US006319953B1 (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 WO 95/08549 3/1995 (W0). ANXIETY WITH FLUOXETINE AND AN WO 95/18124 7/1995 (W0). NK-1 RECEPTOR ANTAGONIST W0 96/05181 2/1996 (W0). W0 96/18643 6/1996 (W0). (75) Inventors: Emma Joanne Carlson, Puckeridge; W0 96/19233 6/1996 (W0). Nadia Melanie Rupniak, Bishops W0 96/24353 8/1996 (W0). W0 98/15277 4/1998 (W0). Stortford, both of (GB) OTHER PUBLICATIONS (73) Assignee: Merck Sharp & Dohme Ltd., Hoddesdon (GB) Aguiar, M., et al., Physiology& Behavior, 1996, 60(4) 1183—1186. ( * ) Notice: Subject to any disclaimer, the term of this Barden, N., et al., J. Neurochem., 1983, 41, 834—840. patent is extended or adjusted under 35 BristoW, L., et al., Eur J. Pharmacol., 1994, 253, 245—252. U.S.C. 154(b) by 0 days. Brodin, E., et al., Neuropharmacology, 1987, 26(6) 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. N0.: 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 US. Application Data File, S. E., Pharm. Biochem. Behavior, 1997, 58, 3, 747—752. (60) Division of application No. 08/994,063, ?led on Dec. 19, Kramer, et al., Science, 1998, 281, 1640—1645. 1997, now Pat. No. 6,117,855, which is a continuation-in LoWe, J., et al., Drug News Perspect, 1992, 5(4), 223. part of application No. PCT/GB97/02748, ?led on Oct. 7, 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), 509—516. Oct. 7, 1996 (GB) ...... 9620880 Aug. 4, 1997 (GB) 9716458 Roccon, et al., Pharmacological Research, 1995, 31, 191. Aug. 4, 1997 (GB) ...... 9716460 Rupniak, N., et al., Eur. J. Pharmacol., 1994, 265, 179—183. Shaikh, M., et al., Brain Research, 1993, 625, 283—294. (51) Int. Cl.7 ...... 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) US. 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 speci?c class of NK-1 receptor antagonists FOREIGN PATENT DOCUMENTS and ?uoXetine. 0 577 394 1/1994 (EP). 8 Claims, 2 Drawing Sheets U.S. Patent Nov. 20, 2001 Sheet 1 of2 US 6,319,953 B1
l_|.3 o5E3868mc?amzmE3358m Q552532mg3632 {3P 2:858m52 (W Tom -3 UOHWHUUI % BfmczmwonPEEQEEPP
_,3 Ll o+mDESQES259631@2888 @2333:2:5 Umvmg m@53589: bN.1 .3 .8 UOWCHLIUI 0/0 BfmevmmouucoEwEEwi NOE lrl 0<95868$19631 E3858<+ @2333: ".5532mg <95858To? I3,1 {. -Ow 1% US 6,319,953 B1 1 2 TREATMENT OF DEPRESSION AND considered in International (PCT) patent speci?cation No. ANXIETY WITH FLUOXETINE AND AN WO 96/24353 (published Aug. 15, 1996) Which claims NK-l RECEPTOR ANTAGONIST 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 ef?cacy This application is a division of Ser. No. 08/994,063, ?led and in particular there is no direction toWards speci?c Dec. 19, 1997, US. Pat. No. 6,117,855, Which is a combinations Which might potentiate the antidepressant or continuation-in-part of PCT Application No. PCT/GB97/ 10 anxiolytic effects of the individual therapeutic agents. There 02748, ?led Oct. 7, 1997, Which claims priority from Great is no clear direction from WO 96/24353 to Which class of Britain Application No. 96208806, ?led Oct. 7, 1996, Great tachykinin antagonist (e.g. NK-l, NK-2 or NK-3 receptor Britain Application No. 97164586 ?led Aug. 4, 1997, and antagonists) Would be of use in the claimed combinations, Great Britain Application No. 97164602, ?led 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 speci?c class of NK-l 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-l receptor antagonists. 20 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-l receptor antagonist, Which combination provides an Treatment regimens commonly include the use of tricy 30 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-l receptor antagonists have been developed including selective serotonin reuptake inhibitors found to provide an unexpected effect relevant to the treat (SSRIs), speci?c 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 45 Anxiety disorders are generally treated using benZodiaZ penetrant NK-l 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 vocalisations in guinea-pig pups. This is indicative of ef? dependency may limit their long-term use. 5-HT1A receptor 50 partial agonists also have useful anxiolytic and other psy 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-l; 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 ?gures. 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-l 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 speci?cation Nos. WO vocalisation assay. As further described herein, administra 95/16679, WO 95/18124 and WO 95/23798). tion of the highly CNS penetrant NK-l 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 sc) 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-l 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-l receptor speci?city of this effect Was con?rmed 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-l receptor antagonist 10 then Within one hour, the CNS-penetrant penetrant NK-l With the antidepressant agent, ?uoxetine, 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 NKl receptor antagonist provides effective delivery of the medicament. Test compound A (0.25 mg/kg s.c.), or ?uoxetine (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 ?uocetine (2 mg/kg ip virtually abolished depression; melancholic depression including anorexia, separation-induced vacalisations. The NK-l receptor speci 20 Weight loss, insomnia and early morning Waking, and psy ?city of this effect Was con?rmed 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 ?uoxatine 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-l 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. 30 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-l receptor hypnotics, anxiolytics and other substances; schiZoaffective 35 antagonist and an amount of an antidepressant or anti 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-l receptor antagonist and an antidepressant or 40 includes anxiety disorders, such as panic disorder With or anti-anxiety agent, together With at least one pharmaceuti Without agoraphobia, agoraphobia Without history of panic cally acceptable carrier or excipient. disorder, speci?c phobias, for example, speci?c animal It Will be appreciated that the CNS-penetrant NK-l 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 de?ned as an extended depression and/or anxiety. Such combined preparations may period (eg 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, dif?culty penetrant NK-l 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 de?ned 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-l 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, speci?c 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 dif?cult 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 “speci?c phobia” US 6,319,953 B1 5 6 is characterised by clinically signi?cant anxiety provoked by Suitable reversible inhibitors of rnonoarnine oxidase of exposure to a speci?c feared object or situation. Speci?c use in the present invention include: rnoclobernide, and phobias include the following subtypes: anirnal type, cued pharrnaceutically 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 storrns, of use in the present invention include: venlafaxine, and heights or Water; blood-injection-injury type, cued by the pharrnaceutically 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 cornpounds described in International Patent type, cued by a speci?c situation such as public Speci?cation Nos. WO 94/13643, WO 94/13644, WO transportation, tunnels, bridges, elevators, ?ying, driving or 10 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. Speci?c phobias may also be referred to as simple invention include: bupropion, lithiurn, nefaZodone, traZ phobias. A “social phobia” is characterised by clinically odone and viloxaZine, and pharrnaceutically acceptable salts signi?cant anxiety provoked by exposure to certain types of thereof. Another suitable atypical antidepressant is sibutra social or performance circurnstances. Social phobia may rnine. 15 also be referred to as social anxiety disorder. Other antidepressants of use in the present invention Other anxiety disorders encornpassed Within the term include adinaZolarn, alaproclate, arnineptine, arnitriptyline/ “anxiety” include anxiety disorders induced by alcohol, chlordiaZepoxide cornbination, atiparneZole, aZarnianserin, arnphetarnines, caffeine, cannabis, cocaine, hallucinogens, baZinaprine, befuraline, bifernelane, binodaline, bipenarnol, inhalants, phencyclidine, sedatives, hypnotics, anxiolytics brofarornine bupropion, caroxaZone, cericlarnine, and other substances, and adjustment disorders With anxiety cianoprarnine, cirnoxatone, citaloprarn, clerneprol, or with mixed anxiety and depression. clovoxarnine, daZepinil, deanol, dernexiptiline, dibenZepin, Anxiety may be present With or Without other disorders dothiepin, droxidopa, enefexine, estaZolarn, etoperidone, such as depression in mixed anxiety and depressive disor fernoxetine, fengabine, feZolarnine, ?uotracen, idaZoxan, ders. The compositions of the present invention are therefore indalpine, indeloxaZine, iprindole, levoprotiline, litoxetine, useful in the treatment of anxiety With or Without accorn 25 panying depression. lofeprarnine, rnedifoxarnine, rnetaprarnine, rnetralindole, The compositions of the present invention are especially rnianserin, rnilnacipran, rninaprine, rnirtaZapine, rnontirelin, useful for the treatment of or prevention of depression nebracetarn, nefoparn, nialarnide, nornifensine, and/or anxiety Where the use of an antidepressant or anti nor?uoxetine, orotirelin, oxa?oZane, pinaZeparn, pirlindone, anxiety agent is generally prescribed. By the use of a piZotyline, ritanserin, roliprarn, serclorernine, setiptiline, combination of a CNS-penetrant NK-l receptor antagonist sibutrarnine, sulbutiarnine, sulpiride, teniloxaZine, and an antidepressant or anti-anxiety agent in accordance thoZalinone, thyrnoliberin, tianeptine, ti?lucarbine, With the present invention, it is noW also possible to treat or tofenacin, to?soparn, toloxatone, tornoxetine, veralipride, prevent depression and/or anxiety in patients for whom viqualine, Zirnelidine and Zornetapine, and pharrnaceutically conventional antidepressant or anti-anxiety therapy might acceptable salts thereof, and St. John’s Wort herb, or Hyperi 35 not be Wholly successful or Where dependance upon the 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-HT1A 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 rnonoarnine oxidase inhibitors (MAOIs), reversible inhibi benZodiaZepines, other suitable classes of anti-anxiety agent tors of rnonoarnine oxidase (RIMAs), serotonin and norad are nonbenZodiaZepine sedative-hypnotic drugs such as renaline reuptake inhibitors (SNRIs), corticotropin releasing Zolpidern; rnood-stabiliZing drugs such as clobaZarn, factor (CRF) antagonists, ot-adrenoreceptor antagonists and gabapentin, larnotrigine, lorecleZole, oxcarbarnaZepine, stir atypical antidepressants. ipentol and vigabatrin; and barbiturates. Another class of antidepressant agent of use in the present 45 invention are noradrenergic and speci?c serotonergic anti Suitable benZodiaZepines of use in the present invention depressants (NaSSAs). A suitable example of a NaSSA is include: alpraZolarn, chlordiaZepoxide, clonaZeparn, rnirtaZapine chloraZepate, diaZeparn, halaZeparn, loraZeparn, oxaZeparn Suitable norepinephrine reuptake inhibitors of use in the and praZeparn, and pharrnaceutically acceptable salts present invention include tertiary amine tricyclics and sec thereof. ondary arnine tricyclics. Suitable examples of tertiary amine Suitable 5-HT1A receptor agonists or antagonists of use in tricyclics include: arnitriptyline, clorniprarnine, doxepin, the present invention include, in particular, the 5-HT1A irniprarnine and trirniprarnine, and pharrnaceutically accept receptor partial agonists buspirone, ?esinoxan, gepirone and able salts thereof. Suitable exarnples of secondary arnine ipsapirone, and pharrnaceutically acceptable salts thereof. tricyclics include: arnoxapine, desiprarnine, rnaprotiline, 55 An example of a compound With 5-HT1A receptor nortriptyline and protriptyline, and pharrnaceutically 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 cornpounds described in International Patent present invention is reboxetine. Speci?cation Nos. WO 94/13643, WO 94/13644, WO Suitable selective serotonin reuptake inhibitors of use in 94/13661, WO 94/13676 and WO 94/13677. the present invention include: ?uoxetine, ?uvoxarnine, par Another class of anti-anxiety agent of use in the present oxetine and sertraline, and pharrnaceutically acceptable salts invention are compounds having rnuscarinic cholinergic thereof. activity. Suitable compounds in this class include rnl rnus Suitable rnonoarnine oxidase inhibitors of use in the carinic cholinergic receptor agonists such as those corn present invention include: isocarboxaZid, phenelZine, tranyl 65 pounds described in European Patent Speci?cation Nos. 0 cyprornine and selegiline, and pharrnaceutically acceptable 709 093, 0 709 094 and 0 773 021, and International patent salts thereof. Speci?cation 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 carbarnaZepine, larnotrigine (Y) heXahydroaZepinyl, and valproate, and pharrnaceutically acceptable salts (Z) oXanyl, thereof. (AA) piperaZinyl, Particularly preferred CNS-penetrant NK-l receptor (AB) piperidinyl, antagonists are those described in European Patent Speci? (AC) pyrrolidinyl, cation No. 0 577 394, ie compounds of formula (I): (AD) tetrahydrofuranyl, and (AE) tetrahydrothienyl, (1) and Wherein the heterocylcle is unsubstituted or substituted With one or more substituent(s) selected from: (i) C1_6alkyl, unsubstituted or substituted With R2R31 XIT R4R5 halo, —CF3, —OCH3, or phenyl, 15 (ii) C1_6alkoXy, (iii) oXo, (iv) hydroXy, or a pharrnaceutically acceptable salt thereof, Wherein: (v) thioXo, R1 is selected from the group consisting of: (vi) —SR9, Wherein R9 is as de?ned above, (1) hydrogen; (vii) halo, (2) C1_6alkyl, unsubstituted or substituted With one or (viii) cyano, more of the substituents selected from: (iX) phenyl, (a) hydroXy, (X) tri?uorornethyl, (b) 0110, (Xi) —(CH2)m—NR9R1O, Wherein In is 0, 1 or 2, (C) C1-6a1kOXy> 25 and R9 and R10 are as de?ned above, (d) phenyl-C1_3alkoXy, (Xii) —NR9COR1O, Wherein R9 and R10 are as (e) phenyl, de?ned above, (Xiii) —CONR9R1O, Wherein R9 and R10 are as (g) halo, de?ned above, (h) —NR9R10, Wherein R9 and R10 are indepen (Xiv) —CO2R9, Wherein R9 is as de?ned above, dently selected from: and (i) hydrogen, (Xv) —(CH2)m—OR9, Wherein In and R9 are as (ii) C1-6a1kyL de?ned above; (iii) hydroXy—C1_6alkyl, and (3) C2_6alkenyl, unsubstituted or substituted With one (iv) phenyl, 35 or more of the substituent(s) selected from: (i) —NR9COR1O, Wherein R9 and Rare as de?ned (a) hydroXy, above, (b) 0110, —NR9CO2R1O, Wherein R9 and R10 are as de?ned (C) C1-6a1kOXy> above, (d) phenyl-C1_3alkoXy, (k) —CONR9R1O, Wherein R9 and R10 are as de?ned (e) phenyl, above, (1) —COR9, Wherein R9 is as de?ned above, (g) halo, (In) —CO2R9, Wherein R9 is as de?ned above, (h) —CONR9R1O, Wherein R9 and R10 are as de?ned (n) heterocycle, Wherein the heterocycle is selected above, from the group consisting of: 45 (i) —COR9, Wherein R9 is as de?ned above, (A) benZirnidaZolyl, —CO2R9, Wherein R9 is as de?ned above, (B) benZofuranyl, (k) heterocycle, Wherein the heterocycle is as de?ned (C) benZthiophenyl, above; (D) benZoXaZolyl, (4) C2.6a11 (Ha) A1 or a pharmaceutically acceptable salt or prodrug thereof, 45 Wherein R1 is hydrogen, halogen, C1_6alkyl, C1_6alkoXy, CF3, A2 N02, CN, SR“, SOR“, SO2R“, COZRH, cONRaRb, C2_6alkenyl, C2_6alkynyl or C1_4alkyl substituted by C1_4alkoXy, Where R“ and Rb each independently rep resent hydrogen or C1_4alkyl; R2 is hydrogen, halogen, C1_6alkyl, C1_6alkoXy substi tuted by C1_4alkoXy or CF3; Wherein: R3 is hydrogen, halogen or CF3; 55 A1 is ?uorine or CF3; R4 is hydrogen, halogen, C1_6alkyl, C1_6alkoXy, CF3, A2 is ?uorine or CF3; N02, CN, SR“, SOR“, SO2R“, COZR“, cONRaRb, C2_6alkenyl, C1_6alkynyl or C1_4alkyl substituted by A3 is ?uorine or hydrogen; C1_4alkoXy, Where R“ and Rb each independently rep and X, Y and R6 are as de?ned in relation to formula (II). Particularly preferred compounds of formula (II) include: resent hydrogen or C1_4alkyl; 2-(R)-(1-(R)-(3,5-bis(tri?uoromethyl)phenyl)ethoXy)-4-(5 R5 is hydrogen, halogen, C1_6alkyl, C1_6alkoXy substi (dimethylamino)methyl-1,2,3-triaZol-4-yl)methyl-3-(S) tuted by C1_4alkoXy or CF3; phenylmorpholine; 2-(R)-(1-(R)-(3,5-bis(tri?uoromethyl) R6 is a S-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-?uorophenyl)morpholine; and by =0, =S or a C1_4alkyl group, and optionally 65 pharmaceutically acceptable salts thereof. substituted by a group of the formula ZNR7R8 Where Further preferred CNS-penetrant NK-l receptor antago Z is C1_6alkylene or C3_6cycloalkylene; nists are those described in European Patent Speci?cation US 6,319,953 B1 17 18 No. WO 95/23798, i.e. compounds of formula (III): —NR9COR1O, Wherein R9 and R10 are as de?ned above, (III) (k) —NR9CO2R10, Wherein R9 and R10 are as de?ned above, (1) —CONR9R1O, Wherein R9 and R10 are as de?ned above, (In) —CO2NR9R1O, Wherein R9 and R10 are as de?ned above, (n) —COR9, Wherein R9 is as de?ned above, 10 (0) —CO2R9, Wherein R9 is as de?ned above; and the groups R2 and R3 may be joined together to form a carbocyclic ring selected from the group con sisting of: (a) cyclopentyl, 15 (b) cycloheXyl, or a pharrnaceutically acceptable salt thereof, wherein: (c) phenyl, R2 and R3 are independently selected from the group and Wherein the carbocyclic ring is unsubstituted or consisting of: (1) hydrogen, substituted With one or more substituents selected from: 2 C 1 _ 6 alkyl, unsubstituted or substituted With one or more of the substituents selected from: (ii) C1_6alkoXy, (a) hydroXy, (iii) —NR9R10, Wherein R9 and R10 are as de?ned (b) 0110, above, (c) C1_6alkoXy, (iv) halo, and (v) tri?uorornethyl; (d) phenyl-C1_3alkoXy, 25 (e) phenyl, and the groups R2 and R3 may be joined together to (f) —CN> form a heterocyclic ring selected from the group con (g) halo, sisting of: (h) —NR9R10, Wherein R9 and R10 are indepen (a) pyrrolidinyl, dently selected from: (b) piperidinyl, (I) hydrogen, (C) pyrrolyl, (ii) C1_6a11 AA,I AA,H AA, (10) —SR14, Wherein R14 is hydrogen or C1_5alkyl, X (11) —SOR14, Wherein R14 is as de?ned above, X X (12) —SO2R14, Wherein R14 is as de?ned above, 45 \ _E N—& N—N/ (13) NR9COR1O, Wherein R9 and R10 are as de?ned above, (14) CONR9COR10, Wherein R9 and R10 are as de?ned AN/KS X NXS X Nxs above, | H (15) NRgRlo, Wherein R9 and R10 are as de?ned above, X (16) NR9CO2R1O, Wherein R9 and R10 are as de?ned X X above, (17) hydroXy, (18) C1_6alkoXy, (19) COR9, Wherein R9 is as de?ned above, 55 (20) COZRQ, Wherein R9 is as de?ned above, (21) 2-pyridyl, (22) 3-pyridyl, x T 1 21T ITT T X (23) 4-pyridyl, (24) 5-tetraZolyl, X X X (25) 2-oXaZolyl, and /X H /X (26) 2-thiaZolyl; R11, R12 and R13 are independently selected from the de?nitions of R6, R7 and R8, or —OX; [A [A [A A is selected from the group consisting of: 65 H I H (1) C1_6alkyl, unsubstituted or substituted With one or more of the substituents selected from: US 6,319,953 B1 21 -continued [l T row X X X 20 l T 25 X and wherein the heterocycle may be substituted in addition to —X With one or more substituent(s) 3 selected from: (i) C1_6alkyl, unsubstituted or substituted With halo, —CF3, —OCH3, or phenyl, (ii) C1_6alkoXy, (iii) oXo, (iv) hydroXy, 35 (v) thioXo, (k) hydrogen, With the proviso that if p is 0 and none (vi) —SRQ, Wherein R9 is as de?ned above, of R11, R12 or R13 are —OX, then X is other than (vii) halo, hydrogen; (viii) cyano, (iX) phenyl, Y is selected from the group consisting of: (X) tri?uorornethyl, (1) a single bond, (Xi) —(CH2)m—NR9R1O, Wherein In is 0, 1 or 2, and R9 and R10 are as de?ned above, (Xii) —NR9COR1O, Wherein R9 and R10 are as de?ned 45 above, (6) —CHR15—, and (Xiii) —CONR9R1O, Wherein R9 and R10 are as de?ned (7) —CR15R16—, Wherein R15 and R16 are indepen above, dently selected from the group consisting of: (Xiv) —CO2R9, Wherein R9 is as de?ned above, and (a) C1_6alkyl, unsubstituted or substituted With one (Xv) —(CH2)m—OR9, Wherein In and R9 are as de?ned or more of the substituents selected from: above; (i) hydroXy, p is 0 or 1; (ii) 0110, X is selected from: (iii) C1_6alkoXy, (a) —PO(OH)O_.M+, Wherein M+ is a pharrnaceuti (iv) phenyl-C1_3alkoXy, cally acceptable rnonovalent counterion, 55 (v) phenyl, (vi) —CN, (c) —PO(O_)2.D2+, Wherein D2+ is a pharrnaceutically (vii) halo, acceptable divalent counterion, (viii) —NRgRlo, Wherein R9 and R10 are as (d) —CH(R4)—PO(OH)O_.M+, Wherein R4 is hydro de?ned above, gen or C1_3alkyl, (iX) —NR9COR1O, Wherein R9 and R10 are as de?ned above, (X) —NR9CO2R10, Wherein R9 and R10 are as de?ned above, (Xi) —CONR9R1O, Wherein R9 and R10 are as 65 de?ned above, —CH(CH3)—O—CO—R5, Wherein R5 is selected (Xii) —COR9, Wherein R9 is as de?ned above, from the group consisting of: and US 6,319,953 B1 23 24 (Xiii) —CO2R9, wherein R9 is as de?ned above; -continued (b) phenyl, unsubstituted or substituted With one or X X more of the substituent(s) selected from: \ H H / (i) hydroXy, N—N N—N N—N (ii) C1_6alkoXy, N 5 N S N s (iii) C1_6alkyl, I H (iv) C2_5alkenyl, X (v) halo, (vi) —CN, X X (vii) —NO2, 10 (viii) —CF3, (iX) —(CH2)m—NR9R1O, Wherein In, R9 and R10 AX,» AX,» A,» are as de?ned above, (X) —NR9COR1O, Wherein R9 and R10 are as /X H de?ned above, (Xi) —NR9CO2R1O, Wherein R9 and R10 are as de?ned above, 1311 [k [X (Xii) —CONR9R1O, Wherein R9 and R10 are as T T T O T O de?ned above, (Xiii) —CO2NR9R10, Wherein R9 and R10 are as /X X H HX de?ned above, (Xiv) —CORQ, Wherein R9 is as de?ned above, and [X XX, [NA/X (Xv) —CO2R9, Wherein R9 is as de?ned above; H | Z is selected from: (1) hydrogen, (2) C1_6alkyl, and (3) hydroXy, With the proviso that if Y is —O—, Z is other than hydroXy, or if Y is —CHR15—, then Z and R15 may be joined together to form a double bond. Particularly preferred compounds of formula (III) are those Wherein: p is 0 or 1; R2 and R3 are independently selected from the group 35 X is selected from: consisting of: (a) —PO(OH)O_.M+, Wherein M+ is a pharrnaceuti (1) hydrogen, cally acceptable rnonovalent counterion, (2) C1_6alkyl, (3) C2_6alkenyl, and (b) —PO(O_)2.2M+, (4) phenyl; (c) —PO(O_)2.D2+, Wherein D2+ is a pharrnaceutically R6, R7 and R8 are independently selected from the group acceptable divalent counterion, consisting of: (d) —CH(R4)—PO(OH)O_.M+, Wherein R4 is hydro (1) hydrogen, gen or C1_3alkyl, (2) C1-6a1kyL 45 (e) —CH(R4)—PO(O_)2.2M+, (3) ?uoro, (t) —cH(R4>—PO(O-)2-D2+, (4) chloro, (5) brorno, (i) —CO—CH2CH2—CO2_.M+, (6) iodo, and —CH(CH3)—O—CO—R5, Wherein R5 is selected (7) —CF3; from the group consisting of: R11, R12 and R13 are independently selected from the group consisting of: (1) ?uoro, (2) chloro, (3) brorno, and 55 (4) iodo; A is unsubstituted 1_6alkyl; B is selected from the group consisting of: co2-M+, —& N—N/ \N—§ (iv) XIX, Ax, AX, COZ'M" I H 65 US 6,319,953 B1 -continued (V) \O/Y CO2‘, NH3+ (Vi) COZ'M" —o co2'M*, R9bR9310 N COZ'M" \ (vii) \ COZ'MJ‘; and 15 O / R5 / X Wherein X is a group of the formula NR6R7 or a C- or N-linked irnidaZolyl ring; Y is —O—; Y is hydrogen or C1_4alkyl optionally substituted by a Z is hydrogen or C1_6alkyl; hydroXy group; 25 R1 is hydrogen, halogen, C1_6alkyl, C1_6alkoXy, CF , N02, CN, SR“, SOR“, 502R“, COZR“, CONR“R , and pharrnaceutically acceptable salts thereof. C2_6alkenyl, C2_6alkynyl or C1_4alkyl substituted by C1_4alkoXy, Wherein R“ and Rb each independently represent hydrogen or C1_4alkyl; Particularly preferred compounds of formula (III) R2 is hydrogen, halogen, C1_6alkyl, C1_6alkoXy substi include: tuted by C1_4alkoXy or CF3; R3 is hydrogen, halogen or CF3; R4 is hydrogen, halogen, C1_6alkyl, C1_6alkoXy, hydroXy, CF3, N02, CN, SR“, SOR“, SOZR“, COZRH, cONRaRb, 35 C2_6alkenyl, C2_6alkynyl or C1_4alkyl substituted by (1) 2-(S)-(3,5-bis(tri?uorornethyl)benZyloXy)-3-(S)-phenyl C1_4alkoXy, Wherein R“ and Rb are as previously 4-(3-(5-oXo-1H,4H-1,2,4-triaZolo)rnethyl)rnorpholine de?ned; N-oXide; R5 is hydrogen, halogen, C1_6alkyl, C1_6alkoXy substi (2) 2-(S)-(3,5-bis(tri?uorornethyl)benZyloXy)-3-(S)-phenyl tuted by C1_4alkoXy or CF3; 4-(3-(4-(ethoXycarbonyloXy-1-ethyl)-5-oXo-1H-1,2,4 R6 is hydrogen, C1_6alkyl, C3_7cycloalkyl, C3_7cycloalkylC1_4alkyl, phenyl, or C2_4alkyl substi triaZolo)rnethyl)rnorpholine; tuted by C1_4alkoXy or hydroXy; (3) 2-(R)-(1-(R)-(3,5-bis(tri?uorornethyl)phenyl)ethoXy)—3 R7 is hydrogen, C1_6alkyl, C3_7cycloalkyl, (S)-(4-?uorophenyl)—4-(3-(4-rnonophosphoryl-5-oXo C3_7cycloalkylC1_4alkyl, phenyl, or C2_4alkyl substi 1H-1,2,4-triaZolo)rnethyl)rnorpholine; 45 tuted by one or tWo substituents selected from (4) 2-(R)-(1-(R)-(3,5-bis(tri?uorornethyl)phenyl)ethoXy)—3 C1_4alkoXy, hydroXy or a 4, 5 or 6 rnernbered het (S)-(4-?uorophenyl)—4-(3-(1—rnonophosphoryl-5-oxo eroaliphatic ring containing one or tWo heteroatorns 1H-1,2,4-triaZolo)rnethyl)rnorpholine; selected from N, O and S; (5) 2-(R)-(1-(R)-(3,5-bis(tri?uorornethyl)phenyl)ethoXy)—3 or R6 and R7, together With the nitrogen atom to Which (S)-(4-?uorophenyl)—4-(3-(2-rnonophosphoryl-5-oXo they are attached, form a saturated or partially saturated 1H-1,2,4-triaZolo)rnethyl)rnorpholine; heterocyclic ring of 4 to 7 ring atoms, which ring may (6) 2-(R)-(1-(R)-(3,5-bis(tri?uorornethyl)phenyl)ethoXy)—3 optionally contain in the ring one oxygen or sulphur (S)-(4-?uorophenyl)-4-(3-(5-oXyphosphoryl-1H-1,2,4 atom or a group selected from NR8’ S(O) or S(O)2 and triaZolo)rnethyl)rnorpholine; Which ring may be optionally substituted by one or tWo (7) 2-(S)-(1-(R)-(3,5-bis(tri?uorornethyl)phenyl)ethoXy)—3 55 groups selected from hydroXyC1_4alkyl, C1_4alkoXyC1_ (S)-(4-?uorophenyl)—4-(3-(1—rnonophosphoryl-5-oxo 4alkyl, oXo, COR“ or COZR“ Where R“ is as previously 4H-1,2,4-triaZolo)rnethyl)rnorpholine; de?ned; or R6 and R7 together With the nitrogen atom to Which they are attached, form a non-arornatic aZabicyclic ring system of 6 to 12 ring atoms; R8 is hydrogen, C1_4alkyl, hydroXyC1_4alkyl or and pharrnaceutically acceptable salts thereof. C1_4alkoXyC1_4alkyl; and R9“ and Rgb are each independently hydrogen or C1_4alkyl, or R9“ and Rgb are joined so, together With Further preferred CNS-penetrant NK-l receptor antago 65 the carbon atoms to Which they are attached, there is nists are those described in European Patent Speci?cation formed a C5_7 ring; and pharrnaceutically acceptable No. WO 96/05181, i.e. compounds of formula (IV): salts thereof. US 6,319,953 B1 29 30 R6 is hydrogen, C1_6alkyl, C3_7cycloalkyl, Speci?c compounds of formula (V) of use in the present C3_7cycloalkylC1_4alkyl, phenyl, or C2_4alkyl substi invention include: tuted by C1_4alkoXy or hydroXy; R7 is hydrogen, C1_6alkyl, C3_7cycloalkyl, 4-(2-aminoethyl)-2-(R)-(1-(R)-(3,5-bis(tri?uoromethyl) C3_7cycloalkylC1_4alkyl, phenyl, C2_4alkyl substituted phenyl)ethoXy)-3-(S)-(4-?uorophenyl)morpholine; by C _4alkoXy or hydroXy, or the group C(=NRC) 2-(R)-(1-(R)-(3,5-bis(tri?uoromethyl)phenyl)ethoXy)-3 NRaR , Where R“ and Rb are as previously de?ned and (S)-(4-?uorophenyl)-4-(2-pyrrolidinoethyl)morpholine; RC is hydrogen, C1_6alkyl, CN or COR“; 2-(R)-(1-(R)-(3,5-bis(tri?uoromethyl)phenyl)ethoXy)-3 or R6 and R7, together With the nitrogen atom to Which (S)-(4-?uorophenyl)-4-(2-morpholinoethyl)morpholine; they are attached, form a saturated heterocyclic ring of 2-(R)-(1-(R)-(3,5-bis(tri?uoromethyl)phenyl)ethoXy)-4-(2 4 to 7 ring atoms Which may optionally contain in the (2‘-(S)-carboXypyrrolidino)ethyl)-3-(S)-(4-?uorophenyl) ring one oxygen or sulphur atom or a group selected morpholine; from NR8, S(O) or S(O)2 and Which ring may be 2-(R)-(1-(R)-(3,5-bis(tri?uoromethyl)phenyl)ethoXy)-3 optionally substituted by one or tWo groups selected (S)-(4-?uorophenyl)-4-(2-(2‘-(R) from phenyl, benZyl, hydroXyC1_4alkyl, C1_4alkoXyC1_ 15 hydroXymethylpyrrolidino)ethyl)morpholine; 4alkyl, hydroXy, oXo, COR“ or COZR“ Where R“ is as 2-(R)-(1-(R)-(3,5-bis(tri?uoromethyl)phenyl)ethoXy)-4-(2 previously de?ned; (4‘-carbomethoXy-2‘-oXopyrrolidino)ethyl)-3-(S)-(4 or R6 and R7’ together With the nitrogen atom to Which ?uorophenyl)morpholine; they are attached, form a piperidino ring substituted by 2-(R)-(1-(R)-(3,5-bis(tri?uoromethyl)phenyl)ethoXy)-4-(2 a spiro-fused indene or indoline group, each of Which (N‘-carboethoXy)-guanidino)ethyl)-3-(S)-(4 may be unsubstituted or substituted on any available ?uorophenyl)morpholine; carbon atom by a group selected from C1_6alkyl, 2-(R)-(1-(R)-(3,5-bis(tri?uoromethyl)phenyl)ethoXy)-3 C1_6alkoXy, hydroXy, halogen, cyano, tri?uoromethyl, (S)-phenyl-4-(2-(4-phenylpiperidino)ethyl)morpholine; SO2C1_6alkyl, NRaRb, NRaCORb or CONRaRb; 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-(tri?uoromethyl)phenyl)ethoXy)morpholine; a group selected from C1_6alkyl, C3_7cycloalkyl, 2-(R)-(1-(R)-(3-?uoro-5-(tri?uoromethyl)phenyl)ethoXy) C3_7cycloalkylC1_4alkyl, phenylC1_4alkyl, COZRH, 3-(S)-phenyl-4-(2-(spiro(indene-3‘,4-piperidino))ethyl) morpholine; cONRaRb, SOR“ or SOZR“, Where R“ and Rb are as 2-(R)-(1-(R)-(3-?uoro-5-(tri?uoromethyl)phenyl)ethoXy) previously de?ned; 3-(S)-phenyl-4-(2-(4-phenylpiperidino)ethyl)morpholine; R8 is hydrogen, C1_4alkyl, hydroXyC1_4alkyl or 2-(R)-(1-(R)-(3-?uoro-5-(tri?uoromethyl)phenyl)ethoXy) C1_4alkoXyC1_4alkyl; 4-(2-(1‘-methylsulfonyl-spiro(indoline-3‘,4-piperidino)) R9“ and Rgb are each independently hydrogen or ethyl)-3-(S)-phenylmorpholine; C1_4alkyl, or R9” and Rgb are joined so, together With 2-(R)-(1-(R)-(3-?uoro-5-(tri?uoromethyl)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(tri?uoromethyl)phenyl)methyloXy)-3-(S) X is selected from —CH2CH2—, —COCH2— or phenyl-4-(2-(4-phenylpiperidino)ethyl)morpholine; —CH2CO—; and 4-(2-(4-benZylpiperidino)ethyl) -2-(S)-(3,5 -bis Y is hydrogen, or C1_4alkyl optionally substituted by a (tri?uoromethyl)phenyl)-methyloXy)-3-(S) hydroXyl group; phenylmorpholine; or a pharmaceutically acceptable salt thereof. 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 line ring in the cis arrangement, the preferred stereochem (Va) istry being as shoWn in the folloWing general formula: A1 Where the benZyloXy moiety is ot-substituted, the pre ferred stereochemistry of the ot-carbon is either (R) When the substituent is an alkyl (e.g. methyl) group or (S) When the substituent is a hydroXyalkyl (e.g. hydroXymethyl) group Unless otherWise de?ned herein, suitable alkyl groups Wherein include straight-chained and branched alkyl groups contain A1 is hydrogen, ?uorine or CF3; ing from 1 to 6 carbon atoms. Typical eXamples include A2 is ?uorine or CF3; 65 methyl and ethyl groups, and straight-chained or branched A3 is ?uorine or hydrogen; and X, Y, R6 and R7 are as propyl and butyl groups. Particular alkyl groups are methyl, de?ned in relation to formula ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl. US 6,319,953 B1 31 32 Unless otherwise de?ned herein, suitable alkenyl groups It Will be appreciated that the CNS-penetrant NK-l 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 de?ned 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 de?ned 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-l 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 de?ned 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-C1_6alkyl, e.g. phenyl-C1_6alkyl, group is 15 In a preferred aspect, the present invention accordingly benZyl. provides the use of a CNS-penetrant NK-l receptor antago Unless otherWise de?ned 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 ?uorine, nin and noradrenaline reuptake inhibitors, corticotropin chlorine, bromine and iodine. releasing factor (CRF) antagonists, ot-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-l receptor antagonists of use in the present treatment an amount of a CNS-penetrant NK-l 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, ot-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 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-l 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-l 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-l receptor antagonist selected from the (CRF) antagonists, ot-adrenoreceptor antagonists and atypi compounds of formulae (I), (II), (III), (IV) and (V) and an 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-l 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-l 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 inhibitors, corticotropin releasing factor (CRF) antagonists, relief. ot-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-l 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-l 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 ?uoxetine, 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 de?ned solutions or sus treatment an amount of a CNS-penetrant NK-l receptor pensions. Alternatively, the active ingredients may be antagonist selected from the compounds of formulae (I), (II), presented in ready-prepared volume de?ned 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-l 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, eg 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-l 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 Aparticularly preferred class of anti-anxiety agent is the described above containing from 0.1 to about 500 mg of the 5-HT1A agonists or antagonists, especially the 5-HT1A 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-l 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. Avariety of materials can treatment an amount of a CNS-penetrant NK-l 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 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 ?avoured syrups, penetrant NK-l receptor antagonist selected from the com 45 aqueous or oil suspensions, and ?avoured emulsions With pounds of formulae (I), (II), (III), (IV) and (V) and a 5 -HT1A 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 gums such as tragacanth, acacia, alginate, dextran, sodium NK-l receptor antagonist selected from the compounds of carboxymethylcellulose, methylcellulose, polyvinyl formulae (I), (II), (III), (IV) and (V) and a 5-HT1A receptor pyrrolidone 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-l 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 CNS-penetrant NK-l 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-l receptor antagonist and an antide the CNS-penetrant NK-l 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-l receptor antagonist of formu penetrant NK-l receptor antagonist and an antidepressant or