Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems

Definitions

• the present invention relates to dihydropyrazino [1,2-a] indole-1-one derivatives, their preparation and their therapeutic use.
• R- L and R 2 each independently of one another represent either a hydrogen atom, a halogen atom, an amino group, a hydroxy group, a nitro group, or a cyano group , either a (C ⁇ Cg) alkyl group, or a (CACg) alkoxy group, or a trifluoromethyl group, or a trifluoromethoxy group, or a group -COOH, or a group -COOR 4 , or a group -CONH 2 , or a group -C0NHR 4 , or a group -CONR 4 R 5 / or a group -SR 4 , or a group -S0 2 R 4 , or a group -NHCOR 4 , or a group -NHS0 2 R 4 , or a group -N (R 4 ) 2 where R 4 and R 5 are each a group
• Q represents either two hydrogen atoms or one oxygen atom
• Z represents either a nitrogen atom or a group -CH-
• A represents either a group (1) or a group (2)
• B being chosen from oxygen and sulfur atoms and the groups -NH- and -N (R 4 ) - and R 6 being, independently of R x and R 2 , either a hydrogen atom or a d atom halogen or an amino group or a hydroxy group, a nitro group, a cyano group or a (C ⁇ ⁇ -C6) alkyl or a (C 1 -C 6) alkoxy, or a group trifluoromethyl, either a trifluoromethoxy group, or a group -COOH, or a group -COOR 4 , or a group -CONH 2 , or a group -CONHR 4 , or a group -CONR 4 R 5 or a group -SR 4 , or a group -S0 2 R 4 , either a group -NHCOR 4 , or a group -NHS0 2 R 4 , or a group -N (R 4 ) 2 where R 4 and R 5
• the preferred compounds are the compounds of formula (I) in which
• R x and R 2 each represent independently of one another, either a hydrogen atom, or a halogen atom, or a cyano group, or a (C 1 -C 6 ) alkoxy group, or a group
• R g is a hydroxy group or -NR 4 R 5
• (CH) n C0NAA where AA is an amino acid residue
• a group - (CH 2 ) n C0NHR 4 where R 4 and R 5 are each a (C 1 -C 4 ) alkyl group, n is equal to
• Q represents either two atoms of hydrogen, or one atom of oxygen
• Z represents either a nitrogen atom or a -CH- group
• A represents either a group (1) or a group (2)
• R 4 and R 6 being, independently of R and R 2 , either a hydrogen atom, a halogen atom, or a (C 1 -C 6 ) alkyl group, or a (C 1 -C 6 ) alkoxy group, or a trifluoromethyl group, or a group - NHC0R 4 , or a group -NHS0 2 R 4 where R 4 and R 5 are each a (C 1 -C 4 ) alkyl group, as well as their addition salts with acids or with pharmaceutically acceptable bases.
• the particularly preferred compounds according to the invention are the compounds of formula (I) in which
• R represents a halogen atom and R 2 a hydrogen atom
• R 3 represents either a (C ⁇ Cg) alkyl group, or a group - (CH 2 ) p 0H, or a group - (CH 2 ) n C0NH 2 , or a group
• Z represents either a nitrogen atom or a group -CH-
• A represents either a group (1) or a group (2)
• R 4 and R 5 are each a group (C 1 -C 4 ) alkyl, as well as their addition salts with pharmaceutically acceptable acids or bases.
• Certain compounds of formula (I) may exist in the form of racemates, pure enantiomers or a mixture of enantiomers which are also part of the invention.
• a compound of formula (II) is reacted (in which R and R 2 are as defined above) with ethanedioyl dichloride at room temperature in an aprotic solvent such as ether to prepare an intermediate compound which is taken up in an alcohol comprising from 1 to 4 carbon atoms , for example ethanol, and a compound of formula (III) is obtained which is treated pa a hydride in an aprotic solvent such as, for example, lithium aluminum hydride in tetrahydrofuran at room temperature.
• an aprotic solvent such as, for example, lithium aluminum hydride in tetrahydrofuran at room temperature.
• a compound of formula (IV) is then obtained, the alcohol function of which is protected by a protective group P, for example by treatment with (1,1-dimethylethyl) dimethylsilyl chloride in the presence of a weak base such as imidazole and a compound of formula (V) is obtained which is subjected to a lithiation directed by successive treatments with a strong base such as for example n-butyllithium at ⁇ 70 ° C.
• R 3 H sodium in dimethylformamide at room temperature and then with chloroacetonitrile to obtain a compound of formula (VII) whose nitrile function is reduced by conventional techniques known to those skilled in the art, for example by Raney nickel, diborane or hydrogen in the presence of palladium or platinum, and a compound of formula (VIII) is obtained which is cyclized by heating in the presence of a base in a polar solvent such as for example sodium ethylate in ethanol to obtain a compound of formula (IX).
• a polar solvent such as for example sodium ethylate in ethanol
• Iodine is performed ortho to the amino function of a compound of formula (XV) in which R and / or R 2 represent either a nitro group or a cyano group, for example with iodine monochloride in an aprotic solvent as Diagram 2
• the compounds of formula (Ie) are prepared in which R x and / or R 2 represent either an amino group, or a group -COOH, or a group -COOR 4 , or a group -CONH 2 , or a group -CONHR 4 , either a group -CONR 4 R 5 , or a group -NHC0R 4 , or a group -NHS0 2 R 4 , or a group -N (R 4 ) where R 4 and R 5 are each a group (C x -C 4 ) alkyl, from the corresponding compounds of formula (Ie) in which R x and / or R 2 represent either a nitro group or a cyano group, by conventional techniques known to those skilled in the art.
• R ⁇ and / or R 2 represent either an amino group, or a nitro group, or a cyano group, or a group - COOH, either a group -COOR 4 , or a group -C0NH 2 , or a group -CONHR 4 , or a group -CONR 4 R 5 / or a group -NHC0R 4 , or a group -NHS0 2 R 4 , or a group -N (R 4 ) 2 where R 4 and R 5 are each an (C 1 -C 4 ) alkyl group, R 3 is a hydrogen atom, Q represents two hydrogen atoms and A and Z are such that defined previously then the compound of formula (IX) is deprotected according to conventional techniques known to those skilled in the art and the procedure is continued according to the various steps described above for the compounds of formula (Ib).
• a compound of formula (VI) in which R x R 2 and P are as defined above is reacted with a compound of formula C1CH 2 C0 2 R in which R represents an (C 2 -C 6 ) alkyl group in the presence of '' a strong base such as
• the starting compounds are commercially available or described in the literature or can be prepared according to methods which are described therein or which are known to those skilled in the art.
• VIII is inspired by the method described by S. Inaba et al., Chem. Pharm. Bull. , ___, n ° 8, pp. 1628-1636 (1972) and those described in US patents US 4,022,778, and German DE 1906,254, DE 2005,845 and DE 2017,857.
• Certain 3- (piperazin-1-yl) benz [d] isoxazoles are prepared according to known methods such as, for example, those described by J. Yevich et al., J. Med. Chem. , 2_, n ° 3, pp 359-369 (1986), described in patent applications WO 9412495 and in US patents 4,355,037 and US 5,143,923.
• 6-fluoro-3- (piperidin-4-yl) -1-methylindazole is prepared according to the method described in the patent applications
• Example 1 7-fluoro-10- [2- [4- (6-fluoro-1, 2-benzisothiazol-3-yl) iperazin-1-yl] ethyl] -2-methyl- hydrochloride 3, 4- dihydropyrazino [1, 2-a] indol-1 (2H) -one (2: 1)
• the mixture is stirred for 16 hours under a pressure of 0.1 MPa (1 atm) of hydrogen at room temperature.
• the reaction mixture is then filtered on celite and rinsed several times with ethanol.
• the filtrate is concentrated to dryness, then the residue is taken up in 100 ml of absolute ethanol.
• 0.10 g of sodium ethylate is added and the solution is heated at 60 ° C for 1.5 hours.
• the reaction medium is evaporated to dryness and then taken up in 200 ml of ethyl acetate. This solution is washed with water and the organic phase is dried over sodium sulfate, filtered and concentrated.
• the residue is purified by chromatoflash on silica, eluting with a ⁇ -heptane: ethyl acetate mixture (1: 1) containing traces of ammonia.
• the temperature of the reaction medium is allowed to return to room temperature and it is left stirring for 4.5 hours at this temperature.
• the reaction medium is acidified to pH 2 with a 6N aqueous hydrochloric acid solution.
• the yellow precipitate obtained is drained and taken up in a solution of 14 g of sodium carbonate in 200 ml of hot water.
• the white precipitate thus obtained is drained, filtered and the filtrate is acidified to pH 1-2.
• the second white precipitate is drained, the precipitates are combined and dried in an oven at 40 ° C.
• the reaction medium is then evaporated to dryness and the residue is taken up in 150 ml of dichloromethane.
• the solution is washed with water and then with a saturated aqueous solution of sodium chloride.
• the organic phase is dried over sodium sulfate, filtered and concentrated.
• the hydrochloride is prepared in a methanol mixture: 2N hydrochloric ether
• Example 2 7-fluoro-10- [2- [4- (6-fluoro-1, 2-benzisothiazol-3-yl) hydrochloride piperidin-1-yl] ethyl] -l- oxo-1,2,3,4-tetrahydro-pyrazino [1, 2-a] indole-2-acetamide (1: 1)
• the filtrate is diluted with 200 ml of dichloromethane and washed with water.
• the organic phase is recovered, dried over sodium sulfate, filtered and concentrated.
• the residue is purified by chromatography on a column of silica gel, eluting successively with an n-heptane: ethyl acetate mixture (1: 4), with ethyl acetate and then with an ethyl acetate: methanol mixture. (95: 5).
• the reaction mixture is cooled to room temperature and then diluted in 150 ml of dichloromethane and 50 ml of water.
• the organic phase is decanted, dried over sodium sulfate, filtered and concentrated.
• the residue is purified by chromatoflash on silica, first eluting with an ethyl acetate: methanol mixture (95: 5) containing traces of ammonia, then with a dichloromethane: methanol mixture (9: 1) also containing traces of ammonia.
• the hydrochloride is prepared in a methanol mixture: 2N hydrochloric ether.
• Example 3 (Compound No. 10) 7-fluoro-10- [2- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) piperidin-1-yl] ethyl] -1-oxo- hydrochloride 1,2,3,4-tetrahydropyrazino [1,2-a] indole-2-acetamide (1: 1)
• reaction medium is then evaporated to dryness and the residue is taken up in 150 ml of chloroform and 50 ml of water.
• organic phase is decanted, dried over sodium sulfate, filtered and concentrated.
• the residue is then purified by chromatoflash on silica, eluting with a dichloromethane: methanol mixture (95: 5 then 90:10) containing traces of ammonia.
• This solution is stirred at -70 ° C for 1 hour, the temperature of the reaction medium is allowed to rise to -30 ° C in one hour, it is hydrolyzed at -60 ° C by addition of 100 ml of a saturated aqueous chloride solution of ammonium and the mixture is extracted several times with ether. The organic phases are washed with water and then with a saturated aqueous solution of sodium chloride. Then dried over magnesium sulfate, filtered and concentrated. The residue is purified by chromotoflash on silica, eluting with ⁇ -heptane and then with an n-heptane: ethyl acetate mixture. (95: 5).
• the mixture is stirred for 1 hour at 0-5 ° C and then for 20 hours at room temperature, the reaction medium is then evaporated to dryness and the residue is taken up in 300 ml of chloroform. We wash this solution with water and the organic phase is dried over sodium sulfate, filtered and concentrated. The residue is purified by chromatoflash on silica, eluting with an ethyl acetate: methanol mixture (98: 2, 95: 5 then 90:10) containing traces of ammonia.
• reaction medium is then hydrolyzed by the addition of 10 ml of a saturated aqueous solution of ammonium chloride and then extracted with ether.
• organic phase is dried over magnesium sulfate, filtered and concentrated.
• residue obtained is purified by chromatoflash on silica, eluting with a mixture of ethyl acetate n-heptane (4: 1). 0.43 g (80%) of a pale yellow oil is obtained.
• the reaction mixture is cooled to room temperature, 50 ml of water are added and the mixture is extracted with dichloromethane. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue is purified by chromatoflash on silica first eluting with an ethyl acetate: methanol mixture (95: 5) containing traces of ammonia and then with a dichloromehane: methanol mixture (9: 1) also containing traces of ammonia. 0.085 g of base is obtained in the form of an off-white solid.
• Example 5 8-fluoro-10- [2- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) piperidin-1-yl] ethyl] -2-methyl- hydrochloride 3,4-dihydropyrazino [1,2-a] indol-1 (2H) -one (1: 1)
• the reaction mixture is evaporated to dryness and the residue is taken up in 150 ml of chloroform.
• the solution is washed with water and then with a saturated aqueous solution of sodium chloride.
• the organic phase is dried over sodium sulfate, filtered and concentrated.
• Example 6 8-fluoro-10- [2- [4- (4-fluorobenzoyl) piperidin-1-yl] ethyl] -2-methyl-3,4-dihydropyrazino hydrochloride [1,2- a] indol-1 (2H) -one (1: 1)
• the reaction mixture is evaporated to dryness and the residue is taken up in 150 ml of chloroform.
• the solution is washed with water and then with a saturated aqueous solution of sodium chloride.
• the organic phase is dried over sodium sulfate, filtered and concentrated.
• the product is purified by chromatoflash on silica, eluting with an ethyl acetate: methanol mixture (95: 5 then 90:10) containing traces of ammonia.
• the hydrochloride is prepared in a methanol mixture: 2N hydrochloric ether
• Example 8 (compound No. 41) 8-fluoro-10- [2- [4- (4-fluorobenzoyl) piperidin-1-yl] ethyl] -2- (2-hydroxyethyl) -3,4-dihydropyrazino hydrochloride 1,2-a] indol-1 (2H) -one (1: 1)
• Example 9 (compound No. 7) 8-cyano-10- [2- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) piperidin-1-yl] ethyl] -2-methyl- hydrochloride 3, 4 -dihydropyrazino [1,2-a] indol-1 (2H) -one (1: 1)
• the reaction medium is diluted in 600 ml of ethyl acetate and the solution is washed with a 20% aqueous solution of sodium thiosulfate and then with a saturated aqueous solution of sodium chloride.
• the organic phase is dried over magnesium sulfate, filtered and evaporated to dryness.
• Extract with acetate ethyl and the organic phase is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated.
• the residue is purified by filtration on a silica pad, eluting first with ethyl acetate, then with a dichloromethane: methanol mixture (9: 1).
• the reaction medium is diluted in 700 ml of chloroform and the solution is washed with water and then with a saturated aqueous solution of sodium chloride.
• the organic phase is dried over sodium sulfate, filtered and concentrated.
• the residue is purified by chromatography on silica, eluting with a mixture of n-heptane: ethyl acetate (90:10, 85:15 then 75:25) containing traces of triethylamine.
• the mixture is stirred for 20 minutes at this temperature and then a solution of 14.7 ml (0.154 mol) of ethyl chloroformate diluted in 75 ml of tetrahydrofuran is added dropwise.
• the mixture is stirred at -70 ° C for 1.5 hours then the mixture is allowed to rise room temperature in 1 hour.
• the reaction medium is cooled to -60 ° C. and hydrolyzed by the addition of 450 ml of a saturated aqueous solution of ammonium chloride. It is extracted several times with ether and the organic phases are washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated.
• the reaction medium is evaporated to dryness and the residue is taken up in 300 ml of dichloromethane.
• the solution is washed with a saturated aqueous solution of ammonium chloride, then with a saturated aqueous solution of sodium chloride.
• the organic phase is dried over sodium sulfate, filtered and concentrated.
• the residue is purified by chromatoflash on silica, eluting with an n-heptane: ethyl acetate mixture (1: 1) containing traces of triethylamine. 3.57 g of product are obtained in the form of a pale yellow solid.
• reaction medium is evaporated to dryness and the residue is taken up in 100 ml of dichloromethane.
• the solution is washed twice with water and the organic phase is dried over sodium sulfate, filtered and then concentrated. 0.41 g of product is obtained in the form of a beige solid.
• Example 10 (Compound No. 8) 10- [2- [4- (6-fluoro-1,2,2-benzisoxazol-3-yl) piperidin-1-yl] ethyl] -2-methyl -1-oxo- hydrochloride 1, 2, 3,4-tetrahydropyrazino [1, 2-a] indole-8-carboxamide (1: 1)
• Example 11 hydrochloride of 10- [2- [4- (3-methoxybenzoyl) piperidin-1-yl] ethyl] -2 -methyl -3,4-dihydropyrazino [1,2-a] indol- 1 [2 H) -one (1: 1)
• N-acetylisonipecinic acid 10.0 g (58.41 mmol) of N-acetylisonipecinic acid are added to 60 ml of thionyl chloride with stirring at room temperature. After 15 minutes, 80 ml of petroleum ether are added, the solid is drained, rinsed with petroleum ether and dried under vacuum. The product obtained is suspended with 6.27 g (64.27 mmol) of N, O-dimethylhydroxylamine hydrochloride in 10 volumes of 1,2-dichloroethane at room temperature. 10.3 ml (0.13 mole) of pyridine are added dropwise and the mixture is stirred for 2 hours at this temperature.
• Example 12 (Compound No. 47) 10- [2- [4- (6-fluoro-1, 2-benzisoxazol-3- yl) piperidin-1-yl] ethyl] pyrazino [1,2-a] indole hydrochloride -1, 3- (2DD, 4H) - dione (1: 1)
• the hydrochloride is prepared in a methanol: 2N hydrochloric ether mixture.
• the reaction medium is then evaporated to dryness and the residue is taken up in 150 ml of dichloromethane.
• the solution is washed with water, the organic phase is dried over sodium sulfate, filtered and concentrated.
• the hydrochloride is prepared in a methanol mixture: 2N hydrochloric ether
• HC1 represents a hydrochloride and (x: y) the ratio (acid: base); the absence of any mention means that the compound is in the base form, - in the "Melting point" column: (d) corresponds to a fusion with decomposition. Board
• the compounds of the invention have been the subject of pharmacological studies which have demonstrated their antagonistic properties of serotonin and their advantage as substances with therapeutic activity.
• the compounds of the invention were subjected to a test for inhibition of the vasopressor effect of serotonin.
• Male rats Sprague-Dawley, Charles River France) weighing 250 to 300 g are used, which are anesthetized with sodium pentobarbital (60 mg / kg / ip) and which are maintained under artificial respiration (Harvard TM respirator - breathing rate of 70 ml per minute, air volume 1 ml per 100 g of body weight).
• the animals are amyele using a metal rod, introduced by the orbit of the right eye down along the spine.
• the right and left vagus nerves are sectioned (bivagotomy), the right carotid artery is ligated, the left carotid artery being catheterized to measure blood pressure using a pressure cell (Statham P23Db type).
• a femoral vein is catheterized for the administration of various compounds.
• the increases in mean arterial pressure induced by serotonin administered intravenously at a dose of 30 ⁇ g / kg are measured.
• the compounds of the invention or the vehicle are administered 5 minutes (for the i.v. studies) or 75 minutes (for the oral studies) before the administration of serotonin.
• the compounds of the invention are administered in doses ranging from 0.001 to 10 mg / kg.
• the percentage inhibition of the control response to serotonin is used to assess the antagonistic potential for serotonin of the compounds of the invention.
• the compounds of the invention have also been the subject of an inhibition test of the binding of [ 3 H] spiroperidol to the serotonergic receptors 5-HT 2 of the rat cerebral cortex.
• the homogeneous mixture is centrifuged at 40,000 xg for 10 minutes then, twice, the pellet is recovered, it is washed by suspending it in the same buffer mixture, it is homogenized again and it is centrifuged.
• the final pellet is diluted in the same buffer mixture at the rate of 500 mg of wet tissue per 10 ml of buffer.
• the tissue is then subjected to a preliminary incubation of 10 minutes at 37 ° C in the presence of 10 ⁇ m / 1 of pargyline, then to an incubation of 20 minutes at 37 ° C in the presence of 3 H-spiroperidol (specific activity: 19 Ci per mmol) at the concentration of 0.3 nM and of the compound to be studied at concentrations ranging from 0.0001 to 100 ⁇ M.
• the IC 50 is determined graphically, a concentration which inhibits 50% of the specific binding.
• the specific binding is defined as being the binding displaced by 100 ⁇ M of 5-HT.
• the IC 50 values of the compounds of the invention are less than 1 ⁇ M.
• the compounds of the invention have also been tested in a sumatriptan vasoconstriction model of the saphenous vein isolated from dogs (antagonistic activity at the level of the 5-HT 1 _ like receptor, according to HUMPHREY et al.
• Saphenous veins of Beagles or Anglopoitevin dogs are removed under pentobarbital anesthesia administered by intravenous injection.
• the vessel is cut into a helix 0.4 cm wide and then divided into segments 0.5 cm long.
• Each fragment, mounted between two clamps, is placed in a tank with isolated organs containing 20 ml of a physiological Krebs solution of the following composition (m): NaCl 118; KCl 4.7; MgCl 2 1.2; CaCl 2 2.6; NaHC0 3 25; Glucose 11.1; ascorbic acid 0.11.
• the organ maintained at 37 ° C under a current of carbogen (95% 0 2 -5% C0 2 ) at pH 7.4 is connected to a Hugo Sachs type 351 isometric sensor under a voltage basal of 2 g and connected to a Gould 2400S polygraph allowing the recording of blood pressure variations. Data acquisition is automated by microinformatics system.
• the organ is stimulated by 3 ⁇ M of noradrenaline in order to check its viability.
• a concentration-response contractile curve for Sumatriptan is then constructed cumulatively between 10 nM and 10 ⁇ M.
• the maximum contraction is obtained (plateau of the effect at two consecutive concentrations of Sumatriptan)
• the preparation is rinsed thoroughly by intercalating periods of rest to allow the organ to return to the initial tension.
• the compound to be studied is then added to the organ bath 15 minutes before a second concentration-response curve for Sumatriptan is constructed.
• the contraction responses obtained in the presence of the compound are expressed as a percentage of the maximum contraction observed during the first curve with Sumatriptan.
• the curves are analyzed by non-linear regression in order to determine the E max (maximum response) and the EC 50 (concentration producing 50% of the maximum response).
• K B [concentration of the compound in M] / (CR - 1) where CR represents the ratio of the EC 50 of Sumatriptan in the presence and in absence of the compound.
• sarcoma can be used in the treatment and prevention of various forms of pathology involving serotonin, such as arterial, venous, pulmonary, portal, renal or ocular hypertension, cardiac, renal, ocular, cerebral ischemia, or lower limbs, heart failure, myocardial infarction, angina, or coronary vasospasms peripheral, thrombosis (alone or as an adjunct to thro bolysis), arteritis, intermittent claudication, restenosis after angioplasty and various pathological conditions associated with atherosclerosis, microcirculation disorders or pulmonary dysfunctions. They can also be used, alone or in combination with other substances in vascular grafting procedures.
• serotonin such as arterial, venous, pulmonary, portal, renal or ocular hypertension, cardiac, renal, ocular, cerebral ischemia, or lower limbs, heart failure, myocardial infarction, angina, or coronary vasospasms peripheral, thrombosis (alone or as
• the compounds of the invention can be used in combination with other substances with cardiovascular or cardiopulmonary activity, such as antithrombotics, thrombolytics, ⁇ -blockers, calcium antagonists, thromboxane antagonists, thromboxane inhibitors synthetase.
• these compounds can be presented in any form suitable for oral or parenteral administration, such as tablets, dragees, capsules, capsules, topical ocular formulations in association with suitable excipients. These forms are dosed to allow administration of 0.1 mg to 1 g, one to several times a day.

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