HUT70528A - 2-(4-hydroxypiperidino)-1-alkanol derivatives as antiischemic agents and process for production thereof - Google Patents

Description

The present invention relates to neuroprotective / anti-ischemic, excitatory amino acid receptor blocker / 2- / 4-hydroxy-piperidino-1-alkanol derivatives, pharmaceutically acceptable salts thereof, and traumatic, brain and spinal cord injury in mammals, especially humans. neurological degenerative diseases such as Alzheimer's disease, Huntington's disease and Parkinson's syndrome. The invention also provides certain intermediates for the synthesis of these compounds.

Ifenprodil is represented by the racemic, so-called. dl-erythro, which is marketed, together with a number of close analogues, as antihypertensive agents (Carron et al., U.S. Patent 3,509,164); Carron et al., Drug Slit. 21, 1992-1999 / 1971 //. More recently, ifenprodil has been shown to have both an ischemic and excitatory amino acid receptor blocking activity / Gotti et al., J. Pharm. Exp. Ther. 247. 1211-1221 (1988); Carter et al., J. Pharm. Exp. Ther. 247. 1222-1232 / 1988 //. See also French Patent No. 2546166 and European Patent Application EP-A1-351282, published January 17, 1990.

It is also an object of the present invention to provide compounds with potent neuroprotective properties which, however, have a negligible or no effect on blood pressure.

Some analgesic properties of 1-phenyl-3- (4-aryl-4-acyloxy-piperidino) -1-propanol derivatives have also been described (U.S. Patent No. 3,294,804); the analgesic, antihypertensive, psychotropic and anti-inflammatory effects of 1- (4- / amino- and hydroxyalkyl-phenyl) -2- (4-hydroxy-4-tolyl-piperazino) -1-alkanols and alkanones have also been reported / Japanese Kokai 53-02, 474 / Chemical Abstracts 89: 43498y; Derwent Abs. 14858A / 53-59,675 / CA 89: 146938w; Derwent Abs., 48671A_7; and 2-piperidino-1-alkanol derivatives as potent anti-ischemic agents are described in EP 398,578-A and Dér 90-350,327 / 47.

The present invention relates to compounds of formula (I) wherein

R _q , R g and R 4 are each independently hydrogen, C 1-6 alkyl, phenyl or hydroxy, C 1-4 alkyl, chloro, bromo, fluoro, trifluoromethyl, amino, nitro or 1-4. phenyl substituted with C alk alkoxy; obsession

- R 4 and R 8 taken together form methylene, ethylene, propylene or butylene;

m is Ο, 1 or 2;

n is 1 or 2;

X and Y are each independently hydrogen, chlorine, bromine, fluorine, trifluoromethyl, C1 -C4 alkoxy, C1 -C4 alkyl, hydroxy, amino, nitro, or hydrogen, hydroxy, Phenoxy substituted with C 4 alkyl, chloro, bromo, fluoro, trifluoromethyl, nitro, amino or C 1-4 alkoxy;

M and Q are each independently hydrogen, hydroxy, amino, chloro, bromo, fluoro, trifluoromethyl, nitro, C 1-4 alkyl, C 1-4 alkoxy, N, N-di- C 1-4 -alkyl-amino, N- (C 1-4 -alkyl) -amino, -NHCOR ^, -NHCOOR ^ or -NHSOgRg in which:

R 4 is substituted with hydrogen, C 1-6 alkyl, phenyl, or hydroxy, chloro, bromo, fluoro, trifluoromethyl, amino, nitro, C 1-4 alkyl or C 1-4 alkoxy. phenyl;

R 4 and Ηθ are each independently C 1-6 alkyl, phenyl, or hydroxy, chloro, bromo, fluoro, trifluoromethyl, amino, nitro, C 1-4 alkyl, or C 1-4 alkoxy. phenyl; obsession

Together, M and Q form a bivalent radical of formula Z, where

Z is / a, / b, / c where Ry and R _{q are} hydrogen or methyl, / d /, / e /, / f / or / g / and and pharmaceutically acceptable acid addition salts thereof.

Pharmaceutically acceptable acid addition salts include, for example, hydrochloride, hydrobromide, hydroiodide, nitrate, hydrogen sulfate, dihydrogen phosphate, mesylate, maleate and succinate. Such salts may be prepared in conventional manner by reacting the free base compound of formula (I) with about 1 molar equivalent of a suitable acid in a solvent. Non-precipitating salts are usually isolated by evaporation of the solvent or addition of a solvent which has no solubility and subsequent filtration.

According to the invention, a group of compounds is preferred wherein M and Q together form a radical of formula Z wherein

Z is / d /, and

R 4 and R 8 are hydrogen and

R 1 represents a methyl group and the relative stereochemistry of the compounds at the 1- and 2-positions of the propanol chain corresponds to the structure Ir, 2s or erythro in the structure (1).

In another preferred group of compounds of the invention, M and Q together form a radical of formula wherein:

Z is (f), and

R 4 and R 8 are hydrogen and

R 1 represents a methyl group and the relative stereochemistry of the compounds at the 1- and 2-position of the propanol chain can be represented by Is / 2s or threo form with the structure (2).

The invention also relates to pharmaceutical compositions containing the compounds of formula (I) according to the invention and to a method of treating a mammal, particularly a human, having a central nervous system disorder, comprising administering to the mammal an effective neuroprotective amount of the compound of formula (I). These disorders and procedures are particularly significant in the brain and spinal cord traumatic injury, stroke, Alzheimer's disease,

For the treatment of Parkinson's syndrome, Huntington's disease and other disorders of the central nervous system.

The present invention is furthermore of formula IV. refers to intermediates in which hydrogen is independently

C 1-6 alkyl, phenyl or phenyl substituted with hydroxy, C 1-4 alkyl, chloro, bromo, fluoro, trifluoromethyl, amino, nitro or C 1-4 alkoxy;

0, 1 or 2;

or 2;

X and Y are each independently hydrogen, chlorine, bromine, fluorine, trifluoromethyl, (C 1 -C 4) alkoxy, (C 1 -C 4) alkyl, hydroxy, amino, nitro, or hydrogen, hydroxy, Phenoxy substituted with C 4 alkyl, chloro, bromo, fluoro, trifluoromethyl, nitro, amino or C 1-4 alkoxy;

m is the value of n

M and Q are independently hydrogen, hydroxy, amino, chlorine, bromine, fluorine, trifluoromethyl, nitro,

C 1-4 alkyl, C 1-4 alkoxy, N, N-di (C 1-4 alkyl) amino, N- (C 1-4 alkyl) amino, -NHCOR ^, -NHCOOR ^ or -NHSOgRg in which

R 4 is hydrogen, C 1-6 alkyl, phenyl or phenyl substituted with hydroxy, chloro, bromo, fluoro, trifluoromethyl, amino, nitro, C 1-4 alkyl or C 1-4 alkoxy; and

R 6 and R 8 are independently C 1-6 alkyl, phenyl or phenyl substituted with hydroxy, chloro, bromo, fluoro, trifluoromethyl, amino, nitro, C 1-4 alkyl or C 1-4 alkoxy. means; obsession

Together, M and Q form a bivalent radical of formula Z, where

Z is a group, a, / b,

- a group of formula 9 / c - wherein

Ry and Rg are each independently hydrogen or methyl, d /, e, f or g.

Depending on the particular meaning of the substituents R 1, R 8 and R 8, the compounds of formula (I) may contain one or two centers of asymmetry and thus exist in different isomeric forms. All such isomers are within the scope of the invention. The individual isomers can be separated by well known classical methods.

A. Compounds of formula (I) of the present invention are generally readily prepared by reaction of the chlorinated compound (11) with piperidine (111) and subsequent reduction of the resulting ketone (IV) to the alcohol described below.

Ketone precursors are usually first protected first

It is prepared in the form of -OH and -NHg substituent groups, i.e. compounds of formula IV contain -OAj or -NHAg groups. The meanings of Aj and Ag are given below. These protected ketones are generally prepared by reacting an appropriately substituted 2-halo-1-alkanone of formula (11) with an appropriately substituted piperidino derivative of formula (111), for example, Scheme 1.

The compound of formula (11) is represented by the compound of formula (111).

With a compound of Formula 10 under normal conditions of nucleophilic substitution. If the two reagents are available in approximately equal amounts, substantially molar equivalents will be used, but if one reagent is more readily available, it will generally be advantageous to use an excess in order to effect the bimolecular reaction in less time. The reaction is usually carried out in the presence of at least 1 molar equivalent of base; the piperidine base itself can be used as long as it is readily available, but tertiary amines having a base strength at least comparable to nucleophilic piperidine are commonly used. The reaction is carried out in an inert solvent such as alcohol. The reaction may be catalyzed, if necessary, by the addition of 1 molar equivalent or more of iodide salts (e.g. The temperature is not critical, but for a faster reaction we use a slightly higher temperature which does not cause unwanted decomposition yet. In general, a temperature range of 5 ° to 12 ° C is satisfactory. The temperature may conveniently be the reflux temperature of the reaction mixture.

The term inert solvent as used herein refers to solvents which do not react with starting materials, intermediates or end products and do not adversely affect the expected yield of the product.

If desired, the -OH or -NHg group is protected

• the · ·· ···

- The protecting groups of the ketone intermediates of formula (IV) containing OA 4 or NHAg can be removed at this stage by conventional methods.

For example, when A 1-4 is triisopropylsilyl or tert-butyldimethylsilyl, the protecting group may conveniently be removed by reaction with tetrabutylammonium fluoride (usually 2 molar equivalents) in an inert solvent such as tetrahydrofuran. When a benzyl group A or a benzyloxycarbonyl group Ag is used, the protecting group is usually removed by hydrogenolysis over a noble metal catalyst using an inert solvent such as 10% Pd / C at low pressure (e.g. 1 to 10 ^{7 bar} ) and at a temperature of about 20 ° C to about 75 ° C, in an inert solvent such as methanol.

The ketone intermediates of formula (IV) are generally readily converted to the corresponding alcohols by one or two conventional reduction processes to selectively produce threo or erythro compounds of formula (I).

As mentioned above, the definition of threo or lr *, 2s ^K for the relative stereochemistry of the 1 and 2 positions of the propanol chain and the erythro or Irish, 2s denotes the relative positions 1 and 2 of the propanol chain. refers to his stereochemistry.

If the erythoform of the compound of formula (1) is to be prepared, the appropriate compound of formula (IV) should be prepared.

The ketone intermediates 12 are suitably reduced with an excess of potassium borohydride (e.g., more than 5 molar equivalents) in the presence of glacial acetic acid in a protonated solvent such as ethanol, generally at 15-25 ° C.

In order to obtain the desired threo compounds of formula (1), the corresponding ketone intermediates (IV) are suitably reduced in excess (e.g., more than 5 molar equivalents) of sodium borohydride in a protonated solvent such as ethanol, generally at 15-25 ° C. range. The resulting reaction mixture is chromatographed on a silica gel column to give the threo compound (1).

The protecting groups still present after the reduction of the ketone are then removed by the above-mentioned known methods.

The starting materials and reagents required for the synthesis of the compounds of the invention are either commercially available or known in the art or are prepared as described below. Examples are readily available.

The compounds of formula (I) according to the invention have anti-ischemic activity and are neuroprotective by virtue of their ability to block excitatory amino acid receptors, but have little or no hypotensive effect. The anti-ischemic activity of these compounds was determined by the above procedures detailed by Gotti et al., And Carter et al.,

- 13 or the like.

The excitatory amino acid receptor blocking ability of the compounds of the invention is demonstrated by the fact that these compounds rescue fetal rat neurons exposed to excitotoxic glutamate in culture. The following is a typical procedure.

Part 1: Cell isolation

On day 17 of pregnancy, rat embryos are excised from the animal and placed in Tyrode's solution. The brains were removed and placed in fresh Tyrode's solution. Using the rhino iris knife, the dorsal hub and the thalamus are cut out. The forebrain is separated into two hemispheres and the cerebral hemispheres are carefully removed. The hippocampus appears as a dark, wrinkled area on the inside of the edge of the cortex. The hippocampus is carefully separated from the rest of the brain tissue and placed in a separate corner of a vessel. After all excisions, the hippocampal tissue in the separated corner is chopped into 1 mm pieces. The slices were transferred to a sterile tube with a Pasteurpipette. The Tyrode solution is carefully aspirated and replaced with a calcium-magnesium-free Tyrode solution. The tissue was washed three times with calcium-magnesium-free Tyrode solution. The final tissue in the wash was incubated for 15 minutes at 37 ° C. The buffer is aspirated again and replaced with 1 ml of fresh calcium-magnesium-free Tyrode solution.

- We sit down. Then, at a final concentration of 0.1%, trypsin is added to the tube at 100 µl / 10 mg / ml sterile stock solution. The tube is incubated for 1 hour at 37 ° C. After incubation with trypsin, the tissue is washed with media containing serum to stop the effect of trypsin. The tissue was resuspended in 1 ml of fresh medium and resuspended in a fine-bore Pasteur pipette.

Cells were counted with a hemocytometer and transferred to a 96-well Falcon Primeria tissue culture plate inoculated with 75,000 cells in wells containing complete medium. Complete medium consists of Minimum Essential Medium containing Earle Salt (ME), 10% Fetal Bovine (Hyclone), 10% Horse, L-Glutamine (2 mM), Penicillin-Streptomycin (100 U / ml) and Glucose / 21 For a final concentration of mM, 27.8 g / 100 ml stock solution is prepared /. Fresh medium was added to the plates on day 3 and 10 µmol of cytosine arabinoside was added to the cultures on fresh day 6. After 2 days, the cytosine arabinoside is removed and replaced with Maintenance medium, a complete medium without fetal calf serum. The plates are renewed twice a week. Three weeks after excision, the plates are used in glutamate toxicity experiments to ensure proper neuronal development in the culture.

Part 2: After glutamate treatment and subsequent drug addition weekly, the culture medium is aspirated from the cells and washed with a controlled, chloride-free saline solution (CSS-C1). The composition of the CSS-C1 solution was 69 mM Na ₂ SO ₄ , 2.67 mM K ₂ SO ₄ , 0.33 mM NaHPO _4> 0.44 mM KH 8 PO ₄ , 1 mM MgSO ₄ , 10 mM HEPES / IT- (2-Hydroxyethyl) -piperazine-N '-? - ethanesulfonic acid, 22.2 mM glucose and 71 mM sucrose, pH 7.4. After washing, 1-3 mM glutamate in CSS-C1 buffer was added to the cells using wells containing glutamate-free buffer as a control. The plates were incubated at 37 ° C for 15-20 minutes. After incubation with glutamate, the plates are washed twice with serum-free medium. Appropriate concentrations of test compounds are prepared in serum-free medium and added to appropriate wells (100 µl / well) of the microtiter plate. Negative control wells were supplemented with medium containing only serum free and no test compound. Some troughs treated with glutamate are also supplemented with serum- and antifungal medium; these wells serve as positive controls. Plates were incubated overnight at 37 ° C and the next day cell viability assay for LDH / lactic dehydrogenase / activity and MTT / 3- / 4,5-dimethylthiazol-2-yl / -2,5-diphenyltetrazolium bromide / probe.

Part 3: Investigation of cell viability

100 µl of medium is aspirated from each plate and transferred to a clean plate to determine the amount of LDH released, and 100 µl of MTT solution is added to each well. The latter is prepared by adding 10 µl MTT stock solution (5 mg per ml PBS / phosphate buffered saline) to 100 µl volumes of serum free medium. The plates were incubated at 37 ° C for 4-6 hours. Subsequently, 100 µl of an acid-alcohol solution (0.08N HCl in isopropanol) is added to the troughs and the contents are well mixed to dissolve the bibsin formazan crystals. Control wells contain no cells, only MTT and acid-alcohol solution. In the plates, the absorbance of the transformed dye is read on two light path spectrophotometers at 570 nm, subtracting the background absorbance at 630 nm. Plates should be evaluated within 1 hour.

The LDH activity of the removed medium is then determined. Equal volumes of the samples are added to the LDH reaction mixture. The contents of the appropriate wells are pooled / pooled to obtain 500 ul samples. For each sample, a reaction mixture consisting of 480 µl of 0.1 M sodium phosphate buffer, pH 7.5, 10 µl of sodium pyruvate (66 mM) and 10 µl of reduced NADH / nicotinamide adenine dinucleotide, reduced form / is prepared. to the vials containing 5 mg of NADH was added 440 µL of 0.1N NaOH and the resulting

10 to 10 ul of the 17 solutions are used for the samples. The sample is quickly added to the reaction mixture in the cuvettes and the decrease in absorbance is determined using a Beckman DU-8 spectrophotometer.

The undesirable antihypertensive effect is also determined by known methods, such as those already described by Carron et al.

Selective neuroprotective, anti-ischemic and excitatory amino acid blocking activities render the compounds of the present invention suitable for the treatment of brain and spinal cord traumatic injuries, degenerative central nervous system disorders such as stroke, Alzheimer's disease, Parkinson's syndrome and Huntington's disease. When systemically treated in humans with neuroprotective doses of the compounds of Formula (I), doses ranging from about 0.02 to 10 mg / kg / day / 50 mg bodyweight human beings are administered in single or divided doses regardless of administration. mode. Of course, depending on the particular compound and the exact nature of the particular disease, doses outside the above range may be prescribed by the attending physician. Oral administration is generally preferred. However, parenteral i.v. is preferred in cases of inability to swallow or other obstruction of oral absorption. or iv / or the local application.

• ·

The compounds of the invention are generally used in the form of pharmaceutical compositions containing at least one compound of formula (I) and a pharmaceutically acceptable carrier or diluent in a ratio of 1:20 to 20: 1. These compositions are generally formulated in a conventional manner using solid or liquid vehicles or diluents suitable for the intended route of administration: tablets, hard or soft gelatine capsules, suspensions, granules, powders and the like for oral use; injectable solutions or suspensions for parenteral administration and the like; and for topical application, formulations, lotions, ointments and the like are prepared.

^The invention is further illustrated by the following examples, which are not intended to limit the invention in any way.

For convenience and maximum yield, non-aqueous reactions are conducted under dry, oxygen-free nitrogen gas. The solvents / diluents are dried according to known methods or obtained in pre-dried form. The NMR spectra were recorded at 300 MHz and the distance of the sample spectral lines to the trimethylsilane reference line was reported in ppm. Unless otherwise indicated, deuterochloroform (CDCl3) is used as the solvent. The bands of the IR spectra are in um and generally only the strong signals are indicated.

• · · ♦ ·

- 19 • ·

Example 1 (+) - 3,4-Dihydro-6- (1-hydroxy-2- [1- (4-hydroxy-4-phenoxymethyl) piperidinyl] ethyl] quinolin-2-lH-one

300 mg (1.23 mmol) of 4-hydroxy-4- (phenoxymethyl) -piperidine hydrochloride, 409 mg (1.84 mmol) of 6- (2-chloroacetyl) -3,4-dihydroquinoline-2 A mixture of 1H and 0.514 ml (0.373 g, 3.7 mmol) of triethylamine in 25 ml of acetonitrile was heated at 60 ° C overnight. The solvent was evaporated in vacuo, the residue was shaken with water and ethyl acetate and the organic layer was washed again with water and brine. The ethyl acetate layer was dried with sodium chloride and magnesium sulfate and the solvent was evaporated to give 3,4-dihydro-6- (1-oxo-2-yl) -4-hydroxy-4-phenoxymethyl / piperidinyl] -ethyl-7 Quinolin-2- (1H) -one is obtained as a brown solid which is used in the next reduction without further purification.

The above ketone is dissolved in 2.5 ml of absolute ethanol and 500 mg / 13.1 mmol / NaBH 4 is added portionwise over 20 minutes. After stirring at room temperature for 4 hours, the solvent was removed and the residue was shaken with water and ethyl acetate. After drying, the ethyl acetate was removed in vacuo and the residue chromatographed on silica gel to give 73 mg (15%) of product; mp 186-188 ° C. NMR (CD3 OD) delta 1.70-2.10 / 4H, m /, 2.52-3.07 / 10H, m /, 3.33 / 2H, s /, 3.83 / 2H, s / 6.82-7.38 (8H, m).

• · ·

- Example 2 2 - (+) - 5- (1-Hydroxy-2- [1- (4-hydroxy-4-phenoxymethyl) -piperidinyl] -ethyl) -benzimidazolin-2-one

Using the procedure described in Example 1, the title compound was obtained from 4-hydroxy-4- (phenoxymethyl) -piperidine hydrochloride (1.23 mmol), 5- (2-chloroacetyl) -2-hydroxybenzimidazole (1.84). and triethylamine (3.7 mmol) in 25 ml of acetonitrile. The resulting ketone was mixed with sodium borohydride (13.1 mmol) in absolute ethanol and then chromatographed on silica gel to give the expected product. Yield 35%, m.p. 232-235 ° C.

Elemanalysis a

• Based on the HgO formula:

Calculated: 0: 62.81; H: 6.77; N: 10.46;

Found: C, 62.98 H; 6.54 N: 10.32%.

Example 3

-Hydroxy-2-1- (4-hydroxy-4-phenoxymethyl) -piperidinyl] -ethyl] -2-oxindole

In the same manner as in Example 1, the title compound was obtained from 4-hydroxy-4- (phenoxymethyl) -piperidine hydrochloride (1.23 mmol), 5- (2-chloroacetyl) -oxindole (1.84 mmol) and triethylamine (3.7 mmol) in 25 mL of acetonitrile. The resulting ketone was mixed with sodium borohydride (13.1 mmol) in absolute ethanol and then chromatographed on silica gel to give the expected product. Yield 40%, m.p. 171-174 ° C.

- Example 21 4 + + - Erythro-5- N -hydroxy-2- [1- (4-hydroxy-4-phenoxymethyl) -piperidinyl] -propyl] -benzimidazolin-2-one

933 mg (2.36 mmol) of (+) - 1- (5- (2-hydroxybenzimidazolyl) -7-2-trans - 4-hydroxy-4-phenoxymethyl) -piperidinyl] -propan-1-one Dissolve in a mixture of glacial acetic acid (10 mL) and absolute ethanol (50 mL), add potassium borohydride (944 mg / 17.48 mmol) in portions at 15-20 ° C and stir at room temperature overnight. The reaction mixture is evaporated to dryness and the residue is taken up in a little water. By adjusting the solution to pH 7-8 with solid NaHCO3, a precipitate is formed which is insoluble in chloroform and relatively insoluble in ethyl acetate. The mixture was again evaporated to dryness, the crystallized residue was dissolved in ethanol and the salts were removed by filtration. The ethanol was evaporated and the residue was dissolved in isopropanol and treated with ether saturated with HCl gas. The precipitated amorphous salt was separated by filtration and dried under a stream of dry nitrogen. The material was dissolved in hot ethyl acetate containing methanol, clarified with activated carbon and the methanol was evaporated. After cooling, colorless crystals were obtained (450 mg, 40%), m.p. 254-255 ° C. IR / KBr / 5.90 µm; MR (CD ₃₀ 0D) δ 1.22 / 3H, d, J = 7 /, 1.95-2.09 / 2H, m /, 2.15-2.30 / 2H, m /, 3.42-. 3.76 / 4H, m /,

3.91 (2H, s), 5.47 (1H, s), 6.92-7.35 (8H, m).

• * · • · ·

Example 5 [+] - Treo-5- (1-hydroxy-2-1- (4-hydroxy-4-phenoxymethyl) -piperidinyl-propyl) -benzimidazolin-2-one

325 mg (0.82 mmol) of (+) - 1- (5- (2-hydroxybenzimidazolyl) -2- [1- (4-hydroxy-4-phenoxymethyl) piperidinyl] -popan-1-one and To a suspension of absolute ethanol (20 ml) was added portionwise sodium borohydride (700 mg / 18.4 mmol) and the reaction mixture was stirred overnight at room temperature. The solvent was evaporated and the residual foam was shaken with water and ethyl acetate and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate extracts were dried and evaporated. The residual foam was chromatographed on silica gel eluting with ethanol-ethyl acetate 1: 1 / white solid; mp> 25 ° C.

NMR (acetone-dg): delta 0.79 (3H, d, J = 7), 1.71-1.88 (2H, m /), 11.90-2.08 (2H, m /), 2.48. -2.88 (4H, m /, 3.01 (1H, t, J = 7),

3.88 (2H, s), 4.26 (1H, d, J = 7), 6.86-7.32 (8H, m). Elemental analysis: Calculated for C22 H25 N2 O3 H4 O: G, 62.24; H, 7.12; N, 9.89;

Found: C, 61.72; H, 6.73; N, 9.03.

·

Example 6 [+] - Eritro-3,4-dihydro-6- (1-hydroxy-2-y- (4-hydroxy-4-phenoxymethyl) -piperidinyl 1-propyl-7-quinoline-2 (1H) - you

7.13 g (17.5 mmol) of (+) - 1 - [5- (1,2,3,4-tetrahydro-2-oxo-quinolinyl) -7-2- [1- (4-hydroxy-4-) Phenoxymethyl-piperidinyl-7-propan-1-one was dissolved in a mixture of absolute ethanol (135 mL) and glacial acetic acid (70 mL) and treated with 6.22 g / 115 mmol KBH 4 in portions at 15-20 ° C. Allow to warm to room temperature. The reaction mixture was evaporated to dryness and the residue was taken up in ice / cold water and basified with solid NaHCO3. The precipitate was collected by filtration, washed with water and air dried to give 3.66 g of crystalline free base; mp 192-196 ° C. The filtrate was extracted with ethyl acetate and the combined extracts were dried over sodium chloride and magnesium sulfate. After evaporation, an additional 786 mg (62% overall yield) was obtained. A sample of this material (510 mg) was dissolved in ethyl acetate and treated with ether saturated with HCl gas to give 475 mg of crystalline hydrochloride salt; mp 214-216 ° C (dec).

IR / KBr / µm;

MR / CD ₃₀ 0D / delta 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, a /, 5.34 (1H, s), 6.81-6.96 (4H, m /), 7.17-7.28 (4H), m /.

• «· • · ·

- Example 24 - (+) - Treo-3,4-dihydro-6- (T-hydroxy-2- [1- (4-hydroxy-4-phenoxymethyl) -piperidinyl] -propyl] -quinoline-2H /-you

700 mg (1.71 mmol) of (+) - 1 - [(5- (2-hydroxybenzimidazolyl) -7-2- [1- (4-hydroxy-4-phenoxymethyl) piperidinyl] propan-1-one). and 20 ml of absolute ethanol slurry was added in portions to 1.50 g / 39.5 mmol / lBiOH, and the reaction mixture was stirred overnight at room temperature. The solvent was evaporated and the residual foam was shaken with ethyl acetate and water and the aqueous layer was extracted with ethyl acetate. The combined extracts were dried and evaporated and the residual foam was chromatographed on silica gel, eluting with ethanol-ethyl acetate 1: 1 / white solid; mp 192-196 ° C. During this reduction, little erythro compound is formed, which is eluted from the column in a separate fraction. IMR / CD ₃₀ 0D / delta 0.82 / 3H, d, J = 7 /, 1.72-2.06 / 4H, m /, 2.50-2.82 / 6H, m /, 2.88-. 3.02 (2H, t, J = 7), 3.02 (1H, t, J = 7), 3.84 (2H, s), 4.28 (1H, d, J = 7), 6, 80-7.34 (8H, m).

ANALYSIS a ^ 22 ^ 27 ^ 304 * 1 »5 HgO formula: date: C: 65.88 H, 7.60 N: 6.40; found: C: 65.74 H, 7.09 N, 6.31.

· «« ♦ ♦; # 4 »« · '• »· ♦ · •« · AAA · · A · ·

- Example 8 [+] - Erythro-5- (1-hydroxy-2- {1- (4-hydroxy-4-phenoxymethyl) -piperidinyl} -propyl] -oxindole

0.5 g (2.05 mmol) of 4-hydroxy-4-phenoxymethyl-piperidine hydrochloride, 0.5 g (2.25 mmol) of 5- (2-chloropropionyl) oxindole, 1 ml A mixture of 0.725 g, 7.18 mmol / triethylamine and 20 ml of acetonitrile was refluxed for 24 hours. The solvent was then removed in vacuo and the residue was shaken with ethyl acetate and water. The ethyl acetate layer was washed with water and brine, dried over magnesium sulfate and evaporated to give the ketone as a tan foam which was used in the next reaction without further purification (537 mg, 66%).

500 mg / 1.26 mmol / ketone was dissolved in 20 ml of ethanol, treated in portions with 1.0 g / 26.3 mmol / NaBH 4 and the resulting mixture was stirred at room temperature for 24 hours. The solvent was removed in vacuo and the residue was shaken with ethyl acetate and water. The ethyl acetate layer was washed, dried with brine and MgSO 4 and then evaporated to dryness.

⁴ ^ en

The residue was chromatographed on silica gel, eluting with ethyl acetate / increasing fractions containing increasing concentrations of ethanol, to give 121 mg of the threo compound; mp 204207 ° C.

MR / _DMSO-d6 / delta 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 (s), 4.20 (1H), d, J = 7 (6.70-7.35). 8H, m /, 10.34 (1H, s).

999

Λ «• <· ·· *

Example 9 (+) - 1- (6- (1,2,3,4,4-Tetrahydro-2-oxo-quinolinyl) -7-2- [1- (4-hydroxy-4-phenoxymethyl) -piperidinyl] - propan-l-one

8.30 g (34.06 mmol) of 4-hydroxy-4 "-phenoxymethylpiperidine hydrochloride and 8.09 g of (34 x 0.6 mmol) 6- (2-chloro-1-propionyl) -1,2,2 A suspension of 3,4-tetrahydroquinolin-2 (1H) -one in 100 ml of acetonitrile was treated with 16.61 ml / 12.04 g, 0.12 mol / triethylamine and the mixture was refluxed for 3 hours and then stirred at room temperature overnight. .

The reaction mixture was poured into water and extracted three times with ethyl acetate, and the combined extracts were dried with brine and magnesium sulfate and evaporated. The foam formed was dissolved in hot methanol-ethyl acetate. After cooling, a precipitated yellow solid was discarded and the starting chloro ketone was discarded. The filtrates were concentrated, dissolved in ethyl acetate and ether was added to facilitate crystallization. The precipitate was filtered off and washed with ether to give 8.84 g (63.6%) of a cream solid; 137-139 ° C. The analytical sample was crystallized from hot ethyl acetate.

NMR (GD ₃ OD) δ 1.28 (3H, d, J = 7), 1.60-1.92 (4H, m /), 2.52-2.84 (6H, m /, 3.00). 2H, t, J = 7 /, 3.75 / 2H, s /, 4.22 (1H), q, J = 7 /, 6.82-7.00 (4H, m /, 7.16 / 2H, m, 7.82-7.98 (2H, m).

• ·

Example 10 (+) - 1- (5- (2-Hydroxybenzimidazolyl) -7-2- (1- (4-hydroxy-4-phenoxymethyl) piperidinyl) -piperidin-1-one

2.43 g (10.0 mmol) of 4-hydroxy-4-phenoxymethylpiperidine hydrochloride and 2.25 g (10.0 mmol) of 5- (2-chloro-1-propionyl) -2-hydroxy A suspension of benzimidazole in 40 mL of acetonitrile was treated with 4.88 mL / 3.53 g, 35.0 mmol / triethylamine, heated at reflux for 90 minutes and allowed to stand at room temperature over the weekend.

The reaction mixture is then poured into a mixture of water and ethyl acetate and the solid in the suspension is filtered off; After drying, 1.15 g of pure product are obtained. The filtrate was adjusted to pH 7.0 and extracted several times with ethyl acetate. Drying with brine and magnesium sulfate gave a colorless solid. Recrystallization from hot ethyl acetate / methanol gave an additional 560 mg (43% overall yield); m.p. 23 DEG-235 DEG C. (dec.). MR (DMSO) ₃ OD (DMSO-d 6 -7 delta 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 / + / - 1- (3-Oxindolyl-7-2- [1- (4-hydroxy-4-phenoxymethyl) -piperidinyl] -propan-1-one)

As described in Preparation 10 in the title

- 28 were prepared from 4-hydroxy-4-phenoxymethylpiperidine hydrochloride (10.0 mmol), 5- (2-chloropropionyl) oxindole (10 mmol) and triethylamine (35 mmol) in 50 mL of acetonitrile. . The product was crystallized from hot ethyl acetate-methanol to give an amorphous foam. Yield 66.4%.

NMR (CDCl ₃ ) delta 1.28 (3H, d, J = 7), 1.58-1.78 (4H, m /), 2.40-2.84 (4H, m /, 3.54 / 2H). , s /, 3.76 (2H, s), 4.09 (1H, q, J = 7), 6.78-6.96 (3H, m /), 7.14-7.26 (2H, m). (, 7.84-8.05 (3H, m), 9.52 (1H, broad s), 9.64 (1H, broad s)).

Preparation 1

3,4-dihydroquinoline-2- / lH / C.

A suspension of 50.0 g / 0.259 mol / o-nitro cinnamic acid in 500 ml of ethanol was treated with 5 coffee spoons of Raney nickel and hydrogenated in a Parr apparatus overnight at an initial pressure of 350 kPa. In the morning, the pressure was again raised to 350 kPa and the reaction continued for 5 hours. The reaction mixture was filtered to remove the catalyst and washed on a silica gel bed with ethyl acetate-ethanol to remove residual nickel salts. After evaporation of the filtrate, the expected product yield is 57%.

NMR (DMSO-d6) delta 2.45 (2H, t, J = 7), 2.87 (2H, t, J = 7),

6.87 (2H, dd, J = 7, 7 /, 7.12 / 2H, dd, J = 7, 10 /, 10.08 (1H, s). M.p. 165-166 ° C.

- 29 Preparation 2

6/2-Chloro-propionyl / -3,4-dihydroquinoline-2 ~ / H / ~ C.

72: A suspension of 5 g (0.544 mol) of AlCl 2 and 800 ml of CSg was stirred under dry Ng gas while 14.1 ml / 20.0 g of 0.177 mol of 2-chloropropionyl chloride and then 20.0 g (0.136 mol) of 3,4-dihydroquinolin-2 (1H) -one is added. The reaction mixture is refluxed for 4 hours, at which time phase separation is observed. The mixture was poured onto ice with vigorous stirring to stop the reaction. The resulting pale yellow precipitate was isolated by filtration, washed with water and dried over phosphorus pentaoxide overnight. 27.7 g (91%) of the expected product are obtained, m.p. 236.5-238 ° C.

3. Preparation

5- / 2-Chloro-propionyl / -2-hydroxy-benzimidazole

In the same manner as in Preparation 2, the title compound was prepared from 2-hydroxybenzimidazole (0.136 mol), Aida (0.544 mol) and 2-chloropropionyl chloride (0.177 mol) in 800 ml CSg. The title compound is isolated by filtration. Yield 92%, m.p. 245 ° C / dec.

ANALYSIS a C ₁₀ H ₉ ClN ₂ ° 2 formula: date: C: 53.47 H: 4.04 N: 12.47; found: C: 54.41 H; 4.07 N: 13.25%.

- 30 4 «preparation

5- (2-Chloropropionyl) oxindole

Using the procedure of Preparation 2, the title compound is prepared from oxindole (0.136 mol), aluminum chloride (0.544 mol) and 2-chloropropionyl chloride (0.177 mol) in 800 ml of carbon disulfide. The product was isolated by filtration. Yield 91%, m.p. 157-158 ° C.

5. Preparation

6- (2-Chloroacetyl) -3- (4-dihydroquinolin-2H) -one

Using the procedure described in Preparation 2, the title compound is prepared from 3,4-dihydroquinolin-2- (1H) -one (0.136 mol), aluminum chloride (0.544 mol) and 2-chloroacetyl chloride (0.177 mol). 800 ml of carbon disulfide. The title compound was isolated by filtration. Yield 50%, m.p. 215-216 ° C.

6. Preparation

5- / 2-chloroacetyl / -2-hydroxy-benzimidazole

Using the procedure described in Preparation 2, the title compound was prepared from 2-hydroxybenzimidazole (0.136 mol), aluminum chloride (0.544 mol) and 2-chloroacetyl chloride (0.177 mol) in 800 ml of carbon disulfide. The product was isolated by filtration. Yield: m.p. 273-275 ° C (dec.).

• ·

7. Preparation

5- / 2-chloroacetyl / oxindole

Using the procedure described in Preparation 2, the title compound was prepared from oxindole (0.136 mol), aluminum chloride (0.544 mol) and 2-chloroacetyl chloride (0.177 mol) in 800 ml of carbon disulfide. The product was isolated by filtration. Yield 90%, m.p. 236.5-239 ° C.

8. Preparation

4-Hydroxy-4-phenoxymethylpiperidine hydrochloride Under nitrogen gas, anhydrous sodium hydride (2.16 g, 0.09 M) was added to anhydrous dimethyl sulfoxide (250 mL) and the mixture was heated to 60-65 ° C. until a homogeneous black solution is formed (about 1 hour). Then 19.83 g (0.09 M) of trimethylsulfoxonium iodide (slightly exothermic) is added and the mixture is stirred until a brown solution is formed (about 30 minutes). A solution of 13.40 g (67.3 mM) of N-tert-butyloxycarbonyl-4-piperidone in 50 mL of dimethyl sulfoxide was stirred at room temperature for 1 hour. The reaction mixture is poured into 1 liter of cold water and the whole is extracted with 4 x 100 ml of hexane. The combined hexane extracts were washed with water and brine, dried over magnesium sulfate, filtered and evaporated.

11.75 g of a white crystalline product, 6-tert-butyloxycarbonyl-1-oxa-6-azaspiro (2.57 octane, 78%) are obtained.

The aqueous layer was re-extracted with 3 x 50 mL hexane.

32 additional 650 mg of product were obtained; total yield 82.5% · Melting point 57.5-59.5 ° C. IR / KBr / 5.90 µm.

NMR delta 1.32-1.48 (2H, m /, 1.42 / 9H, 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 CΟΟHΗΗ ^ΝΟΝΟ: C, 61.94; H, 8.98; N, 6.57;

Found: C, 62.05; H, 9.09; N, 6.58.

To a solution of 10.37 g of phenol in 0.11 M / 100 ml of anhydrous dimethyl sulfoxide was added in portions 1.99 g / 82.8 mmol of anhydrous sodium hydride while maintaining the temperature at 20-25 ° C using a cold water bath. . The reaction mixture is then stirred at room temperature for 45 minutes to form a gray suspension. A solution of 11.75 g (55.2 mmol) of 6-tert-butyloxycarbonyl-1-oxa-6-azaspiro / 2.57-octane in 65 ml of dimethylsulfoxide is added dropwise and the reaction mixture is stirred for 7 hours at 55 ° C. It is heated at 60 ° C and then stirred overnight at room temperature.

The reaction mixture was then poured into 1 liter of cold water and extracted 4 times with ether. The combined ethereal extracts were washed with 10% NaOH and brine, dried over magnesium sulfate and evaporated. The expected product in the form of an oil, N-terbutyloxycarbonyl-4-hydroxy-4-phenoxymethylpiperidine (17.01 g, 100%) is obtained.

IR / film / 5.91; 2.95 µm.

NMR / CDCl ₃ / delta 1.46 / 9H, s /, 1.53-1.80 / 4H, m /, · · · · · ·

- 33 3.13 - 3.30 / 2Η, m /, 3.80 / 2Η, g /, 3.80 - 3.98 / 2Η, m /, 6 - 4-6.99 / 2Η, m /, 7.22-7.44 / 3Η, m /,

Elemental analysis based on the formula:

Calculated: C, 66.42; H, 8.20; N, 4.56;

Found: C, 65.72; H, 8.21; N, 4.77.

A solution of 17.0 g / 0.055 M / N-tert-butyloxycarbonyl-4-hydroxy-4-phenoxymethylpiperidine in 150 ml of methanol was saturated with hydrogen chloride gas. After cooling, it is again saturated with hydrogen chloride gas and this operation is repeated. After crystallization, the reaction mixture was treated with 500 ml of anhydrous ether and stirred at room temperature overnight.

The product was filtered off, washed with anhydrous ether and dried under a stream of dry Ng to give 10.85 g (80.6%) of crystals; mp 202-204 ° C. IR / KBr / 3.06; 3.14; 3.44; 3.57; 3.56; 6.33; 8.06 µm.

NMR (D 8 O) delta 2.00 (4H, br s), 3.34 (4H), br s (s), 4.00 (2H, s), 6.98-7.09 (3H, m / 7.30). -7.43 (2H, m).

ANALYSIS date: the C: According to the formula C12H17NO2.HCI: 59.13 H, 7.44 N, 5.75; found: C: 58.98 H, 7.11 N; 5.65%.

»·

Claims (21)

Compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein R f, R g and R 4 are each independently hydrogen, C 1-6 alkyl, phenyl or phenyl substituted with hydroxy, C 1-4 alkyl, chloro, bromo, fluoro, trifluoromethyl, amino, nitro or C 1-4 alkoxy; obsession Rf and Rg taken together form methylene, ethylene, propylene or butylene; m is 0, 1 or 2; n is 1 or 2; X and Y are each independently hydrogen, chlorine, bromine, fluorine, trifluoromethyl, C 1-4 alkoxy, C 1-4 alkyl, hydroxy, amino, nitro, or hydrogen, hydroxy, Phenoxy substituted with C 1-4 alkyl, chloro, bromo, fluoro, trifluoromethyl, nitro, amino or C 1-4 alkoxy; M and Q are each independently hydrogen, hydroxy, amino, chloro, bromo, fluoro, trifluoromethyl, nitro, C 1-4 alkyl, C 1-4 alkoxy, N, N-di- C 1-4 -alkyl-amino, N- (C 1-4 -alkyl) -amino, -NHCOR ^, -NHC00R ₅ or -NHSOgRg in which: R 4 is hydrogen, C 1-6 alkyl, phenyl or phenyl substituted with hydroxy, chloro, bromo, fluoro, trifluoromethyl, amino, nitro, C 1-4 alkyl or C 1-4 alkoxy; and R 4 and R 8 are independently C 1-6 alkyl, phenyl, or phenyl substituted with hydroxy, chloro, bromo, fluoro, trifluoromethyl, amino, nitro, C 1-4 alkyl or C 1-4 alkoxy; -obsession M and Q hold together a bivalent radical of formula Z - 36 forms where Z is selected from the group consisting of: a, / b, Ry and Rg are hydrogen or methyl, or / d, / e, / f or / g. Compounds according to claim 1, wherein Rg is hydrogen, Rg is hydrogen or methyl; and that The substituents M and Q form a radical of formula Z which is / a /, / f / or / b. Compounds according to claim 2, wherein n is 1 and m is 0. Compounds according to claim 3, wherein Rf is hydrogen. Compounds according to claim 4, wherein Rg is hydrogen. The compound of claim 5, wherein X and Y are hydrogen. Compounds of formula (V) according to claim 4. The compound of claim 7, wherein: X and Y are hydrogen. Compounds of formula VI according to claim 4. 10. X and Y are hydrogen atoms in claim 9. 11. Z of claim 6 is a group of formula (a) 12. Claim 6 is a group of formula f. 13. Claim 6 is a group of formula (b). 14. Claim 8 is Z is a group 15. Claim 8 is a group of formula f. 16. Claim 8 is a group of formula (b). of compounds where of compounds where of compounds where Z of compounds where Z of compounds where Compounds of formula (I) wherein Z is a compound wherein Z The compound of claim 10, wherein Z is a group of formula (a). 18. A pharmaceutical composition comprising a neuroprotective amount of a compound according to claim 1 together with pharmaceutically acceptable carriers. 19. A method of treating traumatic brain, spinal cord injury, stroke or degenerative stone diseases of the central nervous system in a human, comprising administering to the patient a neuroprotective amount of a compound according to claim 1. 20. Compounds of formula IV wherein R8 and R6 are each independently hydrogen, C1-6alkyl, phenyl, or hydroxy, C1-4alkyl, chloro, bromo, fluoro, trifluoromethyl. , phenyl substituted with amino, nitro or C 1-4 alkoxy; m is 0, 1 or 2; n is 1 or 2; X and Y are each independently hydrogen, chlorine, bromine, fluorine, trifluoromethyl, (C 1 -C 4) alkoxy, (C 1 -C 4) alkyl, hydroxy, amino, nitro, or hydrogen, hydroxy, Phenoxy substituted with C 4 alkyl, chloro, bromo, fluoro, trifluoromethyl, nitro, amino or C 1-4 alkoxy; M and Q are independently hydrogen, hydroxy, amino, chlorine, bromine, fluorine, trifluoromethyl, nitro, - 39 C 1-4 alkyl, C 1-4 alkoxy, N, N-di (C 1-4 alkyl) amino, N- (C 1-4 alkyl) amino, -NHCOR 4, -NHCOOR 8 or -NHSOgRg in which R 4 is hydrogen, C 1 -C 6 alkyl, phenyl or hydroxy substituted phenyl, chloro, bromo, fluoro, trifluoromethyl, amino, nitro, C 1 -C 4 alkyl or C 1 -C 4 alkoxy; and R 8 and R 8 are independently C 1-6 alkyl, phenyl or phenyl substituted with hydroxy, chloro, bromo, fluoro, trifluoromethyl, amino, nitro, C 1-4 alkyl or C 1-4 alkoxy; or M and Q are taken together to form a bivalent radical of formula Z, wherein Z is a group of formula (a /, / b), of formula / c / - in which «·« * j ··· · «· · ♦ 40 βγ and Rg are each independently hydrogen or methyl, or / d /, / e /, / f / or / g /. A process for the preparation of a compound of formula (I) and pharmaceutically acceptable salts thereof wherein R p is R 8 and R 6 are each independently hydrogen, C 1-6 alkyl, phenyl or hydroxy, C 1-4 alkyl, chloro, bromo, phenyl substituted with fluorine, trifluoromethyl, amino, nitro or C 1-4 alkoxy; or Rj. and Rg, taken together, is methylene, ethylene, propylene or butylene; m is 0, 1 or 2; n is 1 or 2; X and Y are each independently hydrogen, chlorine, bromine, fluorine, trifluoromethyl, (C 1 -C 4) -alkoxy, (C 1 -C 4) -alkyl, hydroxy, amino, nitro, or hydrogen, hydroxy, -C4 alkyl, chlorine, bromine, fluorine, trifluoromethyl, nitro, amino, or • ························································ «· · · Denotes phenoxy substituted with C 1-4 alkoxy; M and Q are each independently hydrogen, hydroxy, amino, chloro, bromo, fluoro, trifluoromethyl, nitro, C 1-4 alkyl, C 1-4 alkoxy, N, N-di- l-4 alkyl / -amino, N / 1-4 alkyl / amino, -NHCOR _4, or ₅ -NHC00R -NHSOgRg group of formula in which R 4 is hydrogen, C 1-6 alkyl, phenyl, or phenyl substituted with hydroxy, chloro, bromo, fluoro, trifluoromethyl, amino, nitro, C 1-4 alkyl, or C 1-4 alkoxy; and R 6 and R 8 are independently C 1-6 alkyl, phenyl, or phenyl substituted with hydroxy, chloro, bromo, fluoro, trifluoromethyl, amino, nitro, C 1-4 alkyl or C 1-4 alkoxy. · ··· - group 42 ν; obsession Together, M and Q form a bivalent radical of formula Z, where Z is / a, / b, / c where Ry and Rg are hydrogen or methyl, or / d /, / e /, / f / or / g /. The Trustee: ífj, Admiral of St. Petersburg; í /; '