MXPA99003834A - Benzoxazole derivative with an affinity to binding sites of amino acid receptors - Google Patents

Abstract

The compound 6-{3-[4-(fluorobenzyle)-piperidine-1-yl]-propionyl}-3H-benzoxazole-2-one having formula (I) and its physiologically acceptable salts. Said compound can be used as an excitatory amino acid antagonist to combat neurodegenerative diseases including cerebrovascular diseases, epilepsy, schizophrenia, Alzheimer's disease, Parkinson's disease or Huntingdon's disease, cerebral ischemias, heart infarctions or psychoses.

Description

DERIVATIVE OF BENZOXAZOLE DESCRIPTION OF THE INVENTION The invention relates to compound 6-. { 3- [4- (4-fluorobenzyl) piperidin-1-yl] propionyl) -3H-benzoxazol-2-one of the formula I and their physiologically acceptable salts. EP 0 709 384 A1 discloses benzylpiperidine derivatives having a high affinity for the binding sites of amino acid receptors. With respect to this document, the compound according to the invention should be considered as a selection invention. The aim of the invention was to develop new compounds with valuable properties, in particular compounds that can be used in the manufacture of medicines. It was found that the compound of the formula I and its salts are very well tolerated and have very valuable pharmacological properties and markedly superior to REF. : 29806 those of the compounds of the prior art. This compound shows above all a particularly high affinity for the binding sites of the amino acid receptors, in particular for the binding site of ifenprodil of the NMDA receptor (NMDA = N-methyl-D-aspartate) which allosterically modulates the site of Polyamine binding. The compound is suitable for the treatment of neurodegenerative diseases including cerebrovascular diseases. In addition, this new active compound can be used as an analgesic or anxiolytic and also for the treatment of epilepsy, schizophrenia, Alzheimer's disease, Parkinson's disease or Huntington's disease, cerebral ischaemia or heart attacks. In addition, the compound is suitable for the treatment of psychic diseases caused by an excessively high level of amino acids. The f 3 H] -CGP-39653 binding assay for the glutamate binding site of the NMDA receptor can be carried out, for example, by the method of M.A. Stills and collaborators; described in Eur. J. Pharmacol. 192, 19-24 (1991). The assay for the glycine binding site of the JNMDA receptor can be carried out by the method of M.B. Baron and collaborators; described in Eur. J. Pharmacol. 206, 149-154 (1991). The in-vitro release of the amino acid can be checked according to the method of D. Lobner and P. Lipton (Neurosci Lett. 169-174 (1190)). The effect against Parkinson's disease, ie the enhancement of contralateral rotation induced by L-DOPA in hemiparkinsonian rats, can be discovered according to the method of U. Ungerstedt and G. Arbuthnott, Brain Res 24, 485 (1970). The compound is particularly suitable for the treatment or prophylaxis of strokes, for protection against and for the treatment of cerebral edema and central nervous system conditions with oxygen deficiency, especially hypoxia or anoxia. The named effects can also be checked or rehearsed based on the methods described in the following texts: J.. McDonald, F.S. Silverstein and M.V. Johnston, Eur.

J. Pharmacol 140, 359 (1987); R. Gilí, A.C. Foster and G.N. Oodruff, J. Neurosci. 1, 3343 (1987); YE.

Roth ann, J.H. T urston, R.E. Hauhart, G.D. Clark and J.S.

Just an, Neurosci. 21, 73 (1987) or M.P. Goldbert, P.C.

Pha and D. Choi, Neurosci. Lett. 80, 11 (1987).

Various antagonists capable of blocking different binding sites of the NMDA receptor are described in the literature below: W. Danysz, C.G. Parsons, I. Bresink and G. Quack, Drug, News & Perspectives 8., 261 (1995), K.R. Gee, Exp. Opin. Invest. Drugs 3, 1021 (1994) and J.J. Kulagowski and L.L. Iversen, J. Med. Chem. 3_7, 4053 (1994). Ifenprodil and eliprodil of formulas III and IV can block the JNMDA receptor by canceling an interaction with the polyamine binding modulator site (CJ Carter, KG Lloyd, B. Zivkovic and B. Scatton, J. Pharmacol. 253, 475 (1990)).

Surprisingly it was found that the compound of the invention shows a markedly better binding "than that of eliprodil and ifenprodil.The results of pharmacological tests are summarized in table I. Since ifenprodil and eliprodil interact with the polyamine binding site. of the MNDA receiver, the antagonist activity was checked by means of a [3H] MK-801 (dizocilpine) stimulation assay stimulated with spermine. In the presence of saturation concentrations of glycine and NMDA, the spermine can still increase the binding of MK-801, which is inhibited by ifenprodil, eliprodil and particularly effective by the compound of the invention. Additionally, all three compounds were compared in a [3 H] GABA (y-aminobutyric acid) release assay carried out analogously to that of J. Dreijer, T. Honoré and A. Schousboe in Neurosci. 1, 2910 (1987), which describes the antagonistic function in the cell as an in vitro model. In this case, the compound of the invention also exhibits the highest activity (table I). Therefore, the object of the invention is constituted by the compound of formula I, according to claim 1, and / or its physiologically acceptable salts thereof for the preparation of a medicament that acts as an antagonist in excitatory amino acid receptors such as, for example, glutamic acid or its salts. The invention provides in particular, the compound of formula I, according to claim 1, and / or its physiologically acceptable salts thereof for preparing a medicament for the treatment of neurodegenerative diseases including cerebrovascular diseases, epilepsy, schizophrenia, Alzheimer's disease, Parkinson's disease or Huntington's disease, cerebral ischemia, heart attacks and psychoses. The compound of formula I can be used in medicine and veterinary medicine as the drug active substance. The invention further provides a process for preparing the compound of the formula I, according to claim 1, and its salts, characterized in that: a) a compound of the formula II wherein X represents Cl, Br, I, OH or an esterified reactive OH group, with 4- (4-fluorobenzyl) -piperidine, and / or b) the compound of the formula I is converted into one of its salts by treatment with an acid. The compound of formula I and also the starting materials for its preparation are prepared according to known methods, such as those described in the literature (for example, in certain works such as that of Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Georg-Thieme-Verlag, Stuttgart) and under reaction conditions that are known and suitable for the reactions mentioned. You can also make use of known variants of these methods, but they are not mentioned in detail in this text. If desired, the starting materials can be prepared in situ, but in such a way that they are not isolated from the reaction mixture, but additionally they are immediately reacted to provide the compound of formula I. The compound of formula I is preferably obtained by reacting compounds of formula II with 4- (4-fluorobenzyl) piperidine. In general, the starting compounds of formula II are new. However, they can be prepared according to methods known per se.

In the compounds of the formula II, X is preferably Cl, Br, I or an OH group functionally transformed into a reactive group such as alkylsulfonyloxy having 1 to 6 carbon atoms (preferably methylsulfonyloxy) or arylsulfonyloxy having 6 to 10 carbon atoms (preferably phenylsulphonyloxy or p-tolylsulfonyloxy). In general, the reaction of the compounds of the formula II is carried out in an inert solvent in the presence of an acid trapping agent, preferably an organic base such as triethylamine, dimethylaniline, pyridine or quinoline. The addition of an alkali metal hydroxide or alkaline earth metal hydroxide, alkali metal carbonate or alkali metal carbonate or alkaline earth metal carbonate or alkali metal bicarbonate or alkaline earth metal bicarbonate or another alkali metal salt may also be advantageous. or alkaline earth metal or a weak acid, preferably a salt of potassium, sodium, calcium or cesium. The reaction time may be, depending on the conditions employed, from a few minutes up to 14 days and the reaction temperatures are between about -30 ° and 140 °, generally between -10 ° and 90 °, in particular between about 0 ° and approximately 70 °. Suitable inert solvents include, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols such as methane ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers such as ethylene glycol onomethyl ether (methyl glycol) or ethylene glycol monoethyl ether (ethyl glycol), ethylene glycol dimethyl ether (diglyme); ketones such as acetone or butanone; amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); carbon sulfide; carboxylic acids such as formic or acetic acid; nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate, water or mixtures of the solvents mentioned.

A base of the formula I can be converted into the salt by the addition of a corresponding acid using an acid, for example, by reaction of equivalent amounts of the base and the acid in an inert solvent such as ethanol and followed by evaporation. Acids which form physiologically acceptable salts are particularly suitable for this reaction. Thus, inorganic acids can be used, for example, sulfuric acid, nitric acid, hydrocides such as hydrochloric or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, and also organic acids, in particular acids aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic or polybasic, sulfonic or sulfuric carboxylic acids, for example, formic, acetic, propionic, pivalic, diethylacetic, malonic, succinic, pimelic, fumaric, maleic, lactic, tartaric, malic, citric acid , gluconic, ascorbic, nicotinic, isonicotinic, methanesulfonic or ethanesulfonic, ethanedisulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, naphthalene-sulfonic, naphthalenedisulfonic and lauryl-sulfuric acids. Salts of physiologically unacceptable acids, for example picrates, can be used to isolate and / or purify the compounds of the formula I. The invention additionally provides the use of the compound of the formula I and / or its physiologically acceptable salts thereof. the same to prepare pharmaceutical preparations, in particular by a non-chemical route. For these purposes, the compounds can be brought into a suitable dosage form, together with at least one solid, liquid and / or semi-liquid auxiliary excipient or auxiliary product and, optionally, in combination with one or more additional active ingredients. The invention further provides pharmaceutical preparations containing an effective amount of the compound of formula I and / or a physiologically acceptable salt thereof. These preparations can be used as medicines in humans or veterinary medicine. Among the excipients there may be mentioned organic or inorganic substances which are suitable for enteral (for example, oral), parenteral, topical or administration administration in the form of an inhalant aerosol solution, and which do not react with the new compounds. Examples of these excipients are water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerin triacetate, gelatin, hydrocarbons such as lactose or starch, magnesium stearate, talc and petrolatum. For oral administration, tablets, pills, capsules, powders, granules, syrups, juices or drops are used in particular for rectal administration, suppositories for parenteral administration, solutions, preferably oily solutions or aqueous, and also suspensions, emulsions or implants, and for topical administration ointments, creams or powders. The new compounds can also be lyophilized and the resulting lyophilized products can be used, for example, for the preparation of injectable preparations. The aforementioned preparations can be sterilized and / or contain auxiliary substances such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifying agents, salts for influencing the osmotic pressure, pH regulating substances, dyes, taste-correcting substances and / or other additional active substances such as, for example, one or several vitamins. For administration in the form of aerosol inhaling solution, aerosols containing the active substance either dissolved or suspended in a carrier gas or in a mixture of gases (for example, C02 or chlorofluorocarbons) can be used. The active substance particles usually have a micron size, and it is also possible to add one or more additional solvents that are physiologically acceptable, for example, ethanol. Inhalant solutions can be administered using conventional inhalers. The compound of formula I and its physiologically acceptable salts thereof can be used as excitatory amino acid antagonists in the treatment of diseases., in particular, for the treatment of neurodegenerative diseases including cerebrovascular diseases, epilepsy, schizophrenia, Alzheimer's disease, Parkinson's disease or Huntington's disease, cerebral ischaemia, heart attacks and psychoses. In these treatments, the substance according to the invention is generally administered analogously to other known and commercially available compounds, preferably in doses comprised between approximately 0.05 and 500 mg, in particular between 0.5 and 100 mg per dosage unit. The daily dose is preferably comprised between approximately 0.01 and 2 mg / kg of body weight. However, the particular dose for each patient depends on a wide variety of factors, for example, the effect of the particular compound used, age, body weight, general state of health, sex, diet, of the moment and the form of administration, the rate of excretion, the combination of medications and the severity of the particular disease to which the therapy is applied. Parenteral administration is preferred. All temperatures of the present text are given in ° C. In the examples that follow, the expression "is worked (or treated) in a conventional manner" means the following, if necessary, water is added, if necessary the pH is adjusted between 2 and 10 depending on the constitution of the final product The mixture is extracted with ethyl acetate or dichloromethane, the organic phase is separated, dried over sodium sulphate and evaporated, and the residue is purified by chromatography on silica gel and / or by recrystallization.

Example 1 A suspension of 5.5 g of 6- (3-chloropropionyl) -2,3-dihydrobenzoxazol-2-one in 50 ml of ethanol is added with 5.7 g of 4- (4-fluorobenzyl) piperidine hydrochloride and 7.2 ml of triethylamine. It is stirred for one hour at room temperature and then the mixture is worked in a usual manner, obtaining 8.5 g of 6-. { 3- [4- (4-fluorobenzyl) piperidin-1-yl] propionyl} -3H-benzoxazol-2-one, p.f. 162-170 °. The product obtained in this manner is suspended in 85 ml of isopropanol, mixed with 8.5 ml of HCl / diethyl ether (saturated) and stirred for one hour at room temperature. The hydrochloride is separated from 6-. { 3- [4- (4-Fluorobenzyl) piperidin-1-yl] propionyl) -3H-benzoxazol-2-one precipitated and dried (8.8 g, mp 198-202 °).

Pharmacological Assays 1. Radioactive ligand binding assay carried out for [3 H] MK-801. The bark of Wistar rats was homogenized. The homogenate was then centrifuged (2100 rpm, 20 min., 4 ° C, Sorvall SS-34 rotor) and the supernatant centrifuged at 20,000 rpm for 10 minutes. The pellet (or pellets) was suspended in ice water and centrifuged. This procedure was repeated three times. It was then resuspended in 5 mM tris-HCl, pH 7.4. The pellet was suspended in tris buffer to be used in the test. The incubation solutions contained 8 nM of [3H] MK-801, 10 mg / ml of original tissue, 100 μM of NMDA, 5 μM of glycine and 7.5 μM of spermine, and also contained in each case different concentrations of ifenprodil, eliprodil or 6-. { 3- [4- (4-fluorobenzyl) piperidin-1-yl] propionyl} -3H-benzoxazol-2-one and incubated at 0 ° C for one hour. The incubation was terminated by means of a rapid filtration (Whatman GF / C). The non-specific binding was determined in the presence of 100 μM of MK-801. The results of the binding assays carried out with ifenprodil, eliprodil and 6-. { 3- [4- (4-fluorobenzyl-) piperidin-1-yl] propionyl} -3H-benzoxazol-2-one ("A") are summarized in Table I below. The IC 50 values, ie the concentrations in nmol / liter, which inhibit the binding of the ligands to the corresponding receptor by 50%, are indicated. Additionally, the result of the [3 H] GABA release assay, also expressed in nmol / liter, is indicated.

Table I Union and release of ifenprodil, eliprodil and "A" IC50 values in nMol / liter, n = number of trials.

Ligand Site of Ifenprodil Eliprodil [H] ife? binding of the NMDA receptor prodr: ifenprodil 23.3 + 5.1 97.0 + 12.1 3.9 + 1.6 (n = 3) (n = 3) (n = 3) Ligand: Ifenprodil site Eliprodil [3H] MK-801 NMDA receptor binding: polyamine 5950 + 3985 6630 + 2800 16.7 + 2.5 (n = ll) (n = 3) (n = 3) [-?] GABA Stimulus: 690 + 173 1760 + 851 77.8 + 56 5 μM NMDA (N = 4) (N = 5) (N = I2) The pharmacological data demonstrate the surprisingly good antagonist activity of the compound of the formula I according to the invention for the MNDA receptor. The following examples relate to pharmaceutical preparations.

EXAMPLE A: Bottles for injections The pH of a solution of 100 g of active substance of the formula I and 5 g of disodium acid phosphate in 3 1 of bidistilled water is adjusted to pH 6.5 with 2 N hydrochloric acid, then filtering in sterile conditions, this solution is introduced into the bottles, lyophilized and finally the bottles are closed in sterile conditions. Each bottle for injection contains 5 mg of the active ingredient.

Example B: Suppositories A mixture of 20 g of the active ingredient of the formula I is melted with 100 g of soya lecithin and 1400 g of cocoa butter, the melt is poured into the molds and allowed to cool. Each suppository contains 20 mg of the active ingredient.

Example C: Solution A solution is prepared with 1 g of the active ingredient of the formula I, 9.38 g of NaH2P04x2H20, 28.48 g of Na2HPO4xl2H20 and 0.1 g of benzalkonium chloride in 940 ml of bidistilled water. The pH is adjusted to 6.8, brought to a volume of 1 1 and sterilized by irradiation. This solution can be used in the form of eye drops.

Example D: Ointment Under aseptic conditions 500 mg of the active ingredient of the formula I are mixed with 99.5 g of Vaseline. Example E: Tablets A mixture composed of 1 kg of the active ingredient of formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed in the form of tablets, so such that each tablet contains 10 mg of the active ingredient.

Example F: Dragees Tablets are formed analogously to that described in Example E and then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and dye.

Example G: Capsules With 2 kg of the active ingredient of the formula I are filled with hard gelatin capsules, in a conventional manner each capsule contains 20 mg of the active ingredient.

Example H: Ampoules A solution of 1 kg of the active ingredient of the formula I in 60 1 of bidistilled water filtered under sterile conditions, the ampoules are filled with this solution and then lyophilized under sterile conditions, and the ampoules are sealed under sterile conditions. . Each ampoule contains 10 mg of the active ingredient.

Example I: Inhalable aerosol solution 14 g of the active ingredient of the formula I are dissolved in 10 1 of isotonic NaCl solution, and the solution is transferred and commercially available aerosol containers having a vaporizing mechanism are filled. The Solution can be inhaled through the mouth or nose. Each spray (approximately 0.1 ml) corresponds to a dose of approximately 0.14 mq.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (7)

1. The compound 6-. { 3- [4- (4-fluorobenzyl) piperidin-1-yl] -propionyl} -3H-benzoxazol-2-one of the formula I and their physiologically acceptable salts thereof.

2. Process for preparing the compound of the formula I, according to claim 1, and its salts, characterized in that: a) a compound of the formula II wherein X is Cl, Br, I, OH or an esterified reactive OH group, with 4- (4-fluorobenzyl) piperidine, and / or b) the compound of the formula I is converted into one of its salts by treatment with an acid.

3. Process for obtaining a pharmaceutical preparation, characterized in that the compound of formula I, according to claim 1, and / or a physiologically acceptable salt thereof is converted into a suitable dosage form, together with at least one excipient or product auxiliary solid, liquid or semiliquid.

4. Pharmaceutical preparation characterized in that it contains an effective amount of the compound of formula I, according to claim 1, and / or a physiologically acceptable salt thereof.

5. Compound of formula I, according to claim 1, and its physiologically acceptable salts thereof, which acts as an excitatory amino acid antagonist and is suitable for the treatment of neurodegenerative diseases including cerebrovascular diseases, epilepsy, schizophrenia, Alzheimer's disease, Parkinson's disease or Huntington's disease, cerebral ischemia, heart attacks or psychoses.

6. Use of the compound of the formula I, according to claim 1, and / or its physiologically acceptable salts thereof for the preparation of a medicament.

7. Compound of the formula I, according to claim 1, and / or its physiologically acceptable salts thereof, for the preparation of a medicament for use as an antagonist of the excitatory amino acids.