Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• • 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
  • A61P9/06—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

Definitions

• Atrial fibrillation is the most common arrhythmia and is associated with high morbidity including heart failure and heart attacks. It is often found in patients with cardiac pathology such as hypertension, or coronary heart disease or heart valves. The most significant consequences of AF are heart failure, with a 5-fold risk of heart attack and a 2-fold increased risk of death (Duray GZ, Ehriich JR, Hohnloser SH.) Dronedarone: a novel antiarrhythmic agent for the treatment of atrial fibrillation, Curr.Opin.Cardiol 2010; 25: 53-58). Due to the aging of the population, the number of adults with AF is expected to increase over the next decades.
• AF is characterized by the coexistence of numerous activation waves in the atrial myocardium. The mechanism of their initiation and persistence has been much discussed in recent years. Because any form of tachyarrhythmia induces a remodeling dependent frequency, the coexistence of multiple reentry foci could represent the common mechanism responsible for the persistence of AF related to various pathological causes. According to the "leading circle” theory, the maintenance of the reentries depends on the wavelength of the circuit which is the result of the product of the conduction velocity by the effective refractory period (PRE) inside the circuit. The greater the wavelength, the lower the number of FA circuits available in the atrium, and the more likely it is that the reentry circuits will be interrupted simultaneously. Thus, any drug that prolongs atrial RA should have antiarrhythmic properties (Ehriich JR, Nattel S. Novel Approaches for Pharmacological Management of Atrial Fibrillation, Drugs 2009; 69: 757-774).
• indolizine derivatives which have remarkable pharmacological properties, in particular antiarrhythmic properties, are described since these derivatives have proved to be capable of suppressing or preventing atrial rhythm disorders.
• Most of the compounds described have electrophysiological properties of classes 1, 2, 3 and 4 of the Vaughan-Williams classification which confer, in addition to their antiarrhythmic properties, bradycardisant, antihypertensive and antiadrenergic properties a and b uncompetitive . These properties make the compounds in question very useful in the treatment of certain pathological syndromes of the cardiovascular system, particularly in the treatment of angina pectoris, hypertension, ventricular or supraventricular arrhythmia. Similarly, these compounds are used in the treatment of heart failure, myocardial infarction complicated or not heart failure or for the prevention of post-infarction mortality.
• Amiodarone an atrial and ventricular antiarrhythmic drug that is active by the oral and intravenous routes, is a water-insoluble molecule; the injectable solution therefore contains solvents such as polysorbate 80 and benzyl alcohol. These solvents induce in the patient hypotensive and negative inotropic effects.
• the injectable solution also causes local venous intolerances that are avoided by recommending a central injection in a specialized hospital.
• Dronedarone a benzofuran derivative that does not contain iodine in its chemical structure, unlike amiodarone, is also an orally and intravenously active atrial and ventricular antiarrhythmic agent.
• oral anti-arrhythmics of the indolizine type are capable of blocking several ion channels, such as dronedarone, without its limitations and disadvantages.
• the greatest disadvantage of dronedarone is its contraindication in patients with heart failure.
• R2 represents a hydrogen atom, a (C1-C6) alkyl group, a benzyl group, a CH2-CF3 group;
• R3 represents a hydrogen atom, a (C1-C6) alkyl group, a benzyl group;
• R4 represents a hydrogen atom, a (C1 -C4) alkyl group;
• R5 represents a hydrogen atom, a (C1-C5) alkyl group
• R6 represents a nitrile group or a heteroaryl group comprising from 1 to 4 heteroatoms selected from a nitrogen atom and an oxygen atom, said heteroaryl group being optionally substituted by a (C1 -C6) alkyl group
• R7 represents a hydrogen atom, a linear, branched or cyclic (C1-C6) alkyl group
• R8 represents a hydroxyl group, a cyano group
• X represents a bond or an oxygen atom
• R16 represents a hydrogen atom, a (C1-C6) alkyl group
• R17 represents a hydrogen atom, a (C1-C6) alkyl group
• R18 represents a branched or cyclic (C1 -C6) alkyl group
• R19 and R20 represent a hydrogen atom, a (C1-C6) alkyl group, or form a (C3-C6) spiroalkyl group
• m represents an integer equal to 0 or 1
• n represents an integer equal to 1 or 2;
• r represents an integer equal to 1 or 2;
• s represents an integer equal to 1 or 2;
• t represents an integer between 2 and 4.
• the compounds of formula (I) may comprise one or more asymmetric carbon atoms. They can therefore exist as enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including the racemic mixtures, form part of the invention.
• the compounds of formula (I) may exist in the form of bases or salified by acids or bases, in particular pharmaceutically acceptable acids or bases. Such addition salts are part of the invention.
• salts are advantageously prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, for the purification or the isolation of the compounds of formula (I), also form part of the invention.
• halogen atom a fluorine, a chlorine, a bromine or an iodine
• an alkyl group a linear, branched or cyclic saturated aliphatic group.
• a spiroalkyl group a bicycle whose cycles are connected by a single atom.
• the cycles may be of the same or different length or nature;
• a haloalkyl group an alkyl group in which one or more hydrogen atoms have been substituted with a halogen atom;
• aryl group a cyclic aromatic group comprising between 6 and 10 carbon atoms.
• aryl groups mention may be made of phenyl, benzyl or naphthyl;
• a heteroaryl group a cyclic aromatic group comprising 2, 3, 4 or 5 carbon atoms and comprising from 1 to 4 heteroatoms chosen from a nitrogen atom and an oxygen atom, independently of one another, so that they are identical or different, when there are 2 or independently of each other, to be identical or different, when they are 3 in number. mention the pyridyl, furanyl and pyrrolyl groups;
• a hydroxyl group an -OH group.
• compound No. 15 [(3- ⁇ 4- [3- (1-Amino-cyclopentyl) -propyl] -benzoyl ⁇ -2-ethyl-indolizine-7-carbonyl) -isopropyl-amino] -acetic acid methyl ester ;
• compound no. 16 [(2-Ethyl-3- ⁇ 4- [3- (1-methylamino-cyclopentyl) -propyl] -benzoyl ⁇ -indolizine-7-carbonyl) -isopropyl-amino] -acetic acid methyl ester ;
• compound No. 32 ( ⁇ 2-Ethyl-3- [4- (3-isopropylamino-propyl) -benzoyl] -indolizine-7-carbonyl ⁇ -isopropyl-amino) -acetic acid methyl ester; compound no. 33: ( ⁇ 3- [4- (3-Cyclopentylamino-propyl) -benzoyl] -2-ethyl-indolizine-7-carbonyl ⁇ -ethyl-amino) -acetic acid ethyl ester;
• compound no. 49 3- [4- (3-tert-Butylamino-propyl) -benzoyl] -2-ethyl-indolizine-7-carboxylic acid 2-methyl-2H-tetrazol-5-ylmethyl ester; compound 50: (S) -1- ⁇ 3- [4- (3-tert-Butylamino-propyl) -benzoyl] -2-ethyl-indolizine-7-carbonyl ⁇ -2-methyl-pyrrolidine-2 carboxylic acid methyl ester;
• compound no. 66 2-Butyl-3- (4-piperidin-4-yl-benzoyl) -indolizine-7-carboxylic acid diethylamide; compound no. 67: ( ⁇ 2-Butyl-3- [4- (piperidin-4-yloxy) -benzoyl] -indolizine-7-carbonyl ⁇ -isopropyl-amino) -acetic acid methyl ester;
• a group of compounds is constituted by the following compounds: compound No. 3: (R) -1- ⁇ 2-Butyl-3- [4- (3-dibutylamino-propyl) -benzoyl] -indolizine-7-carbonyl ⁇ -pyrrolidine-2-carboxylic acid methyl ester;
• a protective group is understood to mean a group which makes it possible, on the one hand, to protect a reactive function such as a hydroxyl or an amine during a synthesis and, on the other hand, to regenerate the function reactive intact at the end of synthesis.
• protecting groups and methods of protection and deprotection are given in "Protective Groups in Organic Synthesis", Green et al., 3 rd Edition (John Wiley & Sons, Inc., New York).
• leaving group (Lg) is meant, in what follows, a group that can be easily cleaved from a molecule by breaking a heterolytic bond, with the departure of an electronic pair. This group can thus be easily replaced by another group during a substitution reaction, for example.
• Such leaving groups are, for example, halogens or an activated hydroxy group such as mesyl, tosyl, triflate, acetyl, etc. Examples of leaving groups as well as references for their preparation are given in Advances in Organic Chemistry, J. March, 3 rd Edition, Wiley Interscience, p. 310-316.
• the compounds of formula (I) can be prepared with R 1, R 7 , X and Am which have the same meaning as above according to the following process, illustrated in Schemes 1, 2, 3, 4 and 5.
• step iv A Friedel-Crafts acylation reaction of the 3-position with an acid chloride (VII) where Y represents a halogen atom (step iv), leads, after heating, to the ketone derivative (VI).
• step (iv ') the acylation can be carried out with an acid chloride (VIT) with X-Am bearing an amine function masked in an amide or formate group, unmasked at the end of synthesis to drive to the compound (I), or again engaged in a second protective group compatible with the saponification conditions in step (vi) and released again after the final step (vii).
• step vi) of the ester (IV) with sodium hydroxide in a solvent such as dioxane followed by activation (step vii) of the corresponding carboxylic acid (III) (which corresponds to a compound of formula (I) in which R 1 represents OR 12 with R 12 H) with a coupling agent such as O-benzotriazolyl- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethyluronium tetrafluoroborate (TBTU), in the presence of the amine derivative or alcohol RH (II) and a base such as ⁇ , ⁇ -diisopropylethylamine (DIEA) in an aprotic solvent such as dichloromethane (DCM), leads to the compounds of general formula (I) according to the present invention.
• a coupling agent such as O-benzotriazolyl- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethyluronium tetrafluoroborate (TBTU)
• the X-Am chain can be introduced from a Sonogashira reaction between an alkyne derivative (V) and a halogenated derivative (VI), prepared as described in Scheme 1, where Z represents a halogen, preferably an iodine atom.
• the coupling is carried out in the presence of an organic base such as DIEA and a catalytic amount of copper (I) such as Cul or CuBr, and of palladium such as PdCl 2 (PPh 3 ) in a polar solvent such as acetonitrile heated to 50 ° C.
• step (iii) the triple bond of the alkyne derivative (IV) is then reduced completely under a hydrogen atmosphere or with a hydrogen transfer agent such as ammonium formate in the presence of a catalytic amount of palladium. on charcoal (Pd-C) in a protic solvent such as ethanol or methanol.
• a hydrogen transfer agent such as ammonium formate
• Pd-C palladium. on charcoal
• a protic solvent such as ethanol or methanol.
• the Sonogashira coupling can be carried out with an alkyne derivative functionalized with a precursor of an amino function such as a carboxylic acid function masked in a hydrogenolysable benzyl ester group to ensure efficient orthogonal deprotection in the presence of the second ester function with R as previously described.
• the carboxylic acid function (VII) thus released is converted in step (iii) according to a Curtius rearrangement into a tert-butyl carbamate (V) function in the presence of diphenylphosphoryl azide (DPPA) in tert alcohol. and butyl and a catalytic amount of copper (I) such as CuCl.
• DPPA diphenylphosphoryl azide
• CuCl copper
• the derivative (V) in steps (iv) and (v) is subjected as described in Scheme 1 to a saponification-peptide coupling sequence to yield compound (III).
• an inorganic base such as sodium hydride (NaH)
• an alkyl halide R17X with X which represents a bromine atom or iodine in a polar aprotic solvent such as dimethylformamide (DMF) and lead to the alkylated carbamate derivative (II).
• DMF dimethylformamide
• the X-Am chain, with X represents an oxygen atom and Am functionalized with a protected amine function such as a tert-butyl carbamate, which guarantees a good stability during the saponification stage.
• a protected amine function such as a tert-butyl carbamate
• step (i) the coupling between the derivative (VI) and Z represents a halogen atom such as an iodine atom and HXAm (V) is produced in the presence of a mineral base such as cesium carbonate (Cs 2 CO 3) and a catalytic amount of a phenanthrolidine and copper (I) type ligand such as Cul in an apolar solvent such as toluene heated to reflux.
• a mineral base such as cesium carbonate (Cs 2 CO 3)
• a catalytic amount of a phenanthrolidine and copper (I) type ligand such as Cul
• the ether (IV) in step (iii) is converted into derivative (II) in a saponification-peptide coupling sequence as described in scheme 1.
• the tert-butyl carbamate group is acidolysed with either acid trifluoroacetic acid or with hydrogen chloride in an aprotic solvent such as methylene chloride (CH 2 Cl 2) or ethyl acetate (AcOEt) to give the derivative I.
• an aprotic solvent such as methylene chloride (CH 2 Cl 2) or ethyl acetate (AcOEt)
• the XAm chain can be introduced from a Wittig type reaction.
• step (i) the acylation reaction between indolizine (VIII) and the acid chloride (IX) with X represents a halogen atom such as an atom of chlorine in the presence of an organic base such as lutidine and pyridine in a catalytic amount in an aprotic solvent such as chlorobenzene heated under reflux leads to the compound (VII).
• step (ii) according to Arbusov conditions, the benzyl halide derivative (VII) treated in an excess of phosphite derivative (V) such as refluxed ethyl phosphate is converted into phosphonate (VI).
• step (iii) A Wittig-type reaction in step (iii) between the ester (VI) and a chiral ⁇ -amino-aldehyde derivative (IV), prepared from the parent ⁇ -amino acid compound whose amino function is protected by a tert-butyl carbamate group for a final deprotection in aprotic acid medium, and an inorganic base such as NaH in an aprotic solvent such as THF leads to the alkene (III).
• step (v) the alkene is converted according to a hydrogenation-saponification-peptide coupling-acidolysis sequence, as described in Scheme 2, into derivative (I).
• the various substituents, when their definition is not specified, are as defined in general formula (I).
• the invention also relates to the compounds of formulas (VI)
• R7 is as defined in claim 1;
• R represents a (C 1 -C 4) alkyl group
• R ' represents a (C 1 -C 4) alkyl group
• the retention time is recorded by Tr.
• a mixture of 1.19 g (55.7 mmol) of 1-methylethyl 2-chloro-6-methylpyridine-4-carboxylate and 1.2 g of 10% active palladium on charcoal in 150 mL of iPrOH is stirred 24 h at room temperature under 4 bar of hydrogen.
• ambient temperature is meant a temperature of between 5 and 25 ° C.
• the reaction mixture is filtered and the filtrate is concentrated under reduced pressure.
• the residue obtained is then taken up in 200 ml of water, neutralized at 0 ° C. with Na 2 CO 3 , and then extracted with 3 ⁇ 200 ml of DCM.
• the organic phases are combined, dried over sodium sulfate, filtered and concentrated under reduced pressure.
• the hydrochloride is prepared by taking up the base with a 0.1 N solution of hydrochloric acid in iPrOH (1.1 eq.) which is then concentrated under reduced pressure and the residue obtained is chromatographed on RP18 reverse phase, eluting with gradient CH 3 CN / H 2 0 (0.01 N HCl) from 0 to 100% of CH 3 CN and then lyophilized.
• reaction mixture is then neutralized with a 2N aqueous solution of hydrochloric acid, concentrated under reduced pressure and the precipitate thus obtained is filtered, washed with ice water and then with ether. After drying under reduced pressure, 1 l, 4 g of 2-butyl-3 - ( ⁇ 4- [3- (dibutylamino) propyl] phenylcarbonylindolizine-7-carboxylic acid as a yellow solid.
• the reaction mixture is taken up in 150 ml of DCM, washed successively with 2 ⁇ 75 ml of a saturated solution of NaHCO 3, 2 ⁇ 75 ml of water and 75 ml of brine, dried over Na 2 SO 4 , filtered and the filtrate is then treated with 1 ml of sodium hydroxide. 4N solution of hydrogen chloride in dioxane and then concentrated under reduced pressure. The residue obtained is chromatographed on RP18 reverse phase by eluting with a CH 3 CN / H 2 0 (0.01 N HCl) gradient from 0 to 100% CH 3 CN.
• Example 3 Compound No. 3: Methyl (?) - 1 - ⁇ [2-butyl-3 - ( ⁇ 4- [3- (dibutylpropyl) phenyl ⁇ carbonyl) indolizin-7-yl] carbonyl ⁇ prolinate hydrochloride The procedure is the same as in Example 2.2.
• Example 4 Compound No. 4: 2-Butyl-3 - ( ⁇ 4- [3- (dibutylamino) propyl] phenyl ⁇ carbonyl) -N-ethyl-yV- (2-methoxyethyl) indolizine-7-carboxamide hydrochloride
• Example 6 Compound No. 6: W - ⁇ [2-Butyl-3 - ( ⁇ 4- [3- (dibutylamino) propyl] phenyl ⁇ carbonyl) indolizin-7-yl] carbonyl ⁇ - / V-ethylglycine hydrochloride
• Example 7 Compound No. 7: 3 - ( ⁇ 2-Butyl-3- [4- (3-dibutylamino-propyl) -benzoyl] -indolizine-7-carbonyl ⁇ -ethyl-amino) -propionic acid hydrochloride
• Example 8 Compound No. 8: W - ⁇ [3 - ( ⁇ 4- [3- (Cyclopentylamino) propyl] phenyl ⁇ carbonyl) -2-ethylindolizin-7-yl] carbonyl ⁇ -yV-propan-2H hydrochloride methylglycinate. 8.1 2-Methyl-1- (2-oxopropyl) -4-r (propan-2-yloxy) carbonylpyridinium bromide
• Example 2.2 Apart from the salification step, the procedure is the same as in Example 2.2. Thus, from 2.29 g (4.42 mmol) of 3 - [(4- ⁇ 3 - [(ie / f-butoxycarbonyl) (cyclopentyl) amino] propyl ⁇ phenyl) carbonyl] -2-ethylindolizine acid.
• Example 9 Compound No. 9: 2-Butyl-3 - ( ⁇ 4- [3- (dibutylamino) propyl] phenyl ⁇ carbonyl) -N-ethyl-yV - [(2-methyl-2H-tetrazol-5) hydrochloride -yl) methyl] indolizine-7-carboxamide
• reaction mixture is washed successively with 2 ⁇ 100 ml of water and 2 ⁇ 100 ml of saturated K 2 CO 3 solution , dried over MgSO 4 , filtered and then concentrated under reduced pressure. 0.1 g of ⁇ 2 - [(2-cyanoethyl) are thereby obtained. tert-butyl amino-2-oxoethyl-ethylcarbamate as a white solid used as such in the next step.
• the reaction mixture is taken up in 250 ml of AcOEt, washed successively with 2x100 ml of water and 2x100 ml of brine, dried over MgSO 4 , filtered and then concentrated under reduced pressure.
• the residue obtained is purified by chromatography on a column of silica gel, eluting with an AcOEt / cyclohexane gradient of 0 to 40% AcOEt. After concentration under reduced pressure, 3.2 g of tert-butyl ⁇ [1- (2-cyanoethyl) -1H-tetrazol-5-yl] methyl ⁇ ethylcarbamate are obtained in the form of a reddish oil. .
• the reaction mixture is taken up in 150 ml of AcOEt, washed successively with 2 ⁇ 100 ml of water and 100 ml of brine, dried over Na 2 SO 4 , filtered and then concentrated under reduced pressure.
• the residue obtained is purified by chromatography on a silica column eluting with an AcOEt / cyclohexane gradient of 0 to 40% AcOEt. After concentrating under reduced pressure, 0.95 g of ethyl [(2-methyl-2H-tertazol-5-yl) methyl] carbamate of n-butyl and 0.76 g of ethyl are isolated. (2-Methyl-2H-tetrazol-5-yl) methyl] carbamate, n-butyl ester as colorless oils.
• 10.40-10.30 (m, 1H); 9.40 (d, 1H); 7.80-7.70 (m, 1H); 7.60 (d, 2H); 7.50 (d, 2H); 7.00-6.90 (m, 1H); 7.70 (s, 1H); 5.00-4.80 (m, 2H); 4.40 (s, 3H); 3.55-3.40 (m, 2H); 3.15-3.00 (m, 6H); 2.80-2.70 (t, 2H); 2.30 - 2.20 (t, 2H); 2.10-1.95 (m, 2H); 1.70-1.60 (m, 4H); 1.45-1.25 (m, 6H); 1, 20-1, 10 (t, 2H); 1, 10-1, 00 (m, 2H); 1.00 (t, 6H); 0.70 (t, 3H).
• Example 10 Compound No. 10: 2-Butyl-3- ( ⁇ 4- [3- (dibutylamino) propyl] phenyl ⁇ carbonyl) -N-ethyl-N - [(3-methyl-1,2) hydrochloride 4-oxadiazol-5-yl) methyl] indolizine-7-carboxamide
• Example 11 Compound No. 11: 2-Butyl-3 - ( ⁇ 4- [3- (dibutylamino) propyl] phenyl ⁇ carbonyl) -N-ethyl-yV- (1H-tetrazol-5-ylmethyl) indolizine hydrochloride -7- carboxamide
• Example 12 Compound No. 12: N - [(2-Butyl-3 - ⁇ [4- (piperidin-4-yl) phenyl] carbonyl ⁇ indolizin-7-yl) carbonyl] -A-propyl hydrochloride Methyl 2-ylglycinate
• the reaction mixture is concentrated under reduced pressure, taken up in 400 ml of AcOEt, washed successively with 200 ml of water and 200 ml of brine, dried over Na 2 SO 4, filtered and then again concentrated under reduced pressure.
• the residue obtained is purified by chromatography on a silica column, eluting with a cyclohexane / AcOEt mixture of 0 to 30% AcOEt.
• Example 13 Compound No. 13: 4 - ⁇ [2-Butyl-3 - ( ⁇ 4- [3- (dibutylamino) propyl] phenyl ⁇ carbonyl) indolizin-7-yl] carbonyl ⁇ piperazin-2-one hydrochloride
• Example 15 Compound No. 15: W - ⁇ [3 - ( ⁇ 4- [3- (1-Aminocyclopentyl) propyl] phenyl ⁇ carbonyl) -2-ethylindolizin-7-yl] carbonyl ⁇ -yV-propanol hydrochloride Methyl 2-ylglycinate
• the mixture is taken up in 300 ml of AcOEt, washed successively with 2 ⁇ 100 ml of water and 100 ml of brine, dried over MgSO 4 , filtered and then concentrated under reduced pressure.
• the residue obtained is purified by chromatography on a silica column eluting with an AcOEt / cyclohexane gradient of 0 to 10% AcOEt.
• reaction mixture After stirring for 3 h at RT, the reaction mixture is taken up in 200 ml of AcOEt, washed successively with 2x 50 ml of water and 50 ml of brine, dried over MgSO 4 , filtered and then concentrated under reduced pressure. In a sealed tube, a solution of the resulting residue and 0.1 g (1 mmol) of CuCl in 50 mL of t-BuOH anh. is heated 18h at 1 15 ° C. The reaction mixture is concentrated under reduced pressure and then purified by chromatography on a silica column eluting with an AcOEt / cyclohexane gradient of 0 to 15% AcOEt.
• the reaction mixture is then treated with 50 ml of a saturated aqueous NH 4 Cl solution and then extracted with 2x100 ml of ether.
• the organic phases are combined, washed successively with 2x50 mL of water and 50 mL of brine, dried over Na 2 SO 4 , filtered and then concentrated under reduced pressure.
• the residue obtained is taken up in 10 ml of dioxane, then 4 ml of a 1N aqueous NaOH solution are added dropwise at RT. After stirring for 18 h, the reaction mixture is cooled to 0 ° C. and then neutralized with 4 ml of NaOH. mL of a 1 N aqueous HCl solution and extracted with 2x100 mL of AcOEt.
• Example 2.2 Apart from the final salification step, the procedure is the same as in Example 2.2. Thus, from 1.1 g ((2.08 mmol) of 3 - ⁇ [4- (3- ⁇ 1 - [(ie-n-butoxycarbonyl) (methyl) amino] cyclopentyl ⁇ propyl) phenyl] acid.
• Example 17 Compound No. 17: 3 - ( ⁇ 4- [3- (tert-Butylamino) propyl] phenyl ⁇ carbonyl) -N, 2-diethyl-N - [(2-methyl-2H-tetrazol-5)] hydrochloride -yl) methyl] indolizine-7-carboxamide
• Example 18 Compound No. 18: 3 - ( ⁇ 4- [3- (tert-Butylamino) -3-methylbutyl] phenyl ⁇ carbonyl) -W, 2-diethyl-W - [(2-methyl-2H) -hydrochloride tetrazol-5-yl) methyl] indolizine-7-carboxamide
• Example 19 Compound No. 19: N- ⁇ [3 - ( ⁇ 4- [3- (Cyclopentylamino) -3-methylbutyl] phenyl ⁇ carbonyl) -2-ethylindolizin-7-yl] carbonyl ⁇ -yV-propan Hydrochloride Methyl 2-ylglycinate 19.1 Propan-2-yl 3-amino-3-amino-3-methylbut-1-yn-1-yl) phenylcarbonyl) -2-ethylindolizine-7-carboxylate
• Example 20 Compound No. 20: (R, S) yV, 2-diethyl-3 - ( ⁇ 4- [3-
• the residue obtained is taken up in 500 ml of AcOEt, washed successively with 2x200 ml of water and 100 ml of brine, dried over Na 2 SO 4 , filtered and then concentrated under reduced pressure.
• the residue obtained is chromatographed on a silica column eluting with a cyclohexane / AcOEt gradient from 0 to 100%. After concentration under pressure reduced, 12.8 g of propan-2-yl 3 - ( ⁇ 4 - [(diethoxyphosphoryl) methyl] phenyl ⁇ carbonyl) -2-ethylindolizine-7-carboxylate are obtained in the form of a brown oil which is used as such at room temperature. the next step.
• reaction mixture After 30 min at 0 ° C., the reaction mixture is cooled to -78 ° C. and then a solution of 1.17 g (3.47 mmol) of (R, S) / f-butyl ethyl [ 3-methyl-1-oxobutan-2-yl] carbamate in 5 mL of THF anh. It is allowed to return slowly to RT and stirring is continued for 18 hours. The reaction mixture is then cooled again to 0 ° C., treated with 30 ml of a saturated aqueous NH 4 CI solution and then extracted with 3 ⁇ 70 ml of AcOEt.
• reaction mixture is then taken up in 200 ml of AcOEt, washed successively with 100 ml of water, and 50 ml of brine, dried over Na 2 SO 4 , filtered and then concentrated under reduced pressure.
• the residue obtained is chromatographed on a silica column eluting with a cyclohexane / AcOEt gradient from 0 to 40% AcOEt.
• concentration under reduced pressure 2.45 g of (3R) -1- (ie / f-butoxycarbonyl) piperidin-3-yl 3 - [(4 - ⁇ [(3R) -1- (ie / f) are obtained.
• solubility results S are expressed in mg / ml.
• the compounds of the formula of the present invention have a solublity S ⁇ 4 mg / mL at pH ⁇ 4. Among them we can mention the solubilities of the following compounds in the table below:
• the heart was exposed after a left thoracotomy and supported by a pericardial cradle.
• the animals are ventilated by respiratory assistance (Air / Oxygen).
• the analysis of the blood gases (p0 2 , pC0 2 ) was performed at regular intervals to control the oxygen supply given by the respirator and maintain a p0 2 > 100 mmHg and a pC0 2 ⁇ 35 mmHg.
• Millar PC 350 electronic catheters are implanted in the left femoral artery (BPs / d: English abbreviations for blood pressure systolic / distolic), the pulmonary artery and in the left ventricle via the artery.
• BPs / d English abbreviations for blood pressure systolic / distolic
• pulmonary artery and in the left ventricle via the artery.
• right carotid LVP, LVEPD, and HR: English abbreviations for left ventricular pressure, left ventricular end-diastolic pressure and heart rate respectively.
• ECGs Bipolar surface electrocardiograms
• Electrophysiological data are recorded and stored continuously on the hard disk of a computer via an online acquisition and analysis system (Hem Notocord Evolution, Croissy-sur-Seine, France).
• Left and right atrial refractions are measured according to the S1-S2 incrementation protocol with baseline cycle lengths of 240, 300 and 400ms before and after administration of the vehicle or test compound at regular intervals (15, 30, 60, 90, 120 min).
• the QT interval assessment was performed during right atrial pacing, the frequency of which was increased by 10 beats per minute relative to the sinus rate during the first 15 minutes after administration to avoid having to correct the duration of the procedure.
• QT interval and monophasic action potential (MAP) versus heart rate For this purpose, a stimulation electrode is placed on the proximal portion of the right atrium. This procedure differentiates between compounds that affect ventricular repolarization (prolongation of the QT interval is an undesirable effect because it promotes ventricular arrhythmias).
• Electrophysiological recording identifies typical side effects that are often related to blocking potassium, sodium and calcium channels at the cardiac level (QT prolongation, atrioventricular block, conduction delays). Hemodynamic monitoring makes it possible to distinguish adverse effects related to inappropriate blocking of potassium channels [increase in blood pressure (BP) and pulmonary pressure (PP)], sodium and calcium channels (negative inotropic effects, fall in blood pressure). .
• BP blood pressure
• PP pulmonary pressure
• the compound of the invention is evaluated on 2 to 4 pigs at 3 mg / kg iv, bolus or infusion 15 min, and with 3 pacing frequencies (150, 200 and 250bpm).
• the results obtained are expressed in% increase in right and left atrial refractory periods (LAERP and RAERP respectively), in% decrease in left atrial vulnerability (episodes of S2-induced atrial fibrillation, LAV) compared to the base and the duration of action is expressed in hours (h).
• the compounds according to the invention have an interesting pharmacological activity, especially antiarrhythmic properties.
• the compounds according to the invention can therefore be used for the preparation of medicaments, in particular antiarrhythmic drugs.
• the subject of the invention is medicaments which comprise a compound of formula (I), or an addition salt thereof to a pharmaceutically acceptable acid of the compound of formula (I).
• Atrial tachyarrhythmia atrial fibrillation, atrial flutter, atrial tachycardia, ventricular tachyarrhythmia, ventricular extrasystoles, ventricular tachycardia, ventricular flutter and fibrillation; angina pectoris, hypertension, cerebral circulatory insufficiency, cardiac insufficiency, myocardial infarction with or without cardiac insufficiency or the prevention of post-infarction stroke.
• the invention relates to the use of a compound of formula (I) for the preparation of a medicament for the treatment of pathological syndromes of the cardiovascular system.
• the present invention relates to pharmaceutical compositions comprising, as active principle, a compound according to the invention.
• These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt of said compound, as well as at least one pharmaceutically acceptable excipient.
• Said excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known to those skilled in the art.
• the active ingredient of formula (I) above, or its salt may be administered in unit dosage form, in admixture with conventional pharmaceutical excipients, to animals and humans for the treatment of the above disorders or diseases.
• Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal forms of administration by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants.
• the compounds according to the invention can be used in creams, gels, ointments or lotions.
• a unitary form of administration of a compound according to the invention in tablet form may comprise the following components:
• the dosage appropriate to each patient is determined by the physician according to the mode of administration, the weight and the response of said patient.
• the present invention also relates to a method of treatment of the pathologies indicated above which comprises

Landscapes

• Chemical & Material Sciences (AREA)
• Health & Medical Sciences (AREA)
• Organic Chemistry (AREA)
• Life Sciences & Earth Sciences (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Cardiology (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Heart & Thoracic Surgery (AREA)
• Urology & Nephrology (AREA)
• Vascular Medicine (AREA)
• Epidemiology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=43923771

Family Applications (1)

Country Status (14)

Families Citing this family (1)

Family Cites Families (5)

• 2010
  • 2010-11-17 FR FR1059445A patent/FR2967412B1/fr not_active Expired - Fee Related
• 2011
  • 2011-11-16 US US13/885,866 patent/US20130245006A1/en not_active Abandoned
  • 2011-11-16 CA CA2818279A patent/CA2818279A1/fr not_active Abandoned
  • 2011-11-16 MX MX2013005624A patent/MX2013005624A/es not_active Application Discontinuation
  • 2011-11-16 WO PCT/FR2011/052661 patent/WO2012066234A1/fr active Application Filing
  • 2011-11-16 JP JP2013539312A patent/JP2014500256A/ja not_active Withdrawn
  • 2011-11-16 RU RU2013127239/04A patent/RU2013127239A/ru not_active Application Discontinuation
  • 2011-11-16 BR BR112013012300A patent/BR112013012300A2/pt not_active IP Right Cessation
  • 2011-11-16 EP EP11796752.1A patent/EP2640724A1/fr not_active Withdrawn
  • 2011-11-16 CN CN201180065218XA patent/CN103313986A/zh active Pending
  • 2011-11-16 SG SG2013038138A patent/SG190825A1/en unknown
  • 2011-11-16 AU AU2011330996A patent/AU2011330996A1/en not_active Abandoned
  • 2011-11-16 KR KR1020137015316A patent/KR20140014082A/ko not_active Application Discontinuation
• 2013
  • 2013-05-16 IL IL226388A patent/IL226388A0/en unknown

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events