Isovaleramide-antispastic and anticonvulsant drug, extract from plants of the family valerianaceae or hop - treatment for the symptom of spasticity and remedy for this symptom, the method of treatment of a pathology, remove the central mediated by reduced muscle tone


The invention relates to medicine, in particular, neurology, and for the treatment of symptoms of spasticity and spasms, which are avoided by a centrally mediated decrease in muscle tone. I propose to use amide isovalerianic acids, including, in the extract isolated from plants of the family Valerianaceae or hops. For this purpose I propose to use isovalerianic acid, or a pharmaceutically acceptable ester of this acid. The invention allows for antispastic and anticonvulsant effect in the elimination of excessive sedative and muscle weakness. 4 N. p. F.-ly, 2 tab., 4 Il.

The technical field to which the invention relates

The present invention relates to the treatment of pathological conditions such as spasticity and spasms, symptoms of which are partially removed by moderate inhibition activity of the Central nervous system (CNS), without causing undesirable excessive sedative or muscle weakness in mammals, including humans. More specifically, the invention relates to the use of amide isovalerianic acid, isovalerianic acid, and the relationship is Nicky

Many medicinal agents, currently used in the treatment of such pathologies, such as spasticity and seizures, are associated with adverse side effects that limit their long clinical use. Such compounds can be specified, for example, the benzodiazepines, which can cause confusion. Two other medicinal agents include valproate, showing hepatotoxic effects, and baclofen, which can cause excessive muscle weakness and sedative effect, thus limiting therapeutic potential uses for both drugs.

The invention

In line with this, the aim of the present invention is to provide a therapeutic approach for the treatment of various pathological conditions through the provision of a moderate inhibitory effect on the activity of the Central nervous system, without giving excessive sedative effect, muscle weakness, fatigue or toxic effects on the liver.

Another objective of the present invention is to provide a method for eliminating one or more symptoms caused by a disease state, such as spasticity, of the invention is to provide a new method anticonvulsant therapy.

To achieve these and other objectives of the present invention, in accordance with one variant of implementation, involves the use of compounds selected from the group consisting of isovalerianic acid, pharmaceutically acceptable salts isovalerianic acid, pharmaceutically acceptable ether complex isovalerianic acid and pharmaceutically acceptable amide isovalerianic acid to prepare a pharmaceutical drug used in the treatment of a pathological condition, which eliminates through moderate inhibition activity of the Central nervous system, which results in the elimination of at least one symptom of a pathological condition.

Thus, the present invention also relates to a method of treatment, characterized by the fact that a patient suffering from a pathology addressed by moderate inhibition activity of the Central nervous system, is administered a therapeutically effective amount of a medicinal product, comprising a pharmaceutically acceptable carrier and a composition selected from the aforementioned group of agents.

In accordance with one embodiment of the invention, as a pathological condition that can be treated with the claimed s syndrome pain headache or syndrome excited state. In another embodiment of the invention pathological condition can be resolved by CNS-mediated reduction of muscle tone, which is illustrated on the example of spasticity.

In accordance with another aspect of the present invention provides the use of Valerianaceae Valerian extract, bark viburnum red, black hawthorn, or hop in the preparation of a pharmaceutical composition that can be used to treat symptom of spasticity, with the specified extract contains at least one compound which is hydrolyzed in vivo with the formation of isovalerianic acid or isovaleramide. In addition, the present invention provides a method of removing the symptom of spasticity in an individual in need of treatment, characterized by the fact that includes the introduction of a therapeutically effective amount of the extract described above.

Other objectives, features and advantages of the present invention will become obvious to a person skilled in the further consideration of the detailed description of the invention. However, it should be borne in mind that the detailed description and specific examples, while disclosing Pravasi what is meant, that various changes and modifications within the essence and scope of the invention which are obvious to specialists when considering the following detailed description.

List of figures

In Fig.1 presents the chemical structure of various compounds, including isovaleramide.

In Fig.2 shows the influence of isovaleramide (at a dose of 300 mg/kg, intraperitoneally) on the observed indicators spasticity in rats with induced chronic lesion of the spinal cord received with use of a metal probe when applying it to the abdomen of the animal.

Each rat served as its own control; group included three rats. The location of the rod at the zero time point is used as reference values before treatment.

In Fig.3 shows a dose - and gramasevaka reduction of reflex on the part of the muscle flexor during electrophysiological study measure spasticity in rats with chronic spinal pathology. The results of isovaleramide (when administered orally at a dose of 300, 600 and 1200 mg/kg), baclofen (10 mg/kg, subcutaneously) and media (water, 12 ml/kg, orally) can be given when removing indicators prior to their introduction (0 point timing is e reflex on the part of the muscle flexor than observed with the introduction of baclofen. Statistical significance was evaluated using one-step variance analysis (ANOVA) and t-test according to the method Dunnet: p<0,05 (*); p<0,01 (**); NS = insignificant.

In Fig.4 shows a diagram indicating that isovaleramide and baclofen, known as antispastic agent, cause the same reduction of reflex muscle flexor in rats with chronic spinal injuries.

Results response of Fig.3 were converted into the format indicating the total area under the curve at two-hour readout. The parameters in all groups treated with medications, significantly differed from that group, which used the media (p < 0,05, ANOVA).

Information confirming the possibility of carrying out the invention

1. Overview

In the course of developing the invention, it was found that isovalerianic acid and its pharmaceutically acceptable salts, amides, for example of isovaleramide, and esters of alcohols, such as utilizabilitate and-sitosterolemia can lead by taking them to moderate inhibition in vivo activity of the Central nervous system.

In other words, these medicinal substances depress Central nervous system functions by strengthening oppressive (or reduce vosburgh Asim invention, thus, the individual when receiving these funds is not shown clearly expressed sedative effect, painkiller or paralytic effects from the viewpoint of, for example, the rate of reduction of epileptic seizures (absence of analgesic effect), reduced muscle tone (no paralysis), having a calming effect (no sedation), or elimination syndrome ambulatory, such as spasticity (no weakness or lethargy).

A number of pathologies, followed by affective mental disorders, headaches (type of chronic, hemicrania, migraine), syndrome of the excited state, neurological pain syndrome, impaired motor function, syndrome spasticity and convulsions States have at least one symptom, which can be addressed through moderate inhibition of Central nervous system function. Accordingly, the individual suffering from such pathologies, is a potential candidate for treatment, which, in accordance with the present invention, is realized by means of patient a pharmaceutical composition containing isovaleramide, isovalerianic acid or related compound.

I guess systematic mechanism and, hence, possess pharmacological similarity to known drugs that are believed to lead to the strengthening of the functions of the Central GABAergic neuromotor transmission. Similarly, many of the currently available drugs, such as barbiturates, benzodiazepines, gabapentin, valproate, vigabatrin and progabid, the compounds of the invention are effective in treating pathological conditions mentioned above, which are considered to be the result of a defect in regulation of inhibitory (GABA and/or glycine-mediated) neuromuscular transmission.

This regulation is implemented either through direct or modulatory actions on receptors in the Central nervous system, and by affecting the way metabolic processes, resulting in increased levels of GABA or glycine and/or lower levels of excitatory neurotransmitters such as glutamate (see Ruggero et al., in Handbook of Antiepileptic Drugs,( 4th edition), S. 581-588 (Raven Press, 1995); Nogrady, Medicinal Chemistry: A Biochemical Approach (2nd edition ), S. 225-239 (Oxford University Press, 1988); Fonnum and Morselli, respectively, Psychopharmacology: The Third Generation of Progress, S. 173-182 and 183-195 (Raven Press, 1987). Despite pharmacological similarity to known lateline side effects, which usually occur when treatment is well known in this field of knowledge of drugs, such as toxic effects on the liver, which occurs while receiving valproate.

2. Examples of pathological conditions, symptoms which are removed by moderate inhibition activity of the Central nervous system.

Spasticity: Spasticity is often defined as a dysfunction of the upper (i.e. CNS) motor neurons, characterized by dependent on the speed of the increase in tonic stretch reflexes (muscle tone) with increased tendon reflexes due to increased excitability of the stretch reflex (see materials Symposium Lance, Symposia synopsis in Spasticity - Disordered Motor Control, edited by Feldman and others, 1980. The increase in tonic stretch reflexes, however, is only one of many symptoms of a pathology associated with impaired motor function caused by damage to the upper motor neurons in a variety of neurological disorders; and thus, this disturbed motor function varies according to its etiology and manifestation.

The main diseases and pathological conditions associated with the syndrome spasticity are closed craniocerebral injury. There are "positive symptoms", which can be observed in spasticity, such as symptom Babinski, painful spasms of the muscles of the flexor or extensor, increase or increase in deep tendon reflexes and clonus. Other signs called "negative symptoms include weakness, fatigue, clumsiness, and paralysis. It is this combination of positive and negative signs and symptoms characterizes the condition referred to in clinical practice as spasmopriv" (spastic paralysis). Pain, sleep deprivation and various forms of defects in motor function are also associated with the syndrome spasticity.

Pathological conditions that can be observed in spasticity at the physiological level are fundamentally different from the well-known acute muscle pain, muscle stresses and sprains, which arise from localized external lesions to specific muscles, i.e. outside or peripheral to the Central nervous system. These pathological conditions are also different from the normal involuntary contractions of smooth muscle, such as vascular spasm, writing spasm and bronchospasm. Such respecticely (not mediated CNS) or peripheral Lok is Tami, but they are not usually used for treatment of syndrome spasticity (see Cedarbaum and Schleifer, "Drugs for PA's Disease, Spasticity and Acute Muscle Spasms" (Drugs for Parkinson's disease, spasticity, and acute muscle spasms) in the directory Goodman and Gilman, The PharmacologicaL Basis of Therapeutics, 8th edition (hereinafter referred to as Reference Goodman and Gilman, S. 463-484 (Pergamon Press, 1990).

The pharmaceutical compositions used in accordance with the present invention can provide a CNS-mediated reduction of muscle tone and, therefore, suitable for removing one or more symptoms of acute or chronic spasticity. In this context, the term "plasticity" refers to the increased tone of skeletal muscles, which manifests itself, but is not limited to such symptoms, such as painful cramps flexor or extensor, the raised or increased deep tendon reflexes, hyperreflexia, loss of "right-handedness", myasthenia gravis, increased tendon convulsive twitching and clonus. The term "antispastic agent" in this description should be understood composition, which is used for symptomatic treatment of spasticity by removing at least one of the following symptoms: painful is aforecast", male, increased tendon convulsive twitching and clonus. Accordingly, the term "elimination" syndrome spasticity in this description refers to the removal of one or more symptoms, including (but not limited to, painful spasms of the flexor or extensor, increased deep tendon reflexes, hyperreflexia, loss of "right-handedness", myasthenia gravis, increased tendon reflexes and clonus.

Syndrome spasticity can be caused by multiple sclerosis, strokes, traumatic brain injury, spinal cord injury, cerebral palsy and other diseases, disorders and conditions associated with degenerative changes in the nervous system. Spasticity is different from acute myotonica spasms, which can be caused by many factors other than those that lead to the development of spasticity. These causal factors of acute mythicism spasm include trauma, inflammation, fear and/or pain.

The differences that exist between syndrome spasticity and acute mythicism spasm evidenced by the fact that the funds used for the treatment of acute myotonica spasms not Prague). Similarly, medicinal agents commonly used to treat spasticity caused by chronic neurological disorders, were not used in the treatment of acute mythicism spasm with the exception of benzodiazepines, such as diazepam (Valium®), which are known to have a soothing muscle action, as well as anxiolytic and analgesic ability. In contrast, the present invention provides CNS-mediated reduction of muscle tone, which, in turn, associated with specific symptoms of spasticity.

Disorder, accompanied with a convulsive States

Due to the possibility of widespread use of animal models for prediction and experimental verification of convulsive States, we developed and obtained for use in clinical practice, many anticonvulsants (for example, see Cereghino et al., section "Introduction," in the book of Antiepileptic Drugs, 4th edition, S. 1-11 (Raven Press, 1995). Dichter et al. in the journal Drug Therapy, vol.334, S. 1583, 1996 note: "most patients with epileptic seizures can remove the currently available anti-epileptic drugs, but 25-30% of patients with seizures, despite optimal

Thus, many anxiolytic drug in clinical use have shortcomings that cause significant side effects, including undesirable daytime sedation, muscle weakness (myasthenia), intolerance, gingival hyperplasia, blood dyscrasias and potentially fatal hepatotoxicity. Many of these side effects are subject to the special care in clinical practice in the treatment of epilepsy in children.

The present invention can find use for the treatment of convulsive States, such as epilepsy. That is, the proposed pharmaceutical compositions (formulations) exhibit anticonvulsant activity, as evidenced by the reduction in the severity, number, or duration of convulsive States in model animals with induced epilepsy. Accordingly, the proposed pharmaceutical compositions should find use for the treatment of such conditions (but without limitation of their volume), simple partial seizures, complex partial seizures, status epilepticus and induced injury seizures seizures that occur after a head injury or surgical together the factors and which is difficult to control, and often require treatment for many years to control epileptic seizures. "At present there is no satisfactory method of treatment of epilepsy a significant portion of patients. Clinical trials have shown that some patients have a better response to one drug than another, even when patients experience similar forms of epileptic seizures and the medications have the same mechanisms of action. The frequency and severity of side effects of drugs also vary significantly. Thus, a large number of products with different mechanisms of action and different related side effects will be necessary for the treatment of epilepsy up until or not it will be possible a complete cure of epilepsy, or cannot be found or developed powerful secure a new drug with a wide range of actions" (Dichter et al., 1996, see above).

Affective mental disorders

This category includes pathological conditions, ranging from depression to dysphoric mania, i.e., mania, schizoaffective disorder, aggressive state, indutsirovannogo behavior. Affective mental disorders (disorders of the emotional sphere) was treated mainly lithium salts for the prevention since the 1950's in Europe and in the 1970s in the United States (Emrich et al., J. Affective Disorders, vol.8, S. 243-250, 1985). In recent years conducted research on the development of drug treatment as an alternative to lithium therapy, which led to some problems. For the latest alternative therapies for affective mental disorders are methods of treatment with anticonvulsants, such as carbamazepine, benzodiazepines, valpromide and valproate (Room et al., in article Anticonvulsants in Affective Disorders (Anticonvulsants in affective disorders), S. 14-32, Excerpta Medica, 1984). Valproate has a lower propensity to induce inhibition reactions, thought processes, memory impairment, confusion compared to commemorate the benzodiazepines. Despite the demonstrated efficacy of valproate in numerous affective disorders, hepatotoxicity, mutagenicity and gastric disorders observed when taking it, highlight the need for new therapeutic agents and menu has efficacy in the treatment, especially regarding improved side effect profile. Despite some perceived structural similarities, for example, valpromide and isovaleramide (see Fig.1), expect no side effects noted in valproate, or their presence should not detract from the effectiveness of the present invention in the treatment of a range of affective mental disorders.

Central neurological pain syndromes

Syndromes in this category, including neuropathic pain, occur in a significant number of patients suffering from lesions of the brain or spinal cord, apoplexy, multiple sclerosis and various forms of diabetes (Casey, in the book of Pain and Central Nervous System Disease (Pain and diseases of the Central nervous system (Raven, 1991). Many GABA-ergicheskie compounds are effective in various models of loss of sensitivity, designed to identify therapeutic candidates for the treatment of neurological pain (see Lloyd and Morselli, in Handbook of Psychopharmacology: The Third Generation of Progress, Raven Press, 1987)). In the literature, there is documentary evidence about the extensive use of anticonvulsants, similar to valproate for the treatment of various pain syndromes (Swendlow, J. Clin. Neuro way to relieve neurological pain.


Headaches, such as migraine (Hering and Kuritzky, Cephalalgia, vol.12, S. 81-84,1992), hemicrania (Hering and Kuritzky, see above, vol.9, S. 195-198, 1989) and chronic type (Mathew and Sabiha, Headache, vol.31, S. 71-74 (1991)) were treated with the use of valproate. Interaction with the GABAergic system are believed to play a major role in the etiology of these headaches and therapy, associated with the use of valproate. Based on this, the present invention can be used to alleviate symptoms associated with each of the three types of headaches, without causing adverse side effects from treatment with valproate.

Syndrome excited state

The term "syndrome of the excited state (or hyperkinetic syndrome) refers to somatic (not mental) arousal, characterized by involuntary movements of the limbs, and a feeling of physical (mostly not mental) arousal, which does not depend on emotionally charged and, therefore, differs in its essence from hyperkinesia (see Sachdev et al., Austral. New Zealand J. Psychiatry, vol.30, S. 38-53, 1996).

Forms an excited state, including numerous manifestations can be observed in many organic is Denia (delayed type, chronic and akathisia cancel), drug-induced extrapyramidal symptoms are one of the most typical side effects of drug therapy with neuroleptics. Also in the category of this disease includes the so-called "tired leg syndrome" and "involuntary periodic twitching of the lower extremities during sleep", i.e. pathology, the cause of which can be injuries to the head and/or spinal cord lesions spinal cord.

Idiopathic tired leg syndrome has autosomal dominant inheritance, the clinical manifestation of a symptom has different variations.

Reduced GABAergic neuromotor transfer implies the neurochemical basis of the syndromes of the excited state. In accordance with this concept, efficacy, for example, benzodiazepines, baclofen, valproate, and gabapentin in the treatment of tired leg syndrome is an important indication (see O'keefe, Arch. Intern. Med., vol.156, S. 243-248, 1996; Danek et al., in the book of Neurological Disorders: Course and Treatment, S. 819-23, Academic Press, 1996; Mellick and Mellick, Neurology, vol.45 (Ni.), S. 285-286, 1995). More specifically, the present invention provides an effective method of treatment of syndromes of an excited state with a minimum number on which akinesia, characterized by motor disorders such as Parkinson's disease, chorea of Huntington (Huntington), late dyskinesia syndrome and rigidity. This fact has highlighted the role of Central GABAergic function in the mechanism of regulation and modulation of excitability and motor activity of the Central nervous system (Lloyd and Morselli, 1987, see above). In other words, the proposed method of treatment allows to reduce the degree of activity of the Central nervous system, presumably through GABA-ergicheskie mechanisms, and to eliminate one or more symptoms of movement disorders.

3. Methods of obtaining pharmaceutical compositions

Rhizomes with roots of Valeriana spp. (traditional name: Valerian; the family Valerianaceae) is used for medicinal purposes since ancient times. The most traditionally used Valerian preparations include water and Vodopyanova extracts, such as tinctures, intended for oral administration. In addition, ammonium Valerian used for medicinal purposes in English-speaking countries since at least the early seventeenth century (Hobbs, HerbalGram, No.21, S. 19-34, 1989). In the last three decades soothing and antispasmodic ability of Valerian preparations were mainly attributed Preseren-epoxy-truefire (ATA)").

The most common among this class of compounds include valepotriates, valtrate didrovaltrate, each of which contains two isovalerate residue esterified in Central ericoideae the nucleus (Lin et al., Pharm. Res., vol.8, S. 1094-02, 1991). These acid and teplostojka substances undergo hydrolysis in the gastrointestinal tract after oral administration, however release two mole of isovalerianic acid for each mol of valepotriates. In addition, aqueous extracts of rhizomes with roots of Valerian retain their bioactive properties even though valepotriates truefire insoluble in water (Bos et al., Phytochem. Anal. vol.7, S. 143-151, 1996).

It is established that the main water-soluble active principle traditionally used Valerian extracts and other preparations such as aqueous or hydroalcoholic extracts or tinctures, is the product of the hydrolysis of ester, isovalerianic acid. Isovalerate ammonium and isovaleramide receive in the form of ammonia liquors (Balandrin et al., J. Toxicol. - Toxin Rev., vol.14, S. 165, 1995). The chemical structure of isovaleramide and related compounds is shown in Fig.1. Thus, chemically unstable valepotriates and other selected from valerytut as "prodrugs" and chemical precursors isovalerianic acid, its salts and isovaleramide.

Isovaleramide was isolated from the plant Valerian, most likely in the form of isolate-artifact with the subsequent processing of ammonia (Buckova et al., Cesk. Farm., 26:308 (1977); Chem. Abstr., 88: 86063z (1978); see also Bos et al. and Fuzzati et al., Phytochem. Anal., vol.7, S. 143, 176 (1996). Earlier it was found that isovaleramide exhibits low acute toxicity in vivo, showed no mutagenic action and possesses anxiolytic ability that allows it to clinical use (see U.S. patent No.5506268; PCT application WO 94/28888). Methods of obtaining isovaleramide well known.

Extracts of medicinal plants that can be used to treat symptoms of spasticity and spasms, can be prepared by the method of extraction in an aqueous, hydroalcoholic or alcoholic solution or extraction with other suitable solvents in accordance with methods known in the art. In the context of the present invention, suitable for use extracts contain at least one of the following ingredients: isovalerianic acid, its salts or complexes, utilizabilitate (ethyl ester of isovalerianic acid), isovaleramide, N-utilizabilitate and their helices is Larionova acid and/or isovaleramide hydrolysis in vivo. Standard methods of obtaining such extracts can be found in publications prior to 1950, the U.S. Pharmacopoeia (Pharmacopoeia (U. S. P.) and National Formulary (N. F.), and is well known to specialists sources of literature, for example, Ed. by Gennaro, Remington's Pharmaceutical Sciences, 18th-oe edition (Mack Publishing Co., 1990), Tyler et al., Pharmacognosy, 9th edition (Lea and Febiger, 1988), and'hare et al., The National Standard Dispensatory (Lea Brothers, 1905). In addition, links can be found in U.S. patent No.5506268 and international PCT application WO 94/28888. The main known sources of natural isovalerianic acid include rhizomes and roots of Valerian, and closely related plants of the family Valerianaceae. As discussed Hobbs (1989), see above, in this family include the usual Valerian, Valeriana officinalis L, and East Indian Valerian, V. wallichii DC. and biblical aralia Nardostachys jatamansi (Roxb). DC. In addition to rhizomes with roots of Valerian, it is known that other plants, traditionally used as a sedative or anticonvulsant" herbal remedies that contain or form isovalerianic acid. These include hops (Humulus lupulus L, family Moraceae, which is often used in phyto-preparations in combination with Valerian ), "bark" or "simple viburnum (Viburnum opulus L, family family Caprifoliaceae), and "black haw" (V. 71, 1572, 1619, 1620, 1631-1633, 1661 and 1662 (Lea Brothers 1905); Heyl et al., J. Am. Chem. Soc., vol.42, S. 1744, 1920); Grier, Pharm. J. Pharm., vol.68, S. 302,1929); Grier, Chem. Drug., vol.110, 420 S., London, 1929); Grieve, A Modem Herbal, S. 35-40, 265-276, 381, 382, 411-415, 744-746, 781, 782 and 824-830 (Hafner 1959); Holbert, J. Am. Pharm. Assoc., Sci. Ed., vol.35, 315 S. (1946); Hoffmann, The Herbal Handbook: A User's Guide to Medical Herbalism, S. 38, 39, 83 and 84 (Healing Arts Press, 1989).

As in the case of the rhizomes and roots of Valerian, hops generates isovalerianic acid of the more chemically complex precursors in the oxidation or enzymatic hydrolysis (Millspaugh, American Medicinal Plants, An Illustrated and Descriptive Guide to the American plants used as homeopathic remedies (an Illustrated guide to the American plants used as homoeopathic medicines), S. 622-626, (Dover, 1974); Hare et al., The National Standard Dispensatory, S. 766-767 (Lea Brothers, 1905); Grier, Chem. Drug., vol.110, 420 S., London, 1929); Grieve, A Modern Herbal, S. 411-415 (Hafner 1959); Stevens, Chem. Rev., vol.67, S. 19, 1967); Duke, CRC Handbook of Medicinal Herbs, S. 557, CRC Press, 1985).

To pharmaceutically acceptable salts of organic acids, such as isovalerianic acid, which have been approved by the U.S. Department food and drug administration for commercial sale, include salts of sodium, potassium, lithium, zinc, aluminum, calcium, or magnesium (Remington's Pharmaceutical Sciences, 18th-oe edition, S. 1445, Mack Publishing Co., 1990). Salt isovalerianic acid, cosmeceutically acceptable alcohols can form esters with isovalerianic acid via the corresponding chlorides and/or anhydrides isovalerianic acid well-known methods in the art. See, for example, March, Advanced Organic Chemistry: Reactions, Mechanisms and structure, 4th edition (John Wiley and Sons, 1992). Such alcohols contain at least one hydroxyl or phenolic residue and are well absorbed in vivo. Suitable alcohols can be, for example, ethanol, some carbohydrates and related compounds, such as glucose, fructose, sucrose, xylose and lactose, alcohol-based sugars, such as dulcet, mannitol and sorbitol, acid-based sugars: gluconic and glucuronic acid, glycerin, polylines, benzyl alcohol, some phenols, for example phenol, salicylic acid, saligenin, salicylamide, vanillin, p-hydroxyurea acid (p-coumaric acid, caffeic acid, ferulic acid, Gallic acid, ellagic acid, quercetin and eugenol. Other examples of suitable alcohols include alkaloids and biogenic amines such as ephedrine, pseudoephedrine, phenylpropanolamine, tyramine and dopamine, vitamins such as ascorbic acid (vitamin C), thiamine (vitamin B1), Riboflavin (vitamin B2), pyridoxine (vitamin B6), cyanocobalamin (vitamin B12), Tocopherols (vitamin E), choline, folic acid and Pantothenic acid, monoterpenoid alcohols, such as geraniol, nerol and linalool, natural RUB and ursolic acid, bile acids such as cholic acid, desoxycholic acid and human beings need it to acid and well-known natural plant sterols (phytosterols), for example-sitosterol, stigmasterol, campesterol and brassicasterol (Tyler et al., Pharmacognosy, 9th edition, Lea and Febiger, 1988). Other well-tolerated hydroxyl and finasteride connection can easily identify experts in this field when accessing the standard reference books, such as The Merck Index and Remington's Pharmaceutical Sciences, 18th-oe edition (Mack Publishing Co., 1990). Esters isovalerianic acid, which are offered for sale in the United States, include bornyl, ethyl, n-butyl, isoamyl and kernelsource.

Isovalerianic acid, isovaleric ammonium and esters of utilizability, itemresource, 2-motivationalist, cinnamylpiperazine, methylisocyanate, bornylisovalerare, isobutylether and methylisocyanate, along with other isovalerate esters, included in the List of the Code of Federal Regulations FDA as acceptable flavoring components that can be used in food products ( 21CFR 172.515 (1991). Rhizomes and roots of Valerian (Valeriana officinalis L.), and bark of the black hawthorn ((Viburnu and natural adjuvants. Hops and lupulin" mentioned in the List of 21 CFR 182.20 ("GRAS"). (1991) among other substances, which are considered safe for health.

In General, esters of isovalerianic acid, assumed to undergo hydrolysis in vivo is well known esteraznam enzymes so that there is a release isovalerianic acid components and alcohol or phenol. As a particularly preferred isovalerate esters can serve as glyceryl mono-, di - and especially triisocyanate ("triazavirin"), isovaleryl salicylic acid or salicylate (isovalerate salicylic acid), utilizabilitate and-sitosteryl isovalerate (Cm. Fig.1). The hydrolysis of these esters (isovalerate) in vivo is the release of isovalerianic acid and glycerol (glycerin), salicylic acid (anti-inflammatory analgesic and antipyretic agent), ethanol (ethyl alcohol, known as "alcohol" as a depressant of the Central nervous system) and-sitosterol (safe phytosterols), respectively. With the exception of utilizability, these esters are not volatile or have only neznachitel volatility that allows you to minimize any odors. In addition, in its pure form is extremely unpleasant smells isovalerianic acid and its salts, for example, isovalerate ammonium, sodium, potassium or zinc. Utilizabilitate is a liquid, and glyceryl mono-, di - and triisocyanate, isovalerylglycine and-sitosteryl isovalerate at room temperature are solid substances. Thus, easier technology of preparation of the pharmaceutical composition in a variety of standard solid and liquid pharmaceutical dosage forms for oral administration, which are known to experts in this field, for example, in the form of tablets (pills, tablets with intersolubility coated tablets film-coated), capsules, gel capsules, powders, concentrates (drops), elixirs, tinctures and syrups.

In addition to isovaleramide you can get a variety of substituted amides of isovalerianic acid well-known methods in the art (see, for example, March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th ed. (John Wiley and Sons, 1992). It is preferable Amida include N-utilizabilitate, N-methylisourea, N,N-dimethylethylene, N-methyl-, N-utilizabilitate, N-isovaleryl-GABA and N-isovalerylglycine (see, for example, Tanaka et al., J. Biol. Chem., vol.242, 2966 S. (1967). N,N-diethylethanamine ("Cut down"), although, as it has overwhelming (the cramps) ability; see U.S. patent No.5506268 and international PCT application WO 94/28888, see above. Amide isovalerianic acid in the form of the product with p-aminophenol can also be obtained using standard methods of obtaining connection isovaleramide", which is structurally similar to the drug acetaminophen (tylenol®; see Fig.1).

Similarly isovalerate esters, these substituted amides must be either hydrolyzed in vivo (in this case via the hepatic amidase enzymes) with the release of isovaleramide or isovalerianic acid.

Connections and preparations which are discussed above, are alternative forms for the delivery of isovalerianic acid or isovaleramide in vivo. In some cases, for example in the case of isovalerylglycine and utilizability, pharmacologically active residue corresponding part of the alcohol or phenol, as you might expect, exerts its own pharmacological action. For example, such compounds as "isovaleramide", as should be expected to show "Tylenol-like" effect, and the effect expected from isovalerianic acid or isovaleramide group. These new chemical combinations of previously known pharmacologically active is retene.

The pharmaceutical compositions of the present invention can be prepared according to known methods, which use the technology of pharmacy in which the active components are connected with a pharmaceutically acceptable carrier. For example, see Remington's Pharmaceutical Sciences, as well as Goodman and Gilman, who cited above. Consider that the composition is in a "pharmaceutically acceptable carrier", if the recipient patient can move his admission. Sterile phosphate-buffered saline solution may serve as one example of a pharmaceutically acceptable carrier. Other suitable media (e.g., saline or ringer's solution) is well known to experts in the art (see, for example, Remington's Pharmaceutical Sciences, cited above).

In General, dosage protivoastmaticheskih and anticonvulsant agents described in this application, vary depending on such factors as age, body weight, height, sex, General health and prior medical history of the patient. The purpose of therapy, the compound of the present invention and a pharmaceutically acceptable carrier is administered to an individual in need of treatment a therapeutically effective amount. Consider, kolichestvo plays a physiologically important role. An agent is physiologically significant if its presence results in significant changes in the physiology of a recipient patient. In this context, for example, antispastic agent is considered physiologically significant if its presence results in withdrawal syndrome, spasticity, with anticonvulsant drug is physiologically significant if the presence of the specified funds reduce the severity, number, or duration of convulsive States.

Isovaleramide and related compounds can be given orally in solid dosage forms for oral administration, for example, in the form of tablets with intersolubility coating, film-coated tablets, gelatin capsules or capsules, or in liquid dosage forms, such as syrups or elixirs.

The prescribed dosage of isovaleramide and related compounds as anti-spastic means is of the order of 100-1000 mg per dose, and preferably 300-600 mg per dose. A single solid dosage form for oral administration is believed to contain approximately 200-350 mg of active substance per tablet or capsule, which usually 1-2 thing at one time to maxelsbutt in the form of compositions, containing the active substance, so that the dosage was 1-2 teaspoons per reception. In addition, the proposed connection can also be used in Pediatrics for release in the form of chewing gum or liquid form with reduced dose. These compounds can also be added to food and drinks in the form of drops (Nakayama pipette from the concentrated preparation) for oral administration. In addition, compounds such as isovaleramide, can be produced in the form of chewing gum to facilitate its delivery and absorption.

Alternatively, isovaleramide and related compounds can be introduced by injection or other routes, such as transdermal introduction or introduction through the mucous membrane, for example, nasal, buccal or rectal use candles. However, the significant advantage of oral administration is the ease of use, and therefore he preferred.

When using anticonvulsant composition in a form for oral administration the active ingredient(s) it is about 100-1000 mg per dose, preferably 200-600 mg per dose, or at the rate of 1-20 mg/kg of body weight.

Besides man, and is the author of agents for treatment of animals, for example, cats, dogs, birds, horses, cattle, mink, poultry and fish. In such cases, the active compound can be entered parenteral or other delivery systems, such as transdermal introduction or introduction through the mucous membrane (for example, rectal administration via suppository) or orally by adding in food or drink. As an antispasmodic agent, the dose for oral administration isovaleramide and/or related compounds is approximately 1-1000 mg/kg of body weight of the animals depending on its type and route of administration. The preferred dose for oral administration is approximately 200-600 mg/kg of body weight.

As anticonvulsant agents isovaleramide and/or related compounds administered to the animals orally at a dose of about 1-1000 mg/kg of body weight depending on the species and route of administration. The preferred dose for oral administration is approximately 100-600 mg/kg of body weight.

The present invention also includes within its scope various pharmaceutical compositions containing as active ingredients amide isovalerianic acid, isovalerianic acid and/or its pharmaceutical, TRANS-dermal, injection through the mucous membrane, nasal, buccal or rectal administration. Although such compounds may be present as incidental by-products in some pharmaceutical compounds, which are not included in the scope of the present invention, a common feature of the proposed formulations is that the amide isovalerianic acid, isovalerianic acid and/or its pharmaceutically acceptable salts, substituted amides and esters of the alcohols present in the standard amount. In other words, the pharmaceutical compositions of the invention contain pre-defined, chemically defined and measured quantity of at least one of these compounds, which allows to determine the exact amount of a particular compound required to achieve the levels of activity in the dosages disclosed in this application.

It should also be borne in mind that isovaleramide and/or related compounds can be used in combination with other pharmaceutically active ingredients.

4. Demonstration of the effectiveness of therapy

The safety and efficacy of the pharmaceutical composition to facilitate any pathological conditions discussed in the a).

(a) Mutant spastic mouse

As mutant spastic mouse homozygous use the mouse, carrying autosomal dominant type symptoms hereditary spasticity.

A mouse without abnormalities at birth to two to three weeks of age marked pathology characterized krupnorazmernymi tremor, abnormal gait, rigidity of skeletal muscles and abnormal installation reflexes. No constitutional anomalies were observed. In addition, mouse detected failure glycine receptors throughout the Central nervous system. Pharmaceutical agents that enhance or binding, GABA or its synthesis, such as valproate and benzodiazepines, are active connections to eliminate some of the symptoms of spasticity in this animal model and in humans. The assessment rate of spasticity in this mutant mouse can also be based on electrophysiological studies, for example, EMG, described below. More rough value can be obtained when using as a criterion the installation of reflex. In these mice is observed anomalously retarded installation reflex, when you put them on the back. Any installation reflex the stump shake in mice can be defined, holding them by the tail, using a subjective evaluation system as "missing", "weak", "moderate" or "severe". For estimating the flexibility of the mouse placed on a glass plate with evenly rounded grooves in the mandrel. This glass plate raise approximately 30 cm (12 inches) above the table and slowly tilt to almost vertical position. Normal mouse clamber over the surface of the plate for a minute or more before they will fall down to his feet. Spastic mouse usually remain in a stationary position and quickly fall back (Chai et al., Proc. Soc. Exptl. Biol. Med., vol.109, S. 491, 1962).

(b) an Experiment on the rat with acute/chronic disorders, induced dissection of the vertebral column, and the rat with acute violation after decerebration

There neskolko models of spasticity, including rats with acute violation after decerebration, with acute or chronic violation after dissection of the vertebral column and with acute or chronic affection of the spine. A model of acute disorders though and have value for evidence of the mechanisms involved in the development process spasticity, are criticized because of the very acute form of the disease. Animals usually umisho intervention, in contrast to developing the human form, which in the most frequent cases manifests itself mainly in the form of peripheral paralysis. In humans, only a few weeks and months clearly are the symptoms of spasticity. Some animals with a pronounced chronic form of lesion of spinal cord or decerebrated animal models clearly observed in the postoperative period peripheral paralysis. Approximately 4 weeks after decerebration or dissection of the spinal cord, peripheral paralysis goes into the forms of the syndrome spasticity of varying severity. Although all these models have specific disadvantages and do not give a true picture of the development of spasticity in humans, they are still quite informative regarding its nature. These models also allowed us to develop a methodology to test the different paradigms of therapy that helped to develop the same treatment approaches that have on the person. Many of these models also can be used on various kinds of animals such as cats, dogs and monkeys. Baclofen, diazepam, and tizanidine are effective at improving parameters when electrophysio is, is hyperreflexia) in these models.

(C) reference test method Irwin rats

This research method is based on the method described by Irwin log Psychopharmacologia, vol.13, S. 222-257 (1968). It is used to check the effect of the tested substances on the physiology and behavior of the animal, as well as test the toxicity of the given dosages, which can then be used in subsequent experiments. Usually rats (three per group) injected with the test substance and then see in comparison with the control group treated with the carrier. Indicators of changes in behavioral responses, symptoms of neurotoxicity, the pupil diameter and rectal temperature record on standardized grids observations, obtained on the basis of the method Irwin. In this grid includes the following features: mortality, sedation, agitation, aggressiveness, reflex Straub, cruciani, convulsions, tremor, exophthalmos, salivation, lacrimation, piloerection, defecation, fear, dragging of feet, the reactivity to touch, loss of installation reflexes, sleep disturbance, impaired coordination of movement, muscle tone, perception of stereotypes, swinging his head, catalepsy, the ability of grip, ptosis, pocillovy, rectal temperature and pupil diameter. Observations carried out at 15, 30, 60, 120 and 180 minutes after administration of the test substance, and also after 24 hours. The test substance is usually injected intraperitoneally (br.).

(g) Test on the rotating rod using rats and mice

This experiment is conducted to test neurological disorders in accordance with the methodology described by Dunham et al. in the journal J. Am. Pharm. Assoc., vol.46, S. 208-209, 1957).

Rats or mice are placed on a rod rotating at a speed of 8 rpm Number of animals that fall from the rod for three minutes, and count and record the time of the fall (maximum: 180). Each group includes 10 rats, and the test is carried out blind. The test compound is administered intraperitoneally 60 minutes prior to testing. Diazepam, a benzodiazepine is administered intraperitoneally at a dose of 8 mg/kg as a reference. The control group treated with the carrier, also include in the study.

(d) Anticonvulsant activity

There are numerous models in vivo, in which developing various forms of seizures and behavioral responses that can be associated with clinically severe form of epilepsy. Thus, it seems appropriate the efforts of their simplification and conclusion that the same mechanism underlies all manifestations of seizure activity.

As an example, a suitable model can serve as a reflective epilepsy induced in mice Frings, susceptible to the development of reflex auditory epidemicheskogo seizure. During the test, each mouse was placed in a round chamber made of plexiglass and is subjected to ultrasonic impact 110 decibels at 11 kHz for 20 seconds. Animals that are not marked tonic stretch reflexes of the lower extremities, are considered protected. In addition, the indicator convulsive status of each mouse can be determined in accordance with the following ball system evaluation: (1) seizures lasting less than 10 seconds; (2) seizures lasting longer than 10 seconds; (3) clonic activity of the limbs and/or tactile organ; (4) the reflex of the upper limb extensor and flexor reflex of the lower extremities; and (5) the stretch reflex of the lower extremities.

The average seizures can be calculated for each group of mice used in the experiment, based on the study of responses depending on the dose. When studying each dose mice also placed on the rotating rod for the assessment of sing a period of testing on the terminal size 2.5 cm (1 inch) in diameter, rotating with a speed of 6 rpm when the mouse falls from the rotating rod three times within three minutes, this behavior is considered as a reaction to toxic effect.

(e) Antigenically activity

To assess the possible use of the compounds in the treatment of affective mental disorders you can use the model rat with amphetamine-induced hyperactivity. In addition to the test of classical and atypical neuroleptic (antipsychotic) activity, this technique has also been proposed as a simple model manic syndrome in animals (see Costall et al., Brain Res., vol.123, S. 89-111, 1977).

(g) Neurological meningeal inflammation

Neurological meningeal inflammation was suggested to use as a particular case of the main pathological conditions accompanied by headache type migraine (Lee et al., Brit. J. Pharmacol., vol.116, S. 1661-67, 1995). Compounds were tested for ability to block the loss of radioactively-labeled serum albumin at postrijennoi stimulation of the Dura.

(C) the characteristics of the violations of pain sensitivity

There are many different quantitative pain, syndrome electric tile, clicking on the tail, arthritic pain, tests on compression paws and models of neurological pain syndrome Bennet or Chung (Albe-Fessard et al., in book 13 Advances in Pain Research And Therapy (13 Progressive advances in the study of pain syndrome and its treatment), S. 11-27 (Raven Press, 1990).

(and) Therapeutic effects in musculoskeletal disorders and syndromes increased excitability

There are animal models for the study of movement disorders and syndromes increased excitability, such as model drug akathisia, serotonin syndrome, unilateral had nigral-induced rotation (Lloyd and Morselli (1987), see above). In addition, the source for confirmation therapeutic indications can serve as the medical history of patients, which was remarkable effectiveness of these compounds ( Mellick and Mellick (1995), above; Olson et al., Am. J. Med., vol.102, S. 60-66 (1997).

Therapeutic effects isovaleramide acid, isovalerianic acid and related compounds defined in various quantitative analyses described above, considering the fact that they have no toxicity, allow us to make the assumption that the compounds of the present invention are the perfect tool for the CTE, for a better understanding of the present invention the following examples of the invention, which serve only for illustration and should not limit the scope of the invention.

Example 1

Drug use Valerian to relieve symptoms of spasticity caused by multiple sclerosis

The patient, a woman of 42 years, having one or more symptoms of multiple sclerosis, have experienced significant emotional stress and difficulties quick sleep and lack of sleep duration. During sleep she had seen a disturbing dreams and often woke up at night. The patient also during sleep occurred painful flexor spasms of the muscles, from which she often woke up. The next day these painful muscle spasms caused her tendon muscle pain (feeling injury), followed by stiffness of the joints.

The patient decided to take the drug Valerian, which is well known as a tool to promote the onset of sleep. The drug Valerian, "Baldriparan, standard cleaning, available in tablet form in Germany, contains extracts of Valerian root, hops and lemon balm. Coated compressed tablets each containing 95 mg vissenaken./wt.) and 85 mg of the dried aqueous extract of lemon balm. Surprisingly, the drug Valerian not only improved sleep and quality of sleep in the patient, but also eliminated the painful spasms of the muscles of the extensor. The patient, when woke up in the toilet, felt no painful muscle spasms, no sensation of stiffness of the joints in the legs. The patient continues to take the same drug Valerian to relieve these symptoms, if circumstances require, and continues to experience a sense of relief when it is received.

Example 2

Drug use Valerian to relieve symptoms of spasticity caused by damage to the spine

The patient, male 38 years old, suffered from symptoms of spasticity (hyperreflexia, tendon reflexes and muscle spasms extensor).

All these symptoms due to a previous traumatic injury of the spine, broke the sleep of the patient and its quality. After taking the same drug Valerian made in Germany, described in Example 1, the patient noted significant improvement in sleep quality, as well as a significant reduction in nighttime injury of extensor muscle. The patient continues to take the drug, if circumstances require, to relieve these symptoms.

Example 3

In these studies, subjects of interest used mice male albino line Holtzman (Harlan Sprague-Dawley Laboratories), weighing 270-530, Animals were placed individually and provided free access to food and water during the whole time of the experiments. All experimental procedures were reviewed and approved by the Committee on care, maintenance and use of animals. Animals were given General anesthesia with the use of a mixture izoflurana and oxygen at 4 l/min the Rats were then placed in a stereotaxic frame and anesthesia was continued. The incision is performed so that you can take back paraspinal muscles, and then performed a laminectomy between T6-T9. 1-2 mm segment of the vertebral column was removed by resection and replaced the gel gemostaticescoy sponge to reduce bleeding, after which the incision is closed in layers.

After surgery, rats were placed in a room where the ambient temperature was increased by conditioning before 26,27(80F) to maintain body temperature. The next morning after the operation, the rear hole in rats with a remote cord, washed and collected urine by manually pressing on the bladder. Experime inside of 0.25 ml of the suspension of the antibiotic of sulfatrim, used in pediatric patients for the prevention of bladder infection. Commercially available cream-based antibiotic applied to any area of the skin upon detection of pressure ulcers. For about two weeks, each animal was under control until normal function of the bladder, and then therapy antibiotic they no longer received. Advokat, Brain Res., vol.684, S. 8, 1995). The assessment rate of spasticity was performed before and after treatment drug so that each animal served as its own control.

Originally indicator spasticity was evaluated by the method of subjective evaluation of the rate of change of the received response spasticity identified with harmless stimulus, i.e. a metal probe, which was held in four locations in the lower abdomen. Figure spastic reactions were estimated for each of these four tests using a rating system from 0 (no spastic response in all four trials) to 4 (maximum, tonic-clonic reaction taking place across four trials). All the results of the evaluation measure spasticity, obtained before and after treatment, was transformed into the form ukasoanya indicators were processed by the method of forward variance analysis ANOVA.

As shown in Fig.2, isovaleramide, at a dose of 300 mg/kg, intraperitoneally, has been active on 15, 30, 60 and 120 min after its introduction, leading to a reduction in the increased muscle tone (45-65%). The next day, that is 1440 minutes (24 hours), indicators of spasticity almost returned to baseline values. At this dose not marked marked behavioral toxicity or deterioration of motor responses. Rats were movable and capable of capturing nephrolithotomy front paws, as in the case of the control group of rats not receiving treatment.

When referring to Fig.3 one can see that the polysynaptic reflexes of the muscles of the flexor, to test stimulus that activates vysokonogoye the afferents were recorded on EMG activity from the ipsilateral muscle tendon. Supramaximal electric shock exerted on the lower limb, and the recording electrodes were placed on the double-headed polyoxazolines muscle. Five series of stimulation of muscle action potentials conducted at each point of time. Reflex flexor muscles were removed before treatment and after treatment, every 30 minutes immediately after achieving a stable baseline responses (see Nao et al., Eur. J. Pharmacol., vol.191, 407 S., 1990).

So, naprimer and every 30, 60, 90 and 120 minutes after administration of isovaleramide (at a dose of 300, 600 and 200 mg/kg, orally), baclofen (10 mg/kg, subcutaneously) and media (water, 12 ml/kg, orally), respectively.

Isovaleramide all doses, as shown, reduces the magnitude response of the muscles of the flexor each time point in mice with induced decerebrate chronic spinal pathology, and thus the measure of spasticity. In this model, it was not observed any changes in the rate of reflex N/M when administered baclofen and isovaleramide.

In Fig.4 indicators of the response of Fig.3 were converted into the format with getting the total value for all points under the curve, which covered a period of two hours removing measurements. The parameters in all groups treated with the drug, significantly differed from the group that used the media (p<0,05), which was calculated on the basis of forward-variational analysis. No significant difference in the total decrease of the reflex to the muscles of the flexor during a two-hour period is not observed between the groups treated with the drug (pairwise multiple comparison values by the method according to student-Newman-Kaula).

(2) the Control test in the rat is about at doses up to 256 mg/kg, comparable to control groups that received an injection of saline. Dose of 512 mg/kg observed a slight sedative effect with 60 120 minute, loss of traction (only observed in one of the three rats) for 120 min and low muscle tone from 60 to 120 minute. Dose of 1024 mg/kg was observed significantly pronounced sedative effect up to 30 minutes, turning into a "moderate" to 120 minutes, and then in the "weak" with 180 minutes. At this dose also observed a decrease in fear for up to 30 minutes, while one out of three rats for up to 120 minutes. At this dose also noted reduced reactivity to touch up to 120 minutes, low muscle tone up to 180 minutes, a slight hypothermia to 120 minutes, and abnormal gait (rotation) 60 80 minute. Loss of reflex grasping and installation of reflex observed at this dose in one of the three rats at 15 minutes.

(3) Test on the rotating rod of the mouse and rat lines Frinqs

Isovaleramide, administered at doses of 128, 256 and 512 mg/kg (intraperitoneally) for 60 minutes prior to testing on a rotating rod, does not significantly affect the coordination of locomotion in rats (see Table 1). In contrast, diazepam caused a dose-dependent decrease coordination of movement when tested in urasawa) for 15 minutes before testing on a rotating rod, not significantly affect the specified parameter rats Frings. In contrast, doses of 300 mg/kg 600 mg/kg and 1000 mg/kg (intraperitoneally) caused a decrease of this parameter in the test on the rotating rod 1/8, 4/8 and 8/8 rats Frings, respectively.

Example 4

Anticonvulsant activity as demonstrated on the model of epilepsy in mice Frings, tend to reflex sound convulsive seizures

The results are shown in Table 2, demonstrate anticonvulsant activity isovaleramide in models of epilepsy on this animal. Isovaleramide also demonstrated the rapid manifestation of anticonvulsant activity, but relatively short period of its validity. Anticonvulsant activity was observed already at 15 minutes, but was significantly reduced at 2 o'clock. All quantitative research therefore, was conducted on the 15 minute. At this point of time, the average effective dose (ED50to protect the animal from the development of the tonic stretch reflex was 126 mg/kg intraperitoneal injection. In addition, at this point of time was marked dose-dependent decrease of convulsive seizure. With the introduction in doses significantly higher than those that are against Swamy their inability to maintain balance on a rotating rod. With the introduction of doses less than 300 mg/kg was noted to have any toxic effects. The average toxic dose (TD50), leading to decreased ability to maintain balance on a rotating rod, amounted to 531 mg/kg intraperitoneal injection. Thus, the estimated protective factor (TD50/ED50) was about 4.2. Therefore, despite the relatively low activity isovaleramide in this model, it still showed a relatively good separation between activity and toxicity. So, isovaleramide demonstrated surprising and unexpected anticonvulsant activity, based on the existing relationship between the activity-structure for amides and their corresponding acids, in model mice Frings, tend to reflex sound convulsive seizures. Profile activity isovaleramide similar marked the anticonvulsant agent with a wide spectrum of action of valproate sodium. In early publications demonstrated that compounds having structural similarity with valproate, as well as with isovalerianic acid, increase the levels of GABA throughout the CNS. It is this action, apparently, is primarily associated with anticonvulsant actively the Leno, not showing anticonvulsant activity, although there are reports that it causes a slight increase in the content of GABA in the brain in mice. For example, see Loscher et al., Neuropharmacology, vol.24, S. 427, 1985; Keane et al., see above, vol.22, S. 875, 1983; Keane et al., Pharmacol. Res. Commun., vol.17, S. 547, 1985.

Generally speaking, in the currently available literature about the relationship between activity-structure anticonvulsant effect among compounds similar to valproate, there is no mention of the simple, unsubstituted compounds, such as amides of isovalerianic acid. Really surprising and unexpected observation is that isovaleramide demonstrated the same efficacy as that of valproate in the experiment on the model of the mouse line Fringes, prone reflex sound of seizures, and a similar division of activity between efficacy and toxicity, as defined by the reaction in the test on the rotating rod. These observations suggest that isovaleramide is an active compound for therapeutic use as anti-convulsants a wide spectrum of action. Know who And No. 5506268 and PCT application WO 94/28888. On the other hand, it is well known that valproate has a profile that causes hepatotoxicity (e.g., see Loscher et al., Neuropharmacology, vol.24, S. 427, 1985).

Although the above describes only specific embodiments of the invention, it is necessary to bear in mind that the present invention should not be limited to the stated options. Specialists in the art it is obvious that various changes may be made in the described ways, not beyond the scope and substance of the present invention defined in the following claims.

All publications and patent applications mentioned in the description of the present invention, serve as evidence of prior art to which this invention relates. All publications and patent applications included in this invention by reference as if each individual publication or patent application does not specify individually and that it is included in the scope of this application as a whole.


1. Application isovaleramide as antispastic and anti-convulsants for the treatment of pathology of the removed Central-oposredovannaya seizures.

2. Application of the extract containing isovaleramide, isolated from a plant selected from the group consisting of the family Valerianaceae and hop, as a means to treat symptom of spasticity.

3. The method of treatment of a pathology, which is removed centrally-mediated decrease in muscle tone, wherein the patient suffering from this pathology, is administered a therapeutically effective amount of a pharmaceutical composition containing a pharmaceutically acceptable carrier and a compound selected from the group consisting of isovalerianic acid, pharmaceutically acceptable salts isovalerianic acid, pharmaceutically acceptable ether isovalerianic acid and pharmaceutically acceptable amide isovalerianic acid, other than N,N-diethylethanamine, and eliminate at least one symptom of said pathology.

4. Troubleshooting symptom of spasticity in individuals in need of treatment, wherein the specified individual is administered a therapeutically effective amount of the extract containing isovaleramide isolated from plants of the family Valerianaceae or hops.


Same patents:

The invention relates to medicine and concerns the use of compounds selected from D--hydroxybutiric acid and/or its metabolic precursor, as an active agent, drug or food product for the treatment of diabetes, reversion, slowing or prevention of neurodegenerative disorders and epilepsy, new compounds and method for their synthesis

The invention relates to pharmaceutical industry and relates to a method of receiving anticonvulsant drug, which is a 3-benzylpyrrolidine-2,4-dione (1), namely, that the aminouksusnoy acid esters acelerou anhydrides of monoamino malonic acid in the presence of the solvent chloroform, the resulting product is converted into 3-alkoxycarbonylmethyl-2,4 in an alcohol solvent in the presence of ciclismo agent sodium alcoholate, the resulting product carbalkoxy by three times with boiling acetonitrile, at a concentration of product (V) 20-30 g/l in the reaction mixture, followed by cooling, filtration, distillation of acetonitrile, the resulting pyrrolidin-2,4-dione is administered in the reaction with the corresponding dialkylated of dimethylformamide or triakontameron, the resulting product is treated with benzylamine at 0-5oWith subsequent isolation of the target product

The invention relates to medicine, to use rihanana as anti-convulsants, excelling activity reference drugs and does not cause allergic reactions

The invention relates to new derivatives of benzothiadiazole, benzoxazoles and benzodiazines formula I in free base form or in the form of a pharmaceutically acceptable acid salt additive that can be used as an anxiolytic drug in the treatment of any condition, which is associated with increased endogenous levels of CRF or in which violated the regulation of the hPa system (hypothalamic - pituitary), or various diseases that are caused by CRF1or the manifestation of which contributes CRF1such as arthritis, asthma, allergies, anxiety, depression, etc

The invention relates to medicine and can be used to treat epilepsy

The invention relates to novel benzimidazole compounds represented by the General formula I

< / BR>
where denotes the number 0, 1, 2 or 3; R1represents an alkyl group, phenyl group or a monocyclic heterocyclic group containing as the heteroatom N or O, and these groups may be substituted once or more than once, by substituents selected from alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy, cyano, amino and nitro; or R1represents cyano or a group of formula-alkyl-CO2R2alkenyl-CO2R2, -CO-R2, -CO2(CH2)mR2or-C(R3)=N-OR2where m denotes the number 0, 1, 2 or 3; R2represents hydrogen, alkyl, phenyl, benzyl, 5 - or 6-membered heterocyclic group, which 5 - or 6-membered heterocyclic group may be substituted once or more than once by alkyl or alkoxy; or R2may represent a group of the formula -(CH2)q-NR4R5, -(CH2)q-CON(R4R5), -(CH2)q-CO2R4or-alkyl-CO2R4where R4and R5independently представляюUP> represents a group of General formula-CO2-R9where R9represents an alkyl or R9can represent a 6-membered heterocyclic group, and this 6-membered heterocyclic group may be substituted once or more than once by alkyl or alkoxy; or R9represents a group of General formula-alkyl-N(R10R12), where R10and R12independently represent hydrogen or alkyl; or R11represents a group of General formula II

< / BR>
where n denotes the number 0, 1, 2 or 3; R' and R" together with the N atom to which they are attached, form a heterocyclic ring with the number of members from 5 to 7, and this heterocyclic ring can contain as a ring member, one oxygen atom and/or one additional nitrogen atom; and in this formula, a heterocyclic ring with the number of members from 5 to 7, formed by R' and R", may be substituted once or more than once by a group of the formula -(CH2)px, where p denotes the number 0, 1, 2 or 3; X represents hydrogen, hydroxyl, alkyl or alkenyl, and these alkyl and alkenyl can be possibly substituted by one or more the>R6or-CON-R6R7where R6and R7independently represent hydrogen or alkyl; or R11may represent a group of General formula III

< / BR>
where n denotes the number 1; R' represents hydrogen or alkyl; R'" and R" 'together with the atoms to which they are attached, form a heterocyclic ring with the number of members from 5 to 7, and this heterocyclic ring can contain as a ring member one chain-CH=CH-; and in this formula, a heterocyclic ring with the number of members from 5 to 7, formed R'" and R"", may be substituted once or more than once by a group of the formula -(CH2)pX, where p denotes the number 0, 1, 2 or 3; X represents hydrogen, alkyl; or its pharmaceutically acceptable salt; provided that if R11is morpholinyl, R1may not represent tert-butyl; pharmaceutical compositions having the properties of the modulator of the GABAANDreceptors and the treatment of disorders and diseases of the living organism, and it is a disorder or disease responsive to modulation of GABAAND-receptor complex of the Central nervous

The invention relates to new pyrazole[3,4-d]pyrimidines having anticonvulsant and anti-allergic/asthma action methods for their preparation (options) and pharmaceutical compositions based on them

The invention relates to a new 2-{4-[4-(4,5-dichloro-2-Mei-1-yl)butyl]-1-piperazinil}-5-torpedinidae formula I (see

The invention relates to medicine, specifically to the means of the treatment of seizures predominantly toxic etiology on the basis of anticonvulsant class of benzodiazepines sibazona

The invention relates to cosmetic and medical industries and relates to the application of herbal extracts as anti-inflammatory agents

The invention relates to medicines, in particular to a mixture of isomers (9)-tetradecanoate

The invention relates to novim retinoid compounds of General formula I, II, III, IV with retinoid negative hormone biological activity and/or activity of antagonist retinoids, compositions based on them, a method of determining the retinoid antagonists hormones,the method of treating a pathological state in a mammal, vospriimchivosti to treatment with retinoid antagonist or negative hormone by injection of compound I or II

The invention relates to new compounds of General formula I

< / BR>
in which R1selected from the group consisting of hydrogen, unsubstituted or optionally substituted aralkyl, unsubstituted or optionally substituted orelkinoservisa, unsubstituted or optionally substituted allyloxycarbonyl, unsubstituted or optionally substituted alkyl and hydroxyamino group; R2selected from the group consisting of hydrogen, unsubstituted or optionally substituted orelkinoservisa, unsubstituted or optionally substituted allyloxycarbonyl, aminosidine group; R3selected from the group consisting of hydrogen, unsubstituted or optionally substituted alkyl and unsubstituted or optionally substituted aralkyl; R4selected from the group consisting of unsubstituted or optionally substituted alkyl and unsubstituted or optionally substituted aralkyl; R5and R6that may be the same or different, each independently selected from the group consisting of hydrogen, unsubstituted or optionally substituted alkyl, unsubstituted or optionally substituted cycle>and R6taken together with the nitrogen atom to which they are attached, form an unsubstituted or optionally substituted heterocyclic group; R7selected from the group consisting of hydrogen, hydroxy, unsubstituted or optionally substituted alkyl and unsubstituted or optionally substituted aralkyl; R8selected from the group consisting of hydrogen, hydroxy, unsubstituted or optionally substituted alkyl and unsubstituted or optionally substituted aralkyl, and R9selected from the group consisting of hydrogen, hydroxy, amino and a group of the formula-X-Y, in which X is selected from the group consisting of unsubstituted or optionally substituted (C1-C6)-alkylene and unsubstituted or optionally substituted phenylene, and Y denotes a group of formula-a-b or a-B, where a is selected from the group consisting of unsubstituted or optionally substituted (C1-C6)-alkylene, imino and unsubstituted or optionally substituted (C1-C6)-alkylamino, and selected from the group consisting of hydrogen, amino, amidino, acylmethyl, unprotected or optionally protected bis (phosphono)methyl, provided that R7, R8and R are not simultaneously represent

The invention relates to chemical-pharmaceutical industry, concerns the solution of isotretinoin (13-CIS-retinoic acid) and treatment of skin diseases

The invention relates to medicine, namely to urology, and for the treatment of urinary incontinence
The invention relates to medicine, namely to surgery, and can be used for the treatment of chronic wound healing processes

Cytotoxic agents // 2187499

The invention relates to medicine, in particular to urology, and for the treatment of urinary incontinence

The invention relates to pharmaceutical compositions that increase fetal hemoglobin of the patient or accelerating differentiation of cells containing an effective amount of butyrate precursor drug of formula I in which a and D are independently from each other selected from the group comprising hydrogen, or C(1-4) straight or branched alkyl, S(2-4), straight or branched alkenyl or quinil, which may be independently substituted by hydroxy, alkoxy, carboxylation, alkylamides and so on, provided that a and D are not both hydrogen, R is oxygen, NH, NC(1-5) alkyl straight or branched chain or NHС(2-5)of alkenyl straight or branched chain, any of which may be optionally substituted by a residue of carbocycle or heterocycle, Z is hydrogen, C(1-4) alkyl straight or branched chain, With(2-4) alkenyl or quinil straight or branched chain, carbocyclic or heterocyclic residue and so on, and each stereogenic carbon atom can be R or S configuration, and pharmaceutically acceptable adjuvant or carrier

The invention relates to medicine, namely to Oncology, and can be used for the treatment of patients with malignant tumors of the organs of the oral cavity and pharynx