MXPA98003272A - N-oxido de lubelo - Google Patents

Abstract

This invention relates to lubeluzol N-oxide (s), compositions containing N-oxide (s), methods for preparing them and their use as a medicament, in particular for the treatment of conditions related to cerebral hypoxia.

Description

N-OXIDO DE LUBELOZOL DESCRIPTIVE MEMORY This invention relates to the neuroprotective forms of lubelozole N-oxide, to compositions containing that (those) N-oxide (s), methods for preparing them and their uses as a medicament, in particular for the treatment of conditions relating to hypoxia cerebral. In the patent of E.U.A. No. 4,861,785 describes benzoxazole- and benzothiazolamine derivatives having anti-hypoxic and anti-anoxic activity. In the patent W0-92 / 14,731 some of these benzothiazolamine derivatives having useful activity against attacks were described. Injectable formulations of (S) -4 - [(2-benzothiazolyl) methylamino] -a - [(3,4-difluoro-phenoxy) methyl] -l-piperidine-ethanol (generically known as lubelozol) are described in the application European Patent No. 94203422.4 filed on November 24, 1994. The conditions relating to cerebral hypoxia consist of attack, in particular ischemic attack, intracerebral hemorrhage and subarachnoid hemorrhage, and brain injury. Currently, the treatment of conditions related to cerebral hypoxia consists mainly of neuroprotectors and therapeutic strategies that are atol- ogic. Still need to determine optimal therapies. An optimal therapy for the treatment of hypoxia is the subject of this invention. In particular, it consists of supplying a lubelozole N-oxide, a pharmaceutically acceptable acid addition salt form, a solvate or a stereochemically isomeric form thereof, as a new medicament for the treatment of conditions relating to cerebral hypoxia. The product is suitable for intravenous and intradermal administration by injection which is the most appropriate route of administration for hypoxic patients, and also orally, this route is more suitable for maintaining therapy. Experiments with the cis-form of lubelozol N-oxide in a model test with animals on acute attack indicate that it has a superior neuroprotective activity better than the lubelozol compound. It is assumed that the lubelozole N-oxides consist of those compounds in which one or more of the nitrogen atoms are oxidized, in particular those in which the piperidino nitrogen is oxidized. More particularly, this invention relates to lubelozole N-oxide, its cis and trans forms which are represented by the following formulas: [cis, (S)] The pharmaceutically acceptable acid addition salts consist of the therapeutically active and non-toxic salt forms obtained by treating a base form with an acid such as, for example, an inorganic acid, ie hydrochloric acid, hydromethoxide, sulfuric acid , nitric, phosphoric; or an organic acid, ie acetic, propanoic, hydroxyacetic, lactic, pyruvic, malonic, succinic, maleic, fumaric, tartaric, citric, methanol-sulphonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclic, salicylic, p-aminosalicylic, pa.ic acid . The solvates of the lubelozole N-oxide are, for example, hydrates, alcolates. Particularly preferred is cis-oriented lubelozole N-oxide, and the most preferred form thereof is the hemihydrate, i.e., hemihydrate, ie, (-) - [cis] N -oxide oxide of lubelozole- The N or the N Lublozole Oxide (s) can be prepared following the procedures of the known art to prepare oxides of nitrogen-containing products. It is conveniently prepared by dissolving lubelozol in a solvent and adding a sufficient amount of a suitable oxidant. Examples of these oxidants are hydrogen peroxide, peroxide acids, ie acid-chloroperbenzoic acid, metal oxides, ie NaW04 and the like. Suitable solvents are, for example, water and halogenated hydrocarbons, in particular dichloromethane. In the following, the amounts of each of the ingredients in liquid compositions will be expressed as percentages by weight based on the total weight of the formulation, unless otherwise indicated. The amounts of the solid preparations will be expressed as percentages by weight based on the total weight of the formulation, unless otherwise indicated. The pharmaceutical compositions of lubelozole N-oxide suitable as medicaments according to this invention consist of a pharmaceutically effective amount of active ingredient and one or more pharmaceutically acceptable excipients or carriers known in the art. The pharmaceutical compositions are adapted for oral or parenteral administration (including intramuscular, subcutaneous, intradermal and intravenous). The formulations are presented more conveniently in discrete dose units. Generally, the pharmaceutically acceptable carrier for formulating the lubelozol N-oxide neuroprotector as an injection is an aqueous solution (a) consisting of water; an isotonizing agent; and acid, base or regulating substances to adjust the pH of the solution in the range of 2.5 to 3.6. In particular, the concentration of lubelozole N-oxide in this solution (a) can vary from 0.005% to 5%, preferably from 0.01% to 1%, and even more preferably from 0.02% to 0.2% and in particular is of around 0.05%. In addition, these solutions (a) conveniently consist of 1 to 10% isotonizing agent. The use of glucose as an isotonizing agent has the advantage that very clear solutions are obtained. Preferably, the glucose is used in concentrations of 2 to 10%, and still more preferably of about 5%. The solutions (a) furthermore consist of acidic substances and base to maintain the pH of the solution on a scale of 2.5 to 3.6, preferably on the scale of 3.0 to 3.4, even more preferably of about 3.2. Preferably, 1 pH of the solutions (a) is adjusted with suitable amounts of hydrochloric acid and sodium hydroxide. The pH can also be adjusted by regulation systems consisting of mixtures of suitable amounts of an acid such as phosphoric, tartaric or citric acid, and a base, in particular sodium hydroxide. To increase the solubility of lubelozole N-oxide in these formulations, a solute can be used. Suitably, a cyclodextrin (CD) or a derivative thereof can be used. Suitable derivatives of the cyclodextrin are a-, 3-, t-cyclodextrins or mixed ethers and ethers thereof in which one or more of the hydroxyl groups of the anhydroglucose units of the cyclodextrin are substituted with Ci-βalkyl, particularly methyl , ethyl or isopropyl, i.e., randomly methylated ß-cyclodextrin; hydroxy-Ci-βalkyl, particularly hydroxyethyl, hydroxypropyl or hydroxybutyl; carboxy-C-βalkyl, particularly carboxymethyl or carboxyethyl; Ci-βalkylcarbonyl, particularly acetyl; Ci-βalkyloxycarbonylCí-alkyl or carboxyCi-βalkyloxy-Ci-ealkyl, particularly carboxymethoxypropyl or carboxyethoxy-propyl; Ci-βalkylcarbonyloxyCi-dalkyl, particularly 2-acetyloxypropyl. In particular, β-CD, 2,6-dimethyl-β-CD, randomly methylated-cyclo-dextrin, 2-hydroxyethyl-β-CD, 2-hydroxyethyl-t-CD, 2-hydroxypropyl-t are not valid. -CD and (2-cartooxymethoxy) propyl- &-CD, and in particular 2-hydroxypropyl-β-CD. The term "mixed ether" denotes cyclodextrin derivatives in which at least two hydroxyl groups of cyclodextrin are etherified with different groups such as, for example, hydroxypropyl and hydroxyethyl. The average molar substitution (M.S.) is used as a measure of the average number of moles of alkoxyl units per mole of anhydroglucose. The value of M.S. it can be determined by various analytical techniques such as nuclear magnetic resonance (NMR), mass spectrometry (MS) and infrared (IR) spectroscopy. Depending on the technique used, slightly different values can be obtained for a given cyclodextrin derivative. In the hydroxyalkyl derivatives of cyclodextrin for use in the compositions according to this invention the M.S. As determined by mass spectrometry, it is on a scale of 0.125 to 10, in particular 0.3 to 3, or 0.3 to 1.5. Preferably the M.S. it varies from about 0.3 to about 0.8, in particular from about 0.35 to about 0.5 and more particularly it is about 0.4. The values of M.S. determined by NMR or IR vary preferably from 0.3 to 1, in particular from 0.55 to 0.75. The average degree of substitution (D.S.) refers to the average number of substituted hydroxyls per anhydroglucose unit. The D.S. value it can be determined by various analytical techniques such as nuclear magnetic resonance (NMR), mass spectrometry (MS) and infrared (IR) spectroscopy. Depending on the technique used, slightly different values can be obtained for a given cyclodextrin derivative. In the cyclodextrin derivatives for use in compositions according to this invention, the D.S. As determined by the MS, it is on the scale of 0.125 to 3, in particular 0.2 to 2 or 0.2 to 1.5. Preferably the D.S. varies from about 0.2 to about 0.7, in particular from about 0.35 to about 0.5 and more particularly is between 0.4. The D.S. determined by NMR or IR preferably vary from 0.3 to 1, in particular from 0.55 to 0.75.

More particularly the hydroxyalkyl derivatives of β- and t-cyclodextrin for use in the compositions according to this invention are partially substituted cyclodextrin derivatives in which the average degree of alkylation in the hydroxyl groups of different unit positions of anhydroglucose is from approximately 0% to 20% for position 3, from 2% to 70% for position 2 and approximately from 5% to 90% for position 6. Preferably the amount of β- or t-cyclodextrin does not substituted is less than 5% of the total cyclodextrin content and in particular is less than 1.5%. Another particularly interesting cyclodextrin derivative is randomly methylated ß-cyclodextrin. The most preferred cyclodextrin derivatives for use in this invention are those partially substituted β-cyclodextrin ethers or the mixed ethers containing hydroxypropyl, hydroxyethyl and in particular 2-hydroxypropyl and / or 2- (1-hydroxypropyl) substituents. The most preferred cyclodextrin derivatives for use in the composition of this invention is hydroxypropyl-β-cyclodextrin which has an M.S. which varies from 0.35 to 0.50 and containing less than 1.5% unsubstituted β-cyclodextrin. The values of M.S. determined by NRM or IR preferably vary from 055 to 0.75. To reduce the risk of adverse reactions, an intravenous (or intradermal) formulation preferably contains the least possible number of ingredients. Therefore, a formulation without a solute such as a cyclodextrin is preferred. In addition, the neuroprotective solution (a) preferably does not contain any preservative. Oral liquid formulations on the other hand can consist of either a solute or cyclodextrin or one or more preservatives. In particular, this invention relates to neuroprotective solutions (a) which contain: (i) 0.005 to 5% lubelozole N-oxide or a pharmaceutically acceptable addition salt or a solute thereof; (ii) 1 to 10% isotonizing agent; (iii) acid and / or base subetanciae to adjust the pH ranging from 2.5 to 3.6; and (iv) water q.s. ad 100% Preferably, the invention relates to neuroprotective solutions (a) which contain: (i) from 0.01 to 1% lubelozole N-oxide or a pharmaceutically acceptable addition salt or a solute thereof; (ii) 2 to 10% glucose; (iii) hydrochloric acid and sodium hydroxide to adjust the pH from 3.0 to 3.4; and (iv) water q.s. ad 100% Most preferably, the invention relates to neutralizing solutions (a) that approximately contain: (i) 0.05% N-oxide of ublozole or a pharmaceutically acceptable additive salt or a solute of it; (ii) 5% glucose; (iii) hydrochloric acid and sodium hydroxide to adjust the pH to about 3.2; and (iv) water q.s. ad 100% The solutions (a) are sterilized using the known techniques. The neuroprotective solution (a) of this product is conveniently used in the treatment of patients suffering from acute hypoxia. It is generally contemplated that an effective treatment for acute hypoxia consists in administering to the patient by injection an amount of lubelozole N-oxide on a scale of 10 to 30 ml of solution (a) or 5 to 15 mg of the active ingredient during the first hour of therapy. During the next 24 hours approximately 4/3 or 133% of this amount can be administered. That is to say, it starts first with a relatively high initial flow that then decreases considerably. The maintenance dose can be administered for several consecutive days. Preferably about 15 ml of solution or about 7.5 mg of the active ingredient is administered by injection during the first hour of therapy, followed by about 20 ml of solution or about 10 ml of active ingredient for the next 24 hours. It is obvious that said effective amount can be decreased or increased depending on the response of the subject treated and / or depending on the evaluation of the physician prescribing the instant invention compound. The effective scales of the aforementioned amount are therefore guides only and are not intended to limit the scope or use of the invention in any way. Lubelozole N-oxide solutions can be conveniently administered together with a physiological saline solution following injection procedures known in the art. They can also be accompanied by the administration of other anti-hypoxic narcotics such as NMDA receptor antagonists., that is, aptiganel, eliprodil, selfotel, tirilazad or remacemida; antithrombotic, ie, tPA, streptokinase, ethephiloquinaea, heparin or similar agents. Since it is assumed that the product should be urgently administered to patients suffering from hypoxia, for example in the ambulance, in the emergency room or in the intensive care unit, an injection device or pack for the treatment of hypoxia containing the product together with an independent and disposable driving unit is considered to be the most useful presentation of the product in accordance with this invention. As separate driving units for refilling syringes, in particular pre-filled syringes, it can be referred to as a gas-operated conductor or a vacuum-operated conductor. An interesting intradermal narcotic-releasing device operated with gas that allows the release of a narcotic at a slow rate that can be controlled accurately, is described in Patent W0-95 / 13838, corresponding to US-5,527,288. The device connects a housing with one or more narcotic reels and a single recessed needle projecting outward a sufficient distance to penetrate through the horny layer and the epidermis towards the dermie when the housing is pressed against the skin. The device can be of modular design consisting of disposable cartridge units that contain exhaustible components (active ingredient, power source) and a reusable driving unit that connects the electronic housing and controls among other things. This invention obviously also concerns the use of a product as described above for the preparation of a medicament for the treatment of acute hypoxia. Similarly, this invention relates to a method for treating patients suffering from hypoxia, which involves administering a pharmaceutically effective amount of an N-oxide product as described above.

EXPERIMENTAL EXAMPLE 1: Preparation of lubelozol N-oxide (-) - [cis] hemidrate. To a stirred solution of lubelozole (11.6 g, 27 mmol) in dichloromethane (700 ml), cooled to -10 ° C, m-d chlorope benzoic acid (6.7 g, 31 mmol) was added. The mixture obtained from the reaction was stirred for 24 hours, and then washed with an aqueous solution of ammonium (2%, 3 times) and water (3 times). The organic phase was dried with MgSOu, filtered and evaporated, relaxing 9.6 of raw material. The (-) - Ccis] product of Lubelozole N-oxide hemidrate was purified by recrietalization of methyl-eopropyl ketone (mp 182.8 ° C) (relax: 4.7 g, 38.7%) [OI] D20 = -8.73 ° (1% in methanol (comp.1).

Example 2: Pharmacological Example The useful anti-poxy properties of the product of this invention can be demonstrated in the following procedure test.

Treatment after a rat photochemical attack model. Male Wistar rats, weighing 260-280 g, were anesthetized with halothane in a mixture of N2O / O2. The animals were placed in a stereotactic apparatus, the scalp was cut to expose the surface of the skull, and a catheter was inserted into a lateral vein of the tail. Rose Bengal (30mg / kg, 15 mg / ml in 0.9% NaCl) was injected intravenously for two minutes in animals with hemodynamics and normal blood gases. Afterwards, the skull was illuminated focally with cold white light for 5 minutes by means of a fiber optic bundle inside a lens with a diameter of 1 mm. The light was directed to the metanephric area of the neo-cortex of the right parietal cortex. Five minutes after induction of infarction (ie 5 minutes after the light was euepended), lubelozol or lubelozole N-oxide (Compound 1) was injected into the rats. The neurological tests, which included limb position reactions, were conducted the first two days after the infarction at 24-hour intervals after induction. The front and lateral tactile position were tested by lightly touching the edge of the table with the dorsal or lateral aspect of a leg (2 tests). Proportional and lateral proprioceptive position included pushing the leg against the edge of the table to stimulate the muscles of the extremities and joints (2 tests). The rats were also placed along the edge of a raised platform to evaluate proprioceptive abduction: one of the legs was pulled lightly downward and outward from the edge of the platform, and, when released suddenly, its recovery was checked and position (1 test). For each of the 5 tests, the position points are: 0, without position; 1, incomplete and / or delayed position; or 2, immediate and complete position. For each limb, the sum of the tactile / proprioceptive position scores, including the platform test, is maximum 10. The results are reported from the deficient metensephalic infarction contralateral to the neocortical xinfart. Six rats were used for each dose.

From these results it can be concluded that test animals receiving lubelozole N-oxide recover better from induced attack than those that received only lubelozole.

Claims (20)

NOVELTY OF THE INVENTION CLAIMS

1. A form of ubeluzol N-oxide, a pharmaceutically acceptable acid addition salt form, a solute or a stereochemically isomeric form thereof.

2. An N-oxide according to claim 1 further characterized in that the piperidino nitrogen is oxidized.

3. An N-oxide according to claim 2 further characterized in that the cis and trans forms are represented by the formulas: teis (S)] [trans, (S)]

4. - An N-oxide according to claim 1 further characterized in that the compound is a lubeluzol N-oxide (-) - [cis] hemihydrate.

5. A process for preparing a lubeluzol N-oxide consisting of the steps of dissolving lubeluzol in a solute and adding a sufficient amount of a suitable oxidant.

6. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound as claimed in any of claims 1 to 4 and a pharmaceutically acceptable carrier.

7. A composition according to claim 6 adapted for oral or parenteral administration.

8. A composition according to claim 7 further characterized in that the N-oxide is formulated in an aqueous solution that connects with water; an iaotonizing agent; and acid, base or pH regulating substances sufficient to adjust the pH of the solution on a scale of 2.5 to 3.6.

9. A composition according to claim 8 further characterized in that the neuroprotective efflux (a) contains: (i) 0.005 to 5% Lubeluzol N-oxide or a pharmaceutically acceptable addition salt or an eolute of the honeycomb; (ii) 1 to 10% isotonizing agent; (iii) acid and / or base subetancies to adjust the pH to a scale of 2.5 to 3.6; and (iv) water q.e. ad 100%

10. - A composition according to claim 8 further characterized in that the neuroprotective solution (a) consists of: (i) 0.01 to 1% lubeluzol N-oxide or a pharmaceutically acceptable addition salt or a solute thereof; (ii) 2 to 10% glucose; (iii) hydrochloric acid and sodium hydroxide to adjust the pH to a scale of 3.0 to 3.4; and (iv) water 1.2. ad 100%

11. A composition according to claim 8 further characterized in that the neuroprotective solution (a) consists of: (i) 0.05% (x / v) lubeluzol N-oxide or a pharmaceutically acceptable acid addition salt or an eolute of the member; (ii) 5% (w / v) glucose; (iii) hydrochloric acid and eodium hydroxide to adjust the pH to approximately 3.2; and (iv) water q.s. ad 100%

12. A composition according to claim 8 further characterized in that the neuroprotective solution (a) is present in an amount of 10 to 30 ml, and consists of about 5 to 15 mg of lubeluzol N-oxide.

13. A composition according to claim 8 further characterized in that the neuroprotective solution (a) is present in an approximate amount of 15 ml, and consists of approximately 7.5 mg of lubeluzol N-oxide.

14. A composition according to claim 8 further characterized in that the neuroprotective solution (a) is present in an approximate amount of 20 ml, and contains approximately 10 ml of lubeluzol N-oxide.

15. An injection device or package for the treatment of attacks that connects an N-oxide product according to any of the claims 1 to 4, with an independent and disposable conductive unit.

16. An infusion package according to claim 15 further characterized in that the independent conductive unit is operated with gas or is operated under vacuum.

17. A product as claimed in any of claims 1 to 4 for use as a medicine.

18. A product as claimed in claim 17 for use in the treatment of conditions related to cerebral hypoxia.

19. A product as claimed in claim 17 for use in the treatment of attacks and brain injury.

20. A product as claimed in claim 17 for use in the treatment of ischemic attack, intracerebral hemorrhage and subarachnoid hemorrhage.