MXPA06004814A - Use of a hydroximic acid halide derivative in the treatment of neurodegenerative diseases - Google Patents

Abstract

The invention relates to the use of a chemical substance selected from the group consisting of N-`2-hydroxy-3- (l -piperidinyl)-propoxyl !-pyridine-1-oxide-3-carboximidoyl chloride, the optically active enantiomers and the mixtures of enantiomers thereof and pharmaceutically acceptable salts of the racemic and optically active compounds in the preparation of a pharmaceutical composition for the treatment or prevention of neurodegenerative diseases.

Description

USE OF A HYDROXIMIC ACID HALIDE DERIVATIVE IN THE TREATMENT OF NEURODEGENERATIVE DISEASES TECHNICAL FIELD The present invention relates to the use of N- [2-hydroxy-3- (1-piperidinyl) -propoxy] -pyridine-1-oxide-3-carboximidoyl chloride in the treatment of neurodegenerative diseases.

PREVIOUS TECHNIQUE As is known, neurodegenerative diseases are progressive, devastating, chronic age-related disorders. With increasing life expectancy the incidence of these age-related diseases will dramatically increase in the following decades. The treatment of these diseases is currently only symptomatic, there is no causal therapy due to the cause (s) largely unknown (s) of these multietiological diseases. Although the etiology and the current location of cell loss and damage in the central nervous system (CNS) in these disorders -such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), neuropathies, Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) - may differ, there are several common points in the development of the disease, and in intracellular cases. Although great progress has been made in the symptomatic treatment of a number of neurodegenerative disorders, there is still an immense unmet need for biopharmacological and pharmacological treatments that will decrease and probably stop the progression of these diseases. AD is the most common neurodegenerative disease and the most common form of dementia (responsible for approximately 80% of all cases). AD is characterized by memory loss, language impairment, impaired visuospatial skills, poor judgment, indifferent attitude, but preserved motor function. The symptoms of Alzheimer's disease appear first as a decrease in memory and, through several years, destruction of knowledge, personality, and the ability to function. Confusion and restlessness may also arise. The amyloid plaques and neurofibrillary tangles in the brain are the hallmarks of the disease, there is also a loss of nerve cells in areas of the brain that are vital for memory and other mental abilities. The disease usually begins after the age of 60, and the risk increases with age. While younger people may also have Alzheimer's, it is much less common. Approximately 3 percent of men and women ages 65 to 74 have AD, and almost half of those age 85 and older may have the disease. Today there is no cure for Alzheimer's disease and patients usually live approximately 8 to 10 years from the time of diagnosis. There are a number of drugs on the market, which can help prevent some symptoms from getting worse for a limited time. In addition, some medicines can help control the symptoms of AD behavior. Currently there are four drugs approved by the FDA to treat symptoms of moderate to moderate AD. These drugs are known as inhibitors of holineterase, whose research suggests, act to prevent the breakdown of acetylcholine, a brain chemical considered to be important for memory and thinking. Although none of these medications stops the disease on its own, they can help slow or prevent the symptoms from getting worse for a limited time and can help maintain independence for a longer period of time. As the disease progresses, the brain produces loss and less acetylcholine, and the medications may eventually lose their effect. Exelon and Reminyle are the most successful and commercialized drugs of this class (See: Neurodegenerative Disorders: The World market 2002-207, to Visiongain Report, VISIONGAIN ™, 2003, see also: Ferry AV and Buccafusco JJ: The cholinergic hypothesis of age and Alzheimer's disease related cognitive deficits: recent challenges and their implications for novel drug development; The Journal of pharmacology and experimental therapeutics, 306: 821-27, 2003; and Cummings JL: Use of cholinesterase inhibitors in clinical practice: evidence based recommendations: Am J Geriatr Psychiatry 1 1: 131 -45, 2003.). Other trials of treatment for AD include the Ginko-biloba extract as an antioxidant, but studies so far do not demonstrate clear efficacy among patients with AD. The non-steroidal anti-inflammatory agents tested to date have not proved effective. Recently approved in Europe, Ebixa (Memantine), a non-specific NMDA antagonist that is being marketed by Merz and Lundbeck, is set to compete with the gold standard treatment standard, Aricept. So far clinical trials have yielded positive results (Mintzer JE: The search for better noncholinergic treatment options for Alzheimer's disease, J Clin Psychiatry 64, suppl 9: 18-22, 2003, and Reisberg B ef al .; Memantine in modérate to severe Alzheimer's disease, N Engl J Med 348: 1333-41, 2003). Another, so far controversial procedure was immunization in order to develop drugs that are able to reduce the production of amyloid beta, and clean the amyloid deposits by immunization. PD is the second neurodegenerative disorder in incidence and importance. Parkinson's occurs when certain brain cells in an area of the brain known as the substantia nigra die or deteriorate. The exact cause of neuronal death is unknown, but the oxidative stress and mitochondrial electron transport chain dysfunction - especially the reduced activity of the I complex - is widely accepted. These neurons produce an important chemical known as dopamine, a chemical messenger responsible for transmitting signals between the substantia nigra and the striatum. Symptoms of Parkinson's disease include the following: tremor, or the rhythmic and involuntary movements of the hands, arms, legs and jaw, is the main feature. Classically, tremor appears while the individual is at rest and improves with intentional movement; Gradual loss of spontaneous movement, which frequently leads to a variety of problems such as "freezing," rapidity or reduced mental ability, voice changes, and reduced facial expression; Muscular rigidity, or stiffness of the extremities, occurs in all muscle groups but is more common in the arms, shoulders or neck; Postural instability, or a flexed posture, paralyzed with curvature in the elbows, knees and hips; Gradual loss of automatic movement, including eye blinking and reduced frequency of ingestion: Walking wobbly; Depression and dementia Patients of the disease currently have a large number of treatment options and this number will also grow over the next 10 to 15 years. The first effective therapy for the treatment of Parkinson's, carbidopa / levodopa (Sinemet-Bristol Myers Squibb), was introduced in 1970 and revolutionized treatment of the disease. The therapy proved very effective in the control of symptoms such as tremor, bradykinesia, balance, and stiffness. However, the dyskinetic side effects and the reduced effect with prolonged treatment approved the need for alternative treatments and / or ancillary drugs to balance the side effects. These drugs have proven effective as a type of dopamine regulator and as a monotherapy in delaying the need for carbidopa / levodopa therapy in newly diagnosed Parkinson's patients. Other recently developed therapies such as COMT inhibitors, anticholinergics, and selegiline / deprenyl have also had an effect, despite being less commercialized, in the PD market (See: Neurodegenerative Disorders: The World market 200-207; a Visiongain Report; VISIONGAIN ™, 2003). Amyotrophic lateral sclerosis (ALS), sometimes called Lou Gehrig's disease, is an invariably fatal, rapidly progressive neurological disease that attacks the nerve cells (neurons) responsible for controlling the voluntary muscles. The disease is the most common neuronal motor disease, characterized by gradual degeneration and death of motor neurons (Rowland LP, Schneider NA: Amyotrophic lateral sclerosis, N Engl J Med 344: 1688-1700, 2001). Motor neurons are nerve cells located in the brain, brainstem, and spinal cord that serve as controlling units and vital communication links between the nervous system and the voluntary muscles of the body. The messages of motor neurons in the brain (called upper motor neurons) are transmitted to the motor neurons in the spinal cord (called lower motor neurons) and from them to the particular muscles. In ALS, both upper motor neurons and lower motor neurons degenerate or die, sending messages to the muscles. Unable to function, the muscles gradually weaken, become consumed (atrophy), and pull (fascicular contractions). Eventually, the brain's ability to initiate and control the voluntary movement of control is lost. Most people with ALS die of respiratory failure, usually within 3 to 5 years from the onset of symptoms. The cause of ALS is not known. However, an important step towards answering that question comes in 1993 when scientists discovered that mutations in the gene that produces the SOD1 enzyme were associated with some cases of familial ALS (Rosen DR et al .: Mutations in Cu / Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis, Nature, 362: 59-62, 1993). This enzyme is a powerful antioxidant that protects the body from damage caused by free radicals. Free radicals are highly unstable molecules produced by cells during normal metabolism (the main source is the mitochondrion). If they are not neutralized, free radicals can accumulate and cause random damage to DNA, membrane lipids and proteins within cells. Although it is not clear how the SOD1 gene mutation leads to motor neuron degeneration, researchers have had the theory that an accumulation of free radicals can occur as a result of the imperfect functioning of this gene. Although several distinct characteristics occur in neurodegenerative diseases, the common characteristic is cell loss, progressive and gradual degeneration of certain areas of the central nervous system. The imbalance in the production of reactive oxygen species (ROS) and the ability to neutralize is growing with aging, and neurodegenerative diseases worsen this. The role of SOD in ALS was previously described as a powerful antioxidant that protects the brain from damage caused by free radicals. In Parkinson's disease, ROS is generated by autoxidation during normal dopamine metabolism or by the action of monoamine oxidase (Lev N et al .: Apoptosis and Parkinson's disease).; Progress in Neuro-Psychopharmacology and Biological Psychiatry 27: 245-50, 2003). In AD, the exact onset events that lead to the development of the disease are complete, but it is widely accepted that neuronal death is partially mediated by free radical injury (Practical D and Ahead: Oxidative injury in diseases of the central nervous system system: Focus on Alzheimer's disease, Am J Med 1 09: 577-85, 2000). Currently, the therapy approved in a unique way by patients suffering from ALS, Riluzole, extends survival for approximately 3 months. (Millar, R.G., Mitchell, J.D., Lyon, M &Moore, D.H. Riluzole for amyotrophic lateral sclerosis (ALS) / motor neuron disease (MND), Cochrane, Datábase, Syst. Rev. CD001447 (2002)). Therefore, the identification of new therapeutic strategies to be employed by ALS treatment remains a priority. It is known from WO 97/16439 that various types of hydroxylamine derivatives improve the expression of chaperone in cells exposed to physiological stress and are useful in the treatment of diseases connected with the chaperone system function. Several new categories of hydroxylamine derivatives are described in this published patent application. A certain class of N- [2-hydroxy-3- (1-piperidinyl) -propoxyl] -pyridine-1-oxido-3-carboximidoyl chloride of hydronimic acid halides belongs to also defined but N- [2-hydroxy] chloride -3- (1-piperidinyl) -propoxy] -pipdine-1-oxide-3-carboximidoyl is not mentioned explicitly. Chloride N- [2-hydroxy-3- (1-piperidinyl) -propoxy] -pyridine-1-oxide-3-carboximidoyl is first described and is claimed in WO 00/50403 as an eminent species capable of decreasing the resistance to insulin. As established, it is useful in the treatment of a series of chronic diabetic complications especially reduction retinopathy, neuropathy and neuropathy and pathological neurodegeneration caused by diabetes while reducing insulin resistance in the patient. The chemical properties of this compound and the details of the synthetic process of its preparation are also described in said paper. Another utility of N- [2-hydroxy-3 .- (1-piperidinyl) -propoxy] -pyridine-1-oxido-3-carboximidoyl chloride in diabetic therapy especially in type II diabetes therapy (non-insulin dependent, N IDDM) is described in WO 03/026653. The invention described herein relates to an orally-applicable antihyperglycemic composition containing a combination of metformin and N- [2-hydroxy-3- (1-piperidinyl) -propoxy] -pyridine-1-oxide-3-carboximidoyl chloride as an active ingredient . The outstanding antihyperglycemic effect is based on synergism that derives from the combination of the two active agents. None of the patent publications in relation to N- [2-hydroxy-3- (1-piperidinyl) -propoxy] -pyridine-1-oxide-3-carboximidoyl chloride suggests the use of this compound outside of diabetes therapy.

DESCRIPTION OF THE INVENTION We have found that N- [2-hydroxy-3- (1-piperidinyl) -propoxy] -pyridine-1-oxide-3-carboximidoyl chloride has biological properties that make it useful in the therapy of neurodegenerative diseases. In a research study, conducted in mSOD1 (G93A) transgenic mice, N- [2-hydroxy-3- (1-piperidinyl) -propoxy] -pyridine-1-oxido-3-carboximidoyl chloride prevented the progressive loss of motor neurons and the muscle function that normally occurs in this mouse model of ALS. Based on the above recognition, the invention provides a new use of N- [2-hydroxy-3- (1-piperidinyl) -propoxy] -pyridine-1-oxide-3-carboxy-imidoyl chloride in the preparation of pharmaceutical compositions for the treatment or prevention of neurodegenerative diseases.

Preferably, the invention provides a new use of N- [2-hydroxy-3- (1-piperidinyl) -propoxy] -pyridin-1-oxide-3-carboxy-imidoyl chloride in the preparation of pharmaceutical compositions for the treatment or prevention of Amyotrophic Lateral Sclerosis. In addition, the invention provides a method of treating or preventing neurodegenerative diseases wherein a therapeutically effective amount of N- [2-hydroxy-3- (1-piperidinyl) -propoxy] -pyridine-1-oxide-3-carboximidoyl chloride is administer to a patient. Preferably, the invention provides a method of treating or preventing amyotrophic lateral sclerosis wherein a therapeutically effective amount of N- [2-hydroxy-3- (1-piperidinyl) -propoxy] -pyridine-1-oxide-3-carboximidoyl chloride it is administered to a patient. Regarding the invention, the term chloride N- [2-hydroxy-3- (1-piperidinyl) -propoxy] -pyridine-1-oxido-3-carboximidoyl refers to N- [2-hydroxy-3- (1-chloride -piperidinyl) -propoxy] -pyridine-1-oxido-3-carboximidoyl as a free base, a pharmaceutically acceptable acid addition salt thereof formed with an organic or mineral acid as well as the racemic compound and each of the optically enantiomers active ingredients and mixtures of enantiomers and pharmaceutically acceptable salts of the optically active enantiomers or mixtures of enantiomers. It will be marketed that N- [2-hydroxy-3- (1-piperidinyl) -propoxy] -pyridine-1-oxide-3-carboxy-oxidoyl chloride is preferably used in the form of an acid addition salt. It will further be marketed that optically active forms of this compound are preferable, especially (+) - R-N- [2-hydroxy-3- (1-piperidinyl) -propoxy] -pyridine-1-oxido-3-carboximidoyl. More preferable are the acid addition salts of the latter optically active and the most preferable is chloride citrate (+) - RN- [2-hydroxy-3- (1-piperidinyl) -propoxy] -pyridine-1-oxide -3-carboximidoyl. The term "neurodegenerative disease" refers to known types of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS), and several types of neuropathies.

BEST MODE FOR CARRYING OUT THE INVENTION The following biological tests were carried out with chloride citrate (+) - RN- [2-hydroxy-3- (1-piperidinyl) -propoxy] -pyridine-2-oxide-3- carboxyimidoyl as a test compound. This chemical compound will be referred to as compound A. Transgenic mSOD1 (G93A) mice of both sexes were used in this study. All the experimental animals were treated daily with compound A (10 mg / kg, i.p.) 35 days of age, following a regimen similar to that previously described by Zhu et al. 2002 (Zhu, S. et al., Minocycline inhibits cytochrome c relay and delays progression of amyotrophic lateral sclerosis in mice, Nature 417, 74-78 (2002)).

Assessment of muscle function and motor unit number. The in vivo live electrophysiological assessment of the muscle function of the hind paw was carried out on the digitorum longus extensor muscles (EDL) on both hind legs determining the degree of disease progression, isometric stress records and number assessment of the motor unit. Both transgenic animals and their wild-type baits were anesthetized with doral hydrate (4% hydrate doral; 1 ml / 100 g of body weight, i.p.), and the EDL muscles were prepared for in vivo assessment of their contractile properties and motor unit number. The distal tendons of the EDL muscles were cut and joined to the isometric force transducers (Dynamometer UFI Devices) by means of silk threads. Both legs were rigidly secured to the table with pins. The sciatic nerve was cut free, and all its ramifications, apart from the nerve for the EDL muscle, were cut. The distal end of the nerve was thus stimulated using bipolar silver electrodes. The muscle length was adjusted until the maximum tic occurred in the nerve stimulation. Isometric contractions occurred when stimulating the cut end of the motor nerve using a pulse width of 0.02 ms. Tetanic contractions occurred when stimulating the EDI muscle at 40, 80 and 100 Hz for 500 ms. To estimate the number of motor units in each muscle, the motor nerves of the EDL muscles were stimulated every 4 s. The stimulus resistance was gradually increased to obtain incremental increases in tic stresses, as individual motor axons were collected. The number of incremental increments was counted to give an estimate of the number of motor units present in each muscle. (Dick, J., Greensmith, L. &Vrbova, G. Blocking of NMDA receptors during a critical state of development reduces the effects of nerve injury at birth on muscles and motor neurons, Neuromuscul, Disord.5, 371-382 (1995 )). From the tic tension records we assess some of the contractile characteristics of the EDL muscles in treated and untreated mSOD1 (G93A) transgenic mice including the measured relaxation time of EDL, a measure of the time it takes for the muscle to relax after contraction .

Fatigue model Since EDL is normally a fast number, it fatigates quickly when it is continually stimulated to produce a characteristic fatigue pattern. To evaluate the fatigue model of EDL in these experiments, the muscles in both hind legs were stimulated at 40 Hz for 250 ms, every second for 3 minutes and muscle contractions were recorded.

Muscle histology At the end of the experiment the EDL muscles in both legs were removed and weighed, and were suddenly frozen in molten isopentane. Muscles were stored at -80 ° until processing for histological analysis.

Survival assessment of motor neuron. Following the completion of the physiological experiments, the survival of the motor neuron was assessed by counting the number of motor neurons in the motor group of sciatica in the ventral tubes of the lumbar spinal cord cross sections. (White, C.M., Greensmith, L & Vrbova, G. Repeated stimuli for axonal growth causes motoneuron death in adult rats: the effect of botulinum toxin followed by partial denervation., Neuroscience 95, 1 101 -1109 (2000)). The mice were deep anesthetized (4% doral hydrate, 1 ml / 100 g body weight i.p.) and prefused transcardially with a fixative containing 4% paraformaldehyde. The spinal cords were removed and the lumbar region post-fixed for 2 h in the same fixative, cryoprotected in sucrose (30% in MPB) and frozen cross-sections cut in a 30 μm cryostat and collected on substitute slides. The sections were thus slightly contrasted with a Nissl dye (gallocyanine), the number of motor neurons painted with Nissl in both ventral tubes was counted under a light microscope. In order to avoid counting the same cell twice in consecutive sections, survival of the motor neuron was assessed in the motor group of sciatica in each 3rd section of the lumbar region of the spinal cord between levels L2-L5. Only those neurons in which the nucleolus was clearly visible at high magnification were included in the counts.

Statistical analysis For all the parameters assessed, the results were analyzed using the U Mann-Whitney test for comparison of independent samples. The tests with two tails were used in all cases, and the importance was fixed at P < 0.05.

Results At 35 days of age, transgenic mSOD1 mice (G93A) already show microscopic characteristics of lumbar motor neuron degeneration, and paralysis of the hind paw manifests by 1 to 10 days of age. The effect of treatment with compound A on muscle function of the hind paw as well as the motor unit and survival of motor neurons was assessed at 120 days of age when the transgenic mice mSOD1 (G93A) are in the last stage of the illness.

Survival of the motor unit In wild type mice there are normally 28 +/- 0.6 (average +/- S. E.M., n = 1 1) motor units in the EDL muscles. In transgenic mSOD1 (G93A) mice at 120 days of age there was only 8.3 +/- 0.7 (average +/- S. E.M., n = 10) motor units. However, in mSOD1 (G93A) transgenic mice treated with compound A there is a significant improvement in motor unit survival, and 14.3 +/- 0.6 (average +/- SEM, n = 10) of motor units survived the 120 days of age (p = 0.003). Contractile characteristics of the EDL muscles i) measured relaxation time of the EDL muscles From the records of the tic tension we also evaluated some of the contractile characteristics of the EDL muscles in treated and untreated mSOD1 (G93A) transgenic mice. EDL is normally a fast, fatiguing muscle and in wild type mice the average relaxation time of EDL, a measure of time is taken for the muscle to relax after concentration, is 25.8 ms +/- 2.4 (average + S. E. M., n = 10). In contrast, in untreated mice, the mean relaxation time decreases as a consequence of muscle deviation and atrophy and was found to be 43.3 ms +/- 6.93 (average +/- S.E.M., n = 1 9). However, in mice treated with compound A, the mean relaxation time was significantly improved, and was found to be 32.2 ms +/- 1.80 (average +/- SEM n = 10), (p = 0.030) . ii) Fatigue model and fatigue index of EDL muscles Since EDL is normally a fast muscle it fatigates rapidly when it is continuously stimulated to produce a characteristic fatigue pattern. The fatigue model of the EDL muscles was evaluated in transgenic mSOD1 (G93A), wild type, and mSOD1 (G93A) transgenic mice treated. The reduction in tension after 3 minutes of stimulation was measured and a fatigue index (Fl) was calculated. In mSOD1 (G93A) transgenic mice at 120 days of age the EDL muscle becomes resistant to fatigue as a result of motor neuron degeneration, denervation and consequent changes in muscle fiber phenotype. Thus, in transgenic mice mSOD1 (G93A) at 120 days of age EDL has a fatigue index of 0.255 +/- 0.04 (average +/- SMEM, n = 10), compared to 0.0848 +/- 0.028 (average +/- SEM, n = 10) in wild type mice. However, in mice treated with compound A EDL it has a fatigue index of 0.416 +/- 0.07 (average +/- S.E. M., n = 10). Thus, the EDL fatigue index was significantly improved in treated mSOD1 (G93A) transgenic mice compared to the untreated mSOD1 (G93A) baits (p = <; 0.05).

Motor neuron survival Following the consumption of physiological experiments, motor neuron survival was assessed by counting the number of motor neurons in the motor group of sciatica in the ventral tubes of the lumbar spinal cord cross sections. Corresponding to the observed increase in motor unit survival, the number of motor neurons surviving in the sciatica motor group of treated mSOD1 (G93A) transgenic mice was also significantly increased compared to their untreated mSOD1 (G93A) baits. In wild type mice there were 593 +/- 15.8 averaged +/- S.E. M., n = 13) of motor neurons in the segment of the motor group of sciatica evaluated. In mSOD1 transgenic mice (G93A) untreated at 120 days of age a significant number of motor neurons had died, and only 237 +/- 14 (average +/- S. E.M., n = 7) of motor neurons survive. However, in the transgenic mSOD1 (G93A) mice treated with compound A, there is a dramatic increase in motor neuron survival with 412 +/- 28 (average +/- SEM, n = 4) of surviving motor neurons, still at 120 days of age (p = 0.002). These results show that following the daily treatment of transgenic mice mSOD1 (G93A) with compound A (10 mg / kg; ip) there is a significant increase in both the motor unit and motor neuron survival, as well as an improvement in the muscular function of the hind leg in the later stages of the disease (120 days).

Life Time In view of the significant improvements in motor unit number and motor neuron survival observed in mSOD1 (G93A) transgenic mice treated at 120 days of age, in a separate group of mice we evaluated whether treatment with compound A could have an effect on the lifetime of the mSOD1 transgenic mice (G93A). We found that untreated mSOD1 (G93A) transgenic mice had an average lifespan of 125 +/- 1 .8 (average +/- SEM, n = 18) days, as determined by both a mouse inability to straighten up self when it is placed on its side and the loss of approximately 20% of body weight. However, in the group treated with compound A, the decline in body weight was delayed and the lifetime was significantly improved, and the mSOD1 (G93A) mice lived on average for 153 +/- 2.6 (average +/- SEM) , n = 7) days. This represents a significant increase in the lifetime of more than 22% (p = &0.001). The above biological properties made the chloride N- [2-hydroxy-3- (1-piperidinyl) -propoxy] -pyridine-1-oxido-3-carboximidoyl useful in the treatment of neurodegenerative diseases. Although all types of neurodegenerative diseases can be taken into account, the compound of the invention is particularly useful in the treatment of ALS. The dose of the compounds depends on the condition and disease of the patient, and the daily dose is 0.1-400 mg / kg, preferably 0.1-100 mg / kg body weight. In human therapy, the oral daily dose is preferably 10-300 mg. These doses are administered in unit dosage forms, which can be divided into 2-3 smaller doses for each day in certain cases, especially in the oral treatment. Preferably, the stereoisomer of the racemic compound, more preferably the (+) enantiomer is used. In this case, a smaller amount of active ingredient within the above limits will be sufficient for the treatment.

The active substance can be formulated into the usual pharmaceutical compositions in a manner known in the art. These pharmaceutical compositions contain, in addition, to the customary excipients and vehicles, the N- [2-hydroxy-3- (1-piperidinyl) -propoxy] -pyridine-1-oxide-3-carboximidoyl chloride or one of its stereoisomers, or an acid addition salt of one of them as active ingredients. The pharmaceutical compositions can be prepared in the form of a solid or fluid preparation generally used in therapy. Coated or simple tablets, dragees, granules, capsules, solutions or syrups can be prepared for oral administration. These medicines can be produced by the usual methods. The products may contain fillers such as microcrystalline cellulose, starch or lactose, lubricants such as stearic acid or magnesium stearate, coating materials such as sugar, film-forming materials such as hydroxy-methyl-cellulose, flavors or sweeteners such as methyl-paraben or saccharin, or coloring substances.

Claims (9)

1. CLAIMS 1. Use of a chemical selected from the group consisting of N- [2-hydroxy-3- (1-piperidinyl) -propoxy] -pyridine-1-oxide-3-carboximidoyl chloride, an optically active enantiomer or mixture of enantiomers thereof and a pharmaceutically acceptable salt of the optically active or racemic compound in the preparation of a pharmaceutical composition for the treatment or prevention of neurodegenerative diseases.
2. 2. A use according to claim 1 wherein the chemical is chloride (+) - R-N- [2-hydroxy-3- (1-piperidinyl) -propoxy] -pyridine-1-oxide-3-carboximidoyl.
3. 3. A use according to claim 2 wherein the chemical is a (+) - R-N- [2-hydroxy-3- (1-piperidinyl) -propoxy] -pyridine-1-oxide-3-carboximidoyl chloride salt.
4. 4. A use according to claim 3 wherein the chemical is chloride citrate (+) - R-N- [2-hydroxy-3- (1-piperidinyl) -propoxy] -pyridine-1-oxide-3-carboximidoyl.
5. 5. A use according to any of claims 1 to 4 wherein the neurodegenerative disease is amyotrophic lateral sclerosis.
6. 6. Method of treating or preventing a neurodegenerative disease wherein a therapeutically effective amount of a chemical selected from the group consisting of N- [2-hydroxy-3- (1-piperidinyl) -propoxy] -pyridine-1-chloride Oxido-3-carboximidoyl, an optically active enantiomer or mixture of enantiomers thereof and a pharmaceutically acceptable salt of the optically active or racemic compound is administered to a patient.
7. 7. A method according to claim 6 wherein the chemical is chloride (+) - R-N- [2-hydroxy-3- (1-piperidinyl) -propoxy] -pyridine-1-oxide-3-carboximidoyl.
8. 8. A method according to claim 7 wherein the chemical is a (+) - RN- [2-hydroxy-3- (1-piperidinyl!) -propoxy] -pyridine-1-oxide-3-carboximidoyl chloride salt .
9. 9. A method according to claim 8 wherein the chemical is chloride citrate (+) - R-N- [2-hydroxy-3- (1-piperidinyl) -propoxy] -pyridine-1-oxide-3-carboximidoyl. 1 0. A method according to any of claims 6 to 9 wherein the neurodegenerative disease is amyotrophic lateral sclerosis.