ES2364575T3 - DERIVATIVES OF PIRIDINE AND ITS USE IN THE TREATMENT OF PSYCHOTIC DISORDERS. - Google Patents

Abstract

A compound that is 2- [3,5-bis (trifluoromethyl) phenyl] -N- {4- (4-fluoro-2-methylphenyl) -6 - [(7S, 9aS) -7- (hydroxymethyl) hexahydropyrazine [2 , 1-c] [1,4] oxazin-8 (1 H) -yl] -3-pyridinyl} -N, 2-dimethylpropanamide or a pharmaceutically acceptable salt thereof.

Description

The present invention relates to new bicyclic derivatives containing nitrogen that have pharmacological activity, methods for their preparation, compositions containing them and their use in the treatment of psychotic disorders, in particular schizophrenia.

WO 2005/002577 (F. Hoffmann-La Roche AG) describes a series of pyridine derivatives that are claimed to be dual NK1 / NK3 antagonists for treating schizophrenia.

The present invention provides, in a first aspect, the compound of the formula (I) which is 2- [3,5bis (trifluoromethyl) phenyl] -N- {4- (4-fluoro-2-methylphenyl) -6- [ (7S, 9aS) -7- (hydroxymethyl) hexahydropyrazine [2,1-c] [1,4] oxazin10 8 (1H) -yl] -3-pyridinyl} -N, 2-dimethylpropanamide thereof:

image 1

The compound of the formula (I) can form acid addition salts with acids, such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, sulfate, citric, lactic, mandelic, tartaric and methanesulfonic. Salts, solvates and hydrates

15 of the compound of the formula (I) therefore form an aspect of the invention.

As used herein, the term "salt" refers to any salt of a compound according to the present invention prepared from an inorganic or organic acid or base, quaternary ammonium salts and internally formed salts. Physiologically acceptable salts are particularly suitable for medical applications due to their greater solubility in water compared to that of the 20 parent compounds. Such salts should clearly have a physiologically acceptable anion or cation. Suitably the physiologically acceptable salts of the compounds of the present invention include acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric and with organic acids, such as tartaric, acetic acids , trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, 25 succinic, camphorsulfuric, isotionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, ascorbic, ascorbic, ascorbic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinyl, alginic, galacturonic and arylsulfonic, for example benzenesulfonic and ptoluenesulfonic; base addition salts are formed with alkali metals and alkaline earth metals and organic bases such as N, N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine,

30 meglumaine (N-methylglucamine), lysine and procaine; and salts formed internally. Salts having a physiologically unacceptable anion or cation are within the scope of the invention as useful intermediates for the preparation of physiologically acceptable salts and / or for use in non-therapeutic situations, for example, in vitro.

The present invention also includes isotopically labeled compounds, which are identical to those that are

35 cited in formula (I) and following, except for the fact that one or more atoms are replaced by an atom that has an atomic mass or a different mass number of the atomic mass or mass number that is usually found in nature . Examples of isotopes that can be incorporated into compounds of the invention and their pharmaceutically acceptable salts include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2H, 3H, 11C, 13C, 14C, 15N, 17O, 18O, 31P, 32P, 35S, 18F,

40 36Cl, 123I and 125I.

The compounds of the present invention and pharmaceutically acceptable salts of said compounds containing the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. The isotopically labeled compounds of the present invention, for example those incorporating radioactive isotopes such as 3H, 14C, are useful in the drug and / or substrate tissue distribution assays. Tritiated isotopes, i.e. 3H, and carbon 14, that is, 14C, are particularly preferred for ease of preparation and detectability. The 11C and 18F isotopes are

particularly useful in PET (positron emission tomography), and 125I isotopes are particularly useful in SPECT (single photon emission computed tomography), both useful in brain imaging. In addition, substitution with heavier isotopes such as deuterium, i.e. 2H, may provide certain therapeutic advantages due to greater metabolic stability, for example a

5 increased half-life in vivo or a need for lower doses and, therefore, may be preferred in some circumstances. The isotopically labeled compounds of formula I and following of this invention can generally be prepared by performing the procedures described in the Schemes and / or in the Examples below, substituting an isotopically unlabeled reagent for an easily available isotopically labeled reagent.

The present invention also provides a process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, a process comprising:

(a) reacting a compound of the formula (II)

image2

wherein L represents a suitable leaving group such as a halogen atom (eg chlorine), with a compound of the formula (III)

image2

or an optionally protected derivative thereof, optionally thereafter followed by deprotection of the compound of the formula (I) that is protected.

In one embodiment, the deprotection step can be carried out on the derivative in which the hydroxyl group

20 is protected in the form of an O-TBDMS derivative, in a suitable solvent such as toluene, in the presence of a suitable catalyst such as bis-tri-tert-butylphosphine palladium, a suitable base such as aqueous sodium hydroxide and a transfer catalyst of suitable phase such as aqueous hexadecyltrimethylammonium chloride at a temperature such as 80-95 ° C. This procedure can continue with the removal of the TBDMS protecting group using tetrabutylammonium fluoride in a suitable solvent such as THF, or acid.

Hydrochloric in a suitable solvent such as methanol.

Examples of protecting groups and the means for their elimination can be found T. W. Greene "Protective Groups in Organic Synthesis" (J. Wiley and Sons, 1991). Suitable amine protecting groups include sulfonyl (for example tosyl), acyl (for example acetyl, 2 ', 2', 2'-trichloroethoxycarbonyl, benzyloxycarbonyl or tutoxycarbonyl) and arylalkyl (for example benzyl), which can be removed by hydrolysis (by Example 30 using an acid such as hydrochloric acid in dioxane or trifluoroacetic acid in dichloromethane) or by reduction (for example hydrogenolysis of a benzyl group or reductive elimination of a 2 ', 2', 2'trichloroethoxycarbonyl group using zinc in acetic acid) according be appropriate Other suitable amine protecting groups include trifluoroacetyl (-COCF3) which can be removed by base catalyzed hydrolysis or a benzyl group attached to a solid phase resin, such as a 2,6-dimethoxybenzyl group bonded to Merrifield resin

35 (Ellman linker), which can be removed by acid catalyzed hydrolysis, for example with trifluoroacetic acid.

A compound of the formula (II) can be prepared according to the methodology provided in WO 2005/002577.

The compound of the formula (III) wherein the hydroxyl group is protected as the TBDMS derivative, can be prepared according to the following scheme:

image3

wherein P1 represents a suitable protecting group such as Boc.

Step (i) typically comprises reacting the carboxylic acid (IV) with the amine of formula (V), wherein R is hydrogen or a suitable nitrogen protecting group (eg a benzyl group) in a suitable solvent such as dichloromethane , in the presence of a suitable coupling reagent such as O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium tetrafluoroborate (TBTU) and a suitable base such as diisopropylethylamine at a suitable temperature, such as the room temperature.

Step (ii) typically comprises deprotection of (VI) using a suitable reagent such as trifluoroacetic acid, followed by purification in a SCX silica cartridge (strong cation exchange) and subsequent cyclization at a suitable temperature. , such as 50 ° C, to give the compound

(VII) when R is a benzyl group and to give compound (VIII) when R is hydrogen.

Step (iii) typically comprises reduction of (VII) or (VIII) using a suitable reducing agent such as BH3-THF at a suitable temperature such as reflux to give (IIIa) and (IIIb), respectively.

Step (iv) typically comprises the reaction of (IIIa) or (IIIb) with tert-butyldimethylsilyl chloride (TBDMSCl) in a suitable solvent, such as dichloromethane, in the presence of a suitable base, such as triethylamine at a suitable temperature, such as room temperature. The reaction of (IIIa) is followed by the removal of the benzyl group and the reaction of (IIIb) is followed by the separation of the required diastereoisomer.

The compounds of formulas (IV) and (V) are either known or can be prepared according to known procedures.

The compounds of the formula (I) and their pharmaceutically acceptable salts have affinity and are antagonists of the NK1 and NK3 receptor and thus can be used in the treatment of psychotic disorders.

In the context of the present invention, the terms describing the indications used herein

25 reports are classified in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, published by the American Psychiatric Association (DSM-IV) and / or The International Classification of Diseases, 10th Edition (ICD10). The various subtypes of the disorders mentioned herein are contemplated as part of the present invention. The numbers in brackets after the diseases listed below refer to the DSM-IV classification code.

In the context of the present invention, the term "psychotic disorder" includes:

Schizophrenia that includes the subtypes of the paranoid type (295.30), disorganized type (295.10), catatonic type (295.20), undifferentiated type (295.90) and residual type (295.60); Schizophreniform Disorder (295.40); Schizoaffective disorder (295.70) that includes the Bipolar Type and Depressive Type subtypes; Delusional disorder

(297.1) which includes the subtypes Erotomanic Type, Grand Type, Jealous Type, Persecuting Type, Type

35 somatic, mixed type and unspecified type; Brief psychotic disorder (298.8); Shared psychotic disorder (297.3); Psychotic disorder due to a general medical condition that includes the Delirious and Hallucinations subtypes; Substance-induced psychotic disorder that includes the Delirious (293.81) and Hallucinations (293.82) subtypes; and unspecified psychotic disorder (298.9).

The compounds of the formula (I) and their pharmaceutically acceptable salts and solvates may also be useful in the treatment of the following disorders:

Depression and mood disorders that include major depressive episode, manic episode, mixed episode and hypomanic episode; Depressive disorders including Major depressive disorder, Dysthymic disorder (300.4), Unspecified depressive disorder (311); Bipolar disorders that include Bipolar I disorder, Bipolar II disorder (recurrent major depressive episodes with hypomanic episodes) (296.89), Cyclothymic disorder (301.13) and Unspecified bipolar disorder (296.80); Other Mood Disorders that include Mood Disorder due to a general medical condition (293.83) that includes subtypes With depressive characteristics, With major depressive episode, with manic and mixed characteristics), Mood disorder substance-induced (which includes subtypes with depressive characteristics, with manic characteristics and with mixed characteristics) and unspecified mood disorder (296.90).

Anxiety disorders that include panic attack; Panic disorder that includes panic disorder without agoraphobia (300.01) and panic disorder with agoraphobia (300.21); Agoraphobia; Agoraphobia without a history of panic disorder (300.22), Specific phobia (300.29, previously called Simple phobia) that includes the subtypes Animal type, Natural environment type, Blood-injection-injury type, Situation type and Other type), Social phobia ( Social anxiety disorder, 300.23), Obsessive-compulsive disorder (300.3), Post-traumatic stress disorder (309.81), Acute stress disorder (308.3), Generalized anxiety disorder (300.02), Anxiety disorder due to a general medical condition ( 293.84), Substance-induced anxiety disorder, Separation anxiety disorder (309.21), Adjustment disorders with anxiety

(309.24) and Unspecified anxiety disorder (300.00).

Substance-related disorders that include Substance Abuse Disorders such as Substance Dependence, Substance Avidity and Substance Abuse; Substance-induced disorders such as substance intoxication, substance withdrawal, substance-induced delirium, persistent substance-induced dementia, substance-induced persistent amnesic disorder, substance-induced psychotic disorder, substance-induced behavioral disorder, substance-induced anxiety disorder , Substance-induced sexual dysfunction, substance-induced sleep disorder and hallucinogenic persistent perception disorder (Flashbacks); Alcohol-related disorders such as Alcohol dependence (303.90), Alcohol abuse (305.00), Alcohol poisoning (303.00), Alcohol withdrawal (291.81), Alcohol intoxication delirium, Alcohol withdrawal delirium, Induced persistent dementia by alcohol, Alcohol-induced persistent amnesic disorder, Alcohol-induced psychotic disorder, Alcohol-induced behavioral disorder, Alcohol-induced anxiety disorder, Alcohol-induced sexual dysfunction, Alcohol-induced sleep disorder and Disorder related to unspecified alcohol (291.9); Amphetamine-related disorders (or amphetaminoid substances) such as amphetamine dependence (304.40), Amphetamine abuse (305.70), Amphetamine poisoning (292.89), Amphetamine withdrawal (292.0), Amphetamine poisoning delirium, Psychotic disorder induced amphetamines, amphetamine-induced behavioral disorder, amphetamine-induced anxiety disorder, amphetamine-induced sexual dysfunction, amphetamine-induced sleep disorder, and unspecified amphetamine-related disorder (292.9); Caffeine-related disorders such as caffeine poisoning (305.90), Caffeine-induced anxiety disorder, Caffeine-induced sleep disorder and Unspecified caffeine-related disorder (292.9); Cannabis-related disorders such as Cannabis dependence (304.30), Cannabis abuse (305.20), Cannabis poisoning (292.89), Cannabis poisoning delirium, Cannabis-induced psychotic disorder, Cannabis-induced anxiety disorder and Cannabis-related disorder unspecified cannabis (292.9); Cocaine-related disorders such as Cocaine Dependence (304.20), Cocaine Abuse (305.60), Cocaine Poisoning (292.89), Cocaine Withdrawal (292.0), Cocaine Intoxication Delirium, Cocaine-induced Psychotic Disorder, Induced Behavioral Disorder by cocaine, Cocaine-induced anxiety disorder, Cocaine-induced sexual dysfunction, Cocaine-induced sleep disorder and Unspecified cocaine-related disorder (292.9); Hallucinogen-related disorders such as Hallucinogen Dependency (304.50), Hallucinogen Abuse (305.30), Hallucinogen Poisoning (292.89), Hallucinogenic Persistent Perception Disorder (Flashbacks) (292.89), Hallucinogenic Induced Intoxication Trauma, hallucinogens, hallucinogen-induced behavioral disorder, hallucinogen-induced anxiety disorder and hallucinogen-related disorder unspecified (292.9); Disorders related to inhaled substances such as Dependence on inhaled substances (304.60), Abuse of inhaled substances (305.90), Intoxication by inhaled substances (292.89), Delirium from poisoning with inhaled substances, Persistent dementia induced by inhaled substances, Psychotic disorder induced by substances inhaled, Behavioral disorder induced by inhaled substances, Anxiety disorder induced by inhaled substances and Disorder related to unspecified inhaled substances (292.9); Nicotine-related disorders such as nicotine dependence (305.1), nicotine withdrawal (292.0) and unspecified nicotine-related disorder (292.9); Opioid related disorders such as Opioid dependence (304.00), Opioid abuse (305.50), Opioid poisoning (292.89), Opioid withdrawal (292.0), Opioid intoxication delirium, Opioid-induced psychotic disorder, Behavioral disorder induced by opioids, opioid-induced sexual dysfunction, opioid-induced sleep disorder and unspecified opioid-related disorder (292.9); Phencyclidine-related disorders (or phencyclidine-type substances) such as Phencyclidine Dependency (304.60), Phencyclidine Abuse (305.90), Phencyclidine Poisoning (292.89), Phencyclidine Intoxication Delirium, Phencyclic-induced Induced Phencyclidine Disorder , Phencyclidine-induced anxiety disorder and Unspecified phencyclidine-related disorder (292.9); Sedative, hypnotic-related disorders

or anxiolytics such as sedative, hypnotic or anxiolytic dependence (304.10), sedative, hypnotic or anxiolytic abuse (305.40), sedative, hypnotic or anxiolytic poisoning (292.89), sedative, hypnotic or anxiolytic withdrawal (292.0), sedative, hypnotic or anxiolytic intoxication, sedation, hypnotic or anxiolytic withdrawal delirium, persistent sedative, hypnotic or anxiolytic dementia, persistent sedative, hypnotic or anxiolytic amnesic disorder, sedative-induced hypnotic or anxiety-induced psychotic disorder by sedatives, hypnotics or anxiolytics, sedative-induced anxiety disorder, hypnotics or anxiolytics, sexual dysfunction, sedative-induced, hypnotic or anxiolytic, sedative-induced, hypnotic or anxiolytic-induced sleep disorder, sedative-related disorder, hypnotic or anxiolytic (292.9 ); Multiple substance related disorder such as Multiple Substance Dependence (304.80); and Disorders related to other (or unknown) substances such as anabolic steroids, inhaled nitrate substances and nitric oxide.

Sleep disorders that include primary sleep disorders such as dysomnias such as primary insomnia (307.42), primary hypersomnia (307.44), narcolepsy (347), sleep disorders related to breathing (780.59), circadian rhythm sleep disorder (307.45 ) and unspecified dysomnia (307.47); Primary sleep disorders such as Parasomnias such as Nightmare Disorder (307.47), Sleep Horror Disorder (307.46), Sleepwalking Disorder (307.46) and Unspecified Parasomnia (307.47); Sleep disorders related to another mental disorder such as Insomnia related to another mental disorder (307.42) and Hypersomnia related to another mental disorder (307.44); Sleep disorder due to a general medical condition, particularly sleep disorders associated with diseases such as neurological disorders, neuropathic pain, restless legs syndrome, heart and lung diseases; and Substance-induced sleep disorder that includes the subtypes Insomnia Type, Hypersomnia Type, Parasomnia Type, and Mixed Type; Sleep apnea and schedule change syndrome.

Eating disorders such as Anorexia nervosa (307.1) that include the subtypes Type restrictive and Type binge / purge; Bulimia nervosa (307.51) which includes the subtypes Type purgative and Type non-purgative; Obesity; Binge eating disorder; Binge eating disorder; and Unspecified eating disorder (307.50):

Autism spectrum disorders including Autistic Disorder (299.00), Asperger Disorder (299.80), Rett Disorder (299.80), Childhood Disintegrating Disorder (299.10) and Generalized Unspecified Disorder (299.80, which includes atypical Autism).

Attention deficit / hyperactivity disorder that includes the subtypes Attention deficit / hyperactivity disorder of the combined type (314.01), Attention deficit / hyperactivity disorder predominantly of the type of lack of attention (314.00), Attention deficit / hyperactivity disorder Hyperactive-Impulsive (314.01) and Attention Deficit / Hyperactivity Disorder (314.9); Hyperkinetic disorder; Altered behavior disorders such as Behavioral disorder that includes the subtypes of childhood onset type (321.81), type of onset in adolescence (312.82) and unspecified onset (312.89), Oppositional defiant disorder (313.81) and Altered unspecified behavior disorder; and tic disorders such as Tourette's disorder (307.23).

Personality disorders including subtypes Paranoid personality disorder (301.0), Schizoid personality disorder (301.20), Schizotypal personality disorder (301.22), Antisocial personality disorder (301.7), Borderline personality disorder (301.83), Histrionic personality (301.50), Narcissistic personality disorder (301.81), Avoidance personality disorder (301.82), Dependent personality disorder (301.6), Obsessive-compulsive personality disorder (301.4) and Unspecified personality disorder (301.9).

Enhancement of cognition that includes the treatment of cognitive impairment in other diseases such as schizophrenia, bipolar disorder, depression, other psychiatric disorders and psychotic conditions associated with cognitive impairment, for example Alzheimer's disease: and

Sexual dysfunctions that include sexual desire disorders such as hypoactive sexual desire disorder (302.71), and sexual aversion disorder (302.79); sexual arousal disorders such as female sexual arousal disorder (302.72) and male erectile disorder (302.72); Orgasmic disorders such as Female Orgasmic Disorder (302.73), Male Orgasmic Disorder (302.74) and Premature Ejaculation (302.75); sexual pain disorder such as Dyspareunia (302.76) and Vaginismus (306.51); Unspecified sexual dysfunction (302.70); paraphilias such as Exhibitionism (302.4), Fetishism (302.81), Froteurismo (302.89), Pedophilia (302.2), Sexual Masochism (302.83), Sexual Sadism (302.84), Transvestite Fetishism (302.3), Voyeurism (302.82) and Unspecified Paraphilia (302.9); sexual identity disorders such as sexual identity disorder in children (302.6) and sexual identity disorder in adolescents or adults (302.85); and unspecified sexual disorder (302.9).

All of the various forms and subforms of the disorders mentioned herein are contemplated as part of the present invention.

Thus the invention also provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof, for use as a therapeutic substance in the treatment or prophylaxis of the previous psychotic disorders, in particular schizophrenia.

The invention further provides a method for treating schizophrenia which comprises administering to a host in need thereof an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides the use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of schizophrenia.

The invention further provides a method of treatment or prophylaxis of the above disorders, in mammals that include humans, which comprises administering to the sufferer a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides the use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of the above disorders.

When used in therapy, the compounds of the formula (I) are usually formulated in the form of a conventional pharmaceutical composition. Such compositions can be prepared using standard procedures.

Thus, the present invention further provides a pharmaceutical composition for use in the treatment of the above disorders comprising the compound of the formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The present invention further provides a pharmaceutical composition comprising the compound of the formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The compounds of the invention can be used in combination with the following agents to treat or prevent psychotic disorders: i) antipsychotics; ii) drugs for extrapyramidal side effects, for example anticholinergics (such as benzotropin, biperiden, procyclidine and trihexyphenyl), antihistamines (such as diphenohydramine) and dopamine drugs (such as amantadine); iii) antidepressants; iv) anxiolytics; and v) cognition enhancers for example cholinesterase inhibitors (such as tacrine, donepezil, rivastigmine and galantamine).

The compounds of the invention can be used in combination with antidepressants to treat or prevent depression and mood disorders.

The compounds of the invention can be used in combination with the following agents to treat or prevent bipolar disease: i) mood stabilizers; ii) antipsychotics; and iii) antidepressants.

The compounds of the invention can be used in combination with the following agents to treat or prevent anxiety disorders: i) anxiolytics; and ii) antidepressants.

The compounds of the invention can be used in combination with the following agents to improve nicotine withdrawal and reduce nicotine anxiety: i) nicotine substitution treatment for example a sublingual formulation of nicotine beta-cyclodextrin and nicotine patches; and ii) bupropion.

The compounds of the invention can be used in combination with the following agents to improve alcohol withdrawal and reduce alcohol anxiety: i) NMDA receptor antagonists eg acamprosate; ii) GABA receptor agonists for example tetrabamate; and iii) opioid receptor antagonists for example naltrexone.

The compounds of the invention can be used in combination with the following agents to improve opioid withdrawal and reduce opioid anxiety: i) opioid receptor agonist mu / opioid receptor antagonist kappa for example buprenorphine; ii) opioid receptor antagonists for example naltrexone; and iii) vasodilator antihypertensors for example lofexidine.

The compounds of the invention can be used in combination with the following agents to treat or prevent sleep disorders: i) benzodiazepines for example temazepam, lormetazepam, estazolam and triazolam; ii) non-benzodiazepine hypnotics for example zolpidem, zopiclone, zaleplon and indiplon; iii) barbiturates for example approbital, butabarbital, pentobarbital, secobarbital and phenobarbital; iv) antidepressants; v) other sedative-hypnotics for example chloral hydrate and chlormethiazole.

The compounds of the invention can be used in combination with the following agents to treat anorexia: i) appetite stimulants for example cyproheptidine; ii) antidepressants; iii) antipsychotics; iv) zinc; and v) premenstrual agents for example pyridoxine and progesterones.

The compounds of the invention can be used in combination with the following agents to treat or prevent bulimia: i) antidepressants; ii) opioid receptor antagonists; iii) antiemetics for example ondansetron; iv) testosterone receptor antagonists for example flutamide; v) mood stabilizers; vi) zinc; and vii) premenstrual agents.

The compounds of the invention can be used in combination with the following agents to treat or prevent autism: i) antipsychotics; ii) antidepressants; iii) anxiolytics; and iv) stimulants for example methylphenidate, amphetamine and pemoline formulations.

The compounds of the invention can be used in combination with the following agents to treat or prevent ADHD: i) stimulants for example methylphenidate, amphetamine and pemoline formulations; and ii) non-stimulants for example norepinephrine reuptake inhibitors (such as atomoxetine), alpha 2 adrenoceptor agonists (such as clonidine), antidepressants, modafinil, and cholinesterase inhibitors (such as galantamine and donezepil).

The compounds of the invention can be used in combination with the following agents to treat personality disorders: i) antipsychotics; ii) antidepressants; iii) mood stabilizers; and iv) anxiolytics.

The compounds of the invention can be used in combination with the following agents to treat or prevent male sexual dysfunction: i) phosphodiesterase V inhibitors, for example vardenafil and sildenafil; ii) dopamine agonists / dopamine transport inhibitors for example apomorphine and buproprion; iii) alpha adrenoceptor antagonists for example phentolamine; iv) prostaglandin agonists for example alprostadil; v) testosterone agonists such as testosterone; vi) serotonin transport inhibitors for example serotonin reuptake inhibitors; v) noradrenaline transport inhibitors for example reboxetine and vii) 5-HT1A agonists, for example flibanserin.

The compounds of the invention can be used in combination with the same agents that are specified for male sexual dysfunction to treat or prevent female sexual dysfunction, and also an estrogen agonist such as estradiol.

Antipsychotic drugs include typical antipsychotics (for example chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, thiothixin, haloperidol, molindone and loxapine); and atypical antipsychotics (eg clozapine, olanzapine, risperidone, quetiapine, aripyrazole, ziprasidone and amisulpride).

Antidepressant drugs include serotonin reuptake inhibitors (such as citalopram, escitalopram, fluoxetine, paroxetine and sertraline); dual serotonin and norepinephrine reuptake inhibitors (such as venlafaxine, duloxetine and milnacipran); norepinephrine reuptake inhibitors (such as reboxetine); tricyclic antidepressants (such as amitriptyline, clomipramine, imipramine, maprotiline, nortriptyline and trimipramine); monoamine oxidase inhibitors (such as isocarboxazide, moclobemide, phenelzine and tranylcypromine); and others (such as bupropion, mianserin, mirtazapine, nefazodone and trazodone).

Mood stabilizing drugs include lithium, sodium valproate / valproic acid / divalproex, carbamazepine, lamotrigine, gabapentin, topiramate and thiagabine.

Anxiolytics include benzodiazepines such as alprazolam and lorazepam.

The invention thus provides, in a further aspect, a combination comprising a compound of the formula (I) or a pharmaceutically acceptable derivative thereof together with another or other additional therapeutic agents.

The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention. The individual components of such combinations can be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.

When a compound of the formula (I) or a pharmaceutically acceptable derivative thereof is used in combination with a second therapeutic agent active against the same disease state, the dose of each compound may be different than when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.

A pharmaceutical composition of the invention, which can be prepared by mixing properly, at room temperature and atmospheric pressure, is usually adapted to oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders granules, dragees, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.

Tablets and capsules for oral administration may be in single-dose form and may contain conventional excipients, such as binding agents, fillers, lubricants for the formation of tablets, disintegrants and acceptable wetting agents. The tablets may be coated according to procedures notorious in normal pharmaceutical practice.

The oral liquid preparations may be in the form, for example, of an aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or they may be in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives and, if desired, conventional flavors or colorants.

For parenteral administration, fluid unit dosage forms are prepared using a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle. The compound, depending on the vehicle and the concentration used, can either be suspended or dissolved in the vehicle. In the preparation of the solutions, the compound can be dissolved to be injected and sterilized by filtration before introducing it into a suitable vial or vial and sealing. Advantageously, adjuvants, such as a local anesthetic, preservatives and buffering agents, are dissolved in the vehicle. To improve stability, the composition can be frozen after filling the vial and the water removed in vacuo. Parenteral suspensions are prepared in substantially the same way, but the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be achieved by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending it in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

Compositions suitable for transdermal administration include ointments, gels and patches.

The composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration. The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual manner depending on the severity of the disorders, the weight of the one suffering from them and other similar factors. However, as a general guide, suitable unit doses can be from 0.05 to 1000 mg, more suitably from 1.0 to 200 mg, and such unit doses can be administered more than once a day, for example two or three a day. Such treatment can be prolonged for a number of weeks or months.

Experimental section

The following descriptions and examples illustrate the preparation of compounds of the invention.

Proton nuclear magnetic resonance (NMR) spectra were recorded in Varian apparatus at 300, 400

or 500 MHz, in a 300 MHz Bruker apparatus, chemical shifts are expressed in ppm (�) using the residual solvent line as the internal standard. The splitting patterns are called s, singlet; d, double up; t, triplet; q, quartete; m, multiplet; b, and br. width. NMR spectra were recorded at a temperature ranging from 25 to 90 ° C; when more than one conformer was detected, the chemical shifts that are reviewed are those of the most abundant. Mass spectra (MS) were obtained on a 4 quadrupole triple mass spectrometer (Micromass United Kingdom) or on an Agilent MSD 1100 mass spectrometer, set in ES (+) and ES (-) ionization mode or in a Agilent CL / MSD 1100 mass spectrometer, set to ES (+) and ES (-) ionization mode coupled to an Agilent 1100 Series HPLC device. The analysis of [LC / MS-ES (+): was performed on a Supelcosil ABZ + Plus device (33 x 4.6 mm, 3 µm) (mobile phase: 100% of [water + 0.1% HCO2H] for 1 minute, then from 100% of [water + 0.1% HCO2H] to 5% of [water + 0.1% HCO2H] and [CH3CN] 95% in 5 minutes, finally in these conditions for 2 minutes; T = 40 ° C; flow rate = 1 ml / minute; LC / MS -ES (-) analysis: performed on a Supelcosil ABZ + Plus device (33 x 4.6 mm, 3 µm) (mobile phase: 100% of [water + 0.05% NH3] for 1 minute, then from 100% of [water + 0.05% NH3] to 5% of [water + 0.05% NH3] and 95% of [CH3CN] in 5 minutes, finally under these conditions for 2 minutes; T = 40 ° C; flow rate = 1 ml / minute.] In the mass spectra only a peak of the molecular ion pool is reflected.The optical rotations were determined at 20 ºC with a Jasco DIP360 device (l = 10 cm, cuvette volume = 1 ml, � = 589 nm) unless it is

indicate otherwise. Flash chromatography on silica gel was performed with silica gel 230-400 mesh provided by Merck AG Darmstadt, Germany or with previously packaged Varian cartridges Mega Be-Si or with previously packaged Biotage silica cartridges.

HPLC (walk-up) refers to HPLC analysis performed on a Luna C18 column (mobile phase: 100% of [water + 0.05% TFA] to 5% of [water + 0.05% TFA] and 95% of [CH3CN + 0.05% TFA] in 8 minutes; T = 40 ºC; flow rate = 1 ml / minute).

UPLC refers to the UPLC analysis performed on a UPLC Waters Acquity System. UPLC / EM refers to UPLC analysis performed on a UPLC Waters Acquity System coupled to a Waters ZQ EM Detector (single square), 100-1000 em range. UPLC mobile phase data:

Gradient before the sample organizer

A = H2O + 0.1% formic acid B = MeCN + 0.075% formic acid

Flow Time% A% B curve (minutes) (ml / minute)

one.

Initial 1,000 97.0 3.0 initial

2.

0.10 1,000 94.0 6.0 6

3.

0.60 1,000 30.0 70.0 6

Four.

1.10 1,000 1.0 99.0 6

5.

1.45 1,000 97.0 3.0 11

Gradient after the sample organizer (adjusted to provide the same retention times as those achieved before the installation of the sample organizer)

Flow Time% A% B Curve (minutes)

one.

Initial 1,000 97.0 3.0 Initial

2.

0.05 1,000 94.0 6.0 6

3.

0.57 1,000 30.0 70.0 6

Four.

1.06 1,000 1.0 99.0 6

5.

1.45 1,000 97.0 3.0 11

curve 6 = linear gradient curve 11 = change at the end

Waters Acquity 2996 PDA

Initial wavelength (nm) 210.00 Final wavelength (nm) 350.00 Resolution (nm) 2.4 Sampling rate (spectrum / s) 20,000 Filter response 0 Exposure time (ms) Automatic Interpolar 656 Yes Acquisition stop time (minutes) 1.50

TLC refers to thin layer chromatography on 0.25 mm plates of silica gel (60F-254 Merck) and visualized with UV light. For phase separations performed using microfiltration devices: phase separation cartridge with polypropylene frit from Whatman or Alltech. SCX means: SCX cartridge (loading 0.75 mmol \ g) of Varian.

The solutions were dried over anhydrous sodium sulfate.

The following abbreviations are used in the text: DCM = methylene chloride, Et2O = diethyl ether, EtOH = ethanol, MeOH = methanol, THF = tetrahydrofuran, TFA = trifluoroacetic acid, CH3CN = acetonitrile, std = saturated.

Description 1

(7R, 9aR) -7- (Hydroxymethyl) hexahydropyrazine [2,1-c] [1,4] oxazin-6,9-dione and (7R, 9aS) -7- (hydroxymethyl) hexahydropyrazine [2,1-c ] [1,4] oxazin-6,9-dione (D1)

image2 image2 OR image2 OR image2 image2 OR image2 image2 OHO

N

NOH OMe NN NBoc O OBoc O OH OH

N-Boc-morpholin-2-carboxylic acid (Astatech, 1.34 g, 5.80 mmol) was suspended in 15 ml of anhydrous dichloromethane, and treated with O-benzotriazol-1-yl-N tetrafluoroborate, N, N ', N'-tetramethyluronium (TBTU) (2.4 g, 7.47 mmol) and diisopropylethylamine (2 ml, 11.47 mmol). The reaction was stirred for 40 minutes. He prepared a

5 solution of D-serine methyl ester hydrochloride (1.8 g, 11.57 mmol) and diisopropylethylamine (2 ml, 11.47 mmol) in dichloromethane (15 ml) and added to the reaction mixture. The reaction was allowed to stir at room temperature overnight. The UPLC-EM analysis showed the conversion in the product. The reaction was diluted with dichloromethane (40 ml) and extracted with saturated NaHCO3 (2 x 40 ml), dried (Na2SO4), and the solvent was removed. The crude product was taken to the next stage without further purification.

10 It was dissolved in 20 ml of dichloromethane and treated with 10 ml of TFA. The reaction was stirred at room temperature and checked by UPLC-MS after 4 hours which showed the disappearance of the peak of the initial material, which was replaced by a new one for the unprotected species (m / z = 233, M + 1) . The reaction mixture was loaded as is in an SCX cartridge, washed with MeOH (4 column volumes) and eluted with 0.5 M methanolic ammonia. The basic, ninhydrin positive fractions were collected and the solvent was collected.

15 removed. The residue was dissolved in 10 ml of MeOH and stirred at 50 ° C under N2 overnight (16 hours). The reaction was cooled and a precipitate formed, which was collected by filtration to provide 370 mg of the title compound. Direct MS: m / z = 223 (M + Na).

1H NMR: consistent with the structure. Approx. from 60:40 between diastereoisomers:

1H NMR (400 MHz, DMSO-d6) � ppm 8.17 -8.26 (s, 0.4 H) 8.09 -8.17 (s, 0.6 H) 5.17 -5.25 (m, 0.4 H) 5.09

20 5.17 (m, 0.6 H) 3.95 -4.29 (m, 3 H) 3.60 -3.91 (m, 3 H) 3.33 -3.55 (m, 2 H ) 2.61 -2.90 (m, 0.6 H) 1.03 -1.15 (t, 0.4 H).

Description 2

(7S, 9aR) -Octahydropyrazine [2,1-c] [1,4] oxazin-7-ylmethanol and (7S, 9aS) -octahydropyrazine [2,1-c] [1,4] oxazin7-ylmethanol (D2)

image2 OR image2 OH

HON

N N

NO

OH OH

25

(7R, 9aR) -7- (Hydroxymethyl) hexahydropyrazine [2,1-c] [1,4] oxazin-6,9-dione and (7R, 9aS) -7- (hydroxymethyl) hexahydropyrazine [2,1-c ] [1,4] oxazin-6,9-dione (D1) (365 mg, 1.82 mmol) were treated with 20 ml of 1 M solution of BH3THF at room temperature. The suspension was refluxed for 17 hours and checked by direct MS, which showed complete conversion into the product. It was cooled to 0 ° C, and 2 ml of MeOH 30 was added slowly, followed by 1 ml of concentrated HCl (at pH <1). The solution was heated to 70 ° C, stirred for 2 hours and checked by direct MS. The solution was brought to room temperature, the solvent was removed and the residue was dissolved in MeOH (a few drops of water were added), loaded into an SCX cartridge, washed with MeOH (5 column volumes) and eluted with 2M methanolic ammonia. Ninhydrin positive fractions were collected and the solvent removed, leaving the title product as an oil.

35 transparent. 320 mg Direct MS: m / z = 173 (M + 1).

1H NMR consistent with the structure, seems to be a mixture of diastereoisomers in a ratio approx. from 60:40:

1 H NMR (400 MHz, DMSO-d6) � ppm 4.50 -4.59 (m, 0.4 H) 4.38 -4.48 (m, 0.6 H) 2.96 -3.74 (m, 6 H) 2.57 2.78 (m, 2 H) 2.34 -2.41 (m, 2 H) 1.86 -2.28 (m, 4 H) 1.69 (t, 1 HOUR).

40 Description 3 and Description 4 (7S, 9aS) -7 - ({[(1,1-Dimethylethyl) (dimethyl) silyl] oxy} methyl) octahydropyrazine [2,1-c] [1,4] oxazine (D3) and (7S, 9aR) -7 - ({[(1,1-dimethylethyl) (dimethyl) silyl] oxy} methyl) octahydropyrazine [2,1-c] [1,4] oxazine (D4)

image2

OR image2

image2 OR

image2 OR image2

H

H

H

N

image2 N

N

image2

image2 N image2 N

image2 N

OH OTBDMS

OTBDMS

D22 D23

5 (7S, 9aR) -Octahydropyrazine [2,1-c] [1,4] oxazin-7-ylmethanol and (7S, 9aS) -octahydropyrazino [2,1-c] [1,4] oxazin-7-methanol (D2 ) (315 mg, 1.83 mmol) was dissolved in 10 ml of anhydrous dichloromethane and treated with Et3N (600 µL, 4.30 mmol) and TDBMSCl (590 mg, 3.91 mmol). The reaction was stirred overnight at room temperature (17 hours). It was diluted with dichloromethane (30 ml) and extracted with saturated NaHCO3 (2 x 20 ml). TLC analysis (EtOAc: MeOH 95: 5) showed 2 main products. The organic components were dried and the solvent was

10 removed leaving an oil, which was purified by flash chromatography (silica, EtOAc�EtOAc: MeOH 90:10). Two products were isolated:

(7S, 9aS) -7 - ({[(1,1-Dimethylethyl) (dimethyl) silyl] oxy} methyl) octahydropyrazine [2,1-c] [1,4] oxazine (D3), 253 mg. Direct MS: m / z = 287 (M + 1).

1 H NMR (500 MHz, DMSO-d6) � ppm 3.72 -3.79 (m, 1 H) 3.62 -3.71 (m, 2 H) 3.37 -3.56 (m, 2 H) 2.99 (t, 1 15 H) 2.65 -2.78 (m, 1 H) 2.55 -2.64 (m, 1 H) 2.25 -2.44 (m, 3 H ) 2.02 -2.16 (m, 2 H) 1.90 -2.02 (m, 1 H) 0.75 0.90 (s, 9 H) -0.05 -0.05 (s, 6 H).

Identified as the cis isomer based on the cross peaks of ROESY.

(7S, 9aR) -7 - ({[(1,1-Dimethylethyl) (dimethyl) silyl] oxy} methyl) octahydropyrazine [2,1-c] [1,4] oxazine (D4), 202 mg. Direct MS: m / z = 287 (M + 1).

20 1H NMR (500 MHz, DMSO-d6) � ppm 3.68 (d, 1 H) 3.56 (d, 1 H) 3.47 (t, 1 H) 3.36 -3.43 (m , 2 H) 3.02 (t, 1 H) 2.68 -2.76 (m, 1 H) 2.62 -2.68 (m, 2 H) 2.50 -2.56 (m, 1 H) 2.22 (t, 1 H) 2.11 -2.18 (m, 1 H) 1.90 -1.97 (m, 1 H) 1.70 (t, 1 H) 0.84 ( s, 9 H) 0.02 (s, 6 H).

Identified as the trans isomer based on the cross peaks of ROESY.

Description 5

2- 2- 3,5-Bis (trifluoromethyl) phenyl] -N- [6 - [(7S, 9aS) -7 - ({[(1,1-dimethylethyl) (dimethyl) silyl] oxy} methyl) hexahydropyrazino [ 2,1-c] [1,4] oxazin-8 (1H) -yl] -4- (4-fluoro-2-methylphenyl) -3-pyridinyl] -N, 2-dimethylpropanamide (D5)

image2 OR image2 HN

CF3 image2 N image2 N

image2 OR

OTBDMS N CF3

image2

F

Procedure a):

(7S, 9aS) -7 - ({[(1,1-Dimethylethyl) (dimethyl) silyl] oxy} methyl) octahydropyrazine [2,1-c] [1,4] oxazine (D22) (250 mg, 0.872 30 mmol) was dissolved in 3.8 ml of toluene. To this solution was added 2- [3,5-bis (trifluoromethyl) phenyl] -N- [6-chloro-4- (4fluoro-2-methylphenyl) -3-pyridinyl] -N, 2-dimethylpropanamide [WO 2005 / 002577] (460 mg, 0.863 mmol),

followed by bis-tri-tert-butylphosphine palladium (110 mg, 0.215 mmol), hexadecyltrimethylammonium chloride (45 µl of a 25% aqueous solution) and sodium hydroxide solution (85 µl of a 50% aqueous solution, 0.85 mmol). The solution was degassed by 3 cycles of freezing, pumping and thawing, then stirred at 90 ° C. After 4 hours, analysis by UPLC / MS indicated conversion into the target compound and no trace

5 of the initial chloropyridine. The reaction was brought to room temperature, diluted with EtOAc (20 ml) and washed with saturated NaHCO3 (10 ml). The organic components were dried and the solvent evaporated. The product was isolated by flash chromatography (cyclohexane -> cyclohexane: EtOAc 85:15) as a white solid: 390 mg (0.498 mmol, 57%) which was taken to the next stage without further characterization.

Procedure b):

10 To a stirring solution of (7S, 9aS) -7 - ({[(1,1-dimethylethyl) (dimethyl) silyl] oxy} methyl) octahydropyrazine [2,1c] [1,4] oxazine (D107, 5 g, 17.45 mmol) in 150 ml of dry toluene at room temperature under a nitrogen atmosphere, a solution of 2- [3,5-bis (trifluoromethyl) phenyl] -N- [6-chloro-4- ( 4-fluoro-2-methylphenyl) -3-pyridinyl] N, 2-dimethylpropanamide (7.75 g, 14.54 mmol) in 50 ml of dry toluene, followed by sodium tert-butoxide (2.1 g, 21, 81 mmol) and bis (tri-tert-butyl phosphine) palladium (1.49 g, 2.908 mmol). The resulting mixture was heated to

15 reflux temperature for 4 hours. The mixture was allowed to cool to room temperature and filtered over Sterimat. The filtrate was then diluted with ethyl acetate (200 ml) and with sodium hydrogen carbonate (saturated solution, 200 ml). The phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 150 ml). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to a residue, which was purified by chromatography on silica gel eluting with 10-20% EtOAc / cyclohexane to provide the compound.

20 of the title in the form of light yellow foam (10.1 g).

UPLC / MS: peak at Tr = 1.26 minutes with m / z = 783.35 [M + H] +

HPLC (walk-up): Tr = 6.98 minutes (% of area = 98.22)

Description 6: N- (phenylmethyl) -D-methyl serinate (D102)

image4

The title compound was prepared according to the literature (ref. JOC, 1990, 55 (1), 111-122) starting from (D) -serine methyl ester hydrochloride (98%, from Aldrich). (D) Serine methyl ester hydrochloride (10 g, 0.065 mol) was suspended in 50 ml of anhydrous methanol and cooled to 0 ° C under a nitrogen atmosphere. Triethylamine (9 ml, 0.065 mol) was added dropwise, followed by benzaldehyde (6.6 ml, 0.065 mol). The reaction mixture was then heated and stirred at room temperature for 2 hours. Be

30 added sodium borohydride (4.85 g, 0.13 mol) in small portions for 2 hours. The resulting mixture was stirred at room temperature overnight. The mixture was then added slowly to 50 ml of HCl (20% solution) at 0 ° C and the resulting solution was washed with diethyl ether (50 ml). The aqueous phase was then brought to basic pH by adding solid potassium carbonate and extracted with diethyl ether (3 x 50 ml). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give the title compound.

35 in the form of colorless oil (10.95 g).

m / z = 210 [M + H] +.

Description 7: (3R) -3 - {[[(1R) -1- (hydroxymethyl) -2- (methyloxy) -2-oxoethyl] (phenylmethyl) amino] carbonyl} -4morpholinecarboxylate 1,1-dimethylethyl (name not preferred ) (D7)

image5

image6

To a stirring suspension of (R) -4-Boc-morpholin-3-carboxylic acid (30 g, 0.13 mol, of J&W PharmLab) in 500 ml of anhydrous DCM at room temperature under nitrogen atmosphere, were added in portions of N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (37.4 g, 0.195 moles) and hydrated 1-hydroxybenzotriazole (19.3 g, 0.133 moles). At the end of the addition, the suspension became an almost transparent solution. The mixture was stirred at room temperature for 45 minutes and then N- (phenylmethyl) -D-methyl serinate (D6, 28.6 g, 0.137 mol) and N, N-diisopropylethylamine (45.3 ml, 0.26) were added moles) in small portions. The mixture was stirred at room temperature for 26 hours and then ammonium chloride (saturated solution, 250 ml) and DCM (150 ml) were added. The phases were separated and the aqueous phase was extracted with DCM (3 x 150 ml) and

10 EtAc (1 x 200 ml). The combined organic extracts were washed with brine (2 x 500 ml), dried (Na2SO4), concentrated in vacuo and the residue was purified by silica gel chromatography eluting with 0 to 30% EtOAc / cyclohexane to provide the compound of title in the form of yellow oil (38.7 g).

UPLC / MS: peak at Tr = 0.62 minutes with m / z = 423.1 [M + H] +.

Description 8: (7R, 9aR) -7- (hydroxymethyl) -8- (phenylmethyl) hexahydropyrazino [2,1-c] [1,4] oxazin-6,9-dione) (D8)

To a stirring solution of (3R) -3 - {[[(1R) -1- (hydroxymethyl) -2- (methyloxy) -2-oxoethyl] (phenylmethyl) amino] carbonyl} -4morpholincarboxylate 1,1-dimethylethyl ( D7, 38.7 g, 0.092 mol) in 400 ml of DCM at room temperature, trifluoroacetic acid (68.3 ml, 0.92 mol) was added slowly. The resulting orange solution was stirred at room temperature overnight. It was then cooled by a water and ice bath and brought to pH = 7-8 by adding sodium hydrogen carbonate (saturated solution, 250 ml and as a solid). The phases were separated and the aqueous phase was extracted with DCM (3 x 300 ml). The combined organic extracts were dried (Na2SO4), concentrated in vacuo to provide a residue, which was dissolved in 270 ml of methanol and heated at 56-58 ° C for 2 hours. The mixture was then allowed to cool to room temperature and the solvent was removed in vacuo to provide a solid residue, which was treated with 100 ml of an 8/2 cyclohexane / EtOAc mixture. The

The resulting suspension was stirred at room temperature for 30-40 minutes and then the solid was filtered off and collected to give the title compound (18.7 g) as a white solid.

UPLC / MS: peak at Tr = 0.49 minutes with m / z = 291.09 [M + H] +.

1H NMR (400 MHz, DMSO-d6) � ppm 7.26-7.37 (m, 5 H) 5.41 (t, 1 H) 5.09 (d, 1 H) 4.31 (dd, 1 H) 4.23 (dd, 1 H) 4.01 -4.07 (m, 2 H) 3.69 -3.84 (m, 4 H) 3.59 (t, 1 H) 3.33 (td, 1 H) 2.85 (td, 1 H).

Description 9: [(7S, 9aS) -8- (phenylmethyl) octahydropyrazino [2,1-c] [1,4] oxazin-7-yl] methanol (D9)

image2 OH

N N

OH

To a stirring suspension of (7R, 9aR) -7- (hydroxymethyl) -8- (phenylmethyl) hexahydropyrazino [2,1-c] [1,4] oxazin-6,9dione) (D8, 18,7 g, 0.064 mol) in 190 ml of anhydrous THF at 0 ° C under a nitrogen atmosphere, 1 M solution of borane complex and THF, in THF, (385 ml, 0.386 mol) was added for 45 minutes keeping the internal temperature below 10 ºC. At the end of the addition the mixture became a colorless solution. The

The mixture was then allowed to warm to room temperature and then heated at 70 ° C for 28 hours.

The mixture was then allowed to cool to room temperature and then at 0 ° C by means of a water and ice bath. Then methanol (47 ml, 1.15 mol) and 6 M HCl (32 ml, 0.128 mol) were added slowly, with caution controlling gas evolution. The resulting mixture was then allowed to warm to room temperature and stirred overnight. The mixture was then heated at 55 ° C for 8 hours and then cooled to room temperature. The white precipitate was removed by filtration and the filtrate was concentrated in vacuo to provide a residue, which was dissolved in 50 ml of water and 100 ml of DCM. The white precipitate that had previously been filtered off was collected and dissolved in 70 ml of water and added to the previous mixture. The phases were separated and the aqueous phase was extracted with DCM (3 x 150 ml). The aqueous phase was then brought to pH = 7 by adding 250 ml of 3 N NaOH and extracted again with DCM (3 x 100 ml) and

15 ethyl acetate (3 x 200 ml). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give the title compound as a light yellow foam (16.9 g).

UPLC / MS: peak at Tr = 0.40 minutes with m / z = 263.13 [M + H] +

Description 10: (7S, 9aS) -7 - ({[(1,1-dimethylethyl) (dimethyl) silyl] oxy} methyl) -8- (phenylmethyl) octahydropyrazine [2,1c] [1,4] oxazine (D10 )

image7

Procedure a):

To a stirring solution of [(7S, 9aS) -8- (phenylmethyl) octahydropyrazino [2,1-c] [1,4] oxazin-7-yl] methanol (D9, 15.3 g, 0.058 mol) in 153 ml of DCM at room temperature, imidazole (4.76 g, 0.070 mol) and tert-butyldimethylsilyl chloride (8.35 g, 0.055 mol) were added. The resulting mixture was stirred at room temperature for 1 hour. Then imidazole (0.476 g, 5.8 mmol) and tert-butyldimethylsilyl chloride (8.35 g, 0.055 mol) were added a second time and the mixture was stirred overnight. Then imidazole (0.476 g, 0.006 mol) and tert-butyldimethylsilyl chloride (5.27 g, 0.035 mol) were added a third time and the mixture was stirred for a further 4 hours. DCM (153 ml) was added and then imidazole (2.4, 0.035 mol) and tert-butyldimethylsilyl chloride (5.27 g, 0.035 mol) were added a fourth time. The mixture was stirred overnight. Later

30 added water (150 ml) and sodium hydrogen carbonate (saturated solution, 150 ml) and the phases were separated. The aqueous phase was extracted with DCM (150 ml) and the combined organic extracts were dried (Na2SO4) and concentrated in vacuo to a residue, which was purified by silica gel chromatography eluting with 510% EtOAc / cyclohexane to provide the compound. of the title in the form of an oil (22.2 g).

1 H NMR (500 MHz, DMSO-d6) � ppm 7.32 -7.36 (m, 4 H) 7.24 -7.29 (m, 1 H) 4.00 (t, 1 H) 3, 90 (dd, 1 H)

35 3.88 (d, 1 H) 3.77 (dd, 1 H) 3.70 (d, 1 H) 3.52-3.58 (m, 1 H) 3.48-3.56 (m , 1 H) 3.07 (t, 1 H) 2.75 -2.83 (m, 2 H) 2.25 -2.37 (m, 4 H) 2.12 -2.23 (m, 2 H) 0.90 (s, 9 H) 0.08 (s, 3 H) 0.06 (s, 3 H).

HPLC (walk-up): Tr = 4,826 minutes (% area = 98.69).

Procedure b):

To a stirring solution of [(7S, 9aS) -8- (phenylmethyl) octahydropyrazino [2,1-c] [1,4] oxazin-7-yl] methanol (D9, 29,8

40 g, 0.114 mol) in 447 ml of DCM at room temperature, imidazole (9.27 g, 0.136 mol) and tert-butyldimethylsilyl chloride (42.7 g, 0.284 mol) were added. The resulting mixture was stirred at room temperature overnight. Water (300 ml), sodium hydrogen carbonate (saturated solution, 300 ml) and DCM (150 ml) were then added and the phases were separated. The aqueous phase was extracted with DCM (300 ml) and the combined organic extracts were dried (Na2SO4) and concentrated in vacuo to a residue, which was purified by chromatography on

45 silica gel eluting with 5-10% EtOAc / cyclohexane to provide the title compound as a light yellow oil (50.95 g).

HPLC (walk-up): Tr = 4,865 minutes (% of area = 99.55).

Description 11: (7S, 9aS) -7 - ({[(1,1-dimethylethyl) (dimethyl) silyl] oxy} methyl) octahydropyrazine [2,1c] [1,4] oxazine (D11)

image8

To a stirring solution of (7S, 9aS) -7 - ({[(1,1-dimethylethyl) (dimethyl) silyl] oxy} methyl) -8- (phenylmethyl)

5 octahydropyrazine [2,1-c] [1,4] oxazine (D10, 22.2 g, 0.059 mol) in 660 ml of methanol at room temperature under nitrogen atmosphere, palladium on carbon (10% by weight, wet, 6.28 g, 0.006 mol) and ammonium formate (37.2 g, 0.59 mol). The resulting mixture was stirred at 80 ° C for 1-1.5 hours. The resulting mixture was then allowed to cool to room temperature and filtered over Celite. The filtrate was concentrated in vacuo to give the title compound (16 g) as a pale yellow oil.

10 UPLC / EM: peak not visible by UV. Mass m / z = 287.18 [M + H] +.

CASS ID 8341, NMR and CL / MS

1 H NMR (500 MHz, DMSO-d6) � ppm 3.74 (t, 1 H) 3.62 -3.70 (m, 2 H) 3.48 (dd, 1 H) 3.39 -3, 46 (m, 1 H) 2.98 (t, 1 H) 2.67 -2.73 (m, 1 H) 2.60 (dd, 1 H) 2.40 (dd, 1 H) 2.26 -2.37 (m, 2 H) 2.23 (br. S., 1 H) 2.12 (dd, 1 H) 2.04 -2.10 (m, 1 H) 1.90 -2, 00 (m, 1 H) 0.81 (s, 9 H) -0.00 (s, 6 H).

15 Cross-peak pattern ROESY agrees with relative stereochemistry without.

20 Example 1

2- [3,5-Bis (trifluoromethyl) phenyl] -N- {4- (4-fluoro-2-methylphenyl) -6 - [(7S, 9aS) -7

(hydroxymethyl) hexahydropyrazine [2,1-c] [1,4] oxazin-8 (1H) -yl] -3-pyridinyl} -N, 2-dimethylpropanamide (E1)

OH image2 CF3 N

OR

HO N CF3

F

2- [3,5-Bis (trifluoromethyl) phenyl] -N- [6 - [(7S, 9aS) -7 - ({[(1,1-dimethylethyl) (dimethyl) silyl] oxy} methyl) hexahydropyrazine [2 ,one

25 c] [1,4] oxazin-8 (1H) -yl] -4- (4-fluoro-2-methylphenyl) -3-pyridinyl] -N, 2-dimethylpropanamide (D5) (390 mg, 0.498 mmol) It was dissolved in 17 ml of methanol. To this solution was added concentrated HCl (0.9 ml) at 0 ° C, and stirring was continued at room temperature for 3 hours (complete conversion). The reaction mixture was loaded into an SCX cartridge and washed with MeOH. The product was eluted with 0.5 M methanolic ammonia. Fractions containing product were evaporated, leaving the target compound as a white solid: 310 mg, 0.464

30 mmol, 93%.

UPLC / MS: m / z = 669 (M + 1).

1H NMR (DMSO-d6): � (ppm) 8.07-7.97 (s, 1H), 7.88-7.81 (s, 1H), 7.79-7.69 (br. S , 2H), 7.19-7.11 (d, 1H), 7.14-7.06 (br. S, 2H) 6.64-6.56 (s, 1H), 4.75-4, 65 (m, 1H), 4.31-4.13 (br. S, 1H), 4.15-4.01 (br. S, 1H), 3.80-3.68 (m, 3H), 3.58-3.49 (t, 1 H); 3.43-3.34 (m, 1 H); 3.18-3.09 (t, 1 H); 3.04-2.98 (d, 1 H); 2.68-2.58 (d, 1 H); 2.51-2.45

35 (s, 3 H); 2.20-2.13 (s, 3H); 2.29-2.00 (m, 4H); 1.54-1.39 (s, 3 H); 1.39-1.28 (s, 3H).

Example 2 2- [3,5-bis (trifluoromethyl) phenyl] -N- {4- (4-fluoro-2-methylphenyl) -6 - [(7S, 9aS) -7- (hydroxymethyl) hexahydropyrazine [2 , 1-c] [1,4] oxazin-8 (1H) -yl] -3-pyridinyl} -N, 2-dimethylpropanamide (E2)

image9

image10

To a solution of 2- [3,5-bis (trifluoromethyl) phenyl] -N- {4- (4-fluoro-2-methylphenyl) -6 - [(7S, 9aS) -7- (hydroxymethyl)

5 hexahydropyrazine [2,1-c] [1,4] oxazin-8 (1H) -yl] -3-pyridinyl} -N, 2-dimethylpropanamide (E1) (300 mg, 0.449 mmol) in 2 ml of diethyl ether 0.6 ml of a 1 M solution of HCl in diethyl ether was added. A white precipitate formed. The solvent and excess HCl were removed in a stream of nitrogen and the residue was triturated with 1 ml of pentane: Et2O 1: 1. The white solid was collected by filtration and left under high vacuum to give the title compound 280 mg, 0.397 mmol, 88% yield.

10 1 H NMR (500 MHz, DMSO-d6) � ppm 10.24 (br. S., 1 H) 8.03 (br. S., 1 H) 7.90 (br. S., 1 H) 7.55 -7.82 (m, 2 H) 6.89 -7.24 (m, 3 H) 6.77 (br. S., 1 H) 4.65 (br. S., 1 H) 4.45 (br. S., 1 H) 3.92 -4.15 (m, 2 H) 3.76 -3.90 (m, 2 H) 3.34 -3.55 (m, 2 H ) 3.09 -3.36 (m, 2 H) 2.84 -3.04 (m, 1 H) 2.49 -2.62 (m, 2 H) 2.01 -2.30 (m, 6 H) 1.10 1.58 (m, 8 H).

�D (c = 0.5 in MeOH) = -39.6 obtained using a polarimeter polAAR 3000, � = 589.4 nm, volume of the

15 cuvette = 1.3 ml, travel length, l = 1 dm. (This value was determined with a different sample, spectroscopically equal to the one described above and prepared analogously).

Biological data

The compounds of the invention can be analyzed to determine in vitro biological activity according to the following tests:

NK binding affinity measurement

The NK binding affinity of the compounds of the invention was determined using the following proximity scintillation assay (SPA) (see HM Sarau et al., J. Pharmacol. Experimental Therapeutics 1997, 35 281 (3), 1303-1311 ; HM Sarau et al., J. Pharmacol. Experimental Therapeutics 2000, 295 (1), 373-381; GA

M. Giardina et al. J. Med. Chem 1999, 42, 1053-1065). 125I-Substance P, 125I-NKA and 125I- [MePhe7] NKB were used in the NK1, NK2 and NK3 receptor binding SPA, respectively. WGA-SPA Polystyrene Lead (Amersham Biosciences) beads were mixed with plasma membrane prepared from CHO cell lines expressing NK1, NK2 or NK3 with a ratio between beads and membrane of 20: 1 (w / w) in 40 buffer Test (75 mM Tris at pH 7.8, 75 mM NaCl, 4 mM MnCl2, 1 mM EDTA, 0.05% Chaps, 1 mM PMSF). The mixture was introduced on ice for 20 minutes allowing formation of the membrane complex and beads before adding BSA at a final concentration of 1%. After another 20 minutes of incubation on ice, the membrane and pearl complex was washed twice and suspended in assay buffer. Then 125I labeled ligands were added to the membrane complex and beads. Then 10 µl of the resulting mixture was dispensed into each well of a 384-well Greiner plate of reduced volume with 100 nl of compound previously dispensed in 100% DMSO. The plates were then sealed and centrifuged at 1100 rpm. After 2-3 hours of incubation at room temperature with stirring, the plates were centrifuged for 2 minutes at 1100 rpm and measured in a Viewlux imager (PerkinElmer) for 5 minutes with a 618 nm filter. Inhibition of the binding of the radioactive ligand to its respective receptor is

50 measured by signal reduction. The pKi was calculated using the Kd of each radioactive ligand that was determined in a different experiment.

Measurement of functional affinity for NK:

Calcium mobilization assay in (FLIPR): NK receptors expressed in Bacman

The compounds of the invention were further characterized with a functional assay using FLIPR technology.

55 for the determination of its inhibitory effect of intracellular calcium release induced by the interaction of NK receptors with their respective ligands. The studies used transiently transduced human U2OS cells with recombinant BacMan viruses expressing the NK1, NK2 and NK3 receptors (see JP Condreay et al., Proc. Natl. Acad. Sci. USA 1999, 96 (1): 127 -132). In summary, U2OS cells were collected from tissue culture flasks, resuspended with a cell density of 200-300K / ml and mixed with recombinant BacMan viruses carrying the NKR gene with a ratio between virus and 1% cells (v / v). After 10K-15K cells / well were seeded in a 384-well Greiner bio-one plate in culture medium (DMEM with 10% FBS), they were incubated overnight in CO2 at 37 ° C. After aspirating the medium, the cells were charged 18-24 hours later with a Calcium 3 dye cytoplasmic calcium indicator (Molecular Devices Co.) in 30 l / well buffer (Hank's balanced salts with 20 mM Hepes) and incubated in CO2 at 37 ° C for 60 minutes. Then 10 µl / well of assay buffer (Hank's balanced salts with 20 mM Hepes) containing different concentrations of compounds were added to the cells for incubation for 30 minutes at 37 ° C. Finally, 10 µl / well of NKR ligands in assay buffer containing 0.1% BSA were added to the cells and the fluorescent signal was read with a FLIPR system. Substance P, NKA and NKB peptides were used as ligands for the NK1, NK2 and NK3 receptors, respectively. The IC50 values of each compound were determined by an 11-point inhibition curve and 3-fold dilution. The potency of each antagonist (fpKi) was calculated from pCI50 using the Cheng-Prusoff equation using the EC50 of the ligand determined in a different experiment.

Measurement of functional affinity for NK3

Calcium mobilization assay in (FLIPR): NK receptors stably expressed

Human cloned neuroquinine 3 (NK3) receptors stably expressed in human embryonic kidney cells (HEK 293) were maintained in Minimum Essential Medium (MEM, 31095-029 Invitrogen Life Technologies, Paisley, UK) supplemented with fetal bovine serum at 5%, 1% L-glutamine and 400-500 µg of geneticin and were subcultured using Accutase (PAA Labs, Austria). The cells were maintained at 37 ° C 5% CO2 / O2 with a humidified incubator. Changes in intracellular Ca2 + were determined using a Fluorescence Imaging Plate Reader (FLIPR) fluorescent imaging plate reader (Molecular Devices, Sunnyvale CA, USA) by a procedure similar to that described by Jerman et al., ( 2001). HEK 293 cells expressing the human NK3 receptor stably were seeded in 96-well plates coated with transparent base poly-d-lysine and black walls (Costar, United Kingdom) at a density of 25,000 cells per well incubated overnight . Cells were incubated (37 ° C for 60 minutes) with Calcium Plus Reagent (Molecular Devices) in Tyrodes buffer (NaCl, 145 mM; KCl, 2.5 mM; HEPES, 10 mM; Glucose, 10 mM; MgCl2, 1.2 mM; CaCl2, 1.5 mM) containing probenecid (2.5 mM), before incubating (30 minutes at 37 ° C) or with buffer or with antagonist (50 µl). The plates were then introduced into the FLIPR and 50 µl of NKB (final concentration of 10 pM -1 µM) was added and the changes in fluorescence were monitored. The maximum changes in fluorescence occurred in the first 5 seconds and were expressed after subtracting the initial level. The concentration response curves were analyzed using a 4-parameter logistic equation (GraphPad Prism, GraphPad Software Inc.) obtaining the pCE50 values (-log CE50), the pA2 values were obtained by Schild analysis. The data is the mean ± d.t. from the average of three different experiments.

[3 H] -inositol phosphate accumulation assay

The accumulation of phosphates of [3 H] -inositol was measured using the methodology of Brandish et al. (2003). In summary, human osteosarcoma cells (U-2OS cells) were grown in Dulbecco-modified Eagle's medium (DMEM) with 10% fetal calf serum. The cells were maintained at 5% CO2 / O2 with a humidified incubator at 37 ° C. All cell culture reagents were obtained from Invitrogen, Paisley, United Kingdom. U-2OS cells were grown to confluence, collected, and suspended in growth medium at a density of 250,000 cells per ml. Human Bacmam NK3 virus was then added at a concentration of 50 plaque forming units per cell. 25,000 cells were seeded per well in 96-well plates of transparent base and black walls (Corning Costar, United Kingdom) and incubated overnight.

After aspiration of the growth medium, the cells were washed with 2 x 200 µl of test medium without inositol (IF), 3% bovine serum albumin, 2 µM L-Glutamine. The cells were incubated for 16 hours with DMEM without inositol in the presence of 1 µCi [3 H] -mio-inositol per well (Amersham United Kingdom).

The growth medium was then aspirated and the cells were washed with 2 x 200 µl of DMEM IF. Cells were pre-incubated (30 minutes, 37 ° C) in the absence or presence of test compounds before the addition of various concentrations of NKB (0.1 nM-10 mM) in the presence of LiCl (5 mM). After 30 minutes of incubation with the agonist, the assay was terminated by aspiration of the test medium and the addition of 200 μl of 0.1 M formic acid to the cells. After one hour of incubation, 20 µl aliquots were mixed with 80 µl of yttrium silicate beads in solid white beak-plates (PerkinElmer). The plates were shaken gently for 1 hour before allowing the pearl mixture to settle for 2 hours. The plates were counted in a TopCount (PerkinElmer). The data is presented in terms of the percentage of the maximum response to NKB. Response curves as a function of concentration were analyzed using an equation

4-parameter logistics (GraphPad Prism, GraphPad Software Inc). PA2 values were obtained by Schild analysis. The data is the mean ± d.t. from the average of three different experiments.

Claims (20)

 Results The compounds of Examples E1 and E2 were analyzed in the NK1 binding affinity assay and showed a binding affinity> 8.5 pKi. 1. A compound that is 2- [3,5-bis (trifluoromethyl) phenyl] -N- {4- (4-fluoro-2-methylphenyl) -6 - [(7S, 9aS) -7 (hydroxymethyl) hexahydropyrazine [ 2,1-c] [1,4] oxazin-8 (1H) -yl] -3-pyridinyl} -N, 2-dimethylpropanamide image 1 or a pharmaceutically acceptable salt thereof. 2. A compound that is 2- [3,5-bis (trifluoromethyl) phenyl] -N- {4- (4-fluoro-2-methylphenyl) -6 - [(7S, 9aS) -7 (hydroxymethyl) hexahydropyrazine [ 2,1-c] [1,4] oxazin-8 (1H) -yl] -3-pyridinyl} -N, 2-dimethylpropanamide. image 1 3. A compound or a pharmaceutically acceptable salt thereof as defined in claim 1 or 2 for use in therapy.

Four.

A compound or a pharmaceutically acceptable salt thereof as defined in claim 1 or 2 for use in the treatment of psychotic disorders.

5.

A compound or a pharmaceutically acceptable salt thereof as defined in claim 4, wherein the psychotic disorder is schizophrenia.

A compound or a pharmaceutically acceptable salt thereof as defined in claim 1 or 2 for use in the treatment of depressive disorders. 7. A compound or a pharmaceutically acceptable salt thereof as defined in claim 1 or 2 for use in the treatment of bipolar disorders. 8. A compound or a pharmaceutically acceptable salt thereof as defined in claim 1 or 2 for use in the treatment of alcohol-related disorders.

9.

A compound or a pharmaceutically acceptable salt thereof as defined in claim 8, wherein the alcohol-related disorder is alcohol dependence.

10.

The use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 in the manufacture of a medicament for the treatment of psychotic disorders.

The use of a compound or a pharmaceutically acceptable salt thereof as defined in claim 10, wherein the psychotic disorder is schizophrenia.

12.

The use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 in the manufacture of a medicament for the treatment of depressive disorders.

13.

The use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 in the manufacture of a medicament for the treatment of bipolar disorders.

14.

The use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 in the manufacture of a medicament for the treatment of alcohol-related disorders.

fifteen.

The use of a compound or a pharmaceutically acceptable salt thereof as defined in claim 14, wherein the alcohol-related disorder is alcohol dependence.

16.

A pharmaceutical composition comprising a compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

17.

A pharmaceutical composition for use in the treatment of psychotic disorders comprising a compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

18.

A pharmaceutical composition according to claim 17, wherein the psychotic disorder is schizophrenia.

19.

A pharmaceutical composition for use in the treatment of depressive disorders, comprising a compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

twenty.

A pharmaceutical composition for use in the treatment of bipolar disorders, comprising a compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

twenty-one.

A pharmaceutical composition for use in the treatment of alcohol-related disorders, comprising a compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

22

A pharmaceutical composition according to claim 21, wherein the alcohol-related disorder is alcohol dependence.