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WO1999025364A1 - Procede de traitement du trouble deficitaire de l'attention - Google Patents

Procede de traitement du trouble deficitaire de l'attention Download PDF

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Publication number
WO1999025364A1
WO1999025364A1 PCT/US1998/024634 US9824634W WO9925364A1 WO 1999025364 A1 WO1999025364 A1 WO 1999025364A1 US 9824634 W US9824634 W US 9824634W WO 9925364 A1 WO9925364 A1 WO 9925364A1
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WO
WIPO (PCT)
Prior art keywords
phenyl
receptor antagonist
alkyl
neurokinin
substituted
Prior art date
Application number
PCT/US1998/024634
Other languages
English (en)
Inventor
David L. Glatt
Mark S. Kramer
Nadia Rupniak
Original Assignee
Merck & Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9810176.9A external-priority patent/GB9810176D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to JP2000520797A priority Critical patent/JP2001523643A/ja
Priority to EP98959502A priority patent/EP1030672A1/fr
Priority to AU15289/99A priority patent/AU745524B2/en
Priority to CA002309392A priority patent/CA2309392A1/fr
Publication of WO1999025364A1 publication Critical patent/WO1999025364A1/fr

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • Attention deficit disorder is a learning disorder which relates to developmentally inappropriate inattention and impulsivity which may be present with or without hyperactivity. Attention deficit disorder is implicated in learning disorders and can influence the behavior of children at any cognitive level. ADD is primarily a disorder experienced by children, but it may be present in adults as well. ADD is estimated to affect 5 to 10% of school-aged children, precipitating half of the childhood referrals to diagnostic clinics and it is seen 10 times more frequently in boys than girls. A common disorder, ADD probably accounts for more child mental health referrals than any other single disorder. Attention deficit disorder may also be referred to as disruptive behavior disorder. The primary signs of attention deficit disorder with or without hyperactivity are a subject's display of inattention and impulsivity.
  • Attention deficit disorder with hyperactivity is diagnosed when the signs of overactivity are obvious. Inappropriate inattention causes increased rates of activity and impersistence or reluctance to participate or respond.
  • a subject suffering from ADD exhibits a consistent pattern of inattention and/or hyperactivity-impulsivity that is more frequent and severe than is typically observed in individuals at a comparable level of development. Such subjects must suffer clear evidence of interference with developmentally appropriate social, academic, or occupational functioning.
  • subjects with ADD and without hyperactivity may not manifest high activity levels, most exhibit restlessness or jitteriness, short attention span, and poor impulse control. These are qualitatively different from those seen in conduct and anxiety disorders.
  • Inattention is described as a failure to finish tasks started, easy distractibility, seeming lack of attention, and difficulty concentrating on tasks requiring sustained attention.
  • Impulsivity is described as acting before thinking, difficulty taking turns, problems organizing work, and constant shifting from one activity to another. Impulsive responses are especially likely when involved with uncertainty and the need to attend carefully.
  • Hyperactivity is featured as difficulty staying seated and sitting still, and
  • DSM-III-R lists 14 signs, 8 of which must be present for the diagnosis of attention deficit disorder. These are (1) often fidgets with hands or feet or squirms in seat (restlessness), (2) has difficulty remaining seated when required to do so, (3) is easily distracted by extraneous stimuli, (4) has difficulty awaiting turn in games or group situations, (5) often blurts out answers before questions are completed, (6) has difficulty following through on instructions from others (not due to oppositional behavior or failure of comprehension), (7) has difficulty sustaining attention in tasks or play activities, (8) often shifts from one uncompleted task to another, (9) has difficulty playing quietly, (10) often talks excessively, (11) often interrupts or intrudes on others, (12) often does not seem to listen to what is being said, (13) often loses things necessary for tasks or activities at school or home, and (14) often engages in physically dangerous activities without considering possible consequences.
  • attention deficit disorder shall include disruptive behavior disorder as characterized in DSM-IV-R (Diagnostic and Statistical Manual of Mental Disorders. Revised) as categories 314.xx (including 314.01, 314.00 and 314.9), 312.xx and 313.xx.
  • DSM-IV-R Diagnostic and Statistical Manual of Mental Disorders. Revised
  • xx including 314.01, 314.00 and 314.9
  • 312.xx and 313.xx The skilled artisan will recognize that there are alternate nomneclatures, nosologies, and classification systems for pathological conditions and that these systems evolve with medical scientific progress.
  • ADD signs Some children with ADD signs also have been less responsive to positive and negative reinforcement. They often seem to lack intrinsic motivation and do not consider long-term consequences of their behavior. In general, children with ADD during the school years are a more homogeneous group than those referred before age 6 yr. Many ADD signs expressed during the preschool years indicate communication disorders, anxiety, and conduct disorders. During later childhood, ADD signs usually are specific and qualitatively distinct; eg, such children often exhibit continuous movement of the lower extremities, motor impersistence such as the purposeless movement and fidgeting of hands, impulsive talking, and a seeming lack of awareness of their environment. Commonly, they are not aggressive or oppositional.
  • Adolescents and adults may display residual symptoms of inattention and impulsivity such as fidgetiness, restlessness, difficulty completing assigned tasks (eg, homework), difficulty focusing attention for extended periods of time and difficulty engaging in quiet sedentary activities. Although hyperactivity tends to diminish with age, residual symptoms and signs can extend well into adulthood.
  • follow-up studies have found that children identified as having ADD do not grow out of their difficulties. Later problems in adolescence and adulthood occur predominantly as academic failure, low self-esteem, and difficulty learning appropriate social behavior.
  • Methylphenidate is the drug of choice for the treatment of prevention of ADD. Methylphenidate is generally more effective than tricyclic antidepressants (eg, imipramine), caffeine, and other psychostimulants (eg, pemoline and deanol) and has fewer side effects than does dextroamphetamine.
  • tricyclic antidepressants eg, imipramine
  • caffeine e.g., imipramine
  • psychostimulants eg, pemoline and deanol
  • a preferred form in development is d-methylphenidate hydrochloride.
  • Common side effects of methylphenidate are sleep disturbances (eg, insomnia), depression or sadness, headache, stomachache, suppression of appetite, elevated BP, and, with large continuous doses, a reduction of growth. Long-term benefits of medication with methylphenidate, however, have not been demonstrated conclusively. Some research indicates that use of medication permits participation in activities previously inaccessible because of poor attention and impulsivity. These approaches
  • neuropeptide receptors for substance P are widely distributed throughout the mammalian nervous system (especially brain and spinal ganglia), the circulatory system and peripheral tissues (especially the duodenum and jejunum) and are involved in regulating a number of diverse biological processes. This includes sensory perception of olfaction, vision, audition and pain, movement control, gastric motility, vasodilation, salivation, and micturition (B. Pernow, Pharmacol. Rev.. 1983, 35, 85-141).
  • NK-1 and NK-2 receptor subtypes are implicated in synaptic transmission (Laneuville et al., Life Sci.. 42, 1295-1305 (1988)).
  • Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt contractile action on extravascular smooth muscle tissue.
  • the tachykinins are distinguished by a conserved carboxyl- terminal sequence.
  • the known mammalian tachykinins include neurokinin A and neurokinin B.
  • the current nomenclature designates the receptors for substance P, neurokinin A, and neurokinin B as neurokinin-1, neurokinin-2, and neurokinin-3, respectively.
  • Substance P is a pharmacologically-active neuropeptide that is produced in mammals and acts as a vasodilator, a depressant, stimulates salivation and produces increased capillary permeability. It is also capable of producing both analgesia and hyperalgesia in animals, depending on dose and pain responsiveness of the animal (see R.C.A. Frederickson et al., Science. 199. 1359 (1978); P. Oehme et al., Science. 208. 305 (1980)) and plays a role in sensory transmission and pain perception (T.M. Jessell, Advan. Biochem. Psychopharmacol. 28. 189 (1981)).
  • Substance P is an excitatory neurotransmitter which stimulates the activity of dopamine and perhaps other neurotransmitters thought to be involved in movement and attention.
  • a neurokinin- 1 receptor antagonist should be effective in directly reducing hyperactive states and in focusing the attention of a patient with attention deficit disorder.
  • 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, PCT Patent Publication Nos. WO 95/16679, WO 95/18124 and WO 95/23798).
  • the present invention relates to the use of a tachykinin receptor antagonist, in particular a neurokinin- 1 receptor antagonist, for the treatment, prevention or amelioration of attention deficit disorder comprising the administration of a tachykinin antagonist, in particular a neurokinin- 1 receptor antagonist.
  • the present invention provides a method for treating or attention deficit disorder comprising the administration of a tachykinin receptor antagonist, in particular a neurokinin- 1 receptor antagonist.
  • the present invention is directed to a method for treating or preventing attention deficit disorder in a patient comprising the administration of a tachykinin receptor antagonist, in particular an NK-1 receptor antagonist.
  • the present invention provides a method for treating or preventing attention deficit disorder in a patient comprising the administration of a tachykinin receptor antagonist, in particular an NK-1 receptor antagonist.
  • the present invention further provides a pharmaceutical composition for attention deficit disorder in a patient comprising a tachykinin receptor antagonist, in particular an NK-1 receptor antagonist, together with at least one pharmaceutically acceptable carrier or excipient.
  • a tachykinin receptor antagonist in particular an NK-1 receptor antagonist
  • the tachykinin receptor antagonist is administered to a patient in a quantity sufficient to treat or prevent the symptoms and/or underlying etiology associated with attention deficit disorder in a patient.
  • a pharmaceutical composition for the treatment or prevention of attention deficit disorder in a patient comprising a NK-1 receptor antagonist, together with at least one pharmaceutically acceptable carrier or excipient.
  • the present invention also provides the use of a NK-1 receptor antagonist for the manufacture of a medicament for treating or preventing attention deficit disorder in a patient.
  • a NK-1 receptor antagonist for the manufacture of a medicament for treating or preventing attention deficit disorder in a patient.
  • the present invention is useful in any mammal suffering from attention deficit disorder, a preferred subject is a human, especially a child.
  • the tachykinin receptor antagonists of use in the present invention may be any tachykinin antagonist known from the art.
  • the tachykinin receptor antagonist is a neurokinin- 1 (NK-1) or neurokinin-2 (NK-2) receptor antagonist, especially a neurokinin-1 (NK-1) receptor antagonist.
  • the tachykinin antagonist may be peptidal or non-peptidal in nature, however, the use of a non-peptidal tachykinin receptor antagonist is preferred. In addition, for convenience the use of an orally active tachykinin receptor antagonist is preferred.
  • the tachykinin receptor antagonist is active upon the central nervous system (CNS), such as the brain, following systemic administration, i.e. that it readily penetrates the CNS.
  • a preferred tachykinin antagonist for use in the present invention is a CNS-penetrating tachykinin antagonist, especially a CNS-penetrating NK-1 antagonist.
  • An especially 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.
  • Neurokinin- 1 receptor antagonists of use in the present invention are fully described, for example, in U.S. Patent Nos.
  • NK-1 receptor antagonists are those described in PCT International Patent Publication No. WO 95/16679 and European Patent Publication No. 0 577 394 as compounds of formula (I):
  • Rl is selected from the group consisting of:
  • Ci-6 alkyl unsubstituted or substituted with one or more of the substituents selected from:
  • halo wherein halo is fluoro, chloro, bromo or iodo
  • -NR9R10 wherein R9 and RlO are independently selected from: (i) hydrogen
  • heterocycle wherein the heterocycle is selected from the group consisting of:
  • Ci-6 alkyl unsubstituted or substituted with halo, -CF3, -OCH3, or phenyl
  • d R3 are independently selected from the group consisting of:
  • Rl and R2 may be joined together to form a heterocyclic ring selected from the group consisting of: (a) pyrrolidinyl, (b) piperidinyl,
  • R6, R7 and R8 are independently selected from the group consisting of: (1) hydrogen;
  • Rll, Rl2 and Rl3 are independently selected from the definitions of R ⁇ , R7 and R8 ;
  • X is selected from the group consisting of:
  • Y is selected from the group consisting of:
  • Rl5 and Rl6 are independently selected from the group consisting of: (a) Cl-6 alkyl, unsubstituted or substituted with one or more of the substituents selected from: (i) hydroxy, (ii) oxo,
  • Z is Ci-6 alkyl.
  • Particularly preferred compounds of formula (I) include: 4-(3-(l,2,4-triazolo)methyl)-2(S)-(3,5-bis(trifluoro- methyl)benzyloxy)-3(S)-phenyl-morpholine; 4-(3-(l,2,4-triazolo)methyl)-2(S)-(3,5-bis(trifluoro- methyl)benzyloxy)-3(R)-phenyl-morpholine;
  • NK-1 receptor antagonists are those described in PCT International Patent Publication No. WO 95/18124 as compounds of formula (II):
  • Rl is hydrogen, halogen, Ci-6alkyl, Ci-6alkoxy, CF3, NO2, CN, SR a , SOR a , SO2R a , CO2R a , CONR a R», C2-6 a lkenyl, C2-6 lkynyl or Ci-4alkyl substituted by Ci-4alkoxy, where R a and R" each independently represent hydrogen or Cl-4alkyl; R2 is hydrogen, halogen, Ci-6alkyl, Ci-6alkoxy substituted by Ci-4alkoxy or CF3;
  • R3 is hydrogen, halogen or CF3
  • R 4 is hydrogen, halogen, Ci-6alkyl, Ci-6alkoxy, CF3, NO2, CN, SR a , SOR a , SO2R a , CO2R a , CONR a Rb, C2-6 a lkenyl, C2-6 a lkynyl or Ci-4alkyl substituted by Cl-4alkoxy, where R a and R D each independently represent hydrogen or Cl-4alkyl;
  • R5 is hydrogen, halogen, Ci-6alkyl, Cl-6alkoxy substituted by Ci-4alkoxy or CF3;
  • Z is Ci-6alkylene or C3-6cycloalkylene;
  • R? is hydrogen, Cl-4alkyl, C3-7cycloalkyl or C3- 7cycloalkylCi-4alkyl, or C2-4alkyl substituted by Ci-4alkoxy or hydroxyl;
  • R8 is hydrogen, Ci-4alkyl, C3-7cycloalkyl or C3- 7cycloalkylCl-4alkyl, or C2-4alkyl substituted by one or two substituents selected from C ⁇ _4alkoxy, hydroxyl or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O a nd S; or , R8 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by a hydroxy group, and optionally containing a double bond, which ring may optionally contain an oxygen or sulphur ring atom, a group S(O
  • R a and R b are each independently hydrogen or C ⁇ _4alkyl, or R9 a and R9b are joined so, together with the carbon atoms to which they are attached, there is formed a C5-7 ring;
  • X is an alkylene chain of 1 to 4 carbon atoms optionally substituted by oxo;
  • Y is a Ci-4alkyl group optionally substituted by a hydroxyl group; with the proviso that if Y is Ci-4alkyl, R > is substituted at least by a group of formula ZNR ⁇ R ⁇ as defined above.
  • Particularly preferred compounds of formula (II) include:
  • NK-1 receptor antagonists are those described in PCT International Patent Publication No. WO 95/23798 as compounds of formula (III):
  • R2 and R3 are independently selected from the group consisting of:
  • Ci-6alkyl (i) Ci-6alkoxy, (iii) -NR9R10, (iv) halo, and v) trifluoromethyl; and, alternatively, the groups R and R3 are joined together to form a heterocyclic ring selected from the group consisting of:
  • R ⁇ , R7 and R8 are independently selected from the group consisting of:
  • Rll, R12 and Rl3 are independently selected from the definitions of R ⁇ ,
  • A is selected from the group consisting of:
  • Cl-6 alkyl unsubstituted or substituted with one or more of the substituents selected from: (a) hydroxy,
  • B is a heterocycle, wherein the heterocycle is selected from the group consisting of:
  • heterocycle is substituted in addition to -X with one or more substituent(s) selected from:
  • p is 0 or 1;
  • X is selected from:
  • Y is selected from the group consisting of:
  • Rl5 and Rl6 are independently selected from the group consisting of:
  • Z is selected from:
  • a particularly preferred compound of formula (III) is 2-(R)-(l- (R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)-phenyl-4-(3-(l- monophosphoryl-5-oxo-lH-l,2,4-triazolo)methyl)morpholine, or a pharmaceutically acceptable salt thereof.
  • the bis(N-methyl- D-glucamine) salt is preferred.
  • NK-1 receptor antagonists are those described in European Patent Specification No. WO 96/05181, i.e. compounds of formula (IV):
  • X is a group of the formula NR 6 R 7 or a C- or N-linked imidazolyl ring;
  • Y is hydrogen or C ⁇ alkyl optionally substituted by a hydroxy group;
  • R 1 is hydrogen, halogen, C ⁇ alkyl, C ⁇ alkoxy, CF 3 , NO 2 , CN, SR a , SOR a , SO 2 R a , CO 2 R a , CONR a R b , C 2 . 6 alkenyl, C 2 . 6 alkynyl or C ⁇ alkyl substituted by C ⁇ alkoxy, wherein R a and R b each independently represent hydrogen or C ⁇ alkyl;
  • R 2 is hydrogen, halogen, C ⁇ alkyl, C ⁇ alkoxy substituted by C ⁇ alkoxy or CF 3 ;
  • R 3 is hydrogen, halogen or CF 3 ;
  • R 4 is hydrogen, halogen, C ⁇ alkyl, C ⁇ alkoxy, hydroxy, CFg,
  • R 5 is hydrogen, halogen, C ⁇ alkyl, C 1 6 alkoxy substituted by C ⁇ alkoxy or CF 3 ;
  • R 6 is hydrogen, C ⁇ alkyl, C 3.7 cycloalkyl, C 3.7 cycloalkylC M alkyl, phenyl, or C 2.4 alkyl substituted by C ⁇ alkoxy or hydroxy;
  • R 7 is hydrogen, C ⁇ alkyl, C 3.7 cycloalkyl, C g ⁇ cycloalkylC ⁇ 4 alkyl, phenyl, or C ⁇ alkyl substituted by one or two substituents selected from C 1.4 alkoxy, hydroxy or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S; or R 6 and R 7 , together with the nitrogen atom to which they are attached, form a saturated or partially saturated heterocyclic ring of 4 to 7 ring atoms, which ring may optionally contain in the ring one oxygen or sulphur atom or a group selected from NR 8 , S(O) or S(O) 2 and which ring may be optionally substituted by one or two groups selected from hydroxyC x .
  • R 8 is hydrogen, C ⁇ alkyl, hydroxyC 1 . 4 alkyl or C 1 . 4 alkoxyC 1.4 alkyl; and R 9a and R 9b are each independently hydrogen or C ⁇ alkyl, or
  • R 9a and R 9b are joined so, together with the carbon atoms to which they are attached, there is formed a C 5 . 7 ring; and pharmaceutically acceptable salts thereof.
  • Specific compounds of formula (IV) of use in the present invention include:
  • NK-1 receptor antagonists are those described in European Patent Publication No. 0 436 334 as compounds of formula (V):
  • 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 (CH2)n may optionally be replaced by a carbon-carbon double bond, and wherein any one of the carbon atoms of said (CH2)n may optionally be substituted with R4, and wherein any one of the carbon atoms of said (CH2)n may optionally be substituted with R ' ;
  • 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 (CH2) may optionally be substituted with R°;
  • Rl is hydrogen or Cl-8alkyl optionally substituted with hydroxy, Ci-4alkoxy or fluoro;
  • R2 is a radical selected from hydrogen, Cl-6 straight or branched alkyl, C3-7cycloalkyl wherein one of the CH2 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-C2-6 a lkyl, 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- ⁇ alkyl, Ci-6
  • R 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 (CH2) 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, Cl-6alkyl, Ci-6alkoxy, trifluoromethyl, amino, Cl-6alkylamino, -CO-NH-
  • R and R ⁇ are each independently selected from hydroxy, halogen, halo, amino, oxo, cyano, methylene, hydroxymethyl, halomethyl,
  • R ⁇ is -NHCOR 9 , -NHCH2R 9 , SO2R 8 or one of the radicals set forth in any of the definitions of R2, R4 and R ⁇ ;
  • R9 is Cl-6alkyl, hydrogen, phenyl or phenylCi- ⁇ alkyl; with the proviso that (a) when m is 0, R 8 is absent, (b) when R4, R ⁇ , R7 or R8 is as defined in R2, it cannot form together with the carbon to which it is attached, a ring with R ⁇ , and (c) when R4 and R? are attached to the same carbon atom, then either each of R4 and R? is independently selected from hydrogen, fluoro and Cl-6alkyl, or R4 and R ⁇ , together with the carbon to which they are attached, for a C3-6 saturated carbocyclic ring that forms a spiro compound with the nitrogen-containing ring to which they are attached.
  • a particularly preferred compound of formula (V) is (2S,3S)- cis-3-(2-methoxybenzylamino)-2-phenylpiperidine; or a pharmaceutically acceptable salt thereof.
  • Another class of NK-1 receptor antagonists is as disclosed in PCT International Patent Publication No. WO 93/21155 as compounds of formula (VI):
  • radicals R are phenyl radicals optionally 2- or 3-substituted by a halogen atom or a methyl radical;
  • Rl is optionally substituted phenyl, cyclohexadienyl, naphthyl, indenyl or optionally substituted heterocycle
  • R2 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 is OH or fluorine when R ⁇ is H; or R4 and R 5 are OH; or R4 and R together form a bond.
  • a particularly preferred compound of formula (VI) is (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(2S)-(2-methoxy- phenyDpropionyl] perhydroisoindol-4-ol; or a pharmaceutically acceptable salt thereof.
  • NK-1 receptor antagonists of use in the present invention is that described in European Patent Publication No. 0 591 040 as compounds of formula (VII):
  • Ar represents an optionally substituted mono-, di- or tricyclic aromatic or heteroaromatic group
  • T represents a bond, a hydroxymethylene group, a Cl-4alkoxymethylene group or a Ci-5alkylene group;
  • Ar' represents a phenyl group which is unsubstituted or substituted by one or more substituents selected from halogen, preferably chlorine or fluorine, trifluoromethyl, Ci-4alkoxy, Cl-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, Ci-4alkyl, -Cl-4alkoxyCi-4alkyl, or - C2-4alkanoyloxyC2-4alkyl;
  • Q represents hydrogen; or Q and R together form a 1,2-ethylene, 1,3-propylene or 1,4- butylene group;
  • A" represents a pharmaceutically acceptable anion.
  • a particularly preferred compound of formula (VII) is (+) l-[2-[3-(3,4-dichlorophenyl)-l-[(3-isopropoxyphenyl)acetyl]-3- piperidinyl]ethyl]-4-phenyl-l-azabicyclo[2,2,2]octane; or a pharmaceutically acceptable salt, especially the chloride, thereof.
  • NK-1 receptor antagonists of use in the present invention is that described in European Patent Publication No. 0 532 456 as compounds of formula (VIII):
  • Rl represents an optionally substituted aralkyl, aryloxyalkyl, heteroaralkyl, aroyl, heteroaroyl, cycloalkylcarbonyl, aralka noyl, heteroarylalkanoyl, aralkoxycarbonyl or arylcarbamoyl group or the acyl group of an (-amino acid optionally N-substituted by a lower alkanoyl or carbamoyl-lower alkanoyl group;
  • R2 represents cycloalkyl or an optionally substituted aryl or heteroaryl group
  • R represents hydrogen, alkyl, carbamoyl or an alkanoyl or alkenoyl group optionally substituted by carboxy or esterified or amidated carboxy
  • R4 represents an optionally substituted aryl group or an optionally partially saturated heteroaryl group
  • Xl represents methylene, ethylene, a bond, an optionally ketalised carbonyl group or an optionally etherified hydroxymethylene group
  • X2 represents alkylene, carbonyl or a bond
  • X3 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 (-position) hydroxy.
  • a particularly preferred compound of formula (VIII) is (2R*,4S*)-2-benzyl-l-(3,5-dimethylbenzoyl)-N-(4-quinolinylmethyl)-4- piperidineamine; or a pharmaceutically acceptable salt thereof.
  • NK-1 receptor antagonists of use in the present invention is that described in European Patent Publication No. 0 443 132 as compounds of formula (IX):
  • Rl is aryl, or a group of the formula:
  • X is CH or N
  • Z is O or N-R5, in which Bp is hydrogen or lower alkyl
  • R2 is hydroxy or lower alkoxy
  • R3 is hydrogen or optionally substituted lower alkyl
  • R4 is optionally substituted ar(lower)alkyl
  • A is carbonyl or sulfonyl
  • Y is a bond or lower alkenylene.
  • a particularly preferred compound of formula (IX) is the compound of formula (LXa)
  • NK-1 receptor antagonists of use in the present invention is that described in PCT International Patent Publication No. WO 92/17449 as compounds of the formula (X):
  • 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 C 3.7 cycloalkyl may optionally be substituted with one or two substituents, said substituents being independently selected from chloro, fluoro, bro o, iodo, nitro, C j . ⁇ alkyl optionally substituted with from one to three fluoro groups, C ⁇ alkoxy optionally substituted with from one to three fluoro groups, amino, C ⁇ alkyl-S-, C 1.10 alkyl-S(O)-, C ⁇ alkyl-SO jj -, phenyl, phenoxy
  • 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, C 1.10 alkyl optionally substituted with from one to three fluoro groups and C j ⁇ alkoxy optionally substituted with from one to three fluoro groups.
  • a particularly preferred compound of formula (X) is (25,3-3)- 3-(2-methoxy-5-trifluoromethoxybenzyl)-amino-2-phenylpiperidine; or a pharmaceutically acceptable salt thereof.
  • NK-1 receptor antagonists of use in the present invention is that described in PCT International Patent Publication No. WO 95/08549 as compounds of formula (XI):
  • R is a Cl-4alkoxy group ;
  • R is a hydrogen or halogen atom
  • R4 and R° may each independently represent a hydrogen or halogen atom, or a Ci-4 alkyl, Ci-4 alkoxy or trifluoromethyl group;
  • R6 is a hydrogen atom, a Ci-4 alkyl, (CH2) cyclopropyl, - S(O) n Cl-4 alkyl, phenyl, NR 7 R 8 , CH2C(O)CF3 or trifluoromethyl group;
  • R? and R 8 may each independently represent a hydrogen atom, or a Cl-4 alkyl or acyl group; x represents zero or 1; n represents zero, 1 or 2; m represents zero or 1; and pharmaceutically acceptable salts and solvates thereof.
  • a particularly preferred compound of formula (XI) is [2-methoxy-5-(5-trifluoromethyl-tetrazol-l-yl)-benzyl]-(2S-phenyl- piperidin-3S-yl)-amine; or a pharmaceutically acceptable salt thereof.
  • NK-1 receptor antagonists of use in the present invention is that described in PCT International Patent Publication No. WO 97/49710 as compounds of formula (XII):
  • Rl, R 2 , R3, R4 R5 ? R6 ? R9 ? RlO, a nd X are as defined therein.
  • Particularly preferred compounds of formula (XII) are (3S,5R,6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]-6- phenyl- l-oxa-7-aza-spiro [4.5] decane; (3R,5R,6S)-3-[2-cyclopro ⁇ oxy-5-(trifluoromethoxy)phenyl]-6- phenyl-l-oxa-7-aza-spiro[4.5]decane; or a pharmaceutically acceptable salt thereof.
  • tachykinin receptor antagonists of use in the present invention is that described in PCT International Patent Publication No. WO 95/06645 as compounds of formula (XIII):
  • R represents a hydrogen atom or a Ci-4 alkoxy group
  • Rl is selected from phenyl, optionally substituted by a group -(CH2) n CONR 3 R4 0 r S(O) m R 3 ; or a 5- or 6-membered aromatic heterocycle containing 1, 2, 3 or 4 heteroatoms selected from oxygen, nitrogen, or sulphur, optionally substituted by a Ci-4 alkyl, trifluoromethyl or cyano group or a group -(CH2)n ONR3R4;
  • R2 represents a hydrogen or halogen atom
  • R3 and R4 independently represent hydrogen or Ci-4 alkyl; n represents zero, 1 or 2; m represents zero, 1 or 2; z represents zero or 1; and pharmaceutically acceptable salts and solvates thereof.
  • a particularly preferred compound of formula (XIII) is [5-(5-methyl-tetrazol-l-yl)-benzofuran-7-ylmethyl]-(2S-phenyl-piperidin- 3S-yl)-amine; or a pharmaceutically acceptable salt thereof.
  • tachykinin receptor antagonists of use in the present invention is that described in PCT International Patent Publication No. WO 95/14017, i.e. compounds of formula (XIV) or a pharmaceutically acceptable salt thereof, wherein m 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, C ⁇ . 3 alkoxy, trifluoromethyl, C ⁇ alkyl, phenyl-C ⁇ alkoxy, or C ⁇ alkanoyl groups;
  • R 1 is trityl, phenyl, diphenylmethyl, phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, hexamethyleneiminyl, benzofuranyl, tetrahydropyridinyl, quinolinyl, isoquinolinyl, reduced quinolinyl, reduced isoquinolinyl, phenyl-(C 1 . 4 alkyl)-, phenyl-(C 1 .
  • R 1 groups may be substituted with phenyl, piperazinyl, C 3 _ 8 cycloalkyl, benzyl, C ⁇ alkyl, piperidinyl, pyridinyl, pyrimidinyl, C 2 . 6 alkanoylamino, pyrrolidinyl, C 2 .
  • R 5 is pyridyl, anilino-(C 1 . 3 alkyl)-, or anilinocarbonyl;
  • R 2 is hydrogen, C ⁇ alkyl, C ⁇ alkylsulfonyl, carboxy-(C x. 3 alkyl)-, or -CO-R 6 ;
  • R 6 is hydrogen, C ⁇ alkyl, C ⁇ haloalkyl, phenyl, C ⁇ alkoxy, C j.g hydroxy alkyl, amino, di(C 1 . 4 alkyl)amino, or -(CH 2 ) q -R 7 ; q is zero to 3;
  • R 7 is carboxy, C ⁇ alkoxycarbonyl, C ⁇ alkylcarbonyloxy, amino, C ⁇ alkylamino, di(C 1 . 4 alkyl)amino, C L galkoxycarbonylamino, or phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, benzofuranyl, quinolinyl, phenyl-(C 1. 4 alkyl)-, quinolinyMC ⁇ alkyl)-, isoquinolinyl-(C 1 . 4 alkyl)-, reduced quinolinyl-(C 1 .
  • R 8 is hydrogen or C ⁇ alkyl
  • R 3 is phenyl, phenyMC ⁇ alkyl)-, C 3 . 8 cycloalkyl, C 5 . gCycloalkenyl, C ⁇ alkyl, naphthyl, C 2.8 alkenyl, or hydrogen; any one or which groups except hydrogen may be substituted with one or two halo, C ⁇ alkoxy, C ⁇ alkylthio, nitro, trifluoromethyl, or C h alky 1 groups; and
  • R 4 is hydrogen or C 1.3 alkyl; with the proviso that if R 1 is hydrogen or halo, R 3 is phenyl, phenyl-(C 1 . 6 alkyl)-, C 3 _ 8 cycloalkyl, Cg .8 cycloalkenyl, or naphthyl.
  • a particularly preferred compound of formula (XIII) is [N-(2- methoxybenzyl)acetylamino]-3-(lH-indol-3-yl)-2-[N-(2-(4-piperidin-l- yl)piperidin-l-yl)acetylamino]propane; or a pharmaceutically acceptable salt thereof.
  • the preferred stereochemistry of the ⁇ -carbon is either (R) when the substituent is an alkyl (e.g. methyl) group or (S) when the substituent is a hydroxyalkyl (e.g. hydroxymethyl) group.
  • 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 straight-chained or branched propyl and butyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert- butyl.
  • 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.
  • suitable aryl groups include phenyl and naphthyl groups.
  • a particular aryl-Cl-6alkyl, e.g. phenyl-Cl- ⁇ alkyl, group is benzyl.
  • suitable heteroaryl groups include pyridyl, quinolyl, isoquinolyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furyl, benzofuryl, thienyl, benzthienyl, imidazolyl, oxadiazolyl and thiadiazolyl groups.
  • 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.
  • attention deficit disorder includes attention deficit disorder and disruptive behavior disorder each of which may be present with or without hyperactivity.
  • Suitable pharmaceutically acceptable salts of the NK-1 receptor antagonists of use in the present invention include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or sulphuric acid.
  • Salts of amine groups may also comprise the quaternary ammonium salts in which the amino nitrogen atom carries an alkyl, alkenyl, alkynyl or aralkyl group.
  • the present invention also contemplates salts thereof, preferably non-toxic pharmaceutically acceptable salts thereof, such as the sodium, potassium and calcium salts thereof.
  • the above compounds are only illustrative of the neurokinin- 1 antagonists which are currently under investigation.
  • the methods of the present invention may employ any neurokinin- 1 receptor antagonist, in particular a neurokinin- 1 receptor antagonist which is orally active, long acting and CNS-penetrant. Accordingly, the present invention is not strictly limited to any particular structural class of compound.
  • the present invention accordingly provides the use of a NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII) and (XIV) for the manufacture of a medicament for treating or preventing attention deficit disorder in a patient.
  • a NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XIII) and (XIV) for the manufacture of a medicament for treating or preventing attention deficit disorder in a patient.
  • the present invention also provides a method for treating or preventing attention deficit disorder in a patient, which method comprises administration to a patient in need of such treatment an effective amount of a NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII) and (XIV).
  • a NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII) and (XIV).
  • a pharmaceutical composition for treating or preventing attention deficit disorder in a patient comprising a NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (DC), (X), (XI), (XII), (XIII) and (XIV), together with at least one pharmaceutically acceptable carrier or excipient.
  • a NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (DC), (X), (XI), (XII), (XIII) and (XIV), together with at least one pharmaceutically acceptable carrier or excipient.
  • a compound as a tachykinin receptor antagonist in particular, a neurokinin- 1 receptor antagonist, and thus able to have utility in the present invention may be readily determined without undue experimentation by methodology well known in the art.
  • a tachykinin receptor antagonist may be administered alone or in combination by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant), nasal, vaginal, rectal, sublingual, or topical routes of administration and can be formulated in dosage forms appropriate for each route of administration.
  • parenteral e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant
  • nasal, vaginal, rectal, sublingual, or topical routes of administration and can be formulated in dosage forms appropriate for each route of administration.
  • the compositions according to the present invention are in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, by inhalation or insufflation or administration by trans-dermal patches or by buccal cavity absorption wafers.
  • 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.
  • 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
  • a pharmaceutical carrier e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium
  • 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.
  • 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.
  • 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.
  • liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, peanut oil or soybean oil, as well as elixirs and similar pharmaceutical vehicles.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
  • 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 (e.g. TweenTM 20, 40, 60, 80 or 85) and other sorbitans (e.g. SpanTM 20, 40, 60, 80 or 85).
  • Compositions with a surface-active agent will conveniently comprise between 0.05 and 5% surface-active agent, and preferably between 0.1 and 2.5%. 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 LipiphysanTM.
  • the active ingredient may be either dissolved in a pre-mixed emulsion composition or alternatively it may be dissolved in an oil (e.g. soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and an emulsion formed upon mixing with a phospholipid (e.g. egg phospholipids, soybean phospholipids or soybean lecithin) and water.
  • an oil e.g. soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil
  • a phospholipid e.g. egg phospholipids, soybean phospholipids or soybean lecithin
  • 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 20%.
  • the fat emulsion will preferably comprise fat droplets between 0.1 and l.O ⁇ m, particularly 0.1 and 0.5 ⁇ m, and have a pH in the range of 5.5 to 8.0.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above.
  • 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. It will be known to those skilled in the art that there are numerous compounds which may be used for treating or preventing attention deficit disorder in a patient. Combinations of these therapeutic agents some of which have also been mentioned herein with a tachykinin receptor antagonist will bring additional, complementary, and often synergistic properties to enhance the desirable properties of these various therapeutic agents. In these combinations, the tachykinin receptor antagonist and the therapeutic agents may be independently present in dose ranges from one one-hundredth to one times the dose levels which are effective when these compounds are used singly. In such combination therapy, the tachykinin receptor antagonist may be administered with the other therapeutic agent (e.g., concurrently, concombinantly, sequentially, or in a unitary formulation) such that their therapeutic efficacy overlap.
  • the other therapeutic agent e.g., concurrently, concombinantly, sequentially, or in a unitary formulation
  • the tachykinin receptor antagonist may be employed in conjunction with an agent selected from the group consisting of: stimulants, hypnotics, anxiolytics, antipsychotics, antianxiety agents, minor tranquilizers, benzodiazepines, barbituates, serotonin agonists, selective serotonin reuptake inhibitors, 5HT-2 antagonists, non-steroidal anti-inflammatory drugs, monoamine oxidase inhibitors, muscarinic agonists, norephinephrine uptake inhibitiors, essential fatty acids, and the like, or the tachykinin receptor antagonist may be administered in conjunction with the use of physical methods such as electrical stimulation.
  • an agent selected from the group consisting of: stimulants, hypnotics, anxiolytics, antipsychotics, antianxiety agents, minor tranquilizers, benzodiazepines, barbituates, serotonin agonists, selective serotonin reuptake inhibitors, 5HT-2 antagonists,
  • a tachykinin receptor antagonist may be given in combination with such compounds as: adinazolam, allobarbital, alonimid, alprazolam, amitriptyline, amobarbital, amoxapine, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, caffeine, capuride, carbocloral, chloral betaine, chloral hydrate, chlordiazepoxide, clomipramine, cloperidone, clorazepate, clorethate, clozapine, cyprazepam, deanol, desipramine, dexclamol, dextroamphetamine, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, duloxetine, estazolam, ethchlorvyn
  • the individual daily dosages for these combinations may range from about one-fifth of the minimally recommended clinical dosages to the maximum recommended levels for the entities when they are given singly.
  • the recommended clinical dose is generally from approximately 5 mg/day to approximately 20 mg/day, however, the dosage may be titrated, beginning at low doses and increasing to optimal levels (decrease in symptoms, improvement in task performance, and no side effects).
  • a tachykinin receptor antagonist effective clinically at a given daily dose range may be effectively combined, at levels which are equal or less than the daily dose range, with the aforementioned compounds. It will be readily apparent to one skilled in the art that the tachykinin receptor antagonist may be employed with other agents for treating or preventing attention deficit disorder in a patient.
  • these dose ranges may be adjusted on a unit basis as necessary to permit divided daily dosage and, as noted above, the dose will vary depending on the nature and severity of the disease, weight of patient, special diets and other factors.
  • These combinations may be formulated into pharmaceutical compositions as known in the art and as discussed herein.
  • the dosage of active ingredient in the compositions of this invention may be varied, however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained.
  • the active ingredient may be administered to patients (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy.
  • the selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment.
  • the dose will vary from patient to patient depending upon the nature and severity of disease or disorder, the patient's weight, special diets then being followed by a patient, concurrent medication, the intrinsic tachykinin receptor antagonist activity of the compound, the bioavailability upon oral administration of the compound and other factors which those skilled in the art will recognize.
  • an appropriate dosage level will generally be about 0.01 ⁇ g to 50 mg per kg patient body weight per day which may be administered in single or multiple doses.
  • the dosage level will be about 0.1 ⁇ g to about 25 mg/kg per day; more preferably about 0.5 ⁇ g to about 10 mg/kg per day.
  • a suitable dosage level is about 0.1 ⁇ g to 25 mg/kg per day, preferably about 0.5 ⁇ g to 10 mg/kg per day, and especially about 1 ⁇ g to 5 mg/kg per day.
  • a typical indicated dose is about 300 ⁇ g to 400 mg orally.
  • a compound may be administered on a regimen of several times per day, for example 1 to 4 times per day, preferably once or twice per day.
  • a suitable dosage level is about 0.1 ⁇ g to 10 mg/kg per day, preferably about 0.5 ⁇ g to 5 mg/kg per day, and especially about 1 ⁇ g to 1 mg/kg per day.
  • a typical indicated dose is about 100 ⁇ g to 100 mg i.v.
  • a compound may be administered on a regimen of several times per day, for example 1 to 4 times per day, preferably once or twice per day, and more preferably once a day.
  • compositions of the present invention may be provided in a solid dosage formulation preferably comprising about 100 ⁇ g to 500 mg active ingredient, more preferably comprising about 100 ⁇ g to 250 mg active ingredient.
  • the pharmaceutical composition is preferably provided in a solid dosage formulation comprising about 100 ⁇ g, 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg or 300 mg active ingredient.
  • a minimum dosage level for the NK-1 receptor antagonist is generally about 5mg per day, preferably about lOmg per day and especially about 20mg per day.
  • a maximum dosage level for the NK-1 receptor antagonist is generally about 1500mg per day, preferably about lOOOmg per day and especially about 500mg per day.
  • the amount of the NK-1 receptor antagonist required for use in treating or preventing attention deficit disorder in a patient 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 length of time during which a tachykinin receptor antagonist will be given varies on an individual basis.
  • (VIII), (IX), (X), (XI), (XII), (XIII) and (XIV) 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, WO 97/49710, WO 95/06645 and WO 95/14017, respectively.
  • NK-1 receptor antagonists of the formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII) and (XTV) for use in the present invention are compounds which are potent NK-1 receptor antagonists, i.e. compounds with an NK-1 receptor affinity (IC 50 ) of less than lOnM.
  • NK-1 receptor antagonists 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 for treating or preventing attention deficit disorder in a patient represents a further aspect of the present invention.
  • the present invention provides the use of a CNS penetrant NK-1 receptor antagonist in an oral, once-a-day medicament for treating or preventing attention deficit disorder in a patient.
  • the compounds of this class advantageously exhibit a rapid onset of action and a reduced side-effect profile when compared against conventional methods for treating or preventing attention deficit disorder in a patient.
  • 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 treating or preventing attention deficit disorder in a patient.
  • the exceptional pharmacology of the class of NK-1 receptor antagonists of use in the present invention enables treating or preventing attention deficit disorder in a patient, without the need for concomitant therapy and in particular, without the need for concomitant use of a serotonin agonist or an SSRI.
  • the present invention accordingly provides the use of an orally active, long acting, CNS-penetrant NK-1 receptor antagonist (as hereinafter defined) for the manufacture of a medicament adapted for oral administration for treating or preventing attention deficit disorder in a patient.
  • the present invention also provides a method for treating or preventing attention deficit disorder in a patient, 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 defined herein).
  • an oral pharmaceutical composition for treating or preventing attention deficit disorder in a patient which comprises an orally active, long acting, CNS-penetrant NK-1 receptor antagonist (as hereinafter defined), together with a pharmaceutically acceptable carrier or excipient.
  • NK-1 receptor antagonists for use in the present invention as orally active, long acting, CNS-penetrant NK-1 receptor antagonists are selected from the classes of compounds described in European Patent Specification No. 0 577 394, and International Patent Specification Nos. 95/08549, 95/18124, 95/23798, 96/05181 and WO 97/49710.
  • NK-1 receptor antagonists of use in the present invention include: ( ⁇ )-(2R3R, 2S3S)-N- ⁇ [2-cyclopro ⁇ oxy-5-(trifluoromethoxy)- phenyl] methyl ⁇ -2-phenylpiperidin-3- amine;
  • 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. Typically, the receptor is expressed at a level of 3xl0 5 receptors per cell. Cells are grown in monolayer culture, detached from the plate with enzyme-free dissociation solution (Speciality Media Inc.), and washed prior to use in the assay.
  • 125 I-Tyr 8 - substance P (O.lnM, 2000Ci/mmol; New England Nuclear) is incubated in the presence or absence of test compounds (dissolved in 5 ⁇ l dimethylsulphoxide, DMSO) with 5xl0 4 CHO cells.
  • Ligand binding is performed in 0.25ml of 50mM Tris-HCl, pH7.5, containing 5mM MnCl 2 , 150mM NaCl, 0.02% bovine serum albumin (Sigma), 50 ⁇ g/ml chymostatin (Peninsula), O.lnM phenylmethylsulphonyl fluoride, 2 ⁇ g/ml pepstatin,
  • 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 anxiogenic agents (such as pentagastrin) or central infusion of NK-1 receptor agonists such as GR73632, or caused by aversive stimulation such as foot shock or single housing, based on the method of Rupniak & Williams, Eur. J. Pharmacol , 1994, 265, 179.
  • anxiogenic agents such as pentagastrin
  • aversive stimulation such as foot shock or single housing
  • 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.
  • test compounds may be administered orally or by subcutaneous or intraperitoneal routes. The wound is closed and a second skin incision is made in the midline of the scalp to expose the skull.
  • An anxiogenic agent e.g. pentagastrin
  • a selective NK-1 receptor agonist e.g.
  • GR73632 (d Ala[L-Pro 9 ,Me-Leu 10 ]- substance P-(7-ll))) is infused directly into the cerebral ventricles (e.g. 3pmol in 5 ⁇ l i.c.v. depending upon the agent) 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 20cm).
  • the duration and/or intensity of hind foot tapping is then recorded continuously for 5 minutes.
  • the ability of test compounds to inhibit foot tapping evoked by aversive stimulation such as foot shock or single housing, may be studied using a similar method of quantification.
  • a suitable selection cascade for NK j antagonists of use according to the present invention is as follows:
  • 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 (i) 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.
  • HSA human serum albumin
  • a NK-1 receptor antagonist of use in the present invention is the compound 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)- phenyl)-ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-lH,4H-l,2,4- triazolo)methyl)-morpholine, the preparation of which is described in PCT Patent Publication No. WO 95/16679. In the aforementioned assays, this compound has the following activity:
  • 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 then compressed into tablets containing 50mg, lOOmg and 300mg of the NK-1 receptor antagonist per tablet.
  • Subjects are observed at four visits to provide baseline measurements and at visits 5-30 to provide measurements during treatment. During the visits the subjects are observed with respect to social interaction and behavioral, intellectual and concentration abilities. Efficacy of the test compound is assessed by reference to rating scales and checklists, as well as the ability of a child to perform specific tasks; eg, vigilance and reaction-time tasks, tasks sampling paired associate learning, and tasks increasing response uncertainty. Treatment groups are compared with respect to the number and percentage of subjects who had the symptom during the double-blind portion of the study relative to that during the baseline visits. The results of the foregoing study would indicate that the administration of a neurokinin- 1 antagonist would be expected to have a positive effect with respect to placebo in enhancing attention and reducing impulsiveness following drug treatment.

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Abstract

Un antagoniste du récepteur de tachykinine est utile pour traiter ou prévenir, chez un patient, le trouble déficitaire de l'attention, facultativement associé à l'hyperactivité.
PCT/US1998/024634 1997-11-19 1998-11-18 Procede de traitement du trouble deficitaire de l'attention WO1999025364A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP2000520797A JP2001523643A (ja) 1997-11-19 1998-11-18 注意力欠如障害の治療方法
EP98959502A EP1030672A1 (fr) 1997-11-19 1998-11-18 Procede de traitement du trouble deficitaire de l'attention
AU15289/99A AU745524B2 (en) 1997-11-19 1998-11-18 Method for treating attention deficit disorder
CA002309392A CA2309392A1 (fr) 1997-11-19 1998-11-18 Procede de traitement du trouble deficitaire de l'attention

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US6619197P 1997-11-19 1997-11-19
US60/066,191 1997-11-19
GBGB9810176.9A GB9810176D0 (en) 1998-05-13 1998-05-13 Method for treating attention deficit disorder
GB9810176.9 1998-05-13

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008090117A1 (fr) 2007-01-24 2008-07-31 Glaxo Group Limited Nouvelles compositions pharmaceutiques
WO2022162199A3 (fr) * 2021-01-29 2022-09-15 3Z Ehf Nouveaux traitements

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
XX; 1 January 1900 (1900-01-01), XP002916133, Database accession no. 96-37787 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008090117A1 (fr) 2007-01-24 2008-07-31 Glaxo Group Limited Nouvelles compositions pharmaceutiques
WO2022162199A3 (fr) * 2021-01-29 2022-09-15 3Z Ehf Nouveaux traitements

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EP1030672A1 (fr) 2000-08-30
CA2309392A1 (fr) 1999-05-27
AU745524B2 (en) 2002-03-21
AU1528999A (en) 1999-06-07

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