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  • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

• the present invention relates to new isoquinoline derivatives, their synthesis and their use in the prevention and / or treatment of pathologies that result from activation of the RhoA / ROCK pathway and phosphorylation of the myosin light chain.
• agonists such as angiotensin II, 5-hydroxytryptamine or Pendothelin
• membrane protein RhoA belonging to the family of small GTP-related proteins, acquires the active GTP-related configuration under the control of specific exchange of adenyl nucleotides. This active membrane form allows the binding to the Rhokinase protein and the activation of the latter.
• Rhokinase is a serine / threonine kinase with a molecular weight of 160 kdaltons and one of the many targets of the RhoA protein.
• Two isoforms of Rho-kinase, Rhokinase ⁇ / ROCK ⁇ / plOROCK or ROCK1 and Rho-kinase oc / ROCK a or ROCK2, encoded by two different genes, have been identified. Both isoforms are ubiquitously expressed, ROCK2 particularly in vascular smooth muscle cells, the heart and the brain.
• ROCK1 is preferentially expressed on non-nervous tissues such as the lung, liver, spleen, kidney and testes.
• RhoA-GTP The activation of ROCK by RhoA-GTP leads to the phosphorylation and inhibition of a regulatory subunit of myosin phosphatase and thus allows to maintain the myosin light chain in a phosphorylated state, regardless of the Ca concentration. intracellular (so-called Ca 2+ sensitization process). Phosphorylation of the myosin light chain is responsible for the increased contractility of the actin cytoskeleton, which results from slippage between the actin and myosin filaments.
• RhoA / ROCK pathway Activation of the RhoA / ROCK pathway is implicated in the following dysfunctions and the pathologies associated with them: vasoconstriction by increased myogenic tone (Rattan et al, Pharmacological Sciences, 880: 1-10, 2011),
• diabetes hyperglycemia, insulin resistance, diabetic nephropathies (Kikuchi et al, J. Endocrinol., 192: 595-603, 2007; Kolavennu et al, Diabetes, 57: 714-723, 2008) and renal failure, renal fibrosis, nephrosclerosis (Matsuoka et al, J. Hypertens, 26 (9): 1837-48, 2008),
• liver astrocytes and liver diseases such as cirrhosis, hepatitis and cancer (WO2000064478A1, 2000),
• neuronal degeneration such as Alzheimer's disease (Zhou et al., Science, 302: 1215-1217, 2003; Song et al., CNS Neurosci, Ther., 19, 603-610, 2013), neuropathic pain (Xiao et al, Brain , Behavior and Immunity, 23 (8): 1083-88, 2009),
• a compound that has the ability to inhibit Rho kinase and phosphorylation of the myosin light chain could prevent or treat cardiovascular or non-cardiovascular diseases such as: systemic hypertension, pulmonary arterial hypertension , glaucoma, retinopathies, optic nerve degeneration, corneal pathologies, coronary heart disease such as angina, myocardial infarction, post-angioplasty restenosis, aortic aneurysm, arterial occlusion peripheral disorders, atherosclerosis, cardiac fibrosis and heart failure, erectile dysfunction, broncho-obstructive pulmonary diseases such as asthma or adult respiratory distress syndrome, post-radiation bowel fibrosis, multiple sclerosis cutaneous systemic, pulmonary fibrosis associated with pulmonary arterial hypertension, prevention or treatment of liver diseases s, fibrosis and renal glomerulosclerosis, diabetic nephropathies induced or not by hypertension, thrombotic diseases, cerebral vasospasm and resulting cerebral
• the application WO2005 / 035 503 describes Rho kinase inhibitors for the treatment of glaucoma.
• EP 0 187 371 discloses Rho kinase inhibitors having an isoquinoline backbone with a sulfonamide function for the treatment of glaucoma, and in particular Fasudil.
• the present invention relates to compounds of formula (I)
• Ri t represents a hydrogen atom or a hydroxyl group, it being understood that the compounds of formula (I) for which R 1 represents a hydroxyl group may be represented in the following tautomeric form:
• R 1 and R 3 which are identical or different, each represent a hydrogen atom, a (C 1 -C 6 ) alkyl group or a halogen atom,
• Ri 6 , Ri 7 and Ri 8 which may be identical or different, each represent a hydrogen atom or a halogen atom
• Rai and Ra identical or different, each represent a hydrogen or halogen atom, a -O (C 1 -C 6 ) alkyl group or a (C 1 -C 6 ) alkyl group,
• Ra 2 represents a hydrogen or halogen atom, a hydroxyl group, a -CXQ-C4 alkyl group, a (C 1 -C 6 ) alkyl group, a 3 to 7-membered nitrogen heterocycle or a group -O- (CH2) m -NR'R ",
• Ra 3 represents a hydrogen atom, a group -O (C 1 -C 6 ) alkyl, a group - (C 1 -C 6 ) alkyl, a nitrogenous heterocycle having from 3 to 7 members, or a group -CRy 1 Ry 2 NH (Ry 3 )
• R 4 represents a hydrogen or halogen atom, a group -0 (C 1 - C 6) alkyl, a - (Ci-C 6) alkyl, or a group
• Ra l5 Ra 2 , Ra 3 , Ra 4 and Ra 5 can not simultaneously represent a hydrogen atom, • Ra 3 and Ra 4 can not simultaneously represent a group -CRy 1 Ry 2 NH (Ry 3 ),
• Rai and Ra 2 may together form with the carbon atoms which carry them a 4- to 7-membered heterocycle selected from tetrahydrofuran, 1,4-dioxane, tetrahydropyran, tetrahydro-2H-pyran-4-amine or 1- (tetrahydro-2H-pyran-4-yl) methanamine, and
• Ra 2 and Ra 3 may form together with the carbon atoms which carry them a 4- to 7-membered hydrogen-carbon ring selected from cyclopentane, cyclopentanamine, N-cyclopentylglysinamide or 1-methylcyclopentanamine,
• n is an integer whose value is set to 1, 2 or 3,
• R 'and R " which are identical or different, each represent - (Q-C 6 ) alkyl groups, or together form, with the nitrogen atom which carries them, a heterocycle having from 3 to 7 members,
• - Ry ! represents a hydrogen atom, a - (C 1 -C 6 ) alkyl group, a -CH 2 -cyclohexyl group, or a 3-methoxyphenyl group,
• Ry 2 represents a hydrogen atom or a (C 1 -C 6 ) alkyl group
• a group -C ( O) -CHRy 4 -NHRy 5 with Ry 4 representing a hydrogen atom or a group (C 1 -C 6 ) alkyl and Ry 5 representing a hydrogen atom or a methyl group, or
• a -C 1 -C 4 alkyl group which may be substituted with a hydroxyl group, a -O (C 1 -C 3 ) alkyl group, a cyclohexyl group or a methylsulfonyl group,
• pharmaceutically acceptable acids mention may be made, without limitation, of hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic and methanesulphonic acids. N-toluenesulfonic, benzenesulfonic, camphoric, pamoic, 1,5-naphthalenedisulfonic.
• the (C 1 -C 6 ) alkyl groups may be linear or branched.
• this heterocycle is preferably chosen from morpholine, pyrrolidine, piperidine or N- methylpiperidine.
• Ra 2 or Ra 3 represents a nitrogen heterocycle having 3 to 7 members
• this heterocycle may be chosen from the following nonlimiting list: aziridine, azetidine, imidazoline, pyrrolidine, piperidine, piperazine, imidazole, pyrrole, pyridine, pyrimidine, pyridazine , 1,2,3,4-Tetrahydropyrimidine, hexahydropyrimidine, hexahydropyridazine.
• Another aspect of the invention relates to the compounds of formula (I) for which R 1 represents a hydroxyl group, their optical isomers when they exist, as well as their addition salts with a pharmaceutically acceptable acid and their hydrates.
• R 1 or R 3 represents a (C 1 -C 6 ) alkyl group, more particularly a methyl group. or ethyl, their optical isomers when they exist, as well as their addition salts with a pharmaceutically acceptable acid and their hydrates.
• Another aspect of the invention relates to the compounds of formula (I) for which Ri 2 and / or Ri 3 represent a hydrogen atom, their optical isomers when they exist, as well as their addition salts with a pharmaceutically acid acceptable and their hydrates.
• Another aspect of the invention relates to the compounds of formula (I) for which Ri 6 and / or Ri 7 and / or Ri 8 represent a hydrogen atom, their optical isomers when they exist, as well as their salts. addition to a pharmaceutically acceptable acid and their hydrates.
• Another aspect of the invention relates to the compounds of formula (I) for which Ri 2 , Ri 6 , Ri 7 and Ri 8 each represent a hydrogen atom, their optical isomers when they exist, as well as their salts. addition to a pharmaceutically acceptable acid and their hydrates.
• Another aspect of the invention relates to the compounds of formula (I) for which Rai and / or Ra represent a hydrogen atom or a halogen atom, more particularly a chlorine or fluorine atom, their optical isomers when they exist, as well as their addition salts with a pharmaceutically acceptable acid and their hydrates.
• Another aspect of the invention relates to compounds of formula (I) wherein Rai and R 5 each represent a fluorine atom, their optical isomers when they exist, and addition salts thereof with a pharmaceutically acceptable acid, and hydrates.
• Another aspect of the invention relates to the compounds of formula (I) for which Ra 2 represents a hydrogen atom, their optical isomers when they exist, as well as their addition salts with a pharmaceutically acceptable acid and their hydrates.
• Ra 3 and Ra 4 represent a hydrogen atom or a group -CRy ! Ry 2 NH (Ry 3 ), being understood that Ra 3 and Ra 4 can not simultaneously represent a group -CRy ! Ry 2 NH (Ry 3 ), their optical isomers when they exist, as well as their addition salts with a pharmaceutically acceptable acid and their hydrates.
• Another aspect of the invention relates to the compounds of formula (I) for which Ra 3 or Ra 4 represents a group -CRy ! Ry 2 NH (Ry 3 ), their optical isomers when they exist, as well as their addition salts with a pharmaceutically acceptable acid and their hydrates.
• Ra 3 or Ra 4 represents a group -CRy 1 Ry 2 NH (Ry 3 ) and:
• - Ry ! represents a hydrogen atom or a - (C 1 -C 6 ) alkyl group
• Ry 2 represents a group - (C 1 -C 6 ) alkyl
• Ry 3 represents a hydrogen atom
• Another aspect of the invention relates to the compounds of formula (I) for which Ra 3 represents a group -CRy ! Ry 2 NH (Ry 3 ) and Rai and Ra 2 together with the carbon atoms carrying them a heterocycle having from 4 to 7 members, their optical isomers when they exist, as well as their addition salts with a pharmaceutically acid acceptable and their hydrates.
• a heterocycle is chosen from tetrahydrofuran, 1,4-dioxane or tetrahydropyran.
• Another aspect of the invention relates to compounds of formula (I) for which Ra 3 represents a hydrogen atom and Ra 2 and Ra 2 together with the carbon atoms carrying them form a heterocycle having from 4 to 7 members, their optical isomers when they exist, as well as their addition salts with a pharmaceutically acceptable acid and their hydrates.
• a heterocycle is chosen from tetrahydro-2H-pyran-4-amine or 1- (tetrahydro-2H-pyran-4-yl) methanamine.
• Another aspect of the invention relates to the compounds of formula (I) for which Ra 2 and Ra 3 together with the carbon atoms which carry them have a 4- to 7-membered hydrogen-carbon ring, their optical isomers when they exist, as well as their addition salts with a pharmaceutically acceptable acid and their hydrates.
• such a hydrocarbon-based ring is chosen from cyclopentane and its derivatives, more particularly cyclopentanamine, N-cyclopentylglysinamide or 1-methylcyclopentanamine.
• cyclopentane and its derivatives more particularly cyclopentanamine, N-cyclopentylglysinamide or 1-methylcyclopentanamine.
• Rit represents a hydrogen atom or a hydroxyl group
• Ri 2 , Ri 6 , Ri 7 and Rig each represent a hydrogen atom and Ri 3 represents a hydrogen atom or a (C 1 -C 6 ) alkyl group,
• Rai and Ra 5 which are identical or different, each represent a hydrogen or fluorine atom, or a (Ci-C6) alkyl group,
• Ra 2 represents a hydrogen atom or a (C 1 -C 6 ) alkyl group
• Ra 3 represents a hydrogen atom, a piperidine group, or a group -CRy 1 Ry 2 NH (Ry 3 ),
• Ra 4 represents a hydrogen atom or a group -CRy 1 Ry 2 NH (Ry 3 ), it being understood that Ra 3 and Ra 4 can not simultaneously represent a group - CRy 1 Ry 2 NH (Ry 3 ), and that:
• Ra 3 representing a group -CRy 1 Ry 2 NH (Ry 3 ), Rai and Ra 2 may form together with the carbon atoms which carry them a tetrahydrofuran, 1,4-dioxane or tetrahydropyran group, or
• Ra 3 represents a hydrogen atom
• Rai and Ra 2 may form together with the carbon atoms which carry them a tetrahydro-2H-pyran-4-amine or 1- (tetrahydro-27J-pyran-4-yl) group
• methanamine, or Ra 2 and Ra 3 may form together with the carbon atoms which carry them a cyclopentanamine or 1-methylcyclopentanamine group
• Ryi represents a hydrogen atom, a (C 1 -C 6 ) alkyl group, or a -CH 2 -cyclohexyl group,
• Ry 2 represents a hydrogen atom or a (C 1 -C 6 ) alkyl group
• Ry 3 represents a hydrogen atom or a (C 1 -C 6 ) alkyl group which may be substituted by a hydroxyl group
• Another aspect of the invention relates to the compounds of formula (I) chosen from:
• rhodium and palladium catalysts that can be used to carry out the coupling reaction between the compound of formula (II) and the compound of formula (III)
• mention may be made, without limitation, of the following catalysts: ([Rh (CH 2) CH 2 ) 2 Ci] 2 J Rh (acac) (co) 2 (co cyclooctene) and the complex of tris (dibenzylideneacetone) dipalladium / chloroform (Pd 2 dba 3 -CHCl 3 ).
• organic solvents that can be used to carry out the coupling reaction between the compound of formula (II) and the compound of formula (III)
• This reduction reaction can be carried out in the presence of hydride donors, such as sodium tetraborohydride (NaBH 4 ).
• hydride donors such as sodium tetraborohydride (NaBH 4 ).
• the compounds of formula (Ib) thus obtained can then be converted into compounds of formula (Ic), in particular cases of compounds of formula (I) for which X represents - CH 2 -, by a new reduction reaction, which can be carried out in the presence of trifluoroacetic acid and triethylsilane:
• optically active forms of the compounds of formula (I) are obtained, either from optically active forms of the compound of formula (III), or by resolution of the racemic forms of the compounds of formula (I), according to methods known from the literature .
• the subject of the present invention is also pharmaceutical compositions containing as active principle a compound of formula (I), or its addition salt with a pharmaceutically acceptable acid, in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or vehicles. .
• compositions according to the invention mention will be made more particularly of those which are suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), per-or transcutaneous, nasal, rectal, perlingual, ocular or respiratory administration, and in particular single or coated tablets, sublingual tablets, capsules, capsules, suppositories, creams, ointments, dermal gels, injectable or drinkable preparations, aerosols, eye drops or nasal drops.
• compositions according to the invention contain one or more excipients or vehicles such as diluents, lubricants, binders, disintegrating agents, absorbents, dyes, sweeteners.
• excipients or vehicles such as diluents, lubricants, binders, disintegrating agents, absorbents, dyes, sweeteners.
• ⁇ for diluents lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycerin,
• ⁇ for lubricants silica, talc, stearic acid and its magnesium and calcium salts, polyethylene glycol,
• ⁇ for the binders magnesium aluminum silicate, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone,
• ⁇ for disintegrators agar, alginic acid and its sodium salt, effervescent mixtures.
• the percentage of active ingredient of formula (I) in the pharmaceutical composition is preferably between 5% and 50% by weight.
• the appropriate dosage varies according to the age and weight of the patient, the route of administration, the nature and severity of the condition, and any associated treatments and ranges from 0.5 mg to 500 mg. one or more shots per day.
• Boc 2 0 di-tert-butyl dicarbonate
• Hepes 4- (2-hydroxyethyl) -1-piperazine ethanesulfonic acid
• HRMS high resolution mass spectrometry (high resolution mass spectrometry)
• KHMDS potassium hexamethyl disilazane
• Tris trishydroxymethylaminomethane or 2-amino-2-hydroxymethyl-1,3-propanediol
• Infrared spectra were recorded using a Bruker TENSOR 27 Fourier Transform Spectrometer in ATR mode.
• the mass spectra are recorded on a TSQ 7000 spectrometer.
• the chromatographies were carried out with a MERCK 60 silica gel (0.040-0.063 mm) or with Interchim or Grace prepacked silica columns.
• the filtrations were carried out on Millipore type GVHP (0.22 ⁇ ) filters for the organic phases and on filters of the Whatman GF / A cat. No 1820-070 for aqueous phases.
• Intermediate 754 was prepared from Intermediate 2 according to the following protocol: To a solution of concentrated H 2 SO 4 (48 mL) at room temperature is added Intermediate 2 (10 g, 48 mmol), then N-chlorosuccinimide (25 g, 187 mmol). The The mixture is heated at 80 ° C for 5 days. The reaction medium is poured into an ice / water mixture (33 g / 300 ml) and then a solution of 28% NH 4 OH is added until the pH is 8. The precipitate formed is filtered off and then dissolved in AcOEt. The organic phase is dried over MgSO 4 , the concentration in vacuo gives intermediate 754 as a beige solid (11 g) which can be used without further treatment in the next step.
• IR 1 1607, 1568, 830, 631.
• Protocol III Preparation of isoquinoline carbonyl intermediates according to a halogenated metal exchange reaction followed by a formylation.
• intermediate 653 To a solution of 37% HCl (137 ml) is added intermediate 653 and the mixture is refluxed for 20 hours. After returning to ambient temperature, the precipitate is collected on sintered material, washed with acetone and dried in an oven at 50 ° C. under vacuum (10 -2 mbar) The hydrochloride of intermediate 654 is obtained in the form of a white solid (33 g) used in the next step without further purification.
• intermediate 158 tert-butyl [2- (4-bromo-3,5-difluorophenyl) propan-2-yl] carbamate is described below:
• Protocol VIII Obtaining ketones by reaction of a magnesian on benzonitriles
• methyl magnesium iodide (3M in diethyl ether) (17 mL, 51 mmol is added dropwise to a solution of commercial 4-bromo-3-methyl benzonitrile (10 g, 51 mmol). ) in diethyl ether (100 mL)).
• the reaction medium is refluxed for 16 hours.
• 60 ml of 6N hydrochloric acid are added, the medium is then heated under reflux for 6 hours.
• the aqueous and organic phases are separated and the aqueous phase is extracted with 40 ml of ethyl acetate.
• intermediate 36 (5.4 g, 20.6 mmol) dissolved in THF (75 mL) is treated with a solution of methyl magnesium bromide (3M in diethyl ether) ( 8.1 mL, 24 mmol). The medium is stirred with cooling to room temperature for 3 hours before being poured onto 1N aqueous HCl solution at 0 ° C. The product is extracted with AcOEt, the organic phase is washed with saturated aqueous NaCl solution, dried over MgSO 4 and then concentrated under vacuum. Intermediate 37 is obtained as a solid (3.6 g).
• Protocol XI Obtaining ketones by rearranging Fries
• Protocol XII Transformation of ketones into racemic amines
• This procedure is used to prepare the racemic amines in the form of hydrochlorides or free bases.
• Protocol XI 1b alternative method of converting ketones to racemic amines
• Protocol XIII Transformations of ketones into cholinated fert-butanesulfinyl amine intermediates
• reaction medium at room temperature is cautiously treated with methanol (56 ml) and then diluted with AcOEt (300 ml) and an aqueous NaCl solution (700 ml).
• the resulting mixture is filtered through Celite ® , which is rinsed with THF and AcOEt.
• the filtrate is decanted, the organic phase is dried over MgSO 4 .
• Evaporation under reduced pressure leads to the production of a white solid, which is purified on silica gel using an elution gradient AcOEt / methylene chloride 0/100 to 40/60.
• Diastereoisomer 286 (18 g) is isolated as a white solid.
• Protocol XIV Transformation of commercial aldehydes into chiral tert-butanesulfinylamine intermediates.
• intermediate 497 N- [1- (3,5-difluorophenyl) -2-methylpropyl] -2-methylpropane-2-sulfonamide is described below:
• intermediate 496 To a solution of intermediate 496 (3 g, 12 mmol) in THF (60 mL), cooled to -65 ° C is added a solution of isopropylMgBr (3M / ether) (9 mL, 27 mmol) in 20 minutes. After checking, the reaction mixture is hydrolysed at -40 ° C. with saturated aqueous NH 4 Cl solution. The medium is decanted in the presence of ethyl ether, the organic phase is washed with a saturated solution of NaCl, dried over MgSO 4 and then concentrated. Chromatography on silica (eluent CH 2 Cl 2 / AcOEt 99/1 to 85/15) leads to obtaining intermediate 497 (2.7 g) in the form of an oil.
• silica eluent CH 2 Cl 2 / AcOEt 99/1 to 85/15
• Protocol XV Preparation of tert-butyl carbamate derivatives
• the chiral auxiliary was cleaved in an acid medium according to the following protocol:
• Protocol XVI Preparation of trifluoroacetamide derivatives
• a suspension of the intermediate obtained above (5 g, 11 mmol, 1 eq) in diethylaniline (7 mL) is heated in the microwave oven (EMC, DISCOVER, standard mode) for 40 minutes at 210 ° C.
• the reaction medium is poured into a water / ice / AcOEt mixture (0.2 L / 0.2 kg / 0.2 L) with stirring, then treated with 12N HCl to pH 1 stable, the organic phase is washed saturated NaCl solution (IL) and then dried over MgSO 4 .
• Evaporation under reduced pressure leads to the production of an oil which is chromatographed on silica gel using a CH 2 Cl 2 / cyclohexane (30/70 to 50/50) eluent mixture.
• the mixture of two compounds a and b (2.3 g) is obtained in the form of a yellow oil (ratio a / b: 56/43).
• Intermediates 145 and 146 can also be obtained from intermediates 166 and 161, respectively, using the conditions of protocol XV.
• Intermediate 166 :
• Intermediate 13 can also be obtained from Intermediate 459 using the conditions of Protocol XV.
• Intermediate 116a is obtained in the form of a brown solid (7 g) (which can be chromatographed on silica gel (cyclohexane / methylene chloride 80/20 to 0/100)).
• the reaction medium is stirred for 72 hours at room temperature, and then it is poured on water.
• the precipitate collected on sintered material is dried under vacuum.
• reaction mixture is stirred for 72 hours at room temperature, then it is poured into water and extracted with ethyl ether. The organic phase is washed with water, dried over

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