ITRM930654A1 - GUANIDINE DERIVATIVES FOR THERAPEUTIC USE. - Google Patents
GUANIDINE DERIVATIVES FOR THERAPEUTIC USE. Download PDFInfo
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- ITRM930654A1 ITRM930654A1 IT000654A ITRM930654A ITRM930654A1 IT RM930654 A1 ITRM930654 A1 IT RM930654A1 IT 000654 A IT000654 A IT 000654A IT RM930654 A ITRM930654 A IT RM930654A IT RM930654 A1 ITRM930654 A1 IT RM930654A1
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- 229940083094 guanine derivative acting on arteriolar smooth muscle Drugs 0.000 title claims description 5
- 230000001225 therapeutic effect Effects 0.000 title description 6
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical class NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims description 41
- -1 o-hydroxy phenyl Chemical group 0.000 claims description 11
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 7
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 6
- 238000011282 treatment Methods 0.000 claims description 6
- 150000002357 guanidines Chemical class 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims 4
- 150000004702 methyl esters Chemical class 0.000 claims 2
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims 1
- 125000003917 carbamoyl group Chemical class [H]N([H])C(*)=O 0.000 claims 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 53
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 25
- 239000000243 solution Substances 0.000 description 19
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 230000008018 melting Effects 0.000 description 10
- 238000002844 melting Methods 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 229940125904 compound 1 Drugs 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 239000004475 Arginine Substances 0.000 description 3
- 239000003146 anticoagulant agent Substances 0.000 description 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 3
- 210000004204 blood vessel Anatomy 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 230000032050 esterification Effects 0.000 description 3
- 238000005886 esterification reaction Methods 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- DSGKWFGEUBCEIE-UHFFFAOYSA-N (2-carbonochloridoylphenyl) acetate Chemical compound CC(=O)OC1=CC=CC=C1C(Cl)=O DSGKWFGEUBCEIE-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- 101150041968 CDC13 gene Proteins 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- 102000009123 Fibrin Human genes 0.000 description 2
- 108010073385 Fibrin Proteins 0.000 description 2
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- HAMNKKUPIHEESI-UHFFFAOYSA-N aminoguanidine Chemical class NNC(N)=N HAMNKKUPIHEESI-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N anhydrous trimethylamine Natural products CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229950003499 fibrin Drugs 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-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 1
- XFDUHJPVQKIXHO-UHFFFAOYSA-N 3-aminobenzoic acid Chemical group NC1=CC=CC(C(O)=O)=C1 XFDUHJPVQKIXHO-UHFFFAOYSA-N 0.000 description 1
- SJXHSFSHNKFRLN-UHFFFAOYSA-N 5-chlorosulfonyl-2-hydroxybenzoic acid Chemical compound OC(=O)C1=CC(S(Cl)(=O)=O)=CC=C1O SJXHSFSHNKFRLN-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 206010011091 Coronary artery thrombosis Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000283977 Oryctolagus Species 0.000 description 1
- 206010059440 Platelet toxicity Diseases 0.000 description 1
- 208000001435 Thromboembolism Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000000702 anti-platelet effect Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- QVFWZNCVPCJQOP-UHFFFAOYSA-N chloralodol Chemical compound CC(O)(C)CC(C)OC(O)C(Cl)(Cl)Cl QVFWZNCVPCJQOP-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 208000002528 coronary thrombosis Diseases 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 239000007933 dermal patch Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 230000003284 homeostatic effect Effects 0.000 description 1
- 125000003151 isocoumarinyl group Chemical group C1(=O)OC(=CC2=CC=CC=C12)* 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 231100000668 minimum lethal dose Toxicity 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
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- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 210000004896 polypeptide structure Anatomy 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000003998 snake venom Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000001732 thrombotic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- JCMLRUNDSXARRW-UHFFFAOYSA-N trioxouranium Chemical compound O=[U](=O)=O JCMLRUNDSXARRW-UHFFFAOYSA-N 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
GUANIDINE AD USO TERAPEUTICO GUANIDINS FOR THERAPEUTIC USE
RIASSUNTO DERIVATI GUANIDINICI AD USO TERAPEUTICO STATO DELLE CONOSCENZE DESCRIZIONE DELL'INVENZIONE SUMMARY OF GUANIDINE DERIVATIVES FOR THERAPEUTIC USE STATE OF KNOWLEDGE DESCRIPTION OF THE INVENTION
PARTE SPERIMENTALE EXPERIMENTAL PART
Chimica Chemistry
Attivit? farmacologica e tossicit? Activities pharmacological and toxicity?
RIVENDICAZIONI
BREVETTO - PROGETTO PATENT - PROJECT
GUANIDINE AD USO TERAPEUTICO GUANIDINS FOR THERAPEUTIC USE
RIASSUNTO. SUMMARY.
La presente invenzione riguarda nuovi derivati guanidinici formula generale (1) . The present invention relates to new guanidine derivatives general formula (1).
Questi derivali possiedono propriet? farmacologiche e terapeutiche utili ed importanti. In modo specifico possiedono un'attivit? vasodilatatrice, inibitrice dell'aggregazione piastrinica e pi? generalmente anti-trombotica. Do these derivatives possess properties? useful and important pharmacological and therapeutic treatments. Do they specifically own a business? vasodilator, inhibitor of platelet aggregation and pi? generally anti-thrombotic.
GUANIDINE AD USO TERAPEUTICO. GUANIDINS FOR THERAPEUTIC USE.
La presente invenzione riguarda nuove guanidine sostituite, i rispettivi singoli isomeri ottici e la loro utilizzazione in campo farmaceutico. The present invention relates to new substituted guanidines, the respective single optical isomers and their use in the pharmaceutical field.
STATO DELLE CONOSCENZE. STATE OF KNOWLEDGE.
Malgrado siano stati fatti, nel corso degli ultimi anni, notevoli progressi nel trattamento delle malattie tromboemboliche, le malattie cardiovascolari rimangono la maggior causa di morbilit? e mortalit? nei paesi industrializzati. Although considerable progress has been made in the treatment of thromboembolic diseases over the last few years, cardiovascular disease remains the major cause of morbidity. and mortality? in industrialized countries.
Fenomeni trombotici, che possono verficarsi sia nelle arterie che nelle vene, sono dovuti all'occlusione parziale o totale di vasi sanguigni da componenti del sistema omeostatico quali aggregati piastrinici e fibrina. La rottura di una placca aterosclerotica e conseguente accumulo e aggregazione piastrinica con successiva formazione di fibrina sono i fenomeni tipici della trombosi coronarica ( V. Fuster, L. Badimon, J.H. Clieesebro N. Engl. J. Med. Thrombotic phenomena, which can occur in both arteries and veins, are due to partial or total occlusion of blood vessels by components of the homeostatic system such as platelet aggregates and fibrin. The rupture of an atherosclerotic plaque and consequent accumulation and platelet aggregation with subsequent formation of fibrin are the typical phenomena of coronary thrombosis (V. Fuster, L. Badimon, J.H. Clieesebro N. Engl. J. Med.
1992, 326. 242 ; ibid 1992, 326, 310 ). 1992, 326, 242; ibid 1992, 326, 310).
L'aggregazione piastrinica essendo quindi uno dei mecanismi coinvolti nell'occlusione dei vasi sanguini, essa pu? essere la causa di infarto del miocardo. ( R.E. Scharf, L.A. Barker Blut 1987, 55. 131 ). Platelet aggregation being therefore one of the mechanisms involved in the occlusion of blood vessels, it can? be the cause of myocardial heart attack. (R.E. Scharf, L.A. Barker Blut 1987, 55.131).
Derivati guanidinici sono ben noti e l'aminoacido arginina ? uno di questi. Infatti l'arginina ? presente in sequenze polipeptidiche di varia origine come per esempio estratti di veleno di serpenti (R. J. Gould, M.A. Polokoff, P.A. Friedman, T. Huang, J.C. Holt, J.J. Cook, S. Niewarowski Proc. Soc. Exp. Biol. Med. 1990, 195, 168 ), estratti di sanguisughe ( J.L. Seymour, W.J. Henzel, B. Nevins, J.T. Stuls, R.A. Lazarus J. Biol. Chem. 1990, 265, 10143 ) e questi possiedono effettivamente un'attivit? anti-aggregante piastrinica. Inoltre polipeptidi ciclici ad attivit? anti-aggregante piastrinica contenenti un gruppo guanidinico di origine argininica sono stati descritti ( J. Samanen, F. Ali, R. Calvo, E. Sorensen, J. Vasko, D. Berry, D. Bennett, M. Strohsacker, D. Powers, I. Stadel, A. Nichols J. Med. Chem. 1991. 34. 3114 ). Oltre queste strutture polipeptidiche complesse, sono stale descritte varie strutture pi? semplici contenenti un gruppo guanidinico, nelle quali il gruppo guanidinico ? legato tramite una catena a tre atomi di carbonio, ad un ciclo azelidinonico ( W.T. Han US Patent 1991 , 5.037.819 ) oppure ? direttamente legato ad un anello iso-cumarinico (C.M. Kam, K. Fujikawa, J.C. Powers Biochemisiry 19 8 8. 27 . 2547 ). L'arginina, la quale contiene un gruppo guanidinico, ? stala legata ad un acido m-aminobenzoico sostituito tramite un legame amidico fra la sua funzione carbossilica ed il gruppo aminico aromatico (L. Alig, A. Edenhofer, P. Hadvary, M. Hiirzeler, D. Knopp, M. Muller, B. Steiner, A. Trzeciak, T. Weller J. Med. Chem. 1992, 35. 4393 ) , mentre nella nostra invenzione il gruppo aminico di una catena lineare amino-guanidinica o amino-guanidinica sostituita, ? legato ad un radicale aromatico quali fenile e naftile, tramite una funzione carbossile o sulfonile. Guanidine derivatives are well known and the amino acid arginine? one of these. Indeed arginine? present in polypeptide sequences of various origins such as snake venom extracts (R. J. Gould, M.A. Polokoff, P.A. Friedman, T. Huang, J.C. Holt, J.J. Cook, S. Niewarowski Proc. Soc. Exp. Biol. Med. 1990, 195, 168), leech extracts (J.L. Seymour, W.J. Henzel, B. Nevins, J.T. Stuls, R.A. Lazarus J. Biol. Chem. 1990, 265, 10143) and these actually own a business anti-platelet aggregation. Furthermore, cyclic polypeptides with activity? anti-platelet aggregates containing a guanidine group of arginine origin have been described (J. Samanen, F. Ali, R. Calvo, E. Sorensen, J. Vasko, D. Berry, D. Bennett, M. Strohsacker, D. Powers , I. Stadel, A. Nichols J. Med. Chem. 1991. 34. 3114). In addition to these complex polypeptide structures, various larger structures have been described. simple containing a guanidine group, in which the guanidine group? linked through a chain with three carbon atoms, to an azelidinonic cycle (W.T. Han US Patent 1991, 5,037,819) or? directly linked to an iso-coumarin ring (C.M. Kam, K. Fujikawa, J.C. Powers Biochemisiry 19 8 8. 27. 2547). Arginine, which contains a guanidine group,? was linked to an m-aminobenzoic acid substituted through an amide bond between its carboxy function and the aromatic amino group (L. Alig, A. Edenhofer, P. Hadvary, M. Hiirzeler, D. Knopp, M. Muller, B. Steiner, A. Trzeciak, T. Weller J. Med. Chem. 1992, 35. 4393), while in our invention the amino group of a substituted amino-guanidine or amino-guanidine linear chain,? bonded to an aromatic radical such as phenyl and naphthyl, through a carboxyl or sulfonyl function.
DESCRIZIONE DELL'INVENZIONE. DESCRIPTION OF THE INVENTION.
Nella formula generale (1) dell'invenzione, A rappresenta un gruppo aromatico quale fenile o naftile variamente sostituito secondo la formula (2) e contenente almeno un gruppo carbonile, In the general formula (1) of the invention, A represents an aromatic group such as phenyl or naphthyl variously substituted according to formula (2) and containing at least one carbonyl group,
e nel quale: and in which:
A' rappresenta: -H, -COOH, -COOCH3, -CO-X, -S02-X, -S03H (Na) A 'represents: -H, -COOH, -COOCH3, -CO-X, -S02-X, -S03H (Na)
B? rappresenta: -H, -OH, -OCH3, -OR, -CO-X, -COOCH3, -NH2 B? represents: -H, -OH, -OCH3, -OR, -CO-X, -COOCH3, -NH2
C rappresenta: -H, -OH, -OR, -OCH3, -O-benzile, -OCOCH3.-NH2, -NHCOCH3 dove R rappresenta una catena comprendente da 1 a 8 atomi di carbonio con 0 a 3 doppi legami e dove -X- rappresenta: -NH-, -NH(CH3)-. C represents: -H, -OH, -OR, -OCH3, -O-benzyl, -OCOCH3.-NH2, -NHCOCH3 where R represents a chain comprising 1 to 8 carbon atoms with 0 to 3 double bonds and where - X- represents: -NH-, -NH (CH3) -.
1 composti preferiti essendo quelli nei quali: The preferred compounds being those in which:
A' rappresenta: -H e A 'represents: -H and
B' rappresenta: -CO-X-, dove -X- nella formula (1) rappresenta -NH- e C rappresenta: -OH, -OCH3, -O-benzile, -OCOCH3, -OR, -NHCOR dove R rappresenta una catena da 1 a 8 atomi di carbonio contenente da 0 a 3 doppi legami , *- B 'represents: -CO-X-, where -X- in formula (1) represents -NH- and C represents: -OH, -OCH3, -O-benzyl, -OCOCH3, -OR, -NHCOR where R represents a chain of 1 to 8 carbon atoms containing 0 to 3 double bonds, * -
ugualmente preferiti sono i composti nei quali nella formula (2) equally preferred are the compounds in which in formula (2)
A? rappresenta: -CO-X o -S02-X-B' rappresenta: COOCH3 o -CO-X- e TO? represents: -CO-X or -S02-X-B 'represents: COOCH3 or -CO-X- and
C rappresenta: -OH, -OCH3, -O-benzile, -OR, -OCOCH3, -NHCOCH3, C represents: -OH, -OCH3, -O-benzyl, -OR, -OCOCH3, -NHCOCH3,
-X- e R aventi lo stesso significato di cui sopra. -X- and R having the same meaning as above.
Inoltre nella formula generale (1 ) Also in the general formula (1)
X rappresenta: -NH- o -NH(CH3)-Y rappresenta: -COOH, -COOCH3, -COOC2H5 nelle forma stereochimica RS o nelle singole forme R- o S-, oppure -H X represents: -NH- or -NH (CH3) -Y represents: -COOH, -COOCH3, -COOC2H5 in the stereochemical form RS or in the single forms R- or S-, or -H
n rappresenta un numero da 0 a 6 n represents a number from 0 to 6
Z rappresenta: -H oppure -N02 Z represents: -H or -N02
Il procedimento con il quale vengono preparati i composti dell'invenzione consiste nel lare reagire il radicale aromatico della formula generale (2) sostituito con almeno un gruppo carbossilico o sulfonilico nella posizione A' o in posizione B' che viene trasformato con metodi noti nel corrispondente cloruro dell'acido, con un amina della formula generale (3) nella quale Y e n hanno il significato di cui sopra. La condensazione viene eseguita in un solvente polare come per esempio metanolo, etanolo o acqua, in presenza di una base, come per esempio carbonato di sodio, metilato o etilato di sodio o anche di una base organica come per esempio piridina, trimetil o trietilamina. Quando desideralo, la trasformazione del gruppo -N02 in -H avviene per riduzione catalitica . The process by which the compounds of the invention are prepared consists in reacting the substituted aromatic radical of the general formula (2) with at least one carboxylic or sulfonyl group in position A 'or in position B' which is transformed by known methods into the corresponding acid chloride, with an amine of the general formula (3) in which Y and n have the above meaning. The condensation is carried out in a polar solvent such as methanol, ethanol or water, in the presence of a base, such as sodium carbonate, sodium methylate or ethylate or also an organic base such as pyridine, trimethyl or triethylamine. When desired, the transformation of the -N02 group into -H occurs by catalytic reduction.
Allo scopo di illustrare l'invenzione, ma senza che ci? ne costituisca una limitazione, vengono descritti i seguenti esempi. In order to illustrate the invention, but without that limitation, the following examples are described.
PARTE SPERIMENTALE EXPERIMENTAL PART
La purezza di tutti i composti descritti ? stata confermata tramite cromatografia su strato sottile e spettro di massa. The purity of all the compounds described? was confirmed by thin layer chromatography and mass spectrum.
Composto 1 : (MF6) Compound 1: (MF6)
Acido 2(S)-(o-acetossifenil)-acetamido-5-N-nitro-guanidinpentanoico. 2 (S) - (o-acetoxyphenyl) -acetamido-5-N-nitro-guanidinpentanoic acid.
0,548 g (2,5 mmoli) di acido 2(S)-amino-5-N-nitro guanidino-valerico sciolti in 15 mL d'acqua contenente 0,95 g di carbonato di sodio, vengono trattati a 0? C con una soluzione di 0,496 g di o-acetossi-benzoilcloruro in 5 mi di acetone. La miscela di reazione ? lasciata a s? per 60 min. a temperatura ambiente, acidificata con acido cloridrico 1 N ed estratta con acetato di etile. La fase organica, seccata con solfato di sodio anidro, viene evaporata dal solvente. Si ottengono 0,7 g di un prodotto cristallino, praticamente puro alla tic (AcOEt/MeOH 4:1) che ? stato ricri,stallizzato da etanolo. 0.548 g (2.5 mmol) of 2 (S) -amino-5-N-nitro guanidino-valeric acid dissolved in 15 mL of water containing 0.95 g of sodium carbonate, are treated at 0? C with a solution of 0.496 g of o-acetoxy-benzoyl chloride in 5 ml of acetone. The reaction mixture? left to s? for 60 min. at room temperature, acidified with 1 N hydrochloric acid and extracted with ethyl acetate. The organic phase, dried with anhydrous sodium sulphate, is evaporated from the solvent. 0.7 g of a crystalline product are obtained, practically pure at tic (AcOEt / MeOH 4: 1) which? been recycled from ethanol.
Punto di fusione: 95?C i?] D = 7,3? (c= LO28/CH3OH) Melting point: 95? C i?] D = 7.3? (c = LO28 / CH3OH)
1HNMR (CDCI3): 1,6-1, 9 (m 4 H); 2,5 (s 3 H); 3,2 (m 2 H); 4,4 (m 1 H); 6,9-9 (m 8H); 12,1 (s 1 H). 1HNMR (CDCI3): 1.6-1.9 (m 4H); 2.5 (s 3 H); 3.2 (m 2 H); 4.4 (m 1H); 6.9-9 (m 8H); 12.1 (s 1 H).
Composto 2: (MF5) Compound 2: (MF5)
Estere metilico dell'acido 2(S)-(o-acetossifenil)-acetamido-5-N-nitro-guanidin-pentanoico. 2 (S) - (o-acetoxyphenyl) -acetamido-5-N-nitro-guanidine-pentanoic acid methyl ester.
3,3 g di estere metilico dell?acido 2(S)-amino-5-N-nitro-guanidino-valerico, cloridrato (12 mmoli) in 30 mi d? metanolo vengono trattati con 24 mi di una soluzione 0,5 M di metilato di sodio in metanolo. Si evapora a secco ed il residuo viene quindi sciolto in 20 mi di diossano e portato a 0? C con un bagno di ghiaccio. Alla soluzione si aggiungono quindi 2,9 mi di tri-n-butilamina e quindi, goccia a goccia sotto agitazione, 2,4 g (12 moli) di o-acetossibenzoilcloruro in ?0 mi di diossano. Si continua quindi l'agitazione a temperatura ambiente per altri 45 min.. La miscela di reazione ? quindi evaporata del solvente ed il residuo ? ripreso con acetato di etile. La soluzione ? lavata successivamente con acido cloridrico 1 N, acqua, soluzione acquosa di bicarbonato di sodio al 10% ed infine ancora acqua. La fase organica ? quindi portala a secco sotto vuoto. 3.3 g of 2 (S) -amino-5-N-nitro-guanidino-valeric acid methyl ester, hydrochloride (12 mmol) in 30 ml? methanol are treated with 24 ml of a 0.5 M solution of sodium methylate in methanol. It is evaporated to dryness and the residue is then dissolved in 20 ml of dioxane and brought to 0? C with an ice bath. 2.9 ml of tri-n-butylamine are then added to the solution and then, drop by drop under stirring, 2.4 g (12 moles) of o-acetoxybenzoyl chloride in 0 ml of dioxane. The stirring is then continued at room temperature for another 45 min. The reaction mixture? then evaporated of the solvent and the residue? taken up with ethyl acetate. The solution ? subsequently washed with 1 N hydrochloric acid, water, aqueous solution of sodium bicarbonate at 10% and finally water. The organic phase? then bring it to dryness under vacuum.
Si ottengono 2 g del composto 2. Punto di fusione: 90? C. 2 g of compound 2 are obtained. Melting point: 90? C.
1 H-NMR ( CDCI3 ): 1,77 (m 4H); 2 (m 2H); 2,2 (s 3H); 3,3 (m IH); 3,8 (s 3H); 4 (s 3H); 3,3 (m IH); 7 (d IH); 7,1 (t IH); 7,5 (t IH); 7,9 (m IH); 8,1 (d IH); 8,6 (m IH); 9 (d IH). 1 H-NMR (CDCI3): 1.77 (m 4H); 2 (m 2H); 2.2 (s 3H); 3.3 (m 1H); 3.8 (s 3H); 4 (s 3H); 3.3 (m 1H); 7 (d 1H); 7.1 (t 1H); 7.5 (t 1H); 7.9 (m 1H); 8.1 (d 1H); 8.6 (m 1H); 9 (d 1H).
Lo stesso composto 2 si pu? anche ottenere per esterificazione del composto 1 mediante metodi noti come per esempio per trattamento con diazometano o sodio metilato o metanolo in presenza di un acido di Lewis. The same compound 2 can you? also obtain by esterification of compound 1 by known methods such as for example by treatment with diazomethane or sodium methylate or methanol in the presence of a Lewis acid.
Composto 3: (MF7) Compound 3: (MF7)
Acido 2(S)-(o-a ceto ssi fenil)-acetamido-5-guanidin-pentanoico. 2 (S) - (o-a ceto ssi phenyl) -acetamido-5-guanidine-pentanoic acid.
2,0 g del composto 1 sciolti in 50 mi di metanolo vengono idrogenati in un idrogenalore Parr a 5 bar per 24 ore in presenza di 100 mg di carbonio palladiato al 5%. Si filtra quindi il catalizzatore e la soluzione ? evaporata del solvente. Si ottengono ca. 1 g del composto 3 che viene purificato per ricristallizazione da etanolo. Punto di fusione: 105? C. 2.0 g of compound 1 dissolved in 50 ml of methanol are hydrogenated in a Parr hydrogen value at 5 bar for 24 hours in the presence of 100 mg of 5% palladium carbon. Are the catalyst and the solution then filtered? evaporated of the solvent. Approx. 1 g of compound 3 which is purified by recrystallization from ethanol. Melting point: 105? C.
1HNMR (CDCI3 . DMSO-d): 1,8-2 (m 4 H); 2,3 (s 3 H); 3,35 (m 4 H); 4,65 (m 1 H); 6,9-8 (m 6 H); 9,1 (ni 1 H); 9,4 (m 1 H). 1HNMR (CDCI3. DMSO-d): 1.8-2 (m 4H); 2.3 (s 3 H); 3.35 (m 4H); 4.65 (m 1H); 6.9-8 (m 6H); 9.1 (ni 1H); 9.4 (m 1 H).
Composto 4: (MF81 Compound 4: (MF81
Acido 2(S)-(o-idrnssifenil)-acetamido-5-N-nitro-guanidinpentanoico. 2 (S) - (o-hydroxyphenyl) -acetamido-5-N-nitro-guanidinpentanoic acid.
3,81 g (10 mmoli) del composto 1 (MF6) sono trattati con 2 mi di HC1 concentrato in 60 mi di metanolo. La miscela di reazione ? lasciata a s? per due ore a temperatura ambiente. Dopo avere controllato la scomparsa del prodotto di partenza mediante TLC, la miscela ? concentrata nel vuoto ed il residuo ripreso con 60 mL di acetato di etile. La soluzione ? quindi lavata due volte con acqua e seccala su solfato di sodio anidro. Dopo evaporazione del solvente il prodotto grezzo viene triturato in presenza di etere etilico. Si ottengono 3 g del composto 4. 3.81 g (10 mmoles) of compound 1 (MF6) are treated with 2 ml of concentrated HCl in 60 ml of methanol. The reaction mixture? left to s? for two hours at room temperature. After having checked the disappearance of the starting product by means of TLC, the mixture? concentrated in vacuo and the residue taken up with 60 mL of ethyl acetate. The solution ? then washed twice with water and dried over anhydrous sodium sulfate. After evaporation of the solvent, the crude product is triturated in the presence of ethyl ether. 3 g of compound 4 are obtained.
Punto di fusione: 120? C. Melting point: 120? C.
[a] D = 26, 2? (c=l,01/CH3OH) [a] D = 26.2? (c = 1.01 / CH3OH)
1HNMR (CD3 OH): 1, 8-2,1 (m 6 H); 3,4 (m 1 H); 4,95 (t 1 H); 7,9 (m 8 H). 1HNMR (CD3 OH): 1.8-2.1 (m 6H); 3.4 (m 1H); 4.95 (t 1 H); 7.9 (m 8 H).
Composto 5: (MF9) Compound 5: (MF9)
Acido 2(S)-(o-idrossifenil)-acetamido-5-guanidin-pentanoico. 2 (S) - (o-hydroxyphenyl) -acetamido-5-guanidine-pentanoic acid.
1,7 g del composto 4 (MF 8) sono idrogenati in un reattore di Parr in presenza di 300 mg di palladio su carbone al 10% in 50 mi di metanolo a pressione atmosferica. Dopo una notte, il catalizzatore viene rimosso per filtrazione e la soluzione evaporata nel vuoto. 11 residuo ? triturato in presenza di etere etilico. Si ottengono J ,5 g del composto 5. Punto di fusione: 92? C 1.7 g of compound 4 (MF 8) are hydrogenated in a Parr reactor in the presence of 300 mg of palladium on 10% carbon in 50 ml of methanol at atmospheric pressure. After one night, the catalyst is removed by filtration and the solution evaporated in vacuum. 11 residual? triturated in the presence of ethyl ether. J.5 g of compound 5 are obtained. Melting point: 92? C.
1HNMR (CD3 OH): 1,7-2 (m6 H); 3,4 (m 1 H); 3,8 (m 5 H); 4,8 (m 1 H); 7,2 (m 1 H arom); 7,8 (m 1 H arom); 7,9 (s (broad) 1 H); 8,52 (m 1 H arom). 1HNMR (CD3 OH): 1.7-2 (m6H); 3.4 (m 1H); 3.8 (m 5H); 4.8 (m 1H); 7.2 (m 1 H arom); 7.8 (m 1 H arom); 7.9 (s (broad) 1H); 8.52 (m 1 H arom).
Composto 6: (MF101 Compound 6: (MF101
Estere metilico dell?acido 2(S)-(o-metossifenil)-acetamido-5-N-nitro-guanidin-pentanoico. 2 (S) - (o-methoxyphenyl) -acetamido-5-N-nitro-guanidine-pentanoic acid methyl ester.
3,4 g (10 nini oli) del composto 8 (MF 8) in 20 mi di metanolo vengono trattati con una soluzione di diazometano in etere fino a completa esterificazione (TLC). La soluzione viene quindi evaporata del solvente ed il residuo cromatografalo su gel di silice eluendo con cicloesano/acetato di etile (8/2). Si ottengono 3 g del composto 6. Punto di fusione: 123? C. 3.4 g (10 nini oils) of compound 8 (MF 8) in 20 ml of methanol are treated with a solution of diazomethane in ether until complete esterification (TLC). The solution is then evaporated from the solvent and the chromatographic residue on silica gel by eluting with cyclohexane / ethyl acetate (8/2). 3 g of compound 6 are obtained. Melting point: 123? C.
1HNMR (CD3 ): 1,75-2,05 (ni 6 H); 3,35 (m 1 H); 3,8 (s 3 H); 4,1 (s 3 H); 4,95 (m 1 H); 7,05 (d 1 H); 7,15 (dd 1 H arom); 7,55 (dd 1 H arom); 7,9 (s (broad) 1 H); 81 (d I H arom); 8,77 (s(broad) 1 H); 8,98 (dd 1 H arom). 1HNMR (CD3): 1.75-2.05 (ni 6H); 3.35 (m 1H); 3.8 (s 3H); 4.1 (s 3H); 4.95 (m 1H); 7.05 (d 1H); 7.15 (dd 1 H arom); 7.55 (dd 1 H arom); 7.9 (s (broad) 1H); 81 (d I H arom); 8.77 (s (broad) 1H); 8.98 (dd 1 H arom).
Composto 7: (MF 11') Compound 7: (MF 11 ')
Estere metilico dell'acido 2 (S)-(3-car bossi- 4-i d ros s if e n i 1) -su lfonamido-5-N-nitro-guanidin-pentanoico. 2 (S) - (3-carboxy-4-i d ros s if e n i 1) -on phonamido-5-N-nitro-guanidine-pentanoic acid methyl ester.
0,4 g di acido 2(S)-amino-5-N-nitro guanidin-valerico ( K. Hofmann, W.D. Peckam, A. Rheiner, J. Am. Chem. Soc. 1956. 78. 238 ) metilestere cloridrato in 5 mL di metanolo vengono trattati con una soluzione di metossido di sodio preparata da 0,04 g di sodio in 5 mi di metanolo, fino a completa dissoluzione. 0.4 g 2 (S) -amino-5-N-nitro guanidine-valeric acid (K. Hofmann, W.D. Peckam, A. Rheiner, J. Am. Chem. Soc. 1956. 78. 238) methylester hydrochloride in 5 mL of methanol is treated with a sodium methoxide solution prepared from 0.04 g of sodium in 5 ml of methanol, until completely dissolved.
11 metanolo viene quindi evaporato ed il residuo ? sospeso in 5 mi di tetraidrofurano. Si raffredda in bagno di ghiaccio e ? si aggiungono 0,475 g di carbonato sodico in 4 mi di acqua. Successsivamente si fanno gocciolare lentamente 0,355 g di 3-carbossi-4-idrossi-fenilsulfonilcloruro ( .1. Stewart, J. Chem. Soc. 1922, 12 1. 2255 ) in 15 mi di tetraidrofurano. Si tiene in agitazione per 12 ore, si filtra e la soluzione viene evaporata. Si riprende con acido cloridrico diluito al 5%. Si separa un solido bianco insolubile in acqua che viene lavato con acqua per eliminare i sali inorganici. Un ulteriore purificazione del prodotto ottenuto viene effettuata per cromatografia su gel di silice eluendo con acetato di etile/metanolo (95:5). La resa ? del 35%. The methanol is then evaporated and the residue? suspended in 5 ml of tetrahydrofuran. Cools in the ice bath and? 0.475 g of sodium carbonate in 4 ml of water are added. Subsequently 0.355 g of 3-carboxy-4-hydroxy-phenylsulfonyl chloride (.1. Stewart, J. Chem. Soc. 1922, 12 1. 2255) are slowly dripped in 15 ml of tetrahydrofuran. It is kept under stirring for 12 hours, filtered and the solution evaporated. It is taken up with hydrochloric acid diluted to 5%. A white water insoluble solid is separated and washed with water to remove the inorganic salts. A further purification of the obtained product is carried out by chromatography on silica gel eluting with ethyl acetate / methanol (95: 5). The surrender? 35%.
Punto di fusione: 213-215? C. Melting point: 213-215? C.
1HNMR (CD3 OD): 1,47-1,7 (m4 H); 3,1 (T 2 H); 3,2 (m5 H); 3,3 (s 3 H); 3,75 (t 1 H); 6,9 (1 H arom); 7,75 (1 H arem); 8,2 (1 H arom). 1HNMR (CD3 OD): 1.47-1.7 (m4H); 3.1 (T 2 H); 3.2 (m5H); 3.3 (s 3H); 3.75 (t 1H); 6.9 (1Harom); 7.75 (1 H arem); 8.2 (1H arom).
Composto 8: (MF 12) Compound 8: (MF 12)
Estere metilico dell'acido 2(S)-(3-carbossimetil-4-metossifenil)-metilsulfamoil-5-N-nitro-guanidin-pentanoico. 2 (S) - (3-carboxymethyl-4-methoxyphenyl) -methylsulfamoyl-5-N-nitro-guanidine-pentanoic acid methyl ester.
A 1,30 g del composto 7 ( MF 11) in 20 mi di metanolo si addiziona una soluzione eterea di diazometano fino a completa scomparsa del prodotto di partenza (TLC: cloruro di metilene/aceialo di etile/metanolo 50/50/3). La soluzione ? quindi concentrata ed il grezzo viene cromatografato su gel di silice eluendo con cloruro di metilene/acetato di etile 1:1. Si ottengono 0,650 g del composto 8. An ethereal solution of diazomethane is added to 1.30 g of compound 7 (MF 11) in 20 ml of methanol until complete disappearance of the starting product (TLC: methylene chloride / ethyl acetyl / methanol 50/50/3) . The solution ? then concentrated and the crude is chromatographed on silica gel eluting with methylene chloride / ethyl acetate 1: 1. 0.650 g of compound 8 are obtained.
Punto di fusione: 66? C. Melting point: 66? C.
1HNMR (CDCI3): 1,85 (m 4 H); 2,8 (s 3 H); 3,4 (m 2 H); 3,5 (s 3 H); 3,9 (ss 3 H); 4,0 (s 3 H); 4,65 (m 1 H); 7,l-8,3 (m 6 H). 1HNMR (CDCI3): 1.85 (m 4H); 2.8 (s 3 H); 3.4 (m 2 H); 3.5 (s 3H); 3.9 (ss 3H); 4.0 (s 3H); 4.65 (m 1H); 7.1-8.3 (m 6H).
Composi? 9: (MF 131 Composed? 9: (MF 131
Acido 2(S)-2-(o-benzilossi)-benzoilamido-5-N-nitro-guanidinpentanoic?. 2 (S) -2- (o-benzyloxy) -benzoylamido-5-N-nitro-guanidinpentanoic acid ?.
A 1,14 g (5 mmoli) di acido 2-benzilossi-bejizoico, sciolto in 20 mi di letraidrol'urano sono addizionati, a - 10? C, 0,7 mi di trietilamina (5 mmoli) e ? 0,48 mi (5 mmoli) di cloroformi alo d?etile. Dopo 2 min. si aggiunge velocemente una soluzione composta da 30 mi di acqua, 3,6 g di carbonato di potassio e 1,2 g (5 moli) di acido 2(S)-5-N-nitro-guanidin-pentanoico. Dopo 2 ore a 0?C la soluzione ? versata su acqua e ghiaccio, portata a pH 1,5 con acido cloridrico 1:1 ed estratta con acetato di etile. La fase organica viene seccata con solfato di sodio anidro ed evaporata del solvente. Si ottengono 2 g del composto 9. To 1.14 g (5 mmoles) of 2-benzyloxy-beijizoic acid, dissolved in 20 ml of letrahydrol urane are added, at -10? C, 0.7 ml of triethylamine (5 mmol) and? 0.48 ml (5 mmol) of ethyl halo chloroform. After 2 min. a solution consisting of 30 ml of water, 3.6 g of potassium carbonate and 1.2 g (5 moles) of 2 (S) -5-N-nitro-guanidine-pentanoic acid is quickly added. After 2 hours at 0? C the solution? poured on water and ice, brought to pH 1.5 with hydrochloric acid 1: 1 and extracted with ethyl acetate. The organic phase is dried with anhydrous sodium sulphate and evaporated from the solvent. 2 g of compound 9 are obtained.
Punto di fusione: 58-60?C. Melting point: 58-60? C.
[ ?0 D = 3,9? [? 0 D = 3.9?
'H-NMR (CDC13); 1,2-1, 8 (m 4 H); 3 (m 2H); 4,5 (m IH); 5,05 (m 2H); 6, 8-8, 5 'H-NMR (CDC13); 1.2-1.8 (m 4H); 3 (m 2H); 4.5 (m 1H); 5.05 (m 2H); 6, 8-8, 5
( 13H). (13H).
Composto 10: (MF 14) Compound 10: (MF 14)
Estere metilico dell'acido 2(S)-2-(o-benzilossi)-benzoilamido-5-N-nitro -guani din- pentanoico. 2 (S) -2- (o-benzyloxy) -benzoyl starch-5-N-nitro-guani din-pentanoic acid methyl ester.
1,5 g del composto 9 solubilizzati in 10 mi di cloruro di metilene e 3 mi di metanolo sono trattali con una soluzione eterea di diazometano fino a completa esterifiazione. La soluzione viene concentrata nel vuoto ed il residuo cromatografato su colonna di silice eluendo con cicloesano/acetato di etile/metanolo 2:8:0, 5. Si ottengono 1,2 g del composto 10. 1.5 g of compound 9 solubilized in 10 ml of methylene chloride and 3 ml of methanol are treated with an ethereal solution of diazomethane until complete esterification. The solution is concentrated in vacuo and the residue chromatographed on a silica column by eluting with cyclohexane / ethyl acetate / methanol 2: 8: 0, 5. 1.2 g of compound 10 are obtained.
Punto di fusione: 44-45? C. Melting point: 44-45? C.
[?3 D = -0,73? [? 3 D = -0.73?
?H-NMR (CDC13); 1,5-2 (m 4H); 3,3 (m IH); 3,7 (m 4H); 5,88 (m IH); 5,3 (m 2H); 7, 1-8,9 (m 13H). ? H-NMR (CDC13); 1.5-2 (m 4H); 3.3 (m 1H); 3.7 (m 4H); 5.88 (m 1H); 5.3 (m 2H); 7, 1-8.9 (m 13H).
Attivit? farmacologica e tossicit?: Activities pharmacological and toxicity:
L'atlivit? inibitrice suH'aggregazione piastrinica e la tossicit? dei vari composti ? stata determinata con i seguenti metodi ed i risultati sono riportati nella Tabella 1. The activity? inhibitor of platelet aggregation and toxicity of the various compounds? was determined with the following methods and the results are reported in Table 1.
a) Attivit? in vitro su "Platelet Ridi Plasma" (PRP) di coniglio: a) Activities in vitro on rabbit "Platelet Ridi Plasma" (PRP):
Agonista: Collagene (Sigma cod. 885-1) Agonist: Collagen (Sigma code 885-1)
Animali: Conigli New Zealand, peso g. 1500 /- 300 Animals: New Zealand rabbits, weight g. 1500 / - 300
Il sangue viene prelevalo per puntura intracardiaca usando citrato di sodio quale anticoagulante (concentrazione finale: 0,38%). Si centrifuga a 150 g per ottenere il PRP. E stalo usato PRP contenente 350.000 piastrine/ml. Blood is drawn by intracardiac puncture using sodium citrate as an anticoagulant (final concentration: 0.38%). It is centrifuged at 150 g to obtain the PRP. PRP containing 350,000 platelets / ml was used.
La misura del l?aggregazione ? stata effettuata con un aggregometro Elvi-Logos mod. 840, secondo il metodo di Borii ( G.V.R. Born Nature 1962, 194, 927 ). The extent of the aggregation? was carried out with an Elvi-Logos aggregometer mod. 840, according to Borii's method (G.V.R. Born Nature 1962, 194, 927).
b) Attivit? ex-vivo su PRP di coniglio: b) Activities ex vivo on rabbit PRP:
Il sangue viene prelevato 1 ora dopo la somministrazione seguendo la tecnica di cui sopra. Blood is drawn 1 hour after administration following the above technique.
c) Tossicit?: c) Toxicity:
E siala determinala la dose minima letale (DML) per via intra-peritoneale sul topo. And determine the minimum lethal dose (DML) intra-peritoneally on the mouse.
TABELLA 1 TABLE 1
COMPOSTO N? CI 50 ?? (In Vitro) % inhib. a 10mg/Kg DML nig/Kg (Ex-Vivo) Ci p ) COMPOUND N? CI 50 ?? (In Vitro)% inhib. at 10mg / Kg DML nig / Kg (Ex-Vivo) Ci p)
1 3 100%(lora/os) 1000 1 3 100% (lora / os) 1000
2 3 100%(lora/ip) 2 3 100% (hour / ip)
3 5 2000 3 5 2000
4 2 4 2
5 1 5 1
Aspirina 220 Aspirin 220
L'esame dei dati della tabella 1 mostra che i composti dell?invenzione posseggono nell'intervallo di concentrazione fra 1 e 5 yUM una forte attivit? inibitrice sull'aggregazione piastrinica, di circa 150 volLe superiore a quella dell'Aspirina presa come composto di riferimento. Questa propriet?, come pure la loro bassa tossicit? rendono i composti dell'invenzione particolarmente utili per la prevenzione e la terapia di malattie cardiovascolari quali per esempio, la trombosi, l'infarto del miocardo, l?angina pectoris e pi? generalmente tutte le malattie conseguenti ad un occlusione totale o parziale dei vasi sanguini. The examination of the data of table 1 shows that the compounds of the invention possess a strong activity in the concentration range between 1 and 5 µm. inhibitor on platelet aggregation, approximately 150 volLe higher than that of aspirin taken as reference compound. This property, as well as their low toxicity? make the compounds of the invention particularly useful for the prevention and therapy of cardiovascular diseases such as, for example, thrombosis, myocardial infarction, angina pectoris and more? generally all diseases resulting from a total or partial occlusion of blood vessels.
I composti dell?invenzione possono essere inclusi, quali ingredienti attivi, in preparazioni farmaceutiche adatte all'uso in medicina per la prevenzione e la cura delle malattie sopra citate. The compounds of the invention can be included, as active ingredients, in pharmaceutical preparations suitable for use in medicine for the prevention and treatment of the aforementioned diseases.
I composti (Jell'invenzione possono essere somministrati per via orale, parenterale, endovenosa, rettale e topica, nelle forme galeniche usuali ossia: compresse, capsule, soluzioni, soluzioni iniettabili, supposte, "skin patch", in combinazione con eccipienti e diluenti non tossici e farmaceuticamente accettabili. The compounds (the invention can be administered orally, parenterally, intravenously, rectally and topically, in the usual galenic forms, that is: tablets, capsules, solutions, injectable solutions, suppositories, "skin patch", in combination with excipients and diluents not toxic and pharmaceutically acceptable.
Claims (31)
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ITRM930654A IT1261994B (en) | 1993-09-28 | 1993-09-28 | Guanidine derivatives for therapeutic use |
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ITRM930654A IT1261994B (en) | 1993-09-28 | 1993-09-28 | Guanidine derivatives for therapeutic use |
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