Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
  • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans 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 carbon atoms of the hetero ring
  • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • 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
  • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/06—Antiarrhythmics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
  • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
  • C07D307/80—Radicals substituted by oxygen atoms

Definitions

• the present invention relates, in general, to new heterocyclic derivatives as well as to their process of preparation.
• the invention relates to new benzofuran or benzothiopene derivatives, which can be represented by the general formula:
• C ⁇ C represents the group - CH- ⁇ CH- or the group - c ⁇ C—
• A represents an alkylene group, linear or branched, of CrC- 3 or alkenylene of C 2 -C 3 ,
• T represents hydrogen or a C 1 -C 4 alkyl radical
• R represents:
• R represents an alkyl group -C 6 cycloalkyl or C 3 -C 6, • a carboxyl group of general formula:
• R 5 represents hydrogen or an alkali metal atom
• R 1 ⁇ , R ⁇ and R 18 identical or different, represent an alkylene group, linear or branched, in CrC, Ri represents hydrogen, an alkyl group, linear or branched, in Ci-Ce, C 3 -C cycloalkyl - C 6 , or phenyl,
• R 2 and R 3 identical or different, represent hydrogen, an alkyl group, linear or branched, in CrC 6 or a cycloalkyl group in C 3 -C 6 , or R 2 and R 3 , when taken together , represent a linear or branched C 3 -C 10 alkylene group, these alternatives R 2 and R 3 identical or different and R 2 and R 3 taken together being represented in formula (1) by the symbol
• ⁇ CH CR 9 , R 8 and R 9 being identical or different and representing hydrogen, a halogen atom for example chlorine or bromine, an alkyl radical in dC 4 such as methyl or an alkoxy radical in CC such as methoxy , X represents -O- or -S-, these benzofuran or benzothiphene derivatives being in the form of individual isomers or mixtures thereof.
• benzofuran or benzothiopene derivatives according to the invention are characterized in that
• CC represents the grouping -CH CH- Classes of preferred compounds of the invention can be represented by the compounds of formula (1):
• R ⁇ and / or R 2 and / or R 3 represent the n-butyl group - or in which X represents -O-.
• Another class of preferred compounds of formula (1) is that in which
• the compounds of formula (1) may be in the form of geometric E or Z isomers. Consequently, the invention relates both to the individual isomers of the compounds of formula (1) as well as to their mixtures.
• the invention also relates to the pharmaceutically acceptable salts of the compounds of formula (1) formed from an organic or inorganic acid.
• organic salts include the oxalate, maleate, fumarate, methanesulfonate, benzoate, ascobate, pamoate, succinate, hexamate, bismethylenesalicylate, ethanedisulfonate, acetate, propionate, tartrate, salicylate, citrate, gluconate, lactate, malate , cinnamate, mandelate, citraconate, aspartate, palmitate, stearate, itaconate, glycolate, p-aminobenzoate, glutamate, benzenesulfonate, p-toluenesulfonate and theophylline acetate as well as the salts formed from an amino acid such as the lysine salt or histidine.
• inorganic salts of this kind mention may be made of the hydrochloride, hydrobromide, sulphate, sulphamate, phosphate and nitrate.
• the compounds of the invention have been found to have remarkable pharmacological properties, in particular anti-arrhythmic properties since they have been shown to be able to suppress or prevent disorders of the ventricular and atrial rhythm.
• Most of the compounds of the invention have electrophysiological properties of classes 1, 2, 3 and 4 of the Vaughan-Williams classification which confer bradycardizing, anti-hypertensive and anti-adrenergic ⁇ and ⁇ properties.
• most of the compounds have also revealed antioxidant properties, an affinity for sigma receptors and an ability to increase the synthesis of NO.
• these compounds of the invention exhibit inhibitory properties of various hormonal agents such as for example angiotensin II, arginine vasopressin, neuropeptide Y or endothelin.
• the compounds in question are capable of making the compounds in question very useful in the treatment of certain pathological syndromes of the cardiovascular system, in particular in the treatment of angina pectoris, hypertension, arrhythmia, in particular atrial, ventricular or supraventricular, cerebral circulatory failure.
• the compounds of the invention may be used in the treatment of heart failure, of myocardial infarction whether or not complicated by heart failure or for the prevention of post-infarction mortality.
• the compounds of the invention could be useful as potentiators of anticancer agents.
• the invention also relates to a medicament, characterized in that it comprises a compound derived from benzofuran or benzothiophene, or a pharmaceutically acceptable salt of the latter, according to the invention.
• the invention also relates to pharmaceutical or veterinary compositions containing as active principle, at least one compound of the invention, in combination with a suitable pharmaceutical vehicle or excipient.
• the daily dosage for a human being weighing 60 kg will be between 2 and 2000 mg of active principle, in particular between 50 and 500 mg of active principle.
• the compounds of formula (1) can be prepared according to the following methods: A. - In the case where R represents the cyano group, the formyl group, a group (a) or a group (c) and when the compound of formula ( 1) is in the form of an isomer of configuration E, by reacting a compound of general formula:
• R ′ represents the cyano group, the formyl group, a group (a) or a group (c)
• Rio represents a halogen atom preferably bromine or iodine or the trifluoro ethanesulfonyloxy group and R ⁇ T, X, W, W and Z have the same meaning as above, with an organostannic derivative of configuration E corresponding to the general formula:
• R 2 and R 3 have the same meaning as above and Ru represents a CC alkyl radical, in particular butyl, after protection of the ain function when R 2 and / or R 3 represent hydrogen, presence of lithium chloride and an organopalladiate derivative such as tetrakis (triphenylphosphine) palladium, then deprotecting, if necessary, the compound thus formed, which provides, in the form of a free base, the desired compounds of formula (1) .
• the reaction takes place at the reflux temperature of the solvent, which can be, for example, an ether such as dioxane.
• the protection of the amino function of the compound of formula (3) that is to say the protection envisaged when R 2 and / or R 3 represent hydrogen can be obtained for example by treatment with a compound allowing the attachment of an easily removable group, in particular by means of a t- anhydride butoxycarbonyl and the deprotection takes place thereafter, in this case, after treatment in an acid medium.
• reaction is carried out in a solvent such as an aromatic hydrocarbon, for example toluene, and at room temperature.
• a solvent such as an aromatic hydrocarbon, for example toluene
• R represents a group (b)
• a basic agent namely an alkali metal hydroxide, for example sodium hydroxide
• A, Ri, R 2 , R 3 , R 4 , T, W, W and Z have the same meaning as above, which provides, in the form of a free base, the compounds of formula (1) in which R 5 represents an alkali metal atom, compounds which are treated, if necessary, with a strong acid, for example hydrochloric acid, which provides, in the form of a free base, the desired compounds of formula (1) in which R 5 represents hydrogen.
• R 1 f R 2 , R 3 , T, X, W, W and Z have the same meaning as above and this, by means of pyridine p-toluenesulfonate and preferably at reflux temperature, which provides the desired compounds of formula (1) in the form of the free base.
• R 1t R 2 , R 3 , T, W, W, X and Z have the same meaning as above, are themselves intermediates of synthesis for the preparation of compounds of formula (1).
• the compounds of formula (1) in which R represents a group (c) in which R 6 and R are identical and each represent hydrogen can be prepared alternatively, by reacting a compound of formula (7) in question using dicyclohexylcarbodiimide in the presence of hydroxybenzotriazole and ammonia, which provides the desired compounds of formula (1) in the form of the free base.
• reaction is preferably carried out in an aprotic solvent such as an aromatic hydrocarbon, for example benzene or toluene and usually at the reflux temperature of the medium, a compound of formula (8) with a (trialkyl CC) tin azido, for example tributyltin azide, which provides, in the form of a free base, the desired compounds of formula
• R ', R 1 f T, W, W, X and Z have the same meaning as above and this, with trifluoromethanesulfonic anhydride in the presence of an acid acceptor such as pyridine, which provides the compounds of formula (2).
• stannic compounds of formula (3) they can be obtained by reacting an alkynylamine of general formula:
• the compounds of formula (4) can be prepared by reacting a compound of formula (2) with an alkyne derivative of formula (12), after protection of the amino function when R 2 and / or R 3 represent the hydrogen and this, in the presence of an organopalladie compound as catalyst essentially a palladium (II) salt preferably complexed with at least one organophosphorus compound comprising trivalent phosphorus for example dichloro bis- (triphenylphosphine) palladium, then deprotects, if necessary the compound thus formed, which provides the desired compounds of formula (4).
• an organopalladie compound as catalyst essentially a palladium (II) salt preferably complexed with at least one organophosphorus compound comprising trivalent phosphorus for example dichloro bis- (triphenylphosphine) palladium
• the protection of the amino function of the compound of formula (12), that is to say the protection envisaged when R 2 and / or R 3 represent hydrogen, can be obtained for example by treatment with a compound allowing the fixing of an easily removable group, in particular by means of a t-butyoxycarbonyl anhydride, and the deprotection takes place thereafter, in this case, by treatment in an acid medium.
• the compounds of formula (6) can be prepared starting from an ester of formula (1) in which R represents a group (a):
• the preparation of the ester of formula (19) can be carried out according to the method described above but starting from an acid of formula (17) in the form of acyl halide obtained after treatment of the derivative d benzoic acid of formula (17) using a halogenating agent, for example thionyl chloride, phosgene or oxalyl chloride.
• a halogenating agent for example thionyl chloride, phosgene or oxalyl chloride.
• Ri, T and X have the same meaning as above and R 'represents the cyano or carboxylic group, which provides either the desired compounds of formula (9) when R " ⁇ represents the cyano group or an acid when R" ⁇ represents the carboxylic group, d) this acid is esterified with an alcohol of formula (18), which provides the desired compounds of formula (9).
• the compounds of formula (9) in which R ′ is located in position 5 and represents the cyano group or a group (a) and R 1 is in position 2 can also be prepared as follows:
• R represents a group (a): a) first treating a benzoate of general formula:
• this ester of formula (32) is treated with formic acid or trifluoroacetic acid, which provides the acids of general formula:
• this compound (33) is cyclized in the presence of benzenesulfonyl chloride or of p-toluenesulfonyl and of an acid acceptor such as triethylamine , which gives the desired compounds of formula (9).
• this ester of formula (38) is saponified in the presence of a basic agent such as an alkali metal hydroxide and the acid thus obtained is cyclized in the presence of benzenesulfonyl chloride or p-toluenesulfonyl and an acid acceptor such as triethylamine, which provides the desired compounds.
• a basic agent such as an alkali metal hydroxide
• the acid thus obtained is cyclized in the presence of benzenesulfonyl chloride or p-toluenesulfonyl and an acid acceptor such as triethylamine, which provides the desired compounds.
• R i2 represents a cyano or formyl group and T and X have the same meaning as above and this, with methyl iodide in the presence of an alkali metal hydride to give a compound of general formula:
• R 12 represents the formyl group, with an alkali metal cyanide in the presence of manganous oxide and acetic acid to give a compound of general formula:
• the other compounds of formula (9), that is to say the compounds of formula (9) in which R situated in position 7 represents a group (a), with the exception of the methoxycarbonyl group, can be obtained by saponifier an ester of formula (9) in which R situated in position 7 represents the methoxycarbonyl group and this, in the presence of a basic agent such as an alkali metal hydroxide to give a salt which is acidified with a strong acid such that hydrochloric acid to give a derivative of 7-carboxy-benzofuran which is esterified with an alcohol of general formula:
• R ' 4 represents a C 2 -C 6 alkyl or C 3 -C 6 cycloalkyl group, which provides the desired compounds of formula (9).
• the compounds of formula (9) in which R ′ represents the formyl group can be prepared by oxidizing with oxalyl chloride, an alcohol of general formula:
• the compounds of formula (10) can be obtained by following the following steps: a) acylation of a compound of general formula:
• Hal represents a halogen atom such as chlorine or bromine and this, in the presence of a Lewis acid as catalyst, for example ferric chloride, aluminum chloride or tin tetrachloride, which provides the derivatives methoxy of general formula:
• R ', R. ,, T, W, W, X and Z have the same meaning as above, methoxy derivatives which are demethylated by heating in the presence, for example, of aluminum chloride, to form the desired compounds.
• R ′ represents a group (a), a group (b) or a group (c) for carrying out different methods by which:
• R 1 f T, W, W, X and Z have the same meaning as previously R ⁇ 4 represents a C ⁇ -C 4 alkyl radical, preferably methyl or ethyl and R 15 represents hydrogen or the radical methyl and this, with an alkali metal hydroxide to obtain the compounds of formula (11) or of formula (52) in which R represents a group (b) in which R 6 represents an alkali metal atom, * the derivative is treated of alkali metal thus formed with a strong acid such as hydrochloric acid to obtain an acid, that is to say the compounds of formula (11) or of formula (52) in which R represents a group (b) in which R 6 represents hydrogen,
• Benzothiophene derivatives are already known comprising a 1- alkenylbenzoyl chain and variously substituted on the homocycle. Such compounds have been described for example in patents or patent applications US 5827876 or WO9701549 where they are presented as having properties that inhibit bone loss or for the treatment of menopausal symptoms or also for the treatment of restenosis.
• benzofuran or benzothiophene derivatives comprising an aminoalkenylbenzoyl chain as well as other groups attached to the heterocycle via a carbon atom, have very interesting pharmacological properties including antiarrhythmic properties while providing very good metabolic stability, very acceptable solubility and very good bioavailability by the oral route.
• the results of pharmacological tests carried out in order to determine the properties of the compounds of the invention on the cardiovascular system are listed below.
• Rats, divided into lots, are first anesthetized with sodium pentobarbital (60 mg / kg intraperitoneally) then they are intubated and kept under assisted respiration.
• a cannula for intravenous administration in the right jugular vein, an intravenous dose of the test compound is administered and 5 minutes later, a ligature loop is placed around the left anterior descending coronary artery and in the immediate vicinity of His origin. This artery is then occluded for 5 minutes by traction on the ends of the ligature so as to induce reperfusion by releasing the tension.
• the arrhythmias induced by this reperfusion are then evaluated. A similar test was performed orally.
• the compound to be studied is administered 120 minutes before ligation of the left anterior descending coronary artery.
• the purpose of this test is to determine the capacity of the compounds of the invention to reduce the increase in blood pressure induced by phenylephrine (anti- ⁇ effect) and the acceleration of the heart rate induced by isoprenaline (effect anti- ⁇ ). in dogs before anesthesia with pentobarbital and chloralose. We first determine for each dog the dose of phenylephrine (5 or
• the percentage reduction, by the test compound, of the induced acceleration of the heart rate is recorded.
• test is to evaluate the effectiveness of the compounds of the invention vis-à-vis the atrial fibrillation induced by permanent stimulation of the vagus nerve in the dog anesthesia according to the method described in Circulation 1993; 88: 1030- 1044.
• the test compounds are administered at cumulative doses of 3 and 10 mg / kg as slow 10-minute intravenous infusions during an episode of sustained atrial fibrillation.
• the compounds of the invention generally convert 100% of the atrial fibrillations into sinus rhythm and prevent re-induction in 50 to 100% of the cases. At this dose, increases are observed significant of the cardiac period as well as the effective refractory atrial periods for different basal values of the cardiac period. IV. Inhibiting effects of the neuro-hormonal system
• the purpose of this test is to search for the inhibitory effects of the compounds of the invention vis-à-vis the vasoconstrictor effects induced by different peptides such as norepinephrine (NA), angiotensin II (A-II), arginine vasopressin (AVP), neuropeptide Y (NPY) and endothelin (ET) and also vis-à-vis the tachycardic effects induced by isoprenaline (Iso) in the alert rat.
• NA norepinephrine
• A-II angiotensin II
• AVP arginine vasopressin
• NPY neuropeptide Y
• ET endothelin
• an arterial catheter (right carotid artery) for measuring blood pressure and a venous catheter (right jugular vein) for injection of the products are implanted 24 hours before the test. to study.
• the rats are placed in cylindrical boxes and the arterial catheter is connected to a pressure sensor via a rotary joint on a pendulum. This pressure sensor is itself connected to a polygraph for recording blood pressure.
• the various peptic agonists are first dissolved in 0.9% physiological saline and the compound to be studied in an appropriate solvent. These bolus peptides are then injected in a volume of 0.05 ml / kg, 30 and 10 minutes before the intravenous administration of 0.1 ml / kg of a solution of the compound to be studied or of solvent. These peptide injections are then repeated 10, 30, 60 and 120 minutes after the administration of the compound to be studied. Depending on the duration of action of the test compound, these injections can possibly be extended every 30 minutes without ever exceeding 5 hours in total.
• the variations in blood pressure after administration of a given peptide are then evaluated by measuring, at different times, the difference between the maximum effect induced by the peptide agonist and the basal value of blood pressure.
• the results obtained show that NA, FA-II, FAVP, NPY and FET induce respective increases in blood pressure of 45 ⁇ 3, 40 + 3, 30 ⁇ 2 and 34 ⁇ 4 mmHg and Flso an increase in frequency heart rate of 209 + 7 beats per minute.
• the compounds of the invention antagonize in a dose-dependent manner the vasoconstrictor effects induced by NA, FA-II and FAVP. They also antagonize the effects induced by NPY and by FET and the increase in heart rate induced by Flso.
• the maximum inhibition obtained after 15 minutes varies between 40 and 80% and the duration of action is at least greater than or equal to 30 minutes.
• the toxicity of the compounds of the invention has been found to be compatible with their use in therapy.
• compositions according to the invention can be presented in any form suitable for administration in human or veterinary therapy.
• the pharmaceutical compositions of the present invention can be formulated for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal or rectal administration.
• this may take the form, for example, of a tablet, a dragee, a capsule, a capsule, a powder, a suspension, syrup or granules for oral administration, a suppository for rectal administration or a solution or suspension for parenteral administration.
• compositions of the invention may comprise, per administration unit, for example from 50 to 500 mg by weight of active ingredient for oral administration, from 50 to 200 mg of active ingredient for rectal administration and from 50 150mg of active ingredient for parenteral administration.
• the pharmaceutical or veterinary compositions of the invention will be prepared by combining at least one of the compounds of formula (1) or a pharmaceutically acceptable salt of this compound with an appropriate excipient, the latter possibly consisting of example of at least one ingredient selected from the following substances: lactose, starches, talc, magnesium stearate, polyvinylpyrrolidone, alginic acid, colloidal silica, distilled water, benzyl alcohol or sweetening agents.
• the mixture is stirred at ambient temperature for approximately 8 hours and concentrated to dryness. It is taken up in ethyl acetate and washed with water, dilute hydrochloric acid, a sodium hydrogencarbonate solution, water and finally with a solution of sodium chloride. It is then purified by chromatography on silica (eluent: dichloromethane).
• 0.680 g of compound obtained in the previous step are introduced into 20 ml of ethanol and hydrogenation is carried out in the presence of 0.090 g of palladium-on-carbon from Lindlar. 0.120 is then added successively; 0.160 and 0.200 g of palladium-on-carbon depending on the degree of progress of the reaction. Then filtered on diatomaceous earth and purified by chromatography on silica (eluent: dichloromethane / methanol / ammonia 100/3 / 0.2), which provides 0.340 g (yield: 67%) of the desired compound in basic form.
• Example 37 Solvent: DMSO ⁇ (ppm): 7.4-8.4 (solid, 7H); 5.12 (quintuplet, 1 H); 3.69 (singlet, 2H); 2.4-2.7
• EXAMPLE 22 According to known pharmaceutical techniques, a capsule was prepared containing the following ingredients:

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