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WO1999064009A1 - Utilisation d'un antagoniste du recepteur nk-1 dans le traitement des troubles cognitifs - Google Patents

Utilisation d'un antagoniste du recepteur nk-1 dans le traitement des troubles cognitifs Download PDF

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Publication number
WO1999064009A1
WO1999064009A1 PCT/GB1999/001818 GB9901818W WO9964009A1 WO 1999064009 A1 WO1999064009 A1 WO 1999064009A1 GB 9901818 W GB9901818 W GB 9901818W WO 9964009 A1 WO9964009 A1 WO 9964009A1
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WO
WIPO (PCT)
Prior art keywords
treatment
disorders
cognitive disorders
triazol
bis
Prior art date
Application number
PCT/GB1999/001818
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English (en)
Inventor
Nadia Melanie Rupniak
Original Assignee
Merck Sharp & Dohme Limited
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Filing date
Publication date
Application filed by Merck Sharp & Dohme Limited filed Critical Merck Sharp & Dohme Limited
Priority to CA002334606A priority Critical patent/CA2334606A1/fr
Priority to EP99955426A priority patent/EP1119358A1/fr
Priority to AU42795/99A priority patent/AU4279599A/en
Publication of WO1999064009A1 publication Critical patent/WO1999064009A1/fr

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Classifications

    • 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

Definitions

  • This invention relates to the treatment or prevention of certain cognitive disorders by the administration of a NK-1 receptor antagonist, in particular, 2-(R)-(l-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)- 3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt thereof.
  • a NK-1 receptor antagonist in particular, 2-(R)-(l-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)- 3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt thereof.
  • Cognitive disorders include dementia, amnestic disorders and cognitive disorders not otherwise specified.
  • the prominent disturbance associated with these conditions is a clinically significant deficit in cognition or memory that represents a significant change from a previous level of functioning.
  • dementia is now defined as a syndrome consisting of progressive impairment in two or more areas of cognition (i.e. memory, language, visuospatial and perceptual ability, thinking and problem solving, and personality) sufficient to interfere with work, social function or relationships.
  • areas of cognition i.e. memory, language, visuospatial and perceptual ability, thinking and problem solving, and personality
  • An amnestic disorder is characterised by memory impairment in the absence of other significant cognitive impairments.
  • 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 imphcated include disorders of the central nervous system such as anxiety, depression and psychosis (see, for instance, International (PCT) patent specification Nos. WO 95/16679, WO 95/18124 and WO 95/23798). More recently, International (PCT) patent specification No.
  • WO 96/24353 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).
  • SSRI serotonin agonist or selective serotonin reuptake inhibitor
  • the present invention provides the use of 2-(R)-(l-(S)-(3,5- bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4- (l,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt thereof in an oral, once-a-day medicament for the treatment of cognitive disorders.
  • the compounds of this class advantageously exhibit a rapid onset of action and a reduced side-effect profile when compared against conventional antidepressant or antipsychotic agents.
  • the exceptional pharmacology of the NK- 1 receptor antagonist of use in the present invention enables the treatment of cognitive disorders, without the need for concomitant therapy using tricyclic antidepr ess ants or monoamine oxidase inhibitors, or antipsychotic agents, or in particular, without the need for concomitant use of a serotonin agonist or an SSRI. Furthermore, the exceptional pharmacology of the NK- 1 receptor antagonist of use in the present invention results in a rapid onset of action.
  • the present invention accordingly provides the use of 2-(R)-(l-(S)- (3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)- 4-(l,2,4-triazol-3-yl)methylmorphohne, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament adapted for oral administration for the treatment or prevention of cognitive disorders.
  • the present invention also provides a method for the treatment or prevention of cognitive disorders, which method comprises the oral administration to a patient in need of such treatment of an effective amount of 2-(R)-(l-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)- 3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3-yl)methylmorphohne, or a pharmaceutically acceptable salt thereof.
  • an oral pharmaceutical composition for the treatment of cognitive disorders which comprises 2-(R)-(l-(S)-(3,5-bis(trifluoromethyl)phenyl)-2- hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3- yl)methylmorpholine, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.
  • the present invention accordingly provides the use of 2-(R)-(l-(S)- (3 , 5 -bis(trifluoromethyl)phenyl) -2 -hy droxy ethoxy)- 3 - (S) - (4-fl.uorophenyl) - 4-(l,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament adapted for oral administration for the treatment or prevention of cognitive disorders in a patient who is non-responsive to heterocycHc antidepressants (TCAs, tetracyclics, and the like), SSRIs, serotonin agonists or antagonists, mixed serotonin and norepinephrine selective reuptake inhibitors, dopamine reuptake inhibitors or MAOIs, or for whom heterocycHc antidepressants (TCAs, tetracycHcs, and the Hke), SSRIs, serot
  • the present invention also provides a method for the treatment or prevention of cognitive disorders in a patient who is non-responsive to heterocycHc antidepressants (TCAs, tetracycHcs, and the Hke), SSRIs, serotonin agonists or antagonists, mixed serotonin and norepinephrine selective reuptake inhibitors, dopamine reuptake inhibitors or MAOIs, or for whom heterocycHc antidepressants (TCAs, tetracycHcs, and the Hke), SSRIs, serotonin agonists or antagonists, mixed serotonin and norepinephrine selective reuptake inhibitors, dopamine reuptake inhibitors or MAOIs are contraindicated, which method comprises oral administration to the patient in need of such treatment of an effective amount of 2 - (R) - ( 1 - (S) - (3 , 5 -bis(trifluoromethyl)phenyl) - 2
  • the present invention also provides a method for the treatment or prevention of cognitive disorders in the patient who is non-responsive to antipsychotic agents, or for whom antipsychotic agents are contraindicated, which method comprises oral administration to the patient in need of such treatment of an effective amount of 2-(R)-(l-(S)- (3 , 5 -bis(trifluoromethyl)phenyl) -2 -hy droxyethoxy)- 3 - (S)- (4-fluorophenyl) - 4-(l,2,4-triazol-3-yl)methylmorphoHne, or a pharmaceuticaUy acceptable salt thereof.
  • the term "cognitive disorders” includes dementia, amnestic disorders and cognitive disorders not otherwise specified.
  • the term "cognitive disorders” includes dementia caused by degenerative disorders, lesions, trauma, infections, vascular disorders, toxins, anoxia, vitamin deficiency and endocrine disorders.
  • specific examples of these causes include degenerative disorders such as Alzheimer's disease, multiple sclerosis, Parkinson's disease, normal pressure hydrocephalus and Huntington's chorea; space occupying lesions including tumors and chronic subdural haematoma; trauma including severe head injury; infections including postencephaHtis and syphiHs; vascular disorders including multi-infarct dementia; toxins including alcohol; anoxia caused by cardiac arrest and carbon monoxide poisoning, vitamin deficiencies including lack of vitamin B12; and endocrine disorders including hypothyroidism.
  • cognitive disorders includes amnestic disorders caused by alcohol (Korsakoff psychosis) and other causes of thiamine deficiency; bilateral temporal lobe damage due to herpes simplex encephafitis and other Hmbic encephahtis, neuronal loss secondary to anoxia/hypoglycaemia/severe convulsions, and surgery; degenerative disorders including Alzheimer's and Pick's diseases; vascular disorders including bilateral infarction, hippocampal infarction and bilateral cingulate cortex infarction; and pathology around ventricle III including tumors, chronic meningitis and neurosarcoidosis.
  • cognitive disorders includes cognitive impairment resulting from other medical conditions, most especiaUy resulting from depression and/or anxiety.
  • treatment refers both to the treatment and to the prevention or prophylactic therapy of the aforementioned conditions.
  • Suitable pharmaceuticaUy acceptable salts of the NK-1 receptor antagonist 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 pharmaceuticaUy 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.
  • compositions containing the NK-1 receptor antagonist of use according to the present invention are in unit dosage forms such as tablets, piUs, capsules, wafers and the Hke.
  • the NK- 1 receptor antagonist of use according to the present invention may be presented as granules or powders for extemporaneous formulation as volume defined solutions or suspensions.
  • the NK-1 receptor antagonist of use according to the present invention may be presented in ready-prepared volume defined solutions or suspensions.
  • Preferred forms are tablets and capsules.
  • soHd 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 dUuents, e.g. water, to form a soHd preformulation composition containing a homogeneous mixture of a compound of the present invention, or a non-toxic pharmaceuticaUy 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 dUuents, e.g. water
  • preformulation compositions 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 reacUly subdivided into equaUy effective unit dosage forms such as tablets, piUs and capsules.
  • This soHd 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 piU 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 sheUac, cetyl alcohol and ceUulose acetate.
  • compositions of the present invention may be incorporated for administration oraUy
  • aqueous solutions suitably flavoured syrups, aqueous or oU suspensions, and flavoured emulsions with edible oUs such as cottonseed oU, sesame oU, coconut oU, peanut oU or soybean oU, as weU as ehxirs and similar pharmaceutical vehicles.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylceUulose, methylceUulose, polyvinyl-pyrroHdone or gelatin.
  • Compositions of the present invention may also be administered via the buccal cavity using conventional technology, for example, absorption wafers.
  • compositions in the form of tablets, piUs, capsules or wafers for oral administration are particularly preferred.
  • a minimum dosage level for the NK- 1 receptor antagonist is about lmg per day, preferably about 5mg per day and especiaUy about lOmg per day.
  • a maximum dosage level for the NK-1 receptor antagonist is about 1500mg per day, preferably about lOOOmg per day and especiaUy about 500mg per day. The compounds are administered once a day.
  • the amount of the NK- 1 receptor antagonist required for use in the treatment or prevention of cognitive disorders wiU 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 wiU ultimately be at the discretion of the patient's physician or pharmacist.
  • the activity of the NK- 1 receptor antagonist of use in the present invention may be measured using the foUowing assays:
  • NK-1 Receptor binding NK-1 receptor binding assays are performed in intact Chinese hamster ovary (CHO) ceUs 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.
  • TypicaUy the receptor is expressed at a level of 3xl0 5 receptors per ceU.
  • CeUs are grown in monolayer culture, detached from the plate with enzyme-free dissociation solution (SpeciaHty Media Inc.), and washed prior to use in the assay.
  • 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 ceUs. Ligand binding is performed in 0.25ml of 50mM Tris-HCl, pH7.5, containing 5mM MnCl 2>
  • GerbU Foot-Tapping CNS-penetrant NK-1 receptor antagonists for use in the present invention can be identified by their abiHty to inhibit foot tapping in gerbUs 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 & WiUiams, Eur. J. Pharmacol., 1994, 265, 179.
  • Male or female MongoHan gerbUs (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 oraUy or by subcutaneous or intraperitoneal routes. A skin incision is then made in the midHne of the scalp to expose the skuU.
  • 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-l l)) is infused directly into the cerebral ventricles (e.g. 3pmol in 5 ⁇ l i.c.v., depending on test substance) by vertical insertion of a cuffed 27 gauge needle to a depth of 4.5mm below bregma. The scalp incision is closed and the animal aUowed 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 approximately 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.
  • ASSAY 3 Ferret Emesis IndividuaUy housed male ferrets (1.0 -2.5 kg) are dosed oraUy by gavage with test compound. Ten minutes later they are fed with approximately lOOg of tinned cat food. At 60 minutes foUowing 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 Hgated and the skin incision closed. The ferrets recover rapidly from the anaesthetic and are mobUe within 10-20 minutes.
  • the animals are observed continuously during recovery from the anaesthetic and for 4 hours foUowing the cisplatin injection, after which time the animals are kiUed humanely.
  • the numbers of retches and vomits occurring during the 4 hours after cisplatin administration are recorded by trained observers.
  • mice Male and female guinea-pigs pups are housed in family groups with their mothers and Httermates 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 vocaHsation response is reproducibly eHcited foUowing maternal separation. The pups are placed individuaUy 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 vocaHsation during this baseHne period is recorded.
  • CNS-penetrant refers to NK-1 receptor antagonists which are able to inhibit NK-1 receptor antagonist-induced foot-tapping in the gerbU as hereinafter defined.
  • the NK- 1 receptor antagonist is administered oraUy, 1 hour prior to GR73632 chaUenge, wherein the foot- tapping over a period of five minutes foUowing recovery from anaesthesia is inhibited with an IDso ⁇ 30mg/kg, and preferably with an IDso ⁇ lOmg/kg.
  • CNS-penetrant NK-1 receptor antagonists of use in the present invention are also effective in the attenuation of separation-induced vocaHsations by guinea-pig pups as hereinafter defined.
  • a vocaHsation response in guinea-pig pups is induced by isolation from their mothers and Httermates, which response is attenuated when a CNS-penetrant NK-1 receptor antagonist is administered subcutaneously 30 minutes prior to isolation, wherein vocaHsations during the first 15 minutes of isolation are attenuated with an ID5o ⁇ 20mg/kg, preferably with an ID ⁇ o ⁇ lOmg/kg, and especiaUy with an IDso ⁇ mg/kg.
  • the NK-1 receptor antagonist is administered oraUy, 4 hours prior to isolation, wherein vocaHsations during the first 15 minutes of isolation are attenuated with an IDso ⁇ 20mg/kg, preferably with an IDso ⁇ lOmg/kg, and especially with an IDso ⁇ mg/kg.
  • a suitable selection cascade for NKi antagonists of use according to the present invention is as foUows: (i) Determine affinity for human NKi receptor in radioHgand binding studies (Assay 1); select compounds with IC ⁇ o ⁇ lOnM, preferably IC50 ⁇ 2nM, especiaUy ICso ⁇ InM.
  • step (iv) Determine oral bioavaUabiHty of compounds by pharmacokinetic analysis, activity in gerbU foot tapping assay foUowing oral administration and/or by abiHty to inhibit cisplatin-induced emesis in ferrets (Assay 3); select compounds with ID90 ⁇ 3mg/kg p.o., and preferably Particularly preferred compounds of use in the present invention are identified using steps (i) to (iv) foUowed by step (v):
  • step (v) Determine activity of compounds in assays sensitive to conventional antidepressant/anxiolytic drugs (inhibition of pharmacologicaUy evoked foot tapping in gerbUs and/or inhibition of distress vocaHsations in guinea-pig pups (Assay 4)).
  • 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
  • the NK- 1 receptor antagonist of use in the present invention is the compound 2-(R)-(l-(S)-(3,5-bis(trifl.uoromethyl)phenyl)-2-hydroxyethoxy)- 3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3-yl)methylmorphoHne, the preparation of which is described in International Patent Specification No. WO 95/18124 and US Patent No. 5,612,337. In the aforementioned assays, this compound has the foUowing activity:
  • the foUowing example illustrates pharmaceutical compositions according to the invention.

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  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne l'utilisation d'un antagoniste du récepteur NK-1 (neurokinine 1) pour la fabrication d'un médicament, administrable par voie orale, intervenant dans le traitement ou la prévention de troubles cognitifs, ainsi que des techniques de traitement médical au moyen d'un tel antagoniste du récepteur NK-1 et des compositions pharmaceutiques renfermant ledit antagoniste.
PCT/GB1999/001818 1998-06-11 1999-06-08 Utilisation d'un antagoniste du recepteur nk-1 dans le traitement des troubles cognitifs WO1999064009A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CA002334606A CA2334606A1 (fr) 1998-06-11 1999-06-08 Utilisation d'un antagoniste du recepteur nk-1 dans le traitement des troubles cognitifs
EP99955426A EP1119358A1 (fr) 1998-06-11 1999-06-08 Utilisation d'un antagoniste du recepteur nk-1 dans le traitement des troubles cognitifs
AU42795/99A AU4279599A (en) 1998-06-11 1999-06-08 Use of an nk-1 receptor antagonist for treating cognitive disorders

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9812662.6 1998-06-11
GBGB9812662.6A GB9812662D0 (en) 1998-06-11 1998-06-11 Therapeutic use

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WO1999064009A1 true WO1999064009A1 (fr) 1999-12-16

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EP (1) EP1119358A1 (fr)
AU (1) AU4279599A (fr)
CA (1) CA2334606A1 (fr)
GB (1) GB9812662D0 (fr)
WO (1) WO1999064009A1 (fr)

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WO2001052844A1 (fr) * 2000-01-18 2001-07-26 F. Hoffmann-La Roche Ag Methode de traitement de lesion cerebrale et spinale et de deficit neurologique
WO2002016343A1 (fr) * 2000-08-22 2002-02-28 Merck Sharp & Dohme Limited Derives tetrahydropyranes en tant qu'antagonistes de recepteur nk-1
WO2004018441A1 (fr) * 2002-08-23 2004-03-04 Eli Lilly And Company Derives de morpholine arylee et heteroarylee
US7384941B2 (en) 2002-08-23 2008-06-10 Eli Lilly And Company 2-(phenoxymethyl)-and 2-(phenylthiomethyl)-morpholine derivatives for use as selective norepinephrine reuptake inhibitors

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WO1996024353A1 (fr) * 1995-02-10 1996-08-15 Eli Lilly And Company Procede de traitement ou de prevention de troubles psychiatriques
WO1996029328A1 (fr) * 1995-03-18 1996-09-26 Merck Sharp & Dohme Limited Derives de la morpholine, compositions les contenant et leur utilisation comme agents therapeutiques
WO1996029326A1 (fr) * 1995-03-21 1996-09-26 Glaxo Group Limited 3-benzylamino-2-phenylpiperidines en tant qu'antagonistes de neurokinine
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WO1998013369A1 (fr) * 1996-09-25 1998-04-02 Merck Sharp & Dohme Limited Derives spiro-azacycliques, preparation de ces derives et leur utilisation comme antagonistes de la tachykinine
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WO1999007375A1 (fr) * 1997-08-04 1999-02-18 Merck Sharp & Dohme Limited Utilisation d'antagonistes du recepteur nk-1 pour le traitement de troubles du comportement agressifs
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Cited By (15)

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US6841551B2 (en) 2000-01-18 2005-01-11 Hoffmann-La Roche Inc. Brain, spinal, and nerve injury treatment
JP4794794B2 (ja) * 2000-01-18 2011-10-19 エフ．ホフマン−ラ ロシュ アーゲー 脳、脊髄および神経損傷の治療
JP2003520232A (ja) * 2000-01-18 2003-07-02 エフ．ホフマン−ラ ロシュ アーゲー 脳、脊髄および神経損傷の治療
KR100780119B1 (ko) * 2000-01-18 2007-11-27 에프. 호프만-라 로슈 아게 뇌, 척수 및 신경 손상 치료
EP1261335A4 (fr) * 2000-01-18 2004-09-22 Hoffmann La Roche Methode de traitement de lesion cerebrale et spinale et de deficit neurologique
US10201568B2 (en) 2000-01-18 2019-02-12 Eustralis Pharmaceuticals Limited Brain, spinal, and nerve injury treatment
WO2001052844A1 (fr) * 2000-01-18 2001-07-26 F. Hoffmann-La Roche Ag Methode de traitement de lesion cerebrale et spinale et de deficit neurologique
US9186404B2 (en) 2000-01-18 2015-11-17 Eustralis Pharmaceuticals Limited Brain, spinal and nerve injury treatment
RU2276996C2 (ru) * 2000-01-18 2006-05-27 Ф.Хоффманн-Ля Рош Аг Лечение повреждений головного мозга, спинного мозга и нервов
HRP20020593B1 (en) * 2000-01-18 2011-03-31 F. Hoffmann - La Roche Ag Brain, spinal and nerve injury treatment
WO2002016344A1 (fr) * 2000-08-22 2002-02-28 Merck Sharp & Dohme Limited Derives de tetrahydropyrane utilises comme antagonistes du recepteur de nk-1
WO2002016343A1 (fr) * 2000-08-22 2002-02-28 Merck Sharp & Dohme Limited Derives tetrahydropyranes en tant qu'antagonistes de recepteur nk-1
WO2004018441A1 (fr) * 2002-08-23 2004-03-04 Eli Lilly And Company Derives de morpholine arylee et heteroarylee
US7354920B2 (en) 2002-08-23 2008-04-08 Eli Lilly And Company Aryl and heteroaryl morpholine derivatives
US7384941B2 (en) 2002-08-23 2008-06-10 Eli Lilly And Company 2-(phenoxymethyl)-and 2-(phenylthiomethyl)-morpholine derivatives for use as selective norepinephrine reuptake inhibitors

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AU4279599A (en) 1999-12-30
EP1119358A1 (fr) 2001-08-01
GB9812662D0 (en) 1998-08-12
CA2334606A1 (fr) 1999-12-16

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