AU738047B2 - Use of NK-1 receptor antagonists for treating mania - Google Patents

Use of NK-1 receptor antagonists for treating mania Download PDF

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AU738047B2
AU738047B2 AU91606/98A AU9160698A AU738047B2 AU 738047 B2 AU738047 B2 AU 738047B2 AU 91606/98 A AU91606/98 A AU 91606/98A AU 9160698 A AU9160698 A AU 9160698A AU 738047 B2 AU738047 B2 AU 738047B2
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receptor antagonist
treatment
phenyl
mania
formula
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AU9160698A (en
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Nadia Melanie Rupniak
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Organon Pharma UK Ltd
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Merck Sharp and Dohme Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Description

W0.99/07376 PCTIEP98/04934 -1- USE OF NK-1 RECEPTOR ANTAGONISTS FOR TREATING MANIA This invention relates to the treatment or prevention of mania by the administration of a NK-1 receptor antagonist.
A Manic Episode is defined bya distinct period during which there is an abnormally and persistently elevated, expansive, or irritable mood.
This period of abnormal mood must last at least 1 week (or less if hospitalization is required). The mood disturbance must be accompanied by at least three additional symptoms from a list that includes inflated self-esteem or grandiosity, decreased need for sleep, pressure of speech, flight of ideas, distractibility, increased involvement in goal-directed activities or psychomotor agitation, andexcessive_ involvement.inpleasurable activities with a high potential of painful consequences. If the mood is irritable (rather than elevated or expansive), at least four of the above symptoms- mustbe-present. The disturbance must be sufficiently severe to cause marked impairment in social or occupational functioning or to require hospitalization, or it is characterised by the presence of psychotic features. The episode must not be due to the direct physiological effects of a drug of abuse, a medication, other somatic treatments for depression-(eg., electroconvulsive therapy or light therapy) or toxin exposure. The episode must also not be due to the direct physiological effects of a general medical condition multiple sclerosis, brain tumour). (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, American Psychiatric Association, 1994).
The elevated mood of a Manic Episode may be described as euphoric, unusually good, cheerful, or high. Although the person's mood may initially have an infectious quality for the uninvolved observer, it is recognized as excessive by those who know the person well. The expansive quality of the mood is characterised by unceasing and indiscriminate enthusiasm for interpersonal, sexual or occupational interactions.
WO.99/07376 PCT/EP98/04934 -2- Although the elevated mood.is considered the prototypical symptom, the predominant mood disturbance may be irritability, particularly when the person's wishes are thwarted. Lability of mood the alternation between euphoria and irritability) is frequently seen.
Treatment of mania is with drugs and psychological management.
Typically, drugs such as haloperidol or chlorpromazine may be used to control symptoms. After more than one episode of mania, lithium carbonate is often prescribed. Drugs such as haloperidol and chlorpromazine are typically associated with a number of side-effects, 0o including extrapyramidal symptoms, acute dystonias, tardive dyskinesias, akathesia, tremor, tachycardia, drowsiness, confusion, postural hypotension, blurring of vision, precipitation of glaucoma, dry mouth, constipation, urinary hesitance and impaired sexual function. The therapeutic index of lithium is low and close control of plasma concentrations is required for its safe clinical application. Side-effects of lithium include tremor, nausea, diarrhoea, thirst and polyuria.
Neurokinin- 1 (NK-1; substance P) receptor antagonists are being developed for the treatment of a number of physiological disorders associated with an excess or imbalance of tachykinins, and in particular substance P. Examples of conditions in which substance P has been implicated include disorders of the central nervous system such as anxiety, depression and psychosis (see, for instance, International (PCT) patent specification Nos. WO 95/16679, WO 95/18124 and WO 95/23798).
International (PCT) patent specification No. WO 96/24353 (published 15th August 1996) suggests that psychiatric disorders may be treated using a combination of a tachykinin antagonist and a serotonin agonist or selective serotonin reuptake inhibitor (SSRI). There is no disclosure in WO 96/24353 that would lead one to conclude that an NK-1 receptor antagonist alone would be effective in the treatment of mania or hypomania. Furthermore, there is no direction in WO 96/24353 that would lead the skilled reader to the identificatin of any NK-1 receptor antagonist that would be effective in the treatment of mania or hypomania. Also, it will be appreciated that agonism of the 5-HTIA receptor and inhibition of serotonin reuptake are not mechanisms generally associated with the action of antipsychotic drugs.
In view of the short-comings of existing agents for the treatment of mania, there is a need for new, safe and effective treatment of mania.
The present invention accordingly provides, in a first embodiment, a method for the treatment or prevention of mania or hypomania, which method comprises the oral administration to a patient in need of such treatment of an effective amount of a NK-1 receptor antagonist, wherein the NK-1 receptor antagonist is a compound of formula
R
3 X R 4 R2 N R R
(I)
wherein R' is selected from the group consisting of: Ci-6alkyl, substituted with one or more of the substituents selected from: heterocycle, wherein the heterocycle is selected from the group 15 consisting of benzimidazolyl, imidazolyl, isoxazolyl, isothiazolyl, 20 oxadiazolyl, pyrazinyl, pyrazolyl, pyridyl, pyrrolyl, tetrazolyl thiadiazolyl triazolyl, and piperidinyl, and wherein the heterocycle is unsubstituted or substituted with one or more substituents(s) selected from: [I:\DAYLIB\Iibzj05522doc:Iam
C
1 6 alkyl, unsubstituted or substituted with halo, -CF 3 -OCH'i, or phenyl, 0ii) C 1 6 alkoxy, (111) oxo, (IV) thioxo, cyano, (vi1) -SCH 3 (vii) phenyl, (Viii) hydroxy, (ix) trifluoromethyl,
-(CH
2 9 Rl 0 wherein m is 0, 1 or 2, and R 9 and R1 0 are independently selected fr-om: hydrogen, (11) C 16 alkyl, 15 (MI) hydroxyC,- 6 alkyl, and (TV) phenyl, (xi) -1NR9CJUK, wherein R 9 and R 1 0 are as defined above, and (xii) -CONR 9
R'
0 wherein R 9 and R1 0 are as defined above, 2 and R 3 are independently selected from the group consisting of: 20(1) hydrogen;
CI-
6 a lkyl
C
2 6 alkenyl, and phenyl; X is R 4 is 6_
R
z R8 R 5 is phenyl, unsubstituted or substituted with halo; R 6 R 7 and R 8 are independently selected from the group consisting of hydrogen, C I 6 alkyl, [I:\DAYLIB\libz]05522.doc: lam halo, and -CF3; Y is and Z is hydrogen or C 14 alkyl; and pharmaceutically acceptable salts thereof.
In a second embodiment, the invention provides a method for the treatment or prevention of mania or hypomania, which method comprises the oral administration to a patient in need of such treatment of an effective amount of a NK-1 receptor antagonist, wherein the NK-1 receptor antagonist is a compound of formula (Ha):
A
1 2
NA
R A (IIa) wherein: SA' is fluorine or CF 3 15
A
2 is fluorine or CF 3
A
3 is fluorine or hydrogen;
R
6 is a 5-membered or 6-membered heterocyclic ring containing 2 or 3 nitrogen atoms optionally substituted by or a CI-4alkyl group, and optionally substituted by a group of the formula ZNR 7
R
8 where Z is C 1 -6alkylene or C3.6cycloalkylene; 7 i*o R 7 is hydrogen, C-4alkyl, C3-7cycloalkyl or C3-7cycloalkylCl-4alkyl, or C2-4alkyl substituted by C 1 4 alkoxy or hydroxyl; R is hydrogen, Cl.
4 alkyl, C3-7cycloalkyl or C3-7cycloalkylC 1 4 alkyl, or C24alkyl substituted by one or two substituents selected from Ci-4alkoxy, hydroxyl or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and
S;
or R R 8 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by a hydroxy group, and optionally containing a double bond, which ring may optionally contain an oxygen or sulphur ring [I:\DAYLIB\ibz]05522.doc:am atom, a group S(O) or S(O) 2 or a second nitrogen atom which will be part of a NH or NRc moiety where Rc is C 1 4 alkyl optionally substituted by hydroxy or CI 4 alkoxy; or R 7
R
8 and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms; or Z, R 7 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms which may optionally contain an oxygen ring atom; X is an alkylene chain of 1 to 4 carbon atoms optionally substituted by oxo; and Y is a C]- 4 alkyl group optionally substituted by a hydroxyl group; with the proviso that if Y is C 1 4 alkyl, R 6 is substituted at least by a group of formula ZNR 7
R
8 as defined above; or a phanraceutically acceptable salt thereof.
In a third embodiment, the invention.provides a method for the treatment or prevention of mania or hypomania, which method comprises the oral administration to a patient in need of such treatment of an effective amount of a NK-1 receptor antagonist, wherein the NK-1 receptor antagonist is a compound of formula (IVa):
A
1
A
0 2
A
OO 3 (IVa) Swherein: X is a group of the formula NR 6
R
7 or a C- or N-linked imidazolyl ring; Y is hydrogen or C1.
4 alkyl optionally substituted by a hydroxy group; A' is fluorine or CF 3 A is fluorine or CF 3 3 is fluorine or hydrogen;
R
6 is hydrogen, CI.
6 alkyl, C3.7cycloalkyl, C3-7cycloalkylC.
4 alkyl, phenyl, or ^C2-4alkyl substituted by C 1 4alkoxy or hydroxy; [I:\DAYLIB\1ibz105522.doc:am
R
7 is hydrogen, C 1 6 alkyl, C 3 7 cycloalkyl, C3-7cycloalkylj__jalkyl, phenyl, or
C
2 -4alkyl substituted by one or two substituents selected from Ci-4alkoxy, hydroxy or a 4, or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S; or R 6 and R 7 together with the nitrogen atom to which they are attached, form a saturated or partially saturated heterocyclic ring of 4 to 7 ring atoms, which ring may optionally contain in the ring one oxygen or sulphur atom or a group selected from NR 8 S(0) or S(0)2 and which ring may be optionally substituted by one or two groups selected from hydroxyCl-4alkyl, Cl-4alkoxyCi 4 alkyl, oxo, CORa or CO 2 Ra where Ra is hydrogen or Ci- 4 alkyl; or R 6 and R 7 together with the nitrogen atom to which they are attached, form a non-aromatic azabicydic ring system of 6 to 12 ring atoms; Rg is hydrogen, Ci-4alkyl, hydroxyCl4alkyl or Ci.4alkoxyC 1 i 4 alkyl; or a pharmaceutically acceptable salt thereof.
The invention further provides a compound of formula (IIa) or (IVa) as defined above when used for the treatment or prevention of mania or hypomania.
The invention still further provides the use of a compound of formula (IIa) or (IVa) as defined above for the manufacture of a medicament for the treatment or prevention of mania or hypomania.
20 In a further aspect of the present invention, there is provided a pharmaceutical composition for the treatment or prevention of mania comprising a NK-1 receptor antagonist of formula (IIa) or (IVa), together with at least one pharmaceutically acceptable carrier or excipient.
Included within the scope of the present invention is the use of NK-1 receptor antagonists in the treatment or prevention of hypomania. A hypomanic episode is .distinguished from a manic episode in that it is not severe enough to cause marked impairment in social and occupational functioning or to require hospitalisation, and there are no psychotic features.
It will be appreciated that a combination of a conventional antipsychotic drug with a NK-1 receptor antagonist may provide an enhanced effect in the treatment of mania. Such a combination would be expected to provide for a rapid onset of action to treat a manic episode thereby enabling prescription on an "as needed basis".
Furthermore, such a combination may enable a lower dose of the antipsychotic agent to be used without compromising the efficacy of the antipsychotic agent, thereby S 3 ;minimising the risk of adverse side-effects. A yet further advantage of such a [I:\DAYLIB\libz]05522.doc:lam combination is that, due to the action of the NK-1 receptor antagonist, adverse sideeffects caused by the antipsychotic agent such as acute dystonias, dyskinesias, akathesia and tremor may be reduced or prevented.
Thus, according to a further aspect of the present invention there is provided the use of a NK-1 receptor antagonist of formula (IIa) or (IVa) and an antipsychotic agent for simultaneous, separate or sequential administration the manufacture of a medicament for the treatment or prevention of mania or hypomania.
The present invention also provides a method for the treatment or prevention of mania or hypomania, which method comprises administration to a patient in need of such treatment of an amount of a NK-1 receptor antagonist of formula (IIa) or (IVa) and an amount of an antipsychotic agent, such that together they give effective relief.
The present invention also provides a NK-1 receptor antagonist of formula (Ia) or (IVa) and an antipsychotic agent, when used for the treatment or prevention of mania or hypomania.
There is also disclosed a pharmaceutical composition comprising .a NK-1 receptor antagonist of formula (IIa) or (IVa) and an antipsychotic agent, together with at least one pharmaceutically acceptable carrier or excipient.
It will be appreciated that the NK-1 receptor antagonist and the antipsychotic agent may be present as a combined preparation for simultaneous, separate or sequential 20 use for the treatment or prevention of mania. Such combined preparations may be, for example, in the form of a twin pack.
o .There is therefore also disclosed a product comprising a NK-1 receptor antagonist and an antipsychotic agent as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of mania.
25 It will be appreciated that when using a combination of the present invention, the NK-1 receptor antagonist and the antipsychotic agent may be in the same pharmaceutically acceptable carrier and therefore administered simultaneously. They may be in separate pharmaceutical carriers such as conventional oral dosage forms which are taken simultaneously. The term "combination" also refers to the case where the compounds are provided in separate dosage forms and are administered sequentially.
Therefore, by way of example, the antispsychotic agent may be administered as a tablet and then, within a reasonable period of time, the NK-1 receptor antagonist may be administered either as an oral dosage form such as a tablet or a fast-dissolving oral dosage form. By a "fast-dissolving oral formulation" is meant, an oral delivery form which when Splaced on the tongue of a patient, dissolves within about 10 seconds.
[I:\DAYLIB\ibz05522.doc:am Included within the scope of the present invention is the use of NK-1 receptor antagonists in combination with an antipsychotic agent in the treatment or prevention of hypomania.
As used herein, the term "treatment" refers both to the treatment and to the prevention or prophylactic therapy of mania or hypomania.
NK-1 receptor antagonists of use in the present invention are described in published European Patent Specification No 0 577 394 and in International Patent Specification Nos. 95/18124 and 96/05181.
Suitable antipsychotic agents of use in combination with a NK-1 ieceptor antagonist include the phenothiazine, thioxanthene, heterocyclic, dibenzazepine, butyrophenone, diphenylbutylpiperidine and indolone classes of antipsychotic agent.
Suitable examples of phenothiazines include chlorpromazine, mesoridazine, thipridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitable examples of thioxanthenes include chlorprothixene and thiothixene. Suitable examples of dibenzazepines include clozapine and olanzapine. An example of a butyrophenone is haloperiodol. An example of a diphenylbutylpiperidine is pimozide. An example of an indolone is molindolone. Other antipsychotic agents include loxapine, sulpiride and risperiodone. It will be appreciated that the antipsychotic agents when used in combination with a NK-1 receptor antagonist may be in the form of a pharmaceutically 20 acceptable salt, for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, o flurphenazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and molindone hydrochloride. Perphenazine, chlorprothixene, clozapine, olanzapine, haloperidol, 25 pimozide and risperidone are commonly used in a non-salt form.
Certain NK-1 receptor antagonists are described in European Patent Specification No. 0 577 394, i.e. compounds of formula R3 X R 4 R N R 1 R
(I)
or a pharmaceutically acceptable salt thereof, wherein: R' is selected from the group consisting of: [I:\DAY LIB\Iibz]05522.doc: lam hydrogen;
CI-
6 alkyl, 1.n1SUbstitUted or substitUted with one or more of the substituents selected fromn: hydroxy, oxo, Cj- 6 alkoxy, PhenIYl-C 1 3 alkoxy, phenyl,
-CN,
halo, I:DAY LIB\libz]05522.doc: lam WO99/07376 PCT/EP98/04934 -8- -NR9RO,- wherein R 9 and RIO are independently selected from: hydrogen, (ii) Ci-Galkyl, (iii) hydroxy-Ci.Galkyl, and (IV) phenyl, Wi -NR9COR1O, wherein R9~ and RIO are as defined above, -j NR9CO 2 R'0, wherein R 9 and RIO are as defined above, -CONR9RO, wherein R9 and Rio are as defined above, -COR9, wherein R9 is as defined above, (in) -CO 2 R9, wherein R9 is as defined above, heterocycle, wherein the heterocycle is selected from the group consisting of: benzimidazolyl, benzofuranyl, benzthiophenyl, benzoxazolyl, furanyl, imidazolyl, indolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl., pyridyl, pyrimidyl, pyrrolyl, quinolyl, tetrazolyl, WO 99/07376 PCT/EP98/04934 -9thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, oxanyl, (AA) piperazinyl, (AB) piperidinyl, (AC) pyrrolidinyl, (AD) tetrahydrofuranyl, and (AE) tetrahydrothienyl, and wherein the heterocylcle is unsubstituted or substituted with one or more substituent(s) selected from: C1-6alkyl, unsubstituted or substituted with halo, -CF 3
-OCH
3 or phenyl, (ii) Ci-calkoxy, (iii) oxo, (iv) hydroxy, thioxo, (vi) -SR 9 wherein R 9 is as defined above, (vii) halo, (viii) cyano, (ix) phenyl, trifluoromethyl, (xi) -(CH 2 )m-NR9R1 l wherein m is 0, 1 or 2, and R 9 and Ro 1 are as defined above, (xii) -NR9COR 1 I, wherein R 9 and Rio are as defined above, (xiii) -CONR9Rio, wherein R 9 and Rio are as defined above, (xiv) -CO 2
R
9 wherein R 9 is as defined above, and 1, WO99/07376 PCT/EP98/04934 (xv) -(CH2)m-OR 9 wherein m and R 9 are as defined above; C2.6alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: hydroxy, oxo, C1.6alkoxy, phenyl-C1-3alkoxy, phenyl,
-CN,
halo, -CONR9R1i, wherein R 9 and Rio are as defined above,
-COR
9 wherein R 9 is as defined above, -C0 2
R
9 wherein R 9 is as defined above, heterocycle, wherein the heterocycle is as defined above; C2-6alkynyl; phenyl, unsubstitued or substituted with one or more of the substituent(s) selected from: hydroxy, Ci-calkoxy, Cl-6alkyl, halo,
-CN,
-NO
2
-CF
3 -(CH2)m-NR 9 Rlo, wherein m, R 9 and Rio are as defined above, -NR9CORio, wherein R 9 and Rio are as defined above, -NR9C0 2
R
10 wherein R 9 and Rio are as defined above,
-CONR
9 RIO, wherein R 9 and Rio are as defined above, WO 99/07376 PCT/EP98/04934 11
-CO
2 NRRO, wherein R 9 and Ro 1 are as defined above,
-COR
9 wherein R 9 is as defined above, -C0 2
R
9 wherein R 9 is as defined above;
R
2 and R 3 are independently selected from the group consisting of: hydrogen; Ci.6alkyl, unsubstituted or substituted with one or more of the substituents selected from: hydroxy, oxo, C-.6alkoxy, phenyl-Cl.3alkoxy, phenyl,
-CN,
halo, -NR9R 1 wherein R 9 and Ro 1 are independently selected from: -NR9COR 1 I, wherein R 9 and R 1 i are as defined above,
-NR
9
CO
2 RiO, wherein R 9 and R' 1 are as defined above, -CONR9R 1 wherein R 9 and Rio are as defined above,
-COR
9 wherein R 9 is as defined above, and
-CO
2
R
9 wherein R 9 is as defined above; C2-6alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: hydroxy, oxo, Ci-6alkoxy, phenyl-Ci-salkoxy, phenyl,
-CN,
halo, WO.99/07376 PCT/EP98/04934 -12- -CONR9R1I wherein R 9 and RI 1 are as defined above,
-COR
9 wherein R 9 is as defined above,
-CO
2
R
9 wherein R 9 is as defined above; C2-6alkynyl; phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: hydroxy, Ci-ealkoxy, Ci.-alkyl, halo,
-CN,
-NO
2
-CF
3 -(CH2)m-NR9R 1 o, wherein.m,.R9 and Ro 1 are as defined -NR9COR 1 0 wherein R 9 and R 10 are as defined above,
-NR
9
CO
2
R
1 wherein R 9 and R o 1 are as defined above, -CONR9R1', wherein R 9 and R 10 are as defined above,
-CO
2 NR9R1 0 wherein R 9 and R 1 0 are as defined above, -COR9, wherein R 9 is as defined above,
-CO
2
R
9 wherein R 9 is as defined above; above, and the groups R 1 and R2 may be joined together to form a heterocyclic ring selected from the group consisting of: pyrrolidinyl, piperidinyl, pyrrolyl, pyridinyl, imidazolyl, oxazolyl, and W0C)99/07376 PCTIEP98/04934 13thiazolyl, and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituent(s) selected from: C1.salkyl, (ii) oxo, (iii) Ci.
6 alkoxy, (iv) -NR9R1', wherein R 9 and R 1 0 are as defined above, halo, and (vi) trifluoromethyl; and the groups R 2 and-R 3 may be joined together to form a carbocyclic ring selected from the group consisting of: cyclopentyl, cyclohexyl, phenyl, and wherein the carbocyclic ring is unsubstituted or substituted with one or more substituents selected from: C1.salkyl, (ii) C1.ialkoxy, (iii) -NR9R1o, wherein R 9 and Rio are as defined above, (iv) halo, and trifluoromethyl; and the groups R 2 and R 3 may be joined together to form a heterocyclic ring selected from the group consisting of: pyrrolidinyl, piperidinyl, pyrrolyl, pyridinyl, imidazolyl, furanyl, WO 99/07376 PCT/EP98/04934 -14oxazolyl, thienyl, and thiazolyl, and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituent(s) selected from: Ci-.alkyl, (ii) oxo, (iii) Cl.salkoxy, (iv) -NR9Rio, wherein R9 and Rio are as defined above, halo, and (vi) trifluoromethyl; X is selected from the group consisting of: and
-SO
2
R
4 is selected from the group consisting of: (1)
R
6 YR7 z
R
-Y-Cl.salkyl, wherein alkyl is unsubstituted or substituted with one or more of the substituents selected from: hydroxy, oxo, C1.6alkoxy, phenyl-Cl.aalkoxy, phenyl, WO 99/07376 PCT/EP98/04934
-CN,
halo, -NR9R10, wherein R 9 and R10 are as defined above, -NR9COR 10 wherein R 9 and Rio are as defined above, -NR9CO 2
R
10 wherein R 9 and Ri 1 are as defined above,
-CONR
9 R1 0 wherein R 9 and RiO are as defined above,
-COR
9 wherein R 9 is as defined above,
-CO
2
R
9 wherein R 9 is as defined above; -Y-C2-6alkenyl, wherein the alkenyl is unsubstituted or substituted with one or more of the substituent(s) selected from: hydroxy, oxo, C1-galkoxy, phenyl-C.i-alkoxy, phenyl,
-CN,
halo,
-CONR
9 RIo, wherein R 9 and Ro 1 are as defined above,
-COR
9 wherein R 9 is as defined above,
-CO
2
R
9 wherein Rs is as defined above, -O(CO)-phenyl, wherein the phenyl is unsubstituted or substituted with one or more of R 6
R
7 and R 8
R
5 is selected from the group consisting of: phenyl, unsubstituted or substituted with one or more of R 11
R
12 and R13 Ci-salkyl, unsubstituted or substituted with one or more of the substituent(s) selected from: hydroxy, oxo, C1-6alkoxy, WO. 99/07376 PCT/EP98/04934 16phenyl-C-.3alkoxy, phenyl,
-CN,
halo, -NR9R1O, wherein R 9 and Ro 1 are as defined above, -NRSCORO, wherein R 9 and RiO are as defined above, -NR9CO 2
R
1 O, wherein R 9 and Rio are as defined above, -CONR9R 1 O, wherein R 9 and RiO are as defined above,
-COR
9 wherein R 9 is as defined above,
-CO
2
R
9 wherein R 9 is as defined above; C2-6alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: hydroxy, oxo, Ci-.alkoxy, phenyl-Cl.3alkoxy, phenyl,
-CN,
halo, -CONR9SR, wherein R 9 and R 10 are as defined above,
-COR
9 wherein R 9 is as defined above,
-CO
2 R9, wherein R 9 is as defined above; heterocycle, wherein the heterocycle is as defined above;
R
G
R
7 and R 8 are independently selected from the group consisting of: hydrogen; C1.6alkyl, unsubstituted or substituted with one or more of the substituents selected from: hydroxy, oxo, Ci-ralkoxy, W0.99/07376 PCT/EP98/04934 17 phenyl-Cl.3alkoxy, phenyl,
-CN,
halo, -NR9RO, wherein R 9 and R' 0 are as defined above, -NR9CORO, wherein R9 and RIO are as defined above, (j -NR9CO 2 RIO, wherein R 9 and RIO are as defined above, -CONR9RO, wherein R9 and RIO are as defined above,
-COR
9 wherein R 9 -is as defined above, and (in) -CO 2 R9, wherein R9 is as defined above; C2G6alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: hydroxy, oxo, CI-6alkoxy, phenyl-Cl.3alkoxy, phenyl,
-CN,
halo, -CONR9RO wherein R9 and RIO-are as defined above, -COR9 wherein R9 is as defined above, -C0 2 R9, wherein R9 is as defined above; C2.6alkynyl; phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: hydroxy, CI-6alkoxy, Ci- 6 alkyl, halo,
-CN,
WO 99/07376 PCT/EP98/04934 18-
-NO
2
-CF
3 -(CH2)m-NR 9
R
1 wherein m, R 9 and Rio are as defined above, -NR9CORio, wherein R 9 and Rio are as defined above, -NR9CO 2
R
10 wherein R 9 and RIO are as defined above, -CONR9R1i, wherein R 9 and Rio are as defined above,
-CO
2 NR9R 1 O, wherein R 9 and R 10 are as defined above,
-COR
9 wherein R 9 is as defined above; -C0 2
R
9 wherein R 9 is as defined above; halo,
-CN,
-CF
3
-NO
2
-SR
14 wherein R 1 4 is hydrogen or (11) -SOR 14 wherein R 1 4 is as defined above, (12) -SO 2
R
14 wherein R 14 is as defined above, (13) NR 9 COR10, wherein R 9 and RiO are as defined above, (14) CONR 9 CORio, wherein R 9 and Rio are as defined above, NR9Ri1, wherein R 9 and Rio are as defined above, (16) NR 9
CO
2 R1 0 wherein R 9 and Rio are as defined above, (17) hydroxy, (18) Ci-6alkoxy, (19) COR 9 wherein R 9 is as defined above,
CO
2
R
9 wherein R 9 is as defined above,
R
11 R12 and R 13 are independently selected from the definitions of R
G
R
7 and R 8 or -OX; Y is selected from the group consisting of: a single bond, WO 99/07376 PCT/EP98/04934 19 -C0-,
-OH
2 -CHR15-, and -CR1 5 R16_, wherein R15 and RIG are independently selected from the group consisting of: Cl-6alkyl, unsubstituted or substituted with one or more of the substituents selected from: hydroxy, (ii) oxo, (iii) C1ioalkoxy, (iv) phenyl-CI-3alkoxy, phenyl, (vi) -CN, (vii) halo, (viii) -NR9R1O, wherein R9 and RIO are as defined above, (ix) -NR9C0R1O, wherein R9 and-R' 0 -are as defined above, -NR9C0 2 R'O, wherein-R 9 and-Ri 0 are as defined above, (xi) -C0NR9R10, wherein R9 and RIO are as defined above, (xii) -C0R9, wherein R9 is as defined above, and (xiii) -C0 2 R9, wherein R9 is as defined above; phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: hydroxy, (ii) Ci-6alkoxy, (iii.) Ci.6alkyl, (iv) halo, (vi) -ON, (vii) -NO 2 (viii) -CF 3 (ix) -(CH 2 )m-NR 9 Ro 0 wherein m, R 9 and R' i are as defined above,
-NR
9
COR
1 0 wherein R 9 and R 1 0 are as defined above, (xi) -NR'CO 2
R
1 0 wherein R 9 and R' i are as defined above, (xii) -CONR 9
R'
1 wherein R 9 and R' 1 are as defined above, (xiii) -CO 2
NR
9 R'O, wherein R 9 and R 1 0 are as defined above, (xiv) -COR 9 wherein R 9 is as defined above, (xv) -C0 2
R
9 wherein R 9 is as defined above, Z is selected from: hydrogen, Ci- 4 alkyl, and hydroxy, with the proviso that ifY is Z is other than hydroxy, or if Y is -CHR' then Z and R 5 may be joined together to form a double bond.
For use in the present invention, NK-1 receptor antagonists are compounds of formula wherein: R is selected from the group consisting of: Ci- 6 alkyl, substituted with one or more of the substituents selected from: heterocycle, wherein the heterocycle is selected from the group consisting of 20 benzimidazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, S 25 pyrazinyl, pyrazolyl, pyridyl, pyrrolyl, [I:\DAYLIB\libz]05522.doc:Iam WO 99/07376 PCT/EP98/04934 21 tetrazolyl, thiadiazolyl, triazolyl, and piperidinyl, and wherein the heterocycle is unsubstituted or substituted with one or more substituent(s) selected from: Wi C1.
6 alkyl, unsubstituted or substituted with halo, -CF 3
-OCH
3 or phenyl, (ii) Cl.ralkoxy, 0 (iii) oxo, (iv) thioxo, cyano, (vi) -SCH 3 (vii) phenyl, (viii) hydroxy, (ix) trifluoromethyl, Wx -(CH2)m-NR 9
R
0 wherein mn is 0, 1 or 2, and R9 and RIO are independently selected from: hydrogen, .0 (II) Cl-6alkyl, (III) hydroxyCl- 6 alkyl, and (MV phenyl, (xi) -NR9COR1O, wherein R9 and Rio are as defined above, and (xii) -CONR9RO, wherein R9 and RIO are as defined above,
R
2 and R3 are independently selected from the group consisting of: hydrogen; CI.Galkyl C2.calkenyl, and phenyl; X is -22- R is z
R
8
R
5 IS phenyl, unsubstituted or substituted with halo; R 6
R
7 and R 8 are independently selected fromn the group conisisting of 1) hydrogen, 2) CI- 6 alkyl, 3) halo, and 4) -CF 3 Y is and Z is hydrogen or C I 4 alkyl; and pharmnaceutically acceptable salts thereof.
Particularly preferred compounds of formula are: 15 4-(3-(1I,2,4-tniazolo)methyl)-2(S)-(3 ,5-bstilooehlbezlx)3S-hnl morpholine; P. 2 4 -triazolo)methyl)-2(S)-(3,5bis(trifluoromethyl)benzyloxy)-3(R)-phenylmorpholine; 4-(3 -oxo- 1 H,4H- 1 ,2,4-triazolo)methyl)-2(S)-(3 ,5-bi s(ti fluorom ethyl)benzyloxy-3 20 phenyl-morpho line; and 3 ,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)(4-luorophenyl)-4-(3 1 H,4H- 1, 2 4 -triazolo)methyl)morpholine; or a pharmnaceutically acceptable salt thereof.
Further NK-1 receptor antagonists are described in International (PCT) Patent Specification No. WO 95/18124, i.e. compounds of formnula (1I): I:DAY LIBM ibz]05522.doc: lam WO99/07376 PCT/EP98/04934 23-= R 9 a 0 Y RI R 4 6"
R
R~R or a pharmaceutically acceptable salt or prodrug thereof, wherein R' is hydrogen, halogen, C1.6alkyl, C1.6alkoxy,
CF
3 N0 2 CN, SRa, SORa, SO 2 Ra, CO 2 Ra, CONRaRb, C2-Galkenyl, C2G6alkynyl or Cl-4alkyl substituted by CI-4alkoxy, where Ra and Rb each independently represent hydrogen or C1.4alkyl; R2 is hydrogen, halogen, CL..6alkyl, C1l6alkoxy substituted by CI.4alkoxy or CF 3 R3 is hydrogen, halogen or OF3; R4 is hydrogen, halogen, C1.6alkyl, Cl-6alkoxy,
CF
3
NO
2 CN, SRa, SORa, SO 2 Ra, CO 2 Ra, CONRaRb, C2.6alkenyl, C2-oalkynyl or Cl-4alkyl substituted by CI-4alkoxy, where Ra and Rb each independently represent hydrogen or C1.4alkyl; R5 is hydrogen, halogen, C1.Galkyl, Cilcalkoxy substituted by CI-4alkoxy or CF 3 R6 is a 5-membered or 6-membered heterocyclic ring containing 2 or 3 nitrogen atoms optionally substituted by =S or a C1.4alkyl group, and optionally substituted by a group of the formula ZNR7R8 where Z is C1.6alkylene or C3.6cycloalkylene; R7 is hydrogen, C1.4alkyl, C3-7cycloalkyl or C3.7cycloalkylC 1 4 alkyl, or C2-4alkyl substituted by C1.4alkoxy or hydroxyl; R8 is hydrogen, C1.4alkyl, C3.7CYCloalkyl or C37cycloalkylCl 1 4 alkyl, or C2.4alkyl substituted by one or two substituents selected from Cl-4alkoxy, hydroxyl. or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, 0 and S; or R 7
R
8 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by a hydroxy group, and optionally containing a double bond, which ring may optionally contain an oxygen or sulphur ring atom, a group S(O) or S(0)2 or a second nitrogen atom which will be part of a NH or NRc moiety where Rc is C 14 alkyl optionally substituted by hydroxy or Ci-4alkoxy; or R 7 R and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms; or Z, R 7 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms which may optionally contain an oxygen ring atom;
R
9 and R 9 b are each independently hydrogen or Cl_ 4 alkyl, or R 9 and R 9 b are joined so, together with the carbon atoms to which they are attached, there is formed a C5-7 ring; X is an alkylene chain of 1 to 4 carbon atoms optionally substituted by oxo; and Y is a Ci-4alkyl group optionally substituted by a hydroxyl group; with the provision that if Y is Ci-4alkyl, R 6 is substituted at least by a group of formula ZNR 7
R
8 as defined above.
Compounds of formula (II) of use in the present invention are those of formula (IIa) and pharmaceutically acceptable salts thereof:
:A
0 2
*N
R
6
A
S(IIa) Swherein: A' is fluorine or CF 3
A
2 is fluorine or CF 3
A
3 is fluorine or hydrogen; and X, Y and R 6 are as defined in relation to formula (II).
Particularly preferred compounds of formula (II) include: -(R)-(3,5-bis(trifluoromethyl)phenyl)ethxy)-4-(5-(dimethyamino)methyl- 1,2,3triazol-4-yl)methyl-3-(S)-phenylmorpholine; [1:\DAYLIB\Iibz]05522.doc:Iam 1 ,5 -bis(trifluorornethyl)phenyl)ethoxy-4-(5 -(dimiethiylainio)miethly] I,2,3 triazol-4-yl)r-nethyl-3 -(S).-(4-fluorophienyl)rnorpholinie; and pharniaceutically acceptable salts thereof.
0 6 [1:\DAYLIB\Iibz]05522.doc:lam -26- Yet further NK-lI receptor antagonists are those described in International Patent Specification No. WO 96/05181, i.e. compounds of formnula (IV): R 2
R
9 ax b~ 0 R 9b N wherein X is a group of the formnula NR 6 R 7 or a C- or N-linked imidazolyl ring; a.' a a a a a a a a a a a
S
a.
a a a
S
9.a a a a a a a 1\DAYLIB\Iibzj05522. doe:]am Y is hydrogen Or CI.'Ialkv] optionially Subsri utlied by,' ihvdrv~) '_ZFOup1J R) is hydrogen, halogen., Ci-ralkvl. C-Icalkoxy), CF'. NC),,C:SR SOII&', SO 2 lR", CO0 2 CONRaRb, C2,calkenyl. I kynvi 0or C'I-1C N substituted by' C]Aalkoxy, wherein PVI anid Ph~ eaich idepenidentlY reipresent~ hydrogen or Ci~alkyl: shydrogeni, hialogen. ,ayl CiralkoxY substiluvec by%.
C 1,1koxyv or C R3 is hydrogen, halogeni or Cl? 2 R-1 is hYdrogen, halogen, CI-.,alkyl,
C
1 ralkoxy, hydroxy,
CF
3
NO
2 CN, SRW', SO0Th, SO 2 R;I, CO 2 Ra. CONRaFU. C2-4;alkeiiy] C.,cakynyl or C1.4alkyl substituted bY C 1 .,alkox\v, whiereini R: and 'are aS pr] \'i11uSl\ defined;
R
5 is hydrogen, halogen, CI-c,,alkyl, CI-n-alkoxy substituted by CI.4alkoxy or CF 3 RG is hydrogen, Cjicalkyl, C3-7cyeloalkyl, C3b7c 'Vcloalkv IC]..alkvl, *00phenyl, or C2-4alkyl substituted by Ci- 4 alkoXy or hy1d roxy;
*R
7 is hydrogen, Ci.calkyl, C3-7cycloalkyl, C3.7cycloalkyl Cj.alkyl, phenyl, or C2- 4 alkyl substituted by one or two substituents selected from 20 CI.
4 alkoxy, hydroxy or a 4, 5 or 6 membered heteroaliphatic ringcontaining one or two heteroatoms selected from N,"O and S; or 6 nd ~,together with the nitrogen atom to which they) are attached, form a saturated or partially saturated heterocyclic ring of 4 to 7 6 0 S ring atoms, which ring may optionally contain in the ring one oxygen or 0SS00 25 sulphur atom or a group selected from NR8, S(O) or S(0)2 and which ring may be optionally substituted by one or two groups selected from hydroxyCI- 4 alkyl, CI~alkoxyCl.
4 alkyl, oxo, CORa or CO 2 Ra Where R" is as previously defined; or RG and R 7 together with the nitrogen atom to which they are attached, form a non-aromatic azabicyclic ring system of 6 to 12 ringy atoms;
R
8 is hydrogen, CI- 4 alkyl, hydroxyC 1 4 alkyl or CI- 4 alkoxyC, 1 4 alkyl; and R 9 a and R 9 b are each independently hydrogen or CI- 4 alkyl, or R 9 and R 9 b are joined so, together with the carbon atoms to which they are attached, there is formed a
C
5 7 ring; and pharmnaceutically acceptable salts thereof.
Compounds of formula (TV) of use in the present invention are those of formula (IVa) and pharmaceutically acceptable salts thereof:
A
1 Y 2 (0 0
N
3 aA 66x (IVa) **.~*;wherein: A' is fluorine or C17 3 A 2is fluorine or CF 3
A
3 is fluorine or hydrogen; 15 and X, Y are as defined in relation to formula (1) Specific compounds of formula (TV) of use in the present invention include: 1 R-(,5.-bis(trifluoromethyl)phenyl)ethoxy)-3 4-fluuiuoienyl)-.4-(morpholinobut-2-yn-yl)morpholine; 1 ,5 -bis(tri fluoromethyl)phenyl)ethoxy-4(4-N,N-dimethylaminobut-2-ynyl)- 3 4 -fluorophenyl)morpho line; 4-(4-azetidinylbut2ynyl-2-(R>( 1 ,5 -bis(trifluoromethyl)phenyl)ethoxy-3 4 -fluorophenyl)morpho line; lADAYLD3\Iibz]05522.doc: lam (I (R(-43i 1UdZlybL2 inv)orp1oiith 1-(4 -ON -IIIthyipipe-a zi nvl) 1.u t- 2 -n -yl 110o1in e, 2 s(rfuoon t l u r eten) Ii ye toxy3S(4loxy l u o )lI1 I 4 pyrro Iidi1no b u t-2 -ny1) m orp h oli e; 3(S) f u orop he nyl) 2- (3 f uoro -5 (tri fl u oro me thl N7h] v thoxy)-4 -rnor-plolinobut-2-.yny1),)morpholjne; -ae rdpheu-2nv) -morp ooutvn vi) -2 -R(3 (11f uoroeth,I)p le ny1)ethoxy)m-orphoine; 4 )-1R)(Izeidil btr' -4-3S(4lolohe l2-1ill uoromethy)p he nyl)ethoxy)mopoie s 5 -bils(trifluoromethy1I)phen1I)ethox3 7 yI -(4-(N-(2colr1,
IN
2 -methoxvethyl)anino)but2-nT1-3-(S)-phelmlorpholin.
2- 5 -bis(trifluoromethyl)phenyl)ethoxy)-4-( 4 sopropyl miethioxyethyI)amlino)but-2yny31-3(S)phen.NrImorphol 1 je (3 fl uoro -5 (trifl uo romethyl)p heny1. 2 hydroxye thoxy) morp h ie 4 4 azetidinylb ut-2yny) 3 (S)(4fluorop heny) 2(R) -fluoro 5 0 0 (trifluoromethyl)phen1-2.hdroxyethoxy)morpholine; 2 R i (rfurmty~h y)-2 hydroxyethoy- 4 N dimnethylamino)b ut 2ynyl) -(4-fluorop hen),r1)morp l.e hvdroxyethoxy) 4 -fiuorophenyl)morpholine; 4 4 N-bis( 2 -me thoxy)ethyl -Nme thyamino)b ut2ynyl)- 2 1- b is(trifluorometh3yl)p henyl)ethoxy)- 3 (4-fl uorop he nyl) norp holine; I ,5 -bis(trifluoromethyl)phenyl)etoxy)3(S-(4uoroplheziy1-4(4(2(S)- (methoxymethiyl)pyrrolidino)but-2-yn-yl)morphioline; 4-(4-(7-azabicyclo[2.2. 1 ]heptano)but-2-yn-yl)-2-(R)-( I bis(tri fluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophienyl)morpholine; 1 ,5-bis(trifluioromethyI)phenyl)ethoxy)-4-(4-diisopropylai.iinobut-2-yni-yl) 3 -(S)-(4-fluorophenyl)morpholine; I -fluoro-5-(trifluoromethyl)phenyl)ethoxy-4(4(2-(S) (nmethoxym-ethiyI)pyrrolidino)but-2-yn-yl)-2(S-ple yliiorpholine; 1 ,5 -bis(tri fluoromethyl)plhenyl)ethoxy)-3 -(S)-(4-fluorophenyl)-4-(4-(2-(S)- (hydroxymethyl)pyrrolidi no)but-2-yn-yl)morpho line; and pharmaceutically acceptable salts thereof.
[I:\DAYLDB\fibz]05522.doc:Iam The preferred compounds of formi-ulae (Ila) and (IVa) will have the 2- and 3substituents on the morpholine ring in the cis arrangement, the preferred sterochemnistry being as shown in the following general formula: Where the benzyloxy mnoiety is u-substituted, the preferred sterochemnistry of the ux-carbon is either when the substituent is an [I:\DAYLIB\libz]05522.doc:Iam alkyl methyl) group or when the suLstituent is a hydroxyalkyl hydroxymethyl) group.
Unless otherwise defined herein, suitable alkyl groups include straight-chained and branched alkyl groups containing from 1 to G carbon Satoms. Ty)pical examples include methyl and ethyl groups, and straightchained or branched propyl and butyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butvl.
Unless otherwise defined herein, suitable alkenyl groups include straight-chained and branched alkenyl groups containing from 2 to 6 carbon atoms. Typical examples include vinyl and allyl groups.
Unless otherwise defined herein, suitable alkynyl groups include straight-chained and branched alkynyl groups containing from 2 to 6 carbon atoms. Typical examples include ethynyl and propargyl groups.
Unless otherwise defined herein, suitable cycloalkyl groups include 15 groups containing from 3 to 7 carbon atoms. Particular cycloalkyv groups are cyclopropyl and cyclohexyl.
*oooo Unless otherwise defined herein, suitable aryl groups include phenyl and naphthyl groups.
A particular aryl-C Galkyl, e.g. phenyl-Ci.c,alkyl, group is benzyl.
20 Unless otherwise defined herein, suitable heteroaryl groups include pyridyl, quinolyl, isoquinolyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furyl, benzofuryl, thienyl, benzthienyl, imidazolyl, oxadiazolyl and thiadiazolyl groups.
The term "halogen" as used herein includes fluorine, chlorine, bromine and iodine.
The compounds of use in this invention may have one or more asymmetric centres and can therefore exist as enantiomers and possibly as diastereoisomers. It is to be understood that the present invention relates to the use of all such isomers and mixtures thereof.
Suitable pharmaceutically acceptable salts of the NK-1 receptor Santagonists of use in the present invention include acid addition salts
L
which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or sulphuric acid. Salts of amine groups may also comprise the quaternary ammonium slats in which the amino nitrogen atom carries an alkyl, alkenyl, alkynyl or aralkyl group. Where the compound carries an acidic group, for example a carboxylic acid group, the present invention also contemplates salts thereof, preferably non-toxic pharmaceutically acceptable salts thereof, such as the sodium, potassium and calcium salts thereof.
Suitable pharmaceutically acceptable salts of the antipsychotic agents used in combination with a NK-1 receptor antagonist of formula (IIa) or (IVa) according to the present invention include those salts described above in relation to the salts of NK-1 receptor antagonists.
The present invention accordingly provides the use of a NK-1 receptor 15 antagonist selected from the compounds of formulae (IIa) and (IVa)' for the manufacture of a medicament for the treatment or prevention of mania.
The present invention also provides a method for the treatment or prevention of mania, which method comprises administration to a patient in need of such treatment of an effective amount of a NK-1 receptor antagonist selected from the compounds of formulae (IIa) and (IVa).
In a further aspect of the present invention, there is provided a pharmaceutical composition for the treatment or prevention of mania comprising a NK-1 receptor antagonist selected from the compounds of formulae (IIa) and (IVa) together with at *least one pharmaceutically acceptable carrier or excipient.
25 Preferably the compositions according to the present invention are in unit dosage forms such as tablets, pills, capsules, powders, granules, [I:\DAYLIB\ibz05522.doc:lam solutions or suspensions, or suppositories, for oral, parenteral] or rect;] administration, by inhalation or insufflation or administration by transiermnal patches or by buccal cavity absorption wafers.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the id present invention, or a non-toxic pharmaceutically acceptable salt thereof.
When referring to these preformulation compositions as homogeneous, is 1 meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
1i This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about. 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the 2 0 tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
GThe two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, peanut oil or soybean oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending ageni.s for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethvlcellulose Smethylcellulose, polyvinyl-pyrrolidone or gelatin.
Preferred compositions for administration by injection include those comprising a NK-1 receptor antagonist as the active ingredient, in association with a surface-active agent (or wetting agent or surfactant) or in the form of an emulsion (as a water-in-oil or oil-in-water emulsion).
Suitable surface-active agents include, in particular, non-ionic agents, sucras polyoxyethylenesorbitans TweenT 20, 40, 60,.80.or and other sorbitans Span 20, 40, 60, 80 or 85). Compositions with a surface-active agent will conveniently comprise between 0.05 and 5% surface-active agent, and preferably between 0.1 and It will be 15 appreciated that other ingredients may be added, for example mannitol or other pharmaceutically acceptable vehicles, if necessary.
Suitable emulsions may be prepared using commercially available fat emulsions, such as Intralipid, LiposynT, InfonutrolM, LipofundinM and LipiphysanTM. The active ingredient may be either dissolved in a premixed emulsion composition or alternatively it may be dissolved in an oil soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and an emulsion formed upon mixing with a phospholipid egg phospholipids, soybean phospholipids or soybean lecithin) and water. It will be appreciated that other ingredients may be added, for example glycerol or glucose, to adjust the tonicity of the emulsion. Suitable emulsions will typically contain up to 20% oil, for example, between 5 and The fat emulsion will preferably comprise fat droplets between 0.1 and 1.
0 m, particularly 0.1 and 0.5um, and have a pH in the range of to Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, ST 1 xA l or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulised by use of inert gases. Nebulised solutions may be breathed directly from the nebulising device or the nebulising device may be attached to a face mask.
tent or intermittent positive pressure breathing machine. Solution.
suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
Compositions of the present invention may also be presented for administration in the form of trans-dermal patches using conventional technology. The compositions may also be administered via the buccal S 15 cavity using, for example, absorption wafers.
Compositions in the form of tablets, pills, capsules or wafers for oral S* administration are particularly preferred.
The present invention further provides a process for the preparation of a pharmaceutical composition comprising a NK-1 receptor antagonist 20 and an antipsychotic agent, which process comprises bringing a NK-1 receptor antagonist and an antipsychotic agent, into association with a pharmaceutically acceptable carrier or excipient.
When administered in combination, either as a single or as separate pharmaceutical composition(s), the NK-1 receptor antagonist and an antipsychotic agent are presented in a ratio which is consistent with the manifestation of the desired effect. In particular, the ratio by weight of the NK-1 receptor antagonist and the antipsychotic agent will suitably be between 0.001 to 1 and 1000 to 1, and especially between 0.01 to 1 and 100 to 1.
A minimum dosage level for the NK-1 receptor antagonist is about per day, preferably about 10mg per day and especially about -37per day. A maximum dosage level of or the NK-1 receptor antagonist is about 1500mg per day, preferably about 1000mg per day and especially about 500mg per day. The compounds are administered one to three times daily, preferably once a day.
A minimum dosage level for the antipsychotic agent will vary depending upon the choice of agent, but is typically about 0.5mg per day for the most potent compounds or about 20mg per day for less potent compounds. A maximum dosage level for the antipsychotic agent is typically 30mg per day for the most potent compounds or 200mg per day for less potent compounds. The compounds are administered one to three times daily, preferably once a day.
It will be appreciated that the amount of the NK-1 receptor antagonist required for use in the treatment or prevention of mania will vary not only with the particular compounds or compositions selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the patient's physician or pharmacist.
When used in combination, it will be appreciated that the amount of the NK-1 receptor antagonist and the antipsychotic agent required for use in the treatment or prevention of mania will vary not only with the particular compounds or compositions selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of o 20 the patient's physician or pharmacist.
The compounds of formulae (IIa) and (IVa) may be prepared by the methods described in EP-A-0 577 394 (or WO 95/16679), WO 95/18124 and WO 96/05181 ,o respectively.
Particularly preferred NK-1 receptor antagonists of the formulae (IIa) and 25 (IVa) for use in the present invention are compounds which are potent NK-1 receptor antagonists, i.e. compounds with an NK-1 receptor affinity (ICso) of less than A particularly preferred class of NK-1 receptor antagonist of use in the present invention are those compounds which are orally active, long acting and CNS-penetrant.
Such compounds may be identified using the pharmacological assays described hereinafter. The use of this sub-class of NK-1 antagonists in the treatment or prevention of mania represents a further aspect of the present invention.
Thus, the present invention provides the use of a CNS penetrant NK-1 receptor antagonist in an oral, once-a-day medicament for the treatment of mania. The compounds of this class advantageously exhibit a rapid onset of action and a reduced side-effect P 35 q ofile when compared against conventional treatments of mania.
[I:\DAYLB\Jibz05522.doc:am In particular, the present disclosure provides a means for the identification of NK-1 receptor antagonists which would be especially effective in an oral once-a-day medicament for the treatment of mania.
The exceptional pharmacology of the class of orally active, long acting, CNSpenetrant NK-1 receptor antagonists (as hereinafter defined) of use in the present invention enables the treatment of mania, without the need for concomitant therapy and in particular, without the need for concomitant use of antipsychotic agents.
Furthermore, the exceptional pharmacology of the class of NK-1 receptor antagonists of use in the present invention results in a rapid onset of action.
The present invention accordingly provides the use of an orally active, long acting, CNS-penetrant NK-1 receptor antagonist (as hereinafter defined) for the manufacture of a medicament adapted for oral administration for the treatment or prevention of mania.
^tc'.
[I:\DAYLIB\libz]05522.doc:1am The present invention also provides a method for the treatment or prevention of mania, which method comprises the oral administration to ;W pati.ent in need of such treatment of an effective amount of an ora lI ;active long acting, CNS-penetrant NK-1 receptor antagonis. (as h ereinafter defined).
In a further aspect of the present invention, there is provided an oral pharmaceutical composition for the treatment of mania which comprises an orally active, long acting, CNS-penetrant NK-] receptor antagonist (as hereinafter defined), together with a pharmaceutically acceptable carrier or excipient.
There exists a patient population in whom mania is inadequately treated with lithiun. Furthermore, some patients may be adversely affected by the side-effects of lithium.
The present invention accordingly provides the use of an orally 15 active, long acting, CNS-penetrant NK-1 receptor antagonist for the o:oo manufacture of a medicament adapted for oral administration for the treatment or prevention of mania in a patient who is non-responsive to lithium or for whom lithium is contraindicated.
The present invention also provides a method for the treatment or 20 prevention of mania in a patient who is non-responsive to lithium or for whom lithium is contraindicated, which method comprises oral administration to a patient in need of such treatment of an effective amount of an orally active, long acting, CNS-penetrant NK-1 receptor antagonist.
25 There also exists a patient population in whom mania is inadequately treated with antipsychotic agents. Furthermore, some patients may be adversely affected by the side-effects of antipsychotic agents such that the use of an antipsychotic agent, alone or in combination with a NK-1 receptor antagonist, would be undesirable.
The present invention accordingly provides the use of an orally Sactive, long acting, CNS-penetrant NK-1 receptor antagonist for the manufacture of a medicament adapted for oral administration for the treatment or prevention of mania in a patient who is non-responsive to antipsychotic agents or for whom antipsychotic agents are is contraindicated.
The present invention also provides a method for the treatment or prevention of mania in a patient who is non-responsive to antipsychotic agents or for whom antipsychotic agents are contraindicated, which method comprises oral administration to a patient in need of such treatment of an effective amount of an orally active, long acting, CNS-penetrant NK-1 receptor antagonist.
Preferred NK-1 receptor antagonists for use in the present invention as orally active, long acting, CNS-penetrant NK-1 receptor antagonists are selected from the classes of compounds described in European Patent Specification No. O 577 394, and International Patent Specification Nos. 95/18124 and 96/05181. The preparation of such compounds is fully described in the aforementioned publications.
Thus, further particularly preferred NK-1 receptor antagonists of use in the present invention include: 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3(S)-(4-fluorophenyl)-4-(3-(5-oxo- H,4H- 1, 2 4 -triazolo)methyl)morpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(3-(5-oxo 1H,4H-1,2,4triazolo)methyl)-3-(S)-phenyl-morpholine; 2 3 ,5-bis(trifluoromethyl)benzyloxy)-4-(3-(5-oxo -IH,4H-1,2,4-triazolo)methyl)-3- (S)-phenyl-morpholine; -(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo- 1H,4H-1 2 4 -triazolo)methyl)morpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-dimethylamino)methyl- 1,2,3-triazol-4-yl)methyl-3-(S)-phenylmorpholine; -(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-dimethylamino)methyl- 1,2,3-triazol-4-yl)methyl-3-(S)-( 4 -fluorophenyl)morpholine; 1 -(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-N,N-dimethylaminobut-2-yn- 4 -fluorophenyl)morpholine; -(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4fluorophenyl)- 4-(1, 2 4 -triazol-3-yl)methylmorpholine or a pharmaceutically acceptable salt thereof.
Full descriptions of the preparation of the NK-1 receptor antagonists may be found in the references cited herein.
[I:\DAYLIB\ibz]05522.doc:Iam Particularly preferred NK-1 receptor antagonists of use in the present invention are compounds which are potent NK-1 receptor antagonists, i.e. compounds with an NK-I receptor affinity (ICso) of less than 10nM, favourably less than 2nM and preferably less than nM.
The class of orally active, long acting, CNS-penetrant NK-1 receptor antagonists of use in the present invention is identified using a combination of the following assays: ASSAY 1: NK-1 Receptor binding NK-1 receptor binding assays are performed in intact Chinese hamster ovary (CHO) cells expressing the human NK-1 receptor using a modification of the assay conditions described by Cascieri et al, J Pharmacol. Exp. Ther., 1992, 42, 458. The receptor is expressed at a level of 3x10 5 receptors per cell. Cells are grown in monolayer culture, detached from the plate with enzyme-free dissociation solution (Speciality Media Inc.), and washed prior to use in the assay. 125 I-Tyr 8 -substance P (0.lnM, 2000Ci/mmol; New England Nuclear) is incubated in the presence or absence of test compounds (dissolved in 5[l dimethylsulphoxide, DMSO) with 5x10 4 CHO cells. Ligand binding is preformed in 0.25ml of 50mM Tris-HC1, pH7.5, containing 5mM MnCI 2 150mM NaCI, 0.02% bovine *o [I:\DAYL1B\libz]05522.doc:am rum albumin (Sigma), 50ig/inl chymostatin (Peninsula), 0. InM )c Illmeithlsulphon11 vl fluoride, 2p1g/ml pepstatin, 2 pg/ml leupeptin and 2 .8pig/m furoyl saccharine. The incubation proceeds at, room temperature until equilibrium is achieved (>40 minutes) and the receptor-ligand complex is harvested by filtration over GF/C filters pre-soaked in 0.1% polyve tylenimine u-sing a Tomtk 96-well harvester. Non-specific bindin is determined using excess substance P and represents <10% of I tl binding.
ASSAY 2: Gerbil Foot-Tapping CNS penetrant NJK-1 receptor antagonists for use in the preseni invntion can be identified by their ability to inhibit foot tapping in gerbils induced by central infusion of NK-1 receptor agonists such as GR73632 based on the method of Rupniak Williams, Eur. J. Pharinacol., 1994, 265, 179.
.*Briefly, male or female Mongolian gerbils 3 5 7 0g) are anaesthetised )by inhalation of an isoflurane/oxygen mixture to permit SCexposure of the jugular vein in order to permit administration of test compounds or vehicle in an injection volume of 5ml/kg i.v. Alternatively, Lest conmpounds may be administered orally or by subcutaneous or intraperitoneal routes. A skin incision is then made in the midline of the scalp to expose the skull. A selective NKI-1 receptor agonist GR73632 (d Ala[L-Pro,Me-Leu1o]-substance is infused directly into the a cerebral ventricles 3pmol in 5pl depending on test substance) by vertical insertion of a cuffed 27 gauge needle to a depth of 4 .5mm below bregma. The scalp incision is closed and the animal allowed to recover from anaesthesia in a clear perspex observation box (25cm x 20cm x The duration of hind foot tapping is then recorded continuously for approximately 5 minutes.
ASSAY 3: Ferret Emesis Individually housed male ferrets (1.0 -2.5 kg) are dosed oraliv hv gavage with test compound. Ten minutes later they are fed with approximately 100g of tinned cat food. At 60 minutes following oral Sdosing, cisplatin (10mg/kg) is given i.v. via a jugular vein catheter inserted under a brief period of halothane anaesthesia. The catheter is then removed, the jugular vein ligated and the skin incision closed. The ferrets recover rapidly from the anaesthetic and are mobile within 10-20 minutes. The animals are observed continuously during recovery from the anaesthetic and for 4 hours following the cisplatin injection. The numbers of retches and vomits occurring during the 4 hours after cisplatin administration are recorded by trained observers.
ASSAY 4: Separation-Induced Vocalisation I Male and female guinea-pigs pups are housed in family groups with their mothers and littermates throughout the study. Experiments are commenced after weaning when the pups are 2 weeks old. Before entering an experiment, the pups are screened to ensure that a vigorous vocalisation response is reproducibly elicited following maternal 20 separation. The pups are placed individually in an observation cage x 39cm x 19cm) in a room physically isolated from the home cage for minutes and the duration of vocalisation during this baseline period is recorded. Only animals which vocalise for longer than 5 minutes are employed for drug challenge studies (approximately 50% of available pups may fail to reach this criterion). On test days each pup receives an oral dose or an s.c. or i.p. injection of test compound or vehicle and is then immediately returned to the home cage with its mother and siblings for to 60 minutes before social isolation for 15 minutes as describe'd above.
The duration of vocalisation on drug treatment days is expressed as a percentage of the pre-treatment baseline value for each animal. The same subjects are r.ested once weekly for up to C weeks. Between- G and 8 animals receive each test compound.
As used herein, the term "CNS-penetrant" refers to NK-] receptor antagonists which are able to inhibit NK-1 receptor antagonist-induced foot-tapping in the gerbil as hereinafter defined.
Essentially, hind foot-tapping in the gerbil induced by infusion ofthe NK-1 receptor agonist, GR73632 (d Ala[L-Pro,Me-Leuloj-substance
P-
under anaesthesia, directly into the central ventricles is inhibited when a CNS-penetrant NK-1 receptor antagonist is administered intravenously immediately prior to GR73632 challenge, wherein hind foottapping over a period of five minutes following recovery from the anaesthesia is inhibited with an IDs,503mig/kg, and preferably with an In an alternative method, the NK-1 receptor antagonist is 15 administered orally, 1 hour prior to GR73632 challenge, wherein the foottapping over a period of five minutes following recovery from anaesthesia is inhibited with an ID5o030mg/kg, and preferably with an IDsoIl0mg/kg.
CNS-penetrant NK-1 receptor antagonists of use in the present ivnention are also effective in the attenuation of separation-induced 20 vocalisations by guinea-pig pups as hereinafter defined.
Essentially, a vocalisation response in guinea-pig pups is induced by isolation from their mothers and littermates, which response is attenuated when a CNS-penetrant NK-1 receptor antagonist is administered subcutaneously 30 minutes prior to isolation, wherein vocalisations during the first 15 minutes of isolation are attenuated with an IDs5o20mg/kg, preferably with an ID5oslOmg/kg, and especially with an In an alternative method, the NK-1 receptor antagonist is administered orally, 4 hours prior to isolation, wherein vocalisations during the first 15 minutes of isolation are attenuated with an ID5so20mg/kg, preferably with an IDo51lOmg/kg, and especially with an A,<S n A suitable selection cascade for NKi anutivonists of use( accordi I to the present invention is as follows: Detiermine affinity for human NK 1 receptyor in radol igand binding studies (Assay select compounds with 1C,, 1OnnM prelerabhI SIC0o 5 2nM, especially IC 50
IM.
Determine ability of compounds to penetrate CNS byV their ability to inhibit foot tapping in gerbils induced by central injection of an t, cent. injection of' "InLIII.
I
NK agonist (Assay select compounds that inhibit foot tapping with
ID
5 o 3mg/kg and preferably IDso Img/kg i.v. when administered immediately prior to central NKi agonist challenge, or ID 50 30mg/kg p.o.
and preferab] il),r 10mg/kg p.o. 1 hour prior to challenge (iii) Determine central duration of action of compounds in gerbil foot tapping assay following intravenous administration 24 hours prior to central NKi agonist challenge; select compounds showing fold loss of potency compared with ID 5 o determined in step (ii) above with the proviso that ID 5 0 n 10mg/kg and preferably 5mo/kg i.v. after 294 hour pre-treatment.
(iv) Determine oral bioavailability of compounds by pharmacokinetic analysis, activity in gerbil foot tapping assay following 20 oral administration and/or by ability to inhibit cisplatin-induced emesis in ferrets (Assay select compounds with ID 90 3mg/kg and preferably
ID
9 o 1mg/kg p.o.
Particularly preferred compounds of use in the present invention are identified using steps to (iv) followed by step Determine activity of compounds in assays sensitive to conventional antipsychotic drugs (inhibition of distress vocalisations in guinea-pig pups (Assay Select compounds with IDo 5 20mng/kg, and preferably
ID
5 0 5 Yet further preferred compounds of use in the present invention may be selected from those compounds which satisfy the NK-1 recep~tor hiin(li n( criteria of step 0i) wich, InI addI (iti0l. have _<5-fold si f-I III affinitv when incub~ated In the pre(SnC(*C Of hun serum alb~um (1-SA) to shww non-specific protein binlding.Z1 One example of a NIL-i receptor anta,-onist, of, use, In the present i nv~entIon Is the. compound S-bis(t~rifluor-omietli,,)l)lreNlwI)ethoXv) 3 (4 -fluorop henyJ)-4 5-oxo- 1H,.41-11 4 -tri zolco))IetlW)1 morpholine, the preparation of which is described inI International Pa-tent Specification No. WO 95/16679. In the aforementioned assays, this comp~ound has the following activity: humani NIL-i receptor binding: gerbil foot-tappi ng (5 mnins.): gerbil foot-tapping (24 hrs.): ferret. emesis: guinea pig vocalisation (4 hr. pre-treatment): IC50=0. 1.11M ITD50=0.36mg-/kg I.v.
ID ,o=0.33ing/kg iAv.
TD9o<3mg/kg p.o.
ID~ro=0.73rng/kg p.o.
00 0 Lo 0 et 0 be*.
0 0 g o A further example of a NIL-i receptor antagonist of use in the present invention is the compound bis(trifluoromethylI)phenyly)2-hydroxyethox3f) 3 4 -fluorophenyl)-4 15 (l, 2 4 -triazol-3-yl)methylmorpholine, the preparation of which is described in International Patent Specification No. WO7 95/18124 and US Patent No.
5,612,337.. In the aforementioned assays, this compound has the following activity: human NK-1 receptor binding: gerbil foot-tapping (5 mins.): gerbil foot-tapping (24 hrs.): ferret emesis: guinea-pig vocalisation (4 hr. pre-treatment):
IC
5 0z
ID
50 o
ID
5 0z ID,,go 0.12 nM 0.38 mg/kg i.
2.2 mg/kg I.
1 mg/kg p.o.
1Df 5 o 0.91 mag/kg p.o.
The following example illustrates pharmaceutical compositions according to the invention.
EXAMPLE Tabets containing 50-300mg of NIK-i antaonist Amount mg NK-1 antagonist 50.0 100.0 300.0 Microcrystalline cellulose 80.0 80.0 80.0 Modified food corn starch 80.0 80.0 80.0 Lactose 189.5 139.5 139.5 Magnesium Stearate 0.5 0.5 The active ingredient, cellulose, lactose and a portion of the corn starch are mixed and granulated with 10% corn starch paste. The resulting granulation is sieved, dried and blended with the remainder of 10 the corn starch and the magnesium stearate. The resulting granulation is then compressed into tablets containing 50mg, 100mg and 3 0 0mg of the NK-1 receptor antagonist per tablet.
0
S
p 0
S.
0
S
5 0 EXAMPLE 2 Parenteral injection 15 Active Ingredient Citric Acid Monohydrate Sodium Phosphate Sodium Chloride Water for injection Amount 10 to 300mg 0.75mg 9mg to The sodium phosphate, citric acid monohydrate and sodium chloride are dissolved in a portion of the water. The active ingredient is dissolved or suspended in the solution and made up to volume.
Phiarm-aceutical 1COmposition 'oprsing a con-bination of a NK-i recepwtr antagonist, and an antip-coic agent mnay elrrdwt separate active ingredients or with a combination of active Jn uede11"q one composition. In such comnbined preparations, the ratio of the NVr-] receptor antagonist- and the antipsychotic ae. ill depend upon tHie ch-oice of active ingredients.
EXAMVVNPLE 3 Tablets containing 50-300mg of NVT-1 antagonis. andl Omg of haloperidol NV- I gonisl lia1101) iido] Ilicrocrystalline cellulose M\4odified food corn starchi Lactose Magnesi'um Stearate 50.0 5. 0 80.0 80.0 184.5 0.5 150.0 10.0 80.0 80.0 179.5 -0.5 Amnount mg 100.0 100.0 5.0 10.0 80.0 80.0 80.0 80.0 134.5 129.5 0.5 0.5 80.0 80.0 1134.5 0. 5 10.0 80.0 80.0 129.5 *00 00 0 0 b 000.
0000 0 0 0600 00 00 0 @0 0 0000 0 0000..
S
000.
00 00 ~0 0 0000..
0 0000
S
0 OOOk 00 000 0 0000 0 0000 0 600000 o 0 100000 0 0 EXAMPLE 4 Tablets containing 5O-300mg of NK- I antagonist and 2 of chlorpromazine hydrochloride NK-1 antagonist chlorpromazine hydrochloride Micro crystalline cellulose Modified food corn starch Lactose Magnesium Stearate Amount me, 50.0 100.0 300.0 25.0 25.0 25.0 80.0 80.0 80.0 80.0 80.0 80.0 164.5 114.5 114.5 0.5 0.5 The active ingredients, cellulose, lactose and a portion of the corn starch are mixed and granulated with 10% corn starch paste. The rc~ ring jira no lario iS sicved, dried and blended with the remainder of, Ow corn starch and the ma gonesi ui ste arate. The resulting granulation iS tlen compressed into tablets containing 5 Om.19, lOOm-ng and 300ing of the GNS-penetra f: NE-1 receptor llta gom st per tablet.
Ile

Claims (12)

1. A method for the treatment or prevention of mania or hypomania, which method comprises the oral adcninistration to a patient in need of such treatment of an effective amount-of a NK- 1 receptor antagonist, wherein the NK- 1 receptor antagonist is a compound of formula X 1 (1) 2 N 1 R R wherein 10 R 1 is selected from the group consisting of: Cil.alkyl, substituted with one or more of the substituents o: selected from: heterocycle, wherein the heterocycle is selected from the group consisting of: benzimidazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, 20 pyrazinyl, pyrazolyl, pyridyl, pyrrolyl, tetrazolyl, thiadiazolyl, triazolyl, and piperidinyl, S S S and wherein the heterocycle is unsubstituited or suibstituted with one or more substituent(s) selected from: Ci-(;alkyl, unsubstituteci or substituted with halo. -OF: 3 -OCI-li, or phenyl, oxo, (iv) thioxo, cyano, (vi) -SCH:i, phenyl, (viii) hyd-roxy, (ix) trifluoromethyl, (x -(CH2),l,-NR9RO, wherein m, is 0, 1 or 2, and R 9 'and RJO are independently selected from: hydrogen, (III) hydroxyC]icalkyl, and (IV) phenyl, (x1) -NR9CORO, wherein R9 and RIO are as defined above, and (xii) -CONR 9 RO, wherein R9 and RIO are as defined above, W 2 and R3 are independently selected from the group consisting of: hydrogen; CI-6alkyl C2-6alkenyl, and phenyl; X is R 4 1is Z I is phenyl, unsubstituted or substituted with halo; R 6 R 7 and R 8 are independently selected from the group consisting of: hydrogen, C.calkyl, halo, and -CF 3 Yis and Z is hydrogen or C i.alkyl; 10 or a pharmaceutically acceptable salt thereof.
2. A NK-1 receptor antagonist of formula as defined in Claim 1 when used for the treatment or prevention of mania or hypomania. prevention of mania or hypomania.
4. A method for the treatment or prevention of mania or hypomania, which method comprises the oral administration to a patient in need of such treatment of an effective amount of a NK-1 receptor antagonist, wherein the NK- 1 receptor antagonist is a compound of formula (Ha): formula (IIa): (I In) wherein: A' is fluorine or CF 3 A 2 is fluorine or CF 3 A 3 is fluorine or hydrogen; RG is a 5-membered or 6-membered heterocyclic ring containing 2 or 3 nitrogen atoms optionally substituted by =S or a Ci. 4alkyl group, and optionally substituted by a group of the formula ZNR7R8 where 1 0 Z is Ci-6alkylene or C3.scycloalkylene; ;R 7 is hydrogen, C1.4alkyl, Cs.7cycloalkyl or C3-7cycloalkylCi. 4alkyl, or C2-4alkyl substituted by C1.4alkoxy or hydroxyl; R8 is hydrogen, Ci-4alkyl, C3.7cycloalkyl or C3-7cycloalkylCi. 4alkyl, or C2.4alkyl substituted by one or two substituents selected from Ci. 15 4alkoxy, hydroxyl or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, 0 and S; or R 7 R8 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by a hydroxy group, and optionally containing a double bond, which ring may optionally contain an oxygen or sulphur ring atom, a group S(0) or S(0) 2 or a second nitrogen atom which will be part of a NH or NR moiety where Rc is Ci-4alkyl optionally substituted by hydroxy or CI.4alkoxy; or R 7 R 8 and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms; -54- or Z, R 7 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms which may optionally contain an oxygen ring atom; X is an alkylene chain of 1 to 4 carbon atoms optionally substituted by oxo; and Y is a Ci.-alkyl group optionally substituted by a hydroxyl group;- with the proviso that if Y is Ci-,ialkyl, R is substituted at least by a group of formula ZNR7RS as defined above; or a pharmaceutically acceptable salt thereof. A NK-1 receptor antagonist of formula (Ia) as defined in Claim 4 when used for the treatment or prevention of mania or hypomania.
6. Use of a NK-1 receptor antagonist of formula (IIa) as defined in Claim 4 for the manufacture of a medicament for the treatment or prevention of mania or hypomania. 20 7. A method for the treatment or prevention of mania or hypomania, which method comprises the oral administration to a patient in need of such treatment of an effective amount of a NK-1 receptor antagonist, wherein the NK-1 receptor antagonist is a compound of formula Va): formula (IVa): ring. Y is hyrogen or Ci e fo iyi oi NR Bonall su- or N -ti ke by aI i (I aol y A' is fluorine or A 2 is fluorine or OF 3 :NA is fluorine or hydrogen; R 6 is hydrogen, CI1.6alkyl, C3-7cycloalkyl, C:3-7cycloalkylC .,alkyl, phenyl, Or C2. 4 alkyl substituted byC CI4alkoxy or hydroxy; R 7 is hydrogen, Cl-calkyl, C:37cycloalkyl, C3.7cycloalkylC.,ialky1, phenyl, Or C2-4alkyl substituted by one or two substituents selected from C 1-4alkoxy, hydroxy or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, 0 and S; or W 6 and R 7 together with the nitrogen atom to which they are attached, form a saturated or partially saturated heterocyclic ring of 4 to 7 ring atoms, which ring may optionally contain in the ring one oxyg en or sulphur atom or a group selected from NR 8 S(0) Or S(0) 2 and which ring may be optionally substituted by one or two groups selected from hydroxyCl. 4 alkyl, C 1.4alkoxyC]-4alkyl, oxo, C0R,, or CO2R- where Rn is hydrogen or CI~alkyl; or R' and R 7 together with the nitrogen atom to which they are attached, form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms; R 8 is hydrogen, Ci.alkyl, hydroxyCi-alkyl. or Ci-i.alkoxyC_-ialkyl; or a pharmaceutically acceptable salt thereof.
8. A NK-1 receptor antagonist of formula (IVa) as defined in Claim 7 when used for the treatment or prevention of mania or hypomania.
9. Use of a NK-1 receptor antagonist of formula (IVa) as defined in Claim 7 for the manufacture of a medicament for the treatment or "".prevention of mania or hypomania. 15 10. A pharmaceutical composition for the treatment or prevention of mania or hypomania comprising a NK-1 receptor antagonist :of formula (IIa) or (IVa) as defined in claims 1, 4 or 7, respectively, together with at least one pharmaceutically acceptable carrier or excipient.
11. A composition according to claim 11 which further comprises an antipsychotic agent.
12. A method for the treatment or prevention of mania or hypomania, which method comprises administration to a patient in need of such treatment of an amount of a NK- 1 receptor antagonist of formula (IIa) or (IVa) as defined in claims 1, 4 or 7, respectively, and an amount of an antipsychotic agent, such that together they give effective relief.
13. A NK- 1 receptor antagonist of formula (Hla) or (IVa) as defined iM claims 1, 4 or 7, respectively, and an antipsychotic agent, when used for the treatment or prevention of mania or hypomania.
14. Use of a NK- I receptor formula (Ia) or (IVa) as defined in claims 1, 4 or 7, respectively, and an antipsychotic agent for simultaneous. separate or sequential administration for the manufacture of a medicament for the treatment or prevention of mania or hypomania.
15. A method, NK-1 receptor antagonist or use according to any one of claims 1 to 3 and 12 to 14, or a composition according to claim 10 or 11, wherein the NK-I receptor antagonist is selected from 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)3 (S)-(4-fluorophenyl)-4-(3-(5-oxo- lH,4H- 1,2 4 -triazolo)methyl)morpholine; 2 -(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy).4-(3(5-oxo 1H,4H- 1,2 4 -triazolo)methyl)-3 -(S)-phenyl-morpholne; 2 -(S)-(3,5-bis(trifiuoromethyl)benzyloxy)-4-(3.(5-oxo- lH,4H- 1,2,4- triazolo)methyl)-3-(S)-phenyl-morpholine; 2 -(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)3-(S)-(4-fluorophenyl)- 4 lH,4H-1,2, 4 -triazolo)methyl)morpholine; or a pharmaceutically acceptable salt thereof.
16. A method, NK-1 receptor antagonist or use according to any one of claims 4 to 6 and 12 to 14, or a composition according to claim 10 or 11, wherein the NK- 1 receptor antagonist is selected from 2-(R)-((R)-(3,5-bis(trifluoromhnlethoxy-4-5-(,N dimethylamino)methyl 1,2,3-triazol-4-yl)nethyl-3-(S)-phenylmorpholne; dimethylamino)methyl. 1,2,3-triazol-4-yl)nethyl-3-(S)-(4- fluorophenyl)morpholine; -S )(85-hi. s(I rif I uo roni ciii l) I) heny I) -2-hN dlroxyet I 1-11001] henI vi. 1411 1 -rizo -\1l)1methyIIImo rp hohneI:( Or 1I 1)1ai cwicii cep tlale salt, th ereof" 1 i. A' inotho(1 NNi- I r.ecep]tlo ant~ago ni st, or use accor I I g to anly 01 O,,I o I nlis 7 to 9 aind 1 2 to I1. Or a com I)os Ition a ccord-ing2 to c Ia In 10 orI 1 \l we rein the NlxK- 1. rOe) to v antagonist;- is selected fromn .5-1)1s(tri L 1-11 e Homett)ph)11ellYl)etho11Xy N dinmethya Ifll~-- -I--S-4i.oohnlmrhhe H or a phamaetciyacceptable salt-, thereof. Dated 10 July, 2001 Merck Sharp Dohme Limited Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON
AU91606/98A 1997-08-04 1998-07-31 Use of NK-1 receptor antagonists for treating mania Ceased AU738047B2 (en)

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GB9812612 1998-06-11
GBGB9812612.1A GB9812612D0 (en) 1998-06-11 1998-06-11 Therapeutic use
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