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WO2010133569A1 - Dérivés d'azabicyclo[4.1.0]heptane - Google Patents

Dérivés d'azabicyclo[4.1.0]heptane Download PDF

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Publication number
WO2010133569A1
WO2010133569A1 PCT/EP2010/056774 EP2010056774W WO2010133569A1 WO 2010133569 A1 WO2010133569 A1 WO 2010133569A1 EP 2010056774 W EP2010056774 W EP 2010056774W WO 2010133569 A1 WO2010133569 A1 WO 2010133569A1
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WIPO (PCT)
Prior art keywords
compound
dichlorophenyl
disorder
azabicyclo
mmol
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PCT/EP2010/056774
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English (en)
Inventor
Giorgio Bonanomi
Fabrizio Micheli
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Glaxo Group Ltd
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Glaxo Group Ltd
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Publication of WO2010133569A1 publication Critical patent/WO2010133569A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to novel compounds, processes for their preparation, intermediates used in these processes, pharmaceutical compositions containing the compounds and their use in therapy as inhibitors of serotonin (5-HT), dopamine (DA) and norepinephrine (NE) reuptake.
  • 5-HT serotonin
  • DA dopamine
  • NE norepinephrine
  • the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof
  • R1 is H, halo, C-
  • R3 is 3,4-dichlorophenyl or naphthyl;
  • R4 is C-
  • R5 is C-
  • the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof
  • R1 is H, halo, C-
  • R4 is C-
  • R ⁇ is C-
  • R ⁇ and R ⁇ together with the atoms to which they are attached, form a tetrahydrofuran ring.
  • alkyl is a univalent radical derived by removal of a hydrogen atom from an acyclic alkane of formula C n H2n+2-
  • .galkyl is alkyl comprising from 1 to 6 carbon atoms.
  • Alkyl may be straight chain or branched chain. Examples of alkyl are methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso-pentyl and neo-pentyl.
  • halo is a fluorine, chlorine, bromine or iodine radical, i.e. fluoro, chloro, bromo or iodo.
  • haloalkyl is alkyl (as defined hereinbefore) substituted by one or more halo substituents (as defined hereinbefore), which halo substituents may be the same or different.
  • .galkyl is haloalkyl consisting of 1 to 6 carbon atoms.
  • haloalkyl are monofluoromethyl, difluoromethyl, trifluoromethyl and 1-chloro-2-fluoroethyl.
  • alkoxy is a group of formula "R-O-" where R is alkyl (as defined hereinbefore).
  • .galkoxy is alkoxy consisting of 1 to 6 carbon atoms.
  • alkoxy examples include methoxy, ethoxy, n-propoxy, n-butoxy, n-pentoxy, n- hexyloxy, iso-propoxy, iso-butoxy, sec-butoxy, tert-butoxy, iso-pentoxy and neo- pentoxy.
  • alkenyl is a univalent radical derived by removal of a hydrogen atom from an acyclic alkene.
  • C2-6alkenyl is alkenyl consisting of 2 to 6 carbon atoms.
  • Alkenyl contains one or more double bonds and may be straight or branched chain. Examples of alkenyl are vinyl, 1-propenyl, allyl, 1 ,3-butadienyl, isopropenyl and 3-methylbut-2-enyl).
  • cycloalkyl is a univalent radical derived by removal of a hydrogen atom from a monocyclic cycloalkane.
  • C3_gcycloalkyl is cycloalkyl consisting of 3 to 6 ring-carbon atoms.
  • Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 3 and -CH(R 4 )(OR 5 ) i.e. the radicals attached to the two fused carbons
  • R 3 and -CH(R 4 )(OR 5 ) possess a cis relationship, i.e. both R3 and -CH(R 4 )(OR5) are on the same face of the bicyclic ring system.
  • R ⁇ and R ⁇ are different, the carbon to which they are attached is stereogenic.
  • the carbon attached to R 4 is also stereogenic. It will be appreciated therefore that compounds of formula (I) may exist in a variety of stereoisomers.
  • Mixtures of enantiomers may be separated by appropriate optical resolution techniques (for example chiral HPLC).
  • R ⁇ and R ⁇ are H.
  • R ⁇ is 3,4-dichlorophenyl. In an embodiment, R ⁇ is C-
  • the compound defined in the first aspect is selected from the list:
  • the compounds of formula (I) as defined in the first aspect contain a basic centre and may form non-toxic acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, with carboxylic acids or with organo-sulfonic acids.
  • inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, with carboxylic acids or with organo-sulfonic acids.
  • Examples include the HCI, HBr, HI, sulfate or bisulfate, nitrate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, saccharate, fumarate, maleate, lactate, citrate, tartrate, gluconate, camsylate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate salts.
  • suitable pharmaceutical salts see Berge et al, J.
  • the salt is pharmaceutically acceptable.
  • pro-drugs examples include Drugs of Today, Volume 19, Number 9, 1983, pp 499 - 538 and in Topics in Chemistry, Chapter 31 , pp 306 - 316 and in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference). It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as “pro- moieties”, for example as described by H. Bundgaard in "Design of Prodrugs” (the disclosure in which document is incorporated herein by reference) may be placed on appropriate functionalities when such functionalities are present within the compounds defined in the first aspect. Therefore, in a further aspect, the invention provides a prodrug of a compound defined in the first aspect.
  • the compounds defined in the first aspect, their salts or prodrugs, may exist in solvated or hydrated form. Therefore, in a further aspect, the invention provides a solvate or hydrate of a compound defined in the first aspect or a salt thereof.
  • the compounds of formula (I) and their salts, as defined in the first aspect or solvates or hydrates of either, may exist in one or more polymorphic form. Therefore, in a further aspect, the invention provides a polymorph of a compound of formula (I) defined in the first aspect or their salts, or a polymorph of a solvate or hydrate of a compound of formula (I) defined in the first aspect, or a salt thereof.
  • compounds of formula (I) as defined in the first aspect their salts and prodrugs; any solvates or hydrates of any salt or prodrug; and any polymorph of any compound, salt, solvate or hydrate are referred to as "compounds of the invention”.
  • the term “compounds of the invention” also includes all embodiments of the first aspect.
  • the invention also includes all suitable isotopic variations of a compound of the invention.
  • An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 0, 35 S, 18 F and 36 CI, respectively.
  • isotopic variations of the invention are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e., 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances.
  • Isotopic variations of the compounds of the invention can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the Experimental section hereafter using appropriate isotopic variations of suitable reagents.
  • Compounds of formula (V) may also be prepared according to reaction scheme 6 from compounds of formula (Vl) by treatment with UAIH4 or DIBAL-H in THF between 0 0 C and room temperature.
  • Compounds of formula (Via), i.e. compounds of formula (Vl) wherein R 1 is alkoxy, may be prepared according to reaction scheme 7 by akylating compounds of formula (VII) under standard conditions, e.g. using NaH in DMF between O 0 C and room temperature,
  • VIM Compounds of formula (VIb) may be obtained according to reaction scheme 9 from compounds of formula (VII) by an oxidation process. Typical conditions comprise treatment with Jones reagent at 0 0 C in DCM or Dess-Martin periodinane.
  • Compounds of formula (VId) may be prepared according to reaction scheme 1 1 from compounds from compounds of formula (IX), by standard treatment with Selectfluor (N-fluoro-N'-chloromethyl triethylenediamine bis tetrafluoroborate).
  • a specific enantiomer or diastereoisomer of a compound of the invention may be obtained for example by optical resolution of a mixture of enantiomers or diastereoisomers using conventional methods, such as chiral chromatography.
  • the compounds of the invention may be used to treat diseases or conditions for which inhibition of 5-HT, DA and NE re-uptake is beneficial, i.e. inhibition of their respective monoamine transporter proteins referred to as SERT for 5-HT, DAT for DA and NET for NE. Therefore according to a further aspect, the invention provides a compound of the invention for use in treating a disease or condition.
  • the disease or condition is a human disease or condition.
  • the invention provides a compound of the invention for use in treating a disease or condition for which inhibition of monoamine neurotransmitter re-uptake is beneficial, i.e. inhibition of one or more of SERT, NET and DAT.
  • the disease or condition which may benefit from inhibition of monoamine neurotransmitter re-uptake i.e. inhibition of one or more of 5-HT, DA and NE re-uptake
  • DSM-IV 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 (ICD-10).
  • DSM-IV American Psychiatric Association
  • ICD-10 International Classification of Diseases, 10th Edition
  • compression includes:
  • Depression and mood disorders including Major Depressive Episode, Manic Episode, Mixed Episode and Hypomanic Episode; Depressive Disorders including Major Depressive Disorder, Dysthymic Disorder (300.4), Depressive Disorder Not Otherwise Specified (311 ); Other Mood Disorders including Mood Disorder Due to a General Medical Condition (293.83) which includes the subtypes With Depressive Features, With Major Depressive-like Episode, With Manic Features and With Mixed Features), Substance-Induced Mood Disorder (including the subtypes With
  • Bipolar Disorders including Bipolar I Disorder, Bipolar Il Disorder (Recurrent Major Depressive Episodes with Hypomanic Episodes) (296.89), Cyclothymic Disorder (301.13) and Bipolar Disorder Not Otherwise Specified (296.80);
  • anxiety disorders includes:
  • subject related disorder includes:
  • Substance-related disorders including Substance Use Disorders such as Substance Dependence, Substance Craving and Substance Abuse; Substance-Induced Disorders such as Substance Intoxication, Substance Withdrawal, Substance- Induced Delirium, Substance-Induced Persisting Dementia, Substance-Induced Persisting Amnestic Disorder, Substance-Induced Psychotic Disorder, Substance- Induced Mood Disorder, Substance-Induced Anxiety Disorder, Substance-Induced sexual Dysfunction, Substance-Induced Sleep Disorder and Hallucinogen Persisting Perception Disorder (Flashbacks); Alcohol-Related Disorders such as Alcohol
  • Alcohol Abuse (305.00
  • Alcohol Intoxication 303.00
  • Alcohol Withdrawal (291.81 )
  • Alcohol Intoxication Delirium Alcohol Withdrawal Delirium
  • Alcohol-Induced Persisting Dementia Alcohol-Induced Persisting Amnestic Disorder, Alcohol-Induced Psychotic Disorder, Alcohol-Induced Mood Disorder, Alcohol- Induced Anxiety Disorder, Alcohol-Induced Sexual Dysfunction, Alcohol-Induced Sleep Disorder and Alcohol-Related Disorder Not Otherwise Specified (291.9);
  • Amphetamine or Amphetamine-I_ike-Related Disorders such as Amphetamine Dependence (304.40), Amphetamine Abuse (305.70), Amphetamine Intoxication (292.89), Amphetamine Withdrawal (292.0), Amphetamine Intoxication Delirium, Amphetamine Induced Psychotic Disorder, Amphetamine-Induced Mood Disorder, Amphetamine-
  • Opioid-Related Disorders such as Opioid Dependence (304.00), Opioid Abuse (305.50), Opioid Intoxication (292.89), Opioid Withdrawal (292.0), Opioid Intoxication Delirium, Opioid-lnduced Psychotic Disorder, Opioid-lnduced Mood Disorder, Opioid- Induced Sexual Dysfunction, Opioid-lnduced Sleep Disorder and Opioid-Related Disorder Not Otherwise Specified (292.9); Phencyclidine (or Phencyclidine-Like)- Related Disorders such as Phencyclidine Dependence (304.60), Phencyclidine Abuse (305.90), Phencyclidine Intoxication (292.89), Phencyclidine Intoxication Delirium, Phencyclidine-lnduced Psychotic Disorder, Phencyclidine-
  • Sleep disorder includes:
  • Sleep disorders including primary sleep disorders such as Dyssomnias such as Primary Insomnia (307.42), Primary Hypersomnia (307.44), Narcolepsy (347), Breathing-Related Sleep Disorders (780.59), Circadian Rhythm Sleep Disorder
  • treating disorder includes:
  • Eating disorders such as Anorexia Nervosa (307.1 ) including the subtypes Restricting Type and Binge-Eating/Purging Type; Bulimia Nervosa (307.51 ) including the subtypes Purging Type and Nonpurging Type; Obesity; Compulsive Eating Disorder; Binge Eating Disorder; and Eating Disorder Not Otherwise Specified (307.50):
  • Attention-Deficit/Hyperactivity Disorder includes:
  • Attention-Deficit/Hyperactivity Disorder including the subtypes Attention-Deficit /Hyperactivity Disorder Combined Type (314.01 ), Attention-Deficit /Hyperactivity Disorder Predominantly Inattentive Type (314.00), Attention-Deficit /Hyperactivity Disorder Hyperactive-Impulse Type (314.01 ) and Attention-Deficit /Hyperactivity Disorder Not Otherwise Specified (314.9); Hyperkinetic Disorder; Disruptive
  • Behaviour Disorders such as Conduct Disorder including the subtypes childhood- onset type (321.81 ), Adolescent-Onset Type (312.82) and Unspecified Onset (312.89), Oppositional Defiant Disorder (313.81 ) and Disruptive Behaviour Disorder Not Otherwise Specified; and Tic Disorders such as Tourette's Disorder (307.23);
  • Cognitive impairment includes:
  • Cognition impairment including cognition impairment in other diseases such as schizophrenia, bipolar disorder, depression, other psychiatric disorders and psychotic conditions associated with cognitive impairment, e.g. Alzheimer's disease;
  • Sexual dysfunctions including 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 ); Sexual Dysfunction Not Otherwise Specified (302.70); paraphilias such as Exhibitionism (302.4), Fetishism (302.81 ), Frotteurism (302.89), Pedophilia (302.2), Sexual Masochism (302.83), sexual Sadism (302.84), Transvestic Fetishism (302.3), Voyeurism (302.82) and Paraphilia Not Otherwise Specified (302.9); gender identity disorders such as Gender Identity Disorder in Children (302.6) and Gender Identity Disorder in Adolescents or Adults (302.85); and
  • Obsessive compulsive spectrum disorder includes:
  • Obsessive compulsive spectrum disorder including Obsessive compulsive disorders (300.3), somatoform disorders including body dysmorphic disorder (300.7) and hyperchondriasis (300.7), bulimia nervosa (307.51 ), anorexia nervosa (307.1 ), eating disorders not elsewhere classified (307.50) such as binge eating, impulse control disorders not elsewhere classified (including intermitted explosive disorder (312.34), compulsive buying or shopping, repetitive self-mutilation, onychophagia, psychogenic excoriation, kleptomania (312.32), pathological gambling (312.31 ), trichotillomania (312.39) and internet addiction), paraphilia (302.70) and nonparaphilic sexual addictions, Sydeham's chorea, torticollis, autistic disorders (299.0), compulsive hoarding, and movement disorders, including Tourette's syndrome (307.23).
  • somatoform disorders including body dysmorphic disorder (300.7) and hyperchondriasis (300.7
  • compounds of the invention may be useful as analgesics.
  • they may be useful in the treatment of chronic inflammatory pain (e.g. pain associated with rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis); musculoskeletal pain; lower back and neck pain; sprains and strains; neuropathic pain; sympathetically maintained pain; myositis; pain associated with cancer and fibromyalgia; pain associated with migraine; pain associated with influenza or other viral infections, such as the common cold; rheumatic fever; pain associated with functional bowel disorders such as non-ulcer dyspepsia, non-cardiac chest pain and irritable bowel syndrome; pain associated with myocardial ischemia; post operative pain; headache; toothache; and dysmenorrhea.
  • chronic inflammatory pain e.g. pain associated with rheumatoid arthritis, osteoarthritis, rheumatoid
  • Neuropathic pain syndromes can develop following neuronal injury and the resulting pain may persist for months or years, even after the original injury has healed.
  • Neuronal injury may occur in the peripheral nerves, dorsal roots, spinal cord or certain regions in the brain.
  • Neuropathic pain syndromes are traditionally classified according to the disease or event that precipitated them.
  • Neuropathic pain syndromes include: diabetic neuropathy; sciatica; non-specific lower back pain; multiple sclerosis pain; fibromyalgia; HIV-related neuropathy; post-herpetic neuralgia; trigeminal neuralgia; and pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions.
  • neuropathic pain are incredibly heterogeneous and are often described as spontaneous shooting and lancinating pain, or ongoing, burning pain.
  • pain associated with normally non-painful sensations such as "pins and needles" (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static or thermal allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia).
  • Compounds of the invention may also be useful in the amelioration of inflammatory disorders, for example in the treatment of skin conditions (e.g. sunburn, burns, eczema, dermatitis, psoriasis); ophthalmic diseases such as glaucoma, retinitis, retinopathies, uveitis and of acute injury to the eye tissue (e.g. conjunctivitis); lung disorders (e.g. asthma, bronchitis, emphysema, allergic rhinitis, respiratory distress syndrome, pigeon fancier's disease, farmer's lung, chronic obstructive pulmonary disease, (COPD); gastrointestinal tract disorders (e.g.
  • aphthous ulcer Crohn's disease, atopic gastritis, gastritis varialoforme, ulcerative colitis, coeliac disease, regional ileitis, irritable bowel syndrome, inflammatory bowel disease, gastroesophageal reflux disease); other conditions with an inflammatory component such as migraine, multiple sclerosis, myocardial ischemia.
  • compounds of the invention are useful in the treatment of depression and anxiety disorders.
  • compounds of the invention are useful in the treatment of depression.
  • Treatment includes prophylaxis, where this is appropriate for the relevant condition(s).
  • the compounds of the invention may also be used in combination with other therapeutic agents.
  • the invention thus provides, in a further aspect, a combination comprising a compound of the invention together with a further therapeutic agent.
  • the compounds of the invention may 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 benztropine, biperiden, procyclidine and trihexyphenidyl), antihistamines (such as diphenhydramine) and dopaminergics (such as amantadine); iii) antidepressants; iv) anxiolytics; and v) cognitive enhancers for example cholinesterase inhibitors (such as tacrine, donepezil, rivastigmine and galantamine).
  • anticholinergics such as benztropine, biperiden, procyclidine and trihexyphenidyl
  • antihistamines such as diphenhydramine
  • dopaminergics such as amantadine
  • antidepressants such as amantadine
  • iv) anxiolytics such as anxio
  • the compounds of the invention may be used in combination with antidepressants to treat or prevent depression and mood disorders.
  • the compounds of the invention may be used in combination with the following agents to treat or prevent bipolar disease: i) mood stabilisers; ii) antipsychotics; and iii) antidepressants.
  • the compounds of the invention may be used in combination with the following agents to treat or prevent anxiety disorders: i) anxiolytics; and ii) antidepressants.
  • the compounds of the invention may be used in combination with the following agents to improve nicotine withdrawal and reduce nicotine craving: i) nicotine replacement therapy for example a sublingual formulation of nicotine beta- cyclodextrin and nicotine patches; and ii) bupropion.
  • the compounds of the invention may be used in combination with the following agents to improve alcohol withdrawal and reduce alcohol craving: i) NMDA receptor antagonists for example acamprosate; ii) GABA receptor agonists for example tetrabamate; and iii) Opioid receptor antagonists for example naltrexone.
  • the compounds of the invention may be used in combination with the following agents to improve opiate withdrawal and reduce opiate craving: i) opioid mu receptor agonist/opioid kappa receptor antagonist for example buprenorphine; ii) opioid receptor antagonists for example naltrexone; and iii) vasodilatory antihypertensives for example lofexidine.
  • the compounds of the invention may be used in combination with the following agents to treat or prevent sleeping 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 aprobarbital, butabarbital, pentobarbital, secobarbita and phenobarbital; iv) antidepressants; v) other sedative-hypnotics for example chloral hydrate and chlormethiazole.
  • benzodiazepines for example temazepam, lormetazepam, estazolam and triazolam
  • non-benzodiazepine hypnotics for example Zolpidem, zopiclone, zaleplon and indiplon
  • barbiturates for example
  • the compounds of the invention may 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) premenstral agents for example pyridoxine and progesterones.
  • the compounds of the invention may 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 stabilisers; vi) zinc; and vii) premenstral agents.
  • the compounds of the invention may 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 formulations and pemoline.
  • the compounds of the invention may be used in combination with the following agents to treat or prevent ADHD: i) stimulants for example methylphenidate, amphetamine formulations and pemoline; 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 may be used in combination with the following agents to treat personality disorders: i) antipsychotics; ii) antidepressants; iii) mood stabilisers; and iv) anxiolytics.
  • the compounds of the invention may 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; vii) noradrenaline transport inhibitors for example reboxetine and viii) 5-HT1A agonists, for example flibanserine.
  • phosphodiesterase V inhibitors for example vardenafil and sildenafil
  • dopamine agonists/dopamine transport inhibitors for example apomorphine and buproprion
  • the compounds of the invention may be used in combination with the same agents specified for male sexual dysfunction to treat or prevent female sexual dysfunction, and in addition an estrogen agonist such as estradiol.
  • Antipsychotic drugs include Typical Antipsychotics (for example chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, thiothixine, haloperidol, molindone and loxapine); and Atypical Antipsychotics (for example clozapine, olanzapine, risperidone, quetiapine, aripirazole, ziprasidone and amisulpride).
  • Typical Antipsychotics for example chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, thiothixine, haloperidol, molindone and loxapine
  • Atypical Antipsychotics for example clozapine, olanzapine, risperidone, quetiapine,
  • Antidepressant drugs include serotonin reuptake inhibitors (such as citalopram, escitalopram, fluoxetine, paroxetine and sertraline); dual serotonin/noradrenaline reuptake inhibitors (such as venlafaxine, duloxetine and milnacipran); Noradrenaline 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).
  • serotonin reuptake inhibitors such as citalopram, escitalopram, fluoxetine, parox
  • Mood stabiliser drugs include lithium, sodium valproate/valproic acid/divalproex, carbamazepine, lamotrigine, gabapentin, topiramate and tiagabine.
  • Anxiolytics include benzodiazepines such as alprazolam and lorazepam.
  • the compounds of the invention will normally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient by an appropriate route. Accordingly, in another aspect, the invention provides pharmaceutical compositions comprising a compound of the invention and one or more pharmaceutically-acceptable excipients.
  • pharmaceutically acceptable excipient means any pharmaceutically acceptable material present in the pharmaceutical composition or dosage form other than the compound or compounds of the invention. Typically the material gives form, consistency and performance to the pharmaceutical composition.
  • compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. In addition, the pharmaceutical compositions of the invention may comprise one or more additional pharmaceutically active compounds.
  • compositions of the invention may be prepared and packaged in bulk form wherein a safe and effective amount of a compound of the invention can be dispensed and then given to the patient such as with powders or syrups.
  • the pharmaceutical compositions of the invention may be prepared and packaged as dosage forms wherein each physically discrete dosage form contains a safe and effective amount of a compound of the invention.
  • the invention provides dosage forms comprising pharmaceutical compositions of the invention. Each discrete dosage form typically contains from 1 mg to 500 mg of a compound of the invention.
  • compositions of the invention will typically be formulated into dosage forms which are adapted for administration to the patient by the desired route of administration.
  • dosage forms include those adapted for (1 ) oral administration such as tablets, capsules, caplets, pills, lozenges, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets and cachets; (2) parenteral administration such as sterile solutions, suspensions, implants and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal and vaginal administration such as suppositories, pessaries and foams; (5) inhalation and intranasal such as dry powders, aerosols, suspensions and solutions (sprays and drops); (6) topical administration such as creams, ointments, lotions, solutions, pastes, drops, sprays, foams and gels; (7) ocular administration such as drops, ointment, sprays, suspensions and inserts; (8) buccal and sub
  • Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form chosen.
  • suitable pharmaceutically acceptable excipients may be chosen for a particular function that they may serve in the composition.
  • certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms.
  • Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms.
  • Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of the compound or compounds of the invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body.
  • Certain pharmaceutically acceptable excipients may be chosen for their ability to enhance patient compliance.
  • Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the release of the compound of the invention at the appropriate rate to treat the condition.
  • Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavouring agents, flavour masking agents, colouring agents, anticaking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, rate modifying agents, antioxidants, preservatives, stabilizers, surfactants and buffering agents.
  • compositions of the invention may be prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
  • the compounds of the combination or composition may be administered simultaneously (either in the same or different pharmaceutical formulations), separately or sequentially.
  • a compound of the invention in the manufacture of a medicament in treating a disease or condition for which inhibition of monoamine neurotransmitter re-uptake is beneficial, i.e. inhibition of one or more of SERT, NET and DAT.
  • a disease or condition for which inhibition of monoamine neurotransmitter re-uptake is beneficial i.e. inhibition of one or more of SERT, NET and DAT.
  • the disease or condition is depression or an anxiety disorder.
  • the disease or condition is an eating disorder
  • a method of treating a disease or condition for which inhibition of monoamine neurotransmitter re-uptake is beneficial i.e. inhibition of one or more of SERT, NET and DAT in a mammal (preferably a human) comprising administering an effective amount of a compound of the invention.
  • the disease or condition is a depression or an anxiety disorder.
  • the disease or condition is an eating disorder.
  • Proton Magnetic Resonance ( ⁇ H NMR) spectra are typically recorded either on a Varian instrument at 300, 400 or 500 MHz or on a Bruker instrument at 300 and 400 MHz. Chemical shifts are reported in ppm ( ⁇ ) using the residual solvent line as internal standard. Splitting patterns are designed as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; b, broad. The NMR spectra were recorded at a temperature ranging from 25 to 9O 0 C. When more than one conformer is detected the chemical shifts for the most abundant one is reported.
  • DAD chromatographic traces, mass chromatograms and mass spectrums may be taken on a on a UPLC/MS AcquityTM system coupled with a Micromass ZQTM mass spectrometer operating in ESI positive or negative.
  • the phases used are: A) H 2 O/ACN 95/5 + 0,1 % TFA; B) H 2 O/ACN 5/95 + 0,1% TFA.
  • Flash silica gel chromatography was carried out on silica gel 230-400 mesh (supplied by Merck AG Darmstadt, Germany) or over Varian Mega Be-Si pre-packed cartridges or over pre-packed Biotage silica cartridges.
  • SPE-SCX cartridges are ion exchange solid phase extraction columns supplied by Varian.
  • the eluent used with SPE-SCX cartridges is methanol followed by 2N ammonia solution in methanol.
  • SPE-Si cartridges are silica solid phase extraction columns supplied by Varian.
  • a number of the supporting compounds have been prepared as racemic mixtures and a number have been prepared as single enantiomers.
  • the absolute stereochemistry of those compounds prepared as single enantiomers have not been assigned, but may be assigned using ab initio vibrational circular dichroism (VCD).
  • VCD ab initio vibrational circular dichroism
  • VCD is the differential interaction of a chiral molecule with left and right circularly polarized infrared radiation during vibrational excitation.
  • VCD The VCD spectrum of a chiral molecule is dependent on its three-dimensional structure. Most importantly, the VCD spectrum of a chiral molecule is a function of its absolute configuration and, in the case of flexible molecules, of its conformation. In principle, therefore, VCD permits the determination of the structure of a chiral molecule.
  • VCD spectra were first measured in the 1970s. Subsequently, VCD instrumentation has developed enormously in spectral range and in sensitivity.
  • IR fundamental infrared
  • FT Fourier Transform
  • the method entails comparison of observed IR and VCD spectra with calculations of the spectra for a specific configuration and provides information both on the absolute configuration and on the solution conformation.
  • VCD spectra are always measured simultaneously with vibrational unpolarized absorption spectra ("infrared (IR) spectra") and the two vibrational spectra together provide more information than does the VCD spectrum alone.
  • vibrational unpolarized absorption spectra are automatically predicted simultaneously with VCD spectra.
  • VCD and unpolarized IR spectra were calculated using the Gaussian 98 software package.
  • Still further NaH (0.00530 g, 0.133 mmol) and methyl iodide (0.176 mmol, 11 ⁇ l) were added and the reaction mixture was stirred at RT over night. Still further NaH (0.0106 g, 0.266 mmol) and methyl iodide (0.352 mmol, 22 ⁇ l) were added and the reaction stirred at RT for 5.5 hours. Still further NaH (0.0106 g, 0.266 mmol) and methyl iodide (0.352 mmol, 22 ⁇ l) were added and the reaction stirred at RT for 2h. NH4CI sat. solution (4 ml) was added and the mixture was extracted with ethyl acetate (4 x 4 ml).
  • Still further NaH (0.018 g, 0.449 mmol) and methyl iodide (0.037 ml, 0.598 mmol) were added and the reaction was stirred at RT for 2h. The temperature was brought to 4O 0 C and the reaction was stirred for 3h. Still further NaH (0.018 g, 0.449 mmol) and methyl iodide (0.037 ml, 0.598 mmol) were added at RT and the reaction mixture was stirred at 6O 0 C for 3.5 hours and then at RT overnight.
  • UV detection Diode-array 210-350nm MS detection: Electrospray, +ve, 100-900amu, centroid mode
  • Lung Carcinoma Porcine tubule Kidney (LLCPK) cell lines Lung Carcinoma Porcine tubule Kidney (LLCPK) cell lines
  • Stable cell lines may be generated as follows: i) hSERT - generated by transfecting LLC-PK1 or LLCPK cells with hSERT cloned into the mammalian expression vector pCDNA3.1 Hygro(+); ii) hNET - generated by transfecting LLCPK cells with hNET cloned into the mammalian expression vector pRC/CMV; iii) hDAT- generated by transfecting LLCPK cells with hDAT cloned into the mammalian expression vector pDESTCDNA3.1 (an example of a procedure for transfecting LLCPK cells with hDAT, hSERT and hNET may be found in H. Gu, S. C. Wall and G. Rudnick, J. Biol. Chem. (1994) 269 : 7
  • Each cell line is cultured independently in Dulbecco's modified Eagle's medium (DMEM) containing 10% of Foetal Bovine Serum (FBS) supplemented with 400 ⁇ g/ml hygromicin (hSERT) or geneticin at 500 ⁇ g/ml (hNET) or at 1000 ⁇ g/ml (hDAT).
  • DMEM Dulbecco's modified Eagle's medium
  • FBS Foetal Bovine Serum
  • hSERT hygromicin
  • hNET ⁇ g/ml
  • hDAT ⁇ g/ml
  • the culture medium is removed and the cells harvested with phosphate buffered saline (PBS) containing 5 mM EDTA.
  • PBS phosphate buffered saline
  • the cell suspension is centrifuged at 90Og for 5 minutes at 4 0 C.
  • the resultant pellets are re-suspended in 30-50 volumes of Assay Buffer (5OmM Tris pH 7.7 containing 12OmM NaCI, 5mM KCI, 10 ⁇ M pargyline and 0.1% ascorbic acid) and homogenized using a glass-teflon Potter homogeniser and centrifuged at 4800Og for 20 minutes at 4 0 C.
  • Assay Buffer 5OmM Tris pH 7.7 containing 12OmM NaCI, 5mM KCI, 10 ⁇ M pargyline and 0.1% ascorbic acid
  • the resultant membrane pellets are re-suspended in the same volume of Assay Buffer, incubated for 20 minutes at 37 0 C and centrifuged as before at 4800Og. The final protein concentration for each preparation is adjusted to give approximately 480 ⁇ g protein/ml for hSERT-LLCPK, hDAT-LLCPK and hNET-LLCPK, as determined by the Bio-Rad Protein Assay kit. Membranes are stored at -80 0 C as 1 ml aliquots until required.
  • the affinity of the compounds of the invention to bind the re-uptake site of SERT may be assessed using [3
  • the competition binding assay is conducted in deep-well 96 well plates (1 ml, NUNC, cod.260252) in a total volume of 400 ⁇ l, with each concentration in duplicate.
  • test compound 100X solution in neat DMSO as 7 point curve ranging from 10 "6 to 10 "12 M, final concentration
  • DMSO to define total binding
  • 10 ⁇ M fluoxetine in DMSO to define non-specific binding, NSB
  • 200 ⁇ l of [N-Methyl- 3 H]citalopram Amersham Biosciences, 80 Ci/mmol
  • the reaction is started by adding 200 ⁇ l/well of membranes diluted 1 :80 in Assay Buffer at concentration of about 2.5 ⁇ g/well of protein.
  • the reaction is carried out at room temperature for 2 hours and then stopped by rapid filtration through GF/B Unifilter 96-filterplate (Perkin-Elmer) pre-soaked in 0.5% polyethylenimmine (PEI) using a Perkin-Elmer FilterMat-196 harvester. Filterplate is washed 3 times with 1 ml/well ice-cold 0.9% NaCI solution. The plate is dried in an oven for 60 min at 50 0 C then opaque bottom-seal is placed on the underside of the plate and 50 ⁇ l of Microscint 20 (Perkin-Elmer) added to each well. Plate is sealed with a TopSeal and the radioactivity in the samples is counted for 4 min using TopCount liquid scintillation counter (Packard-Perkin-Elmer) and recorded as counts per minute (CPM).
  • TopCount liquid scintillation counter Packard-Perkin-Elmer
  • Competition binding assay for hNET may be conducted essentially as previously reported for hSERT in 96 well format and in a final assay volume of 400 ⁇ l, except for the use of hNET-LLCPK cell membranes (1 :40 dilution i.e. 4.8 ⁇ g of protein/well) and [ 3 H]nisoxetine as radioligand (1.5nM [N-methyl- 3 H]nisoxetine, Amersham Biosciences, 84 Ci/mmol). 10 ⁇ M desipramine is used for NSB.
  • Competition binding assay for hDAT may also be conducted essentially as previously reported for hSERT and hNET in 96 well format and in a final assay volume of 400 ⁇ l, except for the use of hDAT-LLCPK cell membranes (1 :20 i.e. 9.6 ⁇ g of protein/well) and [ 3 H]WI N-35,428 as radioligand (1OnM [N-Methyl- 3 H]WIN-35,428, Perkin Elmer, 85.6 Ci/mmol). Furthermore, 10 ⁇ M GBR-12909 is used for NSB and the incubation time of the binding reaction is 1 hour at room temperature.
  • Membranes for the SPA-binding assays are produced by HEK-293F cell infection with BacMam viruses generated for each single human SERT, NET, and DAT transporter.
  • hSERT and hDAT are cloned into pFBMRfA vector whereas hNET is cloned into pFASTBacMami vector.
  • the generation and use of BacMam viruses is described in Condreay JP et al, Proc. Natl. Acad. Sci. USA, 1999, 96:127-132 and Hassan NJ et al, Protein Expression and Purification, 47(2): 591-598, 2006.
  • the HEK-293F suspension cell line (Invitrogen) is routinely grown in 293_Freestyle Expression media (Invitrogen) in shake flask suspension culture.
  • the culture is transduced with the appropriate transporter BacMam at a MOI (multiplicity of infection) of 100 virus particles per cell and incubated for 48hrs at 37 0 C, 5% CO 2 in air, shaken at 90rpm in a humidified shaker incubator.
  • the culture is then harvested by centrifugation at 1000g, 4 0 C, for 10 minutes and the cell pellet stored at -8O 0 C until required.
  • Transduced cell pellets are re-suspended to 10x volume with buffer-A (5OmM HEPES, 1 mM EDTA, 1 mM leupeptin, 25ug/ml_ bacitracin, 1 mM phenylmethylsulfonylfluoride, PMSF, 2 ⁇ M pepstatin A, pH 7.7) and homogenised with 2x 15 second bursts in a glass Waring blender. The homogenate is then centrifuged for 20 minutes at 50Og. Following this, the supernatant is pooled and centrifuged at 13,00Og for 30 minutes.
  • buffer-A 5OmM HEPES, 1 mM EDTA, 1 mM leupeptin, 25ug/ml_ bacitracin, 1 mM phenylmethylsulfonylfluoride, PMSF, 2 ⁇ M pepstatin A, pH 7.7
  • the homogenate is then centrifuged for 20 minutes at 50O
  • the affinity of the compounds of the invention for hSERT, hNET or hDAT may also be assessed by using the [ 3 H]citalopram, [ 3 H]nisoxetine or [ 3 H]WI N-35, 428 binding assays with the SPA technology on BacMam-recombinant human SERT, NET and DAT membranes produced as described before.
  • SPA technology GE
  • the protocol for hSERT binding SPA is based on Trilux beta-counter (Wallac, Perkin- Elmer). Briefly, 0.5 ⁇ l_ of test compound in neat DMSO (or 1 ⁇ M fluoxetine as positive control) is added by 50 ⁇ l_ of the SPA mixture, containing 2mg/ml_ SPA beads (Amersham RPNQ0001 ), 4 ⁇ g/ml_ hSERT Bacmam membranes, 0.01% pluronic F- 127, 2.5nM [ 3 H]citalopram in the assay buffer (2OmM HEPES, 145mM NaCI, 5mM KCI, pH 7.3). Incubation are performed at room temperature for at least 2 hours. Counts are stable and could be read up to 3 days.
  • hDAT hNET and hSERT SPA-binding assays are performed by using a Viewlux beta-counter (Wallac, Perkin-Elmer) with imaging PS-WGA beads (Amersham RPNQ0260) in a final assay volume of 30 ⁇ l_ and in a 384-well plate format (Greiner 781075).
  • Viewlux beta-counter Wallac, Perkin-Elmer
  • PS-WGA beads Amersham RPNQ0260
  • 0.3 ⁇ l_ of test compound in neat DMSO and 0% and 100% effect controls (DMSO for total binding and 10 or 1 ⁇ M indatraline as positive control) are added to the wells by using a Hummingbird (Genomic Solutions), followed by the addition of 30 ⁇ l_ of the SPA mixture, containing 1 mg/mL SPA beads (hSERT) or 2mg/ml SPA beads (hDAT and hNET), 40 ⁇ g/ml or 20 ⁇ g/ml or 6 ⁇ g/ml of hDAT or hNET or hSERT BacMam membranes, 0.02% pluronic F-127, 1OnM
  • the affinity of the compounds of the invention for a particular transporter may be calculated from the IC 50 obtained in competition experiments as the concentration of a compound necessary to displace 50% of the radiolabeled ligand from the transporter, and is reported as a "K,” value calculated by the following equation: ⁇ _ IC 50

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Abstract

La présente invention concerne des composés de formule (I), des procédés pour les préparer, des intermédiaires utilisés dans ces procédés, des compositions pharmaceutiques les contenant et leur utilisation en thérapeutique, en tant qu'inhibiteurs de la recapture de la sérotonine (5-HT), de la dopamine (DA) et de la norépinéphrine (NE).
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102906102A (zh) * 2010-03-31 2013-01-30 吉利德制药有限责任公司 含磷活性物的立体选择性合成
US8859756B2 (en) 2010-03-31 2014-10-14 Gilead Pharmasset Llc Stereoselective synthesis of phosphorus containing actives

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