MXPA00005543A - Anticonvulsant and central nervous system-active bis(fluorophenyl)alkylamides - Google Patents

Abstract

Bis(Fluorophenyl)alkylamides have been chemically synthesized which possess beneficial pharmacological properties (e.g., anticonvulsant activity) useful for the treatment of neurological disease or disorders, such as, for example, epilepsy, convulsions, and seizure disorders. The preferred compounds of the invention also cause little sedation and have high therapeutic and protective indices in animal models of epilepsy. These compounds further possess long pharmacologic half-lives, which, in practical clinical therapeutic application, should translate into once-a-day dosing, of great benefit to patients suffering from these diseases and/or disorders. These compounds may also be of further clinical utility in the treatment of other diseases and disorders of the central and peripheral nervous systems, or diseases or disorders affected by them, including, but not limited to, spasticity, skeletal muscle spasms and pain, restless leg syndrome, anxiety and stress, and bipolar disorder.

Description

BIS (FLUOROFENIL) ACTIVE ALKYLAMIDES OF THE CENTRAL NERVOUS SYSTEM AND ANTICONVULSIVES, CORRESPONDING ACIDS AND USES Field of the Invention The present invention relates to compounds useful in the treatment of pathological conditions, such as seizures and spasticity, without producing sedation or undesirable muscular weakness in animal subjects, including humans. More particularly, the invention relates to the preparation, biological activities and therapeutic uses of 3, 3-bi s (3-fluorophenyl) propanamide and related compounds in patients suffering from pathologies of this nature.

Background of the Invention The following is a description of the relevant art, nothing of which is admitted to be prior art with respect to the claims.

A number of states, diseases and pathological conditions are characterized by a profound aberration in the normal function of the central nervous system (CNS). REF; 120606 Such conditions include multiple sclerosis, seizures, spinal cord injuries, chronic neurodegenerative conditions and diseases such as Parkinson's and Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease) and epilepsy. At the clinical level, these states usually respond only to pharmacological intervention with compounds or substances that have significant activity at the CNS level.

Due to the availability of experimentally accessible and reasonably predictable animal models of convulsive states, a number of clinically useful anticonvulsants have been prepared and developed in the 20th century, many of these compounds have been originally developed as anxiolytic or sedative hypnotic agents. In current medical practice, many of these compounds in clinical use for symptomatic spas tity treatments are several types of central muscle relaxants, which have usually been developed first for the treatment of other clinical indications. Most of these medicinal agents are burdened with undesirable discomfort, and side effects poorly tolerated in spasticity treatment and all are far from being the ideal clinical entities in this application (MERCK INDEX, 12th ed., Merck &Co., Rah ay, NJ, 1996).

Similarly, many anticonvulsants and anti-sepsis in clinical use are plagued by the presence of significant side effects that limit their long-term clinical usefulness, including annoying daytime sedation (drowsiness, cognitive dullness and / or "hangover") / muscle weakness, tolerance, gingivitis and bowel recession (gingival hyperplasia) and potentially fatal blood dyscrasias and hepa toxicities (some of which "are or may be fatal." These agents include benzodiazepines, which cause cognitive dullness. agents, such as valproate and phenytoin (Dilantin) can cause or produce hepatoxicity and gingival hyperplasia, respectively, among other side effects that limit their therapeutic potential.Many of these side effects are especially problematic in the clinical treatment of pediatric epilepsy (or epilepsy in children.) In this way, there is a clear need and persis for the development of new clinical entities with profiles of improved side effects and efficiency for the treatment of conditions or convulsive conditions.

In addition, there is a need for the development of new clinical entities with improved side effect profiles and efficiency for the treatment of spasticity and epilepsy. Certain bis (fluorophenyl) alkylamides are described in U.S. S.N. 08 / 873,011, filed June 11, 1997, which is commonly held with the present invention, and is hereby incorporated by reference in its entirety.

BRIEF DESCRIPTION OF THE INVENTION Therefore, it is an object of the present invention to provide compounds and a new therapeutic method for the treatment of various pathologies, effecting a modulation in the activity of the CNS without producing excessive sedation, muscle weakness, fatigue, gingival hyperplasia, blood dyscrasias or hepat or toxicity.

Also, it is an object of the present invention to provide a method for alleviating one or more symptoms associated with a condition, such as seizures and spasticity, which is improved by means of the modulating activity of the CNS.

It is another object of the present invention to provide a new anticonvulsant therapy In the performance of these and other objects, a use of a new compound selected from the group consisting of 3,3-bis (3-fluorophenyl) propanamide and the bis (according to one aspect of the present invention) has been provided. f 1 uorof in i 1) to 1 qui 1 ami da s and structurally related acids (see for example, Figures 1 and 2) in the preparation of a formulation or pharmaceutical composition for use in a method to treat a pathology that is improved by a modulation of the activity of the CNS, so that at least one symptom of said pathology is alleviated. Thus, The present invention also contemplates a method of treatment comprising the step of administering, to a patient that of a pathology that is enhanced by a modulation of the activity of the CNS, a therapeutically effective amount of a pharmaceutical formulation comprising a pharmaceutically vehicle. acceptable and a new composition selected from the group of agents mentioned above.

Continuing with one embodiment of the invention, the treated pathology is seizures, an affective mood condition, such as bipolar mood disorder, a neuropathic pain syndrome, a headache, such as a migraine headache or a migraine headache syndrome. restlessness. For another modality, the pathology in question is improved by a centrally mediated decrease in muscle tone, and is illustrated by spasticity- According to another aspect of the present invention, there is provided a use for new compositions of interest comprising 3,3-bis (3-fluorophenyl) propanamide and the structurally related amide and acid compounds in the preparation of a pharmaceutical formulation for the use in a method to treat a symptom of spasticity. In the same way, the invention provides a method for alleviating a symptom of spasticity in a subject in need of such treatment, comprising the step of administering a therapeutically effective amount of one of the novel compositions as described above.

Thus, in a preferred embodiment of the invention, a compound having the formula is provided where : And it is independently selected from the group consisting of -H, -F and Cl; X is either -NH'Fr or -OR1; R1 is selected from the group consisting of -H, alkyl and hydroxyalkyl; R2 is selected from the group consisting of -H, methyl and ethyl; and n is 0, 1, 2, 3 or 4. Preferably, R1 is selected from the group consisting of -H, methyl, ethyl, isopropyl, isobutyl, tert-butyl, hydroxyisopropyl and hydroxyethyl.

Thus, in another preferred embodiment of the invention, a compound having the formula is provided where : each F is independently in the meta-or para- position; R1 is selected from the group consisting of -H, alkyl and hydroxyalkyl; R2 is selected. from the group consisting of -H, methyl and ethyl; and n is 0, 1, 2, 3 or 4. Preferably, R1 s-e is selected from the group consisting of -H, methyl, ethyl, isopropyl, isobutyl, tert-butyl, hydroxyisopropyl, and hydroxyethyl.

In a more preferred embodiment, a compound having the formula is provided where n is 0, 1 or 2 both F are in the meta- or para- position; R1 is selected from the group consisting of -H, • alkyl and hydroxyalkyl; Y R2 is selected from the group consisting of -H, methyl ethyl More preferably, R 'is • H. More preferably, the compound is selected from the group consisting of compound 1, 2, 3, 7, 8, 9, 10, 11, 12, 13, 14 and 15. In the most preferred embodiments, the compound is compound 1.

In other preferred embodiments of the invention, there is provided a method for treating a patient having a disease or neurological condition comprising administering a compound of the formula where : And it is independently selected from the group consisting of -H, -F and -Cl; X is either -NR'R2 'or -OR1; R: is selected from the group consisting of -H, alkyl and hydroxyalkyl; R2 is selected from the group consisting of -H, methyl and ethyl; and n is 0, 1, 2, 3 and 4. Preferably, R1 is selected from the group consisting of -H, methyl, ethyl, isopropyl, isobutyl, tert-butyl, hydroxyisopropyl and hydroxyethyl.

Thus, in another preferred embodiment of the invention, there is provided a method for treating a patient having a disease or neurological condition comprising administering a compound of the formula where: each F is independently in the meta-or para- position; R1 is selected from the group consisting of -H, alkyl and hydroxyalkyl; R2 is selected from the group consisting of -H, methyl and ethyl; and n is 0, 1, 2, 3 or 4. Preferably, R1 is selected from the group consisting of -H, methyl, ethyl, isopropyl, isobutyl, tert-butyl, hydroxyisopropyl and hydroxyethyl.

In a more preferred embodiment, a method is provided for treating a patient having a disease or neurological condition comprising administering a compound of the formula where : n e s 0, 1 or 2; both F are in the meta- or para- position; R1 is selected from the group consisting of -H, alkyl and hydroxyalkyl; and R2 is selected from the group consisting of -H, methyl and ethyl. More preferably, R2 is -H. More preferably, the compound is selected from the group consisting of Compound 1, 2, 3, 7, 8, 9, 10, 11, 12, 13, 14 and 15. In the most preferred embodiments, the compound is compound 1.

In other preferred methods, the disease or neurological condition is selected from the group consisting of epilepsy, seizure and attack diseases. In other preferred aspects, the patient's treatment relieves or prevents seizures in the patient. In other preferred aspects, the disease or neurological disorder is associated with spasticity. In other preferred aspects, the disease or neurological condition is a neurodegenerative condition. Preferably, the disease or neurological condition is selected from the group consisting of spasticity, skeletal muscle spasms, restless legs syndrome, anxiety, tension, multiple sclerosis, seizure, head trauma, spinal cord injury, Parkinson's disease , Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, migraine headaches and bipolar disorder.

Other preferred embodiments of the invention include methods for relieving or preventing spasticity, or one or more symptoms of spasticity, in a patient, which comprises administering a compound of the invention.

Also provided are pharmaceutical compositions, which comprise a compound of the invention, and a pharmaceutically effective carrier. Preferably, the pharmaceutical composition comprises a compound selected from the group consisting of compounds 1, 2, 3, 7, 8, 9, 10, l ?, 12, 13, 14 and 15, and a "pharmaceutically acceptable carrier." More preferably , the pharmaceutical composition comprises compound 1.

Also provided in the present invention is a method for making a therapeutic agent, comprising the steps of screening the agent to determine whether the agent relieves spasticity and synthesizing the therapeutic agent in an amount sufficient to provide the agent in a therapeutically effective amount at a patient. Preferably, the therapeutic agent comprises a compound of the invention.

Also provided in the present invention is a method for modulating CNS activity, which comprises administering to a patient a compound of the invention. Preferably, the modulation of CNS activity relieves a symptom associated with seizures, spasticity, a mood disorder, a neuropathic pain syndrome, a headache, a restlessness syndrome or a movement disorder.

Other objects, features and advantages of the present invention will be apparent from the following detailed description. However, it should be understood that the detailed description and specific examples, while indicating the preferred embodiments of the present invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent. apparent to those skilled in the art of this detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 depicts structures and anticonvulsant activities in vivo, as tested using the methods described herein of 3, 3-bis (3-f luoropheni 1) propanamide and several of the analogs and substituted congeners.

Figure 2 depicts the structures of 3, 3-bis (3-fluorophenyl) propanamide and the additional analogues and congeners.

Figure 3 depicts the reduction in muscle reflex in anesthetized normal rats obtained by Compound 1 compared to baclofen, as tested using the methods described herein.

DETAILED DESCRIPTION OF THE PREFERRED MODALITIES 1. POINT OF VIEW The inventors have discovered that 3, 3-bis (3-fluorophenyl) propanamide and certain of its pharmacologically active analogs and congeners can be administered to effect a modulation of CNS activity. That is, these agents modulate the SNC activity, improving the inhibitory neurotransmission or decreasing the neurotransmission centrally, without completing the suppression of all the activity. Following the present invention, therefore, a subject receiving such an agent does not sedate, is openly anesthetized or paralyzed in the context of, for example, decreased seizures (without anesthesia), decreased muscle tone (without paralysis), obtain a calming effect (without sedation) or improve an outpatient syndrome such as spasticity (no weakness or flaccidity).

A number of pathologies, exemplified by seizures (crises), spasticity, affectionate mood disorders, such as bipolar mood suffering, headaches (chronic migraine, migraine), restlessness syndromes, neuropathic pain and movement disorders, are at least a symptom that is relieved by a modulation of the activity of the CNS. Therefore, an individual suffering from such pathology is a candidate for the therapy which, following the present invention, entails that the individual receives a pharmaceutical formulation of the composition containing 3, 3-bis (3-fluorophenyl) propanamide or one of its analogues or structurally related congeners as one of the main active ingredients. 2. EXEMPLARY PATHOLOGIES IMPROVED BY A MODULATION OF THE ACTIVITY OF THE CENTRAL NERVOUS SYSTEM (CNS) CONVULSIONS: Epilepsy is a common condition that has many causes, and can be very difficult to control clinically, often requires treatment for many years to keep the crisis under control. Researchers have stated that "up to this point, there is no satisfactory treatment for epilepsy in a substantial proportion of patients." Clinical trials have shown that certain patients have a better response to one drug than to another, even when patients have different types. The frequency and severity of side effects also vary substantially, so that multiple medications with different mechanisms of action and concomitant side effects will be needed for the treatment of epilepsy. that epilepsy can be cured or discovered "and a new, potent, safe drug with broad activity is developed. Dichter e.t al., Drus Theraov 334: 1583 (1996).

Due to the extended bioavailability of experimentally accessible and reasonably predictive animal models of convulsive statesA number of clinically useful anticonvulsants have been prepared and developed. For example, see Cereghino et al., "Introduction", in ANT I EPILEPT IC DRUGS, 4th ed., Pages 1-11 (Raven Press 1995), which states: "In many patients, seizures can be controlled with antiepileptic drugs. currently available, but 25 to 30 percent of patients continue to have seizures despite optimal therapy, while many others experience unacceptable side effects. " Dichter et al. (1996) supra.

Thus, many anticonvulsants in clinical use are plagued by the presence of significant side effects, including sedation of the annoying day, muscle weakness, tolerance, gingival hyperplasia and potentially fatal blood dyscrasias and hepat ot. Many of these side effects are of particular interest in the clinical management (treatment) of epilepsy in children.

The present invention can be used to treat convulsive conditions such as epilepsy. That is, the compositions and formulations and pharmaceutical compositions of the invention exhibit "anticonvulsant activity", which is evidenced by a reduction in the severity, number or duration of seizures in animal models of epilepsy. To alleviate seizures it is included reducing the severity, number or duration of seizures in a patient. Therefore, new compositions and formulations and pharmaceutical compositions should be useful in the treatment of conditions such as, but not limited to, generalized tonic-clonic seizures, absence seizures, myoclonic seizures, simple partial seizures, complex partial seizures, Secondarily generalized partial seizures, status epilepticus and trauma-induced crises as they occur after injury or head surgery.

SPASTICITY: Spasticity is a condition characterized by an increase in tonic stretch reflexes (muscle tone) with exaggerated tendon jerks that result from the hyperexcitability of the muscle reflex. Lance, Symposia synopsis, in SPASTICITY - DISORDERED MOTOR CONTROL, Feldman et al. (Eds.) (1980). The conditions and conditions of major diseases associated with spasticity include multiple sclerosis, cerebral palsy, seizures, trauma or spinal cord injury and head trauma. Symptoms that occur with spasticity include painful muscle spasms, increased or exaggerated deep tendon reflexes, clone, muscle weakness, fatigue, lack of dexterity, various degrees of loss of general motor function, paralysis, and sleep damage.

The pathological states observed in spasticity are fundamentally different at the pathological level from experienced acute pain, strains and muscle strains that occur from a localized external trauma to a particular muscle, i.e., outside or the periphery of the CNS. These pathological states are also different from the relatively common involuntary spasms of smooth muscle, such as vascular spasms, bladder spasms and bronchial spasms. Such non-spastic (not CNS), peripheral or localized symptoms are commonly treated with so-called "antispasmodic" or "spasmolytic" agents, but these are generally not useful in the treatment of spasticity. Cedarbaum & Schleifer, "Drugs for Parkinso-n's Disease, Spasticity and Acute Muscle Spasms", in GOODMAN AND GILMAN'S THE PHARMACOLOGICAL BASIS OF THERAPEUT I CS, 8th ed. [subsequently GOODMAN AND GILMAN'S], pages 463-484 (Pergamon Press 1990).

The compositions of the material and the formulations and pharmaceutical compositions used in accordance with the present invention can effect a centrally mediated decrease in muscle tone and, therefore, are useful for the chronic or acute relief of one or more symptoms or side effects of Spasticity In this context, "spasticity" refers to an increased tone of skeletal muscle manifested by symptoms such as, but not limited to, painful muscle spasms, increased or exaggerated deep tendon reflexes, hyperreflexia, loss of skill, muscle weakness. , exaggerated tendon jerks and clone. The phrase "antispassticity agent" refers herein to a composition that is useful for the symptomatic treatment of spasticity, as demonstrated by the relief of at least one of the following manifestations or collateral effects of spasticity: painful muscle spasms, deep tendon reflexes increased or exaggerated, hiperref le'xi a, loss of dexterity, muscle weakness, exaggerated tendon shaking and cloning, or the reduction of the frequency of these manifestations or side effects.

Therefore, the "relief" of spasticity refers here to the decrease of one or more symptoms of spasticity, including, but not limited to, painful muscle spasms, increased or exaggerated deep tendon reflexes, hyperreflexia, loss of dexterity, muscle weakness, exaggerated tendon shaking and cloning, or the reduction of the frequency of these manifestations or side effects.

AFFECTIVE HUMOR CONDITIONS: These include conditions in the range from depression to dysphoria mania, for example, mania, streptococcal disease, aggression induced by traumatic brain injury, post-traumatic stress disorder, and behavioral discontrol syndromes. . See Emrich et al., J. Affective Disorders 8: 243-150 (1985) and Bernasconi et al., In ANTICONVULSANTS IN AFFECTIVE DISORDERS, pages 14-32 (Excerpta Medica 1984). The new compositions and formulations and pharmaceutical compositions according to the present invention are affective in the treatment of these diseases, conditions and conditions and should exhibit improved side effect profiles when compared to the therapeutic agents currently existing in this therapeutic category.

NEUROPATHIC PAIN SYNDROMES: The conditions in this category, which involve "neuropathic pain," affect a significant number of patients suffering from brain or spinal cord disorders, such as seizures, trauma, multiple sclerosis, and diabetes.

Casey, in PAIN AND CENTRAL NERVOUS SYSTEM DISEASE (Raven 1991). The use of anticonvulsants to treat various pain states has been documented extensively. Swendlow, J. Clin. Neuropharmacol. 7: 51-82 (1994). Thus, a new composition or formulation or pharmaceutical composition of the present invention can be applied in a similar manner to improve neuropathic pain.

HEADACHES: Migraine headaches (Hering and Kuritzky, Cephalalsia 12: 81-84 (1992)), the type of migraine (Hering and Kuritzky, loe.

Cit. 9: 195-198 (1989)), and the chronic type (Mathew and Sabiha, Headache 31: 71-74 (1991)) have been treated with anti- convulsives. The compositions and formulations of the present invention can be used, therefore, to alleviate the symptoms associated with each of these three types of headaches, without the adverse side effects of current existing therapies.

CONCERNS SYNDROME: The phrase "restlessness syndrome" represents a somatic (non-mental) restlessness characterized by involuntary movement of the limbs, as well as a sense of physical agitation (rather than mental agitation), which is independent of mood and, therefore, it differs from restlessness per se. (See Sachev et al., Austral. New Zealand J. Psvchiatry 30: 38-53 (1996)).

Symptoms of restlessness, including numerous indications, can be observed in association with many psychiatric organic and non-organic diseases. For example, drug-induced restlessness (Late, chronic and symptomatic akathisias), such as drug-induced extirpable ramire symptoms, is one of the most common side effects of neuroleptic drug therapy. Also within the rubric of the restlessness syndrome is the so-called "restless legs syndrome" and the "periodic movements of the legs related to sleep", pathologies that can be associated with the head trauma and / or the spinal cord and with spinal cord injuries. Idiopathic restless legs syndrome follows an autosomal dominant inheritance, with an expression of variable clinical symptoms. See O'Keefe, Arch. Intern. Med. 156: 243-248 (1996); Danek et al., In NEUROLOGICAL DISORDERS: COURSE AND TREATMENT, pages 819-823 (Academic Press 1996); Mellick and Mellick, Neurology 45 (suppl.): 285-286 (1995). The present invention provides an effective therapy for restlessness syndromes with minimal side effects.

MOVEMENT THREATS: Several agents are known to decrease the movement disorders that characterize the movement of dyskinesia, such as Parkinson's disease, Huntington's chorea, Alzheimer's disease, tardive dyskinesia and the still-man syndrome. Lloyd and Morselli, in PSYCHOPHARMACOLOGY: THE THIRD GENERATION OF PROGRESS (Raven Press 1987). A therapy within the present invention alleviates one or more symptoms of a movement disorder.

The compounds of the invention could also be useful as anxiety reducing agents (anxiolytics).

By "neurological disease or condition" is meant a condition or disease of the nervous system that includes, but is not limited to, epilepsy, anxiety, multiple sclerosis, seizures, head trauma, spinal cord injuries and chronic neurodegenerative diseases such as diseases of Parkinson and Huntington, Alzheimer's disease and amyotrophic lateral sclerosis. "Neurological illness or disease" is also understood as the conditions and conditions of diseases in which an antispasmodic or anti-seizure could be indicated, used or recommended and / or prescribed.

By "neurodegenerative disease" is meant diseases such as, but not limited to, Huntington's disease, Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis (ALS).

By "anticonvulsant" is meant a compound capable of reducing the severity, number or duration of seizures produced, observed or found in conditions such as generalized seizures, absence seizures, myoclonic seizures, simple partial seizures, complex partial seizures, secondarily generalized partial seizures, epilepticus status and trauma - induced crises, as they appear after. damage or head surgery.

By "anticonvulsive activity" is meant the efficiency to reduce the severity, number or duration of seizures produced, observed or found in conditions such as generalized tonic-clonic seizures, absence seizures, myoclonic seizures, simple partial seizures, complex partial seizures , secondarily generalized partial seizures, epilepticus status and trauma-induced crises, as they occur after damage or head surgery.

By "therapeutic dosage" is meant an amount of a compound that releases to some degree one or more symptoms of the release or condition of the patient. Additionally, by "therapeutic dosage" is meant an amount that returns to normal parameters, either partially or completely, physiological or biochemical associated with or causing the disease or condition. In general, it is an amount between about 0.1-15-20-30 mg / kg of body weight, depending on the age, size and disease associated with the patient. The dosage can be from one to four times per day.

By "pharmaceutical composition" is meant a therapeutically effective amount of a compound of the present invention in a pharmaceutically acceptable carrier, i.e., a formulation to which the compound can be added to dissolve or otherwise facilitate the administration of the compound. Examples of pharmaceutically acceptable carriers include water, saline and physiologically buffered saline. Such a pharmaceutical composition is provided in an appropriate dosage. Such compositions are, in general, those that are approved for use in the treatment of a condition specified by the FDA or its equivalent in non-U.S. countries.

By "patient" is meant any animal that presents a symptom that can be alleviated by the administration of an anticonvulsant or antispastic composition. Preferably, the animal is a mammal. More preferably, the animal is a human.

By "alkyl" is meant a branched or unbranched hydrocarbon chain containing between 1 and 6, preferably between 1 and 4, carbon atoms, such as, eg, methyl, ethyl, n-propyl, iso-propyl, n- butyl, sec-butyl, iso-butyl, tert-butyl, 2-methyl protyl, cyclopropylmethyl, allyl and cyclobutylmethyl.

By "lower alkyl" is meant a branched or unbranched hydrocarbon chain containing between 1 and 4 carbon atoms, of which examples are listed here.

By "hydroxyalkyl" is meant an alkyl group as defined above, substituted with a hydroxyl group 3. METHODS FOR PREPARING FORMULATIONS AND PHARMACEUTICAL COMPOSITIONS As demonstrated herein, the useful compounds of this invention and their pharmaceutical compositions could be used to treat neurological conditions or diseases. While these compounds will typically be used in therapy for human patients, they could also be used to treat similar or identical diseases in other vertebrates, such as primates, domestic animals, breeding animals such as pigs, cattle and chicken and animals and sports pets. , such as horses, dogs and cats.

The formulations and pharmaceutical compositions of the present invention can be prepared according to known methods for preparing pharmaceutically useful compositions, whereby active agents are combined in a mixture with a pharmaceutically acceptable carrier. For example, see Gennaro (Ed.), REMINGTON'S PHARMACEUTICAL SCIENCES, 18th ed. (Mack Publishing Co. 1990) and GOODMAN AND GILMAN'S, cited above. A composition is said to be in a "pharmaceutically acceptable vehicle" if its administration can be tolerated by a recipient patient. The saline solution buffered with sterilized phosphate is an example of a pharmaceutically acceptable vehicle. Other suitable vehicles (e.g., salt and Ringer solutions) are well known to those skilled in the art. See, for example, REMINGTON'S PHARMACEUTI CAL SCIENCES, supra.

The pharmaceutically acceptable salts are in general, well known to those skilled in the art, and could include, by way of example, but not limitation, sodium, potassium, calcium, magnesium, lithium salts and other pharmaceutically acceptable salts that could be found in, for example, Rem in gt on 's Ph a rma ce uti ca l S ci ces, Mack Publishing Co., Easton, PA (lth ed., 1990).

The useful compounds of this invention could also be in the form of pharmaceutically acceptable complexes. Pharmaceutically acceptable complexes are known to those skilled in the art.

The pharmaceutical compositions of the present invention could be made in a manner that is itself known, e.g., by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.

In general, dosages of the anticonvulsant and antispasmodic agents described herein will vary depending on such factors as the patient's age, weight, height, sex, general medical condition, and prior medical history. For the purposes of therapy, a compound of the present invention and a pharmaceutically acceptable carrier are administered to a subject in need of such treatment in a therapeutically effective amount. The combination of the active agent and the vehicle is said to be administered in a "therapeutically effective amount" if the amount administered is physiologically significant. An agent is physiologically significant if its presence results in a detectable change in the physiology of a patient. In the present context, for example, the anticonvulsant agent is physiologically significant if the presence of the agent results in the reduction of the severity, number or duration of the convulsions, while an antispasmodic agent is physiologically significant if the presence of the Agent results in relief of one or more symptoms of spasticity.

The compositions and formulations of the present invention can be orally administered using solid oral dosage forms such as, for example, enteric coated tablets., coated capsules, gelatin capsules, sprays or capsules, or via liquid dosage forms such as syrups or elixirs. The indicated dosage of 3, 3-bi s (3-fluoropheni 1) propanamide and the structurally related bis (fluorophenyl) alkylamide compounds as anticonvulsants is in the order of 1-1000 mg per dosage, and preferably 10-500 mg per dosage . The solid oral dosage forms preferably contain about 10-250 mg per tablet or capsule, which should preferably be taken 1-2 at a time for a maximum of two times per day, at a dosage of approximately 0.1-15 mg / kg of weight bodily. Liquid formulations can also be employed with the active ingredient compositions to provide 1-2 tablespoons per dosage. Oral liquid dosage forms and the correspondingly reduced pediatric chewable dosage can also be administered. These compounds can also be added to foods and beverages in the form of drops (with a dropper of a "concentrated" preparation) for oral administration. In addition, the compounds of the invention could be formulated in chewable gums to facilitate oral delivery and absorption.

Alternatively, the compounds of the invention can be administered by injection or other systemic routes, such as transdermal or transmucosal administration, for example, nasally, buccally or rectally, via suppositories or using sublingual, vaginal or intestinal administration; parenteral release, including intramuscular, subcutaneous and / or intramedullary injections, as well as intrathecal, direct intravenous, intravenous, intraperitoneal, intranasal or infraocular injections. However, oral administration is much more convenient, and therefore is preferred.

For use in an oral antiseptic formulation or composition, the dosage level of the active ingredient is in the order of 1-1000 mg per dosage, and preferably, 10-250 mg per dosage or 0.1-15 mg /. kg of body weight. The exact formulation, route of administration and dosage can be chosen by the individual's physician from the point of view of the patient's condition. (See E. Fingí et al., In The Pharmacolosical Basis of Therapeutics, 1975, Ch. 1, p.1).

It should be noted that the attending physician would know how and when to terminate, interrupt or adjust the administration due to organ toxicity or dysfunction. Conversely, the attending physician would also know how to adjust the treatment to higher levels if the clinical responses were not adequate (excluding toxicity). The magnitude of a dosage administered in the management of the condition of interest will vary with the severity of the condition to be treated and with the route of administration. The severity of the condition, for example, could be evaluated in part, through the methods of evaluating standard forecasts. In addition, the dosage and perhaps the dosage frequency will also vary according to the age, body weight and response of the individual patient. . A program comparable to the one discussed above could be used in veterinary medicine.

By injection, the agents of the invention could be formulated in aqueous solutions, preferably in physiologically compatible buffers, such as Hank's solution, Ringer's solution or physiological saline buffer. For transdermal administration, appropriate penetrants are used in the formulation to the barrier which is permeable. Such penetrants are generally known in the art.

Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in the water-soluble form. Additionally, suspensions of the active compounds could be prepared as oily appropriate injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil or synthetic fatty acid esters, such as ethyl oleate or triglycerides or liposomes. Suspensions of aqueous injections may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension could also contain stabilizers or appropriate agents that increase the solubility of the compounds, to allow the preparation of highly concentrated solutions.

In addition to a use in humans, the compounds of the invention can be used in veterinary applications, for example, as convulsive agents, anxiolytic agents, or antispasmodic agents, in animals such as cats, dogs, birds, horses, cattle, mink, chicken and fish. In such cases, the active compounds could be administered by injection or other systemic routes, such as transdermal or transmucosal administration (eg, rectal administration via suppositories), or orally by addition to the food or beverage. As an anticonvulsant agent, the indicated oral dosage of the compounds of the invention per kilogram of body weight of such animals is about 1-1000 mg / kg, depending on the species of animals and the route of administration. A preferred range for oral dosing is approximately 10-500 mg / kg body weight.

The indicated oral dosage of the compounds of the invention per kilogram of body weight as antispasmodic agents for animals is in the range of about 1-1000 mg / kg, depending on the species of animals and the route of administration. A preferred range for oral dosing is approximately 5-500 mg / kg body weight.

Thus, the present invention contemplates a variety of pharmaceutical compositions containing the compounds of the invention as active ingredients that are suitable for oral, parenteral, transdermal, transmucosal, intranasal, buccal or rectal administration.

It is further understood that the compounds of the invention can be used in combination with other pharmaceutically active ingredients. 4. ACTIVITY THAT INVOLVES DEMONSTRATION THERAPY The appropriate form and effectiveness of a given compound, pharmaceutical formulation or composition for the relief of a pathology, as discussed above, can be demonstrated using the appropriate animal models such as (but not limited to) those described below. (a) Anticonvulsive activity Methods for determining and evaluating the anti-convulsive activity of test compounds in experimental animals (eg, rodents) are well known in the art (Foye, WO (Ed.), Principies of Medicinal Chemistry, 3rd. ed. (1989) Lea and Febiger, Philadelphia, PA, pp. 173-178; Gilman, AG, et al., Goodman and Gilman's The Pharmacological, Basis of Therapeutics, 9th ed. (1996) Pergamon Press, New York, pp. 461-486; Wolff, ME, Burger's Medicinal Chemistry, 5th ed. (1996), Wiley Int erscience, New York, pp. 182-198. Relevant animal models include tests of the mouse susceptible to Frings audiogenic crisis and the MES rat (Elect rochoque maximum) Both of these tests were used to verify the anticonvulsant properties of the test compounds For the general methods and terminology that refer to the anticonvulsant tests, see J. A. Life, "Ant. iconvul sant s ", in WO Foye et al. (Eds.), Principies of Medicinal Ch emistry, 4th Ed. (1995) pp. 182-198.

There are many different models that involve different types of crises or behavioral effects, which are relevant to the different clinically epileptic forms. Therefore, they are useful for testing effects in more than one model.

Loscher and Schmidt (Epilepsy Research 17: 95-134, 1994) proposes a hierarchical test in several models of epilepsy animals for the pharmacological evaluation of antiepileptic drugs. A more detailed description of these various models, as well as possible referrals to human epilepsy, can be found in reviews of H.S. White (in Antiepi lept ic Drugs, Fourth Edition, edited by RH Levy, RH Mattson, and BS Meldrum, Raven Press, Ltd., New York, 1995, pp 99-110) and H. Kupferberg (Epilepsy 30 suppl 1) : S51-S56, 1989).

A useful model for the mouse susceptible to Fringe audiogenic crisis, a model of reflex epilepsy, is provided. The mouse susceptible to audiogenic crisis Frings is a genetic mouse model of epilepsy used to indicate a general, preliminary level of efficiency and therapeutic potential, but it is not predictive of any particular human crisis condition. The compounds measured for their ability to block the tonic extension waves induced by sound (White et al., 1995). At the time of the test, the individual mice are placed in a round Plexiglas chamber and exposed to a sound stimulus of 110 decibels, 11 kHz, for 20 seconds. Animals that do not expose extensions of the hind leg are considered protected. In addition, the outcome of the crisis for each mouse can be recorded as: (1) run for less than 10 seconds; (2) run for more than 10 seconds; (3) clonic activity of the legs and / or vibriosis; (4) extension flexion of the front leg / back leg; and (5) extension of the back leg.

The average crisis record can be calculated for each of the groups of mice used in the study of the response to the dosage. At each dosage, the mice were also tested on a rotary bar to test motor damage ("toxicity"). The test for motor damage on the rotary bar involves placing a mouse for a period of three minutes on a one-inch diameter bar and rotating at six revolutions per minute. If the mouse falls off the rotary bar three times within the three minute period, it is considered a toxic response. b) Echo Rochoque Maximum Crisis Test (MES) The elect rochoque crisis test (MES) is an animal crisis model highly predictive of generalized tonic-clonic seizures in humans. In the MES test, an alternating current of 60 Hz is released for 0.2 sec through corneal electrodes in the mice. The abolition of the tonic muscle component of the hind leg is taken as the final point for this test. The absence of this component suggests that the test substance has the ability to prevent diffusion of the shock discharge through neural tissue (White et al., 1995). c) Rats cut transversally spinally and acute descerebrate rats There are several models of spasticity, including the acute brainless rat, the rat cut in a spinally chronic transverse manner and the injured rat of the spinal cord chronically. (See, e.g., Bertman and Adkovat, Brain Res. 684: 8-18 (1995); Chen et al., Neuroscience 23: 641-647 (1987)). The acute models, although of proven value to elucidate the mechanisms involved in the development of spasticity, have come under criticism due to the fact that they are very acute.

Animals usually die and have total recovery from spasticity. Spasticity develops immediately from the intervention, unless spasticity is involved in the human condition of spasticity, which most of the time initially manifests as flaccid paralysis. Only after weeks and months does spasticity develop in humans. Some of the models cut in a spinal or chronic lesion with chronic spasticity are post-operative and show flaccid paralysis. At about four weeks post-injury / t-section, flaccidity changes to spasticity of varying severity.

Although all these models have their own particular disadvantages and lack of real representation of the spastic condition in humans, they have provided much more information about the nature of spasticity. These models have also provided the methods to test several treatment paradigms that have led to similar treatments that are tested in humans. Many of these models have also made use of different species, such as cats, dogs and primates.

Baclofen, diazepam (Valium) and tizanidine are effective on the different parameters of spasticity (EMG records, H reflex, the H / M ratio, mono and polyacryptic reflexes, clone, hyperreflexia) in these models. The muscle reflex is a polyps response caused by the stimulation of the lower part of the foot and models the absence reflex. Compounds such as baclofen, benzodiazepines, tizanifine and NMDA receptor antagonists have been shown to reduce muscle reflex in rodents (cut off normally or spinally) and are also effective antispastic in humans (Bertman and Advokat, 1995; , 1990; Young, 1994; Davidof, 1985). (d) Irwin Primary Observation Test in the Rats This method is based on that described by Irwin, Psychopharmacologia 13: 222-257 (1968). It is used to detect the physiological, behavioral and toxic effects of a test substance and indicates a range of dosages that can be used for the final experiments. Typically, the rats (three per group) are administered the test substance and then observed in comparison to a given vehicle control group. Behavioral changes, symptoms of neurotoxicity, pupil diameter and rectal temperature are recorded according to a standardized observation mesh derived from Irwin's. The mesh contains the following points: mortality, sedation, excitement, aggressiveness, Straub's tail, writhing, convulsions, shivering, exophthalmos, salivation, lacrimation, piloerection, defecation, fear, traction, reactivity to touch, loss of reflexes of precision, sleep , motor incoordination, muscle tone, stereotypes, head tissue, catalepsy, greed, ptosis, breathing, corneal reflex, analgesia, abnormal steps, passage of front legs, loss of balance, sudden head movements, rectal temperature and pupil diameter. The observations are made at 15, 30, 60, 120 and 180 minutes after the administration of the test substance and also 24 hours later. (e) Test of the Rotary Bar in Rats and Mice This is a test for neurological deficits using the method described by Dunham et al., J. Am. Pharm. Assoc. 46: 208-209 (1957). Rats and mice are placed on a rotating bar at a speed of six to eight turns per minute. The number of animals that fall from the bar before three minutes is counted and the times of falls are recorded (maximum: 180 sec). Eight to ten rats are studied per group and the test is carried out blindly. The test compound is administered i.p. 60 min before the test. Diazepam (Valium), a benzodiazepine at 8 mg / kg, i.p., is administered as the reference substance. The vehicle administered to the control group is also included in the study. (f) Anti-manic activity To verify the possible use of the compounds in the treatment of affective mood disorders, such as bipolar humor, the model of hyperreactivity induced by amphetamines in rats can be used. In addition to a test for atypical and classic antipsychotic activity, this procedure has also been proposed as a simple animal model of manic behavior. Costall et al., Brain Re s. 123: 89-111 (1977). g) Neurogenic Inflammation of Meninges Neurogenic inflammation within the meninges has been proposed as a case in the fundamental pathology of migraine headaches. Lee et al., Bri t J. Pharma col. 116: 1661-1667 (1995). The compounds are tested for their ability to block the spillage of radiolabeled bovine serum albumin within post trigeminal dura stimulation. (h) Analgesic Properties There are many tests of complete animals to determine the analgesic properties, such as writhing, hot plate, tail movement, arthritic pain, paw pressure tests and Bennett or Chung models of neuropathic pain. Albe-Fessard et al., In ADVANCES IN PAIN RESEARCH AND THERAPY 13, pages 11-27 (Raven Press 1990). (i) Therapeutic Benefit in Relation to Movement Conditions and Disability Syndromes Animal models exist for the study of movement disorders and syndromes of concern, for example, drug-induced akathisias, serotonin syndrome, and rotation induced by unilateral nigral lesions. Lloyd and Morselli (1987), supra. Additionally, the reports of individual cases of the anecdotal efficiency of compounds in humans has been a source for the support of these indications. Mellick and Mellick (1995), supra; Olson et al., Am. J. Med. 102: 60-66 (1997).

The anxiolytic activity of the compounds of the invention can be demonstrated using the appropriate methods known in the art, such as those described in Balandrin et al., Pat. U.S. 5,506,268 (1996).

The therapeutic effects of the compounds of the invention in several of the tests described above, combined with a general lack of toxicity, make the compounds of the present invention ideal agents for the treatment of the pathologies described above, including convul sions / cris is (epilepsy) and spasticity. With this background, the present invention will be more readily understood with reference to the following examples, which are provided for purposes of illustration and are not intended to limit the invention.

Although the above refers to the preferred embodiments, it will be understood that the present invention, in this way, is not limited. It will be presented to those skilled in the art, that various modifications could be made to the described embodiments and that such modifications are intended to be within the scope of the present invention, which is defined by the subsequent claims.

All publications mentioned in this specification are indicative of the level of those skilled in the art for which the invention relates. All publications are incorporated herein by reference to the same degree as if each individual publication was specific and individually indicated and is incorporated by reference in its entirety.

EXAMPLES Example 1 - Anticonvulsive Activity The desired properties of an anticonvulsant drug include: the drug can be administered by oral or injectable routes, the drug exhibits effective anticonvulsant activity against various types of seizures, including, but not limited to, generalized tonic-clonic seizures, absence seizures, myoclonic seizures, simple partial seizures, complex partial seizures, secondarily generalized partial seizures, epilepticus status and trauma-induced seizures, as they occur after injury or head surgery; and the drug is exempt or has minimal side effects, such as damage or cognition, interruption of motor performance, sedation or hyperexcitability.

E-jem.plo 2 - Synthesis of Compounds The results of the low resolution mass spectrum and capillary gas chromatography were obtained using a Hewlett-Packard (HP) 5890 Series II Gas Chromatograph coupled to an HP 5971 Selective Mass Detector [Ultra Performance Ultra-2 Hair Column (silicone of PhMe at 5% cross-linking); length of the column, 25 m; column i.d., 0.20 mm; Helium flow rate, 60 mL / min; injector temperature, 250 ° C; temperature program, 20 ° C / min from 125 to 325 ° C for 10 min, then kept constant at 325 ° C for 6 min].

Thin layer chromatography was performed using Analytech Uniplate 250 μm silica gel HP TLC plates. UV light in conjunction with ninhydrin and Dragendorff atomization reagents (Sigma Chemical Co.) were used to detect the compounds in the TLC plates. Most of the reagents used in the reactions were purchased from Aldrich Chemical Co. (Milwaukee, Wl), Sigma Chemical Co. (Saint Louis, MO), Fluka Chemical Corp. (Milwaukee, Wl), Fisher Scientific (Pittsburgh, PA), TCI America (Portland, OR) or Lancaster Synthesis (Windham, NH ).

Preparation of 4, 4-bis (4-fluorophenyl) bu tanamide (Compound 12) (a) Preparation of l-acetoxy-4, 4-bis (4-p 1 or phenyl) butane A solution of -chloride (20.0 g, 71.2 mmol) in DMF (50 mL) and potassium acetate (14.0 mg, 142 mmol) was heated at 140 ° C for 60 min (start time 12:36 min). It was cooled to 25 ° C, poured into 200 mL of sat. NaCl, and the product was extracted with EtOAc (2 x 100 mL), the EtOAc layer was washed with sat. NaCl. (3 x 100 mL), dried (Na2SO4), and evaporated in vacuo to provide 19.43 g, 89.9% yield of an orange oil. (b) Preparation of 4, 4-bis (-fluoropheni 1) -butan- 1 -ol A solution of the ester (19.4 g, 63.9 mmol) in EtOH abs. (250 mL) and NaOH ION (6.4 mL, 64 mmol) was heated to reflux for 60 min. The solvent was then evaporated in vacuo. The residue was dissolved in EtOAc (200 mL), sat. NaCl. (100 mL) and H20 (10 mL). The layers were separated and the organic layer was washed with sat. NaCl. (3 x 50 mL), dried (anhydrous Na 2 SO 4), and evaporated in vacuo to provide 15.4 g, 92.2% yield of an oil. TLC (Hex / EtOAc, 3: 1), Rf = 0.23. (c) Preparation of the acid 4, 4-bis (3-f luoro feni 1) but ir ico Chromium trioxide (27.9 g, 279 mmol) was dissolved in H20 (42 mL) and cooled in an ice bath. Concentrated H2SO4 (24 mL) was added with stirring. This suspension was added dropwise to a solution of ethanol (15.4 g, 55.8 mmol) in acetone for 10 min. It was stirred vigorously for 15 min, then H20 (200 mL) was added and the product was extracted with EtOAc (2 x 100 mL). The organic layer was washed with H20 (2 x 50 mL), dried (Na2SO4), and evaporated in vacuo to provide 14.0 g, 90.7% green glass. This material was chromatographed on silica gel (50 x 300 mm) elution with CHC13 (1 L), 3% MeOH / CHCl3 (0.5 L), then Hex / EtOAc [1: 1] (1 L) to provide 10.3 g , 67.1% carboxylic acid as a viscous oil: GC / MS: Rt = 7.56 min, m / z 276. (d) Preparation of 4,4-bis (3-fluoro-phenyl) butyryl chloride A mixture of the carboxylic acid (10.3 g, 37.5 mmol) and thionyl chloride (8.20 mL, 112 mmol) was heated to 85 ° C in an oil bath with vigorous stirring for 6 h. The solution was then cooled to room temperature and the excess thionyl chloride was removed by rotary evaporation (1 h, 1 mmHg, 100 ° C) and the residual thionyl chloride was subjected to azeotropy with benzene (2 x 100 mL). This procedure provided the acid chloride as a liquid, 10.5 g, 95.1%. (e) Preparation of 4, 4 -bi s (4-fluorofeni 1) but anamide A solution of the acid chloride (1.75 g, 5.94 mmol) in EtOAc (50 mL) was added dropwise over a period of 15 min to a vigorously stirred solution of aq NH4OH. conc. (2.1 mL, 17.8 mmol, 3 equivalents) in H20 (50 mL). The biphasic mixture was then stirred for 1 h at room temperature. The organic layer was separated and washed with 1M HCl (3 x 25 mL), 1M NaOH (2 x 30 mL) and aq NaCl. sat (2 x 25 L), it was filtered again and the solvent was removed in vacuo, to give the crude product as an oil which crystallized when it remained static. This material was chromatographed on silica gel, eluted with hex / EtOAc (1: 1) followed by 5% MeOH / CHCl 3, the fractions containing the product were poured and evaporated in vacuo to provide 1.13 g, 72.3% yield of the amide as a colorless oil that crystallized when it remained static. TLC Hex / EtOAc [1: 1], Rf 0.23; GC / EIMS, Rt = 64 min m / z 263.

Preparation of 4, 4-bis (3-fluorophenyl) bu so ami da (Compound 11) (a) Preparation of 3,3-bis (3-fluoro-phenyl) -3-hydroxypropyl chloride Cerium hept ahydrate (81.8 g, 220 mmol, 3.0 equivalents) was finely ground in a mortar, then placed in a 1 L flask and heated in a vacuum oven at 130 ° C and 0.1 mmHg for 18 h . The anhydrous cerium chloride was then suspended in THF (400 mL). Then 3-chloropropion t or ethyl (10.0 g, 73.2 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The mixture was then cooled in an ice bath and stirred for 30 min at 0 ° C.

Meanwhile, the Grignard reagent was prepared as follows. In a 3-neck flask of 500 mL, it was added to a suspension of Mg (5.34 g, 220 mmol) in THF (320 mL) 1/20 bromofluorobenzene (39.7 g, 227 mmol) with I2 (1 crystal). The reaction mixture was heated to reflux. After initiation, the rest of the bromide was added dropwise over a period of 10 min. The reaction was then refluxed for 30 min. The solution was cooled to 0 ° C in an ice bath and transferred by cannula to the mixture of cerium chloride and ester in THF over a period of 20 min. The reaction was stirred for 1 h at 0 ° C, then 1 h at room temperature. After 1 h at room temperature, it was cooled in an ice bath, ac HCl was added. to 10% (250 mL), and the layers separated. The aqueous layer was washed with CHC13 (2 x 100 mL). The organic layers were combined and evaporated in vacuo to yield 22.3 g, 108% of a green-brown oil. (b) Preparation of 3,3-bis (3-fluorophenyl) -2-propenyl chloride A solution of 22.3 g, 78.9 mmol of tertiary alcohol was stirred at 100 ° C with conc. HCl. (200 mL) for 1 h. The reaction was then cooled and diluted with H20 (300 mL). The mixture was extracted with CHC13 (4 x 50 mL) and evaporated in vacuo to give the crude product. This material was chro- mated on a 50 x 30 * 0 silica column. mm (elution with Hex / EtOAc (30: 1), then (20: 1). Fractions containing the products were combined and evaporated to provide 11.4 g (54% yield) of the product as a colorless oil. (c) Preparation of 4,4-bis (3-fluoropheni-1) -3-but in-ni toryl 6.94 g, 26.2 mmol of chloride in EtOH (100 mL) was dissolved. KCN (17.1 g, 262 mmol, powder) was added and the reaction mixture was refluxed. After 3 h, the volatiles were evaporated in vacuo. The residue was dissolved in diethyl ether (100 mL), washed with H20 (3 x 25 mL), dried (anhydrous Na2SO4) and evaporated to give the crude product. Chromatography on silica gel (50 x 300 mm), Hex / EtOAc [10: 1] provided 5.05 g, 75.6% yield of a yellow oil. TLC (Hex / EtOAc, [10: 1] Rf = 0.32. (d) Preparation of 4, 4-bis (3-fluorophenyl) -3-butylnitrile . 05 g, 19.8 mmol of alkene was dissolved in EtOH (100 mL). 10% Pd / C was added and the mixture was hydrogenated in a Parr apparatus at .25 ° C, 60 psig. After stirring for 0.5 h, the mixture was filtered through Celite and the filtrate was evaporated in vacuo to yield 4.5 g (88.4%) of a colorless oil. (e) Preparation of 4, 4 -bi s (3- f luorofeni 1) but anamida The nitrile (4.50 g, 17.5 mmol) was dissolved in concentrated H2SO4 (10 mL). The reaction solution was then stirred for 30 min at room temperature. The reaction was then heated to 50 ° C in an oil bath. After 1.75 h at 50 ° C, the reaction solution was poured into a water / ice mixture (100 mL). The solution was extracted with hot EtOAc (8 x 100 mL), dried (Na2SO4) and evaporated in vacuo to give the crude product as a thick oil. This material was chromatographed on silica gel (50 x 300 mm, elution with 5% MeOH / CHCl3) and rechromatographed with 3% MeOH / CHCl3. Evaporation of these fractions containing the product gave 0.771 g, 16.0% of a white powder.

Synthesis of 3, 3-bis (3-fluorophenyl) propanamide (Compound? ±. (a) Preparation of 3, 3-bis (3-fluorophenyl) ethyl acrylate A suspension (under argon) of sodium hydride (3.63 g, 151.2 mmol) in dimethylformamide (DMF, 500 mL) was treated dropwise with a solution of triethyl phosphonoacetate (37.0 g, 165.0 mmol) in DMF (200 mL) . The reaction was heated at 65 ° C for 2 h. After this time, the reaction was cooled to 0 ° C and treated with a solution of 3,3 '-di f luorobenzophenone (30.0 g, 137.5 mmol) in DMF (200 mL).

The reaction was stirred at room temperature for 16 h. The reaction was quenched by the addition of water (1 L) and equilibrated with hexane-ethyl acetate (1: 1, 2 L). The aqueous phase was separated and washed an additional time with hexane-acetate. of ethyl (1: 1, 2 L). The organic phases were combined, washed with brine, dried with anhydrous MgSO 4, filtered and concentrated to provide 38.81 g (98%) of the title compound as a clear, colorless oil. The GC / EI-MS analysis yielded a single component Rt = 6.38 min, m / z (int. Re) 288 (M +, 11), 259 (8), 243 (54), 214 (100), 194 (53 ), 175 (30), 123 (38), 120 (48), 94 (38) and 75 (74). (b) Preparation of ethyl 3, 3-bis (3-fluorophenyl) propionate A solution of 3, 3-bis (3-fluoropheni-1) ethyl ethyl ester (38.81 g, 134.8 mmol) in absolute ethanol (300 mL) was hydrogenated in the presence of palladium hydroxide on carbon (5 g wet, Degasse type). ) at 60 psi H2 for 30 min at room temperature. After this time, the reaction was filtered and concentrated to provide 39.08 g (100%) of the title compound as a clear, colorless oil. The GC / EI-MS analysis yielded a simple component: Rt = 6.21 min, m / z (int. Re.) 290 (M +, 6), 262 (1), 244 (5), 216 (100), 203 ( 67), 201 (48), 183 (63), 101 (41), 96 (17) and 75 (25). (c) Preparation of 3, 3 bis (fluorophenyl) propionic acid A solution of ethyl 3, 3 -bi s (3-fluorophenyl) propionate (39.08 g, 134.8 mmol) in absolute ethanol (500 mL) was treated with 5N NaOH and stirred at room temperature for 16 h. After this time the reaction mixture was concentrated (removal of ethanol) in a rotary evaporator and diluted with water (1 L). The aqueous mixture was washed once with diethyl ether (500 mL) and the remaining aqueous mixture was acidified (pH 1) by the addition of concentrated HCl. The aqueous phase was extracted with methylene chloride (4 x 250 mL). The combined organic extracts were dried with MgSO 4, filtered and concentrated to provide 31.76 g (90%) of the title compound as a white solid. The GC / EI-MS analysis gave a simple component. Rt = 60 min, m / z (int. Re) 262. (M +, 13), 243 (1), 216 (40), 203 (85), 201 (54), 183 (100), 170 (11 ), 121 (31), 101 (43), 96 (24) and 75 (45). (d) Preparation of 3-bis (3-fluorophenyl) propanamide The 3, 3-bi s (f luoro-phenyl-1) propionic acid (31.31 g, 119.5 mmol) was dissolved in thionyl chloride (100 mL) and heated to reflux for 16 h. After this time the excess of chloride of. Thionyl was removed by distillation and the remaining oil, the acid chloride product, was dissolved in dichloromethane (200 mL). The solution of the acid chloride was added dropwise to a stirred solution (-78 ° C) of ammonia (35 mL) in dichloromethane (500 mL), followed by the addition of pyridine (100 mL). The reaction was stirred at room temperature for 1 h and quenched with 10% HCl (500 mL). After equilibration, the aqueous phase was removed and the remaining organic phase was washed with 10% HCl (3 x 500 mL). The organic phase was dried with anhydrous MgSO 4, filtered and concentrated to a solid. The solid was dissolved in diethyl ether (1 L) and washed with IN NaOH (4 x 500 mL), 10% HCl (3 x 500 mL) and brine (500 mL). The organic solution was dried with Anhydrous MgSO 4, filtered and concentrated to a solid (28.24 g). Recrystallization of this material from hot toluene (100 mL, washing with 100 mL of toluene at 0 ° C), gave 25.39 g (81%) of the title compound as a white, crystalline solid: m.p. 103-105 ° C; The GC / EI-MS analysis gave a simple component to Rt = 7.43 min, m / z (int. Re) 261 (M +, 15), 244 (2), 216 (27), 203 (25), 201 (41J, 183 (57), 170 (7), 164 (9), 149 (8), 133 (6) U 21 (52), 111 (15), 109 (20), 101 (41), 96 (27), 95 (2 4), 75 (42) and 44 (100).

Synthesis of . N-tert-butyl-3, 3 -bi s (3-fluorophenyl) propanamide (Compound 5) '' CÍ '-r To a solution at -78 ° C of the acid chloride (5 g, 17.8 mmol) [15.5 mmol present] in CH2C12 (50 mL) was added in a stream of t-butyl amine (5.6 mL 3.91 g, 53.8 mmol, 3 equivalents). The dry ice bath was removed and the reaction mixture was then stirred for 4 h at room temperature. The mixture was then poured into diethyl ether (100 mL) and the organic layer was washed with 1M HCl (4 x 50 mL), 1 M NaOH (3 x 50 mL) and H20 (3 x 50 mL). The organic layer was then filtered (paper), dried (anhydrous Na 2 SO 4), filtered again and the solvent removed under vacuum to provide 4.34 g, 93% of the product as a cream colored powder. TLC analysis: Hex / EtOAc [3: 1], showed a major light spot. This material was recrystallized from EtOH abs. [1: 1] (100 mL) plus EtOH abs. (10 mL, to dissolve) to provide 3.59 g, 76.7% yield of the product as colored needles, light straw. TLC Hex / EtOAc [1: 1], Rf = 0.76; GC / EIMS, Rt = 7.55 min, m / z = 317.

Synthesis of 3, 3-bis (4-fluorophenyl) propanamide (Compound 10J_ (a) P r a p a c i n g 3-b i s (4-fluorophenyl) acrylonitrile Using a nitrogen atmosphere, to a solution of diethyl cyanomethylphosphonate (8.52 g, 48.1 mmol) dissolved in DMF (100 mL) was added NaH (2.02 g, 50.4 mmol, 60% dispersion in mineral oil) in portions during a period of 5 min. The reaction was stirred at 25 ° C for 15 min. Then di-fluorobenzophenone (10 g, 45.8 mmol) was added. and the reaction was stirred 18 h at room temperature. The reaction mixture was then poured into H20 (400 mL) and extracted with CHC13 (7 x 100 mL). The combined organic layers were evaporated in vacuo and the residue redissolved in diethyl ether (150 mL). The ether layer was washed with brine (3 x 100 mL), dried (anhydrous NaSO4), and evaporated in vacuo to provide 9.53 g, 86.3% of the crude product as a light purple solid. GC / EIMS Rt = 6.15 min m / z = 241; TLC: Hex / EtOAc [10: 1] Rf = 34, main light spot, > 95%, clear impurity at the origin. (b) Prepa ration of 3-b i s (4-fluorophenyl) propionitrile A solution of 9.53 g, 39.5 mmol of alkylenitrile dissolved in EtOH (80 mL) was hydrogenated at 60 psig of H2 over 10% Pd (OH) 2 / C (20% Pd, Fluka, 1.90 g. ). After stirring for 8 h, the catalyst was removed by filtration through calcined glass. The solvent in the filtrate was evaporated in vacuo and the crude product was isolated as an oil. This material was chrome-free (50 mm x 300 mm, elution with hexane / ethyl acetate [10: 1] to [8: 1]). The fractions containing the product were combined and evaporated to provide 9.66 g, 100% of the product as a yellow oil. GC / EIMS, Rt = 7.18 min, m / z = 243; TLC (c) Preparation of 3, 3-bis (4-fluorophenyl) propanamide The nitrile (9.66 g, 39.8 mmol) was dissolved in concentrated H2SO4 (12 mL). The reaction solution was then stirred for 15 min at room temperature followed by 15 min at 50 ° C. Water (200 mL) was added to the cooled reaction mixture followed by ethyl acetate (100 mL). The layers were separated and the aqueous layer was extracted with EtOAc (100 mL). The combined organic layers were washed with H20 (2x50 mL), aq NaHCO3. Saturated (50 mL), dried (anhydrous Na2SO4), and evaporated in vacuo to give the crude product. This material was chromatographed (50 x 300 mm, elution with ethyl acetate / hexane [1: 3]). The fractions containing the product were combined and evaporated to provide 2.34 g, 22.5% of the product as a white solid. GC / MS, R t = 7.93 min m / z = 261; TLC: Hex / EtOAc [1: 1], Rf = 0.20, UV / Vis simple light spot; XH-NMR 2.87 (d, J = 8 Hz, 2H), 4.55 (t, J = 8 Hz, 1H), 5.38 (bs, 1H), 5.63 (bs, 1H), 6.94-7.00 (m, 4H), 7.15-7.19 (m, 4H).

Synthesis of 3, 3-bis (3-fluorofen l) clothing of N-xsopropyl (Compound 4) To a solution at -78 ° C of the acid chloride (5 g, 17.8 mmol) [15.5 mmol present] in CH2C12 (50 mL) was added in a stream of isopropylamine (4.6 mL, 3.16 g, 53.5 mmol, 3 equivalents ). The ice bath was removed and the reaction mixture was then stirred for 4 h at room temperature. The mixture was then poured into diethyl ether (100 mL) and the organic layer was washed with 1M HCl (4 x 50 mL), 1M NaOH (3 x 50 mL) and H20 (3 x 50 mL). The organic layer (paper) was then filtered, dried (anhydrous Na 2 SO 4), filtered again, and the solvent removed in vacuo to provide 3.17 g, 71% of the product as a cream-colored powder. TLC analysis: Hex / EtOAc [3: 1], showed a major light spot. This material was recrystallized from absolute EtOH / H20 [1: 1] (60 mL) plus K20 (10 mL to the point of "turbidity) to provide 3.06 g, 68% yield of the product as a white, chalky powder. : Hex / EtOAc [1: 1], Rf = 0.53, GC / EIMS, Rf = 7.55 min, m / z 303.

Synthesis of N-T (3-hydroxy-2-methyl) -2-propyl-3, 3-bis (3-fluorophenyl) -hyphenamide (Compound 6) To a solution at -78 ° C of the acid chloride (5 g, 17.8 mmol (15.5 mmol present) in CH2C12 (50 mL) was added in a stream of ethanolamine (5.1 mL, 4.77 g, 53.5 mmol, 3 equivalents). The ice bath was removed and the reaction mixture was then stirred at room temperature.The mixture was then poured into ethyl acetate (1000 mL) and the organic layer was washed with 1M HCl / saturated, with NaCl (2 x 50 mL), saturated NaOH 1M, with NaCl (2 x 50 mL), and saturated aqueous NaCl (2 x 50 mL). The organic layer (paper) was then filtered, dried (Na 2 SO 4), filtered again, and the solvent removed in vacuo to give ~ 4 g of the product as an almost white powder. TLC analysis: Hex / EtOAc [3: 1], showed a main light spot. This material was recrystallized from absolute EtOH / H20 [1: 1] (50 mL) plus absolute H20 (40 mL, to the point of turbidity) to provide 2. 70 g, 47.6% yield of the product as a white powder. TLC: Hex / EtOAc [1: 1], Rf = 0.27, GC / EIMS Rt = 6.80 min, m / z = 315 (dehydration product), GC / EIMS, unfinished mixture; The analysis of 2H-NMR indicated product present and of high purity.

Synthesis of N-methyl-2, 2-bis (4-fluorophenyl) acetamide (Compound 14) (a) Preparation of 2, 2-bis (4-fluorophenyl) acetic acid A 4, 4 '-dif luorobenzidrol (10.0 g, 45.4 mmol, 1 equivalent) in H2SO. (37 M, 200 mL, 7.4 mol, 160 equivalents) in an ice bath, formic acid (20 mL, 24 g, 0.53 mol, 12 equivalents) was added without stirring. After a few seconds, the evolution of carbon monoxide was observed. The reaction was allowed to stop without stirring for 3.5 h. The reaction mixture was carefully poured into H20 (1000 mL) (highly exothermic). The aqueous mixture was extracted with EtOAc (1 x 250 mL). The organic layer was dried (anhydrous Na 2 SO 4) and rotary evaporated (75 ° C) to yield 11.7 g of an orange oil. This oil was dissolved in Et20 (100 mL) and extracted with 2M NaOH (1 x 50 mL). The aqueous layer was then acidified with 12M HCl (8 mL) and extracted with EtOAc (1 x 50 mL). The organic layer was dried (anhydrous Na 2 SO 4), rotary evaporated (75 ° C) and placed under high vacuum for 16 h. This gave 6.15 g (54.6%) of the product as a yellow, crystalline solid. (b) Preparation of 2,2-bis (4-fluoro-phenyl) -acetyl chloride The carboxylic acid (6.15 g, 24.8 mmol, 1 equivalent) in thionyl chloride (12 mL, 20 g, 160 mmol, 6.6 equivalents) was refluxed under N2 for 2 h. The reaction solution was then evaporated on a rotary evaporator (95 ° C). This provided 6.45 g (97.6%) of the product as an orange-brown oil. (c) Preparation of N-methyl-2, 2-bis (4-fluorophenyl) acetamide It was diluted with H20 (30 mL) methylamine (40% in H20, 1.5 mL, 1.4 g, 0.54 g of amine, 17 mmol, 3.1 equivalents). Acid chloride (1.50 g, 5.62 mmol, 1 equivalent) in EtOAc (30 mL) was added to the vigorously stirred aqueous solution over a period of 3 min. The biphasic reaction mixture was stirred vigorously for 15 min. The organic layer was separated and washed with lM HCl / saturated aqueous NaCl (3 x 10 mL), lM NaOH / saturated aqueous NaCl (2 x 10 mL) and saturated aqueous NaCl (2 x 10 mL). The organic layer was then dried (anhydrous Na 2 SO 4), evaporated on a rotary evaporator and placed under high vacuum for 17 h. This provided 1.19 g (81.0%) of the product as a finely crystalline, almost white solid. This solid was dissolved in EtOAc (25 mL) and filtered through a disc filter. of 0.45 μ. Hexane (25 mL) was added to the filtrate. The crystallized solution was allowed to stand for 15 min. The resulting crystals were filtered, washed with hexane (2 x 25 mL) and dried under high vacuum for 22 h to provide 547 mg (37.2%) of the product as a finely crystalline, white solid.

These and other examples and compounds of the present invention can be readily prepared by those skilled in the art, using similar synthetic methods, analogs and / or homologs known in the art.

Other embodiments are within the following claims.

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

Having described the invention as above, the content of the following is claimed as property.

Claims (30)

1. A compound that has the formula characterized because: And it is independently selected from the group consisting of -H, -F and Cl; X is either -NH ^ 2 or -OR1; R1 is selected from the group consisting of -H, alkyl and hydroxyalkyl; R2 is selected from the group consisting of -H, methyl and ethyl; and n is 0, 1, 2, 3 or 4, except for 3, 3-bis (3-fluorophenyl) propanamide, N-? t? ethyl-3, 3-bis (3-fluorophenyl) propanamide, N-ethyl - 3, 3-bis (3-fluorophenyl) propanamide, N, N-dimethyl-3, 3-bis (3 f 1 uo rof in i 1) pr opanami da and N, N-diethi 1 - 3, 3-bis ( 3 fluorophenyl) propanamide.

2. A compound that has the formula characterized because: each F is independently in the meta-or para- position; R1 is selected from the group consisting of -H, alkyl and hydroxyalkyl; R2 is selected from the group consisting of -H, methyl and ethyl; and n is 0, 1, 2, 3 or 4, except for 3,3-bis (3-fluorophenyl) propanamide, N-methyl-3, 3-bis (3-fluorophenyl) propanamide, N-et il-3, 3-bis (3-fluorophenyl) -propanamide, N, N-dimethyl-3, 3-bis (3 -f luor of in i 1) pr opanami da and N, -diethyl-3, 3-bis (3-fluorophenyl) propanamide.

3. The compound of claim 1, characterized in that R1 is selected from the group consisting of -H, methyl, ethyl, isopropyl, isobutyl, tert-butyl, hydroxyisopropyl and hydroxyethyl, and R2 is -H,

4. A compound that has the formula characterized because n is 0, 1 2; both F are either in the meta- or para- position; R1 is selected from the group consisting of -H, alkyl and hydroxyalkyl; Y R2 is selected from the group consisting of -H, methyl and ethyl, except for 3,3 -bis (3-fluorophenyl) propanamide, N-methyl-3, 3-bis (3-fluorophenyl) propanamide, N-ethyl- 3, 3-bis (3-fluorophenyl) propanamide, N, N-dimethyl-3, 3-bis (3-f 1 uo rof in i 1) pr opanami da and N, N-di eti 1 - 3, 3 - is (3-fluorophenyl) propanamide.

5. The compound of claim 1, characterized in that the compound is selected from the group consisting of compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 , 17 and 18.

6. The compound of claim 1, characterized in that the compound is selected from the group consisting of compound 1, 2, 3, 7, 8, 9, 10, 11, 12, 13, 14, and 15.

7. The compound of claim 1, characterized in that the compound is Compound 1.

8. A method for treating a patient having a disease or neurological condition, characterized in that a compound having the formula is administered where : And it is independently selected from the group consisting of -H, -F and -Cl; X is either -NR'R2 or -OR1; R1 is selected from the group consisting of -H, alkyl and hydroxyalkyl; R2 is selected from the group consisting of -H, methyl and ethyl; and n is O, 1, 2, 3 or 4.

9. The method of claim 8, characterized in that R1 is selected from the group consisting of -H, methyl, ethyl, isopropyl, isobutyl, hydroxyisopropyl and hydroxyethyl and R2 is -H

10. The method of claim 8, characterized in that the compound is selected from the group consisting of the compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 and 18.

11. The method of claim 8, characterized in that the compound is selected from the group consisting of compound 1, 2, 3, 7, 8, 9, 10, 11, 12, 13, 14, and 15.

12. The method of claim 8, characterized in that the compound is Compound 1.

13. A method for treating a patient having a disease or neurological condition, characterized in that it comprises administering a compound having the formula where: each F is independently in the meta-or para- position; R1 is selected from the group consisting of -H, alkyl and hydroxyalkyl; R2 is selected from the group consisting of -H, methyl and ethyl; and n is O, 1, 2, 3 or 4

14. A method for treating a patient having a disease or neurological condition, characterized in that it comprises administering a compound having the formula where: n is 0, 1 or 2 both F are in the meta- or para- position; R1 is selected from the group consisting of -H, alkyl and hydroxyalkyl; Y R2 is selected from the group consisting of -H, methyl and ethyl.

15. The method of claim 8, characterized in that the disease or neurological condition is selected from the group consisting of epilepsy, seizure and crisis conditions.

16. The method of claim 8, characterized in that the treatment of the patient relieves or prevents convulsions in the patient.

17. The method of claim 8, characterized in that the disease or neurological condition is associated with spasticity.

18. The method of claim 15, characterized in that the disease or neurological condition is a disease or neurodegenerative condition

19. The method of claim 8, characterized in that the disease or neurological condition is selected from the group consisting of spasticity, spasms of skeletal muscle, restless legs syndrome, anxiety, tension, multiple sclerosis, attack, head trauma, injury of spinal cord, Parkinson's disease, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, migraine headaches and bipolar disorder.

20. A method for alleviating or preventing a symptom of spasticity, one or more collateral effects of spasticity, in a patient, characterized in that it comprises administering a compound of any of claims 1-4 or 7.

21. A pharmaceutical composition, characterized in that it comprises a compound of claim 1, and a pharmaceutically acceptable carrier.

22. A pharmaceutical composition, characterized in that it comprises a compound of claim 2, and a pharmaceutically acceptable carrier.

23. A pharmaceutical composition, characterized in that it comprises a compound of claim 3, and a pharmaceutically acceptable carrier.

24. A pharmaceutical composition, characterized in that it comprises a compound of claim 4, and a pharmaceutically acceptable carrier.

25. A pharmaceutical composition, characterized in that it comprises a compound of claim 5, and a pharmaceutically acceptable carrier.

26. A pharmaceutical composition, characterized in that it comprises a compound of claim 7, and a pharmaceutically acceptable carrier.

27. A method for making a therapeutic agent, characterized in that it comprises the steps of screening the agent by determining whether the agent alleviates a symptom of spasticity and by synthesizing the therapeutic agent in an amount sufficient to provide the agent in a therapeutically effective amount to a patient.

28. The method of claim 18, characterized in that the therapeutic agent comprises a compound of claim 1

29. A method for modulating CNS activity, characterized in that it comprises administering to a patient a compound of claim 1.

30. The method of claim 29, characterized in that the modulation of the activity of the CNS alleviates a symptom associated with seizures, spasticity, a mood disorder, a neuropathic pain syndrome, a headache, a restlessness syndrome or a condition of movement.