SK42299A3 - N-(benzothiazol-2-yl) piperidine-1-ethanamine derivatives, their preparation and application in therapeutics - Google Patents

Abstract

The invention discloses compounds complying with general formula (I) in which n represents number 0, 1, 2 or 3, R1 represents one hydrogen or halogen atom or a methyl or methoxy group, R2 represents one hydrogen atom or one methyl group, and R3 represents one hydrogen atom or one or two halogen atoms. The invention is applicable in therapeutics.

Description

Technical field

The present invention relates to N- (2-benzothiazolyl) -1-piperidineaethanamine derivatives, a process for their preparation and pharmaceutical compositions containing them.

BACKGROUND OF THE INVENTION

Compounds with a similar chemical structure are described in European patent applications no. 0 184 257 and 0 199 400 and in Annales Pharmaceutiques Frangaises, vol. 35, no. 7, July 1977, pp. 295-307. None of these documents disclose compounds of the invention, nor does it relate to compounds having affinity for D4 dopaminergic receptors.

SUMMARY OF THE INVENTION

The present invention relates to compounds of formula I

wherein n is an integer of 0, 1, 2 or 3;

R ¹ is a hydrogen atom, a halogen atom, a methyl group or a methoxy group;

R ² is H or methyl, and

R ³ is a hydrogen atom or one or two halogen atoms.

The compounds of the invention may exist in the form of the free base or in the form of an acid addition salt.

In accordance with the present invention, compounds of Formula I may be prepared according to the method illustrated by the scheme that follows.

In the case of compounds wherein R ² is a hydrogen atom and according to Scheme 1, a compound of formula II, wherein R ¹ is as defined above, is reacted with chloroacetyl chloride of formula III under similar conditions to those described in Bull. Soc. Chim. France 1962, 736-737, i.e. in an aprotic solvent such as dioxane at a temperature of 20 to 100 ° C.

An amide of formula IV is obtained, which is reacted with a piperidine of formula V, wherein R ³ is as defined above, in an aprotic solvent, for example N, N-dimethylformamide, at a temperature of 50 to 80 ° C and in the presence of an inorganic base such as potassium carbonate. To give an amide of formula VI, which is finally reduced to an amine of formula I ^(R2 is hydrogen) with a simple or complex reducing agent, such as an alkali metal hydride or other metal hydride, e.g. lithium aluminum hydride, boron hydride, a boron hydride complex / tetrahydrofuran or a boron hydride / methylsulfide or aluminum hydride complex, in an aromatic or ethereal inert solvent such as toluene, xylene, diethyl ether, tetrahydrofuran or dioxane, at a temperature of 30 to 140 ° C depending on the solvent.

Scheme 1

R ¹

(II)

HM

'(CH ₂₎ n \ _r ^ t ⁵ \ + ^{R 3} (V)

(I, R ² = CH ₃₎

The compounds of the formula I, wherein R ² is methyl, and of Scheme 2, the compound of formula II wherein R ² is as defined above, is reacted first with an acid anhydride of acetic and formic acid using similar conditions as described in Tetrahedron Lett . 23 (33), 3315-3318 (1982) and in J. Med. Chem. 9, 830-832 (1966), i.e. in an inert solvent, for example tetrahydrofuran, at 20 to 40 ° C, and the N-formyl intermediate thus prepared is then reduced as previously described in relation to the compound. of formula VI to give N-methyl-2-benzothiazolamine of formula VII.

Separately, the piperidine compound of formula V, where R ¹ is as defined above, is reacted with 1-bromo-2-chloroethane using standard conditions for this type of reaction, i.e. in a polar solvent, for example Ν, Ν-dimethylformamide, in the presence of an inorganic base. e.g. potassium carbonate, at a temperature of 50 to 80 ° C.

There is obtained a chlorinated derivative of the general formula IX which is finally reacted with N-methyl-2-benzothiazolamine of the general formula VII in a polar solvent, for example in Ν, Ν-dimethylformamide, in the presence of an inorganic base such as potassium carbonate at 80 to 100 ° C; to give a compound of formula I (R ² is methyl).

Scheme 2

The starting compounds of formula II are commercially available.

The starting compounds of formula V are commercially available or described in patent applications EP-0109317 and EP-0524846.

The examples that follow illustrate in detail the preparation of some of the compounds of the invention. Elemental analysis, IR and NMR spectra are consistent with the structures of the desired compounds.

DETAILED DESCRIPTION OF THE INVENTION

The numbers of the compounds in brackets correspond to those in the table.

Example 1 (Compound No. 1)

N- (2-benzothiazolyl) -4-phenyl-l-piperidineethanamine

1.1. N- (2-Benzothiazolyl) -2-chloroacetamide hydrochloride g (0.1 mol) of 2-benzothiazolamine and 200 ml of dioxane are placed in a 1 l round-bottom flask, stirred until complete dissolution, and a solution of 11.3 is added. g (0.1 mol) of chloroacetyl chloride and the mixture was heated in an oil bath at 50 ° C for 24 hours. An additional 5.6 g (0.05 mol) of chloroacetyl chloride dissolved in 50 ml of dioxane was added and heating at 50 ° C was continued overnight. The mixture was allowed to cool and the precipitate was filtered off, washed with a small amount of dioxane and then with petroleum ether and dried in the presence of phosphorus pentoxide. 25.49 g of product are obtained, which product is used as is in the following stage.

1.2 N- (2-Benzothiazolyl) -4-phenyl-1-piperidineacetamide

2.63 g (0.01 mol) of N-2- (benzothiazolyl) -2-chloroacetamide hydrochloride, 1.61 g (0.01 mol) of 4-phenylpiperidine, 2.76 g of potassium carbonate and 80 ml of N, N- of dimethylformamide is placed in a 500 ml round bottom flask and the mixture is heated for

The mixture is allowed to cool, 160 ml of water are added and the precipitate is filtered off and dried. 3.15 g of product are obtained, which product is used as is in the following stage.

1.3. N- (2-Benzothiazolyl) -4-phenyl-1-piperidineethanamine

430 mg (0.0112 mol) of lithium aluminum hydride and then 60 ml of tetrahydrofuran are placed in a 500 ml round bottom flask and the suspension is heated to boiling. 2 g (0.0056 mol) of N- (2-benzothiazolyl) -4-phenyl-1-piperidineacetamide dissolved in 30 ml of tetrahydrofuran are added dropwise and heating is continued for a further 15 minutes. The mixture was cooled, 56 ml of ethyl acetate and 22 ml of water were added, the organic layer was separated after settling, the solvents were evaporated under reduced pressure and the oily residue was dried under reduced pressure. 2.48 g of crude product are obtained, which is purified by silica gel column chromatography, eluting with a 9: 1 mixture of dichloromethane and methanol, to give 1.6 g of a pale yellow oil which crystallizes. After recrystallization from 2-propanol and drying under reduced pressure, 0.81 g of compound is isolated.

M.p .: 140-141 ° C.

Example 2 (Compound No. 3)

N- (2-Benzothiazolyl) -4 - [(4-fluorophenyl) methyl] -1-piperidineaethanamine ethanedioate

2.1. N- (2-Benzothiazolyl) -4- (4-fluorophenyl) methyl-1-piperidineacetamide

2.26 g (0.0086 mol) of N- (2-benzothiazolyl) -2-chloroacetamide hydrochloride, 2.29 g (0.01 mol) of 4 - [(4-fluorophenyl) methyl] piperidine hydrochloride, 4.14 g (0.03 mol) of potassium carbonate and 80 ml of N, N-dimethylformamide are placed in a 500 ml round bottom flask and the mixture is heated at 50 ° C for 2.5 hours. The mixture is allowed to cool, 240 ml of water are added. The mixture was cooled in an ice bath and the white precipitate was filtered off, washed thoroughly with water and dried in the presence of phosphorus pentoxide. 2.9 g of product are obtained, which product is recrystallized from 30 ml of ethanol. After drying, 2.42 g of compound is obtained.

M.p .: 141-142 ° C.

2.2 N- (2-Benzothiazolyl) -4 - [(4-fluorophenyl) methyl] -1-piperidineaethanamine ethanedioate

Dissolve 1.3 g (0.00349 mol) of N- (2-benzothiazolyl) -4 - [(4-fluorophenyl) methyl] -1-piperidineacetamide in 25 ml of dry tetrahydrofuran and place in a 250 ml three-necked flask under nitrogen. round bottom flasks, 1.09 ml, 3 equivalents, of borane / methylsulfide complex is added and the mixture is heated at reflux for 4 hours. The mixture is allowed to cool to room temperature, a mixture of 53 ml of 2N hydrochloric acid and 25 ml of methanol is added and the mixture is again heated to boiling point for

1.5 hours and allowed to stand overnight. Concentrated sodium hydroxide is added to the mixture until the pH becomes alkaline and the mixture is extracted three times with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and filtered, and the filtrate was evaporated under reduced pressure. 1.6 g of an oily product are obtained, which product is purified by silica gel column chromatography, eluting with a 95: 5 mixture of dichloromethane and methanol. 0.83 g of an opaque oil is obtained, which is dissolved in 2-propanol with one equivalent of oxalic acid. After recrystallization, filtration and drying, 0.73 g of compound is isolated.

M.p .: 155-156 ° C.

Example 3 (Compound No. 4)

N- (2-benzothiazolyl) -N-methyl-4- (phenylmethyl) -1-piperidineaethanamine ethanedioate

3.1 N-Methyl-2-benzothiazolamine

Place 10.2 ml of acetic anhydride in a round-bottomed flask, add dropwise with stirring 4.3 ml formic acid and heat the mixture at 50 ° C for 2 hours. Cool the mixture to room temperature, add 10 ml dry tetrahydrofuran, a solution of 11.25 g (0.075 mol) of 2-benzothiazolamine in 30 ml of dry tetrahydrofuran is added dropwise so that the temperature does not exceed 40 ° C and the mixture is allowed to stand for 2 days. The solvent was evaporated under reduced pressure and the crystalline residue was washed twice with petroleum ether and dried in the presence of phosphorus pentoxide. 13 g of intermediate N- (2-benzothiazolyl) formamide are obtained. A suspension of 0.854 g (0.0224 mol) of lithium aluminum hydride in 50 ml of tetrahydrofuran is prepared and heated to boiling and a solution of 2 g (0.0112 mol) of the formyl intermediate in 100 ml of tetrahydrofuran is added and heating is continued for 30 minutes. The mixture is cooled, 100 ml of ethyl acetate are added, 38 ml of water are added dropwise, the organic layer is separated after settling and evaporated under reduced pressure and the residue is crystallized from petroleum ether, filtered off and dried in the presence of phosphorus pentoxide. 1.5 g of compound are obtained.

3.2 1- (2-Chloroethyl) -4- (phenylmethyl) piperidine

2.5 g (0.02 mol) of 4- (phenylmethyl) piperidine dissolved in 50 ml of N, N-dimethylformamide are placed in a round-bottomed flask and 2.86 g (0.02 mol) of 1-bromo-2 are added. chloroethane and 2.76 g (0.02 mol) of potassium carbonate, and the mixture was stirred vigorously for 1 hour at room temperature. The mixture was poured into 250 ml of ice-water and extracted twice with 150 ml of ethyl acetate. The organic layer was washed with brine and the solvent was evaporated under reduced pressure. 7 g of an oily product are obtained, which product is purified by silica gel column chromatography, eluting with ethyl acetate. 2.1 g of pure product are obtained in the form of an oil.

3.3. N- (2-Benzothiazolyl) -N-methyl-4- (phenylmethyl) -1-piperidineaethanamine ethanedioate g (0.00421 mol) of 1- (2-chloroethyl) -4- (phenylmethyl) piperidine is dissolved in 25 ml of N , N-dimethylformamide, 0.7 g (0.00426 mol) of N-methyl-2-benzothiazolamine and 0.8 g of potassium carbonate are added and the mixture is heated at 100 ° C for 1 hour. The mixture is cooled in an ice bath. 50 ml of water are added, the mixture is extracted twice with 100 ml of ethyl acetate and the organic layer is washed with brine and evaporated. An oily residue is obtained, which is purified by two successive silica gel column chromatography, eluting first with dichloromethane / methanol 90: 10 and then with ethyl acetate. 0.3 g of compound is obtained, 0.1 g of which is converted into the oxalate form in ethanol.

Melting point: 164-166 ° C.

Example 4 (Compound No. 11)

N- (2-Benzothiazolyl) -4- [2- (4-fluorophenyl) ethyl] -1-piperidinoethanamine

4.1. N- (2-Benzothiazolyl) -4- [2- (4-fluorophenyl) ethyl] -1-piperidineacetamide

2.63 g (0.01 mol) of N- (2-benzothiazolyl) -2-chloroacetamide hydrochloride, 2.44 g (0.01 mol) of 4- [2- (4-fluorophenyl) ethyl] piperidine hydrochloride, 4, 14 g (0.03 mol) of potassium carbonate and 80 ml of N, N-dimethylformamide are placed in a 500 ml round-bottom flask and the mixture is heated at 50 ° C for 3.5 hours. The mixture is allowed to cool, 240 ml are added. ml of water and extracted with 300 ml of ethyl acetate. The organic layer was washed with water and then with saturated sodium chloride solution, dried over sodium sulfate and filtered, and then the filtrate was evaporated under reduced pressure. A brown oily product is obtained which is used without further purification in the next step.

4.2. N- (2-Benzothiazolyl) -4- [2- (4-fluorophenyl) ethyl] -1-piperidinoethanamine

0.96 g (0.025 mol) of lithium aluminum hydride and 140 ml of dry tetrahydrofuran are placed under nitrogen in a 500 ml three-necked round-bottomed flask, the suspension is heated to boiling and 5.0 g (0.01 mol) of N- (dropwise) are added dropwise. 2-Benzothiazolyl) -4- [2- (4-fluorophenyl) ethyl] -1-piperidineacetamide dissolved in 60 mL dry tetrahydrofuran and heating was continued for 30 minutes. The mixture was cooled, 140 ml of ethyl acetate and 51 ml of water were added, the organic layer was separated, the solvents were evaporated under reduced pressure and the residue was purified by silica gel column chromatography eluting with 9: 1 dichloromethane: methanol. 1.6 g of an oil are obtained, which crystallizes. After recrystallization from ethanol-water and drying under reduced pressure, 1.23 g of the desired compound is isolated.

Melting point: 107-108 ° C.

The table that follows illustrates the chemical structures and physical properties of several compounds of the invention. In the column " salt " means oxalate or ethanedioate and "fum. means fumarate or (E) -2-butenedioate. The molar acid / base ratio is shown in brackets.

table

No. n R ¹ R ² R ³ salt T. t. [° C] 1 0 H H H - 140-141 2 1 H H H ox. (1.05: 1) 141-142 3 1 H H 4-F ox. (1: 1) fum. (1.2: 1) 155-156 150-151 4 1 H ch ₃ H ox. (1.15: 1) 164-166 5 1 H ch ₃ 4-F fum. (1.9: 1) 137-140 6 1 6-C1 H 4-F - 118-119 7 1 _6-CH3 H 4-F - 148-149 8 1 6-OCH3 H H - 123-124 9 1 6-OCH3 H 4-F - 107-108 10 2 H H H ox. (2: 1) 189-190 11 2 H H 4-F - 107-108 12 2 6-OCH3 H H - 129-130 13 3 H H H ox. (2: 1) 179-180 14 2 H H 2-F fum. (1: 2) 159-160 15 2 H H 3-F fum. (1: 2) 168-169 16 2 H H 2,4-F fum. (2: 1) 156-158 17 2 H H 3,4-F fum. (1.2: 1) 100-138 18 2 H H 3,5-F fum. (1: 2) 158-159

The compounds of the invention were tested to demonstrate their efficacy as therapeutically active agents.

Their neuroprotective activity was studied in a model of permanent focal ischemia produced by intraluminal occlusion of the middle cerebral artery in rats according to the method described in Stroke 20, 84-91 (1989).

Under anesthesia with sodium salt of metohexiton, the pterigopalatin artery, carotid artery and left external carotid artery are ligated and a polyamide fiber about 18 mm in length is inserted into the inner carotid artery, corresponding to the distance separating the origin of the inner carotid artery and the middle cerebral artery.

Study compounds are administered intravenously after closure.

hours after the cerebral artery occlusion, the animals are sacrificed and the brain removed.

The volume of cerebral infarction is evaluated from the measured area of necrosis in 6 coronary sections with 2,3,5-triphenyltetrazolium chloride. For example, compound no. 11 in the above table significantly reduces infarct volume from about 48% at a dose of 1 mg / kg by intravenous administration at 10 minutes, 1.5 hours, 3 hours and 6 hours after occlusion.

The compounds of the invention were also subjected to a total brain ischemia test in mice.

Ischemia was caused by cardiac arrest induced by rapid intravenous administration of magnesium chloride. In this test, the survival time, which is the interval between the injection of magnesium chloride and the last observable breathing movement in each mouse, is measured. This last movement is considered to be the last sign of central nervous system functioning. Respiratory arrest occurs about 19 seconds after the injection of magnesium chloride.

A group of 10 male mice (Charles River CD1) were studied. Mice were fed prior to the test and given water as needed.

Survival time was measured 10 minutes after intraperitoneal administration of a compound of the invention. The results are presented as the difference between the survival time not measured in the group of 10 mice receiving the compound and the survival time measured in the group of 10 mice receiving only the liquid carrier. Relationships between survival time adjustment and compound dose are plotted graphically according to the semi-logarithmic curve.

From this curve, a "three-second effective dose (ED 3--)", which is the dose (in mg / kg) that gives an increase in survival time of 3 seconds relative to a control group of 10 untreated mice, is calculated. An increase in survival time of 3 seconds is both statistically significant and reproducible. The values ED _3; - the most active compounds of the invention are less than 5 mg / kg via the intraperitoneal route of administration.

The compounds of the invention have also been subjected to an in vitro study of the affinity for D ₄ dopaminergic receptors obtained by transfecting human D4.4 receptors into CHO cells, essentially as described in Van Tol et al., Nature 350, 610-614 (1991) and Van Tol et al.,

Nature 358, 149-152 (1992).

On the day of the experiment, membrane formulations (Receptor Biology, Inc., Glen Echio, MD20812, USA) were thawed at -80 ° C rapidly and then diluted with 20-fold volume of incubation buffer (50 mM Tris-HCl, 120 mM sodium chloride). , 5 mM potassium chloride, 2 mM calcium chloride, 5 mM magnesium chloride, pH = 7.5).

The membrane suspension (100 μΐ, 78 μg membranes) is incubated at 25 ° C for 60 minutes in the presence of 0.5 nM [ ³ H] spiperone (specific activity 17 to 20 Ci / mmol, New England Nuclear / Du Pont de Nemours, Boston, MA, USA) in a final volume of 1 ml incubation buffer in the presence or absence of test compound.

The incubation is terminated by filtration using Whatman GB / B® filters pretreated with polyethyleneimine (0.5%).

Each reaction tube is rinsed three times with 3 ml of Tris-NaCl buffer (50 mM Tris-HCl, 120 mM sodium chloride, pH = 7.5).

The filters are dried in an oven at 120 ° C for 5 minutes. Residual radioactivity on the filters is determined by liquid scintigraphy. Non-specific binding is determined in the presence of 1 μΜ haloperidol.

For each concentration of study compound, the percent inhibition of the specific binding of [ ³ H] spiperone is calculated and then the IC ₅₀ , the concentration that inhibits 50% of the binding, is determined.

IC 50 values of the compounds of the invention range from 3 to 30 nM.

The test results show that the compounds of the present invention have neuroprotective properties in vivo and prevent the in vitro specific binding of [ ³ H] spiperone to human D ₄ . ₄ dopaminergic receptors.

Thus, they can be used on the one hand to treat and prevent cerebrovascular disorders of ischemic or hypoxic origin (cerebral infarction, cranial or spinal cord trauma, cardiac or respiratory arrest, transient ischemic weakness), glaucoma, progressive neurodegenerative disorders such as Alzheimer's dementia, disease, vascular dementia, Parkinson's disease, Huntington's disease, olivopontocerebral atrophy, amiotrophic lateral sclerosis, neurodegenerative disorders of viral origin and the like) and also to prevent cerebral ischemic events associated with cardiac and vascular surgery or endovascular therapy.

On the other hand, the compounds of the invention may be used to treat psychosis, particularly schizophrenia (deficient and productive forms) and acute and chronic extrapyramidal symptoms induced by neuroleptics or originating from Parkinson's disease, to treat various forms of anxiety, panic attacks, phobias, obsessive disorders, for the treatment of various forms of depression, including psychotic depression, for the treatment of drug and alcohol dependence and hypothalamic pituitary disorders, and for the treatment of cognitive disorders associated with age or Alzheimer's disease.

The compounds of the present invention may be present in all pharmaceutically acceptable dosage forms in combination with suitable excipients for enteral, parenteral or transdermal administration, for example in the form of tablets, dragees, capsules including hard gelatin capsules, solutions or suspensions for oral administration or injection, suppositories , patches and the like, containing doses corresponding to a daily dose of 1 to 500 mg of the active ingredient.

Claims (4)

PATENT CLAIMS N - (2-benzothiazolyl) -1-piperidineaethanamine derivatives of the general formula I R 3 (I) wherein n is an integer of 0, 1, 2 or 3; R ¹ is a hydrogen atom, a halogen atom, a methyl group or a methoxy group; R ² is H or methyl, and R ³ is hydrogen or one or two halogen atoms; in the form of the free base or in the form of an acid addition salt. A process for the preparation of a compound according to claim 1, characterized in that for the preparation of a compound of the formula I wherein R ² is a hydrogen atom a compound of the formula II (II) wherein R ¹ is as defined in claim 1, reacts with chloroacetyl chloride to form an amide of formula IV (IV) which is reacted with piperidine of formula HN. -JR ³ (V) wherein R ³ is as defined in claim 1, to form an araid of formula VI (VI) which is ultimately reduced to an amine of formula I (where R ² is hydrogen) or alternatively to prepare a compound of formula I wherein R ² is methyl, a compound of formula II S (II) R ¹ '2 wherein R ¹ is as defined in claim 1, is first reacted with a mixture of formic acid and acetic anhydride, and the thus obtained N-formyl intermediate is then reduced to give N-methyl-2-benzothiazolamine of formula VII R ¹ N (VII) and, separately, the piperidine compound of formula (V): ^{R 3} X / (V) where R ¹ is as defined in claim 1, reacts with 1-bromo-2-chloroethane to provide a chlorinated derivative of formula IX Cl (IX) R 3 which finally reacts with N-methyl-2-benzothiazolamine of formula VII to give a compound of formula I (where R ² is a methyl group) R 3 (CH _{2) n} (I, R ² = CH ₃₎ Medicament, characterized in that it comprises a compound according to any one of claims 1 and 2. A pharmaceutical composition comprising a compound according to any one of claims 1 and 2 in combination with an additive.