EP1098888A1 - Piperazinonen derivate und deren verwendungen - Google Patents

Piperazinonen derivate und deren verwendungen

Info

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Withdrawn
Application number
EP99929496A
Other languages
English (en)
French (fr)
Inventor
Christophe Yue
Marguerite Henry
Thierry Giboulot
Brigitte Lesur
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cephalon France SAS
Original Assignee
Laboratoire L Lafon SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Laboratoire L Lafon SA filed Critical Laboratoire L Lafon SA
Publication of EP1098888A1 publication Critical patent/EP1098888A1/de
Withdrawn legal-status Critical Current

Links

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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
EP99929496A 1998-07-17 1999-07-16 Piperazinonen derivate und deren verwendungen Withdrawn EP1098888A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9809168A FR2781220B1 (fr) 1998-07-17 1998-07-17 Piperazinones substituees en beta
FR9809168 1998-07-17
PCT/FR1999/001747 WO2000004000A1 (fr) 1998-07-17 1999-07-16 Derives de piperazinones et leurs applications

Publications (1)

Publication Number Publication Date
EP1098888A1 true EP1098888A1 (de) 2001-05-16

Family

ID=9528734

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99929496A Withdrawn EP1098888A1 (de) 1998-07-17 1999-07-16 Piperazinonen derivate und deren verwendungen

Country Status (11)

Country Link
US (1) US6344456B1 (de)
EP (1) EP1098888A1 (de)
JP (1) JP2002520401A (de)
CN (1) CN1188402C (de)
AU (1) AU752632B2 (de)
BR (1) BR9912839A (de)
CA (1) CA2337849C (de)
EA (1) EA003511B1 (de)
FR (1) FR2781220B1 (de)
NZ (1) NZ509166A (de)
WO (1) WO2000004000A1 (de)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EA200401335A1 (ru) * 2002-04-08 2006-02-24 Ранбакси Лабораторис Лимитед Производные карбоксимида в качестве уроселективных блокаторов альфа-1a адренорецепторов
US20060247249A1 (en) * 2005-11-16 2006-11-02 Mohammad Salman Carboximide derivatives as useful uro-selective alpha-1a adrenoceptor blockers
KR100967171B1 (ko) 2007-12-26 2010-07-05 재단법인서울대학교산학협력재단 Δ5-2-옥소피페라진 유도체 및 그의 고체상 합성 방법
US20140205566A1 (en) 2012-11-30 2014-07-24 Novartis Ag Cyclic nucleuoside derivatives and uses thereof
CN106860480A (zh) * 2017-02-13 2017-06-20 武汉贝纳科技服务有限公司 一种血小板及含有血小板的制剂的制备方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4234295A1 (de) * 1992-10-12 1994-04-14 Thomae Gmbh Dr K Carbonsäurederivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung
DE4302485A1 (de) * 1993-01-29 1994-08-04 Merck Patent Gmbh Piperazinderivate

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0004000A1 *

Also Published As

Publication number Publication date
AU4629199A (en) 2000-02-07
CA2337849A1 (en) 2000-01-27
FR2781220A1 (fr) 2000-01-21
NZ509166A (en) 2004-01-30
EA003511B1 (ru) 2003-06-26
WO2000004000A1 (fr) 2000-01-27
CA2337849C (en) 2009-03-17
AU752632B2 (en) 2002-09-26
EA200100151A1 (ru) 2001-06-25
CN1309648A (zh) 2001-08-22
JP2002520401A (ja) 2002-07-09
US6344456B1 (en) 2002-02-05
CN1188402C (zh) 2005-02-09
BR9912839A (pt) 2001-06-05
FR2781220B1 (fr) 2000-10-13

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