WO2001034172A2 - Procedes et compositions pour traiter un syndrome d'insatisfaction - Google Patents

Procedes et compositions pour traiter un syndrome d'insatisfaction Download PDF

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Publication number
WO2001034172A2
WO2001034172A2 PCT/US2000/030312 US0030312W WO0134172A2 WO 2001034172 A2 WO2001034172 A2 WO 2001034172A2 US 0030312 W US0030312 W US 0030312W WO 0134172 A2 WO0134172 A2 WO 0134172A2
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WO
WIPO (PCT)
Prior art keywords
selegiline
maob
rds
administered
mgs
Prior art date
Application number
PCT/US2000/030312
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English (en)
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WO2001034172A3 (fr
Inventor
Gregory M. Sullivan
Original Assignee
Vela Pharmaceuticals Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Vela Pharmaceuticals Inc. filed Critical Vela Pharmaceuticals Inc.
Priority to AU13598/01A priority Critical patent/AU1359801A/en
Publication of WO2001034172A2 publication Critical patent/WO2001034172A2/fr
Publication of WO2001034172A3 publication Critical patent/WO2001034172A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to methods for treating Reward Deficiency Syndrome by using a therapeutically effective amount of a monoamine oxidase B inhibitor.
  • the present invention also relates to compositions for treating Reward Deficiency Syndrome comprising selegilme in very low dose.
  • Monoamine oxidases are iron containing enzymes that exist as two isozymes A (MAOA) and B (MAOB) .
  • Monoamine oxidases generate hydroxy radicals which may be involved in neurodegenerative disorders such as Parkinson's Disease.
  • MAOA is thought to be primarily involved m the deammation of serotonin, epinephnne, norepinephnne and tyramme.
  • MAOB is thought to be primarily involved m the deammation of dopamme and ⁇ -phenylethylamme .
  • MAOB inhibitors known m the art are selegilme (Jumex ⁇ , Jumexal® Carbex®, Eldepryl®, Movergan®; Aptapryl®, Anipryl®; Eldeprme®; Plurimen®) , desmethylselegil e, paragylme (Eudatm®, Supirdyl®, Eutonyl®) [U.S. patent
  • Selegilme also known as 1-deprenyl
  • the smallest dosage forms of selegilme on the market is believed to be 5mg tablets or capsules, which are not scored (i.e., Carbex®) .
  • the pharmacokmetics and pharmacodynamics of selegilme have been reported (e.g., Mahmood I, Clinical Pharmacokmet . 33:91-102 (1997)).
  • Methods for preparing selegilme are known the art (e.g., J.S. Fowler, J. Or ⁇ . Chem. 42:2637 (1977); U.S. patent 4,564,706) .
  • United States patent 4,868,218 proposes the transdermal administration of selegilme in an amount of 5mgs to 50mgs per day for the treatment of depression.
  • no clinical data is provided.
  • Subsequent clinical studies have shown that oral administration of less than lOmgs/day is not effective at treating depression whereas administration of greater than lOmgs/day of selegilme is effective for treating depression (e.g., Kuhn, W., et al . , J. Neural. Transm. Suppl ⁇ 48:85-93 (1996)).
  • Reward Deficiency Syndrome is a disorder first described by Blum and co-workers as a form of sensory deprivation of the brain' s pleasure mechanisms. [Blum, K., et al . , "Reward Deficiency Syndrome, " American Scientist, (March-April 1996) ] Subsequent studies have proposed that RDS has a biochemical basis that manifests as an inability to derive reward from ordinary, everyday activities. Id. Patients suffering from RDS may also suffer from impulsive, compulsive or addictive disorders such as severe alcoholism, Tourette' s Syndrome and Attention- Deficit Disorder. However, not all patients suffering from these impulsive, compulsive or addictive disorders also suffer from RDS.
  • D 2 dopamine D2 receptor
  • an object of this invention is to provide a method for treating RDS by administering an amount of MAOB-I necessary to inhibit MAOB but cause little or reduced inhibition of MAOA activity.
  • the MAOB-I is selegilme administered in an amount of lOmgs/day or less per day. In a preferred embodiment, selegilme is administered in an amount of less than lOmgs/day.
  • Another object of this invention is to provide a composition comprising selegilme for treating RDS, which is better suited for treating RDS than the currently available dosage forms.
  • a selegilme composition of this invention would be prepared as a single unit comprising less than 2.5 mg of selegilme or as a unit that is pre-prepared into separable portions, each portion of which comprises less than 2.5 mg of selegilme, such that selegilme may be administered accurately and quantitatively to patients in the low dosages necessary to treat RDS.
  • An advantage of this composition is that a practitioner may be better able to determine the appropriate dosage regimen for a patient.
  • a MAOB inhibitor according to this invention is a compound that inhibits MAOB but causes much less or no inhibition of MAOA activity or a compound that selectively inhibits MAOB (e.g., within a particular dosage range) .
  • the activity of a MAOB inhibitor as used according to this invention will be referred to as "selective MAOB-I activity.”
  • the MAOB inhibitor is selected from the group consisting of selegilme, desmethylselegilme, paragylme, rasagilme [R (+ ) N-propargyl-lammomdan] , 3-N-phenylacetylammo-2, 5-p ⁇ pe ⁇ dmed ⁇ one and caroxyazone.
  • the MAOB inhibitor is a derivative or metabolite of selegilme, desmethylselegilme, paragylme, rasagilme [R(+)N- propargyl-la momdan] , 3-N-phenylacetylammo-2, 5- pipe ⁇ dmedione and caroxyazone.
  • Said derivative or metabolite should have substantially the same or better selective MAOB-I activity as its unde ⁇ vatized or unmetabolized form.
  • a MAOB inhibitor of this invention, including selegilme, pargylme, or a derivative or metabolite thereof, as used herein may be administered m the form of a prodrug, i.e., drugs that are metabolized m vivo into the active agent.
  • Prodrugs useful according to this invention have substantially the same selective MAOB-I activity or better than the non-prodrug form.
  • Methods for making prodrugs are readily known m the art (e.g., Balant, L.P., "Prodrugs for the Improvement of Drug Absorption Via Different Routes of Administration, " Eur . J. Drug Metab. Pharmacokmet . 15:143-153 (1990); and Bundgaard, H., “Novel Chemical Approaches m Prodrug Design, " Drugs of the Future 16:443-458 (1991); incorporated by reference herein).
  • MAOB inhibitor including selegilme, pargylme, or a derivative or metabolite thereof, as used herein includes pharmaceutically acceptable salts of those compounds and their prodrugs.
  • Pharmaceutically acceptable salts of MAOB-I, selegilme or pargylme useful according to the methods of this invention are salts prepared from pharmaceutically acceptable reagents known m the art.
  • said pharmaceutically acceptable salt is the hydrochloride salt of selegilme or pargylme.
  • MAOB activity should be decreased greater than 80% compared to MAOB enzyme activity before treatment. In a preferred embodiment, MAOB activity is decreased greater than 90% or 95% compared to MAOB activity before treatment.
  • MAOA inhibitory activity may be evaluated by measuring levels of 3-methoxy-4- hydroxyphenylglycol (MHPG) or 5-hydroxymdoleacet ⁇ c acid (5-HIAA) m the plasma of blood or m cerebral spinal fluid (CSF) by using gas chromatography-mass spectroscopy (gc-ms) .
  • MHPG 3-methoxy-4- hydroxyphenylglycol
  • 5-HIAA 5-hydroxymdoleacet ⁇ c acid
  • CSF m cerebral spinal fluid
  • plasma MHPG levels should not be reduced lower than 45% of pretreatment levels of plasma MHPG.
  • plasma MHPG or CSF 5-HIAA levels should not be reduced more than 80% of pretreatment levels of MHPG or 5-HIAA levels, respectively.
  • MAOB inhibitors for use in this invention may be prepared as a composition comprising a therapeutically effective amount of MAOB inhibitor and a pharmaceutically acceptable carrier.
  • a preferred composition according the present invention comprises a pharmaceutically acceptable carrier together with less than 2.5 mg of selegilme or a prodrug thereof, formulated into a single unit, or a unit that is pre-prepared into separable portions (hereinafter, "separable composition"), each portion of which comprises less than 2.5 gs of seleglme or a prodrug thereof.
  • the composition or each portion of the separable composition comprises less than 2.5 mgs of seleglme or a prodrug thereof.
  • the composition or each portion of the separable composition comprises less than or equal to 2 mg or 1 mg of seleglme or a prodrug thereof.
  • a separable composition is a scored tablet.
  • a composition according the present invention may further comprise another therapeutic agent.
  • the therapeutic agent is a benzodiazepme .
  • Benzodiazepmes useful according to this invention include chlordiazepoxide, clorazepate, diazepam, flurazepam, halazepam, prazepam, alprazolam, clonazepam, flunitrazepam, lorazepam, midazolam, oxazepam, quazepam, temazepam, and triazolam.
  • Said therapeutic agents may be administered according to methods of this invention before, during or after the administration of the MAOB inhibitor.
  • RDS Reward Deficiency Syndrome
  • RDS is a chronic and pervasive inability or deficient ability to experience pleasure and/or comfort from ordinary daily activities that are generally emotionally-rewarding m nature.
  • patients suffering from RDS typically complain of two or more, if not all of the following: lack of satisfaction or enjoyment from work, lack of satisfaction or enjoyment from social interaction with friends or family, and lack of satisfaction or enjoyment from hobbies and interests.
  • Individuals suffering soley from an inability to work or socialize, often associated with depression, should not be confused with RDS patients who are unable to obtain or have a reduced capacity to obtain pleasure from activities.
  • An RDS patient will have experienced RDS throughout his/her life, but usually acknowledges the severity of some of the symptoms of RDS as early as puberty.
  • RDS patient One hallmark of an RDS patient is the inability to complete projects or hobbies. As a result of this inability or deficient ability, the patient may feel uncomfortable, anxious, angry, depressed and/or crave the ability to experience reward and pleasure. However, a patient suffering from any one of those emotions may not necessarily suffer from RDS. Behavior symptoms that an RDS patient may experience include:
  • ADHD Alzheimer's disease impulsive symptom criteria
  • subsyndromal ADHD that includes inattentive and/or impulsive symptom criteria
  • the reward-deprived emotional state may result frequent attempts to experience pleasure, comfort, or relief m ways that may be self-damagmg such as danger/thrill-seekmg behavior involving life threatening activities, damaging activities or illegal activities; compulsive gambling; binge eatmg/overeatmg; addictive behavior (e.g., alcohol, substance use, tobacco use, sexually compulsive behavior); and suicidal ideation and/or attempts.
  • All RDS patients have clinically significant distress or impairment m social, occupational, or other important areas of functioning. However, an individual suffering from any one of those behavioral symptoms or self- damagmg proclivities may not necessarily suffer from RDS.
  • the methods and compositions provided herein are useful for treating RDS or one or more of the symptoms of RDS m a patient suffering from RDS. Accordingly, the methods of this invention are useful for RDS patients who do not also suffer from any one of the following symptoms selected from the group consisting of: depressed mood and/or anhe ⁇ onia, social anxiety, frequent agitation, aggressiveness and/or explosive temper, easy irritability, low frustration tolerance, Attention Deflcit/Hyperactivity Disorder (ADHD) , and subsyndromal ADHD that includes inattentive and/or impulsive symptom criteria, Tourette' s syndrome, compulsive or addictive behavior such as substance abuse or sexually compulsive behavior, self-damagmg behavior and suicidal ideation.
  • a patient according to this invention is a human, including children and adults, suffering from RDS.
  • any suitable route of administration may be employed for providing the patient with an effective dosage of an MAOB-I of this invention.
  • oral, rectal, parenteral, transdermal, subcutaneous, sublmgual, mtranasal, intramuscular, mtrathecal and the like may be employed as appropriate.
  • parenteral as used herein includes subcutaneous, mtracutaneous, intravenous, intramuscular, mtra- articular, mtrasynovial, mtrasternal, mtrathecal, tralesional and mtracranial injection or infusion techniques .
  • Dosage forms include tablets, scored tablets, coated tablets, caplets, capsules (e.g., hard gelatin capsules) , troches, dragees, dispersions, suspensions, solutions, transdermal patches and the like, including sustained release formulations well known in the art.
  • the dosage form is a scored tablet or a transdermal patch.
  • compositions and separable compositions useful according to this invention include those suitable for oral, rectal, transdermal, sublmgual, and parenteral administration (including subcutaneous, intramuscular, mtrathecal and intravenous), and transdermal, although the most suitable route m any given case may depend on the patient and the nature and/or severity of the condition being treated.
  • a preferred route of administration according to the methods of the present invention is the oral route or the transdermal route.
  • the composition may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.
  • the compositions or separable compositions of this invention may be orally administered m any orally acceptable dosage form including, but not limited to, capsules, tablets, and aqueous suspensions and solutions.
  • compositions according to this invention may be m the form of a sterile mjectable preparation, for example, as a sterile mjectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to techniques known m the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
  • the sterile mjectable preparation may also be a sterile mjectable solution or suspension m a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution m 1 , 3-butaned ⁇ ol .
  • the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and lsotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides .
  • Fatty acids such as oleic acid and its glyceride derivatives are useful m the preparation of mjectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially m their polyoxyethylated versions.
  • oils such as olive oil or castor oil, especially m their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant such as Ph. Helv or a similar alcohol.
  • compositions or separable compositions of this invention may also be administered m the form of suppositories for rectal administration.
  • These compositions or separable compositions can be prepared by mixing a compound of this invention w th a suitable non-imtatmg excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt m the rectum to release the active components.
  • suitable non-imtatmg excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt m the rectum to release the active components.
  • Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols .
  • compositions of this invention may be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well- known m the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizmg or dispersing agents known m the art.
  • the magnitude of a prophylactic or therapeutic dose of the active ingredient (i.e., MAOB inhibitor) m the prevention or treatment of a human will vary with the symptoms being exhibited, the severity of the patient's affliction and the route of administration.
  • the dose and dose frequency will also vary according to the age, weight and response of the individual patient.
  • treatment for RDS will be ongoing although the intensity of treatment may vary depending on the patient' s condition and exposure to biochemical and environmental stimuli that may warrant a variation on the treatment.
  • selegilme is given twice a day (bid) , m the morning and late afternoon.
  • the treating physician will know how to increase, decrease or interrupt treatment based upon the patient's response. For example, qualitative determinations of improvement may be assessed by the patient's reports of improved enjoyment or satisfaction of several ordinary activities such as work, social interaction with friends or family, hobbies and interests .
  • a therapeutically effective amount is that amount at which monoamine oxidase B is inhibited but monoamine oxidase A exhibits slight or no reduction m activity m the patient.
  • the dosage of selegilme is an amount equal to or less than lOmgs per day. In a preferred embodiment, selegilme is administered m an amount less than lOmgs/day. In another embodiment, the dosage of pargylme is less than 30 mgs/day.
  • Patient X is a man m his late 40' s who works as a professional. He was m the midst of a divorce from his first and only marriage at the time of his initial visit. He has three children. He presented with depressed mood and suicidal ideation. He described a daily mood pattern of severe depression upon awakening that was severe for about three hours and became less in the late morning. He would often go to his job about an hour late because of this mood. The rest of the day, his mood was improved but was in the depressive range. The patient's suicidal ideation was relatively constant and severe, often including plans that were easy to accomplish. He experienced prominent, generalized anxiety. His sleep was not significantly disturbed, though he had much difficulty getting out of bed in the morning because of his low mood and energy.
  • patient X came to the applicant for treatment. He was initially treated with lithium up to 900mgs/day together with gabapentin up to 32000mg/day and light therapy. The timing of his worst period of depression was moved back by 30 minutes, but the severity of his depression did not decrease. Melatonin was added to his treatment, but it had no effect. The melatonin treatment was discontinued. Applicant next administered bupropion at 37.5 mg bid. However, the patient became agitated, extremely irritable, and had excessive suicidal ideation. The bupropion treatment was rapidly discontinued. Applicant noted the patients' frequent, chronic complaints about the inability to reach destinations without distraction.
  • methylphenidate i.e., Ritalin®
  • the patient experienced improved morning mood (from a depressed to a euthymic state) and experienced new desires. However, during the course of the day, he also experienced rapid and abrupt deteriorations in mood. Further, the positive effects of methylphenidate treatment decreased after the initial weeks of treatment. Applicant decreased the patient's doses of lithium and gabapentin and then discontinued them. Applicant added clonazepam to the treatment. However, the patient experienced no clinical change. Applicant discontinued administering Ritalin®.
  • Patient X has begun to develop a new life. He has a new interest in pursuing love relationships, and he pursues many hobbies and activities that he never considered possible in the past. He has begun an exercise regimen and changed his diet to one that is more nutritious and less caloric thereby allowing him to lose weight. He has not experienced any manic, hypomanic, or agitated behavior during his treatment with selegiline.
  • patient X ran out of selegline and went a few days without it. Within a day or so, he experienced a dramatic return of suicidal ideation and previous mood and anxiety symptoms as well as a loss of the pleasure he had been feeling.

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Abstract

L'invention concerne des procédés et des compositions pour traiter le Syndrome d'insatisfaction (RDS) par une quantité thérapeutiquement efficace d'inhibiteur B mono-amine oxydase. L'invention concerne également des compositions utilisées pour traiter le RDS comportant de la sélégiline à très faible dose.
PCT/US2000/030312 1999-11-05 2000-11-03 Procedes et compositions pour traiter un syndrome d'insatisfaction WO2001034172A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU13598/01A AU1359801A (en) 1999-11-05 2000-11-03 Methods and compositions for treating reward deficiency syndrome

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US16370899P 1999-11-05 1999-11-05
US60/163,708 1999-11-05

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WO2001034172A2 true WO2001034172A2 (fr) 2001-05-17
WO2001034172A3 WO2001034172A3 (fr) 2001-10-25

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Cited By (18)

* Cited by examiner, † Cited by third party
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US6660736B2 (en) 2002-03-27 2003-12-09 Hoffmann-La Roche Inc. Phthalimido derivatives and a process for their preparation
US6762320B2 (en) 2002-05-29 2004-07-13 Hoffman-La Roche Inc. N-acylamino benzyl ether derivatives
US6818774B2 (en) 2002-04-26 2004-11-16 Hoffman-La Roche Inc. Isoquinoline derivatives
US6846832B2 (en) 2002-08-07 2005-01-25 Hoffman-La Roche Inc. 2,3-dihydro-isoindol-1-one derivatives
US6900354B2 (en) 2002-07-15 2005-05-31 Hoffman-La Roche Inc. 3-phenyl-propionamido, 3-phenyl-acrylamido and 3-phenyl-propynamido derivatives
EP1588704A1 (fr) * 2004-04-22 2005-10-26 Newron Pharmaceuticals S.p.A. Dérivés d'alpha-aminoamides utiles dans le traitement de l'acroparesthésie nocturne et des troubles de toxicomanie
US7037935B2 (en) 2002-09-20 2006-05-02 Hoffmann-La Roche Inc. 4-Pyrrolidino-phenyl-benzyl ether derivatives
US7087612B2 (en) 2002-12-13 2006-08-08 Hoffmann-La Roche Inc. 3H-quinazolin-4-one derivatives as MAO-B inhibitors
US7148362B2 (en) 2003-09-18 2006-12-12 Hoffmann-La Roche Inc. Process for the preparation of enantiopure pyrrolidin-2-one derivatives
US7173023B2 (en) 2003-10-23 2007-02-06 Hoffmann-La Roche Inc. Bicyclic compounds
US7253318B2 (en) 2004-06-23 2007-08-07 Hoffman-La Roche Inc. Benzyloxy derivatives as MAOB inhibitors
US7456210B2 (en) 2004-08-02 2008-11-25 Hoffmann-La Roche Inc. Benzyloxy derivatives
EP2011488A1 (fr) * 2006-03-06 2009-01-07 Chongqing Pharmaceutical Research Institute Co., Ltd. Timbre transdermique contenant de la rasagiline utilise dans le traitement ou la prevention de maladies du systeme nerveux et procede de preparation associe
US7485731B2 (en) 2005-03-15 2009-02-03 Hoffmann-La Roche Inc. Method for preparing enantiomerically pure 4-pyrrolidinophenylbenzyl ether derivatives
US7501528B2 (en) 2005-03-15 2009-03-10 Hoffmann-La Roche Inc. Method for preparing enantiomerically pure 4-pyrrolidino phenylbenzyl ether derivatives
US8595055B2 (en) 2001-03-27 2013-11-26 Points.Com Apparatus and method of facilitating the exchange of points between selected entities
EP3230255A4 (fr) * 2014-12-09 2018-08-01 Ezekiel Golan Régulateurs du comportement de consommation compulsive
EP3230256A4 (fr) * 2014-12-09 2018-08-01 Ezekiel Golan Substituts de boissons alcoolisées

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US5721258A (en) * 1993-08-17 1998-02-24 Asta Medica Aktiengesellschaft Primary and secondary neuroprotective effect of flupirtine in neurodegenerative diseases

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US8595055B2 (en) 2001-03-27 2013-11-26 Points.Com Apparatus and method of facilitating the exchange of points between selected entities
US6903095B2 (en) 2002-03-27 2005-06-07 Hoffmann-La Roche Inc. Phthalimido derivatives and a process for their preparation
US6660736B2 (en) 2002-03-27 2003-12-09 Hoffmann-La Roche Inc. Phthalimido derivatives and a process for their preparation
US6818774B2 (en) 2002-04-26 2004-11-16 Hoffman-La Roche Inc. Isoquinoline derivatives
US7053245B2 (en) 2002-05-29 2006-05-30 Hoffmann-La Roche Inc. N-acylamino benzyl ether derivatives
US6762320B2 (en) 2002-05-29 2004-07-13 Hoffman-La Roche Inc. N-acylamino benzyl ether derivatives
US6900354B2 (en) 2002-07-15 2005-05-31 Hoffman-La Roche Inc. 3-phenyl-propionamido, 3-phenyl-acrylamido and 3-phenyl-propynamido derivatives
US6846832B2 (en) 2002-08-07 2005-01-25 Hoffman-La Roche Inc. 2,3-dihydro-isoindol-1-one derivatives
US7037935B2 (en) 2002-09-20 2006-05-02 Hoffmann-La Roche Inc. 4-Pyrrolidino-phenyl-benzyl ether derivatives
US7235581B2 (en) 2002-09-20 2007-06-26 Hoffman-La Roche Inc. 4-pyrrolidino-phenyl-benzyl ether derivatives
US7122562B2 (en) 2002-09-20 2006-10-17 Hoffmann-La Roche Inc. 4-pyrrolidino-phenyl-benzyl ether derivatives
US7151111B2 (en) 2002-09-20 2006-12-19 Hoffmann-La Roche Inc. 4-pyrrolidino-phenyl-benzyl ether derivatives
US7087612B2 (en) 2002-12-13 2006-08-08 Hoffmann-La Roche Inc. 3H-quinazolin-4-one derivatives as MAO-B inhibitors
US7148362B2 (en) 2003-09-18 2006-12-12 Hoffmann-La Roche Inc. Process for the preparation of enantiopure pyrrolidin-2-one derivatives
US7173023B2 (en) 2003-10-23 2007-02-06 Hoffmann-La Roche Inc. Bicyclic compounds
US8445513B2 (en) 2004-04-22 2013-05-21 Newron Pharmaceuticals S.P.A. α-Aminoamide derivatives useful in the treatment of restless legs syndrome
NO338870B1 (no) * 2004-04-22 2016-10-31 Newron Pharm Spa Alfa-aminoamidderivater nyttige i behandlingen av addiktive forstyrrelser
JP2007533691A (ja) * 2004-04-22 2007-11-22 ニューロン・ファーマシューティカルズ・ソチエタ・ペル・アチオニ 下肢静止不能症候群および嗜癖障害の処置に有用なα−アミノアミド誘導体
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