HK1076726A - Highly selective norepinephrine reuptake inhibitors and methods of using the same - Google Patents

Description

Highly selective norepinephrine reuptake inhibitors and uses thereof

The invention relates to a divisional application of Chinese patent application 00808485.8 with the application date of 2000, 6, month and 22, and the invention of the original application is named as a highly selective norepinephrine reuptake inhibitor and a using method thereof.

Background

Technical Field

The present invention relates to methods of treating a variety of disease states in a subject suffering therefrom in which inhibition of reuptake of norepinephrine is beneficial. Specifically, the present invention relates to a method of treatment comprising administering to an individual a compound, such as (S, S) -reboxetine, wherein the compound has a higher pharmacological selectivity for the norepinephrine reuptake site than the serotonin reuptake site. The invention also relates to a composition containing the compound and a preparation method of a medicine containing the composition.

Brief description of the related art

Many types of depression, mental, behavioral and neurological disorders arise from disorders of the brain circuit that use certain monoamine neurotransmitters to convey signals. Monoamine neurotransmitters include, for example, norepinephrine (norepinephrine), serotonin (5-HT), and dopamine. Sub-normal levels of norepinephrine are associated with various symptoms, including a lack of energy, motivation, and life interest. Thus, normal levels of norepinephrine are an element of maintaining beneficial driving force and ability.

These neurotransmitters pass from the end of a neuron across a small cleft (i.e., synaptic cleft), and bind to receptor molecules on the surface of a second neuron. This binding causes intracellular changes that elicit or activate a response or change in the postsynaptic neurons. Inactivation occurs primarily when the neurotransmitter is transported (i.e., reuptake) back to the presynaptic neuron. Abnormalities in noradrenergic transmission lead to various types of depression, psychiatric, behavioral and neurological disorders, which are attributed to a variety of symptoms including a lack of energy, motivation and life interest. See generally r.j. baldesarini "for drugs and treatments of psychiatric disorders: depression and Mania "(" Durgs and The Treatment of psychiatric Disorders: Depression and Mania ", Goodman and Gilman's The Pharmacological Basis of Therapeutics, McGraw-Hill, NY, NY, pp.432-439 (1996)).

Reboxetine (i.e., 2- [ (2-ethoxyphenoxy) (phenyl) methyl ] morpholine) increases the concentration of physiologically active norepinephrine, for example, by preventing reuptake of norepinephrine. Reboxetine is a norepinephrine reuptake inhibitor and has been shown to be effective for both short-term (i.e., less than eight weeks) and long-term treatment of depression. In fact, reboxetine has been shown to have efficacy similar to the well-established antidepressants fluoxetine, imipramine and desipramine in both adult and elderly patients. See s.a. montgomery "reboxetine: additional Benefits for depressed patients "[ psychopharmacology ] (Rebotatine: Additional peptides to the depressed Patient) (Oxf) 11: 4 suppl, S9-15 (abstract) (1997).

Antidepressants are sometimes divided into several "generations". The first generation includes monoamine oxidase inhibitors (e.g., isocarboxazid and phenylhydrazine) and tricyclic drugs (e.g., imipramine). Second generation antidepressants include compounds such as mianserin and trazodone. The third generation includes drugs known as selective reuptake inhibitors (e.g., fluoxetine, sertraline, paroxetine, and reboxetine). Such drugs are characterized by relatively selective effects on only one of the three major monoamine systems believed to be associated with depression, namely 5-HT (serotonin), noradrenaline (norepinephrine) and dopamine. Textbook of APP psychopharmacology (APP Textbook of Psychopharmacology) (A.F. Schatzberg and C.B. Nemeroff), American Psychiatric Press, 2d.ed., (1998); a thesaurus of psychiatry, Neurology and neuroscience (Lexicon of psychiatry, Neurology and neurosciences) (F.J.Ayd, Jr.) Williams and Wilkins (1995). Evidence for the therapeutic efficacy of reboxetine in antidepressant is its ability to prevent resperine-induced blepharospasm and hypothermia, beta-adrenergic receptor down-regulation, and desensitization of norepinephrine-coupled adenylate cyclase in mice. See M.Brunello and G.Racagni "principles of development of Inhibitors for norepinephrine Reuptake" [ human psychopharmacology ] ("ratio for the development of Noradrenaline Reuptake Inhibitors", HumanPsychopharmacology), vol.13, S-13-519, Supp.13-519 (1998).

Desipramine, maprotiline and lofepramine are relatively selective norepinephrine reuptake inhibitors with reliable efficacy according to the Brian e.leonard survey. These drugs increase norepinephrine and can alleviate depression. Mianserin and mirtazapine rely on blocking presynaptic alpha₂Adrenoreceptors, increasing the availability of noradrenaline, also showing antidepressant-like effects. Furthermore, oxaprotiline, fezolamine and tomoxetine are potent selective norepinephrine reuptake inhibitors that lack neurotransmitter receptor interactions and therefore do not cause many of the side effects characteristic of classical tricyclic antidepressants. See Brian E.Leonard "Review of The role of norepinephrine in Depression" [ Journal of psychopharmacology ] ("The Roleof Noradrenaline in Depression: A Review", Journal of Psychopharmacology), "vol.11, No.4(Suppl.), pp.S39-S47 (1997).

Reboxetine is also a selective norepinephrine reuptake inhibitor, producing fewer side effects associated with the administration of classical tricyclic antidepressants. Evidence for the therapeutic efficacy of reboxetine in antidepressant is its ability to prevent resperine-induced blepharospasm and hypothermia, beta-adrenergic receptor down-regulation, and desensitization of norepinephrine-coupled adenylate cyclase in mice. See m.brunello and g.racagni "principles of Development of noradrenaline Reuptake Inhibitors" human psychopharmacology ("ratio for the Development of noradrenaline Reuptake Inhibitors", HumanPsychopharmacology), vol.13(Supp.)13-519 (1998).

Reboxetine is generally described in Melloni et al U.S. Pat. Nos.4,229,449, 5,068,433 and 5,391,735 and GB2,167,407, the disclosures of which are incorporated herein by reference. Chemically, reboxetine has two chiral centers and thus two enantiomeric pairs of diastereomers exist, as shown in the following isomers (I) to (IV):

(R, R)2- [ (2-ethoxyphenoxy) (phenyl) methyl ] morpholine

(S, S)2- [ (2-ethoxyphenoxy) (phenyl) methyl ] morpholine

(R, S)2- [ (2-ethoxyphenoxy) (phenyl) methyl ] morpholine

(S, R)2- [ (2-ethoxyphenoxy) (phenyl) methyl ] morpholine

Many organic compounds exist in optically active form, i.e., they have the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes R and S are used to designate the absolute configuration of the molecule with respect to its chiral center. The prefixes D and L or (+) and (-) specify the sign of rotation of the compound's plane-polarized light, L or (-) indicating that the compound is levorotatory. In contrast, compounds with the prefix D or (+) are dextrorotatory. There is no correlation between nomenclature for absolute stereochemistry and enantiomeric rotation. Thus, D-lactic acid is identical to (-) -lactic acid, and L-lactic acid is identical to (+) -lactic acid. With respect to a given chemical structure, each pair of enantiomers are identical, but they are non-overlapping mirror images of each other. Particular stereoisomers may also be referred to as enantiomers, and mixtures of such isomers are often referred to as enantiomeric or racemic mixtures.

Stereochemical purity is of great importance in the pharmaceutical field, and chirality is present in many of the most commonly used drugs. For example, the L-enantiomer of the beta-adrenergic blocker propranolol is known to be 100-fold more potent than its D-enantiomer. In addition, optical purity is of great importance in the pharmaceutical field, since it has been found that certain isomers bring about harmful effects, rather than advantageous or inert effects. For example, the D-enantiomer of thalidomide is believed to be a safe and effective sedative when used to control nausea in pregnant women during pregnancy, while its corresponding L-enantiomer is believed to have potent teratogenic effects.

When two chiral centers are present within a molecule, there are four possible stereoisomers: (R, R), (S, S), (R, S) and (S, R). Where (R, R) and (S, S) are examples of a pair of enantiomers (mirror images of each other), they generally share chemical properties and melting points, just like any other enantiomer pair. However, the mirror images of (R, R) and (S, S) may not be superimposed on top of (R, S) and (S, R). This relationship is referred to as diastereomeric, the (S, S) molecule is a diastereomer of the (R, S) molecule, and the (R, R) molecule is a diastereomer of the (S, R) molecule.

Currently, reboxetine is only commercially available as a 1: 1 racemic mixture of enantiomers (R, R) and (S, S), and the generic name "reboxetine" referred to herein refers to such enantiomeric or racemic mixtures. A commercially available commercial product of reboxetine is EDRONAX^TM、PROLIFT^TM、VESTRA^TMAnd NOREBOX^TM. As mentioned above, reboxetine has been shown to be useful in the treatment of depression in humans. Reboxetine for oral administration is readily absorbed and once or twice daily administration is required. Preferred daily dosages for adults range from about 8 to about 10 milligrams (mg). The effective daily dose of reboxetine for children is small, typically in the range of about 4 to about 5 mg. However, the optimal daily dosage for each patient must be determined by the attending physician after considering the patient's weight, other medications that the patient may take, the nature and severity of the particular disorder, and all other conditions of the patient.

However, administration of reboxetine may result in undesirable side effects associated with drug-drug interactions and other undesirable effects such as dizziness, insomnia, dizziness, changes in blood pressure, sweating, gastrointestinal disorders, male sexual dysfunction, certain anticholinergic-like effects (e.g., tachycardia and urinary retention). It has been found that such side effects occur in part because reboxetine lacks sufficiently high selectivity for inhibiting norepinephrine reuptake. In other words, reboxetine blocks the reuptake of other monoamines, like serotonin and dopamine, to a sufficient extent to cause unwanted side effects.

Other antidepressants have been reported to have a high pharmacological selectivity for inhibiting norepinephrine reuptake. For example, oxaprotiline is pharmacologically selective with respect to inhibition of norepinephrine reuptake, K compared to serotonin reuptake_iThe ratio of values is about 4166. The corresponding pharmacological selectivity is about 377 for desipramine and about 446 for maprotiline. See Elliott Richelson and Michael Pfenning "antidepressants and related compounds block biogenic amine uptake by rat brain synaptosomes: most antidepressants selectively block norepinephrine uptake"European Journal of Pharmacology" ("Block by inhibitors and Related Compound genomic Amine Uptake in Rat Brain synoptomes: Mostinhibitors Selectively Block Norepipineph Uptake", European Journal of Pharmacology), vol.14, pp.277-286 (1984). Although hydroxypropiophilin, desipramine and maprotiline have relatively high selectivity, these, together with other known drugs, undesirably block other neurotransmitter receptors to a sufficient extent to also cause adverse side effects.

Accordingly, there is a need in the art for methods of treating a variety of disease states in an individual with a disease in which inhibition of reuptake of norepinephrine provides a benefit, while reducing or eliminating the adverse side effects associated with conventional norepinephrine reuptake inhibitors. There is also a need for methods of selectively inhibiting the reuptake of norepinephrine, but not other neurotransmitters, like serotonin and dopamine. In particular, there is a need in the art for highly selective (at one reuptake site), specific (inactive against other receptors) and potent norepinephrine reuptake inhibitors. In addition, there is a need for pharmaceutical compositions containing highly selective and potent norepinephrine reuptake inhibitors. Furthermore, there is a need for medicaments comprising such pharmaceutical compositions, and the use of such compositions in the manufacture of such medicaments.

Summary of The Invention

The present invention relates generally to compositions and methods for treating or preventing a variety of human conditions in which inhibition of norepinephrine reuptake would be beneficial, and more particularly where selective, specific and effective inhibition of norepinephrine would be beneficial. More specifically, the present invention relates to the effective treatment or prevention of such disorders comprising administering to a human a compound such as reboxetine or its optically pure (S, S) stereoisomer.

Accordingly, one embodiment of the present invention is directed toAnd a method of selectively inhibiting norepinephrine reuptake comprising the step of administering to a subject a therapeutically effective amount of a composition comprising a compound which is serotonin (K)_i) Noradrenaline (K)_i) Is at least about 5,000, preferably at least about 10,000, more preferably at least about 12,000.

Another embodiment of the invention is directed to a method of treating a human having a disorder or preventing the disorder wherein inhibition of reuptake of norepinephrine provides a benefit, comprising the step of administering a therapeutically effective amount of a composition comprising a compound whose serotonin (K) is a member of the group_i) Noradrenaline (K)_i) Is at least about 5,000, preferably at least about 10,000, more preferably at least about 12,000.

Another embodiment of the invention relates to the preparation of a medicament from a composition comprising a compound, serotonin (K)_i) Noradrenaline (K)_i) Has a pharmacological selectivity of at least about 5,000, preferably at least about 10,000, more preferably at least about 12,000, for use in the treatment or prevention of at least one nervous system disorder selected from the group consisting of: addictive disorders (including those caused by alcohol, nicotine and other psychotropic substances) and de-addiction syndrome, adjustment disorders (including depressive mood, anxiety, mixed anxiety and depressive mood, behavioral disorders, and mixed behavioral and mood disorders), age-related learning and mental disorders (including Alzheimer's disease), anorexia nervosa, apathy, attention-deficit (or other cognitive) disorder caused by general medical conditions, attention-deficit hyperactivity disorder (ADHD), bipolar disorders, bulimia nervosa, chronic fatigue syndrome, chronic or acute stress, chronic pain, behavioral disorders, cyclothymic disorders, depression (including adolescent depression and unrepression), dysthymia, fibromyalgia and other psychotropic disorders (including symptomatic somatization disorder), and mood disorders, Transition disorder, pain disorder, hypochondriacal disorder, physical disorder with no difference, somatoform disorderPsychiatric disorders and somatoform NOS), Generalized Anxiety Disorder (GAD), incontinence (i.e., stress incontinence, genuine stress incontinence and mixed incontinence), inhalation disorders, toxicosis (alcohol addiction), mania, migraine, obesity (i.e., reduction of body weight in obese or overweight patients), obsessive-compulsive disorders and related disorders, oppositional disorders, panic disorders, peripheral neuropathy, post-traumatic stress disorder, premenstrual dysphoric disorder (i.e., premenstrual syndrome and late luteal phase anxiety disorder), psychosis (including schizophrenia, schizoaffective disorder and schizophreniform disorder), social phobias (including social anxiety disorder), specific developmental disorders, Selective Serotonin Reuptake Inhibition (SSRI) "fatigue" syndrome (i.e., after an initial satisfactory response to SSRI therapy, patients fail to maintain a satisfactory response) and TIC disorders (i.e., tourette's disease).

Another embodiment of the invention relates to the use of a composition comprising a compound of serotonin (K) for the manufacture of a medicament_i) Noradrenaline (K)_i) Has a pharmacological selectivity of at least about 5,000, preferably at least about 10,000, more preferably at least about 12,000, for use in the treatment or prevention of at least one of the above-mentioned nervous system disorders.

Serotonin (K)_i) Noradrenaline (K)_i) An example of a compound having a pharmacological selectivity of at least about 5,000 is optically pure (S, S) reboxetine, substantially free of its (R, R) stereoisomer. Individuals treated with optically pure (S, S) reboxetine do not experience the adverse side effects associated with administration of the racemic mixture of (R, R) and (S, S) reboxetine. The present invention therefore encompasses the administration of optically pure (S, S) reboxetine to humans to selectively inhibit the reuptake of norepinephrine, thereby controlling, reducing or eliminating the adverse effects caused by reboxetine racemate administration.

More specifically, another embodiment of the invention relates to a method of treating or preventing a condition in a human wherein inhibition of reuptake of norepinephrine results in a benefit. The method includes the step of administering a therapeutic amount, typically from about 0.5 to about 10 mg/day, of optically pure (S, S) reboxetine or pharmaceutically acceptable salt thereof. The optically pure (S, S) reboxetine is substantially free of (R, R) reboxetine.

Optically pure (S, S) reboxetine is superior to previous therapeutic or prophylactic methods that employ racemic mixtures of (R, R) and (S, S) reboxetine. Specifically, it has been found that the use of a composition comprising optically pure (S, S) reboxetine inhibits norepinephrine reuptake by a factor of about 5 to about 8.5 times greater than a composition comprising a racemic mixture of (R, R) and (S, S) reboxetine. Thus, a blocking effect of reuptake can be achieved with a lower dose. Thus, due to the use of optically pure (S, S) reboxetine, the present invention can greatly reduce the customary daily dose of racemic mixtures (i.e., commercially available reboxetine) by about 50% to about 80%. In addition, treatment with optically pure (S, S) reboxetine can result in fewer undesirable treatment-related adverse side effects because of the higher selectivity and potency of (S, S) reboxetine with respect to inhibiting norepinephrine reuptake.

Another embodiment of the present invention relates to a method of treating or preventing a nervous system disorder, comprising the step of administering to a subject a therapeutically effective amount of racemic reboxetine, wherein the disorder is at least one of an adaptive disorder, an age-related learning and mental disorder, anorexia nervosa, apathy, an attention-deficit disorder elicited by general medical conditions, bipolar disorders, bulimia nervosa, chronic fatigue syndrome, chronic or acute stress, chronic pain, cyclothymic disorder, dysthymic disorder, fibromyalgia and other somatoform disorders, incontinence, mania, migraine, obesity, peripheral neuropathy, post-traumatic stress disorder, premenstrual dysphoric disorder, a psychotic disorder, a seasonal affective disorder, a sleep disorder, a specific developmental disorder, SSRI "poop out" syndrome, and TIC disorder. Other embodiments of the present invention relate to the preparation of a medicament from a composition comprising reboxetine and the use of reboxetine in the manufacture of a medicament for the treatment or prevention of at least one of the above-mentioned nervous system disorders.

Additional benefits and features of the present invention will become apparent to those skilled in the art upon review of the following detailed description when taken in conjunction with the examples and appended claims. It should be noted, however, that while the present invention is susceptible of embodiment in various forms, there is described hereinafter a specific preferred embodiment of the invention with the understanding that the present disclosure is to be considered an exemplification and is not intended to limit the invention to the specific embodiment illustrated herein.

Detailed description of the preferred embodiments

Reboxetine is a known compound that is active in the central nervous system and has been used as an antidepressant. To date, the use of reboxetine has been limited to the treatment of depression, oppositional disorders, attention deficit/hyperactivity disorder, and behavioral disorders. These suggested treatments are disclosed in international patent publications nos. WO 99/15163, WO 95/15176 and WO 99/15177. These methods of treatment are limited to the administration of racemic mixtures of (S, S) and (R, R) reboxetine stereoisomers.

Reboxetine does not function as well as most antidepressants. Unlike tricyclic antidepressants, and even Selective Serotonin Reuptake Inhibitors (SSRIs), reboxetine is ineffective in the 8-OH-DPAT hypothermia test, indicating that reboxetine is not an SSRI. Brian E.Leonard "norepinephrine in basic depression model" ("Noradrenaline in basic models of depression" ("Depression", European-Neuropsychopharmacol), 7 suppl.1 pp.S11-6 and S71-3 (1997.4.). Reboxetine is a selective norepinephrine reuptake inhibitor with only minimal serotonin reuptake inhibitory activity and no dopamine reuptake inhibitory activity. Reboxetine showed no anticholinergic binding activity in different animal models and was essentially devoid of monoamine oxidase (MAO) inhibitory activity. Serotonin (K) expressed by racemic reboxetine_i) NorAdrenalin (K)_i) Has a pharmacological selectivity of about 80. K_iThe values are discussed in detail below.

Another embodiment of the invention encompasses a method for selectively inhibiting norepinephrine reuptake comprising the step of administering to a subject a therapeutically effective amount of a composition comprising a compound which is serotonin (K)_i) Noradrenaline (K)_i) Is at least about 5,000, preferably at least about 10,000, more preferably at least about 12,000.

Another embodiment of the invention relates to a composition comprising a compound, serotonin (K)_i) Noradrenaline (K)_i) Is at least about 5,000, preferably at least about 10,000, more preferably at least about 12,000. The compositions of the invention are useful in the treatment or prevention of diseases, disorders, and conditions (described in detail below) in which inhibition of norepinephrine reuptake is beneficial. An example of such a compound is the optically pure (S, S) stereoisomer of reboxetine or a pharmaceutically effective salt thereof.

To determine the degree of selectivity of binding of a compound to the norepinephrine reuptake site, the inhibition constant (or K) of the compound with respect to the serotonin reuptake site is determined_iValue) divided by K for the norepinephrine reuptake site_iThe value is obtained. K for norepinephrine reuptake_iLower values indicate a higher binding affinity for the noradrenaline receptor. Serotonin (K)_i) Noradrenaline (K)_i) A higher ratio indicates a higher selectivity with respect to binding to the norepinephrine receptor. Thus, the present invention relates to a composition comprising a compound, serotonin (K) thereof_i) Noradrenaline (K)_i) Is at least about 5,000, preferably at least about 10,000, more preferably at least about 12,000, as described above. Furthermore, it is conceivable that selectivity values well in excess of 12,000 are also beneficial, e.g., 25,000, 50,000, 75,000, even 100,000 or more.

The compositions of the present invention, when used in effective amounts in accordance with the present invention, are selective with respect to the site of norepinephrine reuptake but do not result in significant receptor blockade associated with undesirable side effects, such as receptors for serotonin and dopamine. In other words, the amount of the composition of the invention that inhibits norepinephrine reuptake is essentially ineffective in causing blockade of other neurotransmitter receptors. Inhibition constants (K) according to the enzyme reactions of Y.C.Cheng and W.H.Prusoff_i) With Inhibitor Concentration (IC) resulting in 50% inhibition₅₀) Relationship Between them "[ Biochemical pharmacology ] (" Relationship Between Between and the inhibition Constant (K)_i)andthe Concentration of Inhibitor Which Cause 50％Inhibition(IC₅₀) of an Enzymatic Reaction ", Biochemical Pharmacology), vol.22, pp.3099-3108(1973), from IC₅₀Value calculation inhibition constant (K)_iValues), typically expressed in nanomolar units (nM).

Another embodiment of the invention relates to an effective method of treating or preventing a disorder using an optically pure (S, S) stereoisomer of reboxetine, wherein inhibition of norepinephrine reuptake is beneficial. (S, S) reboxetine is a potent, selective inhibitor of norepinephrine reuptake, and therefore can be substantially reduced in dosage levels compared to racemic reboxetine. In addition, individuals treated with optically pure (S, S) reboxetine do not experience certain adverse side effects associated with administration of a racemic mixture of (R, R) and (S, S) reboxetine. Accordingly, another embodiment of the invention comprises administering a therapeutic amount of optically pure (S, S) reboxetine to a human to inhibit the reuptake of norepinephrine and control, reduce or eliminate the adverse effects associated with the administration of racemic reboxetine.

Another embodiment of the invention relates to a method of treating or preventing a condition in a human wherein inhibition of reuptake of norepinephrine results in a benefit. The method comprises the step of administering, preferably orally, to the subject an optically pure (S, S) reboxetine or pharmaceutically acceptable salt thereof in a total dose of about 0.1 mg/day to about 10 mg/day, more preferably about 0.5 to about 10 mg/day.

The term "reboxetine" as used herein refers to a racemic mixture of the (R, R) and (S, S) enantiomers of reboxetine. In contrast, the term "(S, S) reboxetine" refers only to the (S, S) stereoisomer. Similarly, the term "(R, R) reboxetine" refers only to the (R, R) stereoisomer.

The phrases "optically pure (S, S) reboxetine" and "substantially free of its (R, R) stereoisomer" as used herein mean that the composition contains a greater proportion of (S, S) reboxetine relative to (R, R) reboxetine. In a preferred embodiment, these phrases indicate that the composition contains at least 90 weight percent (wt.%) of (S, S) reboxetine and 10 wt.% or less of (R, R) reboxetine. In a more preferred embodiment, these phrases indicate that the composition contains at least 97 wt.% of (S, S) reboxetine and 3 wt.% or less of (R, R) reboxetine. In yet a more preferred embodiment, these phrases indicate that the composition contains at least 99 wt.% of (S, S) reboxetine and 1 wt.% or less of (R, R) reboxetine. In a most preferred embodiment, the phrases "optically pure (S, S) reboxetine" and "substantially free of its (R, R) stereoisomer" as used herein mean that the composition contains more than 99 wt.% of (S, S) reboxetine. The above percentages are based on the total amount of reboxetine present in the composition. The phrases "substantially free of (R, R) reboxetine", "substantially optically pure (S, S) stereoisomer of reboxetine", "substantially optically pure (S, S) reboxetine", "optically pure (S, S) stereoisomer of reboxetine" and "optically pure (S, S) reboxetine" are also encompassed by the above amounts.

The phrase "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to salts prepared from pharmaceutically acceptable acids or bases, including organic and inorganic acids and bases. Since the active compound used in the present invention, i.e. (S, S) reboxetine, is basic, salts can be prepared from pharmaceutically acceptable acids. Suitable pharmaceutically acceptable acids include acetic acid, benzenesulfonic acid (benzenesulfonate), benzoic acid, p-bromophenylsulfonic acid, camphorsulfonic acid, carbonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid (methanesulfonate), mucic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid and the like. Examples of such pharmaceutically acceptable salts of (S, S) reboxetine thus include, but are not limited to, acetate, benzoate, beta-hydroxybutyrate, bisulfate, bisulfite, bromide, butyne-1, 4-dioate, hexanoate, chloride, chlorobenzoate, citrate, dihydrogenphosphate, dinitrobenzoate, fumarate, glycolate, heptanoate, hexyne-1, 6-dioate, hydroxybenzoate, iodide, lactate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, oxalate, phenylbutyrate, phenylpropionate, phosphate, phthalate, phenylacetate, dihydrogenate, dihydrogenbenzoate, dihydrogenphosphate, dihydrogensulfate, fumarate, glycolate, heptanoate, hexyne-1, 6-dioate, hydroxybenzoate, iodide, lactate, maleate, malonate, propanesulfonates, propiolates, propionates, pyrophosphates, pyrosulfates, sebacates, suberates, succinates, sulfates, sulfites, sulfonates, tartrates, xylenesulfonates, and the like. The preferred (S, S) reboxetine drug salt is the mesylate salt, which is prepared using methanesulfonic acid.

The phrases "side effects", "adverse effects" and "adverse side effects" related to reboxetine include, but are not limited to, dizziness, insomnia, dizziness, changes in blood pressure, gastrointestinal disorders, male sexual dysfunction, extrapyramidal side effects, certain anticholinergic-like effects (e.g., tachycardia, blurred vision) and unwanted side effects associated with drug-drug interactions.

The verbs "treat" and noun "treat" as used herein refer to: (a) preventing the occurrence of a disease, disorder or condition in a human who may have a previous predisposition to the disease, disorder and/or condition, but has not yet been diagnosed as diseased; (b) inhibiting the disease, disorder or condition, i.e., arresting its development; and (c) alleviating, i.e., causing regression of, the disease, disorder or condition. In other words, the verbs "treatment" and the noun "treatment" extend to prophylaxis, in other words the verbs "prophylaxis" and the noun "prophylaxis" and treatment of established disorders. Thus, use of the verbs "prevent" and the noun "prevent" would be to administer a pharmaceutical composition to a person who had previously suffered from a condition described above, such as migraine, but who did not suffer from the condition at the time the composition was administered. For the sake of brevity, the term "disorder" as used hereinafter encompasses conditions, diseases and disorders.

The methods and compositions of the invention are useful for treating a condition in a human wherein inhibition of reuptake of norepinephrine results in a benefit. The method comprises the step of administering, preferably orally, a sufficient amount of a compound of the invention to a subject to provide a total dose of the selective compound of from about 0.1 to about 10 mg/day.

More particularly, administration of the compositions of the present invention (e.g., compositions containing optically pure (S, S) reboxetine) is effective for the treatment of a variety of human conditions, including, but not limited to, addictive disorders (including those caused by alcohol, nicotine, and other psychotropic substances) and de-addiction syndrome, adaptive disorders (including depressive mood, anxiety, mixed anxiety and depressive mood, behavioral disorders, and mixed behavioral and mood disorders), age-related learning and mental disorders (including Alzheimer' S disease), anorexia nervosa, apathy, attention-deficit (or other cognitive) disorder caused by general medical conditions, attention-deficit hyperactivity disorder (ADHD), bipolar disorders, bulimia nervosa, chronic fatigue syndrome, chronic or acute stress, chronic pain, behavioral disorders, cyclothymic disorder, attention-deficit disorder (ADHD), attention-deficit hyperactivity disorder (ADHD), bipolar disorder, chronic fatigue syndrome, chronic or acute stress, chronic pain, behavioral disorders, and other disorders of the, Depression (including adolescent depression and minor depression), dysthymia, fibromyalgia and other somatoform disorders (including somatoform, transition, pain, hypochondriasis, somatoform, undifferentiated somatoform and somatoform NOS), Generalized Anxiety Disorder (GAD), incontinence (i.e., stress incontinence, genuine stress incontinence and mixed incontinence), inhalation disorders, intoxication (alcohol addiction), mania, migraine, obesity (i.e., reduction of body weight in obese or overweight patients), a range of disorders in which obsessive-compulsive disorders are implicated, oppositional disorders, panic disorders, peripheral neuropathy, post-traumatic stress disorder, premenstrual dysphoric disorder (i.e., premenstrual syndrome and late luteal anxiety disorder), psychosis (including schizophrenia, schizoaffective disorder and schizophreniform disorder), Social phobia (including social anxiety disorder), specific developmental disorders, Selective Serotonin Reuptake Inhibition (SSRI) "tiredness" syndrome (i.e., the patient's inability to maintain a satisfactory response after an initial satisfactory response period to SSRI therapy), and TIC disorders (i.e., tourette's disease).

Administration of the compositions of the present invention is very effective for the treatment of the following conditions: addictive disorders and withdrawal syndromes, adaptive disorders, apathy, attention-deficit hyperactivity disorder, attention-deficit disorder caused by medical conditions, bulimia nervosa, chronic fatigue syndrome, chronic or acute stress, depression, dysthymia, Generalized Anxiety Disorder (GAD), nicotine addiction, panic disorder, post-traumatic stress disorder, premenstrual dysphoric disorder, schizoaffective disorder, and SSRI "tired out" syndrome. Furthermore, administration of (S, S) reboxetine is particularly effective for the treatment or prevention of the following conditions: addictive disorders and withdrawal syndromes, apathy, attention-deficit hyperactivity disorder, attention-deficit disorder caused by medical conditions, chronic fatigue syndrome, chronic or acute stress, dysthymia, depression, nicotine addiction, obesity, post-traumatic stress disorder, and SSRI "tiredness" syndrome.

Treatment of "nicotine addiction" as used herein also includes treatment for smoking cessation. Many of the above human conditions are generally described in publications of the American psychiatric society, entitled "handbook of diagnosis and statistics of mental disorders" (Diagnostic and Statistical Manual of mental disorders ") 4 th edition (Washington D.C.1994), the disclosure of which is incorporated herein by reference. General descriptions of addictive disorders, including those involving toxicosis and addiction to nicotine by inhalants, may be found in a number of standard references, such as R.E. Hales et al, American psychiatric edition, psychiatric Textbook ("The American psychiatric Press Textbook of Psychiatry") 3 rd edition (1999), The disclosure of which is incorporated herein by reference.

The compositions of the present invention may also be used to treat migraine. In addition, the compositions of the present invention may be used to treat headaches in migraine sufferers or persons suffering from migraine headaches, including treatment of existing headache symptoms, prevention of headache onset, enhancement and duration of treatment, prophylactic use to prevent or reduce the incidence or duration of migraine, efficacy as an adjuvant to facilitate abortive drug therapy or co-administration with other drug therapies, including abortive drug therapy, to reduce the dosages (and side effects) required for these drug therapies.

A preferred embodiment of the composition of the present invention comprises (S, S) reboxetine. Commercially available reboxetine is known to be a racemic mixture of the (R, R) and (S, S) enantiomers of 2- [ (2-ethoxyphenoxy) (phenyl) methyl ] morpholine. It has now been found that the (S, S) stereoisomer is the most active and selective stereoisomer with respect to inhibiting reuptake of norepinephrine. In addition, when administered to an individual in optically pure form (i.e., substantially free of its (R, R) diastereomer) at the dosages described herein, the individual does not experience many of the adverse side effects associated with the administration of commercially available reboxetine. Furthermore, it has further been found that the (S, S) and (R, R) enantiomers have opposite activity on norepinephrine neurotransmitter relative to serotonin neurotransmitter, and that optically pure (S, S) reboxetine is much more effective in inhibiting norepinephrine reuptake than either the (R, R) enantiomer or the racemic mixture of the (S, S) and (R, R) enantiomers.

In particular, it has been found that compositions containing optically pure (S, S) reboxetine are about 5 to about 8.5 times more effective in inhibiting norepinephrine reuptake than compositions containing racemic mixtures of the (R, R) and (S, S) stereoisomers. Thus, when using optically pure (S, S) reboxetine, a typical daily dose of the racemic mixture (i.e. commercially available reboxetine) can be reduced by about 50% to about 80%. Reduction of the dosage did not result in a reduction in efficacy, but various adverse side effects were observed to be reduced or eliminated.

In particular, because optically pure (S, S) reboxetine selectively inhibits the reuptake of norepinephrine as compared to the reuptake of serotonin, the adverse side effects associated with serotonin reuptake are reduced or eliminated. Such adverse side effects include, but are not limited to, gastrointestinal disturbances, anxiety, sexual dysfunction, and unwanted side effects associated with drug-drug interactions.

The synthesis of racemic mixtures of reboxetine is disclosed in Melloni et al, U.S. patent No.4,229,449. The resolution of the racemic mixture of enantiomers can be carried out using conventional methods well known to those skilled in the art to obtain the various stereoisomers of reboxetine. Such methods include, but are not limited to, resolution by simple crystallization and chromatographic processes, such as described in GB2,167,407.

While it is possible to administer a highly selective norepinephrine reuptake inhibitor directly without any formulation, the composition is preferably administered in the form of a medicament comprising a selective norepinephrine reuptake inhibitor. The compositions of the present invention may be administered in oral unit dosage forms, such as tablets, capsules, pills, powders or granules. The compositions of the invention may also be administered parenterally (e.g., subcutaneously, intravenously or intramuscularly) using dosage forms known in the pharmaceutical art. The compositions of the present invention may further be administered rectally or vaginally in dosage forms such as suppositories or rods. The compositions of the invention may also be administered by topical or transdermal means, by means of "patches" containing the active ingredient. Transdermal delivery patches may be used to provide continuous, pulsed or on-demand delivery of the compositions of the present invention in controlled amounts. The construction and use of transdermal delivery patches are well known in the pharmaceutical arts, for example, as described in U.S. Pat. Nos.3,742,951, 3,797,494, 3,996,934, 4,031,894, and 5,023,252.

It may be desirable or necessary to introduce a composition of the invention or a pharmaceutical composition containing a selective norepinephrine reuptake inhibitor directly or indirectly into the brain. Direct procedures typically involve the placement of a suitable drug-releasing catheter within the ventricular system to bypass the blood-brain barrier. One such suitable delivery system for the transport of biological agents to specific anatomical sites of the body is described in U.S. Pat. No.5,011,472, the disclosure of which is incorporated herein by reference.

In general, the preferred route of administration of the compositions of the present invention is oral, once or twice daily. The dosage regimen and amount of the compositions of the present invention for treating a patient will be selected in accordance with a variety of factors including, for example, the type, age, body weight, sex and physical condition of the patient, the severity of the condition, the route of administration and whether the particular compound employed is a racemate or a pure enantiomer. An ordinarily skilled physician or psychiatrist can readily determine and prescribe an effective (i.e., therapeutic) amount of the compound to prevent or arrest the progress of the condition. In this process, the physician or psychiatrist may first use a relatively low dose, and then increase the dose until a maximal response is obtained.

Pharmaceutical compositions suitable for oral administration may be in any convenient dosage form, for example, cachets, tablets, capsules, pills or aerosols, each containing a predetermined amount of powder or granules of the active compound, or a solution or suspension in an aqueous liquid, a non-aqueous liquid, or an oil-in-water or water-in-oil emulsion. Such compositions may be prepared according to any method, including the step of bringing into intimate association the active compound with a carrier, which carrier constitutes one or more necessary or desirable ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired dosage form.

For example, tablets may be prepared by compression or molding processes, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing the active ingredient in a suitable machine in a free-flowing form such as a powder or granules. The compressed free-flowing form may then optionally be mixed with binders, diluents, lubricants, disintegrants, effervescent agents, dyes, sweeteners, wetting agents and non-toxic pharmacologically inactive substances which are normally present in pharmaceutical compositions. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

Binders suitable for use in pharmaceutical formulations include, for example, starch, gelatin, methyl cellulose, acacia, tragacanth and polyvinylpyrrolidone. Diluents suitable for use in pharmaceutical formulations include, for example, lactose, dextrose, sucrose, mannitol, sorbitol and cellulose. Lubricants suitable for use in pharmaceutical formulations include, for example, silicon dioxide, talc, stearic acid, magnesium or calcium stearate and/or polyethylene glycol. Suitable disintegrants for use in pharmaceutical formulations include, for example, starch, alginic acid and alginates. Wetting agents suitable for use in pharmaceutical formulations include, for example, lecithin, polyethoxylate, and lauryl sulfate. Generally, any effervescent agent, dye and/or sweetener known to one of ordinary skill in the art may be used in the formulation of the pharmaceutical composition.

Desirably, the daily dose of the composition (e.g., tablet, cachet, or capsule) contains from about 0.1 to about 10mg of optically pure (S, S) reboxetine, substantially free of its (R, R) stereoisomer. More preferably, each compound contains from about 0.5 to about 8mg of the active ingredient optically pure (S, S) reboxetine, substantially free of its (R, R) stereoisomer. Yet even more preferably, each dose contains from about 0.5 to about 5mg of the active ingredient, e.g. optically pure (S, S) reboxetine, substantially free of its (R, R) stereoisomer. Such dosage forms provide a sufficient daily dosage of about 0.5 to about 2.5mg in one or two oral administrations. This would allow the tablet to contain 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4 or 2.5mg of optically pure (S, S) reboxetine.

In another embodiment, a preferred daily dose of the composition (e.g., a tablet, cachet, or capsule) contains from about 0.1 to about 0.9mg of optically pure (S, S) reboxetine, substantially free of its (R, R) stereoisomer. More preferably, each dose of the composition contains from about 0.5 to about 0.8mg of the active ingredient as optically pure (S, S) reboxetine, substantially free of its (R, R) stereoisomer. Yet even more preferably, each dose contains from about 0.5 to about 0.75mg of the active ingredient as optically pure (S, S) reboxetine, substantially free of its (R, R) stereoisomer. Such dosage forms provide a sufficient daily dosage of about 0.5 to about 0.9mg in one oral administration.

Patients suffering from depression, nicotine addiction, behavioral disorders, oppositional disorder and/or attention deficit hyperactivity disorder will benefit from administration of the compositions of the present invention, particularly compositions containing optically pure (S, S) reboxetine, regardless of these or other co-morbid conditions. Diagnostic criteria for these disorders are generally provided by the American psychiatric society, see their handbook of diagnosis and statistics of mental disorders ("diagnostic and Statistical Manual of mental disorders") 4 th edition (Washington D.C.1994), and International patent publications Nos. WO 99/15177, WO 99/15176 and WO 99/15163, the disclosures of which are incorporated herein by reference.

In addition, patients suffering from addictive disorders and withdrawal syndromes, adjustment disorders, apathy, attention-deficit hyperactivity disorder, attention-deficit disorder caused by medical conditions, bulimia nervosa, chronic fatigue syndrome, chronic or acute stress, depression, dysthymia, Generalized Anxiety Disorder (GAD), nicotine addiction, panic disorder, post-traumatic stress disorder, premenstrual dysphoric disorder, schizoaffective disorder, and SSRI "fatigue" syndrome would benefit from administration of the compositions of the present invention, particularly compositions containing optically pure (S, S) reboxetine.

These disorders behave in a similar manner in children, adolescents and adults. Thus, the methods of the present invention are effective for the treatment of pediatric, adolescent and adult patients. For purposes of the present invention, a child is considered a person of an age below adolescence, an adolescent is considered a person of an age between adolescence and about 18 years, and an adult is typically a person of an age of at least about 18 years. As previously mentioned, the optimal daily dosage for each patient must be determined by the attending physician after considering the weight of each patient, the other medications that the patient may take, the nature and severity of the particular disorder, and all other conditions of the patient.

As mentioned above, reboxetine acts as an antidepressant. However, reboxetine does not function as well as most antidepressants. Unlike tricyclic antidepressants, and even Selective Serotonin Reuptake Inhibitors (SSRIs), reboxetine is ineffective in the 8-OH-DPAT hypothermia test, indicating that reboxetine is not a selective serotonin reuptake inhibitor. In contrast, reboxetine is selective for the noradrenergic system. Reboxetine is not an SSRI but is a novel selective Norepinephrine Reuptake Inhibitor (NRI). Leonard "Noradrenaline in basic model of depression" [ European neuropsychology ] ("Noradrenaline in basic models of depression", European-Neuropsychopharmacol), 7 suppl.1 pp.S11-6 and S71-3 (1997). Unlike most prior generation drugs, reboxetine is a highly selective norepinephrine reuptake inhibitor with only minimal serotonin reuptake inhibitory activity and no dopamine reuptake inhibitory activity. Reboxetine showed no anticholinergic binding activity in different animal models and lacked monoamine oxidase (MAO) inhibitory activity.

Reboxetine is also a highly potent pharmacologically specific, fast-acting drug. Studies have shown that reboxetine has potent anti-reserpine activity, combines the inhibitory properties of classical tricyclic antidepressants for norepinephrine reuptake with the ability to desensitize beta-adrenergic receptor function, and does not exhibit any appreciable blocking effects on muscarinic, cholinergic, histaminergic, and alpha-adrenergic receptors. Moreover, reboxetine showed less vagal relaxation activity than the tricyclic antidepressant and no evidence of cardiotoxicity.

Thus, in another embodiment of the present invention, racemic reboxetine can be used to treat or prevent a number of psychiatric and neurological disorders. In particular, reboxetine has been found to be particularly useful for treating or enhancing the therapeutic or prophylactic effects of various psychiatric symptoms or disorders with greater efficacy and fewer side effects than treatment with known drugs. In addition, reboxetine can also be used to treat other specific psychiatric symptoms or disorders or to enhance their therapeutic or prophylactic effect.

Psychiatric and neurological disorders which may be treated or prevented by the administration of a therapeutically effective amount of racemic reboxetine (or a derivative or pharmaceutically acceptable salt thereof) include, but are not limited to, adaptive disorders (including depressive mood, anxiety, mixed anxiety and depressive mood, behavioral disorders and mixed behavioral and mood disorders), age-related learning and mental disorders (including alzheimer's disease), anorexia nervosa, apathy, attention deficit (or other cognitive) disorder resulting from general medical conditions, bipolar disorders, bulimia nervosa, chronic fatigue syndrome, chronic or acute stress, chronic pain, cyclothymic disorders, dysthymic disorders, fibromyalgia and other somatoform disorders (including somatoform disorders, conversion disorders, pain disorders, psychosis, schizophrenia, anxiety, depression, anxiety disorders, depression disorders, anxiety disorders, mental retardation disorders, depression disorders, mental retardation disorders, mental depression, anxiety disorders, mental retardation disorders, anxiety disorders, Hypochondriacal disorders, somatoform disorders, undifferentiated somatoform disorders and somatoform NOS), incontinence (i.e., stress incontinence, genuine stress incontinence and mixed incontinence), mania, migraine, obesity (i.e., reduction of body weight in obese or overweight patients), peripheral neuropathy, post-traumatic stress disorder, premenstrual dysphoric disorder (i.e., premenstrual syndrome and late luteal phase anxiety disorder), psychosis (including schizophrenia, schizoaffective disorder and schizophreniform disorder), seasonal affective disorder, sleep disorders (e.g., narcolepsy and enuresis), specific developmental disorders, Selective Serotonin Reuptake Inhibition (SSRI) "fatigue" syndrome and TIC disorders (i.e., tourette's disease).

Similar to (S, S) reboxetine, racemic reboxetine can also be used to treat humans suffering from migraine, particularly to reduce the frequency, duration, intensity, and/or complications due to migraine. In addition, racemic reboxetine can be used to prevent migraine.

In addition, racemic reboxetine can be used to treat incontinence (i.e., stress incontinence, genuine stress incontinence, and mixed incontinence). Stress incontinence is a condition in which urine is lost involuntarily when any activity is performed that raises intra-abdominal pressure, such as coughing or sneezing. Stress incontinence is also a clinical sign, and it can be observed by caregivers that urine is ejected from the urethral opening (ostium) when a patient coughs or struggles. Genuine stress incontinence is a pathological diagnosis of urethral sphincter insufficiency by urodynamic testing. Mixed incontinence is a combination of stress incontinence and urgency incontinence. The latter is part of overactive bladder syndrome. The cause of retention may be outflow obstruction (e.g., high urethral pressure), poor detrusor (bladder muscle) contraction, or lack of coordination between detrusor contraction and urethral relaxation.

The racemic form of reboxetine is well tolerated and has a wide safety profile. The amount of racemic reboxetine administered to a subject can range from about 2 to about 20 milligrams per person per day (mg/day), preferably from about 4 to about 10 mg/day, more preferably from about 6 to about 10 mg/day. The total daily dose may be administered in small amounts up to twice daily, depending on the formulation and the disorder suffered by the individual. Reboxetine is typically administered orally, for example in the form of a tablet, but can also be administered parenterally, transdermally, rectally, or vaginally.

A preferred method of administration of racemic reboxetine is once or twice daily oral administration. It may also be administered at a dose of about 2, 4, 6, 8, 10 or 12 mg/day or fractions thereof. For example, a suitable administration may be about 4mg in the morning, about 2 or about 4mg in the afternoon or evening. For some patients, the ideal administration will be about 3 to about 5mg in the morning and about 3 to about 5mg in the afternoon. The precise level of administration can be determined by a skilled physician or psychiatrist. The ideal administration is customarily determined on the basis of clinical trial evaluation and the needs of the particular patient.

According to the present invention, racemic reboxetine can also be administered as the free base or a pharmaceutically acceptable salt thereof. The phrase "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to salts prepared from pharmaceutically acceptable acids or bases, including organic and inorganic acids and bases, as described above with respect to salts of optically pure (S, S) reboxetine. The preferred reboxetine drug salt is the mesylate salt, which is prepared with methanesulfonic acid.

Treatment or prevention of the above disorders involves administration of reboxetine in certain forms and dosage forms to reduce the symptoms of the disease or disorder. Generally, the symptoms exhibited by children, adolescents and adults are similar to each other. Thus, as noted above, the methods of the present invention are effective for the treatment of pediatric, adolescent and adult patients.

Examples

This example demonstrates the superior pharmacological selectivity and efficacy of the compositions according to the invention. More specifically, this example demonstrates the superior pharmacological selectivity and potency of (S, S) reboxetine compared to its (R, R) stereoisomer and racemic reboxetine.

Sprague-Dawley rats weighing about 250 to about 300 grams (g) were decapitated and brain cortical tissue was immediately removed. The brain cortex was homogenized in media each containing 0.32 moles (M) of sucrose using a rotary pestle. The resulting homogenate is centrifuged at about 1,000Xg for about 10 minutes at about 4 ℃. The supernatant was collected and centrifuged further at about 20,000Xg for about 20 minutes at a temperature of about 4 ℃. The protein particles obtained from the centrifugation step were resuspended in Kreb's-Hepes buffer to give a protein concentration of about 2mg/ml buffer. The buffer is maintained at a pH of about 7.0 and contains therein: 20mM Hepes, 4.16mM NaHCO₃、0.44mM KH₂PO₄、0.63mMNaH₂PO₄、127mM NaCl、5.36mM KCl、1.26mM CaCl₂And 0.98mM MgCl₂。

The protein/buffer suspension was added to 166 assay tubes, and approximately 30. mu.g (10) of each of the 166 assay tubes was added^-6Grams) to about 150 μ g protein (i.e., 80 per transport assay). Binding to serotonin and norepinephrine reuptake sites was determined as follows. The following measurements were made³Synaptosomal uptake of H-noradrenaline. Using about 1.4 nanomolar³H]Cisplatin and about 1.9nM [ sic ]³H]Nisoxetine, labeling the serotonin and norepinephrine reuptake sites, respectively. Non-specific binding is defined by 100 micromolar (. mu.M) fluoxetine (for serotonin) and 10. mu.M desipramine (for norepinephrine). The total assay volume was about 500 microliters (μ l), and the incubation was performed for about 60 minutes (for serotonin) and 120 minutes (for norepinephrine). Both thermostats were carried out at about 25 ℃ and at the end filtered rapidly through a GFB filter (pre-impregnated with about 0.5PEI for about 4 hours) into a 48-well cell harvester, washed with 3X 5ml ice-cold 200mM tris-HCl, pH 7.0. Catapult filters (Punched-outfilters) were placed in 7ml vials and radioactivity was determined by liquid scintillation counting.

Using two radioligands [ alpha ], [³H]Cisplatin and [ sic ], [ solution of cisplatin ]³H]Nisoxetine, the ability of reboxetine (i.e., a racemic mixture of (R, R) and (S, S) reboxetine), (R, R) reboxetine and (S, S) reboxetine to bind to the reuptake site of norepinephrine and serotonin is evaluated in a binding assay. The concentration of test compound required to inhibit specific binding at both reuptake sites by 50% (IC) was determined by non-linear least squares regression analysis₅₀Value). IC Using the following Cheng-Prassoff equation₅₀Value to K_iConversion of the values:

K_i＝IC₅₀/(1+([L]/[ K of L_d]))

Wherein [ L ] is]Is the radioligand concentration, in nM, K_dIs the binding affinity of L, expressed in nM. See y.c. cheng and inhibition constant (K) of the W.H.Prusoff "enzyme reaction_i) With Inhibitor Concentration (IC) resulting in 50% inhibition₅₀) Relationship Between them "[ Biochemical pharmacology ] (" Relationship Between Between and the inhibition Constant (K)_i)and theConcentration of Inhibitor Which Cause 50％Inhibition(IC₅₀)of an Enzymatic Reaction”，Biochemical Pharmacology)，vol.22，pp.3099-3108(1973)。

The following table provides K calculated according to the Cheng-Prassoff equation_iThe value:

watch (A)

Compound (I)	Norepinephrine reuptake (K)i，nM)	Serotonin reuptake (K)i，nM)	Serotonin/norepinephrine KiSelectivity is
				(S, S) reboxetine (R, R) reboxetine	0.23±0.067.0±1.7	2937±246104±43	12,77015
Reboxetine	1.6±0.6	129±13	81

Data display, (S, S) RuiThe effect of bocicline in inhibiting norepinephrine reuptake is about five to about eight times stronger than that of reboxetine racemate. In addition, racemic reboxetine was 81 times more selective for norepinephrine reuptake inhibition than serotonin reuptake inhibition. Surprisingly, the (S, S) and (R, R) reboxetine stereoisomers are quite different with respect to their enantioselectivities for inhibiting norepinephrine and serotonin reuptake. The (S, S) enantiomer is very poor at inhibiting serotonin reuptake (i.e., K)_iHigh) and therefore has a surprisingly high selectivity for the norepinephrine reuptake site. Specifically, the selectivity of serotonin-norepinephrine increased from 81 (for the racemate) to 12,770 (for optically pure (S, S) reboxetine). Thus, administration of a therapeutic dose of (S, S) reboxetine effectively inhibited norepinephrine reuptake, while serotonin reuptake was essentially unaffected. Similarly, there is a further increase in the independence between the norepinephrine reuptake site and the action of other receptors. As a result, no adverse side effects associated with inhibiting serotonin reuptake and blocking other receptors were exhibited.

Surprisingly, this effect was not observed with (R, R) reboxetine, but the opposite. With respect to reuptake of norepinephrine, (R, R) reboxetine is a weaker inhibitor than (S, S) reboxetine, that is, with respect to affinity (K) of (R, R) reboxetine_i) Is 7nM and K for (S, S) reboxetine_iIt was 0.23 nM. In addition, (R, R) reboxetine is much more effective at inhibiting serotonin reuptake than (S, S) reboxetine, that is, with respect to K of (R, R) reboxetine_i104nM and K for (S, S) reboxetine_iIt was 2937 nM. Thus, (R, R) reboxetine has low selectivity for norepinephrine reuptake inhibition-serotonin reuptake inhibition.

The surprising higher potency of the (S, S) enantiomer over racemic reboxetine and (R, R) reboxetine provides the ability of the attending physician to specify an effective dose of the norepinephrine reuptake inhibitor, i.e., (S, S) reboxetine, that only requires about 10% to about 20% of the current daily reboxetine (racemate) dose to achieve the same reuptake inhibition of the norepinephrine site. In addition, the surprisingly high selectivity of inhibition of optically pure (S, S) reboxetine is essentially limited to inhibition of norepinephrine reuptake, thereby reducing the adverse side effects associated with inhibition of serotonin reuptake sites and blocking of other receptors.

The foregoing description is provided for clarity of understanding only, and no unnecessary limitations should be understood therefrom, as modifications within the scope of the invention may be apparent to those having ordinary skill in the art.

Claims (13)

1. Use of optically pure (S, S) -reboxetine, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of incontinence, said compound being substantially free of (R, R) -reboxetine.

2. Use according to claim 1, wherein (S, S) -reboxetine is administered in an amount of 0.1-10 mg/day.

3. Use according to claim 2, wherein (S, S) -reboxetine is administered in an amount of 0.5-8 mg/day.

4. Use according to claim 3 wherein (S, S) -reboxetine is administered in an amount of 0.5-5 mg/day.

5. Use according to claim 4 wherein (S, S) -reboxetine is administered in an amount of 0.5-2.5 mg/day.

6. Use according to claim 5, wherein (S, S) -reboxetine is administered in an amount of 0.5-0.9 mg/day.

7. Use according to claim 6, wherein (S, S) -reboxetine is administered in an amount of 0.5-0.8 mg/day.

8. The use of claim 7 wherein (S, S) -reboxetine is administered in an amount of 0.5-0.75 mg/day.

9. The use according to any one of claims 1 to 8 wherein the pharmaceutically acceptable salt of (S, S) -reboxetine is the mesylate salt.

10. The use of any one of claims 1-8, wherein the optically pure (S, S) -reboxetine or pharmaceutically acceptable salt thereof comprises at least 90 wt.% of (S, S) -reboxetine and less than 10 wt.% of (R, R) -reboxetine, based on the total weight of the (S, S) and (R, R) reboxetine present.

11. The use of claim 10 wherein the optically pure (S, S) -reboxetine or pharmaceutically acceptable salt thereof comprises at least 97 wt.% of (S, S) -reboxetine and less than 3 wt.% of (R, R) -reboxetine, based on the total weight of the (S, S) and (R, R) reboxetine present.

12. The use of claim 11 wherein the optically pure (S, S) -reboxetine or pharmaceutically acceptable salt thereof comprises at least 99 wt.% of (S, S) -reboxetine and less than 1 wt.% of (R, R) -reboxetine, based on the total weight of the (S, S) and (R, R) reboxetine present.

13. The use of claim 1, wherein the incontinence comprises stress incontinence, genuine stress incontinence or mixed incontinence.