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WO1999025364A1 - Method for treating attention deficit disorder - Google Patents

Method for treating attention deficit disorder 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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WIPO (PCT)
Prior art keywords
phenyl
receptor antagonist
alkyl
neurokinin
substituted
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/US1998/024634
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French (fr)
Inventor
David L. Glatt
Mark S. Kramer
Nadia Rupniak
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
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Filing date
Publication date
Priority claimed from GBGB9810176.9A external-priority patent/GB9810176D0/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Priority to AU15289/99A priority Critical patent/AU745524B2/en
Priority to JP2000520797A priority patent/JP2001523643A/en
Priority to CA002309392A priority patent/CA2309392A1/en
Priority to EP98959502A priority patent/EP1030672A1/en
Publication of WO1999025364A1 publication Critical patent/WO1999025364A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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

A tachykinin receptor antagonist is useful for treating or preventing attention deficit disorder, optionally associated with hyperactivity, in a patient.

Description

TITLE OF THE INVENTION
METHOD FOR TREATING ATTENTION DEFICIT DISORDER
BACKGROUND OF THE INVENTION Attention deficit disorder (ADD) 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. Although 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 running or climbing excessively.
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. As used herein, the term 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. 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.
Primary signs tend to appear when the attention deficit disorder patient is involved in vigilance and reaction-time tasks and tasks requiring visual and perceptual search, paired associate learning, systematic listening, continuous performance, and directed attention. Inattention and impulsivity restrict development of academic skills and concepts, thinking and reasoning strategies, motivation for school, and adjustment to social demands. Behavior of patients suffering from attention deficit disorder often is more resistant to treatment than that of patients with other behavioral disorders. Associated or secondary signs are frequently noted: motor incoordination, nonlocalized "soft" neurologic findings, perceptual-motor dysfunctions, EEG abnormalities, emotional lability, opposition, anxiety, aggressiveness, low frustration tolerance, and poor peer relationships.
Onset of attention deficit disorder occurs typically before age 4 yr and invariably before age 7 yr. The peak age for referral has been between 8 and 10 yr. Early indicators vary, but most children diagnosed as having ADD with or without hyperactivity at school age exhibited delays in motor development, tended to have brief attention spans (eg, did not play with toys or did so in brief intervals), and usually had higher activity levels than normal during their preschool years. Children with hyperactivity often were described as hyperexcitable and were difficult to manage as toddlers and preschoolers. In school these signs persist, and difficulty with visual motor tasks such as copying and printing may become apparent. Right-left confusion and immature coordination after age 7 yr are prevalent in both types of ADD. 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. Some studies have found that about 20% have learning disabilities, 40% exhibit depressed behavior by adolescence, 60% have problems such as aggressiveness, temper tantrums, and low frustration tolerance with little provocation, and 90% have academic problems. 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. Some studies have found that adolescents and adults with histories of ADD with impulsivity have a high incidence of personality trait disorders and antisocial behavior; most continue to display impulsivity, restlessness, and poor social skills. ADD individuals with hyperactivity seem to adjust better in work than in academic situations. Interpersonal and social problems often persist into adulthood; suicide attempts (not related to methylphenidate) have been reported as higher when compared with those in the normal population. Low intelligence, aggressiveness, social and interpersonal problems, and parental psychopathology are predictors of poor outcomes in adulthood. No single treatment has been completely effective for attention deficit disorder. Psychostimulant medications combined with behavioral and cognitive therapies (eg, self-recording, self-monitoring, modeling, and role-playing) have the greatest controlling influence on symptom expression. Used alone, medication has been effective predominantly with less aggressive ADD children coming from stable home environments. Elimination diets, megavitamin treatments, psychotherapy, and biochemical interventions (eg, the administration of neurochemicals) have had only minor, unsustained effects.
Methylphenidate (RITALIN®) 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. 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 have had limited success, however, and an alternate means of treating or preventing attention deficit disorders would be of great benefit.
The neuropeptide receptors for substance P (neurokinin-1; NK-1) 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). The
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. In addition to SP 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. In accordance with the present invention, 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). More recently, PCT Patent Publication No. WO 96/24353 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. Currently there are only limited means for treating attention deficit disorder. In view of the short-comings of existing agents, there is a need for new effective methods for treating or preventing attention deficit disorder.
SUMMARY OF THE INVENTION
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. In a preferred embodiment, 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.
DESCRIPTION OF THE INVENTION
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.
In a preferred embodiment, 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.
In accordance with the present invention 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.
In a further aspect of the present invention, there is provided 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. Although 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. Preferably, 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.
In the present invention, it is preferred that 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. Accordingly, 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. 5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,496,833, 5,637,699; European Patent Publication Nos. EP 0 360 390, 0 394 989, 0 428 434, 0 429 366, 0 430 771, 0 436 334, 0 443 132, 0 482 539, 0 498 069, 0 499 313, 0 512 901, 0 512 902, 0 514 273, 0 514 274, 0 514 275, 0 514 276, 0 515 681, 0 517 589, 0 520 555, 0 522 808, 0 528 495, 0 532 456, 0 533 280, 0 536 817, 0 545 478, 0 558 156, 0 577 394, 0 585 913,0 590 152, 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, 0 709 375, 0 709 376, 0 714 891, 0 723 959, 0 733 632 and 0 776 893; PCT International Patent Publication Nos. WO 90/05525, 90/05729, 91/09844, 91/18899, 92/01688, 92/06079, 92/12151, 92/15585, 92/17449, 92/20661, 92/20676, 92/21677, 92/22569, 93/00330, 93/00331, 93/01159, 93/01165, 93/01169, 93/01170, 93/06099, 93/09116, 93/10073, 93/14084, 93/14113, 93/18023, 93/19064, 93/21155, 93/21181, 93/23380, 93/24465, 94/00440, 94/01402, 94/02461, 94/02595, 94/03429, 94/03445, 94/04494, 94/04496, 94/05625, 94/07843, 94/08997, 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, 95/18124, 95/18129, 95/19344, 95/20575, 95/21819, 95/22525, 95/23798, 95/26338, 95/28418, 95/30674, 95/30687, 95/33744, 96/05181, 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, and 97/49710; and in British Patent Publication 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, and 2 302 689. The preparation of such compounds is fully described in the aforementioned patents and publications. Particularly preferred 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):
Figure imgf000011_0001
or a pharmaceutically acceptable salt thereof, wherein: Rl is selected from the group consisting of:
(1) hydrogen;
(2) Ci-6 alkyl, unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy,
(b) oxo,
(c) Ci-6 alkoxy,
(d) phenyl-Cχ-3 alkoxy, (e) phenyl,
(f) -CN,
(g) halo, wherein halo is fluoro, chloro, bromo or iodo, (h) -NR9R10, wherein R9 and RlO are independently selected from: (i) hydrogen,
(ii) C 1-6 alkyl, (iii) hydroxy-Cι_6 alkyl, and (iv) phenyl, (i) -NR9COR10,
Figure imgf000011_0002
(k) -CONR9R10, (1) -COR9,
Figure imgf000012_0001
(n) heterocycle, wherein the heterocycle is selected from the group consisting of:
(A) benzimidazolyl,
(B) benzofuranyl,
(C) benzothiophenyl,
(D) benzoxazolyl,
(E) fur any 1,
(F) imidazolyl,
(G) indolyl,
(H) isooxazolyl,
(I) isothiazolyl,
(J) oxadiazolyl,
(K) oxazolyl,
(L) pyrazinyl,
(M) pyrazolyl,
(N) pyridyl,
(O) pyrimidyl,
(P) pyrrolyl,
(Q) quinolyl,
(R) tetrazolyl,
(S) thiadiazolyl,
(T) thiazolyl,
(U) thienyl,
(V) triazolyl,
(W) azetidinyl,
(X) 1,4-dioxanyl,
(Y) hexahydroazepinyl,
(Z) piperazinyl,
(AA) piperidinyl,
(AB) pyrrolidinyl,
(AC) tetrahydrofuranyl, and
(AD) tetrahydrothienyl, and wherein the heterocycle is unsubstituted or substituted with one or more substituent(s) selected from:
(i) Ci-6 alkyl, unsubstituted or substituted with halo, -CF3, -OCH3, or phenyl,
(ii) Ci-6 alkoxy,
(iii) oxo,
(iv) hydroxy,
(v) thioxo,
(vi) -SR9,
(vii) halo,
(viii) cyano,
(ix) phenyl,
(x) trifluoromethyl,
(xi) -(CH2)m-NR9RlOj wherein m is 0, 1 or
2,
(xii) -NR9COR10,
(xiii) -CONR9R10,
Figure imgf000013_0001
(3) C2-6 alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy,
(b) oxo,
(c) Ci-6 alkoxy,
(d) phenyl-Cl-3 alkoxy,
(e) phenyl,
(f) -CN,
(g) halo,
(h) -CONR9R10,
(i) -COR9,
Figure imgf000013_0002
(k) heterocycle;
(4) C2-6 alkynyl; (5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from: (a) hydroxy,
(b) Ci-6 alkoxy,
(c) Cl-6 alkyl,
(d) C2-5 alkenyl,
(e) halo,
(f) -CN,
(g) -NO2,
(h) -CF3,
Figure imgf000014_0001
(1) -CONR9R10,
Figure imgf000014_0002
(n) -COR9,
Figure imgf000014_0003
d R3 are independently selected from the group consisting of:
(1) hydrogen,
(2) Cl-6 alkyl, unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy,
(b) oxo,
(c) Cl-6 alkoxy,
(d) phenyl-Cl-3 alkoxy,
(e) phenyl,
(f) -CN,
(g) halo,
(h) -NR9R10,
Figure imgf000014_0004
(k) -CONR9R10,
(1) -COR9, and
Figure imgf000014_0005
(3) C2-6 alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy,
(b) oxo,
(c) Cl-6 alkoxy,
(d) phenyl-Ci-3 alkoxy,
(e) phenyl,
( ) -CN,
(g) halo,
(h) -CONR9R10,
(i) -COR9, and
Figure imgf000015_0001
(4) C2-6 alkynyl;
(5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy,
(b) Cl-6 alkoxy,
(c) Ci-6 alkyl,
(d) C2-5 alkenyl,
(e) halo,
(f) -CN,
(g) -NO2,
(h) -CF3,
Figure imgf000015_0002
(1) -CONR9R10,
Figure imgf000015_0003
(n) -COR9, and
Figure imgf000015_0004
and the groups Rl and R2 may be joined together to form a heterocyclic ring selected from the group consisting of: (a) pyrrolidinyl, (b) piperidinyl,
(c) pyrrolyl,
(d) pyridinyl,
(e) imidazolyl,
(f) oxazolyl, and
(g) thiazolyl, and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituent(s) selected from
(i) Ci-6alkyl,
(ii) oxo,
(iii) Ci-βalkoxy,
(iv) -NR9R10,
(v) halo, and
(vi) trifluoromethyl;
and the groups R2 and R3 may be joined together to form a carbocyclic ring selected from the group consisting of:
(a) cyclopentyl,
(b) cyclohexyl, (c) phenyl, and wherein the carbocyclic ring is unsubstituted or substituted with one or more substituents selected from:
(i) Cl-6alkyl,
(ii) Cl-6alkoxy, (iii) -NR9R10,
(iv) halo, and
(v) trifluoromethyl;
and the groups R2 and R3 may be joined together to form a heterocyclic ring selected from the group consisting of:
(a) pyrrolidinyl,
(b) piperidinyl,
(c) pyrrolyl,
(d) pyridinyl, (e) imidazolyl, (f) furanyl,
(g) oxazolyl, (h) thienyl, and (i) thiazolyl, and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituent(s) selected from:
(i) Ci-6alkyl,
(ii) oxo,
(iii) Ci-βalkoxy, (iv) -NR9R10,
(v) halo, and
(vi) trifluoromethyl;
R6, R7 and R8 are independently selected from the group consisting of: (1) hydrogen;
(2) Cl-6 alkyl, unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy,
(b) oxo, (c) Cl-6 alkoxy,
(d) phenyl-Ci-3 alkoxy,
(e) phenyl,
(f) -CN,
(g) halo, (h) -NR9R10,
(i) -NR9COR10,
Figure imgf000017_0001
(k) -CONR9R10,
(1) -COR9, and
Figure imgf000017_0002
(3) C2-6 alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy,
(b) oxo, (c) Cl-6 alkoxy, (d) phenyl-Ci-3 alkoxy,
(e) phenyl,
(f) -CN,
(g) halo,
(h) -CONR9R10,
(i) -COR9, and
Figure imgf000018_0001
(4) C2-6 alkynyl;
(5) phen^ yl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy,
(b) Cl-6 alkoxy,
(c) Cl-6 alkyl,
(d) C2-5 alkenyl,
(e) halo,
(f) -CN,
(g) -NO2,
(h) -CF3,
Figure imgf000018_0002
(j) -NR9COR10,
Figure imgf000018_0003
(1) -CONR9R10,
Figure imgf000018_0004
(n) -COR9,
Figure imgf000018_0005
(6) halo,
(7) -CN,
(8) -CF3 •>
(9) -NO2
(10) -SR14, wherein Rl4 is hydrogen or Ci-5alkyl,
(11) -SOR14,
Figure imgf000018_0006
(13) NR9COR10,
(14) CONR9COR10, (15) NR9R10,
Figure imgf000019_0001
(17) hydroxy,
(18) Ci-6alkoxy,
(19) COR9,
Figure imgf000019_0002
(21) 2-pyridyl,
(22) 3-pyridyl,
(23) 4-pyridyl,
(24) 5-tetrazolyl,
(25) 2-oxazolyl, and
(26) 2-thiazolyl;
Rll, Rl2 and Rl3 are independently selected from the definitions of Rβ, R7 and R8;
X is selected from the group consisting of:
(1) -O-,
(2) -S-, (3) -SO-, and
(4) -SO2-;
Y is selected from the group consisting of:
(1) a single bond, (2) -O-,
(3) -S-,
(4) -CO-,
(5) -CH2-,
(6) -CHR15-, and (7) -CR15R16-, wherein 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,
(iii) Cl-6 alkoxy,
(iv) phenyl-Cl-3 alkoxy,
(v) phenyl,
(vi) -CN,
(vii) halo,
(viii) -NR9R10,
(ix) -NR9COR10,
Figure imgf000020_0001
(xi) -CONR9R10,
(xii) -COR9, and
Figure imgf000020_0002
(b) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(i) hydroxy,
(ϋ) Ci-6 alkoxy,
(iii) Ci-6 alkyl,
(iv) C2-5 alkenyl,
(v) halo,
(vi) -CN,
(vii) -NO2,
(viii) -CF3,
Figure imgf000020_0003
(xiv) -COR9, and
Figure imgf000020_0004
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;
4-(3-(5-oxo-lH,4H-l,2,4-triazolo)methyl)-2(S)-(3,5- bis(trifluoromethyl)benzyloxy)-3(S)-phenyl-morpholine; and 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; or a pharmaceutically acceptable salt thereof.
An especially preferred compound of formula (I) is
2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)- (4-fluorophenyl)-4-(3-(5-oxo-lH,4H-l,2,4-triazolo)methylmorpholine; or a pharmaceutically acceptable salt thereof.
Further preferred NK-1 receptor antagonists are those described in PCT International Patent Publication No. WO 95/18124 as compounds of formula (II):
Figure imgf000022_0001
or a pharmaceutically acceptable salt or prodrug thereof, wherein
Rl is hydrogen, halogen, Ci-6alkyl, Ci-6alkoxy, CF3, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaR», C2-6alkenyl, C2-6 lkynyl or Ci-4alkyl substituted by Ci-4alkoxy, where Ra 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;
R4 is hydrogen, halogen, Ci-6alkyl, Ci-6alkoxy, CF3, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, C2-6alkenyl, C2-6alkynyl or Ci-4alkyl substituted by Cl-4alkoxy, where Ra and RD each independently represent hydrogen or Cl-4alkyl;
R5 is hydrogen, halogen, Ci-6alkyl, Cl-6alkoxy substituted by Ci-4alkoxy or CF3;
R6 is a 5-membered or 6-membered heterocyclic ring containing 2 or 3 nitrogen atoms optionally substituted by =O, =S or a Cl- 4alkyl group, and optionally substituted by a group of the formula ZNR7R8 where
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 Cι_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) or S(O)2 or a second nitrogen atom which will be part of a NH or NRC moiety where Rc is Ci-4alkyl optionally substituted by hydroxy or C -4alkoxy; or R' , R° and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms; or Z, R? 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 a and R b are each independently hydrogen or Cι_4alkyl, or R9a 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; and
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:
2-(R)- 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4- (5-(dimethylamino) methyl-l,2,3-triazol-4-yl)methyl-3-(S)- phenylmorpholine ;
(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4- ((dimethylamino-methyl)-l,2,3-triazol-4-yl)methyl)-3-(S)-(4- fluorophenyDmorpholine; or a pharmaceutically acceptable salt thereof. Further preferred NK-1 receptor antagonists are those described in PCT International Patent Publication No. WO 95/23798 as compounds of formula (III):
Figure imgf000024_0001
or a pharmaceutically acceptable salt thereof, wherein:
R2 and R3 are independently selected from the group consisting of:
(1) hydrogen,
(2) Cl-6 alkyl, unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy,
(b) oxo,
(c) Cl-6 alkoxy,
(d) phenyl-Ci-3 alkoxy,
(e) phenyl,
(f) -CN,
(g) halo,
(h) -NR9R10, wherein R9 and RlO are independently selected from:
(i) hydrogen,
(ii) Cl-6 alkyl,
(iii) hydroxy-C 1-6 alkyl, and
(iv) phenyl,
(i) -NR9COR10,
Figure imgf000024_0002
(k) -CONR9R10, (1) -COR9, and
Figure imgf000025_0001
(3) C2-6 alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy,
(b) oxo,
(c) Cl-6 alkoxy,
(d) phenyl-Ci-3 alkoxy,
(e) phenyl,
(f) -CN,
(g) halo,
(h) -CONR9R10,
(i) -COR9, and
Figure imgf000025_0002
(4) C2-6 alkynyl;
(5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy,
(b) Cl-6 alkoxy,
(c) Cl-6 alkyl,
(d) C2-5 alkenyl,
(e) halo, ω -CN,
(g) -NO2,
(h) -CF3,
Figure imgf000025_0003
(1) -CONR9R10,
Figure imgf000025_0004
(n) -COR9, and
Figure imgf000025_0005
and, alternatively, the groups R and R3 are joined together to form a carbocyclic ring selected from the group consisting of: (a) cyclopentyl,
(b) cyclohexyl,
(c) phenyl, and wherein the carbocyclic ring is unsubstituted or substituted with one or more substituents selected from:
(i) Ci-6alkyl, (ii) 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:
(a) pyrrolidinyl,
(b) piperidinyl, (c) pyrrolyl,
(d) pyridinyl,
(e) imidazolyl,
(f) furanyl,
(g) oxazolyl, (h) thienyl, and
(i) thiazolyl, and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituent(s) selected from: (i) Ci-6alkyl, (ii) oxo,
(iii) Ci-6alkoxy,
(iv) -NR9R10,
(v) halo, and
(vi) trifluoromethyl;
Rβ, R7 and R8 are independently selected from the group consisting of:
(1) hydrogen;
(2) Cl-6 alkyl, unsubstituted or substituted with one or more of the substituents selected from: (a) hydroxy, (b) oxo,
(c) Cl-6 alkoxy,
(d) phenyl-Cl-3 alkoxy,
(e) phenyl,
(f) -CN,
(g) halo,
(h) -NR9R10,
(i) -NR9COR10,
Figure imgf000027_0001
(k) -CONR9R10,
Figure imgf000027_0002
(3) C2-6 alkenyl, unsubstituted or substituted with one or more ! of the substituent(s) selected from:
(a) hydroxy,
(b) oxo,
(c) Cl-6 alkoxy,
(d) phenyl-Ci-3 alkoxy,
(e) phenyl,
(f) -CN,
(g) halo,
(h) -CONR9R10,
Figure imgf000027_0003
(4) C2-6 alkynyl;
(5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy,
(b) Cl-6 alkoxy,
(c) Cl-6 alkyl,
(d) C2-5 alkenyl,
(e) halo,
(f) -CN,
(g) -NO2,
(h) -CF3,
Figure imgf000028_0001
(1) -CONR9R10,
Figure imgf000028_0002
(n) -COR9, and
Figure imgf000028_0003
(6) halo,
(7) -CN,
(8) -CF3,
(9) -NO2,
(10) -SR14, wherein Rl4 is hydrogen or Cl-5alkyl,
(11) -SOR14,
Figure imgf000028_0004
(13) NR9COR10,
(14) CONR9COR10,
(15) NR9R10,
Figure imgf000028_0005
(17) hydroxy,
(18) Ci-6alkoxy,
(19) COR9,
Figure imgf000028_0006
(21) 2-pyridyl,
(22) 3-pyridyl,
(23) 4-pyridyl,
(24) 5-tetrazolyl,
(25) 2-oxazolyl, and
(26) 2-thiazolyl;
Rll, R12 and Rl3 are independently selected from the definitions of Rβ,
R7 and R* $, or -OX;
A is selected from the group consisting of:
(1) Cl-6 alkyl, unsubstituted or substituted with one or more of the substituents selected from: (a) hydroxy,
(b) oxo,
(c) Cl-6 alkoxy,
(d) phenyl-Ci-3 alkoxy,
(e) phenyl, ω -CN,
(g) halo,
(h) -NR9R10,
(i) -NR9COR10,
Figure imgf000029_0001
(k) -CONR9R10,
(1) -COR9, and
Figure imgf000029_0002
(2) C2-6 alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy,
(b) oxo,
(c) Ci_6 alkoxy,
(d) phenyl-Cl-3 alkoxy,
(e) phenyl,
(f) -CN,
(g) halo,
(h) -CONR9R10,
(i) -COR9 , and
Figure imgf000029_0003
(3) C2-6 alkynyl;
B is a heterocycle, wherein the heterocycle is selected from the group consisting of:
Figure imgf000030_0001
Figure imgf000030_0002
N-N N=N
N N X ,
I
X 364
Figure imgf000031_0001
Figure imgf000031_0002
and wherein the heterocycle is substituted in addition to -X with one or more substituent(s) selected from:
(i) hydrogen; WO 99/25364 rti/usvβw
(ii) Cl-6 alkyl, unsubstituted or substituted with halo, -CF3, -OCH3, or phenyl,
(iii) Cl-6 alkoxy,
(iv) oxo,
(v) hydroxy,
(vi) thioxo,
(vii) -SR9,
(viii) halo,
(ix) cyano,
(x) phenyl,
(xi) trifluoromethyl,
(xii) -(CH2)m-NR9RlO, wherein m is 0, 1 or
2,
(xϋi) -NR9COR10,
(xiv) -CONR9R10,
Figure imgf000032_0001
p is 0 or 1;
X is selected from:
(a) -PO(OH)O" • M+, wherein M+ is a pharmaceutically acceptable monovalent counterion,
(b) -PO(O")2 • 2M+,
(c) -PO(O")2 • D +, wherein D2+ is a pharmaceutically acceptable divalent counterion,
(d) -CH(R4)-PO(OH)O- • M+, wherein R4 is hydrogen or C1-3 alkyl,
(e) -CH(R4)-PO(O->2 • 2M+,
(f) -CH(R4)-PO(O-)2 • D +,
(g) -SO3- • M+,
Figure imgf000032_0002
(i) -CO-CH2CH2-CO2- • M+,
(j) -CH(CH3)-0-C0-R5, wherein R^ is selected from the group consisting of:
Figure imgf000033_0001
Figure imgf000033_0002
(k) hydrogen, with the proviso that if p is 0 and none of Rll, Rl2 or Rl3 are -OX, then X is other than hydrogen;
Y is selected from the group consisting of:
(1) a single bond,
(2) -O-,
(3) -S-, (4) -CO-,
(5) -CH2-,
(6) -CHR15-, and
(7) -CR15R16-, wherein 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,
(iii) Cl-6 alkoxy,
(iv) phenyl-Cl-3 alkoxy,
(v) phenyl,
(vi) -CN,
(vii) halo,
(viii) -NR9R10,
(ix) -NR9COR10,
Figure imgf000034_0001
(xi) -CONR9R10,
(xii) -COR9, and
Figure imgf000034_0002
(b) phen; γ\, unsubstituted or substituted with one or more of the substituent(s) selected from:
(i) hydroxy,
(ϋ) Cl-6 alkoxy,
(iii) Cl-6 alkyl,
(iv) C2-5 alkenyl,
(v) halo,
(vi) -CN,
(vii) -NO2,
(viii) -CF3,
Figure imgf000034_0003
(x) -NR9COR10,
Figure imgf000034_0004
(xii) -CONR9R10,
Figure imgf000034_0005
(xiv) -COR9, and
Figure imgf000035_0001
Z is selected from:
(1) hydrogen,
(2) Cl-6 alkyl, and
(3) hydroxy, with the proviso that if Y is -O-, Z is other than hydroxy, or if Y is -CHR15-, then Z and Rl5 are optionally joined together to form a double bond.
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. In particular, the bis(N-methyl- D-glucamine) salt is preferred.
Further preferred NK-1 receptor antagonists are those described in European Patent Specification No. WO 96/05181, i.e. compounds of formula (IV):
Figure imgf000035_0002
wherein:
X is a group of the formula NR6R7 or a C- or N-linked imidazolyl ring; Y is hydrogen or C^alkyl optionally substituted by a hydroxy group;
R1 is hydrogen, halogen, C^alkyl, C^alkoxy, CF3, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, C2.6alkenyl, C2.6alkynyl or C^alkyl substituted by C^alkoxy, wherein Ra and Rb each independently represent hydrogen or C^alkyl;
R2 is hydrogen, halogen, C^alkyl, C^alkoxy substituted by C^alkoxy or CF3;
R3 is hydrogen, halogen or CF3; R4 is hydrogen, halogen, C^alkyl, C^alkoxy, hydroxy, CFg,
NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, C2.6alkenyl, C2.6alkynyl or C^alkyl substituted by C^alkoxy, wherein Ra and Rb are as previously defined;
R5 is hydrogen, halogen, C^alkyl, C1 6alkoxy substituted by C^alkoxy or CF3;
R6 is hydrogen, C^alkyl, C3.7cycloalkyl, C3.7cycloalkylCMalkyl, phenyl, or C2.4alkyl substituted by C^alkoxy or hydroxy;
R7 is hydrogen, C^alkyl, C3.7cycloalkyl, Cg^cycloalkylC^ 4alkyl, phenyl, or C^alkyl substituted by one or two substituents selected from C1.4alkoxy, hydroxy or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S; or R6 and R7, 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(O) or S(O)2 and which ring may be optionally substituted by one or two groups selected from hydroxyCx.4alkyl, C1.4alkoxyC1.4alkyl, oxo, CORa or CO2Ra where Ra is as previously defined; or R6 and R7 together with the nitrogen atom to which they are attached, form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms;
R8 is hydrogen, C^alkyl, hydroxyC1.4alkyl or C1.4alkoxyC1.4alkyl; and R9a and R9b are each independently hydrogen or C^alkyl, or
R9a and R9b 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. Specific compounds of formula (IV) of use in the present invention include:
2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)ρhenyl)ethoxy)-3-(S)-(4-fluorophenyl)-
4-(4-morpholinobut-2-yn-yl)morpholine;
2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-N,N- dimethylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine;
4-(4-azetidinylbut-2-yn-yl)-2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl) ethoxy)-3-(S)-(4-fluorophenyl)morpholine;
2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-
4-(4-imidazolylbut-2-yn-yl)morpholine; 2-(R)-(l-(R)-(3,5-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)-(l-(R)-(3,5- bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine;
2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)- 4-(4-pyrrolidinobut-2-yn-yl)morpholine;
3-(S)-(4-fluorophenyl)-2-(R)-(l-(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)-(l-(R)-(3-
(trifluoromethyl)phenyl)ethoxy)morpholine; 4-(4-azetidinylbut-2-yn-yl)-3-(S)-(4-fluorophenyl)-2-(R)-(l-(R)-(3-
(trifluoromethyl)phenyl)ethoxy)morpholine;
2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-(N-(2- methoxyethyl)-N-methyl)aminobut-2-3πι-yl)-3-(S)-phenylmorpholine;
2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-(N-cyclopropyl-N- (2-methoxyethyl)amino)but-2-yn-yl)-3-(S)-phenylmorpholine;
2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-(N-isopropyl-N-(2- methoxyethyl)amino)but-2-3πι-yl)-3-(S)-phenylmorpholine;
4-(4-(N,N-dimethylamino)but-2-yn-yl)-3-(S)-(4-fluorophenyl)-2-(R)-(l-(S)-
(3-fluoro-5-(trifluoromethyl)phenyl-2-hydroxyethoxy)morpholine; 4-(4-azetidinylbut-2yn-yl)-3-(S)-(4-fluorophenyl)-2-(R)-(l-(S)-(3-fluoro-5- (trifluoromethyl)phenyl)-2-hydroxyethoxy)morpholine; 2-(R)-(l-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-4-(4-(N,N- dimethylamino)but-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine; 4-(4-azetidinylbut-2-yn-yl)-2-(R)-(l-(S)-(3,5-bis(trifluoromethyl)phenyl-2- hydroxyethoxy)-3-(S)-(4-fluorophenyl)morpholine;
4-(4-N-bis(2-methoxy)ethyl-N-methylamino)but-2-yn-yl)-2-(R)-(l-(R)-(3,5- bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine; 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)- 4-(4-(2-(S)-(methoxymethyl)pyrrolidino)but-2-yn-yl)morpholine; 4-(4-(7-azabicyclo[2.2.1]heptano)but-2-yn-yl)-2-(R)-(l-(R)-(3,5- bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine; 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4- diisopropylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine; 2-(R)-(l-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)-4-(4-(2-(S)- (methoxymethyl)pyrroli no)but-2-yn-yl)-3-(S)-phenylmorpholine; 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)- 4-(4-(2-(S)-(hydroxymethyl)p3nrrolidino)but-2-yn-yl)morpholine; and pharmaceutically acceptable salts thereof.
Further preferred NK-1 receptor antagonists are those described in European Patent Publication No. 0 436 334 as compounds of formula (V):
Figure imgf000038_0001
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 (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-C2-6alkyl, 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- βalkyl, Ci-6alkoxy, trifluoromethyl, amino, Ci-6alkylamino, Ci-6alkyl-O- CO, Ci-6alkyl-O-CO-Ci-6alkyl, Ci-6alkyl-CO-O, Ci-6alkyl-CO-Ci-6alkyl- O-, Ci-6alkyl-CO,
Ci-6alkyl-CO-Ci-6alkyl-, di-Ci-6alkylamino, -CONH-Ci-6alkyl, Ci-6alkyl-CO-NH-Ci-6alkyl, -NHCOH and -NHCO-Ci-6alkyl; and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl; R5 is hydrogen, phenyl or Ci-6alkyl; or R2 and R^ together with the carbon to which they are attached, form a saturated ring having from 3 to 7 carbon atoms wherein one of the CH2 groups in said ring may optionally be replaced by oxygen,
NH or sulfur; 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-
Cl-6alkyl, Ci-6alkyl-CO-NH-Ci-6alkyl, -NHCOH and -NH CO-Cl-6alkyl; R and R^ are each independently selected from hydroxy, halogen, halo, amino, oxo, cyano, methylene, hydroxymethyl, halomethyl,
Cl-6alkylamino, di-Cl-6alkylamino, Ci-6alkoxy, Ci-6alkyl-O-CO, Cl- 6alkyl-O-CO-Ci-6alkyl, Cl-6alkyl-CO-O, Ci-6alkyl-CO-Ci-6alkyl-O-, Ci-
6alkyl-CO-, Cl-6alkyl-CO-Ci-6alkyl, and the radicals set forth in the definition of R2;
Rβ is -NHCOR9, -NHCH2R9, SO2R8 or one of the radicals set forth in any of the definitions of R2, R4 and R^; R8 is oximino (=NOH) 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-βalkyl; with the proviso that (a) when m is 0, R8 is absent, (b) when R4, Rβ, 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):
Figure imgf000041_0001
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;
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 R5 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.
Another class of 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):
R Q
I I
Ar-T—CO-N-CH2-C— CH2-CH2-Am + A "
Ar' wherein
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;
Am+ represents the radical
X2— N +
I 3 in which Xi, X2 and X3, 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. 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.
Another class of 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):
Figure imgf000043_0001
or a pharmaceutically acceptable salt thereof, wherein
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; and 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.
Another class of 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):
Figure imgf000044_0001
or a pharmaceutically acceptable salt thereof, wherein wherein Rl is aryl, or a group of the formula:
Figure imgf000044_0002
or a pharmaceutically acceptable salt thereof, wherein
X is CH or N; and
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; and
Y is a bond or lower alkenylene.
A particularly preferred compound of formula (IX) is the compound of formula (LXa)
Figure imgf000045_0001
Another class of 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):
Figure imgf000045_0002
or a pharmaceutically acceptable salt thereof, wherein
R1 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 C3.7cycloalkyl may optionally be substituted with one or two substituents, said substituents being independently selected from chloro, fluoro, bro o, iodo, nitro, Cj.^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-, C1.10alkyl-S(O)-, C^alkyl-SOjj-, phenyl, phenoxy, C1.10alkyl-SO2NH-, C^^alk l-SO^H-C^oalkyl-, C1.10alkylamino-diC1.10alkyl-, cyano, hydroxy, cycloalkoxy having 3 to 7 carbon atoms,
Figure imgf000045_0003
HC(O)NH- and C1.10alkyl-C(O)NH-; and R2 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, C1.10alkyl optionally substituted with from one to three fluoro groups and Cj^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.
Another class of 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):
Figure imgf000046_0001
wherein R is a Cl-4alkoxy group ; R is
Figure imgf000046_0002
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)nCl-4 alkyl, phenyl, NR7R8, CH2C(O)CF3 or trifluoromethyl group;
R? and R8 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.
Another class of 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):
Figure imgf000047_0001
wherein Rl, R2, R3, R4( R5? R6? R9? RlO, and 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-cycloproρoxy-5-(trifluoromethoxy)phenyl]-6- phenyl-l-oxa-7-aza-spiro[4.5]decane; or a pharmaceutically acceptable salt thereof.
Another class of 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):
Figure imgf000048_0001
wherein
R represents a hydrogen atom or a Ci-4 alkoxy group;
Rl is selected from phenyl, optionally substituted by a group -(CH2)nCONR3R4 0r S(O)mR3; 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.
Another class of 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)
Figure imgf000049_0001
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, Cα. 3alkoxy, trifluoromethyl, C^alkyl, phenyl-C ^alkoxy, or C^alkanoyl groups;
R1 is trityl, phenyl, diphenylmethyl, phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, hexamethyleneiminyl, benzofuranyl, tetrahydropyridinyl, quinolinyl, isoquinolinyl, reduced quinolinyl, reduced isoquinolinyl, phenyl-(C1.4alkyl)-, phenyl-(C1.4alkoxy)-, quinolinyl-(C1.4alkyl)-, isoquinolinyl-(Cwalkyl)-, reduced quinolinyl-(C1.4alkyl)-, reduced isoquinolinyl-(CMalkyl)-, benzoyl-(C1.3alkyl)-, C^alkyl, or -NH-CH^-R5; any one of which R1 groups may be substituted with halo, Cx. 4alkyl, C^alkoxy, trifluoromethyl, amino, C1.4alkylamino, dKC^ 4alkyl)amino, or C^alkanoylamino; or any one of which R1 groups may be substituted with phenyl, piperazinyl, C3_8cycloalkyl, benzyl, C^alkyl, piperidinyl, pyridinyl, pyrimidinyl, C2.6alkanoylamino, pyrrolidinyl, C2.6alkanoyl, or C^alkoxycarbonyl; any one of which groups may be substituted with halo, C^ 4alkyl, C^alkoxy, trifluoromethyl, amino, C1.4alkylamino, di(C1. 4alkyl)amino, or C2.4alkanoylamino; or R1 is amino, a leaving group, hydrogen, C^alkylamino, or dKC^alkyDamino;
R5 is pyridyl, anilino-(C1.3alkyl)-, or anilinocarbonyl;
R2 is hydrogen, C^alkyl, C^alkylsulfonyl, carboxy-(Cx. 3alkyl)-,
Figure imgf000050_0001
or -CO-R6;
R6 is hydrogen, C^alkyl, C^haloalkyl, phenyl, C^alkoxy, Cj.ghydroxy alkyl, amino,
Figure imgf000050_0002
di(C1.4alkyl)amino, or -(CH2)q-R7; q is zero to 3;
R7 is carboxy, C^alkoxycarbonyl, C^alkylcarbonyloxy, amino, C^alkylamino, di(C1.4alkyl)amino, CLgalkoxycarbonylamino, or phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, benzofuranyl, quinolinyl, phenyl-(C1. 4alkyl)-, quinolinyMC^alkyl)-, isoquinolinyl-(C1.4alkyl)-, reduced quinolinyl-(C1.4alkyl)-, reduced isoquinolinyHC^alkyl)-, benzoyl-CLgalkyl; any one of which aryl or heterocyclic R7 groups may be substituted with halo, trifluoromethyl, C^alkoxy, C^alkyl, amino, Cx. 4alkylamino, di(C1.4alkyl)amino, or C2.4alkanoylamino; or any one of which R7 groups may be substituted with phenyl, piperazinyl, C3.8cycloalkyl, benzyl, piperidinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, C2.6alkanoyl, or C^alkoxycarbonyl; any of which groups may be substituted with halo, trifluoromethyl, amino, C^alkoxy, Cx.4alkyl, C1.4alkylamino, di(C1.4alkyl)amino, or C2_4alkanoylamino;
R8 is hydrogen or C^alkyl;
R3 is phenyl, phenyMC^alkyl)-, C3.8cycloalkyl, C5. gCycloalkenyl, C^alkyl, naphthyl, C2.8alkenyl, or hydrogen; any one or which groups except hydrogen may be substituted with one or two halo, C^alkoxy, C^alkylthio, nitro, trifluoromethyl, or Chalky 1 groups; and
R4 is hydrogen or C1.3alkyl; with the proviso that if R1 is hydrogen or halo, R3 is phenyl, phenyl-(C1.6alkyl)-, C3_8cycloalkyl, Cg.8cycloalkenyl, 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 compounds of formulae (I), (II), (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:
Figure imgf000051_0001
Where the benzyloxy moiety is -substituted, the preferred stereochemistry of the α-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.
The preparation of the foregoing compounds is fully described in the referenced patents and publications.
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 straight-chained 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-Cl-6alkyl, e.g. phenyl-Cl- βalkyl, 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.
As used herein, the general term "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. 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.
The above compounds are only illustrative of the neurokinin- 1 antagonists which are currently under investigation. As this listing of compounds is not meant to be comprehensive, 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.
Certain of the above defined terms may occur more than once in the above formula and upon such occurrence each term shall be defined independently of the other. Similarly, the use of a particular variable within a noted structural formula is intended to be independent of the use of such variable within a different structural formula.
Full descriptions of the preparation of the tachykinin receptor antagonists which are employed in the present invention may be found in the references cited herein.
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.
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). In a further aspect of the present invention, there is provided 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.
The identification of 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. Preferably 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.
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 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. 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 (e.g. Tween™ 20, 40, 60, 80 or 85) and other sorbitans (e.g. Span™ 20, 40, 60, 80 or 85). Compositions with a surface-active agent will conveniently comprise between 0.05 and 5% surface-active agent, and preferably between 0.1 and 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 Intralipid™, Liposyn™, Infonutrol™, Lipofundin™ and Lipiphysan™. 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. 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 20%. The fat emulsion will preferably comprise fat droplets between 0.1 and l.Oμm, particularly 0.1 and 0.5μm, 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. 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. 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 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.
For example, for treating or preventing attention deficit disorder in a patient 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, ethchlorvynol, etomidate, fenobam, flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam, hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, methylphenidate (including d-methylphenidate, especially d-methylphenidate hydrochloride), midaflur, midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline, omega-3 fatty acids, oxazepam, paraldehyde, paroxetine, pemoline, pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protriptyline, quazepam, reclazepam, roletamide, secobarbital, sertraline, suproclone, temazepam, thioridazine, tracazolate, tranylcypromaine, trazodone, triazolam, trepipam, tricetamide, triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam, valproate, venlafaxine, xanomeline, zaleplon, zolazepam, zolpidem, and salts thereof, and combinations thereof, and the like, as well as admixtures and combinations thereof.
Typically, 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. In the case of methylphenidate 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). To illustrate these combinations, 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.
Naturally, 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.
In the treatment of a condition in accordance with the present invention, an appropriate dosage level will generally be about 0.01 μg to 50 mg per kg patient body weight per day which may be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 μg to about 25 mg/kg per day; more preferably about 0.5 μg to about 10 mg/kg per day. For example, for treating or preventing attention deficit disorder in a patient, a suitable dosage level is about 0.1 μg to 25 mg/kg per day, preferably about 0.5 μg to 10 mg/kg per day, and especially about 1 μg to 5 mg/kg per day. In larger mammals, for example humans, a typical indicated dose is about 300 μg 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. When using an injectable formulation, a suitable dosage level is about 0.1 μg to 10 mg/kg per day, preferably about 0.5 μg to 5 mg/kg per day, and especially about 1 μg to 1 mg/kg per day. In larger mammals, for example humans, a typical indicated dose is about 100 μg 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.
Pharmaceutical compositions of the present invention may be provided in a solid dosage formulation preferably comprising about 100 μg to 500 mg active ingredient, more preferably comprising about 100 μg to 250 mg active ingredient. The pharmaceutical composition is preferably provided in a solid dosage formulation comprising about 100 μg, 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.
It will be appreciated that 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. The compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII),
(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. Particularly preferred 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 (IC50) of less than lOnM.
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 for treating or preventing attention deficit disorder in a patient 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 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.
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 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.
Furthermore, the exceptional pharmacology of the class of NK-1 receptor antagonists of use in the present invention results in a rapid onset of action. The present invention accordingly provides the use of an orally active, long acting, CNS-penetrant NK-1 receptor antagonist (as hereinafter defined) for the manufacture of a medicament adapted for oral administration for 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).
In a further aspect of the present invention, there is provided 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.
It will be appreciated to those skilled in the art that reference herein to treatment extends to prophylaxis (prevention) as well as the treatment of the noted diseases/disorders and symptoms. Because the specific diagnosis of attention deficit disorder in a particular patient may be difficult, the patient may benefit from the prophylactic administration of a subject compound in accordance with the present invention.
Preferred NK-1 receptor antagonists for use in the present invention as orally active, long acting, CNS-penetrant NK-1 receptor antagonists are selected from the classes of compounds described in European Patent Specification No. 0 577 394, and International Patent Specification Nos. 95/08549, 95/18124, 95/23798, 96/05181 and WO 97/49710.
Thus, further particularly preferred NK-1 receptor antagonists of use in the present invention include: (±)-(2R3R, 2S3S)-N-{ [2-cycloproρoxy-5-(trifluoromethoxy)- phenyl] methyl} -2-phenylpiperidin-3- amine;
2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3(S)-(4- fluorophenyl)-4-(3-(5-oxo-lH,4H-l,2,4-triazolo)methyl)morpholine;
2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(3-(5- oxo-lH,4H-l,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine;
2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(3-(5-oxo-lH,4H- l,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine;
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; 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5- (N,N-dimethylamino)methyl-l,2,3-triazol-4-yl)methyl-3-(S)- phenylmorpholine;
2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5- (N,N-dimethylamino)methyl-l,2,3-triazol-4-yl)methyl-3-(S)-(4- fluorophenyl)morpholine;
(3S,5R,6S)-3- [2-cyclopropoxy-5-(trifluoromethoxy)phenyl] -6- phenyl-l-oxa-7-aza-spiro[4.5]decane;
(3R,5R,6S)-3- [2-cyclopropoxy-5-(trifluoromethoxy)phenyl] -6- phenyl- 1 -oxa-7-aza-spiro [4.5] decane ;
2-(R)-(l-(S)-(3,5-bis(trifluoromethyl)phenyl)-2- hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3- yl)methylmorpholine;
2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4- fluorophenyl)-4-(3-(4-monophosphoryl-5-oxo- 1H- 1 ,2,4- triazolo)methyl)morpholine;
2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4- fluorophenyl)-4-(3-(l-monophosphoryl-5-oxo-lH-l,2,4- triazolo)methyl)morpholine; 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4- fluorophenyl)-4-(3-(2-monophosphoryl-5-oxo-lH-l,2,4- triazolo)methyl)morpholine;
2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4- fluorophenyl)-4-(3-(5-oxyphosphoryl-lH-l,2,4-triazolo)methyl)morpholine; 2-(S)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4- fluorophenyl)-4-(3-(l-monophosphoryl-5-oxo-4H-l,2,4- triazolo)methyl)morpholine;
2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-N,N- dimethylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine; or a pharmaceutically acceptable salt thereof.
Full descriptions of the preparation of the tachykinin receptor antagonists which may be employed in the present invention may be found in the references cited herein. The following examples are provided for the purpose of further illustration only and are not intended to be limitations on the disclosed invention.
EXAMPLE 1
NK-1 Receptor binding Assay
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 3xl05 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. 125I-Tyr8- substance P (O.lnM, 2000Ci/mmol; New England Nuclear) is incubated in the presence or absence of test compounds (dissolved in 5μl dimethylsulphoxide, DMSO) with 5xl04 CHO cells. Ligand binding is performed in 0.25ml of 50mM Tris-HCl, pH7.5, containing 5mM MnCl2, 150mM NaCl, 0.02% bovine serum albumin (Sigma), 50μg/ml chymostatin (Peninsula), O.lnM phenylmethylsulphonyl fluoride, 2μg/ml pepstatin,
2μg/ml leupeptin and 2.8μg/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 (lμM) and represents <10% of total binding.
EXAMPLE 2
Gerbil Foot-Tapping Assay
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.
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. 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) or a selective NK-1 receptor agonist (e.g. GR73632 (d Ala[L-Pro9,Me-Leu10]- substance P-(7-ll))) is infused directly into the cerebral ventricles (e.g. 3pmol in 5μl 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. Alternatively, 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.
EXAMPLE 3
Ferret Emesis Assay
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 lOOg of tinned cat food. At 60 minutes following oral dosing, cisplatin (lOmg/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, after which time the animals are killed humanely. The numbers of retches and vomits occurring during the 4 hours after cisplatin administration are recorded by trained observers. EXAMPLE 4
Separation-Induced Vocalisation Assay Male and female guinea-pigs pups are housed in family groups with their mothers and littermates throughout the study. Experiments are commenced after weaning when the pups are 2 weeks old. Before entering an experiment, the pups are screened to ensure that a vigorous vocalisation response is reproducibly elicited following maternal separation. The pups are placed individually in an observation cage (55cm x 39cm x 19cm) in a room physically isolated from the home cage for 15 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 a 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 30 minutes to 60 minutes (or for up to 4 hours following an oral dose, dependant upon the oral pharmacokinetics of the test compound) 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 at each dose tested. A suitable selection cascade for NKj antagonists of use according to the present invention is as follows:
(i) Determine affinity for human NKX receptor in radioligand binding studies (Assay 1); select compounds with IC50 < lOnM, preferably IC50 < 2nM, especially IC50 < 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: agonist (Assay 2); select compounds that inhibit foot tapping with ID50 < 3mg/kg i.v., and preferably ID50 < lmg/kg i.v. when administered immediately prior to central NKα agonist challenge, or ID50 < 30mg/kg p.o., and preferably ID50 < lOmg/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 NKX agonist challenge; select compounds showing < 25- fold loss of potency compared with ID50 determined in step (ii) above with the proviso that ID50 < lOmg/kg i.v., and preferably < 5mg/kg i.v. after 24 hour pre-treatment.
(iv) Determine oral bioavailability of compounds by phaπnacokinetic analysis, activity in gerbil foot tapping assay following oral administration and/or by ability to inhibit cisplatin-induced emesis in ferrets (Assay 3); select compounds with ID90 < 3mg/kg p.o., and preferably ID90 < lmg/kg p.o.
Particularly preferred compounds of use in the present invention are identified using steps (i) to (iv) followed by step (v):
(v) Determine activity of compounds in assays sensitive to conventional antidepressant drugs (inhibition of pharmacologically evoked foot tapping in gerbils and/or inhibition of distress vocalisations in guinea- pig pups (Assay 4)). Select compounds with ID50 < 20mg/kg, and preferably ID50 ≤ 10mg/kg.
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.
One example of 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:
human NK-1 receptor binding: IC50=0.1nM gerbil foot-tapping (5 mins.): ID50=0.36mg/kg i.v. gerbil foot-tapping (24 hrs.): ID50=0.33mg/kg i.v. ferret emesis: ID90<3mg/kg p.o. guinea-pig vocalisation ID50=0.73mg/kg p.o. (4hr. pre-treatment):
The following example illustrates pharmaceutical compositions according to the invention.
EXAMPLE 5
Tablet formulation containing 50-300me of NK-1 antagonist
Amount mg
NK-1 antagonist 50.0 100.0 300.0
Microcrystalline cellulose 80.0 80.0 80.0
Modified food corn starch 80.0 80.0 80.0
Lactose 189.5 139.5 439.5
Magnesium Stearate 0.5 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 then compressed into tablets containing 50mg, lOOmg and 300mg of the NK-1 receptor antagonist per tablet.
EXAMPLE 6
Parenteral injection formulation
Amount
Active Ingredient 10 to 300mg
Citric Acid Monohydrate 0.75mg
Sodium Phosphate 4.5mg
Sodium Chloride 9mg
Water for injection to 10ml 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.
EXAMPLE 7
Double-Blind, Parallel, Placebo-Controlled Study to Determine the Effect of a Neurokinin- 1 Antagonist on Attention Deficit Disorder in Children Approximately fifty children suffering from attention deficit disorder receive either the neurokinin-1 receptor antagonist 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 (30 mg/day) or a placebo. Each subject participates in 6 randomized test periods; in 3 of the test periods, each is given the neurokinin- 1 antagonist and in the other 3 test periods, is given a placebo. 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.
While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention. For example, effective dosages other than the particular dosages as set forth herein above may be applicable as a consequence of variations in the responsiveness of the mammal being treated for any of the indications with the compounds of the invention indicated above. Likewise, the specific pharmacological responses observed may vary according to and depending upon the particular active compounds selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be defined by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.

Claims

WHAT IS CLAIMED IS:
1. A method for the treatment or prevention of attention deficit disorder in a patient which comprises administering an effective amount of a tachykinin receptor antagonist.
2. The method of Claim 1 wherein the tachykinin receptor antagonist is a neurokinin-1 receptor antagonist.
3. The method of Claim 2 wherein the neurokinin- 1 receptor antagonist is a CNS-penetrating neurokinin- 1 receptor antagonist.
4. The method of Claim 3 wherein the neurokinin- 1 receptor antagonist is an orally active neurokinin- 1 receptor antagonist.
5. The method of Claim 4 wherein the neurokinin- 1 receptor antagonist possesses a long duration of action.
6. The method of Claim 2 wherein the neurokinin- 1 receptor antagonist is a non-peptidal neurokinin- 1 receptor antagonist.
7. The method of Claim 1 wherein the attention deficit disorder in the patient is further associated with hyperactivity.
8. The method of Claim 1 wherein the tachykinin antagonist is 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, and essential fatty acids; or in conjunction with the use of electrical stimulation.
9. The method of Claim 1 wherein the tachykinin antagonist is employed in conjunction with the administration of methylphenidate .
10. The method of Claim 1 wherein the tachykinin antagonist is employed in conjunction with the administration of d-methylphenidate hydrochloride.
PCT/US1998/024634 1997-11-19 1998-11-18 Method for treating attention deficit disorder Ceased WO1999025364A1 (en)

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WO2008090117A1 (en) 2007-01-24 2008-07-31 Glaxo Group Limited Pharmaceutical compositions comprising 3, 5-diamin0-6- (2, 3-dichl0phenyl) -l, 2, 4-triazine or r (-) -2, 4-diamino-5- (2, 3-dichlorophenyl) -6-fluoromethyl pyrimidine and an nk1
WO2022162199A3 (en) * 2021-01-29 2022-09-15 3Z Ehf Compounds for use in the treatment of attention deficit hyperactivity disorder

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008090117A1 (en) 2007-01-24 2008-07-31 Glaxo Group Limited Pharmaceutical compositions comprising 3, 5-diamin0-6- (2, 3-dichl0phenyl) -l, 2, 4-triazine or r (-) -2, 4-diamino-5- (2, 3-dichlorophenyl) -6-fluoromethyl pyrimidine and an nk1
WO2022162199A3 (en) * 2021-01-29 2022-09-15 3Z Ehf Compounds for use in the treatment of attention deficit hyperactivity disorder

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