GB1596971A - N2-arylsulfonyl-l-argininamides and the pharmaceutically acceptable salts thereof - Google Patents
N2-arylsulfonyl-l-argininamides and the pharmaceutically acceptable salts thereof Download PDFInfo
- Publication number
- GB1596971A GB1596971A GB2063/78A GB206378A GB1596971A GB 1596971 A GB1596971 A GB 1596971A GB 2063/78 A GB2063/78 A GB 2063/78A GB 206378 A GB206378 A GB 206378A GB 1596971 A GB1596971 A GB 1596971A
- Authority
- GB
- United Kingdom
- Prior art keywords
- alkoxy
- alkyl
- aralkyl
- optionally substituted
- hydroxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 150000003839 salts Chemical class 0.000 title claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 46
- 150000001875 compounds Chemical class 0.000 claims abstract description 29
- 125000003118 aryl group Chemical group 0.000 claims abstract description 23
- 239000002253 acid Substances 0.000 claims abstract description 14
- -1 furfuryl Chemical group 0.000 claims description 685
- 125000003545 alkoxy group Chemical group 0.000 claims description 157
- 125000004432 carbon atom Chemical group C* 0.000 claims description 146
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 119
- 125000000217 alkyl group Chemical group 0.000 claims description 82
- 125000005843 halogen group Chemical group 0.000 claims description 70
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 69
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 69
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 68
- 125000001188 haloalkyl group Chemical group 0.000 claims description 66
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 66
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 65
- 125000003282 alkyl amino group Chemical group 0.000 claims description 63
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 62
- 125000004414 alkyl thio group Chemical group 0.000 claims description 60
- 125000004442 acylamino group Chemical group 0.000 claims description 59
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 58
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 56
- 229910052739 hydrogen Inorganic materials 0.000 claims description 56
- 239000001257 hydrogen Substances 0.000 claims description 56
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 51
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 51
- 125000003396 thiol group Chemical class [H]S* 0.000 claims description 48
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 45
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 45
- 125000005113 hydroxyalkoxy group Chemical group 0.000 claims description 42
- 125000001624 naphthyl group Chemical group 0.000 claims description 32
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 30
- 239000002904 solvent Substances 0.000 claims description 28
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 27
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 25
- 125000005118 N-alkylcarbamoyl group Chemical group 0.000 claims description 23
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 22
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims description 18
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 18
- 125000001424 substituent group Chemical group 0.000 claims description 17
- 125000006350 alkyl thio alkyl group Chemical group 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 16
- 229910052760 oxygen Inorganic materials 0.000 claims description 15
- 125000003342 alkenyl group Chemical group 0.000 claims description 14
- 125000004687 alkyl sulfinyl alkyl group Chemical group 0.000 claims description 14
- 150000003862 amino acid derivatives Chemical class 0.000 claims description 14
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 14
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 claims description 14
- 125000002529 biphenylenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C12)* 0.000 claims description 13
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 claims description 13
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 claims description 13
- 125000004988 dibenzothienyl group Chemical group C1(=CC=CC=2SC3=C(C21)C=CC=C3)* 0.000 claims description 12
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 12
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 12
- 125000000850 2H-chromenyl group Chemical group O1C(C=CC2=CC=CC=C12)* 0.000 claims description 11
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 claims description 11
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 11
- 238000009835 boiling Methods 0.000 claims description 11
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 11
- 125000005561 phenanthryl group Chemical group 0.000 claims description 11
- 125000005493 quinolyl group Chemical group 0.000 claims description 11
- ULEBESPCVWBNIF-BYPYZUCNSA-N L-arginine amide Chemical compound NC(=O)[C@@H](N)CCCNC(N)=N ULEBESPCVWBNIF-BYPYZUCNSA-N 0.000 claims description 10
- 125000000304 alkynyl group Chemical group 0.000 claims description 10
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 10
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 claims description 9
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 9
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 8
- 125000004062 acenaphthenyl group Chemical group C1(CC2=CC=CC3=CC=CC1=C23)* 0.000 claims description 8
- 125000004054 acenaphthylenyl group Chemical group C1(=CC2=CC=CC3=CC=CC1=C23)* 0.000 claims description 8
- 125000005083 alkoxyalkoxy group Chemical group 0.000 claims description 8
- 125000003828 azulenyl group Chemical group 0.000 claims description 8
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 claims description 8
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 claims description 8
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 8
- 125000002192 heptalenyl group Chemical group 0.000 claims description 8
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 8
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 8
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 claims description 8
- 125000005954 phenoxathiinyl group Chemical group 0.000 claims description 8
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 claims description 8
- 125000004627 thianthrenyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3SC12)* 0.000 claims description 8
- 125000001819 4H-chromenyl group Chemical group O1C(=CCC2=CC=CC=C12)* 0.000 claims description 7
- 125000005085 alkoxycarbonylalkoxy group Chemical group 0.000 claims description 7
- 125000005093 alkyl carbonyl alkyl group Chemical group 0.000 claims description 7
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 7
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 7
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 7
- 125000001041 indolyl group Chemical group 0.000 claims description 7
- 125000005990 isobenzothienyl group Chemical group 0.000 claims description 7
- 125000003384 isochromanyl group Chemical group C1(OCCC2=CC=CC=C12)* 0.000 claims description 7
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 claims description 7
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 7
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 7
- 125000005605 benzo group Chemical group 0.000 claims description 6
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 239000002775 capsule Substances 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 239000003826 tablet Substances 0.000 claims description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 239000005864 Sulphur Substances 0.000 claims description 4
- 239000012298 atmosphere Substances 0.000 claims description 4
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 4
- 230000002140 halogenating effect Effects 0.000 claims description 3
- 239000012442 inert solvent Substances 0.000 claims description 3
- 239000002552 dosage form Substances 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical group 0.000 claims description 2
- 239000007937 lozenge Substances 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims 15
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims 13
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims 5
- 238000009472 formulation Methods 0.000 claims 4
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims 3
- 125000005955 1H-indazolyl group Chemical group 0.000 claims 2
- 239000007795 chemical reaction product Substances 0.000 claims 2
- 125000003427 indacenyl group Chemical group 0.000 claims 2
- 125000000172 C5-C10 aryl group Chemical group 0.000 claims 1
- 125000005228 aryl sulfonate group Chemical group 0.000 claims 1
- 125000004093 cyano group Chemical group *C#N 0.000 claims 1
- 239000007972 injectable composition Substances 0.000 claims 1
- 239000007788 liquid Substances 0.000 claims 1
- 230000003472 neutralizing effect Effects 0.000 claims 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 abstract description 8
- 108090000190 Thrombin Proteins 0.000 abstract description 8
- 229960004072 thrombin Drugs 0.000 abstract description 8
- 208000007536 Thrombosis Diseases 0.000 abstract description 6
- 229930064664 L-arginine Natural products 0.000 abstract description 4
- 238000011282 treatment Methods 0.000 abstract description 4
- 235000014852 L-arginine Nutrition 0.000 abstract description 3
- 230000002401 inhibitory effect Effects 0.000 abstract description 3
- 239000000825 pharmaceutical preparation Substances 0.000 abstract 1
- 238000011321 prophylaxis Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 46
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 33
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 32
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 27
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 26
- 150000002431 hydrogen Chemical group 0.000 description 25
- 230000015271 coagulation Effects 0.000 description 23
- 238000005345 coagulation Methods 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 20
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 16
- 239000000047 product Substances 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 14
- 239000007858 starting material Substances 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 10
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 9
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 9
- 238000009833 condensation Methods 0.000 description 9
- 230000005494 condensation Effects 0.000 description 9
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 9
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 9
- 238000002844 melting Methods 0.000 description 9
- 230000008018 melting Effects 0.000 description 9
- 239000000523 sample Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 8
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 8
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 8
- 125000000143 2-carboxyethyl group Chemical group [H]OC(=O)C([H])([H])C([H])([H])* 0.000 description 7
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 7
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 description 7
- 125000005997 bromomethyl group Chemical group 0.000 description 7
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 238000000921 elemental analysis Methods 0.000 description 7
- 238000001704 evaporation Methods 0.000 description 7
- 230000008020 evaporation Effects 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 235000001014 amino acid Nutrition 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000006482 condensation reaction Methods 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 6
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 5
- 108010049003 Fibrinogen Proteins 0.000 description 5
- 102000008946 Fibrinogen Human genes 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 239000000908 ammonium hydroxide Substances 0.000 description 5
- 229940012952 fibrinogen Drugs 0.000 description 5
- 150000003254 radicals Chemical class 0.000 description 5
- 229910052717 sulfur Inorganic materials 0.000 description 5
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 229910006069 SO3H Inorganic materials 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 230000002785 anti-thrombosis Effects 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 3
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 239000003146 anticoagulant agent Substances 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 239000003456 ion exchange resin Substances 0.000 description 3
- 229920003303 ion-exchange polymer Polymers 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 125000004043 oxo group Chemical group O=* 0.000 description 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- LDKSCZJUIURGMW-UHFFFAOYSA-N 1-isothiocyanato-3-methylsulfanylpropane Chemical group CSCCCN=C=S LDKSCZJUIURGMW-UHFFFAOYSA-N 0.000 description 2
- 125000005999 2-bromoethyl group Chemical group 0.000 description 2
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 2
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 2
- KKZUMAMOMRDVKA-UHFFFAOYSA-N 2-chloropropane Chemical group [CH2]C(C)Cl KKZUMAMOMRDVKA-UHFFFAOYSA-N 0.000 description 2
- 125000006024 2-pentenyl group Chemical group 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
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- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 125000005767 propoxymethyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])[#8]C([H])([H])* 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 238000001226 reprecipitation Methods 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000005583 trifluoroacetylation reaction Methods 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000005866 tritylation reaction Methods 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
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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
- 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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- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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- 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
- C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/16—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with acylated ring nitrogen atom
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- 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
- C07D307/14—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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- 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
- C07D307/34—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
- C07D307/38—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 with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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- C07D309/02—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
- 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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- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
- C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
- C07D311/14—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 6 and unsubstituted in position 7
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- C07D327/02—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms one oxygen atom and one sulfur atom
- C07D327/06—Six-membered rings
- C07D327/08—[b,e]-condensed with two six-membered carbocyclic rings
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- C07K5/06086—Dipeptides with the first amino acid being basic
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Abstract
The arginamides correspond to the formula: <IMAGE> in which Ar represents various aromatic groups and R represents one of the following groups: <IMAGE> The detailed definition of the Ar groups and the symbols in the R groups is found in Claim 1. The compounds and their acid addition salts are prepared from L-arginine by a three-step process. They have a specific inhibitory action against thrombin and can be used, preferably in the form of pharmaceutical preparations, for the treatment and for the prophylaxis of thromboses.
Description
(54) N2-ARYLSULFONYL-L-ARGININAMIDES AND THE
PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
(71) We, MITSUBISHI CHEMICAL INDUSTRIES LIMITED, aJaanese Body Corporate, of 5-2, Marunouchi 2-chome, Chiyoda-ku, Tokyo, Japan and
SHOSUKE OKAMOTO, a Citizen of Japan, of 15-18, Asahigaoka 3-chome,
Tarumi-ku, Kobe-shi, Hyogo, Japan, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:
This invention relates to N2-arylsulfonyl-L-argininamides and the pharmaceutically and veterinarily acceptable salts thereof, examples of which are found to possess especial value in view of their outstanding antithrombotic properties and low toxicities.
In the past, there have been many attempts to obtain new and improved agents for the treatment of thrombosis. The N2-(p-tolysulfonyl)-L-arginine esters have been found to be one type of agent which can be used and these have been found to be effective in dissolving blood clots. (U.S. Patent No. 3,622,615, issued November 23, 1971). One family of compounds which have been found to be particularly useful as highly specific inhibitors of thrombin for the control of thrombosis is the
N2-dansyl-L-arginine ester or amide. (Our pending U.S. Application Serial No.
496,939, filed August 13, 1974 now U.S. Patent No. 3,978,045). However, there is a continuing need for a highly specific inhibitor of thrombin for the control of thrombosis, which exhibits lower toxicity.
The present invention provides an N2-arylsulfonyl-L-argininamide of the formula (I):
wherein R is
wherein R, is C2 to C,0 alkyl, C3 to C10 alkenyl C2 to C10 alkynyl, C2 to C,0 alkoxyalkyl, C2 to C,0 alkylthioalkyl, C2 to C,0 alkylsulfinylalkyl, C, to C,0 hydroalkyl, C3 to C,0 alkoxycarbonylalkyl, C3 to C,0 alkylcarbonylalkyl, C, to C,0 haloalkyl, C, to C15 aralkyl, C, to C15 a-carboxyaralkyl, C3 to C,0 cycloalkyl, C4 to
C10 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl optionally substituted with one or more of C, to C5 alkyl and/or C, to C5 alkoxy, 3-furylmethyl, tetrahydro-3-furylmethyl optionally substituted with one or more of C, to C5 alkyl and/or C, to C5 alkoxy, tetrahydro-2 (3 or 4)-pyranylmethyl (i.e. tetrahydro-2-pyranylmethyl, tetrahydro-3-pyranylmethyl, or tetrahydro-4-pyranylmethyl) optionally substituted with one or more of C, to C5 alkyl and/or C1 to C5 alkoxy, 1,4-dioxa-2-cyclohexylmethyl optionally substituted with one or more of C, to C5 alkyl and /or C1 to C5 alkoxy, 2thenyl, 3-thenyl, tetrahydro-2-thenyl optionally substituted with one or more of C1 to C5 alkyl and/or C1 to C5 alkoxy, or tetrahydro-3-thenyl; R2 is hydrogen, C1 to C10 alkyl, C6 to C10 aryl or C, to C12 aralkyl; and n is 1, 2 or 3,
wherein R3 is hydrogen, C1 to C10 alkyl, C3 to C10 alkenyl, C3 to C10 alkynyl, C2 to
C10 alkoxyalkyl, C2 to C10 alkylthioalkyl, C2 to C10 alkylsulfinylalkyl, C1 to C10 hydroxyalkyl, C3 to C10 alkoxycarbonylalkyl, C3 to C10 alkylcarbonylalkyl, C1 to C10 haloalkyl, C, to C15 aralkyl, Cue to C15 a-carboxyaralkyl, C3 to C10 cycloalkyl, C4 to
C10 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl optionally substituted with one or more of C1 to C5 alkyl and/or C1 to C5 alkoxy, 3-furylmethyl, tetrahydro-3-furylmethyl optionally substituted with one or more of C1 to C5 alkyl and/or C1 to C5 alkoxy, tetrahydro-2(3 or 4)-pyranylmethyl optionally substituted with one or more of C1 to C5 alkyl and/or C, to C5 alkoxy, 1,4-dioxa-2-cyclohexylmethyl optionally substituted with one or more of C, to C5 alkyl and/or C1 to C5 alkoxy, 2-thenyl, 3thenyl, tetrahydro-2-thenyl optionally substituted with one or more of C1 to C5 alkyl and/or C1 to C5 alkoxy, or tetrahydro-3-thenyl;
R4 is C1 to C10 alkyl, phenyl optionally substituted with one or more of C1 to C5 alkyl and/or C1 to C5 alkoxy, C, to C12 aralkyl or ring substituted benzyl wherein said substituent is C1 to C5 alkyl or C1 to C5 alkoxy;
R5 is hydrogen, C1 to C10 alkyl, Cue to C10 aryl or C, to C12 aralkyl; and m is 0,1 or 2
wherein Ra is-COOR5 wherein Era is hydrogen, C1 to C10 alkyl, Cue to C10 aryl or to C12 aralkyl; each R, independently is C, to C,0 alkyl, phenyl, C, to C5 alkoxy, C2 to C6 alkoxycarbonyl or carboxyl; p is O or an integer from I to 4; RO is substituted at the 2 or 3-position; and R7, if present, is substituted at the 2, 3, 4, 5 or 6-position,
optionally substituted with one or more of C, to C5 alkyl and/or C1 to C5 alkoxy, wherein R9 is hydrogen, C1 to C,0 alkyl, Cue to C10 aryl or C, to C12 aralkyl; and r is 1, 2 3 or 4,
wherein R10 is hydrogen, C1 to C10 alkyl, Cue to C10 aryl or C, to C12 aralkyl;
Z is oxygen, sulphur or sulfinyl; and q is 0 to 1, or
wherein R11 is hydrogen, C1 to C10 alkyl, Cue to C10 aryl or C, to C12 aralkyl; i is 0, 1 or 2; j is 0, 1 or 2; and the sum of i +j is 1 or 2; and Ar is phenyl or naphthyl, substituted with at least one of sulfoamino, carbamoyl, C3 to C10 N,N-dialkylcarbamoyl, C2 to C5 N-alkylcarbamoyl, amino, C1 to C10 alkylamino, mercapto, C1 to C10 alkylthio, C, to C12 aralkyl, carboxyl, C2 to
C10 alkoxycarbonyl, C2 to C10 carboxyalkyl, C1 to C10 acylamino, C2 to C10 alkylcarbonyl, C1 to C10 hydroxyalkyl, C1 to C10 haloalkyl, C1 to C10 hydroxyalkoxy, and/or phenyl (optionally substituted with one or more of hydroxy, and/or C1 to C5 alkoxy); phenyl or naphthyl, substituted with at least one of halo, nitro, cyano, hydroxy, C1 to C10 alkyl, C1 to C10 alkoxy and/or C2 to C20 dialkylamino, and at least one of sulfoamino, carbamoyl, C3 to C10 N,N-dialkylcarbamoyl, C2 to C6 N-alkylcarbamoyl, amino, C1 to C10 alkylamino, mercapto, C1 to C,0 alkylthio, C7 to C12 aralkyl, carboxyl, C2 to C10 alkoxycarbonyl, C2 to C10 carboxyalkyl, C, to C,0 acylamino, C2 to C,0 alkylcarbonyl, C, to C,0 hydroxyalkyl, C1 to C10 haloalkyl, C1 to C10 hydroxyalkoxy, and/or phenyl (optionally substituted with one or more of hydroxy, and/or C, to C5 alkoxy); oxanthrenyl or dibenzofuranyl substituted with at least one of halo, nitro, cyano, hydroxy, C2 to C20 dialkylamino, sulfoamino, carbamoyl, C3 to C N,N-dialkylcarbamoyl, C2 to C6 N-alkylcarbamoyl, amino, C1 to C10 alkylamino, mercapto, C1 to C10 alkylthio, C7 to C12 aralkyl, carboxyl, C2 to C10 alkoxycarbonyl, C2 to C10 carboxyalkyl, C, to C10 acylamino, C2 to C10 alkylcarbonyl, C1 to C10 hydroxyalkyl,
C1 to C10 haloalkyl, C1 to C10 hydroxyalkoxy, and/or phenyl (optionally substituted with one or more of hydroxy and/or C1 to C5 alkoxy); oxanthrenyl or dibenzofuranyl substituted with at least one of C1 to C10 alkyl and/or
C1 to C10 alkoxy, and at least one of halo, nitro, cyano, hydroxy, C2 to C20 dialkylamino, sulfoamino, carbamoyl, C3 to C10N,N-dialkylcarbamoyl, C2 to C8 Nalkylcarbamoyl, amino, C1 to C10 alkylamino, mercapto, C1 to C10 alkylthio, C7 to
C12 aralkyl, carboxyl, C2 to C10 alkoxycarbonyl, C2 to C10 carboxyalkyl, C1 to C10 acylamino, C2 to C,0 alkylcarbonyl, C1 to C10 hydroxyalkyl, C1 to C,0 haloalkyl, C, to C10 hydroxyalkoxy, and/or phenyl (optionally substituted with one or more of hydroxy and/or C1 to C5 alkoxy); tetrahydronaphthyl, 1,2-ethylenedioxyphenyl, chromanyl, 2,3ethylenedioxynaphthyl or xanthenyl, substituted with at least one of halo, nitro, cyano, hydroxy, C2 to C20 dialkylamino, sulfoamino, carbamoyl, C3 to C10 N,Ndialkylcarbamonyl, C2 to C8 N-alkylcarbamoyl, amino, C1 to C,0 alkylamino, mercapto, C1 to C10 alkylthio, C7 to C12 aralkyl, carboxyl, C2to C10 alkoxycarbonyl,
C2 to C10 carboxyalkyl, C1 to C10 acylamino, C2 to C10 alkylcarbonyl, C1 to C10 hydroxyalkyl, C1 to C10 haloalkyl, C1 to C10 hydroxyalkoxy, oxo and/or phenyl (optionally substituted with one or more of hydroxy, and/or C1 to C5 alkoxy); tetrahydronaphthyl, 1,2-ethylenedioxyphenyl, chromanyl, 2,3ethylenedioxynaphthyl or xanthenyl, substituted with at least one of C1 to C10 alkyl and/or C1 to C10 alkoxy, and at least one of halo, nitro, cyano, hydroxy, C2 to C20dialkylamino, sulfoamino, carbamoyl, C3 to C10 N,N-dialkylcarbamonyl, C2 to C5 N-alkylcarbamoyl, amino, C1 to C10 alkylamino, mercapto, C1 to C10 alkylthio, C7 to C12 aralkyl, carboxyl, C2to C10 alkoxycarbonyl, C2 to C10 carboxyalkyl, C1 to C10 acylamino, C2 to C10 alkylcarbonyl, C1 to C10 hydroxyalkyl, C, to C,0 haloalkyl, C, to C10 hydroxyalkoxy, oxo, and/or phenyl, (optionally substituted with one or more
of hydroxy and/or C1 to C5 alkoxy; naphthoquinonyl, anthryl, phenanthryl, pentalenyl, heptalenyl, azulenyl, biphenylenyl, asym-indacenyl, sym-indacenyl, acenaphthylenyl, phenylcarbonylphenyl, phenoxyphenyl, benzofuranyl, isobenzofuranyl, benzo (b) thienyl, isobenzothienyl, thianthrenyl, dibenzothienyl, phenoxathiinyl, indolyl, 1 H- indazolyl, quinolyl isoquinolyl, phthalazinyl, 1,8 naphthridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, or benzimidazolyl optionally substituted with one or more of halo, nitro, cyano, hydroxy, C1 to C10 alkyl, C1 to C10 alkoxy, C2 to C20 dialkylamino,. sulfoamino, carbamoyl, C3 to C10 N,N-dialkylcarbamoyl, C2 to C8 N-alkylcarbamoyl, amino, C1 to C,0 alkylamino, mercapto, C1 to C10 alkylthio, C7 to C12 aralkyl, carboxyl, C2 to C10 alkoxycarbonyl, C2 to C10 carboxyalkyl, C1 to C10 acylamino, C2 to C10 alkylcarbonyl, C1 to C10 hydroxyalkyl, C1 to C10 haloalkyl, C, to C10 hydroxyalkoxy, and/or phenyl (optionally subsituted with one or more of hydroxy and/or C1 to C8 alkoxy);
C7 to C12 aralkyl, C8 to C18 cycloalkylphenyl, C10 to C18 cycloalkylalkylphenyl, C9 to
C18 cycloalkyloxphenyl, C9 to C1, cycloalkylthiophenyl, 9,10-dihydroanthryl, 5,6,7,8-tetrahydroanihryl, 9,10-dihydrophenanthryl, 1,2,3,4,5,6,7,8-oxtanhydro- phenanthryl, indenyl, indanyl, fluorenyl, acenaphthenyl, phenylthicphenyl. isochromanyl, 2 2,3-dihydrobenzofuranyl, 1 1,3-dihydroiosbenzofuranyl, thioxanthenyl, 2H-chromenyl, 3,4-dehydro - 1 -isochromanyl, 4H-chromenyl, indolinyl, isoindolinyl, 1 ,2,3,4-tetrahydroquinolyl or 1 ,2,3,4-tetrahydroisoquinolyl optionally substituted with one or more of halo, nitro, cyano, hydroxy, C1 to C10 alkyl, C1 to C10 alkoxy, C2 to C20 dialkylamino, sulfoamino, carbamoyl, C3 to C10 N,N-dialkylcarbamoyl, C2 to C8 N-alkylcarbamoyl, amino, C, to C,0 alkylamino, mercapto, C1 to C10 alkylthio, C7 to C12 aralkyl, carboxyl, C2to C10 alkoxycarbonyl,
C2 to C10 carboxyalkyl, C1 to C10 acylamino, C2 to C10 alkylcarbonyl, C1 to C10 hydroxyalkyl, C1 to C10 haloalkyl, C1 to C10 hydroxyalkoxy, oxo and/or phenyl (optionally substituted with one or more of hydroxyl and/or C1 to C5 alkoxy), or phenyl substituted with at least one of alkyl, alkoxy, haloalkoxy, aloxyalkyl, alkoxyalkoxy, alkoxycarbonylalkyl and alkoxycarbonylalkoxy, the said substituent containing 3 to 7 carbon atoms and the said substituted phenyl group being optionally subsituted further with one or more of methyl, ethyl, methoxy, ethoxy, hydroxy and/or halo. Also encompassed within this invention are pharmaceutically acceptable and veterinarily salts thereof.
This invention also relates to a method for inhibiting activity and suppressing activation of thrombin in vivo in mammals which comprises administering to a nonhuman mammal a veterinarily (antithrombotically) effective amount of an N2 arylsulfonyl-L-argininamide or the pharmaceutically acceptable salts thereof.
Exemplification of the groups R and Ar will now be provided. R may be
wherein R1 is C2 to C10 alkyl, such as ethyl, propyl, butyl, isobutyl, pentyl, hexyl,
octyl, or decyl, alkenyl of 3 to 10 (preferably 3 to 6) carbon atoms, such as allyl, 2
butenyl, 3-butenyl, 3-butenyl or 2-pentenyl, alkynyl of 3 to 10 (preferably 3 to 6)
carbon atoms, such as 2-propynyl, 2-butynyl, or 3-butynyl, alkoxyalkyl of 2 to 10
(preferably 2 to 6) carbon atoms, such as methoxymethyl, ethoxymethyl,
propoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-propoxyethyl, 2-methoxypropyl,
3-methoxypropyl, 3-ethoxypropyl, 3-propoxypropyl, 4-methoxybutyl, 4
ethoxybutyl, 4-butoxybutyl, or 5 butoxypentyl, alkylthioalkyl or 2 to 10 (preferably
2 to 6) carbon atoms such as methylthiomethyl, ethylthiomethyl, propyl
thiomethyl, 2-methylthioethyl, 2-ethylthioethyl, 2-propylthioethyl, 3
methylthiopropyl, 2-methylthiopropyl, 3-ethylthiopropyl, 3-propylthiopropyl, 4 methylthiobutyl, 4-ethylthiobutyl, 4-butylthiobutyl, or 5-butylthiopentyl,
alkylsulfinylalkyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as methylsuffinyl- methyl, ethylsulfinylmethyl, propylsulfinylmethyl, 2-methylsulfinylethyl, 2-ethyl
sulfinylethyl, 2-propylsulfinylethyl, 3-methylsulfinylpropyl, or 3-ethylsulfinyl
propyl, hydroxyalkyl of 1 to 10 (preferably 1 to 6) carbon atoms, such as hydroxy
methyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl, 3
hydroxybutyl, or 5-hydroxypentyl, alkoxycarbonylalkyl of 3 to 10 (preferably 3 to
8) carbon atoms, such as methoxycarbonylmethyl, 2-ethoxycarbonylethyl, 2
ethoxycarbonylpropyl, 3-methoxycarbonylpropyl, 1-methoxycarbonylbutyl, 2
ethoxycarbonylbutyl or 4-methoxycarbonylbutyl, alkylcarbonylalkyl of 3 to 10
carbon atoms such as methylcarbonylethyl, haloalkyl of 1 to 10 (preferably 1 to 5)
carbon atoms such as chloromethyl, 2-chloroethyl, 2-bromoethyl, 2-chloropropyl,
3-chloropropyl, 2-chlorobutyl or 4-chlorobutyl, aralkyl of 7 to 15 (preferably 7 to
10) carbon atoms, such as benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 6
phenylhexyl, 1 -phenylethyl or 2-phenylpropyl, a-carboxyaralkyl of 8 to 15
(preferably 8 to 12) carbon atoms such as a-carboxybenzyl or a-carboxyphenethyl,
C3 to C10 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cycloexyl,
cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, C4 to C10 cycloalkylalkyl, such
as cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclohexylethyl or
cyclooctylmethyl, furfuryl, tetrahydrofurfuryl, optionally substitutted with one or
more C1 to C8 alkyl, such as methyl, ethyl, propyl or butyl and/or C1 to C5 alkoxy
groups, such as methoxy, ethoxy, propyl, or butoxy, 3-furylmethyl, tetrahydro-3
furylmethyl, optionally substituted with one or more C1 to C5 alkyl such as methyl,
ethyl, propyl, or butyl, and/or C1 to C5 alkoxy groups, such as methoxy, ethoxy,
propoxy, or butoxy, tetrahydro-2(3 or 4)-pyranylmethyl optionally substituted with
one or more C1 to C5 alkyl such as methyl, ethyl, propyl or butyl and/or C, to C5 alkoxy groups, such as methoxy, ethoxy, propoxy or butoxy, 1,4-dioxa-2-cyclo
hexylmethyl optionally substituted with one or more C, to C5 alkyl such as methyl,
ethyl, propyl or butyl and/or C, to C5 alkoxy groups, such as methoxy, ethoxy,
propoxy or butoxy, 2-thenyl, 34henyl, tetrahydro-2-thenyl, optionally substituted
with one or more C1 to C5 alkyl such as methyl, ethyl, propyl or butyl and/or C1 to C5 alkoxy groups such as methoxy, ethoxy, propoxy, butoxy and tetrahydro-3
thenyl;
R2 is hydrogen, Ct to C10 alkyl, such as methyl, ethyl, propyl, butyl, tertbutyl, hexyl,
octyl, or decyl C8 to C10 aryl, such as phenyl, m-tolyl, or naphthyl and aralkyl of 7 to
12 (preferably 7 to 10) carbon atoms, such as benzyl, or phenethyl, and n is 1,2 or 3,
wherein R3 is hydrogen, C1 to C10 alkyl, such as methyl, ethyl, propyl, butyl, isobutyl, pentyl, hexyl, oxtyl, or decyl, alkenyl of 3 to 10 (preferably 3 to 6) carbon atoms, such as allyl, 2-butenyl, 3-butenyl or 2-pentenyl, alkynyl of 3 to 10 (preferably 3 to 6) carbon atoms, such as 2-propynyl, 2-butynyl to 3-butynyl, aloxyalkyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as methoxymethyl, ethoxymethyl, propoxmethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-propoxyethyl, 2methoxypropyl, 3-methoxypropyl, 3-ethoxypropyl, 3-propoxypropyl, 4methoxybutyl, 4-ethoxybutyl, 4-butoxybutyl to 5-butoxypentyl, alkylthioalkyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as methylthiomethyl, ethylthiomethyl, propylthiomethyl, 2-methylthioethyl, 2-ethylthioethyl, 2.propylthioethyl, 3methylthiopropyl, 2-methylthiopropyl, 3-ethylthiopropyl, 3-propylthiopropyl, 4methylthiobutyl, 4-ethylthiobutyl, 4-butylthiobutyl, or 5-butylthiopentyl, alkylsulfinylalkyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as methylsulfinylmethyl, ethylsulfinylmethyl, propylsulfinylmethyl, 2-methylsulfinylethyl, 2ethylsulfinylethyl, 2-propylsulfinylethyl, 3-methylsulfinylpropyl, or 3ethylsulfinylpropyl, hydroxalkyl or 1 to 10 (preferably 1 to 6) carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 4hydroxybutyl, 3-hydroxybutyl, or 5-hydroxypentyl, alkoxycarbonylalkyl of 3 to 10 (preferably 3 to 8) carbon atoms, such as methoxycarbonylmethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylpropyl, 3-methoxycarbonylpropyl, 1 -methoxycarbonylbutyl, 2-ethoxycarbonylbutyl, or 4-methoxycarbonylbutyl, alkylcarbonylalkyl of 3 to 10 carbon atoms such as methylcarbonylethyl, haloalkyl of 1 to 10 (preferably 1 to 5) carbon atoms such as chloromethyl, 2-chloroethyl, 2bromoethyl, 2-chloropropyl, 3-chloropropyl, 2-chlorobutyl, or 4-chlorobutyl, aralkyl of 7 to 15 (preferably 7 to 10) carbon atoms, such as benzyl, phenethyl, 3phenylpropyl, 4-phenylbutyl, 6-phenylhexyl, l-phenylethyl or 2-phenylpropyl, a- carboxyaralkyl of 8 to 15 (preferably 8 to 12) carbon atoms, such as a-carboxybenzyl or a-carboxyphenethyl, C3 to C10 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or
cyclodecyl, C4 to C10 cycloalkylalkyl, such as cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclohexylethyl or cyclooctylmethyl, furfuryl, tetrahydrofurfuryl optionally substituted with one or more C1 to C5 aikyl such as methyl, ethyl, propyl, or butyl, and/or C1 to C5 alkoxy groups, such as methoxy, ethoxy, propoxy, or butoxy, 3-furylm thyl, tetrahydro-3-furyl- methyl optionally substituted with one or more C1 to C5 alkyl such as methyl, ethyl, propyl, or butyl, and/or Cg to C5 alkoxy groups, such as methoxy, ethoxy, propoxy, or butoxy, tetrahydro-2(3 or 4)pyranylmethyl optionally substituted with one or more C1 to C5 alkyl such as methyl, ethyl, propyl, or butyl and/or C, to C5 alkoxy groups, such as methoxy, ethoxy, propoxy or butoxy, 1 ,4-dioxa-2-cyclo- hexylmethyl optionally substituted with one or more C, to C5 alkyl such as methyl, ethyl, propyl, or butyl, and/or C, to C5 alkoxy groups, such as methoxy, ethoxy, propoxy or butoxy, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl optionally substituted with one or more more C, to C8 alkyl such as methyl, ethyl, propyl or butyl, and/or
C, to C5 alkoxy groups, such as methoxy, ethoxy, propoxy or butoxy, and tetrahydro-3-thenyl;
R4 is alkyl of 1 to 10 (preferably 1 to 5) carbon atoms, such as methyl ethyl, propyl, isopropyl, butyl, isobutyl, sec-pbutyl or pentyl, phenyl optionally substituted with one or more C, to C5 alkyl, such as methyl, ethyl, propyl or butyl, and/or C, to C5 alkoxy groups, such as methoxy, ethoxy, propoxy or butoxy, aralkyl or 7 to 12 (preferably 7 to 10) carbon atoms, such as benzyl, or phenethyl, and ring substituted benzyl wherein said substituent is alkyl of 1 to 5 (preferably 1 to 3) carbon atoms, such as methyl, ethyl, propyl or isopropyl. or alkoxy of 1 to 5 (preferably 1 to 3) carbon atoms, such as methoxy, ethoxy, propoxy or isopropoxy; R5 is hydrogen, C1 to C10 alkyl, such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl oxtyl, or decyl, C6 to C10 aryl, such as phenyl, m-tolyl, or naphthyl, and aralkyl of 7 to 12 (preferably 7 to 10) carbon atoms, such as benzyl, or phenethyl; and m is 0 or 1 or 2.
wherein R5 is -COORa wherein R8 is hydrogen, C, to C,O alkyl, such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl or decyl, C6 to C,0 aryl, such as phenyl, m-tolyl or naphthyl, and aralkyl of 7 to 12 (preferably 7 to 10) carbon atoms, such as benzyl, or phenethyl; each R7 independently is hydrogen, alkyl of 1 to 10 (preferably 1 to 6) carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, hexyl, octyl, or decyl, phenyl,
C1 to C5 alkoxy, such as methoxy, ethoxy, propoxy, or butoxy, C2 to C6 alkoxycarbonyl, such as methoxycarbonyl, or ethoxycarbonyl, or carboxy; p isO or an integer of 1 to 4; R5 is substituted at the 2 or 3-position; and R7, if present, is substituted at the 2, 3, 4, 5 or 6-position
optionally substituted with one or more C1 to C5 alkyl, such as methyl, ethyl, propyl, or butyl, or C1 to C5 alkoxy groups, such as methoxy, ethoxy, propoxy or butoxy wherein R8 is hydrogen, C1 to C10 alkyl, such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl, or decyl, C8 to C10 aryl, such as phenyl, m-tolyl or naphthyl and aralkyl of 7 to 12 (preferably 7 to 10) carbon atoms, such as benzyl or phenethyl and r is 1, 2, 3 or 4,
wherein R10 is hydrogen, C1 to C10 alkyl, such as methyl, ethyl, propyl, butyl, tertbutyl, hexyl, oxtyl or decyl, C8 to C10 aryl, such as phenyl, m-tolyl or naphthyl and aralkyl of 7 to 12 (preferably 7 to 10) carbon atoms, such as benzyl or phenethyl;
Z is oxygen, sulphur sulfinyl (-SO-); q is 0 or 1, and
wherein R11 is hydrogen, C1 to C,0 alkyl, such as methyl, ethyl, propyl, butyl, tertbutyl, hexyl, octyl or decyl, C8 to C,0 aryl, such as phenyl, m-tolyl or naphthyl, and aralkyl of 7 to 12 (preferably 7 to 10) carbon atoms, such as benzyl or phenethyl, i is 0, 1 or 2; is 0, 1 or 2; and the sum ofi +j is 1 or 2; and Ar is phenyl or naphthyl substituted with at least one of sulfoamino, carbamoyl, N,N-dialkylcarbamoyl of 3 to 10 (preferably 3 to 7) carbon atoms, such as N,N-dimethylcarbamoyl, or N,N-diethylcarbamoyl, N-alkylcarbamoyl of 2 to 6 (preferably 2 to 4) carbon atoms, such as N-methylcarbamoyl, or Nethylcarbamoyl, amino, alkylamino 1 to 10 (preferably 1 to 5) carbon atoms, such as methylamino, ethylamino, propylamino or butylamino, mercapto, alkylthio of 1 to 10 (preferably I to 5) carbon atoms, such as methylthio, ethylthio, propylthio, or butylthio, aralkyl of 7 to 12 (preferably 7 to 10) carbon atoms, such as benzyl or phenethyl, carboxyl, alkoxycarbonyl or 2 to 10 (preferably 2 to 6) carbon atoms, such as methoxycarbonyl or ethoxycarbonyl, carboxyalkyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as carboxymethyl, 2-carboxyethyl or 2-carboxypropyl, acylamino such as alkylcarbonylamino or 1 to 10 (preferably I to 5) carbon atoms, such as acetylamino, or propionylamino, alkylcarbonyl of 2 to 10 (preferably 2 to 6) carbon atoms such as acetyl or propionyl, hydroxyalkyl of 1 to 10 (preferably I to 5) carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, or 2-hydropropyl, haloalky of 1 to 10 (preferably 1 to 5) carbon atoms, such as chloromethyl, trifluoromethyl, bromomethyl, or 2-chloroethyl, hydroxyalkoxy of 1 to 10 (preferably 1 to 5) carbon atoms, such as hydroxymethoxy, or 2-hydroxyethoxy and phenyl optionally substituted with at least one hydroxy and/or C, to C5 alkoxy, such as methoxy, ethoxy, propoxy, or butoxy; phenyl or naphthyl, substituted with at least one of sulfoamino, carbamoyl, N,Ndialkylcarbamoyl of 3 to 10 (preferably 3 to 7) carbon atoms, such as N,Ndimethylcarbamoyl or N,N-diethylcarbamoyl, N-alkylcarbamoyl of 2 to 6 (preferably 2 to 4) carbon atoms, such as N-methylcarbamoyl or N-ethylcarbamoyl, amino, alkylamino of 1 to 10 (preferably 1 to 5) carbon atoms, such as methylamino, ethylamino, propylamino, or butylamino, mercapto, alkylthio of 1 to 10 (preferably 1 to 5) carbon atoms, such as methylthio, ethylthio, propylthio, or butylthio aralkyl of 7 to 12 (preferably 7 to 10) carbon atoms, such as benzyl, or phenethyl, carboxyl, alkoxycarbonyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as methoxycarbonyl, or ethoxycarbonyl, carboxyalkyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as carboxymethyl, 2-carboxyethyl, or 2-carboxypropyl, acylamino such as alkylcarbonylamino of 1 to 10 (preferably 1 to 5) carbon atoms, such as acetylamino, or propionylamino, alkylcarbonyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as acetyl, or propionyl, hydroxyalkyl or 1 to 10 (preferably 1 to 5) carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, or 2-hydroxypropyl, haloalkyl of 1 to 10 (preferably 1 to 5) carbon atoms, such as chloromethyl, trifluoromethyl, bromomethyl, or 2-chloroethyl, hydroxyalkoxy of 1 to 10 (preferably 1 to 5) carbon atoms, such as hydroxymethoxy, or 2-hydroxyethoxy, and/or phenyl optionally substituted with one or more of hydroxy and/or C1 to C5 alkoxy, such as methoxy, ethoxy, propoxy or butoxy and at least one of halo, nitro, cyano, hydroxy, alkyl of 1 to 10 (preferably 1 to 5) carbon atoms, such as methyl, ethyl, propyl, or butyl, alkoxy of 1 to 10 (preferably 1 to 5) carbon atoms, such as methoxy, ethoxy, propoxy or butoxy, dialkylamino of 2 to 20 (preferably 2 to 10) carbon atoms, such as dimethylamino, diethylamino, or dipropylamino; oxanthrentyl or dibenzofuranyl substituted with at least one of halo, nitro, cyano, hydroxy, dialkylamino of 2 to 20 (preferably 2 to 10) carbon atoms, such as dimethylamino, diethylamino, or dipropylamino, sulfoamino, carbamoyl, N,Ndialkylcarbamoyl of 3 to 10 (preferably 3 to 7) carbon atoms, such as N,N-dimethylcarbamoyl, or N,N-diethylcarbamoyl, N-alkylcarbamoyl of 2 to 6 (preferably 2 to 4) carbon atoms, such as N-methylcarbamoyl, or N-ethylcarbamoyl, amino, alkylamino of 1 to 10 (preferably 1 to 5) carbon atoms, such as methylamino, ethylamino, propylamino, or butylamino, mercapto, alkylthio of 1 to 10 (preferably 1 to 5) carbon atoms, such as methylthio, ethylthio, propylthio, or butylthio, aralkyl of 7 to 12 (preferably 7 to 10) carbon atoms, such as benzyl or phenethyl, carboxyl, alkoxycarbonyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as methoxycarbonyl, or ethoxycarbonyl, carboxyalkyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as carboxymethyl, 2-carboxyethyl or 2-carboxypropyl, acylamino such as alkylcarbonylamino of 1 to 10 (preferably 1 to 5) carbon atoms, such as acetylamino, or propionylamino, alkylcarbonyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as acetyl, or propionyl, hydroxyalkyl of I to 10 (preferably I to 5) carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, or 2-hydroxypropyl, haloalkyl of 1 to 10 (preferably 1 to 5) carbon atoms, such as chloromethyl, trifluoromethyl, bromomethyl, or 2-chloroethyl, hydroxyalkoxy of 1 to 10 (preferably 1 to 5) carbon atoms, such as hydroxymethoxy, or hydroxyethoxy, and phenyl optionally substituted with one or more of hydroxy and/or C1 to C5 alkoxy, such as methoxy, ethoxy, propoxy, or butoxy; oxanthrenyl or dibenzofuranyl substituted with at least one of alkyl of 1 to 10 (preferably 1 to 5) carbon atoms, such as methyl, ethyl propyl, or butyl, akoxy of 1 to 10 (preferably I to 5) carbon atoms, such as methoxy, ethoxy, propoxy or butoxy, and at least one of halo, nitro, cyano, hydroxy, dialkylamino of 2 to 20 (preferably 2 to 10) carbon atoms, such as dimethylamino, diethylamino, or dipropylamino, sulfoamimo, carbamoyl, N,N-dialkyl (preferably 2 to 6) carbon atoms, such as acetyl, or propionyl, hydroxyalkyl of 1 to 10 (preferably 1 to 5) carbon atoms, such as hydroxymethyI, 2-hydroxyethyl, or 2hydroxypropyl, haloalkyl of I to 10 (preferably 1 to 5) carbon atoms, such as chloromethyl, trifluromethyl, bromomethyl, or 2-chloroethyl, hydroxyalkoxy of 1 to 10 (preferably 1 to 5) carbon atoms, such as hydroxymethoxy, or 2hydroxyethoxy, and phenyl optionally substituted with one or more of hydroxy and/or C1 to C5 alkoxy, such as methoxy, ethoxy, propoxy or butoxy; tetrahydronaphthyl, 1 ,2-ethylenedioxyphenyl, chromanyl, 2,3-ethylenedioxynaphthyl or xanthenyl, substituted with at least one of halo nitro, cyano, hydroxy, dialkylamino of 2 to 20 (preferably 2 to 10) carbon atoms, such as dimethylamino, diethylamino, or dipropylamino, sulfoamino, carbamoyl, N,Ndialkylcarbamoiyl of 3 to 10 (preferably 3 to 7) carbon atoms, such as N,Ndimethylcarbamoyl, or N,N-diethylcarbamoyl, N-alkylcarbamoyl of 2 to 6 (preferably 2 to 4) carbon atoms, such as N-methylcarbamoyl, or N-ethylcarbamoyl, amino, alkylamino of 1 to 10 (preferably 1 to 5) carbon atoms, such as methylamino, ethylamino, propylamino, or butylamino, mercapto, alkylthio of I to 10 (preferably 1 to 5) carbon atoms, such as methylthio, ethylthio, propylthio, or butylthio aralkyl of 7 to 12 (preferably 7 to 10) carbon atoms, such as benzyl, or phenethyl, carboxyl, alkoxycarbonyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as methoxycarbonyl or ethoxycarbonyl, carboxyalkyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as carboxymethyl, 2-carboxyethyl, or 2-carboxypropyl, acylamino such as alkylcarbonylamino of 1 to 10 (preferably 1 to 5) carbon atoms, such as acetylamino, or propionylamino, alkylcarbonyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as acetyl, or propionyl, hydroxyalkyl of 1 to 10 (preferably 1 to 5) carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, or 2-hydroxypropyl, haloalkyl of 1 to 10 (preferably 1 to 5) carbon atoms, such as chloronethyl, trifluoromethyl, bromomethyl, or 2-chloroethyl, hydroxyalkoxy of 1 to 10 (preferably 1 to 5) carbon atoms, such as hydroxymethoxy, or 2-hydroxyethoxy, oxo and/or phenyl optionally substituted with one or more of hydroxy and/or C, to Cs alkoxy, such as methoxy, ethoxy, propoxy, or butoxy; tetrahydronaphthyl, 1,2-ethylenedioxyphenyl, chromanyl, 2,3ethylenedioxynaphthyl or xanthenyl substituted with at least one of alkyl of 1 to 10 (preferably 1 to 5) carbon atoms, such as methyl, ethyl, propyl or butyl, alkoxy of 1 to 10 (preferably 1 to 5) carbon atoms, such as methoxy, ethoxy, propoxy, or butoxy and at least one of halo, nitro, cyano, hydroxy, dialkylamino of 2 to 20 (preferably 2 to 10) carbon atoms, such as dimethylamino, diethylamino, or dipropylamino, sulfoamino, carbamoyl, N,N-dialkylcarbamoyl of 3 to 10 (preferably 3 to 7) carbon atoms, such as N,N-dimethylcarbamoy1, or N,N-diethylcarbamoyl, Nalkylcarbamoyl of 2 to 6 (preferably 2 to 4) carbon atoms, such as N-methylcarbamoyl, or N-ethylcarbamoyl, amino, alkylamino of 1 to 10 (preferably 1 to 5) carbon atoms, such as methylamino, ethylamino, propylamino, or butylamino, mercapto, alkylthio of 1 to 10 (preferably 1 to 5) carbon atoms, such as methylthio, ethylthio, propylthio or butylthio, aralkyl of 7 to 12 (preferably 7 to 10) carbon atolns, such as benzyl or phenethyl, carboxyl, alkoxycarbonyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as methoxycarbonyl, or ethoxycarbonyl, carboxyalkyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as carboxymethyl, 2-carboxyethyl, or 2-carboxypropyl, acylamino such as alkylcarbonylamino of 1 to 10 (preferably 1 to 5) carbon atoms such as acetylamino, or propionylamino, alkylcarbonyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as acetyl, or propionyl, hydroxyalkyl of 1 to 10 (preferably 1 to 5) carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, or 2hydroxypropyl, haloalkyl of 1 to 10 (preferably 1 to 5) carbon atoms, such as chloromethyl, trifluoromethyl, bromomethyl, or 2-chloroethyl, hydroxyalkoxy of 1 to 10 (preferably 1 to 5) carbon atoms, such as hydroxymethoxy, or 2hydroxyethoxy, oxo, and/or phenyl optionally substituted with one or more of hydroxy and/or C, to C5 alkoxy, such as methoxy, ethoxy, propoxy, or butoxy; naphthoquinonyl, anthryl, phenanthryl, pentalenyl, heptalenyl, azulenyl, biphenylenyl, asymmetrical-indacenyl, symmetrical-indacenyl, acenaphthylenyl, phenylcarbonylphenyl, phenoxyphenyl, benzofuranyl, isobenzafuranyl, benzo (b) thienyl, isobenzothienyl, thianthrenyl, dibenzothienyl, phenoxathienyl, indolyl, 1 H- indazolyl, quinolyl, isoquinolyl, phthalazinyl, 1,8-naphthridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl or benzimidazolyl optionally substituted with one or more of halo, nitro, cyano, hydroxy, alikyl of 1 to 10 (preferably 1 to 5) carbon atoms, such as methyl, ethyl, propyl, or butyl, alkoxy of 1 to 10 (preferably 1 to 5) carbon atoms, such as methoxy, ethoxy, propoxy, or butoxy, dialkylamino of 2 to 20 (preferably 2 to 10) carbon atoms, such as dimethylamino, diethylamino or dipropylamino, sulfoamino, carbamoyl, N,N-dialkylcarbamoyl of 3 to 10 (preferably 3 to 7) carbon atoms, such as N,N-dimethylcarbamoyl, or N,N-diethylcarbamoyl, Nalkylcarbamoyl of 2 to 6 (preferably 2 to 4) carbon atoms, such as N-methylcarbamoyl, or N-ethylcarbamoyl, amino, alkylamino of 1 to 10 (preferably 1 to 5) carbon atoms, such as methylamino, ethylamino, propylamino, or butylamino, mercapto, alkylthio of 1 to 10 (preferably 1 to 5) carbon atoms, such as methylthio, ethylthio, propylthio, or butylthio, aralkyl of 7 to 12 (preferably 7 to 10) carbon atoms, such as benzyl or phenethyl, carboxyl, alkoxycarbonyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as methoxycarbonyl, or ethoxycarbonyl, carboxyalkyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as carboxymethyl, 2-carboxyethyl, or 2-carboxypropyl, acylamino such as alkylcarbonylamino of 1 to 10 (preferably I to 5) carbon atoms, such as acetylamino, or propionylamino, alkylcarbonyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as acetyl or propionyl, hydroxyalkyl of I to 10 (preferably 1 to 5) carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, or 2hydroxypropyl, haloalkyl of 1 to 10 (preferably I to 5) carbon atoms, such as chloromethyl, trifluoromethyl, bromomethyl or 2-chloroethyl, hydroxyalkoxy of 1 to 10 (preferably I to 5) carbon atoms, such as hydroxymethoxy, or 2hydroxyethoxy, and/or phenyl optionally substituted with one or more of hydroxy and/or C, to C5 alkoxy, such as methoxy, ethoxy, propoxy or butoxy;
C7 to C,2 aralkyl, C9 to C16 cycloalkylphenyl,C,O to C,8 cycloalkylalkylphenyl, C8 to C, cycloalkyloxyphenyl, C8 to C, cycloalkylthiophenyl, 9,10-dihydroanthryl, 5,6,7,8-tetrahydroanthryl, 9,10 dihydrophenanthryl, 1,2,3,4,5,6,7,8-octahydro- phenanthryl, indenyl, indanyl, fluorenyl, acenaphthenyl, phenylthiophenyl, isochromanyl, 2,3-dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, thioxanthenyl, 2H-chromenyl, 3,4-dehydro-1-isochromanyl, 4H-chromenyl, indolinyl, isoindolinyl, 1 ,2,3,4-tetrahydroquinolyl or 1,2,3 ,4-tetrahydroisoquinolyl, optionally substituted with one or more of halo, nitro, cyano, hydroxy, alkyl, of 1 to 10 (preferably 1 to 5) carbon atoms, such as methyl, ethyl, propyl, or butyl, alkoxy of 1 to 10 (preferably 1 to 5) carbon atoms, such as methoxy, ethoxy, propoxy, or butoxy, dialkylamino of 2 to 20 (preferably 2 to 10) carbon atoms, such as diemethylamino, diethylamino, or dipropylamino, sulfoamino, carbamoyl, N,Ndialkylcarbamoyl of 3 to 10 (preferably 3 to 7) carbon atoms, such as N,N-dimethylcarbamoyl, or N,N-diethylcarbamoyl, N-alkylcarbamoyl of 2 to 6 (preferably 2 to 4) carbon atoms, such as N-methylcarbamoyl, or N-ethylcarbamoyl, amino, alkylamino of 1 to 10 (preferably 1 to 5) carbon atoms, such as methylamino, ethylamino, propylamino, or butylamino, mercapto, alkylthio of 1 to 10 (preferably 1 to 5) carbon atoms, such as methylthio, ethylthio, propylthio, or butylthio, aralkyl of 7 to 12 (preferably 7 to 10) carbon atoms, such as benzyl, or phenethyl, carboxyl, alkoxycarbonyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as methoxycarbonyl, or ethoxycarbonyl, carboxyalkyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as carboxymethyl, 2-carboxyethyl, or 2-carboxypropyl, acylamino such as alkylcarbonylamino of 1 to 10 (preferably 1 to 5) carbon atoms, such as acetylamino, or propionylamino, alkylcarbonyl of 2 to 10 (preferably 2 to 6) carbon atoms, such as acetyl, or propionyl, hydroxyalkyl of 1 to 10 (preferably 1 to 5) carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, or 2-hydroxypropyl, haloalkyl of I to 10 (preferably 1 to 5) carbon atoms, such as chloromethyl, trifluoromethyl, bromoethyl, or 2-chloroethyl, hydroxyalkoxy of 1 to 10 (preferably 1 to 5) carbon atoms, such as hydroxymethoxy, or 2-hydroxyethoxy, oxo, and/or phenyl optionally substituted with one or more of hydroxy and/or C, to C5 alkoxy, such as methoxy, ethoxy, propoxy, or butoxy or phenyl substituted with at least one of alkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkyl and alkoxycarbonylalkoxy, the said substituent containing 3 to 7 carbon atoms, and the said substituted phenyl group being optionally substituted further with at least one of methyl, ethyl, methoxy, ethoxy, hydroxy and halo. Thus the Ar group may be, for example, 3-propyl-4-methoxyphenyl, 3-tert-butyl-4-methoxyphenyl, 3-secbutyl-4-hydroxyphenyl, 3-propoxyphenyl, 3-methoxy-4-propoxyphenyl, 3-propoxy4-methoxyphenyl, 2,4-dimethoxy-3-propoxyphenyl, 3-butoxyphenyl, 2-butoxyphenyl, 2,5-dibutoxyphenyl, 3,4-dibutoxyphenyl, 2,4-dibutoxyphenyl, 3methyl-4-butoxyphenyl, 3 ,5-dimethyl-4-butoxyphenyl, 2,4-dimethoxy-3botoxyphenyl, 2,4-dichloro-3-butoxyphenyl, 3-pentyloxyphenyl, 3isopentyloxyphenyl, , 3,5-dimethyl4-pentyloxyphenyl, 2,4-dimethoxy-3-pentyloxyphenyl, 2,4-dimethoxy-3-hexyloxyphenyl, 2,4-dimethoxy-3-(3-bromopropoxy)- phenyl, 2,4-dimethoxy-3-(2-methoxyethoxy)phenyl, , 2,4-dimethoxy-3-(2
i ethoxyethoxy)phenyl, 3-methyl-4-(2-methoxyethoxy)phenyl, 3-methyl-4-3methoxypropoxy)phenyl, 3 -valeryl-4-methoxyphenyl, or 2,4-dimethoxy-4-(3 methoxycarbonylpropoxy)phenyl.
Preferred R radicals are
wherein R, is C2 to C,0 alkyl, C3 to C,0 alkenyl, C2 to C,0 alkoxyalkyl, C2 to C,0 alkylthioalkyl, C2 to C,0 alkylsulfinylalkyl, C7 to C,6 aralkyl, C3 to C10 cycloalkyl, C4 to C,0 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl, tetrahydro-2(3 or 4)pyranylmethyl or 1,4-dioxa-2-cyclohexylmethyl;
R2 is hydrogen, C1 to C10 alkyl, C6 to C10 aryl or C7 to C12 aralkyl; and n is 1, 2 or 3,
wherein R3 is hydrogen, C, to C,0 alkyl, C3 to C,0 alkenyl, C2 to C,0 alkoxyalkyl, C2 to C,0 alkythioalkyl, C2 to C,0 alkylsulfinylalkyl, C7 to C15 aralkyl, C3 to C,0 cycloalkyl, C4 to C,0 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl, tetrahydro-2 (3 or 4)-pyranylmethyl or 1,4-dioxa-2-cyclohexylmethyl;
R4 is C, to C,0 alkyl, phenyl optionally substituted with one or more of C, to C5 alkyl and/or C, to C5 alkoxy, C7 to C,2 aralkyl or ring substituted benzyl wherein said substituent is C, to C8 alkyl or C, to C5 alkoxy;
R5 is hydrogen, C, to C,0 alkyl, C6 to C10 aryl or C7 to C,2 aralkyl; and m is 0, 1 or 2
wherein Re is -COORe wherein Ra is hydrogen, C, to C10 alkyl, C6 to C,0 aryl or C7 to C,2 aralkyl, each R7 independently is C, to C,0 alkyl or phenyl; p is 0 or an integer of from 1 to 4; Ra is substituted at the 2 or 3-position; and R7 if present is substituted at the 2, 3, 4, 5 or 6-position
optionally substituted with at least one of C1 to C5 alkyl, and/or C1 to C5 alkoxy wherein R9 is hydrogen, C1 to C,0 alkyl, C9 to C10 alkyl, C6 to C,0 aryl or C7 to C,2 aralkyl; and r is 1, 2, 3, or 4,
wherein R10 is hydrogen, C, to C10, alkyl, C8 to C10 aryl or C7 to C12 aralkyl;
Z is oxygen, sulphur or sulfinyl; and q is 0 or 1, and
wherein R11 is hydrogen, C, to C,0 alkyl, C6 to C,0 aryl and C7 to C,2 aralkyl; i is 0, 1 or 2; j is Q, 1 or 2; and the sum of i+j is 1 or 2.
The most preferred R radicals are
wherein R, is C2 to C,0 alkyl, C2 to Ce alkoxyalkyl, C2 to C6 alkylthioalkyl, C7 to C,0 aralkyl, C4 to C,0 cycloalkylalkyl, furfuryl or tetrahydrofurfuryl;
R2 is hydrogen or C1 to C10 alkyl; and n is 1, 2 or 3,
wherein R3 is hydrogen, C, to C10 alkyl, C2 to C8 alkoxyalkyl, C2 to C8 alkoxyalkyl,
C2 to C6 alkylthioalkyl, C7 to C,0 aralkyl, C4 to C,0 cycloalkylalkyl, furfuryl or tetrahydrofurfuryl;
R4 is C, to C5 alkyl;
R5 is hydrogen or C, to C,0 alkyl; and m is 0, 1 or 2,
wherein R6 is-COOR8 wherein R9 is hydrogen or C, to C,0 alkyl; each R7 independently is hydrogen or C, to C5 alkyl; p is 0 or an integer of from I to 4; R5 is substituted at the 2 or 3-position; and R7 if present is substituted at the 2, 3, 4, 5 or 6-position,
optionally substituted with one or more of C, to C8 alkyl, and/or C, to C5 alkoxy wherein Era is hydrogen or C, to C,0 alkyl; and r is 1, 2, 3 or 4,
wherein R10 is hydrogen or C, to C10 alkyl;
Z is oxygen, sulfur or sulfinyl; and q is 0 or 1, and
wherein R" is hydrogen or C, to C,0 alkyl; i is 0, 1 or 2; j is 0, 1 or 2: and the sum of i + j is 1 or 2.
Preferred Ar radicals include phenyl or naphthyl substituted with at least one of sulfoamino, carbamoyl C3 to C10 N,N-dialkylcarbamoyl, C2 to C0 Nalkylcarbamoyl, amino, C1 to C10 alkylamino, mercapto, C1 to C10 alkylthio, C7 to
C12 aralkyl, carboxyl, C2 to C10 alkoxycarbonyl, C2 to C10 carboxyalkyl, C1 to C10 acylamino, C2 to C10 alkylcarbonyl, C1 to C10 hydroxyalkyl, C1 to C10 haloalkyl, C1 to C,0 hydroxyalkoxy, and/or phenyl optionally substituted with one or more of hydroxy and/or C, to C5 alkoxy; phenyl or naphthyl substituted with at least one of halo, nitro, cyano, hydroxy, C, to C10 alkyl, C, to C,0 alkoxy and/or C2 to C20 dialkylamino, and at least one of sulfoamino, carbamoyl, C2 to C,0 N,N-dialkylcarbamoyl, C2 to C6 N-alkylcarbamoyl, amino, C, to C,0 alkylamino, mercapto, C, to C10 alkylthio, C7 to C,2 aralkyl, carboxyl, C2 to C,0 alkoxycarbonyl, C2 to C,0 carboxyalkyl, C1 to Ca0 acylamino, C2 to C,0 alkylcarbonyl, C, to C,0 hydroxy alkyl, C, to C,0 haloalkyl, C, to C,0 hydroxyalkoxy and/or phenyl (optionally substituted with one or more of hydroxy and/or C, to C5 alkoxy); oxanthrenyl or dibenzofuranyl substituted with at least one of halo, nitro, cyano, hydroxy, C2 to C20 dialkylamino, C2 to C6 N-alkylcarbamoyl, C, to C,0 alkylamino, mercapto, C, to C,0 alkylthio, C2 to C,0 alkoxycarbonyl, C, to C,0 hydroxyalkyl, C, to C,0 haloalkyl and/or C, to C,0 hydroxyalkoxy; oxanthrenyl or dibenzofuranyl substituted with at least one of C, to C,0 alkyl and/or
C, to C10 alkoxy, and at least one of halo, nitro, cyano, hydroxy, C2 to C20 dialkylamino, C2 to C8 N-alkylcarbamoyl, C, to C,0 alkylamino, mercapto, C, to C,0 alkylthio, C2 to C10 alkoxycarbonyl, C, to C,0 hydroxyalkyl, C, to C10 haloalkyl and/or C, to C1 hydroxyalkoxy; tetrahydronaphthyl, 1,2-ethylenedioxyphenyl, chromanyl, 2,3-ethylenedioxynaphthyl or xanthenyl substituted with at least one of halo, nitro, cyano, hydroxy, C2 to C20 dialkylamino, C2 to C6N-alkylcarbamoyl, C, to C,0 alkylamino, mercapto, C, to C,0 alkylthio, C2 to C,0 alkoxycarbonyl, C, to
C,0 hydroxyalkyl, C, to C,0 haloalkyl, C, to C10 hydroxyalkoxy, and-or oxo;
tetrahydronaphthyl, 1 ,2-ethylenedioxyphenyl, chromanyl, 2,3-ethylenedioxy
naphthyl or xanthenyl substituted with at least one of C, to C,0 alkyl and C, to C,0
alkoxy, and at least one of halo, nitro, cyano, hydroxy, C2 to C20 dialkylamino, C2 to C5 N-alkylcarbamoyl, C, to C,0 alkylamino, mercapto, C, to C,O alkylthio, C2 to C,O alkoxycarbonyl, C, to C10 hydroxylalkyl, C, to C,0 haloalkyl, Ct to C,0
hydroxyalkoxy, and/or oxo;
anthryl, phenanthryl, biphenylenyl, sym-indacenyl, phenylcarbonylphenyl,
phenoxyphenyl, benzofuranyl, benzo (b) thienyl, thianthrenyl, dibenzothienyl,
phenoxathiinyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, cinnolinyl,
carbazolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl optionally
substituted with one or more of halo, nitro, cyano, hydroxy, C, to C,0 alkyl, C, to
C,0 alkoxy, C2 to C20 dialkylamino and/or C, to C,0 hydroxyalkoxy;
C7 to C,2 aralkyl, C8 to C,8 cycloalkylphenyl, C,0 to C,8 cycloalkylalkylphenyl, C9 to C18 cycloalkyloxyphenyl, 9,10-dihydroanthryl, 5,6,7,8-tetrahydroanthryl, 9,10
dihydrophenanthryl, 1 ,2,3,4,5,6,7,8-octahydrophenanthryl, indenyl, indanyl,
fluorenyl, acenaphthenyl, phenylthiophenyl, 2,3-dihydrobenzofuranyl,
thioxanthenyl, 2H-chromenyl or 1,2,3,4-tetrahydroquinolyl optionally substituted
with one or more of halo, nitro, cyano, hydroxy, C1 to C,0 alkyl, C, to C,0 alkoxy,
C2 to C20 dialkylamino, C2 to C8 N-alkylcarbamoyl, C, to C,0 hydroxyalkoxy,
and/or oxo;
or phenyl substituted with at least one alkyl, alkoxy, haloalkoxy, alkoxyalkyl,
alkoxyalkoxy, alkoxycarbonylalkyl, and/or alkoxycarbonylalkoxy, the said
substituent containing 3 to 7 carbon atoms and the said substituted phenyl group
being optionally substituted further with one or more of methyl, ethyl, methoxy,
ethoxy, hydroxy and/or halo.
More specifically preferred Ar radicals include phenyl or naphthyl, substituted -with at least one of amino, C, to C,0 alkylamino, C, to C,O alkylthio, C, C7 to C,2 aralkyl, C2 to C10 alkoxycarbonyl, C1 to C1i, acylamino, C2 to C10 alkylcarbonyl, C to C10 hydroxyalkyl, C1 to C10 hydroxyalkoxy and/or phenyl;
phenyl or naphthyl substituted with at least one of amino, C, to C,0 alkylamino, C,
to C10 alkylthio, C7 to C12 aralkyl, C2sto C10 alkoxycarbonyl, C1 to C,0 acylamino, C2
to C,0 alkylcarbonyl, C1 to C10 hydroxyalkyl, C1 to C,0 hydroxyalkoxy and/or
phenyl, and at least one of halo, hydroxy, C, to C,0 alkyl, C, to C,0 alkoxy and/or C2
to C, dialkylamino;
dibenzofuranyl substituted with at least one halogen atom;
dibenzofuranyl substituted with at least one of C1 to C,O alkyl and/or C, to C,O alkoxy, and at least one halogen atom;
tetrahydronaphthyl, 1,2-ethylenedioxyphenyl, chromanyl, 2,3
ethylenedioxynaphthyl or xanthenyl, substituted with at least one halogen atom;
tetrahydronaphthyl, 1,2-ethylenedioxyphenyl, chromanyl, 2,3
ethylenedioxynaphthyl or xanthenyl, substituted with at least one of C, to C,0 alkyl
and C1 to C10 alkoxy, and at least one halogen atom;
anthryl, phenanthryl, biphenylenyl, phenoxyphenyl, benzofuranyl, benzo (b)
thienyl, dibenzothienyl, phenoxanthiinyl, quinolyl, isoquinolyl, quinoxalinyl,
acridinyl or phenazinyl, optionally substituted with one or more of halo, hydroxy,
C1 to C10 alkyl, C, to C,O alkoxy and C, to C,0 hydroxyalkoxy;
C7 to C,2 aralkyl, C8 to C16 cycloalkylphenyl, fluorenyl, tnloxantnenyl"n- chromenyl, or 1,2,3,4-tetrahydroquinolyl, optionally substituted with one or more
of C1 to C10 alkyl, C, to C10 alkoxy and/or oxo;
or phenyl substituted with at least one of alkyl, alkoxy, haloalkoxy, alkoxyalkyl,
alkoxyalkoxy, alkoxycarbonylalkyl and/or alkoxycarbonylalkoxy, the said
substituent containing 3 to 7 carbon atoms, and the said substituted phenyl group
being optionally substituted further with one or more of methyl, ethyl, methoxy,
ethoxy, hydroxy and/or halo. The most preferred Ar radicals are phenyl or
naphthyl, substituted with at least one of amino, C, to C,0 alkylamino, C7 to C,2
aralkyl, C, to C,0 acylamino, C, to C,O hydroxyalkyl, and/or C, to C,0
hydroxyalkoxy; phenyl or naphthyl, substituted with at least one of amino, C, to C,0 alkylamino, C7
to C12 aralkyl, C1 to C,0 acylamino, C, to C10 hydroxyalkyl and/or C1 to C10
hydroxyalkoxy and at least one of halo, hydroxy, C1 to C10 alkyl and/or C1 to C,0
alkoxy;
biphenylenyl, phenoxyphenyl, dibenzothienyl, phenoxathiienyl, quinolyl, or
quinoxalinyl optionally substituted with one or more of hydroxy and/or C, to C,O alkyl;
C7 to C,2 aralkyl, C9 to C,, cycloalkylphenyl, fluorenyl, or 2H-chromenyl group optionally substituted with one or more of C, to C,0 alkyl, C, to C,0 alkoxy and/or oxo; or phenyl substituted with at least one of alkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkyl and/or alkoxycarbonylalkoxy, the said substituent containing 3 to 7 carbon atoms, and the said substituted phenyl group being optionally substituted further with one or more of methyl, ethyl, methoxy, ethoxy, hydroxy and/or halo. Typical compounds of this invention include: [N2 - (quinoline - 8 - sulfonyl) - L - arginyl] - 4 - methyl - 2 - piperidine carboxylic acid 1 - [N2 - (3 - methylquinoline - 8 - sulfonyl) - L - arginyl] - 4 - methyl - 2 - piperidinecarboxylic acid I - [N2 - (3 - ethylquinoline - 8 - sulfonyl) - L - arginyl] - 4 - methyl - 2 - piperidinecarboxylic acid 1 - [N2 - (3 - sec - butoxybenzene - 1 - sulfonyl) - L - arginyl] - 4 - methyl - 2 piperidinecarboxylic acid [N2 - (3,5 - dimethyl - 4 - isopropoxybenzene - 1 - sulfonyl) - L - arginyli - 4 - methyl - 2 - piperidinecarboxylic acid 1 - [N2 - (2,4 - dimethoxy - 3 - butoxybenzene - 1 - sulfonyl) - L - arginyl] - 4 - methyl - 2 - piperidinecarboxylic acid I - [N2 - (3 - isopropoxybenzene - 1 - sulfonyl) - L - arginyl] - 4 - methyl - 2 piperidinecarboxylic acid
N2 - (2 - phenoxathiinylsulfonyl) - L - arginyl - N - tetrahydofurfurylglycine
N 2 (2 - fluorenesulfonyl) - L - arginyl - N - (2- methoxyethyl)glycine I - [N2 - (4 - methoxy - 3 - cyclohexylbenzene - I - sulfonyl) - L - arginyli - 4 methyl - 2 - piperidinecarboxylic acid
The pharmaceutically acceptable salts of the above compounds are of course also included within the scope of this invention. For the preparation of the compounds of this invention, various methods can be employed depending upon the particular starting materials and/or intermediates involved. Successful preparation of these compounds is possible by way of several synthetic routes which are outlined below.
(a) Condensation of an L-argininamide with an arylsulfonyl halide.
This process may be illustrated as follows:
In the above formulae, R and Ar are as defined herein above; X is halogen;
R"' is a protective group for the a-amino group, such as benzoyloxycarbonyl or tert-butoxycarbonyl; R' and R" are hydrogen or protective groups for the guanidino group, such as nitro, tosyl, trityl, or oxycarbonyl; and at least one of R' and R" is a protective group for the guanidino group.
The N2-arylsulfonyl-L-argininamide (I) is prepared by the condensation of an
L-argininamide (VI) with a substantially equimolar amount of an arylsulfonyl halide (VIII), preferably a chloride.
The condensation reaction is preferably effected in a suitable reaction-inert solvent in the presence of an excess of a base, such as an organic base (triethylamine, pyridine) or a solution of an inorganic base (sodium hyroxide, potassium carbonate), at a temperature of OOC to the boiling temperature of the solvent for a period of 10 minutes to 15 hours.
The preferred solvents for the condensation include benzene-diethyl ether, diethyl ether-water and dioxane-water.
After the reaction is complete, the formed salt is extracted with water, and the solvent is removed by such standard means as evaporation under reduced pressure to give the N2-arylsulfonyl-L-argininamide (I), which can be purified by trituration or recrystallization from a suitable solvent, such as diethyl ethertetrahydrofuran, diethyl ether-methanol and water-methanol, or may be chromatographed on silica gel.
The L-argininamides (VI) starting materials required for the condensation reaction can be prepared by protecting the guanidino and a-amino groups of Larginine (II) via nitration, acetylation, formylation, phthaloylation, trifluoroacetylation, p-methoxybenzyloxycarbonylation, benzoylation, benzyloxy carbonylation, tert-butoxycarbonylation or tritylation and then condensing the formed N0-substituted-N2-substituted-L-arginine (III) with a corresponding amino acid derivative (IV) by such a conventional process as the acid chloride method, azide method, mixed anhydride method, activated ester method or carbodiimide method, and thereafter selectively removing the protective groups from the formed N-substituted-N2-substituted-L-argininamide (V). The amino acid derivatives (IV) which are the starting materials for the preparation of the NG-substituted-N2- substituted-L-argininamides (V) are represented by the following formulas:
In the above formulae, R1, R2, R3, R4, R5, R6, R7, R9, R10, R11, Z, n, m, r, q, i, and j are as defined herein above.
The amino acid derivatives of the above formula (VIII) or (IX) can be prepared by the condensation of a haloacetate, 3-halopropionate or 4-halobutyrate with an appropriate amine having the formula R,NH2 or ReNH2. (See, J. Org.
Chem., 25 728-732(1960)).
The condensation reaction may be carried out without a solvent or in a solvent, such as benzene or diethyl ether, in the presence of an organic base, such as triethylamine or pyridine, at a temperature of 0 C to 8O0C for a period of 10 minutes to 20 hours. After the reaction is complete, the formed amino acid derivative is separated by such conventional means as extraction with a suitable solvent or evaporation of the reaction solvent and thereafter purified by distillation under reduced pressure.
Among the amino acid derivatives, amino acid tert-butyl ester derivatives are preferred, because they are easily converted to other ester derivativesby acidolysis in the presence of a corresponding alcohol employing an inorganic acid (HCI, H2SO4, etc.) or an organic acid (toluenesulfonic acid, trifluoroacetic acid, etc.). In accordance with the process employed for preparing 2-piperidinecarboxylic acid derivatives (X), the following scheme is illustrative:
In the first reaction of the aforementioned scheme, an appropriately substituted piperidine (XIV) is contacted with an aqueous sodium hypochlorite solution at a temper
(b) Removal of the NG-substituent from an NG-substituted-N2-arylsulfonyl-L- argininamide
This process may be illustrated as follows:
In the above formulae, R, Ar, X, R', R" and R"' are as defined herein above.
The N2-arylsulfonyl-L-argininamide (I) may be prepared by removing the NG- substituent from an NG-substituted-N2-arylsulfonyl-L-argininamide (XX) by means of acidolysis or hydrogenolysis.
The acidolysis may be effected by contacting the NG-substituted-N2- arylsulfonyl-L-argininamide (XX) and an excess of an acid such as hydrogen fluoride, hydrogen chloride, hydrogen bromide or trifluoroacetic acid, without a solvent or in a solvent, such as an ether (tetrahydrofuran, dioxane), an alcohol (methanol, ethanol) or acetic acid at a temperature of -10 C to 1000 C, preferably 10 C to 600C and more preferably at room temperature for a period of 30 minutes to 24 hours. The products are isolated by evaporation of the solvent and the excess acid, or by trituration with a suitable solvent followed by filtration and drying.
Because of the use of the excess acid, the products are generally the acid addition salts of the N2-arylsulfonyl-L-argininamides (I), which can be easily converted to a free amide by neutralization.
The removal of the nitro group and the oxycarbonyl group, e.g., benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, is readily accomplished by the hydrogenolysis.
At the same time, the benzyl ester moiety which can be included in the R group is converted to the carboxyl group by the hydrogenolysis.
The hydrogenolysis is effected in a reaction-inert solvent, e.g., methanol, ethanol tetrahydrofuran or dioxane, in the presence of a hydrogen-activating catalyst, e.g., Raney nickel, palladium, or platinum, in a hydrogen atmosphere at a temperature of 0 C to the boiling temperature of the solvent, and preferably 100C to 80"C for a period of2 hours to 120 hours.
The hydrogen pressure is not critical, and atmospheric pressure is sufficient.
The N2-arylsulfonyl-L-argininamides (I) are isolated by filtration of the catalyst followed by evaporation of the solvent.
The N2-arylsulfonyl-L-argininamides may be purified in the same manner as described above.
The NG-substituted-N2-arylsulfonyl-L-argininamides (XX) starting materials may be prepared by condensing an NG-substituted-N2-substituted L-arginin (III) (generally the NG-substituent is nitro or acyl, and the N2-substituent is a protective group for the amino group, such as benzyloxycarbonyl, tert-butoxycarbonyl, or the like) and a corresponding amino acid derivative (IV), selectively removing only the
N2-substituent of an NG-substituted-N2-substituted L-argininamide (V) by means of catalytic hydrogenolysis or acidolysis, and then condensing the thus obtained NO- substituted-L-argininamide (XIX) with an arylsulfonyl halide (VII), preferably a chloride in the presence of a base in a solvent. These reaction conditions are as described above in the condensation of an L-argininamide with an arylsulfonyl halide, and the removal of the Na-substituent from an Ns-substituted-N2-aryi- sulfonyl-L-argininamide.
(c) Condensation of an N2-arylsulfonyl-L-arginyl halide with an amino acid derivative
This process may be illustrated as follows:
In the above formulae, R, Ar and X are as defined herein above.
The N2-arylsulfonyl-L-argininamide (I) may be prepared by the condensation of an N2-arylsulfonyl-L-arginyl halide (XXII), preferably a chloride with at least an equimolar amount of an amino acid derivative (IV).
The condensation reaction may be carried out without an added solvent in the presence of a base. However, satisfactory results will be obtained with the use of a solvent such as basic solvents (dimethylformamide, dimethylacetamide) or halogenated solvents (chloroform, dichloromethane).
The amount of the solvent to be used is not critical and may vary from 5 to 100 times the weight of the N2-arylsulfonyl-L-arginyl halide (XXII).
Preferred condensation reaction temperatures are in the range of from -10"C to 80"C and preferably from 200C to 500 C. The reaction time is not critical, but varies with the amino acid derivative (IV) employed. In general, a period of from 5 minutes to 10 hours is operable.
The obtained N2-arylsulfonyl-L-argininamide may be isolated and purified in the same manner as described above.
The N2-arylsulfonyl-L-arginyl halide (XXII) starting materials required for the condensation reaction may be prepared by reacting an N2-arylsulfonyl-L-arginine (XXI) with at least an equimolar amount of a halogenating agent such as thionyl chloride, phosphorous oxychloride, phosphorous trichloride, phosphorous pentachloride or phosphorus tribromide. The halogenation may be carried out with or without an added solvent.
The preferred solvents are chlorinated hydrocarbons such as chloroform and dichloromethane, and ethers such as tetrahydrofuran and dioxane.
The amount of the solvent to be used is not critical and may vary from 5 to 100 times the weight of the N2-arylsulfonyl-L-arginine (XXI).
Preferred reaction temperature is in the range of -100C to room temperature.
The reaction time is not critical, but varies with the halogenating agent and reaction temperature. In general, a period of 15 minutes to 5 hours is operable.
The N2-arylsulfonyl-L-arginines (XXI) which are the starting materials for the preparation of the NZ-arylsulfonyl-L-arginyl halides (XXII) may be prepared by the condensation of L-arginine (II) with a substantially equimolar amount of arylsulfonyl halides (VII), by a method similar to that described in the condensation of an L-argininamide with an arylsulfonyl halide.
It is well recognized in the art that and ester derivative of the N2-arylsulfonyl
L-argininamide (I) wherein Re Ra, Re, Rg, R10 or Rt, is alkyl, aralkyl or aryl may be prepared from a carboxylic acid derivative of the N2-arylsulfonyl-L-argininamide wherein R2, Re R8, Re, R10 or R11 is hydrogen, by the conventional esterification methods well known to those skilled in the art. It is also well recognized in the art that the carboxylic acid derivative can be prepared from the ester derivative by the conventional hydrolysis or acidolysis methods. The conditions under which esterification, hydrolysis or acidolysis would be carried out will be each apparent to those skilled in the art.
The N2-arylsulfonyl-L-argininamide (I) of this invention forms acid addition salts with any of a variety of inorganic and organic acids. Some of the N2 arylsulfonyl-l-argininamides containing a free carboxyl group, wherein R2, Ra, Re, Ra, Ro or R11 is hydrogen, forms salts with any of a variety of inorganic and organic bases.
The product of the reactions described above can be isolated in the free form or in the form of salts. In addition, the product can be obtained as pharmaceutically acceptable acid addition salts by reacting one of the free bases with an acid, such as hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, citric, maleic, succinic, lactic, tartaric, gluconic, benzoic, methanesulfonic, ethanesulfonic, benzenesulfonic or p-toluenesulfonic acid. In a similar manner, the product may be obtained as a pharmaceutically acceptable salt by reacting one of the free carboxylic acids with a base, such as sodium hydroxide, possium hydroxide, ammonium hydroxide, triethylamine, procaine, dibenzylamine, 1ephenamine, N,N'-dibenzylethylenediamine or N-ethylpiperidine.
Likewise, the treatment of the salts with a base or acid results in a regeneration of the free amide.
As stated above, the N2-arylsulfonyl-L-argininamide, and the salts therof of this invention are characterized by their highly specific inhibitory activity in mammals against thrombin as well as by their substantial lack of toxicity, and therefore these compounds are useful in the determination of thrombin in blood as diagnostic reagents, and/or for the medical control or prevention of thrombosis.
The compounds of this invention are also useful as an inhibitor of platelet aggregation.
The antithrombotic activity of the N2-arylsulfonyl-L-argininamide of this invention was compared with that of a known antithrombotic agent, N2-(ptolylsulfonyl)-L-arginine methyl ester, by determining the fibrinogen coagulation time. The measurement of the fibrinogen coagulation time was conducted as follows:
An 0.8 ml aliquot of a fibrinogen solution, which had been prepared by dissolving
150 mg of bovine fibrinogen (Cohn fraction I) supplied by Armour Inc. in 40 ml of a borate saline buffer (pH 7.4), was mixed with 0.1 ml of a borate saline buffer, pH 7.4, (control) or a sample solution in the same buffer, and 0.1 ml of a thrombin solution (5 units/ml) supplied by Mochida Pharmaceutical Co., Ltd., was added to
the solutions in an ice bath.
Immediately after mixing, the reaction mixture was transferred from the ice bath to a bath maintained at 250C. Coagulation times were taken as the period between the time of transference to the 25"C bath and the time of the first appearance of fibrin threads. In the cases where no drug samples were added, the coagulation time was 50-55 seconds. The experimental results are summarized in
Table 1. The term "concentration required to prolong the coagulation time by a factor of two" is the concentration of an active ingredient required to prolong the normal coagulation time 50--55 seconds to 100--110 seconds.
The concentration required to prolong the coagulation time by a factor of two for the known antithrombotic agent, N2-(p-tolylsulfonyll)-L-arginine methyl ester, was l,100,um. The inhibitors are shown in Table 1 by indicating R and Ar in the formula (I) and the addition moiety.
When a solution containing an N2-arylsulfonyl-L-argininamide of this invention was administered intravenously into animal bodies, the high antithrombotic activity in the circulating blood was maintained for from one to three hours. The halflife for decay of the antithrombotic compounds of this invention in circulating blood was shown to be approximately 60 minutes; the physiological conditions of the host animals (rats, rabbit, dog and chimpanzee) were well maintained. The experimental decrease of fibrinogen in animals caused
by infusion of thrombin was satisfactorily controlled by simultaneous infusion of the compounds of this invention.
The acute toxicity values (LDso) determined by intravenous administration of
substances of formula (I) in mice (male, 20 g) range from about 150 to 600 milligram
per kilogram of body weight.
Representative LD50 values for the compounds of this invention are shown in the following Table.
Compound C - NH - CH2)3CHC0R Lid50 (mg/kg) F-2Xw NH HNS02Ai; HNS02r Ar R / CH3.N3CH3 173 OC H 3 CH 3 COOH OOH Coon (CHrC)3CH3 wCH3 170 0c113 Coon CH9H3 250 - 300 \ CH3 COOH 250 300 CH3 C00H
Compound C -NH - (CH2)3CHCOR LD50 (mg/kg) HNS02Ar Ar R ,C1I3 Nr) < l 270 N CH3 CO0H C,BgH3 -cH3 300 COOH O R "/CH2 ~ \cFCeoll 260 CH2C00H LD, values for N2-dansyl-N-butyl-L-argininamide and N2-dansyl-N-methyl-Nbutyl-L-argininamide are less than 10 milligrams per kilogram, respectively.
The therapeutic agents in this invention may be aaministerea to mammals
including humans, alone or in combination with pharmaceutically acceptable
carriers, the proportion of which is determined by the solubility and chemical
nature of the compound, chosen route of administration and standard pharma
ceutical practice.
For example, the compounds may be injected parenterally, that is, intramuscularly, intravenously or subcutaneously. For parenteral administration, the compounds may be used in the form of sterile solutions containing other solutes, for example, sufficient saline or glucose to make the solution isotonic. The compounds may be administered orally in the form of tablets, capsules, or granules containing suitable excipients such as starch, lactose and white sugar. The compounds may be administered sublingually in the form of troches or lozenges in which each active ingredient is mixed with sugar or corn syrups, flavoring agents and dyes, and then dehydrated sufficiently to make the mixture suitable for pressing into solid form. The compounds may be administered orally in the form of solutions which may contain coloring and flavoring agents. Physicians will determine the dosage of the present therapeutic agents which will be most suitable for humans, and dosages vary with the mode of administration and the particular compound chosen. In addition, the dosage will vary with the particular patient under treatment.
When the composition is administered orally, a larger quantity of the active agent will be required to produce the same effect as caused with a smaller quantity given parenterally.
The therapeutic dosage is generally 10--50 mg/kg of active ingredient parenterally, 1500 mg/kg orally per day.
Having generally described the invention, a more complete understanding can be obtained by reference to certain specific examples, which are included for purposes of illustration only and are not intended to be limiting unless otherwise specified.
It is to be understood that the present invention includes pharmaceutical compositions containing a compound of the invention as an active ingredient. Such compositions may be in the forms described above. In particular, the invention includes such compositions in unit dosage form.
The invention will now be illustrated by means of Examples in which parts and percentages are by weight.
Example 1.
(A) N2-(2-dibenzothienylsulfonyl)-L-arginine:
To a well stirred solution of 83.6 g of L-arginine in 800 ml of 10% potassium carbonate solution was added 112.7 g of 2-dibenzothiophenesulfonyl chloride in 800 ml of benzene. The reaction mixture was stirred at 600C for 5 hours, during which time the product precipitated. After one hour at room temperature, the precipitate was filtered and washed successively with benzene and water to give
127 g (76 percent) of N2-(2-dibenzothienylsulfonyl)-L-arginine.
(B) N2-(2-dibenzothienylsulfonyl)-L-arginine chloride:
A suspension of 4.21 g of N2-(2-dibenzothienylsulfonyl)-L-arginine in 20 ml of thienyl chloride was stirred for 2 hours at room temperature. Addition of cold dry diethyl ether resulted in a precipitate which was collected by filtration and washed several times with dry diethyl ether to give N2-(2-dibenzothienylsulfonyl)-L-arginyl chloride.
(C) N2-(2-dibenzothienylsulfonyl)-L-arginyl-N-butylglycine tert-butyl ester:
To a stirred solution of 2.67 g of ~ N-butyleneglycine tert-butyl ester in 20 ml of chloroform was carefully added N2-(2-dibenzothienylsulfonyl)-Larginyl chloride obtained above. The reaction mixture was allowed to stand at room temperature for one hour.
At the end of this period, the reaction mixture was washed twice with 20 ml of saturated sodium chloride solution and evaporated to dryness.
The residue was triturated with a small amount of diethyl ether to give an amorphous solid. This was collected by filtration and reprecipitated from ethanol diethyl ether to give 3.1 g (49 percent) of N2-(2-dibenzothienylsulfonyl)-L-arginyl
N-butylglycine tert-butyl ester.
I.R. (KBr): 3350, 1740, 1625 cm-l Analysis -- Calcd. for C28H38O5N5S2.+H2SO3 (percent):
C, 53.31; H, 6.39; N, 11.10 Found (percent):
C, 53.21; H, 6.46; N, 10.89 (D) N2-(2-dibenzothienylsulfonyl)-L-arginyl-N-butylglycine: To a solution of 2.00 g of N2-(2-dibenzothienylsulfonyl)-L-arginyl-N-butylglycine tert-butyl ester in 20 ml of chloroform was added 50 ml of 15% HC1-ethyl acetate. The reaction mixture was stirred for 5 hours at room temperature. At the end of this period, the reaction mixture was evaporated to dryness. The residue was washed several times with dry diethyl ether and chromatographed on 80 ml of
Daiaion SK 102 ion exchange resin (200-300 Japanese Industrial Standard mesh, H+ form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with water and eluted with 3 ammonium hydroxide solution.
The fraction eluted from 3% ammonium hydroxide solution was evaporated to dryness to give 0.9 g (53 percent) of N2-(2-dibenzothienylsulfonyl)-L-arginyl-Nbutyl-glycine as an amorphous solid, I. R. (KBr): 3350, 1640, 1270 cm Analysis -- Calcd. for C24H31N5O5S2 (percent):
C, 54.01; H, 5.86; N, 13.12 Found (percent):
C, 53.78; H, 5.97; N, 12.96
DAIAION is a Registered Trade Mark.
Example 2.
(A) N2-(2-dibenzothienylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester
To a stirred solution of 2.42 g of N-(2-methoxyethyl)glycine ethyl ester and 4.0 ml of triethylamine in 50 ml of chloroform, which was cooled in an ice-salt bath, was added in portions 7.0 g of N2-(2-dibenzothienylsulfonyl)-L-arginyl chloride obtained above. The reaction mixture was stirred overnight at room temperature.
At the end of this period, 50 ml of chloroform was added and the chloroform solution was washed twice with 25 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo. The oily residue was washed with diethyl ether to give 5.5 g of powdery N2-(2-di-benzothienylsulfonyl)- L-arginyl-N-(2-methoxylethyl)glycine ethyl ester.
Analysis calcd. for C25H23O N5S2-+H2SO3 (percent):
C, 50.49; H, 4.07; N, 11.78 Found (percent):
C, 50.22; H, 4.18; N, 11.51 (B) N2-(2-dibenzothienylsulfonyl)- L-arginyl-N-(2-methoxyethyl)glycine: A solution of 5.5 g of N2-(2.dibenzothienylsulfonyl)-L-arginyl-N-(2-methoxy- ethyl)glycine ethyl ester in 15 ml of methanol and 15 ml of 2N-NaOH solution was warmed to 400C and held at that temperature for 10 hours. At the end of this period, the reaction mixture was concentrated and chromatographed on 200 ml of
Daiaion SK 102 ion exchange resin (200-300 JIS mesh, H+ form, manufactured by
Mitsubishi Chemical Industries Limited) packed in water, washed with ethanolwater (1:4) and eluted with ethanol-water-NH4OH (10:9:1).
The main fraction was evaporated to dryness and washed with diethyl ether to give 3.05 g (62 percent) of N2-(2-dibenzothienylsuifonyl)-L-arginyl-N-(2-methoxyethyl) glycine as an amorphous solid.
I.R. (KBr): 3400, 1630, 1280 cm-' Analysis -- Calcd. for C23H28O5N5S2 (percent):
C, 51.57; H, 5.46; N, 13.08 - Found (percent):
C, 51.35; H, 5.63; N, 12.86
Example 3.
(A) NG-nitro-N2-(tert-butoxycarbonyl)-L-arginyl-N-butylglycine benzyl ester
To a solution of 28.4 g of NG-nitro-N2-(tert-butoxycarbonyl)-L-arginine in 450 ml of dry tetrahydrofuran were added in turn 12.4 ml of triethylamine and 12.4 ml of isobutyl chloroformate while keeping the temperature at --50C. After 15 minutes, to this were added 35.0 g of N-butylglycine benzyl ester p-toluenesulfonate, 12.4 ml of triethylamine and dry tetrahydrofuran, and then the mixture was stirred for 15 minutes at -5"C. At the end of this period, the reaction mixture was warmed to room temperature. The solvent was evaporated and the residue taken in 400 ml of ethyl acetate, and washed successively with 200 ml of water, 100 ml of 50o sodium bicarbonate solution, 100 ml of 10% citric acid solution and 200 ml of water. The ethyl acetate solution was dried over anhydrous sodium sulfate.
Upon evaporation of the solvent, the residue was dissolved in 20 ml of chloroform, and the solution was applied to a column (80 cm x 6 cm) of 500 g of silica gel packed in chloroform.
The product was eluted first with chloroform, and then 3 methanolchloroform. The fraction eluted from 3% methanol-chloroform was evaporated to dryness to give 26.0 g (56 percent) of N0-nitro-N2-(tert-butoxycarbonyl)-L-arginyl- N-butylglycine benzyl ester in the form of a syrup.
I.R. (KBr): 3300, 1740, 1690 cm-t (B) NG-nitro-L-arginyl-N-butylglycine benzyl ester hydrochloride:
To a stirred solution of 26.0 g of NG-nitro-N2-(tert-butoxycarbonyl)-L-arginyl- N-butylglycine benzyl ester in 50 ml of ethyl acetate was added 80 ml of 10 o dry HC1-ethyl acetate at OOC. After 3 hours, to this solution was added 200 ml of dry diethyl ether to precipitate a viscous oily product.
This was filtered and washed with dry diethanol ether to give 20.8 g of NG- nitro-L-arginyl-N-butylglycine benzyl ester hydrochloride as an amorphous solid.
(C) N6-nitro-N2-(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl-N-butylglycine
benzyl ester:
To a stirred solution of 2.33 g of NG-nitro-L-arginyl-N-butylglycine benzyl ester hydrochloride in l0ml bf water and 40 ml of dioxane were added in turn 1.26 g. of sodium bicarbonate, and 2.2 g. of 3-cyclohexyl-4-methoxyphenylsulfonyl chloride at 5"C, and stirring was continued for 3 hours at room temperature. At the end of this period, the solvent was evaporated and the residue dissolved in 100 ml of ethyl acetate, and washed successively with 10 ml of 1N hydrochloric acid solution, 20 ml of water, 20 ml of 5% sodium bicarbonate and 10 ml of water.
The ethyl acetate solution was dried over anhydrous sodium sulfate. Upon evaporation of the solvent, the residue was chromatographed on 50 g of silica gel packed in chloroform, washed with chloroform and eluted with 3O,o methanolchloroform. The fraction eluted from 3% methanol-chloroform was evaporated to give 2.6 g (77 percent) of NG-nitro-N2-(3-cyclohexyl-4-methoxyphenylsulfonyl)-L- arginyl-N-butylglycine benzyl ester in the form of an amorphous -solid.
I.R. (KBr): 3300, 2920, 1740, 1640, 1250 cm-' Analysis -- Calcd. for C32H45O8N6S (percent):
C, 56.95; H, 6.87; N, 12.46 Found (percent):
C, 56.49; H, 6.63; N, 12.38 (D) N2-(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl-N-butylglycine To a solution of 3.00 g of NG-nitro-N2-(3-cyclohexyl-4-methoxyphenyl- sulfonyl)-L-arginyl-N-butylglycine benzyl ester in 50 ml of ethanol, 10 ml of acetic acid and 10 ml of water was added 0.5 g of palladium-black and then the mixture was shaken in a hydrogen atmosphere for 50 hours at room temperature. At the end of this period, the ethanol solution was filtered to remove the catalyst and evaporated to dryness. The residue was washed several times with dry diethyl ether and chromatographed on 80 ml of Daiaion SK 102 ion exchange resin (200-300 mesh, H+ form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with water, and eluted with 3% ammonium hydroxide solution.
The fraction eluted from 3% ammonium hydroxide solution was evaporated to dryness to give 1.5 g (72%) of N2-(3-cyclohexyl-4-methoxyphenylsulfonyl)-L- arginyl-N-butylglycine as an amorphous solid.
I.R. (KBr): 3350, 2920, 1630, 1250 cm-l Analysis -- Calcd. for C2sH4,NsO5Si C, 55.63; H, 7.66; N, 12.98 Found (percent): C, 55.32; H, 7.39; N, 12.84 (percent):
Example 4.
(A) Ethyl 1 - [N0 - nitro - N2 - (3 - cyclohexyl - 4 - methoxyphenylsulfonyl) - L arginyli - 4 - methyl - 2 - piperidinecarboxylate
To a well stirred solution of 2.05 g of ethyl l-(NO-nitro-L-arginy1)-4-methyl-2- piperidinelcarboxylate hydrochloride and 1.26 g of NaHCO3 in 10 ml of water and 40 ml of dioxane, was added in portions 2.2 g of 3-cyclohexyl-4-methoxybenz-ne- sulfonyl chloride, while maintaining the temperature at OOC. The reaction mixture was stirred overnight at room temperature. At the end of this period, the reaction mixture was evaporated to dryness. The residue was taken up in 50 ml of ethyl acetate, and the ethyl acetate solution was washed consecutively with 10% citric acid, saturated NaCI, saturated NaRCO3 and saturated NaC1 solutions. The ethyl acetate solution was evaporated and the residue was chromatographed on silica gel packed in chloroform, and eluted from chloroform containing 3% methanol. The main fraction was evaporated to dryness to give 2.6 of ethyl l-NG-nitro-N2-(3- cyclohexyl - 4 - methoxybenzenesulfonyl) - L - arginyl - 4 - methyl - 2 - piperidine- carboxylate.
I.R. (KBr): 3400, 1735, 1635, 1250 (cm-') (B) Ethyl 1 - [N2 - (3 - cyclohexyl - 4 - methoxyphenylsulfonyl) - L - arginyli - 4 - methyl - 2 - piperidinecarboxylate acetate
To a solution of 2.6 g of ethyl 1-[NG-nitro-N-(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl]-4-methyl-2-pipeidinecarboxylate in 40 ml of ethanol, 10 ml of water and 20 ml of acetic acid, was added 0.5 g of palladium black and then the mixture was shaken in a hydrogen atmosphere for 15 hours at room temperature.
The solution was filtered to remove the catalyst and evaporated to give an oily product.
Reprecipitation with ethanol-diethyl ether gave 2.4 g of ethyl l-[N2-(3-cyclohexyl - 4 - methoxyphenylsulfonyl) - L - arginyl] - 4 - methyl - 2 - piperidinecarboxylate acetate.
(C) 1 - [N2 - (3 - cyclohexyl - 4 - methoxyphenylsulfonyl) - L - arginyl] - 4
methyl - 2 - piperidinecarboxylic acid
A solution of 2.4 g of ethyl l-[N2-(3-cyclohexyl-4-methoxyphenylsulfonyl)-L- arginyl]-4-methyl-2-piperidinecarboxylate acetate in 10 ml of ethanol and 10 ml of
NNaOH solution was stirred overnight at room temperature. Then, the reaction mixture was concentrated and dissolved in 10 ml of water. The solution was neutralized with 2N HCI solution to give a white gummy precipitate which was dissolved in 150 ml of chloroform. The chloroform so Various other N-arylsulfonyl-L-argininamides or acid addition salts thereof were synthesized in accordance with the procedures of the above examples, and the test results are summarized in Table 1.
TABLE 1
00 0 3 00 06 0 8 vl e 0, 8 % . X 8 aO S: 8 X N t 9 4 1d N Z N - - ~r o ~ ~ oP S c( a R t r: r: r: N ~~ N E; E; i Y > 4 O tv b X > e rO .t 1 H CO H rl w wt N N N N H -4 ~ H ~ cn 5 a g . o ~ so o < = Physical E d d \o' d r: t \o' d Sample so so O prolonr, the Prepa- o rs t .. --- ------- coagulation ration time by s process Lower: Found Ar R Addition tactor o; two d No.) d cm; noicty (,M) u o u z H N 1 l~ - C:2CH20cH:3 - 20 :3 33.82 6.21 1:3.08 :3,330, 1,630 > F & 4h oCH:3 :kaT: 2 -N - 38 :3 g*s e n o cn n 2 a0,% > o 1:3 e V ,o o 33.32 o co 1,630, o 6au ?1 o . , > r ~. ~ ; 1N0 I, 4' n b 1: u 16 rt: :Kf O tN j e X s . a X; 20 H n 2 -E NO I
~ 1 f fE o o N b 90 fiO \0 ts 90 0 nZ H H ~ H H ~10 o' o o' o ô o o' o O' O o' o A: H o o H o av YE tel o ax O ts H H2NCNH2CH2CH2CHC0R required to Prep Physical -t at 4 N F \0 n' c; r; prolong the a No. N Z CO 92 X "Q coagulation C0 r4 " " " " -l tine o by ls u Ar R Addition ractor of two m N ties n; N (cm ) -oiety t1 H r( (dr(0 O CH2CH2CH2CH3 g n d 32.70 c0 0 t4 Z \0 -1 0 71N' X 32.66 6.19 17.82 1,:380 b b O \0 N 3 CO 0s N ts tE S0 u g k o, 8 1≈ 4 yw Nm .:t I 5.70 15.84 :3,400, 1,6:33 bgS u\ n In n n u\ 4 Q 34.08 5.96 13.7:3 1,510 o 6r 9 N/\H:::2iiCH2CH:3 2 n a a a a oi d g rodu f3 hCA u\ kOObPO q\ -f re Q b 0, 0 v oLau I I (n l l 3,400, 1,625 r8 $ 12 x ~ 0 N m ON x O O X CX) X o 0 O rn D4 ."N 8 wN O zN 8 :? XN 8 = Qz Q o o o o o Q o cJ o xN = N g N N N JN N XN XN SeJ W O O O O O O O O Ox O cX .
X o < (g 0 O (0) = 0 oN @ e b X Ch O H H
o o o o o o u) o o ~ W O N u rv N x 0 ~ . | , H N H wi t4 ri H ~ . o' o o' r, o o' o o o' o' o' O ~ u rv O O en O La co YE w en H cn H n H E H en H n H required two H2x"'CNCH2CH2CH2CHCOR az the Prepa- Physical Upper: Calculated O (KBr) Sample E-N-O2-Ar' coagulation ration N N N O Found d No. time by a proceas ties (cn ) Ar fl a Addition factor of two (Ex. No.) C H N sJ r4 ()6X) tls X rs u o u rs b NO b b b NO NO N r( m 1 Q (ĬI"" 04 ""'c2coo b ob 3.86 N :3,330, 1,640 E Q Q O O b N O O 12.96 N 1,270 w @Z1 Z o vt u YE Z o çE Z o O fiO < 4 b .
14 %ĬOII -N CH2CH2OCH3 2 34.22 3.30 1:3.18 :3,400, 1,700 5' b ''4 H 33.00 A 12.:34 :3,400, 2,920 NCH2O - 0.7 :3 i ""'CH2CO2H 34.86 r( 12.49 ao gpld > 6.9:3 11.19 :3,400, 1,760 16 I, - 2.5 :3 occ2c2e3 5:3.81 ,o o X b u m d d 54.2:3 o S .
1 I < É 13 OH2- I' - 1.3 :3 w 36.39 N çO a, 89 O03: m o~z O O O O I C) O O O O N J f f W M0\N < 0 0-C X X AX @gE @ E H 4 H xo H
l o o o o l o o o ~ n so ew Z i n e Z b fiO H o fiO \0 \ b ~ t H H H ,4 ,1 - t ,1 . o' u o' o o' o o' o o' o o' o K u O An UE o O \0 O 80 O s n H Concentration 8 analysis H * ~ ~ to Sample H2N o ,1 Physical ri - t No. ration \o Lower: Pound Z P. o ol CI S N F? Z A R en n N by a process ties N N N O O Addition ractor or t,'o (Ex'. r4 H . t moiety N E (Y q ? o 3 J ;r V, a, r( o \o \o u, Y\ \O d \d \o u; Y; O gw NO SO MO Y UE u NO fiO aO fiO YE YS C--s- .
8 N o\ (V o Y\ 6 0 r 0 c aS; C; C; O 5 1 bBS y: f @ m u u u u n u u u u Z l | .. goF 21 ;- 1 l8, ;1 12.12 3,:350, 1,640 d O ejd* r? E ld rl (Y OoBe ey Rr 0 aPO n fB I I I I o vv CH2C02C2H3 48.36 .46 | !gg,a K N K C O , W0 S D0 S CS S 0 w N xN X Q ,,N N O Ct s0 ~ < 4 @ t o V1 @ ?\ 8 RO 4 (≈ X [ @ X iF Os O N É ;t t 1 N N N N N Ut
w o o o o o Lt o un o o o ~ N u N Ln N 8A N SO N SO -1 b N 5 O r4 XO r4 xO r1 w -1 ~ X 14 N H -1 H r4 -1 -4 r1 - -1 * Q O O O O O O Ô O uE 2; Ov O ~~ YE t n I O SO r4 ~ tN -1 r4 rt ~ ~ 1 r4 Pd a X O Concentration c\ r; n ri ~ C0 N t.9 NO 4 ""C-NH2CH2CH2CHCOp require to prolong the H -1 N N -1 r4 ri r4 No. Q H-N-SO2-Ar coagulation r I.R. r -1 0 h by r a process CN o , NuFound Ar R Addition ? of two w fiO No.) C w N (cm1) a b h UE \o \o u\ \o \o \o \o a Q m O r( n u, Ir\ n co m co rat \o rr\ m o a -I -rr u\ cu o r( o s s " d d Y; \O C; r; C C a; rh n h u\ m u\ u\ u\ u\ u\ "Bg d o .
R 4, 4; 0.1 2 33.46 3.36 12.47 3,400, 1,623 4 b C r4 r4 YE -1 s r t Ok d d d d 0RA 09 {i ~ ~ | ~ ~ 29 OO S? - 0.6 4 38.08 6.31 13.62 1,383, 1,160 ) 59.18 6.30 13.27 3,330, 1 610 30 0 I? - 0.1 4 '1 g O C N | ~ so 31 = < @ 8 7) O (f ) co ts1 0 @ t X X X X X X @ a it. N No N N N O
H o o o o o o o ~ fO rZt N Cs N N :t b~ SO b \0 C't fiO w tS 4 r4 r4 r4 rl t1 ~( r4 r4 o O O O O u O O O O O O iO C-N-CH2CH2CH2CHCOR Z r4 ~ S 0, 4 N r( V) n ri coagulation ration Pbys . X R KBr e g CE X ri O n Os F O w u o S? m o n o\ cD rpr o \o n aD ?a ri I r( li -r c( cr~ 5 fi ~ 4 5J o ao N \o 1 \o n.
51.77 cry. 3,400, X * * r( V u Y u u fiO \0 N tLs tw b s0 th B1.
%t 00 Y) a C02H 53.63 5.22 CE it 1 b vO fiO s i1 ll u u | u m u u YE U sV . . r da "n?i 34 H - 4 57.32 7.66 12.38 3,400, 1,620 4 4 < t 4 > $CCPIPoX v\ s6.60 d O s ;11 h s 33 r1 ti0 E 36.82 X I CE3 0 CO2C2H 56.85 6.84 11.05 3g400, 1,740 36 x 9 O (p cH3c00K o oN o pv n 4 B x < A} 8 X WE = S @ @ @ 2 N cO Z e .
o u o o o o n o o o o o ~ xO < fE vO NO rt sO t vO rt N Z rt4 r4 rt r4 r4 r4 .-4 ri r4 r1 r4 r4 r4 tt \00 oO O m ts t 4 tq 4 4 st cn < > > :t < r4 r; r4 r4 r4 eo r1 SO fio H Concentration u, m \o r( u, h 44 required It 80 4 to R5 \o' \o' \o' \o' \o' Sawpl r4 rt r4 r4 prolong the Prepa Physical Upper: r4 r 4 ; ration I.R. (KBr) 9 'd-N-502-Ar tine 5 a ci proper- Lower: Found I Addition factor of two cn No.) ties (cm ) Ar R tv : moiety dd dd dud C H N CO2H sO sO xO CO NO 54.74 NO fiO 3,380, sO CR E e e aab -1 -t o :t o Z cn u 37 3N -NH - 0.5 2 powder 1 s 1.4 3 54.81 d 16.43 1,460, 1,373 / n nn nn n k 54.74 + 5 3,400, = : = r cos 0 CE3 54.o 6.23 16.85 1,460, 1,380 I e ad U cu nr - 0.25 2 w N N N N N N P. z CH3 44Jl o < 49 4 4 wo 5 eh a 2 2 34.74 u r; N C 4 0 :% 16.63 b s O O O N 0283 d d d N ocomrt E8"S l CH31N,,,, ,' 2 35.58 6.61 16.21 3,350, 1,620 0 > t vV l l l l 35.38 6.61 16.21 3,373, 1,620 42 II 2 ;-E 6" H3CH2 4oX 5: M = < S e S 4 e n e p ZQ o - Z > Z > Q6t O o o 3: Q n o rt N
o o o o o o A o ~ tA CN N N N N N t 'd t w r4 aO r4 XO r t fiO r4 (t 4 ld r4 r4 r4 r4 r4 r4 r4, r4 r4 b 14 HNH Cwcentration C-NH2CH2CH2CHCOR P?V)rl rt o r; c; I prolong the ri r4 r;;r; C' r4 r4 I.R. (KEr) No. H-N-SO N coagulation r4 proper- Found " time by N ee N ls o Addition factor d two \o' d No.) Ar R ci m (px) C H N rO 'rOl ii rt 3 O YE r4 r4 4 líE N uE iIt x x N r4 t1 O 4 uF n 1 r4 4 N 43 N"'\ sO 2 fiO 33.06 6.20 fiO 3,400, 1,630 0 11 CH2COOH 32.81 sO r4 O no ------- 1,383, 1,130 i;l s S 0 c; d c; d d u\ Y\ 1 n Y( Y) VI V\ 1C\ Ln rt NCH2CH2OCH3 2 31.00 k b t V 4 > -,N1,,, CH2- 2 33.91 6.41 13.72 3,400, 1,620 I C t ffi e z b Vd b N N N N N N 0* b r.4 ooh 51.93 6.34 16.3 3,373, 1,625 4 52.21 6.35 7t rc'd Fh IPIM(dpOr e n rt bO lEi O 2 powder 34.20 7.32 16.49 336o0oroa) 0 F 4 t CO0H 4sst 4 l 48 NH2 'I 2 1,60O(broad) ge " R o o e 14 o :: [3o g Aq g$ O~Z A Q O n xN S t $N t N | tt i j; 5g ut 80\ F xN t n : o = B N eZ < ~~ 4 <
~ tl a a ,: i r X e X t4 1l1 Cl IS S d 4 t5 ed p4 O O O O O O O O O i: r1 1s S4 S ts Sq S.1 Sx S4 P D D :1 o o ,Q . o 00 00^ o oc^, Ooun o̲ P: ~ uAt 2G aA rt CO LA N Lt O O 85 O O a, XO -1 o Concentration Elemental analysis HN H required to X ja oX rt N N Ol E Pt v \ rt Sample RN C-N-OH2CH2CH2C.HCOR prolong the :'repa- Physical Upper: O O t 2 H-N-S02-Ar coagulation ration proper- Lower: Found ion (xBr) h Itl t so v Z at Z o tt n n 4 J a ~~ .4 tt rt rt r4 rt rt rt rt rt ri rt process tis (cr.1) d rt . :i N et O xO r4 NO at XO vO t.
IAr R moiety NO d SO H \6 N m F dd dd dd d I I 49 H e; 2 powder 54.20 7.32 r4 N fiO SO I %S " , , COOH 34.11 7.11 CO Z N E ;d I I r4 1 t4 7 t e e f = = a "a 8 I a I Ipr; I CO r e z 30.63 1 4 14.32 1,155 OCH2CH2OH 841;7 30.49 6.66 L 9.,00 broad ia'3' '0 1,600 biond MPoZ 50.28 6.35 13.89 1,155 33.61 6.56 13.03 3,300 broad 53 ",'H2CHOR 2 1,600 broad CE3 53.42 6.38 13.01 1,133 h-1 l l 33.26 l l 13.43 i 33.36 6.87 13.21 1.155 CH2CH2CH20E ev ≈ N S : O S O~O > rz 14 tr s = 8 3N S 4 ,~a > ~ 2 > t > O 4 ~8 45 USN e rt SrY 4 Z 0 ru C > e Z Va
o a ~ t X X fa b al et so 0 0 at (tt al ~ o o . ~ ~ o o 4 rit .0 ,0 rt rt rt t fbo E F r O O O O O Ln Concentration Elemantal 'rS o U1 -N-CR CR CE N 4 N < n NO rt Sample H N222 < ~w the Prepa- r4 r4 Upper: Calculated Z.R. rt r4 Mo. a H-N-S02-Ar coagulation cn proper- Lower: Found fiO Addition factor or two Z cn No.) 49 Z * e e e @ * e s 0 Ar time by a process ties (em ) R moiety r1 rt rt C H N at ,S N ~ 4 rl 3 so r- t crs 4 O N CO eO rt lit o C 0 9" Q 13.43 3,330(broad) rt O t4 O e w . @ 0 w . * w w 0 Z 0 0 tS b 2 d NO NO u u o u I (u é b b E COR 55.11 6.67 13.39 0 rt \o rt 0 rt 1.135 P, at cu re n oc ri o \o f- r? u\ cu o\ Z%5 U Y; \o' \o' c; o; d, a L CH2CH2CH2CR3 56.39 7.82 os ov ts rt u 88 . 88 g Ln u 4 4 4 4 8 k 8 La a 1Z et o t rt N rt SS4 z S ^ S 58 'I - 0.4 2 C O ~. f o SPS $e hA YL ny g v > t YE ; X Cs dt t X 4 2 1,620 tZ b t 0 4 0 48.22 5.23 11.72 3,360(broad) 1 1,620 A 47.99 5.21 11.56 1,155 7 0 b =n n ~~ n OX tN X o X 1 = OFtJ o t0 x A X t 000 t o 00 O çO S (t J ot oN lP t DN ~ oN Oq'
<t
- o o o o o o o ~ X n N X n N t. N gl ~ 11 fiO xO t9 fiO rt O rs > It b rt rt r1 rss rt rt rt Z O O N O O O u O O O O O O O ~ o fio r1 Z rt ^s 3 XO O O H. Concentration eO rt n rt trz rl HN required to Sl e Co Cq 2 "'C-H2CH2CH2CHC0R prolong the Prepa No. coagulation ration r( ri ri Upper: Nt x \ rt rt H-NTSO2-Ar proper- Lower: Found Os time by a Ar R Addition of two 4. rt N, rt O iciety u C fiO fiO tis t;s NO fiO N ttt b b . ~ E e : ;r rt Os Z Os N aO rt fiO 61 SS > N N 3 N CH2CH2 2 59.24 5.86 N til 2 3 O 39.24 5.77 12.33 1,132 ke a t ~ - - . - - YE 62 ,,,,iI -NI 2 \ ~ 63 V 2 34.74 6.39 16.66N N b Xb b OP) 01 1 wOO-C'O'' 7t4JS 0 dv @ V 7t X v 2, R o X o qc" ~ N 50.41 6.21 16.11 1,380, 1,120 OH3 66 7 CH2CH2OCH3 2 30.36 6.15 16.02 3,400, l,6O -" 50.28 6.09 15.98 1,380, 1,120 S ON g O ~ 0 O =N S 8 O X X O S/ O St A X X X X X X N l; l i; ≈ IZ yX .
* XZ 1 8 ( 3 ! 2 g g So l =g tS t X a,o w so fiO sO w |
t v d cA m r cA cA S:1 X 1t xo r1 xO rl Sx 1 S4 b S 1 td b rt rt . o cn o o o o o o o Ir o rs o o n o n 11N O o c~ Xo H cfit NO o Elemental analysis required to . CN -1 rt CN r1 f n 1 ~ prolong rl ( > rs Sanple 112N ration Physical Lower: a, - o I.R. (KUr) 71 @ O O 4 time by (9 o \o u, proper- (cn1) ; Z Z 4 n CA CN CN CN CN N N I n Ar R Addition factor of two (Ex. No.) o; C H N ?a, I ri (pN) I s S 33.10 7.09 ts r: r: r: I r: X s 1,630 32.93 7.20 tD n b z 4 tn razz (5 14.00 1,160 0 c; N C; N N 53.98 7.29 13.69 Y\ L V\ In m u\ 68 10CHCH 4 1,620 -L @ X 53.98 7.29 13.69 3,300(broad) S ~~~ I' - 0.8 4 53.71 7.21 13.28 1,620 1,15 @4oJJgtzdo > 13.27 --------, N\OH2COOH 52.27 7.19 13.00 1,255, 1,155 s Bg3 d o 1 co pO 0 72 CH2CH2CH3 I CH2-7) 52.41 l l 12.46 l a ~ cos ~~ 20= ~ C0m xN tÇ ; = = 1 8 = 2 1 8 24#7 T ~ do b 4 4 o Q ,{ . t CL O H N E g xo xo t ts rs rs
o o o u u o o o o u n u ( u WN \9 n xO CN t N ~ MI rt aO rt aS rt t.9 r 0 r t fiO m rl r1 rl rt r; r; rl r r; r; ri E o o o u c o o o u uo o o . o o u "o Yo o so o vo rs u o rt tC ~ t.5 N e~i N st N t N o N CN rl n c\ r( o n c\ n n Q H required to c\ n n ao 7t e u N ll the v Physical Upper: c? ? ? q Sarple H"':02-Ar ration proper- Z.R. (KBr) ,r time by a process ties r t rt ,1 H ,i ,t 1 , 9a " " I: o" P 7 r t Cl n SO F NO o N9 rt N O Ar R t N r t N O t 3 N n moiety m E: r; t: r: d d 0 1 I E CE3 tD t rt t d 7.23 13.58 3,330, 1,630 e De > N N n N rl 0s N 0 1 0\ 73 ,'," C'HCH2CR3 ; 6.4 3 rt rt a > :t X N 31.24 7.23 13.58 3,350, 1,630 t b # ~ 1 7.26 n n ffi 1 AA V I 76 II -NH - # 7{ t 54.97 7.48 13.36 1,260, ts e k C EoZ o b pj 8 o k I 77 1 cozy -N . 4 3 32.95 7.31 13.15 1,233, 1,143 CH2C0oH 71 C:i3 ≈ | l | l l I I I 78 OcH2CH2OCH3 . CH2C0OH 43.93 6.90 13.48 1,110 O rnf~ a St O C)z = = Cg = Os+ X X = mN xN 8 xN xN xN XN ~ ~ O O O O k & O O Q O X V ~ ~ Xn Xn R \ tA X Xo X b oX > oxT,o = o e X 40 ~4,wO O O el m n b tes t tto Ctr e Z ~ I S ~ ~
o o o o o o o o o ~ AO N uE xO rl \9 r n n tXt ~ rl r; ri rl r; rl ri rl ri E o o n Concentration uo o o o n u\ o' o 4 required 4E Z to ; H2N"'CNH2CH2CH2C1HCOR prolong the CN Physical CN Calculated ,5 (KBr) P coagulation ration proper- Lower: Found ri No. time by a process tieS (cm os 71 Z of two (H:. No.) 9 H u Ar r1 r r S r r: rt N N) ap 5 a s n o g m o o N VI \O Y\ qg q) \6 y) y q b b ~ g e n fiO r1 rt eE Os 0s eE tr AO 0s in t o . Y\ \3 r( r( h C\ r( V) O\ In car n, \o n oo re a\ ri i % IS 0 Y; J c; 1 ", 'Yn S\n n Y\ Y\ L YI Y\ V\ 1 X 82 t o ,ti )4cE3 t n t 36.39 7.83 12.65 3,350, 1,620 36.43 7.83 12.49 2,380, 1,130 e,,2 gnOgiO7 rt o 83 10 N\CH2COOH 84 e | | H3 | | I I I I I 9 N w : E n ~ n e n 3 / > 0 , xo 40 in ~ o O /o ~~
o c o o o u o o o Y -t m E n so n vo 1.t xO b rs so et sO so .s so et fio rt .1 , i ri rl ri -; r; r; r i ri r; O O O O O O O O O tS ~ O n O n en 1 t i r1 CZ x N n rl / Concen'traticn g rt \0 n co to Elemental analysis * prolong the \0 \0 0 a d Z . t H-NrSO2-ar coaaulatioa .; Physical N Calculated tint by a process proper- Lower: Found rt (KBr) if ot X ~ ~ ~ No. Ar Z O 4 factor of cst rs ts so moiety n ,{ O C ,{ H p: N 5 6. 0 0 Q\ \0 (7 (D (0 \O n QI u\ n u\ Par o C N. ? C: n \o i$S x S $ # a Y; in sit e X O Z X :t :r ts rs N ot r m S; o u u m t S Z u -n ue uo u -t R OCH3 COOH 34.48 7.04 12.63 1,630, 1,130 87 )3CH3 47.58 x -* zss F4lrppl 006 9 I rlrrEoal+r iSEO o'31k eO rot Z aj | ((u:)33H33 b i3 0 t 3,410, 1,630 oC > s X .. o o I I I I Zg -(CH2) 3CH3 , 4 55.35 7.77 12.00 3,420, 1,630 . )3CH3 ~ 7.96 11.82 1,260, 1,163 f o Y cn eq in n n es 1 g srO XO O \ X X N N N N N N O Z Z O O Q X X v n = X o X sN b \ I / O O O O O O ~ < o n oo n i 1 en Q Q Ox < X o < 0 o < 41 '3 ars so is ua ov o
- o-os l ior- coF o t4 fio fiO 0, Ao O AD So sst i rt I ,{ " ,1 i . , O O O O ' O O O O O YE PS ~ CE i m aD O 4 e*. st t O W e~. r j ~ ~ n j en r; n ri H 0 z Concentration HNCNH2CH2CH2CHCOR ee N ne Elemental analy8is Sample i o; Physical Upper: .1 tt N N No. H-N-S 02 -Ar pro long the Prepa time by a process proper- Lower: Found I.R. (KBr) Ar Addition factor of two N O . ie in r l moiety ( x) C H N e b b .
= 10CH3CH3 t CH2i7)0 8 n 4 o 7.36 fl X ~ Z Z 54.03 7.81 No NU A 1 51.68 I e "x 3 - 4 s < e~ ~ iAS t 0 Z eo 4 e eq in n, X 34 i- i < 1 4 2%4~ b b bO 4 n o X i rl O a b e n et S E 0 o b 0, '1:1 É i i l l l O X W Q O X X 0 Z 0 W g; x # C o o T Ox o n X X i4 w 4 8 = : r
o o o o o o o o o ~ N N n CA OX CU 0s N ea b fio so \0 \ \ < 1 0 @ ,1 .1 r; r; ,; r; ~ j r; r; . O O O O O O n o n s: yE os m m o oX iN to m u uE u . in o Z :t o o uE n Z o Z ,Y I (X V\ Y\ r: Elemental ~ H n r( n n n n to Sample R2N C-N-CH2CH2CH2CHCOR prolong the NO n A5 s coagulation ration Physical in n Calculated o (KEr) No. time by a .; Proper- rl r( r( Found 1 ,1 t4 factor of two (Ex. 4 ties r4 r4 ee 2 r ~ Ar R moiety O ,4 O m " N d 12 -f 'V ao re 0 \0 \O V? V) V)V) Le 6 r 6 C X Bt U c; c; P, ao n c n n u\ u\ n n n n m L? I I V\ 4 Y\ I n j;-41 A S 4 Z Z ca n n n n n n n n cn n n n n n n n n n n 53.28 7,28 V I $ a el 53.72 o Z 4 eA4 . n en n n a 4 r eS b m 06006 9 o4 el 4X 99 CH2CH2C00H 55.49 ei 11.31 1,580, 1,090 o,lr 55.33 g b ~ b 274 100 ~ C,7 33.21 6.75 11.34 1,433, 1,090 101 ,,,,,,,, 00H3 -NH3 I . . 53.30 7.41 11.96 3,350, 1,620 0-(CE2)4CH3 w X n 1,433, 1,090 00H3 COOH N x X X ) XN U = mN xN XN XN < O x 3: o o w o v o o o o o k /Lo mN @ ffi s Is os o O H 4 uX - P
n o o o o o o o o n ~ N 0 n Ov N N Os N n b \0 0 so o ao 0 0 19 0 es # ,l4 ,4 ,4 ,1 Elemental analysis g - * H required to Prepa . o o o o 45 H2N C-N-CH2CR2CH2CEC0R prolong the o o cu H 1 2 -f, S (K:1r) H eo 4 Z Z t O ~ t t so t \0 No. E-N-502-Ar time by a process proper- Lower Found -l Addition factor of two o so ties N (7 ) Ar \O FEZ (Y P? ( O N 0s H IID m \0 N > ei 4 ,4 N N ,4 ,4 ,4 ,4 ,4 ,4 O O 5 C ~ Os UE Os N YS n :t O r4 Ch UO ,7 x u AO X b o os o ,4 n t vr w V b b sD fiO NO uo ts N fiO fiO b l E e so w n os so os o os os n r4 D. "13 O O ,4 N F N t O N \0 vr 1 eo 0 3 Z ;t O O u Uv ,4 ,4 \0 \0 N N ~ g W n n n n t Z n uE 4 x =s n S7 b 7V I C a O @ 74 0 t Z t Z n t h4 vza el | 4, 4, 74 b Mo* ow u t r > . H o ~ | 3 Xa 0n l n 14 N N er} 8 \ oX oXN O B Zx Z e x - n N X en xQ X X ~ 8 0 8 0 8 8 8 8 c^w 8 0 er 8 0 n t~ t~ r m r X s 8S m W N
o yE o uE o yE o u o o ~ N N ue r4 u N u N U O n b fio so r1 fiO r4 w r1 fiO r4 t7 r4 iG 4 04 r4 r4 r4 r4 r4 r4 r4 r4 P4 n: ~ o o ;r t X o o X O X H n r4 ~ ~ n eo tS CO n ,4 n ,4 er ,4 E ,4 n r4 f ,4 H " c; n' r; c; 17 to Elemental analysis Sample prolong the Prepa r( r( ri r4 coagulation ration Physical Upper: c( I r( No. time by o process o Lower: ound Addition factor q two O O N o N es Ar R j PI e b 19 C rw H N g b b 8: 1 I m g I m6 8 108 .l O ; P4 Ox b X b r4 13.32 Os Is 1,623 u n n n n n u n rs n n nCR3 COOH 34.15 b o CE3 0.2 2 53.98 7.29 13.69 3,340, 1,620 OCR 'CH2CH3 53.77 7.09 13.38 1,380, 1,153 110 (H2CE"'CR3 S 0.1 2 33.98 ce 13.69 3,340, 1,610 53.79 o 13.81 1,380, 1,133 O O C > ceXlh rl 3 YI arobrror cu e.k d d d d o al-troEov I 53.71 7.08 13.72 1,380, 1,155 113 1CH3 CR3 b 0.6 2 53.98 7.29 13.69 3,300, 1,600 S :x: ; X : = g g = xo XN ~ ol 3: xn s y é s s n 3 n n S n n w-G X 4 4 Q Q @ E Z ~~ o ~ N n
o o o o o o o n o o n O b 0 1 aO r4 no r1 fiO r1 o t r4 YX Q r4 r4 r4 r; r4 r4 r4 r; r; r; r; r; r; E H Concentration Elemental ar'alysia C'--":H2CH2CH2CHC0R n u to Prepa H I the ration Physical Upper: Calculated ri (HEr) Sample 03 coagulation ess proper'- oc Found I No. time by a proc \0 t N ts ) a N' X o; factor o; two (. n N Ar R r( ri ri N N r; H N 5 1: 5 o\ \o co n c\ ob o\ aD oi wa r1 3 Ov Os XO t 't en t Ov N 4 o o o b t u 14.08 n ao re 1,620 114 X x b t 2 e rs b ~ 002H5 33.08 o 0s 14.11 1,380, 1,150 o ao c o\ n o o v, n ri X (CH2)2cH3 2 33.63 n 12.98 3,320, 1,620 "" 0(CH2)2CH? 35.59 m 12.99 1,380, 1,130 R n I o, or I Ic= o,S ac, cu aa I 80m peA0( 6MPOr atomEk 0 0 I0H3"'\CH3 0.1 2 X 7.48 13.32 3,350, 1,615 - + CR3 :e: Z O N N n n N X X X N b o ~ N N Xo X N O O ~ t 0 X X O n \/ X CE n \/ 30 n s F X om 8 o x mo xo xo xo ox xo xo 8 O O o b/ òw On @
o o o u o o o o o o o o b 50 ,1 ~ ~ 9 > r1 N fiO xt7 r1 aO r1 # r r4 r1 r1 r1 r4 ,1 r1 r1 r4 r4 r4 r1 P: u n u so n eo C ers n a7 HN4 -- Concentration Elemental analysis % r1 n r4 CE r1 o r1 n r4 required to Upper: Calculated O X 0s I n prolong or \0 r \0 the Prepa e H-N-S02-Ar coagulation ration Z.R. (KBr) Ne. time by a process proper- Lower: Found S factor of two (H::. No.) ties (cm1) Ar R moiety O o, Z .1 r1 H N S 0. N elE N CE .0 4o N CA Z e-s O O S CH3 to 33.98 7.29 13.69 3,350, 1,610 1 > b b 120 a 002H5 e 2 33.99 7.36 an O SO Os u e A > os os N O ,1 YE t e \ so t ri O O @ * * * * * s CR3 COOR Zl 121 Ca 00H3 2 > ' b < :8a 122 0(CH2)4CR3 2 33.15 7.57 12.86 1,380, 1,160 p+rU N 01 (Y A 123 0CH2CR\CH3 0.75 2 32.43 3 12.26 1,380, 1,160 00H3 S e rf 33.30 7.41 n, 0N n 82f " OCH2CR2CR\CCHR33 A 2 53.36 7.35 12.01 1,380, 1,160 00H3 b < @2 "P ''CR3 2 b X xUl xnxo n n xn xo o\/o X N X X O O X X / u N N O O m u e Q 8 =o X X 2 8 X ~* 8 8 e n ~ ) 4 b o ~ r4 @ O r l N o 4 u e Z rN4 N1 rN1 rN1 r4 rN4
o o o o o o o o o o uE ~ r1 \0 N N. a0 el uo N u N n b so r4 \0 \0 r4 \0 r4 \0 ,1 90 r1 R rl1 1 1 r1 1 r1 r1 r1 r1 r1 1 4 . o o o o o o o o o o o o o o: u 0 o u yE 0 o 0 ua 0 uE 0 H' Elemental analysis to 2CH2CH2CjHCOR cn r1 n to o\ \o u\ 2 H-N-502-Ar prolong the oo coagulation ration Physical fiO Calculated V Z N N by a N N o Lower: Found I 4 r; Mo. -I r( R r4 r4 ,1 r1 r1 r4 of two (E't. r4 ties (cm) 11 rl za 95 Y, rl OI V) y 0 f m "O O: N' O! id V) V) e t f- pe e PI Ce t Ce @ b b Ikk O m r' 0\ 3 0 T' \O 0 Q) re n N O Q\ w" %S O d d ol n; c; r; c; c; c; u\ u\ Y\ Y\ II\ Ln y Y\ I YI p A A R I X (OCHCR3 b s 53.98 7.29 13.69 3,300, 1,620 4 t4'iSv- m f E 33.30 N 11.96 3,330, 1,620 okau 6 4 7.48~ P oN , Do oX XN N O t V O mN AX
o o o o o o o o o o o o ~ N av N 15 N u N bt N UE N 4 b sO O fiO r4 vO r4 0 r1 fiO r4 AO r4 ae r4 r1 r4 r4 r1 r1 1 r1 r1 r1 r1 r4 r4 . o o o o o u o o o o o o yE ll ~ b r1 u r1 f XO :1' n H Concentration r4 CO r4 eo analysis qa Sl en OH CE CHOOR to Rio prolong the Prepa- Upper: Calculated C7 E-N-S02-Ar coagulation ration physical Lower: Found ee eq r4 r4 r1 r4 r1 r1 r1 r4 r4 r4 r4 r4 r4 r1 C C Addition O of two es so No.) ties r4 (cm1) Ar time by Q :t N \0 YE proper moiety o b b C H N od b OR2-(' b ~ 132 0(0H2 ) 3CH3 2 so 52.46 7.08 r4 1,410, 1,090 Bat Y\ N E? N tt T $ s S 0 u\ y\ y\ u n n n "'CR2 ",, n 53.06 n n 3,350, 1,620 -l b b Av C e o r4 r4 r1 r4 r4 r4 134 CH\ 1 b m c o 135 I - 1 0(CR2)2CR3 25 55.56 7.58 12.79 1,380, 1,130 C (d oE N olre oC 2 NCR 54.83 7.48 13.32 Ps04Jt 1,620 136 0CR2 )2CR3 3 1 54.90 7.41 13.29 1,380, 1,130 CR3 COOR 17 (CH2)2CR3 'I 1 34.83 7.48 13.32 3,330, 1,620 f a o O n n n n o ua- l o l o o o o X I 1 N N N N s l X X X X X X C A X C X C X : of n xn x n o oX n N ON B \ eo X X ~ ~ N 5 Zcnl b c-t X O O o O o o e X < o cn 8 - ox o 8 ~b~50 4 Wo o W @ ~ ~ n n n w ~ The compounds shown in Table 2 below are prepared in the same manner. In this table, the prior art reference cited in the second column discloses a method of preparation for the compound listed in the second column.
TABLE 2
k p: C"B I-\ 9: 0 1 0 0 0 r c cu c oi EU h) uu or ArSO3H Starting material - Nil - (CH2)3C1HC0R c, or salt thereof H2N0 llNSO2Ar (Literature reference) Amino acid ester Ar R 1 a SO3H ,,,,, C112-Fj) NCH2 I OL=43 0 Ber. , 1663 2 ; SO31I n n (d Q, h h m Ber. 26, 996 3 Q 5O2C1 IU V o "e" V'V (Vhl EVEV CX p. 5500 H3CO Z \ / C102S C112-Fj3 0 73 4 HN/ N""OH20 - Wn n chim. Acta., o c? c\ h, o Y [ 3 4 t) so o > e Q S wNl m tz v jeo m :q E cJ > Cz m
Product ArSO2CL or ArSO Starting material HN\\ C - NH - (0H2)3C1HC0R No. or salt thereof H2N IiNS02Ar Hof X L i M; 0 1 v 3 q H 5: Ber. 8 12,r4 (1936) 000C2115 z l t z 2 cN O Z ) O U S0H YJ Zhur. Obschei Ichirn s4 866 (1952) C0002H5 6', F, C0OH 7 H1 O HNs Uo 2 oN M o Q" 9 "" Zhur. Ob::chej KIiim o 866 (1932) COOC2H5 F, 3 o ,o 3 e 8 ClO2S 6',N 011 HN CH2 D:16'N OH 6'CH2 h; Patent Published OH N 011 CH2COOC2H5 N"' CH2COOH 26975/1964 J Z^ F3 C Nl V NNI O S4 < S4 g X . m Zf l Z Z X g X = X - H h H X A A S1 fz \=/ N O X tn n uz Q l O O n S; S1 51 V S O N N z uE, Xo rW
Product ArSO2CL or ArSO3H Starting material No. or salt thereof H2NC - Nil - (C112)3C11100R HNSO2Ar (Literature reference) Amino acid ester Ar R L.; OCH3 Az llN""' = 9 Ber., 86, 951 00011 10 Ber., 0O0H3 C00C2H5 000113 c SO3ii - 'cw"',"'','1N1 86, 951 (1953) I rl k Zhur 3 1N HNm 1"",N -N) Obschei Khim, 0 h, IrQ "' 00011 12 sofA""' HNCH3 3 9 - l on O n = ~ n on o 91 h oH oU zA om QS C >
Product ArSO2CL or ArSO3H Starting material IIN""' C - Nil - (Cu2 ) 3C1IICOR r;R i A N l l l sol ---------- Ar R t \ s 8N g X ; --- - 2 H5 COOll 22, k S E a 15 SO 3Na HCH3 O e C N b N ; N a o m ClO2S,,,,,N;%%CONH2 E 1",""'C0NH2 -NH3 0 0 Zhur Obshei Xhirn 18, x Q m i 1 X N Z S O S O U2 R O \~ O = \ N 9 & O X ~ p:t C sN , S0 V V C) .
z N ArSO2CL or ArSO3lI Startin material - Nil 3 No. o salt f Q o o = reference) v Ar R V z )iDrs' h t3 h V h rend =( csl FU t 18 c m m o l X oi m 02 Sz AD rend 198, 2260 (1954) COOC2H5 b S0201 E fa $ $ $ v ud J. o A ov Eng. J)ata ovo oh oN SO2 Cl CH5 0 C113 E rfl J. Pharm. Soc. Japai Z2 1878 (1953) C00C2115 COOH @ oo CA v O J V o O V ~ o o ss N H z H so cM ; sq ; b: fn ~ en > am @ \ O \ o R ^ h n a n fi O o w \n/ 4; x cx 7 < ( -1 | rn | V =\n ~ Fr\n o o v lX H D . 1 o tnz ; o M c Q @ < Ej < D n ~ h R o ; X X V X v v n Y b co a o zi H ~ - H c#i
Product ArSO2OL or ArSO3H Starting material H21""')C - Nij - (112)3C1}lCOR No. or U O U 5U a reference) Amino acid ester Ar R I CO2C2H5 NH COONa 21 N liN i2 -N Z Pharm, Z Japan X S (1938) C02C2115 X COONa H 22 (%1N HN-0CH3 (N'1 -NOCH3 SO3H U.S. 2,476,541 COOC2H5 COOH 23 ()N HN/myMCH 3 (D1N11) -N-CH3 S02C1 E ; 25 Ci)OH o Pr. (2) E 75 I SO3H 24 SNNH2 HNH3 H cO c7 Photophysik Photoohem, ; 3 (1963) COOC2H5 NH2 COOlI Ocq v I $n t t ~ v ~z\ X A O S n "[ Wrn N0 v no O t o =1 n v v Z z A
Product ArSO2CL or ArSO3H Starting material ci = No. or salt thereof H2N'-"'C - Nil - llNS02Ar c reference) Amino acid ester Ar U SO3H 25 il3C0%(y 8e CiHi33 H3C0 )Thr) -N-C,i \- CCHII r Gen. Chem., = Z94 SX $ 11 H - - o Ber. 86, 9'sl (1953) COOC2H5 3 COOH NH H 27 HO3S1 HN CH3 N -N Cfl3 CH3 CH3 Zhur Obsohei IChirn, 30, 1218 (-1960) C0OC2H5 COOlI o O Bull. Soc. Chern. France, v 466 COOC2H5 H COOlI X H rn X 31 > S; t 4 E 8 S 4; O ~ rn aql rn = rn 1 V O O ~ $ D O O r: h 3 Z A c1
Product 01 u H2N I No. or salt thereof }lNSO2Ar Az- reference) Arnino acid ester Ar R 29 502C1 otzx "" Bull. Soc. Cliern. l'rai:ce, 19O, Wv COOC2H5 COOlI 0 0 30 02N yr{1 ---------- CA 62, 14675b C0OC2H3 02N H COOH X QL)i̇;Na HN%cH3 7 m CA 26, 4723 C0002H5 COOH 32 02C1 i12H5 """''''N""'""' E 2 5 d Am., Chem. Soc., X o rn H0 W O V 4 e O =tZ ~ rn X R rn CM tR < v O / J \ / o o o r n~(2 > < < OO OCa @ V ~ rn O 1 01 E m < : < : ze z-- ron
ArSO2CL or ArSO3H Starting material 1iN\\ or salt thereof (Literature reference) Amino acid ster 35 NN)D SO3Na HNC5H7 NNF -N-C3jj7 CA L+ 9063' COOC5 COOlf 0 ocA v < ' ~ Tn a, a v Yo k CH3 O CH 2 . C 8 t S o=N 1,1 L II 135 E < olO A Example 5.
Tablets suitable for oral administration
Tablets containing the ingredients indicated below may be prepared by conventional techniques.
Amount per tablet Ingredient (mg) N2-(3-cyclohexy1-4-methoxyphenyl- 250 sulfonyl)-L-arginyl-N-butylglycine Lactose 140 Corn starch 35 Talcum 20 Magnesium stearate 5 Total 450 mg Example 6.
Capsules for oral administration
Capsules of the below were made up by thoroughly mixing together batches of the ingredients and filling hard gelatin capsules with the mixture.
Amount per capsule Ingredient (mg) N2-(3-cyclohexyl-4-methoxyphenyl 250 sulfonyl)-L-arginyl-N-butylglycine Lactose 250 Total 500 mg Example 7
Sterile solution for infusion
The following ingredients are dissolved in water for intravenous perfusion and the resulting solution is then sterilized.
Ingredients Amount (g) N2-(3-cyclohexy 1-4-methoxyphenyl- 25 sulfonyl)-)-arginy l-N-butylglycine Buffer system As desired Glucose 25 Distilled water 500 PREPARATION A
Arylsulfonyl chlorides
(A) Sodium 3-butoxy-2,4-dimethoxybenzene sulfonate
To a well stirred solution of 50.8 g of 2-butoxy-l ,3-dimethoxybenzene in 160 ml of carbon tetrachloride was added dropwise 16,1 ml of chlorosulfonic acid at a temperature of O to 40C. The reaction mixture was stirred for one hour at room temperature, poured into crushed ice and then diluted to 300 ml with water.
Upon evaporation of carbon tetrachloride, the resulting aqueous layer was extracted with ether and then neutralized with 2NNaOH solution to precipitate white crystals which were filtered and dried to give 64.3 g (85.1%) of sodium 3butoxy-2,4-dimethoxybenzenesulfonate.
(B) 3-butoxy-2,4-dimethoxybenzenesulfonyl chloride
To a stirred suspension of 60.0 g of dry, powdery sodium 3-butoxy-2,4dimethoxybenzenesulfonate in 150 ml of dry dimethylformamide was added dropwise 69 ml of thionyl chloride over a period of 20 minutes at room temperature.
The reaction mixture was stirred for 15 minutes and poured gradually into 1,000 ml of ice water and stirred vigorously. After 1 hour, the aqueous layer was decanted and the residual oil was extracted with benzene, washed with water, dried over anhydrous sodium sulfate, distilled to remove the solvent and then distilled in vacuo to give 47.5 g (80.1%) of 3-butoxy-2,4-dimethoxybenzenesulfonyl chloride (Bp l550C/l mm Hg) Analysis - Calod. for C12H15C1O5S (percent):
C, 46, 68; H, 5.56 Found (percent): C, 46.71; H, 5.60
The following arylsulfonyl chlorides not previously reported in the chemical literature were synthesized by the aforementioned procedure.
TABLE 3
Ar at - S02C1 Boiling point No. Ar melting point) 1 Q 165-1 660C/10 mmHg 1 N O(CH2)2CH3 (57.5 - 58.50C) 2 6 112-1150C/1 mmHg 'O(CH9)3CH3 (33 - ss0C) Q OCI2CH2CH ( C113 127-1290C/0.5 mmHg CH3 4 (ĭ/"'''''O(C112)4CH3 148-1500C/1 mmHg (c 2 )4 3 [S O(CH2 )3CH3 143145 C/1 mmHg 5 UJ o(CH,)3CH3 (48 - 51 C) rnniHg (48 - 510C) 6 0- H,CH2CH3 e (41 (41 - 20C) CH2CH2CH3 OCH3
Ar - S02C1 Boiling point No. (melting point) Ar (melting point) 7 e CH3 139-1400C/1 mmHg OCH3 CH2CH3 8 t CH3 CH3 129.5-1320C/1 mmHg OCH3 CH3 CH3 CH2)3CH3 145-1480C/1 mmHg CH3 10 CH3 10 15l.5-l53.50C/1.5 mmHg CH3 11 COH(C3H2 )3CH3 55-1560C/2 mmHg L 12 OCHZCH20CH3 (44 - 450C)
Ar S02C1 Boi ling point No . Ar ( mel ting point ) 13 ) CE CH 3 1 S C /1 mmHg OCH2CH2CH20CH3 OCH3 14 tOCH3 OCH2CH2CH2Br 198-2000C/2 mmHg OCH3 OCH3 15 $ o ( CH2 ) 3Ct2CH3 210-2200C/l mmHg O(CH2)3C02CH3 OCH3 X OCH3 16 I O(CH2)2CH3 160-162 C/2 Hg OCH3 OCH 3 17 l54l550C/l mg OCH O'U2)3CH3 15-1550C/1 mmHg OCH3 18 Oi OCH3 18 A 0(CH2 )4CH3 170-1720C/2 sHHg OCH3
Ar S02C1 Boiling point No . Ar ( mel ting point ) 19 C (CH2 )5CH3 183-1850C/1 mmHg OCH3 SOCH3 20 A OCHzCH20CH3 (46 - 470C) OCH3 1 21 A 1310C/1 m1II:lg Cl 22 e o(CH2 )2CH3 (63 - 660C) OCH3 23 tE O(CH2 )3CH3 (30 - 320C) I 24 v 208-210 C/1 208-2100C/1 mmHg O(CH2 )3CH3
Ar - S02C1 Boiling point No.
Ar (melting point ) 2 5 /C1 17 8 -17 9 C/2 mmHg j O(CH2 )3CH3 26 lALCO (CH2 )2C113 Oily substance OCH3 OCH5 27 OCH2CH2OCH2CH3 165-l680C/l mmHg OCH3 28 i,"CH3 Oily substance CH2CH3 OC02C2Hj 29 u 109-110 C/1 .5 -Hg OC2Hg O CH) lll-1160C/1 mmHs 30 CH \ CH 111116 C/1 mmHg H\CH3
Ar - S02C1 Boiling point No.
Ar (melting point) 31 t CH3 Oily substance OCHCH2CH3 32 t oCH2CH/CH3 Oily substance O(CH2)4CH3 148-1500C/i m::Hg 34 t CH3 152-1530C/2 3 5 sSjU CH3 13 3 -1 34 C /1 mmHg 36 CH3 36 a CH3 142-1430C/1 mmHg OCH\ CH3
Ar - S02C1 Boiling point No. 1 Ar (melting point) 37 n C2H5 12112 2 C /1 mmHg CH3 38 H (CH2 )2CH3 133-1350C/1 mmHg CH3 CH3 39 ',,'CH3 136-1390C/1 mmHg H\CH3 CH3 OH CH3 CH \ OH3 40 CH \ C113 (95 - 600) N OH3 CH ' 41 (CH2 )2CH3 (101 - 10300) CHCH3 OH3 42 (CH,)2CHs 42 e 142-144 C/1 mmHg u (CH2 )2CH3
Ar - S02C1 Boiling point No. - Ar (melting point) OCH3 43 i0CC2 (so - 510C) OCH3 158-1600C/1 CH3 158-1600C/1 mdlg OCH3 CH3 OCH3 i"'CH3 45 t$CH3H2CH2CHs 159-1600C/1 mmHg OCH3 CH3 OC2H5 46 SZIIa 1.31-20C/1 mmHg OC2H5 47 0;oCH3 47 OCH3 CH3 158-1390C/1 rnmHg
Claims (1)
- WHAT WE CLAIM IS:1. An N2-arylsulfonyl-L-argininamide of the formula (I): wherein R iswherein R, is C2-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C2-C10 alkoxyalkyl, C2-C10 alkythioalkyl, C2-C10 alkylsulfinylalkyl, C1-C10 hydroxyalkyl, C3-C10 alkoxycarbonylalkyl, C3-C10 alkylcarbonylalkyl, C1-C10 haloalkyl, C7-C5 aralkyl, C8-C15 α-carboaralkyl, C3-C10 cycloalkyl, C-C10 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl optionally substituted with one or more of C1-C5 alkyl and/or C1-C5 alkoxy, 3-furylmethyl, tetrahydro-3-furylmethyl optionally substituted with one or more of C1-C5 alkyl and/or C1-C5 alkoxy, tetrahydro-2 pyranylmethyl tetrahydro-3-pyranylmethyl or tetrahydro-4-pyranylmethyl optionally substituted with one or more of C1-C5 alkyl and/or C1-C5 alkoxy, 1,4dioxa-2-cyclohexylmethyl optionally substituted with one or more of C1-C5 alkyl and/or C1-C5 alkoxy, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl optionally substituted with one or more of C1-C5 alkyl and/or C1-C5 alkoxy, or tetrahydro-3-thenyl; R2 is hydrogen, C1-C10 alkyl, C6-C10 aryl or C7-C12 aralkyl; and n is 1, 2 or 3,wherein R3 is hydrogen, C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C2-C10 alkoxyalkyl, C2-C10 alkylthioalkyl, C2-C10 alkylsulfinylalkyl, C1-C10 hydroxyalkyl, C3-C10 alkoxycarbonylalkyl, C3-C10 alkylcarbonylalkyl, C1-C10 haloalkyl, C7-C15 aralkyl, C8-C15 α-carboxyaralkyl, C3-C10 cycloalkyl, C4-C10 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl optionally substituted with one or more C1-C5 alkyl and/or C1-C5 alkoxy, 3-furylmethyl, tetrahydro-3-furylmethyl optionally substituted with one or more of C1-C5 alkyl and/or C1-C5 alkoxy, tetrahydro-2-pyranylmethyl tetrahydro-3-pyranylmethyl or tetrahydro-4pyranylmethyl optionally substituted with one or more of C1-C5 alkyl and/or C1-C5 alkoxy, 1,4-dioxa-2-cyclohexamethyl optionally substituted with one or more of C1-C5 alkyl and/or C1-C5 alkoxy, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl optionally substituted with one or more of C1-C5 alkyl and/or C1-C5 alkoxy or tetrahydro-3-thenyl; R4 is C1-C10 alkyl, phenyl (optionally substituted with one or more of C1-C5 alkyl and/or C1-C5 alkoxy), C7-C12 aralkyl or ring substituted benzyl wherein said substituent is C1-C5 alkyl or C1-C5 alkoxy; R5 is hydrogen, C1-C10 alkyl, C5-C10 aryl or C7-C12 aralkyl; and m is 0, 1 or 2.wherein R6 is -COOR8 wherein R8 is hydrogen, C1-C10 alkyl, C6-C10 aryl or C7-C12 aralkyl; each R7 independently is C1-C10 alkyl, phenyl, C1-C5 alkoxy, C2-C@ alkoxycarbonyl or carboxyl; p is O or an integer of from 1 to 4; R8 is substituted into the ring at the 2 or 3-position; and the R, group or groups if present are substituted into the ring at the 2, 3, 4, 5 or 6-position,optionally substituted with one or more of C1-C5 alkyl and/or C1-C5 alkoxy, wherein R9 is hydrogen, C1-C10 alkyl, C8-C10 aryl or C7-C12 aralkyl; and R is 1, 2,3 or 4,wherein R10 is hydrogen, C1-C10 alkyl, C6-C10 aryl or C7-C12 aralkyl; Z is oxygen, sulphur or sulfinyl; and q is O or 1, orwherein R11 is hydrogen, C1-C10 alkyl, C8-C10 aryl or C7-C12 aralkyl; i is 0,1 or 2; j is 0, 1 or 2; and the sum of i +j is 1 or 2; and Ar is phenyl or naphthyl, substituted with at least one of sulfoamino, carbamoyl, C3-C10 N,N-dialkylcarbamoyl, C2-C6 N-alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto C1-C10 alkylthio, C7-C12 aralkyl, carboxyl, C2-C10 alkoxycarbonyl, C2-C10 carboxyalkyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hdyroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy, and/or phenyl (optionally substituted with one or more of hydroxy and/or C1-C5 alkoxy); phenyl or naphthyl, substituted with at least one of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy or C2-C20 dialkylamino, and with at least one of sulfoamino, carbamoyl, C3-C10 N,N-dialkylcarbamoyl, C2-C6 N-alkylcarbamoyl, amino C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxyl, C2-C10 alkoxycarbonyl, C2-C10 carboxyalkyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy, or phenyl (optionally substituted with one or more of hydroxy and/or C1-C5 alkoxy); oxanthrenyl or dibenzofuranyl substituted with at least one of halo, nitro, cyano, hydroxy, C2-C20 dialkylamino, sulfoamino, carbamoy, C3-C10 N,Ndialkylcarbamoyl, C2-C6 N-alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxyl, C2-C10 alkoxycarbonyl C2-C10 carboxyalkyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy, or phenyl (optionally substituted with one or more of hydroxy and/or C1-C5 alkoxy) oxanthrenyl or dibenzofuranyl substituted with at least one of C1-C10 alkyl and/or C1-C10 alkoxy and with at least one of halo, nitro, cyano, hydroxy, C2-C20 dialkylamino, sulfoamino, carbamoyl, C3-C10 N,N-dialkylcarbamoyl, C2-C6 N-alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxyl, C2-C10 alkoxycarbonyl, C2-C10 carboxylakyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy, and/or phenyl (optionally substituted with one or more of hydroxy and/or C1-C5 alkoxy); tetrahydronaphthyl, 1,2-ethylenedioxyphenyl, chromanyl, 2,3ethylenedioxynaphthyl or xanethenyl, substituted with at least one of halo, nitro, cyano, hydroxy, C2-C20 dialkylamino, sulfoamino, carbamoyl, C3-C10 N,Ndialkylcarbamoyl, C2-C6 N-alkylacarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxyl, C2-C10 alkoxycarbonyl, C2-C10 carboxyalkyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy, oxo, and/or phenyl (optionally substituted with one or more of hydroxy and/or C1-C5 alkoxy); tetrahydronaphthyl, 1 ,2-ethylenedioxyphenyl, chromanyl, 2,3 ethylenedioxynaphthyl or xanthenyl substituted with at least one of C1-C10 alkyl and/or C1-C10 alkoxy, and with at least one of halo, nitro, cyano, hydroxy, C2-C20 dialkylamino, sulfoamino, carbamoyl, C3-C10 N,N-dialkylcarbamoyl, C2-C6 Nalkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxyl, C2-C10 alkoxycarbonyl, C2-C10 carboxyalkyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy, oxo, and/or phenyl (optionally substituted with one or more of hydroxy and/or C1-C5 alkoxy); optionally substituted naphthoquinonyl, anthryl, phenanthryl, pentalenyl, heptalenyl, azulenyl, biphenylenyl, asymmetrical indacenyl, symmetrical indacenyl, acenaphthylenyl, phenylcarbonylphenyl, phenoxyphenyl, benzofuranyl, isobenzofuranyl, benzo (b) thienyl, isobenzothienyl, thianthrenyl, dibenzothienyl, phenoxathiinyl, indolyl, 1H-indazolyl, quinolyl, isoquinolyl, phthalazinyl, 1,8-naphthridinyl, quinoxalinyl, quinzaolinyl, cinnolinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl or benzimidazolyl, the optional substitution being by one or more of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy, C2-C20 dialkylamino, sulfoamino, carbamoyl, C3-C10 N,N-dialkylcarbamoyl, C2-C6 N-alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxyl, C2-C10 alkoxycarbonyl, C2-C10 carboxyalkyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy, and/or phenyl (optionally substituted with one or more of hydroxy and/or C1-C5 alkoxy); optionally substituted C7-C12 aralkyl, C9-C16 cycloalkylphenyl, C10-C18 cycloalkylakylphenyl,, C9-C16 cycloalkyloxyphenyl, C9-C16 cycloalkylthiophenyl, 9,10-dihydroanthryl, 5,6,7,8-tetrahydroanthryl, 9,10-dihydrophenynthryl, 1,2,3,4,5,6,7,8-octahydrophenanthryl, indenyl, indanyl, fluorenyl, acenaphthenyl, phenylthiophenyl, isochromanyl, 2,3-dihydrobenzofuranyl, 1,3dihydroisobenzofuranyl, thioxanthenyl, 2H-chromenyl, 3,4-dehydro-1- isochromanyl, 4H-chromenyl, indolinyl, isoindolinyl, 1,2,3,4-tetrahydroquinolyl or 1,2,3,4-tetrahydroisoquinolyl, the optional substitution being by one or more of halo, nitro, cyano, hydroxy, C1-C10 alkyl, C1-C10 alkoxy, C2-C20 dialkylamino, sulfoamino, carbamoyl, C3-C10 N,N-dialkylcarbamoyl, C2-C8 N-alkylcarbamoyl, amino, C1-C10 alkylamino, mercapto, C1-C10 alkylthio, C7-C12 aralkyl, carboxyl, C2-C10 alkoxycarbonyl, C2-C10 carboxyalkyl, C1-C10 acylamino, C2-C10 alkylcarbonyl, C1-C10 hydroxyalkyl, C1-C10 haloalkyl, C1-C10 hydroxyalkoxy, oxo, and/or phenyl (optionally substituted with one or more of hydroxyl and/or C1-C5 alkoxy); or phenyl substituted with at least one of alkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkyl or alkoxycarbonylalkoxy group, the or each such substituent group containing 3 to 7 carbon atoms and the said substituted phenyl being optionally substituted further with one or more of halo, methyl. ethyl, methoxy, ethoxy, and/or hydroxy.2. A compound as claimed in claim I wherein said R iswherein R, is C2 to C10 alkyl, C3 to C10 alkenyl, C2 to C10 alkoxyalkyl, C2 to C10 alkylthioalkyl, C2 to C10 alkylsulfinylalkyl, C7 to C15 aralkyl, C3 to C10 cycloalkyl, C4 to C10 cycloalkylalkyl, fufuryl, tetrahydrofurfuryl, tetrahydro-2-pyranylmethyl, tetrahydro-3-pyranylmethyl, tetrahydro-4-pyranylmethyl or 1,4-dioxa-2-cyclohexylmethyl; R2 and n are as defined in claim 1;wherein R3 is hydrogen, C1 to C10 alkyl, C3 to C10 alkenyl, C2 to C10 alkoxyalkyl, C2 to C10 alkylthioalkyl, C2 to C10 alkylsulfinylalkyl, C7 to C15 aralkyl, C3 to C10 cycloalkyl, C4 to C10 cycloalkylalkyl, furfuryl, tetrahydrofurfuryl, tetrahydro-2pyranylmethyl, tetrahydro-3-pyranylmethyl, tetrahydro-4-pyranylmethyl or 1,4dioxa-2-cyclohexylmethyl; R4, R5 and m are as defined in claim 1wherein R5 is as defined in claim 1; each R7 independently is C1 to C10 alkyl or phenyl; p is as defined in claim 1; R8 and R7 are substituted as defined in claim Ioptionally substituted as defined in claim I wherein R8 and R are as defined in claim 1wherein R10, Z and q are as defined in claim 1;wherein R11, i and j are as defined in claim 1; and Ar is phenyl or naphthyl substituted with at least one of amino, C1 to C10 alkylamino, C1 to C10 alkylthio, C7 to C12 aralkyl, C2 to C10 alkoxycarbonyl, C1 to C10 acylamino, C2 to C10 alkylcarbonyl, C1 to C10 hydroxyalkyl, C1 to C10 hydroxyalkoxy and phenyl; phenyl or naphthyl substituted with at least one of amino, C1 to C10 alkylamino, C1 to C10 alkylthio, C, to C12 aralkyl. C2 to C10 alkoxycarbonyl, C1 to C10 aoylamino, C, to C10 alkylcarbonyl, C, to C10 hydroxyalkyl, C1 to C10 hydroxyalkoxy and/or phenyl and at least one of halo, hydroxy, C1 to C10 alkyl, C1 to C10 alkoxy and/or C2 to C20 dialkylamino; dibenzofuranyl substituted with at least one halogen atom; dibenzofuranyl substituted with at least one of C1 to C10 alkyl or C1 to C10 alkoxy and at least one halogen atom; tetralhydronaphthyl, 1,2-ethylenedioxyphenyl, chromanyl, 2,3ethylenedioxynaphthyl or xanthenyl, substituted with at least one halogen atom; tetrahydronaphthyl, 1,2-ethylenedioxyphenyl chromanyl, 2,3-ethylenedioxynapthyl or xanthenyl, substituted with at least one of C1 to C10 alkyl or C1 to C10 alkoxy and at least one halogen atom; optionally substituted anthryl, phenanthryl, biphenylenyl, phenoxyphenyl, benzofuranyl, benzo (b) thienyl, dibenzothienyl, phenoxathiinyl, quinolyl, isoquinolyl, quinoxalinyl, acridinyl or phenazinyl, the optional substitution being by one or more of halo, hydroxy, C1 to C10 alkyl, C, to C10 alkoxy and/or C, to C10 hydroxyalkoxy; optionally substituted C7 to C,2 aralkyl, Cog to C,6 cycloalkylphenyl, fluorenyl, thioxanthenyl, 2H-chromenyl or 1 ,2,3,4-tetrahydroquinolyl, the optional substitution being by one or more of C, to C10 alkyl, C, to C10 alkoxy and/or oxo; or phenyl substituted with at least one of alkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkyl and/or alkoxycarbonyalkoxy, the or each such substituent containing 3 to 7 carbon atoms and the said substituted phenyl being optionally substituted further with one or more of halo, methyl, ethyl, methoxy, ethoxy. and/or hydroxy.3. A compound as claimed in claim 2 wherein said R iswherein R1 is C2 to C10 alkyl, C2 to C5 alkoxyalkyl, C2 to C8 alkylthioalkyl, C7 to C10 aralkyl, C4 to C10 cycloalkylalkyl, furfuryl or tetrahydrofurfuryl; R2 is hydrogen or C1 to C10 alkyl; and n is as defined in claim Iwherein R3 is C1 to C10 alkyl, C2 to C, alkoxyalkyl, C2 to C8 alkylthioalkyl, C7 to C10 aralkyl, C4 to C10 cycloalkylalkyl, furfuryl or tetrahydrofurfuryl; R4 is C1 to C5 alkyl; R5 is hydrogen or C1 to C10 alkyl; and m is as defined in claim Iwherein R5 is -COOR8 wherein R8 is hydrogen or C, to C10 alkyl; each R7 independently is C1 to C8 alkyl; p is as defined in claim 1; R8 and R7 are substituted as defined in claim 1optionally substituted as defined in claim 1, wherein R8 is hydrogen C, to C10 alkyl; and R is as defined in claim 1wherein R10 is hydrogen or C, to C10 alkyl; Z and q are as defined in claim 1 andwherein R11 is hydrogen or C1 to C10 alkyl; i and j are as defined in claim 1; and Ar is phenyl or naphthyl, substituted with at least one of amino, C1 to C10 alkylamino, C7 to C,2 aralkyl, C, to C10 acylamino, C, to C10 hydroxyalkyl, and/or C, to C10 hydroxyalkoxy; phenyl or napthyl, substituted with at least one of amino, C, to C10 alkylamino, C7 to C,2 aralkyl, C, to C10 acylamino, C, to C10 hydroxyalkyl and/or C, to C10 hydroxyalkoxy and at least one of halo, hydroxy, C, to C10 alkyl or C, to C10 alkoxy, optionally substituted biphenylenyl, phenoxyphenyl, dibenzothienyl, phenoxyathiinyl, quinolyl, or quinoxalinyl; the optional substitution being by one or more of hydroxy and/or C, to (S,0 alkyl; optionally substituted C7 to C,2 aralkyl, C9 to C16 cycloalkylphenyl, fluorenyl, or 2H-chromenyl, the optional substitution being by one or more of C, to C10 alkyl, C, to C10 alkoxy and/or oxo; or phenyl substituted with at least one of alkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkyl and/cr alkoxycarbonylalkoxy, the or each such substituent containing 3 to 7 carbon atoms and the said substituted phenyl being optionally substituted further with one or more of halo, methyl, ethyl, methoxy, ethoxy and/or hydroxy.4. An N2-arylsulfonyl-L-argininamide having the formula (I) as defined in claim I wherein R iswherein R, is C2 to C10 alkyl,. C3 to C10 alkenyl, C, to C10 alkynyl, C2 to C10 alkoxyalkyl, C2 to C10 alkylthioalkyl, C2 to C10 alkylsulfinylalkyl, C, to C10 hydroxyalkyl, C3 to C10 alkoxycarbonylalkyl, C1 to C10 haloalkyl, C7 to C15 aralkyl, C8 to C15 α- carboxyaralkyl, C3 to C10 cycloalkyl or C4 to C10 cycloalkylalkyl; R2 and n are as defined in claim 1, orwherein R3 is hydrogen, C1 to C10 alkyl, C3 to C10 alkenyl, C3 to C10 alkynyl, C2 to C10 alkoxyalkyl, C2 to C10 alkylthioalkyl, C2 to C10 alkylsulfinylalkyl, C1 to C10 hydroxyalkyl, C3 to C10 alkoxycarbonylalkyl, C1 to C10 haloalkyl, C7 to C15 aralkyl, C8 to C15 a-carboxyaralkyl, C3 to C10 cycloalkyl or C4 to C10 cycloalkylalkyl; R4 is C1 to C5 alkyl, phenyl, C7 to C12 aralkyl or ring substituted benzyl wherein said substituent is C1 to C5 alkyl and/or C1 to C5 alkoxy; R5 and m are as defined in claim 1; Ar is phenyl or naphthyl, substituted with at least one of sulfoamino, carbamoyl, C3 to C10 N,N-dialkylcarbamoyl, amino C1 alkylthio, C7 to C12 aralkyl, carboxyl, C2 ro C10 alkoxycarbonyl, C2 to C10 carboxyalkyl, C1 to C10 acylamino, C2 to C10 alkylcarbonyl, C1 to C10 hydroxyalkyl, C1 to C10 haloalkyl, and/or phenyl (optionally substituted with one or more of hydroxy and/or C, to C5 alkoxy; phenyl or naphthyl, substituted with at least one of sulfoamino, carbamoyl, C3 to C10 N,N-dialkylcarbamoyl, amino, C1 to C10 alkylamino, mercapto, C1 to C10 alkylthio, C7 to C12 aralkyl, carboxyl, C2 to C10 alkoxycarbonyl, C2 to C10 carboxyalkyl, C1 to C10 acylamino, C2 to C10 alkylcarbonyl, C1 to C10 hydroxyalkyl, C1 to C10 haloalkyl, and/or phenyl (optionally substituted with one or more of hydroxy, and/or C1 to C8 alkoxy); and at least one of halo, nitro, cyano, hydroxy, C, to C10 alkyl, C, to C10 alkoxy or C2 to C20 dialkylamino; oxanthrenyl or dibenzofuranyl substituted with at least one of halo, nitro, cyano, hydroxy, C2 to C20 dialkylamino, sulfoamino, carbamoyl, C3 to C;O N,Ndialkylcarbamoyl, amino, C1 to C10 alkylamino, mercapto, C1 to C10 alkylthio, C7 to C12 aralkyl, carboxyl, C2 to C10 alkoxycarbonyl, C2 to C10 carboxyalkyl, C1 to C10 acylamino, C2 to C10 alkylcarbonyl, C1 to C10 hydroxyalkyl, C1 to C10 haloalkyl, and/or phenyl (optionally substituted with one more more of hydroxy and/or C1 to C5 alkoxy); tetrahydronaphthyl, 1,2-ethylenedioxyphenyl, chromanyl, 2,3ethylenedioxynaphthyl or xanthenyl, substituted with at least one of halo, nitro, cyano, hydroxy, C2 to C20 dialkylamino, sulfoamino, carbamoyl, C3 to C10 N,Ndialkylcarbamoyl, amino, C1 to C10 alkylamino, mercapto, C1 to C10 alkylthio, C7 to C12 aralkyl, carboxyl, C2 to C10 alkoxycarbonyl, C2 to C10 carboxyalkyl, C1 to C10 acylamino, C2 to C10 alkylcarbonyl, C1 to C10 hydroxyalkyl, C1 to C10 haloalkyl, oxo, and/or phenyl (optionally substituted with one or more of hydroxy and/or C, to C4 alkoxy); optionally substituted naphthoquinonyl, anthryl, phenanthryl, pentalenyl, heptalenyl, azulenyl, biphenylenyl, asymmetrical-indacenyl, symmetricalindacenyl, acenaphthylenyl, phenylcarbonylphenyl, phenoxyphenyl, benzofuranyl, isobenzofuranyl, benzo(b)thienyl, isobenzothienyl, thianthrenyl, dibenzothienyl, phenoxathiinyl, indolyl, 1 H-indazolyl, quinolyl, isoquinolyl, phthalazinyl, 1,8naphthridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl or benzimidazolyl, the optional substitution being by one or more of halo, nitro, cyano, hydroxy, C, to C10 alkyl, C, to C10 alkoxy, C2 to C20 dialkylamino, sulfoamino, carbamoyl, C3 to C10 N,Ndialkylcarbamoyl, amino, C1 to C10 alkylamino, mercapto, C1 to C10 alkylthio, C7 to C12 aralkyl, carboxy, C2 to C10 alkoxycarbonyl, C2 to C10 carboxyalkyl, C1 to C10 acylamino, C2 to C10 alkylcarbonyl, C1 to C10 hyroxyalkyl, C, to C10 haloalkyl, and/or phenyl (optionally substituted with one or more of hydroxy and/or C1 to C5 alkoxy);, optionally substituted 9,10-dihydroanthryl, 5,6,7,8-tetrahydroanthryl, C7 to C12 aralkyl, 9,10-dihydrophenanthryl, 1,2,3,4.5,6,7,8-octahydrophenanthryl, indenyl, indanyl, fluorenyl, acenaphthenyl, phenylthiophenyl, isochromanyl, 2,3dihydrobenzofuranyl, I ,3-dihydroisobenzofuranyl, thioxanthenyl, 2H-chromenyl, 3 ,4-dehydro- 1 -isochromanyl, 4H-chromenyl, indolinyl, isoindolinyl, 1,2,3,4tetrahydroquinolyl, or i,2,3,4-tetrahydroisoquinolyl, the optional substitution being by one or more of halo, nitro, cyano, hydroxy, C1 to C10 alkyl, C1 to C10 alkoxy, C2 to C, dialkylamino, sulfoamino, carbamoyl, C3 to C10 N,Ndialkylcarbamoyl, amino, C1 to C10 alkylamino, mercapto, C1 to C10 alkylthio, C7 to C12 aralkyl, carboxyl, C2 to C10 alkoxycarbonyl, C2 to C10 carboxyalkyl, C1 to C10 acylamino, C2 to C10 alkylcarbonyl, C1 to C10 hydroxyalkyl, C1 to C10 haloalkyl, oxo, and/or phenyl (optionally substituted with one or more of hydroxy and/or C1 to C5 alkoxy).5. An N2-arylsulfonyl-L-argininamide having the formula (I) as defined in claim I wherein R iswherein R1 is furfuryl, 3-furylmethyl, tetrahydrofurfuryl or tetrahydro-3. furylmethyl; R2 and n are as defined in claim fwherein R3 is furfuryl, 3-furylmethyl, tetrahydrofurfuryl or tetrahydro-3furylmethyl; R4, R5 and m are as defined in claim Iwherein R10 is hydrogen, C1 to C10 alkyl, C8 to C10 aryl or C7 to C12 aralkyl, Z and q are as defined in claim I orwherein R1r, i and j are as defined in claim 1; and Ar is naphthyl, substituted with at least one of halo, hydroxy, nitro, cyano, C1 to C10 alkyl, C1 to C10 alkoxy or C2 to C20 dialkylamino, and at least one sulfoamino, carbamoyl, C3 to C10 N,N-dialkylcarbamoyl, amino, C1 to C10 alkylamino, mercapto, C1 to C10 alkylthio, C7 to C12 aralkyl, carboxyl, C2 to C10 alkoxycarbonyl, C2 to C10 carboxyalkyl, C1 to C10 acylamino, C2 to C10 alkylcarbonyl, C1 to C10 hydroxyalkyl, C1 to C10 haloalkyl or phenyl (optionally substituted with one or more of hydroxy and/or C1 to C8 alkoxy); naphthyl substituted with at least one of sulfoamino, carbamoyl, C3 to C10 N,N-dialkylcarbamoyl, amino, C1 to C10 alkylamino, mercapto, C1 to C10 alkylthio, C7 to C12 aralkyl, carboxyl, C2 to C10 alkoxycarbonyl C2 to C10 carboxyalkyl, C1 to C10 acylamino, C2 to C10 alkylcarbonyl, C1 to C10 hydroxyalkyl, C1 to C10 haloalkyl and/or phenyl (optionally substituted with one or more of hydroxy and/or C1 to C5 alkoxy); 5,6,7,8-tetrahydronaphthyl substituted with at least one of halo, nitro, cyano, hydroxy, sulfoamino, carbamoyl, C3 to C10N,N-dialkylcarbamoyl, amino, C1 to C10 alkylamino, mercapto, C1 to C1, alkylthio, C7 to C12 aralkyl, carboxyl, C2 to C10 alkoxycarbonyl, C2 to C10 carboxyalkyl, C1 to C10 acylamino, C2 to C10 alkylcarbonyl, C1 to C10 hydroxyalkyl, C1 to C10 haloalkyl, oxo, and/or phenyl (optionally substituted with one or more of hydroxy and/or C1 to Cs alkoxy); optionally substituted naphthoquinonyl, anthryl, phenanthryl, pentalenyl, heptalenyl, azulenyl, biphenylenyl, assymmetrical or symmetrical-indacenyl, acenaphthylenyl, phenylcarbonylphenyl, phenoxyphenyl, benzofuranyl, isobenzofuranyl, benzo(b)thienyl, isobenzothienyl, thianthrenyl, dibenzothienyl, phenoxathiinyl, indolyl, 1H-indazolyl, quinolyl, isoquinolyl, phthalazinyl, 1,8naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, acrindyl, phenazinyl, phenothiazinyl, phenoxazinyl or benzimidazolyl, the optional substitution being by one or more of halo, nitro, cyano, hydroxy, C1 to C10 alkyl, C1 to C10 alkoxy, C2 to C20 dialkylamino, sulfoamino, carbamoyl, C3 to C10 N,Ndialkylcarbamoyl, amino, C1 to C10 alkylamino, mercapto, C1 to C10 alkylthio, C7 to C12 aralkyl, carboxyl, C2 to C10 alkoxycarbonyl, C2 to C10 carboxyalkyl, C1 to C10 acylamino, C2 to C10 alkylcarbonyl, C1 to C10 hydroxyalkyl, C1 to C10 haloalkyl, and/or phenyl (optionally substituted with one or more of hydroxy and/or C1 to C5 alkoxy).6. An N,-arylsulfonyl-L-argininamide having the formula (I) as defined in claim l wherein R iswherein R8, R7 and p are as defined in claim 1, R, and R7 are'substituted as defined in claim 1; and Ar is naphthyl substituted with at least one of halo, nitro, cyano, hydroxy, C1 to C10 alkyl, C1 to C5 alkoxy and/or C2 to C20 dialkylamino and at least one of sulfoamino, carbamoyl, C3to C10N,N-dialkylcarbamoyl, amino, C, to C10 alkylamino, mercapto, C1 to C10 alkylthio, C7 to C10 aralkyl, carboxyl, C2 to C10 alkoxycarbonyl, C2 to C10 carboxyalkyl, C1 to C10 acylamino, C2 to C10 alkylcarbonyl, C1 to C10 hdyroxyalkyl, C1 to C10 haloalkyl and/or phenyl (optionally substituted with one or more of hydroxy and/or C1 to C5 alkoxy); naphthyl substituted with at least one of sulfoamino, carbamoyl, C3 to C10 N,Ndialkylcarbamoyl, amino, C, to C10 alkylamino, mercapto, C, to C;O alkylthio, C7 to C12 aralkyl, carboxyl, C2 to C10 alkoxycarbonyl, C2 to C;O carboxyalkyl, C1 to C10 acylamino, C2 to C10 alkylcarbonyl, C1 to C10 hydroxyalkyl, C1 to C10 haloalkyl, and/or phenyl (optionally substituted with one or more of hydroxy and/or C1 to C5 alkoxy), 5,6,7,8-tetrahydronaphthyl substituted with at least one of halo, nitro, cyano, hydroxy, sulfoamino, carbamoyl, C2 to C10 N,N-dialkylcarbamoyl, amino, C1 to C10 alkylamino, mercapto, C, to C10 alkylthio, C7 to C12 aralkyl, carboxyl, C2 to C10 alkoxycarbonyl, C2 to C10 carboxyalkyl, C1 to C10 acylamino, C2 to C10 alkylcarbonyl, C1 to C10 hydroxyalkyl, C1 to C10 haloalkyl or phenyl (optionally substituted with one or more of hydroxy and/or C1 to C5 alkoxy); optionally substituted C7 to C,2 aralkyl, 9,10-dihydroanthryl, 5,6,7,8tetrahydroanthryl, 9,10-dihydrophenanthryl, 1 ,2,3,4,5,6,7,8-octahydrophenanthryl, indenyl, indanyl, fluorenyl, acenaphthenyl, phenylthiophenyl, isochromanyl, 2,3dihydrobenzofuranyl, 1 ,3-dihydroisobenzofuranyl, thioxanthenyl, 2H-chromenyl, 3,4-dehydro- 1 -isochromanyl, 4H-chromenyl, indolinyl, isoindolinyl, 1,2,3,4tetrahydroquinolyl or 1,2,3,4-tetrahydroisquinolyl, the optional substitution being by one or more of halo, nitro, cyano, hydroxy, C, to C10 alkyl, C1 to C10 alkoxy, C2 to C20 dialkylamino, sulfoamino, carbamoyl, C3 to C10 N,N-dialkylcarbamoyl, amino, C, to C10 alkylamino, mercapto, C1 to C10 alkylthio, C7 to C12 aralkyl, carboxyl, C2 to C10 alkoxycarbonyl C2 to C10 carboxyalkyl, C1 to C10 acylamino, C2 to C10 alkylcarbonyl, C1 to C10 hydroxyalkyl, C1 to C10 haloalkyl, oxo, and/or phenyl (optionally substituted with one or more of hydroxy and/or C1 to C5 alkoxy); optionally substituted naphthoquinonyl, anthryl, phenanthryl, pentalenyl, heptalenyl, azulenyl, biphenylenyl, asymmetrical or symmetrical-indacenyl, acenaphthylenyl, phenylcarbonylphenyl, phenoxyphenyl, benzofuranyl, isobenzofuranywherein R5 and m are as defined in claim 1 and either R3 is C2 to C10 alkylcarbonylalkyl, 2-thenyl, 34henyl, or optionally substituted tetrahydrofurfuryl or tetrahydro-3-furylmethyl wherein the optional substitution is by one or more of C1 to C5 alkyl and/or C1 to C5 alkoxy, tetrahydro-2-thenyl, tetrahydro-3-thenyl tetrahydro-2(3 or 4)-pyranylmethyl or 1,4-dioxa-2-cyclohexylmethyl optionally substituted with one or more of C1 to C5 alkyl and/or C1 to C5 alkoxy; and R4 is C1 to C10 alkyl, and/or phenyl (optionally substituted with one or more of C1 to C5 alkyl or C1 to C5 alkoxy); C7 to C12 aralkyl or ring substituted benzyl wherein said substituent is C1 to C5 alkyl or C1 to C5 alkoxy; or R3 is furfuryl, 3-furylmethyl and R4 is phenyl (optionally substituted with one or more C1 to C5 alkyl or C1 to C5 alkoxy), C7 to C12 aralkyl or ring substituted benzyl wherein said substituent is C1 to C5 alkyl or C1 to C5 alkoxyoptionally substituted as defined in claim 1, wherein R9 and r are as defined in claim 1; Ar is phenyl, substituted with one or more of sulfoamino, carbamoyl, C3 to C10 N,N-dialkylcarbamoyl, amino, C1 to C10 alkylamino, mercapto, C1 to C10 alkylthio, C7 to C12 aralkyl, carboxyl, C2 to C10 alkoxycarbonyl, C2 to C10 carboxyalkyl, C1 to C10 acylamino, C2 to C10 alkylcarbonyl, C1 to C10 hydroxyalkyl, C1 to C10 haloalkyl, and/or phenyl (optionally substituted with one or more of hydroxy and/or C1 to C5 alkoxy).8. An N2-arylsulfonyl-L-argininamide having the formula (I) as defined in claim 1 wherein R iswherein R1 is C2 to C10 alkyl, C3 to C10 alkenyl, C3 to C10 alkynyl, C2 to C10 alkoxyalkyl C2 to C10 alkylthioalkyl, C2 to C10 alkylsulfinylalkyl, C1 to C10 hydroxyalkyl, C3 to C10 alkoxycarbonylalkyl, C1 to C10 haloalkyl, C7 to C15 aralkyl, C8 to C15 a- carboxyaralkyl, C3 to C10 cycloalkyl or C4 to C10 cycloalkylalkyl; R2 and n are as defined in claim Iwherein R3 is hydrogen, C, to C10 alkyl, C3 to C10 alkenyl, C3 to C10 alkynyl, C2 to C10 alkoxyalkyl, C2 to C10 alkylthioalkyl, C2 to C10 alkylsulfinylalkyl, C1 to C10 hydroxyalkyl, C3 to C10 alkoxycarbonylalkyl, C1 to C10 haloalkyl, C7 to C15 aralkyl, C8 to C15 α-carboxyaralkyl, C3 to C10 cycloalkyl or C4 to C10 cycloalkylalkyl; R4 is C1 to C5 alkyl, phenyl, C7 to C12 aralkyl or ring substituted benzyl wherein said substituent is C1 to C5 alkyl and/or C1 to C5 alkoxy; R5 and m are as defined in claim 1.Ar is a phenyl or naphthyl, substituted with at least one of sulfoamino, carbamoyl, C3 to C10 N,N-dialkylcarbamoyl, amino, C1 to C10 alkylamino, mercapto, C1 to C10 alkylthio, C7 to C12 aralkyl, carboxyl, C2 to C10 alkoxycarbonyl, C2 to C1O carboxyalkyl, C1 to C10 acylamino, C2 to C10 alkylcarbonyl, C1 to C10 hydroxyalkyl, C1 to C10 haloalkyl and/or phenyl (optionally substituted with one or more of hydroxy and/or C1 to C5 alkoxy); phenyl or naphthyl, substituted with at least one of sulfoamino, carbamoyl, C3 to C10 N,N-dialkylcarbamoyl, amino, C1 to C10 alkylamino, mercapto, C1 to C10 alkylthio, C7 to C12 aralkyl, carboxyl, C; to C10 alkoxycarbonyl, C2 to C10 carboxyalkyl, C1 to C10 acylamino, C2 to C10 alkylcarbonyl, C1 to C10 hydroxyalkyl, C1 to C10 haloalkyl and phenyl (optionally substituted with one or more of hydroxy, and/or. C1 to C8 alkoxy), and at least one of halo, nitro, cyano, hydroxy, C1 to C10 alkyl, C1 to C10 alkoxy and/or C2 to C20 dialkylamino; oxanthrenyl or dibenzofuranyl substituted with at least one of halo, nitro, cyano1 hyroxy, C2 to C20 dialkylamino, sulfoamino, carbamoyl, C3 to C10 N,Ndialkylcarbamoyl, amino, C1 to C10 alkylamino, mercapto, C1 to C10 alkylthio, C7 to C12 aralkyl, carboxyl, C2 to C10 alkoxycarbonyl, C2 to C10 carboxyalkyl, C1 to C10 acylamino, C2 to C10 alkylcarbonyl, C1 to C10 hydroxyalkyl, C1 to C10 haloalkyl, and/or phenyl (optionally substituted with one or more of hydroxy and/or C1 to C5 alkoxy); tetrahydronaphthyl, 1,2-ethylenedioxyphenyl, chromanyl, 2,3ethylenedioxynaphthyl or xanthenyl substituted with at least one of halo, nitro, cyano, hydroxy, C2 to C20 dialkylamino, sulfoamino, carbamoyl, C3 to C10 N,Ndialkylcarbamoyl, amino, C1 to C10 alkylamino, mercapto, C1 to C10 alkylthio, C7 to C12 aralkyl, carboxyl, C2 to C10 alkoxycarbonyl, C2 to C10 carboxyalkyl, C1 to C10 acylamino, C2 to C10 alkylcarbonyl, C1 to C10 hydroxyalkyl, C1 to C10 haloalkyl, oxo, and/or phenyl (optionally substituted with one or more or hydroxy and/or C1 to C5 alkoxy); optionally substituted naphthoquinonyl, anthryl, phenanthryl, pentalenyl, heptalenyl, azulenyl, biphenylenyl, asymmetrical or symmetrical-indacenyl, acenaphthylenyl, phenylcarbonylphenyl, phenoxyphenyl, benzofuranyl, isobenzofuranyl, benzo(b)thienyl, isobenzothienyl, thianthrenyl, dibenzothienyl, phenoxathiinyl, indolyl, 1 H-indazolyl, quinolyl, isoquinolyl, phthalazinyl, 1,8-naphthridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, or benzimidazolyl, the optional substitution being by one or more of halo, nitro, cyano, hydroxy, C1 to C10 alkyl, C1 to C10 alkoxy, C, to C20 dialkylamino, sulfoamino, carbamoyl, C3 to C10N,N-dialkylcarbamoyl, amino, C1 to C10 alkylamino, mercapto, C1 to C10 alkylthio, C, to C12 aralkyl, carboxyl, C2 to C10 alkoxycarbonyl, C2 to C10 carboxyalkyl, C1 to C10 acylamino, C2 to C10 alkylcarbonyl, C1 to C10 hydroxyalkyl, C1 to C10 haloalkyl, and/or phenyl (optionally substituted with one or more of hydroxy and/or C1 to C5 alkoxy); Cs to C16 cycloalkylphenyl, C10 to C18 cycloalkylalkylphenyl, C8 to C18 cycloalkyloxyphenyl, Cos to C1, cycloalkylthiophenyl, 9,10-dihydroanthryl, 5,6,7,8tetrahydroanthryl, 9,10-dihydrophenanthryl, 1,2,3,4,5,6,7,8-octahydrophenanthryl, indenyl, indanyl, fluorenyl, acenaphthenyl, phenylthiophenyl, isochromanyl, 2,3dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, thioxanthenyl, 2H-chromenyl, 3 ,4-dehydro- 1 -isochromanyl, 4H-chromenyl, indolinyl, isoindolinyl, 1,2,3,4tetrahydroquinolyl, or 1,2,3,4-tetrahydroisoquinolyl, the optional substitution being by one or more of halo, nitro, cyano, hydroxy, C1 to C10 alkyl, C1 to C10 alkoxy, C2 to C20 dialkylamino, sulfoamino, carbamoyl, C3 to C10 N,Ndialkylcarbamoyl, amino, 1to C10 alkylamino, mercapto, C1 to C10 alkylthio, C7 to C12 aralkyl, carboxyl. C2 to C10 alkoxycarbonyl, C2 to C10 carboxyalkyl, C1 to C10 acylamino, C to C10 alkylcarbonyl, C1 to C10 hydroxyalkyl, C1 to C10 haloalkyl, oxo, and/or phenyl (optionally substituted with one or more of hydroxyl and/or C, to C5 alkoxy).9. An N2-arylsulfonyl-L-argininamide as claimed in claim 1 wherein R is as defined in claim 1 and Ar is phenyl substituted with at least one of alkyl or alkoxy, the number of the carbon atoms of each substituent which is attached to the phenyl being 3 to 7 and the said phenyl being optionally substituted further with one or more of methyl, ethyl, methoxy, ethoxy, hydroxy and/or halo.10. An N,-arylsulfonyl-L-argininamide having the formula (I) as defined in claim 1 wherein R iswherein R8, R, and p are as defined in claim 1, R, and R, are substituted as defined in claim 1, and Ar is naphthyl substituted with at least one of halo, nitro, cyano, hydroxy, C1 to C10 alkyl or C2 to C20 dialkylamino and at least one of sulfoamino, carbamoyl, C3 to C10 N,N-dialkylcarbamoyl, amino, C1 to C10 alkylamino, mercapto, C1 to C10 alkylthio, C, to C10 aralkyl, carboxyl, C2 to C10 alkoxycarbonyl, C2 to C10 carboxyalkyl, C1 to C10 acylamino, C2 to C10 alkylcarbonyl, C1 to C10 hydroxyalkyl, C1 to C10 haloalkyl, and/or phenyl (optionally substituted with one or more of hydroxy and/or C1 to C5 alkoxy); naphthyl substituted with at least one C1 to C5 alkoxy and at least one of sulfoamino, carbamoyl, C3 to C10 N,N-dialkylcarbamoyl, amino, C1 to C10 alkylamino, mercapto, C1 to C10 alkylthio, C, to C12 aralkyl, carboxyl, C2 to C10 alkoxycarbonyl, C2 to C10 carboxyalkyl, C1 to C,0 acylamino, C2 to C10 alkylcarbonyl, C1 to C10 hydroxyalkyl, C1 to C10 haloalkyl, and/or phenyl (optionally substituted with one or more of hydroxy and/or C1 to C5 alkoxy); phenyl or naphthyl substituted with at least one of sulfoamino, carbamoyl, C3 to C10 N,N-dialkylcarbamoyl, amino, C1 to C10 alkylamino, mercapto, C, to C10 alkylthio, C7 to C12 aralkyl, carboxyl, C2 to C10 alkoxycarbonyl, C2 to C10 carboxyalkyl, C, to C10 acylamino, C2 to C10 alkylcarbonyl, C, to C10 hdyroxyalkyl, C, to C10 haloalkyl, and/or phenyl (optionally substituted with one or more of hydroxy and/or C1 to C5 alkoxy); tetrahydronaphthyl substituted with at least one of halo, nitro, cyano, hydroxy, sulfoamino, carbamoyl, C3 to C10 N,N-dialkylcarbamoyl, amino, C1 to C10 alkylamino, mercapto, C1 to C10 alkylthio, C, to C12 aralkyl, carboxyl, C2 to C10 alkoxycarbonyl, C2 to C10 carboxyalkyl, C1 to C10 acylamino, C2 to C10 alkylcarbonyl, C1 to C10 hydroxyalkyl, C1 to C10 haloalkyl, or phenyl (optionally substituted with one or more of hydroxy and/or C, to C8 alkoxy); optionally substituted C8 to C1r, cycloalkylphenyl, C10 to C18 cycloalkylalkylphenyl, C8 to C16 cycloalkylphenyl, C8 to C1r, cycloalkylthiophenyl, C, to C12 aralkyl, 9,10dihydroanthryl, 5,6,7 ,8-tetrahydroanthryi, 9,10-dihydrophenanthryl, 1,2,3,4,5,6,7,8octahydrophenanthryl, indenyl, indanyl, fluorenyl, acenaphthenyl, phenylthiophenyl, isochromanyl, 2,3-dihydrobenzofuranyl, 1 ,3-dihydroisobenzofuranyl, thioxanthenyl, 2H-chromenyl, 3,4-dehydro-1-isochromanyl, 4H-chromenyl, indolinyl, isoindolinyl, 1,2,3 ,4-tetrahydroquinolyl or 1,2,3 ,4-tetrahydroisoquinolyl, the optional substitution being by one or more of halo, nitro, cyano, hydroxy, C1 to C10 alkyl, C1 to C10 alkoxy, C2 to C20 dialkylamino, sulfoamino, carbamoyl, C3 to C10 N,N-dialkylcarbamoyl, amino, C1 to C10 alkylamino, mercapto, C1 to C10 alkylthio, C, to C12 aralkyl, carboxyl, C2 to C10 alkoxycarbonyl, C2 to C10 carboxyalkyl, C, to C10 acylamino, C2 to C10 alkylcarbonyl, C1 to C10 hydroxyalkyl, C1 to C10 haloalkyl, oxo and/or phenyl (optionally substituted with one or more of hydroxy and/or C1 to C5 alkoxy); optionally substituted naphthoquinonyl, anthryl, phenanthryl, pentalenyl, heptalenyl, azulenyl, biphenylenyl, asymmetrical or symmetrical-indacenyl, acenaphthylenyl, phenylcarbonylphenyl, phenoxyphenyl, benzofuranyl, isobenzofuranyl, benzo(b)thienyl, isobenzothienyl, thianthrenyl, dibenzothienyl, phenoxathiinyl, indolyl, I H-indazolyl, quinolyl, isoquinolyl, phthalazinyl, 1,8-naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl or benzimidazolyl, the optional substitution being by one or more of halo, nitro cyano, hydroxy, C1 to C10 alkyl, Ct to C10 alkoxy, C2 to C20 dialkylamino, sulfoamino, carbamoyl, C3 to C10 N,N-dialkylcarbamoyl, amino, C1 to C10 alkylamino, mercapto, C1 to C10 alkylthio, C, to C12 aralkyl, carboxyl, C2 to C10 alkoxycarbonyl, C2 to C10 carboxyalkyl, C, to C10 acylamino, C2 to C10 alkylcarbonyl, C1 to C,, hydroxyalkyl, C, to C10 haloalkyl, and/or phenyl (optionally substituted with one or more of hydroxy and/or C, to C5 alkoxy).11. 1 - [N(quinoline-8-sulfonyl)-L-arginyl] -4-methyl-2-piperidinecarboxylic acid.12. 1 - [N2-(3-methylquinoline-8-suffonyt)-L-argfnyti-4-methyl-2-piperidine- carboxylic acid.13. 1- [N2-(3-ethylquinoline-8-sulfonyl)- L-arginyl]-4-methyl-2-piperidine- carboxylic acid.14. I-EN2-(3-sec-butoxybenzene-l-sulfonyl)-L-arginyl]-4-methyl-2-piperidine- carboxylic acid.15. 1-[N2-(3,5-dimethyl-4-isopropoxybenzene-1-sulfonyl)-L-arginyl]-4-methyl2-piperidinecarboxylic acid.16. 1 -LN2-(2,4-dimethoxy-3-butoxybenzene- 1 -sulfonyl)-L-arginyl)-4-methyl- 2-piperidinecar60xylic acid.17. I - [N2-(3-isopropoxybenzene- 1 -sulfonyl)-L-arginyl)-4-methyl-2-piperidinecarboxylic acid.18. N-(2-phenoxathiinylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine.19. N2-(2-fluorenesulfonyl)-L-arginyl-N-(2-methoxyethyl)-glycine.20. 1-[N-(4-methoxy-3-cyclohexylbenzene-1-sulfonyl)-L-arginyl]-4-methyl-2piperidinecarboxylic acid.21. A compound as claimed in claim and identified by name of formula in any one of the specific Examples or in any entry in Table 1 or Table 2.22. A pharmaceutically acceptable or veterinarily acceptable salt of a compound as claimed in any preceding claim.23. A process for producing an N2-arylsulfonyl-L-argininamide having the formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof, wherein R and Ar are defined in claim 1, which process comprises removing the or each NG-substituent from an NG-substituted-N2-arylsulfonyl-L-argininamide having the formulawherein r and Ar are as defined herein above; R' and R" are independently hydrogen or a protective group for the guanidino group, at least one of R' and R" being such a protective group, by means cf acidolysis or hydrogenolysis, and, if desired, neutralising or salifying the reaction product obtained above.24. A process as claimed in claim 23 wherein said acidolysis is effected by contacting the N0-substituted-N2-arylsuffonyl-L-argininamide with an excess of an acid at a temperature of -10 C to 100 C.25. A process as claimed in claim 23 wherein said hydrogenolysis is effected in a reaction-inert solvent in the presence of a hydrogen-activating catalyst in a hydrogen atmosphere at a temperature of from 0 C to the boiling temperature of the solvent.26. A process for producing an N2-arylsulfonyl-L-argininamide having the formula (I) as defined in claim 1 or a pharmaceutically or veterinarily acceptable salt thereof, wherein R and Ar are as defined in claim 1, which process comprises reacting an N2-arylsulfonyl-L-arginyl halide having the formula:wherein Ar is as defined herein above and X is halogen, with an amino acid derivative having the formula: RH wherein R is as defined in claim 1, and, if desired salifying the reaction product obtained above.27. A process as claimed in claim 26 wherein the N2-arylsulfonyl-L-arginyl halide is contacted with at least an equimolar amount of the amino acid derivative at a temperature of from -10 C to +800C.28. A process as claimed in claim 23 or claim 26 substantially as hereinbefore described in any one of specific Examples 1 to 3 or substantially as described in any of Examples 1 to 3 as modified by any entry of Table 1 or Table 2.29. A process as claimed in any one of claims 23 to 28 wherein the NO- substitutted-N2-arylsulfonyl-L-argininamide or the N2-arylsulfonyl-L-arginyl halide has been produced by a process including the step of reacting an L-argininamide with an arylsulfonyl halide.30. A process as claimed in claim 29 wherein the arylsulfonyl halide is one hereinbefore identified by its formula in Table 3.31. A process as claimed in claim 29 or claim 30 wherein the arylsulfonyl chloride has been prepared by halogenating an arylsulfonate or arylsulfonic acid.32. A process as claimed in claim 31 wherein the arylsulfonyl chloride has been produced substantially as hereinbefore described in Preparation A or Preparation B, or substantially as described in either of these preparations modified by any entry of Table 3.33. A compound of the Formula (I) as defined in claim 1 or a pharmaceutically or veterinarily acceptable salt thereof when prepared by a process as claimed in any of claims 23 to 32.34. A pharmaceutical or veterinary formulation comprising a compound as claimed in any one of claims 1 to 22 or claim 33.35. A pharmaceutical or veterinary composition comprising a compound as claimed in any one of claims 1 to 22 or claim 33 and a pharmaceutically or veterinarily acceptable carrier therefor.36. A formulation or composition as claimed in claim 34 or 35 in unit dosage form.37. A formulation or composition as claimed in claim 36 in the form of a tablet, capsule, powder packet, lozenge or troche.38. An injectable formulation or an orally administrable formulation comprising a liquid and a compound as claimed in any one of claims 1 to 24 or claim 35.39. A pharamaceutical composition substantially as hereinbefore described in any one of Examples S to 7.
Applications Claiming Priority (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US05/760,745 US4066773A (en) | 1974-11-08 | 1977-01-19 | N2 -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof |
| US05/760,668 US4073913A (en) | 1974-11-08 | 1977-01-19 | N2 -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof |
| US05/760,929 US4101653A (en) | 1974-11-08 | 1977-01-19 | N2 -arylsulfonyl-argininamides and the pharmaceutically acceptable salts thereof |
| US05/760,672 US4093712A (en) | 1974-11-08 | 1977-01-19 | N2 -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof |
| US05/760,676 US4097472A (en) | 1974-11-08 | 1977-01-19 | N2 -arylsulfonyl-l-argininamides and the pharmaceutically acceptable salts thereof |
| US05/776,195 US4097591A (en) | 1974-11-08 | 1977-03-10 | N2 -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof |
| JP6650877A JPS6010028B2 (en) | 1977-06-06 | 1977-06-06 | N↑2-arylsulfonyl-L-argininamides and pharmaceutically acceptable salts thereof |
| US05/804,368 US4131673A (en) | 1974-11-08 | 1977-06-07 | N2 -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof |
| US05/804,331 US4140681A (en) | 1974-11-08 | 1977-06-07 | N2 -Arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB1596971A true GB1596971A (en) | 1981-09-03 |
Family
ID=27577127
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB2063/78A Expired GB1596971A (en) | 1977-01-19 | 1978-01-18 | N2-arylsulfonyl-l-argininamides and the pharmaceutically acceptable salts thereof |
Country Status (17)
| Country | Link |
|---|---|
| CA (1) | CA1131621A (en) |
| CH (2) | CH633773A5 (en) |
| DD (1) | DD137352A5 (en) |
| DE (1) | DE2801478A1 (en) |
| DK (1) | DK150521C (en) |
| FI (1) | FI72316C (en) |
| GB (1) | GB1596971A (en) |
| GR (1) | GR60787B (en) |
| IL (1) | IL53685A (en) |
| IT (1) | IT1126229B (en) |
| NL (1) | NL187746C (en) |
| NO (1) | NO158681C (en) |
| NZ (1) | NZ186198A (en) |
| PH (1) | PH15913A (en) |
| SE (1) | SE452624B (en) |
| SU (1) | SU1181539A3 (en) |
| UA (1) | UA8370A1 (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IE48623B1 (en) * | 1978-08-31 | 1985-03-20 | Mitsubishi Chem Ind | Alpha-(n-arylsulfonyl-l-argininamides,processes for their preparation and pharmaceutical compositions containing these substances |
| SU1042615A3 (en) * | 1978-08-31 | 1983-09-15 | Мицубиси Кемикал Индастриз Лимитед (Фирма) | Process for preparing n2-arylsulfonyl-alpha-arginine amides |
| GB9209032D0 (en) * | 1992-04-25 | 1992-06-10 | Ciba Geigy Ag | New peptide derivatives |
| GB9426038D0 (en) | 1994-12-22 | 1995-02-22 | Iaf Biochem Int | Low molecular weight bicyclic thrombin inhibitors |
| US6057314A (en) * | 1995-12-21 | 2000-05-02 | Biochem Pharma Inc. | Low molecular weight bicyclic thrombin inhibitors |
| FR2761065B1 (en) * | 1997-03-20 | 2000-03-03 | Synthelabo | N- (ARGINYL) BENZENESULFONAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| CN111961114A (en) * | 2020-08-03 | 2020-11-20 | 扬州中宝药业股份有限公司 | Argatroban intermediate and preparation method and application thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3978045A (en) * | 1973-08-13 | 1976-08-31 | Mitsubishi Chemical Industries Ltd. | N2 -dansyl-L-arginine derivatives, and the pharmaceutically acceptable acid addition salts thereof |
-
1977
- 1977-12-16 CA CA293,199A patent/CA1131621A/en not_active Expired
- 1977-12-23 IL IL53685A patent/IL53685A/en unknown
- 1977-12-27 IT IT31297/77A patent/IT1126229B/en active
-
1978
- 1978-01-10 FI FI780073A patent/FI72316C/en not_active IP Right Cessation
- 1978-01-11 NZ NZ186198A patent/NZ186198A/en unknown
- 1978-01-13 DE DE19782801478 patent/DE2801478A1/en active Granted
- 1978-01-13 PH PH20660A patent/PH15913A/en unknown
- 1978-01-13 NL NLAANVRAGE7800448,A patent/NL187746C/en not_active IP Right Cessation
- 1978-01-17 SE SE7800512A patent/SE452624B/en not_active IP Right Cessation
- 1978-01-18 DK DK026378A patent/DK150521C/en not_active IP Right Cessation
- 1978-01-18 GR GR55191A patent/GR60787B/en unknown
- 1978-01-18 NO NO780191A patent/NO158681C/en unknown
- 1978-01-18 UA UA2776611A patent/UA8370A1/en unknown
- 1978-01-18 GB GB2063/78A patent/GB1596971A/en not_active Expired
- 1978-01-18 CH CH51978A patent/CH633773A5/en not_active IP Right Cessation
- 1978-01-18 SU SU782566652A patent/SU1181539A3/en active
- 1978-01-18 CH CH4530/82A patent/CH648293A5/en not_active IP Right Cessation
- 1978-01-19 DD DD78203302A patent/DD137352A5/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NL7800448A (en) | 1978-07-21 |
| DE2801478A1 (en) | 1978-07-20 |
| CH648293A5 (en) | 1985-03-15 |
| UA8370A1 (en) | 1996-03-29 |
| PH15913A (en) | 1983-04-22 |
| FI72316B (en) | 1987-01-30 |
| SE7800512L (en) | 1978-07-20 |
| CA1131621A (en) | 1982-09-14 |
| NO158681C (en) | 1988-10-19 |
| IT1126229B (en) | 1986-05-14 |
| NO780191L (en) | 1978-07-20 |
| NO158681B (en) | 1988-07-11 |
| CH633773A5 (en) | 1982-12-31 |
| IL53685A0 (en) | 1978-03-10 |
| DK150521C (en) | 1987-10-19 |
| DD137352A5 (en) | 1979-08-29 |
| SU1181539A3 (en) | 1985-09-23 |
| GR60787B (en) | 1978-08-28 |
| IL53685A (en) | 1985-12-31 |
| FI780073A (en) | 1978-07-20 |
| DK26378A (en) | 1978-07-20 |
| DE2801478C2 (en) | 1991-01-31 |
| NZ186198A (en) | 1980-12-19 |
| DK150521B (en) | 1987-03-16 |
| SE452624B (en) | 1987-12-07 |
| FI72316C (en) | 1987-05-11 |
| NL187746B (en) | 1991-08-01 |
| NL187746C (en) | 1992-01-02 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PS | Patent sealed [section 19, patents act 1949] | ||
| 704A | Declaration that licence is not available as of right for an excepted use (par. 4a/1977) | ||
| PE20 | Patent expired after termination of 20 years |
Effective date: 19980117 |