EP1098888A1 - Piperazinone derivatives and their uses - Google Patents
Piperazinone derivatives and their usesInfo
- Publication number
- EP1098888A1 EP1098888A1 EP99929496A EP99929496A EP1098888A1 EP 1098888 A1 EP1098888 A1 EP 1098888A1 EP 99929496 A EP99929496 A EP 99929496A EP 99929496 A EP99929496 A EP 99929496A EP 1098888 A1 EP1098888 A1 EP 1098888A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- amino
- group
- alkyl
- groups
- oxopiperazino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical class O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 46
- 239000003146 anticoagulant agent Substances 0.000 claims abstract description 4
- -1 furannyl Chemical group 0.000 claims description 54
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 39
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 31
- 210000001772 blood platelet Anatomy 0.000 claims description 21
- 239000002253 acid Substances 0.000 claims description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 13
- FKRCODPIKNYEAC-UHFFFAOYSA-N propionic acid ethyl ester Natural products CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 230000002401 inhibitory effect Effects 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 208000007536 Thrombosis Diseases 0.000 claims description 9
- 102000008946 Fibrinogen Human genes 0.000 claims description 7
- 108010049003 Fibrinogen Proteins 0.000 claims description 7
- 150000007513 acids Chemical class 0.000 claims description 7
- 230000002776 aggregation Effects 0.000 claims description 7
- 238000004220 aggregation Methods 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 229940012952 fibrinogen Drugs 0.000 claims description 7
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 6
- 150000002431 hydrogen Chemical group 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 230000001732 thrombotic effect Effects 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- 241000124008 Mammalia Species 0.000 claims description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 125000002757 morpholinyl group Chemical group 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 125000003386 piperidinyl group Chemical group 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 2
- 125000005915 C6-C14 aryl group Chemical group 0.000 claims description 2
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- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 claims description 2
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000002619 bicyclic group Chemical group 0.000 claims description 2
- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000001326 naphthylalkyl group Chemical group 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000004043 oxo group Chemical group O=* 0.000 claims description 2
- 239000002243 precursor Substances 0.000 claims description 2
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000005493 quinolyl group Chemical group 0.000 claims description 2
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 2
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- 125000000753 cycloalkyl group Chemical group 0.000 claims 1
- 125000002950 monocyclic group Chemical group 0.000 claims 1
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- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims 1
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- 238000002560 therapeutic procedure Methods 0.000 abstract 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 49
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 37
- 239000007858 starting material Substances 0.000 description 36
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 8
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- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- GGMMDPXWPHUEEJ-UHFFFAOYSA-N 2-[4-(4-cyanophenyl)-2-oxopiperazin-1-yl]acetic acid Chemical compound C1C(=O)N(CC(=O)O)CCN1C1=CC=C(C#N)C=C1 GGMMDPXWPHUEEJ-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
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- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 4
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- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-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
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- 235000011152 sodium sulphate Nutrition 0.000 description 4
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- ZUKVGCCNHNPILB-UHFFFAOYSA-N 2-[4-(4-cyanophenyl)-3-oxopiperazin-1-yl]acetic acid Chemical compound O=C1CN(CC(=O)O)CCN1C1=CC=C(C#N)C=C1 ZUKVGCCNHNPILB-UHFFFAOYSA-N 0.000 description 3
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- CEIPQQODRKXDSB-UHFFFAOYSA-N ethyl 3-(6-hydroxynaphthalen-2-yl)-1H-indazole-5-carboximidate dihydrochloride Chemical compound Cl.Cl.C1=C(O)C=CC2=CC(C3=NNC4=CC=C(C=C43)C(=N)OCC)=CC=C21 CEIPQQODRKXDSB-UHFFFAOYSA-N 0.000 description 3
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- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
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- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
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- 239000000539 dimer Substances 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- VFEUYMRNPSLJPC-UHFFFAOYSA-N ethyl 3-[[2-[2-oxo-4-[4-(piperidine-1-carboximidoyl)phenyl]piperazin-1-yl]acetyl]amino]-5-phenylpentanoate Chemical compound C1CN(C=2C=CC(=CC=2)C(=N)N2CCCCC2)CC(=O)N1CC(=O)NC(CC(=O)OCC)CCC1=CC=CC=C1 VFEUYMRNPSLJPC-UHFFFAOYSA-N 0.000 description 1
- MAEVGYYPAIMXHN-UHFFFAOYSA-N ethyl 3-[[2-[4-(4-cyanophenyl)-2-oxopiperazin-1-yl]acetyl]amino]-5-phenylpentanoate Chemical compound C1CN(C=2C=CC(=CC=2)C#N)CC(=O)N1CC(=O)NC(CC(=O)OCC)CCC1=CC=CC=C1 MAEVGYYPAIMXHN-UHFFFAOYSA-N 0.000 description 1
- OTMJAPMJLPNMNB-UHFFFAOYSA-N ethyl 3-[[2-[4-[4-(n'-hydroxycarbamimidoyl)phenyl]-2-oxopiperazin-1-yl]acetyl]amino]-5-phenylpentanoate Chemical compound C1CN(C=2C=CC(=CC=2)C(N)=NO)CC(=O)N1CC(=O)NC(CC(=O)OCC)CCC1=CC=CC=C1 OTMJAPMJLPNMNB-UHFFFAOYSA-N 0.000 description 1
- VJSABQIJMRZXEH-UHFFFAOYSA-N ethyl 3-amino-3-cyclohexylpropanoate;hydrochloride Chemical compound Cl.CCOC(=O)CC(N)C1CCCCC1 VJSABQIJMRZXEH-UHFFFAOYSA-N 0.000 description 1
- SBQSSJZBFUCTFK-UHFFFAOYSA-N ethyl 3-amino-4,4-dimethylpentanoate;hydrochloride Chemical compound Cl.CCOC(=O)CC(N)C(C)(C)C SBQSSJZBFUCTFK-UHFFFAOYSA-N 0.000 description 1
- JHAWFIWKNHMVGB-UHFFFAOYSA-N ethyl 3-amino-4-methylpentanoate;hydrochloride Chemical compound Cl.CCOC(=O)CC(N)C(C)C JHAWFIWKNHMVGB-UHFFFAOYSA-N 0.000 description 1
- RJCGNNHKSNIUAT-UHFFFAOYSA-N ethyl 3-aminopropanoate;hydron;chloride Chemical compound Cl.CCOC(=O)CCN RJCGNNHKSNIUAT-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 208000000283 familial pityriasis rubra pilaris Diseases 0.000 description 1
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- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
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- 238000011597 hartley guinea pig Methods 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 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 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000011780 sodium chloride 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
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
- 231100000216 vascular lesion Toxicity 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
- C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention relates to new compounds which are inhibitors of the binding of fibrinogen to the Gpllb / IIIa platelet receptors, and which can be used therapeutically as antithrombotics.
- platelet aggregation represents a key stage because it is at the origin of the gravity of the phenomenon. Indeed, from the initiation of the thrombus, in particular in the arterial blood circulation, the bringing into play of several interdependent biochemical reactions induces the aggregation of an increasingly large number of platelets through the transformation of the fibrinogen soluble in insoluble fibrin filaments which increase the size of the platelet cluster, first at the very site of the arterial vascular lesion, then increasingly in the lumen of the vessel.
- Gpllb / IIIa receptors In this mechanism of platelet aggregation, the activation of Gpllb / IIIa receptors is at the origin of the amplification of platelet aggregation. Fibrinogen, which can bind its two dimers to these receptors, enhances the binding of platelets to each other and thus induces the formation of a platelet mass forming a thrombus at the rupture site of the atheroma plaque.
- This platelet aggregation mechanism is particularly active in all arterial thromboses that they appear during interventional cardiology practices (percutaneous transluminal angioplasty; placement of "stents"), cardiac surgery (aorto-coronary artery bypass grafting; valvular surgery), during acute cardiac diseases (myocardial infarction, unstable angina, acute coronary syndromes, etc.) or during certain cerebral ischemias, or finally during myocardial ischemias which can complicate the consequences of antithrombotic treatment.
- interventional cardiology practices percutaneous transluminal angioplasty; placement of "stents”
- cardiac surgery aorto-coronary artery bypass grafting; valvular surgery
- acute cardiac diseases myocardial infarction, unstable angina, acute coronary syndromes, etc.
- cerebral ischemias or finally during myocardial ischemias which can complicate the consequences of antithrombotic treatment.
- Reducing or preventing the activation of platelets in contact with a ruptured atherosclerotic plaque therefore represents an original and effective therapeutic approach to the treatment of thromboses, in particular arterial thromboses and therefore a means of effective prevention of acute coronary syndromes, including angina unstable and myocardial infarction.
- the present invention aims to provide new competitive inhibitors of fibrinogen binding to Gpllb / IIIa receptors which can be used as antithrombotic drugs.
- the present invention further aims to provide compounds which can be administered orally, which allow obtaining a prolonged duration of action and which minimize or avoid the risks of bleeding.
- R is chosen from hydrogen, a CC 4 alkyl or phenyl (C ⁇ C 4 alkyl) group
- R 2 is chosen from hydrogen, the hydroxyl group and a protective group from the amidino group;
- R 3 is chosen from - hydrogen,
- heteroaryl groups chosen from pyridyl, thienyl, furannyl, quinolyl, benzodioxannyl, benzodioxolyl, benzothienyl, benzofuranyl and pyrazinyl groups;
- R 4 and R 5 are chosen independently of one another from hydrogen, an alkyl group or, together with the nitrogen atom, form a group chosen from the piperidinyl and morpholinyl groups, the aryl and heteroaryl groups which may be substituted by one or more groups independently chosen from halogens, CC 4 alkyl, trifluoromethyl, (C 1 -C 4 ) alkyl, thio, C 1 -C 6 alkyl sulfonyl, (C 1 alkyl) groups
- aryl group mention may be made of phenyl, ⁇ -naphthyl, ⁇ -naphthyl and fluorenyl groups.
- the alkyl groups in can be linear or branched.
- methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and pentyl groups examples, mention may be made of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and pentyl groups.
- the alkynyl groups may be, for example, the ethynyl, propargyl, butynyl groups.
- the alkenyl groups can be, for example, vinyl and allyl groups.
- CC 4 alkoxy groups can likewise be linear or branched. As examples, mention may be made of methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy groups.
- the halogens can be chosen from fluorine, chlorine, bromine and iodine.
- salts with pharmaceutically acceptable acids designate the salts which give the biological properties of the free bases, without having an undesirable effect.
- These salts can be in particular those formed with mineral acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; acidic metal salts, such as disodium orthophosphate and monopotassium sulfate, and organic acids.
- the compounds of formula I can be prepared by: a) reaction of an acid of formula
- R is a CC 4 alkyl or phenyl group
- the reaction of the acids of formula II with the amines of formula III can be carried out in a polar solvent such as DMF, THF or ethyl acetate, in the presence of a coupling agent (DCC / HOBT, BOP; isobutyl chloroformate ) at a temperature of 15 to 50 ° C.
- a coupling agent DCC / HOBT, BOP; isobutyl chloroformate
- the group Z can be converted to amidoxime by adding hydroxylamine to the nitrile group in the presence of an appropriate base (K 2 CO 3 , Et 3 N, C 2 H 5 ONa) in an alcoholic solvent.
- an appropriate base K 2 CO 3 , Et 3 N, C 2 H 5 ONa
- the group Z can also be converted to imidate by addition of ethanol in the presence of HCl in ethyl acetate.
- the imidate obtained is then converted into compounds of formula (I) in which R 2 is hydrogen and -NR 4 R 5 is either a piperidinyl group or a morpholinyl group, by reaction with the corresponding amine in ethanol-acetate medium. 'ethyl.
- the 4-fluorobenzonitrile is reacted with an excess of ethylenediamine in an aprotic solvent to give 4- (2-aminoethyl) benzonitrile which is then mono-alkylated with ethyl bromoacetate in a polar solvent such as ethanol or acetonitrile in the presence of an inorganic base or a tertiary amine.
- a polar solvent such as ethanol or acetonitrile
- addition salts are obtained conventionally by reaction of the compound of formula I with a pharmaceutically acceptable acid in an appropriate solvent.
- the bases can be obtained from the addition salts by treatment with a strong base.
- Example 1 The method described in Example 1 was used to prepare the following products:
- Example 12 The method described in Example 12 was used to prepare the following products:
- Example 16 The method described in Example 16 was used to prepare the following products (with transformation of acetate into hydrochloride for the compounds of Examples 17, 19, 28 and 30).
- EXAMPLE 22 Acetate of 3 - ⁇ [2- (4- ⁇ 4- [amino (imino) methyl] phenyl ⁇ -2- oxopiperazino) acetyl] amino ⁇ -5-ethyl phenylpentanoate (CRL 42904)
- Example 18 ( ⁇ 2- [4- (4- ⁇ amino [(ethoxycarbonyl) imino] methyl ⁇ phenyl) -2- oxopiperazino] acetyl ⁇ amino) -3- (1,3-benzodioxol-5-yl) propanoate ethyl (CRL42960)
- the product of Example 18 is transformed into the hydrochloride by the addition of a hydrochloric acid solution HCl 2N followed by filtration.
- Example 32 The method described in Example 32 was used to prepare the following products:
- the study of the inhibitory activity of platelet aggregation of the compounds of formula I was carried out in vitro, that is to say by direct contact of solution of variable concentrations of the compounds with platelets freshly separated from a sample. whole blood, taken under standardized conditions, from laboratory animals (guinea pig) and from healthy human subjects who have not received substances or drugs which may interfere with blood clotting.
- the anti-aggregating activity of platelets has also been studied ex vivo / vitro, that is to say after administration of the substances claimed in the guinea pig to measure the intensity and the duration of the anti-aggregating action induced by the absorbed fraction. and circulating in the blood of the product studied.
- Plasma samples are taken by intracardiac puncture from male Dunkin-Hartley guinea pigs (weight about 330 g), at the rate of 4.5 ml per 0.5 ml of trisodium citrate (concentration of the aqueous solution: 1.55%). in order to prevent any trace of coagulation.
- Platelet rich plasma (PRP) is obtained by centrifuging whole blood tubes for 15 minutes at 150 g.
- the PRPs are grouped into "pools". A count of the platelets contained in these pools is performed using a Coulter ZM type hematology automat: if necessary, a dilution is carried out so that the concentration of plasma in platelets is between 200,000 and 400,000 platelets / mm 3 . Simultaneously, other samples from these pools are used to prepare platelet-poor plasma (PPP) by centrifugation at 1,500 g for 15 minutes.
- PPP platelet-poor plasma
- the kinetic study of platelet aggregation is carried out by adding a collagen solution (1 ⁇ g / ml) to a volume of PRP, using an aggregometer of the Chrono-log Corporation type (490 - D ⁇ or 560 VS) which uses optical detection of the appearance of the thrombus.
- the determination of the inhibitory concentration 50% (Cl ⁇ ) is carried out by adding to samples of PRP pools, a determined volume of solvent (control reference) and increasing concentrations of the compounds: 1.5 x 10 8 M, 7 x 10 "8 M, 1.5 x 10 '7 M, 3 x 10 " 7 M, 7 x 10 "7 M, 1.5 x 10- ° M and 7 x 10 -5 M. Measures of inhibition of aggregation are done after 3 minutes of contact at 37 ° C with stirring.
- venous blood is taken by puncture in a vein of the elbow fold to be collected in a glass tube containing an aqueous solution of sodium citrate. 0.129 M (1 volume of citrate solution for 9 volumes of blood).
- PRP platelet-rich plasma
- PRP platelet-poor plasma
- a platelet count is performed using the Coulter ZM counter.
- Each sample is then used to study the variation in the inhibition of aggregation platelet triggered by the addition of a glucose collagen solution Chromo-par-Reagent from Coultronics (used at a concentration of 5 ⁇ g / ml) according to the addition of increasing concentrations of each compound in a range covering the interval 10 "8 M ⁇ IO " 5 M (example of concentrations: 10 M, 5 x 10 "7 M, 3 x10 " 7 M, 10- 7 M, 8 x10- ° M, 4 x10- ° M, 2 x10 * M, 10 * M, 5 x 10 '5 M, 10 _5 M).
- an aqueous solution at 10 _3 M is prepared.
- a control test is introduced intended to check the possible effect of the solvents (reference value) on the platelet aggregation which is measured after 3 minutes of contact at 37 ° C. with stirring.
- the evaluation of the anti-platelet aggregation activity of the compounds is carried out in the same guinea pigs as those mentioned above (Dunkin-Hartley strain).
- the administration of each product in a dose range which goes from 150 to 10 mg / kg and of each vehicle (5 ml / kg) is made by gastric route (vg) 1 h or 2 h or 4 h or 6 h or 8 h or 12 h before drawing blood from guinea pigs fasted the day before.
- the allocation of treatments to animals is random.
- ND not determinable (insoluble product) -: data not available.
- the potency of the inhibitory activity of platelet aggregation is found at much lower doses. This is for example the case for CRL 42789, CRL 42788 and CRL 42 903 for which the anti-aggregating action, obtained ex vivo in the guinea pig treated with an oral dose (gastric route) of 10 mg / kg, when the administration is carried out 1 hour and 2 hours before the aggregation test, is 69 and 72% (CRL 42789), 57 and 24% (CRL 42788) or 72% (at 1 hour for CRL 42903), respectively.
- the present invention therefore also relates to pharmaceutical compositions comprising an effective amount of a compound of formula I or of a salt thereof with pharmaceutically acceptable acids.
- compositions for inhibiting the aggregation of blood platelets comprising an effective amount of one of these compounds. Its purpose is also
- a method for treating a thrombosis in a patient comprising the administration to this patient of an effective amount of one of these compounds; - A method for preventing the thrombotic risk in a patient comprising the administration to this patient of an effective amount of one of these compounds.
- the compounds of formula I can be used, in particular in the following fields: i) Acute prevention of the arterial thrombotic risk during cardiac surgery (coronary bypass) or interventional cardiology (percutaneous transluminal angioplasty, endartectomy, placement of "stent ”) : in these situations, the compounds are added to the recognized preventive treatment of the arterial thrombotic risk; oral administration of acetylsalicylic acid starting before the intervention (150 to 500 mg / d per os) then continuing thereafter; intravenous infusion of unfractionated heparin started during the intervention and then continued for 48 to 96 hours.
- the administration of the compound of formula I can then be done either orally (0.5 to 1.5 mg / kg) at the same time as the administration of aspirin, or by intravenous infusion (0.25 to 1 mg / kg / 24 h) associated or not with a bolus. After the 48th th hour, if the treatment was administered intravenously, it will be relayed by the oral administration (0.25 to 10 mg / kg in two 12-hour dosing interval) to facilitate the hospitalization care and then in outpatient treatment.
- these compounds may advantageously be administered at the rate of 1 to 3 oral intakes per day, thanks to their high bioavailability and their long duration of action, the dose being chosen from the range 0.5-10 mg / kg.
- compositions which comprise one of the active principles described in the present application incorporate the active substance either in the form of the base, or in the form of a pharmaceutically acceptable salt, or also in the form of a pro-drug comprising one or more functions protected, functions which are then released in vivo after oral administration.
- These pharmaceutical compositions incorporate manufacturing aids, vehicles which are known to those skilled in the art. These are chosen from the panoply of pharmaceutical tools recognized by the Pharmacopoeias. As examples, may be mentioned for the preparation of the dosage forms intended for the oral route: starch, magnesium stearate, talc, gelatin, agar, pectin, lactose, polyethylene glycols, etc.
- the dosage forms usable will be chosen from the proposals following: breakable tablets or not, capsules, lyocs, granules, powders.
- the daily oral dosage will be between 0.02 and 50 mg / kg / day in 1 to 3 doses regularly spaced to maintain an effective occupancy rate of receptors Gpllb / llla platelet.
- the pharmaceutical forms intended for the acute phase of treatment are designed so as to allow an individual dosage adjustment on the basis of the inhibition of the most effective platelet aggregation as a function of the immediate evolution of the operative suites.
- the lyophilisate the ready-to-use solution for infusion, allows the dosage to be individually adjusted in the dose range 0.01 mg / kg / day - 20 mg / kg / day.
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Abstract
The invention concerns compounds of formula (I) wherein: R1, R2, R3, R4 and R5 are as defined in Claim 1. Said compounds are useful in therapy as antithrombotic agents.
Description
Dérivés de pipérazinones et leurs applications Piperazine derivatives and their applications
La présente invention concerne de nouveaux composés qui sont des inhibiteurs de la fixation du fibrinogène sur les récepteurs plaquettaires Gpllb/llla, et qui sont utilisables en thérapeutique comme antithrombotiques.The present invention relates to new compounds which are inhibitors of the binding of fibrinogen to the Gpllb / IIIa platelet receptors, and which can be used therapeutically as antithrombotics.
Au cours des processus pathologiques qui conduisent à la constitution du thrombus (caillot) puis de son extension, l'agrégation plaquettaire représente une étape-clé parce qu'elle est à l'origine de la gravité du phénomène. En effet, dès l'initiation du thrombus, en particulier dans la circulation sanguine artérielle, la mise en jeu de plusieurs réactions biochimiques interdépendantes induit l'agrégation d'un nombre de plus en plus grand de plaquettes par l'intermédiaire de la transformation du fibrinogène soluble en filaments de fibrine insolubles qui augmentent la taille de l'amas de plaquettes, d'abord au siège même de la lésion vasculaire artérielle, puis de plus en plus dans la lumière du vaisseau.During the pathological processes which lead to the constitution of the thrombus (clot) and then its extension, platelet aggregation represents a key stage because it is at the origin of the gravity of the phenomenon. Indeed, from the initiation of the thrombus, in particular in the arterial blood circulation, the bringing into play of several interdependent biochemical reactions induces the aggregation of an increasingly large number of platelets through the transformation of the fibrinogen soluble in insoluble fibrin filaments which increase the size of the platelet cluster, first at the very site of the arterial vascular lesion, then increasingly in the lumen of the vessel.
Dans ce mécanisme d'agrégation plaquettaire, l'activation des récepteurs Gpllb/llla est à l'origine de l'amplification de l'agrégation plaquettaire. Le fibrinogène, qui peut se lier par ses deux dimères à ces récepteurs, amplifie la liaison des plaquettes entre elles et induit ainsi la constitution d'une masse plaquettaire formant un thrombus au site de rupture de la plaque d'athérome. Ce mécanisme d'agrégation plaquettaire est particulièrement actif dans toutes les thromboses artérielles qu'elles apparaissent au cours de pratiques de cardiologie interventionnelle (angioplastie percutanée transluminale ; pose de "stents"), de chirurgie cardiaque (pontage aorto- coronarien ; chirurgie valvulaire), au cours de maladies cardiaques aiguës (infarctus du myocarde, angor instable, syndromes coronariens aigus, ..) ou au cours de certaines ischémies cérébrales, ou enfin au cours des ischémies myocardiques qui peuvent venir compliquer les suites d'un traitement antithrombotique.In this mechanism of platelet aggregation, the activation of Gpllb / IIIa receptors is at the origin of the amplification of platelet aggregation. Fibrinogen, which can bind its two dimers to these receptors, enhances the binding of platelets to each other and thus induces the formation of a platelet mass forming a thrombus at the rupture site of the atheroma plaque. This platelet aggregation mechanism is particularly active in all arterial thromboses that they appear during interventional cardiology practices (percutaneous transluminal angioplasty; placement of "stents"), cardiac surgery (aorto-coronary artery bypass grafting; valvular surgery), during acute cardiac diseases (myocardial infarction, unstable angina, acute coronary syndromes, etc.) or during certain cerebral ischemias, or finally during myocardial ischemias which can complicate the consequences of antithrombotic treatment.
Réduire ou empêcher l'activation des plaquettes au contact d'une plaque athérosclérotique rompue représente donc une approche thérapeutique originale et efficace du traitement des thromboses, en particulier des thromboses artérielles et donc un moyen de prévention efficace des syndromes coronariens aigus, dont l'angor instable et l'infarctus du myocarde.
La présente invention vise à fournir de nouveaux inhibiteurs compétitifs de la fixation du fibrinogène sur les récepteurs Gpllb/llla utilisables comme médicaments antithrombotiques.Reducing or preventing the activation of platelets in contact with a ruptured atherosclerotic plaque therefore represents an original and effective therapeutic approach to the treatment of thromboses, in particular arterial thromboses and therefore a means of effective prevention of acute coronary syndromes, including angina unstable and myocardial infarction. The present invention aims to provide new competitive inhibitors of fibrinogen binding to Gpllb / IIIa receptors which can be used as antithrombotic drugs.
La présente invention vise en outre à fournir des composés qui puissent être administrés par voie orale, qui permettent l'obtention d'une durée d'action prolongée et qui minimisent ou évitent les risques de saignement.The present invention further aims to provide compounds which can be administered orally, which allow obtaining a prolonged duration of action and which minimize or avoid the risks of bleeding.
La présente invention a pour objet des composés de formule générale (I) :The subject of the present invention is compounds of general formula (I):
dans laquelle : R est choisi parmi l'hydrogène, un groupe alkyle en C C4 ou phényl (alkyle en CΓC4) ; in which: R is chosen from hydrogen, a CC 4 alkyl or phenyl (C Γ C 4 alkyl) group;
R2 est choisi parmi l'hydrogène, le groupe hydroxyle et un groupe protecteur du groupe amidino ; R3 est choisi parmi - l'hydrogène,R 2 is chosen from hydrogen, the hydroxyl group and a protective group from the amidino group; R 3 is chosen from - hydrogen,
- les groupes alkyle en C,-^ cycloalkyle mono ou bicyclique en C3-C12, alkényle en C2-C4 ou alkynyle en C2-C4, ces groupes étant éventuellement substitués par des groupes choisis parmi les halogènes et le groupe hydroxy ; - les groupes aryle mono, bi ou tricycliques en C6-C14,- alkyl, C, - ^ cycloalkyl mono or bicyclic C 3 -C 12 alkenyl, C 2 -C 4 alkynyl or C 2 -C 4 alkyl, these groups being optionally substituted by groups selected from halogen and hydroxy group; - mono, bi or tricyclic C 6 -C 14 aryl groups,
- les groupes hétéroaryle choisis parmi les groupes pyridyle, thiényle, furannyle, quinolyle, benzodioxannyle, benzodioxolyle, benzothiényle, benzofurannyle et pyrazinyle ;- heteroaryl groups chosen from pyridyl, thienyl, furannyl, quinolyl, benzodioxannyl, benzodioxolyl, benzothienyl, benzofuranyl and pyrazinyl groups;
- les groupes phénylalkyle(C1-C4) et naphtylalkyle(C1-C4) éventuellement substitués sur le noyau aryle, et pipéronyie,- the phenylalkyl (C 1 -C 4 ) and naphthylalkyl (C 1 -C 4 ) groups optionally substituted on the aryl ring, and piperonyia,
R4 et R5 sont choisis indépendamment l'un de l'autre parmi l'hydrogène, un groupe alkyle en ou forment ensemble avec l'atome d'azote un groupe choisi parmi les groupes pipéridinyle et morpholinyle,
les groupes aryle et hétéroaryle pouvant être substitués par un ou plusieurs groupes choisis indépendamment parmi les halogènes, les groupes alkyle en C C4, trifluorométhyle, alkyl(C1-C4)thio, alky C^C sulfonyle, alkyl(CR 4 and R 5 are chosen independently of one another from hydrogen, an alkyl group or, together with the nitrogen atom, form a group chosen from the piperidinyl and morpholinyl groups, the aryl and heteroaryl groups which may be substituted by one or more groups independently chosen from halogens, CC 4 alkyl, trifluoromethyl, (C 1 -C 4 ) alkyl, thio, C 1 -C 6 alkyl sulfonyl, (C 1 alkyl) groups
C4)oxy, nitro, les groupes -COOR, -CH2COOR ou -O-CH2-COOR, R étant un groupe alkyle en C,-C4, et le groupe oxo est en position 2 ou 3 sur la pipérazine ; et leurs sels d'addition avec des acides pharmaceutiquement acceptables.C 4 ) oxy, nitro, the groups -COOR, -CH 2 COOR or -O-CH 2 -COOR, R being a C 1 -C 4 alkyl group, and the oxo group is in position 2 or 3 on the piperazine ; and their addition salts with pharmaceutically acceptable acids.
Comme exemple de groupe aryle on peut citer les groupes phényle, α-naphtyle, β-naphtyle, fluorényle. Les groupes alcoyle en
peuvent être linéaires ou ramifiés.As an example of an aryl group, mention may be made of phenyl, α-naphthyl, β-naphthyl and fluorenyl groups. The alkyl groups in can be linear or branched.
Comme exemples on peut citer les groupes méthyle, éthyle, propyle, isopropyle, butyle, isobutyle, tertiobutyle, pentyle.As examples, mention may be made of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and pentyl groups.
Les groupes alkynyle peuvent être, par exemple, les groupes éthynyle, propargyle, butynyle. Les groupes alkényle peuvent être, par exemple, les groupes vinyle et allyle.The alkynyl groups may be, for example, the ethynyl, propargyl, butynyl groups. The alkenyl groups can be, for example, vinyl and allyl groups.
Les groupes alcoxy en C C4 peuvent de même être linéaires ou ramifiés. Comme exemples on peut citer les groupes méthoxy, éthoxy, propoxy, isopropoxy, butoxy, isobutoxy. Les halogènes peuvent être choisis parmi le fluor, le chlore, le brome et l'iode.CC 4 alkoxy groups can likewise be linear or branched. As examples, mention may be made of methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy groups. The halogens can be chosen from fluorine, chlorine, bromine and iodine.
Comme groupes protecteurs du groupe amidino, on peut citer les groupes éthoxycarbonyle, benzyloxycarbonyle, p-nitrobenzyloxycarbonyle et t-butoxycarbonyle. Les "sels d'addition avec des acides pharmaceutiquement acceptables" désignent les sels qui donnent les propriétés biologiques des bases libres, sans avoir d'effet indésirable. Ces sels peuvent être notamment ceux formés avec des acides minéraux, tels que l'acide chlorhydrique, l'acide bromhydrique, l'acide sulfurique, l'acide nitrique, l'acide phosphorique ; des sels métalliques acides, tels que l'orthophosphate disodique et le sulfate monopotassique, et des acides organiques.As protecting groups for the amidino group, mention may be made of ethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl and t-butoxycarbonyl groups. The "addition salts with pharmaceutically acceptable acids" designate the salts which give the biological properties of the free bases, without having an undesirable effect. These salts can be in particular those formed with mineral acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; acidic metal salts, such as disodium orthophosphate and monopotassium sulfate, and organic acids.
Les composés de formule I peuvent être préparés par : a) réaction d'un acide de formule
The compounds of formula I can be prepared by: a) reaction of an acid of formula
dans laquelle Z est un groupe précurseur d'un groupein which Z is a precursor group of a group
avec une aminé de formulewith an amine of formula
dans laquelle R est un groupe alkyle en C C4 ou phényl(alkyle r obtenir un composé de formulein which R is a CC 4 alkyl or phenyl group (alkyl r obtain a compound of formula
b) conversion du groupe Z en groupe b) conversion of group Z into group
et c) éventuellement conversion du groupe R en un atome d'hydrogène.and c) optionally converting the group R into a hydrogen atom.
La réaction des acides de formule II avec les aminés de formule III peut être effectuée dans un solvant polaire tel que DMF, THF ou acétate d'éthyle, en présence d'un agent de couplage (DCC/HOBT, BOP; chloroformiate d'isobutyle) à une température de 15 à 50°C.The reaction of the acids of formula II with the amines of formula III can be carried out in a polar solvent such as DMF, THF or ethyl acetate, in the presence of a coupling agent (DCC / HOBT, BOP; isobutyl chloroformate ) at a temperature of 15 to 50 ° C.
Dans le cas où Z est un groupe N≡C-, le groupe Z peut être converti en amidoxime par addition d'hydroxylamine sur le groupe nitrile en présence d'une base appropriée (K2CO3, Et3N, C2H5ONa) dans un solvant alcoolique. L'hydrogénolyse, en présence de palladium sur charbon dans un mélange d'anhydride acétique et d'acide acétique, des composés obtenus conduit aux composés de formule I dans lesquels R2 est l'hydrogène (avec formation directe d'un composé où R.,=H dans le cas où R'1 est un groupe benzyle). Dans le cas où Z est un groupe N≡C-, le groupe Z peut également être converti en imidate par addition d'éthanol en présence d'HCI dans l'acétate d'éthyle. L'imidate obtenu est ensuite converti en composés de formule (I) dans lesquels R2 est un hydrogène et -NR4R5 est soit un groupe pipéridinyle soit un groupe morpholinyle, par réaction avec l'aminé correspondante en milieu éthanol-acétate d'éthyle.In the case where Z is an N≡C- group, the group Z can be converted to amidoxime by adding hydroxylamine to the nitrile group in the presence of an appropriate base (K 2 CO 3 , Et 3 N, C 2 H 5 ONa) in an alcoholic solvent. The hydrogenolysis, in the presence of palladium on carbon in a mixture of acetic anhydride and acetic acid, of the compounds obtained leads to the compounds of formula I in which R 2 is hydrogen (with direct formation of a compound where R ., = H in the case where R'1 is a benzyl group). In the case where Z is an N≡C- group, the group Z can also be converted to imidate by addition of ethanol in the presence of HCl in ethyl acetate. The imidate obtained is then converted into compounds of formula (I) in which R 2 is hydrogen and -NR 4 R 5 is either a piperidinyl group or a morpholinyl group, by reaction with the corresponding amine in ethanol-acetate medium. 'ethyl.
Les composés de formule II à groupe 2-pipérazinone, dans le cas où Z est un groupe nitrile peuvent être obtenus selon le schéma suivant :
00/04000The compounds of formula II with a 2-piperazinone group, in the case where Z is a nitrile group, can be obtained according to the following scheme: 04/04000
bromoacétate d'éthyle ! dnsopropyléthylamme
ethyl bromoacetate! dnsopropylethylamme
Schéma 1Diagram 1
Le 4-fluorobenzonitrile est mis en réaction avec un excès d'éthylènediamine dans un solvant aprotique pour donner le 4-(2- aminoéthyl)benzonitrile qui est ensuite mono-alkylé par le bromoacétate d'éthyle dans un solvant polaire comme l'éthanol ou l'acétonitrile en présence d'une base inorganique ou d'une aminé tertiaire. Une acylation avec du chlorure de chloroacétyle suivi d'une cyclisation et d'une hydrolyse conduisent à l'acide (I).The 4-fluorobenzonitrile is reacted with an excess of ethylenediamine in an aprotic solvent to give 4- (2-aminoethyl) benzonitrile which is then mono-alkylated with ethyl bromoacetate in a polar solvent such as ethanol or acetonitrile in the presence of an inorganic base or a tertiary amine. Acylation with chloroacetyl chloride followed by cyclization and hydrolysis lead to acid (I).
Les composés de formule II à groupe 3-pipérazinone dans le cas où Z est un groupe nitrile peuvent être obtenus selon le schéma suivant :
The compounds of formula II with a 3-piperazinone group in the case where Z is a nitrile group can be obtained according to the following scheme:
Schéma 2Diagram 2
Le 4-(2-aminoéthyl)benzonitrile est dialkylé par le bromoacétate d'éthyle ; la cyclisation s'opère en présence d'une amine tertiaire, d'une base inorganique ou de leur mélange ; après hydrolyse on obtient l'acide (2).4- (2-aminoethyl) benzonitrile is dialkylated with ethyl bromoacetate; cyclization takes place in the presence of a tertiary amine, an inorganic base or a mixture thereof; after hydrolysis, acid (2) is obtained.
Les sels d'addition s'obtiennent de façon classique par réaction du composé de formule I avec un acide pharmaceutiquement acceptable dans un solvant approprié. Inversement, les bases peuvent être obtenues à partir des sels d'addition par traitement par une base forte.The addition salts are obtained conventionally by reaction of the compound of formula I with a pharmaceutically acceptable acid in an appropriate solvent. Conversely, the bases can be obtained from the addition salts by treatment with a strong base.
Les exemples suivants illustrent la préparation des composés de formule I.The following examples illustrate the preparation of the compounds of formula I.
A - Préparation des composés de formule II.A - Preparation of the compounds of formula II.
1. Synthèse de l'acide 2-[4-(4-cyanophényl)-2-oxopipérazino]acétique (1)1. Synthesis of 2- [4- (4-cyanophenyl) -2-oxopiperazino] acetic acid (1)
a) 4-(2-aminoéthylamino)benzonitrilea) 4- (2-aminoethylamino) benzonitrile
Une suspension du 4-fluorobenzonitrile (167 g, 1 ,38 moles), de l'éthylènediamine (330 g, 5,5 moles) et du carbonate de potassium (300 g, 2,17 moles) dans 2 I de toluène est chauffée à reflux pendant 6 heures. Après refroidissement à température ambiante, on filtre et rince avec du toluène, le filtrat est évaporé pour donner une huile jaune qui est cristallisée dans du
toluène. On filtre et rince avec du toluène, sèche sous vide à 50°C et obtient 200 g d'un solide légèrement jaune. Rendement = 90%. Point de fusion = 85°C. 1 H-RMN (400MHz, CDCI3) : δ1 ,2 (bs, 2H), 2,9 (t, 2H), 3,12 (q, 2H), 4,7 (bs, 1H), 6,5 (d, 2H), 7,3 (d, 2H).A suspension of 4-fluorobenzonitrile (167 g, 1.38 moles), ethylenediamine (330 g, 5.5 moles) and potassium carbonate (300 g, 2.17 moles) in 2 l of toluene is heated at reflux for 6 hours. After cooling to room temperature, it is filtered and rinsed with toluene, the filtrate is evaporated to give a yellow oil which is crystallized in toluene. Filtered and rinsed with toluene, dried under vacuum at 50 ° C and obtained 200 g of a slightly yellow solid. Yield = 90%. Melting point = 85 ° C. 1 H-NMR (400MHz, CDCI3): δ1.2 (bs, 2H), 2.9 (t, 2H), 3.12 (q, 2H), 4.7 (bs, 1H), 6.5 ( d, 2H), 7.3 (d, 2H).
b) 2-{2-(chloroacétyl)-2-(4-cyanoanilino)éthylamino}acétate d'éthyleb) 2- {2- (chloroacetyl) -2- (4-cyanoanilino) ethylamino} ethyl acetate
A une suspension du 4-(2-aminoéthylamino)benzonitrile (80,5 g, 0,5 mole) et de diisopropyléthylamine (65 g, 0,5 mole) dans 800 ml d'acétonitrile, est ajouté du bromoacétate d'éthyle (84 g, 0,5 mole). L'agitation est maintenue pendant 18 heures à température ambiante. On évapore la plupart de l'acétonitrile, le résidu est repris dans du dichlorométhane. On lave avec de l'eau, sèche sur du sulfate de sodium ; le produit brut est passé sur une colonne de silice courte [éluant dichlorométhane puis dichlorométhane/méthanol, 20/1 )] pour donner une huile.To a suspension of 4- (2-aminoethylamino) benzonitrile (80.5 g, 0.5 mole) and diisopropylethylamine (65 g, 0.5 mole) in 800 ml of acetonitrile, ethyl bromoacetate ( 84 g, 0.5 mole). Stirring is continued for 18 hours at room temperature. Most of the acetonitrile is evaporated, the residue is taken up in dichloromethane. Wash with water, dry over sodium sulfate; the crude product is passed through a short silica column [eluent dichloromethane then dichloromethane / methanol, 20/1)] to give an oil.
Le produit obtenu ci-dessus est solubilisé dans 11 de tétrahydrofuranne; on ajoute la diisopropyléthylamine (51 g, 0,4 mole); ensuite le chlorure de chloroacétyle (45 g, 0,4 mole) est additionné lentement à ~5°C. Après 18 heures d'agitation à température ambiante, on ajoute 11 d'acétate d'éthyle et lave avec de l'eau 3 fois, sèche sur du sulfate de sodium, puis évapore; on obtient un solide qui est agité avec un mélange dichlorométhane-éther (1/3). On filtre la suspension et rince avec dichlorométhane-éther (1/3), sèche sous vide pour obtenir 100 g d'un solide beige cristallin. Rendement = 62%.The product obtained above is dissolved in 11 of tetrahydrofuran; diisopropylethylamine (51 g, 0.4 mole) is added; then the chloroacetyl chloride (45 g, 0.4 mole) is added slowly at ~ 5 ° C. After 18 hours of stirring at room temperature, 11 ethyl acetate is added and washed with water 3 times, dried over sodium sulfate, then evaporated; a solid is obtained which is stirred with a dichloromethane-ether mixture (1/3). The suspension is filtered and rinsed with dichloromethane-ether (1/3), dried under vacuum to obtain 100 g of a beige crystalline solid. Yield = 62%.
1 H-RMN (400MHz, CDCI3) : δ 1 ,2 (q, 6H), 3,3 (m, 4H), 3,65 (m, 4H), 3,8 (s, 2H), 3,9 (d, 4H), 4,1 (s, 4H), 4,15 (q, 4H), 4,9 (t, 1 H), 5,3 (t, 1 H), 6,5 (dd, 4H), 7,3 (dd, 4H). 1 H-NMR (400MHz, CDCI3): δ 1, 2 (q, 6H), 3.3 (m, 4H), 3.65 (m, 4H), 3.8 (s, 2H), 3.9 (d, 4H), 4.1 (s, 4H), 4.15 (q, 4H), 4.9 (t, 1H), 5.3 (t, 1H), 6.5 (dd, 4H), 7.3 (dd, 4H).
c) 2-[4-(4-cyanophényl)-2-oxopipérazino]acétate d'éthylec) 2- [4- (4-cyanophenyl) -2-oxopiperazino] ethyl acetate
Une suspension du 2-{2-(chloroacétyl)-2-(4-cyanoanilino)éthylamino} acétate d'éthyle (152 g, 0,47 mole), de la diisopropyléthylamine (73 g, 0,57 mole) et de l'iodure de sodium (85 g, 0,57 mole) dans 1 ,2 I d'acétonitrile est
chauffée à reflux pendant 2 heures. On évapore le solvant et le résidu est repris dans du dichlorométhane et lavé à l'eau, séché sur du sulfate de sodium, puis évapore pour donner une huile brune qui est cristallisée dans un mélange cyclohéxane-acétate d'éthyle pour donner 125 g d'un solide cristallin brunâtre. Rendement = 93%.A suspension of 2- {2- (chloroacetyl) -2- (4-cyanoanilino) ethylamino} ethyl acetate (152 g, 0.47 mole), diisopropylethylamine (73 g, 0.57 mole) and l sodium iodide (85 g, 0.57 mole) in 1.2 I acetonitrile is heated at reflux for 2 hours. The solvent is evaporated off and the residue is taken up in dichloromethane and washed with water, dried over sodium sulfate, then evaporated to give a brown oil which is crystallized from a cyclohexane-ethyl acetate mixture to give 125 g of 'a brownish crystalline solid. Yield = 93%.
Point de fusion = 108°C.Melting point = 108 ° C.
1 H-RMN (400MHZ, CDCI3) : δ 1 ,3 (t, 3H), 3,65 (m, 4H), 4,05 (s, 2H), 4,2 (m,1 H-NMR (400MHZ, CDCI3): δ 1, 3 (t, 3H), 3.65 (m, 4H), 4.05 (s, 2H), 4.2 (m,
4H), 6,8 (d, 2H), 7,5 (d, 2H).4H), 6.8 (d, 2H), 7.5 (d, 2H).
d) Acide 2-[4-(4-cyanophényl)-2-oxopipérazino]acétiqued) 2- [4- (4-cyanophenyl) -2-oxopiperazino] acetic acid
Le 2-[4-(4-cyanophényl)-2-oxopipérazino]acétate d'éthyle (20,7 g, 72 mmoles) est solubilisé dans 80 ml de méthanol, 80 ml de tétrahydrofuranne et 100 ml d'eau, ensuite le lithium hydroxyde monohydrate (4 g, 98 mmoles) est ajouté. L'agitation est maintenue pendant 20 minutes puis on élimine le solvant organique sous vide. On rajoute environ 100 ml d'eau à la suspension obtenue et acidifie. On filtre et rince à l'eau, sèche sous vide à 50°C pour obtenir 18,5 g d'une poudre beige. Rendement = 100%. Point de fusion = 215°C (d). 1 H-RMN (200MHz, DMSO-d6) : δ 3,5 (t, 2H), 3,65 (t, 2H), 4,0 (s, 2H), 4,1 (s,2- [4- (4-cyanophenyl) -2-oxopiperazino] ethyl acetate (20.7 g, 72 mmol) is dissolved in 80 ml of methanol, 80 ml of tetrahydrofuran and 100 ml of water, then the lithium hydroxide monohydrate (4 g, 98 mmol) is added. Stirring is continued for 20 minutes and then the organic solvent is removed in vacuo. About 100 ml of water are added to the suspension obtained and acidified. Filtered and rinsed with water, dried under vacuum at 50 ° C to obtain 18.5 g of a beige powder. Yield = 100%. Melting point = 215 ° C (d). 1 H-NMR (200MHz, DMSO-d 6 ): δ 3.5 (t, 2H), 3.65 (t, 2H), 4.0 (s, 2H), 4.1 (s,
2H), 7,0 (d, 2H), 7,6 (d, 2H).2H), 7.0 (d, 2H), 7.6 (d, 2H).
2. Synthèse de l'acide 2-[4-(4-cyanophényl)-3-oxopipérazino]acétique (2)2. Synthesis of 2- [4- (4-cyanophenyl) -3-oxopiperazino] acetic acid (2)
a) 2-[2-(4-cyanoanilino)éthyl(2-éthoxy-2-oxoéthyl)amino]acétate d'éthylea) 2- [2- (4-cyanoanilino) ethyl (2-ethoxy-2-oxoethyl) amino] ethyl acetate
Une suspension du 4-(2-aminoéthylamino)benzonitrile (1a) (32 g, 0,2 mole), du carbonate de potassium (55g, 0,4 mole) et du bromoacétate d'éthyle (67g, 0,4 mole) dans 400 ml d'acétonitrile est chauffée à reflux pendant 18 heures. On filtre et le produit brut est passé sur une colonne courte de silice (éluant : dichlorométhane) pour donner 58 g d'une huile brune. Rendement = 87%.A suspension of 4- (2-aminoethylamino) benzonitrile (1a) (32 g, 0.2 mole), potassium carbonate (55g, 0.4 mole) and ethyl bromoacetate (67g, 0.4 mole) in 400 ml of acetonitrile is heated at reflux for 18 hours. Filtered and the crude product is passed through a short column of silica (eluent: dichloromethane) to give 58 g of a brown oil. Yield = 87%.
1 H-RMN (200MHz, CDCI3) : δ 1 ,3 (t, 3H), 3,05 (t, 2H), 3,4 (s, 2H), 3,55 (s, 2H), 3,8 (t, 2H), 4,2 (q, 2H), 7,45 (d, 2H), 7,6 (d, 2H).
MS-CI m/z : 287 (M+H)+ 1 H-NMR (200MHz, CDCI3): δ 1, 3 (t, 3H), 3.05 (t, 2H), 3.4 (s, 2H), 3.55 (s, 2H), 3.8 (t, 2H), 4.2 (q, 2H), 7.45 (d, 2H), 7.6 (d, 2H). MS-CI m / z: 287 (M + H) +
b) Acide 2-[4-(4-cyanophényl)-3-oxopipérazino]acétiqueb) 2- [4- (4-cyanophenyl) -3-oxopiperazino] acetic acid
Une suspension du 2-[2-(4-cyanoanilino)éthyl(2-éthoxy-2-oxoéthyl) aminojacétate d'éthyle (58 g, 0,174 mole), de la diisopropyléthylamine (4g, 0,03 mole) et du carbonate de potassium (24 g, 0,174 mole) dans 400 ml d'acétonitrile est chauffée à reflux pendant 2 jours. On filtre et rince avec du dichlorométhane. Le filtrat est évaporé pour donner un solide brun qui est solubilisé dans 150 ml de méthanol et 50 ml d'eau, ensuite le lithium hydroxyde monohydrate (8,4 g, 0,2 mole) est ajouté. Après 30 minutes d'agitation à température ambiante, la moitié du méthanol est éliminée sous vide pour donner une suspension. On rajoute environ 100 ml d'eau et acidifie à 5°C. On filtre et rince à l'eau, sèche sous vide à 50°C pour obtenir 27,2 g d'une poudre beige. Rendement = 55%.A suspension of ethyl 2- (2- (4-cyanoanilino) ethyl (2-ethoxy-2-oxoethyl) aminojacetate (58 g, 0.174 mol), diisopropylethylamine (4 g, 0.03 mol) and carbonate potassium (24 g, 0.174 mol) in 400 ml of acetonitrile is heated at reflux for 2 days. It is filtered and rinsed with dichloromethane. The filtrate is evaporated to give a brown solid which is dissolved in 150 ml of methanol and 50 ml of water, then the lithium hydroxide monohydrate (8.4 g, 0.2 mole) is added. After 30 minutes of stirring at room temperature, half of the methanol is removed in vacuo to give a suspension. About 100 ml of water are added and acidified at 5 ° C. Filtered and rinsed with water, dried under vacuum at 50 ° C to obtain 27.2 g of a beige powder. Yield = 55%.
Point de fusion = 120°C.Melting point = 120 ° C.
1 H-RMN (200MHz, DMSO-d6) : δ 2,95 (t, 2H), 3,3 (s, 2H), 3,4 (s, 2H), 3,7 (t, 1 H-NMR (200MHz, DMSO-d 6 ): δ 2.95 (t, 2H), 3.3 (s, 2H), 3.4 (s, 2H), 3.7 (t,
2H), 7,65 (d, 2H), 7,85 (d, 2H).2H), 7.65 (d, 2H), 7.85 (d, 2H).
B - Préparation des produits intermédiaires de formule IVB - Preparation of intermediate products of formula IV
1 - Synthèse du 3-{[2-(4-(4-cyanophényl)-2-oxopipérazino) acétyljamino}- propanoate d'éthyle (intermédiaire B1)1 - Synthesis of 3 - {[2- (4- (4-cyanophenyl) -2-oxopiperazino) acetyljamino} - ethyl propanoate (intermediate B1)
A une suspension de l'acide 2-[4-(4-cyanophényl)-2- oxopipérazinojacétique (2,59g, 10 mmoles), et de la N-méthylmorpholine (2,1 g, 20,8 mmoles) dans 30 ml de tétrahydrofuranne, est ajouté le chloroformiate d'isobutyle (1 ,39 g, 10 mmoles) à 5-10°C, puis le mélange est agité à température ambiante pendant 10 minutes; ensuite le 3-aminopropanoate d'éthyle chlorhydrate (1 ,55 g, 10 mmoles) est ajouté. L'agitation est maintenue pendant une heure; on évapore le solvant et le résidu est purifié par flash
chromatographie (dichlorométhane/methanol, 15/1 ) pour donner 2 g d'un solide blanc.To a suspension of 2- [4- (4-cyanophenyl) -2- oxopiperazinojacetic acid (2.59 g, 10 mmol), and N-methylmorpholine (2.1 g, 20.8 mmol) in 30 ml of tetrahydrofuran, isobutyl chloroformate (1.39 g, 10 mmol) is added at 5-10 ° C, then the mixture is stirred at room temperature for 10 minutes; then ethyl 3-aminopropanoate hydrochloride (1.55 g, 10 mmol) is added. Agitation is maintained for one hour; the solvent is evaporated and the residue is purified by flash chromatography (dichloromethane / methanol, 15/1) to give 2 g of a white solid.
Rendement = 56 %.Yield = 56%.
1 H-RMN (200MHz, CDCI3) : δ 1 ,25 (t, 3H), 2,5 (t, 2H), 3,5 (dd, 2H), 3,65 (m, 4H), 4,05 (s, 2H), 4,08 (s, 2H), 4,1 (q, 2H), 6,75 (bs, 1 H), 6,8 (d, 2H), 7,55 (d, 2H).1 H-NMR (200MHz, CDCI3): δ 1.25 (t, 3H), 2.5 (t, 2H), 3.5 (dd, 2H), 3.65 (m, 4H), 4.05 (s, 2H), 4.08 (s, 2H), 4.1 (q, 2H), 6.75 (bs, 1H), 6.8 (d, 2H), 7.55 (d, 2H ).
La méthode décrite en 1 a été utilisée pour préparer les produits intermédiaires suivants :The method described in 1 was used to prepare the following intermediate products:
2 - 3-{[2-(4-(4-cyanophényl)-2-oxopipérazino)acétyl]amino}propanoate de benzyle (intermédiaire B2)2 - 3 - {[2- (4- (4-cyanophenyl) -2-oxopiperazino) acetyl] amino} benzyl propanoate (intermediate B2)
Produit de départ : le tosylate du 3-aminopropanoate de benzyle. Rendement = 71 %.Starting material: benzyl 3-aminopropanoate tosylate. Yield = 71%.
1H-RMN (200MHz, CDCI3) : δ 2,55 (t, 2H), 3,5 (q, 2H), 3,6 (s, 4H), 4,0 (s, 2H), 4,05 (s, 2H), 5,1 (s, 2H), 6,8 (m, 3H), 7,3 (m, 5H), 7,5 (d, 2H).1H-NMR (200MHz, CDCI3): δ 2.55 (t, 2H), 3.5 (q, 2H), 3.6 (s, 4H), 4.0 (s, 2H), 4.05 ( s, 2H), 5.1 (s, 2H), 6.8 (m, 3H), 7.3 (m, 5H), 7.5 (d, 2H).
3 - 3-(1,3-benzodioxol-5-yl)-3-{[2-(4-(4-cyanophényl)-2-oxopipérazino) acétyl]amino}propanoate d'éthyle (intermédiaire B3)Ethyl 3 - 3- (1,3-benzodioxol-5-yl) -3 - {[2- (4- (4-cyanophenyl) -2-oxopiperazino) acetyl] amino} propanoate (intermediate B3)
Produit de départ le chlorhydrate du 3-amino-3-(1 ,3-benzodioxol-5- yl)propanoate d'éthyle. Rendement = 59%. 1 H-RMN (400MHz, CDCI3) : δ 1 ,15 (t, 3H), 2,8 (m, 2H), 3,65 (m, 4H), 4,1 (m, 6H), 5,3 (q, 1 H), 5,9 (d, 2H), 6,85 (m, 5H), 6,9 (d, 1 H), 7,5 (d, 2H).Starting material ethyl 3-amino-3- (1, 3-benzodioxol-5-yl) hydrochloride propanoate. Yield = 59%. 1 H-NMR (400MHz, CDCI3): δ 1.15 (t, 3H), 2.8 (m, 2H), 3.65 (m, 4H), 4.1 (m, 6H), 5.3 (q, 1H), 5.9 (d, 2H), 6.85 (m, 5H), 6.9 (d, 1H), 7.5 (d, 2H).
4 - 3-(1 ,3-benzodioxol-5-yl)-3-{[2-(4-(4-cyanophényl)-2-oxopipérazino) acétyl]amino}-propanoate de benzyle (intermédiaire B4)Benzyl 4- (1, 3-benzodioxol-5-yl) -3 - {[2- (4- (4-cyanophenyl) -2-oxopiperazino) acetyl] amino} -propanoate (intermediate B4)
Produit de départ : le tosylate du 3-amino-3-(1 ,3-benzodioxol-5-yl)propanoate de benzyle. Rendement = 49%.
1 H-RMN (400MHz, CDCI3) : δ 2,8 (m, 2H), 3,55 (s, 4H), 4,0 (s, 2H), 4,1 (q, 2H), 5,0 (d, 2H), 5,3 (q, 1 H), 5,9 (d, 2H), 6,7 (m, 6H), 7,25 (m, 6H), 7,5 (d, 2H).Starting material: benzyl 3-amino-3- (1,3-benzodioxol-5-yl) tosylate propanoate. Yield = 49%. 1 H-NMR (400MHz, CDCI3): δ 2.8 (m, 2H), 3.55 (s, 4H), 4.0 (s, 2H), 4.1 (q, 2H), 5.0 (d, 2H), 5.3 (q, 1H), 5.9 (d, 2H), 6.7 (m, 6H), 7.25 (m, 6H), 7.5 (d, 2H ).
5 - 3-{[2-(4-(4-cyanophényl)-2-oxopipérazino)acétyl]amino}-3-(pyridinyl) propanoate d'éthyle (intermédiaire B5)5 - 3 - Ethyl {[2- (4- (4-cyanophenyl) -2-oxopiperazino) acetyl] amino} -3- (pyridinyl) propanoate (intermediate B5)
Produit de départ : le dichlorhydrate du 3-amino-3-(pyridinyl)propanoate d'éthyle.Starting product: ethyl 3-amino-3- (pyridinyl) propanoate dihydrochloride.
Rendement = 54%. 1 H-RMN (400MHz, CDCI3) : δ 1 ,05 (t, 3H), 2,85 (m, 2H), 3,65 (m, 4H), 4,1 (m, 6H), 5,4 (q, 1 H), 6,75 (d, 2H), 7,25 (q, 1 H), 7,5 (d, 2H), 7,65 (d, 1 H), 7,75 (bs, 1 H), 8,45 (d, 1 H), 8,55 (s, 1 H).Yield = 54%. 1 H-NMR (400MHz, CDCI3): δ 1.05 (t, 3H), 2.85 (m, 2H), 3.65 (m, 4H), 4.1 (m, 6H), 5.4 (q, 1H), 6.75 (d, 2H), 7.25 (q, 1H), 7.5 (d, 2H), 7.65 (d, 1H), 7.75 (bs , 1H), 8.45 (d, 1H), 8.55 (s, 1H).
6 - 3-{[2-(4-(4-cyanophényl)-2-oxopipérazino)acétyl]amino}-3-(pyridinyl) propanoate de benzyle (intermédiaire B6)6 - 3 - Benzyl {[2- (4- (4-cyanophenyl) -2-oxopiperazino) acetyl] amino} -3- (pyridinyl) propanoate (intermediate B6)
Produit de départ : le ditosylate du 3-amino-3-(pyridinyl)propanoate de benzyle. Rendement = 48%.Starting material: benzyl 3-amino-3- (pyridinyl) propanoate ditosylate. Yield = 48%.
1 H-RMN (400MHz, CDCI3) : δ 2,95 (dd, 2H), 3,6 (s, 4H), 4,0 (s, 2H), 4,1 (q, 2H), 5,0 (s, 2H), 5,45 (q, 1 H), 6,75 (d, 2H), 7,25 (m, 6H), 7,5 (d, 2H), 7,65 (d, 1 H), 7,75 (d, 1 H), 8,5 (d, 1 H), 8,6 (s, 1 H).1 H-NMR (400MHz, CDCI3): δ 2.95 (dd, 2H), 3.6 (s, 4H), 4.0 (s, 2H), 4.1 (q, 2H), 5.0 (s, 2H), 5.45 (q, 1H), 6.75 (d, 2H), 7.25 (m, 6H), 7.5 (d, 2H), 7.65 (d, 1 H), 7.75 (d, 1 H), 8.5 (d, 1 H), 8.6 (s, 1 H).
7 - 3-{[2-(4-(4-cyanophényl)-2-oxopipérazino)acétyl]amino}-5- phénylpentanoate d'éthyle (intermédiaire B7) Produit de départ : le chlorhydrate du 3-amino-5-phénylpentanoate d'éthyle. Rendement = 63%.7 - 3 - {[2- (4- (4-cyanophenyl) -2-oxopiperazino) acetyl] amino} -5- ethyl phenylpentanoate (intermediate B7) Starting material: 3-amino-5-phenylpentanoate hydrochloride ethyl. Yield = 63%.
1 H-RMN (400MHz, DMSO-d6) : δ 1 ,2 (t, 3H), 1 ,8 (m, 2H), 2,5 (dq, 2H), 2,6 (t, 2H), 3,6 (dd, 4H), 4,1 (m, 6H), 4,2 (m, 1 H), 6,65 (d, 1H), 6,75 (d, 2H), 7,1 (m, 3H), 7,2 (m, 3H), 7,5 (d, 2H).1 H-NMR (400MHz, DMSO-d 6 ): δ 1, 2 (t, 3H), 1, 8 (m, 2H), 2.5 (dq, 2H), 2.6 (t, 2H), 3.6 (dd, 4H), 4.1 (m, 6H), 4.2 (m, 1H), 6.65 (d, 1H), 6.75 (d, 2H), 7.1 ( m, 3H), 7.2 (m, 3H), 7.5 (d, 2H).
8 - 3- [2-(4-(4-cyanophényl)-2-oxopipérazino)acétyl]amino}-3-cyclohexyl propanoate d'éthyle (intermédiaire B8)
Produit de départ : le chlorhydrate du 3-amino-3-cyclohexylpropanoate d'éthyle. Rendement = 59%.8 - 3- [2- (4- (4-cyanophenyl) -2-oxopiperazino) acetyl] amino} -3-ethyl cyclohexyl propanoate (intermediate B8) Starting product: ethyl 3-amino-3-cyclohexylpropanoate hydrochloride. Yield = 59%.
1 H-RMN (400MHz, DMSO-d6) : δ °-9 (m. 2H). 1 -1 (m- 3H), 1 ,15 (t, 3H), 1 ,35, (m, 1 H), 1 ,6 (m, 5H), 2,3 (dd, 1 H), 2,5 (dd, 1 H), 3,5 (m, 2H), 3,6 (m, 2H), 4,0 (m, 7H), 6,95 (d, 2H), 7,6 (d, 2H), 7,8 (d, 1 H).1 H-NMR (400MHz, DMSO-d6) : δ ° - 9 ( m . 2H ). 1 - 1 ( m - 3H), 1, 15 (t, 3H), 1, 35, (m, 1H), 1, 6 (m, 5H), 2.3 (dd, 1H), 2, 5 (dd, 1H), 3.5 (m, 2H), 3.6 (m, 2H), 4.0 (m, 7H), 6.95 (d, 2H), 7.6 (d, 2H), 7.8 (d, 1H).
9 - 3-{[2-(4-(4-cyanophényl)-2-oxopipérazino)acétyl]amino}-5-méthyl hexanoate d'éthyle (intermédiaire B9) Produit de départ : le chlorhydrate du 3-amino-5-méthylhexanoate d'éthyle. Le produit brut a été utilisé directement pour l'exemple 9.9 - 3 - {[2- (4- (4-cyanophenyl) -2-oxopiperazino) acetyl] amino} -5-ethyl methyl hexanoate (intermediate B9) Starting material: 3-amino-5- hydrochloride ethyl methylhexanoate. The crude product was used directly for Example 9.
10 - 3- [2-(4-(4-cyanophényl)-2-oxopipérazino)acétyl]amino}-4,4-diméthyi pentanoate d'éthyle (intermédiaire B10)10 - 3- [2- (4- (4-cyanophenyl) -2-oxopiperazino) acetyl] amino} -4,4-dimethyl dimethyl pentanoate (intermediate B10)
Produit de départ : le chlorhydrate du 3-amino-4,4-diméthylpentanoate d'éthyle. Ce produit a été utilisé directement pour l'exemple 10.Starting product: ethyl 3-amino-4,4-dimethylpentanoate hydrochloride. This product was used directly for Example 10.
11 - 3-{[2-(4-(4-cyanophényl)-2-oxopipérazino)acétyl]amino}-4-methyl pentanoate d'éthyle (intermédiaire B11)11 - 3 - {[2- (4- (4-cyanophenyl) -2-oxopiperazino) acetyl] amino} -4-ethyl methyl pentanoate (intermediate B11)
Produit de départ : le chlorhydrate du 3-amino-4-méthylpentanoate d'éthyle. Ce produit a été utilisé directement pour l'exemple 11.Starting product: ethyl 3-amino-4-methylpentanoate hydrochloride. This product was used directly for Example 11.
12 - 3-{[2-(4-(4-cyanophényl)-3-oxopipérazino) acétyl]amino}propanoate d'éthyle (intermédiaire B12)12 - 3 - {[2- (4- (4-cyanophenyl) -3-oxopiperazino) acetyl] amino} ethyl propanoate (intermediate B12)
A une suspension de l'acide 2-[4-(4-cyanophényl)-3- oxopipérazinojacétique (exemple 2b) (2,59g, 10 mmoles), et de la N- méthylmorpholine (2,1 g, 20 mmoles) dans 30 ml de tétrahydrofuranne, est ajouté le chloroformiate d'isobutyle (1 ,39 g, 10 mmoles), puis le mélange est chauffé dans un bain de 40°C pendant 5 minutes; ensuite, le chlorhydrate du 3-
aminopropanoate d'éthyle (1 ,55 g, 10 mmoles) est ajouté. L'agitation est maintenue à température ambiante pendant 18 heures; on évapore le solvant et le résidu est purifié par flash chromatographie (dichlorométhane/methanol, 15/1 ) pour donner 1 ,7 g d'un solide blanc. Rendement = 48%.To a suspension of 2- [4- (4-cyanophenyl) -3- oxopiperazinojacetic acid (example 2b) (2.59 g, 10 mmol), and of N-methylmorpholine (2.1 g, 20 mmol) in 30 ml of tetrahydrofuran, isobutyl chloroformate (1.39 g, 10 mmol) is added, then the mixture is heated in a 40 ° C. bath for 5 minutes; then the 3- hydrochloride ethyl aminopropanoate (1.55 g, 10 mmol) is added. Stirring is maintained at room temperature for 18 hours; the solvent is evaporated off and the residue is purified by flash chromatography (dichloromethane / methanol, 15/1) to give 1.7 g of a white solid. Yield = 48%.
1 H-RMN (200MHz, CDCI3) : δ 1 ,25 (t, 3H), 2,6 (t, 2H), 2,95 (t, 2H), 3,15 (s, 1 H), 3,4 (s, 2H), 3,55 (dd, 2H), 3,8 (dd, 2H), 4,1 (q, 2H), 7,45 (bs, 1H), 7,5 (d, 2H), 7,7 (d, 2H).1 H-NMR (200MHz, CDCI 3 ): δ 1.25 (t, 3H), 2.6 (t, 2H), 2.95 (t, 2H), 3.15 (s, 1H), 3 , 4 (s, 2H), 3.55 (dd, 2H), 3.8 (dd, 2H), 4.1 (q, 2H), 7.45 (bs, 1H), 7.5 (d, 2H), 7.7 (d, 2H).
La méthode décrite en 12 a été utilisée pour préparer les produits intermédiaires suivants :The method described in 12 was used to prepare the following intermediate products:
13 - 3- [2-(4-(4-cyanophényl)-3-oxopipérazino)acétyl]amino}propanoate de benzyle (intermédiaire B13)13 - 3- [2- (4- (4-cyanophenyl) -3-oxopiperazino) acetyl] amino} benzyl propanoate (intermediate B13)
Produit de départ : le tosylate du 3-aminopropanoate de benzyle. Rendement = 69%.Starting material: benzyl 3-aminopropanoate tosylate. Yield = 69%.
1 H-RMN (200MHz, CDCI3) : δ 2,6 (t, 2H), 2,8 (t, 2H), 3,1 (s, 2H), 3,4 (s, 2H), 3,55 (q, 2H), 3,65 (dd, 2H), 5,1 (s, 2H), 7,3 (s, 5H), 7,4 (bs, 1 H), 7,45 (d, 2H), 7,6 (d, 2H).1 H-NMR (200MHz, CDCI3): δ 2.6 (t, 2H), 2.8 (t, 2H), 3.1 (s, 2H), 3.4 (s, 2H), 3.55 (q, 2H), 3.65 (dd, 2H), 5.1 (s, 2H), 7.3 (s, 5H), 7.4 (bs, 1H), 7.45 (d, 2H ), 7.6 (d, 2H).
14 - 3-{[2-(4-(4-cyanophényl)-3-oxopipérazino)acétyl]amino}-3-(1 ,3- benzodioxol-5-yl)propanoate d'éthyle (intermédiaire B14)14 - 3 - Ethyl {[2- (4- (4-cyanophenyl) -3-oxopiperazino) acetyl] amino} -3- (1, 3-benzodioxol-5-yl) propanoate (intermediate B14)
Produit de départ : le chlorhydrate du 3-amino-3-(1 ,3-benzodioxol-5- yl)propanoate d'éthyle. Rendement = 48%.Starting product: ethyl 3-amino-3- (1,3-benzodioxol-5-yl) hydrochloride propanoate. Yield = 48%.
15 - 3-{[2-(4-(4-cyanophényl)-3-oxopipérazino)acétyl]amino}-3-(1 ,3- benzodioxol-5-yl)propanoate de benzyle (intermédiaire B15) Produit de départ : le tosylate du 3-amino-3-(1 ,3-benzodioxol-5-yl)propanoate de benzyle. Rendement = 48%.
EXEMPLE 115 - 3 - {[2- (4- (4-cyanophenyl) -3-oxopiperazino) acetyl] amino} -3- (1,3-benzodioxol-5-yl) benzyl propanoate (intermediate B15) Starting material: benzyl 3-amino-3- (1,3-benzodioxol-5-yl) propanoate tosylate. Yield = 48%. EXAMPLE 1
3-{[2-(4-{4-[amino(hydroxyimino)méthyl]phényl}-2- oxopipérazino)acétyl]amino} propanoate d'éthyle (CRL 42656) Un mélange de l'intermédiaire B1 , le 3-{[2-(4-(4-cyanophényl)-2- oxopipérazino)acétyl]amino}propanoate d'éthyle (6,2 g, 17,3 mmoles), de la triéthylamine (3,8 g, 37,6 mmoles) et de l'hydroxylamine chlorhydrate (2,5 g, 6 mmoles) dans 150 ml d'éthanol est chauffée à reflux pendant 3 heures. Après refroidissement, on filtre et rince à l'éthanol, sèche sous vide pour obtenir 5,2 g de cristaux blancs. Rendement = 77%.3 - {[2- (4- {4- [amino (hydroxyimino) methyl] phenyl} -2- oxopiperazino) acetyl] amino} ethyl propanoate (CRL 42656) A mixture of intermediate B1, 3- { [2- (4- (4-cyanophenyl) -2- oxopiperazino) acetyl] amino} ethyl propanoate (6.2 g, 17.3 mmol), triethylamine (3.8 g, 37.6 mmol) and hydroxylamine hydrochloride (2.5 g, 6 mmol) in 150 ml of ethanol is heated at reflux for 3 hours. After cooling, filtered and rinsed with ethanol, dried under vacuum to obtain 5.2 g of white crystals. Yield = 77%.
1 H-RMN (200MHz, CD3OD) : δ 1 ,25 (t, 3H), 2,55 (t, 2H), 3,45 (t, 2H), 3,58 (dd, 2H), 3,72 (dd, 2H), 4,0 (s, 2H), 4,1 (m, 4H), 7,0 (d, 2H), 7,6 (d, 2H). MS-CI m/z : 392 (M+H)+-1 H-NMR (200MHz, CD3OD): δ 1.25 (t, 3H), 2.55 (t, 2H), 3.45 (t, 2H), 3.58 (dd, 2H), 3.72 (dd, 2H), 4.0 (s, 2H), 4.1 (m, 4H), 7.0 (d, 2H), 7.6 (d, 2H). MS-CI m / z: 392 (M + H) + -
La méthode décrite dans l'exemple 1 a été utilisée pour préparer les produits suivants :The method described in Example 1 was used to prepare the following products:
EXEMPLE 2 3-{[2-(4-{4-[amino(hydroxyimino)méthyl]phényl}-2-oxopipérazino) acétyl]amino}propanoate de benzyleEXAMPLE 2 3 - Benzyl {[2- (4- {4- [amino (hydroxyimino) methyl] phenyl} -2-oxopiperazino) acetyl] amino} propanoate
Produit de départ : intermédiaire B2. Rendement = 71%.Starting material: intermediate B2. Yield = 71%.
1 H-RMN (200MHz, DMSO-dô) : δ 2'55 (t 2H)> 3>4 (m- 6H). 3-85 (s- 2 ). 4.° (s. 2H), 5,1 (s, 2H), 5,6 (s, 2H), 6,9 (d, 2H), 7,34 (m, 4H), 7,55 (d, 2H), 8,05 (t, 1 H), 9,35 (s, 1 H). 1 H-NMR (200MHz, DMSO-dô) : δ 2 '55 (t 2H )> 3 > 4 ( m - 6H ). 3 - 85 ( s - 2 ). 4. ° (s. 2H), 5.1 (s, 2H), 5.6 (s, 2H), 6.9 (d, 2H), 7.34 (m, 4H), 7.55 (d , 2H), 8.05 (t, 1H), 9.35 (s, 1H).
EXEMPLE 3EXAMPLE 3
3-{[2-(4-{4-[amino(hydroxyimino)méthyl]phényl}-2-oxopipérazino)acétyl] amino}-3-(1 ,3-benzodioxol-5-yl)propanoate d'éthyle (CRL42789)Ethyl 3 - {[2- (4- {4- [amino (hydroxyimino) methyl] phenyl} -2-oxopiperazino) acetyl] amino} -3- (1, 3-benzodioxol-5-yl) propanoate (CRL42789 )
Produit de départ : intermédiaire B3.Starting material: intermediate B3.
Rendement = 77%.Yield = 77%.
1 H-RMN (400MHz, DMSO-dβ) : δ 1 ,1 (t, 3H), 2,75 (dd, 2H), 3,4 (bs, 2H), 3,5
(bs, 2H), 3,9 (s, 2H), 4,0 (s, 4H), 5,15 (q, 1 H), 5,65 (s, 2H), 6,0 (s, 2H), 6,85 (m, 5H), 7,55 (d, 2H), 8,4 (d, 1 H), 9,4 (s, 1 H). MS-ES t77/z : 534 (M+Na)+- 1 H-NMR (400MHz, DMSO-dβ): δ 1, 1 (t, 3H), 2.75 (dd, 2H), 3.4 (bs, 2H), 3.5 (bs, 2H), 3.9 (s, 2H), 4.0 (s, 4H), 5.15 (q, 1H), 5.65 (s, 2H), 6.0 (s, 2H ), 6.85 (m, 5H), 7.55 (d, 2H), 8.4 (d, 1H), 9.4 (s, 1H). MS-ES t77 / z: 534 (M + Na) + -
EXEMPLE 4EXAMPLE 4
3-{[2-(4-{4-[amino(hydroxyimino)méthyl]phényl}-2-oxopipérazino) acétyl]amino}-3-(1 ,3-benzodioxol-5-yl)propanoate de benzyleBenzyl 3 - {[2- (4- {4- [amino (hydroxyimino) methyl] phenyl} -2-oxopiperazino) acetyl] amino} -3- (1,3-benzodioxol-5-yl) propanoate
Produit de départ : intermédiaire B4. Rendement = 73%. 1 H-RMN (400MHz, DMSO-d6) : δ 2,8 (dd, 2H), 3,45 (m, 2H), 3,5 (m, 2H), 3,8 (s, 2H), 4,0 (s, 2H), 5,0 (s, 2H), 5,1 (q, 1 H), 5,6 (s, 2H), 6,0 (s, 2H), 6,8 (dd, 2H), 6,9 (m, 3H), 7,3 (m, 5H), 7,55(d, 2H), 8,5 (d, 1 H), 9,4 (s, 1 H).Starting material: intermediate B4. Yield = 73%. 1 H-NMR (400MHz, DMSO-d 6 ): δ 2.8 (dd, 2H), 3.45 (m, 2H), 3.5 (m, 2H), 3.8 (s, 2H), 4.0 (s, 2H), 5.0 (s, 2H), 5.1 (q, 1H), 5.6 (s, 2H), 6.0 (s, 2H), 6.8 ( dd, 2H), 6.9 (m, 3H), 7.3 (m, 5H), 7.55 (d, 2H), 8.5 (d, 1H), 9.4 (s, 1H ).
EXEMPLE 5 3-{[2-(4- 4-[amino(hydroxyimino)méthyl]phényl}-2-oxopipérazino) acétyl]amino}-3-(pyridinyl)propanoate d'éthyle (CRL 42770)EXAMPLE 5 3 - {[2- (4- 4- [amino (hydroxyimino) methyl] phenyl} -2-oxopiperazino) acetyl] amino} -3- (pyridinyl) ethyl propanoate (CRL 42770)
Produit de départ : intermédiaire B5. Rendement = 72%. H-RMN (400MHz, DMSO-d6) : δ 1 ,15 (t, 3H), 3,0 (d, 2H), 3,45 (bs, 2H), 3,65 (bs, 2H), 4,0 (s, 2H), 4,05 (q, 2H), 4,1 (s, 2H), 5,4 (q, 1 H), 7,0 (d, 2H), 7,7 (d, 2H), 8,1 (dd, 1 H), 8,6 (bs, 1 H), 8,65 (d, 1 H), 8,8 (d, 1 H), 8,95 (s, 1 H), 9,15 (bs, 1 H), 9,25 (d, 1 H). MS-ES m/z : 469 (M+H)+-Starting material: intermediate B5. Yield = 72%. H-NMR (400MHz, DMSO-d 6 ): δ 1.15 (t, 3H), 3.0 (d, 2H), 3.45 (bs, 2H), 3.65 (bs, 2H), 4 , 0 (s, 2H), 4.05 (q, 2H), 4.1 (s, 2H), 5.4 (q, 1H), 7.0 (d, 2H), 7.7 (d , 2H), 8.1 (dd, 1H), 8.6 (bs, 1H), 8.65 (d, 1H), 8.8 (d, 1H), 8.95 (s, 1 H), 9.15 (bs, 1 H), 9.25 (d, 1 H). MS-ES m / z: 469 (M + H) + -
EXEMPLE 6EXAMPLE 6
3-{[2-(4- 4-[amino(hydroxyimino)méthyl]phényl}-2-oxopipérazino) acétyl]amino}-3-(pyridinyl)propanoate de benzyleBenzyl 3 - {[2- (4- 4- [amino (hydroxyimino) methyl] phenyl} -2-oxopiperazino) acetyl] amino} -3- (pyridinyl) propanoate
Produit de départ : intermédiaire B6. Rendement = 57%. 1 H-RMN (400MHz, DMSO-d6) : δ 2,9 (d, 2H), 3,5 (m, 4H), 3,85 (s, 2H), 4,0 (s,Starting material: intermediate B6. Yield = 57%. 1 H-NMR (400MHz, DMSO-d 6 ): δ 2.9 (d, 2H), 3.5 (m, 4H), 3.85 (s, 2H), 4.0 (s,
2H), 5,0 (s, 2H), 5,25 (q, 1 H), 5,6 (bs, 2H), 6,85 (d, 2H), 7,3 (m, 6H), 7,5 (d, 2H), 7,7 (d, 1 H), 8,4 (d, 1 H), 8,5 (s, 1 H), 8,6 (d, 1 H), 9,3 (s, 1 H).
EXEMPLE 72H), 5.0 (s, 2H), 5.25 (q, 1H), 5.6 (bs, 2H), 6.85 (d, 2H), 7.3 (m, 6H), 7 , 5 (d, 2H), 7.7 (d, 1H), 8.4 (d, 1H), 8.5 (s, 1H), 8.6 (d, 1H), 9, 3 (s, 1 H). EXAMPLE 7
3-{[2-(4-{4-[amino(hydroxyimino)méthyl]phényl}-2-oxopipérazino) acétyl]amino}-5-phénylpentanoate d'éthyle (CRL42903)Ethyl 3 - {[2- (4- {4- [amino (hydroxyimino) methyl] phenyl} -2-oxopiperazino) acetyl] amino} -5-phenylpentanoate (CRL42903)
Produit de départ : intermédiaire B7.Starting material: intermediate B7.
Rendement = 73%.Yield = 73%.
1 H-RMN (400MHz, DMSO-d6) : δ 1 ,2 (t, 3H), 1 ,75 (m, 2H), 2,45-2,7 (m, 4H), 1 H-NMR (400MHz, DMSO-d 6 ): δ 1, 2 (t, 3H), 1.75 (m, 2H), 2.45-2.7 (m, 4H),
3,5 (dd, 4H), 3,85 (s, 2H), 4,1 (m, 5H), 5,7 (s, 2H), 6,9 (d, 2H), 7,2 (m, 3H), 7,253.5 (dd, 4H), 3.85 (s, 2H), 4.1 (m, 5H), 5.7 (s, 2H), 6.9 (d, 2H), 7.2 (m , 3H), 7.25
(t, 2H), 7,6 (d, 2H), 7,95 (d, 1 H), 9,2 (s, 1H).(t, 2H), 7.6 (d, 2H), 7.95 (d, 1H), 9.2 (s, 1H).
MS-ES m/z : 518 (M+Na)+-MS-ES m / z: 518 (M + Na) + -
EXEMPLE 8EXAMPLE 8
3- [2-(4-{4-[amino(hydroxyimino)méthyl]phényl}-2-oxopipérazino) acétyl]amino}-3-cyclohexylpropanoate d'éthyle (CRL42933)3- [2- (4- {4- [amino (hydroxyimino) methyl] phenyl} -2-oxopiperazino) acetyl] amino} -3-ethyl cyclohexylpropanoate (CRL42933)
Produit de départ : intermédiaire B8. Rendement = 72%.Starting material: intermediate B8. Yield = 72%.
1 H-RMN (400MHz, DMSO-d6) : δ 0,9 (m, 2H), 1 ,1( m, 3H), 1 ,15 (t, 3H), 1 ,35 (m, 1 H), 1 ,6 (m, 5H), 2,3 (dd, 1 H), 2,5 (dd, 1H), 3,5 (m, 2H), 3,6 (m, 2H), 4,0 (m, 7H), 6,95 (d, 2H), 7,6 (d, 2H), 7,8( d, 1H), 9,4 (s, 1H). MS-ES m/z : 496 (M+Na)+-1 H-NMR (400MHz, DMSO-d 6 ): δ 0.9 (m, 2H), 1, 1 (m, 3H), 1.15 (t, 3H), 1.35 (m, 1H) , 1, 6 (m, 5H), 2.3 (dd, 1H), 2.5 (dd, 1H), 3.5 (m, 2H), 3.6 (m, 2H), 4.0 (m, 7H), 6.95 (d, 2H), 7.6 (d, 2H), 7.8 (d, 1H), 9.4 (s, 1H). MS-ES m / z: 496 (M + Na) + -
EXEMPLE 9EXAMPLE 9
3-{[2-(4- 4-[amino(hydroxyimino)méthyl]phényl}-2-oxopipérazino) acétyl]amino}-5-méthylhexanoate d'éthyle (CRL 42935)3 - {[2- (4- 4- [amino (hydroxyimino) methyl] phenyl} -2-oxopiperazino) acetyl] amino} -5-ethyl methylhexanoate (CRL 42935)
Produit de départ : intermédiaire B9. Rendement = 40% (pour les deux étapes).Starting material: intermediate B9. Yield = 40% (for the two stages).
1 H-RMN (400MHz, DMSO-d6) : δ 0,9 (t, 6H), 1 ,17 (t, 3H), 1 ,20 (m, 1 H), 1 ,4 (m, 1 H), 1 ,6 (m, 1 H), 2,4 (d, 2H), 3,4 (m, 2H), 3,5 (m, 2H), 3,8 (s, 2H), 4,0 (d, 2H), 4,1 (q, 2H), 4,18 (m, 1 H), 5,65 (s, 2H), 6,92 (d, 2H), 7,5 (d, 2H), 7,8 (d, 1 H), 9,35 (s, 1 H). MS-ES m/z : 470 (M+Na)+-
EXEMPLE 101 H-NMR (400MHz, DMSO-d 6 ): δ 0.9 (t, 6H), 1.17 (t, 3H), 1.20 (m, 1H), 1, 4 (m, 1H ), 1, 6 (m, 1H), 2.4 (d, 2H), 3.4 (m, 2H), 3.5 (m, 2H), 3.8 (s, 2H), 4, 0 (d, 2H), 4.1 (q, 2H), 4.18 (m, 1H), 5.65 (s, 2H), 6.92 (d, 2H), 7.5 (d, 2H), 7.8 (d, 1H), 9.35 (s, 1H). MS-ES m / z: 470 (M + Na) + - EXAMPLE 10
3-{[2-(4- 4-[amino(hydroxyimino)méthyl]phényl}-2-oxopipérazino) acétyl]amino}-4,4-diméthylpentanoate d'éthyle (CRL 42963) Produit de départ : intermédiaire B10.3 - {[2- (4- 4- [amino (hydroxyimino) methyl] phenyl} -2-oxopiperazino) acetyl] amino} -4,4-ethyl dimethylpentanoate (CRL 42963) Starting material: intermediate B10.
Rendement = 39% (pour les deux étapes).Yield = 39% (for the two stages).
1 H-RMN (400MHz, DMSO-d6) : δ 0,85 (s, 9H), 1 ,20 (t, 3H), 2,25 (dd, 1 H), 2,6 1 H-NMR (400MHz, DMSO-d 6 ): δ 0.85 (s, 9H), 1.20 (t, 3H), 2.25 (dd, 1H), 2.6
(dd, 1 H), 3,45 (m, 2H), 3,5 (m, 2H), 3,85 (s, 2H), 4,05 (m, 5H), 5,7 (s, 2H), 6,95(dd, 1H), 3.45 (m, 2H), 3.5 (m, 2H), 3.85 (s, 2H), 4.05 (m, 5H), 5.7 (s, 2H ), 6.95
(d, 2H), 7,6 (d, 2H), 7,85 (d, 1 H), 9,4 (s, 1 H). MS-ES m/z : 470 (M+Na)+-(d, 2H), 7.6 (d, 2H), 7.85 (d, 1H), 9.4 (s, 1H). MS-ES m / z: 470 (M + Na) + -
EXEMPLE 11EXAMPLE 11
3- [2-(4- 4-[amino(hydroxyimino)méthyl]phényl}-2-oxopipérazino) acétyl]amino}-4-méthylpentanoate d'éthyle (CRL 42965) Produit de départ : intermédiaire B1 1.3- [2- (4- 4- [amino (hydroxyimino) methyl] phenyl} -2-oxopiperazino) acetyl] amino} -4-ethyl methylpentanoate (CRL 42965) Starting material: intermediate B1 1.
Rendement = 36% (pour les deux étapes).Yield = 36% (for the two stages).
1 H-RMN (400MHz, DMSO-d6) : δ 0,85 (d, 6H), 1 ,2 (t, 3H), 1 ,75 (m, 1 H), 2,4 (dd, 1 H), 2,55 (dd, 1 H), 3,45 (m, 2H), 3,55 (m, 2H), 3,8 (s, 2H), 4,1 (m, 5H), 5,7 (s, 2H), 6,95 (d, 2H), 7,6 (d, 2H), 7,85 (d, 1 H), 9,45 (s, 1 H). MS-ES m/z : 456 (M+Na)+-1 H-NMR (400MHz, DMSO-d 6 ): δ 0.85 (d, 6H), 1, 2 (t, 3H), 1.75 (m, 1 H), 2.4 (dd, 1 H ), 2.55 (dd, 1H), 3.45 (m, 2H), 3.55 (m, 2H), 3.8 (s, 2H), 4.1 (m, 5H), 5, 7 (s, 2H), 6.95 (d, 2H), 7.6 (d, 2H), 7.85 (d, 1H), 9.45 (s, 1H). MS-ES m / z: 456 (M + Na) + -
EXEMPLE 12EXAMPLE 12
3- [2-(4-{4-[amino(hydroxyimino)méthyl]phényl}-3- oxopipérazino)acétyl]amino}propanoate d'éthyle (CRL 42655) Une solution de l'intermédiaire B12, le 3-{2-[4-(4-cyanophényl)-3- oxopipérazino)acétyl]amino}propanoate d'éthyle, (4,96 g, 13,9 mmoles), de la triéthylamine (2,9 g, 28,7 mmoles) et de l'hydroxylamine chlorhydrate (2 g, 28,8 mmoles) dans 200 ml d'éthanol, est chauffée à reflux pendant 4 heures, puis le solvant est éliminé sous vide. On ajoute environ 30 ml d'eau et la solution est saturée par du chlorure de sodium. On filtre et rince à l'eau froide, sèche sous vide pour obtenir 3 g de solide beige. Rendement = 55%. H-RMN (200MHz, DMSO-dô) : δ 1 ,10 (t, 3H), 2,75 (t, 2H), 3,0 (s, 2H), 3,2 (s,
2H), 3,25 (m, 4H), 3,65 (t, 2H), 4,0 (q, 2H), 5,75 (bs, 2H), 7,25 (d, 2H), 7,6 (d, 2H), 7,95 (bs, 1 H), 9,5 (s, 1 H). MS-ES m/z : 392 (M+H)+-3- [2- (4- {4- [amino (hydroxyimino) methyl] phenyl} -3- oxopiperazino) acetyl] amino} ethyl propanoate (CRL 42655) A solution of intermediate B12, 3- {2 - [4- (4-cyanophenyl) -3- oxopiperazino) acetyl] amino} ethyl propanoate, (4.96 g, 13.9 mmol), triethylamine (2.9 g, 28.7 mmol) and hydroxylamine hydrochloride (2 g, 28.8 mmol) in 200 ml of ethanol, is heated at reflux for 4 hours, then the solvent is removed in vacuo. About 30 ml of water are added and the solution is saturated with sodium chloride. It is filtered and rinsed with cold water, dried under vacuum to obtain 3 g of beige solid. Yield = 55%. H-NMR (200MHz, DMSO-dô): δ 1, 10 (t, 3H), 2.75 (t, 2H), 3.0 (s, 2H), 3.2 (s, 2H), 3.25 (m, 4H), 3.65 (t, 2H), 4.0 (q, 2H), 5.75 (bs, 2H), 7.25 (d, 2H), 7, 6 (d, 2H), 7.95 (bs, 1H), 9.5 (s, 1H). MS-ES m / z: 392 (M + H) + -
La méthode décrite dans l'exemple 12 a été utilisée pour préparer les produits suivants :The method described in Example 12 was used to prepare the following products:
EXEMPLE 13EXAMPLE 13
3- [2-(4-{4-[amino(hydroxyimino)méthyi]phényl}-3-oxopipérazino) acétyljamino} propanoate de benzyleBenzyl 3- [2- (4- {4- [amino (hydroxyimino) methyi] phenyl} -3-oxopiperazino) acetyljamino} propanoate
Produit de départ : intermédiaire B13. Rendement = 86%.Starting material: intermediate B13. Yield = 86%.
EXEMPLE 14 3-{[2-(4-{4-[amino(hydroxyimino)méthyl]phényl}-3-oxopipérazino) acétyl]amino}-3-(1 ,3-benzodioxol-5-yl)propanoate d'éthyle (CRL42838)EXAMPLE 14 3 - {{2- (4- {4- [amino (hydroxyimino) methyl] phenyl} -3-oxopiperazino) acetyl] amino} -3- (1, 3-benzodioxol-5-yl) propanoate (CRL42838)
Produit de départ : intermédiaire B14. Rendement = 71 %.Starting material: intermediate B14. Yield = 71%.
1 H-RMN (400MHz, DMSO-d6) : δ 1 ,1 (t, 3H), 2,8 (m, 4H), 3,1 (q, 2H), 3,35 (s, 2H), 3,75 (t, 2H), 4,0 (q, 2H), 5,2 (q, 1 H), 5,8 (s, 2H), 6,0 (s, 2H), 6,8 (dd, 2H), 7,0 (s, 1 H), 7,3 (d, 2H), 7,55 (d, 2H), 8,4 (d, 1 H), 9,65 (s, 1 H). MS-ES m/z : 534 (M+Na)+- 1 H-NMR (400MHz, DMSO-d 6 ): δ 1, 1 (t, 3H), 2.8 (m, 4H), 3.1 (q, 2H), 3.35 (s, 2H), 3.75 (t, 2H), 4.0 (q, 2H), 5.2 (q, 1H), 5.8 (s, 2H), 6.0 (s, 2H), 6.8 ( dd, 2H), 7.0 (s, 1H), 7.3 (d, 2H), 7.55 (d, 2H), 8.4 (d, 1H), 9.65 (s, 1 H). MS-ES m / z: 534 (M + Na) + -
EXEMPLE 15 3-{[2-(4-{4-amino(hydroxyimino)phényl}-3-oxopipérazino)acétyl]amino}-3- (1,3-benzodioxol-5-yl)propanoate de benzyleEXAMPLE 15 3 - {[2- (4- {4-amino (hydroxyimino) phenyl} -3-oxopiperazino) acetyl] amino} -3- (1,3-benzodioxol-5-yl) benzyl propanoate
Produit de départ : intermédiaire B15. Rendement = 92%.Starting material: intermediate B15. Yield = 92%.
EXEMPLE 16 acétate du 3-{[2-(4-{4-[amino(imino)méthyl]phényl}-2-oxopipérazino) acétyl]amino}propanoate d'éthyle (CRL 42673)EXAMPLE 16 3 - {[2- (4- {4- [amino (imino) methyl] phenyl} -2-oxopiperazino) acetyl] amino} ethyl acetate propanoate acetate (CRL 42673)
Le 3-{[2-(4-{4-[amino(hydroxyimino)méthyl]phényl}-2oxopipérazino)acétyl]
amino} propanoate d'éthyle (exemple 1 ) (2,88 g, 7,36 mmoles) est solubilisé dans 100 ml d'acide acétique, ensuite de l'anhydride acétique (1 ,5 g, 14,7 mmoles) et 0,5g de palladium sur charbon à 10% sont ajoutés. Le mélange est hydrogéné à température ambiante sous 50 psi pendant 3 heures. On filtre et évapore à sec sous vide pour obtenir une poudre, on ajoute de l'éther à la suspension ainsi obtenue et on filtre, on obtient 2,8 g d'une poudre légèrement rose qui est solubilisée dans 100 ml d'eau, traitée avec du charbon, et filtrée, le filtrat est lyophilisé pour donner 2,5 g d'un solide beige. Rendement = 78%. 1 H-RMN (400MHz, DMSO-dô) : δ 1 ,3 (t, 3H), 1 ,8 (s 3H), 3,4 (dd, 2H), 3,6 (t, 2H), 3,8 (t, 2H), 4,0 (d, 4H), 4,05 (q, 2H), 7,2 (d, 2H), 7,85 (d, 2H), 8,25 (bs, 1 H). MS-ES m/z : 376 (M+H)+ 3 - {[2- (4- {4- [amino (hydroxyimino) methyl] phenyl} -2oxopiperazino) acetyl] amino} ethyl propanoate (example 1) (2.88 g, 7.36 mmol) is dissolved in 100 ml of acetic acid, then acetic anhydride (1.5 g, 14.7 mmol) and 0 , 5 g of 10% palladium on charcoal are added. The mixture is hydrogenated at room temperature under 50 psi for 3 hours. Filtered and evaporated to dryness under vacuum to obtain a powder, ether is added to the suspension thus obtained and filtered, 2.8 g of a slightly pink powder are obtained which is dissolved in 100 ml of water, treated with charcoal, and filtered, the filtrate is lyophilized to give 2.5 g of a beige solid. Yield = 78%. 1 H-NMR (400MHz, DMSO-dô): δ 1, 3 (t, 3H), 1, 8 (s 3H), 3.4 (dd, 2H), 3.6 (t, 2H), 3, 8 (t, 2H), 4.0 (d, 4H), 4.05 (q, 2H), 7.2 (d, 2H), 7.85 (d, 2H), 8.25 (bs, 1 H). MS-ES m / z: 376 (M + H) +
La méthode décrite dans l'exemple 16 a été utilisée pour préparer les produits suivants (avec transformation de l'acétate en chlorhydrate pour les composés des exemples 17, 19, 28 et 30).The method described in Example 16 was used to prepare the following products (with transformation of acetate into hydrochloride for the compounds of Examples 17, 19, 28 and 30).
EXEMPLE 17 Chlorhydrate de l'acide 3-{[2-(4-{4-[amino(imino)méthyl]phényl}-2- oxopipérazino)acétyl]amino} propanoique (CRL 42674)EXAMPLE 17 3 - {[2- (4- {4- [amino (imino) methyl] phenyl} -2) oxopiperazino) acetyl] amino} propanoic acid hydrochloride (CRL 42674)
Produit de départ : exemple 2. Rendement = 88%.Starting material: example 2. Yield = 88%.
1 H-RMN (200MHz, DMSO-d6) : δ 2,35 (t, 2H), 3,25 (dd, 2H), 3,35-3,7 (m, 4H), 4,0 (d, 4H), 7,0 (d, 2H), 7,8 (d, 2H), 8,1 (bs, 1 H), 8,85 (bd, 2H), 9,05 (bs, 2H). MS-ES m/z : 348 (M+H)+ 1 H-NMR (200MHz, DMSO-d 6 ): δ 2.35 (t, 2H), 3.25 (dd, 2H), 3.35-3.7 (m, 4H), 4.0 (d , 4H), 7.0 (d, 2H), 7.8 (d, 2H), 8.1 (bs, 1H), 8.85 (bd, 2H), 9.05 (bs, 2H). MS-ES m / z: 348 (M + H) +
EXEMPLE 18EXAMPLE 18
Acétate du 3-{[2-(4-{4-[amino(imino)méthyl]phényl}-2-oxopipérazino)- acétyl]amino}-3-(1,3-benzodioxol-5-yl)propanoate d'éthyle (CRL42827)Acetate of 3 - {[2- (4- {4- [amino (imino) methyl] phenyl} -2-oxopiperazino) - acetyl] amino} -3- (1,3-benzodioxol-5-yl) propanoate ethyl (CRL42827)
Produit de départ : exemple 3.Starting material: example 3.
Rendement = 68%.Yield = 68%.
1 H-RMN (400MHz, DMSO-dβ) : δ 1 ,1 (t, 3H), 1 ,7 (s, 3H), 2,75 (dd, 2H), 3,5 (t,
2H), 3,7 (t, 2H), 4,0 (m, 6H), 5,2 (q, 1 H), 6,0 (s, 2H), 6,8 (dd, 1 H), 6,85 (d, 1 H), 6,9 (s, 1 H), 7,0 (d, 2H), 7,75 (d, 2H), 8,55 (d, 1 H). MS-ES m/z : 496 (M+H)+ 1 H-NMR (400MHz, DMSO-dβ): δ 1, 1 (t, 3H), 1, 7 (s, 3H), 2.75 (dd, 2H), 3.5 (t, 2H), 3.7 (t, 2H), 4.0 (m, 6H), 5.2 (q, 1H), 6.0 (s, 2H), 6.8 (dd, 1H), 6.85 (d, 1H), 6.9 (s, 1H), 7.0 (d, 2H), 7.75 (d, 2H), 8.55 (d, 1H). MS-ES m / z: 496 (M + H) +
EXEMPLE 19EXAMPLE 19
Chlorhydrate de l'acide 3-([2-(4-{4-[amino(imino)méthyl]phényl}-2- oxopipérazino)acétyl]amino}-3-(1,3-benzodioxol-5-yl)propanoique (CRL 42788)Acid hydrochloride 3 - ([2- (4- {4- [amino (imino) methyl] phenyl} -2- oxopiperazino) acetyl] amino} -3- (1,3-benzodioxol-5-yl) propanoic (CRL 42788)
Produit de départ : exemple 4. Rendement = 47%.Starting material: example 4. Yield = 47%.
1 H-RMN (400MHz, DMSO-de) : δ 2,65 (t, 2H), 3,5 (bs, 2H), 3,7 (bs, 2H), 4,05 (d, 4H), 5,2 (q, 1 H), 6,0 (s, 2H), 6,75 (d, 1H), 6,8 (d, 1 H), 6,9 (s, 1H), 7,05 (d, 2H), 7,8 (d, 2H), 8,7 (d, 1 H), 9,0 (bs, 2H), 9,1 (bs, 2H), 12,3 (bs, 1 H). MS-CI m/z : 468 (M+H)+ 1 H-NMR (400MHz, DMSO-de): δ 2.65 (t, 2H), 3.5 (bs, 2H), 3.7 (bs, 2H), 4.05 (d, 4H), 5 , 2 (q, 1H), 6.0 (s, 2H), 6.75 (d, 1H), 6.8 (d, 1H), 6.9 (s, 1H), 7.05 ( d, 2H), 7.8 (d, 2H), 8.7 (d, 1H), 9.0 (bs, 2H), 9.1 (bs, 2H), 12.3 (bs, 1H ). MS-CI m / z: 468 (M + H) +
EXEMPLE 20EXAMPLE 20
Acétate du 3-{[2-(4-{4-[amino(imino)méthyl]phényl}-2-oxopipérazino)- acétyl]amino}-3-(pyridinyl)propanoate d'éthyle (CRL 42828)Acetate of ethyl 3 - {[2- (4- {4- [amino (imino) methyl] phenyl} -2-oxopiperazino) - acetyl] amino} -3- (pyridinyl) propanoate (CRL 42828)
Produit de départ : exemple 5. Rendement = 75%.Starting material: example 5. Yield = 75%.
1 H-RMN (400MHz, DMSO-d6) : δ 1 ,1 (t, 3H), 1 ,75 (bs, 3H), 2,9 (d, 2H), 3,45 (bs, 2H), 3,7 (bs, 2H), 4,0 (m, 6H), 5,2 (q, 1 H), 7,0 (d, 2H), 7,4 (t, 1 H), 7,8 (bd, 3H), 8,45 (bs, 1 H), 8,5 (bs, 1 H), 8,8 (bd, 1 H). MS-ES m/z : 453 (M+H)+ 1 H-NMR (400MHz, DMSO-d 6 ): δ 1, 1 (t, 3H), 1.75 (bs, 3H), 2.9 (d, 2H), 3.45 (bs, 2H), 3.7 (bs, 2H), 4.0 (m, 6H), 5.2 (q, 1H), 7.0 (d, 2H), 7.4 (t, 1H), 7.8 (bd, 3H), 8.45 (bs, 1H), 8.5 (bs, 1H), 8.8 (bd, 1H). MS-ES m / z: 453 (M + H) +
EXEMPLE 21EXAMPLE 21
Acétate de l'acide 3-{[2-(4-{4-[amino(imino)méthyl]phényl}-2- oxopipérazino)acétyl]amino}-3-(pyridinyl)propanoique (CRL 42799)Acid 3 - {[2- (4- {4- [amino (imino) methyl] phenyl} -2- oxopiperazino) acetyl] amino} -3- (pyridinyl) propanoic acid (CRL 42799)
Produit de départ : exemple 6. Rendement = 67%.Starting material: example 6. Yield = 67%.
1 H-RMN (400MHz, DMSO-d6) : δ 1 ,9 (s, 6H), 2,65 (bs, 2H), 3,5 (bs, 2H), 3,7 (bs, 2H), 3,9 (d, 1 H), 4,05 (s, 2H), 4,2 (d, 1 H), 5,2 (bs, 1 H), 6,9 (d, 2H), 7,3 (dd, 1H), 7,7 (d, 2H), 7,75 (d, 1 H), 8,4 (bs, 2H), 8,55 (s, 1H), 9,4 (bd, 1H), 11 ,1 (bs,
2H). 1 H-NMR (400MHz, DMSO-d 6 ): δ 1, 9 (s, 6H), 2.65 (bs, 2H), 3.5 (bs, 2H), 3.7 (bs, 2H), 3.9 (d, 1H), 4.05 (s, 2H), 4.2 (d, 1H), 5.2 (bs, 1H), 6.9 (d, 2H), 7, 3 (dd, 1H), 7.7 (d, 2H), 7.75 (d, 1H), 8.4 (bs, 2H), 8.55 (s, 1H), 9.4 (bd, 1H), 11, 1 (bs, 2H).
MS-CI m/z : 425 (M+H)+ MS-CI m / z: 425 (M + H) +
EXEMPLE 22 Acétate du 3-{[2-(4-{4-[amino(imino)méthyl]phényl}-2- oxopipérazino)acétyl]amino}-5-phénylpentanoate d'éthyle (CRL 42904)EXAMPLE 22 Acetate of 3 - {[2- (4- {4- [amino (imino) methyl] phenyl} -2- oxopiperazino) acetyl] amino} -5-ethyl phenylpentanoate (CRL 42904)
Produit de départ : exemple 7. Rendement = 70%.Starting material: example 7. Yield = 70%.
1 H-RMN (400MHz, DMSO-d6) : δ 1 ,15 (t, 3H), 1 ,73 (s, 3H), 1 ,74 (m, 2H), 2,45 (m, 2H), 2,6 (m, 2H), 3,5 (m, 2H), 3,7 (m, 2H), 4,0 (m, 7H), 7,05 (d, 2H), 7,2 (m, 3H), 7,26 (t, 2H), 7,75 (d, 2H), 8,0 (d, 1H). MS-ES m/z : 480 (M+H)+ 1 H-NMR (400MHz, DMSO-d 6 ): δ 1.15 (t, 3H), 1.73 (s, 3H), 1.74 (m, 2H), 2.45 (m, 2H), 2.6 (m, 2H), 3.5 (m, 2H), 3.7 (m, 2H), 4.0 (m, 7H), 7.05 (d, 2H), 7.2 (m , 3H), 7.26 (t, 2H), 7.75 (d, 2H), 8.0 (d, 1H). MS-ES m / z: 480 (M + H) +
EXEMPLE 23 Acétate du 3-{[2-(4- 4-[amino(imino)méthyl]phényl}-2- oxopipérazino)acétyl]amino}-3-cyclohexylpropanoate d'éthyle(CRL 42932)EXAMPLE 23 Acetate of 3 - {[2- (4- 4- [amino (imino) methyl] phenyl} -2- oxopiperazino) acetyl] amino} -3-ethyl cyclohexylpropanoate (CRL 42932)
Produit de départ : exemple 8. Rendement = 62%.Starting material: example 8. Yield = 62%.
1 H-RMN (400MHz, D2O) : δ 1 ,05 (m, 2H), 1 ,25 (m, 3H), 1 ,3 (t, 3H), 1 ,5 (m, 1 H), 1 ,75 (m, 5H), 2,0 (s, 3H), 2,55 (dd, 1H), 2,8 (dd, 1H), 3,68 (m, 2H), 3,85 (m, 2H), 4,2 (m, 7H), 7,12 (d, 2H), 7,8 (d, 2H). MS-ES m/z : 458 (M+H)+ 1 H-NMR (400MHz, D 2 O): δ 1.05 (m, 2H), 1.25 (m, 3H), 1, 3 (t, 3H), 1.5 (m, 1H), 1.75 (m, 5H), 2.0 (s, 3H), 2.55 (dd, 1H), 2.8 (dd, 1H), 3.68 (m, 2H), 3.85 (m , 2H), 4.2 (m, 7H), 7.12 (d, 2H), 7.8 (d, 2H). MS-ES m / z: 458 (M + H) +
EXEMPLE 24 Acétate du 3-{[2-(4-{4-[amino(imino)méthyl]phényl}-2- oxopipérazino)acétyl]amino}-5-méthylhexanoate d'éthyle (CRL 42934)EXAMPLE 24 Acetate of 3 - {[2- (4- {4- [amino (imino) methyl] phenyl} -2- oxopiperazino) acetyl] amino} -5-ethyl methylhexanoate (CRL 42934)
Produit de départ : exemple 9. Rendement = 74%.Starting material: example 9. Yield = 74%.
1 H-RMN (400MHz, D2O) : δ 1 ,15 (t, 3H), 1 ,73 (s, 3H), 1 ,74 (m, 2H), 2,45 (m, 2H), 2,6 (m, 2H), 3,5 (m, 2H), 3,7 (m, 2H), 4,0 (m, 7H), 7,05 (d, 2H), 7,2 (m, 3H), 7,26 (t, 2H), 7,75 (d, 2H), 8,0 (d, 1 H). MS-ES m/z : 432 (M+H)+
EXEMPLE 251 H-NMR (400MHz, D 2 O): δ 1.15 (t, 3H), 1.73 (s, 3H), 1.74 (m, 2H), 2.45 (m, 2H), 2 , 6 (m, 2H), 3.5 (m, 2H), 3.7 (m, 2H), 4.0 (m, 7H), 7.05 (d, 2H), 7.2 (m, 3H), 7.26 (t, 2H), 7.75 (d, 2H), 8.0 (d, 1H). MS-ES m / z: 432 (M + H) + EXAMPLE 25
Acétate du 3-{[2-(4-{4-[amino(imino)méthyl]phényl}-2- oxopipérazino)acétyl]amino}-4,4-diméthylpentanoate d'éthyle (CRL 42964)Acetate of 3 - {[2- (4- {4- [amino (imino) methyl] phenyl} -2- oxopiperazino) acetyl] amino} -4,4-dimethylpentanoate (CRL 42964)
Produit de départ : exemple 10.Starting material: example 10.
Rendement = 74%.Yield = 74%.
1 H-RMN (400MHz, D2O) : δ 1 ,0 (s, 9H), 1 ,35 (t, 3H), 2,05 (s, 3H), 2,5 (dd, 1 H),1 H-NMR (400MHz, D 2 O): δ 1, 0 (s, 9H), 1.35 (t, 3H), 2.05 (s, 3H), 2.5 (dd, 1 H),
2,85 (dd, 1 H), 3,7 (m, 2H), 3,85 (m, 2H), 4,2 (m, 7H), 7,15 (d, 2H), 7,8 (d, 2H).2.85 (dd, 1H), 3.7 (m, 2H), 3.85 (m, 2H), 4.2 (m, 7H), 7.15 (d, 2H), 7.8 ( d, 2H).
MS-ES m/z : 432 (M+H)+ MS-ES m / z: 432 (M + H) +
EXEMPLE 26EXAMPLE 26
Acétate du 3- [2-(4-{4-[amino(imino)méthyl]phényl}-2- oxopipérazino)acétyl]amino}-4-méthylpentanoate d'éthyle (CRL 42966) Produit de départ : exemple 11.Acetate of 3- [2- (4- {4- [amino (imino) methyl] phenyl} -2-oxopiperazino) acetyl] amino} -4-methyl methylpentanoate (CRL 42966) Starting product: Example 11.
Rendement = 100%.Yield = 100%.
1 H-RMN (400MHz, D2O) : δ 1 ,0 (t, 6H), 1 ,35 (t, 3H), 1 ,9 (m, 1 H), 2,0 (s, 3H),1 H-NMR (400MHz, D 2 O): δ 1, 0 (t, 6H), 1.35 (t, 3H), 1, 9 (m, 1H), 2.0 (s, 3H),
2,55 (dd, 1 H), 2,8 (dd, 1H), 3,7 (m, 2H), 3,8 (m, 1H), 4,2 (m, 7H), 7,1 (d, 2H),2.55 (dd, 1H), 2.8 (dd, 1H), 3.7 (m, 2H), 3.8 (m, 1H), 4.2 (m, 7H), 7.1 ( d, 2H),
7,8 (d, 2H). MS-ES m/z : 418 (M+H)+ 7.8 (d, 2H). MS-ES m / z: 418 (M + H) +
EXEMPLE 27EXAMPLE 27
Acétate du 3-{[2-(4-{4-[amino(imino)méthyl]phényl}-3-oxopipérazino) acétyljamino} propanoate d'éthyle (CRL 42672)Ethyl 3 - {[2- (4- {4- [amino (imino) methyl] phenyl} -3-oxopiperazino) acetyljamino} acetate propanoate acetate (CRL 42672)
Produit de départ : exemple 12.Starting material: example 12.
Rendement = 53%.Yield = 53%.
1 H-RMN (200MHz, DMSO-dô) : δ 1 ,2 (t, 3H), 1 ,75 (s, 3H), 2,5 (s, 2H), 2 ; 85 (s, 1 H-NMR (200 MHz, DMSO-d6): δ 1, 2 (t, 3H), 1.75 (s, 3H), 2.5 (s, 2H), 2; 85 (s,
2H), 3,3 (s, 4H), 3,8 (s, 2H), 4,05 (d, 2H), 7,6 (d, 2H), 7,8 (d, 2H), 8,1 (s, 1 H).
EXEMPLE 282H), 3.3 (s, 4H), 3.8 (s, 2H), 4.05 (d, 2H), 7.6 (d, 2H), 7.8 (d, 2H), 8, 1 (s, 1 H). EXAMPLE 28
Chlorhydrate de l'acide 3-{[2-(4-{4-[amino(imino)méthyl]phényl}-3- oxopipérazino)acétyl]amino} propanoique (CRL42675)3 - {[2- (4- {4- [amino (imino) methyl] phenyl} -3- oxopiperazino) acetyl] amino} propanoic acid hydrochloride (CRL42675)
Produit de départ : exemple 13.Starting material: example 13.
Rendement = 70%.Yield = 70%.
1 H-RMN (400MHz, DMSO-d6) : δ 2,25 (bs 2H), 2,5 (s, 2H), 2,8 (bs, 2H), 3,1 (s,1 H-NMR (400MHz, DMSO-d 6 ): δ 2.25 (bs 2H), 2.5 (s, 2H), 2.8 (bs, 2H), 3.1 (s,
2H), 3,3( m, 2H), 3,8 (bs, 2H), 7,55 (d, 2H), 7,65 (d, 2H), 8,2 (bs, 1H), 8,9 (bs,2H), 3.3 (m, 2H), 3.8 (bs, 2H), 7.55 (d, 2H), 7.65 (d, 2H), 8.2 (bs, 1H), 8, 9 (bs,
1 H).1 H).
MS-ES m/z : 370 (M+Na)+-MS-ES m / z: 370 (M + Na) + -
EXEMPLE 29EXAMPLE 29
Acétate du 3-{2-[4-(4-[amino(imino)méthyl]phényl}-3-oxopipérazino) acétyl]amino}-3-(1 ,3-benzodioxol-5-yl)propanoate d'éthyle (CRL42837)Ethyl 3- {2- [4- (4- [amino (imino) methyl] phenyl} -3-oxopiperazino) acetyl] amino} -3- acetate (1, 3-benzodioxol-5-yl) ethyl propanoate ( CRL42837)
Produit de départ : exemple 14. Rendement = 80%.Starting material: example 14. Yield = 80%.
1 H-RMN (400MHz, DMSO-dβ) : δ 1 ,1 (t, 3H), 1 ,75 (bs, 3H), 2,8 (m, 4H), 3,1 (q, 2H), 3,3 (s, 2H), 3,75 (bs, 2H), 4,0 (q, 2H), 5,2 (q, 1 H), 6,0 (s, 2H), 6,75 (m, 2H), 6,9 (s, 1 H), 7,55 (d, 2H), 7,8 (d, 2H), 8,45 (d, 1 H). MS-ES m/z : 496 (M+H)+ 1 H-NMR (400MHz, DMSO-dβ): δ 1, 1 (t, 3H), 1.75 (bs, 3H), 2.8 (m, 4H), 3.1 (q, 2H), 3 , 3 (s, 2H), 3.75 (bs, 2H), 4.0 (q, 2H), 5.2 (q, 1H), 6.0 (s, 2H), 6.75 (m , 2H), 6.9 (s, 1H), 7.55 (d, 2H), 7.8 (d, 2H), 8.45 (d, 1H). MS-ES m / z: 496 (M + H) +
EXEMPLE 30EXAMPLE 30
Chlorhydrate de l'acide 3-{[2-(4- 4-[amino(imino)méthyl]phényl}-3- oxopipérazino)acétyl]amino}-3-(1,3-benzodioxol-5-yl)propanoique (CRL42839)3 - {[2- (4- 4- [amino (imino) methyl] phenyl} -3- oxopiperazino) acetyl] amino} -3- (1,3-benzodioxol-5-yl) propanoic hydrochloride CRL42839)
Produit de départ : exemple 15.Starting material: example 15.
Rendement = 76%. H-RMN (400MHz, DMSO-d6) : δ 2,75 (m, 2H), 3,65 (bs, 2H), 4,1 (m, 6H), 5,2Yield = 76%. H-NMR (400MHz, DMSO-d 6 ): δ 2.75 (m, 2H), 3.65 (bs, 2H), 4.1 (m, 6H), 5.2
(q, 1 H), 5,95 (s, 2H), 6,8 (m, 2H), 7,0 (s, 1 H), 7,6 (d, 2H), 7,9 (d, 2H), 9,25 (s, 3H), 9,45 (s, 2H).(q, 1H), 5.95 (s, 2H), 6.8 (m, 2H), 7.0 (s, 1H), 7.6 (d, 2H), 7.9 (d, 2H), 9.25 (s, 3H), 9.45 (s, 2H).
MS-ES m/z : 468 (M+H)+
EXEMPLE 31MS-ES m / z: 468 (M + H) + EXAMPLE 31
3-({2-[4-(4-{amino[(éthoxycarbonyl)imino]méthyl}phényl)-2- oxopipérazino]acétyl}amino)-3-(1,3-benzodioxol-5-yl)propanoate d'éthyle (CRL42960) Le produit de l'exemple 18 est transformé en chlorhydrate par l'addition d'une solution d'acide chlorhydrique HCI 2N suivie de filtration.3 - ({2- [4- (4- {amino [(ethoxycarbonyl) imino] methyl} phenyl) -2- oxopiperazino] acetyl} amino) -3- (1,3-benzodioxol-5-yl) propanoate ethyl (CRL42960) The product of Example 18 is transformed into the hydrochloride by the addition of a hydrochloric acid solution HCl 2N followed by filtration.
A une solution du chlorhydrate ainsi obtenu (2,2 g, 4,1 mmoles) dans 50 ml de DMF, sont ajoutés successivement de la triéthylamine (1 ,1 g, 11 mmoles) et du chloroformiate d'éthyle (0,54 g, 5 mmoles) à 5°C. L'agitation est maintenue à température ambiante pendant 18 heures. On ajoute de l'eau et de l'acétate d'éthyle, la phase organique est lavée à l'eau, séchée sur du sulfate de sodium. On obtient 1 ,3 g d'un solide jaunâtre après chromatographie sur silice (acétate d'éthyle/méthanol, 10/1).To a solution of the hydrochloride thus obtained (2.2 g, 4.1 mmol) in 50 ml of DMF, are successively added triethylamine (1.1 g, 11 mmol) and ethyl chloroformate (0.54 g , 5 mmol) at 5 ° C. Stirring is continued at room temperature for 18 hours. Water and ethyl acetate are added, the organic phase is washed with water, dried over sodium sulfate. 1.3 g of a yellowish solid are obtained after chromatography on silica (ethyl acetate / methanol, 10/1).
Rendement = 55%. 1 H-RMN (400MHz, CDCI3) : δ 1 ,3 (t, 3H), 1 ,5 (t, 3H), 2,9 (dq, 2H), 3,75 (bs,Yield = 55%. 1 H-NMR (400MHz, CDCI 3 ): δ 1, 3 (t, 3H), 1, 5 (t, 3H), 2.9 (dq, 2H), 3.75 (bs,
4H), 4,2 (m, 6H), 4,4 (q, 2H), 5,45 (m, 1 H), 6,05 (d, 2H), 6,9 (m, 5H), 7,55 (d,4H), 4.2 (m, 6H), 4.4 (q, 2H), 5.45 (m, 1H), 6.05 (d, 2H), 6.9 (m, 5H), 7 , 55 (d,
1 H), 8,0 (d, 2H), 9,75 (bs, 1 H).1H), 8.0 (d, 2H), 9.75 (bs, 1H).
MS-ES m/z : 590 (M+Na)+ MS-ES m / z: 590 (M + Na) +
EXEMPLE 32EXAMPLE 32
3-{[2-(4-{4-[imino(pipéridino)méthyl]phényl}-2-oxopipérazino) acétyl]amino}-5-phénylpentanoate d'éthyle (CRL43101)Ethyl 3 - {[2- (4- {4- [imino (piperidino) methyl] phenyl} -2-oxopiperazino) acetyl] amino} -5-phenylpentanoate (CRL43101)
A un mélange du 3-{[2-(4-(4-cyanophényl)-2- oxopipérazino)acétyl]amino}-5-phénylpentanoate d'éthyle (intermédiaire B7) (3,3 g, 7..1 mmoles) dans 5 ml d'éthanol, sont ajoutés 60 ml d'une solution d'acétate d'éthyle chlorhydrique 4N à 5°C. L'agitation est maintenue à température ambiante pendant 40 heures. On évapore à sec pour obtenir un solide jaunâtre.To a mixture of ethyl 3 - {[2- (4- (4-cyanophenyl) -2-oxopiperazino) acetyl] amino} -5-phenylpentanoate (intermediate B7) (3.3 g, 7..1 mmol) 60 ml of a 4N hydrochloric ethyl acetate solution at 5 ° C. are added to 5 ml of ethanol. Stirring is maintained at room temperature for 40 hours. Evaporated to dryness to obtain a yellowish solid.
A une suspension de l'imidate obtenu ci-dessus (2,1 g, 3,8 mmoles) dans 10 ml d'éthanol et 50 ml d'acétate d'éthyle, est ajoutée de la pipéridine (2,6 g, 30,6 mmoles). Après 24 heures d'agitation à température ambiante, le mélange est filtré. Le produit brut est recristallisé dans un mélange d'acétate d'éthyle et d'éthanol pour donner 0,7 g d'un solide beige.
Rendement = 65%To a suspension of the imidate obtained above (2.1 g, 3.8 mmol) in 10 ml of ethanol and 50 ml of ethyl acetate is added piperidine (2.6 g, 30 , 6 mmol). After 24 hours of stirring at room temperature, the mixture is filtered. The crude product is recrystallized from a mixture of ethyl acetate and ethanol to give 0.7 g of a beige solid. Yield = 65%
1 H-RMN (400MHz, DMSO-d6) : δ 1 ,15 (t, 3H), 1 ,7 (m, 8H), 2,5 (m, 3H), 2,6 (m, 1 H), 3,45 (m, 1 H), 3,50 (bs, 4H), 3,70 (bs, 4H), 4,05 (m, 6H), 7,1 (d, 2H), 7,2 (m, 3H), 7,25 (d, 2H), 7,45 (d, 2H), 8,15 (d, 1 H), 9,2 (bs, 2H). MS-ES m/z : 548 (M+H)+ 1 H-NMR (400MHz, DMSO-d 6 ): δ 1.15 (t, 3H), 1.7 (m, 8H), 2.5 (m, 3H), 2.6 (m, 1H) , 3.45 (m, 1H), 3.50 (bs, 4H), 3.70 (bs, 4H), 4.05 (m, 6H), 7.1 (d, 2H), 7.2 (m, 3H), 7.25 (d, 2H), 7.45 (d, 2H), 8.15 (d, 1H), 9.2 (bs, 2H). MS-ES m / z: 548 (M + H) +
La méthode décrite dans l'exemple 32 a été utilisée pour préparer les produits suivants :The method described in Example 32 was used to prepare the following products:
EXEMPLE 33EXAMPLE 33
3-{[2-(4- 4-[imino(morpholino)méthyl]phényl}-2-oxopipérazino) acétyl]amino}-5-phénylpentanoate d'éthyle (CRL43102)3 - {[2- (4- 4- [imino (morpholino) methyl] phenyl} -2 ethyl oxopiperazino) acetyl] amino} -5-phenylpentanoate (CRL43102)
Produit de départ : intermédiaire B7 et morpholine Rendement = 56% 1 H-RMN (400MHz, DMSO-dβ) : δ 1 ,15 (t, 3H), 1 ,7 (m, 2H), 2,5 (m, 3H), 2,6 (m, 1 H), 3,50 (bs, 4H), 3,70 (m, 8H), 4,05 (m, 7H), 7,1 (d, 2H), 7,2 (m, 3H), 7,25 (d, 2H), 7,50 (d, 2H), 8,15 (d, 1 H), 9,4 (bs, 2H). MS-ES m/z : 550 (M+H)+ Starting product: intermediate B7 and morpholine Yield = 56% 1 H-NMR (400MHz, DMSO-dβ): δ 1.15 (t, 3H), 1.7 (m, 2H), 2.5 (m, 3H ), 2.6 (m, 1H), 3.50 (bs, 4H), 3.70 (m, 8H), 4.05 (m, 7H), 7.1 (d, 2H), 7, 2 (m, 3H), 7.25 (d, 2H), 7.50 (d, 2H), 8.15 (d, 1H), 9.4 (bs, 2H). MS-ES m / z: 550 (M + H) +
EXEMPLE 34EXAMPLE 34
Chlorhydrate du 3-(1,3-benzodioxol-5-yl)-3-{[2-(4-{4-3- (1,3-Benzodioxol-5-yl) -3 - {[2- (4- {4-
[imino(pipéridino)méthyl]phényl}-2-oxopipérazino)acétyl] amino}propanoate d'éthyle (CRL43103) Produit de départ : intermédiaire B3 et pipéridine Rendement = 61 % H-RMN (400MHz, DMSO-d6) : δ 1 ,15 (t, 3H), 1 ,65 (bs, 6H), 2,75 (m, 2H), 3,45 (m, 4H), 3,55 (m, 2H), 3,65 (bs, 2H), 4,00 (m, 6H), 5,15 (q, 1 H), 6,00 (s, 2H), 6,8 (d, 1 H), 6,85 (d, 1 H), 6,95 (s, 1 H), 7,05 (d, 2H), 7,45 (d, 2H), 8,7(d, 1 H), 9,15 (bs, 2H).[imino (piperidino) methyl] phenyl} -2-oxopiperazino) acetyl] amino} ethyl propanoate (CRL43103) Starting material: intermediate B3 and piperidine Yield = 61% H-NMR (400MHz, DMSO-d 6 ): δ 1.15 (t, 3H), 1.65 (bs, 6H), 2.75 (m, 2H), 3.45 (m, 4H), 3.55 (m, 2H), 3.65 (bs , 2H), 4.00 (m, 6H), 5.15 (q, 1H), 6.00 (s, 2H), 6.8 (d, 1H), 6.85 (d, 1H ), 6.95 (s, 1H), 7.05 (d, 2H), 7.45 (d, 2H), 8.7 (d, 1H), 9.15 (bs, 2H).
MS-ES m/z : 564 (M+H)+
EXEMPLE 35MS-ES m / z: 564 (M + H) + EXAMPLE 35
Chlorhydrate du 3-(1 ,3-benzodioxol-5-yl)-3-{[2-(4-{4-3- (1, 3-benzodioxol-5-yl) -3 - {[2- (4- {4-
[imino(morpholino)méthyl]phényl}-2-oxopipérazino)acétyl] amino}propanoate d'éthyle (CRL43104) Produit de départ : intermédiaire B3 et morpholine Rendement = 65%[imino (morpholino) methyl] phenyl} -2-oxopiperazino) acetyl] amino} ethyl propanoate (CRL43104) Starting material: intermediate B3 and morpholine Yield = 65%
1 H-RMN (400MHz, DMSO-d6) : δ 1 ,15 (t, 3H), 2,75 (m, 2H), 3,45 (m, 4H), 3,65 (m, 4H), 3,8 (bs, 4H), 4,00 (m, 6H), 5,15 (q, 1 H), 6,00 (s, 2H), 6,75 (d, 1 H), 6,80 (d, 1 H), 6,90 (s, 1 H), 7,05 (d, 2H), 7,45 (d, 2H), 8,65(d, 1 H), 9,30 (bs, 1 H), 9,35 (bs, 1 H). 1 H-NMR (400MHz, DMSO-d 6 ): δ 1.15 (t, 3H), 2.75 (m, 2H), 3.45 (m, 4H), 3.65 (m, 4H), 3.8 (bs, 4H), 4.00 (m, 6H), 5.15 (q, 1H), 6.00 (s, 2H), 6.75 (d, 1H), 6.80 (d, 1 H), 6.90 (s, 1 H), 7.05 (d, 2H), 7.45 (d, 2H), 8.65 (d, 1 H), 9.30 (bs , 1 H), 9.35 (bs, 1 H).
MS-ES m/z : 566 (M+H)+ MS-ES m / z: 566 (M + H) +
L'étude de l'activité inhibitrice de l'agrégation plaquettaire des composés de formule I a été réalisée in vitro, c'est-à-dire par contact direct de solution de concentrations variables des composés avec des plaquettes fraîchement séparées d'un échantillon de sang total, prélevé dans des conditions standardisées, chez des animaux de laboratoire (cobaye) et chez des sujets humains en bonne santé n'ayant pas reçu de substances ou de médicaments pouvant interférer avec la coagulation du sang. L'activité anti- agrégante plaquettaire a été également étudiée ex vivo/vitro, c'est-à-dire après administration des substances revendiquées au cobaye pour mesurer l'intensité et la durée de l'action anti-agrégante induite par la fraction absorbée et circulant dans le sang du produit étudié.The study of the inhibitory activity of platelet aggregation of the compounds of formula I was carried out in vitro, that is to say by direct contact of solution of variable concentrations of the compounds with platelets freshly separated from a sample. whole blood, taken under standardized conditions, from laboratory animals (guinea pig) and from healthy human subjects who have not received substances or drugs which may interfere with blood clotting. The anti-aggregating activity of platelets has also been studied ex vivo / vitro, that is to say after administration of the substances claimed in the guinea pig to measure the intensity and the duration of the anti-aggregating action induced by the absorbed fraction. and circulating in the blood of the product studied.
1. Etudes pharmacoloqiques in vitro1. In vitro pharmacological studies
1 .1. Etudes sur plaquettes de cobaye1 .1. Guinea pig wafer studies
Du sang est prélevé par ponction intracardiaque sur des cobayes Dunkin-Hartley de sexe mâle (poids 330 g environ), à raison de 4,5 ml pour 0,5 ml de citrate trisodique (concentration de la solution aqueuse : 1 ,55 %) afin de
prévenir toute trace de coagulation. Le plasma riche en plaquettes (PRP) est obtenu par centrifugation des tubes de sang total 15 minutes à 150 g.Blood is taken by intracardiac puncture from male Dunkin-Hartley guinea pigs (weight about 330 g), at the rate of 4.5 ml per 0.5 ml of trisodium citrate (concentration of the aqueous solution: 1.55%). in order to prevent any trace of coagulation. Platelet rich plasma (PRP) is obtained by centrifuging whole blood tubes for 15 minutes at 150 g.
Les PRP sont rassemblés en "pools". Une numération des plaquettes contenues dans ces pools est pratiquée à l'aide d'un automate d'hématologie de type Coulter ZM : si nécessaire, une dilution est réalisée afin que la concentration du plasma en plaquettes soit comprise entre 200 000 et 400 000 plaquettes/mm3. Simultanément, d'autres échantillons de ces pools servent à préparer du plasma pauvre en plaquettes (PPP) par centrifugation à 1 500 g pendant 15 minutes. L'étude cinétique de l'agrégation plaquettaire est réalisée par addition d'une solution de collagène ( 1 μg/ml) à un volume de PRP, à l'aide d'un agrégomètre de type Chrono-log Corporation (490 - D^ ou 560 VS) qui utilise une détection optique de l'apparition du thrombus.The PRPs are grouped into "pools". A count of the platelets contained in these pools is performed using a Coulter ZM type hematology automat: if necessary, a dilution is carried out so that the concentration of plasma in platelets is between 200,000 and 400,000 platelets / mm 3 . Simultaneously, other samples from these pools are used to prepare platelet-poor plasma (PPP) by centrifugation at 1,500 g for 15 minutes. The kinetic study of platelet aggregation is carried out by adding a collagen solution (1 μg / ml) to a volume of PRP, using an aggregometer of the Chrono-log Corporation type (490 - D ^ or 560 VS) which uses optical detection of the appearance of the thrombus.
La détermination de la concentration inhibitrice 50 % (Cl^) est réalisée en additionnant à des échantillons des pools de PRP, un volume déterminé de solvant (référence contrôle) et des concentrations croissantes des composés : 1 ,5 xlO"8 M, 7 xlO"8 M, 1 ,5 x10'7 M, 3 x10"7 M, 7 x 10"7 M, 1 ,5 x 10-° M et 7 x 10-5 M. Les mesures de l'inhibition de l'agrégation sont faites après 3 minutes de contact à 37°C sous agitation.The determination of the inhibitory concentration 50% (Cl ^) is carried out by adding to samples of PRP pools, a determined volume of solvent (control reference) and increasing concentrations of the compounds: 1.5 x 10 8 M, 7 x 10 "8 M, 1.5 x 10 '7 M, 3 x 10 " 7 M, 7 x 10 "7 M, 1.5 x 10- ° M and 7 x 10 -5 M. Measures of inhibition of aggregation are done after 3 minutes of contact at 37 ° C with stirring.
1.2 Etude sur plaquettes humaines1.2 Study on human platelets
Chez un groupe d'une dizaine de sujets humains, d'âge homogène et en bonne santé, du sang veineux est prélevé par ponction dans une veine du pli du coude pour être recueilli dans un tube de verre contenant une solution aqueuse de citrate de sodium 0,129 M (1 volume de solution citratee pour 9 volumes de sang). Chaque tube est ensuite centrifugé une première fois à 20°C et 100 g pendant 15 minutes pour obtenir le plasma riche en plaquettes (PRP) ; après prélèvement de ce PRP, le tube est à nouveau centrifugé à 2 000 g pendant 15 minutes pour prélever cette fois le plasma pauvre en plaquettes (PPP).In a group of about ten human subjects, of homogeneous age and in good health, venous blood is taken by puncture in a vein of the elbow fold to be collected in a glass tube containing an aqueous solution of sodium citrate. 0.129 M (1 volume of citrate solution for 9 volumes of blood). Each tube is then centrifuged a first time at 20 ° C and 100 g for 15 minutes to obtain the platelet-rich plasma (PRP); after collection of this PRP, the tube is again centrifuged at 2000 g for 15 minutes to take this time the platelet-poor plasma (PPP).
Pour chaque échantillon identifié de PRP, une numération plaquettaire est réalisée à l'aide du compteur Coulter ZM. Chaque échantillon est alors utilisé pour étudier la variation de l'inhibition de l'agrégation
plaquettaire déclenchée par l'addition d'une solution glucosée de collagène Chromo-par-Reagent de Coultronics (utilisé à la concentration de 5 μg/ml) en fonction de l'addition de concentrations croissantes de chaque composé dans une gamme couvrant l'intervalle 10"8 M→IO"5 M (exemple de concentrations : 10 M, 5 x 10"7 M, 3 x10"7 M, 10-7M, 8 x10-° M, 4 x10-°M, 2 x10*M, 10*M, 5 x 10'5M, 10_5M). Au préalable, pour chaque composé, une solution aqueuse à 10_3M est préparée. Dans chaque série de mesure, est introduit un essai contrôle destiné à vérifier l'effet éventuel des solvants (valeur référence) sur l'agrégation plaquettaire qui est mesurée après 3 minutes de contact à 37°C sous agitation.For each identified PRP sample, a platelet count is performed using the Coulter ZM counter. Each sample is then used to study the variation in the inhibition of aggregation platelet triggered by the addition of a glucose collagen solution Chromo-par-Reagent from Coultronics (used at a concentration of 5 μg / ml) according to the addition of increasing concentrations of each compound in a range covering the interval 10 "8 M → IO " 5 M (example of concentrations: 10 M, 5 x 10 "7 M, 3 x10 " 7 M, 10- 7 M, 8 x10- ° M, 4 x10- ° M, 2 x10 * M, 10 * M, 5 x 10 '5 M, 10 _5 M). Beforehand, for each compound, an aqueous solution at 10 _3 M is prepared. In each measurement series, a control test is introduced intended to check the possible effect of the solvents (reference value) on the platelet aggregation which is measured after 3 minutes of contact at 37 ° C. with stirring.
A partir des pourcentages d'inhibition de l'agrégation plaquettaire mesurés pour chaque concentration de chaque composé, est calculée la concentration inhibitrice 50 % (Cl50).From the inhibition percentages of platelet aggregation measured for each concentration of each compound, the inhibitory concentration 50% (Cl 50 ) is calculated.
2. Etude pharmacoloqique ex vivolvitro chez le cobaye2. Pharmacological study ex vivolvitro in guinea pigs
L'évaluation de l'activité anti-agrégante plaquettaire des composés est réalisée chez les mêmes cobayes que ceux évoqués ci-dessus (souche Dunkin-Hartley). L'administration de chaque produit dans une gamme de doses qui va de 150 à 10 mg/kg et de chaque véhicule (5 ml/kg) est faite par voie gastrique (v.g.) 1 h ou 2h ou 4h ou 6h ou 8h ou 12h avant le prélèvement de sang chez les cobayes mis à jeun la veille. L'allocation des traitements aux animaux est aléatoire.The evaluation of the anti-platelet aggregation activity of the compounds is carried out in the same guinea pigs as those mentioned above (Dunkin-Hartley strain). The administration of each product in a dose range which goes from 150 to 10 mg / kg and of each vehicle (5 ml / kg) is made by gastric route (vg) 1 h or 2 h or 4 h or 6 h or 8 h or 12 h before drawing blood from guinea pigs fasted the day before. The allocation of treatments to animals is random.
Le sang est prélevé puis traité dans les mêmes conditions que celles décrites ci-dessus pour les études in vitro. Les résultats de l'inhibition de l'agrégation plaquettaire obtenus pour chaque concentration essayée, permettent de calculer la concentration Cl50 de chaque produit essayé et la cinétique de l'effet inhibiteur, leur durée d'action.
Les résultats des études de l'inhibition de l'agrégation plaquettaire induite par le collagène sont rassemblés dans le tableau suivant :The blood is taken and then treated under the same conditions as those described above for the in vitro studies. The results of the inhibition of platelet aggregation obtained for each concentration tested, make it possible to calculate the Cl 50 concentration of each product tested and the kinetics of the inhibitory effect, their duration of action. The results of studies on the inhibition of platelet aggregation induced by collagen are collated in the following table:
ND : non déterminable (produit insoluble) - : donnée non disponible.
Pour certains composés, la puissance de l'activité inhibitrice de l'agrégation plaquettaire est retrouvée à des doses beaucoup plus basses. C'est par exemple le cas pour le CRL 42789, le CRL 42788 et le CRL 42 903 pour lesquels l'action anti-agrégante, obtenue ex vivo chez le cobaye traité par une dose orale (voie gastrique) de 10 mg/kg, lorsque l'administration est réalisée 1h et 2h avant le test d'agrégation, est de 69 et 72 % (CRL 42789), 57 et 24 % (CRL 42788) ou 72 % (à 1 h pour le CRL 42903), respectivement.ND: not determinable (insoluble product) -: data not available. For certain compounds, the potency of the inhibitory activity of platelet aggregation is found at much lower doses. This is for example the case for CRL 42789, CRL 42788 and CRL 42 903 for which the anti-aggregating action, obtained ex vivo in the guinea pig treated with an oral dose (gastric route) of 10 mg / kg, when the administration is carried out 1 hour and 2 hours before the aggregation test, is 69 and 72% (CRL 42789), 57 and 24% (CRL 42788) or 72% (at 1 hour for CRL 42903), respectively.
La présente invention a donc également pour objet des compositions pharmaceutiques comprenant une quantité efficace d'un composé de formule I ou d'un de ses sels avec des acides pharmaceutiquement acceptables.The present invention therefore also relates to pharmaceutical compositions comprising an effective amount of a compound of formula I or of a salt thereof with pharmaceutically acceptable acids.
Elle a plus particulièrement pour objet des compositions pour inhiber l'agrégation des plaquettes sanguines comprenant une quantité efficace d'un de ces composés. Elle a également pour objetIt relates more particularly to compositions for inhibiting the aggregation of blood platelets comprising an effective amount of one of these compounds. Its purpose is also
- un procédé pour inhiber la fixation du fibrinogène sur les plaquettes sanguines chez un mammifère comprenant l'administration à ce mammifère d'une quantité efficace d'un de ces composés ;a method for inhibiting the binding of fibrinogen to blood platelets in a mammal comprising the administration to this mammal of an effective amount of one of these compounds;
- un procédé pour inhiber l'aggrégation des plaquettes sanguines chez un patient comprenant l'administration à ce patient d'une quantité efficace d'un de ces composés ;a method for inhibiting the aggregation of blood platelets in a patient comprising the administration to this patient of an effective amount of one of these compounds;
- un procédé pour traiter une thrombose chez un patient comprenant l'administration à ce patient d'une quantité efficace d'un de ces composés ; - un procédé de prévention du risque thrombotique chez un patient comprenant l'administration à ce patient d'une quantité efficace d'un de ces composés.a method for treating a thrombosis in a patient comprising the administration to this patient of an effective amount of one of these compounds; - A method for preventing the thrombotic risk in a patient comprising the administration to this patient of an effective amount of one of these compounds.
Les composés de formule I peuvent être utilisés, tout particulièrement dans les domaines suivants : i) Prévention aiguë du risque thrombotique artériel au cours de la chirurgie cardiaque (pontage coronarien) ou de la cardiologie interventionnelle (angioplastie percutanée transluminale, endartectomie, pose de "stent") : dans
ces situations, les composés sont ajoutés au traitement préventif reconnu du risque thrombotique artériel ; administration orale d'acide acétylsalicylique démarrant avant l'intervention (150 à 500 mg/j per os) puis se poursuivant ensuite ; perfusion intraveineuse d'héparine non fractionnée démarrée pendant l'intervention puis se poursuivant pendant 48 à 96 heures. L'administration du composé de formule I peut alors se faire soit par voie orale (0,5 à 1 ,5 mg/kg) en même temps que l'administration d'aspirine, soit par perfusion intraveineuse (0,25 à 1 mg/kg/24 h) associée ou non à un bolus. Après la 48è e heure, si le traitement a été administré par voie intraveineuse, il sera relayé par l'administration orale (0,25 à 10 mg/kg en deux prises espacées de 12 heures) afin de faciliter les soins en hospitalisation puis en traitement ambulatoire. ii) Prophylaxie secondaire du risque thrombotique artériel chez les patients pouvant présenter des épisodes d'angor instable ou un infarctus du myocarde : dans ces situations, la biodisponibilité importante des composés revendiqués, c'est-à-dire la possibilité d'obtenir rapidement des concentrations circulantes efficaces car capables d'inhiber la fixation du fibrinogène sur les plaquettes permet d'utiliser les médicaments revendiqués par la voie orale pendant la période où les patients présentent ce risque de thrombose artérielle. Dans ces situations, ces composés pourront être administrés avantageusement à raison de 1 à 3 prises orales par jour, grâce à leur biodisponibilité élevée et leur longue durée d'action, la dose étant choisie dans la gamme 0,5-10 mg/kg.The compounds of formula I can be used, in particular in the following fields: i) Acute prevention of the arterial thrombotic risk during cardiac surgery (coronary bypass) or interventional cardiology (percutaneous transluminal angioplasty, endartectomy, placement of "stent ") : in these situations, the compounds are added to the recognized preventive treatment of the arterial thrombotic risk; oral administration of acetylsalicylic acid starting before the intervention (150 to 500 mg / d per os) then continuing thereafter; intravenous infusion of unfractionated heparin started during the intervention and then continued for 48 to 96 hours. The administration of the compound of formula I can then be done either orally (0.5 to 1.5 mg / kg) at the same time as the administration of aspirin, or by intravenous infusion (0.25 to 1 mg / kg / 24 h) associated or not with a bolus. After the 48th th hour, if the treatment was administered intravenously, it will be relayed by the oral administration (0.25 to 10 mg / kg in two 12-hour dosing interval) to facilitate the hospitalization care and then in outpatient treatment. ii) Secondary prophylaxis of arterial thrombotic risk in patients who may have episodes of unstable angina or myocardial infarction: in these situations, the significant bioavailability of the claimed compounds, i.e. the possibility of obtaining rapidly effective circulating concentrations since they are capable of inhibiting the binding of fibrinogen to the platelets makes it possible to use the drugs claimed by the oral route during the period when patients present this risk of arterial thrombosis. In these situations, these compounds may advantageously be administered at the rate of 1 to 3 oral intakes per day, thanks to their high bioavailability and their long duration of action, the dose being chosen from the range 0.5-10 mg / kg.
Les compositions pharmaceutiques qui comprennent l'un des principes actifs décrits dans la présente demande incorporent la substance active soit sous forme de base, soit sous forme de sel pharmaceutiquement acceptable, soit encore sous la forme d'une pro-drogue comprenant une ou plusieurs fonctions protégées, fonctions qui sont ensuite libérées in vivo après administration orale. Ces compositions pharmaceutiques incorporent les adjuvants de fabrication, les véhicules qui sont connus de l'homme de l'art. Ceux-ci sont choisis parmi la panoplie des outils galéniques reconnus par les Pharmacopées. Comme exemples, peuvent être mentionnés pour la préparation des formes galéniques destinées à la voie orale : amidon, stéarate de magnésium, talc, gélatine, agar, pectine, lactose, polyéthylène-glycols, etc.. Les formes galéniques utilisables seront choisies parmi les propositions
suivantes : comprimés sécables ou non, gélules, lyocs, granulés, poudres. Selon les caractéristiques de la pathologie à traiter et la morphologie de chaque patient, la posologie orale quotidienne sera comprise entre 0,02 et 50 mg/kg/jour en 1 à 3 prises régulièrement espacées afin de maintenir un taux d'occupation efficace des récepteurs Gpllb/llla plaquettaires. Pour la voie intraveineuse, les formes pharmaceutiques destinées à la phase aiguë du traitement sont conçues de manière à permettre une adaptation posologique individuelle sur la base de l'inhibition de l'agrégation plaquettaire la plus efficace en fonction de l'évolution immédiate des suites opératoires. Dans ce cadre, le lyophilisât, le soluté pour perfusion prêt à l'emploi, permettent de moduler individuellement la posologie dans l'intervalle de dose 0,01 mg/kg/jour - 20 mg/kg/jour.
The pharmaceutical compositions which comprise one of the active principles described in the present application incorporate the active substance either in the form of the base, or in the form of a pharmaceutically acceptable salt, or also in the form of a pro-drug comprising one or more functions protected, functions which are then released in vivo after oral administration. These pharmaceutical compositions incorporate manufacturing aids, vehicles which are known to those skilled in the art. These are chosen from the panoply of pharmaceutical tools recognized by the Pharmacopoeias. As examples, may be mentioned for the preparation of the dosage forms intended for the oral route: starch, magnesium stearate, talc, gelatin, agar, pectin, lactose, polyethylene glycols, etc. The dosage forms usable will be chosen from the proposals following: breakable tablets or not, capsules, lyocs, granules, powders. Depending on the characteristics of the pathology to be treated and the morphology of each patient, the daily oral dosage will be between 0.02 and 50 mg / kg / day in 1 to 3 doses regularly spaced to maintain an effective occupancy rate of receptors Gpllb / llla platelet. For the intravenous route, the pharmaceutical forms intended for the acute phase of treatment are designed so as to allow an individual dosage adjustment on the basis of the inhibition of the most effective platelet aggregation as a function of the immediate evolution of the operative suites. . In this context, the lyophilisate, the ready-to-use solution for infusion, allows the dosage to be individually adjusted in the dose range 0.01 mg / kg / day - 20 mg / kg / day.
Claims
1. Composés de formule générale (I) :1. Compounds of general formula (I):
dans laquelle :in which :
R est choisi parmi l'hydrogène, un groupe alkyle en C^O, ou phényl (alkyle en C^C ;R is selected from hydrogen, a C ^ O alkyl group, or phenyl (C ^ C alkyl;
R2 est choisi parmi l'hydrogène, le groupe hydroxyle et un groupe protecteur du groupe amidino ; R3 est choisi parmiR 2 is chosen from hydrogen, the hydroxyl group and a protective group from the amidino group; R 3 is chosen from
- l'hydrogène,- hydrogen,
- les groupes alkyle en C Cs, cycloalkyle mono ou bicyclique en C3-C12, alkényle en C2-C4 ou alkynyle en C2-C4, ces groupes étant éventuellement substitués par des groupes choisis parmi les halogènes et le groupe hydroxy ;- alkyl, C -C cycloalkyl, mono or bicyclic C 3 -C 12 alkenyl, C 2 -C 4 alkynyl or C 2 -C 4 alkyl, these groups being optionally substituted by groups selected from halogen and the group hydroxy;
- les groupes aryle mono, bi ou tricycliques en C6-C14,- mono, bi or tricyclic C 6 -C 14 aryl groups,
- les groupes hétéroaryle choisis parmi les groupes pyridyle, thiényle, furannyle, quinolyle, benzodioxannyle, benzodioxolyle, benzothiényle, benzofurannyle et pyrazinyle ; - les groupes phénylalkyle(C1-C4), naphtylalkyle(CrC4) éventuellement substitués sur le noyau aryle, et pipéronyle,- heteroaryl groups chosen from pyridyl, thienyl, furannyl, quinolyl, benzodioxannyl, benzodioxolyl, benzothienyl, benzofuranyl and pyrazinyl groups; - phenylalkyl (C 1 -C 4 ), naphthylalkyl (C r C 4 ) groups optionally substituted on the aryl ring, and piperonyl,
R4 et R5 sont choisi indépendamment l'un de l'autre parmi l'hydrogène, un groupe alkyle en C^Cs, ou forment ensemble avec l'atome d'azote un groupe choisi parmi les groupes pipéridinyle et morpholinyle, les groupes aryle et hétéroaryle pouvant être substitués par un ou plusieurs groupes choisis indépendamment parmi les halogènes, les groupes alkyle en C1-C4, trifluorométhyle, alkyl(C1-C4)thio, alkyl(C1-C4)sulfonyle, alkyl(Cr
C4)oxy, nitro, les groupes -COOR, -CH2COOR ou -O-CH2-COOR, R étant un groupe alkyle en 0,-0-4, et le groupe oxo est en position 2 ou 3 sur la pipérazine ; et leurs sels d'addition avec des acides pharmaceutiquement acceptables. R 4 and R 5 are chosen independently of one another from hydrogen, a C 1 -C 6 alkyl group, or together form with the nitrogen atom a group chosen from piperidinyl and morpholinyl groups, groups aryl and heteroaryl which may be substituted by one or more groups independently chosen from halogens, C 1 -C 4 alkyl, trifluoromethyl, (C 1 -C 4 ) alkyl, thio, (C 1 -C 4 ) alkyl, sulfonyl, alkyl groups (C r C 4 ) oxy, nitro, the groups -COOR, -CH 2 COOR or -O-CH 2 -COOR, R being an alkyl group in 0, -0- 4 , and the oxo group is in position 2 or 3 on the piperazine; and their addition salts with pharmaceutically acceptable acids.
2. Composés selon la revendication 1 qui sont choisis parmi le 3-{[2-(4-{4-2. Compounds according to claim 1 which are chosen from 3 - {[2- (4- {4-
[amino(hydroxyimino)méthyl]phényl}-2-oxopipérazino)acétyl] amino}-3-(1 ,3- benzodioxol-5-yl)propanoate d'éthyle, le 3-{[2-(4-{4-[amino (hydroxyimino) methyl] phenyl} -2-oxopiperazino) acetyl] amino} -3- (1, 3-benzodioxol-5-yl) ethyl propanoate, 3 - {[2- (4- {4-
[amino(hydroxyimino)méthyl]phényl}-2-oxopipérazino) acétyl]amino}-5- phénylpentanoate d'éthyle, l'acide 3-{[2-(4-{4-[amino(imino)- méthyl]phényl}-2- oxopipérazino)acétyl]amino}-3-(1 ,3-benzodioxol-5-yl)- propanoique, et leurs sels d'addition avec des acides pharmaceutiquement acceptables.[amino (hydroxyimino) methyl] phenyl} -2-oxopiperazino) acetyl] amino} -5- ethyl phenylpentanoate, 3 - {[2- (4- {4- [amino (imino) - methyl] phenyl) acid } -2- oxopiperazino) acetyl] amino} -3- (1, 3-benzodioxol-5-yl) - propanoic, and their addition salts with pharmaceutically acceptable acids.
3. Procédé de préparation des composés de formule I selon la revendication 1 par a) réaction d'un acide de formule3. Process for the preparation of the compounds of formula I according to claim 1 by a) reaction of an acid of formula
OO
dans laquelle Z est un groupe précurseur d'un groupein which Z is a precursor group of a group
avec une amine de formule with an amine of formula
dans laquelle R^ est un groupe alkyle en CrC4 ou phényl(alkyle en C,-C4) pour obtenir un composé de formule
00/04000 36 in which R ^ is a C r C 4 alkyl or phenyl (C 1 -C 4 alkyl) group to obtain a compound of formula 04/04000 36
b) conversion du groupe Z en groupeb) conversion of group Z into group
et c) éventuellement conversion du groupe R en un atome d'hydrogène. and c) optionally converting the group R into a hydrogen atom.
4. Composition thérapeutique qui comprend à titre de principe actif un composé tel que défini à la revendication 1 ou à la revendication 2.4. Therapeutic composition which comprises, as active principle, a compound as defined in claim 1 or in claim 2.
5. Utilisation d'un composé tel que défini à la revendication 1 ou à la revendication 2 pour la fabrication d'un médicament antithrombotique.5. Use of a compound as defined in claim 1 or claim 2 for the manufacture of an antithrombotic drug.
6. Procédé pour inhiber la fixation du fibrinogène sur les plaquettes sanguines chez un mammifère, comprenant l'administration à ce mammifère d'une quantité efficace d'un composé selon la revendication 1 ou la revendication 2.6. A method for inhibiting the binding of fibrinogen to blood platelets in a mammal, comprising administering to said mammal an effective amount of a compound according to claim 1 or claim 2.
7. Procédé pour inhiber l'agrégation des plaquettes sanguines chez un patient, comprenant l'administration à ce patient d'une quantité efficace d'un composé selon la revendication 1 ou la revendication 2.7. A method for inhibiting the aggregation of blood platelets in a patient, comprising administering to that patient an effective amount of a compound according to claim 1 or claim 2.
8. Procédé pour traiter une thrombose chez un patient comprenant l'administration à ce patient d'une quantité efficace d'un composé selon la revendication 1 ou la revendication 2.8. A method for treating thrombosis in a patient comprising administering to that patient an effective amount of a compound according to claim 1 or claim 2.
9. Procédé de prévention du risque thrombotique chez un patient, comprenant l'administration à ce patient d'une quantité efficace d'un composé selon la revendication 1 ou la revendication 2.
9. A method of preventing the thrombotic risk in a patient, comprising administering to this patient an effective amount of a compound according to claim 1 or claim 2.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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FR9809168 | 1998-07-17 | ||
FR9809168A FR2781220B1 (en) | 1998-07-17 | 1998-07-17 | SUBSTITUTED BETA PIPERAZINONES |
PCT/FR1999/001747 WO2000004000A1 (en) | 1998-07-17 | 1999-07-16 | Piperazinone derivatives and their uses |
Publications (1)
Publication Number | Publication Date |
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EP1098888A1 true EP1098888A1 (en) | 2001-05-16 |
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Application Number | Title | Priority Date | Filing Date |
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EP99929496A Withdrawn EP1098888A1 (en) | 1998-07-17 | 1999-07-16 | Piperazinone derivatives and their uses |
Country Status (11)
Country | Link |
---|---|
US (1) | US6344456B1 (en) |
EP (1) | EP1098888A1 (en) |
JP (1) | JP2002520401A (en) |
CN (1) | CN1188402C (en) |
AU (1) | AU752632B2 (en) |
BR (1) | BR9912839A (en) |
CA (1) | CA2337849C (en) |
EA (1) | EA003511B1 (en) |
FR (1) | FR2781220B1 (en) |
NZ (1) | NZ509166A (en) |
WO (1) | WO2000004000A1 (en) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MXPA04009821A (en) * | 2002-04-08 | 2004-12-13 | Ranbaxy Lab Ltd | Carboximide derivatives as useful uro-selective alpha-1a adrenoceptor blockers. |
US20060247249A1 (en) * | 2005-11-16 | 2006-11-02 | Mohammad Salman | Carboximide derivatives as useful uro-selective alpha-1a adrenoceptor blockers |
KR100967171B1 (en) | 2007-12-26 | 2010-07-05 | 재단법인서울대학교산학협력재단 | ?5-2-oxopiperazine derivatives and solid-phase synthesis thereof |
US20140205566A1 (en) | 2012-11-30 | 2014-07-24 | Novartis Ag | Cyclic nucleuoside derivatives and uses thereof |
CN106860480A (en) * | 2017-02-13 | 2017-06-20 | 武汉贝纳科技服务有限公司 | A kind of blood platelet and the preparation method containing hematoblastic preparation |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE4234295A1 (en) * | 1992-10-12 | 1994-04-14 | Thomae Gmbh Dr K | Carboxylic acid derivatives, medicaments containing these compounds and process for their preparation |
DE4302485A1 (en) * | 1993-01-29 | 1994-08-04 | Merck Patent Gmbh | Piperazine derivatives |
-
1998
- 1998-07-17 FR FR9809168A patent/FR2781220B1/en not_active Expired - Fee Related
-
1999
- 1999-07-16 AU AU46291/99A patent/AU752632B2/en not_active Ceased
- 1999-07-16 CN CNB998087033A patent/CN1188402C/en not_active Expired - Fee Related
- 1999-07-16 EP EP99929496A patent/EP1098888A1/en not_active Withdrawn
- 1999-07-16 EA EA200100151A patent/EA003511B1/en not_active IP Right Cessation
- 1999-07-16 JP JP2000560107A patent/JP2002520401A/en active Pending
- 1999-07-16 NZ NZ509166A patent/NZ509166A/en unknown
- 1999-07-16 CA CA002337849A patent/CA2337849C/en not_active Expired - Fee Related
- 1999-07-16 BR BR9912839-0A patent/BR9912839A/en not_active Application Discontinuation
- 1999-07-16 US US09/743,411 patent/US6344456B1/en not_active Expired - Fee Related
- 1999-07-16 WO PCT/FR1999/001747 patent/WO2000004000A1/en not_active Application Discontinuation
Non-Patent Citations (1)
Title |
---|
See references of WO0004000A1 * |
Also Published As
Publication number | Publication date |
---|---|
BR9912839A (en) | 2001-06-05 |
EA003511B1 (en) | 2003-06-26 |
AU4629199A (en) | 2000-02-07 |
CA2337849A1 (en) | 2000-01-27 |
FR2781220B1 (en) | 2000-10-13 |
CN1188402C (en) | 2005-02-09 |
AU752632B2 (en) | 2002-09-26 |
FR2781220A1 (en) | 2000-01-21 |
JP2002520401A (en) | 2002-07-09 |
CA2337849C (en) | 2009-03-17 |
EA200100151A1 (en) | 2001-06-25 |
WO2000004000A1 (en) | 2000-01-27 |
NZ509166A (en) | 2004-01-30 |
US6344456B1 (en) | 2002-02-05 |
CN1309648A (en) | 2001-08-22 |
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