JP2001501217A - N- (Benzothiazol-2-yl) -1-piperidineethanamine derivatives, their preparation and therapeutic applications - Google Patents

Abstract

(57) The present invention discloses compounds corresponding to the general formula (I), wherein n represents a number of 0, 1, 2 or 3, and R ₁ represents one hydrogen atom Or a halogen atom or a methyl or methoxyl group, R ₂ represents one hydrogen atom or one methyl group, and R ₃ represents one hydrogen atom or one or two halogen atoms. The invention can be used for therapy.

Description

DETAILED DESCRIPTION OF THE INVENTION N- (Benzothiazol-2-yl) -1-piperidineethanamine derivative, its preparation and therapeutic application The compound of the present invention has the general formula (1): [Wherein, n represents a number of 0, 1, 2, or 3.] R ₁ represents hydrogen, a halogen atom, or a methyl or methoxyl group. R ₂ represents a hydrogen atom or a methyl group. And R ₃ represents a hydrogen atom or one or two halogen atoms]. The compounds of the present invention can exist in free base or in addition salts with acids. According to the present invention, the compound represented by the general formula (I) may be produced according to the steps exemplified in the following reaction formula. When a compound in which R ₂ represents a hydrogen atom is produced according to Reaction Scheme 1, the compound represented by the general formula (II), wherein R ₁ is as defined above, is described in Bull. Soc. Chim. Formula (III) under conditions similar to those described in France (1962), pages 736-737, i.e., in an aprotic solvent such as, for example, dioxane, at a temperature of 20C to 100C. React with chloroacetyl chloride. An amide of the general formula (IV) is obtained, which can be obtained, for example, in an aprotic polar solvent such as N, N-dimethylformamide at a temperature from 50 ° C. to 80 ° C., for example with potassium carbonate. The reaction is carried out in the presence of an inorganic base with a piperidine of the general formula (V), wherein n and R ₃ are as defined above. An amide of the general formula (VI) is obtained, which is finally combined with a simple reducing agent or, for example, an alkali metal hydride or another metal hydride (ie, for example, lithium aluminum hydride, borohydride, borohydride). / Tetrahydrofuran or borohydride / methyl sulfide complex or aluminum hydride) in an aromatic or ethereal inert solvent such as toluene, xylene, diethyl ether, tetrahydrofuran or dioxane. Depending on the temperature, from 30 ° C. to 140 ° C., it is used to reduce to the amine of the general formula (I, R ₂ ＨH). Reaction formula 1 When a compound in which R ₂ represents a methyl group is produced according to Reaction Scheme 2, a compound represented by the general formula (II), in which R ₁ is as defined above, is first treated with Tetrahedron Letters ( 1982) 23 (33), 3315-3318 and J. Am. Med. Chem. Acetic anhydride and formic acid under conditions similar to those described in Vol. 9, pp. 830-832, i.e., in an inert solvent such as, for example, tetrahydrofuran, at a temperature from 20C to 40C. The resulting N-formyl intermediate is then reduced as described above for compounds of general formula (VI) to give N-methyl-2-benzo of general formula (VII) Thiazole amine is obtained. Alternatively, piperidine and 1-bromo-2-chloroethane of the general formula (V), wherein n and R ₃ are as defined above, can be prepared under standard conditions used for this type of reaction. That is, for example, the reaction is carried out in a polar solvent such as N, N-dimethylformamide in the presence of an inorganic base such as potassium carbonate at a temperature of 50 ° C to 80 ° C. A chlorinated derivative represented by the general formula (IX) is obtained, and finally this is combined with N-methyl-2-benzothiazolamine represented by the general formula (VII), for example, N, N-dimethylformamide and the like. For example, in the presence of an inorganic base such as potassium carbonate at a temperature of 80 ° C. to 100 ° C. to obtain a compound represented by the general formula (I, R ₂ ＣＨCH ₃ ). Reaction formula 2 The starting material represented by the general formula (II) can be purchased commercially. Starting materials of the general formula (V) are commercially available or are described in European patent applications EP-0109317 and EP-0524846. The following examples illustrate in detail the preparation of several compounds according to the invention. The structure of the obtained compound is confirmed by trace element analysis and IR- and NMR-spectra. The compound numbers in parentheses in the title of each example correspond to those shown in the table below. Example 1 (Compound No. 1) N- (2-benzothiazolyl) -4-phenyl-1-piperidine ethanamine. 1.1. N- (2-benzothiazolyl) -2-chloroacetamide hydrochloride. 2-benzothiazolamine (15 g, 0.1 mol) and 200 mL of dioxane were placed in a 1 L round bottom flask and stirred until the mixture was completely dissolved, and the acid chloride of chloroacetic acid (11.3 g, 0.1 Mol) are added and the mixture is heated to 50 ° C. for 24 hours on an oil bath. Further, an acid chloride of chloroacetic acid (5.6 g, 0.05 mol) dissolved in 50 mL of dioxane is added, and heating is continued at 50 ° C. overnight. The mixture is allowed to cool, the precipitate is filtered off, washed with a little 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 without further treatment in the next step. 1.2. N- (2-benzothiazolyl) -4-phenyl-1-piperidineacetamide. N- (2-benzothiazolyl) -2-chloroacetamide hydrochloride (2.63 g, 0.01 mol), 4-phenylpiperidine (1.61 g, 0.01 mol), potassium carbonate 2.76 g, and N, N -80 mL of dimethylformamide is placed in a 500 mL round bottom flask and the mixture is heated to 50 ° C for 3 hours 30 minutes. The mixture is allowed to cool, 160 ml of water are added, the precipitate is filtered off and dried. 3.15 g of product are obtained, which product is used without further processing in the next step. 1.3. N- (2-benzothiazolyl) -4-phenyl-1-piperidineethanamine. Lithium aluminum hydride (430 mg, 0.0112 mol) and then 60 mL of tetrahydrofuran are placed in a 500 mL round bottom flask and the suspension is heated to reflux. N- (2-benzothiazolyl) -4-phenyl-1-piperidineacetamide (2 g, 0.0056 mol) is dissolved in 30 mL of tetrahydrofuran and added dropwise, and heating is continued for another 15 minutes. The mixture is cooled, 56 mL of ethyl acetate and 22 mL of water are added, after separation the organic layer is taken off, the solvent is distilled off under reduced pressure and the oily residue is dried under reduced pressure. 2.48 g of crude product are obtained, which product is purified by chromatography on a silica gel column, eluting with a 9: 1 mixture of dichloromethane and methanol, to give 1.6 g of a pale yellow oil which is crystalline. Become After recrystallization in 2-propanol and drying under reduced pressure, finally 0.81 g of the compound is isolated. Melting point: 140-141 [deg.] C. Example 2 (Compound No. 3) N- (2-benzothiazolyl) -4-[(4-fluorophenyl) methyl] -1-piperidineethanamine ethanedioate. 2.1. N- (2-benzothiazolyl) -4-[(4-fluorophenyl) methyl] -1-piperidineacetamide. N- (2-benzothiazolyl) -2-chloroacetamide hydrochloride (2.26 g, 0.0086 mol), 4-[(4-fluorophenyl) methyl] -piperidine hydrochloride (2.29 g, 0.01 mol) , Potassium carbonate (4.14 g, 0.03 mol), and 80 mL of N, N-dimethylformamide in a 500 mL round bottom flask and heat the mixture to 50 ° C. for 2 hours 30 minutes. The mixture is allowed to cool, 240 mL of water are added, the mixture is cooled in an ice bath, the white precipitate is filtered off, washed with plenty of water and dried in the presence of phosphorus pentoxide. 2.9 g of product are obtained, which is recrystallized in 30 ml of ethanol. After drying, 2.42 g of compound are obtained. Melting point: 141-142 ° C. 2.2. N- (2-benzothiazolyl) -4-[(4-fluorophenyl) methyl] -1-piperidineethanamine ethanedioate. N- (2-benzothiazolyl) -4-[(4-fluorophenyl) methyl] -1-piperidineacetamide (1.3 g, 0.00349 mol) was dissolved in 25 mL of dry tetrahydrofuran, and this was dissolved in 250 mL of nitrogen under an atmosphere of nitrogen. Place in a necked round bottom flask, add 1.09 mL, ie, 3 equivalents of borane / methyl sulfide complex, and heat the mixture to 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 thereto, and the mixture is again heated to reflux for 1 hour and 30 minutes, and left overnight. Concentrated sodium hydroxide is added to the mixture until the pH is alkaline, and the mixture is extracted three times with ethyl acetate. The organic layer is washed with water, dried over sodium sulfate, filtered, and the filtrate is evaporated under reduced pressure. 1.6 g of an oily product are obtained, which product is purified by chromatography on a silica gel column, 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 1 equivalent of oxalic acid. After recrystallization, filtration and drying, finally 0.73 g of compound is isolated. Melting point: 155-156 ° C. Example 3 (Compound No. 4) N- (2-benzothiazolyl) -N-methyl-4- (phenylmethyl) -1-piperidineethanamine ethanedioate. 3.1. N-methyl-2-benzothiazolamine. A round-bottomed flask is charged with 10.2 mL of acetic anhydride, 4.3 mL of formic acid is added dropwise with stirring and the mixture is heated to 50 ° C. for 2 hours. The mixture is cooled to room temperature, to which 10 mL of dry tetrahydrofuran is added, and then a solution of 2-benzothiazolamine (11.25 g, 0.075 mol) in 30 mL of dry tetrahydrofuran, so that the temperature does not exceed 40 ° C. Add dropwise and let the mixture stand for 2 days. The solvent is distilled off under reduced pressure and the crystalline residue is washed twice with petroleum ether and dried in the presence of phosphorus pentoxide. 13 g of the intermediate N- (2-benzothiazolyl) formamide are obtained. Prepare a suspension of lithium aluminum hydride (0.854 g, 0.0224 mol) in 50 mL of tetrahydrofuran, heat to reflux, add a solution of the formyl intermediate (2 g, 0.0112 mol) in 100 mL of tetrahydrofuran and heat For 30 minutes. The mixture was cooled, 100 mL of ethyl acetate was added, 38 mL of water was added dropwise, and after separation the organic layer was removed, evaporated under reduced pressure, the crystallized residue was triturated in petroleum ether, filtered and phosphorus pentoxide was added. Dry in the presence of. 1.5 g of compound are obtained. 3.2. 1- (2-chloroethyl) -4- (phenylmethyl) piperidine. 4- (Phenylmethyl) piperidine (3.5 g, 0.02 mol) was dissolved in 50 mL of N, N-dimethylformamide and placed in a round-bottomed flask, to which 1-bromo-2-chloroethane (2.86 g, 0 .02 mol) and potassium carbonate (2.76 g, 0.02 mol) are added and the mixture is stirred vigorously at room temperature for 1 hour. The mixture is poured into 250 ml of ice-cold water and extracted twice with 150 ml of ethyl acetate. The organic layer is washed with a saline solution, and the solvent is distilled off under reduced pressure. 7 g of an oily product are obtained, which product is purified by chromatography on a silica gel column, eluting with ethyl acetate. 2.1 g of purified product are obtained as an oil. 3.3. N- (2-benzothiazolyl) -N-methyl-4- (phenylmethyl) -1-piperidineethanamine ethanedioate. 1- (2-Chloroethyl) -4- (phenylmethyl) -1-piperidine (1 g, 0.00421 mol) was dissolved in 25 mL of N, N-dimethylformamide, and N-methyl-2-benzothiazolamine was added thereto. (0.7 g, 0.00426 mol) and 0.8 g of potassium carbonate are added and the mixture is heated to 100 ° C. for 1 hour. It is cooled in an ice bath, 50 ml of water are added, the mixture is extracted twice with 100 ml of ethyl acetate, the organic layer is washed with a saline solution and evaporated. An oily residue is obtained, which is purified twice by silica gel column chromatography. The first is eluted with a 90:10 mixture of dichloromethane and methanol and the second is eluted with ethyl acetate. 0.3 g of compound is obtained, 0.1 g of which is taken up to form oxalate in ethanol. Melting point: 164-166C. Example 4 (Compound No. 11) N- (2-benzothiazolyl) -4- [2- (4-fluorophenyl) ethyl] -1-piperidineethanamine. 4.1. N- (2-benzothiazolyl) -4- [2- (4-fluorophenyl) ethyl] -1-piperidineacetamide. N- (2-benzothiazolyl) -2-chloroacetamide hydrochloride (2.63 g, 0.01 mol), 4- [2- (4-fluorophenyl) ethyl] piperidine hydrochloride (2.44 g, 0.4 g). 01 mol), potassium carbonate (4.14 g, 0.03 mol) and 80 mL of N, N-dimethylformamide are placed in a 500 mL round bottom flask and the mixture is heated to 50 ° C. for 3 hours 30 minutes. It is allowed to cool, 240 mL of water is added and the mixture is extracted with 300 mL of ethyl acetate. The organic layer is washed with water and then with a saturated sodium chloride solution, dried over sodium sulphate, filtered and the filtrate is evaporated under reduced pressure. A brown oily product is obtained, which is used without further treatment in the next step. 4.2. N- (2-benzothiazolyl) -4- [2- (4-fluorophenyl) ethyl] -1-piperidineethanamine. Lithium aluminum hydride (0.96 g, 0.025 mol) and 140 mL of dry tetrahydrofuran were put in a 500 mL three-necked round bottom flask under a nitrogen atmosphere, and the suspension was heated to reflux, and N- (2- Benzothiazolyl) -4- [2- (4-fluorophenyl) ethyl] -1-piperidineacetamide (5.0 g, 0.01 mol) is added dropwise in 60 mL of dry tetrahydrofuran and heating is continued for 30 minutes. The mixture is cooled, 140 mL of ethyl acetate and 51 mL of water are added, the organic layer is separated, the solvent is distilled off under reduced pressure and the residue is chromatographed on a silica gel column eluted with a 9: 1 mixture of dichloromethane and methanol. To purify. 1.6 g of an oil are obtained, which crystallizes. Recrystallization in a mixture of ethanol and water, followed by drying under reduced pressure, isolates 1.23 g of compound. Melting point: 107-108 ° C. The following table illustrates the chemical structure and physical properties for some compounds. In the "Salt" column, "-" indicates a compound in a basic state, "ox." Indicates oxalate or ethanedioate, and "fum." Indicates fumarate or (E) -2-butane. Indicates Geoate. Acid / base molar ratios are shown in parentheses. table The compounds of the invention have been subjected to tests to prove their value as therapeutically active substances. A study on the neuroprotective activity of each compound in a model of persistent focal ischemia due to middle cerebral artery intraluminal obstruction in rats is described in Stroke (1989), 20: 84-91. Performed according to a method similar to that described above. Under methhexitone sodium anesthesia, the wing palate artery, common carotid artery, and left external carotid artery were ligated, and a polyamide thread having a length of about 18 mm corresponding to the distance separating the start point of the middle carotid artery from the start point of the internal carotid artery in the internal carotid artery was obtained. Introduce. After occlusion, the compound to be tested is administered intravenously. Twenty-four hours after occlusion of the middle cerebral artery, animals are sacrificed and the brain is removed. The necrotic area on six coronal sections stained with 2,3,5-triphenyltetrazolium chloride is measured and the cerebral infarct volume is evaluated from this. As an example, intravenous administration of Compound No. 11 from the preceding table at a dose of 1 mg / kg at 10 minutes, 1 hour 30 minutes, 3 hours, and 6 hours after occlusion significantly reduces infarct volume by about 48% I let it. The compounds of the present invention were also subjected to a global cerebral ischemia test in mice. This ischemia is due to cardiac arrest induced by rapid intravenous injection of magnesium chloride. This test measures "survival time", the interval between the time of magnesium chloride injection and the last respiratory movement observed in each mouse. This last breathing motion is considered to be the last sign of central nervous system function. Respiratory arrest occurs approximately 19 seconds after injection of magnesium chloride. Ten male mice (Charles River, CD1) are tested as a group. Mice are allowed food and water ad libitum prior to testing. The survival time is measured 10 minutes after intraperitoneal administration of the compound of the present invention. The experimental results are shown in the form of the difference between the survival time measured in a group of 10 mice receiving the compound and the survival time measured in a group of 10 mice receiving the vehicle solution. The relationship between the change in survival time and the dose of the compound is recorded as a semi-log graph as a curve. This curve makes it possible to record the “3 second effective dose (ED _{3 ′} )”, ie the dose (mg / kg) that extends the survival time by 3 seconds compared to a control group of 10 untreated mice. The 3 second extension of survival time is statistically significant and reproducible. The ED _{3 ″ of the} compound of the present invention having the highest activity is 5 mg / kg or less when administered by the intraperitoneal route. The compounds of the present invention performs a test in vitro also affinity to D ₄ dopaminergic receptors. This receptor is essentially a Van Tol. Et al., Nature (1991), 350: 610-614 and Van Tol. Besides al, Nature (1992 years), 358 Volume: CHO cells as described on pages 149-152 is obtained by D _4.4 receptors humans to gene transfer. The membrane (Receptor Biology, Glen Echo, MD 20812, USA) stored at -80 ° C was rapidly thawed on the day of the experiment, and the incubation buffer (50 mM-Tris-HCl, 120 mM-NaCl, 5 mM-KCl, 2 mM-CaCl2 _' 5 mM-MgCl2 _' pH = 7.5) Dilute with 20 volumes. This membrane suspension (100 μL, 78 μg as a membrane) is placed in a final volume of 1 mL of incubation buffer at 0.5 nM- [ ³ H] spiperone (specific activity 17-20 Ci / mmol, New England Nuclear / Duclear). Incubate at 25 ° C for 60 minutes in the presence or absence of test compound in the presence of Pont de Nemours, Boston, MA, USA). Incubation is stopped by filtration using Whatman GF / B ™ filters that have been pretreated with polyethyleneimine (0.5%). Wash each reaction tube three times with 3 mL of Tris-NaCl buffer (50 mM-Tris-HCl, 120 mM-NaCl, pH = 7.5). Dry each filter in an oven at 120 ° C. for 5 minutes. The radioactivity retained on the filter is measured by liquid scintigraphy. Non-specific binding is measured in the presence of 1 μM-haloperidol. The percent inhibition of specific binding of [ ³ H] spiperone is calculated for each concentration of test compound, and then the IC ₅₀ , the concentration that inhibits this binding by 50%, is determined. The compound of the present invention has an IC ₅₀ value of about 3 to 30 nM. These compounds of test results invention in vivo neuroprotective action, also shows that replacing the specific binding to ^[3 H] D human spiperone _4.4 dopaminergic receptors in vitro . As a result, these compounds, on the other hand, have cerebrovascular disorders originating from ischemia or hypoxia (cerebral infarction, cranial or spinal cord injury, cardiac arrest or respiratory arrest, transient ischemic stroke, perinatal period) Choking), glaucoma, progressive neurodegenerative diseases (eg, senile dementia such as Alzheimer's disease, vascular dementia, Parkinson's disease, Huntington's chorea, olive bridge cerebellar atrophy, amyotrophic lateral sclerosis, viral Neurodegenerative diseases, etc.) and for the prevention of cerebral ischemic symptoms associated with cardiac and vascular surgery or endovascular therapy. On the other hand, these compounds are useful for the treatment of psychoses, especially schizophrenia (deficient and productive types) and acute and chronic extrapyramidal conditions induced by neuroleptics or due to Parkinson's disease. For treating various types of anxiety, fear attacks, phobias, obsessive-compulsive disorders, for treating various types of depression, including mental depression, for narcotic and alcohol-induced addiction and vision. It can be used for the treatment of hypothalamic pituitary function disorders and for the treatment of cognitive deficits associated with aging or Alzheimer's disease. Finally, the compounds of the present invention can be formulated with suitable excipients, for example, tablets, dragees, capsules, including hard gelatin capsules, solutions or suspensions for oral administration, solutions or suspensions for injection, suppositories, Patches and other dosage forms may be provided for oral, parenteral and transdermal administration in any of the pharmaceutical dosage forms, including those capable of administering a daily dose of 1 to 500 mg of the active substance.

────────────────────────────────────────────────── ─── Continuation of front page    (81) Designated countries EP (AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, L U, MC, NL, PT, SE), OA (BF, BJ, CF) , CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (GH, KE, LS, MW, S D, SZ, UG, ZW), EA (AM, AZ, BY, KG) , KZ, MD, RU, TJ, TM), AL, AM, AT , AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, F I, GB, GE, GH, HU, ID, IL, IS, JP , KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, M W, MX, NO, NZ, PL, PT, RO, RU, SD , SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW (72) Inventor Lardenoi, Patrick             France 92340 Bourg-la-Reine, Li             No. 18 (72) Inventor Frost, Jonathan             Ryu du Pa, France 91320 Vissau             Luke 12 (72) Inventor Shumakel, Johannes             France 91190 Gif sur Yvette,             Are de la la nate 80 (72) Inventors Renone, Maria-Carmen             France 95880 Anjon les Bains, B             L'Avar Dormusson No. 8 (72) Inventor Maga, Pascal             France 91380 Silly Mazarin, Ryu             De La Division Leclair No. 10

Claims (1)

[Claims] 1. General formula (1): [Wherein, n represents a number of 0, 1, 2, or 3.] R ₁ represents hydrogen, a halogen atom, or a methyl or methoxyl group. R ₂ represents a hydrogen atom or a methyl group. And R ₃ represents a hydrogen atom or one or two halogen atoms], and exist in the form of a free base or in the form of an addition salt with an acid. 2. A process for preparing a compound of claim 1, for -R ₂ to produce a compound of the formula shown represents a hydrogen atom the general formula (II): [Where R ₁ is as defined in claim 1] A compound represented by the following formula (IV) is reacted with chloroacetyl chloride: Which is represented by the general formula (V): Wherein n and R ₃ are as defined in claim 1 by reacting with piperidine of the general formula (VI): Which is finally reduced to give an amide of the general formula (I, R ₂ = H): In obtaining a amine represented; or, also, in order -R ₂ to produce a compound of the formula shown represents methyl group, first the general formula (II): Wherein R ₁ is as defined in claim 1) and a mixture of acetic anhydride and formic acid, and the resulting N-formyl intermediate is reduced to give a compound of the general formula (VII) : N-methyl-2-benzothiazolamine represented by the general formula (V): Wherein n- and R ₃ are as defined in claim 1), and reacting 1-bromo-2-chloroethane with the piperidine represented by the general formula (IX): Finally, this derivative is reacted with N-methyl-2-benzothiazolamine represented by the general formula (VII) to obtain a chlorinated derivative represented by the general formula (I, R ₂ ＝ CH ₃₎ ): Obtaining a compound represented by the formula: 3. A medicament characterized by comprising the compound according to any one of claims 1 and 2. 4. A pharmaceutical composition comprising the compound according to claim 1 together with an additive.