IE44361B1 - N2-arylsulfonyl-l-argininamides and the pharmaceutically acceptable salts thereof - Google Patents
N2-arylsulfonyl-l-argininamides and the pharmaceutically acceptable salts thereofInfo
- Publication number
- IE44361B1 IE44361B1 IE331/79A IE33179A IE44361B1 IE 44361 B1 IE44361 B1 IE 44361B1 IE 331/79 A IE331/79 A IE 331/79A IE 33179 A IE33179 A IE 33179A IE 44361 B1 IE44361 B1 IE 44361B1
- Authority
- IE
- Ireland
- Prior art keywords
- naphthylsulfonyl
- alkyl
- arginyl
- compound
- dimethoxy
- Prior art date
Links
- 150000003839 salts Chemical class 0.000 title description 18
- -1 cyano, hydroxy Chemical group 0.000 claims description 152
- 125000000217 alkyl group Chemical group 0.000 claims description 72
- 150000001875 compounds Chemical class 0.000 claims description 70
- 238000000034 method Methods 0.000 claims description 42
- 229910052739 hydrogen Inorganic materials 0.000 claims description 41
- 239000001257 hydrogen Substances 0.000 claims description 40
- 125000003545 alkoxy group Chemical group 0.000 claims description 32
- 230000008569 process Effects 0.000 claims description 24
- 125000004432 carbon atom Chemical group C* 0.000 claims description 22
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 18
- 150000002431 hydrogen Chemical group 0.000 claims description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 17
- 125000003342 alkenyl group Chemical group 0.000 claims description 13
- 125000000304 alkynyl group Chemical group 0.000 claims description 13
- 150000003862 amino acid derivatives Chemical class 0.000 claims description 13
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 12
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 12
- ULEBESPCVWBNIF-BYPYZUCNSA-N L-arginine amide Chemical compound NC(=O)[C@@H](N)CCCNC(N)=N ULEBESPCVWBNIF-BYPYZUCNSA-N 0.000 claims description 11
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 11
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims description 11
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 125000004494 ethyl ester group Chemical group 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 125000001624 naphthyl group Chemical group 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 7
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 6
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 6
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 239000003826 tablet Substances 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 5
- 239000002775 capsule Substances 0.000 claims description 5
- 230000000694 effects Effects 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 4
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 3
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 3
- 230000004913 activation Effects 0.000 claims description 3
- 150000001718 carbodiimides Chemical class 0.000 claims description 3
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 3
- 238000001727 in vivo Methods 0.000 claims description 3
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 239000007937 lozenge Substances 0.000 claims description 2
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 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 claims description 2
- GAZRNXIMWKZADY-UHFFFAOYSA-N 3,5-dimethylpyrazole-1-carboximidamide Chemical compound CC=1C=C(C)N(C(N)=N)N=1 GAZRNXIMWKZADY-UHFFFAOYSA-N 0.000 claims 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 47
- 239000000243 solution Substances 0.000 description 43
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 41
- 239000000843 powder Substances 0.000 description 40
- 239000002904 solvent Substances 0.000 description 37
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 36
- 238000007792 addition Methods 0.000 description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 31
- 238000004458 analytical method Methods 0.000 description 30
- 230000015271 coagulation Effects 0.000 description 27
- 238000005345 coagulation Methods 0.000 description 27
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 26
- 238000002360 preparation method Methods 0.000 description 25
- 239000000523 sample Substances 0.000 description 24
- 239000004471 Glycine Substances 0.000 description 23
- 229960002449 glycine Drugs 0.000 description 23
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 22
- 239000000047 product Substances 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 13
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 13
- 235000019441 ethanol Nutrition 0.000 description 12
- 239000000203 mixture Substances 0.000 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 description 11
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 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 10
- 239000011541 reaction mixture Substances 0.000 description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 150000002148 esters Chemical class 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 108090000190 Thrombin Proteins 0.000 description 8
- 238000009833 condensation Methods 0.000 description 8
- 230000005494 condensation Effects 0.000 description 8
- 229960004072 thrombin Drugs 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 7
- 238000001704 evaporation Methods 0.000 description 7
- 230000008020 evaporation Effects 0.000 description 7
- 239000004615 ingredient Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 239000000908 ammonium hydroxide Substances 0.000 description 6
- 230000002785 anti-thrombosis Effects 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- 238000006482 condensation reaction Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 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
- 208000007536 Thrombosis Diseases 0.000 description 5
- 229940000635 beta-alanine Drugs 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 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 description 5
- 229940012952 fibrinogen Drugs 0.000 description 5
- 238000007327 hydrogenolysis reaction Methods 0.000 description 5
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 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 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 4
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 4
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-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
- 150000001408 amides Chemical class 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 4
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 4
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 4
- 230000002140 halogenating effect Effects 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- YAVXLTMRALFZIS-UHFFFAOYSA-N piperidine-2-carbonitrile Chemical class N#CC1CCCCN1 YAVXLTMRALFZIS-UHFFFAOYSA-N 0.000 description 4
- 125000003386 piperidinyl group Chemical group 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- RRWZZMHRVSMLCT-UHFFFAOYSA-N 2-(butylazaniumyl)acetate Chemical compound CCCCNCC(O)=O RRWZZMHRVSMLCT-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 235000004279 alanine Nutrition 0.000 description 3
- 239000003146 anticoagulant agent Substances 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 3
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- NTNZTEQNFHNYBC-UHFFFAOYSA-N ethyl 2-aminoacetate Chemical compound CCOC(=O)CN NTNZTEQNFHNYBC-UHFFFAOYSA-N 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 3
- 150000003053 piperidines Chemical class 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 238000001226 reprecipitation Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- TXTWXQXDMWILOF-UHFFFAOYSA-N (2-ethoxy-2-oxoethyl)azanium;chloride Chemical compound [Cl-].CCOC(=O)C[NH3+] TXTWXQXDMWILOF-UHFFFAOYSA-N 0.000 description 2
- 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 2
- RNHDAKUGFHSZEV-UHFFFAOYSA-N 1,4-dioxane;hydrate Chemical compound O.C1COCCO1 RNHDAKUGFHSZEV-UHFFFAOYSA-N 0.000 description 2
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 description 2
- RHLQNMMWMDYKFY-UHFFFAOYSA-N 2-(2-methoxyethylazaniumyl)acetate Chemical compound COCCNCC(O)=O RHLQNMMWMDYKFY-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 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
- 125000000143 2-carboxyethyl group Chemical group [H]OC(=O)C([H])([H])C([H])([H])* 0.000 description 2
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 2
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 2
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 2
- ZYUZLEUJKZZXNN-UHFFFAOYSA-N C1=CC(CC(N)C(O)=O)=CC=C1OS(=O)(=O)C1=CC=C(C=CC=C2)C2=C1 Chemical group C1=CC(CC(N)C(O)=O)=CC=C1OS(=O)(=O)C1=CC=C(C=CC=C2)C2=C1 ZYUZLEUJKZZXNN-UHFFFAOYSA-N 0.000 description 2
- 235000008733 Citrus aurantifolia Nutrition 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 229930064664 L-arginine Natural products 0.000 description 2
- 235000014852 L-arginine Nutrition 0.000 description 2
- 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 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 235000011941 Tilia x europaea Nutrition 0.000 description 2
- 125000006350 alkyl thio alkyl group Chemical group 0.000 description 2
- 229960004676 antithrombotic agent Drugs 0.000 description 2
- 238000005976 benzyloxycarbonylation reaction Methods 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 2
- CAFRQFYFJDTUNI-UHFFFAOYSA-N ethyl 2-(2-methoxyethylamino)acetate Chemical compound CCOC(=O)CNCCOC CAFRQFYFJDTUNI-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- FCQJEPASRCXVCB-UHFFFAOYSA-L flavianate Chemical compound C1=C(S([O-])(=O)=O)C=C2C([O-])=C([N+]([O-])=O)C=C([N+]([O-])=O)C2=C1 FCQJEPASRCXVCB-UHFFFAOYSA-L 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 125000001188 haloalkyl group Chemical group 0.000 description 2
- 230000026030 halogenation Effects 0.000 description 2
- 238000005658 halogenation reaction Methods 0.000 description 2
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Landscapes
- Hydrogenated Pyridines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
This invention relates to N -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof.
In the past, there have been many attempts to obtain new and improved agents for the treatment of thrombosis. The ^-(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 10 particularly useful as highly specific inhibitors of thrombin for tho control of thrombosis is the N -dansyl-L-arginine ester or amide. (Our U.S. Patent Specification No. 3,978,045).
However, there is a continuing need for a highly specific inhibitor on thrombin for the control of thrombosis, which exhibits lower toxicity.
It has been discovered that N -arylsulfonyl-L-argininamides exhibit antithrombotic activity and even lower toxicity levels 2 at the same, relative potencies, as compared with the N -dansylL-arginine ester or amide.
This specification is divided out from that filed in respect of Application No 44360 in wlich is described and claimed:2 An N'-arylsulfonyl-L-argininamide having the formula: HN; '· ο- N - OH-CH-CH-CHCOR I 2 2 2I .
H HNSOI 2 Ar (I) or a pharmaceutically acceptable salt thereof, wherein R is (1) -N <^CI,2)nC0OR2 wherein Rg is C2~Cg0 alkyl, C3-CgQ alkenyl, C3-CgQ alkynyl, C2*ClO alkoxyalkyl, C2~Cg0 alkylthioalkyl, C2~Cg0 alkylsulfinyl5 alkyl, Cg-CgQ hydroxyalkyl, C2~CgCl carboxyalkyl, C3~Cg0 alkoxycarbonylalkyl, C3_C-'1O alkylearbonyl alkyl, Cl-C10 hal oalkyl, 0^-0^ aralkyl, Cg-Cgg (ζ-carboxyaralkyl, C3~Cg0 cycloalkyl, C4~Cg0 cycloalkylalkyl, furfuryl, tetrahydrofurfury1 optionally substituted with one or more Cg-Cg alkyl and/or Cg-Cg alkoxy groups, 3-furyImethyI, tetrahydro-3-furylmethyl optionally substituted with one or more Cg-Cg alkyl or Cg-Cg alkoxy groups, tetrahydro2(3 or 4)-pyranylmethyl optionally substituted with one or more Cg-Cg alkyl and/or Cg-Cg alkoxy groups, 1,4-dioxa-2-cyclohexylmethyl optionally substituted with one or more Cg-Cg alkyl and/or Cg-Cg alkoxy groups, 2-thenyl, 3-thenyl, tetrahydro-2-thenyl, optionally substituted with one or more Cg-Cg alkyl or Cg-Cg alkoxy groups, or tetrahydro-3-thenyl; R2 is hydrogen, crcio alkyl, C^-Cg^ aryl, Cy-Cg2 aralkyl or 5-indanyl; and n is 1, 2 or 3, (2) _n/!<3 wherein R3 is hydrogen, Cg-CgQ alkyl, XCU-(CH2)nCOORg R4 C3-CgQ alkenyl, C3-CgQ alkynyl, C2~Cg0 alkoxyalkyl, C2~Cg0 alkylthioalkyl, C2~Cg0 alkylsulfinylalkyl, Cg-CgQ hydroxyalkyl, C2"Cg0 carboxyalkyl, C3~Cg0 alkoxyoarbonylalkyl, C3-CgQ alkylr carbonylaLkyl, Cg-C^ haloalkyl, Cy-Cgg aralkyl, Cg-Cg5 ik-carboxyaralky C3"Cg0 cycloalkyl, C4-CgQ cycloalkylalkyl, furfuryl, tetrahydrofurfuryl optionally substituted with one or more Cg-Cg alkyl or Cg-Cg alkoxy groups, 3-furylmethyl, tetrahydro-3-furylmethyl, 3. optionally substituted with one or more C^-Cg alkyl or C^-Cg alkoxy groups, tetrahydro-2(3 or 4)-pyranylmethyl optionally substituted with one or more C-^-Cg alkyl and/or'C-^-Cg alkoxy groups, l,4-dioxa-2-cyclohexylmethyl optionally substituted with one or more C^-Cg alkyl and/or C^-Cg alkoxy groups,2-thenyJ., 3-thenyl, totrahydro-2-thenyl optionally substitured with one or more C-^-Cg alkyl or C^-Cg alkoxy groups, or tetrahydro-3-thenyl; R4 is alkyl, carboxy, C2-Clo alkoxycarbonyl, phenyl optionally substituted with one or mere Cj-Cg alkyl or C^-Cg alkoxy groups, C7~C^2 aralkyl or ring substituted benzyl wherein said substituent is C-^-Cg alkyl or C^-Cg alkoxy; Rg is hydrogen, C^-C^o alkyl, Cg-C^ aryl, C7~C^2 aralkyl or 5-indanyl; and m is 0, 1 or 2, X6 (3) wherein Rg is -COORg wherein Κθ is hydrogen (R7>p Cj-C^0 alkyl, Cg-C^0 aryl, C7~C-^2 aralkyl or 5-indanyl; each R7 independently is hydrogen, C-^-C^q alkyl, phenyl^C^-Cg alkoxy or carboxy; p is an integer of i to 5, Rg is substituted into the piperidene ring at the 2 or 3-position; and R7 is substituted int· the piperidine ring at the 2, 3, 4, 5 or 6-position COORn (4) (Ch optionally substituted with one or more C^-Cg alkyl or C-^-Cg alkoxy groups, wherein Rg is hydrogen, C-^-C^q alkyl, Cg-Ο^θ aryl, C7’CI2 aralkyl or 5-indanyl; and r is 1, 2, 3, or 4, Ri0 (5) -N \ctt2)c/ wherein R^ is hydrogen, Ο-^-Ο^θ alkyl, Cg-C-^θ aryl, 1C7~C12 ardlkyl or 5-indanyl; Z is oxy, thio or sulfinyl; and q is 0 or 1, or .4.
I (6) -Ν COORn Λ°Π2) wherein RX1 is hydrogen, Ω-^-Ω^θ alkyl,· Cg-CjQ aryl, c7~ci2 aralkyl or 5-indanyl; i is 0, 1 or 2; j is 0, or 2; and the sum i + j is 1 or 2; and Ar is naphthyl, 5,8,7,8tetrahydronaphthyl optionally substituted with one or more Ωχ-Ω5 alkyl or Ω^-Cj alkoxy groups, naphthyl substituted with at least one substituent which is halo, nitro, cyano, hydroxy, cx_c10 alkyl cl-G10 a^-koxy or C2~C2O dialkylamino, phenyl, phenyl substituted with at least one· substituent which is halo, nitro, cyano, hydroxy χ(°"2>ί each optionally substituted, with one or more C^-C^ alkyl or 0^-0^ alkoxy groups, wherein R12 is hydrogen, alkyl or θ£-ε10 alkoxy; provided that . χ·Η1 when R is;- (l) - N ''(CK^COORg wherein R^ is Cg—G-^θ alkyl, alkenyl, C^—Gjq alkynyl, 25 °2"C10 alkoxyalkyl, Gg-C10 carboxyalkyl, G^-C^ alkoxycarbonylalkyl, C7-G10 aralkyl, C^-C^ cycloalkyl or σ4~01θ cycloalkylalkyl; Rg is not hydrogen or G-j-C^q alkyl .
V. when R is:- (2) - N CH - (CH-) COORc i 2 m 5 R4 wherein R3 is hydrogen, C1-C10 alkyl, C3-C1O alkenyl, C3-C10 alkynyl, C2-Cxo aikoxyalkyl, C2--C10 carboxyalkyl, C3-C10 alkoxycarbonylalkyl, C7-C10 aralkyl, C3-C10 eyoloalkyl or Οή,-Οχο cycloalkylalkyl; and R4 is C--C-,- alkyl; R- is not hydrogen or Οχ-Οχο alkyl x 5 wherein Rg is -COORg wherein each R7 independently is hydrogen, Οχ-Οχο alkyl or C1-C5 alkoxy; p is an integer ol* 1 to 5; Rg is substituted into the piperidine ring at the 2 or 3-position; and R7 is substituted into the piperidine ring at tho 2, 3, 4, 5 or 6-position; R^ ia not C^ to Cg alkyl when R ia COORg (4) - N \cHa) optionally substituted with one or more C1-C5 alkyl ar C1-C5 alkoxy groups, Rg is not C-^-Cg alkyl COORjo when R is:- wherein Z is (5) - N oxy or thio; R1Q is not Οχ-Cg alkyl 6. and when R is:GOORxj )-(0¾) (6)'"\(ch2) Rgg is not Cg-Cg alkyl} if Ar is 5,6,7,3-tatrahydronaphthyl, naphthyl, 1-naphthyl substituted with one Bubfstltuent which is halogen, nitro, cyano, hydroxy, Cg-CgQ alkyl, C2-C20 dialkylamino, or Cg-CgQ alkoxy or 2-naphthyl substituted with one substituent which is halogen, nitro, cyano, hydroxy, Cg-Cg alkyl, Cp-C-,θ dialkylamino or O^-^jQ 7.
The present general formula specification relates to compounds of the CHgCEgCHgCBOOR (I) mm, I Ar wherein R is (1) - ν' (CH2)n000R2 wherein R^ is C2 C10 alkyl, G^-C10 alkenyl, Cg-C-^ alkynyl, C2~C10 alkoxyalkyl, Cg-C^Q carboxyalkyl, C^-C^q alkoxyoarbonylalkyl, Ηγ-Ο^θ aralkyl, C^-C^q cycloalkyl or C4-C10 eycloalkylalkyl; Rg is hydrogen or Cl-°10 alkyl; and n is . 1, 2 or 3, R„ (2) - N^ o: R OH - (CH2)m000R5 8. 4436 « wherein R3 is hydrogen, Cl-Cio alkyl, C3-CIO alkenyl, C3-C10 alkynyl, C2-C10 alkoxyalkyl, C2-C10 carboxyalkyl, ¢3-010 alkoxycarbonylalkyl, C7-C10 aralkyl, C3-C10 eycloalkyl or C/,-Οχο cycloalkylalkyl; R4 is C1--C10 alkyl; R5 is hydrogen or Οχ-Οχο alkyl; and m is 0, 1 or 2, wherein Rg is -COORs wherein Ηβ is C1-C9 alkyl; each Ry 10 independently is hydrogen, Οχ-Οχο alkyl or C1-C5 alkoxy; p is an integer of 1 to 5; Rg is substituted into the piperidino ring at the 2 or 3-position; and each Ry independently is substituted into the piperidine ring at the 2, 3, 4, 5 or 6-position, COOR9 ρ,) Hch2); optionally substituted with one or more C1-C5 alkyl or ¢1-05 alkoxy groups, wherein R9 is CI-C9 alkyl; and r is 1, 2, 3 or 4, COORiq /A (5) - Ν Z \ / V(ch4 wherein Rio is C1-C9 alkyl; Z is oxy or thio; and q is 0 25 or 1, or 9. j* 443G i COORjx >(θΗ2)χ· (6) - N< 11 X(CH2)/< wherein Rgg is Cg-Cg alkvl; i is 0, 1 or 2; j is 0, 1 or 2; and the sum i+j is 1 or 2; and Ar is 5,6,7,8-tetrahydronaphthyl, naphthyl, or 2-napbthyl substituted with one substituent which is halogen, nitro, cyano, hydroxy, Cg-Cg^ alkyl, Cg-C^.Q dialkylamino and Cg-Cg^ . 443C1 This invention also relates to a method for inhibiting activity and suppressing activation of thrombin in vivo, which comprises introducing into a living body a pharmaceutically effective amount of an N^-arylsulfonyl-l-argininamide of the invention or a pharmaceutically acceptable salt thereof. As stated above, in the formula:10 H hnso2 (I) R is:- (1) - N 000¾ I ' Ar wherein R^ is Ο^-Ο^θ alkyl such as ethyl, propyl, butyl, isobutyl, pentyl, hexyl, octyl, decyl or the like, alkenyl or 3-10 (preferably 3-6) carbon atoms, 3uch as allyl, 2-butenyl, 3-butenyl, 2,pentenyl or the like, alkynyl of 3-10 (preferably 3-6) carbon atoms, such as 2-propynyl, 2-butynyl, 3-butynyl or the like, alkoxyalkyl of 2-10 (preferably 2-6) carbon atoms, such as methoxymethyl, ethoxymethyl, propoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-propoxyethyl, 2-methoxypropyl, 3-methoxypropyl, 3-ethoxypropyl, 3-propoxypropyl, 4-methoxybutyl, 4-ethoxybutyl, 4-butoxybutyl, 5-butoxypentyl or the like, carboxyalkyl of 2-10 (preferably 2-7) carbon atoms, such as carboxymethyl, 2-carboxyethyl, 2-carboxypropy.l, 3-carboxypropyl, 1-carboxybutyl, 2-carboxybutyl, 4-carboxybutyl or the like, alkoxycarbonylalkyl of 3-10 (preferably 3-8) carbon atoms, such as methoxycarbonylmethyl, 2-etho»ycarbcqyletb|yl, 2-ethcxycarbonylp£X)pyl, 3-me-tixx carbonylpropyl, 1-methoxycarbonylbutyl, 2-ethoxycarbonylbutyl, 4-methoxycarbonylbutyl or tha like, aralkyl of 7-10 carbon atoms, such as bensyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 11. 1-phenylethyl, 2-phenylpropyl or the like, cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, cycloalkylalkyl, such as cyclopropyImethyl, eyclopentyImethyl, cyclohexyImethyl, 2-cyclohexyIethyl, cyclooctylmethyl or the like, Rg is hydrogen, C^-C^q alkyl, such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl, uecyl or the like, and n is 1, 2 or 3, (2) - N CH-(CHg)mC00R5 wherein R~ ίε 5 hydrogen, Cl-°10 alkyl, such as methyl, ethyl, propyl, butyl, isobutyl, pentyl, hexyl, octyl, decyl or the like, alkenyl of 3-10 (preferably 3-6) carbon atoms, such as allyl, 2-butenyl, 3-butenyl, 2-pentenyl or the like, alkynyl of 3-10 (preferably 3- 6) carbon atoms, such as 2-propynyl, 2-butynyl, 3-butynyl or the like, alkoxyalkyl of 2-10 (preferably 2-6) carbon atoms, such as methoxymetbyl, ethoxymethyl, propoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-propoxyethyl, 2-methoxypropyl, 3methoxypropyl, 3-ethoxypropyl, 3-propoxypropyl, 4-methoxybutyl, 4- ethoxybutyl, 4-butoxybutyl, 5-butoxypentyl or the like, carboxyalkyl of 2-10 (preferably 2-7) carbon atoms, such as carboxymethyl, 2-carboxyethyl, 2-carboxypropyl, 3-carboxypropyl, 1-carboxybutyl, 2-carboxybutyl, 4-carboxybutyl or the like, alkoxycarbonylalkyl of 3-10 (preferably 3-8) carbon atoms, such as methoxycarbonyImethyl, 2-methoxycarbonylethyl, 2ethoxycarbonylpropyl, 3-methoxycarbonylpropyl, 1-methoxycarbony Ibutyl , 2-ethoxycarbonylbutyl, 4-methoxycarbonylbutyl or the like, aralkyl of 7-10 carbon atoms, such as benzyl, phenethyl, 3-phenyJ propyl, 4-phenyIbutyl, 1-phenylethyl, 2-phenylpropyl or the like, C.^-G^ cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, eyclononyl or cyclodecyl, θ4-θιθ cycloalkylalkyl, such as cyclopropyImethyl, cyclopentyl5 methyl, cyclohexylmethyl, 2-cyclohexylethyl, cyelooctylmethyl or the like, R^ is alkyl of 1-10 (preferably 1-5) carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl or the like, R^ is hydrogen, or °lC10 alkyl, such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl, decyl or the like, and R, m is 0, 1 or 2, (3) -N wherein Rg is -COORg wherein Rg is C^-Cgalkyl, such as methyl, ethyl, propyl, butyl, tert-butyl hexyl, octyl or the like, each Ry independently is hydrogen, alkyl of 1-10 (preferably 1-6) carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, hexyl, octyl, decyl or the like, C^-C^ alkoxy; p is an integer of 1 to 5; Rg is substituted at the 2 or 3-position; and Ry is substituted at the 2, 3, 4, 5 or 6-position, COOKc, Q wherein R is 13.
Cg-Cg alkyl, such as methyl, ethyl, propyl, butyl, tertbutyl, hexyl, octyl, or the like, and r is 1, 2, 3 or 4, (5) - N Z wherein is C-^-Cg alkyl, such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl, or the like; Z is oxy (-0-), thio (-S-); q is 0 or 1, and C00Rn methyl, ethyl, propyl, butyl, tert-butyl, hexyl, octyl, or the like, 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 naphthyl, such as 1-naphthyl and 2-naphthyl, 5,6,7, 8-tetrahydronaphthyl, such as 5,6,7,8-tetrahydro-l-naphthyl and 5,6,7,8-tetrahydro-2-naphthyl, 1 or 2-naphthyl substituted with one substituent which is halo, such as fluoro, chloro, bromo and iodo, nitro, cyano, hydroxy, alkyl of 1-10 (preferably 1-5) carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or the like, alkoxy of 1-10 (preferably 1-5 carbon atoms, such as methoxy, ethoxy, propoxy isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy or the like and dialkylamino of 2-20 (preferably 2-10) carbon atoms, such as dimethylamino, diethylamino, N-methyl-N-ethylamino or the like 14. 443G1 OR optionally substituted with one or more Cg-C^ alkyl or Og-Cg alkoxy groups wherein R12 is hydrogen, alkoxy of 1-5 carbon atoms, such as methoxy, ethoxy, propoxy or the like.
Suitable illustrations of Rg in the above formula (I) are ^2^10 such as Ρ^θΡΥΐ, butyl, isobutyl, pentyl, hexyl and octyl, C^-Cg alkenyl such as allyl, C^-Cg alkynyl, such as 2-propynyl, C2-Cg alkoxyalkyl, such as 2-methoxyethyl, 2-methoxypropyl, 2-ethoxyethyl and 3-methoxypropyl, Cg-Cy carboxyalkyl, such as 1-carboxybutyl, C^-Cg alkoxycarbonylalkyl, such as 2-ethoxycarbonylethyl, Cy-Cgg aralkyl, such as , 4 3 61 benzyl and phenethyl, C^-G^q cycloalkyl, such as cyclopropyl·, cyclohexyl and cycloheptyl, and Cg-Cg0 cycloalkylalkyl, such as cyclohexylmethyl.
Suitable illustrations of R^ in the above formula (I) are hydrogen, Gl_G10 alkyl, such as methyl, propyl, butyl, isobutyl, pentyl, hexyl and octyl, C^-Cg alkenyl, such as allyl, Cj-Cg alkynyl, such as 2-propynyl, C2-Cg alkoxyalkyl, such as 2-methoxyethyl, 2-methoxypropyl, 2-ethoxyet-hyl and 3-methoxypropyl, Cg-Gy carboxyalkyl, such as 1-carboxybutyl, Cj-Οθ alkoxyoarbonylalkyl, such as 2-ethoxycarbonylethyl, G7-G10 ara-lkyl, such as benzyl and phenethyl and cycloalkyl, such as cyclopropyl, cyclohexyl and cycloheptyl, C^-CgQ cycloalkylalkyl, such as cyclohexylmethyl..
Suitable illustrations of R^ in the above formula (I) are Gg-Gg alkyl, such a:; methyl and propyl.
Suitable illustrations of Ry are hydrogen, C^-Gg alkyl, such as methyl, ethyl, propyl and isopropyl, phenyl and carboxy, and of the suitable position of Ry are 2, 4- or 6.
The preferred Ar groups are 1-naphthyl, 2-naphthyl, 5,6,7,8tetrahydro-l-naphthyl, 5,6,7,8-tetrahydro-2-naphthyl, 5chloro-l-naphthyl, 6-chloro-2-naphthyl, 6-bromo-l-naphthyl, 5-hydroxy-l-naphthyl, 7-hydroxy-2-naphthyl, 6-methyl-2naphthyl, 6-methyl-l-naphthyl, 7-methyl-l-naphthyl, 7-methyl-2-naphthyl, 6-ethyl-2-naphthyl, 6-isopropyl-2-naphthyl, -methoxy-l-naphthyl, 6-methoxy-2-naphthyl, 7-methoxy-2-naphthyl, 4,6-dimethoxy-2-naphthyl, 6,7-dimethoxy-2-naphthyl, 6,7diethoxy-2-naphthyl, 5-dimethylamino-l-naphthyl, 5diniethylamino-2-naphthyI, 5-diethylamino-l-naphthyl, 6-dimethylamino-l-naphthy1, 6-dime thylamin o-2-naphthyl, W' 16. 443G1 Illustrative of suitable N arylsulfonyl-L-argininamides of sufficient activity are the following: GOMPOW NUMBER:5 1 N2-(6,7-dimethoxy-2-naphthylsulfonyl)-l-arginyl-Npropylglycine p N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-Hpropylglycine tort-butyl ester p N'-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-H10 butylglycine N2-(6,7-dimethoxy-2-naphthylsulfonyl)-Ii-arginyl-Nbutylglyoine tert-butyl ester N -(6,7-dimethoxy-2-naphthylsulfonyl)-Ir-arginyl-Nisobutylglyoine 17. 4361 Ν —( 6,7-dime thoxy-2-naphthylsu lfonyl) -L-ar^iny.l-N— pentylglycine * · N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-Nhexylglycine β N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-Noctylglycine N -(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl-Nbutylglyeine N2-(6,7-diethoxy-2-naphthylsulfonyl)-L-arginyl-N10 butylglyoine N -(6-niethoxy-2-naphthylsulfoiiyl)-L-arginyl-N-butylglycine N -(5-methoxy-l-naphthylsull'onyl)-L-arginyl-N-butylglycine N -(7-methoxy-2-naph thylsulfonyl)-L-arginyl-N-propylg.lycine N -(7 -me thoxy-2-naphthylsulfonyl )-L-arginy,l~N-butylglycine N -(7~methoxy-2-naphthylsulfonyl)-L-arginyl-N-pentylglycinc N -(2-naphthylsulfonyl)-L-argiriyl-N-but.ylglycxne ;> N''-(2-naphlhyJ su 1 Cony I.)-L-arginyl -N-bu Lyl gl y o.i uo othyl ester 18. 4 3 81 Η* Ν' -(2-nnphth,vI -ail limy I)-1.-1rgj»v l.-N-huty Ι-β-η >unJnu 1<) Ν' —(‘>.6,7,8-te t. ιη hydro- L-tiaphthy 1 on I fonyl) -I.-:irg i ny I -Nbutyiglycine N2-(5,6.7,6-tetrahydro-2-naphthylsulfonyl)-L-arginyl-N5 pentylglycine N2-(5,6,7,8-tetrahydro-2-naphthylsulfonyl)-i-arginyl-Nbutyl-g-alanine N2-(6-broao-l-naphthylsulfonyl)-1-arginyl-N-butylglycine N2-(6-methyl-2-naphthylsulfonyl)-l-arginyl-N pentylglycine 24 N2-(7-metbyl-2-naphthylrulfonyl)-L-arginyl-N-butylglycine N2 -(5-dimethylaraino-l-naphthylsulfon.yl)-I-arginyl-Nbutylglycine N2-(6,7-dimethoxy-2-naphthylsulfonyl)-Ii-arginyl-N(2-methoxyethyl)glycine ethyl ester 27 N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N(2-methoxyethyl)glycine octyl ester o N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N(2-methoxyethyl)-β-alanine N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N20 (2-methoxyethyl)-P-alanine ethyl ester N2-(6,7-dimethoxy-2-naphthylsulfonyl)-N-(2-methoxyethyl)N-(3-carboxypropyl)-L-argininamide 19. 43 6 ί N -(6,7-dimethoxy-2-naphthylsulfonyl)-N"(2-methoxyethyl)N-3-tert-butoxycarbonylpropyl)-l-argininamide 1^-(6,7 -dimethoxy-2-naphthylsulfonyl)-1-arginyl-N-(3 methoxypropyl)glycine 33 1^-(5,7 -dimethoxy-2-naphthylsulfonyl)-Ii-arginyl-N(2-ethoxyethyl)-β-alanine N2-(6,7-dimethoxy-2-naphthylsulfonyl)-l-arginyl-N(2-methoxypropyl)glycine 1^-(6,7 -diethoxy-2-naphthylsulfonyl)-I-arginyl-N10 (2-methoxyethyl)glycine N2 -(4,6-dimethoxy-2-naphthylsulfonyl)-Ii-arginyl-N(2-methoxyethyl)glycine N^-(4,6-dimethoxy-2-naphthylsulfonyl)-l-arginyl-N(2-methoxyethyl)glycine ethyl ester 38 N2-(6-methoxy-2-naphthylsulfonyl)-l-arginy1-N-(2me thoxy ethyl) glycine N2-(5-methoxy-l-naphthylsulfonyl)-I-arginyl-N-(2me thoxye thyl) gly c ine N2-(7-methoxy-2-naphthylsulfonyl)-I-arginyl-N-(220 methoxyethyl)glycine N2 -(7-methoxy-2-naphthylsulfonyl)-Ii-arginyl-li—(2methoxyethyl)glycine ethyl ester o N -(5-methoxy-l-naphthylsulfonyl)-I-arginy1-N-(2methoxyethyl)-β-alanine .
V N2-(l-naphthylsulfonyl)-Ii-arginyl-Ii-(2-aethoxyethyl)glyciae Ν2-(5,6,7,8-tetrahydro-l-naphthylsulfonyl)-h-arginyl-N(2-methoxyethyl)glycine 45 N2-(5-chloro-l-naphthylsulfonyl)-I-arginyl-li-(2-methoxyethyl) glycine 11^-(6-chloro-2-naphthylsulfonyl)-I-arginyl-H-(2-methoxyethyl)glycine p N -(7-methyl-2-naphthylsulfonyl)-L-arginyl-N-(2~methoxy10 ethyl)glycine N2-(7-methyl-l-naphthylsulfonyl)-L-arginyl-N- (2-methoxyethyl)glycine p N -(5-dimethylamino-l-naph+hylsulfonyl)-1-arginyl-N-(2methoxyethyl)glycine 50 N2-(7-hydroxy-2-naphthylsulfonyl)-l-arginyl-N-(2-methoxyethyl)glycine N2—(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginy1-N(1-carboxybutyl)glyc ine N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N20 (2-ethoxycarbonyle thyl)glyc ine N2-(6,7-dimethoxy-2-naphthylsulfonyl)-l-arginyl-Nbenzylglycine 21. /- (6,7-dimethoxy-2-naphthylsulf onyl) -L-arginy 1-ΐΤbenzylglycine tert-butyl, ester /-(6,7-dimethoxy-2-naphthylsulfonyl)-1-arginyl-Nphenethylglycine 56 /-(6,7 -dimethoxy-2-naphthylsulfonyl)-L-arginy l-tibenzyl-p-alanine /-(6,7-dimethoxy-2-naphthylsulfonyl)-l-arginyl-ITbenzyl-p-alanine tert-butyl ester N -(6,7-dimethoxy-2-naphthylsulfonyl)-l-arginyl-If10 phenethyl-p-alanine /-(4,6-dimethoxy-2-naphthylsulfonyl)-l-arginyl-Nbenzylglycine N -(7-methoxy-2-naphthylsulfonyl)-l-arginyl-Nphenethylglycine 61 /-(7-methoxy-2-naphthylsulfonyl)-l-arginyl-II-benzyl-palanine /-(6-methoxy~2-naphthylsulfonyl)-N-b enzyl-N-(3earboxypropyl)-l-argininamide /-(6-methoxy-2-naphthylsulfonyl)-N-benzyl-N-(3-tert20 butoxycarbonylpropyl)-l-argininamide N-(5-methoxy-l-naphthylsulfonyl)-L-arginyl-Nbenzylglycine 22. 43G1 65 Ν2-(2-naphthylsulfonyl)-L-arginyl-N-benzyl-p-alanine 66 N2-(2-naphthylsulfonyl)-L-argiftyl-N-benzylglycine 67 N2-(5,6,7,8-tetrahydro-l-naphthylsulfonyl)-L-arginyl-N- phene thylglyc ine 5 68 N2-(5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl-Nbenzylglycine 69 N2-(5,6,7,8-tetrahydro-2-naphthylsulfonyl)-L-arginyl-ϊΓ- berzyl-p-alanine 70 N2-(7-methyl-2-naphthylsulfonyl)-l-arginyl-N-phenethyl- 10 glycine 71 N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N- cyclohexylme thylglyc ine 72 N2-(6,7-dimethoxy-2-naphthylsulfonyl)-1-arginyl-Ncyclohexylmethylg3ycine tert-butyl ester 15 73 N2-(6,7-dimethoxy-2-naphthylsulfonyl)-1-arginyl-Ncycloheptylglycine 74 N2-(4,6-dimethoxy-2-naphthylsulfonyl)-1-arginyl-Ncyolohexylglyoine 75 N2-(7-methoxy-2-naphthylsulfonyl)-I-arginyl-N-cycloheXyl- 20 glycine 76 p N- (6-methoxy-2-naphthylsulf onyl) -l-arginyl-N-cyclohaxyl- methylglyoine 23.
N2-(5-methoxy-l-naphthylsulf'onyl)-l-arginyl-IT-cyclohexylmethyl-p-alanine ρ Ν -(5-methoxy-l-naphthylsulfonyl)-L-arginyl-NcyclohexyImethyΙ-β-alanine tert-butyl ester 79 N2-(6,7-dimeth oxy-2-naphthylsulfonyl)-L-arginyl-Ncyclohexylglycine N2-(6,7-dimethoxy-2-naphthylsulfonyl)-1-arginyl-NcyclohexyΙ-β-alanine p N -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N10 cyclohexyl-β-alanine tert-butyl ester p N-cyclopropyl-N-(3-carboxypropyl)-N -(6,7-dimethoxy-2naphthylsulfonyl)-l-argininamide 1^-(1-naphthylsulfonyl)-L-arginyl-N-eyclohexylglycine P N - (5,6,7,8-tetrahydro-l-naphthylsulfonyl) -l-arginyl-ii15 cyclohexylglycine p N -(5,6,7,8-tetrahydro-2-naphthylstilfonyl)-I-arginyl-Ncyclohexylme thylglyc i ne N2-(7-methyl-2-naphthylsulfonyl)-I-arginyl-N-cyclohexylmethylglycine p 87 N -(6,7-dimethoxy-2-naphthylsulfonyl)-Ii-arginyl-Nbutylalanine P N -(6,7-dimethoxy-2-naphthylsulfonyl)-1-arginyl-Nbutylalanine tert-butyl ester 24. Ν2-(6,7-dimethoxy-2-naphthylsulfonyl)-l-arginyl-Npentylalanine ρ Ν -(6,7-dimethoxy-2-naphthylsulfonyl)-1-arginyl-Nbenzylalanine π N-(6,7-dimethoxy-2-naphthylsulfonyl)-I-arginyl-Nphenethylalanine p N -(6,7-dimethoxy-2-naphthylsulfonyl)-1-arginyl-Noyclohexylalanine p N -(4.6-dimethoxy-2-naphthylsulfonyl)-I-arginy1-NcyclohexyImethylalanine p N -(7-methoxy-2-naphthylsulfonyl)-1-arginy1-N-propylalanine N2-(6,7-dime thoxy-2-naphthylsulf onyl)-L-arginyl-N-(2methoxye thyl)alanine p N -(6,7-diraethoxy-2-naphthylsulfonyl)-L-arginylnorvaline π Ethyl l-/N-( 6,7-dimethoxy-2-naphthylsulf onyl)-L-arginyl72- piperidinecarboxylate Ethyl 1-/II2-(5-methoxy-l-naphthylsulfonyl)-1-arginy1/-4methyl-2-piperidinecarboxylate Methyl 1-/&2-(6,7-dimethoxy-2-naphthylsulfonyl)-1-arginyl7 3- piperidinecarboxylate Ethyl l-/ft2-(l-naphthylsulfonyl)-1-arginyl/-4-methyl-2piperidinecarboxylate . 101 Ethyl l-/H2-(2-naphthylsulfonyl)-I-arginlyl7-4-iKopropyl2-piperid.inecarboxylate 102 Ethyl l-/N2-(5,6,7,8-tetrahydro-2-napnthylsulfonyl)-Iarginyl7-4-methyl-2-piperidinecarboxylate 103 Ethyl 1-A2-(7-methy1-2-naphthylsulfonyl)-I-arginy1/-4isopropyl-2-piperi dinecarhoxylate 104 N2-(1,4-benzodioxan-6-sulfonyl)-1-arginyl-N-(2-methoxyethyl )glyci.ne 105 N2~(6,7-ethylenedioxy-2-naphthylsulfonyl)-Ii-arginyl-E" (2~methoxyethy])glycine 106 N2-(6,7-ddmethoxy-2-naphthylsulfonyl)"I-arginyl-E. allylglycine 107 M2-(6,7-dimethoxy-2-naphthylsulfonyl)-Ii-arginyl-H'-(2propynyl)glycine 108 N2-(6,7-dimethoxy-2-naphthylsulfonyl)-l-arginyl-N(2-methoxyethyl)glyc ine Of the compounds of this invention, it will be understood that the following compounds are most preferred due to their high level, of antithrombotic activity and low level of toxicity. ρ N -(6,7-dimethoxy-2-naphthylsulfonyl)-l-;irginyl-Hbutylglycine N -(7-methoxy-2-naphthylsulfonyl)-Ii-arginyl-E-butylglycine 26.
N -(6,7-dimethoxy-2-naphthylsuli'onyl)-1-arginyl-N-(2-methoxyethyl)glycine N2-(6,7-dimethoxy-2-naphthylsulfonyl)-l-arginyl-N-(2-methoxyethyl)glycine ethyl ester N^-4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine N -(7-methoxy-2-naphthylsulfonyl)-I-arginyl-N-2- methoxyethyl) glycine /-(5,6,7,8 -tetrahydro-l-naphthylsulfonyl)-l-arginyl-IT10 (2-methoxyethyl)glycine The pharmaceutically acceptable salts of the above compounds are of course also included within the scope of this invention.
As one skilled in the art can readily appreciate, the carbon atom of the N -arylsulfonyl-largininamides, to which the carboxyl group or the ester thereof is attached can be an asymmetric carbon atom allowing for the existence 27. of two optically active isomers, the D- and L-diastereoisomors, as well as the racemate, llL-mixture.
In accordance with findings concerning the antithrombotic activity of such compounds possessing an asymmetric carbon atom, the compounds of the present invention Iiaving the D-configuration are more active than those of tho Lconfigaration and are the preferred compounds, although the L- and DL-forms of the instant compounds are also considered within the purview of the present invention.
The above compounds arc intended only to illustrate the variety of structures which can bo used in the process of tills invention, arid tho above listing is not to be construed as limiting tho scope of tho invention.
For the preparation of the compounds of this invention, various methods can bo employed depending upon the particular starting materials and/or intermediates involved.
Successful preparation of those compounds is possible by way of several synthetic routes which are outlined below. (a) Condensation of an L-argininamide with an arylsulfonyl halide This process may be illustrated as follows: HN N - CH2CH2Cn2CIIC001I (ll) nh2 28. 4361 HN C — Ν - CH CltjCHgCHCOOlI (III) IIN I ' - 1 I ll UN 11’ I Ri» 4- RH (IV) -> % - N - CH„CH-CH„CHCOR (v) -> INX I " I I R HN If I R1 C - N - CH„CH„CHpCHCOR (VI) Η Nx I I II nh2 + ArS02X (VII) -> HN^ 'C - N - CH-CH-CHpCHCOR (i) Π,,Ν^ I 2 2 2, H llNSO,, I Ar In IJie above formulas, R and Ar are as defined herein above) X is halogen; Π* is a protective group for the -amino group, such as benzyloxycarbonyl or tcrfcbutoxycarbonyl; If and Π are selected from the group consisting of hydrogen and protective groups for tho guanidino group, such as nitro, tosyl, trityl, 29. 443G1 oxycarbonyl and the like; and afc least one of R* and R is a protective group for the guanidine group.
The N^-arylsulfonyl-L-argininamide (l) is prepared by the condensation of an L-argininamide (Vi) with a substantially equimolar amount of an arylsulfonyl halide (VIX), preferably a chloride.
The condensation reaction is generally effected in a suitable reaction-inert solvent in the presence of an excess of a base, such as an organic base (triethyl10 amino, pyridine) or a solution of an inorganic base (sodium hydroxide, potassium carbonate), afc a temperature of 0°C to the boiling temperature of the solvent for a period of 10 minutes fco 15 hours.
Tho preferred solvents for the condensation include J5 bonzeno-diethyl eLber, diethyl ether-water and dioxanewater.
After the reaction is complete, the formed salt is extracted with water, and the solvent is removed by such standard means as evaporation under reduced pressure to give the N2-arylSulfonyl-L-argininamide (1), which can he purified by trituration or recrystallization from a suitable solvent, such as diethyl ethertotrahydroPuran, diethyl cthcr-mothanol. and watermethanol, or may he chromatographed on silica gel.
Tho L-argininamides (VX) starting materials required . 4 3 61 for the condensation reaction can be prepared by protecting the guahidino and (A -amino groups of Larginine (ll) via nitration, acetylation, formylation, tosylation, phthaloylation, trifluoroacetylation, p-methoxy5 benzyloxycarbonylation, benzoylation, benzyloxycarbonylation, tert-butoxycarbonylation or tritylation Γ* 55 and then condensing the formed N-substitutod-Nsubstituted-L-arginine (JH) 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 p removing the protective groups from the formed N 2 substituted-N -substituted-L-argininamide (V).
The amino acid derivatives (XV) which are the starting p materials for the preparation of the N -substituted2 N -aubatituted-L-argininamides (v) are represented by the following formulas: H-N10 appropriate amine having the formula RgNHg or RjNHj. (See, J. Org. Chem., 25 728-732 (i960)).
. The condensation reaction is generally carried out j without a solvent or in a solvent, such as benzene or > ether, in the presence of an organic base, such as | 15 triethylamine or pyridine, at a temperature of 0°C to > 80°C for a period cf 10 minutes to 20 hours. After the J -: reaction ia eonplete, the formed amino acid derivative j 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.Aaong the amino aoid derivatives, amino acid tert-butyl . ester derivatives are preferred, because they are easily eenvorted to other ester derivatives by aoidolysis in 32. tho presence of a corresponding alcohol employing an inorganic acid (HCl, ^SO^, 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: H Cl (XIV) (XV) (XVI) (XVII) (XVHC) In the first reaction of the aforementioned scheme, an appropriately substituted piperidine (XIV) is contacted with an aqueous sodium hypochlorite solution at a temperature of ~5°C to 0°C. The resultant product (XV) is isolated by extraction with a eolvent, e.g., diethyl ether, and then treated with potassium hydroxide in a C^-C^ alkanol solvent to give the 1,2-dehydropiperidine (XVI). The action of cyanogenating agents, e.g., hydrogen cyanide or sodium cyanide converts the 1,2dehydropiperidines (XVI) to the corresponding 2-cyano 33. 4361 analogs (XVII). Hydrolysis of the 2-cyanopiperidines (XVII) to yield the 2-piperidinecarboxylic acids (XVUE) is effected by treatment of the 2-cyanopiperidines (XVII) with an inorganic acid, such as hydrochloric acid or sulfuric acid.
The arylsulfonyl halides (VII) which are the starting 2 materials for the preparation of the N -arylsulfonylL-argininamides (i) can be prepared by halogenating the requisite arylsulfonic acids or their salts, e.g,, sodium salts, by conventional methods well known to those skilled in the art.
In practice, halogenation is carried out without a solvent or in a suitable solvent e.g., halogenated hydrocarbons or DMF in the presence of a halogenating ' agent, e.g., phosphorous oxychloride, thionyl chloride, phosphorous trichloride, phosphorous tribromide or phosphorous pentaohloride, at a temperature of -10°C to 200°C for a period of 5 minutes to 5 hours . After the reaction is complete, the reaction product is poured into ice water and then extracted with a solvent such as ether, benzene, ethyl acetate, chloroform or the like.
The arylsulfonyl halide can be purified by recrystailization from a suitable solvent such as hexane, benzene or the like. 34. 443C^ Q ft (b) Removal of the N -substituent from an N-substituted2 N -arylsulfonyl-L-argininamide This process may be illustrated as follows: HN .C-N-CHpCH9CHpCHC0R (V) HNX I * * 4| R HN R' I Rtlt io HN^ C-N-CH„CH„CHoCHC0R HN I 2 2 2| I R NH„ R' 2 (XIX) ArSOgX (VII) ; HN^. xC-N-CH2CH2CH2CHC0R HN I R’ I R (XX) .'Ό HNS 0P I Ar HN.
H2N· ' C-N-CH-CH.CH.CHCOR I A A 4| H HNSΟΙ 2 Ar (I) 443d In tho above formulas, R, Ar, X, R', R and R' are as defined Herein above» The N -arylsulfonyl-L-argininamide (i) is prepared by G G removing tlie N’-substituent from an N’-substituted— N -arylsulfonyl-L-argininamide (XX) by means of acidolysis or hydrogenolysis .
Tho acidolysis is generally effected by contacting G 2 the N -substituted-N -arylsulfonyl-L-argininamide (XX) and an excess of an acid such as hydrogen fluoride, hydrogen chloride, hydrogen bromide or trifluoroacetic acid, without a solvent or in a solvent, such as an ether (tetrahydrofuran, dioxane), an alcohol (methanol, ethanol) or acetic acid at a temperature of -1O°C to 100°C, and preferably at room temperature for a period of 30 minutes to Zli hours.
Tho 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 2 are genei’ally the acid addition salts of tho N arylsuLfonyl-L-argini.nami.des (l), which can bo easily converted to a free amide by neutralization.
The removal of the nitro group and the oxycarbonyl group, e.g., benzyloxycarbonyl, p-nifcrobonzyloxycarbonyl, is readily accomplished hy tho hydrogenolysis. 36.
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 5 solvent, e.g., methanol, ethanol, tetrahydrofuran or dioxane, in the presence of a hydrogen-activating catalyst, e.g., Raney nickel, palladium, or platinum, in a hydrogen atmosphere at a temperature of 0°C to the boiling temperature of the solvent for a period of 2 hours to 120 hours .
The hydrogen pressure is not critical, and atmospheric pressure is sufficient.
The N -arylsulfonyl-L-argininamides (l) are isolated by filtration of the catalyst followed by evaporation of the solvent.
The N -arylsulfonyl-L-argininamides can be purified in the same manner as described above.
P P The N -substituted-N -arylsulfonyl-L-argininamides (XX) starting materials can be prepared by condensing an λ 2 N -substituted-N -substituted L-arginine (IE) (generally G 2 the N -substituent is nitro or acyl, and the N substituent is a protective group for the amino group, such as benzyloxycarbonyl, tert-butoxycarbonyl, or the like) and a corresponding amino acid derivative (iv)? ?5 selectively removing only the N -substituent of an 37. <* ί/* -substituted-N2-substituted L-argininamide (V) by means of catalytic hydrogenolysis or acidolysis, and then G condensing the thus obtained N -substituted—Larginiuamide (XIX) with an arylsulfonyl halide (VIl), preferably a chloride in the presence of a base in a solvent. Those reaction conditions are as described above in the condensation of an L-argininamide with an G arylsulfonyl halide, and the removal of the N G 2 substituent from an N -substituted-N -arylsulfonyl-ΙΙΟ argininamide. (c) Condensation of an N -arylsulfonyl-L-arginyl halide with an amino acid derivative This process may bo illustrated as follows: II C-N-CI19CH„CII,,CHCOOII 1I„N^ 2 "I NIL, + ArSOgX (IX) (VII) 20 II IM | C-N-C11oC119CH2CHC00II iuc 2 η IINSO„ Ar (XXI) -> 38. Η IIN^. 1 C -N -CH - C H„ CH„ CHC OX HON/ ' I HNSΟΙ 2 Ar + RH 11N^ | e-N-CH CH-CH-CIICOR H.,N^ I IINSO„ I Ar (XXII) (IV) -> (X) In the above formulas, R, Ar and X are as defined herein above.
The N2-aryl sul fonyl.-L-ax’gininaniide (I) is prepared by 2 the condensation of an N -arylsulfonyl-L-arginyl halide (XXII), preferably a chloride with at least an equimolar amount of an amino acid derivative (IV).
The condensation reaction can be carried out without an added solvent in the presence of a base. However, satisfactory results will be obtained with the use of a solvent such as basic solvents (di.nicthylformand.do, dimethyl acetamido, etc.) or halogenated solvents (chloroform, dichloromethane, etc.).
The amount of the solvent to be used is not critical and may vary from about 5 to Ιθθ times the weight of tho N2-arylsul fonyt-J.,-arginyl halide (XXII).
Preferred condensation reaction temperatures are in the range of from -10°C to room temperature. The reaction time is not critical, but varies with the amino acid derivative (IV ) employed. In general, a period of front 5 minutes to 10 hours is operable, The obtained N -arylsulfonyl-L-argininamide can be isolated and purified in the same manner as described above.
Tho N2-aryIsuifonyl-L-arginyl halide (XXII) starting materials required for the condensation reaction can 2 be prepared by reacting an N -arylsulfonyl-L-arginine (XXI) with at least an equimolar amount of a halogenating agent such as thionyl chloride, phosphorous oxychloride, phosphorus trichloride, phosphorous pontachloride or phosphorus tribromide. The halogenation can be carried out with or without an added solvent. The preferred solvents are chlorinated hydrocarbons such as chloroform and dichloromothano, and ethers such as tetrahydrofuran and dioxane.
The amount of the solvent to be used is not critical and may vary from about 5 to 100 times the weight of the N -arylsulfonyl-L-arginine (XXl).
Preferred. reaction temperature are in the range of -10°C to room temperature. The reaction time is not critical, but varies witli tlie halogenating agent and 40. reaction temperature. In general, a period of 15 minutes to 5 hours is operable.
The N -arylsulfonyl-L-arginines (XXI) which are the 2 starting materials for the preparation of the N arylsulfonyl-L-arginyl halides (XXII) can be prepared by the condensation of L-arginine (ll) 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 □ (d) Guanidylation of an N -arylsulfonyl-L-omithinamide or an acid addition salt thereof This process may be illustrated as follows; H2N-CH2CH2CH2CHCOR (XX3H) 'HNSO, I 2 Ar H HN^ I CHtf-CH„CH„CH„CHCOR (i) H„N * HNSO, I 2 Ar In the above formulas, R and Ar are as defined herein above, The N -arylsulfonyl-L-argininamide (l) is prepared by 43. Λ ί 3 θ 1 2 guanidylating an Ν -arylsulfonyl-L-omithinamide (ΧΧ3Ε) with an ordinary guanidylating agent such as an O-alkylisourea, S-alkylisothiourea, l—guanyl-3,5~ dimethylpyrazole or carbodiimide. The preferred guanidylating agents are the O-alkylisourea and the S-alkylisothiourea.
The guanidylation of the N -arylsulfonyl—L-omithinamide (XXH) with the O-alkylisourea or S-alkylisothiourea is generally effected in a solvent in the presence of a base at a temperature of from 0°C to the boiling temperature of the solvent for a period of from 30 minutes to 5θ hours.
Examples of the preferred bases are triethylamine, pyridine, sodium hydroxide and sodium methoxide,' The base is used in an amount of 0.01 to 0.1 equivalent 2 to the N -arylsulfonyl-L-omithinamide .
Examples of the preferred solvents are water, waterethanol and water-dioxane.
After the reaction is complete, the N -arylsulfonyl-Largininamide (l) is isolated by evaporation of the solvent followed by removal of the excess base and the formed salt by a water wash, It is well recognized in the art that an ester derivative of the N -arylsulfonyl-L-argininamide (i) wherein R2, R5, Rg, Rg, R1q or Ru is alkyl 42. 443G1 can be prepared from a carboxylic acid derivative of the N -arylsulfonyl-L-argininamide wherein Rg, R^, Ηθ, R^, R^q or is hydrogen, by the conventional esterification methods well known to those skilled in the art It is also well recognized in the art that the carboxylic acid derivative can be prepared from the ester derivative by the conventional hydrolysis or acidolysis methods. The conditions under which esterification, hydrolysis or acidolysis would be carried out will be each apparent to those skilled in the art.
The N -arylsulfonyl-L-argininamide (l) of this invention forms aoid addition salts with any of a variety of inorganic and organic acids. Some of the N -arylsulfonyl-L-argininamides 15 containing a free carboxyl group, wherein Rg, R^, in 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, 44301 ethanesulfonic, benzenesulfonic, p—toluenesulfonic acid or the like. In a similar manner, the product can be obtained as pharmaceutically acceptable salts by reacting one of the free carboxylic acids with, a base, such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, triethylamine, procaine, dibeuzylamine, 1-ephenamine, N,N'-dibenzylethylenediamine, N-ethylpiperidine or the like.
Ijikewise, treatment of the salts with a base or acid results in a regeneration of the free amide.
As stated above, the N -arylsulfonyl-L-argininamides, and the salts thereof of this invention are characterized by their highly specific inhibitory activity against thrombin . as well aa by their substantial lack of toxicity, and therefore these compounds are useful irt 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-arvlsulfonyl-L20 argininamide of this invention was compared with that of a known anti thrombotic agent, N"-(p-toly.isulfonyl)-bargiiiine methyl ester, by determining the fibrinogen coagulation Lime. The measurement of the fibrinogen coagulation time was conducted as follows: Art 0.8 ml aliquot of a fibrinogen solution, which had been 44. prepared by dissolving 150 ing 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 Moehida Pharmaceutical Co,, Ltd, was added to the solutions in an ice bath.
Immediately after mixing, the reaction mixture was transferred from the ice bath to a bath maintained at 25°C. Coagulation times were taken as the period between the time of transference to the 25°C bath and the time of the first appearance of fibrin threads. in the cases where no drug samples were added, the coagulation time was 5O"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 5Ο-55 seconds to 100-110 seconds, The concentration required to prolong the coagulation time by a factor of two for the known antithrombotic agent, N -(p-tolylsulfonyl)-L-arginino methyl ester, was 1,10(^1 M The inhibitors are shown in Table 1 by indicating R and Ar in the formula (l) and the addition moiety, When a solution containing.an N -naphthylsulfonyl-Largininamide of this invention was administered intravenously 45. 43®* into animal bodies, the high antithrombotic activity in the circulating blood was maintained for from one to three hours. Tho halflife for decay of the anti—thrombotic compounds of this invention in circulating blood was shown to be appro5 5 ximately 60 minutes; the physiological conditions of the host animals (rat, rabbit, dog and chimpanzee) were well maintained. The experimental decrease of fibrinogen in animals caused by infusion of thrombin was satisfactorily controlled by siniui taneous infusion of the compounds of this invention.
The acute toxicity values (LD^^) determined by intraperitonoal administration of substances of formula (i) in mice (male, 20 g) range from about 1,000 to 10,000 milligrams per kilogram of body weight.
Representative LD^Q values for the compounds of this invention are shown in the following Table.
Compound (mg/kg) N2-(7-methyl-2-naphtliylsulfonyl)-Larginyl-N-butylglyeine > 1,500 p K -(6,7-dimethoxy-2-naphthylsulfonyl)-1arginyl-H-(2-methoxyethyl)glycine 1,900-2,400 2 N - (6,7-dimethoxy-2-napkt,hylaulfonyl) -Larginyl-N-(2-e thoxyethyl)-β-alanine 660-1,000 46.
Compound 1D5O (mg/kg) /-(4,6-dimethoxy-2-naphthylsulfonyl)-Iarginy1-N-(2-methoxyethyl)glycine 660-1,000 /-(7-methoxy-2-naphthylsulfonyl)-Larginyl-N-(2-me thoxyethyl)glyc ine 2,000 /-(5,6,7,8-t etrahydro-l-naphthylsulfonyl)L-arginyl-N-(2-methoxyethyl)glycine >1,500 p N -(G^-dimethoxy^-naphthylsulfonylJ-Larginyl-N-benzylglycine >1,000 2 N -(4,6-di.methoxy-2-naphthylsulfonyl)-larginyl-N-benzylglyei.ne >1,000 /-(6,7-dimethoxy-2-naphthylsulfonyl)-Larginyl-N-phenethylglycine >1,500 N -(6,7-dimethoxy-2-naphthylsulfonyl)-1arginyl-N-cyclohexylglycine >1,500 o N -(6,7-dimethoxy-2-naphthylsulfonyl)-Larginyl-N-cyc1 oh exyImethylglyc ine >1,500 2 N -(6,7-dimethoxy-2-naphthylsulfonyl)-1arginyl-N-butylala.nine >1,500 /-(4,6-dimethoxy-2-naphthylsulfonyl)-Larginyl-N-eyclohexylmethylalanine >1,500 Ethyl /1-/- (7-methoxy-2-naphthylsulfonyl) l-arginy l7-4-methyl-2-piperidinecarboxylate 670-1,000 N -(5-me thoxy-1-naphthylsulfonyl)-1arginyl-N-be· zylglycine >1,000 On the other hand, LD^q values for Ng-dansyl-N-butyl-Largininamide and. /-dausyl-N-methyl-N-butyl-l-argininamide are 75 and 70 milligrams per kilogram, respectively. 47. 44364 The therapeutic agents of this invention may he administered alone or in combination vith pharmaceutically acceptable carriers, the proportion of which is determined by the solubility and chemical, nature of the compound, chosen route of administration and standard pharmaceutical practice.
Por example, the compounds may be injected parenterally, that is, intramuscularly, intravenously or subcutaneously, Por parenteral administration, the compounds may be used in the form of sterile solutions containing other solutes, for example, sufficient saline or glucose to make the solution isotonic. The compounds may be administered orally in the form of tablets, capsules, or granules containing suitable excipients such as starch, lactose, white sugar and the like. The compounds may bo 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 tho form of solutions which may contain coloring and flavoring agents. Physicians will determine the dosage of the present therapeutic agents which will be most suitable, and dosages vary with the mode of administration and the particular compound chosen. In addition, the dosage will vary with the particular patient under treatment. When the composition is administered orally, a larger quantity 48. of the active agent will be requix’od to produce the same effect as caused with a Hinaller quantity given parenterally. The therapeutic dosage is generally 10-50 mg/lcg of active ingredient parenterally, 10-500 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 dose form. 49.
EXAMPLE 1 ! (A) N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginine; ! To a well stirred solution of 83.6 g of L—arginine in ι 800 ml of 10$ potassium carbonate solution was added 5 114.7 g of 6,7-dimethoxynaphthalenesulfonyl chloride in 800 ml of benzene. The reaction mixture was stirred at 60°C for 5 hours, during which time the product precipitated. After one hour at room temperature, the precipitate was filtered and washed successively with benzene j 10 and water to give 129 g (76 percent) of N-(6,7-dimethoxy2-naphthyisulfonyl)-L-Arginine, M.P,. 252-5°C.
(B) K — (6,7"dimethoxy-2-naphthylsulfonyl)-L-arginyl chloride; i A suspension of 2.00 g of N -(6,7-dimethoxy-2-naphthyl15 sulfonyl)-L-arginine in 20 ml of thionyl chloride was stirred for 2 hours at room temperature. Addition of cold dry diethyl ether resulted in a precipitate whioh ; was collected by filtration and washed several times with dry diethyl ether to give N -(6,7~dimethoxy-220 naphthylsulfonyl)-L-arginyl chloride, * (c) N -(6,7"dimethoxy-2-naphthylsulfonyl)-L-arginyl-N| butylglyeine tert-butyl ester; ϊ 50.
To a stirred solution of 2,64 g of N-butylglyoine tert-butyl ester in 20 ml of chloroform was carefully added N -(6,7-dimethoxy-2-naphthylsulfonyl)~L-arginyl chloride obtained above. The reaction mixture was allowed to stand at room temperature for one hour. At the end of this period, tho reaction mixture was washed twice with 20 ml of saturated sodium chloride solution and evaporated to dryness.
The residue was triturated with a small amount of water TO to give a crystalline material. This was collected by filtration and reerystallized from ethanol-ethyl ether to give 2.28 g (82 percent) of N2-(6,7-dimethoxy-2~ naphthylsulfonyl)-L-arginyl-N-butylglycine tert-butyl ester, M.P. l64-l66°C, I.R. (KBr): 3,390, 3,165, 1,735, 1,370 cm1.
Analysis - Calcd. for CggH^O^N^S «iHgSOj (percent): C, 52.98; H, 7.00; N, 11.04 Found (percent): C, 52,69; H, 6.98; N, 10.86 o (D) N -(6,7-di me thoxy-2-naphthylsulfonyl)-L-arginyl-N20 butylglycine:2 To a solution of 2.00 g of N -(6,7~dimethoxy-2naphthylsulfonyl)-L-arginyl-N-butylglycine tert-butyl ester in 20 ml of chloroform was added 50 ml oi* 15# HCl-ethyl acetate. The reaction mixture was stirred 51. 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 other' 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 hyd ro xi de so lu ti on .
The fraction eluted from 3$ ammonium hydroxide solution was evaporated to dryness to give 1.43 g (79 percent) of N -(6,7-dimothoxy-2-naphthylsulfonyl)-L-arginyl-Nbutylglycine as an amorphous solid, X.R. (ltllr): 3,360, 3,140, 1,622 cm-1.
Analysis - Calcd, for Cg/jH^N^OyS (percent): C, 53.62; 11, 6.56; N, 13.03 Pound (percent): c, 53.48; H, 6.43; N, 12.98 The following compounds arc prepared in a similar manner: •j N~-f7_mcLhyJ -2-naplit liyJsul fonyl) -b-arginyl-N-butyl —£0 alanine N -(7-methyl-2-naphtliylsulfonyl)-N-(2-mctlioxyothyl)-N-(3carboxypropy.1 )-l,-argi n;i udnil de ?. 443G1 N‘:-(6,7-dimethcxy-2-naphthylsulfonyl)-N-benzyl-N-(3-tertbutoxyearbonylpropyl)-L-argininamide p N -(6,7-diethoxy-2-naphthylsulfonyl)-L-arginy1-NcyclohexyIglycine p 4-N-/N -(6,7-dimethox.y-2-naphthylsulfonyl)-L-arginyl7N-cyclohexylaminobutyric acid p N -(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl-Nphenethyl-p-alanine p N -(6-methoxy-2-naphthylsulfonyl)-1-arginy1-N-(310 phenylpropyl)glycine p N -(5-methoxy-l-naphthylsulfonyl)-L-arginyl-N-benzyl-βalanine N2-(7-me thoxy-2-naphthyl sulfony1)-L-arginvl-N-butylalanine 2 N -(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-pentylalanine p N -(5-methoxy-l-naphthylsulfonyl)-L-arginy1-N-butylalanine N2-(6,7-dimethoxy-2-naphthylsulfonyl)-1-arginyl-Nisobutylalanine p N (7-methoxy-2-naphthylsulfonyl)-1-arginy1-N-benzylalanine N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginy1-N-(320 phenylpropyl)alanine p N -(5-methoxy-l-naphthylsulfonyl)-L-arginy1-N-benzylalanine 53.
U -7-inetrioxy-2-naphthylsulf onyl) -L-arginyl-N-cyclohexylalanine N (6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-Noy clohexylmethylalanin e N -(6,7-dimethoxy-2-naphthylsulfonyl)-l-arginyl-Rbutylbutyrine N - (6,7-dimethoxy-2-napnthylsulfonyl)-L-arginy1-N-(2-acetylethyl) glycine EXAMPLE 2 .
(A) N-6-methoxy-2-naphthylsulfonyl)-L-arginyl chloride.
A suspension of 2.5 g of N -(6-methoxy-2-naphthylsulfonyl)-Larginine in 20 ml of thionyl chloride vas stirred for 2 hours at room temperature. Addition of cold dry ethyl ether resulted in a precipitate which was collected hy filtration and washed several times with dry ethyl ether to give N -(6-methoxy-2-naphthylsulfonyl)-L-arginyl chloride. 54. (li) Ethyl 1- (Ν2-(6-me thoxy-2 -naphthyl sulf onyl)-L-arginyl}2-pi peri dinecarboxylate To a stirred solution of 2.2 g of ethyl 2-piperidinecarboxylato and 4.1 ml of triethylamine in 50 ml of chloroform, which was cooled in an ice-salt bath, was added in portions N''-((i-methoxy-2-naphthylsulfonyl)-Larginyl chloride obtained above. The reaction mixture was stirred overnight at room temperature. At the end of this period, 500 ml of chloroform was added and the chloroform solution was washed twice with 5θ nil of saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo. The oily residue was washed with ethyl ether to give 2.9 G Ot' powdery ethyl 1-£n -(6-methoxy-2-naphthylsulfonyl)-L-arginylJ-2-piperidinecarboxylate.
Por analysis of the product, a portion of the product was converted to the flavianate, M.P. 192-3°C.
I.R. (Klir): 3,210, 1,747, 1,638 cm-1 Analysis - Calcd. foi· 5^'C10^6°8^2S (percent): C, 49*58; 11, 4.87! N, 11.56 Pound (percent): C, 49.24 H, 4.70; N, 11.85 The following compounds are prepared in a similar manner: N‘(6-ohloro-2-naphthylsulfonyl)-L-arginyl-N-hutylgly c ine N2-(7-mothyl-2-naphthylsulfonyl)-I-arginyl-N-(2e thoxyethy1)glycine 55.
N2-(4,6-dimethoxy-2-naphthylsulfonyl)-L~urginyl-Nphenetliyl -alanine N~-(6,7-dimethoxy-2-naphtliylsulfonyl)-N-benzyl-N-(3carboxypropyl)—L-argJninamide N'i-(7-methoxy-2-naphthylsu.lfoiiyl)-L-arg.iiiyl"NcyclohoxyJnorloucine N2-( 7-nie thoxy-2-napht hylsulfonyl)-L-arginyl-Nbntylisoleucine N -(7-mothoxy-2-naphthylsulfonyl)-L-arginyl-N10 pouty 1 -/'-amino butyric acid p N -(6,7-diothoxy-2-naphthylsulfonyl}-L-arginyl-Nbutylalanine <> N"-(6,7-dimethoxy-2-naphthylsulfonyl)-L-argi nyl-Ncyc lollop Lyl a 1 ani no N"-(7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-(2methoxyelhyl)alanine Ν~-( (', ,7-dimo tho'xy-2-riiaphthyl sulfonyl )-L-arginyl-N(2-ettioxyotliyl )aj uninc 56.
N -(7-roethoxy-2-naphthylsulfonyl)-L-arginyl-Ncycloliexyl-^ -alanine 2 N-(7-meihoxy-2-naphthylsulfonyl )-l,-a rginyl-N-(2methoxyethyl )norvaline p N-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-Nbenzylleucine 43 6· Ethyl 4-0^-(4,6-dimethoxy-2-naphthylsulfonyl)-Larginylj morph~line-3-carboxylate EXAMPLE 3 G 2 (Λ) N -nitro-N -(tert-bntoxycarbonyl)-L-arginyl-N-(2methoxyethyl)glycine ethyl ester: Γ* 2 To a stirred solution of 28.3 E °f N -nitro-N -(tertbutoxycarbonyl)-L-arginixie iji 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 o at -5 C. After 15 minutes, to this was added 14.2 g of N-(2-methoxyethyl)glycine ethyl ester, and the mixture was stirred for 15 minutes at -5°C. At the end of this period, tho reaction mixture was warmed to room temperature. The solvent was evaporated and the residue taken up in 400 ml of ethyl acetate, and washed successively with 200 ml of water, 100 ml of 5$ sodium bicarbonate solution, 100 ml of 10$ citric acid solution and 200 ml of water. The ethyl acetate solution was dried over 57. 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 β of silica gel packed in chloroform, Tho product was eluted first with chloroform, and then 3$ methanol-chloroform, The fraction eluted from 3% methanol-chloroform was evaporated to dryness to give Q 2 .8 g (63 percent) of N -nitro-N -(tert-butoxycarbonyi) L-arginyl-N-(2-methoxyethylJglycine ethyl ester in the 1.0 form of a syrup.
I.R. (KBr): 3,300, 1,740, 1,690 cm1 (ll) N°-ni tro-I.,-argiuyl-N-(2~methoxyethyl )glycine ethyl ester hydrochloride: . . ' G 2 To a stirred solution of 2y.8 g of N -uitro-N -(tert1 butoxycarbonyl) -L-arginyi-N-(2-methoxyethyl)glycine ethyl ester in'50 ml of ethyl acetate was added 80 ml of 10$ dry JICl-ethyl acetate at 0°C . After 3 hours, to this solution was added 200 ml of dry ethyl ether to precipitate a viscous oily product.
?.O This was filtered and washed with dry ethyl ether to give 24.1 g of N -nitro-L-arginyl-N-(2-methoxyethyl) glycine ethyl ester hydrochloride as an amorphous solid, P 2 (θ) N -nitro-N -(6,7-dinietIioxy-2-naphtliylsulfonyl)-L-arginyl· N-(2-methoxyethyl)glycine ethyl ester: 58.
I 443G1 rt To a stirred solution of 4.0 g of N -nitro-L-arginylN-(2-methoxyethyl)glycine ethyl ester hydrochloride in 20 ml of water and 20 »1 of dioxane were added in turn 2.5 g of sodium bicarbonate, and 3.5 g of 6,7-dimethoxy5 2-naphthalenesulfonyl chloride in 30 ml of dioxane at °C, and stirring was continued for 3 hours at room temperature. At the end of this period, the solvent was evaporated and the residue dissolved in 40 ml of chloroform, and washed with 10 ml of IN hydrochloric acid solution and 20 ml of water.
The chloroform solution was dried over anhydrous sodium sulfate. Upon evaporation of the solvent, the residue was chromatographed on 50 g of silica gel packed in chloroform, washed with chloroform and eluted with 3$ methanol-chloroform. The fraction eluted from 356 methanol-chloroform was evaporated to give 5.3 g (87 G 2 percent) of N -nitro-N ~(6,7-dimethoxy~2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester in t form of an amoxphous solid.
I.R. (KBr)s 3,240, 1,740, 1,630 cm1 (D) N®-(6,7"dimethoxy-2-naphthylsulfonyl)-L-arginyl-N(2-methoxyethyl)glycine ethyl ester: rt 2 To a solution of 3.00 g of N -nitro-N -(6,7-dimethoxy2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine 59. ethyl ester in .50 ml oT ethanol and 0.5 ml of acetic acidwas added 0.5 g of palladium-black and then the mixture was shaken in a hydrogen atmosphere for 100 hours at room temperature. At the end of this period, the ethanol solution was filtered to remove the catalyst and evaporated to give an oily product. Reprecipitat'ion with ethanol-ethyl ether gave 2,53 g (91%) of N2-(6,7~ dimothoxy-Z-naphthylsulfonyl)-L-arginyl-N-(2-niethoxyethyl) glycine ethyl ester. lO For tuialysis of the product, a portion of the product was converted to the flavianate; M.P. 185°C, I.R. (KBr)i 3,375, 3,200, 1.,740 cm-1.
Analysis - Calcd. for Ο^Η^Ν^Οθδ’CjoR6R2°8S (P®rcen'*:) : C, Λ7.675 H, 4.925 N, 11.12 Pound (percent): c, 47.64; ll, 4.81; N, 11.12 o (E) N-(0,7-diniethoxy-2-naphthylSulfonyl)-L-arginyl-N-(2metlioxyethyl )gl ycino: . Λ solution of 2.5 g of N‘’-(6,7- At the end of this period, the solution was concentrated to 5 ml, chromatographed on 80 ml of Daiaion © SK 102 ion exchange rosin (200 - 300 mesh, llh form manufactured 60. 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, and the residue was purified hy reprecipitation with ethanol-othy.1 ether to give 1.32 g (72 percent) of /-(6,7-dime tho xy-2-naphthylsul fonyl) -L-arginyl -JT-(2mothoxyothyl Jglycine as an amorphous solid. 1.11. (KBr): 3,380, 3,180, 1,630 cm-1 Analysis - Calcd, for Cg^II^^N^OgS (percent): C, 51.20; H, 6.17; N, 12.98 Pound (percent): C, 50.93; H, 6.02; N, 12.63 Tlie foilowing compounds are prepared in a similar manner: /-(5,6,7,8-to traIiydro-2-naphthylsul fonyl)-L-arginyl15 N-(2-ethoxyethyl)glycine N -(5,6,7,8-totrahydro-2-naphthylsulfoiiyl)-L-arginylN-(2-methoxyethyl)glycine N'-(7_elhy t-2 -naphthyl su.1. fonyl )-L-arginy.1. -N-(2mothoxyethyl)glyclne p N-(5-mcthoxy-l-naphthylsulfonyl)-L-arginyl-Ncyci 0 hexyl gly ci 110 61. Ν -(7-methoxy~2-naphtliylsulfonyl)-L-arginyl-N(3-cycloliexyl Jpropylgiycine EXAMPLE 4 (A) L-arginyl-N-(2-methoxyethylJglycine ethyl ester 5 hydrochloride: G To a solution of 4.0 g of N -nitro-L-arginyl-N-(2methoxyethylJglycine ethyl ester hydrochloride in 50 ml of ethanol was-added’ 0,5' g of palladium-black and then the mixture was shaken in a hydrogen atmosphere for I50 hours at room temperature. At the end of this period, the ethanol solution was filtered to remove the catalyst and evaporated to give an oily product. Reprecipitation with ethanol-ethyl ether gave 3.0 g (81#) of L-arginyl -N-(2-rue thoxy ethyl Jglycine ethyl ester hydrochloride in tlie form of a powder. (Β) Ν*-(4,6-dimothoxy-2-naphthylsulfonyl)-Ij-arginyl-N-(2— me tlioxye thyl Jglycine ethyl ester: To a well stirred solution of 2,00 g of L-arginyl-N(2-methoxyethylJglycine ethyl ester hydrochloride and 1 .95 g of K.,GOj in 20 ml of water and 10 ml of dioxane 62. was added dropwise a solution of 2.17 & of 4,6dimethoxy-2-naphthalenesulfonyl chloride in 30 ml of dioxane over a period of 30 minutes while maintaining . the temperature at 0°C. The reaction mixture was stirred for an additional 5 hours at room temperature.
At tho end of tliis period, the solvent was evaporated and the residue taken up in 50 ml of chloroform.
The chloroform solution was filtered to remove the insoluble material and dried over anhydrous sodium sulfate. Addition of 150 ml of ethyl ether to the chloroform solution resulted in a precipitate which was separated by decantation and purified by reprecipitation with ethanol-ethyl ether to givo 2.31 g (72 percent) of N2-(4,6-dime thoxy-2-naphthylsul, fonyl) -L-arginyl -N(2-methoxyothyl)glycine ethyl ester.
For analysis of the product, a portion of the product was converted to the flaviauate; M.P, 225°-227°C, I.R. (Kllr): 3,375, 3,200, 1,742 cm-1.
Analysis - Calcd, for C„_H„_N 0oS ‘C, „Ι1Ζ Jf 5 & J.UO N?O8S (percent): C, 47-67! II, 4 .92 i N, 11.12 Found (percent): C, 47.62 J 11, 4.84; N, 11,18 (n) N2-(4,6-di me thoxy-2 -naph thyl sul. fonyl )-L-argi.nyl-N-(2mothoxyethyl)gl ycino: 63. 443®* ο N -(4,6-dimethoxy-2-naphthylsulfonyl)-L-arginyl-Ν-(2methoxyethyl)glycine was obtained in the form of an amorphous solid in a manner similar to that described in Example 3-(E).
I.R. (KBr): 3,360, 3,180, 1,610 cm-1.
EXAMPLE 5 (A) N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-Nphenetliylglycine: N°-ni tro-N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L— 3,0 arginyl-N-phenethylglycine benzyl ester was prepared by the procedure described in Example 3, and has a melting point of 133-5°C.
To a solution of 3 <00 g of N -nitro-N‘'-(6,7-dimethoxy2-naphthylsulfonyl)-L-arginyl-N-phenethylglycine benzyl 1.5 ester in 50 ml of ethanol and 0.5 ml of acetic acid was added 0.5 g of palladium-black and then the mixture was shaken in a hydrogen atmosphere for 100 hours at room temperature. At the end of this period, the ethanol solution was filtered to remove tho catalyst and evaporated to dryness. The residue was washed several times with dry ethyl ether and chromatographed on 80 ml of Daiaion ® SK 102 ion exchange resin (200 - 300 mesh, II+ fora, manufactured by Mitsubishi Chemical Industries 64.
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 1.71 g (70%) of N2-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginy1-N-phenethyIglycine as an amorphous solid.
I.R. (KBr): 3,360, 3,200, 1,590 cm_1 Analysis - Calcd. for CggH^NgOyS (percent): C, 57.42; H, 6.02; N, 11.97 Found (percent): C, 57.09; H, 6.06; N, 11.74 EXAMPLE 6 (λ) 4-/I12-(7-methyl-2-naphthylsulfonyl)-1-arginy l7 morpholine-3carhoxylic acid chloride hydrochloride: p A suspension of 2.00 g of 4-/& -(7-methyl-2-naphthylsulfonyl) -L-arginyl7morpholine-3-carboxylic acid in thionyl chloride was stirred at room temperature. Addition of cold dry ethyl ether resulted in a precipitate which was collected hy filtration and washed several times with dry ethyl ether to p give 4-/N -(7-methy1-2-naphthylsulfonyl)-L-arginyl/ morpholine-3carboxylic acid chloride hydrochloride.
(B) Ethyl 4-/II2-(7-methyl-2-naphthylsulfonyl)-L-arginyl7 morpholine-3-carboxyla te: A mixture of ethanol and the product obtained above was heated for 50 minutes. At the end of this period, the reaction mixture was cooled, washed several times with dry ethyl ether, and then dissolved in dry ethyl alcohol. Addition of cold dry ethyl ether resulted in a precipitate which was washed p several times with dry ethyl ether to give ethyl 4-/N(7-methy1-2-naphthylsulfonyl)-L-arginyl7morpholine-3-carboxylate. 65. -2ι Various other h Larylsulfonyl-L-argininamides or salts thereof were synthesized in accordance with the procedure of the above Examples, and the test results are summarized in Table 1. 66.
TABLE 1 (Sheet l) Sample No. Compound UN " ^C-S-CHoChUClUCHCOH (i) il,NZ Ή II-N-SO,-Ar Ar R Add!tion moie ty 1 yyy ocn3 och3 (οη2)Λ "A\ CiI2C02H - 2 II _χ/(™2>2«13XCH2C02C(CHg)3 1/2H23O3 3 1} ^,/(^2)3^3 · XCH2C02K - 4 II _ycn2)3cn31 xch2c°2c(ch3)3 l/2H2S03 5 II /CH3 -CIUCH. ' -N^ XCII, \ch2co2h - 6 IIXCH XCICCHVJ -n' ch3XCII2CO?C(CII3)3 !/2H2SO3 7 II _N/4CH3 ^C^COjjH - i TABLE 1 (Sheet 1 cont.) ' .
Concentration required to prolong:the coagulation time by a factor of two Preparation process . (Ex , No .) m.p. (°C), f Elementary analysis Upper; Calculated ($ Lower: Found (%) I.R. (KBr) (JM) (cm-1) C H X 8 1 powder 52-76 52.68 6.55- . 6.21 1 i .13-38 13.30 5,5605,160 '1,620 1 134-6 52.25 52.07 6.82 6.73 11. 29 10. 89 5,560 5,180 1.740 1,575 0.3 1 powder 53.62 53.48 6.56 6.43 13.03 J2 .98 '>,560 3,140 1 »622 1 164-6 52.98 52.69 7.00 6.98 11.04 10.86 3,390 3,165 1,735 1,370 2 1 powder 53.62 53.43 6.56 6.53 13.03 13.12 3,360 3,160 1,620 , 1 tr 52.98 52 .59 7.00 6-.79 11.04 10.89 3,390 3,170 1,737 1,370 5 T u 54-431 54.58 6.76. 6.79 12.70 12.56 3,350 3,180 1,630 .68.
TABLE 1 (sheet 2) Sample No. Compound V C-N-ClLCll./hL.CUCOR (I) H,NX 1 4 H-N-50,,-Ar Ar n Addi tion • moiety 8 9 ^-A^OCH.j _ν/(οπ2)αοη3 ^ch2co2c(ch3)3 l/2H2S03 Ifx(CH„) CH. -N. nCH2CO2H - 10 If /(CHJ OIL· -N. -bi ωι2οο2ο(οπ3)3 l/2HoS0,. *· j 11 If /(cu ) Ch -N. ‘ JxCII2CO2H - 12 II /(CH„) CH, _Νζ - 7 3 'cn2eo2c(CH3),3 l/2H2S03 13 tt , CHoCHpOCH-N ~ 2 . XCI12CO2H • U fl /CH„CH20CH3 _NXCHCOC,,!I OH HO3S^0N°2 no2 69..
TABLE 1 (sheet 2 cont.) Concentratio required to prolong the coagulation time by a factor of two 1 Preparation, process (Ex, No,) m.p . (°C) Elementary analysis J.R. ( ΚΒγ,ι ( cm1) Upper: Lower: C1 Cal cuia t ed ($ Found (-S) il X 1 195-6 53.69 53.40 7.15 7.12 10.30 IO.56 3,380 3,.ISO 1,738 1,375 1.5 1 powder 55.21 54.98 - - 6.95 7.02 .12.38 12.47 3,360 3,200 1,622 1 193-200 54.37 54.30 7.30 7.27 10.57 10.36 3,360 3,160 1,730 1,368 1 powder 56.64 56 .41 7.30 7.17 11,80 .11,51 3,360 3,180 1,620 1 172-174 55-64 55.31 7-59 7.63 10.14 10.18 3,380 3,180 1,740 1,375 0.5 3 powder i 51.20 50.93 6.17 6.02 12.98 12.63 3,380 3,180 1,630 1.5 3 185 47.67 47.64 4.92 4.81 11.12 11 .12 3,375 3,200 1,740 TABLE 1 (sheet 3) Sample No. Compound H UN | .C-N-CH_CH„CHoCHC0R (ϊ) Λ H-N-SOg-Ar ΛΓ tt Addi tion moiety 15 (TOpy00113 ^.CHgCi^OCI^ CS^ClIgCOgll - 16 1» -< 2 2 3 CH2CH?C02C?H. - 17 ft _nXCH2CU20OT3 ^CHgCUgCHnCOgH - 18 II >ch2ch,ociu -N\ J ^CIlgCltgCHgCOgC (CH3) 3 1/2H2SO3 19 11 .ClI,,CH9CH9OCiL· -Nf 2 2 2 3xch2co2ii - 20 (1 ^,θί2αι./'Λί2οα\^ —N. XIHgCOgC(CH3)3 l/2H2S03 21 n .CH.CHoOCyH, _Nf 2 2 2 5 >CH2CH2G02H - ,r\ *' ') 4<36i TABLE 1 (sheet 3 cont.) Concentration required to pro tong this coagulation time by a factor of two (/ >0 Propara tion process (Ex. No.) ηι .ρ , (°C) Elementary analysis Upper: Calculated ify Lower·. Pound $) I.R. (KBr) (cm-1) c H N 2.5 3 powder 52.07 5.2 .21 6.37 6.04 12.67 12.51 3,380 3,200 1,620 3 ir 53.69 53.53 6.76 6.69 12.04 12.38 3,380 3,200 1,740 2-5 I I) 52.9Ο 52 .71 6.57 6 ,43 12.34 12.46 3,350 3,16o 1,640 . I It 52 ./(0 52 .1 6 6.96 7.13 10.54 10.28 3,340 3,160 1,736 1,380 5 1 It 52.07 51.91 6.37 6.19 12.65 12.38 3,360 - 3,160 1,620 1 II 51.68 51.43 6.82 6-.66 10.76 10.58 3,380 3,160 1,740 1,370 A 1 tt 52.90 52.59 6.57 6.41 12.34 12 .16 3,36ο 3,160 i,64o 72.' TABLE 1 (Sheet 4) Sample No. Compound H HN | .C-N-CH-CH-CH9CHCOR (I) H„N^ 2 2 -, Λ H-N-502-Ar Ar R Addi tion moiety 220CII3 OCHg / ch„ch„oc„h, -N. " 5xcii2eu2eo2c(CKg)g 1/211 SO- 23 ?o„, OCHg jxCH-CHo0CH,. -N J ^CHgCOplI 24 ttx CH-CH- OCH,, -N. 4 JxCH2CO2C2H5 Oil ΐίθ2 25 It _N/(CH2)g-CHg ''CHgCOgH - 26 It ^(CH,) -CH -NK ~ J CH2C02C(CHg)g l/2H2S0g 27 ot:; 2 5 y CH9CII,,0CH-N< " CHgCOgH 28 It .CH-CH-OCK_N 2 2 J XCH,,CO C(CHg)g l/2H2S0g ·· ' ν>4?36ί .-·· TABLE 1 (Sheet 4 cont.) Concert t χ·ίΐ tion required to prolong the coagulation time by’ a factor oi* two • y · Preparation process (Ex. No.) . : in f - 1 - m.p. (°C) Elementary analysis Upper: Calculated ($ Lower: Pound I.R. (KBr) (cm"1) c H N ; 1 powder 52-98 52.73 7.00 7.00 11.04 10.82 3,377 3,160 1,740 1,368 ϊ ii If 51.20 51.31 6.17 6.01 12.98 12.67 3,360 3,180 1,610 4 225-7 47.67 47 .62 4.92 4.84 11.12 11.18 3,375 3,200 1,742 2 1 powder 53.62 53.58 6.56 6.48 13.03 12.94 3,380 3,200 1,630 f . Ϊ- ί t · ·'. 1 ’ · . . 224 ; ' 52.98 52.73 1 , 7*00 it- . ’7.OO 11.04 10.82 3,360 3,160 1,740 1,370 . 15 .1 powder 52.89 52.77 i 6.57 6.80 12.34 12.59 3,380' 3,200 1,625 1 « ' It. 52.39 52.10 • 6,97 6.84 10.54 10.21 3.370 3,150 1,740 1.370 ΊΑ TABLE 1 (Sheet 5) Sample No. Compound H (I) HN^ ’ H?N X 1 3-N-CH_CHoCIL,CIIC0R 2 - 1 Il-N-SOg-Ar Ar R Addition moiety 29 UUVil · * 5 > (CH2) ιΟΗλ -nC CH CO„II - -jo It / (C1I9)3CH3 -n' - J J NCII2C02C(CH3)3 , l/2H2S03 3i. 0¾ /(CIio)„CH -N - J JxCH?COaH - 32 tt /(CII )„CH„ -N J Jxcii2co2c(ch3)3 l/2H2S03 33 1! ^CHoCII_0CH„ -N^ - 2 3 C112CO21I - 34 tt /CHoCfi„0CII„ -N< * 2 .3XCII2C02C(CII3)3 1/2H2SO3 35 OX3 / CH„CII2OCH„ -N XCH2C0oII - 44361 - TABLE; 1 (Sheet 5 cont.) I Concentration required to prolong the coagulation time by a factor of two Preparat ion process (Jis, No .) ia.p« (°C) Elementary analysis Upper: Calculated^) Lower: Found ($ I.R. (KBr) (cm-1) C H X i powder 55.20 55-00 6 .95 6.SI 12.3s 12.21 3,360 3,150 1,620 1 u 54.36 54.25 7.30 7.11 10.57 10.81 3.370 3,200 3-,735 1.370 0.5 1 . 1» 54 .43 54 .21 6.55 6.50 13.80 13.79 3,360 3,180 1,632 1 I! 53.63 53.50 7.00 6.79 11.5S 11.40 3,380 3,200 1,740 •1,370 1 II 51.86 51.64 i 6.13 6.09 13.75 13.84 3,370 3,200 1,625 • 1 II 55.21 55.11 I ί 6.95 6.76 12.38 12.27 3,380 - 3,180 1,738 1,3680,5 3 II 51.86 53 .72 6.13 6.11 13.75 13.63 3,370 3,160 1,620 TABLE 1 (Sheet 6) 443G ί Sample No. Compound H IIN% 1 C-N-CILCUpCHpCHCOR (l) H„NX *· , 2 H-N-SO2-Ai’ Ar 11 Addition moiety 36 CO003 .CHoCH„0CH„ .-N - CH„CO.,C.,H_ 2 2 2 j OH no2 37' fl /(cu,)qch3 -Νχ — 3xch2c°2h - 38 If /(CllJpClL· -N -- J ^ch2co2c(ch3)3 1/2H2SO3 39 ' tl ^(ch,)3ch3 -N " J ^CII2C02n •B 40 II /(ch2)3ch3 -Nk nCU2CO2C(CH3)5 .l/ttl2S0 41 fl /(CII.J,fClt3 -N\ xcn?co2ii . - 42 II /(cii2),(ch3 -N< CH2CO2C(CH3)3 l/2H2S03 4436* TABLE 1 (Sheet 6 cont.) Concentration required to prolong' the coagulation time by a factor of two QtM) Preparation process (Ex. No .) m .p · (°C) Elementary analysis Upper: Calculated Lower: Pound (ί) X.It. (KBr) (cm-1) ci II N. 3 158-160 47.94 47.83 4.85 4. SO 11.51 11.43 3,375 3,200 ' 1,740 1 powder 53.53 53.40 6.33 6.21 14.19 14.04 3,375 3,.150 1,620 I 11 52.86 52.77 6.83 6.66 11.86 11.75 3,38a 3,200 1,740 1,370 0.5 1 It 54.43 ι 54 .22 6.55 6.31 13.80 13.59 3,380 3,150 1,620 3. 131-137 (dec.) 53.63 53.40 7.00 7.10 11.58 11.40 3,380 3,160 1,750 1,640 1 powder· 55.26 55 .21 6.76 6.65 13.43 13.29 3,350 1,630 1 169-175 .(dec) - 54 .35 54 .27 7.17 7.00 11.32 11.08 3,350 3,180 1,740 1,64ο TABLE 1 (Sheet 7) Sample No. Compound ILjN''' 11 1 C-N-CH„CH,,CHQCHCOE ** "1 II-N-30q-Ar (I) Ar R Addition moiety 43 ¢9 OCHgx CHoCHo0CH3 -Ny " " CH2C02H 1 t 44 ti , CH CH,OCH-N cii2co2c(cii3)3 45 it (CH ) CHn -N J JXCII2C02U - 46 It (C1Io)3CH„ -n > · XCU2CO;>C(CII3)5 1/2H2SO3 47 It .CHoCIlyGCHQ _N 7 4 JX CHgClIjjCOgH 48 It .Cn„CU„OCH„ -N Λ 'ch2cii2co2c(ch3)3 l/2H2S03 49 VYY oci5 ^>Z3 ^CllgCOgCiCI^J^j 0.5 h2so3 44361 TABLE 1 (Sheet 7 cont.) Concentration required to prolong the coagulation time by a factor of two (>M) Preparation process (lix. No.) m.p. (°C) Klemontary analysis Upper: Calculated $ Lower: Found (--) I.R, (KBr) (cm1) C- H N 2.5 1 powder 51.86 51 -77 6.13 6.00 13.75 I3.72 3,365 3,200 1,620 1 It 51.47 I . 51.20 i 6.65 6.35 11.54 11.24 3.370 3,200 1,740 1.370 1 - .11 1 54.43 56.2 s i 6.35 6.31 13.80 13,70 3,375 3,200 1,622 1 It 1 53.63 53.53 -1 1 7.00 7.08 11.58 11.40 3,380 3,200 1,740 1,370 1 It t 52.76 1 52.47 6.35 6.01 13.38 13.09 3,375 3,180 1,620 • 1 tl 52 .24 52.00 6 .82 6.55 11.28 11.00 3,380 3,200 1,740 1,368 1 189-191 (dec,) 55.68 55.36 6.33 6.35 10.47 10.45 3,360 3,160 1,730 80.
TABLE 1 (Sheet 8) Sample No. Compound II UN | c-n-cn,. on,, cn,. chcor H„N' 2 2 ., 2 H-N-S02-Ar (I) Ar R Addition moiety 50 ca:: -»ζ"2Ό XCH.,CO.,lt - 51 tr 2 57. by 6.02 6.06 11.96 11.74 3,36ο 3,200 1,590 1 . 155-157 (dec.) 1 53.25 53.13 5.30 5.21 10.11 10.03 3,380 3,180 1,720 50 I powder 58.08 57.93 6.22 6.04 11.68 .11.54 3,200-3,380 (broad) 1,020 TABLE 1 (Sheet 9) , ν' 44381 Sample No. Compound 11 11N<< 1 Ο-Ν-ϋΗοΟΙΙ,ΟΗ.,ΟΗΟΟΚ (I) X 2| * H-N-30,-Ar Ar R Addi tion inoiety 57 tjxx„3 ^ch2co2c(ch3)3 OK lK'3s h02 58 tt - TABLE 1 (Sheet 10) Sample No.
Compound H HNS | ^C-N"CH2CH2CH2CHCOR H«N (l) H-N-SOg-Ar Ar R Addition moiety CO5XCH2C02H - CP OCHgXCH2C02C(CHg)g » -b-c'6-O \cu2co2h - tf • W5 -t> - C TABLE 1 (Sheet Ho cont.) I Concentration required to prolong the coagulation · time by a fector of two (,(Ui) Preparation process (Ex. No.) m.p. (°C) 1 Elementary analysis Upper: Calculated ® I - Lower: Found I.R. (KBr) (cm Χ) σ H N 20 1 powder 58.37 t 58.pl 1 6.00 5-93 12 .61 12.46 3,200 (broad) 1,620 1 ft 1 ( 60.29 I 60.21 I 6.58 6.56 11.72 11.64 3,365 3,170 . 1,730 2.0 1 - n I 57.66 57.48 ί 5.77 5,74 12.93 12.84 3,360 3,160 1,610 2 powder 55.40 55*65 6.62 6.81 12.43 12.19 3,220 1,750 1,640 TABLE 1 (Sheet 11) Sample No. Compound H 1 C-N-CH-CH-CI^CIICOR (I) ’ H„NX * ά *Ί H-N-SOg-Ar Ar R Addition moiety 68 ox,, CO^Hg -C OH no2 —... 69 'OX'3 CO-C-H, A 5 V®! CH "V0X2 uo2 70 w OCHg W5 -0°¾ - 4436 i ώ · TABLE 1 (Sheet 11 cont.) Concentration required to prolong tha coagulation time by a factor of two (/-M) Preparation process (Ex. No,)· m.p . (°C) Elementary analysis I.R. (KBr) (cm-1) Upper: Lower: i Calculated (tf) Pound (tf) d H N ---- . - 2 192-193 49 «58 49.24 ! ί 4.87 4.70 II.56 11.85 3,210 1,747 1,638 2 188-190 I 50.:17 50^01 5.03 4.78 11.38 II.56 3,200 1,740 1,635 2 tt ! 57 .'02 56 .81 6.81 6.91 12.79 12.78 3,200 1,740 1,635 88..
TABLE 1 (Sheet 12) Sample No. ‘ Compound 1 C-N-CH-CH-CIIqCHCOR (l) 11-N-S02-Ai· Ar R Addition moiety : 71 pX., OCHg 'C02C2H1 )A -NjHHg OH H03S γ5γ^.-Ν°2 , no2 ---------- 72 'XXX °C2H5 CO2C2H5 -O3 OH ao’sOTN°2, no2 73OC1I3 OCH- CO2C2H5 OH HO^NO, no2 4361 TABUS 1 (Sheet 12 cont.) ύ - I i Concentra tion required to prolong the coagulation time by a factor of two poi) Preparation process (Ex. No.) .-- m.p. (°C) Elementary analysis Upper: Calculated ("3 I.R. (KBr) (cm1) 1 Lower: 1 Pound ($ 1 ci H N - 2 222—3 49 .'82 1 - 49.57 i 5.09 4.88 11.99 .11.68 3,200 1,745 1,630 • 2 154-6 i 50.92 51 .;28 - i 5-37 5.21 10.66 10.59 3,400 1,735 1,635 2 179-180, 1 50.(38 ,1 · 50.34 1 , I 5.23 5'· 18 10.82 II.05 3,380 1,735 1,635 TABLE 1 (Sheet 13) Sample No. Compound UN V .C-N-CH0CHyCH„CHCOR (l) II N ' ~ * "Ί H-N-SOg-Ar Ar R Addition moiety 74 OX5 co,c2h OH 75 %jA3 co2c2h5 -xV~~^>-CII2Cn2CiI3 - 76 II CO2C2H5 -θ-°Η(0Η3)2 - 443 TABLE 1 (Sheet-13 cont. ) Concen fc rati on requircd to prolong tho coagulation time by a factor of two pt M) - -..- .- -- Preparation process (Ex. No.) m.p · (°C) Elementary analysis Upper: Calculated $ Lower: found ($) I. R. (KBr) (cm-1) C J H N.. · 2 125 (soften) 50.73 50.58 5.18 5.11 11.19 10.93 3,380 1,735 1,633 2 -0 57.50 1 57.56 7.15 7.03 H.56 11.71 3,330 2,96ο 1,740 1,640 t 2 »1 ί 57-50 ) 57.15 7.15 7.21 II.56 11.62 3,360 2,960 1,735 \ 92. k c; . TABLET (Sheet 14) Sample No. Compound H ! C-N-CinCH,CH„CHCOR (I) HONX Z Λ 1 * II-N-SO -Ar Ar R Addition moiety 77 7fYY°CH3 OCH3 COgCgHg v CH3 - 78 ΌΧ3 CH3C°2C2H5 -6 - 79 °°Η3 ‘YZAoch3 "O ' OH rio2 80 ' ZYYC!:3 TABLE 1 (Sheet 15) Sample No. Compound H HN 3CtlpCHoCHC0?. (l) IkN · 1 4 H-N-S0,-Ar Ar R Addition moiety 81 OCH3 -Z°"=-O XCH2C02H 82 ItXCH2CO2C(CH3)3 OH H°3ST^V^rN02 83 llsCH2C02H - 84 τφΧ, OCH3XCH2CO2C(CH3)3 OH 11038 x00^N°2 no2 85 II -2C02H - 86 TO003 2co2c(ch3)3 OH 11038 O^N°2 N02 87 tl <0 nCH2C02H i " 1 1 ! TABLE 1 (.Sheet. 1b eont.) -· «383.
Concentration required to prolong the coagulation time by a factor of two / M) Preparation process (Ex. No.) m.p· (°C) Elementary analysis Upper: Calculated $ Lower: Pound i. I.R. (KBr) (cm-1) . 1 σ H N 1 powder i 56.13 56.00 6.81 6.73 12.12 12.01 3,350 (broad) 1,640 1 178-181 (dec.) 51.94 I 52.24 1 ! 5.64 5.60 10.34 10.28 3,400 3,200 1,735 1 powder F 56.13 56 .28 6.81 6.59 12.12 12.31 3,350 (broad) 1,640 1 ‘ I62-165 (dec.) 51-43 51,28 1 5.50 5.21 10.50 10.21 3,370 3,200 1,730 1 powder 1 55.40 •1 55.2s 6.62 6.32 12.43 12.03 3,300 (broad) 1,610 (broad) 1 158-160 (dee.) ' ί 52,75 52.56 5.56 * 5-43 11.04 10.97 3,405 3,220 1,740 1 powder 56.26 56.01 1 f 6.61 6.49 13.13 13.21 3,320 (broad) 1,640 96, 4 3 61 TABLE 1 (Sheet 16) Compound Sample No. Η2Ν·χ( H 1 J-N-CH2CH2CH2CHC0R H-N-SOg-Ar (I) Ar R ' Addition moiety 8Θ TH2C02C(CH3)3 ho3s OH ΌΧ . no2 89 tl <^O xch2co2h / 90 a? OCH3 -'°2: no2 91 M ί 92 °°Η3 XCH2CO2C(CH3)3 1IO3S OK N°2 93 11 -2C02H - 94 11 - IIOjS OH OX2 N02 97.
TABLE 1 (Sheet 16 cont.) ’oi’.een bra tion required to prolong the coagulation time by a actor of two (/4 M) Preparation process (Ex. No.) m ,p . (°C) Elementary analysis I.R. (KBr) (cm-1) Upper: Lower: Calculated ($ Pound $ ( I ' ci H N . 1 160-163 (dec.) i 52.33 52.03 5.60 5-30 10.68 10.28 3,4oo 3,210 1,730 1 powder 57.02 I 57.39 j I 6.81 6.21 12.79 12.38 3,350 (broad) 1,620 . 1 I52-155 (dec.) 52.83 52.53 1 5-73 5.72 IO.52 IO.29 3,390 3,205 1,730 1 powder 57 .'p 57/1 7.00 7.23 12.47 12.28 3,370 1,630 1 170-172 (dec.) 51.43 1 51.09 5.50 5.45 IO.5O 10.28 3,380 3,220 1,740 5 • 1 powder 1 1 55.40 i 55.30 i 6.62 6.28 12.43 12.11 3,400-3,200 (broad) 1,600 i 155-158 (dec.) ! - 51.94 52/a 5.64 5.63 10.34 10.00 3,380 3,200 1,730 98.
TABLE 1 (Sheet 17) ' 4 3 0.1..
Sample No. Compound H HN , C-N-CH,CH,CH_CHCOR . (I) H„N - Z Z| 2 H-N-S02-Ar Ar R Addi tion moiety 95 ox; 2CH2CO2H - 96 II ^CH2CH2CH2C02H - 97 II (ch2)3cu31 ^0110030(0113)3 CH3 OH no2 » 98 It (ch2)3ch3XCHCO„H 1 2 CH3 - 99 It _nX(ch2)Zich3XCHCO2C(CH3)3 ch3 OH ho.s^^no, no2 100 II _n/(ch2)4ch3 ^CIICO.II 1 4 CH3 - 101 II - TABLE 1 (Sheet 18) Sample No. Compound H 1 , χ C-N-CH-CH-CIUCECOR (I) HONX 2 2-(2 H~N-30g-Ar Ar R Addition moiety 102 co:; -zc"2O ^CHCOgH CHg 103 tt /λ-Ο CHCO2C(C!I3)3 cii3 OH no2 104 It _ CH2C„2-Q ΠΗΟΟ,,Η 1 2 ch3 - 105 tt -nC^CZ CIICO2C(CiI3)3 ch3 OH 106 tt χΟ XCHC0„U v - 107 pX, 0CH3jX'CHCO2C(CH3)3 CH3 OH >ν-0γ 108 ll . /O XCI1CO„H 1 2 ch3 - 101 443 61 TABLE 1 (Sheet 18 cont.) Coucen tration required to prolong the Coagulation time by a factor of two UM) z Preparation process (Ex. No.) m ·ρ. f°c) 1 Elementary analysis Upper: Calculated $ 1 Lower: Found 03 f I.R. (KBr) (cm-1)CL II N 2-5. 1 powder 1 5? .,42 57 .;35 f 6.02 5.84 II.96 12.00 3,350-3,160 (broad) 1,600 1 130-135 1 53.25 53.08 1 5.30 5-29 10.11 10,29 3,400 3,200 1,730 1.5 1 powder 58.08 57 .'84 t 6.22 6.13 11.68 11.46 3,360 3,160 1,600 • 1 158-163 (dec.) 1 51.95 1 51 .so 5,64 5.38 10.34 10.30 3,360 3,200 1,74ο 1 powder 56,14 1 55 .'98 ! 6.81 6.79 12.13 12.35 3,380-3,200 (broad) 1,625 1 I6O-I63 (dec,) - i - 52.44 1. 52.39 1 5.76 5.58 10.19 10.00 3,400 3,200 1,740 4.5 _ . z 1 powder 1 56 ?84 56 .72 6.99 6.80 11.84 11,76 3,380-3,250 (broad) 1,595 ?.
TABLE 1 (Sheet 19) 4 4361 Sample No. Compound ll „ C-N-CIHCIH CH„CHCOR Il2NX 2 2 Z| H-N-S02-Ar (I) Ai‘ R Addi tion , moiety 109 CO'3 _iV/ TABLE 1 (Sheet 20 cent.) Concentra tion required to prolong tho COiigul ation lime hy a factor of two yut) Preparation process (Ex -No..) ni.μ . (°C) Elementary analysis Upper: Calculated $ l I.R. (KDr) (cm1) Lower: Found C, H N . • 5 powder 58.90 58.91 i 6.66 6.79 13.22 13.15 3>200 (broad) 1,635 5 It 1 55.73 1 1 55·β1 7.52. 7.4o 14.13 14.10 3,300 (broad) 1,630 5 170-173 1 57.56 57.41 7.54 7.39 13.43 13.50 3,335 1,630 '5 powder i 56 .78 56 .85 7.35 7.29 13.80 13.71 3,200 (broad) 1,630 5 tl 58.96 58.79 6.66 6.51 13.22 13.19 3,300 (broad) 1,630 ’ 5 142-145 j · 49.07 48.90 I 5.49 5-38 13.63 13.42 3,150 1,620 5 powder . 47.47 47.29 5.43 5.31 12.58 12.39 3,150 1,630 106. 43 6 I TABLE 1 (Sheet 21) Sample No. Compound H 1¾ | . C -N-CIL CILjCJl.,CHC OR h2n 4 - ·| H-N-SOg-Ar. (Ϊ) Ar R Addition moiety 123 co.. .CILCILCCH., -N< - Z J CHgCOgE - 124 co., _ν/ΙΙ-<35Η11 xch2co2h - 125 to· -nC j ^CHgCOgli - 126 tl _ν/ΟΗ2οη2«η3X CH2C02H - 127 II ^CIIgCOgH - 128 It CHgCOgH - 129 ¢0 S CH,C1I,CCH. -N. J CilgCOgE - 107 4361 TABLE Γ (Sheet 21 cont.) Concentration required to prolong the coagulation time by a factor of two (/M) Preparation process (Ex . No .) m.p · (°C) Elementary analysis Upper: Calculated ¢3 Lover; pound (fy I.R. (KBr) (cm-1) C H N 5 . powder 49 .07 49.12 5.49 . 5.28 13.63 13.59 3,150 1,630 - 5 123-130 57.01 56.88 6.98 6 .71 13.85 13.65 3,300 1,635 0.3 5 powder 56.19, 56.00 6.77 6 .50 14.25 14.00 3,300 3,150. 1,630 0.2 5 I! 53-53 53.24 6,33 6.19 14.19 13.99 3,300 (broad) 1,630 5 it 60.09 59.79 6.16 6.02 12.93 12.61 3,300 (broad) 1,630 14 5 » 58.73 58.66 7.01 '6 .90 13.17 12.91 3,380 1,635 5 147-150 52 .59 52.31 6.10 6.01 14.61 14.33 3,380 1,640 108. •ji TABLE 1 (Sheet 22) Sample No. HN h2nx Compound H 1 3-N—CH„CII,,CH,,CKC01l 2 . 2, H-N-30 -Ar d) Ar Ii Addition moiety 130 00 -xcii2002e - 151 co „<"2-0 CH2C02« - 132 It /nC4K9 -Νζ J ^CH2CII2C02H - 133 0CP .CH CILCCIL· -N'T J ^CH2CO2K - 134 ¢0,, N xCllg ^CIL.CO,,!! - 155 II ^CH„CH„OCII, -N 2 2 3xCIIC0o!I - 109 4281 TABLE 1 (Sheet 22 cont.) Council tration required to prolong the coagulation time by a · factor ol' two M) Preparation process (Ex. No.) m.p. (°C) Elementary analysis Upper: calculated (?!) bower: Found $ I.R. (KBr) . (cm-1) C, ll N 5 powder 57 .23 56.98 6.61 6.33 13.91 13.81 3,300 (broad) l,63O; 5 If 58.69 58.79 I 1 5.71 5-55 13.69 13.39 3,300 (broad) 3,150 1,630 - 5 ll . 56.19 55-95 6.77 6.58 14.25 13.97 3,190 (broad) 1,620 20 5 130-135 53-53 53.28 6.33 6.19 14.19 13.97 3,350 1,640 4 5 powder 55.36 55.10 6.97 6.76 16.14 16.07 3,380 1,630 . 5 n 52.86 52.71 6.56 6.29 16.08 16.07 110. '4 4 3 61 TABLE 1 (Sheet 23) Sample No. Conpound (I) HN^ H I C-N-CH2CH2CH2CHC0R H-N-SO^-Ar Ar R Addition moi e ty 136 TO° .xCH-CH,OCH. -N. JxCH2C02H - 137 TO ) Concentration required to prolong the coagulation time by a factor of two (AM) Preparation process (Ex. No .) m.p. (°C) Elementary analysis Upper: Calculated ($ Lower: Pound I.R. (KSr) (cm*1) c H N 5 powder 50.90 50.81 5· 90 .5.70 14.13 13.89 3,180 (broad) 1,630 5 H 59.41 59.22 5.95 5.73 13.33 13.28 3,170 (broad) 1,620 6 }} 53.17 52.89 6.69 6.52 12.92 12.74 6 li 57.66 57.31 6.34 6.14 11.59 11.16 - 5 » 55.33 55.26 6.54 6.62 14.67 14.58 3,200 (broad) 1,630 112 TABLE 1 (Sheet 24) Sample No . Compound H HN^ | C-N-Ci!nCH9CH„CHCOR (l) H„N 1 H-N-50-Ar * Ar R Addition moiety 141 tt CO2C2Ii5 CH^COOH j 142 OX’ CO^ CoH(- -n^-ch(ch3)2 l/2lt2S03 143 Wch, C02C2H5 -^2^-ch(ch3)2 CH3COOH 144 -t>3 CH3C00tl 145 wCO2C2H5 -t>H(C«3)2 CHjCOOH 146 xo COzC2H5 X CH3COOH 113 44365TABLE 1 (Sheet 24 cont.) Concentration required to prolong the Coagulation time by a factor of two (/tM) z Preparation process (Ex. No.) m.p · (°C) Elementary analysis Upper: Calculated $) Lower: Found $ I.R.(KBr) (cm1)T C H N 3 tt 56.83 56 .72 6.98 6.81 .11,84 11.56 3,400 (bread) 1,735 1,640 2 powder 55.98 55.69 7.05 7.21 11.66 11.38 3,400 (broad) 1,730 1,635 - 3 - .,- » 58.13 57.98 7.32 7.56 11.30 11.28 3,380 (broad) 1,730 1,630 3 11 56.13 56 .08 6.80 6.83 12.12 12.12 3,400 (broad) 1,740 1,630 3 «' 57.50 57.61 7.15 7.11 II.56 11.81 3,350 (broad) 1,730 1,620 3 II 55.74 55.90 7.45 7.51 12.04 12.18 3,400 (broad) 1,730 1,625 114 TABLE 1 (Sheet 25) Sample No. Compound II (x) 1I,NX 1 :-Ν-οιι.,οιι.,οιι9οιιεοϋ ., -! ll-Ji-SO -Ar Ar R Addition moiety .OCH COgCg^ij 147 Ό0 Γ 3 -N~\ - V_7 148 0C„3 011,,011,,0000,,11,. _N --. A j OCH3X CH^COOH 149 OCII3 /011-011,0011, UM •och3 -N a-3 X‘CiI2COO-n-08lI17 HCl COOH 150 tl /011011.,01:.,01^ "K \ - 0Η2000ΝΗ/( 115. 443s1 TABLE 1 (Sheet 25 cent.) Concontration required to prolong tho coagulation time by a factor of two /M) Preparation process (Ex. No.) in .p . (°C) Elementary ana Lysis Upper: Calculated^ Lower: Pound 1.R. (KBr) (cm-1) C H N 2 powder 52.25 52,36 i 6.03 5.98 12.70 12.51 ' 3,400 1,735 1,640 1,160 6.5 .1 II 54 .63 54 .28 6.42 6-.31 12.74 12.53 3,350 (broad) 1,740 2 6 (I 54 -10 53.81 7.32 7.13 10.18 9.93 3,180 (broad) 1,740 1,630 55 2 II 50.15 49.91 6.41 6.35 14.04 13.83 3,280 1,620 . 116.
TABLE 1 (Sheet 2b) Sampl No. ’ H2N’X Conipound H 1 I—N-CH.jCIioCIl,,CliC0K .. . - , (x) Ar li Addition moj. ety 151 tl -NH-CIICHOCU-CII„ , - 4 -> COOH - 152 TO s CH-CH, O-Cil-N'T " J ^CllgCOOlI - 153 TOO .CH,CH,CCII, x CUjCOO:-: - 154 TOffTO °CK3 OXX-OCHg j.CH,CH=CHnXCH2C02H - 155 ttxcH?c~eK XCH2CO2H - 156 OOH, χχ OCHg ,CH-— CH-CH, -N 2 5xCH2COOH - 117 TABLE 1 (Sheet 26 cont.) Conneii tra tion required to prolong tho coagulation time by a factor of two (/. M) Pi'Qparatxon process (Ex. No.) m.p . (°C) Elementary analysis Upper: Calculated ($ Lower: Found (t) I.R. (KBr) (cm-1) 0 II Ν , 6.5 2 'll 52 .06 52.40 ’ 6.38 6.37 12.65 12 .73 3,350 (broad) 1,620 15 2 h 52,75 52.68 6.36 6.34 13.38 13.41 3,380 (broad) 1,620 5 » 46 .81 46.63 6 .00 5.94 14.37 14.23 3,400 3, 300 1,630 5 powder 51*38 51 -24 5.82 5.79 13.03 12 .87 3,380 3,300 1,6 30 1 »1 52.95 52-79 6.00 5.87 13,43 13.28 3.350 3.I5O 1,620 2 II 52.06 53.74 6.38 6.37 12.55 12.73 3.350 (broad.) 1,620 118 EXAMPLE 7 Tablets suitable for oral administraLien Tablets containing tho ingredients indicated below may be prepared by convontional techniques.
Ingredi ent Amount per tablet (mg) N 2-(7-me tho xy—2-naph thylsulfonyl)L-arginyl-N-(2-methoxyetliyl)glycine 250 Lactose 140 Corn starch 35 Talcum 20 Magnesium stearate 5 To tai 45Ο mg EXAMPLE 8 Capsules for oral administration containing ingredients Capsules / the bolow/were made up by thoroughly mixing togetlior batches of the ingredients and filling hard gelatin capsules with the mixture.
Ingredient Amount per capsule (mg) 2 N -(7~methoxy-2-naphthylsulfonyl)L-nrg.inyl-N-(2-me thoxyethyl) glycine 250 Luctose 250 Total 500 mg 119.
EXAMPLE 9 Sterile solution for infusion Tlie following ingredients aro dissolved in water for inti-avonous perfusion and the I’esu.'l ting solution is then sterilized.
Ingredients Amount (g) 2 , . N -(7-mi}tl>0xy-2-naphUty ism fonyl )L-argjny.l -N-(2-iiietboxycthyl )p;1 yc.i ne 25 Buffer system As desired Glueose 25 Dis I.i 11 ed wa tc? 500 Methods of preparing starting materials for use in the preparations described above are described in Application Xa.zwjlb In so far as the present invention relates to a method of inhibiting the activity and. suppressing the activation of thrombin in vivo, no claim is made herein to any such method used for the prevention or cure of disease in human beings.
Claims (16)
1. An N -arylaulphonyl-L-argininamide having the formula HN 76 - N - CH o CH o CH o CHC0R | Ζ Ζ Z | H 2 N H ' KtiSCL (I) I ά Ar 5 wherein R is X (CH 2 ) n C00R 2 wherein R^ is 0 2 “ C 10 alkyl, C 3 -C io alkenyl, °5“θιο alkynyl, 0 alkoxyalkyl, C 2 -C 10 car1jox y a lkyl, C 3 -C io alkoxycarbonylalkyl, C,?-Ο^θ aralkyl, C^-C^q cycloalkyl or C^-C^q cycloalkylalkyl; R 2 is hydrogen or C l- C 10 alkyl; and n is 1, 2 or 3, X (2) - N CH - (CH 2 ) m 000R 5 121. wherein R3 is hydrogen, Cl-Gio alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C2-C10 alkoxyalkyl, C2-C10 earboxyalkyl, C3-C10 alkoxycarbonylalkyl, C7-C10 aralkyl, C3“Cxo cyclo alkyl or C4--C10 eyeloalkylalkyl; R4 is Οχ-Οχο alkyl; R5 5 is hydrogen or Οχ-Οχο alkyl; and m is 0,,1 or 2, wherein Rg is -COORg wherein Rg is Cx-Cy alkyl; each Ry independently is hydrogen, Οχ-Οχο alkyl or C1-C5 alkoxy; p is an integer of 1 to 5i Ng is substituted, into tlie 10 piperidino ring at the 2 or 3-poaitien; and gach independently ie substituted into the piperidine rin£ at the 2, 5, 4, 5 or 6-position, COOR9 (4) - N optionally substituted with one or more C1-C5 alkyl or 15 C1-C5 alkoxy groups, wherein Rf, is CI-C9 alkyl; and r is 1, 2, 3 or 4, COOR-io ,, P\ (5) - N 2 \ / \-(ch4 wherein Rio is θ!“θ9 alkyl; Z is oxy or thio; and q is 0 or 1, or 122. (6) COORi1 Χ(™2)ΐ. wherein Rn is Cp-Og alkyl; i is 0, 1 or 2; j is 0, 1 or 2; and the sum i+j is 1 or 2; and Ar is 5,6,7,8-teti’ahydronaphthyl, naphthyl, 1 or 2-naphthyl substituted with one substituent which is halogen, nitro, cyano, hydroxy, Cl-Cio alkyl, dialkylamino, coiitaining not more than 20 carbon atoms, C-,-C 1Q alkoxy 125. 4 4361 ί
2. A compound as claimed in claim 1 wherein R is X R i (l) - N wherein is Cg-C 10 X (CE 2 ) n C00R 2 j· Cj-Cg alkenyl, 1 C^-Cgjalkynyl, Cg-Cg alkox y alk yl, ®2 -σ 7 carboxyalkyl, C^-Cg alkoxycarbonylalkyl, Ογ-Ο-^θ aralkyl, 5 θ5 -(3 ιθ °y c l° al ^yl or cycloalkylalkyl; and Rg is hydrogen, or θ 1-°10 alkyl, (2) - N wherein is hydrogen, X OH-(CH 2 ) m OOOR 5 C^-Cjq alkyl, C^-Cg alkenyl, c -j -c g alkynyl, Cg-Cg alkoxyalkyl, Cg-C? carboxyalkyl, C^.-Cg alkoxycarbonylalkyl, σ γ -Ο ιο 10 aralkyl; C^-C^ cycloaikyl, C^-Ο^θ cycloalkylalkyl, and R^ is 0-^-Cg alkyl, A 6 wherein .R? is hydrogen or C x '· Cg alkyl; ' Ar is naphthyl, 5,6,7,8-tetrahydronaphthyl, 1- or 2-naphthyl substituted with one substituent which is halo, nitro, cyano, hydroxy, C^-C^ alkyl, C^-C^ alkoxy j.5 or Cg-C 10 dialkyl amino OR wherein R and,R’ each independent! are C^-C^ alkoxy, 124. wherein R 12 is C^-Cg alkoxy o 5. Λ compound as claimed in claim 1 which is N 5 (7-methoxy-2-naphthylsulfonyl)-L-arginyl-N-butylglycine.
3. 4, A compound as claimed in claim 1 which is N(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl) glycine. [·_ Λ compound as claimed in claim 1 which is N 10 ( 6 '7-dimethoxy-2-naphthylsulfony1)-L-arginyl-K-(2-methoxyethyljglycine ethyl ester. g A compound as claimed in claim 1 which is N (4,6-diniethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyDglycine. 125. 443 s4 7. A compound as claimed in claim 1 which is N -(7methoxy-2-naphthylsulfonyl)-L-arginy1-N-(2-methoxyethyl) glycine. ' g, A compound as claimed in claim 1 which is N -(5,6, g 7,8-tetrahydro-l-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl) glycine. 9. A compound as claimed in any preceding claim having D-configuration in the carbon atan to which the carboxylic group is attached. 10 10. A coinpound as claimed in claim 1 which is any one of compounds Nos. 1 to 108 as hereinbefore designated. 11. A compound as claimed in claim 1 which is any one of the compounds hereinbefore described in Table 1. 12. A process for producing a compound as claimed 15 in claim 1 which process comprises reacting an L-arginamide having tlie formulas UN C - N - CJI-CH,C1LCIICOR / Γ 2 2 2, H 2 N II NH, wherein R is as;, defined in claim 1 with an arylsulfonyl halide having the formula ArS0 2 X wherein Ar is as (3e.Ci.iied in claim 3. and X is halogen. 126. 13· A process as claimed in claim 12 wherein R and Ar are as defined in claim 2. 14. A process for producing a compound as claimed in claim rt 1 which process comprises removing the the N -substituent from rt 2
4. 5 an N -substituted-N -arylsulfonyl-L-argininamide having the formula: C - N - CH,CH,CH,CHCOK UN I “ I I R HNSO, ir I ~ Ar wherein R and Ar are as defined in claim 1; R' and R are each hydrogen atoms or protective groups for the guanidino group, at
5. 10 least one of R' and R being a protective group for the guanidino group.
6. 15. A process as claimed in claim 14 wherein R and Ar are as defined in claim 2; and R' and it are hydrogen, nitro, acyl, tosyl, trityl or oxycarbonyl. 15
7. 16. A process for producing a compound as claimed in claim 1, which process comprises reacting an N -arylsulfonyl-L-arginyl halide having the formula: llN^ - N - CH,CH,CH,CHCOX 1I,N X I -| - || IINSO, I * Ar 127. 443® 1 wherein Ar is as defined in claim 1 and X is halogen, with an amino acid derivative having the formula: RH Wherein R is as defined in claim 1. 5
8. 17. A process as claimed in claim 16 wherein R and Ar are as defined in claim 2.
9. 18. A process for producing a compound as claimed in claim 2 1 which process comprises guanidylating an N -aryl-L-ornithinamide having the formula: gg HgUCH^CH^Ci^CHOOR HNSO.,2 Ar wherein R and Ar are as defined in claim 1 with a guanidylating agent.
10. 19. A process as claimed in claim 18 wherein R and Ar are as defined in claim 2, and the guanidylating agent is an O-alkyli15 sourea, S-alkylisothiourea, 1-guanyl-3,5-dimethylpyrazole or a carbodiimide.
11. 20. A process -for. producing a compound as claimed in claim 1, substantially as described in any one of Examples 1 to 6 with reference to any one of the compounds produced in 2o those Examples. 128.
12. 21. A proceBS for producin,·; a compound au claimed in claim 1, substantially as desci'ibed with reference to any one of Sample Nos 1 to 156.
13. 22. A method of inhibiting the activity and suppresses the 5 activation cf tlranbrn in vivo, which method comprises introducing into a living body a pharmaceutically effective amount of a compound as claimed in any one of claims 1 to 11,
14. 23,, A compound as claimed in claim 1 when produced by a process claimed in any one of claims 12 to 21. 10
15. 24. A pharmaceutical composition comprising at: an active ingredient a compound as claimed in any one of claims 1 to 11 or claim 23.
16. 25. A unit dose of a pharmaceutical composition as claimed in claim 24. 15 26. A unit dose as claimed in claim 25 wliich is a tablet, capsule, troche,or lozenge.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IE331/79A IE44361B1 (en) | 1976-12-07 | 1976-12-07 | N2-arylsulfonyl-l-argininamides and the pharmaceutically acceptable salts thereof |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IE331/79A IE44361B1 (en) | 1976-12-07 | 1976-12-07 | N2-arylsulfonyl-l-argininamides and the pharmaceutically acceptable salts thereof |
| IE267176A IE44360B1 (en) | 1976-12-07 | 1976-12-07 | N2-arylsulfonyl-l-argininamides and the pharmaceutically acceptabel salts thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE790331L IE790331L (en) | 1978-06-07 |
| IE44361B1 true IE44361B1 (en) | 1981-11-04 |
Family
ID=11035959
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE331/79A IE44361B1 (en) | 1976-12-07 | 1976-12-07 | N2-arylsulfonyl-l-argininamides and the pharmaceutically acceptable salts thereof |
| IE267176A IE44360B1 (en) | 1976-12-07 | 1976-12-07 | N2-arylsulfonyl-l-argininamides and the pharmaceutically acceptabel salts thereof |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE267176A IE44360B1 (en) | 1976-12-07 | 1976-12-07 | N2-arylsulfonyl-l-argininamides and the pharmaceutically acceptabel salts thereof |
Country Status (1)
| Country | Link |
|---|---|
| IE (2) | IE44361B1 (en) |
-
1976
- 1976-12-07 IE IE331/79A patent/IE44361B1/en not_active IP Right Cessation
- 1976-12-07 IE IE267176A patent/IE44360B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| IE44360L (en) | 1977-06-09 |
| IE790331L (en) | 1978-06-07 |
| IE44360B1 (en) | 1981-11-04 |
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