^ <br><br> (6) -N 111 \ wherein R-^ selected from the group consisting of hydrogen, alkyl, such as methyl, ethyl, <br><br> propyl, butyl, tert-butyl, hexyl, octyl, decyl or the like, c^-c^q aryl, such as phenyl, m—tolyl, naphthyl or the like, aralkyl of J-12 (preferably 7~10) carbon atoms, such as benzyl,'phenethyl or the like, and 5-indanyl; i is an <br><br> 16. n.2. patent offlcs <br><br> 15 JAN 1979 &lt; <br><br> - i*. f " ' <br><br> 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, such as 1-naphthyl and 2-naphthyl, 5,6,7, 8-tetrahydronaphthyl, such as 5,6,7,8-tetrahydro-l-naphthyl optionally substituted with one or more alkyl or alkoxy groups and 5,6,7,8-tetrahydro-2-naphthyl, <br><br> naphthyl substituted with at least one substituent selected from the group consisting of halo, such as fluoro, <br><br> chloro, bromo and iodo, nitro, cyano, hydroxy, alkyl of 1-10 (preferably 1—5) carbon atoms, such as methyl, ethyl, <br><br> propyl, isopropyl, butyl, isobutyl or the like, alkoxy of <br><br> 1-10 (preferably 1—5) carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec—butoxy, tert-butoxy, <br><br> pentyloxy or the like, and dialkylamino of 2—20 (preferably <br><br> 2-10) carbon atoms, such as dimethylamino, di etliylamino, N-methyl-N-ethylamino or the like, phenyl, phenyl substituted with at least one substituent selected from the group consisting of halo, such as fluoro, chloro, bromo and iodo, <br><br> nitro, cyano, hydroxy, alkyl. of 1-10 (preferably 1—5) carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, <br><br> isobutyl or the Jjke, a.lkoxy of 1-10 (preferably 1-5) carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec—butoxy, tert-butoxy, pentyloxy or the like, and dialkylamino of 2-20 (preferably 2-10) carbon atoms, such as dimethylamino, diethylamino, N-methyl-N-ethylamino or the 3 ike, aralkyl of 7~12 (preferably 7—10) carbon atoms, <br><br> 17. <br><br> 15 JAN 1979 <br><br> 182812 <br><br> -CO <br><br> -©1)0 - -€oO <br><br> -eo- <br><br> optionally substituted with one or more alkyl or C-^ <br><br> alkoxy groups wherein hydrogen, alkyl of 1-10 <br><br> (preferably 1-5) carbon atoms, such, as methyl, ethyl, propyl or the like, or alkoxy of 1-10 (preferably 1—5) carbon atoms, <br><br> such as methoxy, ethoxy, propoxy or the like. (Subject to the above proviso). Suitable illustrations of R^ in the above formula (I) are Cg-C-^o such as propyl, butyl, isobutyl, pen tyl, <br><br> hexyl and octyl, C^-C^ alkenyl such as allyl, C^-C^ alkynyl, <br><br> such as 2-propynyl, ^2~^6 ^^-oxyalkyl, such as 2—met hoxy ethyl, <br><br> 2-methoxypropyl, 2-ethoxyethyl and 3-methoxypropyl, C^—C^ <br><br> alkylthioalkyl, such as 2-ethylthioethyl and 2—methylthioethyl, C2_C6 alkylsulfinylalkyl, such as 2-methylsulfinylethyl, <br><br> C^-Cg hydroxyalkyl, such as 2-hydroxyethyl and 3— hydroxybutyl, C2~Cy carboxyalkyl, such as 1-carboxybutyl, C^-Cg alkoxycarbonyl-alkyl, such as 2-ethoxycarbonylethyl, c^-c^q aralkyl, such as <br><br> 18. <br><br> and <br><br> NX PATENT OFFICE <br><br> 15 JAN 1979 <br><br> ■ o <br><br> 182 <br><br> benzyl and phenethyl, -cartioxyaralkyl, such as ^ — <br><br> carboxyphenethyl, cycl°alkyl, such as cyclopropyl, <br><br> cyclohexyl and cycloheptyl, cycloalkylalkyl, such as cyclohexylmethyl, furfuryl, tetrahydrofurfuryl, 3-furylmethyl, tetrahydro-3-furylmethyl, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl and tetrah.ydro-3-thenyl. <br><br> Suitable illustrations of in the above formula (i) are hydrogen, C1~C10 alkyl, such as methyl, propyl, butyl, <br><br> isobutyl, pentyl, hexyl and octyl, C^-C^ alkenyl, such as allyl, C^-C^ allcynyl, such as 2-propynyl, -C^ alkoxyalkyl, <br><br> such as 2-methoxyethyl, 2-methoxypropyl, 2-ethoxyethyl and <br><br> 3-methoxypropyl, C2~C^ alkylthioalkyl, such as 2-ethylthio- <br><br> ethyl and 2-methylthioethyl, C^—C^ alkylsulfinylalkyl, such as 2-methylsulfinylethyl, hydroxyalkyl, such as 2- <br><br> hydroxyethyl and 3-hydroxybutyl, C^-C^ carboxyalkyl, such as 1-carboxybutyl, C„-C0 alkoxycarbonylalkyl, such as 2- <br><br> J o ethoxycarbonylethyl, c^-c^q aralkyl, such as benzyl and phenethyl, Cg-C12 &lt;j\ -carboxyarallcyl, such as o&lt;. -carboxyphenethyl, C^-C10 cycloalkyl, such as cyclopropyl, cyclohexyl and cycloheptyl, C^-C2.0 cycloalkylalky1 &gt; such as cyclohexylmethyl, furfuryl, tetrahydrofurfuryl, 3—furylmethyl, tetrahydro-3-furylmethyl, 2—thenyl, 3-thenyl, tetrahydro-2-thenyl and tetrahydro-3—thenyl. <br><br> Suitable illustrations of R^ in the above formula (i) are C.-C. alkyl, such as methyl and propyl, carboxy, C9-C_ <br><br> 15 2 <br><br> 182 <br><br> alkoxycarbonyl, such, as ethoxycarbonyl, aralkyl, <br><br> such as benzyl, and ring substituted benzyl wherein said substituent is alkoxy, such as 4-methoxybenzyl» <br><br> Suitable illustrations of are hydrogen, C1~C^ alkyl, such as methyl, ethyl, propyl and isopropyl, phenyl and carboxy, and the suitable position of R^ is 1, 4 or 6. <br><br> COOH <br><br> Suitable —N groups are 3-carboxy-4—morpholino, <br><br> •&lt;1 <br><br> 3-carboxy-4-thiomorpholino, l-oxo-3-carboxy—4—thiomorpholino and 4—carboxy-3-thia^olidinyl. <br><br> COOH <br><br> Suitable -N^ 1|l J groups are 2-carboxy-l,2,3,4- <br><br> N«8)^ <br><br> tetrahydro-l-quinolyl, 3-carboxy-l,2,3,4-tetrahydro-2— isoquinolyl, 1-carboxy-l,2,3,4-tetrahydro-2-isoquinolyl, 2-carboxy-l-indolinyl and l-carboxy-2-isoindolinyl. <br><br> Suitable illustrations of R^, Rg, R^, R^q and R1JL are hydrogen, ci~ci0 alky1» such as methyl, ethyl, tert-butyl and octyl, C^-C1Q aryl, such as phenyl and m-tolyl, <br><br> aralkyl, such as benzyl, and 5-indanyl. <br><br> N.Z. PATENT OFFICE <br><br> 20- " ~ IT"1 <br><br> 15 JAN 1979 <br><br> .rSCBVID <br><br> J 8231 <br><br> Suitable illustrations of Ar in the above formula (l) are naphthyl, such as 1-naphthyl and 2-naphthyl, 5,6,7,8— <br><br> t etrahydronaphthyl, such as 5, 6,7 , 8-tetrahydro-1-naphthyl and 5,6,7,8-tetrahydro-2-naphthyl, naphthyl substituted with at least one substituent selected from the group consisting of halo, such as chloro and bromo, hydroxy, <br><br> C^-Cj, alkyl, such as methyl, ethyl and isopropyl, C^-C^ <br><br> alkoxy , such as methoxy and ethoxy, aad C2~C^ dialkylamino, <br><br> such as dimethylamino and diethylamino, phenyl, phenyl substituted with at least one substituent selected from the group consisting of halo, such as chloro, CC„ alkyl, such <br><br> ■*- 5 <br><br> as methyl, ethyl and isopropyl and C,-C alkoxy, such as <br><br> 15 <br><br> methoxy, aralkyl, such as phenethyl, j , <br><br> The preferred Ar groups are 1-naphthyl, 2-naphthyl, 5,6,7,8-" tetrahydro-1-naphthyl, 5,6,7,8-tetrahydro-2-naphthyl, 5-chloro-1-naphthyl, 6-chloro-2-naphthyl, 6—bromo—1—naphthyl, 5-hydroxy-l—naphthyl, 7-hydroxy-2-naphthyl, 6-methyl -2— naphthyl, 6-methyl-1-naphthyl, 7~me'thyl-l—naphthyl, 7—me "thyl 2-naphthyl, 6-ethyl-2-naphthyl, 6 ,7~dimethyl -1-naphthyl, <br><br> ^ 0 <br><br> such as <br><br> 21. <br><br> HZ. PATENT OFFICE <br><br> ? 15 JAN 1979 <br><br> 1823 <br><br> 6 ,7-dimeth.yl-2-naphthyl, 6-isopropyl-2-naphthyl, 5-methoxy-1-naphthyl, 6-methoxy-2-naphthyl, 7-methoxy-2-naphthyl, 4 ,6-dimethoxy-2-napIithyl, 6 , 7-dimethoxy-2-naphthyl, 6,7-diethoxy-2—naphthyl, 5-dimethyiainino-l-naphthyl , 5— dimethylamino-2-naphthyl, 5-diethylamino-1-naphthyl, 6-dimethylamino-1-naphthyl, 6-dimethylamino-2-naphthyl, 4-chlorophenyl, 2,4,5~trichlorophenyl^p-tolyl, anisyl, 3,4 — dirnethoxyphenyl, 3, 4 , 5-trimethoxyphenyl, , <br><br> 2 <br><br> Illustrative of suitable N —arylsulfonyl-L—argininamides of sufficient activity are the following: <br><br> COMPOUND NUMBER:-2 <br><br> N ~(2-naphthylsulfonyl)-L-arginyl-N~butylglycine benzyl ester <br><br> 2 <br><br> N -(6,7-dime thoxy-2-naphthylsulfony 1.) -L-arginy 1-N-(2-methoxyethyl)glycine "benzyl ester p <br><br> N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine 3-methylphenyl ester p <br><br> N - (6,7-dimethoxy-2-naphthylsulf'onyl) -L-arginyl-N-(2-methoxyethyl)glycine 5-indanyl ester <br><br> (6,7-dimethyl-l-naphthylsulfonyl)-L-arginyl-N-(2-me t hoxy "e thyl) gly c ine n.Z. PATENT OFFICE <br><br> 22. <br><br> 15 JAN 1979 <br><br> f\EC£IVSD <br><br> 6 <br><br> 7 <br><br> 8 <br><br> 9 <br><br> 10 <br><br> 11 <br><br> 12 <br><br> 13 <br><br> 14 <br><br> 15 <br><br> 16 <br><br> i. <br><br> &gt; 182812 <br><br> 2 <br><br> N -(6,7-dimetboxy-2-naphthylsulfonyl)-L-arginyl-N-(2-ethylthioethyl)glycine <br><br> 2 <br><br> N -(7-methoxy-2-naphthyIsulfonyl)-L-arginyl-N-(2-methylth.ioeth.yl) glycine ; <br><br> 2 <br><br> N -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-me thylsulfinyle thyl)glyc ine <br><br> 2 <br><br> N -(6,7-dimethoxy-2~riaphthylsulfonyl)-L-arginyl-N-(2-hydroxye thy1)glyc ine <br><br> 2 <br><br> N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(3-hydro xy "butyl) glycine <br><br> 2 <br><br> N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(a-carboxyphenethyl)glycine <br><br> N^-(7-methyl-2-naphthylsulfonyl)-L-arginyl-N-furfury1-glycine <br><br> 2 <br><br> N ~ (7-me thyl-2-na phthylsulf onyl)-'L-arginyl-N-tetrahydro-furfurylglycine <br><br> 2 <br><br> N - (7-methoxy-2-naphthylsulf'onyl) -L-arginyl-N-furfurylglycine <br><br> 2 <br><br> N -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-furfurylglycine tert-butyi ester <br><br> 2 <br><br> N -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N- <br><br> tetrahydrofurfurylglycirxe N.Z. PAT * " ' <br><br> £ - 1 FEB i979 ^ <br><br> jl received <br><br> 182812 <br><br> N( 5-dime thylamino —1 -naphthylsulfony 1) -L-arginy.1-N-t et rahydro Lurfurylglycirie <br><br> -s. <br><br> —( 5-ehloro-l-naphthylsulfonyl )—L-arginyl— N-t e t rahydro furfurylglycin e ; <br><br> p <br><br> N"-(l-naphthylsulfonyl)-L-arginyl -N-tetrahydrofurfuryl-glycine <br><br> 2 <br><br> N — ( 6 , 7-dimethyl — 1-naphthylsulf onyl ) -l-arginyl—jNi-t e t r ally d rofurfurylglycine <br><br> N —(5,6,7, 8-t"etrahydro—1—naphthylsu.ironyl ) -L~arg-inyl~ N—tetrahydrofurfurylglycine ~ . <br><br> 2 <br><br> N -(6 ,7—dimethoxy—2—naphthylaulfonyl)-L-argj.iiyl—N— t et rahydro fu rfurylglyciue <br><br> 2 <br><br> N -(6,7-dime thoxy—2—naphtbylsulfonyl)-L—arginyl-N— butylaspartic acid- <br><br> 2 <br><br> N,-(6,7-dimetboxy-2-naphthylsulfonyl)-L-arginyl-N-butylaspartic acid diethyl ester <br><br> (6.7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-benzylaspartic acid <br><br> P ' <br><br> N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N- <br><br> benzylaspartic acid diethyl ester <br><br> „2 <br><br> N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-methy1-(3-phenylala.nine <br><br> 24_ <br><br> f. "'FEE 1579 <br><br> 1828)2 <br><br> p <br><br> N — (6 ,7—dimethoxy—2—naphthylsulfonyl )-L-arg.inyl—N—methyl- <br><br> -methoxyphenyl )alanine <br><br> 1—[n2-(6 ,7~dimethoxy-2-naphthylsulfonyl)-L-arginyl]] -2 — piperidinecarboxylic acid <br><br> 1—[N^ — (6-me thoxy-2-naphthylsulf onyl) -L-arginy l]] -2-piperidinecarboxylic acid <br><br> 1-(N2-(6,7 —dimethoxy-2 —nsplit hyl sulfonyl )-L-arginyl]] <br><br> me!;hyl-'2-piperidinecarboxylic acid <br><br> 1 - [*N ~ -( 7 -m e t ho xy-2 -n aplxt liyl a ulfonyl ) -L-a rgin y l]j —h ~m e t h yl -2 piperidinecarboxylic acid l_|^N2-( 5~me thoxy-1 -naphthyl sul fonyl ) -L-arginyl]] -h -me thyl -2 <br><br> p;i per.iclinGcarhoxyli c acicl <br><br> 2 <br><br> 1-(N - (4, 6 -di me thoxy-2 -naphthyl sul fonyl) -L-arginyl] -4— metliyl-2—piperidinecarboxylic acid <br><br> 2 <br><br> 1—[N -(6,7-diethoxy-2-naphthylsulfonyl)-L-arginyl]] ~4 — metliyl—2—piperidinecarboxylic acid <br><br> 1-[N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl) -4-etliyl—2—piperidinecarboxylic acid <br><br> 2 <br><br> 1-(n - ( 7 -:ne thoxy-2 -napbthyls ul fonyl) -L-arginyl]] -4-ethyl-2-piperidinecarboxylic acid <br><br> P <br><br> 1-[]N "-(6,7-dimeth.oxy-2-naplathylsulf onyl )-L-arginyl]) -4 — p ropyl—2-pip e ridin e ca rboxyli c acid <br><br> . 25. <br><br> ?^PAT£NT °FFICE_ <br><br> 15 <br><br> &gt;■* 182812 <br><br> ? <br><br> 1—£N ~ —(6 ,7-dimethoxy-2-naphthylsulfonyl )-L-arginyl) —h — isopropyl-2-piperidinecarboxylic acid r 2 <br><br> 1~^N — (6 f 7-dime thoxy ~2-naphthylsulfonyl) -L-«ax^inyl3 — me thyi-2--piperidinecarboxylic acid <br><br> 1-£n2-( 7-methoxy-2-naphthylsulfonyl) -L-arginyl]— 2-mo thyl -2-piperidinecarboxylic acid <br><br> 1—[N2—( 6 ,7-dimethoxy—2—naphthylsulfonyl) —L— arginyl]] -3— piperidinecarboxylic acid p <br><br> 1—£n -(7—methoxy—2-naphthylsulfonyl)-L—arginyl]—3— <br><br> piperidinecarboxylic acid • . <br><br> p <br><br> 1-(N -(7 —methoxy—2—naphthylsulfonyl)— L—arginyl]] — 2 , 6 — piperidinedicarboxylic acid o <br><br> 1-cn -(6,7-d iniethoxy—2—naphthylsulfonyl) -L—arginyl} —k — phenyl—2-piperidinecarboxylic acid <br><br> 1—[N2-(l—naphthylsulfonyl)—L-arginyl]] -4-methyl-2-piperidinecarboxylic acid <br><br> 2 <br><br> 1-/N -(2-naphthylsulfonyl)-L-arginyl7-4-isopropyl-2-piperidinecarboxylic acid <br><br> 1-/N -(5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl7-4-methyl-2-piperidinecarboxylic acid <br><br> Ki y PATENT OFFICE ; <br><br> 26. 15 JAN 1979 ^ <br><br> % <br><br> r <br><br> J823I2 <br><br> 10 <br><br> 15 <br><br> 2 • <br><br> 49 1-[n- -(6-cbloro-2-napkt liyl s ulfonyl)-L-arginyl]}-4 —is op ropyl— 2—piperidinecarboxylic acic^ <br><br> 50 1—[n2—( 5~dimetliylamino—1-napb.tb.ylsulfonyl)—L—arginyl}— 2—piperidinecarboxylic acid <br><br> 51 1——( 7 —methyl —2 —naphthyl sul f onyl) ~L—arginyl]] —4 —me thyl —2—• piperidinecarboxylic acid <br><br> 52 i-[n2-(7 -metliyl-2-naph.tliylsulf onyl )-L-arginyl] —4-etliyl — 2—piperidinecarboxylic acid <br><br> 53 i-I&gt;2-(7 -me t byi —2 —nap Jit liyl sul To nyl) -L—arginyl] -4 -i s op ropy 1— 2-piperidinecarboxylic acid <br><br> 54 l~[N2-(6-metiiy1-2-^iaplitb.y1siaronyl)-L-arginyl3-4-isopropyl-2—piperidinecarboxylic acid <br><br> 55 1-{N -(7-methyl-2-naph.tliylsulfonyl)-L-arginyl]-2-ticxametliyl en eirrine carboxyli c a cid <br><br> 55 4-(N -(7-rnathoxy-2-naplitliylsulfonyl )-L-arginyl] -3-tiiioinorph.olinecarboxylic acid <br><br> P <br><br> 57 4-{n"-(7 -metb.oxy-2-naplitliylsulfonyl)-L-arginyl] -3-carboxythiomorpboline 1—oxide <br><br> N.Z. patent OFFICE <br><br> 27. 15 JAM 1979 ^ <br><br> 182812 <br><br> 58 4—[n2 — (6,7-dimetb.oxy-2—napb.th.ylsulf onyl) —L—arginyl]] — 3 — morpbolinecarboxylie acid <br><br> 2 <br><br> 59 4—[n —(7-inetb.oxy-2-napb.tliylsulf onyl)-L-arginyl]]—3— inorpholinecarboxylic acid , <br><br> 60 3- [N2-(7-^metlxoxy-2-naplatliylsulf onyl) -L-arginyl]] -4-ttLiazolidinecarboxylic acid <br><br> 61 2— [N2—( 6, 7~dimetb.oxy—2—naplLtliyisulf onyl) -L-arginyl]] — 1,2,3,4—tetraliydroisoquinoline—3—carboxylic acid <br><br> O <br><br> 62 2— (N^—( 6, 7-dimc tb.oxy-2-naplLtliyisulf onyl)-L-arginyl] isoindoline—1—carboxylic acid <br><br> 63 N2—(4—chlo rophenylsul fonyl) - L—argin^'l-N-butylglycine p <br><br> 64 N —(2,4,5-tricliloroplienylsulfonyl)-L~arginyl-N~butylglycine 2 <br><br> 65 N —tosyl-L-arginyl—N-butylglycine 2 <br><br> 66 N '—(4 -me tlio xyp henyl s ul fonyl ) -L-a rginy 1 —N -b enzy 1 gl y c in e <br><br> 67 N —{ 3,4— dimotliC'xyplienylsulfonyl) —L-arginyl-N—(2-metlioxyetii.yl ) glycine <br><br> 68 N2—( 3,4, 5—trimetlioxyp3aenylsulfonyl )-L-arginyl-N—(2— metlioxyetnyl) glycine <br><br> 69 <br><br> l-^2-(2-di bens of uranylsulf onyl) -L-arginyl_/-2-piperidinecarboxylic acid <br><br> 28. <br><br> Of the compounds of this invention, it will be understood that the following compounds are most preferred due to their high level of antithrombotic activity and low level of toxicity. <br><br> 2 / ' x ' <br><br> N -(7-me t ho xy-2-naph t hyls ulfon yl)-L-a rginyl-N-1 e t rahyd ro — <br><br> f u r fu rylglycine <br><br> N -(7-methyl-2-naphthylsulfonyl)-L-arginyl-N-t etrahydro — furfurylglycine <br><br> 2 <br><br> N —(6,7—dimethoxy—2—naphthylsulfonyl)—L—arginyl—N— tetrahydrofurfurylglycine <br><br> 1 — [N — (6 , 7—1dimethoxy—2—naphthylsulfonyl )-L—arginyl]} —4 — methyl-2-piperidinecarboxylic acid <br><br> 1- [N -( 7 -met ho xy-2 -naphthyl sul fonyl ) -L-arginyl]) -h — <br><br> methyl —2-piperidinecarboxylic acid r) <br><br> 1-(N -(7*-methoxy-2-naphthylsulfonyl)-L-arginyl^]-4-e thyl - <br><br> 2—piperidinecarboxylic acid <br><br> The pharmaceutically acceptable salts of the above compounds are of course also included within the scope of this invention. <br><br> As one skilled in the art can readily appreciate, the carbon atom of the —aryl sul fonyl -L-argininamides , to whi ch the carboxyl group or the cstor thereof ;is attached can be an asymmetric carbon atom allowing for the existence n.z. patent office 29. 15 <br><br> 182 <br><br> of two optically active isomers, the D- and L—diastereoisomers, as well as the racemate, DL-mixture. <br><br> In accordance with finding-s concerning the antithrombotic activity of such compounds possessing an asymmetric carbon atom, the compounds of the present invention having the D-configuration are more active than those of the L-configuratien and are the preferred compounds, although the L- and DL-forms of the instant compounds are also considered within the purview of the present invention. <br><br> The above compounds are intended only to illustrate the variety of structures which can be used in the process of this invention, and the above listing is not to be construed as limiting the scope of the invention. <br><br> For the preparation of the compounds of this invention, <br><br> various methods can be employed depending upon the particular starting materials and/or intermediates involved. <br><br> Successful preparation of these compounds is possible by way of several synthetic routes which are outlined below, (a) Condensation of an L—argininamide with an arylsulfonyl halido <br><br> This process may be illustrated as follows: <br><br> HN^ <br><br> C - N - CHpCH„CHoCfIC00H (il) &gt; <br><br> I I N ^ I I <br><br> H NH2 <br><br> 30. <br><br> N.Z. PATENT OFFICE <br><br> , 15 JAM 1979 I <br><br> 182812 <br><br> HN ^ <br><br> C - N - CH C1I CH CHCOOH (IE) <br><br> HN ^ I | <br><br> I R" HN <br><br> R' I <br><br> Rllt <br><br> + RH (IV) <br><br> HN v <br><br> XC - N - CHCHCH CHCOR (v) &gt; <br><br> HN ^ I I <br><br> I R" HN <br><br> R' I <br><br> R"' <br><br> HN ^ <br><br> C - N - CH0CH0CH0CHCOR (VI) <br><br> H2N^ I 2 2 2( <br><br> H NH2 <br><br> + ArSO X (VII) &gt; <br><br> HN . <br><br> C - N - CH„CH0CH0CHCOR (i) H„N I 2 ' 2| <br><br> • H HNSO <br><br> I ^ <br><br> Ar <br><br> In the above formulas, R and Ar are as defined herein above; X is halogen; R"1 is a protective group for the -amino group, such as benzyloxycarbonyl or tert-butoxycarbonyl; R' and R" are selected from the group consisting of hydrogen and protective groups for the guanidino group, such as nitro, tosyl, trityl, <br><br> N.Z. PATENT OFFICE <br><br> 31. 15 <br><br> 18281-2 <br><br> oxycarbonyl and the like; and at least one of R' and R" is a protective group for the guanidino group. <br><br> The N -arylsulfonyl—L-argininamide (i) is prepared by the condensation of an L-argininaniide (VI) with a 5 substantially equimolar amount of an arylsulfonyl <br><br> &gt; <br><br> halide (VIl), preferably a chloride. <br><br> The condensation reaction is generally effected in a suitable reaction-inert solvent in the presence of an excess of a base, such as an organic base (triethyl— amine, pyridine) or a solution of an inorganic base (sodium hydroxide, potassium carbonate), at a temperature of 0°C to the boiling temperature of the solvent for a period of 10 minutes to 15 hours. <br><br> The preferred solvents for the condensation include 15 benzene-diethyl ether, diethyl ether-water and dioxane— <br><br> water. <br><br> After the reaction is complete, the formed salt is extracted with water, and the solvent is removed by such standard means as evaporation under reduced <br><br> 2 <br><br> pressure to give the N -arylsulfonyl—L—argininamide (I), which can be purified by trituration or recrystalli-zation from a suitable solvent, such as diethyl ether-tot rahyd ro ,1'u r au, diethyl e tlier—me tliano 1 and water— methanol, or may be chromatographed on silica gel. 25 ' The L—argininamides (VI.) starting materials required <br><br> 32, <br><br> 182812 <br><br> for the condensation reaction can be prepared by protecting the g-uanidino and [A —amino groups of L— arginine (H) via nitration, acetylation, formylation, phthaloylation, trifluoroacetylation, p-methoxy— benzyloxycarbonylation, benzoylation, benzyloxy— <br><br> carbonylation, tert-butoxycarbonylation,tosylation^ or tritylation <br><br> Gr *2 <br><br> and then condensing the formed N —substituted-N — <br><br> substituted—L-arginine (Hi) with a corresponding amino acid derivative (IV) by such a conventional process as the.acid cbloride method, azide method, <br><br> mixed anhydride method, activated ester method or carbodiimide method, and thereafter selectively <br><br> G <br><br> removing the protective groups from the "foraied N — <br><br> substituted-N —substituted—L—argininamide (v). <br><br> The amino acid derivatives (iv) which are the starting <br><br> Q <br><br> materials for the preparation of the N -substituted— N —substit\ited-L—argininamides (v) are represented by the following formulas: <br><br> (IX) (XI) <br><br> R <br><br> -n-^ x (vm) <br><br> (CH2)nC00R2 <br><br> r6 <br><br> -N <br><br> (X) <br><br> (R„ ) 7 P <br><br> H-N <br><br> \ <br><br> R3 <br><br> CH-(CH2)mc°°R5 R4 <br><br> COOR9 <br><br> H-N <br><br> (ciQ <br><br> 2' r <br><br> N.Z. PAT' • <br><br> r 1 FEB 1979 <br><br> I *« <br><br> receive^ <br><br> 33. <br><br> 182812 <br><br> COORio COOR1:] <br><br> / \ XClizbl <br><br> -N Z (XII) H—N j (xm) <br><br> {CH^ 2'j <br><br> In the above formulas, R_L , R^ R^, R^, R^, R^,(R^,); R^, <br><br> R10' R11' ^ ' ny m;&gt; r ,c3'' and j are as defined herein above .• <br><br> The amino acid derivatives of the above formula (vill) or (IX) can be prepared by the condensation of a haloacetate, 3_halopropionate or 4—halobutyrate with an appropriate amine having the. formula R^NH^ or R3NH2. (See, J. Org. Chem., 2^.728-732 (i960)) . <br><br> The condensation reaction is generally carried out without a solvent or in a solvent, such as benzene or ether, in the presence of an organic base, such as triethylamine or pyridine, at a temperature of- 0°C to 80°C for a period of 10 minutes to 20 hours. After the reaction is complete, the formed amino acid derivative is separated by such conventional means as extraction with a suitable solvent or evaporation of the reaction solvent and thereafter purified by distillation under reduced pressure. <br><br> Among the amino acid derivatives, amino acid tert-butyl <br><br> *• <br><br> ester derivatives are preferred, because they are easily converted to other ester derivatives by acidolysis in iM.Z. K.j r 1 FEB (9/9 <br><br> 34. <br><br> 182812 <br><br> the presence of a corresponding- alcohol employing an inorganic acid (HC1, H2S0^, etc.) or an organic acid (toluenesulforiic acid, trifluoroacetic acid, etc.). In accordance with the process employed for prepaxung 2-piperidinecarboxylic acid derivatives (x), the following scheme is illustrative: <br><br> NaOCl KOK . r ^1 m , HCN v x)p &gt; [ t&lt;vp &gt; p * <br><br> N ^ VN ' * N <br><br> I I <br><br> h ci <br><br> (xiv) (xv) - (xvi) <br><br> Cx <br><br> &lt;riR7) P h2° y N C-N (H + ) ^N-^CO^H <br><br> H * ' <br><br> (xvii) (xvm) <br><br> In the first reaction of the aforementioned scheme, an appropriately substituted piperidine (xiv) is contacted with an aqueous sodium hypochlorite solution at a temperature of ~5°C to 0°C. The resultant product (xv) <br><br> is isolated by extraction with a solvent, e.g., diethyl ether, and then treated with potassium hydroxide in a de.huc(v~of&gt; if&gt; ejr icJ !&gt;i« <br><br> lower (C^-Cg) alkanol solvent to give the 1,2- doh^/ropipeiaidirre (xvi). The action of cyanogenating agents, e.g., hydrogen cyanide or sodium cyanide converts the 1,2 — dehydropiperidines (xvi) to the corresponding 2-cyano <br><br> NXPATL-NT O-RGE; <br><br> - 1 FEB 1979 35 <br><br> received <br><br> Sm <br><br> 18281 <br><br> analogs (XVII). Hydrolysis of the 2 —cyanopiperidines (XVII) to yield the 2-pip eridinecarboxylic acids (XVHl) is effected by treatment of the 2-cyanopiperidines (XVII) with an inorganic acid, such as hydrochloric acid or sulfuric acid. <br><br> The arylsulfonyl halides (VIl) which are the starting <br><br> 2 <br><br> materials for the preparation of the N -arylsulfonyl-L—argininamides (l) can be prepared by halogenating the requisite arylsulfonic acids or their salts, e.g., sodium salts, by conventional methods well known to those skilled in the art. <br><br> In practice, halogenation is carried out without a solvent or in a suitable solvent e.g., halogenated hydrocarbons or DMF in the presence of a halogenating agent, e.g., phosphorous oxychloride, thionyl chloride, phosphorous trichloride, phosphorous tribromide or phosphorous pentachloride, at a temperature of —10°C to 200°C for a period of 5 minutes to 5 hours. After the reaction is complete, the reaction product is poured into ice water and then extracted with a solvent such as ether, benzene, ethyl acetate, chloroform or the like. <br><br> The arylsulfonyl halide can be purified by recrystalli— zation from a suitable solvent such as hexane, benzene or.the like. <br><br> *12. PATENT OFFICE <br><br> 36. j j 15 JAN 1979 <br><br> 182812 <br><br> Gr Gr <br><br> Removal of the N -substituent from an N -substituted- <br><br> 2 ^ <br><br> N -arylsulfonyl-L-argininamide <br><br> This process may be illustrated as follows: <br><br> HN% <br><br> C —N-CHo CH~ CH9 CHCOR (V) -—^ HN I | <br><br> » R" HN <br><br> R1 I <br><br> R'" <br><br> HN^ <br><br> C-N—CH-CH^CHoCHCOR HN I ^ ^ I R" NH <br><br> R' <br><br> (XIX) ArS02X (VII) ^ <br><br> HN <br><br> .C-N-CH0CH0CH9CHCOR (XX) <br><br> HN I ^. d\ I R" HNS Op <br><br> R' I <br><br> Ar <br><br> HN. <br><br> C—N—CHoCHoCHQCHC0R (i) HpN^ (222, <br><br> * H HNSO„ <br><br> 1 ' <br><br> Ar <br><br> N.Z. PATENT OFFICE <br><br> f 15 JAM 1979 <br><br> 18231"' <br><br> In the above formulas, R, Ar, X, R', R" and Rm are as defined herein above. <br><br> 2 &gt; <br><br> The N —arylsulfonyl—L-argininamide (l) is prepared by <br><br> Q Q <br><br> removing the N -substituent from an N -substituted- <br><br> 2 <br><br> N -arylsulfonyl-L-argininamide (XX) by means of acidolysis or hydrogenolysis. <br><br> The acidolysis is generally effected by contacting- <br><br> G" 2. <br><br> the N -substituted-N -arylsulfonyl-L-argininamide <br><br> (XX) and an excess of an acid such as hydrogen fluoride, hydrogen chloride, hydrogen bromide or trifluoroacetic acid, without a solvent or in a solvent, <br><br> such as an ether (tetrahydrofuran, dioxane), an alcohol <br><br> (methanol, ethanol) or acetic acid at a temperature of <br><br> -10°C to 100°G, and preferably at room temperature for a period of 30 minutes to 2b hours. <br><br> The products are isolated by evaporation of the solvent and the excess acid, or by trituration with a suitable solvent followed by filtration and drying. <br><br> Because of the use of the excess acid, the products <br><br> 2 <br><br> arc generally the acid addition salts of the N — arylsulfonyl-L-argininamides (l), which can be easily converted to a free amide by neutralization. <br><br> The removal of the niti^o group mid the oxycarbonyl group, e.g., benzyloxycarbonyl, p-ni troberizyloxy-carbonyl, is readily accomplished by the hydrogenolysis, <br><br> N.Z. PATENT OFFICE <br><br> &lt; 15 JAN-1979 <br><br> 182312 <br><br> At the same time, the benzyl ester moiety which can be included in the R group is converted to the carboxyl group by the hydrogenolysis. . <br><br> The hydrogenolysis is effected in a reaction-inert solvent, e.g., methanol, ethanol, tetrahydrofuran or dioxane, in the presence of a hydrogen-activating catalyst, e.g., Raney nickel, palladium, or platinum, in a hydrogen atmosphere at a temperature of 0°C to the boiling temperature of the solvent for a period of 2 hours to 120 hours. <br><br> The hydrogen pressure is not critical, and atmospheric pressure is sufficient. <br><br> 2 , x <br><br> The N —arylsulfonyl—L—argininamides [X) are isolated by filtration of the catalyst followed by evaporation of the solvent. <br><br> 2 <br><br> The N -arylsulfonyl—L-argininamides can be purified in the same manner as described above. <br><br> Gr 2 <br><br> The N -substituted-N -arylsulfonyl-L-argininamides (XX) <br><br> starting materials can be prepared by condensing an <br><br> Gr 2 <br><br> N -substituted-N -substituted L-arginine (Hi) (generally <br><br> Gr 2 <br><br> the N -substituent is nitro or acyl, and the N — <br><br> substituent is a protective group for the amino group, <br><br> such as benzyloxycarbonyl, tert-butoxycarbonyl, or the like) and a corresponding amino acid derivative (IV)^ <br><br> 2 <br><br> selectively removing only the N•—substituent of an n.z. PATENT OFFICE <br><br> 39' 15 JAN 1979 <br><br> r&gt;^v: • ) <br><br> 182312 <br><br> Gr 2 <br><br> N -substituted-N -substituted L-argininamide (v) by means of catalytic hydrogenolysis or acidolysis, and then <br><br> G <br><br> condensing the thus obtained N -substituted-L-' argininainide (XIX) with an a i^y 1 s u 1 f on yl halide (VTl), preferably a chloride in the presence of a base in a solvent. Those reaction conditions are as described above in the condensation of an L-argininamide with an . <br><br> Q. <br><br> arylsulfonyl halide, and the removal of the N - <br><br> G 2 <br><br> substituent from an N -substituted-N -arylsulfonyl-L— <br><br> argininamide . <br><br> 2 <br><br> Condensation of an N -arylsulfonyl-L-arginyl halide with an amino acid derivative <br><br> This process may be illustrated as follows: <br><br> (") <br><br> (vii) &gt; <br><br> (xxi) &gt; <br><br> H <br><br> HN ^ I <br><br> h2n <br><br> .C-N-CH2CH2CH2CHC00H <br><br> nh2 <br><br> + ArSC^X <br><br> II <br><br> J!N^ | <br><br> C—N—Clip CH CH„ CHC00H II pN ^ ^ <br><br> HNSO I ' <br><br> Ar <br><br> 40. <br><br> n.z. patent office <br><br> * 15 JAM 1979 <br><br> 182812 <br><br> II <br><br> C-N-CHoCH2CH2CHC0)k (XXII) <br><br> h2n hns02 <br><br> Ar <br><br> + rh <br><br> (IV) * <br><br> ii <br><br> HN^ | c-n-i h2n- <br><br> ■CH2CH2CH2CHCOR <br><br> i in so <br><br> (I) <br><br> 2 <br><br> Ar <br><br> In the above formulas, R, Ar and X are as defined herein above. <br><br> halide (XXIl), preferably a chloride with at least an equimolar amount of an amino acid derivative (IV). The condensation reaction can be carried out without an added solvent in the presence of a base. However, satisfactory results will be obtained with the use of a solvent such as basic solvents (dimothylfornianu.de, dimethylacetamide, etc.) or halogenated solvents (chloroform, dichloromethane, etc.). <br><br> The amount of the solvent to be used is not critical and may vary from about 5 to 100 times the weight of <br><br> 2 / \ <br><br> thp N —arylsulfonyl—L—arginyl halide (XXIl). <br><br> 2 <br><br> The n —arylsulfonyl—L-argininamide (l) is prepared by <br><br> 2 <br><br> the condensation of an n -arylsulfonyl-L-arginyl <br><br> 41 <br><br> W.Z. PATENT OFFlCg <br><br> 15 JAM 1979 <br><br> 18281 <br><br> Preferred condensation reaction temperatures are in the range of from -10°C to room temperature. The reaction time is not critical, but varies with 'the amino acid derivative (lV) employed. In general, a period of from 5 minutes to 10 hours is operable. <br><br> 2 <br><br> The obtained N -arylsulfonyl—L-argininamide can be isolated and purified in the same manner as described above. <br><br> 2 <br><br> The N -arylsulfonyl-L-arginyl halide (XXIl) starting materials required for the condensation reaction can <br><br> 2 <br><br> be prepared by reacting an N -arylsulfonyl-L-arginine (XXI) with at least an equimolar amount of a halogenating agent such as thionyl chloride, phosphorous oxychloride, phosphorus trichloride, phosphorous pentachloride or phosphorus tribromide. The halogena— tion can be carried out with or without an added solvent. T*he preferred solvents are chlorinated hydrocarbons such as chloroform and dichloromethane, and ethers such as tetrahydrofuran and dioxane. <br><br> The amount of the solvent to be used is not critical and may vary from about 5 to 100 times the weight of the N -arylsulfonyl-L-arginine (XXl). <br><br> Preferred reaction temperature are in the range of —10°C to room temperature. The reaction time is not critical, but varies with the halogenating agent and <br><br> 42. <br><br> nx PATENT OFFICE <br><br> 15 JAM 1979 <br><br> 18281 <br><br> reaction temperature. In general, a period of 15 minutes to 5 hours is operable. <br><br> 2 <br><br> The N -arylsulfonyl-L-arginines (XXI) -which ar6 the <br><br> 2 <br><br> starting materials for the preparation of the N — arylsulfonyl-L-arginyl halides (XXIl) can be prepared by the condensation of L-arginine (il) with a substantially equimolar amount of arylsulfonyl halides (VTl), by a method similar to that described in the condensation of an L—argininamide with an arylsulfonyl halide. <br><br> 2 <br><br> Guanidylation of an N -arylsulfonyl-L-ornithinamide or an acid addition salt thereof <br><br> This process may be illustrated as follows: <br><br> h2n-ch2ch2ch2chcor (xxhe) ^ <br><br> HNS0o I <br><br> Ar <br><br> H <br><br> HN^ I <br><br> c-n-ch ch2ch2chcor (i) <br><br> h2n i hns0o <br><br> I 2 <br><br> Ar <br><br> In the above formulas, R and Ar are as defined herein above. <br><br> 2 <br><br> The' n -arylsulfonyl-L-argininamide (i) is prepared by <br><br> 43. <br><br> n.z. patent office f 15 JAN 1979 <br><br> 182812 <br><br> 2 <br><br> guanidylating an N -arylsulf onyl-L-omi thinamide <br><br> (XXIEE) with an ordinary guanidylating agent such as an O-alkylisourea, S-alkyliso thiourea, l-guanyl-3,5~ dimethylpyrazole or carbodiimide, The preferred guanidylating agents are the O-alkylisourea and the S-alkylisothiourea. <br><br> 2 <br><br> The guanidylation of the N —arylsulfonyl— L—oraithinamide (XXm) with the O-alkylisourea or S-alkylisothiourea is generally effected in a solvent in the presence of a base at a temperature of from 0°C to the boiling temperature of the solvent for a period of from 30 minutes to 50 hours. <br><br> Examples of the preferred bases are trie thylamine, <br><br> pyridine, sodium hydroxide and sodium methoxide , ' <br><br> The base is used in an amount of 0.01 to 0.1 equivalent 2 <br><br> to the N -arylsulfonyl-L-omithinamide. <br><br> Examples of the preferred solvents are water, watei— <br><br> ethanol and water—dioxane. <br><br> 2. <br><br> After the reaction is complete, the N —arylsulfonyl-L-argininamide (i) is isolated by evapox^ation of the solvent followed by removal of the excess base and the formed salt by a water wash. <br><br> It is well recognized in the art that an ester deriva— tive of the N —arylsulfonyl-L—argininamide (i) wherein <br><br> Rg, Rg, R^, R10 or R1JL is alkyl, aralkyl, aryl or <br><br> NX PATENT OFFICE <br><br> 15 JAN 1979 <br><br> 44. <br><br> 18281 <br><br> 5-indanyl, can be prepared from a carboxylic acid <br><br> 2 <br><br> derivative of the N -arylsulfonyl-L-argininamide wherein R^, R^, Rg, R^, R^q or R^ is hydrogen, by the conventional esterification methods well known to those skilled in the art. It is also well recognized in the art that the carboxylic acid derivative can be prepared from the ester derivative by the conventional hydrolysis or acidolysis methods. The conditions under which esterification, hydrolysis or acidolysis would be carried out will be each apparent to those skilled in the art. <br><br> 2 <br><br> The N -arylsulfonyl-L-argininamide (i) of this invention forms acid addition salts with any of a variet}*- of inorganic <br><br> 2 <br><br> and organic acids . Some of the N -arylsulfonyl-L-argininamides containing a free carboxyl group, wherein R„, R_, R0, R^, <br><br> £ 5 o ? <br><br> R^0 or R^ is hydrogen, forms salts with any of a variety of inorganic and organic bases. <br><br> The product of the reactions described above can be isolated in the free form or in the form of salts. In addition, the product can be obtained as pharmaceutically acceptable acid addition salts by reacting one of the free bases with an acid, such as hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, citric, maleic, succinic, <br><br> lactic, tartaric, gluconic, benzoic, methanesulfonic, <br><br> 45. <br><br> NX PATENT OFFICE <br><br> 15 JAN 1979 <br><br> 18231 <br><br> ethanesulfonic, benzenesulfonic, p—fcoluenesulfonic acid or the lilce. In. a similar manner, the product can be obtained as pharmaceutically acceptable salts by reacting one of the free carboxylic acids with a base, such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, triethylamine, procaine, dibenzylamine, 1—ephenamine, N ,N '—dibenzylethylene— diamine, N-eth.ylpiperid.ine or the like. <br><br> Likewise, treatment of the salts with a base or acid results in a regeneration of the free amide. <br><br> 2 <br><br> As stated above, the N —arylsulfonyl—L-argininamides, and the salts thereof of this invention are characterized by their highly specific inhibitory activity against thrombin as well as by their substantial lack of toxicity, and therefore these compounds are useful in the determination of thrombin in blood as diagnostic reagents, and/or for the medical control or prevention of thrombosis. <br><br> The compounds of this invention are also useful as an inhibitor of platelet aggregation. <br><br> 2 ' <br><br> The antithrombotic activity of the N -arylsulfony1-L-argininamide of this invention was compared with that of a known antd thi-ornbo tic agent, N*~ — (p- tolylsulfonyj ) — L--arginine metliyl ester, by determining the fibrinogen coagulation time . The measuremen t of the fibrinogen coagulation time was conducted as follows: <br><br> An 0.8 ml aliquot of a fibrinogen solution, which had been <br><br> NX PATENT OFFICE <br><br> 46 • 15 JAN 1979 <br><br> i <br><br> 182812 <br><br> prepared by dissolving 150 mg of bovine fibrinogen (Cohn fraction I) supplied by Armour Inc. in 40 ml of a borate saline buffer (pH J.h), was mixed with 0.1 ml of a borate saline buffer, pH 7 •''» (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. <br><br> Immediately after mixing, the reaction mixture was transferred from the ice bath to a bath maintained at 2'5°C . Coagulation times were taken as the period between the time of transference to the 25°C bath and the time of the f\rst 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 aii active ingredient required to prolong the normal coagulation time 5O-55 seconds to 100—3.10 seconds. <br><br> The concentration required to prolong the coagulation time by a factor of two for the known antithrombotic agent, <br><br> 2 <br><br> N —(p—tolylsulfonyl)-L—arginine methyl ester, was 1,100/,^M. The inhibitors are shown in Table 1 by indicating R and Ar in the formula (i) and the addition moiety. <br><br> ? <br><br> Wheal a solution containing an N -naphthylstilf'onyl-L-argininamide of this invention was administered intravenously <br><br> N.Z.PA-R- <br><br> 47, <br><br> | r 1FEB1979 <br><br> fa RECEIVE <br><br> 182812 <br><br> into animal bodies, tlie high antithrombotic activity in the circulating blood was maintained ^for from one to three hours. The halflife for decay of the anti-thrombotic compounds of this invention in circulating blood was shown to be approximately 60 minutes; the physiological conditions of the host animals (rat, rabbit, dog and chimpanzee) were well maintained. The experimental decrease of fibrinogen in animals caused by infusion of thrombin v/as satisfactorily controlled by simultaneous infusion of the compounds of this invention. <br><br> The acute toxicity values (LDK.) determined by intraperito— neal administration of substances of formula (i) in mice (male, 20 g) range from about 1,000 to 10,000 milligrams per kilogram of body weight. <br><br> Representative LDrf. values for the compounds of this inven- <br><br> 5u tion are shown in the following Table. <br><br> N.Z. PATENT OFFICE <br><br> 48. — <br><br> 15 <br><br> t" R£C£:V:0 <br><br> 182812 <br><br> S.1FE6 <br><br> Compound <br><br> LD50 (mg/kg) <br><br> 2 <br><br> N -( 6 , 7 -dime thyl-1 -nap li t hyl sul fonyl ) -L-arginyl -N-( 2-nift t;hox.ye thyl) glycine <br><br> &gt;1, 500 <br><br> i <br><br> 2 <br><br> N -(6,7 -di m e t ho &gt;: y - 2 -1 i ;ij i h t h y 1 s u.1 f o n y 1 ) —L— arginyl-N-(2-ethy.l. Lliio ethyl )g Lycine j &gt;1,000 <br><br> 2 <br><br> N ■-(7~me thyl-2-naph h Ivy I sul fonyl )-L-arginyl—N-tc t rahy d rota rfurylglycine <br><br> 600 <br><br> t <br><br> 2 <br><br> N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine <br><br> 620 <br><br> l-/lf^-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl7-2-piperidinecarboxylic acid <br><br> 1,500 <br><br> 2 <br><br> 1-/N -(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl7-4-methyl-2-piperidinecarboxylic acid <br><br> 670-1,000 <br><br> 2 <br><br> 1-/N -(l-naphthylsulfonyl)-L-arginyl7-4-methyl-2-piperidinecarboxylic acid <br><br> 700-1,000 <br><br> 2 <br><br> 1-/N - (5-dircethylamino-l-naphthyisulf'onyl) -L-arginyl7-?--piperidinecarboxylic acid <br><br> 700-1,000 <br><br> 4-/N^~ (7-methoxy-2-naphthylsulf onyl) -L-'arginyl7-3-morpholinecarboxylic acid <br><br> &gt; 1,000 <br><br> 2-/1^-(6,7-dimethoxy-2~naphthylsulfonyl)-L-arginyl7~l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid <br><br> )► 1,000 <br><br> (6 ,• 7-dime thoxy-2-na.phthylsulf onyl)-L-^frginyl7-l-isoindolinecarboxylic acid <br><br> &gt; 1,000 <br><br> )n the other hand, LI)values, for N -dansyl-N-butyl-L- <br><br> 2 <br><br> argininami.de and N -dansy 1-N-methyl-N-butyl-L-argininamide are 75 and 70 milligrams per kilogram, respectively. <br><br> 182812 <br><br> The therapeutic agents of this invention tnay be administered alone or in combination with pharmaceutically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmaceutical practice. For example, the compounds may be injected parenterally, <br><br> that is, intramuscularly, intravenously or subcutaneously. For parenteral administration, the compounds may be used in the form of sterile solutions containing other solutes, for example, sufficient saline or glucose to make the solution isotonic. The compounds may be administered orally in the form of tablets, capsules, or granules containing suitable excipients such as starch, lactose, white sugar and the like. The compounds may be administered sublingually in the form of troches or lozenges in which each active ingredient is mixed with sugar or corn syrups, flavoring agents and dyes, and then dehydrated sufficiently to make the mixture suitable for pressing into solid form. The compounds may be administered orally in the form of solutions which may contain coloring and flavoring agents. Physicians will determine the dosage of the present therapeutic agents which will be most suitable, and dosages vary with the mode of administration and the particular compound chosen. In addition, the dosage will vary with the particular patient under treatment. When the composition is administered orally, a larger quantity <br><br> 50. <br><br> NZ PATENT OFFICE <br><br> 15 JAN 1979 <br><br> 1828 <br><br> of the active agent will be required to produce the same effect as caused with a smaller quantity given paronterally. The therapeutic dosage is generally 10-50 mg/kg of active ingredient parenterally, 10—500 mg/kg orally per day. <br><br> Having generally described the invention, a more complete understanding can be obtained by reference to certain specific examples, which are included for purposes of illustration only and are not intended to be limiting unless otherwise' specified. <br><br> It is to be understood that the present invention includes pharmaceutical compositions containing a compound of the invention as an active ingredient. - Sach compositions may be in the forms described above. In particular, the invention includes such compositions in unit dose form. <br><br> 51. <br><br> \S JA^W79 <br><br> 182812 <br><br> EXAMPLE 1 <br><br> 2 <br><br> (A) N -(5-methox.y-l-naphthylsulfonyl)-L-arginine: <br><br> To a well stirred solution of 83.6g L-arginine in 800 ml i of 10fo potassium carbonate solution was added 102.6g . <br><br> 5 5-methoxynaphthalenesulfonyl chloride in 800 ml of benzene. The reaction mixture was stirred at 60°C <br><br> for 5 hours, during which time the product precipitated. <br><br> After one hour at room temperature, the precipitate was filtered and washed successively with "benzene and water <br><br> 2 <br><br> 10 to give a 76 percent yield of N -(5-methoxy-l-naphthyl sulf ony 1 ) -L-arginine . <br><br> (B) -(5-methoxy-l-naphthylsulfonyl)-L-argi.nyl chloride: <br><br> 2 <br><br> ' A suspension of 1.87g N - (5-methoxy-l-naphthylsulfony]}-L- <br><br> arginine in 20 ml of thionyl chloride was stirred for 2 <br><br> 15 hours at room temperature. Addition of cold dry diethyl ether resulted in a precipitate which was collected by filtration and washed several times with dry diethyl <br><br> 2 <br><br> ether to jive N -{5-methoxy-l-naphthylsulfonyl)-L-arginyl chloride. <br><br> 2 <br><br> 20 (0) N -.(5-methoxy-l-naphthylsulfonyl)-L-arginyl-N-(2-methyl-thioethyl)glycine tert-butyl ester: <br><br> To a stirred solution of'3.0g N-(2-methylthioethyl)glycine tert-butyl ester in 20 ml of chloroform,was carefully <br><br> 2 <br><br> added N -(5-methoxy-l-naphthylsulfonyl)-L-arginyl chloride 25 obtained above. The reaction mixture was allowed to stand,at room temperature for one hour. At th <br><br> 52. <br><br> f% 1828! 2" <br><br> r this period, the reaction mixture was washed twice with 20 ml of saturated sodium chloride solution and evaporated to dryness. The residue was triturated with a small amount of water to give a crystalline material. This was collected 5 by filtration and recrystallized from ethanol-ethyl ether to give an 82 percent yield of N -(5-methoxy-l-naphthylsulfonyl)-L-argitfyl-N-(2-methylthioethyl)glycine tert-butyl ester. - <br><br> 2 <br><br> (D) N -(5-methoxy-l-naphthylsulfonyl)-L-arginyl-N-(2-methylthioethyl) s^ine: <br><br> 10 To a solution of^/N -(5-methoxy-l-naphthylsulfonyl)-L-arginyl-N- <br><br> (2-methylthioethyl)glycine tert-butyl ester in 20 ml of o ?ewl cf <br><br> , V &lt;i.* chloroform was added^/l5$ HCl-ethyl acetate. The reaction mixture was stirred for 5 hours at room temperature. At the end of this period, the reaction mixture was evaporated to <br><br> 15 dryness. The residue was washed several times with dry f^\ <br><br> diethyl ether and chromatographyd on 80 ml of DaiaionV__/SK 102 <br><br> ion exchange resin (200-300 mesh, H+ form, manufactured by <br><br> Mitsubishi Chemical Industries Limited) packed in water, <br><br> washed with water and eluted with 37° ammonium hydroxide <br><br> 20 solution. <br><br> The fraction eluted from 3f° ammonium hydroxide solution was evaporated to dryness to give a 79 percent yield of 2 <br><br> N -(5-methoxy-1-naphthylsulfonyl)-L-arginyl-N-(2-methylthio-ethyl)glycine as an amorphous solid. <br><br> 25 The following compounds are prepared in a similar manner: <br><br> fiZ. PATENT OFFICE <br><br> * 15 JAM 1979 53' F©x:v <br><br> 182812 <br><br> 2 <br><br> N -(5-methoxy~l-naphthylsulfonyl ) -L-arginyl-N—(2 — meth.ylth.ioethyl) — ^ -alanine <br><br> N -( 6-,7-diethoxy-2—naphthylsulfonyl)-L-arginyl-N— (2-methylthioethyl)glycine <br><br> N -(6-methoxy-2 -naphthylsulfonyl)-L-arginyl-N-(2 — methylthioethyl)glycine <br><br> N —(6,7~1dimethoxy-2-naphthylsulfonyl)-N—(2 — <br><br> methylthioethyl)-N-(3-carboxypropyl)-L-argininamide <br><br> 2 <br><br> N —(6,7"dimethoxy—2-naphthylsulfonyl)-N-(3— methylthiopropyl)glycine <br><br> N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl—N—(2-ethylthioethyl)— f4 -alanine <br><br> 2 <br><br> N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-benzylglycine benzyl ester <br><br> N -(5—nitro-1-naphthylsulfonyl)—L-arginyl-N—tetrahydro — furfurylglycine <br><br> 2 * <br><br> N -(7-hydroxv-2-naphthylsulfonyl)-L-arginyl-N-tet rahydrofurfurylglycine <br><br> 18231 <br><br> N*~-( 5-cyano-1-naphthyl sul fonyl) -L-arginyl -N-tet rahydro -furfu rylglycine <br><br> 2 <br><br> N -(6,7-dimothoxy-2-naphthylsulfonyl)-L-arginyl-N-t etraliydrofur furyl — ^ —alanine <br><br> N^-(7-niotliyJ -2-naphthylsulfony], ) —L-arginy 1 -N-tetrahydrofurfuryl —£) -alanine <br><br> 2 <br><br> N —(6,7-dimethoxy-2—naphthylsulfonyl)-L—arginyl—N— tetrahydrofurfn ry.l al anino <br><br> N -( 7-niethoxy-2-naphthylsulfonyl) -N-( 3-carboxypropyl ) -N—tetrahydrofurfuryl—L-argininamide <br><br> 2 <br><br> N -(6 ,7-dirne thoxy—2-naphthylsulfonyl) -L— arginyl —N — <br><br> ( 3—fury.1 methyl )glycine <br><br> ^-(6,7 -dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(tetrahydro 3-furylmethyl)glycine p <br><br> N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-thenyl)glycine <br><br> 2 <br><br> N -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(3-thenyl) glycine <br><br> 2 <br><br> N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(tetrahydro-2-thenyl)glyc ine <br><br> 5 5 . N.Z. PATENT OFFICE <br><br> t 15 JAM 1979 <br><br> RECCV"? <br><br> 182812 <br><br> N2- (7-meth.oxy-2-naphthylsulfonyl) -L-arginyl-N-) Te trahydro-3-thenyl)glycine <br><br> N2~(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-acetylethyl) /0 glycine <br><br> (7-methoxy-2-raphthylsulfonyl)-L-arginyl-N-(4-methoxy-furyl)glycine <br><br> 5 N2~(7-methyl-2-naphthylsulfonyl)-L-arginyl-N-(5-methyl-furfuryl)glycine <br><br> N2~(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(l,4-diacylohexylmethyl)glycine <br><br> 1-(N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl)-4-10 methoxypiperidine-2-carboxylic acid <br><br> 1-(N2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl)-5-methylbexamethyleneimine-2-carboxylic acid <br><br> 1-(N2-(3,7-dimethyl-2-dibenzofluranyl)-L-arginyl)-4,4-dimethyl-2-piperidine carboxylic acid. <br><br> 15 N2~(3-methoxy-5,6.7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl-N-(tetrahydro-2-pyranylmethyl)glycine <br><br> EXAMPLE 2 <br><br> (A) N^-(6-methoxy-2-naphthylsulfonyl)-L-arginyl chloride: <br><br> 2 <br><br> A suspension of 2.5 g of N -(6-methoxy-2~naphthylsulfonyl)-L-20 arginine in 20 ml of thionyl chloride was stirred for 2 hours at room temperature. Addition of cold dry ethyl ether resulted in a precipitate which was collected by filtration and washed several times with, dry ethyl ether to give <br><br> 2 <br><br> N -(6-methoxy-2-naphthylsulfonyl)-L-arginyl chloride. <br><br> r <br><br> 182 <br><br> (B) Ethyl 1-(n^—(6-methoxy-2-naphthylsulfonyl)-L-arginylJ-2—piperidinecarboxylate : <br><br> To a stirred solution of 2.2 g of ethyl 2-piperidine-carboxylate and 4.1 ml of trietliylamine in 50 ml of chloroform, which was cooled in an ice—salt bath, was <br><br> 2 <br><br> added in portions N -(6-niethoxy-2-naphthylsulfonyl)-L-arginyl chloride obtained above. The reaction mixture was stirred overnight at room temperature. At the end of this period, 500 nil of chloroform was added and the chloroform solution was washed twice with 50 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo. The oily residue was washed with ethyl ether to give <br><br> 2 <br><br> 2.9 g of powdery ethyl 1-[N -(6-methoxy-2-naphthyl-15 sulfonyl) -L-arginyl^) -2-piperidinecarboxylate . <br><br> For analysis of the product, a portion of the product was converted to the flavianate, M.P. 192-3°C . <br><br> I.R. (KBr): 3,210, 1,7^7, 1,638 era"1 <br><br> Analysis - Calc-d. for C0 _II„ _0^N _S «C. II0oN_S (percent): <br><br> &lt;5 35 ® 5 -l-U O O <br><br> ^ C, &gt;19.58; II, h. 87; N, 11.56 Found (percent): C, b9.2k; <br><br> H, k .70; N, 11.85 <br><br> (C) 1 — -(6—methoxy-2-naphthylsulfonyl)-L-arginyl}—2 — —~ piperidinecarboxylic acid: <br><br> A solution of 2.8 g of ethyl 1 -fN*~-(6-methoxy-2 — -5 naphthylsulfonyl )-L-arginyl^)-2-piperidinecarboxylate in <br><br> NX PATENT OFFICE <br><br> 57. ■ <br><br> '$ 15 JAN 5979 <br><br> , <br><br> 182 <br><br> 15 ml of methanol and 10 ml of 2N~NaOH solution was warmed to 60°C and held atx that temperature for 10 hours. At the end of this period, the reaction mixture was concentrated and chrotnatographed on 200 ml of <br><br> Daiaion SK 102 ion exchange resin (200 — 300 mesh, <br><br> •}* <br><br> H form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with ethanol-water (.1:4) and eluted with ethanol—water-NH^OH (10:9^1) • The main fraction was evaporated to dryness and washed with ethyl ether to give 2.0 g of 1-|~N -(6—methoxy—2— naphthylsulfonyl)-L-arginyl]-2-piperidinecarboxylic acid as an amorphous solid. <br><br> I.R. (KBr): 3,200 (broad), 1,620, 1,150 cm"1 Analysis - Calcd. for 023*132 O^N^S (percent): C, 54.64; H, 6.18; N, 13.85 Found (percent): C, 56.88; H, 6.31; N, 13.83 <br><br> The following compounds are prepared in a similar manner: <br><br> p <br><br> N -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methylthioethyl)glycine p <br><br> N -(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-metbylthioethyl)glycine <br><br> imn <br><br> 2 <br><br> 1-/N -(5-methoxy-l-naphthylsulfonyl)-L-arginyl7-4-ethyl-2-piperidinecarboxylic acid <br><br> 1-/N -(6-methoxy-2-naphthylsulfonyl)-L-arginyl7-4-ethyl-2-piperidinecarboxylic acid <br><br> 1-/N -(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl7-4-ethyl-2-piperidinecarboxylic acid <br><br> 2 <br><br> 1-/N -(5-ethoxy-l-naphthylsulfonyl)-L-arginyl7-4-ethyl- <br><br> 2-piperidinecarboxylic acid <br><br> 2 <br><br> 1-/N -(7-ethoxy-2-naphthylsulfonyl)-L-arginyl7-4-ethyl-2-piperidinecarboxylic' acid p <br><br> 1-/N -(6,7-diethoxy-2-naphthylsulfonyl)-L-arginyl7~4-ethyl-2-piperidinecarboxylic acid <br><br> 1-/N^-(7-methoxy-2-naphthylsulfonyl)-L-arginyl7-4-tert-butyl-2-piperidinecarboxylic acid <br><br> 2 <br><br> Phenyl 1-/N -(7-methoxy-2-naphthyisulfonyl)-L-arginyl7-4-ethyl-2-piperidinecarboxylate <br><br> 59. <br><br> N.2. PATENT OFFICE <br><br> f 15 JAN 2979 <br><br> "" 182812 <br><br> 2 <br><br> Benzyl 1-(N -(7-iiiethoxy-2-naphthylsulf onyl )-L-arginyl] -4 —ethyl-2-piperidinecarboxylate <br><br> Benzyl l-^N -( 6 , 7-dime thoxy-2 -naphthylsulfonyl )-L-arginyl3-4-methyl-2-piperidinecarboxylate <br><br> 2 <br><br> 1-QN -( 5_ni tro-1-naphthyl sul fonyl) -L-arginyl3 -4 — methyl-2-piperidinecarboxylic acid <br><br> 1 — Qm -(7~lvydroxy-2-naphthylsulfonyl )-L-arginyl]] -4-e thyl-2 -piperidinecarboxyli c acid <br><br> 2 <br><br> 1 — [N -(5-cyano-1-naphthylsulfonyl)-L-arginyl]) -4—methyl— <br><br> 2—piperidinecarboxylic acid <br><br> 2 <br><br> 1-{N -(7 -me thyl-2-naphthyl sul fonyl)-L-arginyl]] -4-ethyl —2-piperidinecarboxyli c acid <br><br> 2 <br><br> 1 —[]n -( 5-dime thylamino-l-naphthylsulfonyl ) -L-arginyl]] — 4—ethyl.-2-piperidinecarboxylic acid q <br><br> 1 —|]N —(2—naphthylsulfonyl ) —L—arginy l]] —4—ethyl—2— piperidinecarboxylic acid <br><br> 1 —£n^-(5»6,7»8-L etrahydro-2-naphthylsulfonyl)-L-arginy.l J — 4— ethyl— 2— pipei'idi.necarboxyli c acid <br><br> N.Z. PATENT OFFICE <br><br> * 15JA.\':979 <br><br> 60. <br><br> 182812 <br><br> 2 <br><br> 1-(]N -(5-dimethylamino-l-naphthylsulfonyl) -L—arginylj -4-methyl—2-piperidinecarboxylic acid <br><br> 2 <br><br> l-CN -(7 —me thyl-2-naph thyl sul fonyl )-L-arginyl]J —6 — methyl-2-piperidinecarboxylic acid <br><br> 1-[]N2 — (7— methyl -2 -naphthylsulf onyl)-L-arginyl]] —4—tert-butyl-2-piperi dine carboxylic acid <br><br> 2 <br><br> 1-(N -(5-nitro-l-naphthylsulfonyl)-L-arginyl]indoline- <br><br> 2-carboxylic acid <br><br> 2 <br><br> 2-(N -( 5—cyano -1-naphthyl sul fonyl) -L-arginyl] isoindoline— 1-carboxylic acid p <br><br> 4-{n -(7 —methyl—2-naphthylsulfonyl ) -L-arginyl]] thi o — morpholine-3-carboxyli c acid <br><br> 4—(]N ~(6 ,7 -dime thyl -2 -naphthyl sul fonyl) -L-arginyl]] morpholine-3-carboxylic acid <br><br> 4-[N2-(5,6,7 &gt;8-tetrahydro-2-naphthylsulfonyl) —L— <br><br> arginyl]] — 3-carboxy thi omorpho line 1-oxide <br><br> —methyl-2-naphthylsulfonyl)-L—arginyl^Jmorpholine — <br><br> 3-carboxylic acid <br><br> 4 - (]N2 -(7-chloro-2 -naphthyl sul fonyl) -L-arginyl]] mo rpholine— 3-carboxylic acid <br><br> 61. <br><br> N.Z. PATENT OFFICE <br><br> IS JAN 1979 &gt; <br><br> 182812 <br><br> 2 <br><br> 4-[n -(7~hydr,oxy-2-naphthylsulf onyl )-l—arginylj morpholine-3-carboxylic acid <br><br> / . <br><br> 4-qst -( 5-nitro— 1-naphthylsul fonyl) -L-arginyl]) thio -morpholine-3-carboxylic acid <br><br> 4-(n —( 5-cyano-l-naphthylsulfonyl )-L-arginyl]| thio-morpholine-3-carboxylic acid <br><br> 2 <br><br> 4-[]n -( 5-methoxy-l-naphthylsulfonyl)-L-arginyl]] tnorpholine-3-carboxylic acid k—IN2 — ( 5*~ethoxy—1 -naphthylsulf onyl)-L-arginyl]) morphol.ine-3-carboxylic acid <br><br> 4-|]n -(5-dimethylamino—1-naphthylsulfonyl)-L-arginyl) thiomorpholine—3-carboxylic acid <br><br> 3-[n -(1-naphthyl sul fonyl) —L—arginylj thiazolidine—4— carboxylic acid <br><br> 2-{N2-(7-methoxy-2-naphthylsulfonyl)-L-arginyl)— 1,2,3,h—tetrahydroisoquinoline—1-carboxylic acid <br><br> 2 — (n2-(7 —methox}r~2-naphthylsulfonyl )-L—arginyl]] isoindoline—1—carboxylic acid <br><br> 62. <br><br> N.Z. PATENT OFFICE <br><br> I 15 JAN 1979 <br><br> 182812 <br><br> 7 <br><br> 2-/N~- (4, 6-d .ime thoxy-2-naphthylsulf ony 1 )-L-arginyl7~ 1,2,3,4-tetrahydroisoquinolirse-3-carboxylic acid <br><br> 2-/N -(5-methox.y-l-naphthylsulf onyl )-L-arginyl7~ isoindoline-l-carboxylic acid i <br><br> 2-/N^-(5-etlioxy-l-naphthylsulf onyl)-l-arginyl7~l ,2,3,4-tetrahydroiscquinoline-3-carTDoxylic acid <br><br> EXAMPLE 3 <br><br> g _ 2 _ <br><br> N -bitro 2- / N - (tert.-butoxycarbony1) -L-arginy 1_/-1 ,.2 , 3,4- <br><br> tetrahydroisoquinoline-3-carboxylic acid ethyl 'ester: <br><br> 2*'3k 2 <br><br> To a stirred solution of^N -nitro-N - (tert-butoxycarbonyl)-L-arginine in 45© ml of dry tetrahydrofuran were added in turn/triethylamine and^ isobutyl chloroformate while keeping the temperature at -5°C. After 15 minutes, to this was added/1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid ethyl ester, and the mixture was stirred for 15 minutes at -5°G. At the end of this period, the reaction mixture was warmed to room temperature. The solvent was evaporated and the residue taken up in 400 ml of ethyl acetate, and washed.successively with 200 ml of waxer, 100 ml of 5$ <br><br> sodium bicarbonate solution, 100 ml of 10$ citric acid solution and 200 ml of water0 The ethyl acexate solution was dried over anhydrous sodium sulfate. Upon evaporation of the solvent, the residue was dissolved in 20 ml of chloro- <br><br> ' Y. <br><br> form, and the solution was applied to a column (SO cm x 6cm) of 500 g of silica gel packed in chloroform. The product was eluted first with chloroform, and then 3methanol-chloroforrcu. The fraction eluted from 3% rnethanol-chloroforta tFEB»W <br><br> 18 2 812 <br><br> i <br><br> was evaporated to dryness to give a 63 percent yield of G- 2 <br><br> N -nitro~2-/~N - (tert-butoxycarbonyl) -L-ar.ginyl_7~l, 2 , 3 , 4-tetrahydroisoquinoline-3-carboxylic acid ethyl ester in the form of a syrup. <br><br> ? (E) NG-nitro-2-/L-arqinyl_/-l,2,3,4- <br><br> tetrahydroisoauinoline-3-carboxylic acid ethyl ester hydrochloride <br><br> 32 ■%. 2 <br><br> To a stirred solution of/N -nitro-2-/N -fcert-butoxycarbonyl)- <br><br> \\ -L-arginyl7~l ,2,3.4-tetrahydroisoquinoline-3-carboxylic acid <br><br> ■ 'i*11' v ethyl ester in 50 ml of ethyl acetate was added 80 ml of 10% 10 ' dry HCl-ethyl acetate.at 0°C. After 3 hours, to this solution was added 200 ml of dry ethyl ether to precipitate a viscous oily product. <br><br> This was filtered and washed with dry ethyl ether to give <br><br> G <br><br> N -nitro-2-(/L-arginyl_/-l, 2 , 3 , 4- <br><br> 15 tetrahydroisoquinoline-3-carboxylic acid ethyl ester hydrochloride as an amorphous solid. <br><br> '.(C) NG-nitro-2-/N2-(7 -methyl-2-naphthylsulfonyl)-L-argi'nyl7- <br><br> 1,2,3&gt;4-tetrahydroiscquinoline-3-carboxylic acid ethyl ester: To a stirred solution of/N -nitro-2-/L-arginyl7-l,2,3,4-20 tetrahydroisoquinoline-3-carboxylic acid ethyl ester hydrochloride in 20 ml of water and 20 ml of dioxane were oV 2% <br><br> * added in turn 2.5 g of sodium bicarbonate, and/7-methyl-2- <br><br> naphthalenesulfonyl chloride in 30 ml of dioxane at 5°C, <br><br> w* and stirring was continued for 3 hours at room temperature. <br><br> 25 At the end of this period, the solvent was evaporated and the residue dissolved in 40 mi of chloroform, an$ <br><br> 64. . <br><br> 182812 <br><br> \^y with 10 ml of IN hydrochloric acid solution and 20 ml of water. <br><br> The chloroform solution was dried ever anhydrous sodium sulfate. Upon evaporation of the solvent, the residue 5 was chromatographed on 50 g of silica gel packed in chloroform, washed with chloroform and eluted with 3$ methanol-chloroform. The fraction eluted from 3$ methanol-chloroform was evaporated to give an 87 percent yield of NJr-nitro-2-/N^-(7-methyl-2-naphthylsulfonyl)-1-10 arginyl7~l ,2,3? 4-tetrahydroisoquincline-3-carboicylic acid ethyl ester in the form of an amorphous solid. <br><br> (L) 2-/N^- (7-me thyl-2--naphthylsulf onyl) -L-arginyl7-l,2,3,4- <br><br> tetrahydroisoquinoline-3-carboxylic acid ethyl ester: <br><br> q. 2 <br><br> 15 To a solution of^S" -nitro-2-/Tv -(7-methyl-2-naphthylsulfonyl)- <br><br> L~arginyl7-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid ethyl ester in 50 ml of ethanol and 0.5 ml of acetic acid was added 0.5 g of palladium-black and then the mixture was shaken in a hydrogen atmosphere for 100 hours at room 20 temperature. At the end of this period, the ethanol solution was filtered to remove the catalyst and evaporated to give an oily product. Reprecipitation with ethanol-ethyl ether p <br><br> gave a 91 yield of 2-/N -(7-methy1-2-naphthylsulfonyl)-L-arginyl7~l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid •25 ethyl ester. <br><br> s <br><br> (E) 2-/N - (7-methyl-2-naphthylsulfonyl )-I-arginyl7-l, 2 ,3 ,4-;;^Qf?\Ctetrahydroisoquinoline-3-carboxylic acid: <br><br> solution of^2-/N^~(7-methyl-2-naphthylsulfonyl)-L-arginyl/- <br><br> * <br><br> ^,1, 2 , 3 ,4-teti'ah.ydroisoquinoline-3-carboxylic acid ethyl ester <br><br> 'X*S ^ — <br><br> 65. <br><br> 18231 <br><br> in 5 ml of ethanol and 7 ml of IN sodium hydroxide solution was stirred for 30 hours at room temperature. At the end of this period, the solution w£:s concentrated to 5 ml, cbromatogra.phed on 80 ml' of Daiaion SK 102 ion exchange resin (200 - 300 mesh, H+ form manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with water, -and eluted with 3i° ammonium hydroxide solution. The fraction eluted from 3i° ammonium hydroxide solution was evaporated to dryness, and the residue was purified by reprecipitation with ethanol-ethyl ether to give a 72 percent yield of 2-/N^-(7-methyl-2-naphthylsuifonyl)-l-arginyl7-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid as an amorphous solid. <br><br> The following compounds are prepared in a similar manner: <br><br> 2-{]n2-( 7-me thyl -2-naph thyl sul fonyl ) -L-arginyl]) isoindoline-l-carboxylic acid <br><br> 2 - [N2 -(6,7 ~di me thyl -2 -naphthyl s ul fonyl) -L—arginyl") isoindolinc-l-carboxylic acid <br><br> 2-[n -(2 -naphthylsulfonyl ) -L-arginyl]] isoindo line-l-carboxyli c acid <br><br> 2 <br><br> 2-[]N -(5,6 , 7 , 8-tetrahydro-2-naphthylsulfonyl ) —L— <br><br> arginylj -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid <br><br> 2 —(]N2- ( 5,6,7, 8—t e trahydro—1— naph thyl sul fonyl) -L— <br><br> arg.iiiyl]] Lso:i inloJ ino-1-carboxyli c acid NX PATENT OFFICE <br><br> f 15 JAM 1979 ^6* f REC61VFD <br><br> 18281 2 <br><br> O <br><br> O <br><br> —([n** -( *5 — t:111 o ro - 1 -naph thy I.sul fonyl ) -L-arg i ny l")•— <br><br> 1,2,3, — t o t rahytiroi soquinoliiie-3—carbo xy.l i c acid <br><br> 1 —£n'~ - ( 5 - by d ro xy -1 —naph t liyl s ul fonyl) -L-a rginy l] - <br><br> 1 ,2 , 3 , 4 — t c trahydroquino lirie-2-carboxyli c acid <br><br> 2-£n2-( 5-dimethylamino-l-naphthylsulfonyl) -L-arginyl^] isoj.ndo3ine-l-carboxy.lic acid p <br><br> 2 -[N -( 1 -naph I.by 1 «ul fonyl ) -L-arg:i ny I- I ,2 , '} , h -tetrahydroisoquinoline-3-carboxylic acid <br><br> EXAMPLE 4 <br><br> N^-(6,7-dimethyl-l-naphthylsulfonyl)~L-arginyl-N- <br><br> (2-methoxyethyl)glycine: <br><br> q. 2 <br><br> N -nitro-N -(6,7-dimethyl-l-naphthylsulfonyl)-L- arginyl-N-(2-methoxyethyl)glycine "benzyl ester was prepared Toy the procedure described in Example 3. <br><br> 2 <br><br> To a solution of^N -nitro-N -(6,7-dimethyl-l-naphthylsulf onyl) -L-arginyl-N- (2-methoxyethyl)glycine "benzyl ester in 50 ml of ethanol and 0.5 ml of acetic acid was added 0.5 g of palladium-black and then the mixture was shaker. in a hydrogen atmosphere for 100 hours at room temperature. At the end of this period, the ethanol solution was filtered to remove the catalyst and evaporated to dryness. The residue was washed several times with dry ethyl ether and chromatographed on 80 ml of Daiaion SK 102 ion exchange resin (200 - 300 mesh, H+ form, manufactured by Mitsubishi Chemical Industries <br><br> N.Z. PATENT OFFICE 67. — — <br><br> v 15 JAN 1979 <br><br> f '*y*». - <br><br> i ^ <br><br> t <br><br> 182812 <br><br> Limited) packed in water, washed with water, and eluted with y/o ammonium hydroxide solution. The fraction eluted from 3$ ammonium hydroxide solution was evaporated <br><br> 2 <br><br> to dryness to give N - (6, '7-dime thyl-l-naphthylsulf onyl) -L- <br><br> arginyl-N-(2-methoxyethyl)glycine as an amorphous solid. <br><br> I.R. (KBr): 3,350 1,640 cm"1 <br><br> Analysis - Calcd. (percent): C, 54.42; <br><br> H, 6.55; N, 13.80 Found (percent): C, 54.28; <br><br> H, 6.32; N, 13.59 <br><br> 10 EXAMPLE 5 <br><br> 2 <br><br> (A) N -(6,7-diinethoxy-2-naphthylsulfonyl)-L-arginyl-N- <br><br> (2-methoxyethyl)glycyl chloride hydrochloride: <br><br> A suspension of 2.00 g of N -(b,7-dimethoxy-2-naphthyl sulfenyl)-L-arginyl-N-(2-methoxyethyl)glycine in 2- ml <br><br> 15 of thicnyl chloride was stirred for 2 hours at r'Oorn temperature. Addition of cold dry ethyl ether resulted in a precipitate which was collected by filtration and. <br><br> 2 <br><br> washed several times with dry ethyl exiier to give N -(6 ,7-dirQethoxy-2-naphthylsulf onyl)-L-arginyl-N- (2-20 methoxyethyl)glycyl chloride hydrochloride. <br><br> 1828)2 <br><br> 2 <br><br> (B) N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2- <br><br> methoxyethyl)glycine m-tolyl ester hydrochloride: <br><br> 2 <br><br> A mixture of 2.00 g of m-cresol and N —(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-niethoxyethyl)glycyl chloride hydrochloride obtained above was heated at 90°C for 50 minutes. At the end of this period, the reaction mixture was cooled, washed several times with dry ethyl ether, and then dissolved in 10 ml of dry ethyl alcohol. Addition of cold dry ethyl ether resulted in a precipitate which was washed several times with dry ethyl ether to give 2.12 g (86 percent) of N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine m-tolyl ester hydrochloride in the form of a powder. <br><br> I.R. (KBr) : 3,250, 3,100, 1,7**0, 1,640 cm-1. The following compounds are prepared in a similar manner: N2 — (6,7 —dimethoxy-2—naphthylsulfonyl)—L-arginyl—N—(2 — ethylthioethyl)glycine phenyl ester <br><br> 2 <br><br> N - (6 ,7 ~d:i mo thoxy-2-naph thylsu.1 Ton yl ) —L-a rgj ny 1 -N-( 2 -etliy.Lthioethyl )glycine benzyl ester <br><br> N -(6,7-dimethoxy-2—naphthylsulfonyl)-L-arginyl-N— benzylglycine phenyl ester <br><br> 69. 15 JAM <br><br> C <br><br> 182812 <br><br> p <br><br> N "-( 6 ,7 -dime t ho xy-2 -n ap h t hyl sul fonyl ) -L—argdnyl—N — furfurylglycine benzyl ester <br><br> 2 1 <br><br> N -(6,7-dimethoxy-2-naph thylsulfonyl)—L—arginyl— N— <br><br> tetrahydrofurfurylglycine phenyl ester <br><br> Phenyl 1—(n2-(7-methyl-2—naphthylsulfonyl)—L—arginylj• k—ethyl-2—piperidinecarboxylate <br><br> Benzyl 1- (n^-(7-methyl—2-naphthylsulfonyl)—L—arginyl] • h—ethyl-2-piperidinecarboxylate <br><br> Benzyl 1- |n2-(6—chloro-2-naphthylsulfonyl)-L—arginylJ ■ 4-methyl-2-pip eridinecarboxylate <br><br> 2 <br><br> Various other N -arylsulfonyl-L-argini.namides ox- <br><br> salts thereof were synthesized in accordance with the procedure of the above examples, and the test results are summarized, in Table 1 , <br><br> 70. <br><br> N.Z. PATENT OFFICE <br><br> 15 JAN 1979 ' <br><br> 18 2812 <br><br> TABLE 1 . . Sheet 1 <br><br> Sample No. <br><br> Compound <br><br> II <br><br> HN&lt;. j c--n-ch ch0ch„chcor (i) H2N^ | <br><br> H-N-s02-Ar <br><br> Ar <br><br> R <br><br> Addition moiety <br><br> 1 <br><br> tOra,J <br><br> -n^ch2ch2sch3 nvch2c02h <br><br> - <br><br> 2 <br><br> 3 <br><br> ^&gt;^&lt;^OCH3 <br><br> /CH2ch2sc2h -n\ <br><br> nCH2c02c(ch3)3 <br><br> 1/2ii2s03 <br><br> 3 <br><br> ^cii2ch2sc2h5 <br><br> "xch2co2h <br><br> • <br><br> 4 <br><br> YYV501*3'' <br><br> ^^&lt;^och3 <br><br> COpH <br><br> -o <br><br> - <br><br> 5 <br><br> ^^&lt;^och3 <br><br> co2n <br><br> -o <br><br> - <br><br> •■■■ 6 <br><br> •ax:; <br><br> co2h <br><br> -{&gt;ch 3 <br><br> - <br><br> 7 <br><br> n <br><br> ^Q-°ch3 ' <br><br> co h <br><br> - <br><br> 182812 <br><br> Sheet 1 Cont'd <br><br> - <br><br> Co.ncen t ra lion .required to prolong the coagulation • time by a factor of two (/V M) <br><br> J1 repara tion i) ro c o « s (Ex. No.) <br><br> in . p . <br><br> (°C) <br><br> Elementary analysis Upper: Calculated Lower: Found (^) ; <br><br> I.R. (KBr) (cm""1) <br><br> C <br><br> H <br><br> N <br><br> 1 <br><br> 1 . <br><br> Powder <br><br> 50 .25 50 5 <br><br> 5.95 6 .01 <br><br> 13.32 13.15 <br><br> 3,350 1,62 0 1, 380 1,150 <br><br> 1 <br><br> If <br><br> 50.^3 50.57 <br><br> 6.65 6 .58 <br><br> 10.50 1.0.71 <br><br> 3,350 1,7^5 1,650 1,360 <br><br> 5 <br><br> 1 <br><br> 171-2 <br><br> 50 .60 50 .51 <br><br> 6 .19 6 .30 <br><br> 12 .29 .12 .kO <br><br> 3,^00 <br><br> 1,635 1,260 1,160 <br><br> 5 <br><br> 2 <br><br> powder <br><br> 53.82 53 .66 <br><br> 6.21 5.96 <br><br> 13 .08 12 .81 <br><br> 3,350 1,625 1,155 <br><br> r&gt; J <br><br> 2 <br><br> powder <br><br> 5k .6k 56 .88 <br><br> 6 .18 6 .31 <br><br> 13.85 13 .83 <br><br> 3,2 00 (broad) <br><br> 1,620 <br><br> 1,150 <br><br> o .k <br><br> 2 <br><br> II <br><br> r <br><br> 5k .63 5k .50 <br><br> 6 J(2 6 .09 <br><br> 12 .74 12 .SI <br><br> 3,370 1,62 5 1,158 <br><br> 0 .15 <br><br> ——- .. 'if . <br><br> 2 <br><br> powdc r <br><br> 55 -k? 55-k9 <br><br> 6 JiO 6 .33 <br><br> 13.98 13.51 <br><br> 3,250 (broach 1,625 <br><br> 182812 <br><br> Sheet 2 <br><br> Compound <br><br> Sample No . <br><br> HN <br><br> h2-n- <br><br> % <br><br> H I <br><br> * c -n ■-ch2 ch2 ch2 c :-ic or <br><br> H—X-SOg-Ar <br><br> Ar <br><br> R <br><br> (I) <br><br> OCH' <br><br> c°2h <br><br> "0^H3 <br><br> 9 <br><br> OCH, <br><br> OCH- <br><br> co2h <br><br> -0^H3 <br><br> 10 <br><br> OC^H _ OC2H5 <br><br> COpH ) \ <br><br> -N V-CH, <br><br> 11 <br><br> 12 <br><br> 13 <br><br> 0CH3 OCH~ <br><br> 0CH <br><br> 3 <br><br> OCH. <br><br> OCH, <br><br> COpII <br><br> •O <br><br> 2H5 <br><br> C02H <br><br> -(D-C2H5 <br><br> COsH -N VCH2CH2CH3 <br><br> 14 <br><br> co2h <br><br> -0-ck(GH3)2 <br><br> 182812 <br><br> Sheet 2 Cont'd <br><br> ^ -- <br><br> *1; <br><br> Conccn I ra Lion required to prolong tlio coagu.l a (: j on time by a factor ol' l;vo <br><br> (A M)' <br><br> 0.35 <br><br> 0.5 <br><br> l&gt; repn ra I. -j. on p ro c eri s ( Fx . jNo . ) <br><br> 2 <br><br> 2 <br><br> in .p . <br><br> (°C) <br><br> powder powde r <br><br> 1CI cineii t ary anal y.si s Iipper : C alculated (^) Lownr: Found (x) ; <br><br> C <br><br> 55 <br><br> Ji7 55.31 <br><br> II <br><br> 6 Ji 0 <br><br> 6 .68 <br><br> 5;i -63 <br><br> 5'-i .55 <br><br> powder powder <br><br> 56 .13 56 .11 <br><br> 55-bo 55.71 <br><br> 6 .4 2 <br><br> 6 .42 <br><br> 6 .80 <br><br> 6 .85 <br><br> N <br><br> 13.. *18 13.21 <br><br> I.R. (KBr) (cm 1) <br><br> 3,350 1,620 <br><br> 1,150 <br><br> 12 .74 12 .58 <br><br> 12 .12 11 .95 <br><br> 6.62 12.43 <br><br> 6 .48 <br><br> 12 .53 <br><br> 3,350 (broaci^ 1,620 &gt; <br><br> 1,150 <br><br> 3, 300 (broar^ 1,6.10 <br><br> 1,2 55 <br><br> 3,360 1,620 1,150 <br><br> powder <br><br> 56 .26 56 .41 <br><br> 56 .13 56 .11 <br><br> 6 ,61 6 .48 <br><br> 6 .80 6 .81 <br><br> 56 .13 56 .21 <br><br> 6 .SO 6 .81 <br><br> 13.12 13 .27 <br><br> 3, 360 1,62 0 1,158 <br><br> 12 .12 <br><br> 11 .96 <br><br> 12 .12 12 .03 <br><br> 3,400 1,620 <br><br> 3,400 1,620 1,150 <br><br> •c£ <br><br> TVfE&amp;W'/1* <br><br> \ <br><br> - .7 4 - <br><br> 18 2812 <br><br> Sheet 3 <br><br> Sarhple No . <br><br> Compound' <br><br> h <br><br> ^ 1 m <br><br> C-n-ch„ch0ch0chcor (1; <br><br> h?n^ 2 2 -1 <br><br> ^ h-N-S02-Ar <br><br> Ar <br><br> R <br><br> Addition moi ety <br><br> 15 <br><br> 0CH3 <br><br> ock ^ <br><br> 1 <br><br> o ^&gt;£^3 <br><br> 1 <br><br> - <br><br> 16 <br><br> -CO-™5 <br><br> ck^ co k <br><br> -O <br><br> - <br><br> 17 <br><br> ■car, <br><br> /c0oh <br><br> -0 <br><br> - <br><br> 16 ; <br><br> tCCT™' <br><br> _^c0oh <br><br> -o <br><br> - <br><br> 18a <br><br> CH3 <br><br> ^/C1.2CH20CH3 Xvcn2cos,h <br><br> - <br><br> •' 19. <br><br> TOO'™' <br><br> /CH -C0JI <br><br> -N <br><br> xch2c02ri <br><br> - ■ <br><br> 20 <br><br> It <br><br> /CH -C03 <br><br> -N <br><br> ch2c02h <br><br> - <br><br> 182812 <br><br> Sheet 3 Cont'd <br><br> Conc.en fcra Lion required to prolong the coagulation time by a factor of the <br><br> (/M) <br><br> P repara t j.on p ro c. ess (Ex . No.) <br><br> rn . p . <br><br> (°c) <br><br> Elcmei 11 ary analysis <br><br> •s. <br><br> Upper: Calculated ^ Lower: Found ($ , <br><br> I .R. (KBr) (cm -1) <br><br> C <br><br> 11 <br><br> N <br><br> 2 <br><br> Powder <br><br> 5k -63 54 .54 <br><br> 6 .42 6.40 <br><br> 12 .74 12 .68 <br><br> 3, 350 1,620 1,150 <br><br> 2 <br><br> t! <br><br> 5k .63 5k.59 <br><br> 6.42 6 .38 <br><br> 12 .74 12 .68 <br><br> 3,250 1,620 1,160 <br><br> 2 <br><br> powder <br><br> 53 .82 53.68 <br><br> 6 .21 6 .08 <br><br> 13.08 12 .85 <br><br> 3,370 1,635 ,1,255 1,155 <br><br> 2 <br><br> ti <br><br> 54 .64 54 .58 <br><br> 6.18 6 .09 <br><br> 13 .85 13-93 <br><br> 3,370 1,640 1,260 1,155 <br><br> 1 . <br><br> p <br><br> 1 <br><br> i ■ <br><br> 1 <br><br> 10 <br><br> 4 <br><br> 152-&gt;57 <br><br> 5k .42 54 -3S <br><br> 6.5 5 <br><br> 6-32 <br><br> O • SO <br><br> i-3 -59 <br><br> 3,350 l ,635 <br><br> 0.25 <br><br> I <br><br> 1 <br><br> powder <br><br> 55-^7 55-75 <br><br> 6 .40 6 .19 <br><br> 13 .48 13 .26 <br><br> 3,350 (broad) <br><br> 1.630 <br><br> 1,380 <br><br> 0.2 <br><br> 4 <br><br> n <br><br> 55.05 55 .28 <br><br> 1 <br><br> 7 .12 7 .00 <br><br> 13.38 13 .12 <br><br> 3,200 (broad) <br><br> 1,635 1,380 <br><br> 182812 <br><br> Sheet 4 <br><br> Sample No . <br><br> Compound h <br><br> hn% | <br><br> c-n-ch chpch chcor (i) h?n ^ 1 <br><br> H-N-SO -Ar <br><br> Ar r <br><br> Addi tion moi e ty <br><br> 21 <br><br> €0"'' <br><br> /ch -JLoJl. <br><br> -N <br><br> xch2c02H <br><br> — <br><br> 22 <br><br> IT <br><br> /ch2J[oJ1 <br><br> ^ch2c02c(ch3)3 <br><br> - <br><br> 23 <br><br> tf <br><br> /CH "L0J <br><br> -n ch2co2h <br><br> - <br><br> ■ 24 <br><br> t! <br><br> hXCH2^0-J <br><br> -n nCH2c02c(ch3)3 <br><br> — <br><br> 25 <br><br> CQ <br><br> n(ch3)2 <br><br> /ch -l0J <br><br> -n choc0oh ch3c02h <br><br> 26 ' <br><br> dp ■ <br><br> ci <br><br> /CH2-W \ <br><br> nch2c02h <br><br> - <br><br> 27 <br><br> 03 <br><br> -n 0 <br><br> ch2c02h <br><br> - <br><br> 132812 <br><br> Sheet 4 Cont'd <br><br> Cone en t ra t j. on required to prolong the coagu.1 a lion time by a factor or two <br><br> (AM) <br><br> J3 n?para tion u rocoss (i-.'x . \ 1 ! . ) <br><br> m . p . <br><br> (°c) <br><br> Elementary analysis <br><br> Up per: Calculated Lower: Found (jQ <br><br> I.R. (KBr) (cm-1) <br><br> C <br><br> II <br><br> . N <br><br> 0.2 <br><br> 1 <br><br> powder <br><br> 5 k .22 53 .93 <br><br> 5.50 5 .55 <br><br> 13.18 13.24 <br><br> 3,320 (broad) 1,6 30 1, 380 <br><br> 1 <br><br> II <br><br> 57 .22 57 .23 <br><br> 6 .35 6 . 36 <br><br> 11.92 12 .08 <br><br> 3,4 00 (broad) 1,1 hO 1,620 <br><br> 0.15 <br><br> 1 <br><br> 1 <br><br> 53.82 53.78 <br><br> 6.21 <br><br> 6,19 <br><br> 13'. 08 12 .86 <br><br> 3,360 (b road) 1,625 1 , 380 <br><br> 1 <br><br> . <br><br> 1! <br><br> 56 .83 .56 .9 5 <br><br> 6 .98 ■ 6 .83 <br><br> 11.8'+ 11 .98 <br><br> 3,4 00 (broad) <br><br> 1,735 <br><br> 1,630 <br><br> - <br><br> . <br><br> 4 <br><br> n <br><br> 53 .28 53 .13 <br><br> 6.62 6 .82 <br><br> 13.81 13.71 <br><br> 3, 320 (broad ) 1,630 1, 1^0 <br><br> 4 <br><br> tr <br><br> 51 .15 50 .86 <br><br> 5 .60 5 .66 <br><br> 12 .97 12 .87 <br><br> 3,32 0 (broad) <br><br> 1,630 <br><br> 1,380 <br><br> 4 <br><br> 11 <br><br> 5h .64 53 .36 <br><br> 6.18 6 .00 <br><br> 13 .85 13 .53 <br><br> 3,350 (broad) 1,6k 0 1,3 90 <br><br> "fj2.~pATE¥*fl <br><br> | -UEBW9 - 78 - <br><br> f 8 2 8 12r <br><br> Sheet 5 <br><br> Sample No. <br><br> Compound h <br><br> hn^. i c-n-ch ch9ch0ch:or (i) <br><br> h / ~ 1 <br><br> h-N-SO -Ar <br><br> Ar r <br><br> Addition moiety <br><br> 28 <br><br> 1 <br><br> ch3 ' <br><br> -N \ <br><br> xch2c02h <br><br> - <br><br> 29 <br><br> 60 <br><br> /chAoJ \ <br><br> ^chgcqgh <br><br> — <br><br> 30 <br><br> i och^ <br><br> ^N^0ch3 <br><br> CH2-C0J <br><br> -n <br><br> ^ch2c02h f <br><br> s - ■ <br><br> 31 <br><br> fl <br><br> /CH <br><br> ~N\ <br><br> xCH2c02c(ch:))3 <br><br> 32 <br><br> 00°"' <br><br> c02h <br><br> *0^3 <br><br> — <br><br> 33- <br><br> IT <br><br> c02h -N_jKH(CH3)2 <br><br> ■ 182812 <br><br> Sheet 5 Cont'd <br><br> Coii con t ra tion requi rod to prolong the coagu 1 at.'.; on time by a factor of two <br><br> (&gt;LM) <br><br> / <br><br> t' repa ra tion pro coso <br><br> ( Fx . Xo . ) <br><br> m .p . <br><br> (°C) <br><br> i ~ — — <br><br> Elementary analysis Upper: Calcu1a ted ty Lower: Found (V) <br><br> I.R. (KBr) (cm"1) <br><br> C <br><br> 11 <br><br> N <br><br> • <br><br> :4 <br><br> powder <br><br> 56 .27 55-98 <br><br> 6.61 6 .78 <br><br> 13 .12 13.2^ <br><br> 3,350 (broad) 1,630 1 , 380 l,lhO <br><br> • <br><br> 4 <br><br> 1? <br><br> ;h .21 5h.36 <br><br> 6.92 6 .93 <br><br> 13.7'i 13.76 <br><br> 3,300 (broad) <br><br> 1,625 <br><br> 1,380 <br><br> 1,160 <br><br> 1, 2 <br><br> It <br><br> . 53.08 52 .86 <br><br> 6.24 6 .33 <br><br> 12 .38 12 .hi <br><br> 3,300 (broad) 1 ,6ho 1, 160 <br><br> 1 <br><br> tt <br><br> 56 .02 55-83 <br><br> 6 .97 ' 6 .88 <br><br> 11.27 11 .28 <br><br> 3,^00 (broad) <br><br> 1,7^5 1,620 <br><br> 0.2 <br><br> 3 <br><br> I! <br><br> 57 .23 5-6 .89 <br><br> 6 .61 6.5 0 <br><br> 13.91 13.70 <br><br> 3,390 (broad) 1,625 <br><br> - <br><br> 0.1 <br><br> 2 <br><br> ft <br><br> 58.73 58.52 <br><br> 7 .01 <br><br> 6.77 <br><br> 13.17 13.00 <br><br> • <br><br> 3,380 (broad) 1,620 <br><br> i- <br><br> 182812 <br><br> Sheet 6 <br><br> Sample No . <br><br> Compoun.d <br><br> H <br><br> HN^ ! <br><br> C-N-CH^CPIpCHpCKrOR (l) h2N^ I * H-N-502-Ar <br><br> ' Ar <br><br> R <br><br> Addition moi e ty <br><br> 34 <br><br> o <br><br> 1 w <br><br> ' <br><br> C02H <br><br> -rycH(cH3)2 <br><br> — <br><br> 35 <br><br> 60 <br><br> CO H <br><br> -0^H3 <br><br> - <br><br> 36 <br><br> to <br><br> C02H <br><br> -{5&lt;h(ch3)2 <br><br> t s <br><br> / • i <br><br> 37 <br><br> CO <br><br> CH3 \H3 <br><br> C02H <br><br> -0 <br><br> j <br><br> 38 <br><br> OO <br><br> CO H <br><br> ■o, <br><br> - <br><br> "39 <br><br> ox co2h <br><br> -{&gt;CH(CH3)2 <br><br> - <br><br> 40 <br><br> TOO"1' <br><br> co2h <br><br> &gt;~~v <br><br> -N .S <br><br> v_V <br><br> 41 <br><br> » <br><br> — <br><br> co2h \ <br><br> / \ <br><br> -N 0 <br><br> v_y r % <br><br> APR 1979 II <br><br> - 81 - <br><br> ' C.BI <br><br> 182812 <br><br> Sheet 6 Cont'd <br><br> Cone on t ra tion oc[uil rod to pro] on.'- tho coagula t ion t i m o 1) y ;:i factor ol" tv/o <br><br> (A^M) <br><br> / <br><br> P ropa ra Lion p ro ceri -s (Fx . No . ) <br><br> m. p . <br><br> (°c) <br><br> El omcii tary analys i d <br><br> -v <br><br> Upper: Calculated Lov;or: Found (\^ <br><br> I.R.(KBr) <br><br> ( cn"1) <br><br> C <br><br> H <br><br> N <br><br> 3 <br><br> Powder <br><br> 58 - 7 3 58.81 <br><br> 7 .02 7 .03 <br><br> 13 .17 13 .17 <br><br> 3.300 (broad) 1 j 615 1, 380 <br><br> 1 <br><br> 3 <br><br> II <br><br> 56 .4 2 56.38 <br><br> 6 .38 6-. 52 <br><br> lb .31 <br><br> U .53 <br><br> 3,350 (broad) 1,620 1,160 <br><br> 0.5 <br><br> 3 <br><br> ft <br><br> 58.00 57 .83 <br><br> 6 .82 6 -77 <br><br> 13.53 13 .63 <br><br> 3,350 (broad) 1,620 1,160 <br><br> 0.35 <br><br> 3 <br><br> powder <br><br> 55.58 55 .62 <br><br> 6 .61 6 .81 <br><br> 16 .21 16 .03 <br><br> 3,350 (broad) <br><br> 1,620 <br><br> 1,1^0 <br><br> . <br><br> 3 <br><br> ii <br><br> 55.96 56 .12 <br><br> 7 .15 <br><br> 7 .28 <br><br> lb .19 <br><br> 14 .07 <br><br> 3,35° (broad) 1 ,62 0 1,150 <br><br> 3 <br><br> ii <br><br> 5b • 38 5b .08 <br><br> 6 .21 5.91 <br><br> 12 .69 -12.39 <br><br> 3,300 (broad) 1,625 <br><br> . 2 <br><br> f i <br><br> 50.46 50 .61 <br><br> 52 .06 52 .31 <br><br> 5 -58 5-63 <br><br> 13.38 13 . bo <br><br> 3,380 1,620 1,380 1,155 <br><br> ew»__ <br><br> 3 <br><br> ! <br><br> t? <br><br> 5.76 <br><br> cr O -i <br><br> 13.80 J 3.51 <br><br> 3, 32 0 1,62 0 1 . 390 1,155 <br><br> - P. 2 - <br><br> 182812 <br><br> Sheet 7 <br><br> Sample No . <br><br> Compound <br><br> K <br><br> 1 , . C—N-CH CH9CHC)CHCOR (I) " ~l <br><br> * h-N-SO -Ar <br><br> Ar r <br><br> Addi tion mo i e t y <br><br> 42 <br><br> ^ OCH , <br><br> €0 J <br><br> co2h ^—V <br><br> -N SO \__/ <br><br> - <br><br> 43 <br><br> c02h <br><br> "\_y° <br><br> - <br><br> 44 <br><br> ca"' <br><br> c02h <br><br> -\/s <br><br> - <br><br> 45 <br><br> No Sample No. 4 5 <br><br> 46 <br><br> we <br><br> « <br><br> JCO <br><br> 4 <br><br> 47-. <br><br> -30 <br><br> co2h <br><br> — <br><br> 48 <br><br> No Sample No. 4 8 <br><br> * ■ _ • <br><br> - 83 - <br><br> • 182812 <br><br> Sheet 7 Cont'd <br><br> Concon 1' ra t ion required to prolong the cca^u ]. a t j on time b v a factor of two <br><br> (U-&gt;i) <br><br> y <br><br> P ropuration <br><br> J ^ I." O C C-^ s <br><br> (Ex. No.) <br><br> m. p . <br><br> (°c) <br><br> 101 em en t a ry a i i a 1 y ^ i s Upper: Cal culat ecl (f) Lower: Found <br><br> I.R. (KBr) <br><br> ' -1 N cm ) <br><br> C <br><br> H <br><br> N <br><br> § <br><br> n a. <br><br> powder <br><br> 4 8 .96 4 9 • J 3 <br><br> 5. &gt;t 2 5-38 <br><br> 12 .98 12 .7 5 <br><br> 3,350 1,62 0 1,380 1,150 <br><br> 5 <br><br> 2 <br><br> If <br><br> 51-38 51 5 <br><br> 5 .81 5-86 <br><br> 13 .03 13 .12 <br><br> 3,350 1,630 1,255 1,150 <br><br> — <br><br> 2 <br><br> 11 <br><br> 49 .50 '+9 .31 <br><br> 5 .34 5 .4 0 <br><br> 13.75 .13.68 <br><br> 3,350 3,2 00 1,62 2 <br><br> No Sa&lt; <br><br> aple No <br><br> , 45 <br><br> U.£ <br><br> 2 <br><br> 2 <br><br> |a^ococAg^v' <br><br> 57 .62 57 .68 <br><br> 5.70 5o5 <br><br> 12 .00 11 .73 <br><br> 3,300 (broad 1,620 1,2 50 1,150 <br><br> 1.5 <br><br> . 3 <br><br> 11 <br><br> r- <br><br> 56 .93 <br><br> 57 -12 <br><br> 5-^9 5.^3 <br><br> 12 .30 12 .lk <br><br> 3,360 1,625 1,260 1,150 <br><br> • <br><br> No S; <br><br> unple Nc <br><br> &gt;. 48 <br><br> ... <br><br> N.Z-* <br><br> l^tFEbW* - 84 - <br><br> •if- V 5 pECEwed <br><br> 182812 <br><br> Sheet 8 <br><br> S amp1e No . <br><br> Compound <br><br> II <br><br> HN^ | <br><br> C-N—CH?CH CH CK:0R (i) H N i <br><br> H-N-SO -Ar <br><br> Ar <br><br> R <br><br> Addi tion moiety <br><br> 49 <br><br> 0CH3 <br><br> k^s^^vOCH3 <br><br> x°vO <br><br> -N. ^ <br><br> CHCH^COOH <br><br> COONH^ <br><br> - <br><br> 50 <br><br> 11 <br><br> -&lt;CH^ <br><br> CHCH„C00C.H_ \ 2 - 2 C00C„H <br><br> ^ 5 <br><br> 1/2H2S03 <br><br> 51 <br><br> to0™' <br><br> COONa <br><br> -D <br><br> COONa <br><br> - <br><br> 52 <br><br> 0CH3 <br><br> /CH CH„OCH <br><br> "N\ /T\ <br><br> ch2 cooch 2-\_y <br><br> — <br><br> 53 <br><br> t! <br><br> ^CHoCHo0CH. <br><br> ~N J <br><br> XCH COO-lI^ <br><br> ch3 <br><br> ,HC1 <br><br> ' 54" <br><br> ✓CHoCHo0CH„ -N 2 2 j <br><br> N CH2 C 00 <br><br> HC1 <br><br> 182812 <br><br> Shee t 8.Cont1d <br><br> :4*- <br><br> Concen I; ra ti on required to prolong tlie coa;ju.l a tion time by a factor of two <br><br> (/U i) <br><br> 20 <br><br> 30 <br><br> P repara tion process (Ex . No . ) <br><br> rn. p . (°C) <br><br> powder <br><br> EJ cmcn t a r y an a 1 ys i s Upper: Calculated (jv) Lower: Found (■$ <br><br> 53.86 54 .16 <br><br> 5[i .53 54 .23 <br><br> 48.55 48 .31 <br><br> 57 .22 56 .98 <br><br> 54 .09 53.83 <br><br> 55-53 55.37 <br><br> H <br><br> 5.92 5 .62 <br><br> N <br><br> 13 ,00 12 .70 <br><br> 6 .10 5 .30 <br><br> 4 .93 4 .64 <br><br> 6 .24 6 .18 <br><br> 6 .05 5 -97 <br><br> 6 .12 6 .01 <br><br> 9 .64 9-34 <br><br> 11 .80 11 .53 <br><br> 11 .12 11 .31 <br><br> 10.51 10 .36 <br><br> 10 .12 10 .01 <br><br> I.R. (KBr) (em -1) <br><br> 3,100 (broacj? 1,620 <br><br> 1,720 <br><br> 1,630 (broad^ <br><br> 3, 300 (broadj) 1,620 <br><br> 3,300 3,150 1,740 <br><br> 1,650 <br><br> 3,250 3,100 1,740 1,640 <br><br> 3, 350 3,150 1,740 1,650 <br><br> ~~TtFEBt979 <br><br> - 86 - <br><br> 18 2812 <br><br> %. <br><br> Sheet 9 <br><br> Sample No . <br><br> Compound <br><br> H <br><br> C-N-CH-CH-CH-CEZOR (I) H„N ^ ^ d H-N-50 -Ar <br><br> Ar <br><br> R <br><br> Addi tion moiety <br><br> 55 <br><br> tO0CIS' <br><br> -(3° <br><br> COOH <br><br> - <br><br> 56 <br><br> tr r\ <br><br> -N <br><br> \~y <br><br> COOH <br><br> - <br><br> 57 <br><br> och3 OCH- <br><br> -oo <br><br> COOH <br><br> - <br><br> 58 <br><br> ft <br><br> COOH <br><br> CHoC00NH, <br><br> H <br><br> - <br><br> 59 <br><br> M <br><br> /CH3 _ N&gt;CH2-(3 <br><br> COOH <br><br> 1 <br><br> 60 <br><br> to™3 <br><br> _n/CH3 <br><br> N,CHCH2-^r^&gt;-0CH3 COOH <br><br> - <br><br> • f 182812 <br><br> Sheet 9 Cont'd <br><br> Con c e-n t ra ti on required to prolong the co ac;ul a t:i on time b y a factor of." two y-1 M) <br><br> Propara tiori p ro c c s s ( I'.:-; . No . ) <br><br> in . p . <br><br> (°c) <br><br> El ornon ta ry anal ysi s Upper: Calculated Lower: Found ($ <br><br> I.R. (KBr) (cm"1) <br><br> C <br><br> H <br><br> N <br><br> • <br><br> 2 <br><br> powder <br><br> 48 .9 6 49.13 <br><br> 5.42 5 • 36 <br><br> 12 .98 13.01 <br><br> 3, 350 1,620 • 1,380 <br><br> - <br><br> 2.5 <br><br> 2 <br><br> it <br><br> 54 .64 54 .63 <br><br> 6 .42 <br><br> 6 .56 <br><br> 12 .74 13.01 <br><br> 3, 360 2,94 0 1,620 1,380 <br><br> 12 <br><br> 2 <br><br> ii <br><br> 59-89 <br><br> 59.65 <br><br> 4 .52 4 .6 3 <br><br> 11.64 11.81 <br><br> 3, 360 l ,620 1,255 1,150 <br><br> 2 <br><br> ii <br><br> 53.85 53 .61 <br><br> 5.93 5.76 <br><br> 13 .00 12 .84 <br><br> 3, 320 1,610 <br><br> ! F.SS <br><br> ntf/t <br><br> 2 <br><br> 2 <br><br> ii <br><br> 57 .42 57 .37 <br><br> 6 .02 5 • 86 <br><br> 11.96 11.74 <br><br> 3, 300 (broad^ 1,600 <br><br> 2 <br><br> ii <br><br> 57 -41 57 .33 <br><br> 6 .03 5.94 <br><br> 11.96 <br><br> 11.73 <br><br> 3,300 1,610 <br><br> N.Z.PA <br><br> 182812 <br><br> Sheet 10 <br><br> Sample No . <br><br> Compound <br><br> H <br><br> HN. | <br><br> C-N-CH CH CH CHCOR . (i) H0N H <br><br> H-N-50 -Ar <br><br> Ar r <br><br> Addition moiety <br><br> 61 <br><br> ■OX' <br><br> /CK3 -n^chch2-&lt;Q&gt; <br><br> COONa <br><br> - <br><br> 62 <br><br> OX1 <br><br> 3 <br><br> OH <br><br> 1 <br><br> ^CH CH CH-CK„ -N J CH2C00H <br><br> - <br><br> 63 <br><br> 1! <br><br> CH CH CH.CH„ <br><br> -Nv ~ <br><br> CHCHoC00H <br><br> 1 d <br><br> COONH^ <br><br> - <br><br> 64 <br><br> ii <br><br> /CH CH CH,CH„ <br><br> _N <br><br> CHCHoC00CoH_ | 2 2 p <br><br> COOC„H ^ 5 <br><br> 1/2H2S03 <br><br> 65 <br><br> No sample No.6 5 <br><br> — <br><br> 66 <br><br> -fY^toch3 <br><br> -*t) (d) <br><br> COOH <br><br> 2H2° <br><br> 67 <br><br> ii <br><br> ~fZ) tl) <br><br> COOH <br><br> 1/2H20 <br><br> 182812 <br><br> Sheet 10 Cont'd <br><br> Con c en t ra t.ion required lid prolong the ccagula tion time by a factor of two (J-L M) <br><br> 2 . <br><br> 15 <br><br> 1' repa ra I i on p ro cess (Ex. No.) <br><br> /Vo sample. <br><br> ni. p . <br><br> (°C) <br><br> powder <br><br> Elementary an a J. y s .i. :s Upper: Calcujatecl L o v.- e r : Found (■£) <br><br> c <br><br> 53 .98 53.7'* <br><br> 52 .07 51-95 <br><br> /tfo-65 <br><br> 50.97 50.67 <br><br> 52 .01 51.77 <br><br> II <br><br> 5 -38 5-33 <br><br> 6 .37 6 .27 <br><br> N <br><br> 11.66 11 .71* <br><br> 12 .65 12 .84 <br><br> 6 .58 6 .61 <br><br> 6.6 9 6 .50 <br><br> 195-198 <br><br> 50 .42 50 .48 <br><br> 2 2 9 -2 'H <br><br> 52 .94 52 .73 <br><br> 6 .54 6.16 <br><br> 6 .30 6.15 <br><br> 13 .72 13 .39 <br><br> 10.11 10.00 <br><br> I.R. (KBr) (cm-1) <br><br> 3,350 1,630 <br><br> \ <br><br> 3,350 (broar 1,620 <br><br> 3,200 (broa-, 1,610 (broa-y <br><br> 1,72 5 1,620 <br><br> 1 tt .25 12 .31 <br><br> 3, 320 1,620 <br><br> 12 .87 12 .93 <br><br> 3,350 1,620 <br><br> 90 - <br><br> 18 2812 <br><br> Sheet 11 <br><br> S a mp1e No . <br><br> Compound <br><br> H <br><br> HN ^ I <br><br> C-n-ch ch ch,CHCOR h n ~ i h-n-so -aj <br><br> (I) <br><br> Ar <br><br> R <br><br> Addition moi e ty <br><br> 68 <br><br> och, <br><br> —N <br><br> ^CH2CH2S0CHa <br><br> \ <br><br> ch2c00h <br><br> 69 <br><br> toe och, <br><br> ch, <br><br> -N <br><br> ych^ch^ oh <br><br> \ <br><br> ch2c00h <br><br> 70 <br><br> -N <br><br> /CH2-^CH COOH <br><br> 71 <br><br> ■ och. <br><br> -0-OCH3 <br><br> -n <br><br> /CH2CHp0CH3 ch2cooh <br><br> 72 <br><br> -och, <br><br> och, <br><br> -Q- <br><br> och. <br><br> -N <br><br> \ <br><br> ,CH9CH2CH2CH3 ch2ch2c00h <br><br> 73- <br><br> -N <br><br> ^CI^CHgOCH^ <br><br> xch2cooh <br><br> - 91 - <br><br> 182812 <br><br> Sheet 11 Cont'd onr:on ra Li.Oii requi rod o prolong l 1 i (: coa^u! a i. ion. t i m o u y a facto r i.) P I.wo (/UM) <br><br> P ropara L.i. oil j) roc &lt;v.\..s ( Iv'c . No . ) <br><br> ni .p . <br><br> (°C) <br><br> E I. omen ta ry c.ualybi s s. <br><br> Upp c r : C a 1 c u la t o d Lower: Found <br><br> C <br><br> H <br><br> N <br><br> I.R. (KBr) (cm 1) <br><br> 6 .5 <br><br> powder <br><br> 4 8 .?« 48 .5U <br><br> 50.27 50 .11 <br><br> 5-77 5.76 <br><br> 12 .93 13.15 <br><br> 3,320 <br><br> 1,620 <br><br> 1,390 <br><br> 5-95 <br><br> 5 p- <br><br> »-&gt;/ <br><br> 13.33 <br><br> 13.34 <br><br> 3, 390 1,630 1,260 1,160 <br><br> ■53 .76 53 .66 <br><br> 5-95 5-83 <br><br> lU .25 l*t .19 <br><br> 3,400 3,200 l ,635 <br><br> povder <br><br> 46 .62 46 .53 <br><br> 6 .38 6 .21 <br><br> 4 9.71 4 9 .84 <br><br> 7 .02 7 .26 <br><br> 46 .24 46 .31 <br><br> 0.4 0 <br><br> j lb .31 14.43 <br><br> 13 .IS 13 .36 <br><br> 13.48 13.41 <br><br> 3,350 3,150 1,630 <br><br> 3,250 (broad) 3,150 1 ,630 <br><br> 3,320 3,110 1,630 <br><br> - 92 - <br><br> 18 2812 <br><br> Sheet 12 <br><br> Sample No.. <br><br> Compound <br><br> H <br><br> HN% 1 m' <br><br> c-x-ch0cii0ch chcor h0n 2 2 2, <br><br> 2 h-n—S02-Ar <br><br> Ar r <br><br> Additio moiety <br><br> '74 <br><br> -0"ui3 <br><br> _x/ch2ch2ch2ch3 xch2c00h hc1 <br><br> 75 <br><br> ^-C1 <br><br> Cl <br><br> / ch2ch2ch2ch3 nvch2c02h <br><br> 76 <br><br> o o <br><br> -f&gt;c2«5 <br><br> co2h <br><br> - <br><br> 77 <br><br> ^ <br><br> -'.C^)-c2ti5 <br><br> C02H <br><br> - <br><br> 78 <br><br> 0 <br><br> 1 <br><br> o x/ci'2cll2cii2c1i3 "^ch^cogh <br><br> - <br><br> 79 <br><br> ^ocho -f^&gt;-0CH3 ^0ch3 <br><br> "&gt;D" C2H5 <br><br> co2h <br><br> - <br><br> 18 2812 <br><br> Sheet 12 Cont'd <br><br> Coneca t ra tion requi red to prolong the coavyul tion. tinin by a factor of two <br><br> (/.N) <br><br> P rep a ra ti on (Ex. No.) <br><br> . <br><br> n .p . <br><br> •,°C) <br><br> E.Lonion.tary analysis Upper: Calculated Low e r: Found $ <br><br> I.R. (KBr) (cm"1) <br><br> C <br><br> II <br><br> N <br><br> 1 <br><br> Powder <br><br> 1 <br><br> 47 -74 'i7 - 53 <br><br> 1 <br><br> 6 .75 6 .51 <br><br> 1 <br><br> 14 .65 . 14 .41 <br><br> 3,34 0 3, ISO 1,64 0 <br><br> i <br><br> 4 <br><br> i powder <br><br> •10.71 ■4 0 . 6 0 <br><br> 4 .95 4 . 73 <br><br> 13 .19 13 -03 <br><br> 3,360 3,150 <br><br> 1,620 <br><br> 3 <br><br> powder <br><br> 55 • 59 55-54 <br><br> 6 .29 6.14 <br><br> 12 .47 12 .35 <br><br> 3 ,350 3 ,150 <br><br> 1,625 <br><br> j <br><br> 3 1 <br><br> i <br><br> 11 <br><br> 57 .-4 3 57.26 <br><br> 6.13 6 . 04 <br><br> 12 .88 12 .71 <br><br> 3 ,350 3 ,130 <br><br> 1,615 <br><br> 4 <br><br> i i <br><br> 46 . go <br><br> 46.61 <br><br> 6.11 <br><br> 6 . 05 <br><br> 1 5.\6 <br><br> 15.23 <br><br> 3 -375 <br><br> 3 ,150 <br><br> l 630 <br><br> 3 <br><br> M <br><br> 50 82 50. 71 <br><br> b . H ti , <br><br> 6 . 69 <br><br> 12 .89 12 .57 <br><br> 3.360 3 ,120 1,620 <br><br> - 94 - <br><br> 1823T2 <br><br> APPENDIX <br><br> There are now described in greater detail preparation of materials of the kind, used in the foregoing examples. <br><br> PREPARATION A . " <br><br> Arylsulfonyl chlorides <br><br> (A) Sodium 6 ,7—dimethoxy—2-naphthalenesulfonate <br><br> To a well stirred solution of 70.8 g of sodium 6,7"~ dihydroxy-2-naphthaienesulfonate and 77-2 g of sodium hydroxide in 450 nil of water was added dropwise 230 mi of dimethyl sulfate at 60°Q over a period of one hour, <br><br> during- which time the product precipitated. To this reaction mixture was added in portions 38.8 g of sodium hydroxide, and stirring was continued for one hour. <br><br> After one hour at room temperature, the precipitate was filtered, washed with ethanol and dried to give 50 g of sodium 6,7—dimethoxy—2—naphthalenesulfonate. <br><br> (b) 6,7-dimethoxy—2-naphthalenesulfonyl chloride <br><br> To a stirred suspension of 50 g of finely divided sodium 6,7—dimethoxy—2-naphthalenesulfonate in 100 ml of dimethyl— formarnide was added dropwise 62.2 ml of thionyl chloride* <br><br> at room temperature. After 30 minutes, the reaction mixture was poured into 1 JL of ice water, and the precipi~ <br><br> tate filtered and then dissolved into 25O ml of benzene. The benzene solution was repeatedly washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness in vacuo, and the residue was p&amp;tewt OFFICE <br><br> ^ i 15JAf\H979 <br><br> P ^ECr'Vrvrv ' <br><br> 182812 <br><br> recrys talli zed from benzene-n-liexane (1 : 1) to give 32 g of 6,7-dimethoxy-2-naphthalenesulfonyl chloride, M.P . 127 .5 - 12 9 • 5°C <br><br> Analysis - Calcd. for C-^H-^O^SCl (Percent): C, 50.26; <br><br> H, 3.87; Cl, 12.37 Found (percent): C, 50.45; H, 4.00; Cl, 12.33 <br><br> The following arylsulfonyl chlorides not previously reported in the chemical literature were synthesized by the aforementioned procedure which is essentially that as described in E. H. Rodd, "Chemistry of Carbon Compounds", Elsevier Publishing Company, 1954, Vol HI, P. 441-469. <br><br> No . <br><br> Arylsulfonyl Chloride <br><br> M.P. (°C) <br><br> 1 <br><br> C102S <br><br> OC2H5 <br><br> 118 - 119.5 <br><br> 2 <br><br> "V"QCU, <br><br> OCH 3 <br><br> 136.5 - 138.5 <br><br> 3. <br><br> C1V €00 <br><br> 137 - 139 <br><br> &lt;?k <br><br> N.Z. PATENT OFFICE <br><br> 15 JAN J979 s <br><br> '• 182312 <br><br> PREPARATION B <br><br> Amino acid derivatives <br><br> (A) N—butylglycine tert-butyl ester ^ To 36.5 g of butylamine was added with stirring I5.O5 g <br><br> ^ of tert-butyl chloroacetate over a period of 30 minutes, <br><br> while maintaining the temperature at 30-70°C. The reaction mixture was held at 70°C for an additional one ~ hour. At the end of this period, the excess butyl amine was evaporated in vacuo, and the residue was taken up in 0 hO ml of 2N NaOH solution and 50 ml of benzene, transferred into a separatory funnel and well shaken. The benzene solution was separated, washed with water, dried over anhydrous sodium sulfate and filtered. After evaporation of benzene, the residue was distilled under reduced 5 pressure to give 1J ,0 g (90.9 percent) of N-butylglycine tert-butyl ester, B .P . 76°C/h mmiig. <br><br> The following amino acid tert-butyl esters not previously reported in the chemical literature wore synthesized by the aforementioned procedure wliich is essentially that 1 as taught by A. J. Speziale et al . , J. Org. Chcm. 2j^ 731 <br><br> (I960). <br><br> N.Z. PATENT OFFICE <br><br> &lt;?7 <br><br> jiEcavio V! <br><br> 1828/2 <br><br> No . <br><br> Amino Acid Derivative <br><br> B .P . <br><br> 1 <br><br> .(CII ) CH 11N^ J XCH2C02«t-CitH9 <br><br> 95°C/20 mmHgj <br><br> 2 <br><br> .CH CH(CH„)„ HN^ J <br><br> • XCH2C02-t-C4H9 <br><br> 65°C/ 5 mmHg <br><br> 3 <br><br> idj/(ch2)4ch3 <br><br> N:H2C02-t-Ci(H9 <br><br> 89- 90°C/2.5 mmHg k <br><br> .(CH ) CII HN^ 5 J <br><br> NCH2C02-t-Cz|H9 <br><br> 83- 5°C/i.5 mmHg <br><br> 5 <br><br> (CH ) CH HN^ ' J <br><br> NCH2C02-t-CZ|Hg <br><br> 125-130°CA mmHg <br><br> 6 <br><br> CH CH 0CII„ <br><br> HN^ ^ j <br><br> XCH2C02-t-CZtH9 <br><br> 61- 2°C/2 mmHg <br><br> 7 <br><br> ,CHoCII„0CH„ HN^ - 2 3 <br><br> NCIIpClI2C02-t-CitH9 <br><br> 9h°C/ 3 mmHg <br><br> 8 <br><br> .CH„CH„0CHo IIN^ 2 2^ <br><br> \CH2CH2CH2C02-t-CiiH9 <br><br> 60- 3°C/3 mmHg <br><br> 9 <br><br> .CII CH CH 0CLI„ hn\ j <br><br> \ch2c02-t-czfh9 <br><br> 95- 7°C/5 mmHg <br><br> 10 <br><br> .CIloCII?0CH CII„ HN^ " ^ J <br><br> \ch2ch2c02-t-c4h9 <br><br> .102°C/ 'i nmiltg <br><br> N.Z. patent OFFICE <br><br> 15 JAN 1979 i received 1 <br><br> Sfr: <br><br> 182812 <br><br> No . <br><br> Amino Acid Derivative <br><br> B .P . <br><br> 11 <br><br> HN/C,i2CK2-&lt;Q <br><br> XClI^C0Ci-t-Oi)II9 <br><br> 166°C/10 mmHg' <br><br> 12 <br><br> ,CH CH 3CILCH„ <br><br> HN^T j <br><br> CII^CO^—t-C^H^ <br><br> 106- 9°C/l.5 mmHg <br><br> 13 <br><br> /CH CH SCH HN. <br><br> CH2C02-t-C4H9 <br><br> 97°C/ 2.5 mmHg <br><br> 14 <br><br> HN <br><br> XCH2CH2CH2C02-t-Cz+H9 <br><br> 101°C/ 5 mmHg <br><br> 15 <br><br> XCH2G02-t-CuH9 <br><br> 101°C/ 5 mmHg <br><br> 16 <br><br> „-0 <br><br> XcH2CH2C02-t-Ci,H9 <br><br> 105 C/ 4 mmHg <br><br> 17 <br><br> /O <br><br> IIN^ <br><br> CIl2C°2-t-C/11I9 <br><br> 12 9-130°C/8 mmHg <br><br> 18 <br><br> en -Q <br><br> HNtr N—' <br><br> xcii,)co2-t-c/)n9 <br><br> l45°C/lr, rumllg <br><br> 19 <br><br> /Cll2"0 <br><br> HN - V— <br><br> ^CH2CH2C02 —t-C^H <br><br> 156°C/10 mmHg qcj <br><br> WZ.PATEMT OFFICE <br><br> 15 JAN 1979 <br><br> p- received <br><br> 182812 <br><br> No . <br><br> Amino Acid Derivative <br><br> B.P . <br><br> 20 <br><br> /(CH,) Cll HNf_ ' <br><br> CIIC02-t-C4II9 ch3 <br><br> 93°C/26 mmHg <br><br> 21 <br><br> (CH ) CH <br><br> hnCT j <br><br> CHC02-t-C4H9 CH3 <br><br> 110°C/27 mmHg <br><br> 22 <br><br> (CH ),CH <br><br> HN^" <br><br> XCIIC02—t-C^ <br><br> CH3 <br><br> 12/|°C/26 mmHg <br><br> 23 <br><br> /CH CH 0CH„ <br><br> HN. J <br><br> CIICO —t—C, H^ 1 2 4 9 <br><br> CH3 <br><br> 88- 90°C/6 mmHg <br><br> 2k <br><br> /-CH2"0 <br><br> HN <br><br> CHC02-t-C4H9 CH3 <br><br> ll6- 8°C/2 mmHg <br><br> 25 <br><br> . CH0CH0 HN " *" <br><br> XCHC02-t-C^lI9 <br><br> CII.j l67°C/.l 6 nimllg <br><br> 26 <br><br> HN^C^ <br><br> CHC02-t-C4H9 CH3 <br><br> 125°C/l6 mmHg too 86* <br><br> UZ. PATENT OFFICE <br><br> 15 JAM 1979 i <br><br> 182312 <br><br> No . <br><br> Amino Acid Derivative <br><br> B.P. <br><br> 27 <br><br> ch -q <br><br> CHC02-t-C4H9 <br><br> CH3 <br><br> 141°C/15 mmHg <br><br> 28 <br><br> .(CH ) CH HN^ <br><br> XCH2CH2C02-t-C4H9 <br><br> 89°C/ 3 mmHg <br><br> 29 <br><br> /CH 2-toJ HN&lt;t <br><br> CH2C02-t-&lt;;4H9 <br><br> 111°C/ 1 mmHg <br><br> 3° <br><br> NCH2C02-t-C4H9 <br><br> 91- 2°C/1 mmHg <br><br> 31 <br><br> .ch ch CO c„h, hn't <br><br> \CH2C02-t-C^H9 <br><br> 115°C/ 2 mmHg <br><br> 32 <br><br> OH 1 <br><br> /CH CH CHCH„ <br><br> hn't j <br><br> XCH2C02-t-C4H9 <br><br> 82- 84°C/2 mmHg <br><br> 33 <br><br> .ch CH SOCH„ HN v ^ <br><br> CH2C02~t-C4H9 <br><br> 150°C/ 0.5 mmHg <br><br> 34 <br><br> .ch^chpoh <br><br> HNc" <br><br> XCH2C02-t-C4H9 <br><br> 95- 6°C/2 mmHg <br><br> 35 <br><br> yCH C^H HN^ <br><br> \CH2C02-t-C4H9 <br><br> M.2. PATENT OFFICE <br><br> M <br><br> 89T <br><br> 15 JAN 1979 <br><br> nscsvso <br><br> 182812 <br><br> (B) N-(2-methoxyethyl)glycine ethyl ester <br><br> To a stirred solution of l6$?2 g of 2-methoxyethylamine and 202.4 g of triethylamine in 1 £ of benzene was added dropwise a solution of 33^.0 g of ethyl bromoacetate in 200 ml of benzene in one hour at room temperature. At th.e erid of this period, the mixture was heated at reflux for 2 hours to complete the reaction. Upon chilling, the triethylamine hydrobromide , was removed by filtration arid washed with benzene. After removal of the solvent, the product was distilled in vacuo to yield 2^2.8 g (75*3 percent) of N—(2-methoxyethyl)glycine ethyl ester, B.P. 73-5°C/k mmHg. <br><br> . The following amino acid ethyl esters not previously reported in the chemical literature were synthesized by the aforementioned procedure which is essentially that as iaught by A. J. Speziale et al., J. Org. Chem., 2$. 731 (i960). <br><br> No . <br><br> Amino Acid Ethyl Ester <br><br> M.P. (°C) or B.P. (°C/mmHg) <br><br> 1 <br><br> (CH ) CH HN(T J J <br><br> CH2C02C2H5 <br><br> 57— 8°C/3 nimHg <br><br> 2 <br><br> . CHPCH90CH„ IIN. J XCH Cll2CO C2H <br><br> 63- U°C/3 mmHg j0X N.Z. PATENT OFFICE1 <br><br> 9*- 15 JAM 1979 '{ <br><br> i <br><br> 1823 <br><br> No . <br><br> Amino Acid Ethyl Ester"" <br><br> m.p. (°c) or b.p. ( °c/mmllg) <br><br> 3 <br><br> /ch -L0j hn^ <br><br> ch2co2c2h5 <br><br> 91— 3°c/2 mmHg k <br><br> ■ /cii2-&lt;0 <br><br> HN^ <br><br> chchoc0ocoii ' hcl | «=• ^ ^ 5 <br><br> c02c2h5 <br><br> 101-2°c <br><br> 5 <br><br> c0ocoh_ <br><br> mj/ch2cii2ch2ch3 <br><br> xcii2co2c2h5 <br><br> 113- 6°c/3 mmHg <br><br> 6 <br><br> 9°2c2h5 ch-ch -^q, <br><br> hnq xch2co2c2h5 <br><br> 116- 7°C/l mmHg <br><br> 7 <br><br> och a 1 <br><br> /ch chch hnv j xch2co2c2h5 <br><br> 78-80°C/2 mmHg <br><br> 8 <br><br> hn/(ch2)3ch3 <br><br> VXCHC02C2H5 . HCl CH2co2C2h5 <br><br> 63-^°c <br><br> N-(2-methoxyethyl)glycine benzyl ester P-toluenesulfonate To a solution of 55 • 8 S of N-(2-methoxyethyl)glycine tert-butyl ester in 200 ml of benzene was added 63.8 g of benzyl alcohol and 72.9 S of p~toluenesulfonic acid monohydrate. The mixture was heated at reflux for 10 <br><br> 9»JZ. patent qfhce <br><br> 15 JANi979 i <br><br> |0^ <br><br> hecrv-.d " ! <br><br> 182812 <br><br> hours with the continuous removal of water through a Dean-Stark water trap. At the end of this period, the solution was concentrated in vacuo, and to the residue was added 300 nil of dry ethyl ether. After 2 hours at room temperature, the formed precipitate was filtered, washed with dry ethyl ether and then recrystallized from ethyl acetate to yield 99»2 g (85 percent) of N-(2-methoxyethyl)glycine benzyl ester p-toluenesulfonate, M.P. 95-6°C. <br><br> The following amino acid benzyl ester p-toluenesulfonate not previously reported in the chemical literature were synthesized by the aforementioned procedure. <br><br> No . <br><br> Amino Acid Benzyl Ester p-Toluenesulfonate <br><br> 0 <br><br> 0 <br><br> • <br><br> ft • <br><br> 1 <br><br> (CH ) CH <br><br> jp\ <br><br> ch2co2ch2-Q <br><br> 97-9 <br><br> 2 <br><br> • (CH2)„CH3 <br><br> hnxch2co2cii2— /q <br><br> 122 - 4 <br><br> 3 <br><br> cn0cn(cn„)0 <br><br> llv W <br><br> CH2C02CH2-O <br><br> 9l\ - 5 <br><br> h <br><br> (CH ) Oil <br><br> HN <br><br> ^CHoCHoC02CIi2-^^ <br><br> 66 — 8 <br><br> mlf- <br><br> ■ N.Z. PATENT OFFICE <br><br> 15 JAN 1979 1 t.eceivsd <br><br> 182312 <br><br> No . <br><br> Amino Acid Benzyl Ester p—Toluenesulfonat e m.p. (°c) <br><br> 5 <br><br> (CH2)hCH j™xch2co2ch2-&lt;0 <br><br> 101 - 2 <br><br> 6 <br><br> nch2co2ch2-0 <br><br> 140 - 3 <br><br> 7 <br><br> 11n/ch2-0 <br><br> nsch2ch2c0?ch2-^^ <br><br> 154 - 6 <br><br> 8 <br><br> /CH2CH2"0 <br><br> _/T\ <br><br> ch2c02ch2 -o <br><br> 133 - 5 <br><br> 9 <br><br> /7~\\ <br><br> ch2c02ch2"&lt;g&gt; <br><br> 133 - 5 <br><br> 10 <br><br> xch2co2ch2hQ <br><br> 133 - 8 <br><br> 1.1 <br><br> /(ch ) ch <br><br> HN\ ' /F\ <br><br> XCHC02ClI9-^3 <br><br> cii^ <br><br> .103 - 6 . <br><br> 12 <br><br> /(cll )„cll <br><br> UN\ <br><br> flC02CU2~ij <br><br> ■ch <br><br> 92-4 <br><br> ic£ <br><br> : <br><br> n.z. patent office <br><br> 15 JAM 1979 r.eceivso vi <br><br> 182812 <br><br> No . <br><br> Amino Acid Benzyl Ester p~Toluenesulfonate <br><br> M.P . (°C) <br><br> 13 <br><br> /ch2-0 <br><br> HN^ <br><br> YC02CH2-(J <br><br> ch3 <br><br> 123 - 6 <br><br> Ik fhco2ch2-0 ch3 <br><br> 119 - 12 3 <br><br> 15 <br><br> /ch -lqj hn xch2oo2ch2-0&gt; <br><br> 130 - 1 <br><br> PREPARATION C 2-Piperidinecarboxylic acids and esters thereof <br><br> (A) 4—methyl—2 —piperidinecarbonitrile <br><br> To 300 S of 10$ sodium liypociilorite solution cooled in an ice bath, there was added dropwise a solution of 33.6 g (0.21 mole) of 4—methylpiperidine acetate in 10 ml of water over a period of 1 hour. At the end of this period, the reaction product was extracted twice with 500 ml of ethyl ether and dried over anhydrous sodium sulfate . After evaporation of ethyl ether, the <br><br> N.Z. i'ATEwTOFFICE <br><br> 15 JAM 1979 &gt;! <br><br> /&lt;?£&gt; •94% <br><br> 182812 <br><br> residue was addad dropwise to a solution of 11.8 g (0.21 <br><br> mole) of potassium hydroxide in lOQmls-of 96% ethanol uider reflux. <br><br> Refluxing was continued for an additional 10 minutes . <br><br> Ethanol was evaporated, and the residue was dissolved into 50 ml of 2N sodium hydroxide solution and then extracted with ether. ■ ' * <br><br> The ether layer was dried over anhydrous sodium sulfate i <br><br> and then ether evaporated. The residue was added to an ice—cooled solution of 2j g (l 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 20°C for h hours and thereafter made bo.sic 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 S (66$) of 4—methyl—2—piperidinecarbonitrile, B.P. <br><br> 96-97°C/lO mmHg. <br><br> The following 2-piperidinecarbonitriles not previously reported in the chemical literature were synthesized by ths aforementioned procedure which is essentially that as taught by Grundon et al., J. Chem. Soc., 1963« 3898, <br><br> Grundon et al., J. Chem. Soc., 1964. 2448, R. Bonnett et al. y J. Chem. Soc., 19 59. 2092 and H. Bohrae et al., Ber., 21 (1959) • <br><br> Itn 55 JAN 1979 <br><br> 1628! <br><br> (3rR? <br><br> N CN i h <br><br> No . <br><br> R7 <br><br> B .P . <br><br> 1 <br><br> 4-CH2CH3 <br><br> 105-106°C/9 mmHg. <br><br> 2 <br><br> 'J|-CH2CH2CH3 <br><br> ll6°C/8 mmHg. <br><br> 3 <br><br> .CH ^4 -CI J XCH3 <br><br> 10koC/k mmllg. <br><br> k <br><br> 2-CH3 <br><br> 4-Methyl-2-piperidinecarboxylic acid hydrochloride A solution of 16 g of 4-methyl-2-piperidinecarbonitrile in 250 ml of 6N hydrochloric acid was refluxed for 6 hours. After evaporation of the solvent, the residue was recrystallized from water to give 13 g of 4-methyl-2-piperidinecarboxylic acid hydrochloride. <br><br> Ethyl 4-methyl-2—piperi dinecarboxy1 ate <br><br> A solution of 13 g (0,072 mole) of 4-methyl-2-piperidine-carboxylic acid hydrochloride and 50 ml of thionyl chloride in 300 ml of ethanol was refluxed for hours . At the end of this period, the solvent was evaporated under reduced pressure, and the residue was extracted with a solution of chloroform and saturated potassium carbonate solution. <br><br> N.Z. PATENT OFFICE <br><br> 15 JAN 1979 1 <br><br> r.cCEIVED Vi <br><br> 182812' <br><br> The chloroform layer was dried over anhydrous sodium sulfate and then chloroform was evaporated. Distillation of the residue gave 7 -k g (60$) of ethyl 4-methyl-2-piperi dinecarboxylate , B.P. 76—77°C/3 nuullg . <br><br> (D) Benzyl 4-methyl-2-piperidineca.rboxylate p—toluenesulfonate A solution of 20 g (0.112 mole) of 4-methyl-2-piperidinecarboxylic acid hydrochloride, 2k g (0.224 mole) of benzyl alcohol and 25.6 g (0.13^ mole) of p-toluenesulfonic acid monohydrate in 100 ml of benzene was refluxed for 5 hours with the continuous removal of water through a Dean-Stark water trap. At the end of this period, the solvent was distilled off, and the residue was washed with ether-n— <br><br> hexane and recrystallized to give 10 g (22$) of benzyl 4-methyl-2-piperidinecarboxylate p-toluenesulfonate, M.P. 160-163°C. | <br><br> The following 2-piperidinecarboxylates not previously { <br><br> reported in the chemical literature were synthesized by the aforementioned procedure. <br><br> fol <br><br> 15 JAN 1979 <br><br> 182312 <br><br> Or*7 • <br><br> vN/vC0C)CoHc <br><br> I 225 <br><br> H <br><br> No . <br><br> r7 <br><br> Addition moi ety b.p . <br><br> 1 <br><br> 4-CH2CH3 <br><br> — <br><br> 82-4°C/3.5 mmHg <br><br> 2 <br><br> 4-CH2CH2CH3 <br><br> HCl <br><br> 3 <br><br> /CH3 4-ch v j ch3 <br><br> - <br><br> 95~6°C/2 mmHg <br><br> 4 <br><br> 2-CH3 <br><br> — <br><br> 57°C/3 mmHg <br><br> Morpholine—3-carboxylic acid hydrochloride was prepared by the procedure described above, and has a melting point of 200—2°C. <br><br> The following starting materials for the preparation of 2 <br><br> the N -aryl sul fonyl-L-argininamides were prepared by the procedures described in the following literatures: <br><br> Compound <br><br> Li terature co2h hn^~~Ss <br><br> \_y <br><br> J. Org. Chem., 2£ 2203 (1964) <br><br> co2h hn^ ^0 <br><br> J. Org. Chem., 2% 2203 (1964) <br><br> [10 98- <br><br> 182312 <br><br> Compound <br><br> Li te rature co2h lilS\/'S <br><br> j. Am. Chem. Soc., 200 (1937) <br><br> co2h hkQ <br><br> Zh. Obshch. Khim., 2 22^5 (197 3). <br><br> (TY^r <br><br> Ber. , 44. 2034 (19h) <br><br> [ 1 (D) or (L) coph ' k ' 1 ^ <br><br> h <br><br> Ber., 6% 927 (1932) <br><br> The methyl or ethyl ester of the aforementioned compounds were prepared by a conventional esterification procedure. Ethyl thiomorpholine—3-carboxylate has a boiling- point of 108°C/4 mmHg. <br><br> 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—6°C . Isoindolino-1-carboxylic acid was prepared by a procedure similar to that for the preparation of isoquinoline-3— <br><br> i carboxylic acid described in Ber., 44. 2034 (l91l)« Ethyl j so.i-ndo.l in o—1 — carboxy! at e hydrochi or.i do was prepared by <br><br> Iff <br><br> N2. PATgvrr ernes <br><br> 15 JAN 1979 received <br><br> 182812 <br><br> the conventional esterification of isoindoline-1- <br><br> carboxylic acid and has a melting point of 139-140.5°C. <br><br> / <br><br> / <br><br> In so far as the present invention relates to a method of inhibiting the activity and suppressing the activation of thrombin in vivo, no claim is made herein to any such method when used for the prevention or cure of disease in human beings. <br><br> Furthermore no claim is made herein to <br><br> 2 <br><br> N -arylsulfony 1-L-argininaniides of the formula (I): <br><br> HE <br><br> C - N - CIio0HoCHo CHCOR ,Tv j 2 2 2. (I) <br><br> H~N Hi <br><br> hnso2 <br><br> Ar wherein R is <br><br> /R1 <br><br> (1) - N <br><br> (CB2)rC00R2 <br><br> wherein R^ is C2~^l0 a^-kyl». ^3~^10 alkenyl» ^3~^10 al^ynyl» C^-CiQ alkoxyalkyl, C2"C10 alkylthioalkyl, C2 G10 alkylsulf iny1-alkyl,. C^-C^q hydroxyalkyl, C^-C10 alkoxycarbonylalkyl, 0^-C1Q alkylcarbonylalkyl, C-^-C-^q/haloalkyl, Ccy-C-^ aralkyl, Gq-G-^ a-carboxyaralkyl, G^-C-^q cycloalkyl, G^-C-^q Cycloalkylalkyl, furfuryl, tetrahydrofurfuryl optionally substituted with one or more C^-C^ alkyl and/or G-^-C^ alkoxy group, 3-furylmethyl, tetrahydro-3-furylmethyl optionally substituted with one or more G-^-C^ alkyl or C^-C,- alkoxy group, tetrahydro-2(3 or 4)-pyranylmethyl optionally substituted with one or' <br><br> more alkyl and/or G-j^-C^ alkoxy group, l,4-dioxa-2- <br><br> cyclohexylmethyl optionally substituted with one or more Ci-C5 alkyl and/or C-^-C^ alkoxy group, 2-thenyl, <br><br> 182812 <br><br> 3-thenyl, tetra.hydro-2-thenyl optionally substituted with one or more alkyl , or alkoxy group or tetrahydro-3-thenyl; R^ is hydrogen, ^"^lO alkyl, C6 G10 aryl or aralkyl; and n is 1, 2 or 3, <br><br> 5 <br><br> / 3 <br><br> (2) N <br><br> N CH - (CH0) COORr-i 2'm 5 <br><br> wherein R^ is hydrogen, ^"^lO alkyl, C^-C-^q alkenyl, C^-C-^g 10 alkynyl, ^2~^10 alkoxyalkyl, ^2-G10 alkylthioalkyl, °2"C10 <br><br> alkylsulfinylalkyl, ^^"^lO ky^^yalkyl' &gt; G3~G10 alkoxycarbonyl-alkyl, C^-C-^q alkylcarbonylalkyl, C^-C-^q haloalkyl, Cy-C-^ aralkyl, ct-carboxyaralkyl, C^-C-^q cycloalkyl, C4"°10 <br><br> cycloalkylalkyl, furfuryl, tetrahydrofurfuryl optionally 15 substituted with one or more al^yl or ^i~G5 alkoxy group, 3-furylmethyl, tetrahydro-3-furylmethyl optionally substituted with one or more alkyl or . alkoxy group, tetrahydro-2(3 or 4)-pyranylmethyl optionally substituted with one or more. C^-C^ alkyl and/or C^-C^ alkoxy 20 group, 1,4-dioxa-2-cyclohexylmethy.l optionally substituted with one or more alkyl and/pr C-^-C^ alkoxy group, <br><br> 2-thenyl, 3-thenyl, tetrahydro-2-thenyl optionally substituted with one or more C-^-C,- alkyl or G-^-C^ alkoxy group, or -tetrahydro-3-thenyl; R^ is C^-C^q alkyl, phenyl optionally 25 substituted with one or more C-^-C^ alkyl -• or. <br><br> alkoxy group, °7~C12 aralkyl • or ring substituted benzyl wherein said substituent is alkyl or alkoxy; <br><br> - 113 <br><br> 182812 <br><br> R^ is hydrogen, °1 G10 alkyl, C6-C10 aryl . or aralkyl; and m is 0, 1 or 2 <br><br> R. . <br><br> (3) - N <br><br> wherein Rg is -COORg wherein Rg is hydrogen, c1~c1'0 alkyl, <br><br> C6~C10 aryl °r C7~C12 aralky1; each R7 independently is hydrogen, ^-C^ alkyl, phenyl, C1~C5 alkoxy or carboxy; p is an integer of 1 to 4; Rg is substituted into the ring at the 2 or 3-position; and R7 is substituted into the ring at the 2, 3, 4, 5 or 6-position, <br><br> coor9 <br><br> 15 optionally substituted with one or more alkyl or <br><br> G1~G5 alkoxy group, wherein Rg is hydrogen, alkyl,. <br><br> G6-G10 aryl or G7-G12 aralky1; an(^ r ^-s an integer of 1 to 4, <br><br> COOR10 <br><br> ( 5) - N z <br><br> V ^ <br><br> 20 .. ........ <br><br> wherein R1Q is hydrogen, C^-C^ alkyl, C6-C1Q aryl or C?-C12 aralkyl; Z is oxy, thio or sulfinyl; and q is 0 or 1, or <br><br> -114 - <br><br> 182812 <br><br> COORn )-(CH2)i^ <br><br> (6) - N <br><br> ■ MCH2)j' <br><br> wherein R-^ is hydrogen, C-^-C-^q alkyl, Gg-C-^Q aryl or Grj C12 aralkyl; i is 0, lor 2; j isO, 1 or 2; and the sum of i + j is 1 or 2; <br><br> and Ar is ~C12 aralkyj or a phenyl group substituted with one or more alkyl or alkoxy substituents, the number of the carbon atoms of each substituent which is attached to the phenyl group being 3 to 7 and the said phenyl group being optionally substituted further with one or more methyl, ethyl, methoxy, ethoxy, hydroxyl and/or halo substituents, and pharmaceutically acceptable salts thereof. <br><br> i n <br><br> 182812 <br><br> •Subject to the foregoing disclaimer^ what we claim is:- <br><br> tLf.lS. <br><br> 1. An N^-arylsulfonyl-L-argininamide having the formula: <br><br> &lt; ■ c- N - CH CH2CH2CHC0R - (-O <br><br> H9N*^ I I - <br><br> ^ H 1INS0 <br><br> I <br><br> ' Ar or a pharmaceutically acceptable salt thereof, wherein R is <br><br> /Rl <br><br> (.1) -N. <br><br> ^ (ch2),coor2 <br><br> wherein is C2-C10 alky1» C3~C10 alkeny1» C3~C10 alkyny1» ^"^lO <br><br> alkoxyalkyl, G2-C10 alkylthioalkyl, C2-C10 alkylsulfinylalkyl, <br><br> ^ hydroxyalkyl, C^-C-^q carboxyalkyl, G^-C-^q alkoxycarbonylalkyl, G^-C-^q alkylcarbonylalkyl, G-^-C^q haloalkyl, 0^-0-,^ aralkyl, Cg-C-^^-carboxy- <br><br> aralkyl, 0x-0in cycloalkyl, C.-C.,^ cycloalkylalkyl, furfuryl, tetrahvdro- <br><br> 4 10 alkyl and/or G'l-C^ <br><br> furfuryl optionally substituted with one or more C^-C^/alkoxy groups, 3-furylmethyl, tetrahydro-3-furylmethyl optionally substituted with one or more G-^-C^ alkyl or C-^-C^ alkoxy groups,tetrahydro-2 (3 or 4)-pyranylmethyl optionally substituted with one or more G-^-C^ alkyl and/or C^-C^ alkoxy groups, l,4-dioxa-2-cyclohexylmethyloptionally substituted with one or more G^-C^ alkyl and/or G^-C^ alkoxygroups, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl optionally substituted with one or more C-^-C^ alkyl or C-^-C^ alkoxy groups, or tetrahydro-3-thenyl; R2 is hydrogen, G-^-C^q <br><br> — alkyl, Gg-C-^Q aryl, G^-C^ aralkyl or 5-indanyl; and n is 1, 2 or 3,(2) <br><br> n/ii3 <br><br> Nv-CU-(CIl2)mCQOH <br><br> I J • <br><br> wherein R^ is hydrogen alkyl, G^-C10 alkenyl, G^-C-^ alkynyl, C2 <br><br> C10 alkoxyalkyl, C2~C10: alkylthioalkyl, C-p-C^ alky-1-8ul:finylalkyl, <br><br> y hydroxyalkyl, Gg-C-^ carboxyalkyl, G^-C^q alkoxyearbonyfalkyl, C^-G-^q % ^alkyl carbonylalkyl/Gt -G^q haloalkyl, C^-C^ aralkyl, Cg-C^ -carboxy-aralkyi^^^^^^o^^Loalkyi, °4-°10 cycloalkylalkyl, furfuryl, tetrahy- <br><br> - _ 116 _ <br><br> ^8 2812 <br><br> drofurfui'y 1 optionally uubuti lul';d with one or mora' C^-C^ alkyl or G-^-Ct- <br><br> alkoxy groups, 3-furylmethyl, tobra.hydr6-3-:furylmethyly optionally sub- <br><br> alkyl and /or G-^-C^ alkoxy groups, 1,4-dioxa-2-cyclohexylmethyl optionally substituted with one or more C-^-C^ alkyl and /or C^-C^ alkoxy groups, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl optionally substituted with one or more C^-C^ alkyl or G-^-C^ alkoxy groups,or tetrahydro-3-thenyl; is G1~"G10 a-^yl» carboxy, G2~C-^q alkoxycarbonyl, phenyl optionally substituted with one or more G^-C^ alkyl or G-^-C^ alkoxy groups, G^-C^ ara lkyl or ring substituted benzyl wherein- the substituent is G^-C^ alkyl or C^-C^- alkoxy; R^ is hydrogen, G-j_—G-j^q alkyl, Gg-C10 aryl&gt; G^-C^ ara^Lkyl or 5-indanyl; and m is 0, 1 or 2, <br><br> hydrogen, alkyl, C6-C10 aryl, G^-Cl2 aralkyl or 5-indanyl; each fty independently is hydrogen, G^-C^q alkyl, phenyl, C-^-Cj. alkoxy or carboxy; p is an integer of 1 to 5;Rg is substituted into the piperidine ring-atr wherein Rg is- -COORq wherein Rq -is <br><br> (r7^ <br><br> optionally substituted with one or more G-^-C^ alkyl or Gi~G5 <br><br> alkoxy groupsj wherein Rg is hydrogen, C^^IO alk^'G6 C10 ary^' C7~C12 <br><br> -N ' Z <br><br> 18 2812 <br><br> m wherein R1Q is hydrogen, C^-C-^q alkyl, C^-C^q aryl, Crj-G^ aralkyl or 5-indanyl; Z is oxy, thio or sulfinyl; and qj' is 0 or 1, or <br><br> (6) -N <br><br> COOKn <br><br> (CHa)j wherein is hydrogen, alkyl, <br><br> C^-C^q aryl, aralkyl or 5-indanyl; i is 0, 1 or 2; 3 is 0, 1 or <br><br> 2; and the sum i + j is 1 or 2; <br><br> and Ar is naphthyl, 5 ,6f7,8-tetrahydronaphthyl optionally substituted with one or more alkyl or alkoxy groups, naphthyl substituted with at least one substituent which is halo, nitro, cyano, hydroxy, C-^-C^q alkyl, C^-C^q alkoxy or. ^2~^20 <br><br> dialkylamino, phenyl, phenyl substituted with at least one substituent which is halo, nitro, cyano, hydroxy, alkyl, -C^- °10 alkoxy or <br><br> C2~G20 ^iallcylamino ,0^-0^ aralkyl, or <br><br> 0 <br><br> 0 <br><br> or <br><br> -.(TV e V . <br><br> Q_/~R12 each of which is optionally substituted with one or more alkyl or C1~C5 alkoxy groups, wherein R12 i <br><br> C1~C10 alk^1 or ci_cio alkoxy&gt; <br><br> - 118 - <br><br> provided that 1828! <br><br> . / 1 <br><br> when R is:- (l) - N <br><br> \ <br><br> (CH2)nCOOR2 <br><br> wherein R.^ is alkyl, alkenyl, C^-C-^g alkynyl, <br><br> Cg-Cio alkoxyalkyl, CU-C^q carboxyalkyl, C^-C-^g alkoxy-carbonylalkyl, aralkyl, cycloalkyl or G^-C-^g cycloalkylalkyl; R2 is not hydrogen or C-^-C^q alkyl ; <br><br> when R is:- (2) - N <br><br> R3 <br><br> CH - (CH~) COORq t d ra p <br><br> R4 <br><br> wherein Rj is hydrogen, Cl-CiO alkyl, C3-C10 alkenyl, <br><br> Cy-Cio alkynyl, c2-c10 alkoxyalkyl, C2-C10 carboxyalkyl, C3-C10 alkoxycurbonylalkyl, c7-c10 aralkyl, c3-c10 cycloalkyl or Cit~Cio cycloalkylalkyl;and R4 is C-j-CLq alkyl; Rc i not hydrogen, or Ci~Ciq alkyl; <br><br> when R is;- (3) - <br><br> whoruin R£ is -COOHs? each . <br><br> independently is hydrogen, Ci-C^o alkyl or C1-C5 alkoxy; p is fin integer of 1 to 5; R6 is substituted into the piperi dine ring at the 2 or 3—position; and Ry is substituted into the piperidine ring at tho 2, 3» 5 or 6-poiJition; Rg is not to alkyl ; <br><br> when R is:- <br><br> w - <br><br> optionally substituted with one or more C1-C5 alkyl or C1-C5 alkoxy groupu , is not a-^y-l- &gt; <br><br></p> </div>

Claims (1)

  1. <div class="application article clearfix printTableText" id="claims"> <p lang="en"> «<br><br> f » %<br><br> COOR10<br><br> 18 2812<br><br> when R is:- • (5) - n 'Z<br><br> wherein Z is oxy or thio; is not C-^-Cg'alkyl;<br><br> and when R is:- '<br><br> (6) - N<br><br> COORn is not C-^—Gg alkyl; if Ar is 5, 6,7,8-tetrahydronaphthyl, naphthyl, 1-naphthyl substituted, with one substituent which is halogen, nitro, cyano, hydroxy, CI"°10 alkyl, C2-C2q dialkylamino, or C^-C-^q alkoxy, 2-naphthyl aubatituted with one substituent which ia halogen, nitro, cyano, hydroxy, C^-C^q alkyl, C2-C2q dialkylamino or C^-C-^q alkoxyj naphthyl substituted by two C-^-C^q alkoxy groups which may be the same or different,<br><br> ■ &lt;x&gt;<br><br> Rl2 wherein R]_2 is alkoxy; —<br><br> - 120 -<br><br> n<br><br> 182812<br><br> 2. A compound as claimed in claim 1 wherein R is<br><br> ■/Rl<br><br> (1) —N wherein R, is C_-C,_alkyl/<br><br> (CH2)nCOOR2 i 2 lO<br><br> C3~^6 alkenY1' C3~C6 alkYnyl/ C2~C6 alkoxyalkyl/ C2~^6<br><br> alkylthioalkyl, C2~Cg alkylsulfinylalkyl, C2~C6 hydroxyalkyl, C2-C^ carboxyalkyl, C3~C8 alko^ycarbonylalkyl, C^~C5 haloalkyl, C^-C^0 aralkyl, C3-C22 ^~carboxyaralkyl, C^-C^Qcycloalkyl, C4-G^o cycloalkylalkYlf furfuryl, tetrahydrofurfuryl, 3-furylmethyl, tetrahydro-3-furylmethyl, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl or tetrahydro-3-<br><br> J. P. &amp; S.<br><br> thenyl;^R2 is hydrogen, c^-c^o a^kYl' C6~C10 arYl &gt; C7~"C]_q aralkyl or 5-indanyl;<br><br> R-X 3<br><br> (2) — N wherein R_ is hydrogen,<br><br> CH-(CU0) COORc j 2'm 5<br><br> R4<br><br> c±~c±0 alkyl, C3-Cg alkenyl, C^-Cg alkynyl, C2~Cg alkoxyalkyl, C2~Cg alkylthioalkyl, C2~C6 alkylsulfinylalkyl, C2~C6 hydroxyalkyl, C2~C7 carboxyalkyl, ^""Cg alkoxycarbonylalkyl, Cl"C5 haloalkyl, C~]~C2_0 aralkYl/ C8~C12 ^"C^koxyar alkyl, C3-C10 cycloalkyl, c4~cig cycloalkylalkyl, furfuryl, tetrahydrofurfuryl, 3-furylmethyl, tetrahydro-3-furylmethyl, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl or tetrahydro-3-thenyl; R^ is C^-C^ alkyl, carboxy, C2~c$ alkoxycarbonyl,<br><br> phenyl, C_-C,~ aralkyl or ring substituted benzyl wherein IF. AS. 7 10 ,<br><br> the substl.tuent is ^""£3 alkyl or C -C3 alkoxy; is<br><br> - 121 -<br><br> f*<br><br> m<br><br> 1828! 2-<br><br> hydrogen/ alkyl, C6~C10 aryl, C?-C10 aralkyl or<br><br> 5-indanyl;<br><br> R,<br><br> 6<br><br> (3) -N ^ wherein Rg is -COORg wherein Rg<br><br> R7<br><br> J P. &amp; S. hydrogen, C1~C10 alkyl, cq_c^o aryl/ C7~"C10 aralkYl or<br><br> 5-indanyl;aR^ is hydrogen, alkyl, phenyl or carboxy;<br><br> COORC)<br><br> \<br><br> \ _N' j wherein R^ is hydrogen, \cH2V<br><br> C^-C^0 alkyl, c5~gjq a^yl, C7~Cio aralkYl or 5-indanyl; .. COORj 0<br><br> (5) -N Z wherein R^Q is hydrogen,<br><br> V / i r'"^i<br><br> C^-C^0 alkyl, C5~C^0 arY1' C7~C10 ara^-kyl or 5-indanyl; or<br><br> COORT1<br><br> i «* n/kc"2<br><br> \°) wherein R^^ is hydrogen,<br><br> 2 j,<br><br> C1~C10 alky-IL' C6~C10 arY^' C7-C10 a^alkyl or 5-indanyl;<br><br> and Ar is naphthyl, 5, 6,7 ,8-tetrahydronaphthyl, naphthy.l substituted with at least one substituent which is halo,<br><br> nitro, cyano, hydroxy, C^-C^ alkyl, alkoxy or C2"C10<br><br> dialkylamino, phenyl, phenyl substituted with at least one substituent which is halo, nitro, cyano, hydroxy alkyl, C^~C5 alkoxy or C2"~C10 dialkylamino, C7~ci.q aralkyl,<br><br> (22. .N.Z. PATENT QFFlrc<br><br> "*** 1sJANmi&gt;<br><br> 182812<br><br> ^ fii2 wherein is hydrogen, alkyl or<br><br> **<br><br> Cl"C5 alkoxy.<br><br> 3. A compound as claimed in claim 2 wherein R is<br><br> 1) 1<br><br> (CH2)n - COOR2<br><br> wherein is C2_C^0 alkyl, C3-Cg alkenyl, C3~Cg alkynyl,<br><br> i<br><br> C2~C6 alkoxyalkyl, C2~C6 alkylthioalkyl, C2~C6 alkylsulfinylalkyl, C^-Cg hydroxyalkyl, carboxyalkyl, C3-Cg alkoxycarbonylalkyl, cj~ciq aralkyl, C8~ci2 ^-carboxyaralkyl, C3-C10 cycloalkyl, C4~g^q cycloalkylalkyl, furfuryl, tetrahydrofurfuryl, 3-furylmethyl, tetrahydro-3-furylraethyl, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl or tetrahydro-3-thenyl;<br><br> /a*<br><br> WJo jHlfWNTOFRCE IS<br><br> *<br><br> 182812<br><br> 2) /R3<br><br> ~N\<br><br> CH — (CH-) — COOR[-I 2'm 5<br><br> R4<br><br> wherein is hydrogen, c1~c^0 alkyl, C^-Cg alkenyl, C3~Cg alkynyl, C2~CS alkoxyalkYl' C2~C6 alkylthioalkyl, C2~C6 aikylsulfinYlalkyl, Cj_"Cg hydroxyalkyl,<br><br> carboxyalkyl, C^-Cg alkoxycarbonylalkyl, C^-C^q aralkyl,<br><br> C8~C12 ^ -carboxyaralkyl, C3~Gio cYcl°aikyl, C4~C10 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl, 3-furylmethyl, tetrahydro-3-furylmethyl, 2-thenyl, 3-thenyl, tetrahydro-2-theny1 or tetrahydro-3-theny;l; and R^ is<br><br> Cl~('5 a^k'yi' carboxy, C2~C5 alkoxycark°nylf C7~&lt;"'lo arai^yi or ring substituted benzyl wherein the substituent is<br><br> C.-C0 alkoxy;<br><br> 1 3 coorg<br><br> 3) -N<br><br> wherein R^ is hydrogen, c^"~cg alkyl,<br><br> R7<br><br> phenyl or carboxy, and R^ is substituted into the piperidine ring at the 2, 4 or 6 position;<br><br> 4) a group of the formula<br><br> COOH<br><br> which is 3-carboxy-4-morpholino,<br><br> 3-carboxy-4-thiomorpholino, l-oxo-3-carboxy-4-thiomorpholino or 4-carboxy-3~thiazolidinyl;<br><br> " - 124 -<br><br> I ^ 1FEBW79<br><br> n or (5) a group of the formula COOII<br><br> &gt; (CH2&gt;<br><br> (CVj which is 2-carboxy-l,2,3,4-tetrahydro-l-quinolyl, 3-carboxy-1,2,3,4-tetrahydro-2-isoquinolyl, 1-carboxy-l,2,3,4-tetrahydro-2-isoquinolyl, 2-carboxy-l-indolinyl or l-carboxy-2-isoindol-inyl; R2, R^ and RQ in the above formulae "being hydrogen,<br><br> alkyl, C6-C10 aryl, C7-C10 aralkyl or 5-indanyl. ^ _<br><br> 2<br><br> 4. A compound as claimed in claim 1 which is N -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-tetrahydrofurfuryl-glycine.<br><br> 5. A compound as claimed in claim 1 which is,N-(7-methyl-2-naphthylsulfonyl)-L-arginyl-N-tetrahydrofurfuryIglycine.<br><br> 6. A compound as claimed in claim 1 which is N — (6,7 — dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-tetrahydrofurfury1-glycine.<br><br> 7. A compound as claimed in claim 1 which is 1-{n^-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl]-4-methy1-2— piperidinecarboxylic acid.<br><br> * f 2<br><br> 8. A compound as claimed in claim 1 which is 1- [N -{7-r inethoxy-2-naphthylsuifdhyl)-L-arginyl]-4-methyl-2-piperidine-<br><br> - i25 -<br><br> BECEIV6D<br><br> IM8/1<br><br> 9. A compound as claimed in claim 1 which is 1- [n2-(7-methoxy-2-naphthylsulfonyl)-L-arginyl]-4-ethyl-2-piperidine-carboxylic acid.<br><br> 2<br><br> 10. An N -alkoxynaphthalenesulfonyl-L-argininamide having the formula:<br><br> " /»!<br><br> ^c-n-ch2ch2ch3chconC<br><br> h2n/ SU&gt;a x(cH2)n-coon.<br><br> ill or a pharmaceutically acceptable salt thereof, wherein Ar is naphthyl substituted with at least one C^-C^. alkoxy; is aralkyl; is hydrogen, ci"c-xo alkyl, C6~C10 arY^- or C7~C12 ara^cyl? and n is 1, 2 or 3.<br><br> 3L1« A compound as claimed in claim 10 wherein Ar is 5-methoxy-l-naphthyl, 6-methoxy-2-naphthyl, 7-methoxy-2-i^aphthyl, 4,6-dimethoxy-2-naphthyl, 6,7-dimethoxy-2-naphthyl or 6,7-<br><br> diethoxy—2—naphthyl; is benzyl, phenethyl or 3~phenyl— propyl j and Rj is hydrogen, methyl, ethyl, tert-butyl, phenyl or benzyl.<br><br> 12. An N -alkoxynaphthalenesulfonyl-L-argininamide having the formula:<br><br> hn &lt;2<br><br> h I<br><br> ^r.C-N-CH9CH0CH_CHCON r- A »2» ' • 2\ 7(CH0)„-<br><br> hnso-<br><br> I '<br><br> Ar<br><br> - 126 -<br><br> COCTR_ 2 n 2<br><br> &amp;<br><br> 182812<br><br> or a pharmaceutically acceptable salt thereof, wherein Ar is a alkoxy substituted naphthyl group; is. alkyl or C^-C^g alkoxyalkyl; R2 is hydrogen or G-^-C-^q alkyl; and n is 1, 2 or 3.<br><br> 2<br><br> _ An N -alkoxynaphthalenesulfonyl-L-argininamide having the formula:<br><br> V v ✓R<br><br> ^C-N-CH2CHoCHOCHC0NT x H2N^ " 1^S02 ^(C%)n-C00R2<br><br> I<br><br> Ar.<br><br> or a pharmaceutically acceptable salt thereof, wherein Ar is naphthyl substituted with at least one C-^-C^, alkoxy; R^ is C2~^1C al^ylthioalkyl; R2 is hydrogen, C^-C^Q alkyl, Cg-C^Q aryl or C^-C^2 aralkyl; and n is 1, 2 or 3.<br><br> 2<br><br> 14. An N -alkoxynaphthalenesulfonyl-L-argininamide having the formula:<br><br> ,1N' C '' /U1<br><br> JC-N'-CH2Clt-,CII-)CIICON,&lt;f J-<br><br> "2N-/ : -I (CH2)„-COOR2<br><br> I "<br><br> a Ar wherein Ar is naphthyl substituted with at least one c-j_-"c5 alkoxy; is C3""C10 cYcl°alkyl or ^4~cio cycl°alkylalkyl; R2 is hydrogen, ci~ciq alkyl, C5~C]_q aryl or C^-C^ aralkyl; and n is 1, 2 or 3.<br><br> 2<br><br> 15. An N -naphthalenesulfonyl-L-argininamide having the. formula: —-—~<br><br> ^.z.PaT!'-<br><br> 127 -<br><br> o<br><br> 182812<br><br> llN \ i<br><br> ^ C-N-CHoCII-.Cll-.CIICUN ^ ^<br><br> n.,N^ " " "i . x (en-, )Mcouu«<br><br> 11NS0-. v -/|1 2<br><br> - I<br><br> Ar or a pharmaceutically acceptable salt thereof, wherein Ar is naphthyl, 5,6,7,8-tetrahydronaphthyl or naphthyl substituted with at least one substituent which is halo, hydroxy, C^-C^Q<br><br> alkyl or C2~C2o dial^yiainino? is c2~Clo aikY^' C2~&lt;"10 alkoxyalkyl, alkyl't-.hir.nlLyl, C^-C^j- aralkyl, C3~C^q cyclo-alkyl or C4-CX0 cYc}°alkYlalkyl7 R2 is hydrogen, ^i~^io alkyl, C^-C^2 aralkyl or cg~c^Q arY^; and n is 1, 2 or 3.<br><br> 2<br><br> 16. An N -alkoxynaphthalenesulfonyl-L-argininamide having the formula:<br><br> J a r,n„n„/R3<br><br> J. p. &amp; S. 7C-N-CH2CH2CH2QHC0N-C<br><br> ^ ^ r;oo%<br><br> Ar 4 *<br><br> or a pharmaceutically acceptable salt thereof, wherein Ar is i<br><br> naphthyl substituted with at least one alkoxy; R^ is<br><br> C1~c10 a^yl/ c2~c10 alk°xyalkyl, C2*"Gio alkylthi°alkYi/ G7~c^5 araikyi, ^2~cio cyci°alkyi °r c4~cio cyci°aikyiaikyi; R^ is alkyl; and R^ is hydrogen, C]_~C]_o alkyl ' C7~C12<br><br> aralkyl or Cg-C20 arY^*<br><br> 2<br><br> 2.7, An N -naphthalenesulfonyl-L-argininamide having the formula : _<br><br> II<br><br> HN ^ | * .R<br><br> . —^.O-N-OHoCHjjCHpCKCON'^ 3<br><br> ' ^so r'(c"2)n°00B=<br><br> ftev»T&gt; , 2 H<br><br> — h r<br><br> - 128 -<br><br> 182812<br><br> or a pharmaceutically acceptable salt thereof, wherein Ar is naphthyl, 5,6,7,8-tetrahydronaphthyl or naphthyl substituted with at least one substituent which is halo, hydroxy, nitro,<br><br> cyano, c^~c^o alkYl» Cl~Clo ^i^oxy or C2-C20 dialkylamino; R3 is furfuryl, 3-furylmethyl, tetrahydrofurfuryl or tetrahydro 3-furylmethyl; is hydrogen or alkyl; R,- is hydrogen,<br><br> C^-C^0 alkyl, aralkyl or Cg-C^Q aryl; and n is 0, 1 or 2<br><br> 2<br><br> 18. An N -alkoxynaphthalenesulfonyl-L-argininamide having the formula:<br><br> or a pharmaceutically acceptable salt thereof, wherein Ar is naphthyl substituted with at least one alkoxy; R^ is alkyl, C6~C^Q aryl. or cy~c±2 aralkyl; R^ can be substituted at the 2, .3, 4, 5 or 6 - position; and Rg is substituted at the 2 or 3 - position.<br><br> ii<br><br> *v6<br><br> HNSO2 7<br><br> Ar hydrogen or C^-C1Q alkyl; Rg is - COORg wherein Rg is c±~ciq<br><br> 2<br><br> 19. An N -naphthalenesulfonyl-L-argininamide having the formula<br><br> 182812<br><br> or a pharmaceutically acceptable salt thereof, wherein Ar is naphthyl, 5,6,7,8-tetrahydronaphthyl or naphthyl substituted with at least one substituent which is halo, nitro, cyano, hydroxy, c^~c^o ^^Y1 or C2~C20 ^i^kYla^ino; is hydrogen or c^~cio alkYl'" R6 is -COORg wherein Rg is hydrogen, ci~c^q alkyl, cg~c^o arYl or c-j~ci2 aralkYl; can be substituted at the 2, 3, 4, 5 or 6 - position; and Rg is substituted at the 2 or 3 - position.<br><br> 2<br><br> 20. An N -naphthalenesulfonyl-L-argininamide having the formula<br><br> C00R<br><br> '<br><br> Ht,^ i / \<br><br> C-N-CHoCrfoCHoCHC0-N Z<br><br> h2N^ " 2 I \ /<br><br> ms.°2<br><br> ;&gt; Ar ;<br><br> or a pharmaceutically acceptable salt , thereof, wherein Ar. is naphthyl, 5,6,7,8-tetrahydronaphthyl or naphthyl substituted with at least one substituent which is halo, nitro, cyano, hydroxy, alkYl# Cl~Clo alkoxY or C2~C20 dialkylamino;<br><br> R10 is hydrogen, ci~ciq alkyl* C6~C10 ^Y1 or C7~C12 aralkyl; Z is oxy, thio or sulfinyl; and q is O or 1.<br><br> 2<br><br> An N -naphthalenesulfonyl-L-argininamide having the formula<br><br> ' C00R__ H * v I1<br><br> HN^ , , .. ^<br><br> ^cazh<br><br> _ c-n-€hoch„chocuc0n. , , j<br><br> ' 2 2\ ^-(ch2)&lt;<br><br> Ar<br><br> 130 -<br><br> 182812<br><br> or a pharmaceutically acceptable salt thereof, wherein Ar is naphthyl, 5,6,7,8-tetrahydronaphthyl or naphthyl substituted with at least one substituent which is halo, nitro, cyano,<br><br> hydroxy, ci~cio a^-koxy or C2~C20 dialkylamiino;<br><br> R11 is hydrogen, C1-C1Q alkyl, Cg-C10 aryl or C7""C12 aralkyl/ j is 0, 1 or 2; i is 0, 1 or 2; and i + j is 1 or 2,<br><br> 22. A compound as claimed in any preceding claim ■fhe-<br><br> \ having # D-configuration in the carbon atom to which the<br><br> ' .<br><br> carboxylic group or ester thereof is attached.<br><br> 2*5. A compound as claimed in claim 1 which is any one of compounds Nos. 1 to as hereinbefore designated.<br><br> 24. A compound as' claimed in claim 1 which is any one of the compounds hereinbefore described in Table 1.<br><br> 25. A process for producing a compound as claimed in claim 1 which process comprises reacting an L-argininamide having the formula:<br><br> HN<br><br> \<br><br> C - N - CH~CH~CHoCHC0R<br><br> / I 2 2 2\ ,<br><br> H2N H NH2<br><br> wherein R is as-, defined in claim 1 with an arylsulfonyl halide having the formula -<br><br> ArS02X<br><br> wherein Ar is as defined in cleim 1 and X is halogen, R and Ar being such.ttaiC^'e proviso of claim 1 is satisfied.<br><br> .! FE6W7,_ - "1 -<br><br> ^B£CtW<br><br> 182812<br><br> 26. A process as claimed in claim 25 wherein R and Ar are as defined in claim 2.<br><br> 27. A process for producing a compound as claimed in claim<br><br> G<br><br> 1 which process comprises removing the the N -substituent from &lt;<br><br> G 2<br><br> an N -substituted-N -arylsulfonyl-L-argininamide having the<br><br> CH ,CH,.CH0 CHCOR „ * *<br><br> HNSO<br><br> I 2<br><br> Ar wherein R and Ar are as defined in claim 1; R' and R" are each hydrogen atoms or protective groups for the guanidino group, and at least one of R' and R" is a protective group for the guanidino group, R and Ar being such that the proviso of claim 1 is satisfied<br><br> 28. A process as claimed in claim 27 wherein R and Ar are as defined in claim 2; and R' and R1' are each hydrogen, nitro,<br><br> acyl, tosyl, trityl or an oxycarbonyl^as herein defined.<br><br> 29. A process for producing a compound as claimed in claim 1<br><br> 2<br><br> which process comprises reacting an N -arylsulfonyl-L-arginyl halide having the formula;<br><br> CH2CH2CH2CHC0X<br><br> UNS0o I<br><br> formula:<br><br> HN<br><br> C - N<br><br> UN I<br><br> I R"<br><br> It »<br><br> HN<br><br> H Q N '<br><br> C - N -<br><br> I<br><br> 1!<br><br> 182812<br><br> wherein Ar is as defined in claim 1 and X is halogen, with an amino a:cid derivative having the formula;<br><br> RH<br><br> wherein R is as defined in claim 1, R and Ar being such that the proviso of claim 1 is satisfied.<br><br> i<br><br> 30. A process as claimed in claim 29 wherein R and Ar are as defined in claim 2.<br><br> 31. A process for producing a compound as claimed in claim<br><br> 2<br><br> 1 which process comprises guanidylating an N -aryl-L-ornithinamide<br><br> .having the formula:<br><br> #<br><br> H NCHoCHoCHqCHC0R 2 2 2 2 j<br><br> HNS0o<br><br> I 2<br><br> Ar wherein R and Ar are as defined in claim 1 with a guanidylating agent, R and Ar being such that the proviso of claim 1 is satisfied.<br><br> 32„ A process as claimed in claim 31 wherein R and Ar are as defined in claim 2, and the guanidylating agent is an 0-alkyli-e»f soureaJ S-alkylisothiourea / l-guanyl-3, 5-d.imethylpyrazole or<br><br> (t',^ a carbodiimide. „<br><br> hk y<br><br> 33. A process as claimed in any one of claims 25, 27, 29 an&lt;^ 31., and substantially as described in any one of Examples 1 to 5 with reference to any one of the compounds produced in those Examples«,<br><br> —■-■ _ ni _<br><br> rTTfEBVm<br><br> %<br><br> 182812<br><br> Ot)£.<br><br> \\ ^ •tfW<br><br> 34. A process as claimed iri anyof claims 25, 27, 29 and 31^substantially as described with reference to any one of Sample Nos. 1 to 7 8 of Table 1.<br><br> 35. A method of inhibiting the activity and suppressing the activation of thrombin in vivo, which method comprises introducing into a living body a pharmaceutically effective amount of a compound as claimed in any one of claims 1 to 24.. ...<br><br> 36. A compound as claimed in claim 1 when produced by a process claimed in any one of claims 25 to 34.<br><br> 37. A pharmaceutical formulation comprising as active ingredient a compound as claimed in any one of claims 1 to 24 or claim 36.<br><br> 38. A unit dose of a pharmaceutical formulation as claimed in claim 37.<br><br> 39. A unit dose as claimed in claim 38 which is a tablet, capsule, troch2,or lozenge.<br><br> DRH/PJ3/JC<br><br> % tW.<br><br> A-<br><br> ;.mted ti..<br><br> fH!3 (0 rvAv<br><br> /'»i *<br><br> 134 -<br><br> </p> </div>
NZ182812A 1975-12-09 1976-12-06 N2-aryl(or aralkyl)sulphonyl-l-argininamides and pharmaceutical compositions NZ182812A (en)

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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
US05/649,219 US4018913A (en) 1976-01-14 1976-01-14 N2 -alkoxynaphthalenesulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof
US05/653,217 US4055651A (en) 1974-11-08 1976-01-28 N2 -alkoxynaphthalenesulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof
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
US05/669,743 US4070457A (en) 1974-11-08 1976-03-24 N2 -naphthalenesulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof
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
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

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