AU737019B2 - Use of NK-1 receptor antagonists for treating aggressive behaviour disorders - Google Patents

Use of NK-1 receptor antagonists for treating aggressive behaviour disorders Download PDF

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AU737019B2
AU737019B2 AU91605/98A AU9160598A AU737019B2 AU 737019 B2 AU737019 B2 AU 737019B2 AU 91605/98 A AU91605/98 A AU 91605/98A AU 9160598 A AU9160598 A AU 9160598A AU 737019 B2 AU737019 B2 AU 737019B2
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phenyl
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ethoxy
fluorophenyl
bis
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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
    • 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
    • A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine

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Description

WO 99/07375 PCT/EP98104933 -1- USE OF NK-1 RECEPTOR ANTAGONISTS FOR TREATING AGGRESSIVE BEHAVIOUR DISORDERS This invention relates to the treatment or prevention of aggressive behaviour by the administration of a NK-1 receptor antagonist.
Aggressive behaviour when uncontrolled or out of proportion to any provocation may give rise to a condition which requires medication.
Individuals with narcissistic, obsessive, paranoid or schizoid traits may be especially prone to outbursts of aggressive behaviour, especially when under stress. When particularly severe, aggressive behaviour may lead to job loss, difficulties with marriage and interpersonal relationships, school suspension, accidents, hospitalization or incarceration.
Treatment of aggressive behaviour is with drugs and psychological management. Typically, antipsychotic drugs such as haloperidol or chlorpromazine may be used to control symptoms. However, antipsychotic drugs are typically associated with a number of side-effects, 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.
Studies into the possible CNS site for aggressive behaviour have focused upon the amygdala. In cats, electrical stimulation of the amygdala facilitates the emergence of "defensive rage" syndrome elicited by stimulation of the hypothalamus. This syndrome comprises attack behaviour and vocalisation which is accompanied by marked sympathetic arousal. The antidepressants imipramine, desmethylimipramine and chlorimipramine have been found to block attack behaviour caused by hypothalamic stimulation in cats Dubinsky M.E. Goldberg, Neuropharmacology (1971) 10:537). The neurochemical mechanisms underlying amydaloid modulation of aggressive behaviour in the cat have been investigated by Allan Siegel and his co-workers (Aggressive WO 99/07375 PCT/EP98/04933 -2- Behaviour (1995) 21:49-62). Whilst it is clear that substance P has a role as a principle neurotransmitter in the pathway between the medial nucleus of the amygdala to the medial hypothalamus, the apparent organisation of pathways from the amydala which modulate defensive rage behaviour at the level of the medial hypothalamus and the midbrain periaqueductal gray (PAG) sites, suggests that substance P is one of many neurotransmitters which are intimately involved in the aggressive behaviour response.
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).
More recently, International (PCT) patent specification No. WO 96/24353 (published 15th August 1996) suggests that a more efficacious and safe treatment of psychiatric disorders would be achieved using a combination of a tachykinin antagonist and a serotonin agonist or selective serotonin reuptake inhibitor (SSRI). However, such as regimen would not be free of side-effects due to the serotonin agonist or 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 aggressive behaviour disorders. Furthermore, there is no direction in WO 96/24353 that would lead the skilled reader to the identification of any NK-1 receptor antagonist that would be effective in the treatment of aggressive behaviour disorders. Also, it will be appreciated that agonism of the 5-HT1A receptor and inhibition of serotonin reuptake are not generally recognised as mechanisms associated with the action of antipsychotic drugs.
In view of the short-comings of existing agents for the treatment of aggressive behaviour, there is a need for new, safe and effective treatment of aggressive behaviour.
The present invention accordingly provides the use of an orally active, long acting, CNS-penetrant NK-1 receptor antagonist for the manufacture of a medicament for the treatment or prevention of aggressive behaviour.
The present invention also provides a method for the treatment or prevention of aggressive behaviour, which method comprises administration to a patient in need of such treatment of an effective amount of an orally active, long acting, CNS-penetrant
NK-I
receptor antagonist.
In a further aspect of the present invention, there is provided a pharmaceutical composition adapted for oral administration for the treatment or prevention of aggressive behaviour comprising an orally active, long acting, CNS-penetrant NK-1 receptor antagonist, together with at least one pharmaceutically acceptable carrier or excipient.
It will be appreciated that a combination of a conventional antipsychotic drug 1is5 with a NK-1 receptor antagonist may provide an enhanced effect in the treatment of aggressive behaviour. Such a combination would be expected to provide for a rapid onset of action to treat an aggressive outburst thereby enabling use on an "as needed basis".
Furthermore, such a combination may enable a lower dose of the antispychotic agent to be used without compromising the efficacy of the antipsychotic agent, thereby 20 minimising the risk of adverse side-effects. A yet further advantage of such a *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 an orally active, long acting, CNS-penetrant NK-1 receptor antagonist and an antipsychotic agent for the manufacture of a medicament for the treatment or prevention of aggressive behaviour.
The present invention also provides a method for the treatment or prevention of aggressive behaviour, which method comprises administration to a patient in need of such treatment of an amount of an orally active, long acting, CNS-penetrant NK-1 receptor antagonist and an amount of an antipsychotic agent, such that together they give effective relief.
In a further aspect of the present invention, there is provided a pharmaceutical composition comprising an orally active, long acting, CNS-penetrant NK-1 receptor antagonist 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 use for the treatment or prevention of aggressive behaviour. Such combined preparations may be, for example, in the form of a twin pack.
In a further or alternative aspeet of the present invention, there is therefore provided a product comprising an orally active, long acting, CNS-penetrant NK-1 receptor antagonist and an antipsychotic agent when used simultaneously, separately or sequentially in the treatment or prevention of aggressive behaviour.
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 15 are taken simultaneously. The term "combination" also refers to the case where the :o compounds are provided in separate dosage forms and are administered sequentially.
Therefore, by way of example, the antipsychotic 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 20 form. By a O* R1! LIBZ]05507.doc:lam ,.O WO 99/07375 PCT/EP98/04933 "fast-dissolving oral formulation" is meant, an oral delivery form which when placed on the tongue of a patient, dissolves within about 10 seconds.
As used herein, the term "aggressive behaviour" includes explosive personality disorder, intermittent explosive disorder, aggressive personality, aggressive nature, aggressiveness, excessive emotional instability, pathological emotionality, quarrelsomeness, dementia with behavioural disturbance, and personality change of the aggressive type due to a general medical condition.
Aggressive behaviour may also be associated with substance intoxication, substance withdrawal, oppositional defiant disorder, conduct disorder, antisocial personality disorder, borderline personality disorder, a manic episode and schizophrenia.
As used herein, the term "treatment" refers both to the treatment and to the prevention or prophylactic therapy of aggressive behaviour.
NK-1 receptor antagonists of use in the present invention are described in published European Patent Specification Nos. 0 360 390, 0 394 989, 0 429 366, 0 443 132, 0 482 539, 0 512 901, 0 512 902, 0 514 273, 0 514 275, 0 517 589, 0 520 555, 0 522 808, 0 528 495, 0 532 456, 0 533 280, 0 536 817, 0 545 478, 0 577 394, 0 590 152, 0 599 538, 0 610 793, 0 634 402, 0 686 629, 0 693 489, 0 694 535, 0 699 655, 0 699 674, 0 707 006, 0 708 101, 0 714 891, 0 723 959, 0 733 632 and 0 776 893; and in International Patent Specification Nos.
90/05525, 90/05729, 91/09844, 91/18899, 92/01688, 92/06079, 92/12151, 92/15585, 92/17449, 92/20661, 92/20676, 92/21677, 93/00330, 93/00331, 93/01159, 93/01165, 93/01169, 93/01170, 93/06099, 93/09116, 93/10073, 93/14113, 93/18023, 93/19064, 93/21155, 9321181, 93/23380, 93/24465, 94/01402, 94/02461, 94/03429, 94/03445, 94/04494, 94/04496, 94/05625, 94/07843, 94/10165, 94/10167, 94/10168, 94/10170, 94/11368, 94/13639, 94/13663, 94/14767, 94/15903, 94/19320, 94/19323, 94/20500, 94/26735, 94/26740, 94/29309, 95/02595, 95/04040, 95/04042, 95/06645, 95/07886, 95/07908, 95/08549, 95/11880, 95/14017, 95/15311, 95/16679, 95/17382, WO 99/07375 PCT/EP98/04933 -6- 95/18124, 95/18129, 95/19344, 95/20575, 95/21819, 96/22525, 95/23798, 95/26338, 95/28418, 95/30674, 95/30687, 96/05193, 96/05203, 96/06094, 96/07649, 96/10562, 96/16939, 96/18643, 96/20197, 96/21661, 96/29304, 96/29317, 96/29326, 96/29328, 96/31214, 96/32385, 96/37489, 97/01553, 97/01554, 97/03066, 97/08144, 97/14671, 97/17362, 97/18206, 97/19084, 97/19942, 97/21702, 97/30055, 97/38692, 97/49710 and 98/01450 and in British Patent Specification Nos. 2 266 529, 2 268 931, 2 269 170, 2 269 590, 2 271 774, 2 292 144, 2 293 168, 2 293 169, 2 302 689, and 2 309 458.
Suitable antipsychotic agents of use in combination with a NK-1 receptor antagonist include the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and indolone classes of antipsychotic agent. Suitable examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, 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 haloperidol. An example of a diphenylbutylpiperidine is pimozide. An example of an indolone is molindolone. Other antipsychotic agents include loxapine, sulpiride and risperidone. 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 acceptable salt, for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, flurphenazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and molindone hydrochloride. Perphenazine, chlorprothixene, clozapine, olanzapine, haloperidol, pimozide and risperidone are commonly used in a non-salt form.
WO 99/07375 PCT/EP98/04933 -7- Particularly preferred NK-1 receptor antagonists are those described in European Patent Specification No. 0 577 394, i.e. compounds of formula X R 4
R
2 N
R
R'
or a pharmaceutically acceptable salt thereof, wherein:
R
1 is selected from the group consisting of: hydrogen; Ci-6alkyl, unsubstituted or substituted with one or more of the substituents selected from: hydroxy, oxo, C1.6alkoxy, phenyl-Cl.3alkoxy, phenyl,
-CN,
halo, -NR9RI 1 wherein R 9 and Rio are independently selected from: hydrogen, (ii) Cl.Galkyl, (iii) hydroxy-Cl-6alkyl, and (iv) phenyl, -NR9COR 10 wherein R 9 and Rio are as defined above,
-NR
9
CO
2
R
1 o, wherein R 9 and Rio are as defined above, -CONR9RlO, wherein R 9 and R 1 O are as defined above,
-COR
9 wherein R 9 is as defined above, -C0 2
R
9 wherein R 9 is as defined above, WO 99/07375 PCT/EP98/04933 -8heterocycle, wherein the heterocycle is selected from the group consisting of: benzimidazolyl, benzofuranyl, benzthiophenyl, benzoxazolyl, furanyl, imidazolyl, indolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, (L pyrazinyl, pyrazolyl, pyridyl, pyrimidyl, pyrrolyl, quinolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, (WV) azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, oxanyl, r.(AA) piperazinyl, (AB) piperidinyl, (AC) pyrrolidinyl, WO 99/07375 PCT/EP98/04933 -9- (AD) tetrahydrofuranyl, and (AE) tetrahydrothienyl, and wherein the heterocylcle is unsubstituted or substituted with one or more substituent(s) selected from: Cl-Galkyl, 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-NR 9 Ro, wherein m is 0, 1 or 2, and R 9 and RiO are as defined above, (xii) -NR 9 CORO, wherein R 9 and R 1 O are as defined above, (xiii) -CONR9R 10 wherein R 9 and R 10 are as defined above, (xiv) -CO 2
R
9 wherein R 9 is as defined above, and (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, Ci.calkoxy, phenyl-Cl.3alkoxy, phenyl,
-CN,
halo,
-CONR
9 Rio, wherein R 9 and Rio are as defined above, I WO 99/07375 PCTIEP98/04933
-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-Galkynyl; phenyl, unsubstitued or substituted with one or more of the substituent(s) selected from: hydroxy, C1-6alkoxy, Ci-.alkyl, halo,
-CN,
-NO
2
-CF
3
-(CH
2 )m-NR 9 R'o, wherein m, R 9 and R 10 are as defined above, -NRgCOR 10 wherein R 9 and R' 1 are as defined above, -NR9CO 2
R
1 O, wherein R 9 and R' 1 are as defined above, -CONRRo, wherein R 9 and Ri 1 are as defined above,
-CO
2 NR9R1 0 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;
R
2 and R 3 are independently selected from the group consisting of: hydrogen; Ci-ealkyl, unsubstituted or substituted with one or more of the substituents selected from: hydroxy, oxo, Ci-6alkoxy, WO 99/07375 PCT/EP98/04933 11 phenyl-Cl.3alkoxy, phenyl,
-CN,
halo, -NR9Rio, wherein R 9 and Rio are independently selected from: -NR9CORO, wherein R 9 and Rio are as defined above,
-NR
9
CO
2
R
10 wherein R 9 and R 1 O are as defined above,
-CONR
9 RO, wherein R 9 and R 1 O 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-calkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: hydroxy, oxo, Ci-calkoxy, phenyl-Ci-salkoxy, phenyl,
-CN,
halo, -CONR9Ri 1 wherein R 9 and R 1 O 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.-alkynyl; phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: hydroxy, Ci-6alkoxy,
C
1 i-alkyl, halo, WO 99/07375 PCT/EP98/04933 12-
-CN,
-NO
2
-CF
3 -(CH2)m-NR 9 Rlo, wherein m, R 9 and Ri 1 are as defined above, -NR9COR 1 O, wherein R 9 and Ri° are as defined above, -NR9CO 2
R
10 wherein R 9 and R 1 O are as defined above,
-CONR
9
R'
1 wherein R 9 and R 1 0 are as defined above,
-CO
2 NR9R 1 O, wherein R 9 and Rio are as defined above,
-COR
9 wherein R 9 is as defined above, -CO0 2
R
9 wherein R 9 is as defined above; and the groups R 1 and R 2 may be joined together to form a heterocyclic ring selected from the group consisting of: pyrrolidinyl, piperidinyl, pyrrolyl, pyridinyl, imidazolyl, oxazolyl, and thiazolyl, and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituent(s) selected from: C1.6alkyl, (ii) oxo, (iii) Ci-6alkoxy, (iv) -NR9R1I, wherein R 9 and Rio are as defined above, halo, and (vi) trifluoromethyl; WO 99/07375 PCT/EP98/04933 13and 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- 6 alkyl, (ii) C1-6alkoxy, (iii) -NR 9 R1 0 wherein R 9 and R 1 O 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, oxazolyl, thienyl, and thiazolyl, and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituent(s) selected from: Ci.ralkyl, (ii) oxo, (iii) Ci-Galkoxy, (iv) -NR 9 R1O, wherein R 9 and Rio are as defined above, halo, and I WO 99/07375 PCT/EP98/04933 14- (vi) trifluoromethyl; X is selected from the group consisting of: and -SO02-;
R
4 is selected from the group consisting of: (1)
R
6 z
R'
-Y-Ci-salkyl, wherein alkyl is unsubstituted or substituted with one or more of the substituents selected from: hydroxy, oxo, Cl.ralkoxy, phenyl-C1.3alkoxy, phenyl,
-CN,
halo, -NR9R10, wherein R 9 and R10 are as defined above,
-NR
9
COR
1 O, wherein R 9 and R 10 are as defined above, -NR9CO 2 Rl 0 wherein R 9 and R 1 o are as defined above, -CONRR1O, wherein R 9 and R 1 O 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-C
2 -6alkenyl, wherein the alkenyl is unsubstituted or substituted with one or more of the substituent(s) selected from: WO 99/07375 PCT/EP98/04933 hydroxy, oxo, Ci-6alkoxy, phenyl-Ci.-alkoxy, phenyl,
-CN,
halo,
-CONR
9
R'
1 wherein R9 and R 1 I are as defined above,
-COR
9 wherein R 9 is as defined above, -C0 2
R
9 wherein R 9 is as defined above, -O(CO)-phenyl, wherein the phenyl is unsubstituted or substituted with one or more of R 6
R
7 and R8;
R
5 is selected from the group consisting of: phenyl, unsubstituted or substituted with one or more of R 11
R
12 and R 13 Ci.salkyl, unsubstituted or substituted with one or more of the substituent(s) selected from: hydroxy, oxo, Ci-oalkoxy, phenyl-Ci-3alkoxy, phenyl,
-CN,
halo, -NR9R 1 O, wherein R 9 and Rio are as defined above,
-NR
9
COR
1 0 wherein R 9 and RIO are as defined above,
-NR
9
CO
2
R
1 O, wherein R 9 and R 1 O are as defined above, -CONR9RO, 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; WO 99/07375 PCT/EP98/04933 16- C2-6alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: hydroxy, oxo, C1.6alkoxy, phenyl-CI.3alkoxy, phenyl,
-CN,
halo,
-CONR
9
R'
1 wherein R 9 and R 1 0 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; RG, R 7 and R8 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, Ci-salkoxy, phenyl-Cl.3alkoxy, phenyl,
-CN,
halo, -NR9RO, wherein R 9 and Rio are as defined above, -NR9COR1o, wherein R 9 and R 1 0 are as defined above, -NR9CO 2
R
1 0 wherein R 9 and R 1 0 are as defined above, -CONR9R1 0 wherein R 9 and R 1 0 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; WO 99/07375 PCT/EP98/04933 17-
C
2 6 alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: hydroxy, oxo, Ci-.alkoxy, phenyl-C1.3alkoxy, phenyl,
-CN,
halo, -CONR9R 1 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; C2-6alkynyl; phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: hydroxy, Ci.-alkoxy, Ci-ealkyl, halo,
-CN,
-NO
2
-CF
3 -(CH2)m-NR 9
R
1 0 wherein m, R 9 and R 1 O are as defined above,
-NR
9
COR
1 0 wherein R 9 and R 1 o are as defined above, -NR9CO2R 1 O, wherein R 9 and R 10 are as defined above, -CONR9R 1 O, wherein R 9 and R 1 o are as defined above, -C0 2
NR
9
R
1 0 wherein R 9 and Rio are as defined above,
-COR
9 wherein R 9 is as defined above; -CO0 2
R
9 wherein R 9 is as defined above; WO 99/07375 PCT/EP98/04933 18halo,
-CN,
-CF
3
-NO
2 (10) -SR 14 wherein R 14 is hydrogen or C1.salkyl, (11) -SOR 14 wherein R 14 is as defined above, (12) -S0 2
R
1 4 wherein R 14 is as defined above, (13) NR9CORi 1 wherein R 9 and Rio are as defined above, (14) CONR9CORO, wherein R 9 and R 10 are as defined above, (15) NR 9
R
1 0 wherein R 9 and R 10 are as defined above, (16) NR 9
CO
2
R
10 wherein R 9 and Rio are as defined above, (17) hydroxy, (18) C1.6alkoxy, (19) COR 9 wherein R 9 is as defined above, (20) C0 2
R
9 wherein R 9 is as defined above,
R
11
R
1 2 and R 13 are independently selected from the definitions of R 6
R
7 and R 8 or -OX; Y is selected from the group consisting of: a single bond,
-CO-,
-CH
2
-CHR
15 and -CR15Ri 6 wherein R15 and R 1 6 are independently selected from the group consisting of: CI-6alkyl, unsubstituted or substituted with one or more of the substituents selected from: hydroxy, WO 99/07375 PCT/EP98/04933 19 (ii) oxo, (iii) OI-6alkoxy, (iv) phenyl-COl3alkoxy, phenyl, (vi) -CN, (vii) halo, (viii) -NR 9 RO, wherein R 9 and RIO are as defined above, (ix) -NR9COR 10 wherein R 9 and RIO are as defined above, -NR9C0 2 R'O, wherein R9 and R' 0 are as defined above, (xi) -CONR9RIO, wherein R 9 and RIO are as defined above, (xii) -COR9, wherein R9 is as defined above, and (xiii) -C0 2
R
9 wherein R9 is as defined above; phenyl, unsubstituted or substituted with one or more of the sub stituent(s) selected from: hydroxy, (ii) CI-6alkoxy, (iii) O]-6alkyl, (iv) halo, (vi) -ON, (vii) -NO 2 (viii) -OF 3 (ix) -(CH2)m-NR 9
RI
0 wherein m, R9 and RIO are as defined above, -NR900RO, wherein R9 and RIO are as defined above, (xi) -NR 9
CO
2 R'O, wherein R 9 and RIO are as defined jabove, (xii) -CONR9RO, wherein R 9 and RiO are as defined above, (xiii) -OO 2 NR9RiO, wherein R9 and RiO are as defined above, (xiv) -COR9, wherein R9 is as defined above, and (xv) -CO 2 R9, wherein R 9 is as defined above; WO 99/07375 PCT/EP98/04933 20 Z is selected from: hydrogen, C1.
4 alkyl, and hydroxy, with the proviso that if Y is Z is other than hydroxy, or if Y is -CHR 15 then Z and R 15 may be joined together to form a double bond.
Particularly preferred compounds of formula are those wherein:
R
1 is selected from the group consisting of: CI.Galkyl, substituted with one or more of the substituents selected from: heterocycle, wherein the heterocycle is selected from the group consisting of: benzimidazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyrazolyl, pyridyl, pyrrolyl, tetrazolyl, thiadiazolyl, triazolyl, and piperidinyl, and wherein the heterocycle is unsubstituted or substituted with one or more substituent(s) selected from: CI-6alkyl, unsubstituted or substituted with halo, -CF 3
-OCH
3 or phenyl, (ii) Ci.Galkoxy, (iii) oxo, WO 99/07375 PCT/EP98/04933 -21 (iv) thioxo, cyano, (vi) -SCH 3 (vii) phenyl, (viii) hydroxy, (ix) trifluoromethyl, -(CH2)m-NR 9
R
1 0 wherein m is 0, 1 or 2, and R9 and R 1 0 areindependently selected from: hydrogen, (II) C1i6alkyl, (III) hydroxyC1.6alkyl, and (IV) phenyl, (xi) -NR 9
COR
1 0 wherein R 9 and R 1 O are as defined above, and (xii) -CONR 9
R
1 0 wherein R 9 and R 1 O are as defined above,
R
2 and R 3 are independently selected from the group consisting of: hydrogen; Ci-Galkyl C2-6alkenyl, and phenyl; X is
R
4 is
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, Ci-6alkyl, halo, and WO 99/07375 PCT/EP98/04933 22
-CF
3 Y is and Z is hydrogen or C1.4alkyl; and pharmaceutically acceptable salts thereof.
Particularly preferred compounds of formula are: 4. 2, 4-triazolo)methyl)-2(S)-(3, 5-bis(trifluoromethyl)benzyloxy)-3(S)phenyl-morpholine; 4-triazolo)methyl)-2(S)-(3, 5-bis(trifluoromethyl)benzyloxy)- 3(R)phenyl-morpholine; 4-(3-(5-oxo- 1H,4H- 1,2,4-triazolo)methyl)-2(S)-(3,5bis(trifluoromethyl)benzyloxy)- 3(S)-phenyl-morpholine; and 5.bis(trifluoromethyl)phenyl)ethoxy)- (4-fluorophenyl)- 4-(3-(5-oxo- 1H,4H- 1,2, 4-triazolo)methyl)morpholine; or a pharmaceutically acceptable salt thereof.
Further preferred NK-1 receptor antagonists are those described in International (POT) Patent Specification No. WO 95/18124, i.e. compounds of formula (II): R>O R R Ra (IIY)
R
9 b IN4 R ~R or a pharmaceutically acceptable salt or prodrug thereof, wherein R' is hydrogen, halogen, C1.6alkyl, C1.Galkoxy, OF 3 N02, ON, SRa, SORa, SO 2 Ra, OO 2 Ra, CONRaRb, C2.6alkenyl, C2.Galkynyl or C 1 4 alkyl substituted by Ol.4alkoxy, where Ra and Rb each independently represent hydrogen or C1.
4 alkyl;
R
2 is hydrogen, halogen, Ol-Galkyl, Cl.6;alkoxy substituted by C1.4alkoxy or CF 3 WO 99/07375 PCT/EP98/04933 23
R
3 is hydrogen, halogen or CF 3
R
4 is hydrogen, halogen, C1.
6 alkyl, Ci.calkoxy, CF 3
NO
2 CN, SRa, SORa, SO 2
R
a
CO
2
R
a CONRaRb, C2-6alkenyl, C2.Galkynyl or C1.4alkyl substituted by C1.4alkoxy, where Ra and Rb each independently represent hydrogen or C1.4alkyl;
R
5 is hydrogen, halogen, Ci-Galkyl, C1-alkoxy substituted by Ci14alkoxy or CF 3
R
6 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 ZNRTR 8 where Z is C1.-alkylene or C3-6cycloalkylene;
R
7 is hydrogen, C1-4alkyl, C3.7cycloalkyl or C3-7cycloalkylC1.
4 alkyl, or C2- 4 alkyl substituted by C1.4alkoxy or hydroxyl;
R
8 is hydrogen, C1-4alkyl, C3.acycloalkyl or C3-7cycloalkylC1.
4 alkyl, or C2-4alkyl 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, 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 Re is C1.4alkyl optionally substituted by hydroxy or C1.4alkoxy; 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; 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 a and R 9 b are each independently hydrogen or C1.
4 alkyl, or R9a and
R
9 b are joined so, together with the carbon atoms to which they are attached, there is formed a C5-7 ring; WO 99/07375 PCT/EP98/04933 24- X is an alkylene chain of 1 to 4 carbon atoms optionally substituted by oxo; and Y is a C1-4alkyl group optionally substituted by a hydroxyl group; with the proviso that if Y is C1.
4 alkyl, RG is susbstituted at least by a group of formula ZNR 7 R8 as defined above.
Particularly preferred compounds of formula (II) are those of formula (IIa) and pharmaceutically acceptable salts thereof:
A
1
Y
0
A
N A
R
6
A
(IIa) wherein:
A
1 is fluorine or CF 3
A
2 is fluorine or CF 3 A3 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: 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(dimethylamino) methyl-1,2, 3 -triazol- 4 -yl)methyl-3-(S)-phenylmorpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(dimethylamino) methyl-1,2,3-triazol-4-yl)methyl-3-(S)-(4-fluorophenyl)morpholine; and pharmaceutically acceptable salts thereof.
Further preferred NK-1 receptor antagonists are those described in European Patent Specification No. WO 95/23798, i.e. compounds of formula (III): WO 99/07375 PCT/EP98/04933 25
R
6
R
3 X Y R 7 R
N
(0
R(III)
P(O) A I 13 R B R or a pharmaceutically acceptable salt thereof, wherein:
R
2 and R 3 are independently selected from the group consisting of: hydrogen, Cl.-alkyl, unsubstituted or substituted with one or more of the substituents selected from: hydroxy, oxo, C1-6alkoxy, phenyl-Ci-3alkoxy, phenyl,
-CN,
halo, -NR9R 1 o, wherein R9 and Rio are independently selected from: hydrogen, (ii) Ci-6alkyl, (iii) hydroxy-Ci-.alkyl, and (iv) phenyl,
-NR
9
COR
10 wherein R 9 and Rio are as defined above, -NR9CO 2
R
1 O, wherein R 9 and R' 1 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, and
-CO
2
R
s wherein R 9 is as defined above; WO 99/07375 PCT/EP98/04933 26-
C
2 -6alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: hydroxy, oxo, C1.Galkoxy, phenyl-C1.3alkoxy, phenyl,
-CN,
halo, -CONRR1io 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; C2-.alkynyl; phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: hydroxy, Ci.-alkoxy, Ci.-alkyl, halo,
-CN,
-NO
2
-CF
3 -(CH2)m-NR 9 Ro, wherein m, R 9 and Rio are as defined above,
-NR
9 CORio, wherein R 9 and Rio are as defined above, -NR9CO 2
R
10 wherein R 9 and Rio are as defined above, -CONR9Rio, wherein R 9 and Rio are as defined above,
-CO
2 NR9R1O, 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; WO 99/07375 PCT/EP98/04933 27and 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: Ci-6alkyl, (ii) Ci-6alkoxy, (iii) -NR9R 1 O, wherein R 9 and RI 0 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, oxazolyl, thienyl, and thiazolyl, and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituent(s) selected from: Ci-6alkyl, (ii) oxo, (iii) Ci-6alkoxy, (iv) -NR9R 1 O, wherein R 9 and Rio are as defined above, WO 99/07375 PCT/EP98/04933 28 halo, and (vi) trifluoromethyl;
R
6
R
7 and R8 are independently selected from the group consisting of: hydrogen; Ci-.alkyl, unsubstituted or substituted with one or more of the substituents selected from: hydroxy, oxo, C1.Galkoxy, phenyl-C1.3alkoxy, phenyl,
-CN,
halo, -NRgR 1 O, wherein R9 and Rio are as defined above, -NR9COR 1 I, wherein R s and RiO are as defined above,
-NR
9
CO
2
R'
0 wherein R9 and R 1 O are as defined above, -CONR9R1o, wherein R 9 and R 1 O 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.Galkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: hydroxy, oxo, C1.Galkoxy, phenyl-Cl.salkoxy, phenyl,
-CN,
halo, -CONR9Rio wherein R 9 and RIO are as defined above,
-COR
9 wherein R 9 is as defined above, WO 99/07375 PCT/EP98/04933 29 -CO2R 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, Cl.6alkoxy, C-6alkyl, halo,
-CN,
-NO
2
-CF
3 -(CH2)m-NR 9
R
1 o, wherein m, R 9 and Rio are as defined above, (6) (7) (8) (9) (11 (12 (13 (14 (16 -NR9CORO, wherein R 9 and Rio are as defined a -NR9CO 2
R
1 O, wherein R s and Rio are as defined -CONR9R 1 i, wherein R 9 and R 1 O are as defined a
-CO
2 NR9R 1 O, wherein R 9 and R 1 0 are as defined -COR9, 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 R14 is hydrogen or C.-salkyl,
-SOR
14 wherein R 14 is as defined above,
-SO
2
R
14 wherein R 14 is as defined above, NR9COR 10 wherein R 9 and Rio are as defined above, CONR9CORi 1 wherein R 9 and R 10 are as defined above, NR9Rio, wherein R 9 and Ri 1 are as defined above, NRgCO 2
R
l o, wherein R 9 and RI 0 are as defined above, bove, ibove, bove, ibove, WO 99/07375 PCT/EP98/04933 30 (17) hydroxy, (18) Ci.-alkoxy, (19) COR 9 wherein R 9 is as defined above, C0 2
R
9 wherein R 9 is as defined above, (21) 2-pyridyl, (22) 3-pyridyl, (23) 4-pyridyl, (24) 2-oxazolyl, and (26) 2-thiazolyl;
R
11 R1 2 and R 13 are independently selected from the definitions of R 6
R
7 and R8, or -OX; A is selected from the group consisting of: Ci- 6 alkyl, unsubstituted or substituted with one or more of the substituents selected from: hydroxy, oxo, C1.6alkoxy, phenyl-Cl.salkoxy, phenyl,
-CN,
halo, wherein halo is fluoro, chloro, bromo or iodo, -NR9RiO, wherein R 9 and R 1 o are as defined above, -NR9COR 1 I, wherein R 9 and Ri 1 are as defined above, -NR9CO 2 RO, wherein R 9 and R' 1 are as defined above, -CONRRO, 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; WO 99/07375 PCT/EP98/04933 -31- C2-6alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: hydroxy, oxo, C1.6alkoxy, phenyl-Ci-3alkoxy, phenyl,
-CN,
halo, -CONR9R l O wherein R 9 and R 10 are as defined above,
-COR
9 wherein R 9 is as defined above, and -C0 2
R
9 wherein R 9 is as defined above; and C2-6alkynyl; B is a heterocycle, wherein the heterocycle is selected from the group consisting of: N- X X H X H N- \N-N N-N N-N I N N N X H
S
N-N
N s
I
X
X
N-N
N
X
N-N
H
N-N
N 0
N-N
N
N-N
N
X
IN
N
I
X
N-N
<.N
N
X
WO 99/07375 PCT/EP98/04933 32 N=N N HN N>-O
N
N N> 0 N' S H X H
H
1 N H H N N N S X N IN 0N SI X X '-IN N x N x
N
N "kN N X x X and wherein the heterocycle may be substituted in addition to -X with one or more substituent(s) selected from: Cl.6alkyl, unsubstituted or substituted with halo, -CF 3
-OCH
3 or phenyl, (ii) Ci.6alkoxy, (iii) oxo, (iv) hydroxy, thioxo, (vi) -SR9, wherein R9 is as defined above, (vii) halo, (viii) cyano, (ix) phenyl, trifluoromethyl, (xi) -(CH 2 )m-NR9RO, wherein m is 0, 1 or 2, and R 9 and RIO are as defined above, WO 99/07375 PCTJEP98/04933 33 (xii) -NR 9 COR1 0 wherein R 9 and RIO are as defined above, (xiii) -CONR9RO, wherein R 9 and RIO are as defined above, (xiv) -C0 2
R
9 wherein R9 is as defined above, and (xv) -(CH2)m-OR 9 wherein m and R9 are as defined above; p isO0 or 1; X is selected from: -PO(OH)0- wherein M+ is a pharmaceutically acceptable monovalent counterion, -PO(0-) 2 -2M+, -PO(0-) 2
-D
2 wherein D 2 is a pharmaceutically acceptable divalent counterion,
-CH(R
4 )-PO(OH)0- wherein R4 is hydrogen or Ci-3alkyl, -CH(R4)-PO(O-) 2 -2M+, -CH(R4)-PO(0-) 2 -D2+, -SO3&-M+
-CH(R
4 )-S0 3
-CO-CH
2
CH
2 -C0 2 1) -CH(CH 3 )-O-CO-R5, wherein R 5 is selected from the group consisting of: WO 99/07375 PCT/EP98/04933 -34-
H
2
M_
6hi) 0 C02-M+ C0 2 M (IV) 0+ M
O'Y+
NH
3 "IC02_M (vi) -2CM C0 2
'M+
(vii) I; and hydrogen, with the proviso that if p is 0 and none of RI], R' 2 or R 13 are -OX, then X is other than hydrogen; Y is selected from the group consisting of: a single bond,
-CO-,
WO 99/07375 PCT/EP98/04933
-CH
2
-CHR
15 and -CR15R 1 6 wherein R 1 5 and RIG are independently selected from the group consisting of: Ci-alkyl, unsubstituted or substituted with one or more of the substituents selected from: hydroxy, (ii) oxo, (iii) C1.
6 alkoxy, (iv) phenyl-Ci.aalkoxy, phenyl, (vi) -CN, (vii) halo, (viii) -NR9R 1 O, wherein R 9 and R 1 O are as defined above, (ix) -NR9CORi 1 wherein R 9 and Rio are as defined above, -NR9CO 2
R
1 I, wherein R 9 and R 10 are as defined above, (xi) -CONR9R 1 wherein R 9 and Rio are as defined above, (xii) -COR 9 wherein R 9 is as defined above, and (xiii) -C0 2
R
9 wherein R 9 is as defined above; phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: hydroxy, (ii) Ci.Galkoxy, (iii) Ci-Galkyl, (iv) halo, (vi) -CN, (vii) -NO 2 (viii) -CF 3 (ix) -(CH2)m-NR9R 1 O, wherein m, R 9 and R Io are as defined above, WO 99/07375 PCT/EP98/04933 36-
-NR
9
COR
1 0 wherein R 9 and R 1 O are as defined above, (xi) -NR9CO 2 Ro, wherein R 9 and Rio are as defined above, (xii) -CONR9Ro, wherein R 9 and Rio are as defined above, (xiii) -CO 2
NR
9 Ro, wherein R 9 and Ri 1 are as defined above, (xiv) -COR 9 wherein R 9 is as defined above, and (xv) -C0 2
R
9 wherein R 9 is as defined above; Z is selected from: hydrogen, Ci-calkyl, and hydroxy, with the proviso that if Y is Z is other than hydroxy, or if Y is -CHR 15 then Z and RI 5 may be joined together to form a double bond.
Particularly preferred compounds of formula (III) are those wherein:
R
2 and R 3 are independently selected from the group consisting of: hydrogen, Ci-.alkyl, C2-6alkenyl, and phenyl;
R
6
R
7 and R 8 are independently selected from the group consisting of: hydrogen,
C
1 .ialkyl, fluoro, chloro, bromo, iodo, and
-CF
3
R
11
R
12 and R 1 3 are independently selected from the group consisting of: fluoro, chloro, bromo, and WO 99/07375 PTE9/43 PCT/EP98/04933 37 iodo; A is unsubstituted i.6alkyl; B is selected from the group consisting of:
H
N-N IX X\ /N-N N-N IN N 0 X H x
H
N-N
NX
,S
N-
x x
N-N
N
x
N-
H
H
N-N
N 0, x x
N-N
N: Sx
N
x
N
x x
N
H
N S x
H
CN
N 0 x
N
H
H
N S p is 0 or 1; X is selected from: -PO(OH)0- wherein M+ is a pharmaceutically acceptable monovalent counterion, -PO(0-) 2 2M+,
D
2 wherein D 2 is a pharmaceutically acceptable divalent counterion, -CH(R4)-PO(OH)0- wherein R4 is hydrogen or CI.
3 alkyl, WO 99/07375 WO 9907375PCT/EP98/04933 38 2
-D+
-CO-CH
2
CH
2 -C0 2
-CH(CH
3
)-O-CO-R
5 wherein R 5 is consisting of: selected from the group H2+M 0iOH (iii) (iv) (v) (vi) (Vii) 0 002*
M+
C0 2
NH
3 -0 CO 2 .M C0 2
-M+
0 ;and Y is Z is hydrogen or Cl-ralkyl; and pharmaceutically acceptable salts thereof.
WO 99/07375 PCT/EP98/04933 39 Particularly preferred compounds of formula (II include: 5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(3-(5-oxo- 1H, 4W 1, 2,4-triazolo)methyl)morpholine N-oxide; 5-bis(trifluoromethyl)benzyloxy) -3-(S)-phenyl-4- (ethoxycarbonyloxy- 1 -ethyl) 5-oxo- 1 H- 1, 2,4triazolo)methyl)morpholine; 2- 5-bis(trifluoromethyl)phenyl)ethoxy)- fluorophenyl)-4-(3-(4-monophosphoryl-5-oxo- LH- 1,2,4triazolo)methyl)morpholine; 5-bis(trifluoromethyl)phenyl)ethoxy) fluorophenyl)-4-(3-(1-monophosphoryl-5-oxo- 1H- 1,2,4triazolo)methyl)morpholine; 5-bis(trifluoromethyl)phenyl)ethoxy)-3- fluorophenyl)-4-(3-(2-monophosphoryl-5-oxo- 1H-1,2,4triazolo)methyl)morpholine; 5-bis(trifluoromethyl)phenyl)ethoxy)- 3- fiuorophenyl)-4-(3-(5-oxyphosphoryl- 1H- 1,2,4triazolo)methyl)morpholine; 2- 5-bis(trifluoromethyl)phenyl)ethoxy)- 3- fluorophenyl)-4-(3-(1-monophosphoryl-5-oxo-4H-1,2,4triazolo)methyl)morpholine; and pharmaceutically acceptable salts thereof.
Further preferred NK-1 receptor antagonists are those described in European Patent Specification No. WO 96/05181, i.e. compounds of formula (IV): WO 99/07375 PCT/EP98/04933
R
2 R 9 a 0 0
R
3 R9b N
(IV
x wherein X is a group of the formula NR 6
R
7 or a C- or N-linked imidazolyl ring; Y is hydrogen or Cl.
4 alkyl optionally substituted by a hydroxy group;
R
1 is hydrogen, halogen, Ci-(;alkyl, Cl-ralkoxy, CF 3
NO
2 CN, SRa, SORa, SO 2 Ra, CO 2 Ra, CONRaRb, C2-6alkenyl, C2-ralkynyl or C1.4alkyl substituted by Cl.4alkoxy, wherein Ra and Rb each independently represent hydrogen or CI-4alkyl; R2 is hydrogen, halogen, CI- 6 alkyl, Cl-Galkoxy substituted by Ci-4alkoxy or CF 3 R3 is hydrogen, halogen or CF 3
R
4 is hydrogen, halogen, Cl-Galkyl, Cl.6;alkoxy, hydroxy, CF 3
NO
2 CN, SRa, SORa, SO 2 Ra, CO 2 Ra, CONRaRb, C26alkenyl, C2e6alkynyl or C1-4alkyl substituted by C1- 4 alkoxy, wherein Ra and Rb are as previously defined;
R
5 is hydrogen, halogen, Cl.Galkyl, Ci-ralkoxy substituted by C1l4alkoxy or CF 3
R
6 is hydrogen, Ci-ealkyl, C3.7cycloalkyl, C 3 7 cycloalkylCl-4alkyl, phenyl, or C 24 alkyl substituted by C1.4alkoxy or hydroxy;
R
7 is hydrogen, Ci-e;alkyl, C3-7cycloalkyl, C3-7cycloalkylC I.4alkyl, phenyl, or C 2 4 alkyl substituted by one or two substituents selected from WO 99/07375 PCT/EP98/04933 41- C1.
4 alkoxy, hydroxy or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, 0 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 NR8, S(0) or S(0) 2 and which ring may be optionally substituted by one or two groups selected from hydroxyCl-4alkyl, C1i 4 alkoxyCi.
4 alkyl, oxo, CORa or C0 2 Ra where Ra is as previously defined; or R6 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, C1.4alkyl, hydroxyCi.
4 alkyl or C1.
4 alkoxyC1.4alkyl; and R9a and R9b are each independently hydrogen or C1- 4 alkyl, or R9a and
R
9 b are joined so, together with the carbon atoms to which they are attached, there is formed a C5- 7 ring; and pharmaceutically acceptable salts thereof.
Particularly preferred compounds of formula (IV) are those of formula (IVa) and pharmaceutically acceptable salts thereof:
A
1 OVa)
A
3 wherein
A
1 is fluorine or CFa; WO 99/07375 PCT/EP98/04933 42-
A
2 is fluorine or CF 3
A
3 is fluorine or hydrogen; and X and Y are as defined in relation to formula Specific compounds of formula (IV) of use in the present invention include: 5-bis(trifluoromethyl)phenyl)ethoxy)- 3- (S)-(4-fluorophenyl) 4-(4-morpholinobut-2-yn-yl)morpholine; 5-bis(trifluoromethyl)phenyl)ethoxy)-4- Ndimethylaminobut-2-yn-yl)- (4-fluorophenyl)morpholine; 4-(4-azetidinylbut-2-yn-yl)-2(R)-(1-(R)-(3, ethoxy)-3- (S)-(4-fluorophenyl)morpholine; 5-bis(trifluoromethyl)phenyl)ethoxy)-3- (S)-(4-fluorophenyl)- 4-(4-imidazolylbut-2-yn-yl)morpholine; 5-bis(trifluoromethyl)phenyl)ethoxy)-3- (S)-(4-fluorophenyl)- 4-(4-(N-methylpiperazinyl)but-2-yn-yl)morpholine; 4-(4-bis(2-methoxyethyl)aminobut-2-yn-yl)-2-(R)-(-(R)-(3, bis(trifluoromethyl)phenyl)ethoxy)-3-(S)- (4-fluorophenyl)morpholine; 5-bis(trifluoromethyl)phenyl)ethoxy)- 3-(S)-(4-fluorophenyl)- 4-(4-pyrrolidinobut-2-yn-yl)morpholine; 3-(S)-(4-fluorophenyl)-2-(R)-(1-(R)- (3-fluoro-5- (trifluoromethyl)phenyl) ethoxy)-4-(4-morpholinobut-2-yn-yl)morpholine; 3-(S)-(4-fluorophenyl)-4-(4-morpholinobut-2-yn-yl)-2-(R)-(1-(R)-(3- (trifluoromethyl)phenyl)ethoxy)morpholine; 4-(4-azetidinylbut-2-yn-yl)-3-(S)-(4-fluorophenyl)-2-(R)-(-(R)-(3- (trifluoromethyl)phenyl)ethoxy)morpholine; ,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-(N-(2methoxyethyl)-N-methyl)aminobut-2-yn-yl)-3-(S)-phenylmorpholine; 5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-(N-cyclopropyl- N- (2-methoxyethyl)amino)but-2-yn-yl)- 3-(S)-phenylmorpholine; 5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-(N-isopropyl-N-(2methoxyethyl)amino)but-2-yn-yl)-3-(S)-phenylmorpholine; WO 99/07375 PCT/EP98/04933 43 N-dimethylamino)but-2-yn-yl)-3-(S)-(4-fluorophenyl)-2-(R)- (3-fluoro- 5-(trifluoromethyl)phenyl-2-hydroxyethoxy)morpholine; 4-(4-azetidinylbut-2yn-yl)-3-(S)-(4-fluorophenyl)-2-(R)- (trifluoromethyl)phenyl)-2-hydroxyethoxy)morpholine; 2- 5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-4- Ndimethylamino)but-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine; 4-(4-azetidinylbut-2-yn-yl)-2- 5-bis(trifluoromethyl)phenyl-2hydroxyethoxy)-3-(S)-(4-fluorophenyl)morpholine; 4-(4-N-bis(2-methoxy)ethyl-N-methylanino)but-2-yn-yl)-2-(R)-(1-(R)- (3,5 bis(trifluoromethyl)phenyl)ethoxy)- (4-fluorophenyl)morpholine; 5-bis(trifluoromethyl)phenyl)ethoxy)-3 (4-fluorophenyl) (methoxymethyl)pyrrolidino)but-2-yn-yl)morpholine; 4-(4-(7-azabicyclo[2.2. 1]heptano)but-2-yn-yl)-2-(R)-(1-(R)-(3, bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine; 5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4diisopropylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine; (1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)-4-(4-(2- (methoxymethyl)pyrrolidino)but-2-yn-yl)- -phenylmorpholine; 2- 5-bis(trifluoromethyl)phenyl)ethoxy)-3- (S)-(4-fluorophenyl) 4-(4-(2-(S)-(hydroxymethyl)pyrrolidino)but-2-yn-yl)morpholine; and pharmaceutically acceptable salts thereof.
Another class of NK-1 receptor antagonists of use in the present invention is that described in European Patent Specification No.
0 436 334, i.e. compounds of formula (V: R 7 RR1
V
WO 99/07375 PCT/EP98/04933 44 or a pharmaceutically acceptable salt thereof, wherein Y is (CH2)n wherein n is an integer from 1 to 4, and wherein any one of the carbon-carbon single bonds in said (CH 2 )n may optionally be replaced by a carbon-carbon double bond, and wherein any one of the carbon atoms of said (CH 2 )n may optionally be substituted with R 4 and wherein any one of the carbon atoms of said (CH2)n may optionally be substituted with R 7 Z is (CH2)m wherein m is an integer from 0 to 6, and wherein any one of the carbon-carbon single bonds of (CH2)m may optionally be replaced by a carbon-carbon double bond or a carbon-carbon triple bond, and any one of the carbon atoms of said (CH 2 )m may optionally be substituted with
R
8
R
1 is hydrogen or Ci-salkyl optionally substituted with hydroxy, C1-4alkoxy or fluoro;
R
2 is a radical selected from hydrogen, C 16 straight or branched alkyl, C3-7cycloalkyl wherein one of the CH 2 groups in said cycloalkyl may optionally be replaced by NH, oxygen or sulphur; aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl-C2.6alkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl C2.6alkyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, Ci-G alkyl, Ci-.alkoxy, trifluoromethyl, amino, C1-6alkylamino, CI.Galkyl-O-CO, C.-calkyl-O-CO- Ci-6alkyl, Ci-6alkyl-CO-O, C1.6alkyl-CO-Ci-Galkyl-O-, C1-6alkyl-CO, C1-Galkyl-CO-Ci-6alkyl-, di-Cl-6alkylamino, -CONH-C1-.alkyl, Ci- 6 alkyl-CO-NH-Ci- 6 alkyl, -NHCOH and -NHCO-C1i-alkyl; and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;
R
5 is hydrogen, phenyl or Ci.calkyl; WO 99/07375 PCT/EP98/04933 or R 2 and R 5 together with the carbon to which they are attached, form a saturated ring having from 3 to 7 carbon atoms wherein one of the
CH
2 groups in said ring may optionally be replaced by oxygen, NH or sulfur;
R
3 is aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms wherein one of the (CH 2 groups in said cycloalkyl may optionally be replaced by NH, oxygen or sulphur; wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said C3.7cycloalkyl may optionally be substituted with one or two substituents, each of said substituents being independently selected from halo, nitro, C1.Galkyl, Ci-alkoxy, trifluoromethyl, amino, Ci.calkylamino, -CO-NH- C-calkyl, Cl-6alkyl-CO-NH-Cl.6alkyl, -NHCOH and -NHCO-C-.
6 alkyl;
R
4 and R 7 are each independently selected from hydroxy, halogen, halo, amino, oxo, cyano, methylene, hydroxymethyl, halomethyl, C1.6alkylamino, di-CI-6alkylamino, C1.Galkoxy, CI.6alkyl-O-CO, CI-6alkyl-O-CO-Cl-6alkyl, Ci-6alkyl-CO-O, C1.Galkyl-CO-CI.Calkyl-O-, Ci.oalkyl-CO-, C1-6alkyl-CO-C1.Galkyl, and the radicals set forth in the definition of R 2 R6 is -NHCOR 9
-NHCH
2
R
9 S0 2
R
8 or one of the radicals set forth in any of the definitions of R 2
R
4 and R 7 R8 is oximino (=NOH) or one of the radicals set forth in any of the definitions of R 2
R
4 and R 7 R9 is Cl-.alkyl, hydrogen, phenyl or phenylCl.6alkyl; with the proviso that when m is 0, R8 is absent, when R 4
R
G
R
7 or
R
8 is as defined in R 2 it cannot form together with the carbon to which it is attached ,a ring with R 5 and when R 4 and R 7 are attached to the same carbon atom, then either each of R 4 and R 7 is independently selected from hydrogen, fluoro and C1-6alkyl, or R 4 and R 7 together with the carbon WO 99/07375 PCT/EP98/04933 46 to which they are attached, for a C 3 -6 saturated carbocyclic ring that forms a spiro compound with the nitrogen-containing ring to which they are attached.
A particularly preferred compound of formula is (2S,3S)-cis-3-(2methoxybenzylamino)-2-phenylpiperidine; or a pharmaceutically acceptable salt thereof.
Another class of NK-1 receptor antagonists of use in the present invention is that described in International Patent Specification No. WO 93/21155, i.e. compounds of formula (VI): R R 0 N CH-R 1
(VI)
R
5 R 4 or a pharmaceutically acceptable salt thereof, wherein radicals R are phenyl radicals optionally 2- or 3-substituted by a halogen atom or a methyl radical; RI is optionally substituted phenyl, cyclohexadienyl, naphthyl, indenyl or optionally substituted heterocycle;
R
2 is H, halogen, OH, alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkyloxy, alkylthio, acyloxy, carboxy, optionally substituted alkyloxycarbonyl, benzyloxycarbonyl, amino or acylamino; R3 is optionally 2-substituted phenyl;
R
4 is OH or fluorine when R 5 is H; or R 4 and R 5 are OH or R 4 and R 5 together form a bond.
A particularly preferred compound of formula (VI) is (3aS, 4S, 7aS)- 7,7-diphenyl-4-(2-methoxyphenyl)-2-[(2S)-(2-methoxyphenyl)propionyl] perhydroisoindol-4-ol; or a pharmaceutically acceptable salt thereof.
WO 99/07375 PCT/EP98104933 47- Another class of NK-1 receptor antagonists of use in the present invention is that described in European Patent Specification No.
0 591 040, i.e. compounds of formula (VII): R 0 Ar-T-CO-N-CH 2
-CH
2
-CH
2 -Am A (VII) Ar' wherein Ar represents an optionally substituted mono-, di- or tricyclic aromatic or heteroaromatic group; T represents a bond, a hydroxymethylene group, a Ci.
4 alkoxymethylene group or a Ci- 5 alkylene group; Ar' represents a phenyl group which is unsubstituted or substituted by one or more substituents selected from halogen, preferably chlorine or fluorine, trifluoromethyl, C1.4alkoxy, CI-4alkyl where the said substituents may be the same or different; a thienyl group; a benzothienyl group; a naphthyl group; or an indolyl group; R represents hydrogen, C1-4alkyl, 0-C1.4alkoxyC1.
4 alkyl, or
©-C
2 -4alkanoyloxyC2-4alkyl; Q represents hydrogen; or Q and R together form a 1,2-ethylene, 1,3-propylene or 1,4butylene group; Am represents the radical 13+ in which X 1
X
2 and X 3 together with the nitrogen atom to which they are attached, form an azabicyclic or azatricyclic ring system optionally substituted by a phenyl or benzyl group; and A- represents a pharmaceutically acceptable anion.
WO 99/07375 PCT/EP98/04933 48- A particularly preferred compound of formula (VII) is (3,4-dichlorophenyl)- 1- [(3-isopropoxyphenyl)acetyl]-3-piperidinyl] ethyl]-4phenyl-1-azabicyclo[2,2,2]octane; or a pharmaceutically acceptable salt, especially the chloride, thereof.
Another class of NK-1 receptor antagonists of use in the present invention is that described in European Patent Specification No.
0 532 456, i.e. compounds of formula (VIII):
R
3 R1- 4
(VIII)
R
2 1 or a pharmaceutically acceptable salt thereof, wherein
R
1 represents an optionally substituted aralkyl, aryloxyalykl, heteroaralkyl, aroyl, heteroaroyl, cycloalkylcarbonyl, aralkanoyl, heteroarylalkanoyl, aralkoxycarbonyl or arylcarbamoyl group or the acyl group of an a-amino acid optionally N-substituted by a lower alkanoyl or carbamoyl-lower alkanoyl group;
R
2 represents cycloalkyl or an optionally substituted aryl or heteroaryl group;
R
3 represents hydrogen, alkyl, carbamoyl or an alkanoyl or alkenoyl group optionally substituted by carboxy or esterified or amidated carboxy;
R
4 represents an optionally substituted aryl group or an optionally partially saturated heteroaryl group; Xi represents methylene, ethylene, a bond, an optionally ketalised carbonyl group or an optionally etherified hydroxymethylene group;
X
2 represents alkylene, carbonyl or a bond; and
X
3 represents carbonyl, oxo-lower alkyl, oxo(aza)-lower alkyl, or an alkyl group optionally substituted by phenyl, hydroxymethyl, optionally esterified or amidated carboxy, or (in other than the a-position) hydroxy.
A particularly preferred compound of formula (VIII) is 4S*)-2benzyl-1-(3,5-dimethylbenzoyl)-N-(4-quinolinylmethyl)-4-piperidineamine; or a pharmaceutically acceptable salt thereof.
WO 99/07375 PCT/EP98/04933 49 Another class of NK-1 receptor antagonists of use in the present invention is that described in European Patent Specification No.
0 443 132, i.e. compounds of formula (IX) 2
ZC)D
CH
2 N CONH HCON (IX)
R
4 or a pharmaceutically acceptable salt thereof, wherein
R
3 is aryl, or a group of the formula: X is CH or N; and Z is 0 or N-R 5 in which R 5 is hydrogen or lower alkyl;
R
2 is hydroxy or lower alkoxy;
R
3 is hydrogen or optionally substituted lower alkyl;
R
4 is optionally substituted ar(lower)alkyl; A is carbonyl or sulfonyl; and Y is a bond or lower alkenylene.
A particularly preferred compound of formula (IX) is the compound of formula (IXa)
HO
0 tv a i (IXa) f)H WO 99/07375 PCT/EP98/04933 or a pharmaceutically acceptable salt thereof.
Another class of NK-1 receptor antagonists of use in the present invention is that described in International Patent Specification No. WO 92/17449, i.e. compounds of the formula (X) H 1 N R N
'R
2
H
or a pharmaceutically acceptable salt thereof, wherein
R
1 is aryl selected from indanyl, phenyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms, wherein one of said carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said C3scycloalkyl may optionally be substituted with one or two substituents, said substituents being independently selected from chloro, fluoro, bromo, iodo, nitro, Cl-loalkyl optionally substituted with from one to three fluoro groups, Ci-loalkoxy optionally substituted with from one to three fluoro groups, amino, Cl-ioalkyl-S-, Ci.ioalkyl-S(O)-, C-10oalkyl-S0 2 phenyl, phenoxy, C1.loalkyl-SO2NH-, C1iioalkyl-SO 2 NH-Ci.ioakyl-, Ci-ioalkylamino-diC1.ioalkyl-, cyano, hydroxy, cycloalkoxy having 3 to 7 carbon atoms, CiO-alkylamino, C 1 6 dialkylamino, HC(O)NH- and Ci-ioalkyl-C(O)NH-; and
R
2 is thienyl, benzhydryl, naphthyl or phenyl optionally substituted with from one to three substituents independently selected from chloro, bromo, fluoro, iodo, cycloalkoxy having 3 to 7 carbon atoms, Ci-loalkyl optionally substituted with from one to three fluoro groups and Ci.ioalkoxy optionally substituted with from one to three fluoro groups.
A particularly preferred compound of formula is (2S,3S)-3-(2methoxy-5-trifluoromethoxybenzyl)-amino-2-phenylpiperidine; or a pharmaceutically acceptable salt thereof.
WO 99/07375 PCT/EP98/04933 51- Another class of NK-1 receptor antagonists of use in the present invention is that described in International Patent Specification No. WO 95/08549, i.e. compounds of formula (XI)
R
2
(CH
2 )x H I H I R4
(XI)
or a pharmaceutically acceptable salt thereof, wherein
R
1 is a C1.4alkoxy group; R2 is 6
NN
N-N
R
3 is a hydrogen or halogen atom;
R
4 and R 5 may each independently represent a hydrogen or halogen atom, or a C1.
4 alkyl, C1-4alkoxy or trifluoromethyl group;
R
6 is a hydrogen atom, a C1-4alkyl, (CH2)mcyclopropyl, -S(O)nC 1 4 alkyl, phenyl, NRTR8, CH 2
C(O)CF
3 or trifluoromethyl group;
R
7 and R 8 may each independently represent a hydrogen atom, or a Ci1 4 alkyl or acyl group; x represents zero or 1; n represents zero, 1 or 2; and m represents zero or 1.
Particularly preferred compounds of formula (XI) are tetrazol-1-yl-benzyl)-([2S,3S]-2-phenyl-piperidin-3-yl)-amine; and [2methoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-([2S,3S]-2-phenylpiperidin-3-yl)-amine; or a pharmaceutically acceptable salt thereof.
WO 99/07375 PCT/EP98/04933 52 Another class of tachykinin antagonists of use in the present invention is that described in International Patent Specification No. WO 95/14017, i.e. compounds of formula (XII) R8 R4 R-CH)-C-H.-N-(CH
)-R
3 NH R
(CH
2 )m 1 1 (XII)
R
or a pharmaceutically acceptable salt thereof, wherein in is zero, 1, 2 or 3; n is zero or 1; o is zero, 1 or 2; p is zero or 1; R is phenyl, 2- or 3-indolyl, 2- or 3-indolinyl, benzothienyl, benzofuranyl, or naphthyl; which R groups may be substituted with one or two halo, C1.3alkoxy, trifluoromethyl, C 1.4alkyl, phenyl- C 1 3alkoxy, or C l4alkanoyl groups; RI is trityl, phenyl, diphenylmethyl, phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, inorpholinyl, indolinyl, indolyl, benzothienyl, hexamethyleneiminyl, benzofuranyl, tetrahydropyridinyl, quinolinyl, isoquinolinyl, reduced quinolinyl, reduced isoquinolinyl, phenyl-(C 1.4alkyl)-, phenyl-(C1..4alkoxy)-, quinolinyl-(C i-4alkyI)-, isoquinolinyl-(C l.4alkyl)-, reduced quniolinyl- (C 1-4alkyl)-, reduced isoquinolinyl-(Cl.4alkyl)-, benzoyl-(C1.3alkyl)-, C1.4alkyl, or -NH-CH 2 any one of which RI groups may be substituted with halo, CI- 4 alkyl, CI.4alkoxy, trifluoromethyl, amino, CI.4alkylamino, di(Cl-4alkyl)amino, or C2-4alkanoylamino; or any one of which R' groups may be substituted with phenyl, piperazinyl, C3.sCYcloalkyl, benzyl, Ci.
4 alkyl, piperidinyl, pyridinyl, WO 99/07375 PCT/EP98/04933 53 pyrimidinyl, C 2 6 alkanoylaminio, pyrrolidinyl, C 2 .Galkanoyl, or C l4alkoxycarbonyl; any one of which groups may be substituted with halo, Ci.
4 alkyl, C l.4alkoxy, trifluoromethyl, amino, C 1 .4alkylamino, di(C -4alkyl)amino, or C24alkanoylamino; or R1 is amino, a leaving group, hydrogen, C1.4alkylamino, or di(Ci- 4 alkyl)amino;
R
5 is pyridyl, anilino-(C1.3alkyl)-, or anilinocarbonyl;
R
2 is hydrogen, C .4alkyl, C l-4alkylsulfony1, carboxy-(C 1.3alkyl)-, Cli 3 alkoxycarbonyl-(Cl-3alkyl)-, or -CO-RG; RG is hydrogen, Cp.
4 alkyl, Ci.3haloalkyl, phenyl, C1.3alkoxy,
CI-
3 hydroxyalkyl, amino, Cl.4alkylamino, di(Ci .4alkyl)amino, or (CH2)q-R 7 q is zero to 3;
R
7 is carboxy, C l-4alkoxycarbonyl, C 1.4alkylcarbonyloxy, amino, C14alkylamino, di(Cl.4alkyl)amino, Clvoalkoxycarbonylamino, or phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, benzofuranyl, quinolinyl, phenyl-(Cl.4alkyl)-, quinolinyl-(Cl-4alkyl)-, isoquinolinyl- (CI- 4 alkyl)-, reduced quinolinyl- (C i.
4 alkyl)-, reduced isoquinolinyl-(Cl.4alkyl)-, benzoyl- C i.3akyl; any one of which aryl or heterocyclic R 7 groups may be substituted with halo, trifluoromethyl, C1.4alkoxy, C 1 4 alkyl, amino, C 1 4 alkylamino, di(Cl.4alkyl)amino, or C2-4alkanoylamino; or any one of which R 7 groups may be substituted with phenyl, piperazinyl, C3-8cycloalkyl, benzyl, piperidinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, C 2 -6alkanoyl, or Cl.4alkoxycarbonyl; any of which groups may be substituted with halo, trifluoromethyl, amino, C1.4alkoxy, C1.4alkyl, C1-4alkylamino, di(Cl.4alkyl)amino, or C24alkanoylamino; R8 is hydrogen or C1-6alkyl;
R
3 is phenyl, phenyl-(Cl.6alkyl)-, C 3 -8cycloalkyl, Cfj.CYCloalkenyl, CI-salkyl, naphthyl, C2-8alkenyl, or hydrogen; WO 99/07375 PCT/EP98/04933 54any one or which groups except hydrogen may be substituted with one or two halo, Cl.3alkoxy, Ci-3alkylthio, nitro, trifluoromethyl, or C1.-alkyl groups; and
R
4 is hydrogen or C1.3alkyl; with the proviso that if R 1 is hydrogen or halo, R 3 is phenyl, phenyl-(C1.6alkyl)-, Ca3.cycloalkyl, Cs.8cycloalkenyl, or naphthyl.
A particularly preferred compound of formula (XII) is methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4-piperidin-1yl)piperidin-1-yl)acetylamino]propane; or a pharmaceutically acceptable salt thereof.
The above compounds are only illustrative of NK-1 receptor antagonists which are currently under investigation. As this listing of compounds is not meant to be comprehensive, the use and methods of the present invention may employ any NK-1 receptor antagonist, in particular a NK-1 receptor antagonist which is orally active, long acting and CNSpenetrant. Accordingly the present invention is not strictly limited to any particular structural class of compound.
The preferred compounds of formulae (III) and (IV) will have the 2- and 3-substituents on the morpholine ring in the cis arrangement, the preferred stereochemistry being as shown in the following general formula: o o R N Where the benzyloxy moiety is a-substituted, the preferred stereochemistry of the a-carbon is either when the substituent is an WO 99/07375 PCT/EP98/04933 alkyl methyl) group or when the substituent is a hydroxyalkyl hydroxymethyl) group.
Unless otherwise defined herein, suitable alkyl groups include straight-chained and branched alkyl groups containing from 1 to 6 carbon atoms. Typical 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-butyl.
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 groups containing from 3 to 7 carbon atoms. Particular cycloalkyl groups are cyclopropyl and cyclohexyl.
Unless otherwise defined herein, suitable aryl groups include phenyl and naphthyl groups.
A particular aryl-C 1 6 alkyl, e.g. phenyl-Ci.-alkyl, group is benzyl.
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 antagonists of use in the present invention include acid addition salts I WO 99/07375 PCT/EP98/04933 56which 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 salts 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 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 antagonist selected from the compounds of formulae (III), (VII), (VIII), (XI) and (XII) for the manufacture of a medicament for the treatment or prevention of aggressive behaviour.
The present invention also provides a method for the treatment or prevention of aggressive behaviour, 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 (III), (VII), (VIII), (XI) and (XII).
In a further aspect of the present invention, there is provided a pharmaceutical composition for the treatment or prevention of aggressive behaviour comprising a NK-1 receptor antagonist selected from the compounds of formulae (III), (VII), (VIII), (XI) and (XII), together with at least one pharmaceutically acceptable carrier or excipient.
Preferably the compositions according to the present invention are in unit dosage forms such as tablets, pills, capsules, powders, granules, WO 99/07375 PCT/EP98/04933 -57solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, by inhalation or insufflation or administration by transdermal 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 present invention, or a non-toxic pharmaceutically acceptable salt thereof.
When referring to these preformulation compositions as homogeneous, it is 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.
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 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.
The 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 WO 99/07375 PCT/EP98/04933 58oil, sesame oil, coconut oil, peanut oil or soybean oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, 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, such as polyoxyethylenesorbitans Tween
T
M 20, 40, 60, 80 or and other sorbitans Span T M 20, 40, 60, 80 or 85). Compositions with a surface-active agent will conveniently comprise between 0.05 and surface-active agent, and preferably between 0.1 and It will be 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 IntralipidTM, LiposynTM, InfonutrolTM, LipofundinTM and Lipiphysan T M 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 1.0pm, particularly 0.1 and 0.5im, 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, WO 99/07375 PCT/EP98/04933 59or 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 cavity using, for example, absorption wafers.
Compositions in the form of tablets, pills, capsules or wafers for oral administration are particularly preferred.
The present invention further provides a process for the preparation of a pharmaceutical composition comprising a NK-1 receptor antagonist 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 WO 99/07375 PCT/EP98/04933 per day. A maximum dosage level for 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 aritipsychotic 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 aggressive behaviour 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 aggressive behaviour 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.
The compounds of formulae (III), (VII), (VIII), (XI) and (XII) may be prepared by the methods described in EP-A-0 577 394 (or WO 95/16679), WO 95/18124, WO 95/23798, WO 96/05181, EP-A-0 436 334, WO 93/21155, EP-A-0 591 040, EP-A-0 532 456, EP-A-0 443 132, WO 92/17449, WO 95/08549 and WO 95/14017, respectively.
WO 99/07375 PCT/EP98/04933 -61- Particularly preferred NK-1 receptor antagonists of the formulae (III), (VII), (VIII), (XI) and (XII) for use in the present invention are compounds which are potent NK-1 receptor antagonists, i.e. compounds with an NK-1 receptor affinity (IC5o) 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 aggressive behaviour 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 aggressive behaviour. The compounds of this class advantageously exhibit a rapid onset of action and a reduced side-effect profile when compared against conventional treatments of aggressive behaviour.
In particular, the present invention 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 aggressive behaviour.
The exceptional pharmacology of the class of orally active, long acting, CNS-penetrant NK-1 receptor antagonists (as hereinafter defined) of use in the present invention enables the treatment of aggressive behaviour, 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 WO 99/07375 PCT/EP98/04933 62hereinafter defined) for the manufacture of a medicament adapted for oral administration for the treatment or prevention of aggressive behaviour.
The present invention also provides a method for the treatment or prevention of aggressive behaviour, which method comprises the 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 (as hereinafter defined).
In a further aspect of the present invention, there is provided an oral pharmaceutical composition for the treatment of aggressive behaviour which comprises an orally active, long acting, CNS-penetrant NK-1 receptor antagonist (as hereinafter defined), together with a pharmaceutically acceptable carrier or excipient.
There exists a patient population in whom aggressive behaviour 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 active, long acting, CNS-penetrant NK-1 receptor antagonist for the manufacture of a medicament adapted for oral administration for the treatment or prevention of aggressive behaviour in a patient who is nonresponsive to antipsychotic agents or for whom antipsychotic agents are is contraindicated.
The present invention also provides a method for the treatment or prevention of aggressive behaviour in a patient who is non-responsive to antipsychotic agents or for whom antipsychotic agents are 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.
Preferred NK-1 receptor antagonists for use in the present invention as orally active, long acting, CNS-penetrant NK-1 receptor WO 99/07375 .PCT/EP98/04933 63 antagonists are selected from the classes of compounds described in European Patent Specification No. 0 577 394, and International Patent Specification Nos. 95/08549, 95/18124, 95/23798, 96/05181, and 97/497 (Application No. PCT/GB97/0 1630). 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: (3S, 5R, 65)- 3-[2-cyclopropoxy-5-(trifluoromethoxy)phenyl- 1-oxa-7-azaspiro (3R, 5R, 6S)- 3- [2-cyclopropoxy-5- (trifluoromethoxy)phenyl- 1-oxa-7-aza- 5-bis(trifluoromethyl)benzyloxy) (4-fluorophenyl)-4-(3- 1H, 4H- 1, 2,4-triazolo)methyl)morpholine; 5-bis(trifluoromethyl)phenyl)ethoxy)-4-(3-(5-oxo- 1H, 4H- 1,2, 4-triazolo)methyl)-3-(S)-phenyl-morpholine; 5-bis(trifluoromethyl)benzyloxy)-4-(3-(5-oxo- 1H,4H- 1,2,4triazolo)methyl)-3-(S)-phenyl-morpholine; 5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)- 4-(3-(5-oxo- 1H, 4H- 1,2, 4-triazolo)methyl)morpholine; 5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N, Ndimethylamino)methyl- 1, 2,3-triazol-4-yl)methyl-3-(S)-phenylmorpholine; 5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N, Ndimethylamino)methyl- 1,2, 3-triazol-4-yl)methy-3-(S)-(4fluorophenyl)morpholine; 5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)- 4-(3-(4-monophosphoryl-5-oxo- 1H- 1,2, 4-triazolo)methyl)morpholine; 5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)- 4-(3-(1-monophosphoryl-5-oxo- 1H- 1,2,4-triazolo)methyl)morpholine; 5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)- 4-(3-(2-monophosphoryl- 5-oxo- 1H- 1,2, 4-triazolo)methyl)morpholine; WO 99/07375 PCT/EP98/04933 64- ,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl).
4- (5-oxyphosphoryl- 1H- 1,2, 4-triazolo)methyl)morpholine; 2- 5-bis(trifluoromethyl)p henyl)ethoxy)- 3 -(S)-(4-fluorophenyl)- 4-(3-(1-monophosphoryl-5-oxo-4H- 1,2, 4 -triazolo)methyl)morpholine; 5-bis(trifluoromethyl)phenyl)ethoxy)-4- (4-N,Ndimethylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine; 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.
Two compounds of use as orally active, long acting, CNS penetrant NK-1 receptor antagonists in the present invention which are described in International Patent Specification No. WO 97/497 10 (Application No.
PCT/GB97/01630) may be prepared according to the following methods: PREPARATION 1 (2S)-l1-tert-Butox-vcarbonvl-2-phenvlpiperidin-3-one Dimethyl sulfoxide (20.80m1, 22.90g, 29.3mmol) in dichloromethane (75m1) was added dropwise to a cooled solution of oxalyl chloride (13.95m1, 20.30g, l6Ommol) in dichloromethane (350m1). The mixture was stirred at -70*C for 15 minutes, then (2S,3S)-1-tert-butoxycarbonyl-3hydroxy-2-phenylpiperidine (,prepared by the method described in European Patent Specification number 0 528 495-A; 36.91g, l33mmol) in dichloromethane (150m1) was added dropwise. The mixture was stirred at 00 for 20 minutes, then allowed to warm to -30'C. The mixture was cooled to -50 00 and triethylamine (55.95m1, 40.45g, 400mmol) was added slowly. The mixture was allowed to warm to 000 and diluted with icecooled dichioromethane (250m1). The mixture was washed with ice cold aqueous citric acid solution 2x300m1) and water (300m1), dried (MgSO 4 and the solvent was evaporated under reduced pressure to give WO 99/07375 PCT/EP98/04933 the title compound as a yellow oil (42.3g), which was used immediately without further purification. lH NMR (250MHz, CDCl 3 8 7.5-7.3 (5H, in), 5.8 (1H, hr 4.2 (1H, hr 3.4 (1H, in), 2.6 (2H, mn), 2.0 (2H, in), and 1.54 (9H, s).
PREPARATION 2 (2S, 3R)- 1-tert-Butoxycarbonyl-3-hvdroxy- 3-(2-methyvlene-3- Phenoxypropvl)-2-phenvlpiperidine A solution of 3-(chloromagnesio)-2-(phenoxymethyl)- 1-propene in THF (0.91M, 3m1) (Louw et. al., Tetrahedron, 48, 6087-6104, 1992, prepared from 2. 74mmol of 3-chioro- 2-(.phenoxymethyl)-l1-propene) was slowly added to a solution of (2S)-1-tert-butoxycarbonyl-2-phenylpiperidin- 3-one (Preparation 1) in THF (3m1). The mixture was stirred at room temperature for 1 hours, then saturated aqueous ammonium chloride (20m1) was added and the mixture was extracted with ethyl acetate (20m1). The organic phase was washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure The residue was purified by column chromatography on silica gel, eluting with hexane/ethyl acetate (100:0 increasing to 80:20) to give the title compound. 'H NMR (360MHz, CDCl 3 8 7.48 (2H, d, J=6.9 Hz), 7.35-7.2 (6H, in), 6.9-6.88 (3H, in), 5.4 (1H, 5.15 (2H, d, J=13.7 Hz), 4.61 (2H, 4.11 (2H, mn), 3.17 (1H, in), 2.66 and 2.59 (2H, AB d, J=14.0 Hz), 1.95 (2H, in), 1.79 (2H, in), and 1.36 (9H, m/z 424 1).
PREPARATION 3 (5R.6Sr)-3-Methylene-6-lphenvl- 1-oxa-7-(tert-butoxvcarbonvl)aza- To a cooled(-80 00) solution of (2S,3R)-1-tert-butoxycarbonyl-3hydroxy-3-(2-methylene- 3-phenoxypropyl)-2-phenylpiperidine (Preparation 2, 1.53g, 3.62mmol) in THF (20in1) was added n-butyl lithium (2.5M in hexanes, 1.45m1, 3.62minol) followed by a solution of zinc chloride (0.5M in WO 99/07375 PCT/EP98/04933 66- THF, 7.24ml, 3.62mmol). The solution was allowed to warm to room temperature and tetrakis(triphenylphosphine)palladium (0.23g, 0.2mmol) was added. The mixture was degassed with bubbling nitrogen and heated under reflux for 16 hours. The mixture was cooled and the solvent was evaporated under reduced pressure.The residue was partitioned between ethyl acetate and 2M sodium hydroxide. The organic phase was washed with saturated brine, dried (MgSO 4 and purified by chromatography on a column containing silica gel (eluting with hexane containing increasing proportions of ethyl acetate between 0% to Evaporation of the fractions gave (6S,5R)-3-methylene-6-phenyl-1-oxa-7- 1H NMR (360MHz, CDC13) 8 7.58 (2H, d, J=8.4 Hz), 7.32-7.21 (3H, 5.23 (1H, 5.06 (1H, 4.97 (1H, 4.39 (2H, AB d, J=13.3 Hz), 3.99 (1H, dd, J=13.3, 4.48 Hz), 2. 83 (1H, ABd J=15.5 Hz), 2.7 (1H,td J=12.5, 3.93 Hz), 2.5 (1H, ABd, J=15.4 Hz), 2.15 (2H, td, J=12., .4 Hz), 1.69 (2H, and 1.46 m/z (ES 329 (M+2Ht BuOCO).
PREPARATION 4 (5R,6S)-3-Keto-6-phenvl-l-oxa-7-(tert-butoxvcarbonvl)aza-spirof4.51decane Through a cooled (-80 solution of (5R,6S)-3-methylene-6-phenyl- 1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]decane (Preparation 3; 0.665g) in dichloromethane (5ml) and methanol (5ml) was bubbled a mixture of ozone and oxygen for 45 minutes. After the solution had been purged with nitrogen, dimethyl sulphide (0.5ml) was added and then stirred under nitrogen at room temperature for 16 hours. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was dried (MgSO 4 evaporated and the residue purified by chromatography on a column containing silica gel (eluting with hexane containing increasing proportions of ethyl acetate between 0% to Evaporation of the fractions gave the title compound. 1H NMR (250MHz, CDCl 3 8 7.58 (2H, d, J=6.2 Hz), 7.37-7.26 (3H, 5.3 (1H, 4.15 and WO 99/07375 PCT/EP98/04933 67 4.09 (2H, AB d, J=17.4 Hz), 3.97 (111, in), 2.80 (1H, td, J=129, 4.0 Hz), 2.74 and 2.48 (2H, ABd, J=18.1 Hz), 2.29 (2H, in), 1.88-1.63 (2H, mn), and 1.44 (911, m/z (ES-1) 332 6S)-3-Trifluoromethylsulfon-vloxv-6-phenyl- 1 .oxa-7-(tertbutoxycarbon-vl)aza-spiro [4.51 dec-3-ene To a cooled (-80 0 C) solution of 1M sodium hexamethyldisilazide (0.38m1, 0.38mmol) in THF was added a solution of (5R,6S)-3-keto-6phenyl-l1-oxa-7-(tert-butoxycarbonyl)aza-spiro decane (Preparation 4; 0.105mg, 0.3 l9mmol) in THF (3m1). The solution was stirred for 1 hours at -80' C then a solution of 2- chloropyridine (0.163g, 0.4l5mmol) in THE (3ml) was added. The solution was stirred at -80'C for 30 minutes then at room temperature for minutes before being quenched by addition of saturated ammonium chloride solution and ethyl acetate. The dried (MgSO 4 organic phase was purified by chromatography on a column containing silica gel (eluting with hexane containing increasing proportions of ethyl acetate between 0% to Evaporation of the fractions gave the title compound. 'H NMR (360MHz, CDC1 3 8 7.4 (2H, d, J=7.3 Hz), 7.3-7.22 (311, mn), 6.01 (111, t, J=2.13 Hz), 5.13 (111, 4.56 and 4.26 (2H, ABdd, J=12.4, 1.97 Hz),4. (1H1, dt, J=12.6, 4.22 Hz), 3.00 (1H, mn), 2.28-2.04 (211, in), 1.88-1.76 (211, in), and 1.37 (911, m/z 464 PREPARATION 6 (5R,6S)- 3-Trimeth-vlstannvl-6-phenyl- 1-oxa-7-(tert-butoxyvcarbonvl) azaspiro[4.51dec-3-ene To a degassed solution of (5R,6 8 )-3-trifluoromethylsulfonyloxy-6phenyl- 1-oxa-7-(tert-butoxycarbony)aza-spiro [4.51 dec-3-ene (Preparation 5; 0.482g, 1.O4mmol), lithium chloride (0.264g, 6.2Smmol), lithium carbonate (0.076g) and hexainethyl distannane(0.96g, 2.9minol) in THE WO 99/07375 PCT/EP98/04933 68 was added triphenylphosphine palladium (0.06g). The solution was degassed and then heated at 60 0 C for 5 hours under nitrogen. Water and ethyl acetate (20ml) were added and the dried organic phase was purified by chromatography on a column containing silica gel (eluting with hexane containing increasing proportions of ethyl acetate between 0% to Evaporation of the fractions gave the title compound as a crystalline solid. 1H NMR (360MHz, CDC13) 8 7.25 (2H, d, J=7.3 Hz), 7.1- (3H, 5.83 (1H, t, J=2.5 Hz), 4.78 (1H, 4.48 and4.02 (2H, dd, J=12.9, 2.3 Hz), 3.96 (1H, dd, J=6.16, 13.4 Hz), 2.95 (1H, td, J=13.3, Hz), 1.84 (1H, 1.68 (1H, 1.60 (2H, 1.19 (9H, and 0.0 (6H, s).
PREPARATION 7 (2S,3R)-l-tert-Butoxvcarbonyl-3-(3-hvdroxypropyn-l-vl)-2-phenylpiperidin- 3-ol O-Trimethylsilylpropargyl alcohol (24.51ml, 20.47g, 160ml) was added slowly to a cooled solution of ethylmagnesium bromide (1M in tetrahydrofuran, 160ml, 160mmol). The mixture was stirred at 0°C for minutes, then at room temperature for 2 hours. The mixture was cooled to -10*C and a solution of (2S)-l-tert-butoxycarbonyl-2phenylpiperidin-3-one (Preparation 1; 42.3g) in tetrahydrofuran (200ml) was added dropwise over 30 minutes. (Internal temperature below -5 0
C).
The mixture was stirred at room temperature for 14 hours, poured into water (300ml) and saturated aqueous ammonium chloride (300ml) and extracted with ethyl acetate (2x300ml). The combined organic fractions were washed with brine (300ml), dried (MgS04) and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (500ml) and a solution of tetrabutylammonium fluoride (IM in THF, 160ml, 160mmol) was added dropwise. The mixture was stirred at room temperature for 30 minutes, water (300ml) was added, and the layers were separated. The aqueous layer was extracted with ethyl acetate (2x300ml) and the combined organic fractions were washed with WO 99/07375 PCT/EP98/04933 69 water (300ml) and brine (300ml), dried (MgS0 4 and the solvent was evaporated under reduced pressure to give the crude title compound as an orange oil (45g). The crude material was purified by flash column chromatography on silica gel, eluting with hexane/ethyl acetate (90:10 increasing to 25:75) to give the title compound as an amber oil (32.2g). 'H NMR (CDC13) 8 7.53-7.55 (2H, 7.19-7.35 (3H, 5.56 (1H, 4.27 (2H, 3.99-4.03 (1H, 3.25 (1H, br 2.77-2.81 (1H, 2.77 (1H, br s), 2.12-2.20 (1H, 1.91-1.99 (2H, 1.77-1.83 (1H, and 1.39 (9H, s).
PREPARATION 8 2-Bromo-4-(trifluoromethoxv)phenol To a cooled (0 solution of 4-trifluoromethoxyphenol (35.6g, 0.2mol) in chloroform (280ml) was added dropwise a solution of bromine (32g, 0.2mol) in chloroform (50ml). The solution was stirred at 0°C for 1 hour and at room temperature for 2 hours. Dichloromethane (200ml) and water (400ml) ware added and the organic phase was washed further with water(400ml), brine (200ml) and dried (MgS0 4 The solvent was removed and the residue was purified by distillation at reduced pressure to give the title compound. 1H NMR (250MHz, CDC13) 8 7.38 (1H, d, J=2.1 Hz), 7.13 (1H, dd, 2.1 Hz), 7.03 (1H, d, J=9.1 Hz), and 5.53 (1H, s).
PREPARATION 9 2-Bromo-4-(trifluoromethoxy)phenol (Preparation 8; 5g, was dissolved in N,N-dimethylformamide (60ml), and potassium carbonate (5.4g, 40mmol) was added, followed by benzyl bromide (3.5ml, and the reaction was stirred at ambient temperature for 15 hours. The reaction was diluted with water (150ml) and extracted into ethyl acetate (3x60ml). The combined organic fractions were washed with water (100ml), brine (100ml), dried (MgSO 4 and evaporated in vacuo.
Purification on silica, eluting with 2% and 5% ethyl acetate in hexane gave WO 99/07375 PCT/EP98/04933 70 the title compound as a clear oil (6.7g, IH NMR (250MHz, CDC13) 8 5.47 (2H, 7.23 (1H, d, J=9 Hz), 7.43 (1H, dd J=8.2, 2.9 Hz), and 7.75 (6H, m).
PREPARATION Z-(2S,3R)-l-tert-Butoxvcarbonvl-3-(3-hydroxyprop-l-en-l-vl)-2phenylpiperidin-3-ol Palladium on calcium carbonate, poisoned with lead (Lindlar catalyst, 2g) was added to a solution of (2S,3R)-l-tert-butoxycarbonyl-3-(3hydroxypropyn-lyl)-2-phenylpiperidin-3-ol (Preparation 7; 32g, 96.6mmol) in ethyl acetate (300ml) and the mixture was stirred under hydrogen (1 atmosphere) for 4 hours. The mixture was filtered and the solvent was evaporated under reduced pressure to give the title compound as an oil (32g, 100%). 1H NMR (360MHz, CDCI 3 8 7.42 (2H, d, J=7.6 Hz), 7.35-7.25 (3H, 5.83 (1H, d, J12.3 Hz), 5.68 (1H, dt, J=12.3, 6.0 Hz), 5.06 (1H, s), 4.27 (1H, 4.12 (2H, 3.32 (1H, 3.13 (1H, 2.28 (1H, t, J=5.9 Hz), 2.02 (1H, 1.92-1.78 (3H, and 1.32 (9H, m/z (ES 334 PREPARATION 11 (5R,6S)-6-Phenvl-1-oxa-7-(tert-butoxvcarbonyl)aza-spiro[4.51dec-3-ene Diethylazodicarboxylate (18.2ml, 115mmol) in THF (100ml) was added dropwise to a solution of Z-(2S,3R)-l-tert-butoxycarbonyl-3-(3hydroxyprop-l-en-1-yl)-2-phenylpiperidin-3-ol (Preparation 10; 32g, 96mmol) and triphenylphosphine (30.2g, 115mmol) in THF (700ml). The mixture was stirred at 0°C for 30 minutes then at room temperature for hours. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with hexane/ethyl acetate (95:5 increasing to 80:20) to give the title compound as a colorless solid (23.4g, 1H NMR (CDC13) 5 7.45 (2H, d, J=7.4 Hz), 7.27 (2H, t, J=7.4 Hz), 7.20 (1H, t, J=7.4 Hz), 6.03 (1H, dt,
I
WO 99/07375 PCTIEP98/04933 -71 J=6.1, 2.0 Hz), 5.68 (1H, dt, J=6.1, 2.0 Hz), 5.06 (1H, 4.61 (1H, dt, J=13.1, 2.0 Hz), 4.32 (1H, dt, J=13.1, 2.0 Hz), 4.08 (1H, 3.05 (1H, m), 2.05 (1H, 1.75 (3H, and 1.37 (9H, m/z (ES 316 PREPARATION 12 Benzyl bromide (66.17ml, 95.35g, 0.56mol) was added to a mixture of 4-(trifluoromethoxy)phenol (90.26g, 0.51mol) and potassium carbonate (140.97g, 1.2mol) in dimethylformamide (160ml) and the mixture was stirred at room temperature for 72 hours. The mixture was poured into water (1.5 1) and extracted with ethyl acetate (3x500ml). The combined organic fractions were washed with aqueous sodium carbonate (saturated, 500ml), dried (MgSO 4 and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (133.5g, 1H NMR (360MHz, CDCla) 5 7.39 (5H, 7.14 (2H, d, J=9.0 Hz), 6.95 (2H, d, Hz), and 5.05 (2H, s).
PREPARATION 13 Iodine (71.96g, 0.28mol) in chloroform was added dropwise to a mixture of 2-benzyloxy-5-(trifluoromethoxy)benzene (Preparation 12, 73.06g, 0.27mol) and silver trifluoroacetate (71.57g, 0.32mol) in dichloromethane and the mixture was stirred at room temperature for 18 hours. The mixture was filtered through celite, washed with aqueous sodium thiosulfate 2x2 dried (MgSO 4 and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/ethyl acetate, to give the title compound as a colorless oil (108.03g), containing 11% unreacted 2-benzyloxy-5-(trifluoromethoxy)iodobenzene. 1H NMR (360MHz, CDCla) 8 7.67 (1H, d, J=2.8 Hz), 7.40 (5H, 7.16 (1H, dd, J=8.9, 2.8 Hz), 6.82 (1H, d, J=8.9 Hz), and 5.14 (2H, s).
1. f.
WO 99/07375 PCT/EP98/04933 72 PREPARATION 14 (5R,6S)-3-(2-Benzvloxy-5-(trifluoromethoxv)phenyl)-6-u)henvl- l-oxa-7-(tertbutoxycarbonvl)aza-spiro[4. 51dec-3-ene (5R, 68)- 3-Trimethylstannyl-6-phenyl- 1-oxa- 7-(tertbutoxycarbonyl)aza-spiro dec- 3-ene (Preparation 6; 6. 43mmol), lithium chloride 163g), benzyloxy- 5-(trifluoromethoxy)phenol (Preparation 9; 7.7mmol) in toluene (25m1) was degassed before addition of triphenyiphosphine palladium (0.37g). The solution was degassed thoroughly before heating to 110'C for 14 hours. The solution was partitioned between water and ethyl acetate and the dried organic phase was purified by chromatography on a column containing silica gel (eluting with hexane containing increasing proportions of ethyl acetate between 0% to to give the title compound. 1 H NMR (360MHz, CDCla) 6 1.33 (9H, 1.65 (1H, in), 1.76 (2H, in), 2.08 (1H, in), 3.11 (1H, mn), 4.08 (1H, in), 4.60 (1H, dd, J=12.2 Hz, J=2 Hz), 4.92 (1H, dd, J=12.1 Hz, J=1.8 Hz), 5.08 (1H, 5.1 (2H, q, J=11.5 Hz), 6.65 (1H, 6.94 (2H, d, J=8.9 Hz), 7.08 (1H, d, J=9 Hz), 7.18 (2H, t, J=8.1 Hz), 7.25 (3H, in), 7.38 (5H, in).
PREPARATION (3S.SR. 6SV3-(2-Hvdroxy-5- (trifluoromethoxy)phenvl)-6-phenvl- 1-oxa-7 (tert-butoxvcarbonvl)aza-spiro[4. 51 decane 68)-3-(2-Benzyloxy-5- (trifluoromethoxy)phenyl)-6-phenyl- 1-oxa- 7-(tert-butoxycarbonyl)aza-spiro 5]dec-3-ene (Preparation 14) (3 .88g) was dissolved in ethyl acetate (15in1) and methanol (15in1). Palladium hydroxide on carbon (1.00g) was added and the suspension was shaken under a hydrogen atmosphere (50 psi) for 72 hours. The mixture was filtered and the solvent was evaporated under reduced pressure. The residue was purified by medium pressure chromatography on silica gel, eluting with hexane/ethyl acetate (75:25) to give (3R, 5R, 6S)-3-(2-hydroxy- 6-p henyl- 1-oxa- 7-(tert-butoxycarbonyl)aza- WO 99/07375 PCT/EP98/04933 73 (191mg), 'H NMR (250MHz, CDCII3) 8 7.70 (2H, d, J=7.3 Hz), 7.33 (2H, t, J=7.3 Hz), 7.26 (1H, d, J=7.3 Hz), 7.05 (1H, hr 6.96 (2H, mn), 6.82 (1H, d, J=9.4 Hz), 5.43 (1H, 4.27 (1H, mn), 4.01 (1H, in), 3.95 (1H, mn), 3.73 (1H, in), 2.73 (2H, mn), 2.33 (1H, in), 1.87-1.58 (4H, in); and 1.50 (9H, s).and (3S,5R, GS)-3-(2-hydroxy-5-(trifluoromethoxy)phenzyl)- 6-phenyl- 1-oxa- 7-(tert -b utoxycarbonyl)aza-spiro[4. 5]decane 3g), 1H NMR (360MHz, CDCl 3 8 1.38 (9H, 1.73 (2H, mn), 1.81 (1H, in), 2.18 (2H, mn), 2.50 (1H, in), 2.81 (1H, in), 3.62 (1H, t, J=7.2 Hz), 3.92 (1H, mn), 3.98 (1H, d, J=13.2 Hz), 4.23 (1H, in), 5.33 (1H, 6.75 (1H, d, J=8.5 Hz), 6.94 (2H, in), 7.25 (1H, in), 7.31 (2H, in), and 7.55 (2H, d, J=7.8 Hz).
PREPARATION 16 (3R. SR.6S)-3-(2-Benzvloxy- 5-(trifluoromethoxyv)phenvl)-6-phen-vl- 1-oxa- 7- (tert-butoxvcarbonvl)aza-spiro IA. Sdecane A mixture of (Preparation 13, 2 1.8g, 55.2namol), (5R, 6S)-6-phenyl- 1-oxa-7-(tertbutoxycarbonyl)aza-spiro[14.5] dec-3-ene (Preparation 11, 7.0Og, 22.1limol), tetra-n-butylainmoniuin chloride 18g, 22. 2minol), lithium chloride (9.35g, 0.22mo1) and potassium forinate (5.64g, 67.Ominol) in diinethylformainide (lO0mi) was degassed with a firestone valve (5 x).
Palladium acetate (491mg, 2.2mmol) was added and the mixture was degassed with a firestone valve (5 The mixture was stirred at 60'C for hours, then further (Preparation 13, 4.32g, 11.Oiniol), potassium forinate (2.78g, 33.Sminol) and palladium acetate (260mg, 1.linmol) were added. The mixture was stirred at 60'C for 22 hours, cooled and filtered. The solvent was evaporated under reduced pressure, water (600m1) was added and the mixture was extracted with ethyl acetate (2x300m1). The combined organic fractions were washed with brine (300in1), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with WO 99/07375 PCTIEP98/04933 -74 hexane/dichioromethane (75:25 increasing to 0: 100) then dichioromethane/ethyl acetate to give the title compound (9.42g, 1 H NMR (360MHz, CDCl 3 8 7.56 (2H, d, J=7.7 Hz), 7.40-7.20 (8H, in), 7.14 (111, d, J=2.0 Hz), 7.00 (1H, dd, J=8.9, 2.0 Hz), 6.88 (1H, d, J=8.9 Hz), 5.30 (1H, 5.08 (2H, 4.27 (1H, in), 3.97 (1H, in), 3.87 (2H, in), 2.78 (1H, in), 2.56 (1H, in), 2.15 (1H, in), 1.96 (1H, in), 1.67 (3H, in), and 1.42 (9H, s).
PREPARATION 17 (3R, SR.6S)-3-(2-Hyvdroxy-5-(trifluoromethoxv)phenvl)-6-phenvl- -oxa-7- (tert-butoxycarbonyl)aza-spiro [4.51 decane Palladium on carbon 0.59g) was added to a solution of (3R, 5R,6S)- 3-(2-benzyloxy-5-(trifluoromethoxy)phenyl)-6-phenyl- 1-oxa- 7- (tert-butoxycarbonyl)aza-spiro 5]decane (Preparation 16, 6.1l0g, 10.5minol) in methanol-water (99:1, 200m1) and the mixture was stirred under hydrogen (50 psi.) for 72 hours. The mixture was filtered, washing with ethanol, and the solvent was evaporated under reduced pressure.
The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane/ethyl acetate (99:1 increasing to 90:10) to give the title compound. 1H NMR (360MHz, CDCl 3 6 7.70 (2H, d, J=7.3 Hz), 7.33 (2H, t, J=7.3 Hz), 7.26 (1H, d, J=7.3 Hz), 7.05 (1H, br 6.96 (2H, in), 6.82 (1H, d, J=9.4 Hz), 5.43 (1H, 4.27 (1H, in), 4.01 (1H, in), 3.95 (1H, in), 3.73 (1H, in), 2.73 (2H, in), 2.33 (1H, in), 1.87-1.58 (4H, in), and 1.50 (9H, s).
PREPARATION 18 (3S. SR.6S) [2-(1-Phenylthiocvcloprop (trifluoroinethoxy)phenvll -6-phenvli1-oxa-7- (tert-butoxycarbonvl)azaspiro Side cane (38, 5R,6S)-3-(2-Hydroxy-5-(trifluoromethoxy)phenyl)-6-phenyl- 1oxa-7 -(tert-butoxycarbonyl)aza-spiro decane (Preparation 15) (290mg,
I.
WO 99/07375 PCT/EP98/04933 75 0.59mmol) was dissolved in toluene (5mi) and silver carbonate (179mg, 0. 65mmol) was added in one portion. (1-lodocycloprop- 1-yl)phenylsulfide (Cohen T. and Matz J. J. Am. Chem. Soc. 1980, 102, 6902) (180mg, 0.65mmol) was then added over one minute at room temperature. The mixture was stirred at 55 0 C for 4 hours, then further portions of silver carbonate (179mg, 0. 65mmol) and (1 -iodocycloprop -1-yl)phenylsulfide (180mg, 0.65mmol) were added. The mixture was stirred at 55*C for a further 3 hours, cooled, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane/ethyl acetate (90: 10 increasing to 80:20) to give the title compound as a colourless oil (120mg, 'H NMR (250MHz, CDC1 3 8 7.55-7.44 (411, in), 7.36-7.23 (7H, in), 7.13-7.02 (2H, in), 5.16 (1H, br 4.09 (1H, t, J=6 Hz), 4.03-3.92 (1H, in), 3.67-3.49 (211, in), 2.94-2.79 (1H1, mn), 2.26 (1H, dd, J=7.9, 12.9 Hz), 2.15-2.01 (2H, in), 1.76- 1.59 (3H, in), 1.53-1.45 (4H, in), and 1.36 (9H, in/z 642 PREPARATION 19 (3R. 5R. 6S)-3- (1-Phenylthiocvcloprop-l1-VI)oxv-5- (trifluoromethoxv)phenyU -6-phenyvl-l1-oxa- 7-(tert-butox-vcarbonvl)aza- Prepared from (3R,5R,6S)-3-(2-hydroxy-5- (trifluoroinethoxy)phenyl)-6-phenyl- 1-oxa- 7-(tert-butoxycarbonyl)aza- (Preparation 17) according to the method of Preparation 18. 1H NMR (360MHz, CDC1 3 8 7.57 (2H, app. d, J=7.6 Hz), 7.45 (2H, app. d, J=7.7 Hz), 7.36-7.19 (711, in), 7.16-7.06 (2H, 5.28 (111, br s), 4.13 (1H, app. t, J=7.8 Hz), 3.96 (111, br. d, J=13 Hz), 3.80-3.60 (211, in), 2.79 (1H, br. t, J=13 Hz), 2.50 (111, dd, J=13, 7.9 Hz), 2.17 (111, dt, J=13, 4.6 Hz), 1.80 (1H, dd, J=12, 9.8 Hz), 1.75-1.38 (7H, in), and 1.44 (9H1, s).
in/z 642 WO 99/07375 PCT/EP98/04933 76- PREPARATION (3S,5R,6S)-3-[2-Cyclopropoxy-5-(trifluoromethoxv)phenvll-6-phenvl-1-oxa- 7-(tert-butoxvcarbonvl)aza-spiro[4.51decane Naphthalene (120mg, 0.936mmol) was dissolved in THF under nitrogen and freshly cut lithium metal (7.0mg, 0.94mmol) was added. The mixture was then sonicated at room temperature for minutes to produce a dark green solution of lithium naphthalenide. This solution was cooled to -78 then (3S,5R,6S)-3-[2-(l-phenylthiocycloprop- 1-yl)oxy-5-(trifluoromethoxy)phenyl]-6-phenyl-l-oxa-7-(tertbutoxycarbonyl)aza-spiro[4.5]decane (Preparation 18) (120mg, 0.187mmol) in THF (0.5ml) was added over 1 minute. The reaction mixture was stirred for 30 minutes, then water (5ml) and ether (10ml) were added. The layers were separated and the aqueous layer was extracted with ether The combined organic fractions were dried (MgSO 4 and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane/ethyl acetate (90:10 increasing to 80:20) to give the title compound as a colourless oil (58.6mg, lH NMR (250MHz, CDCla) 5 7.58-7.52 (2H, 7.36-7.17 (4H, 7.10-7.01 (2H, 5.18 (1H, br 4.20 (1H, t, J=6.7 Hz), 4.05-3.95 (1H, 3.76-3.55 (3H, 2.92-2.79 (1H, 2.37 (1H, dd, J=12.9, 7.8 Hz), 2.18-2.06 (2H, 1.80-1.67 (3H, 1.38 (9H, and 0.86-0.73 (4H, m/z (ES 534 PREPARATION 21 (3R,5R,6S)-3-[2-Cyclopropoxy-5-(trifluoromethoxv)phenvl-6-phenvl-1-oxa- 7-(tert-butoxvcarbonvl)aza-spiro[4.51decane Naphthalene (120mg, 0.936mmol) was dissolved in THF under nitrogen and freshly cut lithium metal (7.0mg, 0.94mmol) was added. The mixture was then sonicated at room temperature for minutes to produce a dark green solution of lithium naphthalenide. A solution of (3R,5R,6S)-3-[2-(1-phenylthiocycloprop-1-yl)oxy-5q WO 99/07375 PCT/EP98/04933 -77 (trifluoromethoxy)phenyl]-6-phenyl-l-oxa-7-(tert-butoxycarbonyl)aza- (Preparation 19, 135mg, 0.21mmol) in THF (2ml) under nitrogen was cooled to -78 0 C and the solution of lithium naphthalenide in THF was added dropwise until the intense green colour persisted. The reaction was then stirred for one minute, water (5ml) was added and the mixture was warmed to room temperature. Ether (10ml) was added and the layers were separated. The aqueous phase was extracted with a further portion of ether (10ml) and the combined organic phases were dried (MgS0 4 and the solvent was evaporated under reduced pressure.
The residue was purified by column chromatography on silica gel, eluting with hexane/ethyl acetate (50:50) to give the title compound as a colourless oil (87mg, IH NMR (360MHz, CDC13) 8 7.59 (2H, app. d, J=7.6 Hz), 7.32 (2H, app. t, J=7.6 Hz), 7.27-7.18 (2H, 7.11-7.03 (2H, 5.32 (1H, br 4.29-4.21 (1H, 3.97 (1H, br. d, J=13 Hz), 3.83-3.68 (3H, 2.76 (1H, dt, J=13, 4.1 Hz), 2.55 (1H, dd, J=13, 7.2 Hz), 2.22 (1H, dt, J=12, 5.2 Hz), 1.85 (1H, dd, J=13, 9.9 Hz), 1.80-1.63 (3H, 1.46 (9H, and 0.82- 0.76 (4H, m/z (ES 534 COMPOUND A (3S,5R, 6S)-3-[2-Cyclopropoxy-5-(trifluoromethoxv)phenvll-6-phenvl-1-oxa- 7-aza-spiro[4.51decane Hydrochloride Trifluoroacetic acid (2.5ml) was added dropwise to a stirred, cooled 0°C) solution of (3S,5R,6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]- 6-phenyl-l-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]decane (Preparation 20; 492mg, 0.92mmol) in dichloromethane (25ml) and the mixture was stirred at room temperature for 3 hours. The mixture was poured into water (50ml), the pH was adjusted to 10.0 with aqueous sodium hydroxide (4M) and the mixture was extracted with dichloromethane (3x50ml). The combined organic fractions were dried (MgSO 4 and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with WO 99/07375 PCT/EP98/04933 78 dichloromethane/methanol/ammonia (96:4:0.4 increasing to 94:6:0.6).
The residue was dissolved in ethanol (20ml), cooled in ice and ethereal hydrogen chloride (1M, 1.8ml, 1.8mmol) was added dropwise. The mixture was stirred at 0°C for 5 minutes, then the solvent was evaporated under reduced pressure. The residue was crystallized from ether and the solid was collected and dried in vacuo to give the title compound as a colorless solid (354mg, m.p. 214-216 1 H NMR (500MHz, CD 3 OD) 8 7.59 (2H, 7.52 (3H, 7.26 (1H, d, J=8.9 Hz), 7.03 (1H, dd, J=8.9, 2.2 Hz), 6.20 (1H, d, J=2.2 Hz), 4.85 (2H, br 4.43 (1H, 4.19 (1H, t, J=8.0 Hz), 3.87 (1H, quin, J=8.0 Hz), 3.76 (1H, m), 3.44 (1H, 3.25 (2H, m) 2.29-1.78 (6H, 0.80 (2H, and 0.66 (2H, m/z 434 Found: C, 61.41; H, 5.51; N, 3.08.
C
24
H
26
F
3 N0 3 .HCI requires: C, 61.34; H, 5.79; N, 2.98%.
COMPOUND B (3R,5R,6S)-3-[2-Cyclopropoxy-5-(trifluoromethoxv)phenyvll-6-phenyl-1-oxa- 7-aza-spiro[4.51decane Prepared from the compound of Preparation 21 according to the method used for Compound A. 1H NMR (360MHz, CDCl1) 8 7.50-7.42 (2H, 7.36-7.26 (3H, 7.03 (1H, d, J=8.9 Hz), 6.95 (1H, br. d, J=8.9 Hz), 6.81 (1H, br 3.92 (1H, t, J=7.4 Hz), 3.62-3.53 (2H, 3.50 (1H, 3.20 (1H, dd, J=12, 4.2 Hz), 2.77 (1H, dt, J=12, 2.8 Hz), 2.30-1.93 (4H, 1.87 (1H, br 1.71-1.49 (3H, 0.76-0.65 (2H, and 0.65-0.54 (2H, m/z (ES 434 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-1 receptor affinity (IC 5 o) of less than 10nM, favourably less than 2nM and preferably less than InM.
WO 99/07375 PCT/EP98/04933 79- 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. 1 25 I-Tyr 8 -substance P (0.lnM, 2000Ci/mmol; New England Nuclear) is incubated in the presence or absence of test compounds (dissolved in 5ld dimethylsulphoxide, DMSO) with 5x10 4 CHO cells. Ligand binding is performed in 0.25ml of Tris-HC1, pH7.5, containing 5mM MnC12, 150mM NaCl, 0.02% bovine serum albumin (Sigma), 50pg/ml chymostatin (Peninsula), 0.lnM phenylmethylsulphonyl fluoride, 2pg/ml pepstatin, 2tg/ml leupeptin and 2.8pg/ml 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% polyethylenimine using a Tomtek 96-well harvester. Non-specific binding is determined using excess substance P (jIM) and represents <10% of total binding.
ASSAY 2: Gerbil Foot-Tapping CNS penetrant NK-1 receptor antagonists for use in the present invention 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. Pharmacol., 1994, 265, 179.
WO 99/07375 PCT/EP98/04933 80 Briefly, male or female Mongolian gerbils (35-70g) are anaesthetised by inhalation of an isoflurane/oxygen mixture to permit exposure of the jugular vein in order to permit administration of test compounds or vehicle in an injection volume of 5ml/kg i.v. Alternatively, test compounds 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 NK-1 receptor agonist GR73632 (d Ala[L-Pro 9 ,Me-Leu']-substance is infused directly into the cerebral ventricles 3pmol in 5gl 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 orally by gavage with test compound. Ten minutes later they are fed with approximately 100g of tinned cat food. At 60 minutes following oral dosing, 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 Male and female guinea-pigs pups are housed in family groups with their mothers and littermates throughout the study. Experiments are WO 99/07375 PCT/EP98/04933 -81commenced 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 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 described 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 retested once weekly for up to 6 weeks. Between 6 and 8 animals receive each test compound.
As used herein, the term "CNS-penetrant" refers to NK-1 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 of the NK-1 receptor agonist, GR73632 (d Ala[L-Pro 9 ,Me-Leu 10 ]-substance Punder 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 IDs5o3mg/kg, and preferably with an In an alternative method, the NK-1 receptor antagonist is 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 ID5os30mg/kg, and preferably with an ID 5 WO 99/07375 PCT/EP98/04933 82 CNS-penetrant NK-1 receptor antagonists of use in the present ivnention are also effective in the attenuation of separation-induced 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 preferably with an ID5so10mg/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 ID5o<20mg/kg, preferably with an ID5o10mg/kg, and especially with an A suitable selection cascade for NK 1 antagonists of use according to the present invention is as follows: Determine affinity for human NK 1 receptor in radioligand binding studies (Assay select compounds with IC 50 10nM, preferably ICso 2nM, especially IC 5 so InM.
(ii) Determine ability of compounds to penetrate CNS by their ability to inhibit foot tapping in gerbils induced by central injection of an
NK
1 agonist (Assay select compounds that inhibit foot tapping with IDso 5 3mg/kg and preferably IDso 5 Img/kg i.v. when administered immediately prior to central NKi agonist challenge, or ID 5 o 30mg/kg p.o., and preferably IDso 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 25-fold loss of potency compared with ID 5 o determined in step (ii) above with the proviso that IDo 50 10mg/kg and preferably 5mg/kg i.v. after 24 hour pre-treatment.
WO 99/07375 PCT/IEP98/04933 83 (iv) Determine oral bioavailability of compounds by pharmacokinetic analysis, activity in gerbil foot tapping assay following oral administration and/or by ability to inhibit cisplatin-induced emesis in ferrets (Assay select compounds with ID 90 o 3mg/kg and preferably IDo Ilmg/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 ID 5 so 20mg/kg, and preferably ID 50 Yet further preferred compounds of use in the present invention may be selected from those compounds which satisfy the NK-1 receptor binding criteria of step which, in addition, have 5-fold shift in affinity when incubated in the presence of human serum albumin (HSA) to show non-specific protein binding.
One example of a NK-1 receptor antagonist of use in the present invention is the compound 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine, the preparation of which is described in International Patent Specification No. WO 95/16679. In the aforementioned assays, this compound has the following activity: human NK-1 receptor binding: IC5o=0.1nM gerbil foot-tapping (5 mins.): ID5o=0.36mg/kg i.v.
gerbil foot-tapping (24 hrs.): ID5o=0.33mg/kg i.v.
ferret emesis: IDgo<3mg/kg p.o.
guinea pig vocalisation (4 hr. pre-treatment): ID5o=0.73mg/kg p.o.
WO 99/07375 PCT/EP98/04933 84 A further example of a NK-1 receptor antagonist of use in the present invention is the compound bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4- (1,2,4-triazol-3-yl)methylmorpholine, the preparation of which is described in International Patent Specification No. WO 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): IC50= 0.12 nM
ID
5 o 0.38 mg/kg i.v.
ID
50 2.2 mg/kg i.v.
ID
9 oo 1 mg/kg p.o.
ID
5 o 0.91 mg/kg p.o.
The following example illustrates pharmaceutical compositions according to the invention.
EXAMPLE 1 Tablets containing 50-300mg of NK-1 antagonist NK-1 antagonist Microcrystalline cellulose Modified food corn starch Lactose Magnesium Stearate Amount mg 50.0 100.0 300.0 80.0 80.0 80.0 80.0 80.0 80.0 189.5 139.5 139.5 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 the corn starch and the magnesium stearate. The resulting granulation is WO 99/07375 PCT/EP98/04933 85 then compressed into tablets containing 50mg, 100mg and 300mg of the NK-1 receptor antagonist per tablet.
EXAMPLE 2 Parenteral injection 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.
Pharmaceutical compositions comprising a combination of a NK-1 receptor antagonist and an antipsychotic agent may be prepared with separate active ingredients or with a combination of active ingredients in one composition. In such combined preparations, the ratio of the NK-1 receptor antagonist and the antipsychotic agent will depend upon the choice of active ingredients.
EXAMPLE 3 Tablets containing 50-300mg of NK-1 antagonist and 5-10me of haloDeridol NK-1 antagonist haloperidol Microcrystalline cellulose Modified food corn starch Lactose Magnesium Stearate 50.0 5.0 80.0 80.0 184.5 0.5 50.0 10.0 80.0 80.0 179.5 0.5 Amount mg 100.0 100.0 5.0 10.0 80.0 80.0 80.0 80.0 134.5 129.5 0.5 0.5 300.0 5.0 80.0 80.0 134.5 0.5 300.0 10.0 80.0 80.0 129.5 WO 99/07375 PCT/EP98/04933 86- EXAMPLE 4 Tablets containing of chlorpromazine hydrochloride NK-1 antagonist chlorpromazine hydrochloride Microcrystalline cellulose Modified food corn starch Lactose Magnesium Stearate 50-300me of NK-1 antagonist and 50-300mg of NK-I antaeonist and Amount mg 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 resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate. The resulting granulation is then compressed into tablets containing 50mg, 100mg and 300mg of the CNS-penetrant NK-1 receptor antagonist per tablet.

Claims (10)

1. Use of an orally active, long acting, CNS-penetrant NK-1 receptor antagonist for the manufacture of a medicament for the treatment or prevention of aggressive behaviour.
2. Use of an orally active, long acting, CNS-penetrant NK-1 receptor antagonist and an antipsychotic agent for the manufacture of a medicament for the treatment or prevention of aggressive behaviour.
3. A pharmnaceutical composition adapted for oral administration for the treatment or prevention of aggressive behaviour comprising an orally active, long acting, CNS-penetrant NK-1 receptor antagonist, together with at least one pharmaceutically acceptable carrier or excipient. '*ns
4. A composition according to claim 3 which further comprises an antipsychotic agent. 15
5. A product comprising an orally active, long acting, CNS-penetrant NK-1 receptor antagonist and an antipsychotic agent when used simultaneously, separately or sequentially in the treatment or prevention of aggressive behaviour.
6. A method for the treatment or prevention of aggressive behaviour, which method comprises administration to a patient in need of such treatment of an 20 effective amount of an orally active, long acting, CNS-penetrant NK-1 receptor antagonist.
7. A method for the treatment or prevention of aggressive behaviour, which method comprises administration to a patient in need of such treatment of an amount of an orally active, long acting, CNS-penetrant NK-1 receptor antagonist and an amount of an antipsychotic agent, such that together they give effective relief.
8. A use according to claim 1 or 2, a composition according to claim 3 or 4, a product when used according to claim 5 or a method according to claim 6 or 7 wherein the orally active, long acting, CNS-penetrant NK-1 receptor antagonist is selected from the classes of compounds described in EP-A-0577394, WO-A-9508549, WO-A-9518124, WO-A-9523798, WO-A-9605181 and WO-A-9749710.
9. A use according to claim 1 or 2, a composition according to claim 3 or 4, a product when used according to claim 5 or a method according to claim 6 or 7 wherein the NK-1 receptor antagonist is selected from: (3S,5R,6S)-3-[ 2 -cyclopropoxy-5-(trifluoromethoxy)phenyl- 1 -oxa-7-aza-spiro[4.5]decane; IBZ]05507.doc:lai W .r 3 R,5R, 6 S)-3-[2cycopropoxy5(trifluoromethoxy)phenyl- 1 -oxa-7-aza- ,5-bis(tri* fl uoromiethyl)benzyloxy)-3(S)-(4-fluorophenyl-4-(3 -oxo- I H,4H- 1 2 4 -triazolo)miethiyl)miorph oline; -(R)-(3,5-bis(tri fluoroiethyl)pheny)ethoxy-4(3(5oxol IH,4H- 1,2,4- triazolo)methyl)-3(S)-pleinyl-morholine; ,5 -bis(tri 11 uoromiethyl)benzyloxy)-4-(3 -oxo- 1 H,4H- 1 2 4 -tri azo lo)m ethyl)-3 (S)-phenyl-morpliIine; I ,5 -bi s(ti fi uorornethyl)phenyl)ethoxy-3(S)-(4-fluorophenyl>4-(3 I 0 1 H,4H- 1 ,2,4-tri azolIo) nieth yl)morpho line; 1 ,5 -bis(trifluoromethyl)phenyl)ethoxy-4(5-4,Ndimethylamino)methyl- I 2 3 -triazol-4-yl)rnethiyl-3 -(S)-phenylmorpholine; I ,5 -bis(tri fluorornethyl)phenyl)ethoxy)-4-(s -(N,N-dimethylamino)methyl- l, 2 3 -tri azol-4-yi) inethyl -3-S)-(4-fluorophenyl)morpho line; 1 ,5 -bi s(tri fluLoromethyl)phenyl)ethoxy-3 (S)(4-fluorophenyl)-4(3 monophosphoryl-5-oxo- IH-I 2 4 -triazoio)methyl)morpholine; -bis(trifluoromethyl)phenyl)ethoxy-3(S-(4-fluorophenyl)4-(3 -oxo- IH- 1,2 4 -triazolo)methyl)morpholine; 2 1 ,5 -bi1s(tri fl uoromethyl)phenyl)ethoxy-3 (S)(4-fluorophenyl)-4(3 20 monophosphoryl 5-oxo- 1 H-i 2 4 -triazolo)methyl)morphoIine; :2 1 ,5 -bi1s(tri fl uoromethyl)phenyl)ethoxy)-3 fluorophenyl)-4-(3 :ox yphosphoryl- I H-i 1,2,4-tri azo lo)methyl)morpholine; 2 R-35-bi1s(tri fluoromethyl)phenyl)ethoxy)-3 -(S)-(4-fluorophenyl)-4-(3 -oxo-4H- 1, 2 4 -triazolo)methyl)morpholine; 1 -bis(trifluoromethyl)phenyl)ethoxy)4(4N,N-dimethylaminobut2-yn yl) -3 4 fluo roph enyl)in orpho line; 1 ,5 -bis(trifluoromethyl)phenyl)2-hydroxyethoxy)3(S)-(4-fluorophenyl)- 1,2,4-tniazol-3 inethylmorpho line; or a pharmaceutically acceptable salt thereof.
10. A use according to claim 1 or 2, a composition according to claim 3 or 4, a product when used according to claim 5 or a method according to claim 6 or 7 wherein the aggressive behaviour is explosive personality disorder, intermittent explosive disorder, aggressive personality, aggressive nature, aggressiveness, excessive emotional instability, pathological emotionality, quarrelsomeness, dementia with behavioural 89 disturbances, and personality change of the aggressive type due to a general medical condition. Dated 15 June, 2001 Merck Sharp Dohme Limited Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON
AU91605/98A 1997-08-04 1998-07-31 Use of NK-1 receptor antagonists for treating aggressive behaviour disorders Ceased AU737019B2 (en)

Applications Claiming Priority (7)

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GBGB9716457.8A GB9716457D0 (en) 1997-08-04 1997-08-04 Therapeutic agents
GB9716457 1997-08-04
EP97/06689 1997-11-25
PCT/EP1997/006689 WO1999007374A1 (en) 1997-08-04 1997-11-25 Use of nk-1 receptor antagonists for treating aggressive behaviour
GBGB9812615.4A GB9812615D0 (en) 1998-06-11 1998-06-11 Therapeutic use
GB9812615 1998-06-11
PCT/EP1998/004933 WO1999007375A1 (en) 1997-08-04 1998-07-31 Use of nk-1 receptor antagonists for treating aggressive behaviour disorders

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