USOO6319953B1 (12) United States Patent (10) Patent No.: US 6,319,953 B1 Carlson et al. (45) Date of Patent: *Nov. 20, 2001

(54) TREATMENT OF DEPRESSION AND WO95/08549 3/1995 (WO). ANXETY WITH FLUOXETINE AND AN WO95/18124 7/1995 (WO). NK-1 RECEPTOR ANTAGONST WO 96/O5181 2/1996 (WO). WO 96/18643 6/1996 (WO). (75) Inventors: Emma Joanne Carlson, Puckeridge; WO 96/19233 6/1996 (WO). Nadia Melanie Rupniak, Bishops WO 96/24353 8/1996 (WO). Stortford, both of (GB) WO 98/15277 4/1998 (WO). OTHER PUBLICATIONS (73) Assignee: Merck Sharp & Dohme Ltd., Aguiar, M., et al., Physiology& Behavior, 1996, 60(4) Hoddesdon (GB) 1183-1186. (*) Notice: Subject to any disclaimer, the term of this Barden, N., et al., J. Neurochem., 1983, 41, 834-840. Bristow, L., et al., Eur: J. Pharmacol., 1994, 253, 245-252. patent is extended or adjusted under 35 Brodin, E., et al., Neuropharmacology, 1987, 26(6) U.S.C. 154(b) by 0 days. 581-590. This patent is Subject to a terminal dis Brodin, E., et al., Neuropeptides, 1994, 26, 253-260. claimer. Culman, J., et al., J. Physiol. Pharmacol., 1995, 73, 885-891. Cutler, et al., J. Psychopharmacol, 1994, 8, A22, 87. (21) Appl. No.: 09/457,241 Elliott, P. J., Exp. Brain Res. UK, 1988, 73, 354-356. (22) Filed: Dec. 8, 1999 F-D-C Reports-Prescription Pharmaceuticals and Bio technology, Dec. 8, 1997, 59(49), 10. Related U.S. Application Data File, S. E., Pharm. Biochem. Behavior, 1997, 58, 3, 747-752. (60) Division of application No. 08/994,063, filed on Dec. 19, Kramer, et al., Science, 1998, 281, 1640-1645. 1997, now Pat. No. 6,117,855, which is a continuation-in part of application No. PCT/GB97/02748, filed on Oct. 7, Lowe, J., et al., Drug News Perspect, 1992, 5(4), 223. 1997. Malek-Ahmadi, NeuroScience and Behavioral Reviews, 1992, 16, 365-359. (30) Foreign Application Priority Data Rimon, R., et al., Biological Psychiatry, 1984, 19(4), Oct. 7, 1996 (GB) ...... 962O88O 509-516. Aug. 4, 1997 (GB) ...... 9716458 Roccon, et al., Pharmacological Research, 1995, 31, 191. Aug. 4, 1997 (GB) ...... 97.16460 Rupniak, N., et al., Eur: J. Pharmacol., 1994, 265, 179-183. Shaikh, M., et al., Brain Research, 1993, 625, 283-294. (51) Int. Cl." ...... A61K 31/135; A61K 31/675; Shirayama, Y., et al., Brain Research, 1996, 739, 70–78. A61K 31/535; A61K 31/44; A61K 31/445 Siegel, R., et al., Neurochem. Int., 1984, 6(6), 783-789. (52) U.S. Cl...... 514/649; 514/90; 514/236.2; Siegel, A., et al., Aggressive Behavior, 1995, 21, 49-62. 514/278; 514/329 Teixeira, R., et al., European J. Pharm., 1996, 311, 7-14. (58) Field of Search ...... 514/649, 90, 236.2, Vassout, et al., Neuropeptides, 1994, 26 (Suppl. 1), 38. 514/278, 329 Wahlestedt, Science, 1998, 281, 1624–1625. Wall Street Journal, Aug. 13, 1998, B1, Col. 2. (56) References Cited Primary Examiner William R. A. Jarvis U.S. PATENT DOCUMENTS (74) Attorney, Agent, or Firm J. Eric Thies; David L. Rose 5,162,339 11/1992 Lowe, III. (57) ABSTRACT 5,538,982 7/1996 Hagan et al.. 5,612,337 3/1997 Baker et al. . The present invention relates to the treatment or prevention 5,719,147 2/1998 Dorn et al. . of depression and/or anxiety by the administration of a 5,728.695 3/1998 Harrison et al. . combination of a specific class of NK-1 receptor antagonists FOREIGN PATENT DOCUMENTS and fluoxetine. O 577 394 1/1994 (EP). 8 Claims, 2 Drawing Sheets

U.S. Patent US 6,319,953 B1

UOICUU 9/. US 6,319,953 B1 1 2 TREATMENT OF DEPRESSION AND considered in International (PCT) patent specification No. ANXETY WITH FLUOXETINE AND AN WO 96/24353 (published Aug. 15, 1996) which claims NK-1 RECEPTOR ANTAGONST methods for the treatment of psychiatric disorders using a combination of a tachykinin antagonist and a Serotonin CROSS REFERENCE TO RELATED agonist or Selective Serotonin reuptake inhibitor. However, APPLICATIONS the disclosure of WO 96/24353 does not provide any teach ing as to whether the claimed combination has any efficacy This application is a division of Ser. No. 08/994,063, filed and in particular there is no direction towards Specific Dec. 19, 1997, U.S. Pat. No. 6,117,855, which is a combinations which might potentiate the antidepressant or continuation-in-part of PCT Application No. PCT/GB97/ anxiolytic effects of the individual therapeutic agents. There 02748, filed Oct. 7, 1997, which claims priority from Great is no clear direction from WO 96/24353 to which class of Britain Application No. 9620880.6, filed Oct. 7, 1996, Great tachykinin antagonist (e.g. NK-1, NK-2 or NK-3 receptor Britain Application No. 9716458.6 filed Aug. 4, 1997, and antagonists) would be of use in the claimed combinations, Great Britain Application No. 9716460.2, filed Aug. 4, 1997. nor how a perSon of ordinary skill in the art might identify This invention relates to the treatment or prevention of 15 Suitable compounds for use in combination with a Serotonin depression and/or anxiety by the administration of a com agonist or a Selective Serotonin reuptake inhibitor. bination of a Specific class of NK-1 receptor antagonists and Furthermore, there is no teaching which would enable a an antidepressant or anti-anxiety agent. The present inven perSon of ordinary skill in the art to identify those com tion also provides preclinical Screens for anxiolytic and pounds with Sustained activity following oral administration antidepressant activity of NK-1 receptor antagonists. for use in the claimed combinations. At best, WO 96/24353 Major depression is characterised by feelings of intense merely recites m one document that which was already Sadness and despair, mental Slowing and loss of recognised in the art, namely that tachykinin antagonists concentration, pessimistic worry, agitation, and Self might be of use in the treatment of psychiatric disorders and deprecation. Physical changes also occur, especially in that Serotonin agonists and Selective Serotonin reuptake Severe or "melancholic' depression. These include insomnia 25 inhibitors are effective in the treatment of psychiatric dis or hyperSomnia, anorexia and weight loss (or Sometimes orders. overeating), decreased energy and libido, and disruption of There therefore remains a need for an effective combina normal circadian rhythms of activity, body temperature, and tion of an antidepressant and/or an anti-anxiety agent with a many endocrine functions. NK-1 receptor antagonist, which combination provides an Treatment regimens commonly include the use of tricy unexpected and advantageous antidepressant or anxiolytic clic antidepressants, monoamine oxidase inhibitors, Some effect. Such combinations may for example provide an psychotropic drugs, lithium carbonate, and electroconvul enhanced antidepressant or anxiolytic effect. They may also sive therapy (ECT) (see R. J. Baldessarini in Goodman & provide for a rapid onset of action to combat depression Gilman's The Pharmacological Basis of Therapeutics, 9th and/or anxiety thereby enabling prescription on an "as Edition, Chapter 19, McGraw-Hill, 1996 for a review). More 35 needed” basis. recently, new classes of antidepressant drugs are being CNS-penetrant NK-1 receptor antagonists have been developed including Selective Serotonin reuptake inhibitors found to provide an unexpected effect relevant to the treat (SSRIs), specific monoamine reuptake inhibitors and ment and prevention of depression and/or anxiety when used 5-HT1A receptor agonists, antagonists and partial agonists. in combination with an antidepressant or anti-anxiety agent. Anxiety is an emotional condition characterised by feel 40 While not being bound to any particular theory of operation, ingS Such as apprehension and fear accompanied by physical an enhanced effect at treating or preventing a psychological Sympoms Such as tachycardia, increased respiration, Sweat StreSS response in an animal assay is observed with the ing and tremor. It is a normal emotion but when it is Severe combination of drugs than would be expected from either and disabling it becomes pathological. drug alone. In particular, combination therapy of a CNS Anxiety disorders are generally treated using benzodiaz 45 penetrant NK-1 receptor antagonist Selected from the com epine Sedative-antianxiety agents. Potent benzodiazepines pounds of formulae (I), (II), (III), (IV) and (V), and a are effective in panic disorder as well as in generalised Selective Serotonin reuptake inhibitor or a 5-HT1A receptor anxiety disorder, however, the risks associated with drug agonist or antagonist effectively inhibits Separation-induced dependency may limit their long-term use. 5-HT1A receptor Vocalisations in guinea-pig pups. This is indicative of effi partial agonists also have useful anxiolytic and other psy 50 cacy in the treatment of depression and/or anxiety. Such chotropic activity, and less likelihood of Sedation and depen unexpected results would not have been predicted based on dance (see R. J. Baldessarini in Goodman & Gilman's The the disclosures in the art. Pharmacological Basis of Therapeutics, 9th Edition, Chap DETAILED DESCRIPTION OF THE DRAWING ter 18, McGraw-Hill, 1996 for a review). 55 Neurokinin 1 (NK-1; Substance P) receptor antagonists A more complete understanding of the present invention are being developed for the treatment of a number of may be obtained by reading the following description in physiological disorders associated with an exceSS or imbal conjunction with the appended figures. ance of tachykinins, and in particular Substance P. Examples FIG. 1 depicts a Summary of the data from a test of of Such conditions include disorders of the central nervous 60 combinaitons of a CNS-penetrant NK-1 receptor antagonist System Such as anxiety, depression and psychosis (see, for with the anti-anxiety agent, buSpirone, in a guinea-pig instance, International (PCT) patent specification Nos. WO Vocalisation assay. AS further described herein, administra 95/16679, WO95/18124 and WO95/23798). tion of the highly CNS penetrant NK-1 receptor antagonist It might therefore be desirable to investigate the treatment Test Compound A (0.25 mg/kg, s.c.), or buspirone (0.25 of depression and/or anxiety using a combination of a 65 mg/kg S.c.) alone attenuated separation-induced vocalisa tachykinin antagonist and an antidepressant and/or an anti tions by approximately 25% compared with the baseline anxiety agent. Indeed, Such a desideratum has already been Vocalisation response determined using the same animals on US 6,319,953 B1 3 4 the previous day. Combined administration of Test Com of time, the CNS-penetrant NK-1 receptor antagonist may pound A (0.25 mg/kg S.c.) with buspirone (0.25 mg/kg S.c.) be administered either as an oral dosage form Such as a tablet Virtually abolished Separation-induced vocalisations. The or a fast-dissolving oral dosage form. By a “fast dissolving NK-1 receptor specificity of this effect was confirmed by the oral formulation' is meant, an oral delivery form which failure of the less active enantiomer, Test compound B (0.25 when placed on the tongue of a patient, dissolves within mg/kg S.c.) to attenuate separation-induced vocalisations about 10 seconds. when administered alone, or to potentiate the inhibitory By “reasonable period of time” is meant a time period that effect of buspirone (0.25 mg/kg S.c.). is not in excess of about 1 hour. That is, for example, if the FIG. 2 depicts a Summary of the data from a test of antidepressant or anti-anxiety agent is provided as a tablet, combinations of a CNS-penetrant NK-1 receptor antagonist then within one hour, the CNS-penetrant penetrant NK-1 with the antidepressant agent, fluoxetine, in a guinea-pig receptor antagonist should be administered, either in the Vocalisation assay. AS further described herein, administra Same type of dosage form, or another dosage form which tion of the highly CNS penetrant NK1 receptor antagonist provides effective delivery of the medicament. Test compound A (0.25 mg/kg S.c.), or fluoxetine (2 mg/kg The compositions of the present invention are useful for i.p.) alone attenuated separation-induced vocalisations by 15 the treatment of depression. AS used herein, the term approximately 25% compared with the baseline Vocalisation “depression' includes depressive disorders, for example, response determined using the same animals on the previous Single episodic or recurrent major depressive disorders, and day. Combined administration of Test compound A (0.25 dysthymic disorders, depressive neurosis, and neurotic mg/kg S.c.) with fluocetine (2 mg/kg i.p.) virtually abolished depression; melancholic depression including anorexia, Separation-induced vacalisations. The NK-1 receptor Speci weight loSS, insomnia and early morning waking, and psy ficity of this effect was confirmed by the failure of the less chomotor retardation; atypical depression (or reactive active enantiomer, Test Compound B (0.25 mg/kg S.c.) to depression) including increased appetite, hyperSomnia, psy attenuate Separation-induced vocalisaitons when adminis chomotor agitation or irritability, anxiety and phobias, Sea tered alone, or to potentiate the inhibitory effect fluoxatine Sonal affective disorder; or bipolar disorders or manic (2 mg/kg i.p.). 25 depression, for example, bipolar I disorder, bipolar II dis The present invention accordingly provides the use of a order and cyclothymic disorder. CNS-penetrant NK-1 receptor antagonist and an antidepres Other mood disorders encompassed within the term Sant or anti-anxiety agent for the manufacture of a medica “depression” include dysthymic disorder with early or late ment for the treatment or prevention of depression and/or onset and with or without atypical features, dementia of the anxiety. Alzheimer's type, with early or late onset, with depressed The present invention also provides a method for the mood; vascular dementia with depressed mood; mood dis treatment or prevention of depression and/or anxiety, which orders induced by alcohol, amphetamines, cocaine, method comprises administration to a patient in need of Such hallucinogens, inhalants, opioids, phencyclidine, Sedatives, treatment an amount of a CNS-penetrant NK-1 receptor hypnotics, anxiolytics and other Substances, Schizoaffective antagonist and an amount of an antidepressant or anti 35 disorder of the depressed type; and adjustment disorder with anxiety agent, Such that together they give effective relief. depressed mood. In a further aspect of the present invention, there is The compositions of the present invention are useful for provided a pharmaceutical composition comprising a CNS the treatment of anxiety. AS used herein, the term "anxiety’ penetrant NK-1 receptor antagonist and an antidepressant or includes anxiety disorders, Such as panic disorder with or anti-anxiety agent, together with at least one pharmaceuti 40 without agoraphobia, agoraphobia without history of panic cally acceptable carrier or excipient. disorder, Specific phobias, for example, Specific animal It will be appreciated that the CNS-penetrant NK-1 recep phobias, Social phobias, obsessive-compulsive disorder, tor antagonist and antidepressant or anti-anxiety agent may StreSS disorders including post-traumatic StreSS disorder and be present as a combined preparation for Simultaneous, 45 acute StreSS disorder, and generalised anxiety disorders. Separate or Sequential use for the treatment or prevention of "Generalised anxiety' is typically defined as an extended depression and/or anxiety. Such combined preparations may period (e.g. at least six months) of excessive anxiety or be, for example, in the form of a twin pack. worry with symptoms on most days of that period. The In a further or alternative aspect of the present invention, anxiety and worry is difficult to control and may be accom there is therefore provided a product comprising a CNS 50 panied by restlessness, being easily fatigued, difficulty penetrant NK-1 receptor antagonist and an antidepressant or concentrating, irritability, muscle tension, and disturbed anti-anxiety agent as a combined preparation for Sleep. Simultaneous, Separate or Sequential use in the treatment or “Panic disorder” is defined as the presence of recurrent prevention of depression and/or anxiety. panic attacks followed by at least one month of persistent It will be appreciated that when using a combination of 55 concern about having another panic attack. A "panic attack the present invention, both the CNS-penetrant NK-1 recep is a discrete period in which there is a Sudden onset of tor antagonist and the antidepressant or anti-anxiety agent intense apprehension, fearfulneSS or terror. During a panic will be administered to a patient, within a reasonable period attack, the individual may experience a variety of Symptoms of time. The compounds may be in the same pharmaceuti including palpitations, Sweating, trembling, shortneSS of cally acceptable carrier and therefore administered Simulta 60 breath, chest pain, nausea and dizzineSS. Panic disorder may neously. They may be in Separate pharmaceutical carriers occur with or without agoraphobia. Such as conventional oral dosage forms which are taken "Phobias' includes agoraphobia, Specific phobias and simultaneously. The term “combination” also refers to the Social phobias. "Agoraphobia' is characterised by an anxi case where the compounds are provided in Separate dosage ety about being in places or situations from which escape forms and are administered Sequentially. Therefore, by way 65 might be difficult or embarrassing or in which help may not of example, the antidepressant or anti-anxiety agent may be be available in the event of a panic attack. Agoraphobia may administered as a tablet and then, within a reasonable period occur without history of a panic attack. A “Specific phobia' US 6,319,953 B1 S 6 is characterised by clinically significant anxiety provoked by Suitable reversible inhibitors of monoamine oxidase of exposure to a specific feared object or situation. Specific use in the present invention include: moclobemide, and phobias include the following Subtypes: animal type, cued pharmaceutically acceptable Salts thereof. by animals or insects, natural environment type, cued by Suitable Serotonin and noradrenaline reuptake inhibitors objects in the natural environment, for example Storms, of use in the present invention include: Venlafaxine, and heights or water, blood-injection-injury type, cued by the pharmaceutically acceptable Salts thereof. Sight of blood or an injury or by Seeing or receiving an Suitable CRF antagonists of use in the present invention injection or other invasive medical procedure, situational include those compounds described in International Patent type, cued by a Specific Situation Such as public Specification Nos. WO 94/13643, WO 94/13644, WO transportation, tunnels, bridges, elevators, flying, driving or 94/13661, WO 94/13676 and WO 94/13677. enclosed Spaces, and other type where fear is cued by other Suitable atypical antidepressants of use in the present Stimuli. Specific phobias may also be referred to as Simple invention include: bupropion, lithium, nefazodone, traZ phobias. A “social phobia” is characterised by clinically odone and Viloxazine, and pharmaceutically acceptable Salts Significant anxiety provoked by exposure to certain types of thereof. Another Suitable atypical antidepressant is Sibutra Social or performance circumstances. Social phobia may mine. also be referred to as Social anxiety disorder. 15 Other antidepressants of use in the present invention Other anxiety disorders encompassed within the term include adinazolam, alaproclate, amineptine, amitriptyline/ "anxiety' include anxiety disorders induced by alcohol, chlordiazepoxide combination, atipameZole, aZamianserin, amphetamines, caffeine, cannabis, cocaine, hallucinogens, baZinaprine, befuraline, bifemelane, binodaline, bipenamol, inhalants, phencyclidine, Sedatives, hypnotics, anxiolytics brofaromine bupropion, caroXa Zone, cericlamine, and other Substances, and adjustment disorders with anxiety cianopramine, cimo Xatone, citalop ram, cle meprol, or with mixed anxiety and depression. clovoxamine, dazepinil, deanol, demexiptiline, dibenzepin, Anxiety may be present with or without other disorders dothiepin, droxidopa, enefeXine, estazolam, etoperidone, Such as depression in mixed anxiety and depressive disor femoxetine, fengabine, feZolamine, fluotracen, idaZOXan, ders. The compositions of the present invention are therefore indalpine, indeloxazine, iprindole, levoprotiline, litoxetine, useful in the treatment of anxiety with or without accom 25 panying depression. lofepramine, medifoxamine, metapramine, metralindole, The compositions of the present invention are especially mianserin, milnacipran, minaprine, mirtazapine, montirelin, useful for the treatment of or prevention of depression nebracetam, ne fopam, nial amide, nomife nSine, and/or anxiety where the use of an antidepressant or anti norfluoxetine, orotirelin, OxafloZane, pinazepam, pirlindone, anxiety agent is generally prescribed. By the use of a pizotyline, ritanserin, rolipram, Sercloremine, Setiptiline, combination of a CNS-penetrant NK-1 receptor antagonist Sibu tramine, Sulbutiamine, Sulpiride, te niloxazine, and an antidepressant or anti-anxiety agent in accordance thozalinone, thymoliberin, tianeptine, tifilucarbine, with the present invention, it is now also possible to treat or tofenacin, tofisopam, toloxatone, tomoxetine, Veralipride, prevent depression and/or anxiety in patients for whom Vicqualine, Zimelidine and Zometapine, and pharmaceutically conventional antidepressant or anti-anxiety therapy might acceptable salts thereof, and St. John's wortherb, or Hyperi not be wholly Successful or where dependance upon the 35 cum perforatum, or extracts thereof. antidepressant or anti-anxiety therapy is prevalent. Suitable classes of anti-anxiety agent of use in the present Suitable classes of antidepressant agent of use in the invention include benzodiazepines and 5-HTA agonists or present invention include norepinephrine reuptake antagonists, especially 5-HT1A partial agonists, and corti inhibitors, selective serotonin reuptake inhibitors (SSRIs), cotropin releasing factor (CRF) antagonists. In addition to monoamine oxidase inhibitors (MAOIs), reversible inhibi 40 benzodiazepines, other Suitable classes of anti-anxiety agent tors of monoamine oxidase (RIMAS), Serotonin and norad are nonbenzodiazepine Sedative-hypnotic drugs. Such as renaline reuptake inhibitors (SNRIs), corticotropin releasing Zolpidem; mood-stabilizing drugS Such as clobazam, factor (CRF) antagonists, C.-adrenoreceptor antagonists and gabapentin, lamotrigine, lorecleZole, Oxcarbamazepine, Stir atypical antidepressants. ipentol and vigabatrin; and barbiturates. Another class of antidepressant agent of use in the present 45 invention are noradrenergic and Specific Serotonergic anti Suitable benzodiazepines of use in the present invention depressants (NaSSAS). A suitable example of a NaSSA is include: alprazolam, chlordiazepoxide, clonazepam, mirtazapine chloraZepate, diazepam, halazepam, lorazepam, oxazepam Suitable norepinephrine reuptake inhibitors of use in the and prazepam, and pharmaceutically acceptable Salts present invention include tertiary amine tricyclicS and Sec 50 thereof. ondary amine tricyclics. Suitable examples of tertiary amine Suitable 5-HT1A receptor agonists or antagonists of use in tricyclics include: amitriptyline, clomipramine, doxepin, the present invention include, in particular, the 5-HTA imipramine and trimipramine, and pharmaceutically accept receptor partial agonists buSpirone, flesinoxan, gepirone and able Salts thereof. Suitable examples of Secondary amine ipsapirone, and pharmaceutically acceptable Salts thereof. tricyclics include: amoxapine, desipramine, maprotiline, 55 An example of a compound with 5-HT1A receptor nortriptyline and protriptyline, and pharmaceutically accept antagonist/partial agonist activity is pindolol. able salts thereof. Suitable CRF antagonists of use in the present invention Another norepinephrine reuptake inhibitor of use in the include those compounds described in International Patent present invention is reboxetine. Specification Nos. WO 94/13643, WO 94/13644, WO Suitable selective serotonin reuptake inhibitors of use in 60 94/13661, WO 94/13676 and WO 94/13677. the present invention include: fluoxetine, fluvoxamine, par Another class of anti-anxiety agent of use in the present oxetine and Sertraline, and pharmaceutically acceptable Salts invention are compounds having muscarinic cholinergic thereof. activity. Suitable compounds in this class include ml mus Suitable monoamine oxidase inhibitors of use in the carinic cholinergic receptor agonists Such as those com present invention include: isocarboxazid, phenelZine, tranyl 65 pounds described in European Patent Specification Nos. 0 cypromine and Selegiline, and pharmaceutically acceptable 709 093, 0709 094 and 0 773 021, and International patent salts thereof. Specification No. WO 96/12711. US 6,319,953 B1 7 Another class of anti-anxiety agent of use in the present (W) azetidinyl, invention are compounds acting on ion channels. Suitable (X) 1,4-dioxanyl, compounds in this class include carbamazepine, lamotrigine (Y) hexahydroazepinyl, and Valproate, and pharmaceutically acceptable Salts (Z) oxanyl, thereof. (AA) piperazinyl, Particularly preferred CNS-penetrant NK-1 receptor (AB) piperidinyl, antagonists are those described in European Patent Specifi (AC) pyrrolidinyl, cation No. 0.577 394, i.e. compounds of formula (I): (AD) tetrahydrofuranyl, and (AE) tetrahydrothienyl, (I) and wherein the heterocylcle is unsubstituted or substituted with one or more substituent(s) Selected from: (i) Calkyl, unsubstituted or Substituted with halo, -CF, -OCH, or phenyl, 15 (ii) Cigalkoxy, (iii) OXo, (iv) hydroxy, or a pharmaceutically acceptable Salt thereof, wherein: (v) thioxo, R" is selected from the group consisting of: (vi) -SR, wherein R is as defined above, (1) hydrogen; (vii) halo, (2) Coalkyl, unsubstituted or Substituted with one or (viii) cyano, more of the Substituents selected from: (ix) phenyl, (a) hydroxy, (x) trifluoromethyl, (b) oxo, (xi)-(CH2)-NR'R'', wherein m is 0, 1 or 2, (c) Cigalkoxy, 25 and R and R'' are as defined above, (d) phenyl-Calkoxy, (xii) -NRCOR', wherein R and R'' are as (e) phenyl, defined above, (f) -CN, (xiii) -CONR'R'', wherein R and R' are as (g) halo, defined above, (h) -NR'R'', wherein R and R'' are indepen (xiv) -COR, wherein R is as defined above, dently selected from: and (i) hydrogen, (XV)-(CH), OR, wherein m and R are as (ii) Calkyl, defined above; (iii) hydroxy-Calkyl, and (3) Coalkenyl, unsubstituted or Substituted with one (iv) phenyl, 35 or more of the substituent(s) selected from: (i) -NRCOR', wherein R and Rare as defined (a) hydroxy, above, (b) oxo, (j)-NRCOR', wherein RandR'' are as defined (c) Cigalkoxy, above, (d) phenyl-Calkoxy, (k) –CONR'R'', wherein RandR'' are as defined 40 (e) phenyl, above, (f) -CN, (l) -COR', wherein R is as defined above, (g) halo, (m) -COR, wherein R is as defined above, (h)-CONR'R'', wherein RandR'' are as defined (n) heterocycle, wherein the heterocycle is Selected above, from the group consisting of: 45 (i) -COR, wherein R is as defined above, (A) benzimidazolyl, (j) -COR', wherein R is as defined above, (B) benzofuranyl, (k) heterocycle, wherein the heterocycle is as defined (C) benzthiophenyl, above; (D) benzoxazolyl, (4) Calkynyl; (E) furanyl, 50 (5) phenyl, unsubstituted or substituted with one or (F) imidazolyl, more of the substituent(s) selected from: (G) indolyl, (a) hydroxy, (H) isoxazolyl, (b) Coalkoxy, (I) isothiazolyl, (c) Calkyl, (J) oxadiazolyl, 55 (d) C2-salkenyl, (K) oxazolyl, (e) halo, (L) pyrazinyl, (f) -CN, (M) pyrazolyl, (g) -NO, (N) pyridyl, (h) -CF, (O) pyrimidyl, 60 (i) —(CH)-NR'R'', wherein m, R and R' are (P) pyrrolyl, as defined above, (Q) quinolyl, (j)-NRCOR', wherein R and R'' are as defined (R) tetrazolyl, above, (S) thiadiazolyl, (k) —NRCOR', wherein R and R' are as (T) thiazolyl, 65 defined above, (U) thienyl, (1) -CONR'R'', wherein R and Rare as defined (V) triazolyl, above, US 6,319,953 B1 9 10 (m) -CONR'R'', wherein R and R' are as (c) pyrrolyl, defined above, (d) pyridinyl, (n) -COR', wherein R is as defined above, (o) -COR, wherein R is as defined above; (e) imidazolyl, R and R are independently selected from the group (f) oxazolyl, and consisting of: (g) thiazolyl, (1) hydrogen; and wherein the heterocyclic ring is unsubstituted or (2) Coalkyl, unsubstituted or Substituted with one or more of the Substituents selected from: Substituted with one or more substituent(s) selected (a) hydroxy, from: (b) oxo, (i) C-6 alkyl, (c) Cigalkoxy, (ii) oxo, (d) phenyl-Calkoxy, (iii) C-6 alkoxy, (e) phenyl, (iv) —NR'R'', wherein R and R' are as defined (f) -CN, 15 (g) halo, above, (h) -NR'R'', wherein R and R'' are indepen (v) halo, and dently selected from: (vi) trifluoromethyl; (i)-NRCOR', wherein R and R' are as defined and the groups R and R may be joined together to above, form a carbocyclic ring Selected from the group con (j)-NRCOR', wherein RandR'' are as defined Sisting of: above, (k) –CONR'R'', wherein Rand Rare as defined (a) cyclopentyl, above, (b) cyclohexyl, (l) -COR, wherein R is as defined above, and 25 (c) phenyl, (m) -COR', wherein R is as defined above; (3) Coalkenyl, unsubstituted or Substituted with one and wherein the carbocyclic ring is unsubstituted or or more of the substituent(s) selected from: Substituted with one or more Substituents selected from: (a) hydroxy, (i) Calkyl, (b) oxo, (ii) Cigalkoxy, (c) Cigalkoxy, (iii) -NR'R'', wherein R and R'' are as defined (d) phenyl-Calkoxy, above, (e) phenyl, (iv) halo, and (f) -CN, (v) trifluoromethyl; (g) halo, 35 (h)-CONR'R' wherein R and R'' are as defined and the groups R and R may be joined together to above, form a heterocyclic ring Selected from the group con (i) -COR', wherein R is as defined above, Sisting of: (j) -COR, wherein R is as defined above; (a) pyrrolidinyl, (4) Coalkynyl; 40 (b) piperidinyl, (5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: (c) pyrrolyl, (a) hydroxy, (d) pyridinyl, (b) Calkoxy, (e) imidazolyl, (c) C-alkyl, 45 (i) furanyl, (d) Casalkenyl,2-5 y (g) oxazolyl, (e) halo, (h) thienyl, and (f) -CN, (i) thiazolyl, (g) -NO, (h) -CF, 50 and wherein the heterocyclic ring is unsubstituted or (i)-(CH), 'R'', wherein m, RandR'' are as Substituted with one or more substituent(s) selected defined above, from: (j)-NRCOR', wherein R and R' are as defined (i) Cigalkyl, above, (ii) oxo, (k) —NRCOR', wherein R and R'' are as 55 (iii) Cigalkoxy, defined above, (1) -CONR'R'', wherein R and R' are as defined (iv) —NR'R'', wherein R and R' are as defined above, above, (m) -CONR'R'', wherein R and R' are as (v) halo, and defined above, 60 (vi) trifluoromethyl; (n) -COR, wherein R is as defined above, X is Selected from the group consisting of: (o) -COR', wherein R is as defined above; and the groups R' and R may be joined together to (1) -O-, form a heterocyclic ring Selected from the group con (2) -S-, Sisting of: (3) -SO-, and (a) pyrrolidinyl, (4) -SO-; (b) piperidinyl, R" is selected from the group consisting of: US 6,319,953 B1 11 12 (1) (l) -COR', wherein R is as defined above, (m) -COR, wherein R is as defined above; R6 (3) Coalkenyl, unsubstituted or Substituted with one or more of the substituent(s) selected from: 21 i. 5 (a) hydroxy, -Y S x s s?b) Coalkoxy,OXo, R (d) phenyl-Calkoxy, Z. (e) phenyl, 1O (f) -CN, (2) -Y-Cisalkyl, wherein alkyl is unsubstituted or (g) halo, Substituted with one or more of the Substituents (h)-CONR'R'', wherein RandR'' are as defined Selected from: above, (a) hydroxy, (i) -COR, wherein R is as defined above, (b) oxo, 15 (j) -COR', wherein R is as defined above; (c) Cigalkoxy, (4) heterocycle, wherein the heterocycle is as defined (d) phenyl-Calkoxy, above; (e) phenyl, R, R and Rare independently selected from the group (f) -CN, consisting of: (g) halo, 2O (1) hydrogen; (h) -NRR10, wherein R and R10 are as defined (2) Calkyl, unsubstituted or Substituted with one or above, more of the Substituents selected from: (i)-NRCOR', wherein R and R' are as defined (a) hydroxy, above, (b) oxo, (j)-NRCOR', wherein RandR'' are as defined 25 (c) Cigalkoxy, above, 91O 9 O (d) phenyl-Calkoxy, (k) –CONR'R'', wherein RandR'' are as defined (e) phenyl, above, (f) -CN, (l) -COR', wherein R is as defined above, (g) halo, (m) -COR', wherein R is as defined above; 3O (h) -NR'R'', wherein R and R'' are as defined (3) -Y-Calkenyl, wherein the alkenyl is unsub- above, stituted or Substituted with one or more of the (i)-NRCOR', wherein R and R'' are as defined Substituent(s) selected from: above, (a) hydroxy, (j)-NRCOR', wherein RandR'' are as defined (b) oxo, 35 above, (c) Cigalkoxy, (k) –CONR'R'', wherein RandR'' are as defined (d) phenyl-Calkoxy, above, (e) phenyl, (l) -COR', wherein R is as defined above, and (f) -CN, (m) -COR', wherein R is as defined above; (g) halo, 40 (3) Calkenyl, unsubstituted or Substituted with one (h)-CONR'R'', wherein RandR'' are as defined or more of the substituent(s) selected from: above, (a) hydroxy, (i) -COR, wherein R is as defined above, (b) oxo, (j) -COR', wherein R is as defined above, (c) Cigalkoxy, (4) -O(CO)-phenyl, wherein the phenyl is unsubsti. 45 (d) phenyl-Calkoxy, tuted or Substituted with one or more of R, R and (e) phenyl, R; (f) -CN, R is selected from the group consisting of: (g) halo, (1) phenyl, unsubstituted or substituted with one or (h)-CONR'R' wherein R and Rare as defined more of R'', R'' and R'; 50 above, (2) Cisalkyl, unsubstituted or Substituted with one or (i) -COR wherein R is as defined above, more of the substituent(s) selected from: (j) -COR, wherein R is as defined above; (a) hydroxy, (4) Coalkynyl; (b) oxo, (5) phenyl, unsubstituted or substituted with one or (c) Cigalkoxy, 55 more of the substituent(s) selected from: (d) phenyl-Calkoxy, (a) hydroxy, (e) phenyl, (b) Coalkoxy, (f) -CN, (c) Coalkyl, (g) halo, (d) C2-salkenyl, (h) NR'R'', wherein R and R'' are as defined 60 (e) halo, above, (f) -CN, i) - NRCOR', , whereinWherein RK andan R' C S definedCCC g) -INU,NO above, (h) -CF, (i)-NRCOR', wherein RandR'' are as defined (i) —(CH)-NR'R'', wherein m, R and R' are above, 65 as defined above, k)-CONR'R'',, whereinWherein RK anand R' C S CCCdefined (j)-NRCOR', wherein R and Rare as defined above, above, US 6,319,953 B1 13 14 (k) —NRCOR', wherein R and R'' are as (ix)-(CH)-NR'R'', wherein m, Rand R' defined above, are as defined above, (1) -CONR'R'', wherein R and R' are as defined (x) -NRCOR', wherein R and R'' are as above, defined above, (m) -CONR'R'', wherein R and R' are as s (xi) -NRCOR', wherein R and R'' are as defined above, defined above, (n) -COR', wherein R is as defined above; (xii) -CONR'R'', wherein R and R'' are as (o) -COR', wherein R is as defined above; defined above, (6) halo, (Xii) -CONR'R'', wherein R and R'' are as (7) –CN, 1O defined above, (8) -CF, (i) COR , wherein R is as defined above, (9) -NO, (10) - SR", wherein R' is hydrogen or Calkyl, (XV) -COR', wherein R is as defined above; (11) -SOR", wherein R' is as defined above, Z is selected from: (12) -SOR", wherein R' is as defined above, 15 (1) hydrogen, (13) NRCOR, wherein R and R are as defined (2) Calkyl, and above, (3) hydroxy, with the proviso that if Y is -O-, Z is (14) CONRCOR, wherein Rand Rare as defined other than hydroxy, or if Y is -CHR'. , then Zand above, R15 may be joined together to form a double bond. (15)NR'R'', wherein R and Rare as defined above, 2 Particularly preferred compounds of formula (1) are those (16) NRCOR', wherein R and R'' are as defined wherein: R is selected from the group consisting of: above, (1) Calkyl, Substituted with one or more of the Sub (17) hydroxy, Stituents Selected from: (18) Calkoxy, (a) heterocycle, wherein the heterocycle is selected (19) COR, wherein R is as defined above, 25 from group consisting of: (20) COR', wherein R is as defined above, (A) benzimidazolyl, R', R'' and R' are independently selected from the (B) imidazolyl, definitions of R, R7 and R, or -OX; (C) isoxazolyl, Y is Selected from the group consisting of (D) isothiazolyl, (1) a single bond, 3O (E) oxadiazolyl, (2) -O-, (F) pyrazinyl, (3) -S-, (G) pyrazolyl, (4) -CO-, (H) pyridyl, (5) -CH-, (I) pyrrolyl, (6) -CHR'-, and 35 (J) tetrazolyl, (7) –CR'R'' , wherein R and R'' are indepen- (K) thiadiazolyl, dently Selected from the group consisting of: (L) triazolyl,- 0 and (a) Calkyl, unsubstituted or Substituted with one (M) piperidinyl, or more of the Substituents selected from: and wherein the heterocycle is unsubstituted or Substi (i) hydroxy, 40 tuted with one or more substituent(s) selected from: (ii) oxo, (i) Calkyl, unsubstituted or Substituted with halo, (iii) Coalkoxy, -CF, -OCH, or phenyl, (iv) phenyl-Calkoxy, (ii) Cigalkoxy, (v) phenyl, (iii) oxo, (vi) -CN, 45 (iv) thioxo, (vii) halo, (V) cyano, (viii) -NR'R'', wherein R and R' are as (vi) -SCH, defined above, (vii) phenyl, (ix) -NRCOR', wherein R and R' are as (viii) hydroxy, defined above, 50 (ix) trifluoromethyl, (x) -NRCOR', wherein R and R' are as (x)-(CH-)-NR'R'', wherein m is 0, 1 or 2, and R' defined above, and R' are independently selected from: (xi) -CONR'R'', wherein R and R' are as (1) hydrogen, defined above, (II) Coalkyl, (xii) -COR', wherein R is as defined above, 55 (III) hydroxyCoalkyl, and and (IV) phenyl, (xiii) -COR, wherein R is as defined above; (xi) —NRCOR', wherein R and R'' are as defined (b) phenyl, unsubstituted or substituted with one or above, and more of the substituent(s) selected from: (xii) -CONR'R'', wherein R and R'' are as defined (i) hydroxy, 60 above, (ii) Cigalkoxy, R° and R are independently selected from the group (iii) Cigalkyl, consisting of: (iv) Cisalkenyl, (1) hydrogen; (v) halo, (2) Coalkyl (vi) -CN, 65 (3) Coalkenyl, and (vii) -NO, (5) phenyl; (viii) -CF, X is -O-, US 6,319,953 B1 15 16 R" is R" is hydrogen, C-alkyl, C-7 cycloalkyl or C,cycloalkylCalkyl, or C-alkyl Substituted by Calkoxy or hydroxyl, R is hydrogen, C-alkyl, C-7 cycloalkyl or C,cycloalkylCalkyl, or C-alkyl Substituted by one or two Substituents Selected from Calkoxy, hydroxyl or a 4, 5 or 6 membered heteroahphatic ring containing one or two heteroatoms Selected from N, O and S; 1O or R, R and the nitrogen atom to which they are attached R is phenyl, unsubstituted or substituted with halo; form a heteroaliphatic ring of 4 to 7 ring atoms, R, R7 and R are independently selected from the group optionally Substituted by a hydroxy group, and option consisting of: ally containing a double bond, which ring may option (1) hydrogen, ally contain an oxygen or Sulphur ring atom, a group (2) Coalkyl, 15 S(O) or S(O) or a second nitrogen atom which will be (3) halo, and part of a NH or NR moiety where R is Calkyl (4) -CF; optionally Substituted by hydroxy or Calkoxy; Y is -O-, and or R, R and the nitrogen atom to which they are attached Z is hydrogen or Calkyl, form a non-aromatic azabicyclic ring System of 6 to 12 and pharmaceutically acceptable Salts thereof ring atoms, A particularly preferred compound of formula (I) is or Z, R7 and the nitrogen atom to which they are attached 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)pheny)lethoxy)-3- form a heteroaliphatic ring of 4 to 7 ring atoms which (S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo) may optionally contain an oxygen ring atom; methyl)morpholine; or a pharmaceutically acceptable Salt 25 R'' and R'' are each independently hydrogen or thereof. Calkyl, or R'" and R'' are joined so, together with Further preferred CNS-penetrant NK-1 receptor antago the carbon atoms to which they are attached, there is nists are those described in International (PCT) Patent formed a C5-7 ring; Specification No. WO95/18124, i.e. compounds of formula X is an alkylene chain of 1 to 4 carbon atoms optionally (II): Substituted by oxo; and Y is a Calkyl group optionally Substituted by a (II) hydroxyl group; R1 with the proviso that if Y is C, alkyl, R is susbstituted at least by a group of formula ZNRR as defined Sé--R2 35 above. Particularly preferred compounds of formula (II) are those of formula (IIa) and pharmaceutically acceptable Salts thereof.

40 (IIa) Al

or a pharmaceutically acceptable Salt or prodrug thereof, 45 Y wherein O O R" is hydrogen, halogen, C-alkyl, C-calkoxy, CFs, NO, CN, SR', SOR", SOR, COR, CONR'R'', C A2 Coalkenyl, C-alkynyl or Calkyl Substituted by Calkoxy, where R and Reach independently rep 50 X resent hydrogen or Calkyl, R61 A3 R is hydrogen, halogen, Calkyl, Calkoxy Substi tuted by Calkoxy or CF, R is hydrogen, halogen or CF; wherein: R" is hydrogen, halogen, C-alkyl, Calkoxy, CFs, 55 A' is fluorine or CF; NO, CN, SR, SOR', SOR, COR, CONR'R'', A is fluorine or CF; Coalkenyl, Calkynyl or Calkyl Substituted by A is fluorine or hydrogen; Calkoxy, where R" and Reach independently rep and X, Y and Rare as defined in relation to formula (II). resent hydrogen or Calkyl, Particularly preferred compounds of formula (II) include: 60 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5- R is hydrogen, halogen, C-alkyl, C-calkoxy substi (dimethylamino)methyl-1,2,3-triazol-4-yl)methyl-3-(S)- tuted by Calkoxy or CF, phenylmorpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl) R is a 5-membered or 6-membered heterocyclic ring phenyl)ethoxy)-4-(5-(dimethylamino)methyl-1,2,3-triazol containing 2 or 3 nitrogen atoms optionally Substituted 4-yl)methyl-3-(S)-(4-fluorophenyl)morpholine; and by =O, =S or a Calkyl group, and optionally 65 pharmaceutically acceptable Salts thereof. substituted by a group of the formula ZNR'R' where Further preferred CNS-penetrant NK-1 receptor antago Z is Calkylene or Cecycloalkylene; nists are those described in European Patent Specification US 6,319,953 B1 17 18 No. WO95/23798, i.e. compounds of formula (III): (j)-NRCOR', wherein R and R'' are as defined above, (III) (k) —NRCOR', wherein R and R' are as R6 defined above, (1) -CONR'R'', wherein R and Rare as defined --R7 above, R3 X Y. S (m) -CONR'R'', wherein R and R' are as R8 defined above, Z. (n) -COR, wherein R is as defined above, 21 (o) -COR', wherein R is as defined above; R2 1. --R! and the groups R and R may be joined together to (O) s/A-X \! form a carbocyclic ring Selected from the group con R13 R12 Sisting of: (a) cyclopentyl, 15 (b) cyclohexyl, or a pharmaceutically acceptable Salt thereof, wherein: (c) phenyl, R and R are independently selected from the group and wherein the carbocyclic ring is unsubstituted or consisting of: Substituted with one or more Substituents selected from: (1) hydrogen, (i) Cigalkyl, 2) Calkyl,1-6 unsubstituted or Substituted with one or more of the Substituents selected from: (ii) Coalkoxy, (a) hydroxy, (iii) -NR'R'', wherein R and R'' are as defined (b) oxo, above, (c) Cigalkoxy, (iv) halo, and (d) phenyl-Calkoxy, (v) trifluoromethyl; (e) phenyl, 25 and the groups R and R may be joined together to (f) -CN, form a heterocyclic ring Selected from the group con (g) halo, Sisting of: (h) -NR'R'', wherein R and R'' are indepen (a) pyrrolidinyl, dently selected from: (b) piperidinyl, (I) hydrogen, (c) pyrrolyl, (ii) Cigalkyl, (d) pyridinyl, sy lity-Chalkyl, and (e) imidazolyl, IV) pnenyl, (f) furanyl, i)-NRCOR',- , whereinWherein RK andan R' C S definedCCC (g) oxazolyl, above, 35 i)-NRCOR',K., Wnereinwherein RandK an R' C S CCCdefined (h) thienyl, and above, (i) thiazolyl, k)-CONR'R''., whereinWherein RK anand R' C S CCCdefined and wherein the heterocyclic ring is unsubstituted or above, Substituted with one or more substituent(s) selected (l) -COR wherein R is as defined above, and 40 from: (m) -COR', wherein R is as defined above; (i) Calkyl, (3) Calkenyl, unsubstituted or Substituted with one (ii) oxo, or more of the substituent(s) selected from: (iii) Cigalkoxy, (a) hydroxy, (iv) —NR'R'', wherein R and R' are as defined (b) oxo, 45 above, (c) Cigalkoxy, (v) halo, and (d) phenyl-Calkoxy, (vi) trifluoromethyl; (e) phenyl, R, R and Rare independently selected from the group (f) -CN, consisting of: (g) halo, 50 (1) hydrogen; h) - CONR'R' WCCRwherein R anda R' C S definedCCC (2) Coalkyl, unsubstituted or Substituted with one or above, more of the Substituents selected from: (i) -COR wherein R is as defined above, (a) hydroxy, (j) -COR, wherein R is as defined above; (b) oxo, (4) Coalkynyl; 55 (c) Cigalkoxy, (5) phenyl, unsubstituted or substituted with one or (d) phenyl-Calkoxy, more of the substituent(s) selected from: (e) phenyl, (a) hydroxy, (f) -CN, (b) Coalkoxy, (g) halo, (c) C-alkyl, 60 (h) -NR'R'', wherein R and R'' are as defined (d) Cisalkenyl, above, (e) halo, (i)-NRCOR', wherein R and R'' are as defined (f) -CN, above, (g) -NO, (j)-NRCOR', wherein RandR'' are as defined (h) -CF, 65 above, (i) —(CH)-NR'R'', wherein m, R and R' are (k) –CONR'R'', wherein Rand Rare as defined as defined above, above, US 6,319,953 B1 19 20 (l) -COR', wherein R is as defined above, and (a) hydroxy, (m) -COR, wherein R is as defined above; (b) oxo, (3) Coalkenyl, unsubstituted or Substituted with one (c) Cigalkoxy, S. the substituent(s) selected from: (d) phenyl-Calkoxy, (b) y y, 5 (e) phenyl, (C) Coalkoxy, (f) -CN, (d) phenyl-Calkoxy, (g) halo, wherein halo is fluoro, chloro, bromo or (e) phenyl iodo, (f) -CN, s 1O (h) b-NR'R'', wherein R and R'' are as defined (g)(h) -CONR'R'whereinhalo, R and R'' are as defined (i)a b NRCOR",, whereinWherein RK andan RareC asS definedCCC above, above, (i) -COR wherein R is as defined above, (j)-NRCOR', wherein RandR'' are as defined (j) -CO2R, wherein R is as defined above; 15 above, (4) Coalkynyl; (k) —CONR'R'', wherein R and R'' are as defined (5) phenyl, unsubstituted or substituted with one or above, more of the substituent(s) selected from: (l) -COR, wherein R is as defined above, and (a) hydroxy, (m) -COR', wherein R is as defined above; (b) Calkoxy, 2O (2) Coalkenyl, unsubstituted or Substituted with one (c) C-alkyl, or more of the substituent(s) selected from: (d) C2-salkenyl, (a) hydroxy, (e) halo, (b) oxo, (f) -CN, (c) Calkoxy, (g) -NO, 25 (d) phenyl-Calkoxy, (h) -CF, (e) phenyl (i) —(CH)-NR'R'', wherein m, R and R' are (f) –CN s as defined above, (g) halo s (j) it. 9 COR",O wherein R9 and R''O are as defined (h)-CONR'R's wherein R and Rare as defined s 3O above (k)in 9 E O , wherein R 9 and R" O are as (i) -CORs wherein R is as defined above, and (I)-CONR'R'',s wherein Rand R' are as defined (j)i) -CO.R.K., whereinWnereIn RK isIS as delineddefined above,above; andan above (3) C-alkynyl; (m) Co NR'R'', wherein R and R'' are as B is a heterocycle, wherein the heterocycle is Selected defined above,2 s 35 from the group consisting of: (n) -COR, wherein R is as defined above, (o) -COR', wherein R is as defined above; H * X H (6) halo, N-N N-N N-N

8.V-1' 3, " - > O --> O --> O (9) -NO, N (10) - SR", wherein R' is hydrogen or Cisalkyl, X (11) -SOR'', wherein R'' is as defined above, X X (12) -SOR", wherein R' is as defined above, 45 \ , - o M (13) NRCOR, wherein R and R are as defined N-N N-N N-N (14)above, CONRCOR', wherein R and Rare as defined - N > S --> S --> S above, (15)NR'R'', wherein R and R'' are as defined above, so X (16) NRCOR', wherein R and R'' are as defined H X A above, (17)(18) hydroxy,Calkoxy, - -4 --* - %- --* - %- (19) COR, wherein R is as defined above, 55 (20) COR, wherein R is as defined above, \ j \ N (21)(22) 2-pyridyl,3-pyridyl, - y -k -N - -N -SN -Nn X (23) 4-pyridyl, (24) 5-tetrazolyl, 60 X X X (25) 2-oxazolyl, and * * (26) 2-thiazolyl; N N R'', R'' and R' are independently selected from the 4.> 4.> 4.> definitions of R, R7 and R, or -OX; N O N O N S A is Selected from the group consisting of: 65 H H (1) Coalkyl, unsubstituted or Substituted with one or X more of the Substituents selected from: US 6,319,953 B1 21

(i) N1\-1 NH, M, 5 (ii) HM No1N1 N NR9 (iii) 1O No1 Neo-M, - C - C (iv) 15 No COM", (v) tol l 2 COl CO2, No~ NH' (vi) - COM l 25 -O COM,

and wherein the heterocycle may be substituted in COM addition to -X with one or more substituent(s) (vii) Selected from: COM'; and (i) Calkyl, unsubstituted or Substituted with halo, O -CF, -OCH, or phenyl, (ii) Cigalkoxy, (iii) OXo, (iv) hydroxy, 35 (v) thioxo, (k) hydrogen, with the proviso that if p is 0 and none (vi) -SR, wherein R is as defined above, of R', R' or R' are -OX, then X is other than (vii) halo, hydrogen; (viii) cyano, (ix) phenyl, 40 Y is Selected from the group consisting of (x) trifluoromethyl, (1) a single bond, (xi)-(CH), NR'R'', wherein m is 0, 1 or 2, and R' (2) -O-, and R' are as defined above, (3) -S-, (xii) -NRCOR', wherein R and R'' are as defined 45 (5) -CH-, above, (6) -CHR'-, and (xiii) -CONR'R'', wherein RandR'' are as defined (7) –CR'R''-, wherein R' and R are indepen above, dently Selected from the group consisting of: (xiv) -COR', wherein R is as defined above, and (a) Calkyl, unsubstituted or Substituted with one (XV)-(CH), OR, wherein m and Rare as defined 50 or more of the Substituents selected from: above; (i) hydroxy, p is 0 or 1; (ii) oxo, X is selected from: (iii) Cigalkoxy, (a) -PO(OH)O.M", wherein M" is a pharmaceuti (iv) phenyl-Calkoxy, cally acceptable monovalent counterion, 55 (v) phenyl, (b) –PO(O).2M", (vi) -CN, (c)-PO(O).D.", wherein D" is a pharmaceutically (vii) halo, acceptable divalent counterion, (viii) -NR'R'', wherein R and R' are as (d) -CH(R)-PO(OH)O.M", wherein R is hydro defined above, gen or C-alkyl, 60 (ix) -NRCOR', wherein R and R'' are as (e) -CH(R)-PO(O).2M", defined above, (f)-CH(R)-PO(O).D", (x) -NRCOR', wherein R and R' are as (g) -SO.M", defined above, (h)-CH(R)-SO.M", (xi) -CONR'R'', wherein R and R'' are as (i) -CO-CHCH-CO.M", 65 defined above, (j)-CH(CH-)-O-CO-R, wherein R is selected (xii) -COR, wherein R is as defined above, from the group consisting of: and US 6,319,953 B1 23 24 (xiii) -COR, wherein R is as defined above; -continued (b) phenyl, unsubstituted or substituted with one or X X more of the substituent(s) selected from: \ H H M (i) hydroxy, N-N (ii) Cigalkoxy, (iii) Cigalkyl, 1SN > S - N > S - N > S (iv) C2-salkenyl, H (v) halo, X (vi) -CN, X * (vii) -NO, (viii) -CF, 1O - (ix)-(CH)-NR'R'', wherein m, Rand R' - N2. O -X - N > S -X - N2 are as defined above, (x) —NRCOR', wherein R and R' are as X defined above, 15 N-N N \ (xi) -NRCOR', wherein R and R'' are as defined above, - N 3 -C-C-CAN O N O

(xii) -CONR'R'', wherein R and R' are as X X X defined above, 2O (xiii) -CONR'R'', wherein R and R' are as X defined above, M H H (xiv) -COR', wherein R is as defined above, and 25 -C> S -C> S -CN2. O -X (XV) -COR', wherein R is as defined above; Z is selected from: X (1) hydrogen, H (2) Coalkyl, and (3) hydroxy, with the proviso that if Y is -O-, Z is 2. X, other than hydroxy, or if Y is -CHR'-, then Zand 3O 4.N% s1 R" may be joined together to form a double bond. Particularly preferred compounds of formula (III) are those wherein: p is 0 or 1; R° and R are independently selected from the group 35 X is selected from: consisting of: (a) -PO(OH)O.M", wherein M" is a pharmaceuti (1) hydrogen, cally acceptable monovalent counterion, (2) Calkyl, (3) Coalkenyl, and (b) –PO(O).2M", (4) phenyl, 40 (c)-PO(O).D.", wherein D" is a pharmaceutically R, R and Rare independently selected from the group acceptable divalent counterion, consisting of: (d) -CH(R)-PO(OH)O.M", wherein R is hydro (1) hydrogen, gen or C-alkyl, (2) Coalkyl, 45 (e) -CH(R)-PO(O).2M", (3) fluoro, (f)-CH(R')–PO(O).D", (4) chloro, (5) bromo, (i) -CO-CHCH-CO.M", (6) iodo, and (j)-CH(CH4)-O-CO-R, wherein R is selected (7) -CF; 50 from the group consisting of: R'', R'' and R' are independently selected from the group consisting of (i) (1) fluoro, NHM, (2) chloro, No1n- N3 (3) bromo, and 55 (ii) (4) iodo; HM A is unsubstituted alkyl, No1N1 NYOH, B is Selected from the group consisting of: (iii) 60 No1 Neo-M, - - \ (iv) --> --> --> COM' H No COM", US 6,319,953 B1 26 -continued (v) (IV) CO2,

No~ NH' (vi) COM

-O COM, 1O

COM (vii) COM'; and 15 1. O

wherein X is a group of the formula NR'R' or a C- or N-linked imidazolyl ring; Y is -O-, Y is hydrogen or Calkyl optionally Substituted by a Z is hydrogen or Calkyl, hydroxy group; 25 R" is hydrogen, halogen, C1-alkyl, C1-galkoxy, CFs, NO, CN, SR', SOR', SOR, COR, CONR'R'', and pharmaceutically acceptable Salts thereof. Coalkenyl, C-alkynyl or Calkyl Substituted by Calkoxy, wherein R" and R each independently represent hydrogen or Calkyl, Particularly preferred compounds of formula (III) R is hydrogen, halogen, Calkyl, Calkoxy Substi include: tuted by Calkoxy or CF, R is hydrogen, halogen or CF; R" is hydrogen, halogen, Cisalkyl, C-galkoxy, hydroxy, CF, NO, CN, SR, SOR", SOR, COR, CONR'R'', Coalkenyl, C-alkynyl or Calkyl Substituted by (1) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl 35 Calkoxy, wherein R" and R are as previously 4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine defined; N-oxide; R is hydrogen, halogen, C-alkyl, C-calkoxy substi tuted by Calkoxy or CF, (2) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl R is hydrogen, C-alkyl, Cs, cycloalkyl, 4-(3-(4-(ethoxycarbonyloxy-1-ethyl)-5-oxo-1H-1,2,4- 40 C,cycloalkylCalkyl, phenyl, or Calkyl Substi triazolo)methyl)morpholine; tuted by Calkoxy or hydroxy, (3) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3- R" is hydrogen, C-alkyl, Cs, cycloalkyl, (S)-(4-fluorophenyl)-4-(3-(4-monophosphoryl-5-oxo C,cycloalkylCalkyl, phenyl, or Calkyl Substi 1H-1,2,4-triazolo)methyl)morpholine; tuted by one or two substituents selected from (4) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3- 45 Calkoxy, hydroxy or a 4, 5 or 6 membered het (S)-(4-fluorophenyl)-4-(3-(1-monophosphoryl-5-oxo eroaliphatic ring containing one or two heteroatoms 1H-1,2,4-triazolo)methyl)morpholine; Selected from N, O and S; (5) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3- or R and R', together with the nitrogen atom to which (S)-(4-fluorophenyl)-4-(3-(2-monophosphoryl-5-oxo 50 they are attached, form a Saturated or partially Saturated 1H-1,2,4-triazolo)methyl)morpholine; heterocyclic ring of 4 to 7 ring atoms, which ring may (6) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3- optionally contain in the ring one oxygen or Sulphur (S)-(4-fluorophenyl)-4-(3-(5-oxyphosphoryl-1H-1,2,4- atom or a group selected from NR S(O) or S(O) and triazolo)methyl)morpholine; which ring may be optionally Substituted by one or two (7) 2-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3- 55 groups Selected from hydroxy Calkyl, CalkoxyC. (S)-(4-fluorophenyl)-4-(3-(1-monophosphoryl-5-oxo 4alkyl, oxo, COR" or COR" where R is as previously 4H-1,2,4-triazolo)methyl)morpholine; defined; or R and R together with the nitrogen atom to which they are attached, form a non-aromatic azabicyclic ring 60 System of 6 to 12 ring atoms, R is hydrogen, C-alkyl, hydroxyC-alkyl or CalkoxyC-alkyl, and and pharmaceutically acceptable Salts thereof. R'" and R' are each independently hydrogen or Calkyl, or R'" and R'' are joined so, together with Further preferred CNS-penetrant NK-1 receptor antago 65 the carbon atoms to which they are attached, there is nists are those described in European Patent Specification formed a C-7 ring, and pharmaceutically acceptable No. WO 96/05181, i.e. compounds of formula (IV): Salts thereof.

US 6,319,953 B1 29 30 R is hydrogen, C-alkyl, C-7 cycloalkyl, Specific compounds of formula (V) of use in the present C,cycloalkylCalkyl, phenyl, or Calkyl Substi invention include: tuted by Calkoxy or hydroxy, R" is hydrogen, C-alkyl, C., cycloalkyl, 4-(2-aminoethyl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl) C-7cycloalkylCalkyl, phenyl, Calkyl Substituted phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine; by Calkoxy or hydroxy, or the group C(=NR) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3- NR'R'', where R" and Rare as previously defined and (S)-(4-fluorophenyl)-4-(2-pyrrolidinoethyl)morpholine; R is hydrogen, Calkyl, CN or COR'; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3- or R and R', together with the nitrogen atom to which (S)-(4-fluorophenyl)-4-(2-morpholinoethyl)morpholine; they are attached, form a Saturated heterocyclic ring of 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(2- 4 to 7 ring atoms which may optionally contain in the (2'-(S)-carboxypyrrolidino)ethyl)-3-(S)-(4-fluorophenyl) ring one oxygen or Sulphur atom or a group Selected morpholine; from NR, S(O) or S(O) and which ring may be 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3- optionally Substituted by one or two groups Selected (S)-(4-fluorophenyl)-4-(2-(2'-(R)- from phenyl, benzyl, hydroxy Calkyl, CalkoxyC. 15 hydroxymethylpyrrolidino)ethyl)morpholine; 4alkyl, hydroxy, oxo, COR" or COR" where R is as 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(2- previously defined; (4'-carbomethoxy-2-oxopyrrolidino)ethyl)-3-(S)-(4- or R and R', together with the nitrogen atom to which fluorophenyl)morpholine; they are attached, form a piperidino ring Substituted by 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(2- a Spiro-fused indene or indoline group, each of which (N'-carbo ethoxy)-guanidino)ethyl)-3-(S)-(4- may be unsubstituted or substituted on any available fluorophenyl)morpholine; carbon atom by a group Selected from Calkyl, 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3- Calkoxy, hydroxy, halogen, cyano, trifluoromethyl, (S)-phenyl-4-(2-(4-phenylpiperidino)ethyl)morpholine; SOC-alkyl, NR'R'', NRCOR or CONR'R'; or, in 3-(S)-phenyl-4-(2-(4-phenylpiperidino)ethyl)-2-(R)-(1-(R)- the case of an indoline group, on the nitrogen atom by 25 (3-(trifluoromethyl)phenyl)ethoxy)morpholine; a group Selected from C-alkyl, C-7cycloalkyl, 2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)- C-7cycloalkylCalkyl, phenylC-alkyl, COR', 3-(S)-phenyl-4-(2-(spiro(indene-3',4-piperidino)ethyl) morpholine; CONR'R', SOR or SOR", where R and R are as 2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)- previously defined; 3-(S)-phenyl-4-(2-(4-phenylpiperidino)ethyl)morpholine; R is hydrogen, C. alkyl, hydroxy C1-alkyl or 2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)- CalkoxyCalkyl, 4-(2-(1'-methylsulfonyl-spiro(indoline-3,4-piperidino)) R" and R'' are each independently hydrogen or ethyl)-3-(S)-phenylmorpholine; Calkyl, or R” and R' are joined so, together with 2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)- the carbon atoms to which they are attached, there is 3-(S)-phenyl-4-(2-(4-piperidino)ethyl)morpholine; formed a C5-7 ring; 35 2-(S)-(3,5-bis(trifluoromethyl)phenyl)methyloxy)-3-(S)- X is selected from -CHCH-, -COCH- or phenyl-4-(2-(4-phenylpiperidino)ethyl)morpholine; -CHCO-, and 4-(2-(4-benzylpipe ridino)ethyl)-2-(S)-(3,5-bis Y is hydrogen, or Calkyl optionally Substituted by a (trifluoromethyl)phenyl)-methyloxy)-3-(S)- hydroxyl group; phenylmorpholine; or a pharmaceutically acceptable Salt thereof. 40 Particularly preferred compounds of formula (V) are and pharmaceutically acceptable Salts thereof. those of formula (Va) and pharmaceutically acceptable Salts The preferred compounds of formulae (I), (II), (III), (IV) thereof: and (V) will have the 2- and 3-substituents on the morpho 45 line ring in the cis arrangement, the preferred Stereochem (Va) istry being as shown in the following general formula:

ON &O C D C.

55 R

Where the benzyloxy moiety is C.-substituted, the pre A3 ferred stereochemistry of the C-carbon is either (R) when the 60 Substituent is an alkyl (e.g. methyl) group or (S) when the Substituent is a hydroxyalkyl (e.g. hydroxymethyl) group Unless otherwise defined herein, Suitable alkyl groups wherein include Straight-chained and branched alkyl groups contain A' is hydrogen, fluorine or CF; ing from 1 to 6 carbon atoms. Typical examples include A is fluorine or CF; 65 methyl and ethyl groups, and Straight-chained or branched A is fluorine or hydrogen; and X, Y, R and R7 are as propyl and butyl groups. Particular alkyl groups are methyl, defined in relation to formula (V). ethyl, n-propyl, isopropyl, n-butyl, Sec-butyl and tert-butyl. US 6,319,953 B1 31 32 Unless otherwise defined herein, Suitable alkenyl groups It will be appreciated that the CNS-penetrant NK-1 recep include Straight-chained and branched alkenyl groups con tor antagonist Selected from the compounds of formulae (I), taining from 2 to 6 carbon atoms. Typical examples include (II), (III), (IV) and (V) and and an antidepressant or anti Vinyl and allyl groups. anxiety agent may be present as a combined preparation for Unless otherwise defined herein, Suitable alkynyl groups Simultaneous, Separate or Sequential use for the treatment or include Straight-chained and branched alkynyl groups con prevention of depression and/or anxiety. Such combined taining from 2 to 6 carbon atoms. Typical examples include preparations may be, for example, in the form of a twin pack. ethynyl and propargyl groups. In a further or alternative aspect of the present invention, Unless otherwise defined herein, suitable cycloalkyl there is therefore provided a product comprising a CNS groups include groups containing from 3 to 7 carbon atoms. 1O penetrant NK-1 receptor antagonist Selected from the com Particular cycloalkyl groups are cyclopropyl and cyclo pounds of formulae (I), (II), (III), (IV) and (V) and and an hexyl. antidepressant or anti-anxiety agent as a combined prepara Unless otherwise defined herein, Suitable aryl groups tion for Simultaneous, Separate or Sequential use in the include phenyl and naphthyl groups. treatment or prevention of depression and/or anxiety. Aparticular aryl-C-alkyl, e.g. phenyl-C-alkyl, group is 15 In a preferred aspect, the present invention accordingly benzyl. provides the use of a CNS-penetrant NK-1 receptor antago Unless otherwise defined herein, suitable heteroaryl nist selected from the compounds of formulae (I), (II), (III), groups include pyridyl, quinolyl, isoquinolyl, pyridaZinyl, (IV) and (V) and an antidepressant agent Selected from the pyrimidinyl, pyrazinyl, pyranyl, furyl, benzofuryl, thienyl, group consisting of norepinephrine reuptake inhibitors, benzthienyl, imidazolyl, oxadiazolyl and thiadiazolyl Selective Serotonin reuptake inhibitors, monoamine oxidase groupS. inhibitors, reversible monoamine oxidase inhibitors, Seroto The term “halogen' as used herein includes fluorine, nin and noradrenaline reuptake inhibitors, corticotropin chlorine, bromine and iodine. releasing factor (CRF) antagonists, C.-adrenoreceptor The compounds of use in this invention may have one or antagonists and atypical antidepressants, for the manufac more asymmetric centres and can therefore exist as enanti 25 ture of a medicament for the treatment or prevention of omers and possibly as diastereoisomers. It is to be under depression and/or anxiety. stood that the present invention relates to the use of all Such The present invention also provides a method for the isomers and mixtures thereof. treatment or prevention of depression and/or anxiety, which Suitable pharmaceutically acceptable salts of the CNS method comprises administration to a patient in need of Such penetrant NK-1 receptor antagonists of use in the present treatment an amount of a CNS-penetrant NK-1 receptor invention include acid addition Salts which may, for antagonist Selected from the compounds of formulae (I), (II), example, be formed by mixing a Solution of the compound (III), (IV) and (V) and an antidepressant agent Selected from with a Solution of a pharmaceutically acceptable non-toxic the group consisting of norepinephrine reuptake inhibitors, acid Such as hydrochloric acid, fumaric acid, maleic acid, Selective Serotonin reuptake inhibitors, monoamine oxidase Succinic acid, acetic acid, citric acid, tartaric acid, carbonic 35 inhibitors, reversible monoamine oxidase inhibitors, Seroto acid, phosphoric acid or Sulphuric acid. Salts of amine nin and noradrenaline reuptake inhibitors, corticotropin groups may also comprise the quaternary ammonium Salts in releasing factor (CRF) antagonists, C.-adrenoreceptor which the amino nitrogen atom carries an alkyl, alkenyl, antagonists and atypical antidepressants, Such that together alkynyl or aralkyl group. Where the compound carries an they give effective relief. acidic group, for example a carboxylic acid group, the 40 In a further aspect of the present invention, there is present invention also contemplates Salts thereof, preferably provided a pharmaceutical composition comprising a CNS non-toxic pharmaceutically acceptable Salts thereof, Such as penetrant NK-1 receptor antagonist Selected from the com the Sodium, potassium and calcium Salts thereof. pounds of formulae (I), (II), (III), (IV) and (V) and an Suitable pharmaceutically acceptable Salts of the antide antidepressant agent Selected from the group consisting of: preSSant or anti-anxiety agent of use in the present invention 45 norepinephrine reuptake inhibitors, Selective Serotonin include those salts described above in relation to the salts of reuptake inhibitors, monoamine oxidase inhibitors, revers CNS-penetrant NK-1 receptor antagonists. ible monoamine oxidase inhibitors, Serotonin and norad The present invention accordingly provides the use of a renaline reuptake inhibitors, corticotropin releasing factor CNS-penetrant NK-1 receptor antagonist selected from the (CRF) antagonists, C.-adrenoreceptor antagonists and atypi compounds of formulae (I), (II), (III), (IV) and (V) and an 50 cal antidepressants, together with at least one pharmaceuti antidepressant or anti-anxiety agent for the manufacture of cally acceptable carrier or excipient. a medicament for the treatment or prevention of depression In a further or alternative aspect of the present invention, and/or anxiety. there is provided a product comprising a CNS-penetrant The present invention also provides a method for the NK-1 receptor antagonist Selected from the compounds of treatment or prevention of depression and/or anxiety, which 55 formulae (I), (II), (III), (IV) and (V) and an antidepressant method comprises administration to a patient in need of Such agent Selected from the group consisting of norepinephrine treatment an amount of a CNS-penetrant NK-1 receptor reuptake inhibitors, Selective Serotonin reuptake inhibitors, antagonist Selected from the compounds of formulae (I), (II), monoamine oxidase inhibitors, reversible monoamine oxi (II), (IV) and (V) and an amount of an antidepressant or dase inhibitors, Serotonin and noradrenaline reuptake anti-anxiety agent Such that together they give effective 60 inhibitors, corticotropin releasing factor (CRF) antagonists, relief. C.-adrenoreceptor antagonists and atypical antidepressants, In a further aspect of the present invention, there is as a combined preparation for Simultaneous, Separate or provided a pharmaceutical composition comprising a CNS Sequential use in the treatment or prevention of depression penetrant NK-1 receptor antagonist Selected from the com and/or anxiety. pounds of formulae (I), (II), (III), (IV) and (V) and an 65 A particularly preferred class of antidepressant agent is antidepressant or anti-anxiety agent together with at least the Selective Serotonin reuptake inhibitors, thus in a further one pharmaceutically acceptable carrier or excipient. preferred aspect, the present invention accordingly provides US 6,319,953 B1 33 34 the use of a CNS-penetrant NK-1 receptor antagonist lae (I), (II), (III), (IV) or (V) in combination with a selective selected from the compounds of formulae (I), (II), (III), (IV) Serotonin reuptake inhibitor, Such as fluoxetine, and a com and (V) and a selective serotonin reuptake inhibitor for the pound with 5-HT1A antagonist activity, Such as pindolol. manufacture of a medicament for the treatment or preven Preferably the compositions according to the present tion of depression and/or anxiety. invention are in unit dosage forms Such as tablets, pills, The present invention also provides a method for the capsules, wafers and the like. Additionally, the active ingre treatment or prevention of depression and/or anxiety, which dients may be presented as granules or powders for extem method comprises administration to a patient in need of Such poraneous formulation as Volume defined Solutions or SuS treatment an amount of a CNS-penetrant NK-1 receptor pensions. Alternatively, the active ingredients may be antagonist Selected from the compounds of formulae (I), (II), presented in ready-prepared Volume defined Solutions or (III), (IV) and (V) and an amount of a selective serotonin Suspensions. Preferred forms are tablets and capsules. reuptake inhibitor, Such that together they give effective For preparing Solid compositions Such as tablets, the relief. principal active ingredient is mixed with a pharmaceutical In a further aspect of the present invention, there is carrier, e.g. conventional tableting ingredients Such as corn provided a pharmaceutical composition comprising a CNS 15 Starch, lactose, Sucrose, Sorbitol, talc, Stearic acid, magne penetrant NK-1 receptor antagonist Selected from the com sium Stearate, dicalcium phosphate or gums, and other pounds of formulae (I), (II), (III), (IV) and (V) and a pharmaceutical diluents, e.g. water, to form a Solid prefor Selective Serotonin reuptake inhibitor, together with at least mulation composition containing a homogeneous mixture of one pharmaceutically acceptable carrier or excipient. a compound of the present invention, or a non-toxic phar In a further or alternative aspect of the present invention, maceutically acceptable Salt thereof. When referring to these there is provided a product comprising a CNS-penetrant preformulation compositions as homogeneous, it is meant NK-1 receptor antagonist Selected from the compounds of that the active ingredient is dispersed evenly throughout the formulae (I), (II), (III), (IV) and (V) and a selective sero composition So that the composition may be readily Subdi tonin reuptake inhibitor as a combined preparation for Vided into equally effective unit dosage forms Such as Simultaneous, Separate or Sequential use in the treatment or 25 tablets, pills and capsules. This Solid preformulation com prevention of depression and/or anxiety. position is then Subdivided into unit dosage forms of the type A particularly preferred class of anti-anxiety agent is the described above containing from 0.1 to about 500 mg of the 5-HTA agonists or antagonists, especially the 5-HTA par active ingredient of the present invention. The tablets or pills tial agonists, thus in a further preferred aspect, the present of the novel composition can be coated or otherwise com invention accordingly provides the use of a CNS-penetrant pounded to provide a dosage form affording the advantage NK-1 receptor antagonist Selected from the compounds of of prolonged action. For example, the tablet or pill can formulae (I), (II), (III), (IV) and (V) and a 5-HT1A receptor comprise an inner dosage and an outer dosage component, agonist or antagonist for the manufacture of a medicament the latter being in the form of an envelope over the former. for the treatment or prevention of depression and/or anxiety. The two components can be separated by an enteric layer The present invention also provides a method for the 35 which Serves to resist disintegration in the Stomach and treatment or prevention of depression and/or anxiety, which permits the inner component to pass intact into the duode method comprises administration to a patient in need of Such num or to be delayed in release. A variety of materials can treatment an amount of a CNS-penetrant NK-1 receptor be used for Such enteric layerS or coatings, Such materials antagonist Selected from the compounds of formulae (I), (II), including a number of polymeric acids and mixtures of (III), (IV) and (V) and an amount of a 5-HT1A receptor 40 polymeric acids with Such materials as shellac, cetyl alcohol agonist or antagonist, Such that together they give effective and cellulose acetate. relief. The liquid forms in which the novel compositions of the In a further aspect of the present invention, there is present invention may be incorporated for administration provided a pharmaceutical composition comprising a CNS orally include aqueous Solutions, Suitably flavoured Syrups, penetrant NK-1 receptor antagonist Selected from the com 45 aqueous or oil Suspensions, and flavoured emulsions with pounds of formulae (I), (II), (III), (IV) and (V) and a 5-HTA edible oils. Such as cottonseed oil, Sesame oil, coconut oil, receptor agonist or antagonist, together with at least one peanut oil or Soybean oil, as well as elixirs and Similar pharmaceutically acceptable carrier or excipient. pharmaceutical vehicles. Suitable dispersing or Suspending In a further or alternative aspect of the present invention, agents for aqueous Suspensions include Synthetic and natural there is provided a product comprising a CNS-penetrant 50 gums. Such as tragacanth, acacia, alginate, dextran, Sodium NK-1 receptor antagonist Selected from the compounds of carboxymethylcellulose, methylcellulose, polyvinyl formulae (I), (II), (III), (IV) and (V) and a 5-HT1A receptor pyrrollidone or gelatin. agonist or antagonist as a combined preparation for Compositions of the present invention may also be admin Simultaneous, Separate or Sequential use in the treatment or istered via the buccal cavity using conventional technology, prevention of depression and/or anxiety. 55 for example, absorption wafers. As stated above, the CNS-penetrant NK-1 receptor Compositions in the form of tablets, pills, capsules or antagonist and the antidepressant or anti-anxiety agent may wafers for oral administration are particularly preferred. be formulated in a single pharmaceutical composition or The present invention further provides a process for the alternatively in individual pharmaceutical compositions for preparation of a pharmaceutical composition comprising a Simultaneous, Separate or Sequential use in accordance with 60 CNS-penetrant NK-1 receptor antagonist and an antidepres the present invention. Sant or anti-anxiety agent, which process comprises bringing It will be appreciated that it may be desirable to combine a CNS-penetrant NK-1 receptor antagonist and an antide the CNS-penetrant NK-1 receptor antagonist with more than preSSant or anti-anxiety agent, into association with a phar one antidepressant and/or anti-anxiety agent. Thus “triple maceutically acceptable carrier or excipient. combination” or “multiple combination” therapy is envis 65 When administered in combination, either as a single or aged within the Scope of the present invention, for example, as separate pharmaceutical composition(s), the CNS use of a CNS-penetrant NK-1 receptor antagonist of formu penetrant NK-1 receptor antagonist and an antidepressant or US 6,319,953 B1 35 36 anti-anxiety agent, are presented in a ratio which is consis which response is attenuated when a CNS-penetrant NK-1 tent with the manifestation of the desired effect. In receptor antagonist is administered Subcutaneously 30 min particular, the ratio by weight of the CNS-penetrant NK-1 utes prior to isolation, wherein vocalisations during the first receptor antagonist and the antidepressant or anti-anxiety 15 minutes of isolation are attenuated with an IDsos20 agent will suitably be between 0.001 to 1 and 1000 to 1, and mg/kg, preferably with an IDsos 10 mg/kg, and especially especially between 0.01 to 1 and 100 to 1. with an IDss 5 mg/kg. A suitable dosage level for the CNS-penetrant NK-1 In an alternative method, the NK-1 receptor antagonist is receptor antagonist about 0.05 to 1500 mg per day, prefer administered orally, 4 hours prior to isolation, wherein Vocalisations during the first 15 minutes of isolation are ably about 0.25 to 1500 mg per day, and especially about attenuated with an IDsos 20 mg/kg, preferably with an 0.25 to 500 mg per day. The compounds may be adminis IDsos 10 mg/kg, and especially with an IDsos 5 mg/kg. tered on a regimen of up to 6 times per day, preferably 1 to Whilst it is recognised in many of the aforementioned 4 times per day, especially 2 times per day and most patent Specifications that NK-1 receptor antagonists may be especially once daily. used to treat depression and/or anxiety, there remains a need A Suitable dosage level for the antidepressant agent is for simple and reliable methods for the identification of about 0.5 to 1500 mg per day, preferably about 2.5 to 1000 15 compounds with NK-1 receptor antagonist activity which mg per day, and especially about 2.5 to 500 mg per day. The would be effective in the treatment of depression and/or compounds may be administered on a regimen of up to 6 anxiety. times per day, preferably 1 to 4 times per day, especially 2 The present invention accordingly provides a preclinical times per day and most especially once daily. screen for antidepressant and/or anxiolytic activity of CNS A Suitable dosage level for the anti-anxiety agent is about penetrant NK-1 receptor antagonists, which comprises: 0.5 to 1500 mg per day, preferably about 2.5 to 1000 mg per day, and especially about 2.5 to 500 mg per day. The a) to a guinea-pig pup, administration of a NK-1 receptor compounds may be administered on a regimen of up to 6 antagonist or vehicle by intravenous, Subcutaneous, times per day, preferably 1 to 4 times per day, especially 2 intraperitoneal or oral routes, times per day and most especially once daily. 25 b1) 30-60 minutes after intravenous, subcutaneous or It will be appreciated that the amount of the CNS intraperitoneal administration, Socially isolating the penetrant NK-1 receptor antagonist and the antidepressant or treated guinea-pig pups by removal from their mother anti-anxiety agent required for use in the treatment or and littermates, or prevention of depression and/or anxiety will vary not only b2) up to 4 hours after oral administration, Socially with the particular compounds or compositions Selected but isolating the treated guinea-pig pups by removal from also with the route of administration, the nature of the their mother and littermates, condition being treated, and the age and condition of the c) recording the number or duration of Vocalisations patient, and will ultimately be at the discretion of the (isolation calls) during a specified period and compar patient's physician or pharmacist. ing the effects on guinea-pig pups treated with NK-1 AS used herein the term "patient' includes animals of 35 receptor antagonists against their own baseline or economic importance Such as bovine, Ovine, and porcine against guinea-pig pups that receive no test compound animals, especially those that produce meat, as well as or vehicle. domestic animals (e.g. cats and dogs), Sports animals (e.g. Preferably the NK-1 receptor antagonist is administered horses), Zoo animals, and humans, the latter being preferred. by Subcutaneous injection or orally by gavage. The compounds of formulae (I), (II), (III), (IV) and (V) 40 An advantage of the present invention is that the guinea may be prepared by the methods described in EP-A-0 577 pig is a mammal with human-like NK-1 receptor pharma 394 (or WO95/16679), WO95/18124, WO95/23798, WO cology. 96/05181 and WO 96/07649, respectively. The guinea-pig preclinical Screen described herein has As used herein, the term “CNS-penetrant” refers to NK-1 been shown to be Sensitive not only to the anxiolytic and receptor antagonists which are able to inhibit NK-1 receptor 45 antidepressant effects of NK-1 receptor antagonists, but also antagonist-induced foot-tapping in the gerbil as hereinafter to the effects of established anxiolytic and antidepressant defined. drugs. Thus, for example, buSpirone, diazepam, fluoxetine, Essentially, hind foot-tapping in the gerbil induced by and imipramine were all active in this assay (IDso=0.5 infusion of the NK-1 receptor agonist, GR73632 (d Ala mg/kg S.C., 0.7 mg/kg S.C., 2.7 mg/kg i.p. and 5.4 mg/kg S.C., Pro'.Me-Leu"-substance P-(7-11)), under anaesthesia, 50 respectively). directly into the central ventricles is inhibited when a According to a further aspect of the present invention, CNS-penetrant NK-1 receptor antagonist is administered there is provided a preclinical Screen for antidepressant intravenously immediately prior to GR73632 challenge, and/or anxiolytic activity of CNS-penetrant NK-1 receptor wherein hind foot-tapping over a period of five minutes antagonists, which comprises: following recovery from the anaesthesia is inhibited with an 55 a) to a gerbil, administration of a NK-1 receptor antago IDss3 mg/kg, and preferably with an IDsos 1 mg/kg. nist or vehicle by intravenous, Subcutaneous, intraperi In an alternative method, the NK-1 receptor antagonist is toneal or oral routes, administered orally, 1 hour prior to GR' challenge, b) administration by injection under anaesthetic of NK-1 wherein the foot-tapping over a period of five minutes a receptor agonists or anxiogenic agents, administered following recovery from anaesthesia is inhibited with an 60 centrally or Systemically, or Subjecting the gerbil to IDsos 30 mg/kg, and preferably with an IDsos 10 mg/kg. StreSSorS Such as Single housing or foot Shock; CNS-penetrant NK-1 receptor antagonists of use in the c) recording the duration of repetitive hindfoot tapping present invention are also effective in the attenuation of and comparing the effects on gerbils treated with NK-1 Separation-induced vocalisations by guinea-pig pups as receptor antagonists against gerbils that receive no test hereinafter defined. 65 compound or vehicle. Essentially, a Vocalisation response in guinea-pig pups is Preferably the NK-1 receptor antagonist is administered induced by isolation from their mothers and littermates, by intravenous injection or orally by gavage. US 6,319,953 B1 37 38 Suitable NK-1 receptor agonists which elicit repetitive pounds which satisfy the NK-1 receptor binding criteria of hind foot tapping include GR73632 (d-Ala L-Pro, step (i) which, in addition, have s5-fold shift in affinity Me-Leu" substance P-(7-11)), Sar, Met(O)'substance when incubated in the presence of human Serum albumin P and Substance P. Suitable anxiogenic agents include penta (HSA) to show non-specific protein binding. gastrin and adrenaline. It will be appreciated that, if desired, the above “selection The NK-1 receptor antagonist may be administered intra cascades' may be combined. Thus, a further method for the venously about 5 minutes before challenge with the NK-1 identification of NK-1 receptor antagonists of use as anxi receptor agonist or anxiogenic agent or before the aversive olytic or antidepressant agents involves the use of ASSay 1, stimulation, in order to measure the acute effect of the NK-1 ASSay 2 and ASSay 3, incorporating the Selection criteria receptor antagonist. If oral administration is chosen, it may defined herein. be preferable to administer the NK-1 receptor antagonist at Particularly active CNS-penetrant NK-1 receptor antago least one hour prior to central injection of the NK-1 receptor nists include: agonist or anxiogenic agent, or the aversive Stimulus. In order to measure the central duration of action of a NK-1 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3(S)-(4- receptor antagonist, the test compound is conveniently 15 fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl) administered approximately 24 hours prior to central injec morpholine; tion of the NK-1 receptor agonist or anxiogenic agent, or the 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(3- aversive Stimulus. (5-oxo-1H,4H-1,2,4-triazolo)methyl)-3-(S)-phenyl Whilst there are many different genera of gerbil, the morpholine; preferred genus is the Mongolian gerbil (Meriones 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(3-(5-oxo-1H, unguiculatus). An advantage of the present invention is that 4H-1,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine; the gerbil is a mammal with human-like NK-1 receptor 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3- pharmacology. (S)-(4-fluorophenyl)-4-(3-(5-oxo-1H4H-1,2,4-triazolo) The preclinical screens described herein have been shown methyl)morpholine; to be Sensitive not only to the anxiolytic and antidepressant 25 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5- effects of NK-1 receptor antagonists, but also to the effects (N,N-dimethylamino)methyl-1,2,3-triazol-4-yl)methyl-3- of an established antidepressant drug, imipramine (IDso=3.8 (S)-phenylmorpholine; mg/kg. s.c. following foot-tapping induced by Substance P) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5- and the anxiolytic drug, buspirone (IDso=3.4 mg/kg S.c.). (N,N-dimethylamino)methyl-1,2,3-triazol-4-yl)methyl-3- The identification of CNS-penetrant NK receptor antago (S)-(4-fluorophenyl)morpholine; nists of use as anxiolytic or antidepressant agents is carried 2-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)- out as follows: (4-fluorophenyl)-4-(3-(1-monophosphoryl-5-oxo-4H-1,2, (i) Determine affinity for human NK1 receptor in radio 4-triazolo)methyl)morpholine; ligand binding Studies (ASSay 1); Select compounds 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4- with ICsos 10 nM, preferably ICsos 2 nM, especially 35 N,N-dimethylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl) ICss 1 nM. morpholine; (ii) Determine activity of compounds for their ability to inhibit distress vocalisations in guinea-pig pups (ASSay or a pharmaceutically acceptable Salt thereof. 2)). Select compounds with IDsos 20 mg/kg, and pref According to a further aspect of the present invention, erably IDsos 10 mg/kg, and especially IDsos 5 mg/kg. 40 there is provided the use of a CNS-penetrant NK-1 receptor According to an alternative aspect of the present antagonist identified according to either of the preclinical invention, the identification of NK receptor antagonists of Screens defined herein for the manufacture of a medicament use as anxiolytic or antidepressant agents is carried out as for the treatment or prevention of depression and/or anxiety follows: as previously defined. 45 Similarly, there is also provided a method for the treat (i) Determine affinity for human NK receptor in radio ment or prevention of depression and/or anxiety as previ ligand binding Studies (ASSay 1); Select compounds ously defined, which method comprises administration to a with ICss 10 nM, preferably ICs2 nM, especially patient in need of Such treatment an effective amount of a ICsos 1 nM. CNS-penetrant NK-1 receptor antagonist identified accord (ii) Determine ability of compounds to penetrate CNS by 50 ing to either of the preclinical Screens defined herein. their ability to inhibit foot tapping in gerbils induced by Particularly preferred CNS-penetrant NK-1 receptor central injection of an NK agonist (ASSay 3); Select antagonists of the formulae (I), (II), (III), (IV) and (V) for compounds that inhibit foot tapping with IDsos3 use in the present invention are compounds which are potent mg/kg i.v., and preferably IDsos 1 mg/kg i.v. when NK-1 receptor antagonists, i.e. compounds with an NK-1 administered immediately prior to central NK agonist 55 receptor affinity (ICs) of less than 100 nM. Preferably, the challenge, or IDsos 30 mg/kg p.o., and preferably NK-1 receptor antagonist has ICsos 10 nM, in particular IDsos 10 mg/kg p.o. 1 hour prior to challenge. ICsos 2 nM, and most especially ICsos 1 nM. (iii) Determine central duration of action of compounds in NK-1 receptor binding assays are well known in the art. gerbil foot tapping assay following intravenous admin The following assay is one Such protocol based upon the istration 24 hours prior to central NK agonist chal 60 displacement of 'I-Tyr-substance P binding to cloned lenge; Select compounds showing s 25-fold loss of human NK-1 receptors in vitro: potency compared with IDso determined in Step (ii) ASSAY 1: NK-1 Receptor Binding Assay above with the proviso that IDss 10 mg/kg i.v., and NK-1 receptor binding assays are performed in intact preferably S5 mg/kg i.v. after 24 hour pre-treatment. Chinese hamster ovary (CHO) cells expressing the human Yet further preferred compounds of use as anxiolytic or 65 NK-1 receptor using a modification of the assay conditions antidepressant agents may be Selected, according to either of described by Cascieri et al., J. Pharmacol. Exp. Ther, 1992, the "Selection cascades' described above, from those com 42, 458. Typically, the receptor is expressed at a level of US 6,319,953 B1 39 40 3x10 receptors per cell. Cells are grown in monolayer permit exposure of the jugular vein in order to permit culture, detached from the plate with enzyme-free dissocia administration of test compounds or vehicle in an injection tion Solution (Speciality Media Inc.), and washed prior to Volume of approximately 5 ml/kg i.v. Alternatively, test use in the assay. 'I-Tyr- substance P (0.1 nM, 2000 compounds may be administered orally or by Subcutaneous Ci/mmol; New England Nuclear) is incubated in the pres or intraperitoneal routes. A skin incision is then made in the ence or absence of test compounds (dissolved in 5 ul midline of the Scalp to expose the skull. An anxiogenic agent dimethylsulphoxide, DMSO) with 5x10 CHO cells. Ligand (e.g. pentagastrin) or a selective NK-1 receptor agonist (e.g. GR73632 (d Ala-Pro, Me-Leu-substance P-(7–11)) is binding is performed in 0.25 ml of 50 mM Tris-HCl, pH7.5, infused directly into the cerebral ventricles (e.g. 3 pmol in 5 containing 5 mM MnCl, 150 mM NaCl, 0.02% bovine Ali.c.V., depending on test Substance) by vertical insertion of Serum albumin (Sigma), 50 ug/ml chymostatin (Peninsula), a cuffed 27 gauge needle to a depth of 4.5 mm below 0.1 nM phenylmethylsulphonyl fluoride, 2 ug/ml pepstatin, bregma. The Scalp incision is closed and the animal allowed 2 ug/ml leupeptin and 2.8 Lig/ml furoyl Saccharine. The to recover from anaesthesia in a clear perspex observation incubation proceeds at room temperature until equilibrium is box (approximately 25 cmx20 cmx20 cm). The duration achieved (>40 minutes) and the receptor-ligand complex is and/or intensity of hind foot tapping is then recorded con harvested by filtration over GF/C filters pre-soaked in 0.1% 15 tinuously for approximately 5 minutes. Alternatively, the polyethylenimine using a Tomtek 96-well harvester. Non ability of test compounds to inhibit foot tapping evoked by Specific binding is determined using excess Substance P (1 aversive Stimulation, Such as foot shock or Single housing, uM) and represents <10% of total binding. may be Studied using a similar method of quantification. Pharmacological assays for the Study of antidepressant or It will be appreciated that CNS-penetration as defined by anti-anxiety activity are well known in the art. Many are this assay and as used herein is a property of the NK-1 based upon the ability of antidepressants to Support animal receptor antagonist and is not conferred by behaviour in stressful situations that ordinarily lead to co-administration or co-formulation of the NK-1 receptor diminished behavioural responsiveness (“learned antagonist with a carrier or excipient designed to transiently helplessness”), Such as repeated noxious shocks, forced open the blood-brain barrier. Swimming, or Separation from other animals. For example, 25 One example of a NK-1 receptor antagonist active in the the following assay, which involves the inhibition of preclinical Screens of the present invention is the compound Separation-induced vocalisations in guinea-pig pups, may be 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3- used to evaluate the methods of the present invention in the (S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo) treatment or prevention of depression and/or anxiety. methyl)morpholine, the preparation of which is described in ASSAY 2: Separation-Induced Vocalisation International Patent Specification No. WO95/16679. In the Male and female guinea-pigs pups are housed in family aforementioned assays, this compound has the following groups with their mothers and littermates throughout the activity: Study. Experiments are commenced after weaning when the pups are at least 2 weeks old. Before entering an experiment, the pups may be Screened to ensure that a vigorous vocali 35 sation response is reproducibly elicited following maternal human NK-1 receptor binding: ICs = 0.1 nM Separation. The pups are placed individually in an observa guinea-pig vocalisation IDso = 0.73 mg/kg p.o. (4 hrs. pretreatment) tion cage (approximately 55 cmx39 cmx19 cm) in a room gerbil foot-tapping (5 mins.): IDso = 0.36 mg/kg i.v. physically isolated from the home cage for approximately 15 gerbil foot-tapping (24 hrs.): IDso = 0.33 mg/kg i.v. minutes and the duration and/or number of Vocalisation 40 during this baseline period is recorded. Those animals which Vocalise for longer than 5 minutes may be employed for drug Another example of a NK-1 receptor antagonist active in the preclinical Screens of the present invention is the com challenge Studies (approximately 50% of available pups may pound 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) fail to reach this criterion). On test days each pup receives ethoxy)-4-(5-(N,N-dimethylamino)methyl-1,2,3-triazol-4- an oral dose or an S.c. or i.p. injection of test compound or 45 vehicle and is then immediately returned to the home cage yl)methyl-3-(S)-phenylmorpholine, the preparation of with its mother and siblings, typically for at least 30 to 60 which is described in International Patent Specification No. minutes (or for up to 4 hours following an oral dose, WO95/18124. In the aforementioned assays, this compound dependent upon the oral pharmacokinetics of the test has the following activity: compound) before Social isolation for 15 minutes as 50 described above. The duration and/or number of vocalisa tion on drug treatment days may be expressed as a percent human NK-1 receptor binding: ICs = 0.25 nM age of the pre-treatment baseline value for each animal or guinea-pig vocalisation: IDso = 0.5 mg/kg s.c. gerbil foot-tapping (5 mins.): IDso = 0.12 mg/kg i.v. compared with values obtained in vehicle-treated animals. gerbil foot-tapping (24 hrs.): The same Subjects may be retested once weekly for up to 6 55 IDso = 0.17 mg/kg i.v. weeks. Between 6 and 8 animals typically receive each test compound at each dose tested. Combinations of a CNS-penetrant NK-1 receptor antago ASSAY 3: Gerbil Foot-tapping (CNS Penetration) Assay nist with the anti-anxiety and antidepressant agents, bus CNS-penetrant NK-1 receptor antagonists for use in the pirone and fluoxetine, have been tested in the guinea-pig present invention can be identified by their ability to inhibit 60 vocalisation assay (ASSay 3): foot tapping in gerbils induced by anxiogenic agents (Such Test Compound A is 2-(R)-(1-(R)-(3,5-bis as pentagastrin) or central infusion of NK-1 receptor ago (trifluoromethyl)phenyl)ethoxy)-4-(5-(dimethylamino) nists such as GR73632, or caused by aversive stimulation methyl-1,2,3-triazol-4-yl)methyl-3-(S)-phenylmorpholine. Such as foot Shock or Single housing, based on the method Test Compound B is the less active enantiomer of Test of Rupniak & Williams, Eur, J. Pharmacol., 1994, 265,179. 65 Compound A - i.e. 2-(S)-(1-(R)-(3,5-bis(trifluoromethyl) Male or female Mongolian gerbils (35-70 g) are anaes phenyl)ethoxy)-4-(5-(dimethylamino)methyl-1,2,3-triazol thetised by inhalation of an isofluraneloxygen mixture to 4-yl)methyl-3-(R)-phenylmorpholine. US 6,319,953 B1 41 42 Test Compounds A and B and buspirone were dissolved in during recovery from the anaesthetic and for 4 hours fol 0.9% saline and administered s.c. in the flank. Due to lowing the cisplatin injection. The numbers of retches and limitations of solubility, fluoxetine was suspended in 0.5% Vomits occurring during the 4 hours after cisplatin admin methocel and given i.p. The injection Volume was 1 ml/kg. istration are recorded by trained observers. Results Oral bioavailability of the NK-1 receptor antagonist is Guinea-pig pups isolated from their mothers and litter determined by its ability to inhibit cisplatin-induced emesis mates emitted a vigorous vocalisation response during the in ferrets following oral administration (ASSay 4). Com pounds with an IDs 3 mg/kg p.o., and preferably Doos 1 first 15 minutes of Separation (total duration approximately mg/kg p.o., are considered to be orally active according to 8 minutes during this period). Administration of the highly the present invention. Thus, for example, the NK-1 receptor CNS penetrant NK-1 receptor antagonist Test Compound A antagonist 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) (0.25 mg/kg S.c.), buSpirone (0.25 mg/kg S.c.), or fluoxetine ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4- (2 mg/kg i.p.) alone 30 minutes previously attenuated triazolo)methyl)morpholine, mentioned above, has an IDoo Separation-induced vocalisations by approximately 25% in the ferret emesis assay (ASSay 4) of <3 mg/kg p.o. compared with the baseline vocalisation response deter The following examples illustrate pharmaceutical com mined using the Same animals on the previous day. Com 15 positions according to the invention. bined administration of Test Compound A (0.25 mg/kg S.c.) These formulations may be prepared with Separate active with either buspirone (0.25 mg/kg S.c.) or fluoxetine (2 ingredients or with a combination of active ingredients in mg/kg i.p.) virtually abolished separation-induced vocalisa one composition. In Such combined preparations, the ratio of tions (FIGS. 1 & 2). The NK-1 receptor specificity of this the CNS-penetrant NK-1 receptor antagonist and the anti effect was confirmed by the failure of the less active depressant or anti-anxiety agent will depend upon the choice enantiomer, Test Compound B (0.25 mg/kg S.c.) to attenuate of active ingredients. Separation-induced vocalisations when administered alone, or to potentiate the inhibitory effect of buspirone (0.25 mg/kg. s.c., FIG. 1). The above results provide evidence for a Synergistic 25 EXAMPLE 1. interaction between a centrally acting NK-1 receptor antago Tablets containing 50-300 mg of NK-1 antagonist and nist (Test Compound A) with the anti-anxiety and antide 5-10 mg of buspirOne preSSant drugs buSpirone and fluoxetine in a distreSS Vocali sation assay using guinea-pigs. This appears to reflect a Amount mg NK-1 antagonist SO.O SO.O 1 OOO 10O.O 3OO.O 3OO.O Specific NK-1 receptor mediated interaction, Since buspirone S.O. 10.O S.O. 10.O S.O. 10.0 co-administration of the leSS active enantiomer, Test Com Microcrystalline cellulose 8O.O 8O.O 8O.O 8O.O 8O.O 8O.O pound B, at the same dose failed to potentiate the ability of Modified food corn starch 8O.O 8O.O 8O.O 8O.O 8O.O 8O.O buspirone to inhibit vocalisations. The findings provide the Lactose 1845 179.5 1345 129.5 1345 129.5 first experimental evidence that centrally acting NK-1 recep Magnesium Stearate 0.5 0.5 0.5 0.5 0.5 0.5 tor antagonists may augment the therapeutic response to 35 clinically used anti-anxiety and antidepressant drugs, includ ing agents acting as agonists or antagonists at the 5-HT1A receptor (Such as buspirone), and Selective serotonin reuptake inhibitors (Such as fluoxetine). EXAMPLE 2 It will be appreciated from the foregoing description that 40 Tablets containing 50-300 mg of NK-1 antagonist and 20 mg an advantage of the combinations of the present invention is of fluoxetine the oral bioavailability of the NK-1 receptor antagonists of Amount mg use in Such combinations. Pharmacokinetic analysis to NK-1 antagonist SO.O 1OO.O 3OO.O determine the oral bioavailability of the NK-1 receptor fluoxetine 2O.O 2O.O 2O.O antagonists may be effected Simply by measuring the ability 45 Microcrystalline cellulose 8O.O 8O.O 8O.O of the NK-1 receptor antagonist to inhibit NK-1 receptor Modified food corn starch 8O.O 8O.O 8O.O agonist-induced foot-tapping in the gerbil following oral Lactose 169.5 119.5 119.5 administration of the NK-1 receptor antagonist. Compounds Magnesium Stearate 0.5 0.5 0.5 with an IDsos 30 mg/kg p.o., and preferably IDsos 10 mg/kg p.o., following administration 1 hour prior to central 50 The active ingredients cellulose, lactose and a portion of NK-1 receptor agonist challenge are considered to be orally the corn Starch are mixed and granulated with 10% corn active according to the present invention. Starch paste. The resulting granulation is Sieved, dried and An alternative pharmacokinetic analysis takes advantage blended with the remainder of the corn starch and the of the ability of CNS-penetrant NK-1 receptor antagonists to magnesium Stearate. The resulting granulation is then com atenuate cisplatin-induced emesis. Orally active, CNS 55 pressed into tablets containing 50 mg, 100 mg and 300 mg penetrant NK-1 receptor antagonists demonstrate this activ of the CNS-penetrant NK-1 receptor antagonist per tablet. ity in the following assay: What is claimed is: ASSAY 4: Ferret Emesis 1. A method for the treatment or prevention of depression Individually housed male ferrets (1.0-2.5 kg) are dosed and/or anxiety, which method comprises oral administration orally by gavage with test compound. Ten minutes later they 60 to a patient in need of Such treatment or prevention an are fed with approximately 100 g of tinned cat food. At 60 amount of a NK-1 receptor antagonist and an amount of minutes following oral dosing, cisplatin (10 mg/kg) is given fluoxetine, or a pharmaceutically acceptable Salt thereof, i.V. Via a jugular vein catheter inserted under a brief period Such that together they give effective relief, wherein the of halothane anaesthesia. The catheter is then removed, the NK-1 receptor antagonist is CNS-penetrant as determined jugular vein ligated and the skin incision closed. The ferrets 65 by its ability to inhibit NK-1 receptor agonist-induced recover rapidly from the anaesthetic and are mobile within foot-tapping in the gerbil, and is effective in the attenuation 10–20 minutes. The animals are observed continuously of Separation-induced Vocalisations by guinea-pig pups. US 6,319,953 B1 43 44 2. The method of claim 1 wherein the NK-1 receptor induced foot-tapping in the gerbil, and is effective in the antagonist inhibits NK-1 receptor agonist-induced foot attenuation of Separation-induced Vocalisations by guinea tapping in the gerbil with an IDsos 3 mg/kg i.v. when pig pups. administered immediately prior to central NK-1 receptor 6. The composition of claim 5 wherein the NK-1 receptor agonist challenge, or an IDsos 30 mg/kg p.o. when admin antagonist inhibits NK-1 receptor agonist-induced foot istered 1 hour prior to central NK-1 receptor agonist chal tapping in the gerbil with an IDsos 3 mg/kg i.v. when lenge. administered immediately prior to central NK-1 receptor 3. The method of claim 1 wherein the NK-1 receptor agonist challenge, or an IDsos 30 mg/kg p.o. when admin antagonist attenuates Separation-induced vocalisations by istered 1 hour prior to central NK-1 receptor agonist chal guinea-pig pups with an IDsos 20 mg/kg. lenge. 4. The method of claim 1 wherein the NK-1 receptor antagonist has an affinity for the human NK-1 receptor of 7. The composition of claim 5 wherein the NK-1 receptor ICsos 10 nM. antagonist attenuates Separation-induced vocalisations by 5. An oral pharmaceutical composition comprising an guinea-pig pups with an IDsos 20 mg/kg. NK-1 receptor antagonist and fluoxetine, or a pharmaceuti 15 8. The composition of claim 5 wherein the NK-1 receptor cally acceptable Salt thereof, together with at least one antagonist has an affinity for the human NK-1 receptor of pharmaceutically acceptable carrier or excipient, character ICsos 10 nM. ised in that the NK-1 receptor antagonist is CNS-penetrant as determined by its ability to inhibit NK-1 receptor agonist