EP2807149A2 - Agents pour le traitement de troubles neurodégénératifs - Google Patents

Agents pour le traitement de troubles neurodégénératifs

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Publication number
EP2807149A2
EP2807149A2 EP13722815.1A EP13722815A EP2807149A2 EP 2807149 A2 EP2807149 A2 EP 2807149A2 EP 13722815 A EP13722815 A EP 13722815A EP 2807149 A2 EP2807149 A2 EP 2807149A2
Authority
EP
European Patent Office
Prior art keywords
disorder
syndrome
disease
disorders
medical condition
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.)
Withdrawn
Application number
EP13722815.1A
Other languages
German (de)
English (en)
Inventor
Nina N. MAKHOVA
Vera Y. PETUKHOVA
Alexander V. SHEVTSOV
Vladimir V. NOVAKOVSKIY
Vladimir Vladimirovich KUZNETSOV
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.)
CRO Consulting Ltd
Original Assignee
CRO Consulting Ltd
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Filing date
Publication date
Application filed by CRO Consulting Ltd filed Critical CRO Consulting Ltd
Publication of EP2807149A2 publication Critical patent/EP2807149A2/fr
Withdrawn legal-status Critical Current

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D229/00—Heterocyclic compounds containing rings of less than five members having two nitrogen atoms as the only ring hetero atoms
    • C07D229/02—Heterocyclic compounds containing rings of less than five members having two nitrogen atoms as the only ring hetero atoms containing three-membered 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
    • A61K31/396—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having three-membered rings, e.g. aziridine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular 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
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to compounds of formula I, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, their use for the treatment of mental disorders, especially different depressions.
  • a neurological disorder is a disorder of the body's nervous system. Structural, biochemical or electrical abnormalities in the brain, spinal cord, or in the nerves leading to or from them, can result in symptoms such as paralysis, muscle weakness, poor coordination, loss of sensation, seizures, confusion, pain and altered levels of consciousness.
  • neurological disorders Some relatively common, but many rare. They may be revealed by neurological examination and studied and treated within the specialities of neurology and clinical neuropsychology. Interventions include preventative measures, lifestyle changes, physiotherapy or other therapy, neurorehabilitation, pain management, medication, or operations performed by neurosurgeons.
  • the World Health Organization estimated in 2006 that neurological disorders and their sequelae affect as many as one billion people worldwide, and identified health inequalities and social stigma/discrimination as major factors contributing to the associated disability and suffering.
  • a mental disorder or mental illness is a psychological or behavioral pattern that is generally associated with distress or disability, which is not considered part of normal development or the person's culture. Such disorders are defined by a combination of affective, behavioral, cognitive or perceptual components, which may be associated with particular functions or regions of the brain or nervous system, often in a social context. The recognition and understanding of mental health conditions have changed over time and across cultures, and there are still variations in definition, assessment and classification, although standard guideline criteria are widely used. Over a third of people in most countries report problems at some time in their life which meet criteria for diagnosis of one or more of the common types of mental disorder.
  • Antidepressants are used for the treatment of clinical depression, as well as often for anxiety and a range of other disorders.
  • Anxiolytics including sedatives are used for anxiety disorders and related problems such as insomnia.
  • Mood stabilizers are used primarily in bipolar disorder.
  • Antipsychotics are used for psychotic disorders, notably for positive symptoms in schizophrenia, and also increasingly for a range of other disorders. Stimulants are commonly used, notably for ADHD.
  • the present invention relates to compounds of formula I, use of these compounds to treat mental and neurological disorders, especially depressions and psychoses of different etiology.
  • the compounds provided for the treatment of mental and neurological disorders are presented by a general formula I:
  • R and R' is independently from each other selected from hydrogen, alkyl, haloalkyl, alkoxy, aminoalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, arylalkyl, cycloalkylalkyl, heterocyclylalkyl, heteroarylalkyl, COR 1 , COOR 1 , CONHR 1 , CON(R 1 ) 2 , OR 1 , NR !
  • R 2 N(R 1 ) 2 , SR 1 , NR 1 -S0 2 -R 2 , NR 1 -S0 2 -NR 2 R 3 , NR 1 - CO-NR 2 R 3 , -SO-R 1 , -S0 2 -R 1 , - O-COO-R 1 , -CSR 1 , -C(S)NR 1 R 2 , -SR 1 ,
  • R 1 , R 2 , R 3 is independently selected from hydrogen, amino, alkyl, haloalkyl, alkoxy, aminoalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, arylalkyl, cycloalkylalkyl, heterocyclylalkyl, heteroarylalkyl, wherein each member of R 1 , R 2 , R 3 is optionally substituted,
  • R and R' attached to the same carbon can be taken together with the carbon to which they are attached to form a cycle selected from cycloalkylene, heterocycloalkylene, which can be optionally unsaturated, wherein mentioned cycloalkylene, heterocycloalkylene, is optionally substituted, said cycloalkylene or heterocycloalkylene may be fused to another cycle or cycles,
  • Y is hydrogen, halogen or any isotope of hydrogen, preferably hydrogen, with proviso that if the compounds of general formula I contain 2 or more diaziridine (1,2-diazacyclopropane) rings (cycles) so all said diaziridine (1,2- diazacyclopropane) rings (cycles) are unsubstituted at both of the nitrogen atoms.
  • Compounds of formula I show high antidepressant and neuroprotective activity comparable to known antidepressant drugs. They have a low acute and chronic toxicity compared to known antidepressants, do not produce pathological changes of any internal, hematological and biochemical parameters, and are therefore in long-term application.
  • Novel class of compounds I makes beneficial their use for treatment of patients resistant to therapy by standard neuroprotective agents, including patients resistant to standard antidepressants.
  • This invention also relates to of psychotic and mental disorder of different etiology, including anxiety disorders, adjustment disorders, eating disorders, personality disorders, mood disorders, somatoform disorders, personality disorders, sleep disorders, dyssomnias, psychotic disorders, eating disorders, somatoform disorders, dissociative disorders, sexual disorders, sexual dysfunctions, gender identity disorders, impulse disorders, somatoform disorders, mood disorders, eating disorders, impulse-control disorders.
  • psychotic and mental disorder of different etiology including anxiety disorders, adjustment disorders, eating disorders, personality disorders, mood disorders, somatoform disorders, personality disorders, sleep disorders, dyssomnias, psychotic disorders, eating disorders, somatoform disorders, dissociative disorders, sexual disorders, sexual dysfunctions, gender identity disorders, impulse disorders, somatoform disorders, mood disorders, eating disorders, impulse-control disorders.
  • Compounds of Formula I may also be used for treatment of acute stress disorder, unspecified adjustment disorder, adjustment disorder with anxiety, adjustment disorder with depressed mood, adjustment disorder with disturbance of conduct, adjustment disorder with mixed anxiety and depressed mood, adjustment disorder with mixed disturbance of emotions and conduct, agoraphobia without history of panic disorder, anorexia, anorexia nervosa, antisocial personality disorder, anxiety disorder due to medical condition, anxiety disorder,, avoidant personality disorder, bipolar disorder, bipolar I disorder in full remission, bipolar I disorder in partial remission, mild bipolar I disorder, moderate bipolar I disorder, severe with psychotic features bipolar I disorder, severe without psychotic features bipolar I disorder, bipolar Ii disorder, body dysmorphic disorder, borderline personality disorder, breathing-related sleep disorder, brief psychotic disorder, bulimia nervosa, cannabis compound abuse, circadian rhythm sleep disorder, conversion disorder, cyclothymic disorder, childhood disorders, cognitive disorders, delusional disorder, dependent personality disorder, depersonalization disorder, depression of different etiology, particularly me
  • Compounds of Formula I are also related to treatment of neurological disorder of different etiology. For example abarognosis, acquired epileptiform aphasia, acute disseminated encephalomyelitis, adrenoleukodystrophy, agenesis of the corpus callosum, agnosia, aicardi syndrome, akathisia, Alexander disease, Alien Hand syndrome, allochiria, Alpers' disease, alternating hemiplegia, Alzheimer's disease, amyotrophic lateral sclerosis, anencephaly, Angelman syndrome, angiomatosis, anoxia, aphasia, apraxia, arachnoid cysts, arachnoiditis, Arnold-Chiari malformation, arteriovenous malformation, ataxia telangiectasia, attention deficit hyperactivity disorder, auditory processing disorder, autonomic dysfunction, back pain, Batten disease, Behcet's disease, Bell's palsy,
  • the present invention relates to compounds of formula I for treatment of neurological and mental conditions.
  • the invention also relates to methods for the preparation of compounds of formula I. BRIEF DESCRIPTION OF THE DRAWINGS
  • Figure 1 illustrates the structure of Compound 2 as determined by X-ray diffraction analysis.
  • Figure 2 illustrates an X-ray diffraction pattern for Compound 2.
  • Figure 3 illustrates an X-ray diffraction pattern for Compound 3.
  • Figure 4 illustrates an X-ray diffraction pattern for Compound 5.
  • the compounds of the formula I have a basic nature and are capable of forming a wide variety of different salts with various inorganic and organic acids.
  • the acids that can be used to prepare the pharmaceutically acceptable salts are those which form nontoxic salts, e.g. salts containing pharmaceutically acceptable anions, such as phosphates, acetates, oxalates, succinates, maleates, benzoates, etc.
  • the compounds of the formula I and their pharmaceutically acceptable salts are useful for the treatment of This invention also relates to of psychotic and mental disorder of different etiology, including anxiety disorders, adjustment disorders, eating disorders, personality disorders, mood disorders, somatoform disorders, personality disorders, sleep disorders, dyssomnias, psychotic disorders, eating disorders, somatoform disorders, dissociative disorders, sexual disorders, sexual dysfunctions, gender identity disorders, impulse disorders, somatoform disorders, mood disorders, eating disorders, impulse-control disorders.
  • Compounds of Formula I may also be used for treatment of acute stress disorder, unspecified adjustment disorder, adjustment disorder with anxiety, adjustment disorder with depressed mood, adjustment disorder with disturbance of conduct, adjustment disorder with mixed anxiety and depressed mood, adjustment disorder with mixed disturbance of emotions and conduct, agoraphobia without history of panic disorder, anorexia, anorexia nervosa, antisocial personality disorder, anxiety disorder due to medical condition, anxiety disorder,, avoidant personality disorder, bipolar disorder, bipolar I disorder in full remission, bipolar I disorder in partial remission, mild bipolar I disorder, moderate bipolar I disorder, severe with psychotic features bipolar I disorder, severe without psychotic features bipolar I disorder, bipolar Ii disorder, body dysmorphic disorder, borderline personality disorder, breathing-related sleep disorder, brief psychotic disorder, bulimia nervosa, cannabis compound abuse, circadian rhythm sleep disorder, conversion disorder, cyclothymic disorder, childhood disorders, cognitive disorders, delusional disorder, dependent personality disorder, depersonalization disorder, depression of different etiology, particularly me
  • Compounds of Formula I are also related to treatment of neurological disorder of different etiology. For example abarognosis, acquired epileptiform aphasia, acute disseminated encephalomyelitis, adrenoleukodystrophy, agenesis of the corpus callosum, agnosia, aicardi syndrome, akathisia, Alexander disease, Alien Hand syndrome, allochiria, Alpers' disease, alternating hemiplegia, Alzheimer's disease, amyotrophic lateral sclerosis, anencephaly, Angelman syndrome, angiomatosis, anoxia, aphasia, apraxia, arachnoid cysts, arachnoiditis, Arnold-Chiari malformation, arteriovenous malformation, ataxia telangiectasia, attention deficit hyperactivity disorder, auditory processing disorder, autonomic dysfunction, back pain, Batten disease, Behcet's disease, Bell's palsy,
  • the compounds of Formula I have rather promising antidepressive, antipsychotic, antiamnesic activity and can be accompanied for treatment of variety of neurological and mental conditions.
  • the compounds I may be useful for treatment of patients resistant to therapy by the standard neuroprotective medications.
  • compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers.
  • the active compounds of formula I may be formulated for oral, buccal, intransal, parenteral (e.g. intravenous, intramuscular or subcutaneous) or rectal.
  • Carrier means one or more compatible substances that are suitable for administration to a mammal.
  • Carrier includes solid or liquid fillers, diluents, hydrotopes, surface-active agents, and encapsulating substances.
  • “Compatible” means that the components of the composition are capable of being commingled with the diaziridine compounds represented by structural formula I, and with each other, in a manner such that there is no interaction which would substantially reduce the efficacy of the composition under ordinary use situations.
  • Carriers must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the mammal being treated.
  • the carrier can be inert, or it can possess pharmaceutical benefits, cosmetic benefits, or both.
  • composition may be in a variety of forms, suitable, for example, for systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, or parenteral).
  • systemic administration e.g., oral, rectal, nasal, sublingual, buccal, or parenteral.
  • each component in the pharmaceutical composition depends on various factors.
  • the amount of the diaziridine compound represented by structural formula I depends on the binding affinity (IC50) of the medicament selected.
  • the amount of the carrier employed in conjunction with the medicament is sufficient to provide a practical quantity of material for administration per unit dose of the compound.
  • Techniques and compositions for making dosage forms useful in the methods of this invention are described in the following references: Modern Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd Ed., (1976), the entirety of each of which are incorporated herein in their entirety by reference for showing techniques and compositions of dosage forms.
  • Applicable solid carriers can include, without limitation, one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders, tablet-disintegrating agents, or encapsulating materials.
  • the carrier may be a finely divided solid that may be in admixture with the finely divided active ingredient.
  • the active ingredient may be mixed with a carrier having suitable compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets may contain up to about 99% of the active ingredient.
  • Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes, and ion exchange resins. Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups, and elixirs.
  • the active ingredient of this invention may be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both, or pharmaceutically acceptable oils or fats.
  • a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both, or pharmaceutically acceptable oils or fats.
  • the liquid carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, or osmo-regulators.
  • liquid carriers for oral and parenteral administration include water (particularly containing additives as above, e.g., cellulose derivatives such as, without limitation, a sodium carboxymethyl cellulose solution), alcohols (including, without limitation, monohydric alcohols and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., without limitation, fractionated coconut oil and arachis oil).
  • additives e.g., cellulose derivatives such as, without limitation, a sodium carboxymethyl cellulose solution
  • alcohols including, without limitation, monohydric alcohols and polyhydric alcohols, e.g., glycols
  • oils e.g., without limitation, fractionated coconut oil and arachis oil.
  • the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. Liquid pharmaceutical compositions that are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal, or subcutaneous injection. Sterile solutions can also be administered intravenously.
  • Oral administration may be either in liquid or solid composition form.
  • the pharmaceutical compositions containing the present compounds are in unit dosage form, e.g., as tablets or capsules.
  • the composition may be subdivided in unit dosages containing appropriate quantities of the active ingredients.
  • the unit dosage forms can be packaged compositions, for example, packaged powders, vials, ampoules, prefilled syringes or sachets containing liquids.
  • the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
  • the therapeutically effective dosage to be used may be varied or adjusted by the physician and generally ranges from about 0.5 mg to about 750 mg, according to the specific condition(s) being treated and the size, age, and response pattern of the patient.
  • An effective amount of a compound according to the present invention will vary with the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of treatment, the nature of concurrent therapy, the route of administration, the particular pharmaceutically- acceptable carrier utilized, and like factors within the knowledge and expertise of the attending physician.
  • the compounds of the present invention may be administered to patients at a dosage of from about 0.7 to about 7000 mg per day, particularly about 1.0 to about 1000 mg. For example, for a normal human adult with a body weight of approximately 70 kg, the administration amount is translated into a daily dose of about 0.01 to about 100 mg per kg of body weight.
  • the specific dosage employed, however, may vary depending upon the requirements of the patient, the severity of the patient's condition, and the activity of the compound.
  • optimum dosages for a particular situation may be clinically determined and is within the level of skill of one or ordinary skill in the art. While these dosages are based upon a daily administration rate, the compounds of the present invention may also be administered at other intervals, such as twice per day, twice weekly, once weekly, or once a month. One of ordinary skill in the art would be able to calculate suitable effective amounts for other intervals of administration.
  • the exact amounts of each component in the pharmaceutical composition depend on various factors.
  • the amount of the diaziridine compound added to the pharmaceutical composition is dependent on the IC50 of the compound, typically expressed in nanomolar (nM) units. For example, if the IC50 of the medicament is 1 nM, the amount of the diaziridine compound will be from about 0.001 to about 0.3%. If the IC50 of the medicament is 10 mM, the amount of the diaziridine compound will be from about 0.01 to about 1%. If the IC50 of the medicament is 100 nM, the amount of the diaziridine compound will be from about 0.1 to about 10%.
  • the amount of the diaziridine compound will be 1 to 100%, preferably 5% to 50%. If the amount of the diaziridine compound is outside the ranges specified above (i.e., lower), efficacy of the treatment may be reduced.
  • the remainder of the composition up to approximately 100%, may be a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such a binding agents (e.g.
  • Formulations for injection may be prepared in unit dosage form, e.g. in ampoules or in multi-dose containers, with an added preservative.
  • anhydrous acid used for the preparation of the compound of formula I include, without limitation, hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, benzoic acid, citric acid, malonic acid, salicylic acid, malic acid, fumaric acid, oxalic acid, succinic acid, tartaric acid, lactic acid, gluconic acid, ascorbic acid, maleic acid, aspartic acid, benzene sulfonic acid, methane sulfonic acid, ethane sulfonic acid, hydroxymethane sulfonic acid, hydroxyethane sulfonic acid, and the like.
  • hydrochloric acid sulfuric acid, phosphoric acid, acetic acid, benzoic acid, citric acid, malonic acid, salicylic acid, malic acid, fumaric acid, oxalic acid, succinic acid, tartaric acid, lactic acid, gluconic acid, ascorbic acid, maleic acid, aspartic
  • Liquid N3 ⁇ 4 (50 ml) was added to a stirred solution of 11.2 g (0.1 mol) of 4- methylcyclohexanon in 250 ml MeOH cooled to -30° by means of a Dry Ice-Me2CO bath, a suspension of 15 g. of 95% hydroxylamine-O-sulfonic acid was added over 30 min, the mixture was stirred 4 hrs. at -30°. The cooling bath was removed, the mixture stirred 18 hrs.
  • the compounds formula I were prepared from N-chloroketimines and N3 ⁇ 4 in an ale. solvent.
  • a solution of lmol (132 g) cyclohexyl-N-chloroketimine in 300 ml of MeOH was saturated with N3 ⁇ 4 at 0° C and the mixture kept in a closed vessel overnight and worked up to yield 95 g (85%) 3,3-pentamethylene-l,2-diazacyclopropane (compound 3), m.p. 104-5° (cyclohexane).
  • 3 -Hexyl-3 -methyl- 1 ,2-diazacyclopropane (compound 7) was prepared by saturated of a solution of 162 g (1 mol) 2-octyl-N-chloroketimine in 400 ml iso-PrOH with N3 ⁇ 4 at -10° and the mixture heated in a closed vessel 5 hrs. at 50° C and worked up to yield 1 19 g (83%) compound 7 as undistilled oil.
  • Compound 3 was also prepared by chlorination of a solution of 92 g (0,93 mol) cyclohexylamine and 190 g NaHC0 3 in 1500 ml H 2 0 at 0-5° with 150 g Cl 2 .
  • mice 25-28 g were treated intraperitoneally according to procedure described below.
  • the animals were divided into two groups and treated as follows.
  • the mice of first group were used as controls. They were injected intraperitoneally with distilled water 40 minutes before the experiment.
  • Second group was treated with Compound of Example 3 (3,3-pentamethylene-l,2-diazacyclopropane) i.p. at dose 70 mg/kg 40 minutes before the experiment.
  • the antidepressant activity was assessed by estimating immobility time as a period in which animal remains immobile during swimming (see table 1). Statistical data processing was performed using "BioStat” tool for Windows. Table 1
  • Antipsychotic activity assessed using apomorphine verticalisation model assessed using apomorphine verticalisation model.
  • mice White male mice (23-28 g) were used to investigate biological activity. Verticalisation was induced by administration of apomorphine (5 mg/kg, s.c.) to mouse. This test, described by Protais et al (Psychopharmacologie, 1976, 50, 1-6) allows the evaluation of the dopaminergic antagonist activity of possible antipsychotic products.
  • apomorphine 5 mg/kg, s.c.
  • This test described by Protais et al (Psychopharmacologie, 1976, 50, 1-6) allows the evaluation of the dopaminergic antagonist activity of possible antipsychotic products.
  • a mouse to which apomorphine has been administered and which has been placed in a cage comprising vertical bars remains most of the time immobile at the top of the cage clinging by its 4 paws to the bars. That verticalisation behaviour is blocked if a dopaminergic antagonist product has been administered before the apomorphine.
  • mice After the intraperitoneal (i.p.) administration of tested compound (Example 3, 70 mg/kg) or solvent (control group), the mouse is placed in a cylindrical barred cage having vertical bars. Ten minutes later, the animal receives the apomorphine dose (5 mg/kg, s.c). The animals are observed 40 minutes after the injection of title compound and are given a score 0 (4 paws on the ground), a score 1 (mouse upright with the two front paws on the bars) or a score 2 (mouse clinging by its 4 paws to the bars) each time a measurement is taken.
  • the effect of the product on verticalisation is evaluated by comparing the scores obtained for each group that has been administered a dose of product with those obtained for the control group (see table 2).
  • Passive avoidance test which is a fear-motivated test classically used to assess short-term or long-term memory, was carried out as described elsewhere.
  • the apparatus (Lafayette Instrument Co) was equipped with identical illuminated (400x400x400mm) and non-illuminated (400x400x400mm) boxes with a guillotine door (60x60mm).
  • the illuminated contained a 60W bulb, and the floor of nonilluminated compartment was composed of 2 mm stainless steel rods spaced 1 cm apart. A rat was gently placed in the illuminated compartment for an acquisition trial, and the door between the two compartments was opened 10 s later.
  • Latency for entering the dark compartment was recorded up to 180 s. If a rat did not enter the dark compartment within 180 s, the rat was removed and assigned a latency score of 180 s.
  • Tested drug (Example 3, 70 mg/kg, i.p.) was given 30 min before the scopolamine administration. Memory impairment was induced in mice with scopolamine (1 mg/kg, i.p.) 20 min before learning with electric shock. The control group received vehicle only. The antiamnesic activity was assessed by estimating latent time to dark box entry table 3). Statistical data processing was performed using "BioStat" tool for Windows.
  • the black and white test (also named light-dark test) is based on the conflict of natural tendencies of rodents to avoid lighted and open areas and to explore novel environments. Relative time spent in exploring each compartment indicates the anxiety level of the animal: Avoidance of the brightly lit area is considered reflecting "anxietylike" behaviors. When treated with anxiolytic drugs, rodents spend more time in this area, an effect purportedly due to a decrease in anxiety.
  • mice The learned helplessness test in mice is the well-known animal model to determine antidepressant efficacy of compounds. Basically when animals learned to be helpless are given antidepressant drugs, they unlearn helplessness and start exerting control over their environment.
  • mice were treated intraperitoneally with compounds of formula I intraperitoneally at dose corresponding to 1/3 or 1/13 of lethal dose, then antidepressant activity of compounds was assessed by estimating latency time as a period in which animal is not trying to escape from stress (see table 5 below).
  • Anxiolytic activity was measured using the elevated plus-maze test (Pellow, 1985).
  • the maze consisted of two open (20 cm x 5 cm x 0.2 cm) and two closed (20 cm x 5 cm x 14 cm) arms, extending from a central platform (5 cm x 5 cm) and elevated to a height of 100 cm above the floor.
  • the entire maze was made of clear Plexiglas. Mice were individually placed on the center of the maze facing an open arm, and the number of entries and the time spent in closed and open arms were recorded during a 3-min observation period. Arm entries were defined as entry of all four paws into an arm. The percentage of open arm entries (100 x open/total entries) was calculated for each animal. A selective increase in the parameters corresponding to open arm entry and defecation number reveals an anxiolytic effect.
  • mice of first group were used as controls. They were injected i.p. with distilled water (0.01 ml/10 g weight). Second group was treated with Compound of Example 3 (3,3-pentamethylene- 1,2-diazacyclopropane) i.p. at dose 70 mg/kg 40 minutes before the experiment.
  • mice The sedative/activating effects of the compounds were studied in experiments on mature outbred mice male mice weighted 24-3g
  • the system "Open field' was a square scene 60x60 cm in dimensions, height of walls 15 cm; chamber floor was divided for 9 quadrants 20x20 cm with 16 holes at the intersection of joints 4 cm in diameter.
  • the animal behavior in the open field test was evaluated for 3 min, we recorded horizontal motor activity (number of intercepted lines), vertical motor activity (number of postures), exploratory activity (number of explored holes when an animal put its head into the hole for > 50%), number of grooming episodes and fecal boluses.
  • the animals were randomized to 6 groups:
  • Compound MP-3 was administered as a single intraperitoneal dose 70 mg/kg 40 minutes prior the experiment in volume: 0.1 ml per 100 g of mice weight. Control animals took distilled water in equivalent quantities (0.1 ml per 100 g of mice weight).
  • Compound MP-3 statistically decreased vertical motor activity of animals in the open field in comparison with control. So compound MP-3 decreased vertical activity of mice on 40%,in comparison with values of vertical motor activity in control animals (Table 5). The effect of MP-3 on animals' behavior in the open field.
  • Compound MP-3 reduced motor (horizontal and vertical) activity in a greater extent and exploratory activity - in the lesser extent
  • the maze represented the crossed arms (branches) 20x 5 cm in dimensions. Two opposite branches had vertical walls 15 cm in height (dark arms), and other open arms were open and did not have walls (light open arms). The maze was elevated from the floor for 20 cm. The central platform was located at the junction of arms, 5x5 cm in dimensions. An animal was transferred to central area, with tail directed to the open light arm. The total observation period for each animal was 5 min.
  • compound MP-3 had anxyolitic activity in the basic test "elevated plus maze".
  • the anxyolitic effect of the compounds was shown as their ability to increase reliably residence time in open arms and number of entries, as well as to increase ratio between residence time in open arms and total observation time (anti-anxiety index) in comparison with control (Table 6).
  • Compound MP-3 significantly decreased fecal boluses in the maze in comparison with control (Table 6), which represented somatic-vegetative component of anxiety.
  • Toxicity to mammals was measured after intraperitoneal injections of compounds of formula I to C57BL/6J mice.
  • Median lethal dose (LD50) was calculated as described previously (see table 5).
  • the compounds described herein have a basic nature and, as such, may be subject to degradation in an acidic environment, such as is found in the stomach.
  • the compounds may be administered in an enteric coated dosage form or enteric coated pellets in a capsule.
  • Enteric pharmaceutical formulations are manufactured in such a way that the product passes unchanged through the stomach of the patient, and dissolves and releases the active ingredient quickly when it leaves the stomach and enters the small intestine.
  • Such formations have long been used, and conventionally are in tablet or pellet form, where the active ingredient is in the inner part of the tablet or pellet and is enclosed in a film or envelope, the "enteric coating", which is insoluble in acid environments, such as the stomach, but is soluble in near-neutral environments such as the small intestine.
  • the compound may be provided in the form of enteric coated pellet comprising a) a core consisting of the compound and a pharmaceutically acceptable excipient; b) an optional separating layer; c) an enteric layer comprising an enteric polymer and an optional pharmaceutically acceptable excipient; and d) an optional finishing layer.
  • a preferred core for the pellet is prepared by applying a compound-containing layer to an inert bead.
  • inert beads are conventionally used in pharmaceutical science, and are readily purchased in all industrial countries.
  • a suitable bead is one prepared from starch and sucrose, for use in confectionery as well as in pharmaceutical manufacturing.
  • beads of any pharmaceutically acceptable excipient may be used, including, for example, microcrystalline cellulose, vegetable gums, waxes, and the like.
  • the primary characteristic of the inert bead is to be inert, with regard both to the drug and the other excipients in the pellet and with regard to the patient who will ultimately ingest the pellet.
  • the size of the beads depends on the desired size of the pellet to be manufactured.
  • pellets can be as small as 0.1 mm, or as large as 2 mm.
  • a suitable bead may be from about 0.3 to about 0.8 mm, in order to provide finished pellets in a desired size range of from about 0.5 to about 1.5 mm in diameter.
  • a convenient manner of coating the beads with duloxetine is the "powder coating" process where the beads are moistened with a sticky liquid or binder, duloxetine is added as a powder, and the mixture is dried. Such a process is regularly carried out in the practice of industrial pharmacy, and suitable equipment is in daily use.
  • Additional solids may be added to the layer with the compound. These solids may be added to facilitate the coating process as needed to aid flow, reduce static charge, aid bulk buildup and form a smooth surface. Inert substances such as talc, kaolin, and titanium dioxide, lubricants such as magnesium stearate, finely divided silicon dioxide, crospovidone, and lactose may be used. The amounts of such substances are in the range from about a few tenths of 1% of the product, up to about 20% of the product. Such solids should be of fine particle size, less than 50 microns, to produce a smooth surface.
  • the compound is made to adhere to the beads by spraying a pharmaceutical excipient which is sticky and adherent when it is wet, and dries to a strong, coherent film.
  • a pharmaceutical excipient which is sticky and adherent when it is wet, and dries to a strong, coherent film.
  • Preferred such polymers include hydroxypropylmethylcellulose, hydroxypropylcellulose and polyvinylpyrrolidone. Additional such substances include, for example, methylcellulose, carboxymethylcellulose, acacia and gelatin.
  • the amount of the adhering excipient is in the range from about a few tenths of 1% to about 5% of the product, and depends in large part on the amount of compound to be adhered to the bead.
  • the optional separating layer between the compound-containing core and the enteric layer is not required, but is a useful feature of the formulation if there is any adverse interactions between the compound and the enteric polymer.
  • the other functions of the separating layer are to provide a smooth base for the application of the enteric layer, to prolong the pellet's resistance to acid conditions, and to improve stability by protecting the compound from light exposure.
  • the smoothing function of the separating layer is purely mechanical, the objective of which is to improve the coverage of the enteric layer and to avoid thin spots in it, caused by bumps and irregularities on the core. Accordingly, the more smooth and free of irregularities the core can be made, the less material is needed in the separating layer, and the need for the smoothing characteristic of the separating layer may be avoided entirely when the compound is of extremely fine particle size and the core is made as close as possible to truly spherical.
  • the separating layer can also act as a diffusional barrier to migrating core or enteric layer components dissolved in product moisture.
  • the separating layer can also be used as a light barrier by opacifying it with agents such as titanium dioxide, iron oxides and the like.
  • the separating layer is composed of coherent or polymeric materials, and finely powdered solid excipients which constitute fillers.
  • a sugar is used in the separating layer, it is applied in the form of an aqueous solution and constitutes part of or the whole of the coherent material which sticks the separating layer together.
  • a polymeric material may also be used in the separating layer.
  • substances such as hydroxypropylmethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose and the like may be used in small amounts to increase the adherence and coherence of the separating layer.
  • a filler excipient in the separating layer to increase the smoothness and solidity of the layer.
  • Substances such as finely powdered talc, silicon dioxide and the like are universally accepted as pharmaceutical excipients and may be added as is convenient in the circumstances to fill and smooth the separating layer.
  • the separating layer may be applied by spraying aqueous solutions of the sugar or polymeric material, and dusting in the filler as has been described in the preparation of the compound-containing layer.
  • the smoothness and homogeneity of the separating layer can be improved, however, if the filler is thoroughly dispersed as a suspension in the solution of sugar and/or polymeric material, and the suspension is sprayed on the core and dried.
  • the enteric layer is comprised of an enteric polymer, which must be chosen for compatibility with the compound and to provide the desired pH-dependent release.
  • enteric polymers include: (meth)acrylate copolymer, shellac, HPMCP (hydroxypropylmethylcellulose phthalate), CAP (cellulose acetate phthalate), HPMC-AS (hydroxypropylmethylcellulose acetate succinate), polyvinyl acetate phthalate, carboxymethylethylcellulose, co-polymerized methacrylic acid/methacrylic acid methyl esters such as, for instance, compounds known under the trade name Eudragit L 12.5 or Eudragit L 100 (Rohm Pharma), or similar compounds used to obtain enteric coatings.
  • the enteric coating layer can optionally contain a pharmaceutically acceptable plasticizer such as, for instance, cetanol, triacetin, citric acid esters such as, for instance, those known under the trade name Citroflex (Pfizer), phthalic acid esters, dibutyl succinate or similar plasticizers.
  • a pharmaceutically acceptable plasticizer such as, for instance, cetanol, triacetin, citric acid esters such as, for instance, those known under the trade name Citroflex (Pfizer), phthalic acid esters, dibutyl succinate or similar plasticizers.
  • the amount of plasticizer is usually optimized for each enteric coating polymer(s) and is usually in the range of 1-20% of the enteric coating polymer(s).
  • Dispersants such as talc, colorants and pigments may also be included into the enteric coating layer.
  • a finishing layer over the enteric layer is not necessary in every instance, but frequently improves the elegance of the product and its handling, storage and machinability and may provide further benefits as well.
  • the simplest finishing layer is simply a small amount, less than about 1%, of an anti-static ingredient such as talc or silicon dioxide, simply dusted on the surface of the pellets.
  • Another simple finishing layer is a small amount, about 1%, of a wax such as beeswax melted onto the circulating mass of pellets to further smooth the pellets, reduce static charge, prevent any tendency for pellets to stick together, and increase the hydrophobicity of the surface.
  • More complex finishing layers may constitute a final sprayed-on layer of ingredients.
  • a thin layer of polymeric material such as hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like, in an amount such as from a few tenths of 1% up to about 3%, may be applied.
  • the polymeric material may also carry a suspension of an opacifier, a bulking agent such as talc, or a coloring material, particularly an opaque finely divided color agent such as red or yellow iron oxide.
  • a layer quickly dissolves away in the stomach, leaving the enteric layer to protect the compound, but provides an added measure of pharmaceutical elegance and protection from mechanical damage to the product.
  • the drug layer is to be added to the beads in a CF granulator at a batch size of 3.6 kg.
  • the hydroxypropylcellulose is to be dissolved in a minimum amount of water, and the solution slowly sprayed onto the agitating batch of beads, while the compound, lactose and crospovidone, as a mixture is to be intermittently added at a rate such that it would be adhered to the beads without loss through dusting.
  • the talc is to be added in the same manner, and the beads dried in an oven at 55°C. for 1.5 hours, and then classified between 20 and 42 mesh screens.
  • the separating layer is applied in a Wurster column (Uni-Glatt, Glatt Air Techniques, Inc., Ramsey, N.J.).
  • the hydroxypropylmethylcellulose and the polyethylene glycol are to be dissolved in water, and the talc and titanium dioxide dispersed in the solution with a homogenizer.
  • the resulting suspension is to be sprayed onto the classified beads in the Wurster column.
  • the enteric coating suspension is to be prepared by first dissolving the triethyl citrate in water, cooling the solution to 15°C, and preparing a 7% w/v suspension of the HPMCAS-LF in the cool solution.
  • the HPMCAS-LF and talc are to be added slowly, taking care to avoid foaming or the formation of aggregates of polymer.
  • the partially formed granules are to be added to a fluidized bed coating device, provided with a Wurster column.
  • the batch is to be fluidized with air at 70°-80°C and the enteric suspension sprayed into the batch and adjusting the spray rate and air flow to provide appropriate agitation and avoid agglomeration. When the addition is complete, air flow is to be continued for 30 minutes to dry the batch.
  • finishing layer is to be created by adding the beeswax to the product in the fluidized bed at 60°C.
  • the hydrated silicon dioxide is to be added to the pellets and mixed in the Wurster column.
  • the batch is then to be cooled and filled into number #3 gelatin capsules.
  • the powder mixture of the compound, lactose, polyvinylpyrrolidone, and sodium carbonate were homogenized and granulated by the solution of methyl cellulose and water.
  • the wet mass was dried in a fluidized bed dryer using an inlet air temperature of +50°C for 30 minutes. The dried mixture was then forced through a sieve with an aperture of 0.5 mm. After mixing with magnesium stearate the granulate was tableted on a tableting machine using 6 mm punches. The tablet weight was 100 mg.
  • the tablets of Example 2 is to be subcoated with approximately 10% by weight of hydroxypropyl methylcellulose from a water solution using a perforated coating pan apparatus.
  • the tablets of Example 3 is to be subcoated using the dry coating technique.
  • a tablet granulate containing lactose anhydrous (4,000 grams), polyvinylpyrrolidone (PVP) (180 grams), ethanol 95% (420 grams) and magnesium stearate (42 grams) is to be prepared as follows: granulate the lactose with a solution of PVP in ethanol and dry, and the admix in the magnesium stearate.
  • the tablet granulate is to be dry coated around the tablet cores of Examples 2 and 3 using a Manesty Dry Cota tableting machine.
  • the resulting tablet weight of the dry coated tablets of Example 2 will be approximately 475 mg with 20 mg of the compound.
  • the subcoated tablets obtained above are next to be enteric coated using the same coating solution: Hydroxypropyl methylcellulose phthalate (1,500 g); Cetyl alcohol (105 g), Methylene chloride (15,000 g), Isopropanol (15,000 g) and Distilled water (3,150 g).
  • the coating is to be applied in a perforated coating pan apparatus. An approximate amount of one kg of coating solution is to be applied for each kg of tablets.

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Abstract

La présente invention concerne des composés de formule (I), l'utilisation de ces composés pour traiter des troubles mentaux et neurologiques, en particulier des dépressions et des psychoses d'étiologies différentes. Les composés destinés à traiter des troubles mentaux et neurologiques sont représentés par la formule (I) dans laquelle R, R', R", et Y sont tels que définis dans la description, ou désignent des sels pharmaceutiquement acceptables de ceux-ci, ou des solvates pharmaceutiquement acceptables de ceux-ci, comme des hydrates, et des compositions pharmaceutiquement acceptables contenant lesdits composés.
EP13722815.1A 2012-01-26 2013-01-26 Agents pour le traitement de troubles neurodégénératifs Withdrawn EP2807149A2 (fr)

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