+

WO1996024583A1 - Nouveaux derives de benzamidine et leur composition medicinale - Google Patents

Nouveaux derives de benzamidine et leur composition medicinale Download PDF

Info

Publication number
WO1996024583A1
WO1996024583A1 PCT/JP1996/000274 JP9600274W WO9624583A1 WO 1996024583 A1 WO1996024583 A1 WO 1996024583A1 JP 9600274 W JP9600274 W JP 9600274W WO 9624583 A1 WO9624583 A1 WO 9624583A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
alkyl group
lower alkyl
salt
solvate
Prior art date
Application number
PCT/JP1996/000274
Other languages
English (en)
Japanese (ja)
Inventor
Seijiro Akamatsu
Yuzo Matsumoto
Masato Ichihara
Tomihisa Kawasaki
Seiji Kaku
Isao Yanagisawa
Original Assignee
Yamanouchi Pharmaceutical Co., Ltd.
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
Priority claimed from JP13787795A external-priority patent/JPH08333341A/ja
Application filed by Yamanouchi Pharmaceutical Co., Ltd. filed Critical Yamanouchi Pharmaceutical Co., Ltd.
Priority to EP96901968A priority Critical patent/EP0810215A4/fr
Priority to US08/875,702 priority patent/US5773442A/en
Priority to AU46332/96A priority patent/AU4633296A/en
Publication of WO1996024583A1 publication Critical patent/WO1996024583A1/fr

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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4

Definitions

  • the present invention relates to a novel benzamidine derivative or a salt thereof useful as a medicament, particularly a GPIb / la antagonist, and a pharmaceutical composition containing the compound.
  • Platelets have been discovered by Don ne in 1842 (CR Ac a d. Sci. (Paris) ⁇ , 336-368, 1842), a component in the blood that is necessary for hemostasis for a long time Has been treated as Today, platelets not only play a leading role in the hemostatic mechanism, but also the development of arteriosclerosis, which is attracting clinical attention, circulatory diseases including thrombotic diseases, cancer metastasis, inflammation, rejection after transplantation, and immune response It has been shown to be multifunctional, such as involvement, and thrombotic and ischemic diseases are being treated with drugs or physical methods to resume blood circulation.
  • PTCA therapy has rapidly spread to treatment of diseases based on coronary stenosis and aortic stenosis, such as angina pectoris and myocardial infarction, with some success.
  • this therapy damages vascular tissues including endothelial cells, causing acute coronary occlusion and restenosis that occurs in nearly 30% of patients treated.
  • Platelets play an important role in various thrombotic adverse effects (such as reocclusion) after such revascularization therapy. Therefore, the efficacy of antiplatelet agents is expected, but until the conventional antiplatelet agent proves to be effective enough. Has not been reached.
  • GPIbZBIa is a platelet membrane glycoprotein that is a member of the integrin family (Blood, 80, 1386-1404.1992). This integrin binds to adhesion proteins such as fibrinogen and von Willebrand factor and plays an important role at the very end of platelet aggregation.
  • Monoclonal antibodies against GPEb / EIa and peptide containing an RGD sequence have potent platelet aggregation inhibitory effects, some of which have already been tested in clinical trials.
  • Non-peptide, low molecular weight GPlIbZlEa antagonists are described in JP-A-4-288051, JP-A-6-25227, and LeO et al.
  • EP-A-542363 discloses a GPHbZHIa antagonist which can be orally administered, its oral activity is not sufficient, and a GP ⁇ which is more or less effective by oral administration is disclosed. There is a keen need for bZna antagonists.
  • the compound of the present invention is a novel benzamidine derivative which has a different structure from the compound described in the above patent, exhibits a strong GP lb / Ha antagonistic activity even in particular by oral administration, and has excellent sustained action. is there. Disclosure of the invention
  • the present inventors have conducted intensive studies on the above compounds exhibiting 0 to 1) 1113 antagonistic activity, and as a result, have created novel benzamidine derivatives, and have found that these compounds have good properties. The inventors have found that they have an antagonistic action, and have completed the present invention.
  • the present invention relates to a benzamidine derivative represented by the following general formula (I) or a salt thereof, and a pharmaceutical composition containing these compounds and a pharmaceutically acceptable carrier.
  • R] R 2 : the same or different, a hydrogen atom or an ester residue
  • X 2 a single bond or a lower alkylene group
  • n 0 or 1
  • the compound of the present invention has a structural feature in that it has two carboxylic acid residues on the piperidine ring and one or two oxo groups on the Z or piperazin ring, and has a favorable structure caused by the structure. It has oral activity and sustained action.
  • R ', R 2 are the same or different and each represents a hydrogen atom, or, lower pole alkyl group, lower pole Aruke group, a lower alkynyl group, Halogeno lower alkyl, cycloalkyl, phenyl, naphthyl, indolyl, benzyl, lower alkoxybenzyl, nitrobenzyl, benzhydryl, lower alkoxybenzhydryl, lower alkanoyloxy ⁇ alkyl group, lower alkenyloxy lower alkyl group, lower alkanol lower alkyl group, lower alkenoyl lower alkyl group, lower alkoxy lower alkanoyloxy lower alkyl group, lower alkoxy lower alkenyl lower alkyl group, lower ⁇ Alkoxy lower alkyl group, lower alkoxy lower alkoxy Lower alkyl group, cycloalkyloxycarbonyloxy lower alkyl group,
  • R ', R 2 are the same or different and each represents a hydrogen atom or a lower alkyl group, a lower alkenyl group, a halogeno-lower alkyl group, lower pole alkoxy lower alkyl group, lower pole alkoxy
  • a benzamidine derivative which is an ester residue selected from a cyclocarbonyloxy lower alkyl group, a phenyl group, a benzyl group or a lower alkoxybenzyl group, a salt thereof, a hydrate or a solvate thereof;
  • R 'and R 2 are the same or different and are a hydrogen atom or a lower dialkyl group, a benzamidine derivative, a salt thereof, a hydrate thereof or a solvate thereof;
  • a linear or branched alkylene group having 1 to 6 carbon atoms is preferable.
  • R 1 and / or R 2 is an ester residue itself becomes a drug as an active substance.
  • these compounds are useful as prodrugs which are metabolized in vivo to become active carboxylic acid compounds, and are also useful as intermediates for synthesizing carboxylic acid compounds. Therefore, the ⁇ ester residue '' in R ′ and R 2 includes an ester residue known to those skilled in the art that can be metabolized and hydrolyzed in vivo and serve as a protecting group for Z or carboxyl group. .
  • ester residues include, for example, lower alkyl groups, lower alkenyl groups, lower alkynyl groups, halogeno lower alkyl groups, cycloalkyl groups, phenyl groups, naphthyl groups, indolyl groups, benzyl groups, lower alkoxybenzyl groups Group, nitrobenzyl group, lower alkoxybenzhydryl group, benzhydryl group, lower alkanoyloxy lower alkyl group, lower alkenoyloxy lower alkyl group, lower alkanoyl lower alkyl group, lower alkenoyl lower alkyl group, lower alkoxy lower ⁇ Alkyloxy lower alkyl group, low ⁇ alkoxy lower alkoxy lower alkyl group, lower alkoxy lower alkyl group, lower alkoxy lower alkoxy lower alkyl group, cycloalkyloxycarbonyl lower alkyl group, Lower alkoxycarbonyloxy lower alkyl group, lower alkoxy lower alkoxy carbony
  • a lower alkyl group Preferable are a lower alkyl group, a lower alkenyl group, a halogeno lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxycarboxy lower alkyl group, a phenyl group, a benzyl group and a lower alkoxybenzyl group. Preferably, it is a lower alkyl group.
  • the “lower alkyl group” is a straight or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, and an isobutyl group.
  • the lower alkyl group substituted with various substituents represented as ester residues of R ′ and R 2 is a lower alkyl group in which any hydrogen atom of the lower alkyl group is substituted with each substituent. Show.
  • the “lower alkenyl group” is a linear or branched alkenyl group having 2 to 6 carbon atoms, specifically, a vinyl group, an aryl group, a 1-propenyl group, an isopropyl group, a 1-butenyl group.
  • a vinyl group specifically, an aryl group, a 1-propenyl group, an isopropyl group, a 1-butenyl group.
  • the “lower alkynyl group” is a straight-chain or branched alkynyl group having 2 to 6 carbon atoms, specifically, an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, a 2-alkynyl group. Petenyl, 3-petynyl, 1-methyl-2-propynyl, 1 One pentynyl group and the like can be mentioned.
  • halogeno lower alkyl group examples include groups in which one or more hydrogen atoms of the lower alkyl group have been replaced with a halogen atom consisting of a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Examples thereof include a chloromethyl group, a bromomethyl group, a fluoromethyl group, a trifluoromethyl group, a 1,1-dichloromethyl group, and a 1-chloro-2-bromoethyl group.
  • cycloalkyl group in the "cycloalkyl group” or the “cycloalkyloxycarbonyldialkyl group” is a cycloalkyl group having 3 to 8 carbon atoms, and is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, Examples include a cyclohexyl group and a cycloheptyl group.
  • a lower alkoxy group having the above-mentioned lower alkyl group for example, a methoxy group, an ethoxyquin group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butkin group, a pentyloxy (amylo) group; B) group, is
  • the ⁇ lower alkanoyl group '' in the ⁇ lower alkanoyl lower alkyl group j '', ⁇ lower alkanoyloxy lower alkyl group J '' or ⁇ lower alkoxy lower alkanoyloxy lower alkyl group '' is derived from a saturated aliphatic carboxylic acid.
  • Lower acetyl group having 2 to 6 carbon atoms for example, acetyl group, propionyl group, butyryl group, isobutyryl group, octyleryl group, isovaleryl group, vivaloyl group or hexanoyl group
  • Preferred are aryl groups and the like.
  • the “lower alkenyl lower alkyl group”, the “lower alkenyloxy lower alkyl group” or the “lower alkenyl group” in the “lower alkoxy lower alkenoyloxy lower alkyl group J” has 3 to 3 carbon atoms.
  • Six alkenoyl groups, for example, an acryloyl group, a crotonyl group, a maleoyl group and the like can be mentioned.
  • the “di-lower alkylamino group” in the “di-lower alkylamino lower alkyl group” means an amino group di-substituted by a specific group of the lower alkyl group, and specifically, for example, a dimethylamino group, a getylamino group, Examples thereof include symmetric or asymmetric di-lower alkylamino groups such as a mouth amino group, a diisopropylamino group, a dibutylamino group, a diisobutylamino group, an ethylmethylamino group, and a methylpropylamino group.
  • the compound of the present invention (I) At least one asymmetric carbon atom is present based on the presence of the piperidinyl group contained in the skeleton and the substituents thereof (the group represented by Formula 1 X 2 —COOR 2 ). Further, depending on the type of the substituent, the compound may have another asymmetric carbon atom.
  • the compound of the present invention has optical isomers based on these asymmetric carbon atoms. Further, there may be a tautomer based on the presence of a carbonyl group in the substituent or a geometric isomer based on a double bond.
  • the present invention includes all isolated forms or mixtures of these isomers.
  • the compound (I) of the present invention is preferably a salt capable of forming a salt.
  • a salt is preferably an alkali metal such as a sodium salt, a potassium salt or a calcium salt, or an alkaline earth.
  • Metal salts such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide; carbonates, nitrates, perchlorates, sulfates, phosphates, etc.
  • Inorganic acid salts such as methanesulfonate, trifluoromethanesulfonate and ethanesulfonate; arylsulfonic acids such as benzenesulfonate and p-toluenesulfonate Salts; organic acid salts such as acid salts, trifluoroacetates, fumarate salts, succinates, citrates, tartrate salts, oxalates and maleates; and amino acids such as glutamates and asbalaginates To It can gel.
  • the present invention also includes hydrates, various pharmaceutically acceptable solvates and polymorphs of the compound (I) of the present invention.
  • the compound (I) of the present invention can be produced by applying various production methods.
  • the typical manufacturing method is described below (
  • the compound (I) having an amidino group can be synthesized by the following methods (i), (ii) and (iii). .
  • Acetonitrile (ox) is treated with an alcohol such as methanol or ethanol at a temperature of TC to 0 ° C in the presence of hydrochloric acid gas in the presence of hydrochloric acid to form imidate, ammonia, ammonium carbonate, ammonium chloride, ammonium sulfate React with amines or amine salts such as methanol, ethanol, acetone, tetrahydrofuran and the like.
  • an alcohol such as methanol or ethanol at a temperature of TC to 0 ° C
  • hydrochloric acid gas in the presence of hydrochloric acid to form imidate, ammonia, ammonium carbonate, ammonium chloride, ammonium sulfate React with amines or amine salts such as methanol, ethanol, acetone, tetrahydrofuran and the like.
  • the nitrile form (I) is reacted with hydrogen sulfide in the presence of an organic base such as methylamine, triethylamine, pyridine or picoline to obtain a thioamide form.
  • This thioamide form can also be obtained by reacting the nitrile form ( ⁇ ) with 0,0-diethyl dithiophosphate in the presence of hydrogen chloride.
  • the above thioamide form is reacted with a low alkyl halide such as methyl iodide or thiolated iodide to form a thioimidate form, and then an amine or an amine salt such as ammonia, ammonium carbonate, ammonium chloride or ammonium tallowate is added.
  • a low alkyl halide such as methyl iodide or thiolated iodide
  • an amine or an amine salt such as ammonia, ammonium carbonate, ammonium chloride or ammonium
  • a reagent such as (CH 3 ) 2 NMgBr.
  • chloroform, methanol, ethanol, acetone, tetrahydrofuran, toluene, dimethylformamide and the like are used.
  • a base such as sodium hydride or an acid such as aluminum chloride or p-toluenesulfonic acid may sometimes significantly accelerate the reaction. The reaction can be carried out from cooling to room temperature to heating.
  • Carboxylic acid compounds in which R 1 and Z or R 2 are hydrogen atoms can be obtained by dissolving compound (I) in a suitable solvent and subjecting ordinary ester hydrolysis to basic, acidic, or neutral conditions. To be obtained.
  • ester residues that are susceptible to hydrolysis under acidic conditions for example, tertiary butyl group
  • ester residues that are susceptible to hydrolysis under base conditions for example, methyl ester, ethyl ester
  • acidic conditions for example, tertiary butyl group
  • base conditions for example, methyl ester, ethyl ester
  • a desired ester compound can be obtained.
  • the esterification reaction is appropriately selected according to a conventional method.
  • PC / JP In the compound of the present invention, a compound in which R ′ and Z or R 2 is an ester residue can also be produced from a suitable alcohol by transesterification.
  • an acid or base or other catalyst for example, titanium (W) alkoxide
  • Compound (la) is obtained by dissolving compound (Ha) in a suitable solvent, reacting with compound (IV) amine to form a Schiff base, and then reducing the Schiff base. This Schiff base may be isolated or reduced without isolation.
  • an organic solvent inert to the reaction for example, benzene, toluene, methanol, acetic acid and the like are used.
  • the compound (Ma) and the corresponding amount of the compound (IV) or one of the amines are used in a slight excess, preferably an acid catalyst such as p-toluenesulfonic acid, adipic acid, oxalic acid, pyridine hydrochloride, and acetic acid.
  • an acid catalyst such as p-toluenesulfonic acid, adipic acid, oxalic acid, pyridine hydrochloride, and acetic acid.
  • the compound (ffib) is prepared by dissolving the compound (V) in a suitable solvent, and reacting with a suitable secondary amine to form an enamine, and then reacting the enamine with an alkyl acrylate.
  • Enamine may or may not be isolated.
  • the compound represented by the general formula (VDI) is obtained by reacting a carboxylic acid (VI) with a halogenated fatty acid-protected carboxylic acid ester (eg, ethyl bromoacetate) in the presence of a base (eg, lithium carbonate) to give a compound (VII). And subjecting this compound (II) to dealkoxycarbonylation under appropriate conditions.
  • a halogenated fatty acid-protected carboxylic acid ester eg, ethyl bromoacetate
  • a base eg, lithium carbonate
  • one or two of A 1 to A 4 represent a carbonyl group, and the other represent a methylene group, and Y represents a halogen atom, a hydroxyl group, a lower alkoxy group, a phenoxy group, an imidazolyl group, an arylsulfonyl group.
  • alkoxy group means a de ⁇ de ⁇ such active carboxylic acid derivative
  • Upsilon 2 is 'means a leaving group or a hydrogen atom and described in, X' Y, X 2, R 1 R 2, m 'And n have the above-mentioned meaning.
  • reaction of producing the compound (XI) by reacting the compound (K) with the compound (X) can be carried out in the same manner as in the aforementioned starting compound production method (A).
  • the solvent, catalyst, reaction conditions and the like used in the reaction are the same as in (A) above.
  • This reaction may be performed according to a conventional N-alkylation reaction method. This reaction is carried out while stirring compound (XI) and a corresponding amount of compound (XII) in an inert solvent with cooling or heating. To accelerate the reaction, it is preferable to add a base (for example, an inorganic base such as potassium carbonate, sodium carbonate, sodium hydride, or an organic base such as triethylamine).
  • a base for example, an inorganic base such as potassium carbonate, sodium carbonate, sodium hydride, or an organic base such as triethylamine.
  • the amide compound ( ⁇ ) can be obtained by carrying out an acylation reaction of an amine (XO with a carboxylic acid and its derivative ( ⁇ ) in a suitable solvent.
  • a suitable solvent such as phenolic compounds such as ditrophenol and N-hydroxyamine compounds such as N-hydroxysuccinimide and 1-hydroxybenbuttriazole; monoalkyl carbonates or organic compounds
  • a mixed acid anhydride obtained by reacting with an acid, a phosphoric acid mixed acid anhydride obtained by reacting with diphenylphosphoryl chloride, or N-methylmorpholine; obtained by reacting an ester with hydrazine or alkyl nitrite Acid azides; acid halides such as acid chloride and acid promide; symmetrical acid anhydrides;
  • the compound ( ⁇ ⁇ can also be obtained by an acylation reaction with carboxylic acid (XII) in a suitable solvent in the presence of a condensing agent.
  • the condensing agent may be N, N-zinclohexylcarpoimide (DCC :), 1-ethyl-3- (3- (N, N-dimethylamino) propyl) carbodiimide, carbonyldiimidavour, diphenylphosphoryl azide (DPPA), and dimethylphosphoryl cyanide are preferred.
  • Compound ( ⁇ ⁇ ) is obtained by dissolving the aldehyde compound ( ⁇ ) in a suitable solvent, reacting with the amine of compound (XI), and reducing the resulting imidium ion.
  • the reaction solvent, reducing agent, and reaction conditions are as described in (A) above.
  • Cyclization to an oxobiperazine ring compound (E b) is carried out by reacting the precursor (X [I []) in a suitable solvent without a catalyst or in the presence of a suitable catalyst. At that time, the reaction can be carried out under ice cooling, at room temperature or under heating.
  • the compound of the present invention produced in this manner is isolated or purified as it is or subjected to a salt-forming treatment by a conventional method, and as a salt thereof. Isolation and purification are carried out by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, careful recrystallization, and various types of chromatography.
  • a racemic mixture can be prepared from the pure starting material having the desired stereostructure of the product, or the racemic mixture can be resolved at any convenient stage in the synthesis, with respect to the above process. It is also obvious to those skilled in the art that they can be obtained by performing Resolution of the final product, intermediate or starting material is accomplished by any suitable method apparent to one skilled in the art.
  • the compound of the present invention has a platelet aggregation inhibitory action as a medicament, particularly an orally administrable GPU bZIIIa receptor antagonist, and ischemic heart disease (unstable angina, acute myocardial infarction, and its secondary prevention, After coronary artery bypass surgery, re-occlusion and restenosis after PTCA surgery, drugs for promoting coronary thrombolysis and preventing re-occlusion, adjuvant drugs during cardiac surgery or vascular surgery, cerebrovascular accident (transient cerebral ischemic attack) (TIA :), cerebral infarction, subarachnoid hemorrhage (blood vessel spasm)), and peripheral arterial disease (such as chronic arterial occlusion).
  • ischemic heart disease unstable angina, acute myocardial infarction, and its secondary prevention, After coronary artery bypass surgery, re-occlusion and restenosis after PTCA surgery, drugs for promoting coronary thrombolysis and preventing re-occlusion, adjuvant drugs during
  • the compound of the present invention is excellent in oral absorbability, and is useful as a drug for improving the above-mentioned diseases not only in parenteral administration such as intravenous injection but also in oral administration.
  • the compound of the present invention is excellent in the effect surrounding properties, and has high clinical utility. Further, the compound of the present invention Less toxic than compounds.
  • the pharmacological effects such as the platelet aggregation inhibitory effect of the compound of the present invention were confirmed by the following test methods.
  • GPEbZHa was purified according to the method of Fitzgera id. Fibrinogen was biotinylated using NHS-LC-Bi0tin (Pierec).
  • TBS (2 OmM Tr is -. HC 1 pH7 4, 15 OmM Na C 1, Im CaC 12, 1 mM Mg C 1 2) in 1 gZm 1 and the purified GPH b! 13 100 1 was added to a 96 we 1 1 plate (axi Sorp TM, Nc nc) and left at 4 eC for e . After washing once with TBS, 200 1 of 1% BS AZT BS was added, and the mixture was allowed to stand at 37 ° C for 1 hour. After removing the solution, specimen and Piochin reduction is added Fuiburino one Gen, 37 e C in for 3 hours the reaction was washed three more times with 0. 01% t we en 2 OZTBS .
  • the compound of the present invention exhibited good binding inhibition, and the compound of Example 8 exhibited an IC 5 .
  • the value was 8.4 nM, and the compound of Example 16 showed 10.4 nM.
  • the above-mentioned European Patent which is a prior art
  • Example 15 Compound (hereinafter abbreviated as “preceding compound”) has an IC so value of
  • the cynomolgus monkey under mild anesthesia by intramuscular administration of keyumin hydrochloride was kept on an experimental table, and 3 mg of the compound of the present invention dissolved in 2 ml of distilled water was used in a rubber tube. And administered by gavage. Blood was collected from the femoral vein at a dose of 3 ml (including 1Z10 volume sodium citrate) before administration and after a certain period of time, and then the method of De Marco et al. (J. Clin. Inv. Est., 77, 1) Platelet-rich plasma (PRP) was prepared according to 272–1 277, 198 6).
  • PRP Platelet-rich plasma
  • PRP was prepared at 3 ⁇ 10 8 Zm 1 using an automatic hemocytometer ( ⁇ -5158, Nihon Kohden) and used. Platelet aggregation was induced using 20 uM ADP, 10 g of bovine tendon-derived collagen (Nikko Bioscience), and measured using a platelet aggregometer (NBS Hematrater 811, Nikko Bioscience). . P harmful activity was expressed as an inhibition rate (%) with respect to the maximum aggregation rate in an aggregation curve calculated using PRP of each animal before drug administration.
  • Table 1 shows the results of the above-mentioned cynomolgus monkey eXVivo platelet aggregation inhibitory activity test.
  • the compound of the present invention showed a sufficient platelet aggregation inhibition ratio even after 12 hours of oral administration compared to the preceding compound .
  • the compound of the present invention inhibits fibrinogen binding to human platelets, has a good platelet aggregation inhibitory activity, and has good oral absorption and sustained action. confirmed.
  • a preparation containing one or more of the compound of the present invention or a salt thereof as an active ingredient is prepared by using a carrier, a shaping agent, and other additives commonly used in pharmaceutical preparations.
  • carriers and excipients for pharmaceuticals include solid or liquid non-toxic pharmaceutical substances. These include, for example, lactose, magnesium stearate, starch, yunorek, gelatin, agar, pectin, acacia, olive oil, sesame oil, cocoa butter, ethylene glycol and the like, and other commonly used ones.
  • Administration is oral, such as tablets, pills, capsules, granules, powders, and liquids, or parenteral administration, such as injections such as intravenous and intramuscular injections, suppositories, transdermal agents, and inhalants. May be used.
  • the dose is determined as appropriate depending on the individual case, taking into account the symptoms, age of the subject of administration, gender, etc., but in the case of oral administration, it is usually about 0.01 mg / kg to 10 mg / kg / day for adults. This may be administered once or in 2-4 divided doses.
  • intravenous administration depending on the symptoms, it is usually administered once or more than once a day in the range of 0.001 mg to 1 OmgZkg per adult.
  • the compound of the present invention is not limited to the compounds described in the following Examples, and furthermore, the compound represented by the general formula (I), a salt thereof, a hydrate thereof, a solvate thereof, a geometrical and optical isomer thereof
  • the crystal includes all polymorphs.
  • the starting compounds of the compound of the present invention include novel compounds. Production examples of these compounds will be described as reference examples.
  • Omg is dissolved in 20 ml of ethanol and 1N aqueous sodium hydroxide solution 2. 5 ml was added and the mixture was stirred at room temperature for 5 hours. 2.5 ml of 1 N hydrochloric acid was added to the reaction mixture, and the solvent was distilled off.
  • the solution was dissolved in 20 ml of mid and blown at room temperature until hydrogen sulfide was saturated. After stirring the mixture overnight at room temperature, 200 ml of a 2N aqueous sodium carbonate solution was added, and the mixture was extracted three times with 150 ml of ethyl nitrate. The collected organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated.
  • the residue was dissolved in 100 ml of acetone, 0.3 ml of methyl iodide was added, and the mixture was refluxed for 1 hour and concentrated.
  • the residue was dissolved in 50 ml of methanol, 1.5 g of ammonium St acid was added, and the mixture was refluxed for 2 hours and concentrated.
  • the residue was purified by silica gel column chromatography (eluent: chloroform: methanol: 10: 1), and methyl 4- [4- (4- (amidinophenyl) -111-biperazinyl] -11- (tert-butoxycarbonylmethyl) 0.95 g of 13-piperidinepropionate monohydroiodide was obtained.
  • Raw material compound Ethyl 3-methoxycarbonyl 4 1-year-old oxo 11-biperidine acetate
  • Omg was dissolved in 20 ml of ethanol, and Hydrogen chloride was blown in until saturated with 10 to -2 O'C. After returning to room temperature and stirring overnight, the solvent was distilled off. The obtained residue was dissolved in 20 ml of ethanol, 1.0 g of ammonium carbonate was added, and the mixture was stirred at room temperature overnight.
  • Example 14 The following compounds of Example 14 were obtained in the same manner as in Examples 11 and 12.
  • Ethyl 4-1 [4-1 (4-Cyanophenyl) -1,2,5-dioxo1-1-Biberazinyl] -11-piperidine acetate 0.2 1 g of dry ethanol 20 ml 1 Hydrogen was blown for about one hour. The mixture was gradually returned to room temperature and stirred, and then concentrated under reduced pressure. 20 ml of dry ethanol and 1.56 g of ammonium carbonate were added to the residue, and the mixture was stirred for 3 days.
  • 0.448 g of sodium cyanoborohydride and 0.57 g of drunk acid were sequentially added, followed by stirring for a while. After distilling off the solvent, the residue was added with chloroform and washed with a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was separated and decompressed.
  • Example 17- (3) The following compounds of Example 17- (3) were obtained in the same manner as in Example 15- (6).
  • Example 18 The following compound of Example 18 was obtained in the same manner as in Example 16.
  • Example 191-1 (1) was obtained in the same manner as in Example 15- (3).
  • Example 191-1 (2) The following compound of Example 191-1 (2) was obtained in the same manner as in Example 15- (4).
  • Example 19- (3) The following compounds of Example 19- (3) were obtained in the same manner as in Example 15- (5).
  • Example 191-1 The following compound of Example 191-1 (4) was obtained in the same manner as in Example 15- (6).
  • Example 20 1.21 (3 ⁇ , t) .1.61 (2H.m), 1.77 (2H, m) .2.30 (2H, m), 2.94C2H.m) .3.32 (2H.s), 3.65C2H, m) .4.00 (2H, m) .4.11 (3H, m) .7.67 (2H.d), 7.91 (2H, d)
  • the following compound of Example 20 was obtained in the same manner as in Example 16.
  • Example 15 The following compound of Example 21 (1) was obtained in the same manner as in 5- (4).
  • Example 15 The following compounds of Example 21- (2) were obtained in the same manner as in 5- (5).
  • Example 15 The following compound of Example 21- (3) was obtained in the same manner as in 5- (6).
  • Example 2 1-(3) The following compound of Example 21- (3) was obtained in the same manner as in 5- (6).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

On décrit des dérivés de benzamidine, représentés par la formule générale (I), leurs sels, hydrates ou solvates, ainsi que des compositions médicinales comprenant ces dérivés, sels, hydrates ou solvates et des excipients pharmacologiquement acceptables. Dans cette formule (I), R1 et R2 représentent chacun indépendamment hydrogène ou un reste d'ester, X1 représente alkylène inférieur, X2 représente une liaison unique ou alkylène inférieur, m vaut 0, 1 ou 2, et n vaut 0 ou 1, à condition que si m vaut 0, n vaille 1. Ces composés témoignent d'un antagonisme au récepteur CPIIb/IIIa et se révèlent utiles pour améliorer des troubles ischémiques cardiaques, comme auxiliaires en cas d'opérations chirurgicales cardiaques ou vasculaires, pour améliorer des troubles cérébro-vasculaires et des artères périphériques.
PCT/JP1996/000274 1995-02-10 1996-02-08 Nouveaux derives de benzamidine et leur composition medicinale WO1996024583A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP96901968A EP0810215A4 (fr) 1995-02-10 1996-02-08 Nouveaux derives de benzamidine et leur composition medicinale
US08/875,702 US5773442A (en) 1995-02-10 1996-02-08 Benzamidine derivatives and pharmaceutical composition containing them
AU46332/96A AU4633296A (en) 1995-02-10 1996-02-08 Novel benzamidine derivatives and medicinal composition thereof

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
JP7/22640 1995-02-10
JP2264095 1995-02-10
JP7/81426 1995-04-06
JP8142695 1995-04-06
JP13787795A JPH08333341A (ja) 1995-06-05 1995-06-05 新規なピペラジン誘導体又はその塩
JP7/137877 1995-06-05

Publications (1)

Publication Number Publication Date
WO1996024583A1 true WO1996024583A1 (fr) 1996-08-15

Family

ID=27283920

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1996/000274 WO1996024583A1 (fr) 1995-02-10 1996-02-08 Nouveaux derives de benzamidine et leur composition medicinale

Country Status (2)

Country Link
AU (1) AU4633296A (fr)
WO (1) WO1996024583A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997045413A1 (fr) * 1996-05-30 1997-12-04 Yamanouchi Pharmaceutical Co., Ltd. Derives amidinobenzene substitue et compositions les comportant
EP0849261A1 (fr) * 1996-12-19 1998-06-24 Solvay Pharmaceuticals GmbH Dérivés d'acides pipérazinophényl- et pipérazinophényloxy-carboxyliques ainsi que procédés et produits intermédiaires de leur préparation et médicaments contenant ces composés

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993014077A1 (fr) * 1992-01-21 1993-07-22 Glaxo Group Limited Derives d'acide piperidineacetique servant d'inhibiteurs de l'agregation plaquettaire sanguine dependante du fibrinogene
JPH07501063A (ja) * 1991-11-14 1995-02-02 グラクソ、グループ、リミテッド フィブリノーゲン依存性血小板凝集阻害剤としてのピペリジン酢酸誘導体

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07501063A (ja) * 1991-11-14 1995-02-02 グラクソ、グループ、リミテッド フィブリノーゲン依存性血小板凝集阻害剤としてのピペリジン酢酸誘導体
WO1993014077A1 (fr) * 1992-01-21 1993-07-22 Glaxo Group Limited Derives d'acide piperidineacetique servant d'inhibiteurs de l'agregation plaquettaire sanguine dependante du fibrinogene

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF MEDICINAL CHEMISTRY, Vol. 37, No. 23, (1994), ELDRED C.D. et al., pp. 3882-3885. *
See also references of EP0810215A4 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997045413A1 (fr) * 1996-05-30 1997-12-04 Yamanouchi Pharmaceutical Co., Ltd. Derives amidinobenzene substitue et compositions les comportant
EP0849261A1 (fr) * 1996-12-19 1998-06-24 Solvay Pharmaceuticals GmbH Dérivés d'acides pipérazinophényl- et pipérazinophényloxy-carboxyliques ainsi que procédés et produits intermédiaires de leur préparation et médicaments contenant ces composés
US5843948A (en) * 1996-12-19 1998-12-01 Solvay Pharmaceuticals Gmbh Piperazinophenyl- and piperazinophenyloxycarboxylic acid derivatives, and processes and intermediates for their preparation and pharmaceutical compositions comprising them

Also Published As

Publication number Publication date
AU4633296A (en) 1996-08-27

Similar Documents

Publication Publication Date Title
US6043358A (en) Hexahydro-5-imino-1,4-heteroazepine derivatives as inhibitors of nitric oxide synthases
US5318964A (en) Hydroxamic derivatives and pharmaceutical compositions
JPH072847A (ja) 接着レセプター拮抗物質
PT1638970E (pt) Derivados de pirid(2,1-a)isoquinolina como inibidores de dpp-iv
BG62653B1 (bg) Производни на хидроксамовата киселина
JPH06271549A (ja) ピペラジン誘導体
US5158970A (en) Proline derivatives
KR20220118425A (ko) 핵 수용체 활성 화합물
JP4428053B2 (ja) ガバペンチン若しくはプレガバリンおよびｎ型カルシウムチャンネル拮抗剤を含有する医薬組成物
KR940003297B1 (ko) 1,3,2-디옥사티오렌옥시드 유도체
WO1997003060A1 (fr) Derives de la piperazine et leurs utilisations
EP0518672A2 (fr) Inhibiteurs cycliques de rénine
US5773442A (en) Benzamidine derivatives and pharmaceutical composition containing them
JP2009513484A (ja) 置換ジケトピペラジンオキシトシンアンタゴニストとしてのその使用
WO1996024583A1 (fr) Nouveaux derives de benzamidine et leur composition medicinale
RU2158263C2 (ru) Замещенное производное амидинобензола и фармацевтическая композиция на его основе
JPH08333342A (ja) 新規なベンズアミジン誘導体及びその医薬組成物
EP0432974A1 (fr) Inhibiteurs cycliques de la rénine
JPH0987280A (ja) オキソピペラジン誘導体又はその塩
KR100848490B1 (ko) 베타아미노기를 갖는 1,2,5-트리아제판 유도체, 이의약학적으로 허용 가능한 염 및 이의 제조 방법
MXPA98009568A (en) Derivatives of amidinobenceno substitute and medical compositions of mis
JPS63119442A (ja) アミン化合物
JPH08333341A (ja) 新規なピペラジン誘導体又はその塩
JPH1017564A (ja) 新規チオフェン誘導体
JP2008501629A (ja) 高選択的な新規アミド化法

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AM AU AZ BB BG BR BY CA CN CZ EE FI GE HU IS KE KG KR KZ LK LR LT LV MD MG MK MN MW MX NO NZ PL RO RU SD SG SI SK TJ TM TR TT UA US UZ VN

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): KE LS MW SD SZ UG AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 08875702

Country of ref document: US

WWE Wipo information: entry into national phase

Ref document number: 1996901968

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1996901968

Country of ref document: EP

WWR Wipo information: refused in national office

Ref document number: 1996901968

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1996901968

Country of ref document: EP

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载