WO2010007032A1 - Piperidine based ureas as nk1 antagonists - Google Patents

Piperidine based ureas as nk1 antagonists Download PDF

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Publication number
WO2010007032A1
WO2010007032A1 PCT/EP2009/058937 EP2009058937W WO2010007032A1 WO 2010007032 A1 WO2010007032 A1 WO 2010007032A1 EP 2009058937 W EP2009058937 W EP 2009058937W WO 2010007032 A1 WO2010007032 A1 WO 2010007032A1
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Prior art keywords
methyl
ethyl
phenyl
compound
trifluoromethyl
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PCT/EP2009/058937
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French (fr)
Inventor
Giuseppe Alvaro
Francesca Cardullo
Emiliano Castiglioni
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Glaxo Wellcome Manufacturing Pte Ltd
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Publication of WO2010007032A1 publication Critical patent/WO2010007032A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants

Definitions

  • the present invention relates to novel azabicycle compounds having pharmacological activity, to processes for their preparation, to compositions containing them and to their medical uses.
  • the present invention provides, in a first aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof,
  • the wedge shaped bond in formula (I) indicates that the bond is above the plane of the paper.
  • the compounds of the present invention may be in the form of and/or may be administered as a pharmaceutically acceptable salt.
  • a pharmaceutical acceptable salt may be readily prepared by using a desired acid or base as appropriate.
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • a pharmaceutically acceptable acid addition salt can be formed by reaction of a compound of formula (I) with a suitable inorganic or organic acid (such as hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, formic, acetic, propionic, fumaric, citric, tartaric, lactic, benzoic, salicylic, glutamaic, aspartic, p-toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic such as 2- naphthalenesulfonic, or hexanoic acid), optionally in a suitable solvent such as an organic solvent, to give the salt which is usually isolated for example by crystallisation and filtration.
  • a suitable inorganic or organic acid such as hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, formic, acetic
  • a pharmaceutically acceptable acid addition salt of a compound of formula (I) can comprise or be for example a hydrobromide, hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, formate, acetate, propionate, fumarate, citrate, tartrate, lactate, benzoate, salicylate, glutamate, aspartate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, naphthalenesulfonate (e.g. 2- naphthalenesulfonate) or hexanoate salt.
  • a hydrobromide hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, formate, acetate, propionate, fumarate, citrate, tartrate, lactate, benzoate, salicylate, glutamate, aspartate, p-to
  • a pharmaceutically acceptable base addition salt can be formed by reaction of a compound of formula (I) with a suitable inorganic or organic base (e.g. triethylamine, ethanolamine, triethanolamine, choline, arginine, lysine or histidine), optionally in a suitable solvent such as an organic solvent, to give the base addition salt which is usually isolated for example by crystallisation and filtration.
  • a suitable inorganic or organic base e.g. triethylamine, ethanolamine, triethanolamine, choline, arginine, lysine or histidine
  • a suitable solvent such as an organic solvent
  • compositions include pharmaceutically acceptable metal salts, for example pharmaceutically acceptable alkali-metal or alkaline-earth-metal salts such as sodium, potassium, calcium or magnesium salts.
  • non-pharmaceutically acceptable salts eg. oxalates
  • oxalates may be used, for example in the isolation of compounds of the invention, and are included within the scope of this invention.
  • the invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the salts of the compounds of formula (I).
  • the compounds of formula(l) can exist as zwitterions.
  • Salts having a non-pharmaceutically acceptable anion or cation are within the scope of the invention as useful intermediates for the preparation of pharmaceutically acceptable salts and/or for use in non-therapeutic, for example, in vitro, situations.
  • any such crystalline forms of the compounds of formula (I) may exist as polymorphs, which are included in the present invention.
  • the subject invention also includes isotopically-labelled compounds, which are identical to those recited in formula (I) but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention or pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, iodine, and chlorine, such as 2 H, 3H, H e, 13C, 14C, 15 N , ⁇ 0 , 18 0 , 31 p, 32 P] 35 Sj 18 Fi 36 C
  • Isotopically-labelled compounds of the present invention for example those into which radioactive isotopes such as 3 H, 14c are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14c, isotopes are particularly preferred for their ease of preparation and detectability.
  • ⁇ C and 1 ⁇ F isotopes are particularly useful in PET (positron emission tomography), and 125
  • substitution with heavier isotopes such as deuterium, i.e., ⁇ H can 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, lsotopically labelled compounds of the invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
  • the asymmetric carbon atoms can be represented by the formulas from (Ia) to (Ih) as follows:
  • the wedge shaped bond indicates that the bond is above the plane of the paper.
  • the broken bond indicates that the bond is below the plane of the paper.
  • n 1 or 2.
  • n 1 or 2.
  • n is 1. In a further yet embodiment n is 2.
  • the compound of the invention is : (1R5R)-3-[(2R4S)-1- ⁇ [ ⁇ (1 R)-1-[3,5- bis(trifluoromethyl)phenyl]ethyl ⁇ (methyl)amino]carbonyl ⁇ -2-(4-fluoro-2-methylphenyl)-4- piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylic acid (Ii) or a pharmaceutically acceptable salt thereof.
  • the compound of the invention is : (1 R,5R)-3-[(2R,4S)-1 - ⁇ [ ⁇ (1 R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl ⁇ (methyl)amino] carbonyl ⁇ -2-(4-fluoro-2-methylphenyl)-4-piperidinyl]-3-azabicyclo [3.1.0]hexane-1- carboxylic acid (Ii).
  • the compound of the invention is Sodium salt of (1 R,5R)-3-[(2R,4S)-1- ⁇ [ ⁇ (1 R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl ⁇ (methyl) amino]carbonyl ⁇ -2-(4-fluoro-2-methylphenyl)-4-piperidinyl]-3-azabicyclo[3.1.0]hexane-1- carboxylic acid (Ii).
  • the compound of the invention is : 3-[(2R,4S)-1- ⁇ [ ⁇ (1 R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl ⁇ (methyl)amino]carbonyl ⁇ -2-(4- fluoro-2-methylphenyl)-4-piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylic acid (isomer 2).
  • the compound of the invention is : 3-[(2R ! 4S)-1- ⁇ [ ⁇ (1 R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl ⁇ (methyl)amino]carbonyl ⁇ -2-(4- fluoro-2-methylphenyl)-4-piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylic acid (isomer 2) or a pharmaceutically acceptable salt thereof.
  • the compound of the invention is sodium 3-[(2/?,4S)-1- ⁇ [ ⁇ (1 R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl ⁇ (methyl)amino]carbonyl ⁇ - 2-(4-fluoro-2-methylphenyl)-4-piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylate (isomer 2).
  • the present invention also provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which process comprises: reacting a compound of formula (II), wherein R is C 1.4 alkyl , such as methyl or ethyl, with an aqueous solution of metal hydroxide such as sodium hydroxide and a suitable solvent such as methanol at suitable temperature such as 80-90 0 C optionally under microwaves irradiation.
  • amine (IV) wherein R is C 1.4 alkyl , such as methyl or ethyl and n is 1 or 2, followed by the addition of a suitable reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride.
  • said reductive amination reaction may typically comprise reacting a compound of formula (III) with amine (IV) in a suitable solvent such as dichloroethane or methanol, at a suitable temperature such as r.t, followed by the addition of a suitable reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride.
  • a suitable solvent such as dichloroethane or methanol
  • a suitable reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride.
  • step (i) St ⁇ P (iN) (V) (Vl) (VII) step (vi)
  • Step (i) typically comprises reacting a compound of formula (V), wherein P2 and P3 represent suitable nitrogen protecting groups or P2 and P3 taken together with the nitrogen atom form a protecting group such as phtalimide (European Journal of Medicinal Chemistry, 38(7-8), 729-737; 2003, Organic Letters, 7(4), 733-736; 2005 or commercially available from ABCR GmbH KG Im Schlehert 10 Düsseldorf, D-76187 Germany) with dimethyl diazomalonate in the presence of a suitable catalyst such as Rhodium(ll) acetate dimer in a suitable solvent such as chlorobenzene at a suitable temperature such as 60-
  • Step (ii) typically comprises the removal of the nitrogen protecting group, followed by cyclization to get the lactam (VII).
  • the reaction may be carried out reacting a compound of formula (Vl) with hydrazine in a suitable solvent such as methanol at a suitable temperature such as reflux temperature.
  • Step (iii) typically comprises protection of a compound of formula (VII) with a suitable nitrogen protecting group.
  • step (iii) may typically comprise reacting a compound of formula (VII) with di-te/f-butyl dicarbonate in a suitable solvent such as a mixture of toluene/dichloromethane in the presence of 4- (Dimethylamino)pyridine at a suitable temperature such as reflux temperature.
  • Step (iv) and (v) typically comprises a stepwise reduction of lactam (VIII) to the corresponding amine (X) via an intermediate (IX).
  • step (iv) may be carried out reacting a lactam (VIII) with a suitable reducing agent such as Super-Hydride ® (1.0 M lithium triethylborohydride in tetrahydrofuran)in a suitable solvent such as THF at a suitable temperature such as -10 0 C to get the intermediate (IX), which may be conveniently converted to the amine (X) by treatment with a suitable reducing agent such as triethylsilane in the presence of a suitable Lewis acid such as BF 3 OEt 2 in a suitable solvent such as dichloromethane at a suitable temperature such as -78°C.
  • a suitable reducing agent such as Super-Hydride ® (1.0 M lithium triethylborohydride in tetrahydrofuran)in a suitable solvent such as THF at a suitable temperature such as -10 0 C
  • a suitable reducing agent such as triethylsilane
  • a suitable Lewis acid such as BF
  • Step (vi) typically comprises removal of the nitrogen protecting group.
  • step (vi) may typically comprise reacting a compound of formula (X) with TFA in a suitable solvent such as dichloromethane at a suitable temperature ranging from 0 0 C to r.t.
  • a single enantiomer of a compound of formula (IV) may be obtained by conventional means such as resolution of the racemate by chiral chromatography or forming a salt by reaction with a suitable optically active acid, separating the resultant diastereoisomeric salts by conventional means, e.g. crystallisation or precipitation followed by isolation of the corresponding free base.
  • a suitable optically active acid for use in the process is (2S,3S)-2,3- bis[(phenylcarbonyl)oxy]butanedioic acid.
  • the compounds of formula(IV), wherein n is 1 may be prepared by asymmetric synthesis thus for example as described in the following scheme (II).
  • Step (i) typically comprises the synthesis of a chiral bicyclic lactone (XIII) in one pot from a suitable chiral epichlorohydrin (Xl) by an intramolecular double displacement of an alkyl malonate anion, followed by lactonization.
  • Said alkyl malonate anion may be prepared reacting a suitable alkyl malonate (XII), wherein R' is an alkyl group, such as diethylmalonate, with a suitable base such as sodium ethoxide in a suitable solvent such as ethanol at a suitable temperature such as low temperature (0 0 C).
  • a suitable chiral epichlorohydrin (Xl) such as (R)- epichlorohydrin may be added to the aforementioned alkyl malonate anion solution and the resulting reaction mixture may be refluxed for a suitable time such as 36 hrs to give a compound (XIII). See J. Org. Chem. 2007, 72, 7390-7393.
  • Step (ii) typically comprises reacting the chiral bicyclic lactone (XIII) with a suitable reducing agent such as NaBH 4 in a suitable solvent such as ethanol at a suitable temperature such as room temperature for a suitable time such as few hours to give a compound of formula (XIV).
  • a suitable reducing agent such as NaBH 4
  • a suitable solvent such as ethanol
  • Step (iii) typically comprises the conversion of a compound of formula (XIV) into a suitable derivative (XV), wherein Lg are suitable leaving groups such as a mesylate, reacting (XIV) with a suitable reagent such as methansulfonic anhydride in a suitable solvent such as dichloromethane in the presence of a suitable base such as triethylamine
  • Step (iv) typically comprises reacting a compound of formula (XV) with a suitable amine such as benzylamine in a suitable solvent such as dichloromethane at a suitable temperature such as room temperature, folowed by removal of the benzyl group using standard procedures.
  • compounds of formula (I) as a salt
  • a pharmaceutically acceptable salt this may be achieved by reacting the compound of formula (I) in the form of the free acid with an appropriate amount of a suitable base or a suitable acid and in a suitable solvent such as an alcohol (e.g. ethanol or methanol), an ester (e.g. ethyl acetate) or an ether (e.g. diethyl ether or tetrahydrofuran).
  • a suitable solvent such as an alcohol (e.g. ethanol or methanol), an ester (e.g. ethyl acetate) or an ether (e.g. diethyl ether or tetrahydrofuran).
  • Pharmaceutically acceptable salts may also be prepared from other salts, including other pharmaceutically acceptable salts, of the compounds of formula (I) using conventional methods.
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • Tachykinins are a family of peptides that share a common carboxyl-terminal sequence (Phe-X-Gly-Leu-Met-NH2). They are actively involved in the physiology of both lower and advanced life forms. In mammalian life forms, the main tachykinins are substance P (SP), Neurokinin A (NKA) and Neurokinin B (NKB) which act as neurotransmitters and neuromodulators. Mammalian tachykinins may contribute to the pathophysiology of a number of human diseases.
  • NKI SP-preferring
  • NK2 NKA-preferring
  • NK3 NKB-preferring
  • CNS central nervous
  • compounds of the invention are antagonists of the NK1 receptor.
  • Compounds of the invention are useful in the treatment of conditions for which antagonism of NK1 receptor is beneficial .
  • Depression and mood disorders including Major Depressive Episode, Manic Episode, Mixed Episode and Hypo manic Episode; Depressive Disorders including Major Depressive Disorder, Dysthymic Disorder (300.4), Depressive Disorder Not Otherwise Specified (31 1 ); Bipolar Disorders including Bipolar I Disorder, Bipolar Il Disorder (Recurrent Major Depressive Episodes with Hypo manic Episodes) (296.89), Cyclothymiacs Disorder (301.13) and Bipolar Disorder Not Otherwise Specified (296.80); 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 Depressive Features, With Manic Features and With Mixed Features) and Mood Disorder Not Otherwise Specified (296.90).
  • 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 Dependence (303.90), 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-
  • Sleep disorders including primary sleep disorders such as Dyssomnias such as Primary Insomnia (307.42), Primary Hypersomnia (307.44), Breathing-Related Sleep Disorders
  • Sleep Condition in particular sleep disturbances associated with such diseases as neurological disorders, neuropathic pain, restless leg syndrome, heart and lung diseases; and Substance-Induced Sleep Disorder including the subtypes Insomnia Type, Hypersomnia Type, Parasomnia Type and Mixed Type; sleep apnea and jet-lag syndrome.
  • 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).
  • Autism Spectrum Disorders including Autistic Disorder (299.00), Asperger's Disorder (299.80), Rett's Disorder (299.80), Childhood Disintegrative Disorder (299.10) and Pervasive Disorder Not Otherwise Specified (299.80, including Atypical Autism).
  • Attention-Deficit/Hyperactivity Disorder including the subtypes Attention-Deficit /Hyperactivity Disorder Combined Type (314.01 ), Attention-Deficit /Hyperactivity Disorder
  • Hyperactive-Impulse Type (314.01 ) and Attention-Deficit /Hyperactivity Disorder Not
  • Personality Disorders including the 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 Disorder (301.50), Narcissistic Personality Disorder (301 ,81 ), Avoidant Personality Disorder (301.82), Dependent Personality Disorder (301.6), Obsessive- Compulsive Personality Disorder (301.4) and Personality Disorder Not Otherwise Specified (301.9):
  • Compounds of the invention may be useful for 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 Adol
  • Compounds of the invention may be also useful as anti-inflammatory agents.
  • they may be useful in the treatment of inflammation in asthma, influenza, chronic bronchitis and rheumatoid arthritis; in the treatment of inflammatory diseases of the gastrointestinal tract such as Crohn's disease, ulcerative colitis, inflammatory bowel disease and nonsteroidal anti-inflammatory drug induced damage; inflammatory diseases of the skin such as herpes and eczema; inflammatory diseases of the bladder such as cystitis, overactive bladder and urge incontinence; and eye and dental inflammation.
  • Compounds of the invention may be also useful in the treatment of allergic disorders, in particular allergic disorders of the skin such as urticaria, and allergic disorders of the airways such as rhinitis.
  • Compounds of the invention are also useful in the treatment of emesis, i.e. nausea, retching and vomiting.
  • Emesis includes acute emesis, delayed emesis and anticipatory emesis.
  • Compounds of the invention are useful in the treatment of emesis however induced.
  • emesis may be induced by drugs such as cancer chemotherapeutic agents such as alkylating agents, e.g. cyclophosphamide, carmustine, lomustine and chlorambucil; cytotoxic antibiotics, e.g. dactinomycin, doxorubicin, mitomycin-C and bleomycin; anti-metabolites, e.g.
  • cytarabine methotrexate and 5- fluorouracil
  • vinca alkaloids e.g. etoposide, vinblastine and vincristine
  • others such as cisplatin, dacarbazine, procarbazine and hydroxyurea; and combinations thereof
  • radiation sickness e.g. irradiation of the thorax or abdomen, such as in the treatment of cancer; poisons; toxins such as toxins caused by metabolic disorders or by infection, e.g.
  • gastritis or released during bacterial or viral gastrointestinal infection; pregnancy; vestibular disorders, such as motion sickness, vertigo, dizziness and Meniere's disease; postoperative sickness; gastrointestinal obstruction; reduced gastrointestinal motility; visceral, e.g. myocardial infarction or peritonitis; migraine; increased intercranial pressure; decreased intercranial pressure (e.g.
  • GSD gastro-oesophageal reflux disease
  • erosive GERD and symptomatic GERD or non erosive GERD acid indigestion, over-indulgence of food or drink, acid stomach, sour stomach, waterbrash/regurgitation
  • heartburn such as episodic heartburn, nocturnal heartburn, and meal-induced heartburn, dyspepsia and functional dyspepsia.
  • Compounds of the invention may be also useful in the treatment of gastrointestinal disorders such as irritable bowel syndrome, gastro-oesophageal reflux disease (GERD) such as erosive GERD and symptomatic GERD or non erosive GERD, acid indigestion, over-indulgence of food or drink, acid stomach, sour stomach, waterbrash/regurgitation, heartburn, such as episodic heartburn, nocturnal heartburn, and meal-induced heartburn, dyspepsia and functional dyspepsia (such as ulcer-like dyspepsia ,dysmotility-like dyspepsia and unspecified dyspepsia) chronic constipation; skin disorders such as psoriasis, pruritis and sunburn; vasospastic diseases such as angina, vascular headache and Reynaud's disease; cerebral ischeamia such as cerebral vasospasm following subarachnoid haemorrhage; fibro
  • the term "pain” includes: 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 cluster and chronic daily headache; 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; dysmenorrhea; neuralgia; fibromyalgia syndrome; complex regional pain syndrome (CRPS types I and II); neuropathic pain syndromes (including diabetic neurode), adis,
  • Compounds of the invention may be useful in cachexia including systemic cachexia, cachexia secondary to infection or malignancy and cachexia secondary to AIDS , renal insufficiency, cardiac insufficiency and pulmonary insufficiency.
  • Compounds of the invention may be also useful for treatmenrt of patients suffering from anorexia-cachexia syndrome which is a debilitating condition characterizing the clinical journey of patients suffering from chronic diseases including cancer, chronic obstructive pulmonary disease, tuberculosis, chronic heart failure, and end-stage renal insufficiency .
  • anorexia-cachexia syndrome which is a debilitating condition characterizing the clinical journey of patients suffering from chronic diseases including cancer, chronic obstructive pulmonary disease, tuberculosis, chronic heart failure, and end-stage renal insufficiency .
  • Compounds of the invention are particularly useful in the treatment or prevention of depression, anxiety, sleep disorders or emesis.
  • compounds of the invention are useful in the treatment or prevention of depression.
  • compounds of the invention are useful in the treatment or prevention of anxiety.
  • compounds of the invention are useful in the treatment or prevention of sleep disorders.
  • compounds of the invention are useful in the treatment or prevention of emesis.
  • the invention therefore provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in therapy.
  • the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as a therapeutic substance in the treatment or prophylaxis of the above disorders.
  • the invention further provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of depression, anxiety, sleep disorders or emesis.
  • the invention further provides a method of treatment or prophylaxis of conditions mediated by tachykinins, in mammals including humans, which comprises administering to the sufferer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention further provides a method of treatment or prophylaxis of conditions for which antagonism of NK1 receptor is beneficial, in mammals including humans, which comprises administering to the sufferer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention further provides a method of treatment or prophylaxis of the above disorders, in mammals including humans, which comprises administering to the sufferer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention further provides a method of treatment or prophylaxis of depression, anxiety, sleep disorders or emesis in mammals including humans, which comprises administering to the suffer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of conditions mediated by tachykinins. In another aspect, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of conditions for which antagonism of NK1 receptor is beneficial.
  • the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of the above disorders.
  • the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of depression, anxiety, sleep disorders or emesis.
  • the compounds of formula (I) are usually formulated in a standard pharmaceutical composition.
  • Such compositions can be prepared using standard procedures.
  • the present invention further provides a pharmaceutical composition which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the present invention further provides a pharmaceutical composition for use in the treatment of the above disorders which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • 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 anxi
  • Compounds of the invention may be used in combination with antidepressants to treat or prevent depression and mood disorders.
  • Compounds of the invention may be used in combination with an opioid analgesic to treat and prevent pain.
  • 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.
  • Compounds of the invention may be used in combination with the following agents to treat or prevent anxiety disorders: i) anxiolytics; and ii) antidepressants.
  • 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.
  • NMDA receptor antagonists for example acamprosate
  • GABA receptor agonists for example tetrabamate
  • Opioid receptor antagonists for example naltrexone
  • 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.
  • opioid mu receptor agonist/opioid kappa receptor antagonist for example buprenorphine
  • opioid receptor antagonists for example naltrexone
  • vasodilatory antihypertensives for example lofexidine.
  • Compounds of the invention may 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 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
  • 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) premenstrual agents for example pyridoxine and progesterones.
  • appetite stimulants for example cyproheptidine
  • antidepressants for example cyproheptidine
  • antipsychotics iii) antipsychotics
  • zinc iv
  • premenstrual agents for example pyridoxine and progesterones.
  • 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) premenstrual agents.
  • 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.
  • 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).
  • stimulants for example methylphenidate, amphetamine formulations and pemoline
  • 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).
  • 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.
  • 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; v) noradrenaline transport inhibitors for example reboxetine and vii) 5-HT1A agonists, for example flibanserine.
  • phosphodiesterase V inhibitors for example vardenafil and sildenafil
  • dopamine agonists/dopamine transport inhibitors for example apomorphine and buproprion
  • 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.
  • Opioid analgesics include alfentanil, buprenorphine, butorphanol, carfentanil, codeine, diacetylmorphine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol, lofentanil, meperidine, methadone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, propoxyphenem, remifentanil and sufentanil.
  • Compounds of the invention may be used in combination with Na channel blockers to treat epilepsy, depression and mood disorders, psychotic disorders or pain.
  • epilepsy is intented to include seizure disorders and epilepsy syndromes.
  • the various types of the Epilepsy and seizures mentioned herein below are contemplated as part of the present invention: partial onset seizures (replacing temporal lobe epilepsy, neocortical epilepsy and Rasumssen's), generalized onset seizures, the seizures of the Lennox Gastaut syndrome (tonic, atonic, myoclonic, atypical absence and generalized tonic-clonic), absence seizure syndromes and juvenile myoclonic epilepsy.
  • Combination of compounds of the invention with a Na channel blocker may also be useful in the treatment and/or prevention of disorders treatable and/or preventable with anti- convulsive agents, such as epilepsy including post-traumatic epilepsy, obsessive compulsive disorders (OCD), sleep disorders (including circadian rhythm disorders, insomnia & narcolepsy), tics (e.g. Giles de Ia Tourette's syndrome), ataxias, muscular rigidity (spasticity), and temporomandibular joint dysfunction.
  • epilepsy including post-traumatic epilepsy, obsessive compulsive disorders (OCD), sleep disorders (including circadian rhythm disorders, insomnia & narcolepsy), tics (e.g. Giles de Ia Tourette's syndrome), ataxias, muscular rigidity (spasticity), and temporomandibular joint dysfunction.
  • OCD obsessive compulsive disorders
  • sleep disorders including circadian rhythm disorders, insomnia & narcolepsy
  • psychotic disorder includes: i) Schizophrenia including the subtypes Paranoid Type (295.30), Disorganised Type (295.10), Catatonic Type (295.20), Undifferentiated Type (295.90) and Residual Type (295.60); Schizophreniform Disorder (295.40); Schizoaffective Disorder (295.70) including the subtypes Bipolar Type and Depressive Type; Delusional Disorder (297.1 ) including the subtypes Erotomanic Type, Grandiose Type, Jealous Type, Persecutory Type, Somatic Type, Mixed Type and Unspecified Type; Brief Psychotic Disorder (298.8); Shared Psychotic Disorder (297.3); Psychotic Disorder Due to a General Medical Condition including the subtypes With Delusions and With Hallucinations; Substance-Induced Psychotic Disorder including the subtypes With Delusions (293.81 ) and With Hallucinations (293.82); and Psychotic Disorder Not Otherwise
  • pain includes : 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 cluster and chronic daily headache; 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; dysmenorrhea; neuralgia; fibromyalgia syndrome; complex regional pain syndrome (CRPS types I and II); neuropathic pain syndromes
  • chronic inflammatory pain e.g. pain associated with r
  • depression and mood disorder includes
  • Depression and mood disorders including Major Depressive Episode, Manic Episode, Mixed Episode and Hypo manic Episode; Depressive Disorders including Major Depressive Disorder, Dysthymic Disorder (300.4), Depressive Disorder Not Otherwise Specified (31 1 ); Bipolar Disorders including Bipolar I Disorder, Bipolar Il Disorder (Recurrent Major Depressive Episodes with Hypo manic Episodes) (296.89), Cyclothymiacs Disorder (301.13) and Bipolar Disorder Not Otherwise Specified (296.80); 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 Depressive Features, With Manic Features and With Mixed Features) and
  • the "depression and mood disorder" which may be treated by administration of a combination of compounds of the invention with Na channel blockers is a bipolar disorder.
  • the combination as herein above defined comprises a Na channel blocker selected from the group consisting of: fosphenytoin (CerebyxTM, ProdilantinTM, Pro- EpanutinTM or CereneuTM); oxcarbazepine (TrileptalTM, OxrateTM or WockhardtTM); phenytoin; carbamazepine (Carbatrol, Equetro TM); lidocaine (ALGRX-3268); Safinamide (NW-1015); Ralfinamide (NW-1029); Lacosamide ((2R)-2-(acetylamino)-3-methoxy-N- (phenylmethyl)propanamide); rufinamide (RUF-331 ); 3,5-diamino-6-(2,3-dichlorophenyl)- 1 ,2,4-
  • the combination as herein above defined comprises a Na channel blocker selected from the group consisting of fosphenytoin (CerebyxTM, ProdilantinTM, Pro- EpanutinTM or CereneuTM), oxcarbazepine (TrileptalTM, OxrateTM or WockhardtTM), phenytoin, carbamazepine (Carbatrol, Equetro TM), lidocaine (ALGRX-3268), Safinamide (NW-1015), Ralfinamide (NW-1029), Lacosamide ((2R)-2-(acetylamino)-3-methoxy-N- (phenylmethyl)propanamide), and rufinamide (RUF-331 ).
  • a Na channel blocker selected from the group consisting of fosphenytoin (CerebyxTM, ProdilantinTM, Pro- EpanutinTM or CereneuTM), oxcarbazepine (TrileptalTM, OxrateTM or Wock
  • the combination as herein above defined comprises a Na channel blocker selected from the group consisting of: 3,5-diamino-6-(2,3-dichlorophenyl)-1 ,2,4-triazine;
  • the combination as herein above defined comprises a Na channel blocker which is 3, 5-diamino-6-(2,3-dichlorophenyl)-1 ,2,4-triazine or a pharmaceutically acceptable salt or solvate thereof.
  • the combination as herein above defined comprises a Na Channel blocker which is R(-)-2,4-diamino-5-(2,3-dichlorophenyl)-6-fluoromethyl pyrimidine or a pharmaceutically acceptable salt or solvate thereof.
  • a Na Channel blocker which is R(-)-2,4-diamino-5-(2,3-dichlorophenyl)-6-fluoromethyl pyrimidine or a pharmaceutically acceptable salt or solvate thereof.
  • Compound R(-)-2,4-diamino-5-(2,3-dichlorophenyl)-6-fluoromethyl pyrimidine and pharmaceutically acceptable salts and solvates thereof are described in PCT publication No. WO 97/9317, published 13 March 1997.
  • Compound R(-)-2,4-diamino-5-(2,3- dichlorophenyl)-6-fluoromethyl pyrimidine and pharmaceutically acceptable salts and solvates thereof may be prepared by any method described in WO 97/9317.
  • the combination as herein above defined comprises a Na channel blocker which is (5R)-5-(4- ⁇ [(2-fluorophenyl)methyl]oxy ⁇ phenyl)-L-prolinamide or a pharmaceutically acceptable salt or solvate thereof.
  • the combination as herein above defined comprises a Na Channel blocker which is (2R,5R)-2-(4- ⁇ [(2-fluorophenyl)methyl]oxy ⁇ phenyl)-7-methyl- 1 ,7-diazaspiro[4.4]nonan-6-one or a pharmaceutically acceptable salt or solvate thereof.
  • a Na Channel blocker which is (2R,5R)-2-(4- ⁇ [(2-fluorophenyl)methyl]oxy ⁇ phenyl)-7-methyl- 1 ,7-diazaspiro[4.4]nonan-6-one or a pharmaceutically acceptable salt or solvate thereof.
  • the combination of a compound of the invention with a Na channel blocker comprises a Na Channel blocker which is selected from the group consisting of: fosphenytoin (CerebyxTM, ProdilantinTM, Pro-EpanutinTM or CereneuTM); oxcarbazepine (TrileptalTM, OxrateTM or WockhardtTM); phenytoin; carbamazepine (Carbatrol, Equetro TM); lidocaine (ALGRX-3268); Safinamide (NW-1015); Ralfinamide (NW-1029); Lacosamide ((2R)-2-(acetylamino)-3-methoxy-N-(phenylmethyl)propanamide); rufinamide (RUF-331 ); 3,5-diamino-6-(2,3-dichlorophenyl)-1 ,2,4-triazine, or a pharmaceutically acceptable salt or solvate thereof; R(-)-2,4-d
  • the invention thus provides, in a further aspect, a combination comprising a compound of the invention together with a further therapeutic agent or agents.
  • compositions 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 may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
  • dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
  • a combination of a compound of the invention with a Na channel blocker is provided, wherein at least one of them is at subtherapeutic dose.
  • a subtherapeutic dose is intended to mean a dose of a drug below that required to produce significant clinical benefit for the patient when administered alone.
  • the combination of a compound of the invention with a Na Channel blocker comprises a Na Channel blocker, at subtherapeutic dose, which is selected from the group consisting of: fosphenytoin (CerebyxTM, ProdilantinTM, Pro-EpanutinTM or CereneuTM); oxcarbazepine (TrileptalTM, OxrateTM or WockhardtTM); phenytoin; carbamazepine (Carbatrol, Equetro TM); lidocaine (ALGRX-3268); Safinamide (NW-1015); Ralfinamide (NW-1029); Lacosamide ((2R)-2-(acetylamino)-3-methoxy-N-
  • subtherapeutic dose which is selected from the group consisting of: fosphenytoin (CerebyxTM, ProdilantinTM, Pro-EpanutinTM or CereneuTM); oxcarbazepine (TrileptalTM, OxrateTM or Wock
  • the combination of a compound of the invention with a Na Channel blocker comprises a Na Channel blocker which is selected from the group consisting of: fosphenytoin (CerebyxTM, ProdilantinTM, Pro-EpanutinTM or CereneuTM); oxcarbazepine (TrileptalTM, OxrateTM or WockhardtTM); phenytoin; carbamazepine (Carbatrol, Equetro TM); lidocaine (ALGRX-3268); Safinamide (NW-1015); Ralfinamide (NW-1029); Lacosamide ((2R)-2-(acetylamino)-3-methoxy-N-(phenylmethyl)propanamide); rufinamide (RUF-331 ); 3,5-diamino-6-(2,3-dichlorophenyl)-1 ,2,4-triazine, or a pharmaceutically acceptable salt or solvate thereof; R(-)-2,4-d
  • the combination of a compound of the invention with a Na channel blocker comprises a Na Channel blocker which is selected from the group consisting of: fosphenytoin (CerebyxTM, ProdilantinTM, Pro-EpanutinTM or CereneuTM); oxcarbazepine (TrileptalTM, OxrateTM or WockhardtTM); phenytoin; carbamazepine (Carbatrol, Equetro TM); lidocaine (ALGRX-3268); Safinamide (NW-1015); Ralfinamide (NW-1029); Lacosamide ((2R)-2-(acetylamino)-3-methoxy-N-(phenylmethyl)propanamide); rufinamide (RUF-331 ); 3,5-diamino-6-(2,3-dichlorophenyl)-1 ,2,4-triazine, or a pharmaceutically acceptable salt or solvate thereof; R(-)-2,4
  • the combination of a compound of the invention with a Na Channel blocker comprises a Na Channel blocker, at subtherapeutic dose, which is selected from the group consisting of: fosphenytoin (CerebyxTM, ProdilantinTM, Pro-EpanutinTM or CereneuTM); oxcarbazepine (TrileptalTM, OxrateTM or WockhardtTM); phenytoin; carbamazepine (Carbatrol, Equetro TM); lidocaine (ALGRX-3268); Safinamide (NW-1015); Ralfinamide (NW-1029); Lacosamide ((2R)-2-(acetylamino)-3-methoxy-N-
  • subtherapeutic dose which is selected from the group consisting of: fosphenytoin (CerebyxTM, ProdilantinTM, Pro-EpanutinTM or CereneuTM); oxcarbazepine (TrileptalTM, OxrateTM or Wock
  • the combination of a compound of the invention with a Na Channel blocker comprises a Na Channel blocker which is selected from the group consisting of: fosphenytoin (CerebyxTM, ProdilantinTM, Pro-EpanutinTM or CereneuTM); oxcarbazepine (TrileptalTM, OxrateTM or WockhardtTM); phenytoin; carbamazepine (Carbatrol, Equetro TM); lidocaine (ALGRX-3268); Safinamide (NW-1015); Ralfinamide (NW-1029); Lacosamide ((2R)-2-(acetylamino)-3-methoxy-N-(phenylmethyl)propanamide); rufinamide (RUF-331 ); 3,5-diamino-6-(2,3-dichlorophenyl)-1 ,2,4-triazine, or a pharmaceutically acceptable salt or solvate thereof; R(-)-2,4-d
  • the combination of a compound of the invention with a Na Channel blocker comprises a Na Channel blocker which is selected from the group consisting of: fosphenytoin (CerebyxTM, ProdilantinTM, Pro-EpanutinTM or CereneuTM); oxcarbazepine (TrileptalTM, OxrateTM or WockhardtTM); phenytoin; carbamazepine (Carbatrol, Equetro TM); lidocaine (ALGRX-3268); Safinamide (NW-1015); Ralfinamide (NW-1029); Lacosamide ((2R)-2-(acetylamino)-3-methoxy-N-(phenylmethyl)propanamide); rufinamide (RUF-331 ); 3,5-diamino-6-(2,3-dichlorophenyl)-1 ,2,4-triazine, or a pharmaceutically acceptable salt or solvate thereof; R(-)-2,4
  • the invention also provides a combination of a compound of the invention with a Na channel blocker compound, for use in therapy.
  • the invention also provides a combination of (1 R,5R)3-[(2/?,4S)-1- ⁇ [ ⁇ (1 /?)-1- [3,5bis(trifluoromethyl)phenyl]ethyl ⁇ (methyl)amino] carbonyl ⁇ - 2-(4-fluoro-2-methylphenyl)-4- piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylic acid or a pharmaceutically acceptable salt thereof with a Na channel blocker compound which is selected from the group consisting of: 3,5-diamino-6-(2,3-dichlorophenyl)-1 ,2,4-triazine, or a pharmaceutically acceptable salt or solvate thereof; R(-)-2,4-diamino-5-(2,3-dichlorophenyl)-6-fluoromethyl pyrimidine, or a
  • the invention provides a combination of a compound of the invention with a Na channel blocker compound, for use as a therapeutic substance in the treatment or prophylaxis of epilepsy, depression and mood disorders, psychotic disorders or pain.
  • the invention provides a combination of (1 R,5R)3-[(2/?,4S)-1- ⁇ [ ⁇ (1 /?)-1- [3,5bis(trifluoromethyl)phenyl]ethyl ⁇ (methyl)amino] carbonyl ⁇ - 2-(4-fluoro-2-methylphenyl)-4- piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylic acid ;or a pharmaceutically acceptable salt thereof with a Na channel blocker compound, which is selected from the group consisting of: 3,5-diamino-6-(2,3-dichlorophenyl)-1 ,2,4-triazine, or a pharmaceutically acceptable salt or solvate thereof; R(-)-2,4-diamino-5-(2,3-dichlorophenyl)-6-fluoromethyl pyrimidine, or a pharmaceutically acceptable salt or solvate thereof; (2R,5R)-2-(4- ⁇ [(2- fluorine flu
  • the invention further provides a method of treatment or prophylaxis of epilepsy, depression and mood disorders, psychotic disorders or pain, in mammals including humans, which comprises administering to the sufferer a therapeutically effective amount of a combination of a compound of the invention with a Na channel blocker compound.
  • the invention further provides a method of treatment or prophylaxis of epilepsy, depression and mood disorders, psychotic disorders or pain, in mammals including humans, which comprises administering to the sufferer a therapeutically effective amount of a combination of (1 R,5R)3-[(2R,4S)-1- ⁇ [ ⁇ (1 R)-1-[3,5bis(trifluoromethyl)phenyl]ethyl ⁇ (methyl)amino] carbonyl ⁇ - 2-(4-fluoro-2-methylphenyl)-4-piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylic acid or a pharmaceutically acceptable salt thereof with a Na channel blocker compound, which is selected from the group consisting of: 3,5-diamino-6-(2,3-dichlorophenyl)-1 ,2,4- triazine, or a pharmaceutically acceptable salt or solvate thereof; R(-)-2,4-diamino-5-(2,3- dichlorophenyl
  • the invention provides the use of a combination of a compound of the invention with a Na channel blocker compound in the manufacture of a medicament for use in the treatment of epilepsy, depression and mood disorders, psychotic disorders or pain.
  • the invention provides the use of a combination of (1 R,5R)3-[(2/?,4S)-1- ⁇ [ ⁇ (1/?)-1-[3,5bis(trifluoromethyl)phenyl]ethyl ⁇ (methyl)amino] carbonyl ⁇ - 2-(4-fluoro-2- methylphenyl)-4-piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylic acid or a pharmaceutically acceptable salt thereof with a Na channel blocker compound, which is selected from the group consisting of: 3,5-diamino-6-(2,3-dichlorophenyl)-1 ,2,4-triazine, or a pharmaceutically acceptable salt or solvate thereof; R(-)-2,4-diamino-5-(2,3- dichlorophenyl)-6-fluoromethyl pyrimidine, or a pharmaceutically acceptable salt or solvate thereof; (2R,5R)-2-(4- ⁇ [(2-fluoromethyl
  • the invention provides a pharmaceutical composition treatment of epilepsy, depression and mood disorders, psychotic disorders or pain which comprises combinations of a compound of the invention with a Na channel blocker compound and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition of the invention which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, 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 unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents. The tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or 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 flavourings or colorants.
  • fluid unit dosage forms are prepared utilising a compound of the invention or a pharmaceutically acceptable salt thereof and a sterile vehicle.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle.
  • 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 way with the seriousness of the disorders, the weight of the sufferer, and other similar factors.
  • suitable unit doses may be 0.05 to 1000 mg, more suitably 1.0 to 200 mg, and such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks or months.
  • NMR Nuclear Magnetic Resonance
  • MS Direct infusion Mass spectra
  • MSD 1 100 Mass Spectrometer, operating in ES (+) and ES (-) ionization mode
  • ES (+) Mass range: 100-1000 amu.
  • Infusion solvent water + 0.1 % HCO 2 H / CH 3 CN 50/50.
  • ES (-) Mass range: 100-1000 amu.
  • Infusion solvent water + 0.05% NH 4 OH / CH 3 CN 50/50] (the usage of this methodology is indicated by "MS" in the analytic characterization of the described compounds) or on an Agilent LC/MSD 1100 Mass Spectrometer coupled with HPLC instrument Agilent 1100 Series, operating in positive or negative electrospray ionization mode and in both acidic and basic gradient conditions [Acidic gradient LC/MS - ES (+ or -): analyses performed on a Supelcosil ABZ + Plus column (33 x 4.6 mm, 3 ⁇ m). Mobile phase: A - water + 0.1% HCO 2 H / B - CH 3 CN.
  • Flash+ Biotage manual flash chromatography
  • Biotage automatic flash chromatography Horizon, SP1 and SP4
  • ISCO Companion CombiFlash
  • Flash Master Personal or Vac Master systems Flash chromatography was carried out on silica gel 230-400 mesh (supplied by Merck AG Darmstadt, Germany), Varian Mega Be-Si pre-packed cartridges, pre-packed Biotage silica cartridges (e.g. Biotage SNAP cartridge), KP-NH prepacked flash cartridges or ISCO RediSep 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.
  • Isomer 1 or Isomer 2 means a compound of the invention or an intermediate thereof as a single isomer whose absolute configuration was not determined.
  • Ethyl 3-azabicyclo[3.1.0]hexane-1-carboxylate (Intermediate 2, 64 mg, 0.412 mmol) and (2R)-N- ⁇ (1 R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl ⁇ -2-(4-fluoro-2-methylphenyl)-N-methyl- 4-0X0-1 -piperidinecarboxamide (WO 0232867, 312 mg, 0.619 mmol) were dissolved in dry DCE (3 ml) under Argon atmosphere. TEA (0.059 ml, 0.423 mmol) was added and the mixture was stirred for 1.5 h.
  • Ethyl 3-azabicyclo[3.1.0]hexane-1-carboxylate (Intermediate 22, 50 mg, 0.186 mmol) was dissolved in THF, then it was basified with 1 M NaOH (1 ml) and (2R)-3,3,3-trifluoro-2- (methyloxy)-2-phenylpropanoyl chloride ((R)-(-)-Mosher's acid chloride) (47.1 mg, 0.186 mmol) was added. The mixture was stirred for 10 min. DCM (5 ml) and water (5 ml) were added and the resulting mixture was stirred for 5 mins.
  • Enantiomeric eccess (e.e.) of this batch was checked by chiral HPLC, preparing the corresponding amide (Intermediate 23) with (R)-(-)-Mosher acid chloride.
  • THF Tetrahydrofuran
  • 1 M sodium hydroxide aq. solution was added, followed by (R)-(-)-Mosher acid chloride ( ⁇ 100 ⁇ l). The mixture was shaken at r.t. for -10 minutes, keeping a basic pH with the addition of sodium hydroxide solution.
  • Enantiomeric eccess (e.e.) of this batch was checked by chiral HPLC, preparing the corresponding amide (Intermediate 23) with (R)-(-)-Mosher acid chloride as described before.
  • the aqueous phase was extracted with EtOAc (2X) and the combined organic phases were dried (Na 2 SO 4 ) and evaporated to dryness.
  • the crude was purified by SCX eluting with methanol and then with 0.5 M methanolic ammonia (to elute the desired compound).
  • the fraction eluted with methanolic ammonia was evaporated to dryness and the crude was purified by flash-chromatography with Biotage SP1 (from 85:25 to 7:3 Cyclohexane/EtOAc) to give:
  • Example 1 sodium 3-r(2R4S)-1-m(1 /?)-1-F3,5- bis(trifluoromethyl)phenvnethyl)(methyl)amino1carbonyl)-2-(4-fluoro-2- methylphenvD ⁇ -piperidinvn-S-azabicvclorS.I .OIhexane-i -carboxylate (isomer 1 )
  • the compound of example 2 is believed to be sodium 3-(1S.5S)- r(2R4S)-1-fR(1 /?)-1-[3.5- bis(trifluoromethyl)phenyl1ethyl)(methyl)amino1carbonyl)-2-(4-fluoro-2-methylphenyl)-4- piperidinyll-3-azabicvclor3.1.Olhexane-1 -carboxylate.
  • the atom numbering shown in the following structure is included for the purpose of correlation with the NMR data only.
  • Example 7 (Method B) Sodium (1R5/?)-3-r(2R4S)-1 -m(1 S)-1 -F3.5- bis(trifluoromethyl)phenvnethylMmethyl)amino1carbonyl)-2-(4-fluoro-2- methylphenylM-piperidinyll-S-azabicvclorS.I.Olhexane-i-carboxylate
  • the atom numbering shown in the following structure is included for the purpose of correlation with the NMR data only.
  • Compounds of the invention may be tested for in vitro biological activity in accordance with the assays described here below.
  • Compounds of the inventions tested in the following assays may be not necessarily from the same batch as that of the corresponding examples.
  • the NK1 binding affinity of the compounds of the invention was determined using the following filtration binding assay using [ 3 H]-GR205171 as radioligand for human NK1 receptor stably expressed in CHO (Chinese Hamster Ovary) cells (see C. Griffante et al, Br. J. Pharmacol. 2006, 148, 39-45; H. M. Sarau et al, J. Pharmacol. Experimental Therapeutics 2000, 295(1 ), 373-381 and DT. Beattie et al., Br. J. Pharmacol. 1995, 116, 3149-3157).
  • CHO cells stably expressing the human cloned neurokinin NK1 receptor were cultured in Dulbecco's Modified Eagle's Medium/F12 Ham (DMEM/F12Ham) supplemented with 10% foetal bovine serum and 2 mM L-glutamine. Cells were maintained in 5% CO 2 in a humidified incubator at 37°C. Cells were harvested at confluency with PBS/EDTA (5 mM) and then pelleted by centrifugation (1000 g, 8 min, 4°C). To prepare membranes, cell pellets were homogenised in 10 volumes of membrane preparation buffer and centrifuged (48,000 g, 20 min, 4°C). The membranes were then re-suspended as 500 ⁇ l_ aliquots and stored at -80 0 C until use.
  • DMEM/F12Ham Dulbecco's Modified Eagle's Medium/F12 Ham
  • PBS/EDTA 5 mM
  • centrifugation 1000 g, 8
  • Binding assay was carried out in 96 deep well polypropylene plates (Whatman) in a volume of 400 ⁇ l consisted of 100 ⁇ l of incubation buffer (containing 5OmM HEPES, pH 7.4, 3mM MnCI 2 , and 0.02% BSA), 4 ⁇ l of DMSO (total binding) or increasing concentrations of the compounds in the invention dissolved in DMSO (1 pM-1 ⁇ M final concentration), 10O ⁇ l of the radioligand [ 3 H]-GR205171 (0.2 nM final concentration) in incubation buffer and 200 ⁇ l of human NK1-CHO cell membranes suspension (4 ⁇ g/ml final) in incubation buffer.
  • Non specific binding was defined by the addition of 1 ⁇ M unlabelled GR205171.
  • U2OS cells were harvested from tissue culture flasks, re-suspended to a cell density of 200-300K/ml and mixed with recombinant BacMam virus carrying NKR gene in a virus/cell ratio of 1% (v/v). 10K-15K cells/well were then seeded in 384-well Greiner bio-one plate in culture medium (DMEM with 10% FBS), incubated overnight in 5% CO 2 at 37 0 C.
  • cytoplasmic calcium indicator Fluo-4 Calcium 3 dye (Molecular Devices Co.) in 30uL/well buffer (Hank's balanced salts with 20 mM Hepes) and incubated in CO 2 at 37 0 C for 60 minutes.
  • 10uL/well assay buffer (Hank's balanced salts with 20 mM Hepes) containing different concentrations of compounds were then added to the cells for 30 minutes incubation at 37 0 C.
  • 10uL/well of NKR ligand in assay buffer containing 0.1 % BSA was added to the cells and fluorescence signal read on a FLIPR system.
  • Substance P was used as the ligand for NK1.
  • IC50 values of each compound were determined by an 1 1-point 3X-dilution inhibition curve.
  • the potency each antagonist (fpK,) was calculated from plC50 by the Cheng-Prusoff equation using EC50 of ligand determined in a separate experiment.
  • Example 1 The compounds of Example 1 to 9 were tested in the NK1 functional potency assay.
  • the corresponding pKi values obtained as the average of at least two determinations are given in the following Table 1
  • the ability of the compounds of the invention to penetrate the central nervous system and to bind at the NK 1 receptor may be determined using the gerbil foot tapping model as described by Rupniak & Williams, Eur. Jour, of Pharmacol., 1994.
  • Intracerebroventricular (icv) administration of the NK 1 receptor agonist GR73632 induces a characteristic hind leg foot tapping (GFT) response in gerbils which can be inhibited by NK 1 receptor antagonists.
  • GFT hind leg foot tapping
  • the gerbil foot tapping paradigm was carried out as follows; gerbils were dosed with compound of the invention, and following an appropriate pre-treatment time were anaesthetised using isofluorane / oxygen mixture.
  • GR73632 (3pmol / 5ul) was injected by insertion of a cuffed 25G needle to a depth of 4mm below bregma, directly into the lateral ventricle (intracerebroventricular dosing).
  • gerbils were placed individually into a clear observation box to recover.
  • the duration of repetitive hind foot tapping was recorded over a 5 minute period.
  • the dose of the test compound required to inhibit by 50% the tapping induced by the NK1 agonist expressed as mg/kg is referred to as the ID 50 value.
  • GR73632-induced GFT behaviour was significantly attenuated by Example 6 at all doses tested 0.3mg/kg (P ⁇ 0.05) 0.1 & 1 mg/kg (P ⁇ 0.01 ) and was completely abolished at 3mg/kg (P ⁇ 0.01 ); with a calculated ID 50 of approximately 0.36 mg/kg (blood plasma & brain ID 50S approximately 78 ng/ml & 32 ng/g respectively).
  • Compounds of the invention have also been found to demonstrate anxiolytic activity in validated preclinical tests. For example the marmoset human threat test (Costall et al., 1988
  • test animals were treated orally with vehicle (0.5% HPMC + 0.1% Tween 80 in 25mM glycine buffer) or test compound (1 ml/kg). After a wash-out period of at least three days, treatments were reassigned and the study was complete when all animals had received all treatments. The number of specific behavioural postures in response to the human threat and the number of jumps were analysed in this study. The postures recorded in the test were those described by Costall et al (1988) and the number of jumps performed by the animals provided an index of locomotor activity to assess potential for sedation or locomotor stimulation. Results for compound of Example 6 are summarised in the table 2 below.
  • Pretreatment with Compound of Example 6 caused a reduction in the number of postures without affecting the number of jumps performed by the marmosets. This is consistent with an anxiolytic profile in this test procedure.

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Abstract

The invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2; useful in the treatment of conditions for which antagonism of NK1 receptor is beneficial.

Description

PIPERIDINE BASED UREAS AS NK1 ANTAGONISTS
The present invention relates to novel azabicycle compounds having pharmacological activity, to processes for their preparation, to compositions containing them and to their medical uses.
The present invention provides, in a first aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof,
Figure imgf000002_0001
(I) wherein n is 1 or 2.
The wedge shaped bond in formula (I) indicates that the bond is above the plane of the paper.
The compounds of the present invention may be in the form of and/or may be administered as a pharmaceutically acceptable salt.
Typically, a pharmaceutical acceptable salt may be readily prepared by using a desired acid or base as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
A pharmaceutically acceptable acid addition salt can be formed by reaction of a compound of formula (I) with a suitable inorganic or organic acid (such as hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, formic, acetic, propionic, fumaric, citric, tartaric, lactic, benzoic, salicylic, glutamaic, aspartic, p-toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic such as 2- naphthalenesulfonic, or hexanoic acid), optionally in a suitable solvent such as an organic solvent, to give the salt which is usually isolated for example by crystallisation and filtration. A pharmaceutically acceptable acid addition salt of a compound of formula (I) can comprise or be for example a hydrobromide, hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, formate, acetate, propionate, fumarate, citrate, tartrate, lactate, benzoate, salicylate, glutamate, aspartate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, naphthalenesulfonate (e.g. 2- naphthalenesulfonate) or hexanoate salt.
A pharmaceutically acceptable base addition salt can be formed by reaction of a compound of formula (I) with a suitable inorganic or organic base (e.g. triethylamine, ethanolamine, triethanolamine, choline, arginine, lysine or histidine), optionally in a suitable solvent such as an organic solvent, to give the base addition salt which is usually isolated for example by crystallisation and filtration.
Other suitable pharmaceutically acceptable salts include pharmaceutically acceptable metal salts, for example pharmaceutically acceptable alkali-metal or alkaline-earth-metal salts such as sodium, potassium, calcium or magnesium salts.
Other non-pharmaceutically acceptable salts, eg. oxalates, may be used, for example in the isolation of compounds of the invention, and are included within the scope of this invention.
The invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the salts of the compounds of formula (I).
The compounds of formula(l) can exist as zwitterions.
Salts having a non-pharmaceutically acceptable anion or cation are within the scope of the invention as useful intermediates for the preparation of pharmaceutically acceptable salts and/or for use in non-therapeutic, for example, in vitro, situations.
Compounds of formula (I) may be obtained as crystalline forms.
It is to be understood that any such crystalline forms or a mixture thereof are encompassed within the scope of the invention.
Furthermore, any such crystalline forms of the compounds of formula (I) may exist as polymorphs, which are included in the present invention.
Hereinafter, compounds of formula (I), their pharmaceutically acceptable salts, solvates, hydrates and crystalline forms thereof defined in any aspect of the invention (except intermediate compounds in chemical processes) are referred to as "the compounds of the invention".
The subject invention also includes isotopically-labelled compounds, which are identical to those recited in formula (I) but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention or pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, iodine, and chlorine, such as 2 H, 3H, H e, 13C, 14C, 15N, ^0, 180, 31 p, 32P] 35Sj 18Fi 36C|, 123, and 125,.
Compounds of the invention that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention. Isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as 3 H, 14c are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14c, isotopes are particularly preferred for their ease of preparation and detectability. ^C and 1^F isotopes are particularly useful in PET (positron emission tomography), and 125| isotopes are particularly useful in SPECT (single photon emission computerized tomography), all useful in brain imaging. Further, substitution with heavier isotopes such as deuterium, i.e., ^H, can 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, lsotopically labelled compounds of the invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
It will be appreciated by those skilled in the art that compounds of formula (I)
Figure imgf000004_0001
contain 4 further asymmetric carbon atoms in addition to that at 2 position of the piperidinyl ring (namely the carbon atoms shown as * in the formulae from (Ia) to (Ih).
The asymmetric carbon atoms can be represented by the formulas from (Ia) to (Ih) as follows:
Figure imgf000004_0002
(Ia) (Ib)
Figure imgf000005_0001
(Ic) (Id)
Figure imgf000005_0002
(Ie) (if)
Figure imgf000005_0003
(Ig) (Ih)
The wedge shaped bond indicates that the bond is above the plane of the paper. The broken bond indicates that the bond is below the plane of the paper. The assignment of the R or S configuration to the 5 asymmetric carbon atoms showed above has been made according to the rules of Cahn, lngold and Prelog, Experientia 1956,12, 81.
It will be understood that the invention encompasses all the above isomers such as diastereoisomers or enantiomers of the compounds of formula(l) and the mixture thereof including racemates and the reference to a compound of formula (I) includes all said stereoisomeric forms unless otherwise stated.
In one embodiment of the invention it is provided compounds of formula (IA) or a pharmaceutically acceptable salt thereof,
Figure imgf000006_0001
wherein n is 1 or 2.
In a further embodiment of the invention it is provided compounds of formula (IB) or a pharmaceutically acceptable salt thereof,
Figure imgf000006_0002
wherein n is 1 or 2.
In a further yet embodiment n is 1. In a further yet embodiment n is 2.
In a further embodiment the compound of the invention is selected from a list consisting of
• 3-[(2R,4S)-1-{[{(1 R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}- 2-(4-fluoro-2-methylphenyl)-4-piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylic acid (isomer 1 ). This is (1 R,5R)3-[(2R4S)-1-{[{(1 R)-1-[3,5bis(trifluoromethyl) phenyl]ethyl} (methyl)amino] carbonyl}- 2-(4-fluoro-2-methylphenyl)-4-piperidinyl]-3- azabicyclo[3.1.0]hexane-1-carboxylic acid;
• 3-[(2R,4S)-1-{[{(1 R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}- 2-(4-fluoro-2-methylphenyl)-4-piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylic acid ( isomer 2). This is believed to be (1S!5S)3-[(2R!4S)-1-{[{(1 R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl} (methyl)amino]carbonyl}-2-(4-fluoro-2-methylphenyl)-4-piperidinyl]-3- azabicyclo[3.1.0]hexane-1-carboxylic acid;
• 3-[(2R!4R)-1-{[{(1 R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}- 2-(4-fluoro-2-methylphenyl)-4-piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylic acid; • 3-[(2R,4S)-1-{[{(1 R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-
2-(4-fluoro-2-methylphenyl)-4-piperidinyl]-3-azabicyclo[4.1.0]heptane-1-carboxylic acid ( isomer 1 );
• 3-[(2R,4S)-1-{[{(1 R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}- 2-(4-fluoro-2-methylphenyl)-4-piperidinyl]-3-azabicyclo[4.1.0]heptane-1-carboxylic acid ( isomer 2);
• (1R5R)-3-[(2R ,4S)-1-{[{(1 S)-1-[3, 5- bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl} -2-(4-fluoro-2- methylphenyl)-4-piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylic acid;
• (1R5R)-3-[(2R4R)-1-{[{(1 S)-1- [3,5bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}- 2-(4-fluoro-2- methylphenyl)-4-piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylic acid;
• (15,5S)-S-PR^S)-I-(K(I S)-I-[S1S- bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-2-(4-fluoro-2- methylphenyl)-4-piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylic acid; or a pharmaceutical acceptable salt thereof.
In a further embodiment the compound of the invention is : (1R5R)-3-[(2R4S)-1-{[{(1 R)-1-[3,5- bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-2-(4-fluoro-2-methylphenyl)-4- piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylic acid (Ii)
Figure imgf000008_0001
or a pharmaceutically acceptable salt thereof.
In a further embodiment the compound of the invention is : (1 R,5R)-3-[(2R,4S)-1 -{[{(1 R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl} (methyl)amino] carbonyl} -2-(4-fluoro-2-methylphenyl)-4-piperidinyl]-3-azabicyclo [3.1.0]hexane-1- carboxylic acid (Ii).
In a further embodiment the compound of the invention is Sodium salt of (1 R,5R)-3-[(2R,4S)-1-{[{(1 R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl) amino]carbonyl}-2-(4-fluoro-2-methylphenyl)-4-piperidinyl]-3-azabicyclo[3.1.0]hexane-1- carboxylic acid (Ii).
In a further embodiment the compound of the invention is : 3-[(2R,4S)-1-{[{(1 R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-2-(4- fluoro-2-methylphenyl)-4-piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylic acid (isomer 2).
In a further embodiment the compound of the invention is : 3-[(2R!4S)-1-{[{(1 R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-2-(4- fluoro-2-methylphenyl)-4-piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylic acid (isomer 2) or a pharmaceutically acceptable salt thereof.
In a further embodiment the compound of the invention is sodium 3-[(2/?,4S)-1-{[{(1 R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}- 2-(4-fluoro-2-methylphenyl)-4-piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylate (isomer 2).
The present invention also provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which process comprises: reacting a compound of formula (II),
Figure imgf000009_0001
wherein R is C 1.4 alkyl , such as methyl or ethyl, with an aqueous solution of metal hydroxide such as sodium hydroxide and a suitable solvent such as methanol at suitable temperature such as 80-900C optionally under microwaves irradiation.
Compounds of formula (II) may be prepared by reductive amination of a compound of formula (III)
Figure imgf000009_0002
with an amine (IV), wherein R is C 1.4 alkyl , such as methyl or ethyl and n is 1 or 2, followed by the addition of a suitable reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride.
For example, said reductive amination reaction may typically comprise reacting a compound of formula (III) with amine (IV) in a suitable solvent such as dichloroethane or methanol, at a suitable temperature such as r.t, followed by the addition of a suitable reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride.
When a specific isomer including an enantiomer or a diasteroisomer of a compound of formula (II) is required, this may be obtained, for example reacting compound (III) or a single enantiomer thereof and (IV) using the methodology described above followed by separation of the mixture of isomers. The separation of the mixture of isomers including enantiomers or a diasteroisomers into the single enantiomers or diastereoisomers may be run by conventional means such as chromatography (flash-chromatography on silica gel, Liquid chromatography or chiral chromatography) or crystallisation. Alternatively, when a specific isomer including an enantiomer or a diasteroisomer of a compound of formula (II) is required, this may be obtained, reacting a single enantiomer of compound (III) with a single enantiomer of a compound (IV) using the methodology described above.
Compounds of formula(lll) and enantiomers thereof may be prepared according to the procedure described in WO 0232867.
Compounds of formula (IV), wherein n is 2, may be prepared in accordance with the following scheme (I).
Scheme (I)
step (i) StΘP (iN)
Figure imgf000010_0002
Figure imgf000010_0001
(V) (Vl) (VII) step (vi)
Figure imgf000010_0004
Figure imgf000010_0003
<VIII» (IX) (X) (IV)
Step (i) typically comprises reacting a compound of formula (V), wherein P2 and P3 represent suitable nitrogen protecting groups or P2 and P3 taken together with the nitrogen atom form a protecting group such as phtalimide (European Journal of Medicinal Chemistry, 38(7-8), 729-737; 2003, Organic Letters, 7(4), 733-736; 2005 or commercially available from ABCR GmbH KG Im Schlehert 10 Karlsruhe, D-76187 Germany) with dimethyl diazomalonate in the presence of a suitable catalyst such as Rhodium(ll) acetate dimer in a suitable solvent such as chlorobenzene at a suitable temperature such as 60-
700C.
Step (ii) typically comprises the removal of the nitrogen protecting group, followed by cyclization to get the lactam (VII). For example when P2 and P3 taken together with the nitrogen atom form a nitrogen protecting group such as phtalimide, the reaction may be carried out reacting a compound of formula (Vl) with hydrazine in a suitable solvent such as methanol at a suitable temperature such as reflux temperature.
Step (iii) typically comprises protection of a compound of formula (VII) with a suitable nitrogen protecting group. For example, when P4 is tertbutyloxycarbonyl (Boc), step (iii) may typically comprise reacting a compound of formula (VII) with di-te/f-butyl dicarbonate in a suitable solvent such as a mixture of toluene/dichloromethane in the presence of 4- (Dimethylamino)pyridine at a suitable temperature such as reflux temperature. Step (iv) and (v) typically comprises a stepwise reduction of lactam (VIII) to the corresponding amine (X) via an intermediate (IX). For example, step (iv) may be carried out reacting a lactam (VIII) with a suitable reducing agent such as Super-Hydride® (1.0 M lithium triethylborohydride in tetrahydrofuran)in a suitable solvent such as THF at a suitable temperature such as -100C to get the intermediate (IX), which may be conveniently converted to the amine (X) by treatment with a suitable reducing agent such as triethylsilane in the presence of a suitable Lewis acid such as BF3 OEt2 in a suitable solvent such as dichloromethane at a suitable temperature such as -78°C.
Step (vi) typically comprises removal of the nitrogen protecting group. For example, when P4 represents Boc, step (vi) may typically comprise reacting a compound of formula (X) with TFA in a suitable solvent such as dichloromethane at a suitable temperature ranging from 00C to r.t.
Compounds of formula (IV), wherein n is 1 N-protected derivative thereof, are known compounds or may be prepared according procedures described in WO 2007055093 and WO 2004089363.
A single enantiomer of a compound of formula (IV) may be obtained by conventional means such as resolution of the racemate by chiral chromatography or forming a salt by reaction with a suitable optically active acid, separating the resultant diastereoisomeric salts by conventional means, e.g. crystallisation or precipitation followed by isolation of the corresponding free base.
A suitable optically active acid for use in the process is (2S,3S)-2,3- bis[(phenylcarbonyl)oxy]butanedioic acid.
Alternatively, the compounds of formula(IV), wherein n is 1 , may be prepared by asymmetric synthesis thus for example as described in the following scheme (II).
Scheme (II)
Figure imgf000012_0001
(Xl) (XI I) (Xi Ii) (XIV)
Figure imgf000012_0002
Step (i) typically comprises the synthesis of a chiral bicyclic lactone (XIII) in one pot from a suitable chiral epichlorohydrin (Xl) by an intramolecular double displacement of an alkyl malonate anion, followed by lactonization. Said alkyl malonate anion may be prepared reacting a suitable alkyl malonate (XII), wherein R' is an alkyl group, such as diethylmalonate, with a suitable base such as sodium ethoxide in a suitable solvent such as ethanol at a suitable temperature such as low temperature (00C). After warming up the reaction mixture to room tempertaure, a suitable chiral epichlorohydrin (Xl) such as (R)- epichlorohydrin may be added to the aforementioned alkyl malonate anion solution and the resulting reaction mixture may be refluxed for a suitable time such as 36 hrs to give a compound (XIII). See J. Org. Chem. 2007, 72, 7390-7393.
Step (ii) typically comprises reacting the chiral bicyclic lactone (XIII) with a suitable reducing agent such as NaBH4 in a suitable solvent such as ethanol at a suitable temperature such as room temperature for a suitable time such as few hours to give a compound of formula (XIV).
Step (iii) typically comprises the conversion of a compound of formula (XIV) into a suitable derivative (XV), wherein Lg are suitable leaving groups such as a mesylate, reacting (XIV) with a suitable reagent such as methansulfonic anhydride in a suitable solvent such as dichloromethane in the presence of a suitable base such as triethylamine Step (iv) typically comprises reacting a compound of formula (XV) with a suitable amine such as benzylamine in a suitable solvent such as dichloromethane at a suitable temperature such as room temperature, folowed by removal of the benzyl group using standard procedures.
Where it is desired to isolate compounds of formula (I) as a salt, for example a pharmaceutically acceptable salt, this may be achieved by reacting the compound of formula (I) in the form of the free acid with an appropriate amount of a suitable base or a suitable acid and in a suitable solvent such as an alcohol (e.g. ethanol or methanol), an ester (e.g. ethyl acetate) or an ether (e.g. diethyl ether or tetrahydrofuran).
Pharmaceutically acceptable salts may also be prepared from other salts, including other pharmaceutically acceptable salts, of the compounds of formula (I) using conventional methods. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
Compounds of formula (I) and their pharmaceutically acceptable salts have affinity for and are specific antagonists of tachykinins, including substance P and other neurokinins. Tachykinins are a family of peptides that share a common carboxyl-terminal sequence (Phe-X-Gly-Leu-Met-NH2). They are actively involved in the physiology of both lower and advanced life forms. In mammalian life forms, the main tachykinins are substance P (SP), Neurokinin A (NKA) and Neurokinin B (NKB) which act as neurotransmitters and neuromodulators. Mammalian tachykinins may contribute to the pathophysiology of a number of human diseases.
Three types of tachykinins receptors have been identified, namely NKI (SP-preferring), NK2 (NKA-preferring) and NK3 (NKB-preferring) which are widely distributed throughout the central nervous (CNS) and peripheral nervous system.
Particularly, compounds of the invention are antagonists of the NK1 receptor.
Compounds of the invention are useful in the treatment of conditions for which antagonism of NK1 receptor is beneficial .
Within the context of the present invention, the terms describing the indications used herein 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 (ICD-10). The various subtypes of the disorders mentioned herein are contemplated as part of the present invention. Numbers in brackets after the listed diseases below refer to the classification code in DSM-IV.
Compounds of formula (I) or pharmaceutically acceptable salts thereof may be of use in the treatment of the following disorders:
Depression and mood disorders including Major Depressive Episode, Manic Episode, Mixed Episode and Hypo manic Episode; Depressive Disorders including Major Depressive Disorder, Dysthymic Disorder (300.4), Depressive Disorder Not Otherwise Specified (31 1 ); Bipolar Disorders including Bipolar I Disorder, Bipolar Il Disorder (Recurrent Major Depressive Episodes with Hypo manic Episodes) (296.89), Cyclothymiacs Disorder (301.13) and Bipolar Disorder Not Otherwise Specified (296.80); 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 Depressive Features, With Manic Features and With Mixed Features) and Mood Disorder Not Otherwise Specified (296.90). Anxiety disorders including Panic Attack; Panic Disorder including Panic Disorder without Agoraphobia (300.01 ) and Panic Disorder with Agoraphobia (300.21 ); Agoraphobia; Agoraphobia Without History of Panic Disorder (300.22), Specific Phobia (300.29, formerly Simple Phobia) including the subtypes Animal Type, Natural Environment Type, Blood- Injection-Injury Type, Situational Type and Other Type), Social Phobia (Social Anxiety Disorder, 300.23), Obsessive-Compulsive Disorder (300.3), Posttraumatic 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 Anxiety Disorder Not Otherwise Specified (300.00).
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 Dependence (303.90), 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-Induced Anxiety Disorder, Amphetamine-Induced Sexual Dysfunction, Amphetamine-Induced Sleep Disorder and Amphetamine-Related Disorder Not Otherwise Specified (292.9); Caffeine Related Disorders such as Caffeine Intoxication (305.90), Caffeine-Induced Anxiety Disorder, Caffeine-Induced Sleep Disorder and Caffeine-Related Disorder Not Otherwise Specified (292.9); Cannabis-Related Disorders such as Cannabis Dependence (304.30), Cannabis Abuse (305.20), Cannabis Intoxication (292.89), Cannabis Intoxication Delirium, Cannabis-lnduced Psychotic Disorder, Cannabis-lnduced Anxiety Disorder and Cannabis- Related Disorder Not Otherwise Specified (292.9); Cocaine-Related Disorders such as Cocaine Dependence (304.20), Cocaine Abuse (305.60), Cocaine Intoxication (292.89), Cocaine Withdrawal (292.0), Cocaine Intoxication Delirium, Cocaine-Induced Psychotic Disorder, Cocaine-Induced Mood Disorder, Cocaine-Induced Anxiety Disorder, Cocaine- Induced Sexual Dysfunction, Cocaine-Induced Sleep Disorder and Cocaine-Related Disorder Not Otherwise Specified (292.9); Hallucinogen-Related Disorders such as Hallucinogen Dependence (304.50), Hallucinogen Abuse (305.30), Hallucinogen Intoxication (292.89), Hallucinogen Persisting Perception Disorder (Flashbacks) (292.89), Hallucinogen Intoxication Delirium, Hallucinogen-Induced Psychotic Disorder, Hallucinogen-Induced Mood Disorder, Hallucinogen-Induced Anxiety Disorder and Hallucinogen-Related Disorder Not Otherwise Specified (292.9); Inhalant-Related Disorders such as Inhalant Dependence (304.60), Inhalant Abuse (305.90), Inhalant Intoxication (292.89), Inhalant Intoxication Delirium, Inhalant-Induced Persisting Dementia, Inhalant-Induced Psychotic Disorder, Inhalant-Induced Mood Disorder, Inhalant-Induced Anxiety Disorder and Inhalant-Related Disorder Not Otherwise Specified (292.9); Nicotine- Related Disorders such as Nicotine Dependence (305.1 ), Nicotine Withdrawal (292.0) and Nicotine-Related Disorder Not Otherwise Specified (292.9); 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-lnduced 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-lnduced Mood Disorder, Phencyclidine-lnduced Anxiety Disorder and Phencyclidine-Related Disorder Not Otherwise Specified (292.9); Sedative-, Hypnotic-, or Anxiolytic-Related Disorders such as Sedative, Hypnotic, or Anxiolytic Dependence (304.10), Sedative, Hypnotic, or Anxiolytic Abuse (305.40), Sedative, Hypnotic, or Anxiolytic Intoxication (292.89), Sedative, Hypnotic, or Anxiolytic Withdrawal (292.0), Sedative, Hypnotic, or Anxiolytic Intoxication Delirium, Sedative, Hypnotic, or Anxiolytic Withdrawal Delirium, Sedative-, Hypnotic-, or Anxiolytic-Persisting Dementia, Sedative-, Hypnotic-, or Anxiolytic- Persisting Amnestic Disorder, Sedative-, Hypnotic-, or Anxiolytic- lnduced Psychotic Disorder, Sedative-, Hypnotic-, or Anxiolytic-lnduced Mood Disorder, Sedative-, Hypnotic-, or Anxiolytic-lnduced Anxiety Disorder Sedative-, Hypnotic-, or Anxiolytic-lnduced Sexual Dysfunction, Sedative-, Hypnotic-, or Anxiolytic-lnduced Sleep Disorder and Sedative-, Hypnotic-, or Anxiolytic-Related Disorder Not Otherwise Specified (292.9); Polysubstance-Related Disorder such as Polysubstance Dependence (304.80); and Other (or Unknown) Substance-Related Disorders such as Anabolic Steroids, Nitrate Inhalants and Nitrous Oxide.
Sleep disorders including primary sleep disorders such as Dyssomnias such as Primary Insomnia (307.42), Primary Hypersomnia (307.44), Breathing-Related Sleep Disorders
(780.59), Circadian Rhythm Sleep Disorder (307.45) and Dyssomnia Not Otherwise
Specified (307.47); primary sleep disorders such as Parasomnias such as Nightmare
Disorder (307.47), Sleep Terror Disorder (307.46), Sleepwalking Disorder (307.46) and
Parasomnia Not Otherwise Specified (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, in particular sleep disturbances associated with such diseases as neurological disorders, neuropathic pain, restless leg syndrome, heart and lung diseases; and Substance-Induced Sleep Disorder including the subtypes Insomnia Type, Hypersomnia Type, Parasomnia Type and Mixed Type; sleep apnea and jet-lag syndrome.
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).
Autism Spectrum Disorders including Autistic Disorder (299.00), Asperger's Disorder (299.80), Rett's Disorder (299.80), Childhood Disintegrative Disorder (299.10) and Pervasive Disorder Not Otherwise Specified (299.80, including Atypical Autism).
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):
Personality Disorders including the 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 Disorder (301.50), Narcissistic Personality Disorder (301 ,81 ), Avoidant Personality Disorder (301.82), Dependent Personality Disorder (301.6), Obsessive- Compulsive Personality Disorder (301.4) and Personality Disorder Not Otherwise Specified (301.9):
Compounds of the invention may be useful for 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 Sexual Disorder Not Otherwise Specified (302.9).
Compounds of the invention may be also useful as anti-inflammatory agents. In particular, they may be useful in the treatment of inflammation in asthma, influenza, chronic bronchitis and rheumatoid arthritis; in the treatment of inflammatory diseases of the gastrointestinal tract such as Crohn's disease, ulcerative colitis, inflammatory bowel disease and nonsteroidal anti-inflammatory drug induced damage; inflammatory diseases of the skin such as herpes and eczema; inflammatory diseases of the bladder such as cystitis, overactive bladder and urge incontinence; and eye and dental inflammation.
Compounds of the invention may be also useful in the treatment of allergic disorders, in particular allergic disorders of the skin such as urticaria, and allergic disorders of the airways such as rhinitis.
Compounds of the invention are also useful in the treatment of emesis, i.e. nausea, retching and vomiting. Emesis includes acute emesis, delayed emesis and anticipatory emesis. Compounds of the invention are useful in the treatment of emesis however induced. For example, emesis may be induced by drugs such as cancer chemotherapeutic agents such as alkylating agents, e.g. cyclophosphamide, carmustine, lomustine and chlorambucil; cytotoxic antibiotics, e.g. dactinomycin, doxorubicin, mitomycin-C and bleomycin; anti-metabolites, e.g. cytarabine, methotrexate and 5- fluorouracil; vinca alkaloids, e.g. etoposide, vinblastine and vincristine; and others such as cisplatin, dacarbazine, procarbazine and hydroxyurea; and combinations thereof; radiation sickness; radiation therapy, e.g. irradiation of the thorax or abdomen, such as in the treatment of cancer; poisons; toxins such as toxins caused by metabolic disorders or by infection, e.g. gastritis, or released during bacterial or viral gastrointestinal infection; pregnancy; vestibular disorders, such as motion sickness, vertigo, dizziness and Meniere's disease; postoperative sickness; gastrointestinal obstruction; reduced gastrointestinal motility; visceral, e.g. myocardial infarction or peritonitis; migraine; increased intercranial pressure; decreased intercranial pressure (e.g. altitude sickness); opioid analgesics, such as morphine; and gastro-oesophageal reflux disease (GERD) such as erosive GERD and symptomatic GERD or non erosive GERD, acid indigestion, over-indulgence of food or drink, acid stomach, sour stomach, waterbrash/regurgitation, heartburn, such as episodic heartburn, nocturnal heartburn, and meal-induced heartburn, dyspepsia and functional dyspepsia.
Compounds of the invention may be also useful in the treatment of gastrointestinal disorders such as irritable bowel syndrome, gastro-oesophageal reflux disease (GERD) such as erosive GERD and symptomatic GERD or non erosive GERD, acid indigestion, over-indulgence of food or drink, acid stomach, sour stomach, waterbrash/regurgitation, heartburn, such as episodic heartburn, nocturnal heartburn, and meal-induced heartburn, dyspepsia and functional dyspepsia (such as ulcer-like dyspepsia ,dysmotility-like dyspepsia and unspecified dyspepsia) chronic constipation; skin disorders such as psoriasis, pruritis and sunburn; vasospastic diseases such as angina, vascular headache and Reynaud's disease; cerebral ischeamia such as cerebral vasospasm following subarachnoid haemorrhage; fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; disorders related to immune enhancement or suppression such as systemic lupus erythematosus and rheumatic diseases such as fibrositis; and cough.
Within the context of the present invention, the term "pain" includes: 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 cluster and chronic daily headache; 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; dysmenorrhea; neuralgia; fibromyalgia syndrome; complex regional pain syndrome (CRPS types I and II); neuropathic pain syndromes (including diabetic neuropathy; chemoterapeutically induced neuropathic pain; sciatica; non-specific lower back pain; multiple sclerosis pain; HIV-related neuropathy; post-herpetic neuralgia; trigeminal neuralgia); and pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions.
Compounds of the invention may be useful in cachexia including systemic cachexia, cachexia secondary to infection or malignancy and cachexia secondary to AIDS , renal insufficiency, cardiac insufficiency and pulmonary insufficiency.
Compounds of the invention may be also useful for treatmenrt of patients suffering from anorexia-cachexia syndrome which is a debilitating condition characterizing the clinical journey of patients suffering from chronic diseases including cancer, chronic obstructive pulmonary disease, tuberculosis, chronic heart failure, and end-stage renal insufficiency .
All of the various forms and sub-forms of the disorders mentioned herein are contemplated as part of the present invention.
Compounds of the invention are particularly useful in the treatment or prevention of depression, anxiety, sleep disorders or emesis.
Particularly, compounds of the invention are useful in the treatment or prevention of depression. Particularly, compounds of the invention are useful in the treatment or prevention of anxiety.
Particularly, compounds of the invention are useful in the treatment or prevention of sleep disorders.
Particularly, compounds of the invention are useful in the treatment or prevention of emesis.
The invention therefore provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in therapy.
Thus, the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as a therapeutic substance in the treatment or prophylaxis of the above disorders.
The invention further provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of depression, anxiety, sleep disorders or emesis.
The invention further provides a method of treatment or prophylaxis of conditions mediated by tachykinins, in mammals including humans, which comprises administering to the sufferer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
The invention further provides a method of treatment or prophylaxis of conditions for which antagonism of NK1 receptor is beneficial, in mammals including humans, which comprises administering to the sufferer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
The invention further provides a method of treatment or prophylaxis of the above disorders, in mammals including humans, which comprises administering to the sufferer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
The invention further provides a method of treatment or prophylaxis of depression, anxiety, sleep disorders or emesis in mammals including humans, which comprises administering to the suffer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
In another aspect, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of conditions mediated by tachykinins. In another aspect, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of conditions for which antagonism of NK1 receptor is beneficial.
In another aspect, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of the above disorders.
In another aspect, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of depression, anxiety, sleep disorders or emesis.
When used in therapy, the compounds of formula (I) are usually formulated in a standard pharmaceutical composition. Such compositions can be prepared using standard procedures.
The present invention further provides a pharmaceutical composition which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
The present invention further provides a pharmaceutical composition for use in the treatment of the above disorders which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
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).
Compounds of the invention may be used in combination with antidepressants to treat or prevent depression and mood disorders.
Compounds of the invention may be used in combination with an opioid analgesic to treat and prevent pain.
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. Compounds of the invention may be used in combination with the following agents to treat or prevent anxiety disorders: i) anxiolytics; and ii) antidepressants.
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.
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.
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.
Compounds of the invention may 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 aprobarbital, butabarbital, pentobarbital, secobarbita and phenobarbital; iv) antidepressants; v) other sedative- hypnotics for example chloral hydrate and chlormethiazole.
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) premenstrual agents for example pyridoxine and progesterones.
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) premenstrual agents.
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.
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).
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.
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; v) noradrenaline transport inhibitors for example reboxetine and vii) 5-HT1A agonists, for example flibanserine.
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).
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).
Mood stabiliser drugs include lithium, sodium valproate/valproic acid/divalproex, carbamazepine, lamotrigine, gabapentin, topiramate and tiagabine.
Anxiolytics include benzodiazepines such as alprazolam and lorazepam.
Opioid analgesics include alfentanil, buprenorphine, butorphanol, carfentanil, codeine, diacetylmorphine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol, lofentanil, meperidine, methadone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, propoxyphenem, remifentanil and sufentanil. Compounds of the invention may be used in combination with Na channel blockers to treat epilepsy, depression and mood disorders, psychotic disorders or pain.
Within the context of the combination with Na channel blockers, the term "epilepsy" is intented to include seizure disorders and epilepsy syndromes. The various types of the Epilepsy and seizures mentioned herein below are contemplated as part of the present invention: partial onset seizures (replacing temporal lobe epilepsy, neocortical epilepsy and Rasumssen's), generalized onset seizures, the seizures of the Lennox Gastaut syndrome (tonic, atonic, myoclonic, atypical absence and generalized tonic-clonic), absence seizure syndromes and juvenile myoclonic epilepsy.
Combination of compounds of the invention with a Na channel blocker may also be useful in the treatment and/or prevention of disorders treatable and/or preventable with anti- convulsive agents, such as epilepsy including post-traumatic epilepsy, obsessive compulsive disorders (OCD), sleep disorders (including circadian rhythm disorders, insomnia & narcolepsy), tics (e.g. Giles de Ia Tourette's syndrome), ataxias, muscular rigidity (spasticity), and temporomandibular joint dysfunction.
Within the context of the combination with Na channel blockers the term "psychotic disorder" includes: i) Schizophrenia including the subtypes Paranoid Type (295.30), Disorganised Type (295.10), Catatonic Type (295.20), Undifferentiated Type (295.90) and Residual Type (295.60); Schizophreniform Disorder (295.40); Schizoaffective Disorder (295.70) including the subtypes Bipolar Type and Depressive Type; Delusional Disorder (297.1 ) including the subtypes Erotomanic Type, Grandiose Type, Jealous Type, Persecutory Type, Somatic Type, Mixed Type and Unspecified Type; Brief Psychotic Disorder (298.8); Shared Psychotic Disorder (297.3); Psychotic Disorder Due to a General Medical Condition including the subtypes With Delusions and With Hallucinations; Substance-Induced Psychotic Disorder including the subtypes With Delusions (293.81 ) and With Hallucinations (293.82); and Psychotic Disorder Not Otherwise Specified (298.9).
Within the context of the combination with Na channel blockers, the term "pain" includes : 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 cluster and chronic daily headache; 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; dysmenorrhea; neuralgia; fibromyalgia syndrome; complex regional pain syndrome (CRPS types I and II); neuropathic pain syndromes (including diabetic neuropathy; chemoterapeutically induced neuropathic pain; sciatica; non-specific lower back pain; multiple sclerosis pain;; HIV-related neuropathy; post-herpetic neuralgia; trigeminal neuralgia); and pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions.
Within the context of the combination with Na channel blockers the term "depression and mood disorder" includes
Depression and mood disorders including Major Depressive Episode, Manic Episode, Mixed Episode and Hypo manic Episode; Depressive Disorders including Major Depressive Disorder, Dysthymic Disorder (300.4), Depressive Disorder Not Otherwise Specified (31 1 ); Bipolar Disorders including Bipolar I Disorder, Bipolar Il Disorder (Recurrent Major Depressive Episodes with Hypo manic Episodes) (296.89), Cyclothymiacs Disorder (301.13) and Bipolar Disorder Not Otherwise Specified (296.80); 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 Depressive Features, With Manic Features and With Mixed Features) and
Mood Disorder Not Otherwise Specified (296.90).
In one embodiment, the "depression and mood disorder" which may be treated by administration of a combination of compounds of the invention with Na channel blockers is a bipolar disorder. In one embodiment, the combination as herein above defined comprises a Na channel blocker selected from the group consisting of: fosphenytoin (Cerebyx™, Prodilantin™, Pro- Epanutin™ or Cereneu™); oxcarbazepine (Trileptal™, Oxrate™ or Wockhardt™); phenytoin; carbamazepine (Carbatrol, Equetro ™); lidocaine (ALGRX-3268); Safinamide (NW-1015); Ralfinamide (NW-1029); Lacosamide ((2R)-2-(acetylamino)-3-methoxy-N- (phenylmethyl)propanamide); rufinamide (RUF-331 ); 3,5-diamino-6-(2,3-dichlorophenyl)- 1 ,2,4-triazine, or a pharmaceutically acceptable salt or solvate thereof; R(-)-2,4-diamino-5- (2,3-dichlorophenyl)-6-fluoromethyl pyrimidine, or a pharmaceutically acceptable salt or solvate thereof; (2R,5R)-2-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-1 ,7- diazaspiro[4.4]nonan-6-one, or a pharmaceutically acceptable salt or solvate thereof; (2R,5R)-2-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6- one, or a pharmaceutically acceptable salt or solvate thereof, and (5R)-5-(4-{[(2- fluorophenyl)methyl]oxy}phenyl)-L-prolinamide, or a pharmaceutically acceptable salt or solvate thereof. In a further embodiment, the combination as herein above defined comprises a Na channel blocker selected from the group consisting of fosphenytoin (Cerebyx™, Prodilantin™, Pro- Epanutin™ or Cereneu™), oxcarbazepine (Trileptal™, Oxrate™ or Wockhardt™), phenytoin, carbamazepine (Carbatrol, Equetro ™), lidocaine (ALGRX-3268), Safinamide (NW-1015), Ralfinamide (NW-1029), Lacosamide ((2R)-2-(acetylamino)-3-methoxy-N- (phenylmethyl)propanamide), and rufinamide (RUF-331 ).
In a further embodiment, the combination as herein above defined comprises a Na channel blocker selected from the group consisting of: 3,5-diamino-6-(2,3-dichlorophenyl)-1 ,2,4-triazine;
R(-)-2,4-diamino-5-(2,3-dichlorophenyl)-6-fluoromethyl pyrimidine;
(2R,5R)-2-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-1 ,7-diazaspiro[4.4]nonan-6-one;
(2R,5R)-2-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6- one; (5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinamide or pharmaceutically acceptable salts or solvates thereof.
In an additional further embodiment, the combination as herein above defined comprises a Na channel blocker which is 3, 5-diamino-6-(2,3-dichlorophenyl)-1 ,2,4-triazine or a pharmaceutically acceptable salt or solvate thereof.
Compound 3,5-diamino-6-(2,3-dichlorophenyl)-1 ,2,4-triazine and pharmaceutically acceptable salts and solvates thereof are described in EP granted Patent EP0021 121 B and in US Patent US 4,602,017. Compound 3,5-diamino-6-(2,3-dichlorophenyl)-1 ,2,4-triazine and pharmaceutically acceptable salts and solvates thereof may be prepared by any method described in EP0021121 B and US 4,602,017.
In another embodiment, the combination as herein above defined comprises a Na Channel blocker which is R(-)-2,4-diamino-5-(2,3-dichlorophenyl)-6-fluoromethyl pyrimidine or a pharmaceutically acceptable salt or solvate thereof. Compound R(-)-2,4-diamino-5-(2,3-dichlorophenyl)-6-fluoromethyl pyrimidine and pharmaceutically acceptable salts and solvates thereof are described in PCT publication No. WO 97/9317, published 13 March 1997. Compound R(-)-2,4-diamino-5-(2,3- dichlorophenyl)-6-fluoromethyl pyrimidine and pharmaceutically acceptable salts and solvates thereof may be prepared by any method described in WO 97/9317.
In an additional further embodiment, the combination as herein above defined comprises a Na channel blocker which is (5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinamide or a pharmaceutically acceptable salt or solvate thereof.
Compound (5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinamide and pharmaceutically acceptable salts and solvates thereof are described in PCT publication No. WO2007/042239. Compound (5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-L- prolinamide or pharmaceutically acceptable salts and solvates thereof may be prepared by any method described in WO2007/042239.
In an additional further embodiment, the combination as herein above defined comprises a Na Channel blocker which is (2R,5R)-2-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-7-methyl- 1 ,7-diazaspiro[4.4]nonan-6-one or a pharmaceutically acceptable salt or solvate thereof. Compound (2R,5R)-2-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-7-methyl-1 ,7- diazaspiro[4.4]nonan-6-one and pharmaceutically acceptable salts and solvates thereof are described in PCT publication No. WO2007/042240. Compound (2R,5R)-2-(4-{[(2- fluorophenyl)methyl]oxy}phenyl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one and pharmaceutically acceptable salts and solvates thereof may be prepared by any method described in WO2007/042240.
In one embodiment, the combination of a compound of the invention with a Na channel blocker, comprises a Na Channel blocker which is selected from the group consisting of: fosphenytoin (Cerebyx™, Prodilantin™, Pro-Epanutin™ or Cereneu™); oxcarbazepine (Trileptal™, Oxrate™ or Wockhardt™); phenytoin; carbamazepine (Carbatrol, Equetro ™); lidocaine (ALGRX-3268); Safinamide (NW-1015); Ralfinamide (NW-1029); Lacosamide ((2R)-2-(acetylamino)-3-methoxy-N-(phenylmethyl)propanamide); rufinamide (RUF-331 ); 3,5-diamino-6-(2,3-dichlorophenyl)-1 ,2,4-triazine, or a pharmaceutically acceptable salt or solvate thereof; R(-)-2,4-diamino-5-(2,3-dichlorophenyl)-6-fluoromethyl pyrimidine, or a pharmaceutically acceptable salt or solvate thereof; (2R,5R)-2-(4-{[(2- fluorophenyl)methyl]oxy}phenyl)-1 ,7-diazaspiro[4.4]nonan-6-one, or a pharmaceutically acceptable salt or solvate thereof; (2R,5R)-2-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-7- methyl-1 ,7-diazaspiro[4.4]nonan-6-one, or a pharmaceutically acceptable salt or solvate thereof, and (5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinamide, or a pharmaceutically acceptable salt or solvate thereof; and (1 R,5R)3-[(2R,4S)-1-{[{(1 R)-1- [3,5bis(trifluoromethyl)phenyl]ethyl}(methyl)amino] carbonyl}- 2-(4-fluoro-2-methylphenyl)-4- piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylic acid or a pharmaceutically acceptable salt or solvate thereof.
The invention thus provides, in a further aspect, a combination comprising a compound of the invention together with a further therapeutic agent or 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 may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. When a compound of the invention is used in combination with a second therapeutic agent active against the same disease state the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
Thus, in one embodiment, a combination of a compound of the invention with a Na channel blocker is provided, wherein at least one of them is at subtherapeutic dose.
A subtherapeutic dose is intended to mean a dose of a drug below that required to produce significant clinical benefit for the patient when administered alone.
In one embodiment, the combination of a compound of the invention with a Na Channel blocker, comprises a Na Channel blocker, at subtherapeutic dose, which is selected from the group consisting of: fosphenytoin (Cerebyx™, Prodilantin™, Pro-Epanutin™ or Cereneu™); oxcarbazepine (Trileptal™, Oxrate™ or Wockhardt™); phenytoin; carbamazepine (Carbatrol, Equetro ™); lidocaine (ALGRX-3268); Safinamide (NW-1015); Ralfinamide (NW-1029); Lacosamide ((2R)-2-(acetylamino)-3-methoxy-N-
(phenylmethyl)propanamide); rufinamide (RUF-331 ); 3,5-diamino-6-(2,3-dichlorophenyl)- 1 ,2,4-triazine, or a pharmaceutically acceptable salt or solvate thereof; R(-)-2,4-diamino-5- (2,3-dichlorophenyl)-6-fluoromethyl pyrimidine, or a pharmaceutically acceptable salt or solvate thereof; (2R,5R)-2-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-1 ,7- diazaspiro[4.4]nonan-6-one, or a pharmaceutically acceptable salt or solvate thereof; (2R,5R)-2-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6- one, or a pharmaceutically acceptable salt or solvate thereof, and (5R)-5-(4-{[(2- fluorophenyl)methyl]oxy}phenyl)-L-prolinamide, or a pharmaceutically acceptable salt or solvate thereof; and a compound of the invention.
In another embodiment, the combination of a compound of the invention with a Na Channel blocker, comprises a Na Channel blocker which is selected from the group consisting of: fosphenytoin (Cerebyx™, Prodilantin™, Pro-Epanutin™ or Cereneu™); oxcarbazepine (Trileptal™, Oxrate™ or Wockhardt™); phenytoin; carbamazepine (Carbatrol, Equetro ™); lidocaine (ALGRX-3268); Safinamide (NW-1015); Ralfinamide (NW-1029); Lacosamide ((2R)-2-(acetylamino)-3-methoxy-N-(phenylmethyl)propanamide); rufinamide (RUF-331 ); 3,5-diamino-6-(2,3-dichlorophenyl)-1 ,2,4-triazine, or a pharmaceutically acceptable salt or solvate thereof; R(-)-2,4-diamino-5-(2,3- dichlorophenyl)-6-fluoromethyl pyrimidine, or a pharmaceutically acceptable salt or solvate thereof; (2R,5R)-2-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-1 ,7-diazaspiro[4.4]nonan-6-one, or a pharmaceutically acceptable salt or solvate thereof; (2R,5R)-2-(4-{[(2- fluorophenyl)methyl]oxy}phenyl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one, or a pharmaceutically acceptable salt or solvate thereof, and (5R)-5-(4-{[(2- fluorophenyl)methyl]oxy}phenyl)-L-prolinamide, or a pharmaceutically acceptable salt or solvate thereof; and a compound of the invention , at subtherapeutic dose.
In a further embodiment, the combination of a compound of the invention with a Na channel blocker, comprises a Na Channel blocker which is selected from the group consisting of: fosphenytoin (Cerebyx™, Prodilantin™, Pro-Epanutin™ or Cereneu™); oxcarbazepine (Trileptal™, Oxrate™ or Wockhardt™); phenytoin; carbamazepine (Carbatrol, Equetro ™); lidocaine (ALGRX-3268); Safinamide (NW-1015); Ralfinamide (NW-1029); Lacosamide ((2R)-2-(acetylamino)-3-methoxy-N-(phenylmethyl)propanamide); rufinamide (RUF-331 ); 3,5-diamino-6-(2,3-dichlorophenyl)-1 ,2,4-triazine, or a pharmaceutically acceptable salt or solvate thereof; R(-)-2,4-diamino-5-(2,3-dichlorophenyl)-6-fluoromethyl pyrimidine, or a pharmaceutically acceptable salt or solvate thereof; (2R,5R)-2-(4-{[(2- fluorophenyl)methyl]oxy}phenyl)-1 ,7-diazaspiro[4.4]nonan-6-one, or a pharmaceutically acceptable salt or solvate thereof; (2R,5R)-2-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-7- methyl-1 ,7-diazaspiro[4.4]nonan-6-one, or a pharmaceutically acceptable salt or solvate thereof, and (5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinamide, or a pharmaceutically acceptable salt or solvate thereof; and a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof; such compound of formula (I) and Na Channel blocker compound being both administered at subtherapeutic dose.
In one embodiment, the combination of a compound of the invention with a Na Channel blocker, comprises a Na Channel blocker, at subtherapeutic dose, which is selected from the group consisting of: fosphenytoin (Cerebyx™, Prodilantin™, Pro-Epanutin™ or Cereneu™); oxcarbazepine (Trileptal™, Oxrate™ or Wockhardt™); phenytoin; carbamazepine (Carbatrol, Equetro ™); lidocaine (ALGRX-3268); Safinamide (NW-1015); Ralfinamide (NW-1029); Lacosamide ((2R)-2-(acetylamino)-3-methoxy-N-
(phenylmethyl)propanamide); rufinamide (RUF-331 ); 3,5-diamino-6-(2,3-dichlorophenyl)- 1 ,2,4-triazine, or a pharmaceutically acceptable salt or solvate thereof; R(-)-2,4-diamino-5- (2,3-dichlorophenyl)-6-fluoromethyl pyrimidine, or a pharmaceutically acceptable salt or solvate thereof; (2R,5R)-2-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-1 ,7- diazaspiro[4.4]nonan-6-one, or a pharmaceutically acceptable salt or solvate thereof; (2R,5R)-2-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6- one, or a pharmaceutically acceptable salt or solvate thereof, and (5R)-5-(4-{[(2- fluorophenyl)methyl]oxy}phenyl)-L-prolinamide, or a pharmaceutically acceptable salt or solvate thereof; and (1 R,5R)3-[(2R,4S)-1-{[{(1 R)-1-
[3,5bis(trifluoromethyl)phenyl]ethyl}(methyl)amino] carbonyl}- 2-(4-fluoro-2-methylphenyl)-4- piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylic acid ;or a pharmaceutically acceptable salt or solvate thereof.
In another embodiment, the combination of a compound of the invention with a Na Channel blocker, comprises a Na Channel blocker which is selected from the group consisting of: fosphenytoin (Cerebyx™, Prodilantin™, Pro-Epanutin™ or Cereneu™); oxcarbazepine (Trileptal™, Oxrate™ or Wockhardt™); phenytoin; carbamazepine (Carbatrol, Equetro ™); lidocaine (ALGRX-3268); Safinamide (NW-1015); Ralfinamide (NW-1029); Lacosamide ((2R)-2-(acetylamino)-3-methoxy-N-(phenylmethyl)propanamide); rufinamide (RUF-331 ); 3,5-diamino-6-(2,3-dichlorophenyl)-1 ,2,4-triazine, or a pharmaceutically acceptable salt or solvate thereof; R(-)-2,4-diamino-5-(2,3-dichlorophenyl)-6-fluoromethyl pyrimidine, or a pharmaceutically acceptable salt or solvate thereof; (2R,5R)-2-(4-{[(2- fluorophenyl)methyl]oxy}phenyl)-1 ,7-diazaspiro[4.4]nonan-6-one, or a pharmaceutically acceptable salt or solvate thereof; (2R,5R)-2-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-7- methyl-1 ,7-diazaspiro[4.4]nonan-6-one, or a pharmaceutically acceptable salt or solvate thereof, and (5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinamide or a pharmaceutically acceptable salt or solvate thereof; and (1 R,5R)3-[(2R,4S)-1-{[{(1 R)-1- [3,5bis(trifluoromethyl)phenyl]ethyl}(methyl)amino] carbonyl}- 2-(4-fluoro-2-methylphenyl)-4- piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylic acid ;or a pharmaceutically acceptable salt or solvate thereof, at subtherapeutic dose.
In a further embodiment, the combination of a compound of the invention with a Na Channel blocker, comprises a Na Channel blocker which is selected from the group consisting of: fosphenytoin (Cerebyx™, Prodilantin™, Pro-Epanutin™ or Cereneu™); oxcarbazepine (Trileptal™, Oxrate™ or Wockhardt™); phenytoin; carbamazepine (Carbatrol, Equetro ™); lidocaine (ALGRX-3268); Safinamide (NW-1015); Ralfinamide (NW-1029); Lacosamide ((2R)-2-(acetylamino)-3-methoxy-N-(phenylmethyl)propanamide); rufinamide (RUF-331 ); 3,5-diamino-6-(2,3-dichlorophenyl)-1 ,2,4-triazine, or a pharmaceutically acceptable salt or solvate thereof; R(-)-2,4-diamino-5-(2,3- dichlorophenyl)-6-fluoromethyl pyrimidine, or a pharmaceutically acceptable salt or solvate thereof; (2R,5R)-2-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-1 ,7-diazaspiro[4.4]nonan-6-one, or a pharmaceutically acceptable salt or solvate thereof; (2R,5R)-2-(4-{[(2- fluorophenyl)methyl]oxy}phenyl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one, or a pharmaceutically acceptable salt or solvate thereof, and (5R)-5-(4-{[(2- fluorophenyl)methyl]oxy}phenyl)-L-prolinamide or a pharmaceutically acceptable salt or solvate thereof; and (1 R,5R)3-[(2R,4S)-1-{[{(1 R)-1-
[3,5bis(trifluoromethyl)phenyl]ethyl}(methyl)amino] carbonyl}- 2-(4-fluoro-2-methylphenyl)-4- piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylic acid or a pharmaceutically acceptable salt thereof;
Such a compound (1 R,5R)3-[(2R,4S)-1-{[{(1R)-1-[3,5bis(trifluoromethyl)phenyl] ethyl}(methyl)amino]carbonyl}-2-(4-fluoro-2-methylphenyl)-4-piperidinyl]-3- azabicyclo[3.1.0]hexane-1-carboxylic acid and a Na Channel blocker compound being both administered at subtherapeutic dose.
Thus, the invention also provides a combination of a compound of the invention with a Na channel blocker compound, for use in therapy. Thus, the invention also provides a combination of (1 R,5R)3-[(2/?,4S)-1-{[{(1 /?)-1- [3,5bis(trifluoromethyl)phenyl]ethyl}(methyl)amino] carbonyl}- 2-(4-fluoro-2-methylphenyl)-4- piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylic acid or a pharmaceutically acceptable salt thereof with a Na channel blocker compound which is selected from the group consisting of: 3,5-diamino-6-(2,3-dichlorophenyl)-1 ,2,4-triazine, or a pharmaceutically acceptable salt or solvate thereof; R(-)-2,4-diamino-5-(2,3-dichlorophenyl)-6-fluoromethyl pyrimidine, or a pharmaceutically acceptable salt or solvate thereof; (2R,5R)-2-(4-{[(2- fluorophenyl)methyl]oxy}phenyl)-1 ,7-diazaspiro[4.4]nonan-6-one, or a pharmaceutically acceptable salt or solvate thereof; (2R,5R)-2-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-7- methyl-1 ,7-diazaspiro[4.4]nonan-6-one, or a pharmaceutically acceptable salt or solvate thereof, and (5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinamide or a pharmaceutically acceptable salt or solvate thereof; for use as a therapeutic substance in the treatment or prophylaxis of epilepsy, depression and mood disorders, psycothic disorders or pain.
In one embodiment, the invention provides a combination of a compound of the invention with a Na channel blocker compound, for use as a therapeutic substance in the treatment or prophylaxis of epilepsy, depression and mood disorders, psychotic disorders or pain.
In an embodiment, the invention provides a combination of (1 R,5R)3-[(2/?,4S)-1-{[{(1 /?)-1- [3,5bis(trifluoromethyl)phenyl]ethyl}(methyl)amino] carbonyl}- 2-(4-fluoro-2-methylphenyl)-4- piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylic acid ;or a pharmaceutically acceptable salt thereof with a Na channel blocker compound, which is selected from the group consisting of: 3,5-diamino-6-(2,3-dichlorophenyl)-1 ,2,4-triazine, or a pharmaceutically acceptable salt or solvate thereof; R(-)-2,4-diamino-5-(2,3-dichlorophenyl)-6-fluoromethyl pyrimidine, or a pharmaceutically acceptable salt or solvate thereof; (2R,5R)-2-(4-{[(2- fluorophenyl)methyl]oxy}phenyl)-1 ,7-diazaspiro[4.4]nonan-6-one, or a pharmaceutically acceptable salt or solvate thereof; (2R,5R)-2-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-7- methyl-1 ,7-diazaspiro[4.4]nonan-6-one, or a pharmaceutically acceptable salt or solvate thereof, and (5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinamide, or a pharmaceutically acceptable salt thereof; for use as a therapeutic substance in the treatment or prophylaxis of epilepsy, depression and mood disorders, psychotic disorders or pain.
The invention further provides a method of treatment or prophylaxis of epilepsy, depression and mood disorders, psychotic disorders or pain, in mammals including humans, which comprises administering to the sufferer a therapeutically effective amount of a combination of a compound of the invention with a Na channel blocker compound.
The invention further provides a method of treatment or prophylaxis of epilepsy, depression and mood disorders, psychotic disorders or pain, in mammals including humans, which comprises administering to the sufferer a therapeutically effective amount of a combination of (1 R,5R)3-[(2R,4S)-1-{[{(1 R)-1-[3,5bis(trifluoromethyl)phenyl]ethyl}(methyl)amino] carbonyl}- 2-(4-fluoro-2-methylphenyl)-4-piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylic acid or a pharmaceutically acceptable salt thereof with a Na channel blocker compound, which is selected from the group consisting of: 3,5-diamino-6-(2,3-dichlorophenyl)-1 ,2,4- triazine, or a pharmaceutically acceptable salt or solvate thereof; R(-)-2,4-diamino-5-(2,3- dichlorophenyl)-6-fluoromethyl pyramiding, or a pharmaceutically acceptable salt or solvate thereof; (2R,5R)-2-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-1 ,7-diazaspiro[4.4]nonan-6-one, or a pharmaceutically acceptable salt or solvate thereof; (2R,5R)-2-(4-{[(2- fluorophenyl)methyl]oxy}phenyl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one, or a pharmaceutically acceptable salt or solvate thereof, and (5R)-5-(4-{[(2- fluorophenyl)methyl]oxy}phenyl)-L-polyamide or a pharmaceutically acceptable salt thereof.
In another aspect, the invention provides the use of a combination of a compound of the invention with a Na channel blocker compound in the manufacture of a medicament for use in the treatment of epilepsy, depression and mood disorders, psychotic disorders or pain.
In another aspect, the invention provides the use of a combination of (1 R,5R)3-[(2/?,4S)-1- {[{(1/?)-1-[3,5bis(trifluoromethyl)phenyl]ethyl}(methyl)amino] carbonyl}- 2-(4-fluoro-2- methylphenyl)-4-piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylic acid or a pharmaceutically acceptable salt thereof with a Na channel blocker compound, which is selected from the group consisting of: 3,5-diamino-6-(2,3-dichlorophenyl)-1 ,2,4-triazine, or a pharmaceutically acceptable salt or solvate thereof; R(-)-2,4-diamino-5-(2,3- dichlorophenyl)-6-fluoromethyl pyrimidine, or a pharmaceutically acceptable salt or solvate thereof; (2R,5R)-2-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-1 ,7-diazaspiro[4.4]nonan-6-one, or a pharmaceutically acceptable salt or solvate thereof; (2R,5R)-2-(4-{[(2- fluorophenyl)methyl]oxy}phenyl)-7-methyl-1 ,7-diazaspiro[4.4]nonan-6-one, or a pharmaceutically acceptable salt or solvate thereof, and (5R)-5-(4-{[(2- fluorophenyl)methyl]oxy}phenyl)-L-prolinamide or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of epilepsy, depression and mood disorders, psychotic disorders or pain.
In a further aspect, the invention provides a pharmaceutical composition treatment of epilepsy, depression and mood disorders, psychotic disorders or pain which comprises combinations of a compound of the invention with a Na channel blocker compound and a pharmaceutically acceptable carrier.
A pharmaceutical composition of the invention, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, 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 unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents. The tablets may be coated according to methods well known in normal pharmaceutical practice.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or 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 flavourings or colorants.
For parenteral administration, fluid unit dosage forms are prepared utilising a compound of the invention or a pharmaceutically acceptable salt thereof and a sterile vehicle. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration.
The compound can be sterilised by exposure to ethylene oxide before suspension 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 way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. However, as a general guide suitable unit doses may be 0.05 to 1000 mg, more suitably 1.0 to 200 mg, and such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks or months.
Experimental
The following Intermediates and Examples illustrate the preparation of compounds of the invention. In the procedures that follow, after each starting material, reference to a description is typically provided. This is provided merely for assistance to the skilled chemist. The starting material may not necessarily have been prepared from the batch referred to. Compounds are named using ACD/Name PRO 6.02 chemical naming software (Advanced Chemistry Development Inc., Toronto, Ontario, M5H2L3, Canada).
The yields were calculated assuming that products were 100% pure if not stated otherwise.
Proton Magnetic Resonance (NMR) spectra were recorded either on Varian instruments at 400, 500 or 600 MHz, or on Bruker instruments at 400 MHz. Chemical shifts are reported in ppm (δ) 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, doublets of doublets (dd), multiplets (m) and broad singlets (bs). The NMR spectra were recorded at a temperature ranging from 25 to 90 0C as indicated. When more than one conformer was detected the chemical shifts for the most abundant one is usually reported.
For general structure and purity determination 1 D 1H-NMR spectra and 2D 1H1 1H-COSY spectra were used. The assignment step often was facilitated by means of 2D 1H1 13C- HSQC spectra. Investigations of the relative stereochemistry were carried out by means of 1 D 1H1 1H-NOE difference or 2D 1H1 1H-NOESY or 1H1 1H-ROESY spectroscopy.
HPLC analyses indicated by HPLC (walk-up): rt = x min, were performed on a Agilent 1 100 series instrument using a Luna 3u C18(2) 100A column (50 x 2.0 mm, 3 μm particle size) [Mobile phase and Gradient: 100% (water + 0.05% TFA) to 95% (acetonitrile + 0.05% TFA) in 8 min. Column T = 40 0C. Flow rate = 1 mL/min. UV detection wavelength = 220 nm]. The usage of this methodology is indicated by "HPLC" in the analytic characterization of the described compounds.
Direct infusion Mass spectra (MS) were run on a Agilent MSD 1 100 Mass Spectrometer, operating in ES (+) and ES (-) ionization mode [ES (+): Mass range: 100-1000 amu. Infusion solvent: water + 0.1 % HCO2H / CH3CN 50/50. ES (-): Mass range: 100-1000 amu. Infusion solvent: water + 0.05% NH4OH / CH3CN 50/50] (the usage of this methodology is indicated by "MS" in the analytic characterization of the described compounds) or on an Agilent LC/MSD 1100 Mass Spectrometer coupled with HPLC instrument Agilent 1100 Series, operating in positive or negative electrospray ionization mode and in both acidic and basic gradient conditions [Acidic gradient LC/MS - ES (+ or -): analyses performed on a Supelcosil ABZ + Plus column (33 x 4.6 mm, 3 μm). Mobile phase: A - water + 0.1% HCO2H / B - CH3CN. Gradient (standard method): t=0 min 0% (B), from 0% (B) to 95% (B) in 5 min lasting for 1.5 min, from 95% (B) to 0% (B) in 0.1 min, stop time 8.5 min. Column T = rt. Flow rate = 1 mL/min. Gradient (fast method): t=0 min 0% (B), from 0% (B) to 95% (B) in 3 min lasting for 1 min, from 95% (B) to 0% (B) in 0.1 min, stop time 4.5 min. Column T = rt. Flow rate = 2 mL/min. Basic gradient LC/MS - ES (+ or -): analyses performed on a XTerra MS C18 column (30 x 4.6 mm, 2.5 μm). Mobile phase: A - 5 mM aq. NH4HCO3 + ammonia (pH 10) / B - CH3CN. Gradient: t = 0 min 0% (B), from 0% (B) to 50% (B) in 0.4 min, from 50% (B) to 95% (B) in 3.6 min lasting for 1 min, from 95% (B) to 0% (B) in 0.1 min, stop time 5.8 min. Column T = rt. Flow rate = 1.5 mL/min]. Mass range ES (+ or -): 100-1000 amu. UV detection range: 220-350 nm (the usage of this methodology is indicated by "LC/MS" in the analytic characterization of the described compounds)
Total ion current (TIC) and DAD UV chromatographic traces together with MS and UV spectra associated with the peaks were taken on a UPLC/MS Acquity™ system equipped with 2996 PDA detector and coupled to a Waters Micromass ZQ™ mass spectrometer operating in positive or negative electrospray ionisation mode [LC/MS - ES (+ or -): analyses performed using an Acquity™ UPLC BEH C18 column (50 x 2.1 mm, 1.7 μm particle size). Mobile phase: A - water + 0.1% HCO2H / B - CH3CN + 0.06% HCO2H. Gradient: t = 0 min 3% B, t = 0.05 min 6% B, t = 0.57 min 70% B, t = 1.06 min 99% B lasting for 0.389 min, t = 1.45 min 3% B, stop time 1.5 min. Column T = 40 0C. Flow rate = 1.0 mL/min. Mass range: ES (+): 100-1000 amu. ES (-): 100-800 amu. UV detection range: 210-350 nm. The usage of this methodology is indicated by "UPLC" in the analytic characterization of the described compounds.
Total ion current (TIC) and DAD UV chromatographic traces together with MS and UV spectra associated with the peaks were taken on a UPLC/MS Acquity™ system equipped with PDA detector and coupled to a Waters SQD mass spectrometer operating in positive and negative alternate electrospray ionisation mode [LC/MS - ES+/-: analyses performed using an Acquity™ UPLC BEH C18 column (50 x 2.1 mm, 1.7 μm particle size). Mobile phase: A - 10 mM aqueous solution of NH4HCO3 (adjusted to pH 10 with ammonia) / B - CH3CN. Gradient: t = 0 min 3% B, t = 1.06 min 99% B lasting for 0.39 min, t = 1.46 min 3% B, stop time 1.5 min. Column T = 40 0C. Flow rate = 1.0 mL/min. Mass range: ES (+): 100- 1000 amu. ES (-): 100-1000 amu. UV detection range: 220-350 nm. The usage of this methodology is indicated by "UPLC (basic conditions)" in the analytic characterization of the described compounds.
For reactions involving microwave irradiation, a Personal Chemistry EmrysTM Optimizer was used.
In a number of preparations, purification was performed using Biotage manual flash chromatography (Flash+), Biotage automatic flash chromatography (Horizon, SP1 and SP4), Companion CombiFlash (ISCO) automatic flash chromatography, Flash Master Personal or Vac Master systems. Flash chromatography was carried out on silica gel 230-400 mesh (supplied by Merck AG Darmstadt, Germany), Varian Mega Be-Si pre-packed cartridges, pre-packed Biotage silica cartridges (e.g. Biotage SNAP cartridge), KP-NH prepacked flash cartridges or ISCO RediSep 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.
* indicates a stereocentre of fixed but unknown absolute stereochemistry i.e. either R or S stereochemistry.
Isomer 1 or Isomer 2 means a compound of the invention or an intermediate thereof as a single isomer whose absolute configuration was not determined.
The following table lists the abbreviations used:
BF3.Et2O Boron trifluoride diethyl etherate
BOC2O Di-tert-butyl dicarbonate
DCE Dichloroethane
DCM Dichloromethane
DMSO Dimethyl sulfoxide
EtOAc Ethyl acetate
MeOH Methanol
LC Liquid chromatography
Na2CO3 Sodium carbonate
NaHCO3 Sodium bicarbonate
NaOH Sodium hydroxide
NaOEt Sodium ethoxide
Na2SO4 Sodium sulphate
Pd/C Palladium on carbon
TEA Triethylamine
TFA Trifluoroacetic acid
THF Tetrahydrofuran h Hour min Minute r.t. room temperature
Intermediate 1 3-(1,1 -dimethylethyl) 1 -ethyl S-azabicvclorS.I.Olhexane-I.S-dicarboxylate
Figure imgf000036_0001
To a solution of ethyl 3-(phenylmethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate (WO2004089363(A1 ) or Korean Journal of Medicinal Chemistry (1994) 4(2) 119-25, 4.55 g, 18.55 mmol) in MeOH (200 ml) were added a solution of BOC2O (8.61 ml, 37.1 mmol) in MeOH (50 ml) and then Pd/C 10% (w/w) (490 mg, 0.46 mmol) and the reaction mixture was stirred for 2 hours under H2 atmosphere (P= 1 atm) at r.t. The catalyst was filtered-off and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (Biotage system) on silica gel using a column SNAP 10O g and from cyclohexane to 7:3 cyclohexane/ethyl acetate as eluent affording the title compound (4.63 g, 18.13 mmol, 98% yield) as a colourless oil. 1 H NMR (400 MHz, DMSO-c/6) δ ppm 4.02 - 4.13 (m, 2 H) 3.56 - 3.66 (m, 1 H) 3.49 - 3.56 (m, 1 H) 3.30 - 3.47 (m, 2 H) 1.99 - 2.09 (m, 1 H) 1.41 - 1.49 (m, 1 H) 1.38 (s, 9 H) 1.18 (t, 3 H) 0.77 - 0.84 (m, 1 H).
Intermediate 2 ethyl S-azabicyclorS.I.Olhexane-i -carboxylate
Figure imgf000036_0002
To a solution of 3-(1 ,1-dimethylethyl) 1-ethyl 3-azabicyclo[3.1.0]hexane-1 ,3-dicarboxylate (Intermediate 1 , 4.63 g, 18.13 mmol) in dry Dichloromethane (200 ml) TFA (50 ml, 649 mmol) was slowly added at 00C and the reaction mixture was stirred for 2 hours at the same temperature. The mixture was diluted with DCM (100 ml) and Na2CO3 sat. solution (at 0 0C) was added until pH 8. Two phases were separated and the aqueous layer was extracted with DCM (5 x 100 ml). Combined organic phases were dried (Na2SO4), filtered and evaporated affording the title compound (2.63 g, 16.95 mmol, 93% yield) as a pale yellow oil. 1 H NMR (400 MHz, choloroformio-d) δ ppm 4.15 (q, 2 H) 3.24 - 3.40 (m, 1 H) 2.89 - 3.12 (m, 3 H) 2.18 (br. s., 1 H) 1.87 - 2.05 (m, 1 H) 1.41 - 1.54 (m, 1 H) 1.26 (t, 3 H) 0.82 - 0.94 (m, 1 H).
Intermediate 3 and 4 ethyl 3-K2R4S)-1 A\HΛ fl)-1 -F3.5- bis(trifluoromethyl)phenyllethylMmethyl)aminolcarbonyl)-2-(4-fluoro-2- methylphenylM-piperidinvπ-S-azabicvclorS.I .OIhexane-i-carboxylate (Intermediate 3) and ethyl 3-K2R4fl)-1-mπfl)-1-r3.5- bis(trifluoromethyl)phenyllethylMmethyl)aminolcarbonyl)-2-(4-fluoro-2- methylphenyl)-4-piperidinyll-3-azabicvclor3.1 Olhexane-1<:arboxylate (Intermediate
Figure imgf000037_0001
(3) (4)
Ethyl 3-azabicyclo[3.1.0]hexane-1-carboxylate (Intermediate 2, 64 mg, 0.412 mmol) and (2R)-N-{(1 R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl- 4-0X0-1 -piperidinecarboxamide (WO 0232867, 312 mg, 0.619 mmol) were dissolved in dry DCE (3 ml) under Argon atmosphere. TEA (0.059 ml, 0.423 mmol) was added and the mixture was stirred for 1.5 h. Sodium triacetoxyborohydride (192 mg, 0.907 mmol) was added and the reaction mixture was stirred at room temperature overnight. NaHCO3 sat. solution (5 ml) was added and the aqueous phase was separated and extracted with DCM (3 x 2 ml). Organic phases were collected together and evaporated in vacuo to obtain a yellow foam that was purified on SCX cartridge (2g) eluting at first with three column volumes of MeOH then with 3 column volumes of 2M ammonia solution in methanol. The fractions eluted with ammonia were evaporated in vacuo to afford 222 mg of a crude which was purified by LC chromatography [Analytical chromatographic conditions Column: Gemini C18, 50 x 4.6 mm, 5 μm; Mobile phase: A: NH4HCO3 sol. 10 mM, pH 10; B: CH3CN; Gradient:60% (B) for 0.5 min, 60% to 95% (B) in 4.5 min, 95% (B) for 1.5 min; Flow rate:2 ml/min; UV range:210-350 nm; lonization:ES+; Mass range:100-900 amu; Preparative chromatographic conditions Column: Gemini C18 AXIA, 50 x 21 mm, 5 μm; Mobile phase: A: NH4HCO3 sol. 10 mM, pH 10; B: CH3CN; Gradient: 60% (B) for 1 min, 60% to 95% (B) in 9 min, 95% to 100% (B) in 0.1 min, 100% (B) for 0.9 min; Flow rate: 17 ml/min; UV range: 210-350 nm; Ionization: ES+; Mass range: 100-900 amu) ] to give:
(1st eluted) ethyl 3-[(2R,4S)-1-{[{(1 R)-1-[3,5- bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-2-(4-fluoro-2-methylphenyl)-4- piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylate (Intermediate 3, 63.8 mg, 0.099 mmol, 24% yield) as a mixture of two diastereoisomers. LC/MS (basic conditions): Rt 3.96 min, m/z 644 [M+H]+.
(2nd eluted) ethyl 3-[(2R,4R)-1-{[{(1 R)-1-[3,5- bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-2-(4-fluoro-2-methylphenyl)-4- piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylate (Intermediate 4, 71.3 mg, 0.11 mmol, 27% yield) as a mixture of two diastereoisomers in a ratio ca 50:50 by NMR analysis. 1 H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.72 - 7.81 (m, 1 H) 7.55 - 7.65 (m, 2 H) 7.15 - 7.23 (m, 1 H) 6.82 - 6.88 (m, 1 H) 6.74 - 6.82 (m, 1 H) 5.43 - 5.55 (m, 1 H) 4.69 - 4.80 (m, 1 H) 4.08 - 4.22 (m, 2 H) 2.95 - 3.38 (m, 4 H) 2.64 - 2.76 (m, 4 H) 2.54 - 2.62 (m, 1 H) 2.32 - 2.47 (m, 4 H) 1.52 - 2.04 (m, 5 H) 1.42 - 1.50 (m, 4 H) 1.32 - 1.40 (m, 1 H) 1.20 - 1.30 (m, 3 H). LC/MS (basic conditions): Rt 4.20 min, m/z 644 [M+H]+.
Intermediates 5 and 6 ethyl 3-K2R4S)-1 -f K (1 fl)-1 -F3.5- bis(trifluoromethyl)phenyllethylMmethyl)aminolcarbonyl}-2-(4-fluoro-2- methylphenylM-piperidinyll-S-azabicvclorS.I .Olhexane-i-carboxylate ( isomer 1)
(Intermediate 5) and ethyl 3-r(2R4S)-1-m(1 /?)-1-F3,5- bis(trifluoromethyl)phenvnethylMmethyl)amino1carbonyl)-2-(4-fluoro-2- methylphenylM-piperidinyll-S-azabicvclorS.I .Olhexane-i-carboxylate (isomer 2)
(Intermediate 6)
Figure imgf000038_0001
The mixture of diastereoisomers ethyl 3-[(2R,4S)-1-{[{(1 R)-1-[3,5- bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-2-(4-fluoro-2-methylphenyl)-4- piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylate (Intermediate 3, 63.8 mg, 0.099 mmol) was purified by Chiral Chromatography [Analytical chromatographic conditions Column: Chiralcel OD-H (25 x 0.46 cm); Mobile phase: n-Hexane/2-Propanol 95/5 % v/v; Flow rate: 1.0 ml/min; DAD: 210-340 nm; CD: 240 nm; Preparative chromatographic conditions Column: Chiralcel OD-H (25 x 2.0 cm); Mobile phase n-Hexane/2-Propanol 95/5 % v/v; Flow rate (ml/min) 15.0; UV detection 225 nm; Loop 1100 μl_; injection 13 mg in 2- propanol/n-hexane 50/50 (each injection)] to give: (1st eluted) ethyl 3-[(2R,4S)-1-{[{(1 R)-1-[3,5- bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-2-(4-fluoro-2-methylphenyl)-4- piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylate (isomer 1 ) (Intermediate 5, 29.2 mg). Chiral analysis, chromatographic conditions: [Column: Chiralcel OD-H (25 x 0.46 cm);
Mobile phase: n-Hexane/2-Propanol 95/5 % v/v; Flow rate: 1.0 ml/min; DAD: 210-340 nm; CD: 240 nm] Rt 4.58 min. 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.99 (s, 1 H) 7.66 (s, 2 H) 7.13 - 7.20 (m, 1 H) 6.90 (dd, 1 H) 6.74 (t, 1 H) 5.25 - 5.37 (m, 1 H) 4.12 (dd, 1 H) 4.02 (q, 2 H) 3.25 - 3.38 (m, 1 H) 2.91 - 2.99 (m, 2 H) 2.70 (s, 3 H) 2.62 - 2.76 (m, 2 H) 2.42 (dd, 1 H) 2.34 (s, 3 H) 2.32 - 2.37 (m, 1 H) 1.82 - 1.96 (m, 2 H) 1.81 (d, 1 H) 1.44 - 1.56 (m, 1 H) 1.45 (d, 3 H) 1.24 - 1.38 (m, 1 H) 1.10 - 1.20 (m, 2 H) 1.13 (t, 3 H). (2nd eluted) ethyl 3-[(2R,4S)-1-{[{(1 R)-1-[3,5- bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-2-(4-fluoro-2-methylphenyl)-4- piperidinylJ-S-azabicycloβ.i .OJhexane-i-carboxylate (isomer 2) (Intermediate 6, 27.1 mg). Chiral analysis, chromatographic conditions: [Column: Chiralcel OD-H (25 x 0.46 cm); Mobile phase: n-Hexane/2-Propanol 95/5 % v/v; Flow rate: 1.0 ml/min; DAD: 210-340 nm; CD: 240 nm] Rt 5.24 min. 1 H NMR (400 MHz, DMSOd6) δ ppm 7.97 (s, 1 H) 7.65 (s, 2 H) 7.1 1 - 7.21 (m, 1 H) 6.87 (dd, 1 H) 6.73 (t, 1 H) 5.24 - 5.38 (m, 1 H) 4.10 (d, 1 H) 3.96 - 4.10 (m, 2 H) 3.18 - 3.40 (m, 1 H) 3.02 (d, 1 H) 2.86 (d, 1 H) 2.58 - 2.79 (m, 5 H) 2.33 - 2.43 (m, 2 H) 2.31 (s, 3 H) 1.78 - 1.97 (m, 2 H) 1.76 (d, 1 H) 1.43 - 1.59 (m, 1 H) 1.44 (d, 3 H) 1.17 - 1.34 (m, 1 H) 1.07 - 1.19 (m, 2 H) 1.14 (t, 3 H).
Intermediate 5 (method B) ethyl 3-F(2R4S)-1 -(Kd fl)-1 -F3,5- bis(trifluoromethyl)phenvnethylMmethyl)amino1carbonyl)-2-(4-fluoro-2- methylphenylM-piperidinyll-S-azabicvclorS.I .Olhexane-i-carboxylate (Isomer 1)
Figure imgf000039_0001
To a solution of (2R)-N-{(1 R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2- methylphenyl)-N-methyl-4-oxo-1-piperidinecarboxamide (WO 0232867, 10.56 g, 20.94 mmol) and ethyl 3-azabicyclo[3.1.0]hexane-1-carboxylate (Intermediate 2, 2.6 g, 16.75 mmol) in dry Methanol (16.75 ml) was added Sodium cyanoborohydride (1.58 g, 25.1 mmol) and the reaction mixture was stirred overnight at r.t. The reaction was quenched with Na2CO3 saturated solution (10 ml), diluted with water (20 ml) and extracted with ethyl acetate (3 x 100 ml). The organic layers were combined, dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a column SNAP (34Og) and from cyclohexane to 6:4 cyclohexane/ethyl acetate as eluent affording a mixture of two diastereoisomers. This mixture was purified again on silica gel using a column SNAP (34Og) and 65:35 n-hexane/ethyl acetate as eluent affording the title compound (1.93 g, 3.01 mmol, 17.95 % yield) as a white solid.
1 H NMR (500 MHz, DMSO-d6) δ ppm 7.99 (s, 1 H) 7.67 (s, 2 H) 7.12 - 7.23 (m, 1 H) 6.84 - 6.98 (m, 1 H) 6.68 - 6.81 (m, 1 H) 5.26 - 5.40 (m, 1 H) 4.07 - 4.18 (m, 1 H) 3.99 - 4.08 (m, 2 H) 3.35 - 3.40 (m, 1 H) 2.90 - 3.02 (m, 2 H) 2.70 (s, 3 H) 2.59 - 2.77 (m, 2 H) 2.40 - 2.46 (m, 1 H) 2.33 - 2.38 (m, 1 H) 2.35 (s, 3 H) 1.84 - 1.94 (m, 2 H) 1.77 - 1.85 (m, 1 H) 1.45 - 1.57 (m, 1 H) 1.46 (d, 3 H) 1.23 - 1.39 (m, 1 H) 1.14 (t, 3 H) 1.09 - 1.21 (m, 2 H). HPLC: Rt 5.4 min. Chiral analysis, chromatographic conditions: [Column: Chiralcel OD-H (25 x 0.46 cm); Mobile phase: n-Hexane/lsopropanol 97/3 % v/v; Flow rate: 1.0 ml/min; DAD: 220 nm] Rt 5.19 min.
Intermediate 7 dimethyl 2-r2-(1 ,3-dioxo-1,3-dihvdro-2H-isoindol-2-yl)ethvn-1,1- cvclopropanedicarboxylate
Figure imgf000040_0001
To a mixture of 2-(3-buten-1-yl)-1 H-isoindole-1 ,3(2H)-dione (5.66 g, 28.1 mmol) in Chlorobenzene (200 ml) was added Rhodium(ll) acetate dimer (0.622 g, 1.406 mmol). The suspension was warmed to an internal temperature of 600C and Dimethyl diazomalonate (7.56 g, 47.8 mmol) was added dropwise keeping the internal temperature below 700C. After 1 h, Dimethyl diazomalonate (7.56 g, 47.8 mmol) was added dropwise keeping the internal temperature below 700C and the reaction mixture was stirred for 1 h. The suspension was cooled to r.t., diluted with DCM and the catalyst was filtered-off. Solvent was partially evaporated under vacuum and the residue was purified by SPE-Si (50 g) column (from Cyclohexane to 6:4 Cyclohexane/EtOAc) to afford the title compound (5.45 g, 16.45 mmol, 58.5% yield). 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.80 - 7.90 (m, 2 H) 7.68 - 7.76 (m, 2 H) 3.67 - 3.98 (m, 8 H) 1.89 - 2.02 (m, 1 H) 1.63 - 1.85 (m, 2 H) 1.36 - 1.50 (m, 2 H).
Intermediate 8 methyl 2-oxo-3-azabicyclor4.1.Olheptane-1 -carboxylate
Figure imgf000040_0002
Hydrazine monohydrate (1.277 ml, 41.1 mmol) was added to a solution of dimethyl 2-[2- (1 ,3-dioxo-1 ,3-dihydro-2H-isoindol-2-yl)ethyl]-1 ,1-cyclopropanedicarboxylate (Intermediate 7, 5.45 g, 16.45 mmol) in Methanol (200 ml) and the mixture was heated to reflux. After 24 h, the mixture was cooled to r.t. and the solvent was evaporated under vacuum until 1/4 of the initial volume. CH2CI2 was added and the precipitate was filtered-off, washing with CH2CI2. The resulting solution was evaporated under vacuum and the crude was purified by SPE-Si column (20 g) (from 8:2 Cyclohexane/Acetone to 100% Acetone) to afford the title compound (2.016 g, 11.92 mmol, 72.4% yield). 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.82 - 6.15 (m, 1 H) 3.56 - 3.96 (m, 3 H) 3.18 - 3.35 (m, 1 H) 3.02 - 3.17 (m, 1 H) 1.19 - 2.33 (m, 5 H).
Intermediate 9 3-(1.1 -dimethylethyl) 1 -methyl 2-oxo-3-azabicvclor4.1.OIheptane-1 ,3-dicarboxylate
Figure imgf000041_0001
To a solution of methyl 2-oxo-3-azabicyclo[4.1.0]heptane-1-carboxylate (Intermediate 8, 2.016 g, 11.92 mmol) in a mixture Toluene (60 ml) / Dichloromethane (30 ml) was added 4-(Dimethylamino)pyridine (2.184 g, 17.87 mmol), followed by Di-te/t-butyl dicarbonate (3.32 ml, 14.30 mmol). The resulting mixture was heated to reflux for 1.5 h, diluted with DCM and washed with brine. The organic layer was dried (Na2SO4), filtrated and concentrated. The crude was purified by SPE-Si (50 g) column (from Cyclohexane to 1 :1 Cyclohexane/EtOAc) to afford the title compound (2.24 g, 8.32 mmol, 69.8% yield). 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.70 - 3.85 (m, 4 H) 3.43 - 3.54 (m, 1 H) 2.17 2.30 (m, 1 H) 1.97 - 2.07 (m, 1 H) 1.84 - 1.96 (m, 2 H) 1.42 - 1.59 (m, 10 H).
Intermediate 10
3-(1,1 -dimethylethyl) 1 -methyl 2-hydroxy-3-azabicyclor4.1.0lheptane-1,3- dicarboxylate
Figure imgf000041_0002
1 M Super-Hydride® (1.0 M lithium triethylborohydride solution in THF) (9.98 ml, 9.98 mmol) was added over 30 min to a solution of 3-(1 ,1 -dimethylethyl) 1-methyl 2-oxo-3- azabicyclo[4.1.0]heptane-1 ,3-dicarboxylate (Intermediate 9, 2.24 g, 8.32 mmol) in Tetrahydrofuran (20 ml) cooled to -10 0C. After 3.5 h the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was dried (Na2SO4), filtrated and concentrated. The crude was purified by SPE-Si (25 g) column (from Cyclohexane to 7:3 Cyclohexane/EtOAc) to afford the title compound (1.37, 5.06 mmol, 60.8% yield). UPLC: Rt 0.64 min, m/z 294 [M+Na]+.
Intermediate 11
3-(1 ,1 -dimethylethyl) 1 -methyl 3-azabicyclor4.1.Olheptane-1 ,3-dicarboxylate
Figure imgf000041_0003
A solution of 3-(1 ,1 -dimethylethyl) 1-methyl 2-hydroxy-3-azabicyclo[4.1.0]heptane-1 ,3- dicarboxylate (Intermediate 10, 1.37 g, 5.06 mmol) and Triethylsilane (0.808 ml, 5.06 mmol) in Dichloromethane (40 ml) was cooled to -78 0C and BF3 OEt2 (0.641 ml, 5.06 mmol) was added dropwise under a nitrogen atmosphere. After 30 min further Triethylsilane (0.808 ml, 5.06 mmol) and BF3 OEt2 (0.641 ml, 5.06 mmol) were added and the resulting mixture was stirred at - 78 0C for 1.5h. Then the reaction mixture was allowed to warm-up to r.t, it was diluted with DCM and washed with water. The organic layer was dried (Na2SO4), filtrated and concentrated. The crude was purified by SPE-Si (5g) column (from Cyclohexane to 95:5 Cyclohexane/ EtOAc) to afford the title compound (878 mg, 3.44 mmol, 68% yield). 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.77 - 4.13 (m, 2 H) 3.63 - 3.73 (m, 3 H) 3.34 - 3.54 (m, 1 H) 2.86 - 3.03 (m, 1 H) 1.91 - 2.07 (m, 1 H) 1.64 - 1.86 (m, 2 H) 1.36 - 1.51 (m, 10 H) 0.71 - 0.77 (m, 1 H).
Intermediate 12 methyl 3-azabicvclor4.1.Olheptane-1 -carboxylate trifluoroacetate
Figure imgf000042_0001
3-(1 , 1 -dimethylethyl) i-methyl-S-azabicyclo^.i .OJheptane-i ^-dicarboxylate (Intermediate 11 , 200 mg, 0.783 mmol) was dissolved in a mixture of 3:1 Dichloromethane (6 ml) / trifluoroacetic acid (2 ml, 26.0 mmol) and the reaction mixture was stirred at 00C for 45 min. The solvents were evaporated under vacuum to afford 306 mg of the title compound . This crude was used in the next step without further purification. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.31 - 4.55 (m, 1 H) 3.72 (s, 3 H) 3.00 - 3.35 (m, 2 H) 2.69 - 2.93 (m, 1 H) 2.26 - 2.50 (m, 1 H) 1.88 - 2.15 (m, 2 H) 1.67 - 1.85 (m, 1 H) 0.91 - 1.14 (m, 1 H). Presence of acidic protons (broad signals) in the region between 7.78 - 8.80 ppm.
Intermediates 13, 14, 15 methyl 3-F(2fl,4S)-1 -fffd fl)-1 -F3.5- bis(trifluoromethyl)phenyllethylMmethyl)aminolcarbonyl)-2-(4-fluoro-2- methylphenyl)-4-piperidinvn-3-azabicvclor4.1.01heptane-1-carboxylate (mixture of diastereoisomers) (Intermediate 13); methyl 3-F(2R4fl)-1 -KfM fl)-1 -F3.5- bis(trifluoromethyl)phenvnethylMmethyl)amino1carbonyl)-2-(4-fluoro-2- methylphenyl)-4-piperidinvn-3-azabicvcloF4.1.01heptane-1-carboxylate (isomer 1)
(Intermediate 14) and methyl 3-F(2fl,4fl)-1 -(FId fl)-1 -F3.5- bis(trifluoromethyl)phenyllethylMmethyl)aminolcarbonyl}-2-(4-fluoro-2- methylphenyl)-4-piperidinvn-3-azabicvcloF4.1.01heptane-1-carboxylate
(isomer 2) (Intermediate 15)
Figure imgf000043_0001
Under Argon atmosphere methyl 3-azabicyclo[4.1.0]heptane-1-carboxylate trifluoroacetate (Intermediate 12, 306 mg) and (2R)-N-{(1 R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4- fluoro-2-methylphenyl)-N-methyl-4-oxo-1-piperidinecarboxamide (WO 0232867, 585 mg, 1.16 mmol) was dissolved in dry DCE (4 ml). TEA (0.108 ml, 0.773 mmol) was added, the reaction mixture was stirred for 1.5 h and then Sodium triacetoxyborohydride (360 mg, 1.7 mmol) was added. The reaction mixture was stirred at room temperature overnight, then NaHCO3 saturated solution (5 ml) was added. The aqueous phase was separated and extracted with DCM (3 x 2 ml). Organic phases were collected together and evaporated in vacuo to obtain a yellow foam that was purified on SCX cartridge (2g) eluting at first with 3 column volume of MeOH and then with 3 column volume of 2M ammonia solution in methanol. The fractions eluted with ammonia were evaporated in vacuo to afford 446 mg of a crude that was purified by preparative LC [Analytical chromatographic conditions Column:Acquity UPLC™ BEH Phenyl, 1.7 μm, 2.1 x 50 mm; Mobile phase A: 10 mM aq. sol. NH4HCO3, pH 10; B: CH3CN; Gradient: t=0 min 49% (B), t=4.24 min 49% (B), t=4.25 min 99% (B), t=4.74 min 49% (B), Stop time: 5 min; Flow rate: 1 ml/min; Column temperature: 400C; UV range: 220-350 nm; Ionization: ES+/ES-; Mass range: 100-1000 amu (ES+), 100-900 amu (ES-); Preparative chromatographic conditions Column: XBridge Phenyl PREP, 100 x 19 mm, 5 μm; Mobile phase: A: 10 mM aq. sol. NH4HCO3, pH 10; B: CH3CN; Gradient: 50% to 66% (B) in 16 min, 66% to 100% (B) in 0.1 min, 100% (B) for 1.4 min; Flow rate:17 ml/min; UV range: 210-350 nm; Ionization: ES+; Mass range: 100-900 amu]. The separated aqueous solutions from preparative LC were evaporated in vacuo to afford:
(1st eluted) methyl 3-[(2R,4S)-1-{[{(1 R)-1-[3,5- bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-2-(4-fluoro-2-methylphenyl)-4- piperidinyl]-3-azabicyclo[4.1.0]heptane-1-carboxylate as a mixture of diastereoisomers (Intermediate 13, 147.6 mg, 0.229 mmol). 1 H NMR (500 MHz, acetone) δ ppm 7.93 (s, 1 H) 7.79 (s, 2 H) 7.28 - 7.36 (m, 1 H) 6.86 (dd, 1 H) 6.75 - 6.82 (m, 1 H) 5.53 (q, 1 H) 4.24 - 4.32 (m, 1 H) 3.61 (s, 3 H) 3.48 - 3.55 (m, 1 H) 3.24 (d, 1 H) 2.91 (d, 1 H) 2.84 - 2.88 (m, 1 H) 2.81 (s, 3 H) 2.56 - 2.66 (m, 1 H) 2.45 - 2.51 (m, 1 H) 2.44 (s, 3 H) 2.21 - 2.29 (m, 1 H) 1.80 - 2.01 (m, 3 H) 1.66 - 1.79 (m, 2 H) 1.54 - 1.60 (m, 1 H) 1.55 (d, 3 H) 1.46 - 1.53 (m, 1 H) 1.13 - 1.18 (m, 1 H) 0.97 - 1.02 (m, 1 H). 8(S), 12(R), 30(R), mixture of diastereoisomers (cis), ratio 1 : 1 , visible only at H-7. Dipolar correlations: from H-12 to H-8, -10ax, -28, - 13eq, -23; from H-8 to H-12, -7', -7", -10ax, -2', -2", -13eq, -9eq. The atom numbering shown in the following structure is included for the purpose of correlation with the NMR data only.
Figure imgf000044_0001
LC/MS [Analytical chromatographic conditions Column: Acquity UPLC ^T I MM BEH Phenyl, 1.7 μm 2.1 x 50 mm; Column temperature: 400C; Mobile phase: A: 10 mM NH4HCO3/NH3; B: CH3CN; Gradient: isocratic 49 % (B); Stop time: 5.0 min; Flow rate: 1 ml/min]: Rt 3.27 min (broad peak), m/z 644 [M+H]+.
(2nd eluted) methyl 3-[(2R,4R)-1-{[{(1 /?)-1-[3,5- bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-2-(4-fluoro-2-methylphenyl)-4- piperidinyl]-3-azabicyclo[4.1.0]heptane-1-carboxylate (isomer 1 ) (Intermediate 14, 59 mg, 0.092 mmol). 1 H NMR (400 MHz, acetone) δ ppm 7.92 (s, 1 H) 7.83 (s, 2 H) 7.38 (dd, 1 H) 6.89 (dd, 1 H) 6.78 - 6.85 (m, 1 H) 5.36 (q, 1 H) 4.93 - 5.03 (m, 1 H) 3.61 (s, 3 H) 3.43 - 3.53 (m, 1 H) 3.20 - 3.29 (m, 1 H) 3.22 (d, 1 H) 2.94 (d, 1 H) 2.74 (s, 3 H) 2.57 - 2.66 (m, 1 H) 2.41 - 2.50 (m, 1 H) 2.36 (s, 3 H) 2.16 - 2.26 (m, 1 H) 1.99 - 2.05 (m, 2 H) 1.71 - 1.93 (m, 4 H) 1.59 - 1.66 (m, 1 H) 1.59 (d, 3 H) 1.24 (dd, 1 H) 1.02 - 1.08 (m, 1 H). 8(R), 12(R), 30(R), single diastereoisomer (trans). Dipolar correlations: from H12 to H-10 (3.48 ppm), -7 (2.94 ppm), -28, -27 (weak), -13, -13'; from H-8 to H-7, -7', -10 (3.23 ppm), -2, -13/9 (1.83 ppm), -23; from H-23 to H-22, -30, -31 , -10 (3.23 ppm), -8, -13/9 (1.83 ppm); from H-28 to H-20, -12. The atom numbering shown in the following structure is included for the purpose of correlation with the NMR data only.
Figure imgf000044_0002
LC/MS [Analytical chromatographic conditions Column: Acquity UPLC™ BEH Phenyl, 1.7 μm 2.1 x 50 mm; Column temperature: 400C; Mobile phase: A: 10 mM NH4HCO3/NH3; B: CH3CN; Gradient: isocratic 49 % (B); Stop time: 5.0 min; Flow rate: 1 ml/min]: Rt 3.63 min, m/z 644 [M+H]+. (3rd eluted) methyl 3-[(2R,4R)-1-{[{(1 /?)-1-[3,5- bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-2-(4-fluoro-2-methylphenyl)-4- piperidinyl]-3-azabicyclo[4.1.0]heptane-1-carboxylate (isomer 2) (Intermediate 15, 50.9 mg, 0.079 mmol). 1 H NMR (400 MHz, acetone) δ ppm 7.92 (s, 1 H) 7.82 (s, 2 H) 7.37 (dd, 1 H) 6.89 (dd, 1 H) 6.77 - 6.85 (m, 1 H) 5.37 (q, 1 H) 4.92 - 5.01 (m, 1 H) 3.62 (s, 3 H) 3.39 - 3.49 (m, 1 H) 3.21 - 3.28 (m, 1 H) 3.20 (d, 1 H) 2.90 (d, 1 H) 2.74 (s, 3 H) 2.52 - 2.61 (m, 1 H) 2.42 - 2.52 (m, 1 H) 2.39 (s, 3 H) 2.15 - 2.26 (m, 1 H) 2.04 - 2.11 (m, 2 H) 1.94 - 2.02 (m, 1 H) 1.85 - 1.94 (m, 2 H) 1.72 - 1.85 (m, 1 H) 1.56 - 1.68 (m, 1 H) 1.58 (d, 3 H) 1.23 (dd, 1 H) 1.03 (dd, 1 H). 8(R), 12(R), 30(R), single diastereoisomer (trans). Dipolar correlations: from H12 to H-10 (3.44 ppm), -7 (3.20 ppm), -28, -13, -13', (-27, -2, -2', 30 weak); from H-8 to H-7, -7', -10 (3.24 ppm), -2, -13, -13', -9, -23; from H-23 to H-22, -10 (3.24 ppm), -8, -13; from H-28 to H-20, -12. The atom numbering shown in the following structure is included for the purpose of correlation with the NMR data only.
Figure imgf000045_0001
LC/MS [Analytical chromatographic conditions Column: Acquity UPLC™ BEH Phenyl, 1.7 μm 2.1 x 50 mm; Column temperature: 400C; Mobile phase: A: 10 mM NH4HCO3ZNH3; B: CH3CN; Gradient: isocratic 49 % (B); Stop time: 5.0 min; Flow rate: 1 ml/min]: Rt 3.95 min, m/z 644 [M+H]+.
Intermediate 16 and 17 methyl 3-F(2R,4SH -Wd RH -F3.5- bis(trifluoromethyl)phenyllethylMmethyl)aminolcarbonyl)-2-(4-fluoro-2- methylphenyl)-4-piperidinyll-3-azabicvclor4.1.0lheptane-1-carboxylate (isomer 1)
(Intermediate 16) and methyl 3-K2R.4SH -fffd RH -F3.5- bis(trifluoromethyl)phenyllethylMmethyl)aminolcarbonyl)-2-(4-fluoro-2- methylphenyl)-4-piperidinvn-3-azabicvcloF4.1.01heptane-1-carboxylate (isomer 2)
(Intermediate 17)
Figure imgf000046_0001
The mixture of diastereoisomers methyl 3-[(2R,4S)-1-{[{(1 /?)-1-[3,5- bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-2-(4-fluoro-2-methylphenyl)-4- piperidinyl]-3-azabicyclo[4.1.0]heptane-1-carboxylate (Intermediate 13, 147.6 mg, 0.229 mmol) was purified by Chiral Chromatography [Chromatographic conditions: Column=
WhelkOI ; Mobile phase= n-Hexane/ethanol 90/10 v/v; Flow rate= 1 ml/min; DAD= 210-340 nm; CD=220 nm] to give:
(1st eluted) methyl 3-[(2R,4S)-1-{[{(1 R)-1-[3,5- bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-2-(4-fluoro-2-methylphenyl)-4- piperidinyl]-3-azabicyclo[4.1.0]heptane-1-carboxylate (isomer 1 ) (Intermediate 16, 47 mg, 0.073 mmol). Chiral analysis [Chromatographic conditions: Column= WhelkOI ; Mobile phase= n-Hexane/ethanol 90/10 v/v; Flow rate= 1 ml/min; DAD= 210-340 nm; CD= 220 nm] Rt 22.7 min. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.68 - 7.86 (m, 1 H) 7.49 - 7.64 (m, 2 H) 7.04 - 7.21 (m, 1 H) 6.74 - 6.90 (m, 2 H) 5.51 - 5.63 (m, 1 H) 4.22 - 4.33 (m, 1 H) 3.56 - 3.72 (m, 3 H) 3.23 - 3.42 (m, 2 H) 2.79 - 2.93 (m, 2 H) 2.68 - 2.79 (m, 3 H) 2.50 - 2.64 (m, 1 H) 2.40 - 2.50 (m, 3 H) 2.16 - 2.38 (m, 2 H) 0.78 - 2.10 (m, 12 H).
(2nd eluted) methyl 3-[(2R,4S)-1-{[{(1 R)-1-[3,5- bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-2-(4-fluoro-2-methylphenyl)-4- piperidinyl]-3-azabicyclo[4.1.0]heptane-1-carboxylate (isomer 2) (Intermediate 17, 50 mg, 0.078 mmol). Chiral analysis [Chromatographic conditions: Column= WhelkOI ; Mobile phase= n-Hexane/ethanol 90/10 v/v; Flow rate= 1 ml/min; DAD= 210-340 nm; CD= 220 nm] Rt 24.1 min. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.72 - 7.83 (m, 1 H) 7.54 - 7.63 (m, 2 H) 7.09 - 7.21 (m, 1 H) 6.72 - 6.91 (m, 2 H) 5.50 - 5.62 (m, 1 H) 4.21 - 4.32 (m, 1 H) 3.59 - 3.71 (m, 3 H) 3.28 - 3.41 (m, 2 H) 2.78 - 2.93 (m, 2 H) 2.68 - 2.76 (m, 3 H) 2.48 - 2.61 (m, 1 H) 2.41 - 2.47 (m, 3 H) 2.22 - 2.38 (m, 2 H) 1.53 - 2.06 (m, 6 H) 1.37 - 1.51 (m, 4 H) 1.23 - 1.34 (m, 1 H) 0.76 - 1.01 (m, 1 H).
Intermediate 18 ethyl (I S.δffl-Σ-oxo-S-oxabicvclorS.I .OIhexane-i-carboxylate
Figure imgf000047_0001
21 % NaOEt solution in EtOH (25 ml, 67 mmol) was cooled at O0C and diethylmalonate (10.7 ml, 70.4 mmol) was added. When diethylmalonate was added the mixture became thick. EtOH was added (25 ml, 5 vol). The solution was warmed at room temperature (all solid dissolved) and (R)-epichlorohydrin (5 ml, 63.76 mmol) dissolved in EtOH (2.5 ml, 0.5 vol) was added dropwise (solution became turbid). The mixture was warmed at reflux for 36 hrs. After this time, water was added in order to solubilize the solid. EtOH was removed and the water extracted with DCM (3 x 10 vol); the combined organic phases were dried over Na2SO4 and evaporated. Diethyl malonate was removed by distillation (8O0C) and a yellow oil was obtained (7.7 g). This crude was purified by column chromatography (from 8:2 to 1 :1 Cy: EtOAc) to give the title compound (1.58 g). 1 H NMR (400 MHz, DMSO-c/6) δ ppm 4.33 (dd, 1 H) 4.07 - 4.19 (m, 3 H) 2.80 - 2.92 (m, 1 H) 1.90 (dd, 1 H) 1.46 (dd, 1 H) 1.19 (t, 3 H).
Intermediate 18a ethyl (1 R,2R)-1.Σ-bisfhvdroxymethvDcvclopropanecarboxylate
Figure imgf000047_0002
ethyl (I S.δR^-oxo-S-oxabicycloβ.i .OJhexane-i-carboxylate (Intermediate 18, 1.58 g, 9.28 mmol) was suspended in EtOH (25 ml, 16 vol). NaBH4 (263 mg, 6.96 mmol) was added and the mixture stirred for 2 hrs. After this time, the mixture was slowly quenched with 2M HCI (3 ml) and EtOAc (10 ml). The solid was filtered, the filtrate concentrated; water was added and it was extracted with DCM (6 x 10 vol). The combined organic phases were dried over Na2SO4 and evaporated to give the title compound (1.2 g, 6.9 mmol, 74% yield) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ ppm 4.68 (dd , 1 H) 4.58 (dd , 1 H) 4.05 (qd, 1 H) 3.83 (dd, 1 H) 3.55 - 3.71 (m, 2 H) 3.31 - 3.41 (m, 2 H) 1.65 - 1.78 (m, 1 H) 1.1 1 - 1.24 (m, 4 H) 0.85 (dd, 1 H)
Intermediate 18b ethyl (1 /?,2/?)-1 ,2-bisf rdnethylsulfonvhoxylmethyDcvclopropanecarboxvlate J
Figure imgf000048_0001
ethyl(1 /?,2/?)-1 ,2-bis(hydroxymethyl)cyclopropanecarboxylate (intermediate 18a (also available from APAC Pharmaceutical Product List, 6851 Oak Hall Lane, Suite 101 , Columbia, MD 21045) 200 mg, 1.14 mmol) and TEA (0.63 ml, 4.58 mmol) were dissolved in DCM (3 ml). The temperature was cooled to 00C. Methanesulfonic anhydride was slowly added. The solution was allowed to warm at room temperature and stirred for 1 hr. After this time water was added, the phases were separated and the water phase was back extracted with DCM. The combined organic phases were washed with sat. NaHCO3, dried over Na2SO4, filtered and evaporated to give 420 mg of a yellow oil. By NMR analysis it was a mixture of the title compound (81% pure corresponding to 340 mg, 1.03 mmol, 90 % yield) and DCM. This batch was used in the next step as it was. 1 H NMR (400 MHz, DMSO-d6) δ ppm 4.59 (d, 1 H) 4.42 - 4.51 (m, 2 H) 4.26 - 4.34 (m, 1 H) 4.12 (q, 2 H) 3.16 - 3.24 (m, 6 H) 2.03 - 2.13 (m, 1 H) 1.46 - 1.53 (m, 1 H) 1.25 - 1.31 (m, 1 H) 1.20 (t, 3 H).
Intermediates 19 and 20 ethyl (IRδ^-S-fphenylmethvD-S-azabicvclorS.I .OIhexane-i-carboxylate (Intermediate 19) and ethyl (1 S,5S)-3-(phenylmethyl)-3-azabicvclor3.1.01hexane-1-carboxylate (Intermediate 20)
Figure imgf000048_0002
The racemate ethyl 3-(phenylmethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate (WO2004089363(A1 ) or Korean Journal of Medicinal Chemistry (1994) 4(2) 1 19-25, 1.0 g, 4.08 mmol) was purified by preparative Chiral HPLC [Analytical chiral SFC conditions Column: Chiralpak AD-H (25 x 2.0 cm); Modifier: (Methanol+0.1% isopropylamine) 4%; Flow rate: 2.0 ml/min; Pressure: 100 bar; Temperature: 38°C; UV detection: 220 nm; CD detection: 220 nm; Loop: 10 μL; Enantiomer 1 : Rt 4.4 min (50 % a/a); Enantiomer 2: Rt 5.5 min (50 % a/a); Semipreparative chiral SFC conditions Column: Chiralpak AD-H (25 x 2.1 cm); Modifier: (Methanol+0.1% isopropylamine) 4%; Flow rate: 41 ml/min; Pressure: 100 bar; Temperature: 38°C; UV detection: 220 nm; CD detection: 220 nm; Loop: 500 μL; Injection: 12.5 mg in Methanol] to give: (1st eluted) ethyl (1 /?,5R)-3-(phenylmethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate (Intermediate 19, 0.380 g, 1.55 mmol). Chiral analysis, chromatographic conditions [Column: Chiralpak AD-H (25 x 2.0 cm); Modifier: (Methanol+0.1% isopropylamine) 4%; Flow rate: 2.0 ml/min; Pressure: 100 bar; Temperature: 38°C; UV detection: 220 nm; CD detection: 220 nm; Loop: 10 μl_]: Rt 4.4 mins, 100% e.e.. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.10 - 7.43 (m, 5 H) 4.13 (q, 2 H) 3.56 - 3.69 (m, 2 H) 3.07 (d, 1 H) 2.95 (d, 1 H) 2.73 (d, 1 H) 2.43 (dd, 1 H) 1.89 - 1.96 (m, 1 H) 1.46 - 1.52 (m, 1 H) 1.27 - 1.34 (m, 1 H) 1.24 (t, 3 H). HPLC: 2.78 mins.
(2nd eluted) ethyl (1 S,5S)-3-(phenylmethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate (Intermediate 20, 0.380 g, 1.55 mmol). Chiral analysis, chromatographic conditions [Column: Chiralpak AD-H (25 x 2.0 cm); Modifier: (Methanol+0.1% isopropylamine) 4%; Flow rate: 2.0 ml/min; Pressure: 100 bar; Temperature: 38°C; UV detection: 220 nm; CD detection: 220 nm; Loop: 10 μl_]: Rt 5.5 mins, 100% e.e.. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.10 - 7.39 (m, 5 H) 4.12 (q, 2 H) 3.57 - 3.70 (m, 2 H) 3.07 (d, 1 H) 2.95 (d, 1 H) 2.73 (d, 1 H) 2.43 (dd, 1 H) 1.89 - 1.97 (m, 1 H) 1.49 (t, 1 H) 1.30 (dd, 1 H) 1.24 (t, 3 H). HPLC: 2.74 mins.
Intermediate 19 (method B) ethyl (IRδ^-S-fphenylmethvD-S-azabicvclorS.I .OIhexane-i-carboxylate
Figure imgf000049_0001
ethyl (1 R,2R)-λ ,2-bis{[(methylsulfonyl)oxy]methyl}cyclopropanecarboxylate (Intermediate 18b, 420 mg, 81% pure, 1.03 mmol) was dissolved in DCM (0.5 ml), benzylamine (336 μl, 3.09 mmol) was added and the reaction was stirred overnight. After this time, a solid precipitated (benzylamine mesylate). Additional 0.25 eq (28 μl) of benzylamine were added and the mixture stirred for 2 hrs. After this time no significative improvement observed, additional 0.25 eq of benzylammine were added and the mixture stirred over the week-end. The solid was filtered off and washed with DCM. The organic phase was washed with water (4 times). The solvent was evaporated to give 211 mg of a yellow oil. It was a mixture of the title compound (63% yield calculated by NMR) and benzylamine. 1 H NMR (400 MHz, DMSOd6) ppm 1 H NMR (400 MHz, DMSOd6) d ppm 7.06 - 7.42 (m, 5 H) 4.04 (q, 2 H) 3.59 δ (s, 2 H) 2.79 - 2.98 (m, 2 H) 2.58 - 2.67 (m, 1 H) 2.33 - 2.43 (m, 1 H) 1.77 - 1.96 (m, 1 H) 1.32 - 1.41 (m, 1 H) 1.09 - 1.23 (m, 4 H). HPLC: Rt 1.74 min.
Intermediate 21
3-(1,1 -dimethylethyl) 1 -ethyl (IRδffl-S-azabicvclorS.I.OIhexane-I.S-dicarboxylate
Figure imgf000050_0001
A suspension of ethyl (1 /?,5R)-3-(phenylmethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate (Intermediate 19, 0.380 g, 1.549 mmol), Boc-anhydride (0.539 mL, 2.324 mmol) and 10% Palladium on carbon (0.041 g, 0.039 mmol) in absolute Ethanol (5 mL) was stirred under hydrogen atmosphere (p= 1 atm) for 2 hours. The catalyst was filtered off through a Celite® pad and the solvent was removed under vacuum. The residue (0.530 g) was purified by flash chromatography (Cartridge Sl, 5g) eluting with Cyclohexane/EtOAc from 100:0 to 70:30 to give the title compound (0.352 g, 1.38 mmol, 89% yield) as a colorless oil. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.09 - 4.24 (m, 2 H) 3.50 - 3.83 (m, 3 H) 3.38 - 3.48 (m, 1 H) 1.98 - 2.10 (m, 1 H) 1.49 - 1.64 (m, 1 H) 1.45 (s, 9 H) 1.26 (t, 3 H) 0.81 - 0.88 (m, 1 H).
Intermediate 22 ethyl (IRδ^-S-azabicvclorS.I.OIhexane-i-carboxylate trifluoroacetate
Figure imgf000050_0002
3-(1 , 1 -dimethylethyl) 1 -ethyl (1 R,5R)-3-azabicyclo[3.1.0]hexane-1 ,3-dicarboxylate (Intermediate 21 , 352 mg, 1.38 mmol) was dissolved in Dichloromethane (5 ml). The mixture was cooled down to 00C, then TFA (1.59 mL, 20.68 mmol) was added dropwise and the resulting reaction mixture was stirred at r.t. for 2 hrs. The solvent was evaporated to give 490 mg of the title compound. This crude was used in the next step without further purification. 1 H NMR (400 MHz, DMSOd6) δ ppm 4.11 (q, 2 H) 3.55 - 3.65 (m, 1 H) 3.37 - 3.49 (m, 2 H) 3.27 - 3.35 (m, 1 H) 2.15 - 2.28 (m, 1 H) 1.44 - 1.56 (m, 1 H) 1.12 - 1.27 (m, 4 H). Presence of acidic protons (broad signals) in the region between 8.62 - 9.62 ppm.
Intermediate 23 ethyl (1R5/?)-3-r(2S)-3.3.3-trifluoro-2-(methyloxy)-2-phenylpropanovn-3- azabicyclorS.I .OIhexane-i-carboxylate
Figure imgf000051_0001
Ethyl 3-azabicyclo[3.1.0]hexane-1-carboxylate (Intermediate 22, 50 mg, 0.186 mmol) was dissolved in THF, then it was basified with 1 M NaOH (1 ml) and (2R)-3,3,3-trifluoro-2- (methyloxy)-2-phenylpropanoyl chloride ((R)-(-)-Mosher's acid chloride) (47.1 mg, 0.186 mmol) was added. The mixture was stirred for 10 min. DCM (5 ml) and water (5 ml) were added and the resulting mixture was stirred for 5 mins. Phases were separated and the organic phase was concentrated under reduced pressure to obtain the title compound (40 mg, 0.108 mmol, 57.8% yield). Chiral analysis, chromatographic conditions: [Column: Chiralcel OD-H (25 x 0.46 cm); Mobile phase: n-Hexane/2-Propanol 95/5 % v/v; Flow rate: 1.0 ml/min] Rt 13.4 min; e.e.= 100%]. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.19 - 7.79 (m, 5 H) 2.69 - 4.33 (m, 9 H) 0.21 - 2.09 (m, 6 H).
Intermediate 24
(2S,3S)-2,3-bisr(phenylcarbonyl)oxy1butanedioic acid - ethyl (1R5/?)-3- azabicyclorS.I .OIhexane-i-carboxylate (1 :1)
Figure imgf000051_0002
To a solution of ethyl 3-azabicyclo[3.1.0]hexane-1-carboxylate (Intermediate 2, 2.2 g, 14.18 mmol) in Methanol (20 ml), (2S,3S)-2,3-bis[(phenylcarbonyl)oxy]butanedioic acid (5.4 g, 14.35 mmol) dissolved in Methanol (50 ml) was added dropwise under nitrogen at room temperature. At the end of addition, a cloudy solution was obtained and a white precipitate formed after 5 minutes of stirring. The reaction mixture was stirred at r.t. for 15 minutes and then heated at reflux temperature for 1 hr: no dissolution of the solid was obtained. The mixture was allowed to cool down to r.t. and then filtered over a Gooch funnel to give a 1st batch of the title compound (3.42 g) as a white solid. This solid was suspended in 35 ml of MeOH and heated at reflux temperature for 1 hr. The mixture was allowed to cool down to r.t. and then filtered over a Gooch funnel to give a 2nd batch of the title compound (2.86 g) as a white solid. This solid was suspended in 25 ml of MeOH and heated at reflux temperature for 1 h. The mixture was allowed to cool down to r.t. and then filtered over a Gooch funnel to give a 3rd batch of the title compound (2.54 g) as a white solid. Enantiomeric eccess (e.e.) of this batch was checked by chiral HPLC, preparing the corresponding amide (Intermediate 23) with (R)-(-)-Mosher acid chloride. To a suspension of the title compound (~ 50 mg) in Tetrahydrofuran (THF) (1 ml), 1 ml of 1 M sodium hydroxide aq. solution was added, followed by (R)-(-)-Mosher acid chloride (~ 100 μl). The mixture was shaken at r.t. for -10 minutes, keeping a basic pH with the addition of sodium hydroxide solution. The mixture was then diluted with DCM (2 ml), filtered through a separation tube and the organic phase was concentrated to give a colorless oil, which was injected in chiral HPLC dissolved in 2-Propanol. Chiral analysis, chromatographic conditions: [Column: Chiralcel OD-H (25 x 0.46 cm); Mobile phase: n-Hexane/2-Propanol 95/5 % v/v; Flow rate: 1.0 ml/min; DAD: 210-340 nm] Rt 12.5 min; e.e. - 92%. The 3rd batch of the title compound was then suspended again in 25 ml of MeOH and heated at reflux temperature for 1 hr. The mixture was allowed to cool down to r.t. and then filtered over a Gooch funnel to give a 4th batch of the title compound (2.28 g) as white solid. Enantiomeric eccess (e.e.) of this batch was checked by chiral HPLC, preparing the corresponding amide (Intermediate 23) with (R)-(-)-Mosher acid chloride as described before. Chiral analysis, chromatographic conditions: [Column: Chiralcel OD-H (25 x 0.46 cm); Mobile phase: n- Hexane/2-Propanol 95/5 % v/v; Flow rate: 1.0 ml/min; DAD: 210-340 nm] Rt 11.89 min; e.e. - 96%.
The 4th batch of the title compound was then suspended again in 20 ml of MeOH and heated at reflux temperature for 1 hr. The mixture was allowed to cool down to r.t. and then filtered over a Gooch funnel to give a 5th batch (2.04 g) of the title compound as white solid. Enantiomeric eccess (e.e.) of this batch was checked by chiral HPLC, preparing the corresponding amide (Intermediate 23) with (R)-(-)-Mosher acid chloride as described before. Chiral analysis, chromatographic conditions: [Column: Chiralcel OD-H (25 x 0.46 cm); Mobile phase: n-Hexane/2-Propanol 95/5 % v/v; Flow rate: 1.0 ml/min; DAD: 210-340 nm] Rt 12.6 min; e.e. ~ 96%. The 5th batch of the title compound was then suspended again in 20 ml of MeOH and heated at reflux temperature for 1 hr. The mixture was allowed to cool down to r.t. and then filtered over a Gooch funnel to give a 6th batch of the title compound (1.8 g, 3.51 mmol, 49.5 % yield) as white solid. Enantiomeric eccess (e.e.) of this batch was checked by chiral HPLC, preparing the corresponding amide (Intermediate 23) with (R)-(-)-Mosher acid chloride as described before. Chiral analysis, chromatographic conditions: [Column: Chiralcel OD-H (25 x 0.46 cm); Mobile phase: n-Hexane/2-Propanol 95/5 % v/v; Flow rate: 1.0 ml/min; DAD: 210-340 nm] Rt 12.4 min; e.e. - 98.2%. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.95 (d, 4 H) 7.65 (t, 2 H) 7.52 (t, 4 H) 5.67 (s, 2 H) 4.07 (q, 2 H) 3.41 - 3.49 (m, 1 H) 3.13 - 3.33 (m, 3 H) 2.03 - 2.13 (m, 1 H) 1.27 - 1.36 (m, 1 H) 1.09 - 1.20 (m, 4 H).
Intermediates 25 and 26 ethyl (1 R5/?)-3-r(2R4/?)-1 -(Kd fl)-1 -F3.5- bis(trifluoromethyl)phenyllethylMmethyl)aminolcarbonyl)-2-(4-fluoro-2- methylphenylM-piperidinyll-S-azabicvclorS.I .Olhexane-i-carboxylate (Intermediate
25) and ethyl (1R5fl)-3-r(2R4S)-1-m(1fl)-1-r3,5- bis(trifluoromethyl)phenyllethylMmethyl)aminolcarbonyl)-2-(4-fluoro-2- methylphenylM-piperidinyll-S-azabicvclorS.I .Olhexane-i-carboxylate (Intermediate
26)
Figure imgf000053_0001
To a suspension of (2S,3S)-2,3-bis[(phenylcarbonyl)oxy]butanedioic acid - ethyl (1 R,5R)-3- azabicyclo[3.1.0]hexane-1-carboxylate (1 :1 ) (Intermediate 24, 0.5 g, 0.974 mmol) in Methanol (5 ml) stirred under nitrogen at room temp, neat TEA (0.149 ml, 1.071 mmol) was added. The reaction mixture was stirred at 25°C for 45 minutes. (2R)-N-{(1 R)-1-[3,5- bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl-4-oxo-1- piperidinecarboxamide (WO0232867, 0.589 g, 1.168 mmol), dissolved in Methanol (5 ml), was then added. The obtained pale yellow solution was stirred at r.t. for 2 hrs and then sodium cyanoborohydride (0.092 g, 1.461 mmol) was added. The reaction mixture was allowed to stir at r.t. overnight. The mixture was diluted with EtOAc (30 ml) and Brine (30 ml). Phases were separated and the aqueous was extracted with EtOAc (2 x 50 ml). Combined organic phases were dired over Na2SO4, filtered and concentrated to give 630 mg of a yellow foam. Purification by flash-chromatography (50 g silica cartridge, eluting with 8:2, 7:3 and 6:4 n-Hexane/EtOAc) gave: (1st eluted) ethyl (1 R,5R)-3-[(2R,4R)-1-{[{(1 R)-1-[3,5- bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-2-(4-fluoro-2-methylphenyl)-4- piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylate (Intermediate 25, 40 mg, 0.062 mmol, 6.38 % yield) as a white foam. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.99 (s, 1 H) 7.70 (s, 2 H) 7.18 - 7.27 (m, 1 H) 6.87 - 6.95 (m, 1 H) 6.74 - 6.83 (m, 1 H) 5.19 - 5.30 (m, 1 H) 4.54 - 4.63 (m, 1 H) 4.01 - 4.13 (m, 2 H) 2.98 - 3.38 (m, 5 H) 2.66 (s, 3 H) 2.55 - 2.62 (m, 1 H) 2.23 - 2.43 (m, 4 H) 1.92 - 2.01 (m, 1 H) 1.78 - 1.90 (m, 1 H) 1.56 - 1.77 (m, 3 H) 1.48 (d, 3 H) 1.27 - 1.33 (m, 1 H) 1.20 - 1.26 (m, 1 H) 1.18 (t, 3 H). TLC Rf=0.69 with 6:4 n- Hexane/EtOAc as eluent. UPLC (basic conditions): Rt 1.22 mins, m/z 644[MH]+.
(2nd eluted) ethyl (1 R,5R)-3-[(2R,4S)-1-{[{(1R)-1-[3,5- bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-2-(4-fluoro-2-methylphenyl)-4- piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylate (Intermediate 26, 130 mg, 0.202 mmol, 20.7 % yield) as a white foam. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.99 (s, 1 H) 7.68 (s, 2 H) 7.12 - 7.22 (m, 1 H) 6.86 - 6.94 (m, 1 H) 6.68 - 6.79 (m, 1 H) 5.28 - 5.40 (m, 1 H) 4.09 - 4.17 (m, 1 H) 3.97 - 4.08 (m, 2 H) 3.27 - 3.39 (m, 1 H) 2.90 - 3.02 (m, 2 H) 2.60 - 2.78 (m, 5 H) 2.17 - 2.60 (m, 4 H) 1.75 - 1.96 (m, 4 H) 1.40 - 1.64 (m, 4 H) 1.22 - 1.40 (m, 1 H) 1.08 - 1.22 (m, 5 H). TLC Rf=0.57 with 6:4 n-Hexane/EtOAc as eluent. UPLC (basic conditions): Rt 1.20 mins, m/z 644[MH]+. Compound of intermediate 26 shows the NMR spectrum consistent with the NMR sprectrum of compound of intermediate 5.
Intermediates 27 and 28 ethyl 3-r(2R4fl)-1 -UfCI S)-1 -F3,5- bis(trifluoromethyl)phenyllethylMmethyl)aminolcarbonyl}-2-(4-fluoro-2- methylphenylM-piperidinyll-S-azabicvcloFS.I.Olhexane-i-carboxylate (Intermediate
27) and ethyl 3-F(2R4S)-1 -UfCIS)-I -F3.5- bis(trifluoromethyl)phenvnethylMmethyl)amino1carbonyl)-2-(4-fluoro-2- methylphenylM-piperidinyll-S-azabicvcloFS.I.Olhexane-i-carboxylate (Intermediate
Figure imgf000054_0001
To a solution of ethyl 3-azabicyclo[3.1.0]hexane-1-carboxylate (Intermediate 2, 400 mg, 2.58 mmol) in Methanol (2.5 ml) was added (2R)-N-{(1S)-1-[3,5- bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl-4-oxo-1- piperidinecarboxamide ( WO0232867, 1137 mg, 2.254 mmol) and the reaction mixture was stirred for 10 minutes at r.t. Then Sodium cyanoborohydride (170 mg, 2.70 mmol) was added and the reaction mixture was stirred for 3 hours at r.t. The reaction was quenched with water (5 ml), diluted with brine (10 ml) and extracted with ethyl acetate (3 x 30 ml). The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by SCX cartridge to obtain a yellow oil. This crude was purified by flash chromatography (Biotage system) on silica gel using a column SNAP 100g and from 8:2 to 6:4 Cyclohexane/Ethyl acetate as eluent affording :
(1st eluted) ethyl 3-[(2R,4R)-1-{[{(1 S)-1-[3,5- bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-2-(4-fluoro-2-methylphenyl)-4- piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylate (diastereomeric mixture) (Intermediate 27, 210 mg, 0.326 mmol, 14.5 % yield). UPLC (basic conditions): Rt 1.24 mins, m/z 644 [M+H]+.
(2nd eluted) ethyl 3-[(2R,4S)-1-{[{(1S)-1-[3,5- bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-2-(4-fluoro-2-methylphenyl)-4- piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylate (diastereomeric mixture) (Intermediate 28, 702 mg, 1.09 mmol, 48.6 % yield) as a light yellow solid. UPLC (basic conditions): Rt 1.21 mins, m/z 644 [M+H]+. Intermediates 29 and 30 ethyl (1R5/?)-3-r(2R4/?)-1 -m(1 S)-1-r3,5- bis(trifluoromethyl)phenvnethylMmethyl)amino1carbonyl)-2-(4-fluoro-2- methylphenylM-piperidinyll-S-azabicvclorS.I .Olhexane-i-carboxylate (Intermediate 29) and ethyl (1fl,5fl)-3-r(2fl,4S)-1 -flfM SM -[3,5- bis(trifluoromethyl)phenvnethylMmethyl)amino1carbonyl)-2-(4-fluoro-2- methylphenylM-piperidinyll-S-azabicvclorS.I .Olhexane-i-carboxylate (Intermediate 30, Method A)
Figure imgf000055_0001
To a solution of ethyl (1 /?,5R)-3-azabicyclo[3.1.0]hexane-1-carboxylate trifluoroacetate (Intermediate 22, 40 mg, 0.149 mmol) in Methanol (2 ml) was added at 25 0C, under Nitrogen, TEA (0.023 ml, 0.163 mmol) and the resulting reaction mixture was stirred for 30 mins to get the free base. Then (2R)-N-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4- fluoro-2-methylphenyl)-N-methyl-4-oxo-1-piperidinecarboxamide (WO0232867 94 mg, 0.186 mmol) was added at 25°C and the resulting reaction mixture was stirred for 20 mins. Sodium cyanoborohydride (14.01 mg, 0.223 mmol) was added at 25 0C and the mixture was stirred for 4.5 hrs. Brine and EtOAc were added and the two phases were separated. The aqueous phase was extracted with EtOAc (2X) and the combined organic phases were dried (Na2SO4) and evaporated to dryness. The crude was purified by SCX eluting with methanol and then with 0.5 M methanolic ammonia (to elute the desired compound). The fraction eluted with methanolic ammonia was evaporated to dryness and the crude was purified by flash-chromatography with Biotage SP1 (from 85:25 to 7:3 Cyclohexane/EtOAc) to give:
(1st eluted) ethyl (1 R,5R)-3-[(2R,4R)-1-{[{(1 S)-1-[3,5- bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-2-(4-fluoro-2-methylphenyl)-4- piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylate (Intermediate 29, 13.9 mg, 0.022 mmol, 14.54 % yield) as a yellowish foam. 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.93 (s, 1 H) 7.58 (s, 2 H) 7.21 - 7.29 (m, 1 H) 6.89 (dd, 1 H) 6.77 (t, 1 H) 5.24 - 5.38 (m, 1 H) 4.52 (dd, 1 H) 3.98 - 4.15 (m, 2 H) 2.96 - 3.16 (m, 4 H) 2.77 (s, 3 H) 2.58 (d, 1 H) 2.50 - 2.55 (m, 1 H) 2.38 (dd, 1 H) 2.30 (s, 3 H) 1.94 - 2.02 (m, 1 H) 1.70 - 1.87 (m, 3 H) 1.58 (t, 1 H) 1.48 (d, 3 H) 1.28 - 1.34 (m, 1 H) 1.21 - 1.26 (m, 1 H) 1.17 (t, 3 H). UPLC (basic conditions): Rt 1.24 mins, m/z 644 [M+H]+ . (2nd eluted) ethyl (1 R,5R)-3-[(2R,4S)-1-{[{(1 S)-1-[3,5- bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-2-(4-fluoro-2-methylphenyl)-4- piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylate (Intermediate 30, 24.8 mg, 0.039 mmol, 25.9 % yield) as a yellowish foam. 1 H NMR (500 MHz, DMSO-c/6) δ ppm 7.93 (s, 1 H) 7.53 (s, 2 H) 7.16 - 7.24 (m, 1 H) 6.88 (dd, 1 H) 6.74 (t, 1 H) 5.29 - 5.39 (m, 1 H) 4.12 (dd, 1 H) 4.00 - 4.06 (m, 2 H) 3.33 - 3.42 (m, 1 H) 2.93 - 3.00 (m, 2 H) 2.80 (s, 3 H) 2.59 - 2.71 (m, 2 H) 2.40 - 2.47 (m, 1 H) 2.35 - 2.39 (m, 1 H) 2.34 (s, 3 H) 1.85 - 1.93 (m, 2 H) 1.82 (d, 1 H) 1.47 - 1.53 (m, 1 H) 1.47 (d, 3 H) 1.20 - 1.32 (m, 1 H) 1.17 - 1.20 (m, 1 H) 1.14 (t, 3 H) 1.11 - 1.15 (m, 1 H). UPLC (basic conditions): Rt 1.20 mins, m/z 644[MH]+.
Intermediates 31 and 30 ( method B) ethyl (1 S,5S)-3-F(2R4S)-1 -fffd S)-1 -F3.5- bis(trifluoromethyl)phenyllethylMmethyl)aminolcarbonyl)-2-(4-fluoro-2- methylphenylM-piperidinyll-S-azabicvclorS.I .Olhexane-i-carboxylate (Intermediate 31) and ethyl (1R5fl)-3-r(2R4S)-1 -flfM SM -[3,5- bis(trifluoromethyl)phenyllethylMmethyl)aminolcarbonyl)-2-(4-fluoro-2- methylphenvD^-piperidinvn-S-azabicvclofS.I .OIhexane-i-carboxylate (Intermediate 30, Method B)
Figure imgf000056_0001
The mixture of diastereoisomers ethyl 3-[(2R,4S)-1-{[{(1 S)-1-[3,5- bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-2-(4-fluoro-2-methylphenyl)-4- piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylate (Intermediate 28, 702 mg, 1.09 mmol) was purified by Chiral Chromatography [Analytical chiral HPLC conditions Column: Chiralpak AD-H (25 x 0.46 cm); Mobile phase: n-Hexane/2-Propanol (80/20 for 6 min → 65/35 in 0.5 min) % v/v; Flow rate: 1.0 ml/min; DAD: 210-340 nm; CD: 240 nm; diastereoisomer 1 : Rt 5.25 min (49.82 % a/a); diastereoisomer 2: Rt 15.13 min (50.18 % a/a); Preparative chiral HPLC conditions Column: Chiralpak AD-H (25 x 2.1 cm); Mobile phase: n-Hexane/2-Propanol (80/20 for 6 min → 65/35 in 0.1 min) % v/v; Flow rate: 18.0 ml/min; UV detection: 220 nm; Loop: 1000 μL; injection: 64 mg/inj in 2-Propanol] to obtain:
(1st eluted) ethyl (1 S,5S)-3-[(2R,4S)-1-{[{(1 S)-1-[3,5- bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-2-(4-fluoro-2-methylphenyl)-4- piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylate (Intermediate 31 , 322 mg, 0.500 mmol) as a white solid. 1 H NMR (500 MHz, DMSOd6) δ ppm 7.93 (s, 1 H) 7.54 (s, 2 H)
7.14 - 7.24 (m, 1 H) 6.87 (dd, 1 H) 6.70 - 6.77 (m, 1 H) 5.27 - 5.38 (m, 1 H) 4.08 - 4.13 (m, 1 H) 4.02 - 4.08 (m, 2 H) 3.33 - 3.41 (m, 1 H) 3.06 (d, 1 H) 2.89 (d, 1 H) 2.81 (s, 3 H) 2.61 - 2.74 (m, 2 H) 2.38 - 2.44 (m, 1 H) 2.33 - 2.38 (m, 1 H) 2.33 (s, 3 H) 1.84 - 1 .98 (m, 2 H) 1.80 (d, 1 H) 1.49 - 1.57 (m, 1 H) 1.48 (d, 3 H) 1 .19 - 1.28 (m, 1 H) 1.16 (t, 3 H) 1.09 - 1 .21 (m, 2 H). UPLC (basic conditions): Rt 1.20 mins, m/z 644 [M+H]+.
(2nd eluted) ethyl (1 R,5R)-3-[(2R,4S)-1-{[{(1 S)-1-[3,5- bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-2-(4-fluoro-2-methylphenyl)-4- piperidinylJ-S-azabicycloβ.i .OJhexane-i -carboxylate (Intermediate 30, 301 mg, 0.468 mmol) as a white solid. 1 H NMR (500 MHz, DMSOd6) δ ppm 7.93 (s, 1 H) 7.53 (s, 2 H) 7.16 - 7.24 (m, 1 H) 6.88 (dd, 1 H) 6.74 (t, 1 H) 5.29 - 5.39 (m, 1 H) 4.12 (dd, 1 H) 4.00 - 4.06 (m, 2 H) 3.33 - 3.42 (m, 1 H) 2.93 - 3.00 (m, 2 H) 2.80 (s, 3 H) 2.59 - 2.71 (m, 2 H) 2.40 - 2.47 (m, 1 H) 2.35 - 2.39 (m, 1 H) 2.34 (s, 3 H) 1 .85 - 1.93 (m, 2 H) 1 .82 (d, 1 H) 1.47 - 1.53 (m, 1 H) 1 .47 (d, 3 H) 1 .20 - 1 .32 (m, 1 H) 1.17 - 1 .20 (m, 1 H) 1.14 (t, 3 H) 1.1 1 -
1.15 (m, 1 H). UPLC (basic conditions): Rt 1.20 mins, m/z 644 [M+H]+.
Example 1 sodium 3-r(2R4S)-1-m(1 /?)-1-F3,5- bis(trifluoromethyl)phenvnethyl)(methyl)amino1carbonyl)-2-(4-fluoro-2- methylphenvD^-piperidinvn-S-azabicvclorS.I .OIhexane-i -carboxylate (isomer 1 )
Figure imgf000057_0001
To a solution of ethyl 3-[(2R,4S)-1-{[{(1 R)-1-[3,5- bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-2-(4-fluoro-2-methylphenyl)-4- piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylate (isomer 1 ) (Intermediate 5, 1.91 g, 2.97 mmol) in Methanol (10 ml) a solution of NaOH (0.12 g, 3.00 mmol) in Water (5 ml) was added and the reaction mixture was stirred for 1 hour at 80 0C under microwave irradiation. The solvents were evaporated and the residue was triturated with n-pentane affording the title compound (1.89 g, 2.96 mmol, quantitative yield) as a white solid. 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.98 (s, 1 H) 7.68 (s, 2 H) 7.12 - 7.20 (m, 1 H) 6.87 - 6.93 (m, 1 H) 6.69 - 6.79 (m, 1 H) 5.26 - 5.40 (m, 1 H) 4.13 (d, 1 H) 3.25 - 3.38 (m, 1 H) 2.89 (d, 1 H) 2.70 (s, 3 H) 2.66 - 2.76 (m, 2 H) 2.61 (d, 1 H) 2.34 (s, 3 H) 2.28 - 2.35 (m, 1 H) 2.20 - 2.28 (m, 1 H) 1.74 - 1.91 (m, 2 H) 1.46 - 1.54 (m, 1 H) 1.45 (d, 3 H) 1.22 - 1.34 (m, 2 H) 0.82 - 0.88 (m, 1 H) 0.55 - 0.66 (m, 1 H). HPLC: Rt 5.05 min. Example 2 sodium 3-r(2R4S)-1-m(1 /?)-1-F3,5- bis(trifluoromethyl)phenvnethyl)(methyl)amino1carbonyl)-2-(4-fluoro-2- methylphenvD^-piperidinvn-S-azabicvclorS.I .OIhexane-i-carboxylate (isomer 2)
Figure imgf000058_0001
To a solution of ethyl 3-[(2R,4S)-1-{[{(1 R)-1-
[3,5bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-2-(4-fluoro-2-methylphenyl)-4- piperidinyO-S-azabicycloβ.i .Olhexane-i-carboxylate (isomer 2) (Intermediate 6, 25.2 mg, 0.039 mmol) in Methanol (0.5 ml) was added a solution of Sodium Hydroxide (1.64 mg, 0.041 mmol) in Water (0.25 ml) and the reaction mixture was stirred for 1 h at 900C under microwave irradiation. Solvents were evaporated by Biotage V-10™ solvent evaporation system and the residue was triturated with pentane (3 x 3 ml) to afford the title compound (21.4 mg, 0.0336 mmol, 86% yield) as a solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.72 - 7.78 (m, 1 H) 7.50 - 7.59 (m, 2 H) 7.10 - 7.36 (m, 1 H) 6.70 - 6.83 (m, 2 H) 5.44 - 5.57 (m, 1 H) 4.13 - 4.27 (m, 1 H) 1.35 - 1.52 (m, 3 H) 0.77 - 3.41 (m, 20 H). UPLC: Rt 0.77-0.78 min (broad peak), m/z 616 [M-Na+2H]+.
The following NMR Spectrum was obtained from another batch of example 2: 1 H NMR (500 MHz, DMSO-dfi) d ppm 7.98 (s. 1 H) 7.67 (s, 2 H) 7.1 1 - 7.19 (m, 1 H) 6.85 - 6.92 (m. 1 H) 6.68 - 6.77 (m. 1 H) 5.26 - 5.37 (m. 1 H) 4.10 (dd. 1 H) 3.30 - 3.33 (m. 1 H) 2.84 (d. 1 H) 2.78 (d. 1 H) 2.70 - 2.75 (m. 1 H) 2.70 (s. 3 H) 2.63 (d. 1 H) 2.32 (s. 3 H) 2.24 - 2.29 (m, 1 H) 2.19 - 2.25 (m, 1 H) 1.84 - 1.94 (m, 1 H) 1.71 - 1.80 (m, 1 H) 1.47 - 1.55 (m, 1 H) 1.46.
Following to the assignment of the absolute configuration at carbon 1 and carbon 5 of compound of Example 1 as 1 R ,5R ( see Example 6), the compound of example 2 is believed to be sodium 3-(1S.5S)- r(2R4S)-1-fR(1 /?)-1-[3.5- bis(trifluoromethyl)phenyl1ethyl)(methyl)amino1carbonyl)-2-(4-fluoro-2-methylphenyl)-4- piperidinyll-3-azabicvclor3.1.Olhexane-1 -carboxylate.
Figure imgf000059_0001
Example 3 sodium 3-r(2R4fl)-1 -KfM fl)-1 -F3.5- bis(trifluoromethyl)phenvnethylMmethyl)amino1carbonyl)-2-(4-fluoro-2- methylphenvD^-piperidinvn-S-azabicvclorS.I .OIhexane-i-carboxylate
Figure imgf000059_0002
To a solution of ethyl 3-[(2R,4R)-1-{[{(1/?)-1-[3,5- bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-2-(4-fluoro-2-methylphenyl)-4- piperidinyO-S-azabicycloβ.i .Olhexane-i-carboxylate as a mixture of diastereoisomers (Intermediate 4, 69.5 mg, 0.108 mmol) in Methanol (1 ml) was added a solution of Sodium Hydroxide (4.53 mg, 0.113 mmol) in Water (0.5 ml) and the reaction mixture was stirred for 1 h at 900C under microwave irradiation. Solvents were evaporated by Biotage V-10™ solvent evaporation system and the residue was triturated with pentane (3 x 3 ml) to afford the title compound (56.3 mg, 0.088 mmol, 82% yield) as a solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.71 - 7.80 (m, 1 H) 7.52 - 7.62 (m, 2 H) 7.09 - 7.21 (m, 1 H) 6.59 - 6.84 (m, 2 H) 5.36 - 5.51 (m, 1 H) 4.67 - 4.81 (m, 1 H) 3.18 - 3.37 (m, 1 H) 1.52 - 3.07 (m, 17 H) 1.35 - 1.55 (m, 3 H) 1.18 - 1.33 (m, 1 H) 0.86 - 1.11 (m, 1 H). UPLC: Rt 0.77 min (broad peak), m/z 616 [M-Na+2H]+.
Example 4 sodium 3-K2R.4SM -(WIR)-I -F3.5- bis(trifluoromethyl)phenvnethylMmethyl)amino1carbonyl)-2-(4-fluoro-2- methylphenyl)-4-piperidinvn-3-azabicvclor4.1.01heptane-1-carboxylate (isomer 1)
Figure imgf000060_0001
To a solution of methyl 3-[(2R,4S)-1-{[{(1 R)-1-[3,5- bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-2-(4-fluoro-2-methylphenyl)-4- piperidiny^-S-azabicyclo^.i .Olheptane-i-carboxylate (isomer 1 ) (Intermediate 16, 47 mg, 0.073 mmol) in Methanol (0.6 ml) was added a solution of Sodium Hydroxide (3.07 mg, 0.077 mmol) in water (0.3 ml) and the reaction mixture was stirred for 3h at 800C under microwave irradiation. Solvents were evaporated and the residue was triturated with pentane (3 x 3 ml) to afford the title compound (40.1 mg, 0.061 mmol, 84% yield) as a solid. 1 H NMR (400 MHz, DMSOd6) δ ppm 7.93 - 8.04 (m, 1 H) 7.59 - 7.75 (m, 2 H) 7.08 - 7.24 (m, 1 H) 6.82 - 6.97 (m, 1 H) 6.67 - 6.80 (m, 1 H) 5.25 - 5.42 (m, 1 H) 4.03 - 4.21 (m, 1 H) 2.63 - 2.76 (m, 4 H) 2.55 - 2.62 (m, 1 H) 2.29 - 2.37 (m, 3 H) 2.06 - 2.23 (m, 2 H) 1.51 - 3.49 (m, 7 H) 1.43 - 1.51 (m, 3 H) 1.31 - 1.43 (m, 1 H) 1.1 1 - 1.30 (m, 2 H) 0.72 - 0.91 (m, 1 H) 0.27 - 0.37 (m, 1 H). LC/MS (acidic conditions): Rt 2.0 min, m/z 630 [M-Na+2H]+.UPLC: Rt 0.74 min (broad peak), m/z 630 [M-Na+2H]+.
Example 5 sodium 3-F(2R,4S)-1 -{ Kd RH -F3,5- bis(trifluoromethyl)phenvnethylMmethyl)amino1carbonyl)-2-(4-fluoro-2- methylphenvD^-piperidinvn-S-azabicvclor^i .Oiheptane-i-carboxylate (isomer 2)
Figure imgf000060_0002
To a solution of methyl 3-[(2R,4S)-1-{[{(1 R)-1-[3,5- bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-2-(4-fluoro-2-methylphenyl)-4- piperidinyl]-3-azabicyclo[4.1.0]heptane-1-carboxylate (Isomer 2) (Intermediate 17, 50 mg, 0.078 mmol) in Methanol (0.65 ml) was added a solution of Sodium Hydroxide (3.26 mg, 0.082 mmol) in water (0.325 ml) and the reaction mixture was stirred for 3 h at 800C under microwave irradiation. Solvents were evaporated and the residue was triturated with pentane (3 x 3 ml) to afford the title compound (38.6 mg, 0.059 mmol, 76% yield) as a solid. 1 H NMR (400 MHz, DMSOd6) δ ppm 7.95 - 8.02 (m, 1 H) 7.65 - 7.72 (m, 2 H) 7.13 - 7.21 (m, 1 H) 6.85 - 6.94 (m, 1 H) 6.70 - 6.79 (m, 1 H) 5.28 - 5.39 (m, 1 H) 4.06 - 4.17 (m, 1 H) 2.64 - 2.76 (m, 4 H) 2.53 - 2.61 (m, 1 H) 2.29 - 2.38 (m, 3 H) 2.04 - 2.25 (m, 2 H) 1.51 - 3.49 (m, 7 H) 1.43 - 1.50 (m, 3 H) 1.09 - 1.42 (m, 3 H) 0.72 - 0.91 (m, 1 H) 0.28 - 0.34 (m, 1 H). LC/MS (acidic conditions): Rt 2.0 min, m/z 630 [M-Na+2H]+.UPLC: Rt 0.72 min (broad peak), m/z 630 [M-Na+2H]+.
Example 6
Sodium (1 R5/?)-3-r(2R4S)-1 -f Kf 1 ffl-1 -F3,5- bis(trifluoromethyl)phenyllethylMmethyl)aminolcarbonyl)-2-(4-fluoro-2- methylphenylM-piperidinyll-S-azabicvclorS.I .Olhexane-i-carboxylate
Figure imgf000061_0001
In a capped vial, to a solution of ethyl (1 R,5R)-3-[(2R,4S)-1-{[{(1 R)-1-[3,5- bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-2-(4-fluoro-2-methylphenyl)-4- piperidinylJ-S-azabicycloβ.i .OJhexane-i-carboxylate (Intermediate 26, 25 mg, 0.035 mmol) in Methanol (1.2 ml) stirred under nitrogen at room temperature, sodium hydroxide (1.5 mg, 0.038 mmol) in Water (0.15 ml) was added. The reaction mixture was stirred at 800C for 3 hrs.The mixture was allowed to cool down to r.t. and then solvents were concentrated to give a residue, which was suspended in Et2O (2 ml) and concentrated to give the title compound (24 mg, 90% pure, 0.034 mmol, 97 % yield) as a off-white solid. 1H NMR (400 MHz, DMSO-d6) d ppm 7.98 (br. s., 1 H) 7.68 (br. s., 2 H) 7.12 - 7.20 (m, 1 H) 6.87 - 6.93 (m, 1 H) 6.70 - 6.78 (m, 1 H) 5.28 - 5.38 (m, 1 H) 4.12 (br. d, 1 H) 3.26 - 3.42 (m, 1 H) 2.89 (d, 1 H) 2.65 - 2.76 (m, 5 H) 2.61 (d, 1 H) 2.34 (br. s., 3 H) 2.29 - 2.38 (m, 1 H) 2.19 - 2.29 (m, 1 H) 1.76 - 1.91 (m, 2 H) 1.41 - 1.54 (m, 4 H) 1.21 - 1.34 (m, 2 H) 0.80 - 0.89 (m, 1 H) 0.58 - 0.65 (m, 1 H).
UPLC (basic conditions): Rt 0.75 mins, m/z 616 [M-Na+2H]+.
Compound of Example 6 shows the NMR spectrum consistent with that of the compound of Example 1.
Example 7
Sodium (1R5/?)-3-r(2R4S)-1 -m(1 S)-1-F3.5- bis(trifluoromethyl)phenyllethylMmethyl)aminolcarbonyl)-2-(4-fluoro-2- methylphenylM-piperidinvπ-S-azabicvclorS.I .OIhexane-i-carboxylate
Figure imgf000062_0001
To a solution of ethyl (1 R,5R)-3-[(2R,4S)-1-{[{(1 S)-1-[3,5- bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-2-(4-fluoro-2-methylphenyl)-4- piperidinylJ-S-azabicycloβ.i .OJhexane-i-carboxylate (Intermediate 30 Method A, 22.9 mg, 0.036 mmol) in Methanol (1.2 ml) was added a solution of NaOH (1.44 mg, 0.036 mmol) in Water (0.6 ml) and the resulting mixture was stirred under MW irradiation at 8O0C for 1 hr. Then two drops of 2.4% (w/w) NaOH aq. solution was added and the resulting mixture was stirred under MW irradiation at 900C for 1 hr. The solvents were evaporated to dryness to give the title compound (22 mg, 0.035 mmol, 97 % yield) as a white powder. HPLC: Rt 5.06 mins. MS: m/z 616[M-Na+2H]+, 638[M+H]+. 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.92 (s, 1 H) 7.54 (s, 2 H) 7.15 - 7.23 (m, 1 H) 6.88 (dd, 1 H) 6.70 - 6.77 (m, 1 H) 5.29 - 5.37 (m, 1 H) 4.1 1 (dd, 1 H) 3.30 - 3.39 (m, 1 H) 2.88 (d, 1 H) 2.81 (s, 3 H) 2.71 (d, 1 H) 2.62 - 2.68 (m, 1 H) 2.60 (d, 1 H) 2.34 (s, 3 H) 2.28 - 2.36 (m, 1 H) 2.18 - 2.27 (m, 1 H) 1.87 (d, 1 H) 1.81 (d, 1 H) 1.47 (d, 3 H) 1.39 - 1.54 (m, 1 H) 1.24 - 1.31 (m, 1 H) 1.13 - 1.27 (m, 1 H) 0.79 - 0.85 (m, 1 H) 0.53 - 0.61 (m, 1 H). The stereochemistry of the centre C(7) was determined on the basis of a fixed C(11 ) (R). Dipolar correlations between:
- CH(11 )ax to CH(7)ax at 2.23 ppm and CH2(9)"ax at 2.65 ppm
- CH2(6)" at 0.57 ppm to CH2(5)' at 2.71 ppm and CH2(2)' at 2.88 ppm
- CH2(2)' to CH2(8)eq at 1.87 ppm - CH2(5)' to CH2(12)eq at 1.81 ppm
The atom numbering shown in the following structure is included for the purpose of correlation with the NMR data only.
Figure imgf000062_0002
Example 7 (Method B) Sodium (1R5/?)-3-r(2R4S)-1 -m(1 S)-1 -F3.5- bis(trifluoromethyl)phenvnethylMmethyl)amino1carbonyl)-2-(4-fluoro-2- methylphenylM-piperidinyll-S-azabicvclorS.I.Olhexane-i-carboxylate
Figure imgf000063_0001
To a solution of ethyl (1 R,5R)-3-[(2R,4S)-1-{[{(1 S)-1-[3,5- bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-2-(4-fluoro-2-methylphenyl)-4- piperidinylJ-S-azabicycloβ.i .OJhexane-i-carboxylate (Intermediate 30, Method B, 300 mg, 0.466 mmol) in Methanol (2 ml) a solution of NaOH (18.83 mg, 0.471 mmol) in Water (1 ml) was added and the reaction mixture was stirred for 1 hr at 900C under microwave irradiation. Solvents were evaporated and the residue was triturated with 2:1 n- pentane/Et2O (3 x 5 ml) affording the title compound (291 mg, 0.456 mmol, 98 % yield) as a white solid. 1 H NMR (400 MHz, DMSOd6) δ ppm 7.91 (s, 1 H) 7.53 (s, 2 H) 7.18 (dd, 1 H) 6.86 (dd, 1 H) 6.68 - 6.77 (m, 1 H) 5.33 (q, 1 H) 4.10 (dd, 1 H) 3.33 - 3.39 (m, 1 H) 2.88 (d, 1 H) 2.79 (s, 3 H) 2.71 (d, 1 H) 2.56 - 2.68 (m, 2 H) 2.29 - 2.31 (m, 1 H) 2.33 (s, 3 H) 2.17 - 2.27 (m, 1 H) 1.73 - 1.92 (m, 2 H) 1.46 (d, 3 H) 1.39 - 1.56 (m, 1 H) 1.24 - 1.31 (m, 1 H) 1.15 - 1.24 (m, 1 H) 0.83 (dd, 1 H) 0.53 - 0.63 (m, 1 H). UPLC (basic conditions): Rt 0.75 mins, m/z 616 [M-Na+2H]+.
Example 8
Sodium (1R5/?) -3-r(2R4/?)-1-m(1 S)-1-F3,5- bis(trifluoromethyl)phenvπethylMmethyl)amino1carbonyl)-2-(4-fluoro-2- methylphenylM-piperidinyll-S-azabicvclorS.I.Olhexane-i-carboxylate
Figure imgf000063_0002
To a solution of ethyl (I R1SR)-S-PR^R)-I-(K(IS)-I-[S1S- bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-2-(4-fluoro-2-methylphenyl)-4- piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylate (Intermediate 29, 12.7 mg, 0.020 mmol) in Methanol (0.66 ml) was added a solution of NaOH (0.797 mg, 0.020 mmol) in
Water (0.33 ml) and the resulting mixture was stirred under MW irradiation at 8O0C for 1 hr.
Two drops of 2.4% (w/w) NaOH aq. solution were added and the resulting mixture was stirred under MW irradiation at 8O0C for 1 hr. Then further two drops of 2.4% (w/w) NaOH aq. solution were added and the mixture was stirred under MW irradiation at 9O0C for 1 hr.
The solvents were evaporated to dryness to give the title compound (11.1 mg, 0.017 mmol,
88 % yield) as a white powder. UPLC (basic conditions): Rt 0.81 mins, m/z 616 [M-
Na+2H]+. 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.92 (s, 1 H) 7.57 (s, 2 H) 7.18 - 7.28 (m, 1
H) 6.88 (dd, 1 H) 6.72 - 6.81 (m, 1 H) 5.31 (q, 1 H) 4.53 (dd, 1 H) 2.98 - 3.12 (m, 3 H) 2.85 (d, 1 H) 2.78 (s, 3 H) 2.48 - 2.55 (m, 1 H) 2.39 - 2.45 (m, 1 H) 2.29 (s, 3 H) 2.21 - 2.28 (m, 1
H) 1.75 - 1.82 (m, 2 H) 1.72 (d, 1 H) 1.54 (t, 1 H) 1.48 (d, 3 H) 1.30 - 1.40 (m, 1 H) 0.90 (d,
1 H) 0.69 - 0.75 (m, 1 H). The stereochemistry of the centre C(7) was determined on the basis of a fixed C(1 1 ) (R). Dipolar correlations between:
-CH(11 ) to CH2(6)" at 0.72 ppm and to CH2(9) at 3.05 ppm. -CH(7) to CH2(8)ax and eq at 1.79 ppm, CH2(12)eq at 1.72 ppm and CH2(12)ax at 1.54 ppm.
-CH2(6)" at 0.72 ppm to CH2(5)' at 2.85 ppm, CH2(2)' at 3.05 ppm to CH2(9).
-CH2(5)' to CH2(8) (only) *
-CH2(2)' to CH2(12) eq. (only) * * Hindered rotation of 3.1.0. moiety proposed. Stereochemistry of centres C(3) and C(4) determined based on the proposal.
The atom numbering shown in the following structure is included for the purpose of correlation with the NMR data only.
Figure imgf000064_0001
Example 9
Sodium (1 S.5S)-3-K2R4S)-1 -f KM S)-1 -F3.5- bis(trifluoromethyl)phenvnethylMmethyl)amino1carbonyl)-2-(4-fluoro-2- methylphenylM-piperidinyll-S-azabicvclorS.I .Olhexane-i-carboxylate
Figure imgf000065_0001
To a solution of ethyl (1 S,5S)-3-[(2R,4S)-1-{[{(1 S)-1-[3,5- bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-2-(4-fluoro-2-methylphenyl)-4- piperidinylJ-S-azabicycloβ.i .OJhexane-i-carboxylate (Intermediate 31 , 320 mg, 0.497 mmol) in Methanol (2 ml) a solution of NaOH (20.08 mg, 0.502 mmol) in Water (1 ml) was added and the reaction mixture was stirred for 1 hr at 900C under microwave irradiation. Solvents were evaporated and the residue was triturated with 2:1 n-pentane/Et2O (3 x 5 ml) affording the title compound (302 mg, 0.474 mmol, 95 % yield) as a white solid. 1 H NMR (500 MHz, DMSO-de) δ ppm 7.92 (s, 1 H) 7.54 (s, 2 H) 7.19 (dd, 1 H) 6.87 (dd, 1 H) 6.69 - 6.77 (m, 1 H) 5.33 (q, 1 H) 4.10 (dd, 1 H) 3.34 - 3.42 (m, 1 H) 2.82 - 2.87 (m, 1 H) 2.81 (s, 3 H) 2.79 (d, 1 H) 2.60 - 2.70 (m, 2 H) 2.32 (s, 3 H) 2.25 - 2.29 (m, 1 H) 2.18 - 2.25 (m, 1 H) 1.86 - 1.95 (m, 1 H) 1.74 - 1.83 (m, 1 H) 1.48 (d, 3 H) 1.41 - 1.56 (m, 1 H) 1.24 - 1.30 (m, 1 H) 1.14 - 1.24 (m, 1 H) 0.80 - 0.84 (m, 1 H) 0.58 - 0.62 (m, 1 H). UPLC (basic conditions): Rt 0.75 mins, m/z 616 [M-Na+2H]+.
Biological Data
Compounds of the invention may be tested for in vitro biological activity in accordance with the assays described here below. Compounds of the inventions tested in the following assays may be not necessarily from the same batch as that of the corresponding examples.
Measurement of NK binding affinity
The NK1 binding affinity of the compounds of the invention was determined using the following filtration binding assay using [3H]-GR205171 as radioligand for human NK1 receptor stably expressed in CHO (Chinese Hamster Ovary) cells (see C. Griffante et al, Br. J. Pharmacol. 2006, 148, 39-45; H. M. Sarau et al, J. Pharmacol. Experimental Therapeutics 2000, 295(1 ), 373-381 and DT. Beattie et al., Br. J. Pharmacol. 1995, 116, 3149-3157). CHO cells stably expressing the human cloned neurokinin NK1 receptor were cultured in Dulbecco's Modified Eagle's Medium/F12 Ham (DMEM/F12Ham) supplemented with 10% foetal bovine serum and 2 mM L-glutamine. Cells were maintained in 5% CO2 in a humidified incubator at 37°C. Cells were harvested at confluency with PBS/EDTA (5 mM) and then pelleted by centrifugation (1000 g, 8 min, 4°C). To prepare membranes, cell pellets were homogenised in 10 volumes of membrane preparation buffer and centrifuged (48,000 g, 20 min, 4°C). The membranes were then re-suspended as 500 μl_ aliquots and stored at -80 0C until use.
Binding assay was carried out in 96 deep well polypropylene plates (Whatman) in a volume of 400 μl consisted of 100μl of incubation buffer (containing 5OmM HEPES, pH 7.4, 3mM MnCI2, and 0.02% BSA), 4 μl of DMSO (total binding) or increasing concentrations of the compounds in the invention dissolved in DMSO (1 pM-1 μM final concentration), 10Oμl of the radioligand [3H]-GR205171 (0.2 nM final concentration) in incubation buffer and 200μl of human NK1-CHO cell membranes suspension (4 μg/ml final) in incubation buffer. Non specific binding was defined by the addition of 1 μM unlabelled GR205171. The incubation proceeded at room temperature for 60 minutes. The reaction was stopped by rapid filtration through GF/C filterplates pre-soaked in 0.5% polyetylenimmine (PEI) followed by 3 washes with 1 ml ice cold 0.9% NaCI using a Cell Harvester (Perkin-Elmer). Filterplates were dried and retained radioactivity was counted in a Top Count (Perkin-Elmer). Specific binding was determined by subtracting total binding from nonspecific binding, which was assessed as the binding in the presence of 1 μM GR205171. Percent inhibition of specific binding was determined for each concentration of the compounds of the invention and the IC50, defined as the concentration required inhibiting 50% of the specific binding, obtained from concentration-response curves. The affinity value was expressed as negative logarithm of the inhibition constant (pKi,) and was calculated from the IC50 by the Cheng-Prusoff equation using the dissociation constant (K0) of the radioligand and its concentration in the assay.
The compound of Example 6 was tested in 2 independent experiments and the average affinity value was pKi= 9.63±0.21.
Measurement of NK functional potency:
Compounds of the invention were further characterised in a functional assay using FLIPR technology for the determination of their effect to inhibit the intracellular calcium release induced by interaction of NK receptors with its perspective ligands. Human U2OS cells transiently transduced with recombinant BacMam virus expressing human NK1 , NK2 and NK3 receptors were used in the studies (see J. P. Condreay et al, Proc. Natl. Acad. Sci. USA 1999, 96(1): 127-132). Briefly, U2OS cells were harvested from tissue culture flasks, re-suspended to a cell density of 200-300K/ml and mixed with recombinant BacMam virus carrying NKR gene in a virus/cell ratio of 1% (v/v). 10K-15K cells/well were then seeded in 384-well Greiner bio-one plate in culture medium (DMEM with 10% FBS), incubated overnight in 5% CO2 at 370C. After aspirating the medium, cells were loaded 18-24 hr later with cytoplasmic calcium indicator Fluo-4 Calcium 3 dye (Molecular Devices Co.) in 30uL/well buffer (Hank's balanced salts with 20 mM Hepes) and incubated in CO2 at 370C for 60 minutes. 10uL/well assay buffer (Hank's balanced salts with 20 mM Hepes) containing different concentrations of compounds were then added to the cells for 30 minutes incubation at 370C. Finally, 10uL/well of NKR ligand in assay buffer containing 0.1 % BSA was added to the cells and fluorescence signal read on a FLIPR system. Substance P, was used as the ligand for NK1. IC50 values of each compound were determined by an 1 1-point 3X-dilution inhibition curve. The potency each antagonist (fpK,) was calculated from plC50 by the Cheng-Prusoff equation using EC50 of ligand determined in a separate experiment.
The compounds of Example 1 to 9 were tested in the NK1 functional potency assay. The corresponding pKi values obtained as the average of at least two determinations are given in the following Table 1
Table 1
Figure imgf000067_0001
The ability of the compounds of the invention to penetrate the central nervous system and to bind at the NK1 receptor may be determined using the gerbil foot tapping model as described by Rupniak & Williams, Eur. Jour, of Pharmacol., 1994.
Intracerebroventricular (icv) administration of the NK1 receptor agonist GR73632 (R. M. Hagan et al., Neuropeptides 1991 , 19 (2), 127-135) induces a characteristic hind leg foot tapping (GFT) response in gerbils which can be inhibited by NK1 receptor antagonists. The gerbil foot tapping paradigm was carried out as follows; gerbils were dosed with compound of the invention, and following an appropriate pre-treatment time were anaesthetised using isofluorane / oxygen mixture. The skull was then exposed and GR73632 (3pmol / 5ul) was injected by insertion of a cuffed 25G needle to a depth of 4mm below bregma, directly into the lateral ventricle (intracerebroventricular dosing). Immediately following the injection, gerbils were placed individually into a clear observation box to recover. Upon the gerbil regaining its righting reflex, the duration of repetitive hind foot tapping was recorded over a 5 minute period. The dose of the test compound required to inhibit by 50% the tapping induced by the NK1 agonist expressed as mg/kg is referred to as the ID50value. GR73632-induced GFT behaviour was significantly attenuated by Example 6 at all doses tested 0.3mg/kg (P<0.05) 0.1 & 1 mg/kg (P<0.01 ) and was completely abolished at 3mg/kg (P<0.01 ); with a calculated ID50 of approximately 0.36 mg/kg (blood plasma & brain ID50S approximately 78 ng/ml & 32 ng/g respectively). Compounds of the invention have also been found to demonstrate anxiolytic activity in validated preclinical tests. For example the marmoset human threat test (Costall et al., 1988
The study utilised in house laboratory-bred male and female common marmosets over 2 years of age, weighing 300-50Og. The animals were caged in couples, in a housing room maintained at 25 ± 1°C, 60% humidity and a 12 hour light/dark cycle (lights on at 0600, with 30 min simulated dawn and twilight). Testing was was carried out with the animals situated in the home cage.
One hour before the test animals were treated orally with vehicle (0.5% HPMC + 0.1% Tween 80 in 25mM glycine buffer) or test compound (1 ml/kg). After a wash-out period of at least three days, treatments were reassigned and the study was complete when all animals had received all treatments. The number of specific behavioural postures in response to the human threat and the number of jumps were analysed in this study. The postures recorded in the test were those described by Costall et al (1988) and the number of jumps performed by the animals provided an index of locomotor activity to assess potential for sedation or locomotor stimulation. Results for compound of Example 6 are summarised in the table 2 below.
Table 2
Figure imgf000068_0001
Data are presented as mean±SEM, n=6. Statistically significant differences with respect to vehicle treatment are indicated as *P<0.05 (ANOVA + Dunnett's test).
Pretreatment with Compound of Example 6 caused a reduction in the number of postures without affecting the number of jumps performed by the marmosets. This is consistent with an anxiolytic profile in this test procedure.

Claims

CLAIMS:
1. ceutical acceptable salt thereof
Figure imgf000069_0001
wherein n is 1 or 2.
2. A compound according to claim 1 of formula (IA) or a pharmaceutical acceptable salt thereof
Figure imgf000069_0002
(IA) wherein n is 1 or 2.
3. A compound according to claim 1 which is selected from a list consisting of
• 3-[(2R,4S)-1-{[{(1 R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}- 2-(4-fluoro-2-methylphenyl)-4-piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylic acid (isomer 1 ). This is (1 R,5R)3-[(2R4S)-1-{[{(1 R)-1-[3,5bis(trifluoromethyl) phenyl]ethyl} (methyl)amino] carbonyl}- 2-(4-fluoro-2-methylphenyl)-4-piperidinyl]-3- azabicyclo[3.1.0]hexane-1-carboxylic acid;
• 3-[(2R,4S)-1-{[{(1 R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}- 2-(4-fluoro-2-methylphenyl)-4-piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylic acid ( isomer 2). This is believed to be (1S!5S)3-[(2R!4S)-1-{[{(1 R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl} (methyl)amino]carbonyl}-2-(4-fluoro-2-methylphenyl)-4-piperidinyl]-3- azabicyclo[3.1.0]hexane-1-carboxylic acid; • 3-[(2R!4R)-1-{[{(1 R)-1-[3!5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}- 2-(4-fluoro-2-methylphenyl)-4-piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylic acid;
• 3-[(2R!4S)-1-{[{(1 R)-1-[3!5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}- 2-(4-fluoro-2-methylphenyl)-4-piperidinyl]-3-azabicyclo[4.1.0]heptane-1-carboxylic acid ( isomer 1 );
• 3-[(2R!4S)-1-{[{(1 R)-1-[3!5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}- 2-(4-fluoro-2-methylphenyl)-4-piperidinyl]-3-azabicyclo[4.1.0]heptane-1-carboxylic acid ( isomer 2); • (1R,5R)-3-[(2R,4S)-1-{[{(1 S)-1-[3,5- bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl} -2-(4-fluoro-2- methylphenyl)-4-piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylic acid;
• (1R,5R)-3-[(2R,4R)-1-{[{(1 S)-1- [3,5bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}- 2-(4-fluoro-2- methylphenyl)-4-piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylic acid;
• (1 S,5S)-3-[(2R,4S)-1-{[{(1 S)-1-[3,5- bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-2-(4-fluoro-2- methylphenyl)-4-piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylic acid; or a pharmaceutical acceptable salt thereof.
4. A compound which is (I
Figure imgf000070_0001
bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-2-(4-fluoro-2-methylphenyl)-4- piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylic acid (Ii)
Figure imgf000070_0002
or a pharmaceutically acceptable salt thereof .
5. A compound which is (1 R,5R)-3-[(2R,4S)-1-{[{(1R)-1 -[3,5- bis(trifluoromethyl)phenyl]ethyl} (methyl)amino] carbonyl} -2-(4-fluoro-2-methylphenyl)-4- piperidinyl]-3-azabicyclo [3.1.0]hexane-1-carboxylic acid (Ii).
6. Sodium salt of (1 R,5R)-3-[(2R,4S)-1-{[{(1 R)-1-[3,5- bis(trifluoromethyl)phenyl]ethy(methyl)amino]carbonyl}-2-(4-fluoro-2-methylphenyl)-4- piperidinyl]-3-azabicyclo[3.1.0]hexane-1-carboxylic acid (Ii).
7. A pharmaceutical composition which comprises a compound of formula (I) as defined in any of claims 1 to 6 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
8. A compound as defined in any of claims 1 to 6 for use in therapy.
9. A compound as defined in any of claims 1 to 6 for use in the treatment of conditions for which antagonism of NK1 receptor is beneficial.
10. A compound as defined in any of claims 1 to 6 for use in the treatment of depression, anxiety, sleep disorders or emesis.
11. Use of a compound as defined in any of claims 1 to 6 in the manufacture of a medicament for the treatment of conditions for which antagonism of NK1 receptor is beneficial.
12. Use of a compound as defined in any of claims 1 to 6 in the manufacture of a medicament for the treatment of depression, anxiety, sleep disorders or emesis.
13. A method of treatment or prophylaxis of conditions for which antagonism of NK1 receptor is beneficial in mammals, including humans, which comprises administering to the sufferer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
14 A method of treatment or prophylaxis of depression, anxiety, sleep disorders or emesis in mammals, including humans, which comprises administering to the sufferer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
PCT/EP2009/058937 2008-07-14 2009-07-13 Piperidine based ureas as nk1 antagonists WO2010007032A1 (en)

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CN114957087A (en) * 2022-04-13 2022-08-30 湖南复瑞生物医药技术有限责任公司 Preparation method of intermediate of palovaried
WO2024042043A1 (en) 2022-08-24 2024-02-29 Boehringer Ingelheim International Gmbh A scalable process for the preparation of a glyt-1 inhibitor

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