CZ400892A3 - 2-(4-hydroxypiperidino)-1-alkanol derivatives as anti-ischemic agents, process of their preparation and use - Google Patents

Abstract

A series of 2-(4-hydroxypiperidino)-1-alkanol derivatives (I) are useful as medicaments for the treatment of traumatic injuries to the brain and spinal cord and neuronal degenerative diseases including senile dementias, in mammals, especially humans.

Description

2- (4-Hydroxypiperidino) -1-alkanol derivatives as antiischeraic agents, process for their preparation and use

Technical field

The invention relates to neuroprotective 2- (4-hydroxypiperidino) -1-alkanol derivatives (i.e., anti-ischemic compounds blocking the excitatory activity of the amino acid receptors) as defined below by Formula I, pharmaceutically acceptable salts derived therefrom, a process for the preparation of said compounds and the use of said compounds in the treatment of stroke, traumatic brain and spinal cord injury, degenerative diseases of the nervous system, including senile dementia such as Alzheimer's disease, Huntington's disease and Parkinson's disease in mammals, but are not limited thereto. The present invention also includes certain intermediates used in the preparation of the above compounds.

BACKGROUND OF THE INVENTION

Ifenprodil (A), which is a racemic, so-called dl-erythro compound, is known in the art and has the following general formula with said relative stereochemistry:

The taxo compound is commercially available as a hypotensive, and numerous close analogues of this compound are also useful. Carron et al. U.S. Patent No. 3,509,164 to Carron et al. Drug Res., 21, 1992-1999 (1971). More recently, ifenprodil has been shown to exhibit anti-ischemic activity and block the excitatory activity of amino acid receptors. Gotti et al. J. Pharm. Exp. Therap., V. 247, pp. 1211-1221 (1988); Carter et al., Supra, pp. 1222-1232 (1988).

Reference may also be made in this regard to French Patent No. 2546166 and published European Patent Application No. EP-A1-351282, published Jan. 17, 1990. It is an object of the state of the art to find compounds which exhibit neuroprotective activity in good while at the same time having a reduced or insignificant hypotensive effect, this object has been substantially accomplished by the present invention.

Certain 1-phenyl-3- (4-aryl-4-acyloxy-piperidino) -1-propanols which are useful as analgesics are also known in the art. United States Patent No. 3,294,804; further, 1- [4- (amino and hydroxyalkyl) phenyl] -2- (4-hydroxy-4-tolylpiperazino) -1-alkanols and alkanones, which are said to exhibit analgesic, antihypertensive, psychotropic or anti-inflammatory activity, cf. Japanese Kokai 53-02,474 (CA 89: 43498y; Derwent Abs. 14858A) and 53-59,675 (CA 89: 146938w; Derwent Abs. 48671A); and 2-piperidino-1-alkanol derivatives which are said to be potent anti-ischemic agents. European Patent Application No. 398,578-A and Der 90-350,327 / 47.

SUMMARY OF THE INVENTION

The present invention relates to compounds of formula I:

in which they mean:

, R 6 and R 3 each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, phenyl, and substituted phenyl, wherein the substituent in said phenyl group is selected from hydroxy, C 1-4 alkyl carbon atoms, chlorine, bromine, fluorine, trifluoromethyl, amino, nitro and (C 1 -C 4) alkoxy, or R 1 and R 2 together form a methylene, ethylene, propylene or butylene group, m is 0 to 2, n is 1 or 2,

X and Y are each independently selected from the group consisting of hydrogen, chlorine, bromine, fluorine, trifluoromethyl, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, hydroxy, amino, nitro and substituted phenoxy, wherein the substituent in said substituted phenoxy group is selected from the group consisting of hydrogen, hydroxy, C 1 -C 4 alkyl, chlorine, bromine, fluorine, trifluoromethyl, nitro, amino, and C 1 -C 4 alkoxy,

M and Q each represent a radical selected from the group consisting of hydrogen, hydroxy, amino, chlorine, bromine, fluorine, trifluoromethyl, nitro, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, Ν, (C 1 -C 4) dialkylamino groups in each of said alkyl groups, (C 1 -C 4) alkylamino groups, NHCOR 4, NHCOOR 5 and NHSC 1 R 8, wherein R 4 represents a substituent selected from the group consisting of hydrogen, alkyl groups containing C 1 -C 6, phenyl and substituted phenyl, wherein said substituent in the substituted phenyl group is selected from the group consisting of hydroxy, chlorine, bromine, fluorine, trifluoromethyl, amino, nitro, alkyl of 1 to 4 carbon atoms and (C 1 -C 4) alkoxy groups and wherein R 5 and R 8 are each selected from the group consisting of C 1 -C 6 alkyl, phenyl and substituted phenyl, wherein the substituent in said phenyl group is selected from hydroxy, chloro, bromo, fluoro, trifluoromethyl an amino group, a nitro group, an alkyl group having 1 to 4 carbon atoms and an alkoxy group having 1 to 4 carbon atoms, or M and Q together form a bivalent radical Z, wherein Z is selected from the group consisting of

RRs

wherein R 7 and R 8 are each selected from the group consisting of hydrogen and methyl, and pharmaceutically acceptable acid addition salts thereof.

By the above-mentioned pharmaceutically acceptable acid addition salts is meant, for example, the following salts: hydrochloride, hydrobromide, hydroiodide, nitrate, hydrogen sulfate, dihydrogen phosphate, mesylate, maleate and succinate. These salts are prepared in a conventional manner by reacting the free base form of a compound of formula I with a suitable acid, usually reacting one molar equivalent and reacting in a suitable solvent. These salts, which do not precipitate directly, are usually separated by evaporation of the solvent and / or addition of a non-solvent, followed by filtration.

A preferred group of compounds of the present invention are those wherein M and Q are Z, wherein Z is:

R 1 and R 2 are hydrogen and R 3 is a methyl group, which compounds form the relative stereochemistry of the 1s *, 2s * or erythro arrangement at the 1st and 2nd positions of the propanol chain, i.e.:

A second group of preferred compounds of the present invention are those wherein M and Q are Z, wherein Z is:

R @ 1 and R @ 2 represent a hydrogen atom and R @ 1 represents a methyl group, which compounds form the relative stereochemistry of the 1 ', 2' or threo arrangement. on the 1st and 2nd positions of the propanol chain, that is:

The present invention also provides pharmaceutical compositions comprising a compound of formula I and methods of treating a mammal, particularly a human, suffering from a central nervous system disorder comprising administering to said mammal a neuroprotectively effective amount of a compound of formula I. are particularly useful in the treatment of traumatic brain and spinal cord injury, stroke, Alzheimer's disease, Parkinson's disease, Huntington's disease and similar disorders of the central nervous system.

The present invention also relates to intermediates of formula IV;

in which i;

R 2 and R 3 are each, each selected from hydrogen, C 1 -C 6 alkyl, phenyl, and substituted phenyl, wherein the substituent in said phenyl group is selected from hydroxy, C 1 -C 4 alkyl , chlorine, bromine, fluorine, trifluoromethyl, amino, nitro and (C 1 -C 4) alkoxy, m is 0 to 2, n is 1 or 2,

X and Y are each independently selected from the group consisting of hydrogen, chlorine, bromine, fluorine, trifluoromethyl, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, hydroxy, amino, nitro and substituted phenoxy, wherein the substituent in said substituted phenoxy group is selected from the group consisting of hydrogen, hydroxy, C 1 -C 4 alkyl, chlorine, bromine, fluorine, fluoromethyl, nitro, amino and C 1 -C 4 ocyloxy,

M and Q each represent a radical selected from hydrogen, hydroxy, amino, chlorine, bromine, fluorine, trifluoromethyl, nitro, alkyl of 1 to 9 carbon atoms, alkoxy of 1 to 4 carbon atoms) : t ..

N, N-dialkylamino groups having 1 to 4 carbon atoms in each of said alkyl groups, N-alkylamino groups having 1 to 4 carbon atoms, NHCOR 4, NHCOOR 8 and NHSC 4 R 8.

wherein R 4 is a substituent selected from the group consisting of hydrogen, C 1 -C 6 alkyl, phenyl, and substituted phenyl, wherein said substituent in the substituted phenyl group is selected from hydroxy, chloro, bromo, fluoro, trifluoromethyl , amino, nitro, C 1 -C 4 alkyl and C 1 -C 4 alkoxy, and wherein R 8 and R 8 are each selected from C 1 -C 6 alkyl, phenyl, and substituted phenyl, wherein the substituent in said phenyl group is selected from the group consisting of hydroxy, chloro, bromo, fluoro, trifluoromethyl, amino, nitro, (C 1 -C 4) alkyl and (C 1 -C 4) alkoxy, or M and Q together forms dv and Z is selected from the group consisting of

Ε10

wherein R 1 and R 8 are each selected from the group consisting of hydrogen and methyl.

Depending on the meaning of R 1, R 2 and R 8, the compounds of formula I may have one or two asymmetric centers and therefore exist in different isomeric forms. All such isomers are within the scope of the present invention. The individual isomers may be separated by methods well known in the art.

In general, the compounds of formula (I) may be readily prepared by reacting a chloro compound of formula (II) with piperidine of formula (III) followed by reduction of the thus obtained ketone of formula (IV) to an alcohol as described in detail below. .

The ketone precursors are usually prepared with protected substituents groups -OH and NHg, i.e. in the form of -OA 1 or -NHA 2 groups present in the compounds of formula (IV). These protecting groups A1 and A2 are defined below. Said protected ketones are usually prepared by reaction

1 of a suitable substituted 2-halo-1-alkanone of formula II with a suitable substituted piperidine derivative of formula III, i.e. according to the following reaction scheme:

IN

The reaction of a compound of formula II with a compound of formula III is carried out under conditions customary for general nucleophilic exchange. When the two reactants are available in the same manner, they can be used in approximately molar equivalents, but when one of the reactants is more readily available, it is usually preferred to use the reactants in excess of the molar equivalents. to accelerate this bimolecular reaction and complete it in a shorter reaction interval. The above reaction is usually carried out in the presence of at least one molar equivalent of a base, which may be the piperidine derivative itself, if readily available, but more commonly is the use of a tertiary amine having at least comparable basic capability to said nucleophilic piperidine compound. a reaction solvent such as ethanol. If desired, the reaction is catalyzed by the addition of up to one molar equivalent or even more of an iodide salt (such as sodium iodide NaI and potassium iodide KI). Temperature is not a critical value, but somewhat elevated pressure is typically used to accelerate the reaction and complete it in a shorter time, but not too high pressure, which could lead to undesirable decomposition of the reactants. In general, a suitable temperature is between 50 and 120 ° C. Typically, the reaction mixture is refluxed.

As mentioned above, the term inert reaction solvent refers to any solvent that does not react with the starting materials, reactants, intermediates or products in such a way as to adversely affect the reaction and yield of the desired product.

If desired, said ketone intermediates of formula IV having OH or NH _?

Three groups in protected form (RO is OA or NI ^! And ₉₎ to get rid of these protecting groups at this stage of the process according to conventional methods.

The protecting group may be, for example, a triisopropylsilyl group or a tert-butyldimethylsilyl group, which is typically removed by reaction with tetrabutylammonium fluoride (typically 2 molar equivalents) in an inert reaction solvent such as tetrahydrofuran.

When A 1 is benzyl or A 2 is benzyloxycarbonyl, the protecting group can be removed by conventional hydrogenolysis in the presence of a noble metal catalyst in an inert reaction solvent, e.g. using 10% Pd /. C as a catalyst, preferably at a low pressure (such as at a pressure of from 1 to 10 bar), a low temperature (for example at a temperature of from 20 to 75 ° C) and usually in an inert reaction solvent such as for example methanol.

Typically, ketone intermediates of formula (IV) are converted to the corresponding alcohols using one of the two commonly used reduction methods of the prior art, selectively obtaining either threo or erythro compounds of formula (I).

As mentioned above, the term threo, or lr ', 2.s *, means the following relative stereochemistry at the 1- and 2-positions of the propanol chain:

and the term erythro, or ls *, 2s *, means the following relative stereochemistry at the 1 and 2-position of the propanol chain:

If the aim of the process is to obtain the erythro compounds of the side formula I, then the corresponding ketone intermediates of formula IV are conventionally reduced with potassium borohydride, usually used in excess (e.g. greater than 5 molar equivalents) of glacial acetic acid in the protic solvent. such as ethanol, and this reaction is usually carried out at a temperature in the range of 15 to 25 ° C.

If the aim is a process for obtaining threo compounds of formula I, by treating a corresponding ketone mnprodukty of formula IV in a conventional manner reduces borohydride _of sodium, which is usually used in excess' for example in an amount greater than 5 mole equivalents) in a protic solvent, e.g. ethanol, and this reaction is usually carried out at a temperature in the range of 15-25 ° C. The reaction mixture obtained is chromatographed on a silica gel column to give the threo compounds of formula (I).

Any protecting groups still present after reduction of the ketone compound are then removed by standard methods as described above.

The starting compounds and reagents needed to carry out the synthesis of the compounds of the present invention are readily available, whether commercially available or prepared by methods described in the literature or by methods exemplified by the preparation of starting materials in the Examples section.

The compounds of formula (I) of the present invention exhibit selective neuroprotective activity based on their anti-ischemic activity and ability to block excitatory amino acid receptors, while at the same time having a reduced or insignificant hypotensive activity. The anti-ischemic activity of the compounds of the present invention can be ascertained by one or more of the methods cited hereinabove. references to publications by Gotti et al. and Carter et al., or by other similar methods.

The ability of the compounds of the invention to block excitatory amino acid receptors is demonstrated by the ability of these drugs to reduce the death rate of fetal rat neurons in a culture that has been exposed to the excitotoxic effects of amino acid glutamate. The following is typical

-10 used procedure.

Part I: Isolation of cells.

Rat embryos after 17 days of gestation were removed and placed in Tyrode's solution. The brains were then removed and walls into fresh Tyrode's solution. Eye scalpels were used to remove the posterior (rorabencephaloma) and thalamus. The forebrain was then divided into two hemispheres. The meninges were then carefully removed. The hippocampus had the appearance of a dark, rugged formation on the inner sw.fina of the cortex edge. This hippocampus was then gently licked from the rest of the tissue and placed in a separate place on the working dish. Upon completion of dissection, the collected pppokampus was cut into 1 millimeter pieces. These cannulas were removed using a Pasteur pipette and placed in sterile tubes. The Tyrode's solution was then carefully aspirated, and the next phase without addition of magnesium and palate was added. The tissue was then washed three times with this; with a generic solution without calcium and magnesium. An aliquot of the last saturation was incubated for 15 minutes at 37 ° C. The buffer was then removed again and replaced with 1 µl of fresh calcium and magnesium-free Tyrode solution.

0.1% trypsin (100 μΐ of a sterile, sterile solution of 0.1%) was added

Π (milligrams / milliliter). The tube was then incubated for dsP; 1 hour at 37 ° C. After trypsin incubation, η was washed with serum-containing medium to stop. b-lateral trypsin. The tissue was then resuspended in 1 liter of fresh medium and triturated with a Pasteur pipette through a peri-orifice.

Cells were then counted with a hemocytometer. These cells were then plated into Falcon Primeria 96-well tissue culture plates, with 75,000 cells per well in complex medium. This complex medium contained Minimal Essential Medium (MEM) with Earle's salts, 10% calf fetal calf serum (Hyclone), 10% horse serum, L-glutamine (2 mM), penicillin-streptomycin (100 units per milliliter) and glucose (k adjusting the total concentration to 21 mM a stock solution (100x greater concentration containing 27.8 grams per 100 mL) was prepared).

After three days, the plates were filled with fresh medium. After six days, 10 gm of cytosinarabinose was added to the cultures in fresh medium. After two days, this cytosinarabinose was removed and replaced with maintenance medium, the above-mentioned complex medium containing no fetal calf serum. These plates were then filled twice a week.

Three weeks after dissection, the plates were used to carry out a glutamate toxicity experiment to ensure proper neuronal development in culture.

Part 2: Glutamate treatment and drug addition after glutamate treatment.

After three weeks of contact with the culture, the medium was removed from the cells and these cells were washed three times with a chloride-free salt solution (CSS-C1). This CSS-C1 solution contained 69 mM sodium sulfate Na 2 SO ₄ , 2.67 mM potassium sulfate K 2 SO ₄ , 0.33 mM sodium bicarbonate NaHPO ₄ , 0.44 mM potassium dihydrogen phosphate KH 2 PO 4, mM sodium bicarbonate NaHCO 4, 1 mM magnesium sulfate MgSO 4. , 10 mM HEPES (which is N-2-hydroxyethylpiperazine-N-6-ethanesulfonic acid), 22.2 mM glucose and 71 mM sucrose, the solution having a pH of 7.4. After washing, glutamate was added at a concentration of 1-3 mM

18 in CSS-C1 buffer, wherein the control chambers contained glutamate-free buffer. These plates were incubated at 37 ° C for 15 to 20 minutes. After glutamate incubation, the plates were washed twice with serum-free medium. Test compounds were then prepared at appropriate concentrations in serum-free medium and added to the appropriate wells (100 µΐ per well).

In the negative control chambers, serum-free medium was added without the addition of the test compound (drug). Serum-free medium without test compound (drug) was also added to several chambers after glutamate treatment as positive control experiments. Plates were incubated overnight at 37 ° C, and cell viability was assessed by LDH assay (lactate dehydrogenase) and MTT assay (methylthiotetrazolinium).

Part 3: Evaluation of cell viability.

Next, 100 μΐ of media from each plate was separated and transferred to a clean plate to test for the amount of LDH released. 100 μΐ of MTT solution was then added to each well. This MTT solution was prepared by adding 10 μΐ of MTT stock solution (5 milligrams / milliliter in PBS, phosphate buffered saline) to each 100 μΐ serum-free medium. The plates were then incubated at 37 ° C for 4 to 6 hours. Then, 100 μ kyseliny of an acid in alcohol solution (0.08 N hydrochloric acid in isopropanol) was added to each well, and the wells were then vigorously mixed to dissolve the purple crystals. Control tufts contained medium with MTT-solution and acid / alcohol solution, but without cells. The plates were then read on a microplate counter

1) using a two-wave test filter set at 570 nm and a reference filter set at 630 nm. These plates should be evaluated at one-hour intervals.

The medium was tested for LDH after removal. The LDH reaction mixture was then added to equivalent volumes of extracted samples. In this case, suitable cells were combined to obtain 500 μΐ samples. For each sample, a reaction mixture was prepared by mixing 480 μΐ 0.1 M sodium phosphate buffer pH 7.5, 10 μΐ sodium pyruvate (66 mM) and 10 μΐ reduced NADH (each ampoule containing 5 milligrams of NADH was reconstituted at 440 μΐ 0.1 N NaOH and 10 μΐ of this fraction were then used for each sample). The sample was quickly added to the reaction mixture in cuvettes and the disappearance of absorbance at 340 nm was measured on a Beckman DU-8 spectrophotometer.

The undesired hypotensive activity of the compounds of the present invention has also been determined using known methods, for example the method of Carron et al., Supra, cited above.

This selective neuroprotective anti-ischemic and excitatory amino acid receptor blocking activity enables the compounds of the invention to be used in the treatment of traumatic brain and spinal cord injury, degenerative CNS damage such as stroke, Alzheimer's disease, Parkinson's disease and Huntington's disease without there was a greater risk of a simultaneous drop in blood pressure. For the systemic treatment of these diseases in humans, the neuroprotective dosage amount of the compounds of formula I is usually in the range of about 0.02 to 10 milligrams / kilogram / day (the usual dose in an average person weighing 50 kilograms is in the range of 1 to 500 milligrams per day) in the form of a single dose or multiple divided doses, regardless of the mode of administration of the drug. However, the attending physician may determine a dose that is outside the indicated range, depending on the particular compound employed and the exact nature of the particular disease being treated. Oral administration of these compounds of the invention is generally preferred. However, in cases where the patient is unable to swallow or oral absorption is prevented for another reason, the compounds of the invention are preferably administered parenterally (i.m., i.v.) or topically.

The compounds of the present invention are generally administered in the form of pharmaceutical compositions comprising at least one compound of Formula I in combination with a pharmaceutically acceptable vehicle or diluent in a ratio of 1:20 to 20: 1. wherein solid or liquid carriers or diluents are used according to the desired suitable mode of administration. For oral administration, tablets, hard or soft gelatin capsules, suspensions, granules, powders and the like are used, for parenteral administration, solutions or suspensions for injection and the like are used, and for topical administration solutions, ointments, skin suspensions, pastes and the like.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention and their preparation process will be illustrated with the aid of the following examples, which are for illustrative purposes only, and the scope of the invention is not limited thereto.

All non-aqueous reactions were carried out in a conventional manner under an atmosphere of dry, oxygen-free nitrogen to maximize the yield. All solvents / diluents used were dried using standard published methods or were obtained in pre-dried form. Mixing with either a magnetic stirrer or a mechanical stirrer was used for all reactions performed. NMR spectra were recorded at 300 MHz and are reported in ppm values in descending order away from trimethylsilane. The solvent for NMR was CDCl3 unless otherwise indicated in the specific case. IR spectra (infrared) are reported in micrometers, with only strong signals usually being reported.

Example 1

(±) -3,4-Dihydro-6- (1-hydroxy-2- (1- (4-hydroxy-4-phenoxymethyl) piperidinyl) ethyl) quinolin-2- (1H) -one.

According to this embodiment, the reaction mixture containing 30.0 milligrams (representing 1.23 mmol) of 4-hydroxy-4- (phenoxymethyl) piperidine hydrochloride, 409 milligrams (representing 1.84 mmol) of 6- (2-chloroacetyl) -3,4-dibydroquinoline Of -2 (1H) -one and 0.514 ml (0.373 g or 3.7 mmol) of triethylamine in 25 ml of acetonitrile was heated at 60 ° C overnight. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate, and the organic layer was washed again with water and then brine. The obtained ethyl acetate layer was dried with brine and magnesium sulfate and the solvent was evaporated to give 3,4-dihydro-6- (1-oxo-2- (1- (4-hydroxy-4-phenoxymethyl) piperidinyl) ethyl) quinoline- The 2- (1H) -one was a brown solid which was then used in the next reduction step without further purification.

The ketone thus obtained was dissolved in 25 ml of absolute ethanol and then 500 mg (13.1 mmol) of sodium borohydride NaBH ₄ was added in portions over a 20 minute period. The reaction mixture was stirred at room temperature for 4 hours and the solvent was removed, and the residue was partitioned between water and ethyl acetate. After drying, the ethyl acetate was removed under vacuum and the residue was chromatographed on silica gel to give the desired product 73 mg (15% yield).

Melting point: 186-188 ° C.

NMR (CD ₃ OD) δ:

Δ - 2.10 (4H, 1H, 2 H, s), 82-7.38 (8H,

m).

2.52 - 3.07 (10H, m), 3.83 (2H, s), 1 and 2 of the preparation sequence of (±) -5- (1-hydroxy-2- (1- (4-hydroxy- (4-methoxymethyl) piperidinyl) ethyl) benzimidazolin-2-one.

The procedure described in Example 1 was followed, the title compound being obtained from the hydrochloride salt.

4-hydroxy-4- (phenoxymethyl) piperidine (1.23 mmol),

Of 5- (2-chloroacetyl) -2-hydroxybenzimidazole (1.84 mmol) and triethylamine (3.7 mmol) in 25 mL of acetonitrile. The resulting ketone was stirred with sodium borohydride (13.1 mmol) in absolute ethanol to give the title compound after silica gel chromatography.

Yield: 35%.

C.

Melting point Analysis calculated for:

232

235 ^{° C} 21 ^H 25 ^N 3 ° 4

62.81

62.98

H ₂ o:

H, 6.77; H, 6.54

N, 10.46% N, 10.32%

Example 3

Preparation of (±) -5- (1-hydroxy-2- (1- (4-hydroxy-4-phenoxymethyl) piperidinyl) ethyl) -2-oxindole.

Following the same procedure as in Example 1, the title compound was obtained from 4-hydroxy-4- (phenoxymethyl) piperidine hydrochloride (used at 1.23 mmol), 5- (2-chloroacetyl). of oxindole (used at 1.84 mmol) and triethylamine (at 3.7 mmol) in 25 ml of acetonitrile. The resulting ketone was stirred with sodium borohydride (13.1 mmol) in absolute ethanol to give the title compound after silica gel chromatography. Yield: 40%.

Melting point: 171-174 ^e C.

Example 4

(±) -erythro-5- (1-hydroxy-2- (1- (4-hydroxy-4-phenoxymethyl) piperidinyl) propyl) benzimidazolin-2-one.

In this embodiment, the solution containing 933 milligrams (corresponding to 2.36 mmol) of (±) -1- (5- (2b-hydroxybenzimidazolyl)) -2- (1- (4-hydroxy-4-phenoxymethyl) piperidinyl) propane- Of 1-one in 10 ml of glacial glacial acid and 50 ml of absolute ethanol is treated by sequential addition of 944 mg (17.48 mmol) of potassium borohydride at a temperature in the range of 15 to 20 < -1 > The mixture was stirred overnight at room temperature. The reaction mixture was evaporated to dryness and the residue was taken up in a minimum amount of water. The pH of the solution was then adjusted to 7-8 with solid 4 of sodium bicarbonate NaHCO 3 to precipitate a solid. This material was insoluble in chloroform, relatively insoluble in ethyl acetate. This one. The residue was then re-evaporated to dryness and the residue which was crystallized was placed in a residue. brinol and filtered to separate the salts. The ethanol was evaporated and the residue was taken up in isopropanol and treated with hydrogen chloride gas in ether _; a non-crystalline salt precipitated from the biobas, which was collected by filtration and dried in a stream of dry nitrogen. This material was dissolved in hot ethyl acetate by addition of methanol and purified by removing the color of the wood used to remove the color and distilling off the methanol. Cooling gave 410 mg of a colorless crystalline product. Yield: 40%.

i.a. melting: 254-255 C. C.

IR (KBr): 5.90 gm NMR (CD ₃ OD) δ:

1.22 (3 H, d, J = 7)

1.95 - 2.09 (2H, m),

m), 3.42-3.76 (4H, m),

5.47 (1 H, s),

2.15-2.30 (2H, m 3.91 (2H, s))

6.92-7.35 (8H, m

Example

(±) -threo-5- (1-hydroxy-2- (1- (4-hydroxy-4-phenoxymexyl) piperidinyl) propyl) benzimidazolin-2-one.

According to the xohoxo embodiment, a total of 700 milligrams (18.4 mmol) of sodium borohydride was added portionwise to a slurry containing 325 milligrams (0.82 mmol) of (±) -1- (5- (2-hydroxybenzimidazolyl)) - 2 Of (1- (4-hydroxy-4-phenoxymexyl) piperidinyl) propan-1-one in 20 ml of absolute ethanol was then stirred overnight at room temperature. The solvent was removed by evaporation and the foam residue was taken up in a mixture of ethyl acetate and water and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate extracts were then dried and evaporated, and the foam residue was chromatographed on silica gel with ethanol / ethyl acetate 1: 1. The desired product was obtained as a white solid.

Mp > 250 ° C.

NMR (acetone-dg) δ:

0.79 (3H, d, J = 7), 11.90-2.08 (2H, m), 3.01 (1H, t, J = 7),

1.71-1.88 (2H, m), 2.48-2.88 (4H, m), 3.88 · (2H, s),

4.26 (1H, d, J = 7), Analysis calculated: 62.24 Found: 61.72 ^C 22 ^H 27 ^N 3 ° 4 CC

6.86-7.32 (8H, m). 1.5 H ₂ O;

% H, 7.12;% H, 9.89;

6.73% H 9.03% N.

Example

(±) -erythro-3,4-dihydro-6- (1-hydroxy-2- (1- (4-hydroxy-4-phenoxymethyl) piperidinyl) propyl) quinolin-2 (1H) -one.

In this embodiment, the solution containing 7.13 grams (representing 17.5 mmol) of (±) -1- (6- (1,2,3,4-tetrahydro-2-oxoquinolinyl)) -2- (1- (4- hydroxy-4-phenoxymethyl) piperidinyl) propan-1-one in 135 ml of absolute ethanol and 70 ml of glacial acetic acid is treated by successive addition of 6.22 g (115 mmol) of potassium borohydride KBH ₄ at a temperature ranging from 15 to 20 °. The temperature of the solution was allowed to rise to room temperature over 30 minutes. The reaction mixture was evaporated to dryness and the residue was taken up in ice / cold water and basified by the addition of NaHCO 3. A solid precipitated which was collected by filtration and washed with water and air dried to give 3.66 g of crystalline free basic compound; mp: 192-196 ° C. The filtrate was extracted with ethyl acetate and the combined extracts were dried with brine and magnesium sulfate MgS0 _4, and this proportion was evaporated to give an additional 786 mg of product (overall yield of 62%). A sample weighing 510 mg was then dissolved in ethyl acetate and treated with a solution of hydrogen chloride gas in ether to give 475 mg of the crystalline hydrochloride salt.

Melting point: 214 - 216 ° C (with decomposition).

IR (KBr) ν.

NMR (CD ₃ OD) δ: 1, 15 (3H, d. J = 7), 1.86 - 2, 04 / (2H, m), 3.52 - 3,66 (2H, m) 3.69 - 3, 80 (1H, m), 3.86 (2H, s) F 5.34 (1H, s), 6.81 - 6.96 (4H, m) 7.17 - 7, 28 (4H, m).

Example 7

(±) -threo-3,4-dihydro-6- (1-hydroxy-2- (1- (4-hydroxy-4-phenoxymethyl) piperidinyl) propyl) quinolin-2 (1H) -one.

In total, 1.50 grams (39.5 mmol) of sodium borohydride NaBH4 was added portionwise to a suspension containing 700 milligrams (1.71 mmol) of (±) -1- (5- (2-hydroxybenzimidazolyl) 1- [2- (1- (4-Hydroxy-4-phenoxymethyl) piperidinyl) propan-1-one] in 20 ml of absolute ethanol, and the reaction mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was taken up in ethyl acetate / water and the aqueous layer was extracted with ethyl acetate. The combined extracts were dried and evaporated and the foam residue was chromatographed on silica gel using 1: 1 ethanol: ethyl acetate as the eluent to give the desired product as a white solid; mp: 192-196 ° C. This reduction produced a small proportion of the erythro compound which could be separated in this column.

NMR (CD ₃ OD) δ: 0.82 (3H, d, J = 7), 1.72 - 2.06 (3H, m) • 2.50 - 2,82 (6H, m) 2.88 - 3.02 (2H, t, J = = 7) 3.02 (1 H, t, J = 7), 3.84 (2 H, s) »» 4.28 (1H, d. J = 7), 6.80 - 7.34 (9H, m) Anal; ysis for ^C 22 ^H 27 , N- JO4. 1.5 H 2 O vypoi read: 65.88 % C 7.60% H 6, 40 % nale ' zeno: 65.74 % C 7.09% H 6, 31 %

Example 8

Preparation of (±) -erythro-5- (1-hydroxy-2- (1- (4-hydroxy-4-phenoxymethyl) piperidinyl) propyl) oxindole.

In this embodiment, the mixture was 0.5 g (2.05 mmol) of 4-hydroxy-4- (phenoxymethyl) piperidine hydrochloride, 0.5 g (2.25 mmol) of 5- (2-chloropropionyl) oxindole, and 1 ml (0.725 g or 7.18 mmol) of triethylamine in 20 ml of acetonitrile is heated at reflux for 24 hours. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water and brine, dried over MgSO 4 and concentrated to give the ketone as a red-brown foam, which was used for the next reaction without purification. Yield: 537 mg (66%).

In another method, the solution containing 500 mg (1.26 mmol) of ketone in 20 mL of ethanol was treated portionwise with 1.0 g (26.3 mmol) of sodium borohydride NaBH ^, wherein the final mixture was stirred at ^- room temperature for hours. The solvent was removed under vacuum and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine and dried over magnesium sulfate and MgS0 ₄ and then was evaporated to dryness. The residue was chromatographed on silica gel using ethyl acetate as eluent to give the threo product in pure fractions.

Yield: 121 mg (24%).

Melting point: 204-207 ° C.

NMR (DMSO-d ₆ ) δ;

0.70 (3H, d, J = 7), 1.58-1.92 (4H, m),

2.40 - 2.65 (4H, m), 2.86 (1H, m),

3.32-3.40 (2H, m), 3.79 (2H, s),

4.20 (1H, d, J = 7), 6.70-7.35 (8H, m),

10.34 (1 H, s).

Example 9

Preparation of (±) -1- (6- (1,2,3,4-tetrahydro-2-oxoquinolinyl)) -2- (1- (4-hydroxy-4-phenoxymethyl) piperidinyl) propan-1-one.

In this embodiment, the suspension containing 8.30 grams (34.06 mmol) of 4-hydroxy-4-phenoxymethylpiperidine hydrochloride and 8.09 grams (34.06 mmol) of 6- (2-chloro-1-propionyl) 1,2,3,4-tetrahydroquinolin-2 (1H) -one in 100 ml of acetonitrile, treated with 16.61 ml (12.04 g, or 0.12 mmol) of triethylamine and the mixture thus obtained is heated to boiling at reflux for 3 hours and then stirred overnight at room temperature.

The reaction mixture was poured into water, extracted three times with ethyl acetate, and the combined extracts were dried with brine and magnesium sulfate and evaporated to a foam. The foam was dissolved in hot methanol and ethyl acetate and then cooled to give a reddish-brown solid, which was analyzed as the starting chloroketone and drained. The filtrates were evaporated and dissolved in ethyl acetate and ether was added to facilitate crystallization. The product was filtered and washed with ether to give 8.84 g (63.6% yield) of the desired product as a cream solid, m.p. 137-139 ^e .

The sample for analysis was crystallized from hot ethyl acetate.

(CD ₃ OD) 5:

28 (3H, d) J = 7) * 1, 60 - 1.92 (4H, m), 52 - 2.84 (6H, m), 3, 00 (2 H, t, J = 7) 75 (2H, s) »» 4, 22 (1 H, q, J = 7) 82 - 7.00 (4H, m), 7, 16 (2H, m) : 12 - 7.98 (2H, m). ilýza pro ^C 24 ^H 28 ^N 2 ° 4 counted: 70, 56% 6.91% H 6.86 % N lezeno: 70, 10% C 6.78% H 6.76 % N i i 1 a d 10

Preparation of (±) -1- (5- (2-hydroxybenzimidazolyl)) - 2- (1- (4-hydroxy-4-phenoxymethyl) piperidinyl) propan-1-one.

In this embodiment, the suspension containing 2.43 grams (10.0 mmol) of iHydroxy-4-phenoxymethylpiperidine hydrochloride and 2.25 grams (10.0 mmol) of 5- (2-eh) -or-1-propanol onyl) -2-hydroxybenzimidazole in 40 mL of acetonitrile, treated with 4.88 mL (3.53 g, or 35.0 mmol) of triethylamine, which was then heated at reflux for 90 minutes and then allowed to settle over the weekend at room temperature.

The reaction mixture was poured into a mixture of water and ethyl acetate to give a suspended solid which was collected by filtration to be pure. This product was obtained after drying in an amount of 1.15 g. The filtrate was adjusted to pH = 7.0 and then extracted several times with ethyl acetate, to afford, after drying with brine solution and with magnesium sulfate MgSO ₄ to give a colorless solid which crystallized from hot ethyl acetate / methanol to give an additional 560 milligrams of product.

Total yield: 43%.

Melting point: 230-235 ° C (with decomposition).

NMR (CD ₃ OD / DMSO-d ₆ ) δ:

1.29 (2H, d, J = 7), 1.60-1.92 (4H, m),

2.54 - 2.84 (4H, m), 3.77 (2H, s),

4.26 (1H, q, J = 7), 6.86-7.10 (6H, m),

7.75 - 7.92 (2H, m).

Example 11

Preparation of (±) -1- (5- (oxindolyl)) - 2- (1- (4-hydroxy-4-phenoxymethyl) piperidinyl) propan-1-one.

The procedure of Example 10 was followed from the hydrochloride

4-hydroxy-4-phenoxymethylpiperidine (10.0 mmol),

Of 5- (2-chloropropionyl) oxindole (10 mmol) and triethylamine (35 mmol) in 50 mL of acetonitrile. The title compound was isolated by crystallization from a hot mixture of ethyl acetate and methanol to give an amorphous foam. Yield: 66.4%.

NMR (CDC1 ₃₎ δ:

; 28 (3H, d, J = 7), 2, 40- 2.84 (4H, m), 3.76 (2H, s),

6.78 - 6.96 (3H, m), 83-8.05 (3H, m), 3.64 (1H, belt s).

1.58 - 1.78 (4H, m), 3.54 (2H, s),

4.09 (1H, q, J = 7), 7.14-7.26 (2H, m), 9.52 (1H, s band),

Preparation 1

Preparation of 3,4-dihydroquinolin-2- (1H) -one.

According to this embodiment, the suspension containing 50.0 y sines (representing 0.259 moles) of o-nitro cinnamic acid was

800 milliliters of ethanol was treated by adding five tbsp of Raney nickel, and this was then iv / drogenated in a Parr apparatus overnight at a pressure of 345 kPa. In the morning, the pressure was again raised to kPa and the reaction continued for an additional 5 hours. The reaction mixture was filtered to remove the catalyst and then washed on a bed of silica gel with ethyl acetate / ethanol to remove

b. Gray traces of nickel salts. The desired product was obtained by filtration.

Yield: 57%.

NH 4 (DMSO-d ₆ ) δ: 3.-8 (2H, t, J = 7),

2.87 (2 H, t, J = 7),

6.87 (2H, d of d, J = 7, 7), 7.12 (211, d of d, J = 7, 10),

1.08 (1 H, s).

Melting point: 165-166 ° C.

Preparation 2

Preparation of 6- (2-chloropropionyl) -3,4-dihydroquinolin-2 (1H) -one.

The suspension containing 72.5 grams (0.544 mole) of AlCl4 in 800 milliliters of CS2 carbon disulfide was stirred under a dry nitrogen atmosphere, while 14.1 milliliters (20.0 grams or 0.177 moles) were added simultaneously. )

2-chloropropionyl chloride followed by the addition of 20.0 grams (equivalent to 0.136 mol) of 3,4-dihydroquinolin-2 (1H) -one. The reaction mixture was heated at reflux for 4 hours, after which time phase separation was observed. The reaction was then quenched by pouring onto ice with vigorous stirring. Light yellow crystals were formed which were collected by filtration, washed with water and dried overnight using P2O5 phosphorus pentoxide to give 27.7 g (91% yield) of the desired product.

Melting point: 236.5-238 ° C.

Preparation 3

Preparation of 5- (2-chloropropionyl) -2-hydroxybenzimidazole.

Following the same procedure as in Preparation 2, the above compound was obtained from 2-hydroxybenzimidazole (used at 0.136 mol), aluminum chloride (used at 0.544 mol) and 2-chloropropionyl chloride (used at 0.177 mol) in 800 milliliters of carbon disulfide (50%). The title compound was collected by filtration.

Yield: 92%.

Melting point: 245 ° C (dec.).

N, 12.47. Found: C, 54.41; H, 4.07; H, 13.25%.

Preparation 4

Preparation of 5- (2-chloropropionyl) oxindole.

Following the same procedure as in Preparation 2, the above compound was obtained from oxindole (used at 0.136 mol), aluminum chloride (used at 0.544 mol) and 2-chloropropionyl chloride (used at 0.177 mol) at 800 milliliters of CS2 carbon disulfide · The desired compound was collected by filtration.

Yield: 91%.

Melting point: 157-158 ° C.

Preparation 5

Preparation of 6- (2-chloroacetyl) -3,4-dihydroquinolin2 (1H) -one.

Following the same procedure as in Preparation 2, the above compound was obtained from 3,4-dihydroquinolinolin-2 (1H) -one (used at 0.136 mol), aluminum chloride (used at 0.544 mol) ) and 2-chloroacetyl chloride (used at 0.177 mol) in 800 milliliters of CS2 carbon disulfide. The desired compound was collected by filtration.

216 [deg.] C.

Yield: 50%.

Melting point. Preparation 215 Preparation of 5- (2-chloroacetyl) -2-hydroxybenzimidazole.

The procedure was as described in Preparation 2, the above compound being obtained from 2-hydroxybenzimidazole (used at 0.136 mol), aluminum chloride (used at 0.544 mol) and 2-chloroacetyl chloride (used at 0.177 mol) in 800 ml of carbon disulfide C $ 2. The desired compound was collected by filtration.

Yield: quantitative.

M.p .: 273-275 C (dec.).

Preparation 7

Preparation of 5- (2-chloroacetyl) oxindole.

The procedure of Preparation 2 was followed, the above compound being obtained from oxindole (used at 0.136 mol), aluminum chloride (used at 0.544 mol) and 2-chloroacetyl chloride (used at 0.177 mol) at 800 milliliters of CS2 carbon disulphide. The desired compound was collected by filtration.

Yield: 90%.

Melting point: 236.5-239 ° C.

Preparation8

Preparation of 4-hydroxy-4-phenoxymethylpiperidine hydrochloride.

Oil-free sodium hydride (2.16 g, 0.09 M) was added to dry dimethylsulfoxide (250 mL) under a nitrogen atmosphere, and the mixture was heated at 60-60 ° C. 65 ° C until a uniformly black solution was formed, which took about 1 hour. To this reaction mixture was added 19.83 g (0.09 M) of trimethylsulfoxonium iodide (a slightly exothermic reaction), and the reaction mixture was stirred until a brown solution formed, which took about 30 minutes. Then a solution containing 13.40 grams (representing 67.3 mM) was

The N-t-butyloxycarbonyl-4-piperidone in 50 mL of dimethylsulfoxide was stirred at room temperature for 1 hour. The reaction mixture was poured into one liter of cold water, and the whole was extracted four times with 100 ml portions of hexane. The combined hexane extracts were washed again with 50 ml of water and then brine solution, dried over magnesium sulfate, filtered and evaporated to give 11.75 g of white crystalline product, 6-t-butyloxycarbonyl-1-oxa-6-azaspiro [2.5] octane.

Yield 78%.

Further extraction of the aqueous layers with three 50 mL portions of hexane yielded an additional 650 mg of product with a total yield of 82.5%.

Temperature thaw : 57,5 - 59.5 C • IR (KBr) : 5 , 90 gm. NMR δ: 1.32 - 1 , 48 (2H, m). 1.42 (8H, s), 1,74.- 1 , 80 (2H, m). 2.65 (2H, s), 3.31 - 3 , 43 (2H, m). 3.61 - 3.72 (2H, m)

Analysis calculated for:

^C lll9 ^NO 3 61.94% C 62.05% C

% H, 8.99%

6.57% N

6.58% N.

A solution containing 10.37 g (0.11 M) of phenol in 100 ml of dry dimethylsulfoxide was treated portionwise with 1.99 g (82.8 mmol) of dehydrated sodium hydride, maintaining the temperature in the range of from 20 to 25 ° C in a cold water bath. The reaction mixture was stirred at room temperature for 45 minutes to give a gray suspension. To this suspension was added 11.75 grams (55.2 mmol)

6-t-butyloxycarbonyl-1-oxa-6-azaspiro [2.5] octane dissolved in 65 ml dimethylsulfoxide dropwise and heated at 55-60 ° C. for 7 hours and further stirred at room temperature overnight.

The reaction mixture was poured into one liter of cold water and extracted four times with ether. The combined ether extracts were washed again with 10% sodium hydroxide solution and brine, dried over magnesium sulfate and evaporated to give the desired product. means Nt-butyloxycarbonyl-4-hydroxy-4-phenoxymethylpiperidine, as an oil weighing 17.01 g (100% yield).

IR (film): 5.91, 2.95 μΜ.

NMR (CDC1 ₃₎ δ:

1.46 (9H, s);

3.13-3.30 (2H, m),

3.80 - 3.98 (2H, m),

1.53 - 1.80 (4H, s), 3.80 (2H, s),

6.84 - 6.99 (2H, m),

7.22 - 7.44 1 (3 H, m). Analysis for C ₁₇ H ₂ 5 ^N ° ^4: calculated: 66.42% C 8.20 % H 4,56 % N found: 65.72% C 8.21 % H 4.77 % N. Solution containing 17.0 grams (which is 0.055 M)

i! T-butyloxycarbonyl-4-hydroxy-4-phenoxymethylpiperidine in 150 ml of methanol saturated with hydrogen chloride gas. After cooling, the mixture was re-treated with hydrogen chloride gas and this process was repeated. After crystals were formed, the reaction mixture was treated with 500 ml of anhydrous ether and then allowed to stir at room temperature overnight.

The product obtained was filtered and washed with dry ether and then dried under a stream of dry nitrogen to give 10.85 g (80.6% yield) of crystalline solid.

Melting Fcplot: 202-204 C. C.

(KBr), 06 pm.

3.06, 3.14,

3.44, 3.57, 3.56, 6.33,

NhU (D ₂ 0) δ:

2.00 (4H, s band),

4.00 (2H, s), 7.30 - 7.43 Analysis calculated:

(2H, m).

^c 12 ^H 17 ^NO 2 59.13% C 58.98% C

3.34 (4H, s band) 6.98-7.09 (3H, HCl):

H, 7.44; H, 7.11

m),

5.75% N 5.65% N.

PATENT CLAIM

2- (4-Hydroxypiperidino) -1-alkanol derivatives of the general formula I

in which they also mean:

R ₂ and R _{2 are} each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, phenyl, and substituted phenyl, wherein the substituent in said phenyl group is selected from hydroxy, C 1 -C 6 alkyl; 4 carbon atoms, chlorine, bromine, fluorine, trifluoromethyl, amino, nitro and (C 1 -C 4) alkoxy, or and R ₂ together form a methylene, ethylene, propylene or butylene group, m is 0 to 2, n is 1 or 2,

X and Y are each independently selected from the group consisting of hydrogen, chlorine, bromine, fluorine, trifluoromethyl, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, hydroxy, amino, nitro and substituted phenoxy, wherein the substituent in said substituted phenoxy group is selected from the group consisting of hydrogen, hydroxy, (C 1 -C 4) alkyl, chlorine, bromine, fluorine, trifluoromethyl, nitro, amino and (C 1 -C 4) alkoxy carbon,

M and Q each represent a radical selected from the group consisting of hydrogen, hydroxy, amino, chlorine, bromine, fluorine, trifluoromethyl, nitro, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms,

N, N-dialkylamino groups having 1 to 4 carbon atoms in each of said alkyl groups, N-alkylamino groups having 1 to 4 carbon atoms, NHCOR 4, NHCOOR 5 and NHSC 1 R 8, wherein R 4 represents a substituent selected from the group consisting of hydrogen, alkyl a group containing from 1 to 6 carbon atoms, a phenyl group and a substituted phenyl group, wherein said substituent in the substituted i; is selected from the group consisting of h / hydroxy, chloro, bromo, fluoro, trifluoromethyl, amino, nitro, and C1 -C4 keel and C1 -C4 -cyl groups, and wherein R5 and R 8 are each selected from the group consisting of C 1 -C 6 alkyl, phenyl, and substituted phenyl, wherein the substituent in said phenyl group is v / s selected from hydroxy, chloro, bromo, fluoro, trifluoromethyl, amino C 1 -C 4 alkyl, C 1 -C 4 alkyl, and C 1 -C 4 alkoxy.

Claims (20)

or M and Z is selected from 0 together form a divalent radical Z, a group comprising: R ₈ o Η. Wherein R 7 and R 8 are each selected from hydrogen and methyl, and pharmaceutically acceptable acid addition salts derived from said compounds. A compound according to claim 1, wherein R 2 is a hydrogen atom, R 1 is a hydrogen atom or a methyl group, and M and Q together form a radical Z, which is selected from the group consisting of: Η Ν ' Λ. Ο Ν Η The compound of claim 2, wherein n is 1 and n 1 is 0. A compound according to claim 3, wherein it is hydrogen. A compound according to claim 4, wherein R ₃ is hydrogen. The compound of claim 5, wherein X and Y are each a hydrogen atom. A compound according to claim 4 which is a compound of the general formula: The compound of claim 7, wherein X and Y are each hydrogen. . 3 A compound according to claim 4 which is a compound of the general formula: The compound of claim 9, wherein X and Y are each hydrogen. The compound of claim 6, wherein Z is: A compound according to claim 6, the group: in which Z represents H N H The compound of claim 6, wherein 2 is: represents The compound of claim 8, wherein 2 is: represents A compound according to claim 8, wherein 2 group: represents a group A compound according to claim 8, wherein it is H The compound of claim 10, wherein Z is a group; 18. A pharmaceutical composition comprising a neuroprotective amount of a compound of formula (I) according to claim 1 and a pharmaceutically acceptable carrier. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of traumatic brain and spinal cord injury, stroke or central nervous system degenerative disease in humans. A compound of formula IV; OH M Y (IV in which they mean: ^And each is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, phenyl, and substituted phenyl, wherein the substituent in said phenyl group is selected from hydroxy, C 1 -C 4 alkyl. carbon atoms, chlorine, bromine, fluorine, trifluoromethyl, amino, nitro and (C 1 -C 4) alkoxy, m is 0 to 2, n is 1 or 2, X and Y are each independently selected from the group consisting of hydrogen, chlorine, bromine, fluorine, trifluoromethyl, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, hydroxy, amino, nitro and substituted phenoxy, wherein the substituent in said substituted phenoxy group is selected from the group consisting of hydrogen, hydroxy, C 1 -C 4 alkyl, chloro, bromo, fluoro, trifluoromethyl, nitro, amino, and C 1 -C 4 alkoxy, M and Q each represent a radical selected from the group consisting of hydrogen, hydroxy, amino, chlorine, bromine, fluorine, trifluoromethyl, nitro, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, N, N-dialkylamino groups having 1 to 4 carbon atoms in each of said alkyl groups, N-alkylamino groups having 1 to 4 carbon atoms, NHCOR 4, NHCOOR 5 and NHSC ₄ R 8, wherein R ₄ represents a substituent selected from the group consisting of hydrogen, (C 1 -C 6) alkyl, phenyl, and substituted phenyl, wherein said substituted phenyl substituent is selected from hydroxy, chloro, bromo, fluoro, trifluoromethyl, amino, nitro, (C 1 -C 6) alkyl C 4 -C 4 alkoxy and C 1 -C 4 alkoxy, and wherein R 8 and R 8 are each selected from C 1 -C 6 alkyl, phenyl, and substituted phenyl, wherein the substituent in said phenyl group is selected from the group consisting of: hydroxy, chloro, bromo, fluoro, tri fluoromethyl, amino, nitro, (C 1 -C 4) alkyl and (C 1 -C 4) alkoxy, or M and Q together form a divalent Z moiety, wherein Z is selected from the group consisting of: R- wherein R 7 and R 8 are each selected from the group consisting of hydrogen and methyl. 21. A process for preparing a compound of formula I: in which they mean: R 1, R 2 and R _{3 are} each, each selected from hydrogen, C 1 -C 6 alkyl, phenyl, and substituted phenyl, wherein the substituent in said phenyl group is selected from hydroxy, C 1 -C 6 alkyl; 4 carbon atoms, chlorine, bromine, fluorine, trifluoromethyl, amino, nitro and (C 1 -C 4) alkoxy, or R 1 and R 2 together form a methylene group, an ethylene group, a propylene group or a butylene group, m is 0 to 2 , n is 1 or 2, X and Y are each independently selected from the group consisting of hydrogen, chlorine, bromine, fluorine, trifluoromethyl, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, hydroxy, amino, nitro and substituted phenoxy, wherein the substituent in said substituted phenoxy group is selected from the group consisting of hydrogen, hydroxy, C 1 -C 4 alkyl, chlorine, bromine, fluorine, trifluoromethyl, nitro, amino, and C 1 -C 4 alkoxy, M and Q each represent a radical selected from the group consisting of hydrogen, hydroxy, amino, chlorine, bromine, fluorine, trifluoromethyl, nitro, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, Ν, (C 1 -C 4) dialkylamino groups in each of said alkyl groups, (C 1 -C 4) alkylamino groups, NHCOOR ₄ , NHCOOR 5 and NHSC 1 R 8, wherein R ₄ represents a substituent selected from the group consisting of hydrogen, alkyl (C 1 -C 6) -phenyl, phenyl and substituted phenyl, wherein said substituted phenyl substituent is selected from hydroxy, chloro, bromo, fluoro, trifluoromethyl, amino, nitro, (C 1 -C 4) alkyl carbon atoms and C 1 -C 4 alkoxy groups; and wherein R 5 and R 8 are each selected from C 1 -C 6 alkyl, phenyl, and substituted phenyl, wherein the substituent in said phenyl is selected from hydroxy, chloro, bromo, fluoro, trifluoromethyl an amino group, a nitro group, a (C1-C4) alkyl group and a (C1-C4) alkoxy group, or M and O together form a bivalent radical Z, wherein: Z is selected from the group consisting of RR < H. H in which R? and R 8 are each selected from the group consisting of hydrogen and methyl, and pharmaceutically acceptable acid addition salts thereof. Zastupuje; Dr. Pavel Zelený Annotation (general formulas I and IV)