WO2013111118A2

WO2013111118A2 - Agents for treating neurodegenerative disorders

Info

Publication number: WO2013111118A2
Application number: PCT/IB2013/050682
Authority: WO
Inventors: Nina N. MAKHOVA; Vera Y. PETUKHOVA; Alexander V. SHEVTSOV; Vladimir V. NOVAKOVSKIY; Vladimir Vladimirovich KUZNETSOV
Original assignee: Cro Consulting Limited
Priority date: 2012-01-26
Filing date: 2013-01-26
Publication date: 2013-08-01
Also published as: WO2013111118A3; EP2807149A2; JP2015508417A

Abstract

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: wherein R, R', Y are as defined in specification or pharmaceutically acceptable salts thereof, solvates thereof such as hydrates, and pharmaceutical compositions containing such compounds.

Description

AGENTS FOR TREATING NEURODEGENERATIVE DISORDERS

Cross Reference to Related Applications

This application claims priority from US Provisional Patent Application No. 61/591,270, filed on January 26, 2012, the contents of which are incorporated herein in their entirety by reference.

Background of the Invention

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. There are many recognized 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.

[http://www.who.int/mental_health/neurology/neurodiso/en/index.html] 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.

The causes of mental disorders are varied and in some cases unclear, and theories may incorporate findings from a range of fields. Services are based in psychiatric hospitals or in the community, and assessments are carried out by psychiatrists, clinical psychologists and sometimes psychiatric social workers, using various methods but often relying on observation and questioning. Clinical treatments are provided by various mental health professionals. Psychotherapy and psychiatric medication are two major treatment options, as are social interventions, peer support and self-help. In a minority of cases there be involuntary detention or involuntary treatment where legislation allows. Stigma and discrimination can add to the suffering and disability associated with mental disorders (or with being diagnosed or judged as having a mental disorder), leading to various social movements attempting to increase understanding and challenge social exclusion.

A major option for many mental disorders is psychiatric medication and there are several main groups. 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.

Despite the different conventional names of the drug groups, there may be considerable overlap in the disorders for which they are actually indicated, and there may also be off-label use of medications. There can be problems with adverse effects of medication and adherence to them, and there is also criticism of pharmaceutical marketing and professional conflicts of interest. [WebMD Inc (2005, July 01). Mental Health: Types of Mental Illness. Retrieved April 19, 2007, from http://www.webmd.com/mental- health/mental-health-types-illness].

Therefore there is certain need for design and development of novel class of drugs for treatment of mental and neurological disorders of different etiology.

Summary of the Invention

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:

T R

NT R'

I

Y

wherein

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, COR¹, COOR¹, CONHR¹, CON(R¹)₂, OR¹, NR^!R², N(R¹)₂, SR¹, NR¹-S0₂-R², NR¹-S0₂-NR²R³, NR¹- CO-NR²R³, -SO-R¹, -S0₂-R¹,

- O-COO-R¹, -CSR¹, -C(S)NR¹R², -SR¹,

wherein each member of R and R' is optionally substituted,

R¹, R², R³ is independently selected from hydrogen, amino, alkyl, haloalkyl, alkoxy, aminoalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, arylalkyl, cycloalkylalkyl, heterocyclylalkyl, heteroarylalkyl, wherein each member of R¹, R², R³ 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.

And with proviso that both R and R^' cannot be hydrogens,

or pharmaceutically acceptable derivatives, tautomeric forms, stereoisomers, stereoisomeric mixtures, polymorphs, prodrugs, metabolites, salts or solvates thereof, and pharmaceutical compositions containing such compounds, 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. 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 melancholic depression, resistant depression, severe depression, and psychotic depression, dissociative amnesia, dissociative disorder, dissociative fugue, dissociative identity disorder, dyspareunia, dyssomnia, dyssomnia related to another disorder, dysthymic disorder, eating disorder, exhibitionism, female dyspareunia due to medical condition, female hypoactive sexual desire disorder due to medical condition, female orgasmic disorder, female sexual arousal disorder, fetishism, frotteurism, gender identity disorder in adolescents or adults, gender identity disorder in children, gender identity disorder, generalized anxiety disorder, histrionic personality disorder, hypoactive sexual desire disorder, hypochondriasis, impulse-control disorder, insomnia, insomnia related to another disorder, intermittent explosive disorder, kleptomania, labile or saddened mood, major depressive disorder in full remission, major depressive disorder in partial remission, male dyspareunia due to medical condition, male erectile disorder, male erectile disorder due to medical condition, male hypoactive sexual desire disorder due to medical condition, male orgasmic disorder, mood disorder due to medical condition, narcissistic personality disorder, narcolepsy, nightmare disorder, obsessive compulsive disorder, obsessive-compulsive personality disorder, other female sexual dysfunction due to medical condition, other male sexual dysfunction due to medical condition, pain disorder associated with both psychological factors and medical conditions, pain disorder associated with psychological features, panic disorder with agoraphobia, panic disorder without agoraphobia, paranoid personality disorder, paraphilia, parasomnia, pathological gambling, pedophilia, personality disorder, posttraumatic stress disorder, premature ejaculation, premenstrual associated depression, primary hypersomnia, primary insomnia, psychosis of different etiology, particularly alcohol psychosis, circular psychosis, involutional psychosis, psychosis associated with dementia, psychosis associated with Alzheimer's disease, psychosis associated with an organic brain syndrome, and drug-induced psychosis, psychotic disorder due to medical condition with delusions, psychotic disorder due to medical condition with hallucinations, pyromania, schizoaffective disorder, schizoid personality disorder, schizophrenia of catatonic type, schizophrenia of disorganized type, schizophrenia of paranoid type, schizophrenia of residual type, schizophrenia of undifferentiated type, schizophreniform disorder, schizotypal personality disorder, sexual aversion disorder, sexual disorder, sexual dysfunction, sexual masochism, sexual sadism, shared psychotic disorder, sleep disorder due to a medical condition of hypersomnia type, sleep disorder due to a medical condition of insomnia type, sleep disorder due to a medical condition of mixed type, sleep disorder due to a medical condition of parasomnia type, sleep terror disorder, sleepwalking disorder, social phobia, somatization disorder, somatoform disorder, specific phobia, substance disorder, transvestic fetishism, trichotillomania, undifferentiated somatoform disorder, suicide intention, suicide, unmotivation, vaginismus, voyeurism. 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, benign essential blepharospasm, benign intracranial hypertension, bilateral frontoparietal polymicrogyria, Binswanger's disease, blepharospasm, Bloch-Sulzberger syndrome, brachial plexus injury, brain abscess, brain damage, brain injury, brain tumor, Brown-Sequard syndrome, Canavan disease, carpal tunnel syndrome, causalgia, central pain syndrome, central pontine myelinolysis, centronuclear myopathy, cephalic disorder, cerebral aneurysm, cerebral arteriosclerosis, cerebral atrophy, cerebral gigantism, cerebral palsy, cerebral vasculitis, cervical spinal stenosis, Charcot-Marie-tooth disease, chiari malformation, chorea, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic pain, Coffin-Lowry syndrome, coma, complex regional pain syndrome, compression neuropathy, congenital facial diplegia, corticobasal degeneration, cranial arteritis, craniosynostosis, Creutzfeldt- Jakob disease, cumulative trauma disorders, Cushing's syndrome, cytomegalic inclusion body disease (CIBD), cytomegalovirus infection, Dandy-Walker syndrome, Dawson disease, De Morsier's syndrome, Dejerine-Klumpke palsy, Dejerine-Sottas disease, delayed sleep phase syndrome, dementia, dermatomyositis, developmental dyspraxia, diabetic neuropathy, diffuse sclerosis, Dravet syndrome, dysautonomia, dyscalculia, dysgraphia, dyslexia, dystonia, empty sella syndrome, encephalitis, encephalocele, encephalotrigeminal angiomatosis, encopresis, epilepsy, Erb's palsy, erythromelalgia, essential tremor, Fabry's disease, Fahr's syndrome, fainting, familial spastic paralysis, febrile seizures, Fisher syndrome, Friedreich's ataxia, fibromyalgia, Foville's syndrome, Gaucher's disease, Gerstmann's syndrome, giant cell arteritis, giant cell inclusion disease, globoid cell leukodystrophy, gray matter heterotopia, Guillain-Barre syndrome, HTLV-1 associated myelopathy, Hallervorden-Spatz disease, head injury, headache, hemifacial spasm, hereditary spastic paraplegia, heredopathia atactica polyneuritiformis, Herpes zoster oticus, Herpes zoster, Hirayama syndrome, holoprosencephaly, Huntington's disease, hydranencephaly, hydrocephalus, hypercortisolism, hypoxia, immune-mediated encephalomyelitis, inclusion body myositis, incontinentia pigmenti, infantile phytanic acid storage disease, infantile refsum disease, infantile spasms, inflammatory myopathy, intracranial cyst, intracranial hypertension, Joubert syndrome, Karak syndrome, Kearns-sayre syndrome, Kennedy disease, Kinsbourne syndrome, Klippel feil syndrome, Krabbe disease, Kugelberg-Welander disease, kuru, Lafora disease, Lambert-Eaton myasthenic syndrome, Landau-Kleffner syndrome, lateral medullary (wallenberg) syndrome, learning disabilities, Leigh's disease, Lennox-Gastaut syndrome, Lesch-Nyhan syndrome, leukodystrophy, lewy body dementia, lissencephaly, locked- in syndrome, Lou Gehrig's disease, lumbar disc disease, lumbar spinal stenosis, Lyme disease, Machado-Joseph disease, macrencephaly, macropsia, megalencephaly, Melkersson-Rosenthal syndrome, Menieres disease, meningitis, Menkes disease, metachromatic leukodystrophy, microcephaly, micropsia, migraine, Miller Fisher syndrome, mini-stroke (transient ischemic attack), misophonia, mitochondrial myopathy, Mobius syndrome, monomelic amyotrophy, motor neurone disease, motor skills disorder, moyamoya disease, mucopolysaccharidoses, multi-infarct dementia, multifocal motor neuropathy, multiple sclerosis, multiple system atrophy, muscular dystrophy, myalgic encephalomyelitis, myasthenia gravis, myelinoclastic diffuse sclerosis, myoclonic encephalopathy of infants, myoclonus, myopathy, myotubular myopathy, myotonia congenita, narcolepsy, neurofibromatosis, neuroleptic malignant syndrome, neurological manifestations of aids, neurological sequelae of lupus, neuromyotonia, neuronal ceroid lipofuscinosis, neuronal migration disorders, Niemann-Pick disease, non 24-hour sleep-wake syndrome, nonverbal learning disorder, O'Sullivan-McLeod syndrome, occipital neuralgia, occult spinal dysraphism sequence, Ohtahara syndrome, olivopontocerebellar atrophy, opsoclonus myoclonus syndrome, optic neuritis, orthostatic hypotension, overuse syndrome, palinopsia, paresthesia, Parkinson's disease, paramyotonia congenita, paraneoplastic diseases, paroxysmal attacks, Parry-Romberg syndrome, Pelizaeus-Merzbacher disease, periodic paralyses, peripheral neuropathy, persistent vegetative state, pervasive developmental disorders, photic sneeze reflex, phytanic acid storage disease, Pick's disease, pinched nerve, pituitary tumors, polio, polymicrogyria, polymyositis, porencephaly, post-polio syndrome, postherpetic neuralgia (PHN), postinfectious encephalomyelitis, postural hypotension, Prader-Willi syndrome, primary lateral sclerosis, prion diseases, progressive hemifacial atrophy, progressive multifocal leukoencephalopathy, progressive supranuclear palsy, pseudotumor cerebri, rabies, Ramsay hunt syndrome type I, Ramsay hunt syndrome type II, Ramsay hunt syndrome type III, Rasmussen's encephalitis, reflex neurovascular dystrophy, Refsum disease, repetitive stress injury, restless legs syndrome, retrovirus- associated myelopathy, Rett syndrome, Reye's syndrome, rhythmic movement disorder, Romberg syndrome, Saint Vitus dance, Sandhoff disease, schizophrenia, Schilder's disease, schizencephaly, sensory integration dysfunction, septo-optic dysplasia, shaken baby syndrome, shingles, Shy-Drager syndrome, Sjogren's syndrome, sleep apnea, sleeping sickness, snatiation, Sotos syndrome, spasticity, spina bifida, spinal cord injury, spinal cord tumors, spinal muscular atrophy, spinocerebellar ataxia, Steele-Richardson- Olszewski syndrome, Stiff-Person syndrome, stroke, Sturge-Weber syndrome, subacute sclerosing panencephalitis, subcortical arteriosclerotic encephalopathy, superficial siderosis, Sydenham's chorea, syncope, synesthesia, syringomyelia, tarsal tunnel syndrome, tardive dyskinesia, tardive dysphrenia, Tarlov cyst, Tay-Sachs disease, temporal arteritis, tetanus, tethered spinal cord syndrome, Thomsen disease, thoracic outlet syndrome, tic douloureux, Todd's paralysis, Tourette syndrome, toxic encephalopathy, transient ischemic attack, transmissible spongiform encephalopathies, transverse myelitis, traumatic brain injury, tremor, trigeminal neuralgia, tropical spastic paraparesis, trypanosomiasis, tuberous sclerosis, Von Hippel-Lindau disease (VHL), viliuisk encephalomyelitis (VE), Wallenberg's syndrome, Werdnig-Hoffman disease, West syndrome, whiplash, Williams syndrome, Wilson's disease, Zellweger syndrome.

Many known neuroprotective agents are prepared using complicated multi-step procedures. Moreover know medications are not always effective in treatment of variety of neurological or mental conditions of different etiology. There can be problems with adverse effects of medication and adherence to them. [WebMD Inc (2005, July 01).

Mental Health: Types of Mental Illness. Retrieved April 19, 2007, from

http ://www.webmd.com/mental-health/mental-health-types-illness] .

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.

DETAILED DESCRIPTION OF THE INVENTION

Synthesis of compounds according to formula I can be performed employing simple and convenient one-step procedure. The first synthetic method is presented on Scheme 1 :

Scheme 1

The second method is depicted below (scheme 2)

R

NH-, H,NCI

R' R'

H

Scheme 2

The third method is presented on Scheme 4:

Scheme 3

The fourth method is presented on Scheme 4:

NH

=Q + H₂NOS0₂R" =N-OS0₂R"

R" R" N R'

H

R" = OH, Ar

Scheme 4

The following compounds of the formula I can be prepared using schemes 1-4. These examples of preferred compounds of formula I include but are not limited to:

1. 3,3-dipropyl- 1 ,2-diazacyclopropane

2. 3,3-diisopropyl- 1 ,2-diazacyclopropane

3. 3,3-dibutyl- 1 ,2-diazacyclopropane 4. 3,3-diisobutyl- 1 ,2-diazacyclopropane

5. 3,3-dipentyl- 1 ,2-diazacyclopropane

6. 3,3-dihexyl- 1 ,2-diazacyclopropane

7. 3,3-diheptyl- 1 ,2-diazacyclopropane

8. 3,3-dioctyl- 1,2-diazacyclopropane

9. 3,3-dinonyl- 1 ,2-diazacyclopropane

10. 3,3-didecyl- 1,2-diazacyclopropane

11. 3 -hexyl-3 -methyl- 1,2-diazacyclopropane

The following examples of the preparation of compounds of the formula I illustrate this invention. These examples of preferred compounds of formula I include but are not limited to:

1. 3, 3 -di(2-aminoethyl)- 1,2-diazacyclopropane

2. 3, 3 -di(2-hydroxy ethyl)- 1,2-diazacyclopropane

3. 3,3-di(2-(methylamino)ethyl)- 1 ,2-diazacyclopropane

4. 3,3-di(2-(ethylamino)ethyl)- 1 ,2-diazacyclopropane

5. 3,3-di(2-(dimethylamino)ethyl)- 1 ,2-diazacyclopropane

6. 3,3-di(2-(diethylamino)ethyl)- 1 ,2-diazacyclopropane

7. 3,3-di(2-methoxyethyl)- 1 ,2-diazacyclopropane

8. 3,3-di(2-ethoxyethyl)- 1 ,2-diazacyclopropane

9. 3 ,3 -di(3 -aminopropyl)- 1 ,2-diazacyclopropane

10. 3,3-di(3-hydroxypropyl)- 1,2-diazacyclopropane

1. 3-methyl- 1 ,2-diazacyclopropane

2. 3 -ethyl- 1 ,2-diazacyclopropane

3. 3-propyl- 1 ,2-diazacyclopropane

4. 3-butyl- 1,2-diazacyclopropane

5. 3-pentyl- 1 ,2-diazacyclopropane

6. 3 -hexyl- 1,2-diazacyclopropane

7. 3-heptyl- 1 ,2-diazacyclopropane

8. 3-octyl- 1 ,2-diazacyclopropane 9. 3-nonyl- l,2-diazacyclopropane

10. 3-decyl- l,2-diazacyclopropane

1. 3 -(phenylmethyl)- 1 ,2-diazacyclopropane

2. 3-(l -phenylethyl)- 1 ,2-diazacyclopropane

3. 3-(2-aminoethyl)- 1 ,2-diazacyclopropane

4. 3-(2-hydroxyethyl)-l,2-diazacyclopropane

5. 3-(2-(2-methylphenyl)ethyl)- 1 ,2-diazacyclopropane

6. 3-(2-(3-methylphenyl)ethyl)- 1 ,2-diazacyclopropane

7. 3-(2-(4-methylphenyl)ethyl)- 1 ,2-diazacyclopropane

8. 3-(2-(2-ethylphenyl)ethyl)- 1 ,2-diazacyclopropane

9. 3-(2-(3-ethylphenyl)ethyl)-l,2-diazacyclopropane

10. 3-(2-(4-ethylphenyl)ethyl)-l,2-diazacyclopropane

1. 3,3-hexamethylene- 1 ,2-diazacyclopropane

2. 3,3-octamethylene- 1,2-diazacyclopropane

3. 3 ,3 -( 1 -methylpentamethylene)- 1 ,2-diazacyclopropane

4. 3,3-(l -azapentamethylene)- 1 ,2-diazacyclopropane

5. 3,3-(2-azapentamethylene)- 1,2-diazacyclopropane

6. 3,3-(3-azapentamethylene)- 1 ,2-diazacyclopropane

7. 3,3-(l -oxapentamethylene)- 1 ,2-diazacyclopropane

8. 3,3-(2-oxapentamethylene)- 1 ,2-diazacyclopropane

9. 3,3-(2-ethylpentamethylene)- 1 ,2-diazacyclopropane

10. 3,3-(3-ethylpentamethylene)- 1,2-diazacyclopropane

11. l,2,7,8-tetraazadispiro[2,2,2,2]decane

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 melancholic depression, resistant depression, severe depression, and psychotic depression, dissociative amnesia, dissociative disorder, dissociative fugue, dissociative identity disorder, dyspareunia, dyssomnia, dyssomnia related to another disorder, dysthymic disorder, eating disorder, exhibitionism, female dyspareunia due to medical condition, female hypoactive sexual desire disorder due to medical condition, female orgasmic disorder, female sexual arousal disorder, fetishism, frotteurism, gender identity disorder in adolescents or adults, gender identity disorder in children, gender identity disorder, generalized anxiety disorder, histrionic personality disorder, hypoactive sexual desire disorder, hypochondriasis, impulse-control disorder, insomnia, insomnia related to another disorder, intermittent explosive disorder, kleptomania, labile or saddened mood, major depressive disorder in full remission, major depressive disorder in partial remission, male dyspareunia due to medical condition, male erectile disorder, male erectile disorder due to medical condition, male hypoactive sexual desire disorder due to medical condition, male orgasmic disorder, mood disorder due to medical condition, narcissistic personality disorder, narcolepsy, nightmare disorder, obsessive compulsive disorder, obsessive-compulsive personality disorder, other female sexual dysfunction due to medical condition, other male sexual dysfunction due to medical condition, pain disorder associated with both psychological factors and medical conditions, pain disorder associated with psychological features, panic disorder with agoraphobia, panic disorder without agoraphobia, paranoid personality disorder, paraphilia,, parasomnia, pathological gambling, pedophilia, personality disorder, posttraumatic stress disorder, premature ejaculation, premenstrual associated depression, primary hypersomnia, primary insomnia, psychosis of different etiology, particularly alcohol psychosis, circular psychosis, involutional psychosis, psychosis associated with dementia, psychosis associated with Alzheimer's disease, psychosis associated with an organic brain syndrome, and drug-induced psychosis, psychotic disorder due to medical condition with delusions, psychotic disorder due to medical condition with hallucinations, pyromania, schizoaffective disorder, schizoid personality disorder, schizophrenia of catatonic type, schizophrenia of disorganized type, schizophrenia of paranoid type, schizophrenia of residual type, schizophrenia of undifferentiated type, schizophreniform disorder, schizotypal personality disorder, sexual aversion disorder, sexual disorder, sexual dysfunction, sexual masochism, sexual sadism, shared psychotic disorder, sleep disorder due to a medical condition of hypersomnia type, sleep disorder due to a medical condition of insomnia type, sleep disorder due to a medical condition of mixed type, sleep disorder due to a medical condition of parasomnia type, sleep terror disorder, sleepwalking disorder, social phobia, somatization disorder, somatoform disorder, specific phobia, substance disorder, transvestic fetishism, trichotillomania, undifferentiated somatoform disorder, suicide intention, suicide, unmotivation, vaginismus, voyeurism.

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, benign essential blepharospasm, benign intracranial hypertension, bilateral frontoparietal polymicrogyria, Binswanger's disease, blepharospasm, Bloch-Sulzberger syndrome, brachial plexus injury, brain abscess, brain damage, brain injury, brain tumor, Brown-Sequard syndrome, Canavan disease, carpal tunnel syndrome, causalgia, central pain syndrome, central pontine myelinolysis, centronuclear myopathy, cephalic disorder, cerebral aneurysm, cerebral arteriosclerosis, cerebral atrophy, cerebral gigantism, cerebral palsy, cerebral vasculitis, cervical spinal stenosis, Charcot-Marie-tooth disease, chiari malformation, chorea, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic pain, Coffin-Lowry syndrome, coma, complex regional pain syndrome, compression neuropathy, congenital facial diplegia, corticobasal degeneration, cranial arteritis, craniosynostosis, Creutzfeldt- Jakob disease, cumulative trauma disorders, Cushing's syndrome, cytomegalic inclusion body disease (CIBD), cytomegalovirus infection, Dandy-Walker syndrome, Dawson disease, De Morsier's syndrome, Dejerine-Klumpke palsy, Dejerine-Sottas disease, delayed sleep phase syndrome, dementia, dermatomyositis, developmental dyspraxia, diabetic neuropathy, diffuse sclerosis, Dravet syndrome, dysautonomia, dyscalculia, dysgraphia, dyslexia, dystonia, empty sella syndrome, encephalitis, encephalocele, encephalotrigeminal angiomatosis, encopresis, epilepsy, Erb's palsy, erythromelalgia, essential tremor, Fabry's disease, Fahr's syndrome, fainting, familial spastic paralysis, febrile seizures, Fisher syndrome, Friedreich's ataxia, fibromyalgia, Foville's syndrome, Gaucher's disease, Gerstmann's syndrome, giant cell arteritis, giant cell inclusion disease, globoid cell leukodystrophy, gray matter heterotopia, Guillain-Barre syndrome, HTLV-1 associated myelopathy, Hallervorden-Spatz disease, head injury, headache, hemifacial spasm, hereditary spastic paraplegia, heredopathia atactica polyneuritiformis, Herpes zoster oticus, Herpes zoster, Hirayama syndrome, holoprosencephaly, Huntington's disease, hydranencephaly, hydrocephalus, hypercortisolism, hypoxia, immune-mediated encephalomyelitis, inclusion body myositis, incontinentia pigmenti, infantile phytanic acid storage disease, infantile refsum disease, infantile spasms, inflammatory myopathy, intracranial cyst, intracranial hypertension, Joubert syndrome, Karak syndrome, Kearns-sayre syndrome, Kennedy disease, Kinsbourne syndrome, Klippel feil syndrome, Krabbe disease, Kugelberg-Welander disease, kuru, Lafora disease, Lambert-Eaton myasthenic syndrome, Landau-Kleffner syndrome, lateral medullary (wallenberg) syndrome, learning disabilities, Leigh's disease, Lennox- Gastaut syndrome, Lesch-Nyhan syndrome, leukodystrophy, lewy body dementia, lissencephaly, locked-in syndrome, Lou Gehrig's disease, lumbar disc disease, lumbar spinal stenosis, Lyme disease, Machado-Joseph disease, macrencephaly, macropsia, megalencephaly, Melkersson-Rosenthal syndrome, Menieres disease, meningitis, Menkes disease, metachromatic leukodystrophy, microcephaly, micropsia, migraine, Miller Fisher syndrome, mini-stroke (transient ischemic attack), misophonia, mitochondrial myopathy, Mobius syndrome, monomelic amyotrophy, motor neurone disease, motor skills disorder, moyamoya disease, mucopolysaccharidoses, multi-infarct dementia, multifocal motor neuropathy, multiple sclerosis, multiple system atrophy, muscular dystrophy, myalgic encephalomyelitis, myasthenia gravis, myelinoclastic diffuse sclerosis, myoclonic encephalopathy of infants, myoclonus, myopathy, myotubular myopathy, myotonia congenita, narcolepsy, neurofibromatosis, neuroleptic malignant syndrome, neurological manifestations of aids, neurological sequelae of lupus, neuromyotonia, neuronal ceroid lipofuscinosis, neuronal migration disorders, Niemann-Pick disease, non 24-hour sleep-wake syndrome, nonverbal learning disorder, O'Sullivan-McLeod syndrome, occipital neuralgia, occult spinal dysraphism sequence, Ohtahara syndrome, olivopontocerebellar atrophy, opsoclonus myoclonus syndrome, optic neuritis, orthostatic hypotension, overuse syndrome, palinopsia, paresthesia, Parkinson's disease, paramyotonia congenita, paraneoplastic diseases, paroxysmal attacks, Parry-Romberg syndrome, Pelizaeus-Merzbacher disease, periodic paralyses, peripheral neuropathy, persistent vegetative state, pervasive developmental disorders, photic sneeze reflex, phytanic acid storage disease, Pick's disease, pinched nerve, pituitary tumors, polio, polymicrogyria, polymyositis, porencephaly, post-polio syndrome, postherpetic neuralgia (PHN), postinfectious encephalomyelitis, postural hypotension, Prader-Willi syndrome, primary lateral sclerosis, prion diseases, progressive hemifacial atrophy, progressive multifocal leukoencephalopathy, progressive supranuclear palsy, pseudotumor cerebri, rabies, Ramsay hunt syndrome type I, Ramsay hunt syndrome type II, Ramsay hunt syndrome type III, Rasmussen's encephalitis, reflex neurovascular dystrophy, Refsum disease, repetitive stress injury, restless legs syndrome, retrovirus- associated myelopathy, Rett syndrome, Reye's syndrome, rhythmic movement disorder, Romberg syndrome, Saint Vitus dance, Sandhoff disease, schizophrenia, Schilder's disease, schizencephaly, sensory integration dysfunction, septo-optic dysplasia, shaken baby syndrome, shingles, Shy-Drager syndrome, Sjogren's syndrome, sleep apnea, sleeping sickness, snatiation, Sotos syndrome, spasticity, spina bifida, spinal cord injury, spinal cord tumors, spinal muscular atrophy, spinocerebellar ataxia, Steele-Richardson- Olszewski syndrome, Stiff-Person syndrome, stroke, Sturge- Weber syndrome, subacute sclerosing panencephalitis, subcortical arteriosclerotic encephalopathy, superficial siderosis, Sydenham's chorea, syncope, synesthesia, syringomyelia, tarsal tunnel syndrome, tardive dyskinesia, tardive dysphrenia, Tarlov cyst, Tay-Sachs disease, temporal arteritis, tetanus, tethered spinal cord syndrome, Thomsen disease, thoracic outlet syndrome, tic douloureux, Todd's paralysis, Tourette syndrome, toxic encephalopathy, transient ischemic attack, transmissible spongiform encephalopathies, transverse myelitis, traumatic brain injury, tremor, trigeminal neuralgia, tropical spastic paraparesis, trypanosomiasis, tuberous sclerosis, Von Hippel-Lindau disease (VHL), viliuisk encephalomyelitis (VE), Wallenberg's syndrome, Werdnig-Hoffman disease, West syndrome, whiplash, Williams syndrome, Wilson's disease, Zellweger syndrome.

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.

They have no cardiotoxic and hepatotoxic action, nor influence rhythm, frequency and strength of systoli. They have no direct influence on myocardium, do not reduce conduction time, exert no negative inotropic effect, do not lower arterial pressure, nor change any response to adrenaline. This property is very important as tricyclic antidepressants are know to induce orthostatic hypotension, tachycardia, a reduction of P-Q, Q-R-S and Q-T interval, auricle and ventricle arrhythmia.

The compounds I may be useful for treatment of patients resistant to therapy by the standard neuroprotective medications.

The 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.

In therapeutic use as agents for depression and anxiety the compounds of the present invention are used, alone or in combination with a pharmaceutically acceptable carrier or excipient. Standard pharmaceutical formulation techniques may be used, such as those disclosed in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa. (1990). The compounds of the present invention may be administered orally or parentally, neat or in combination with conventional pharmaceutical carriers. "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.

The choice of carrier depends on the route by which the compounds represented by structural formula I will be administered and the form of the composition. The composition may be in a variety of forms, suitable, for example, for systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, or parenteral).

The exact amounts of each component in the pharmaceutical composition depend 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. In powders, the carrier may be a finely divided solid that may be in admixture with the finely divided active ingredient. In tablets, 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. 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. Suitable examples of 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).

For parenteral administration 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. In one embodiment, the pharmaceutical compositions containing the present compounds are in unit dosage form, e.g., as tablets or capsules. In such form, 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. Alternatively, 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. The determination of 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%. If the IC50 of the medicament is 1000 nM, 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. One skilled in the art understands how to calculate and understand an IC50. The remainder of the composition, up to approximately 100%, may be a pharmaceutically acceptable carrier or excipient. A better understanding of the present invention may be obtained in light of the following examples to illustrate, but are not to be construed to limit, the present invention. For oral administration, 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. polyvinylpyrrolidone or hydroxypropyl methylcellulose), lubricants (e.g. magnesium stearate, talk or silica). Tablets may be created by methods well known in the art using, e.g. acetylphtalylcellulose. Formulations for injection may be prepared in unit dosage form, e.g. in ampoules or in multi-dose containers, with an added preservative.

Specific examples of the 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. For additional acids, one can refer to "Pharmaceutical Salts", J. Pharm. Sci., 1977; 66(1): 1-19.

EXAMPLES

The following Examples serve to further illustrate the present invention and are not to be construed as limiting its scope in any way.

Compounds of the Examples prepared according to methods A-D described below:

1) 3,3-dimethyl-l,2-diazacyclopropane; mass: M⁺ = 73, b.p. 106 °C (760 Torr), m.p.40 °C

2) 3,3-diethyl-l,2-diazacyclopropane; mass: M⁺ = 101, b.p. 58 °C (24 Torr), m.p.56 °C. The structure was supported by X-ray diffraction study (See Figure 1). For spectral data, see Figure 2 below.

3) 3,3-pentamethylene-l,2-diazacyclopropane (DA); mass: M⁺ = 1 13, m.p. 104-105 °C. For spectral data see fig. 3 below.

4) 3,3-heptamethylene - 1 ,2-diazacyclopropane; mass: M⁺= 141, m.p. 40-41 °C.

5) 3,3-(4-methylpentamethylene)-l,2-diazacyclopropane (MP-3); mass: M⁺ = 127, m.p. 81-82 °C.

For spectral data see fig. 4 below.

6) 3 -ethyl-3 -methyl- 1 ,2-diazacyclopropane; mass: M⁺ = 87, b.p. 32 °C (17 Torr), m.p.22 °C 7) 3 -hexyl-3 -methyl- 1,2-diazacyclopropane; M = 142.

8) 3,3-di(2-phenylmethyl)- 1,2-diazacyclopropane; mass: M = 225, m.p. 95-95.5 °C, ^!H NMR: 2.86, 3.04 (both m., 4H, CH₂), 1.7 (br. s. 2H, NH), 7.1-7.6 (Ph).

9) 3 -n.propyl- 1,2-diazacyclopropane; mass: M⁺= 87, b.p. 47-49 (30 Torr),

10) 3-butyl- 1,2-diazacyclopropane; mass: M⁺ = 101.

11) 3-(2-phenylethyl)- 1,2-diazacyclopropane; mass: M⁺= 149.

12) 3-(2-(dimethylamino)ethyl)- 1,2-diazacyclopropane; mass: M = 1 16.

13) 3,3-tetramethylene- 1,2-diazacyclopropane; mass: M⁺ = 99, m.p. 75 °C.

14) 3,3-(2-methylpentamethylene)- 1,2-diazacyclopropane; mass: M = 127.

15) 3,3-(3-methyl-3-azapentamethylene)- 1,2-diazacyclopropane; mass: M = 128.

16) 3, 3-(3-(dimethylamino)pentamethylene)- 1,2-diazacyclopropane; mass: M⁺ = 156.

17) 3, 3 -di(2-pyridin-4-ylethyl)- 1,2-diazacyclopropane; mass: M⁺ = 255.

18) 3,3-(2-oxapentamethylene)- 1,2-diazacyclopropane; mass: M⁺= 1 15, m.p. 133 °C.

19) 3-methyl-3-(acetylaminomethyl)- 1,2-diazacyclopropane; mass: M = 130,

Compounds of the examples were prepared according to general methods A, B, C or D.

Elemental analysis was performed by the CHN Analyzer Perkin-Elmer 2400. All new compounds gave satisfactory elemental analyses. The IR spectra (v, cm^"1) were measured using a SPECORD-M82 spectrometer. The NMR spectra of all compounds were recorded using a Bruker AM-300 spectrometer at 300 MHz for ^!H in CDCI₃ (δ, ppm). The chemical shifts of the signals of CDCI₃ residual proton (7.27 ppm) and carbon (77.0 ppm) were used as the internal standard. Mass-spectra were measured Finigan MAT INCOS-50 instrument. Analytical thin-layer chromatography (TLC) was conducted on silica gel plates (Silufol UV-254).

General methods for the synthesis of 1,2-diazacyclopropane compounds of Formula I:

A. The first method is presented on scheme 1.

R R

^=0 + NH₃ + H₂NOS0₃H - ^HN^7\,.

R' H₂0 N R

Scheme 1

Liquid N¾ (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. at room temperature, the solids filtered off and washed with 3x50 ml of MeOH, and the combined MeOH filtrates evaporated in vacuo on a water bath to yield 5.6 g (50%) of 6-methyl- 1 ,2-diazaspiro [2,5] octane [3,3-(4-methipentamethylene-l,2- diazacyclopropane) (compound 5), m.p. 81-82 °C.

B. The second method is described on scheme 2.

R R

+ NH₃ + H₂NCI - ^ΗΝ ^ρ.

R' H₂0 N ^R

Scheme 2

To solution of 8.6 g (0.1 mol) pentan-3-one in 150 ml MeOH 25 ml of liquid NH₃ was added at -30° and 5.5 g. C¾ was passed at the same temperature. After 4 hrs. at -5° a slurry from which NH₄C1 was filtered out; filtrate was evaporated in vacuo and 4.0 g (40%) of 3,3-diethyl-l,2-diazacyclopropane (compound 2) was isolated; b.p. 58 ⁰ C (24 Torr), m.p. 56° C. Similarly, from CsHnCOEt in EtOH was prepared 3-amyl-3-ethyl- l,2- diazacyclopropane, 78° (2 Torr), from cyclohexanone in ligroine, 3,3-pentamethylene-l,2- diazacyclopropane (compound 3) m.p. 104-5° (recrystallized from cyclohexane).

C. The third method is presented on scheme 3:

^R R NH_{3 Ull} R =0 + H₂NCI - =N-CI → HN——p

R- R- R-

Scheme 3

The compounds formula I were prepared from N-chloroketimines and N¾ in an ale. solvent. Thus, a solution of lmol (132 g) cyclohexyl-N-chloroketimine in 300 ml of MeOH was saturated with N¾ 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 N¾ 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 NaHC0₃ in 1500 ml H₂0 at 0-5° with 150 g Cl₂. The obtained solution of N- dichlorohexylamine was added at 0- 10° to 300 ml MeOH saturated with N¾ to yield a methanolic solution of compound 3 (80% iodomethric titration). D. The forth method is presented on scheme 4.

R NH,

=0 + H₂NOS0₂R" =N-OS0₂R"

R" R" N R"

H

R" = OH, Ar

Scheme 4

Hydroxylamin-O-sulfonic acid (0.5 mol) was added at -10 to -5 °C to a solution of aldehyde (o.5 mol) in water (60 ml) and the mixture was stirred for 15-20 min until it no longer reacted with an acidified solution of KL Then the solution of aldoxime-O- sulfonic acid thus obtained was added dropwise at -20 to - 18 °C to an aqueous solution of ammonia (300 g 47%). The reaction mixture was stirred for 8-10 h at 0-2 °C with a moderate flow of ammonia being passed through. The mixture was then allowed to stand overnight at 0 °C and stirred for 10 h at 18-20 °C under a flow of ammonia. The aqueous diaziridine solution was distilled off using a rotary evaporator into a vessel cooled with dry ice, and the product was distilled three times from solid alkali. Yield for 3-propyl- 1,2-diazacyclopropane (compound 9) 22%.; b.p. 47-49 (30 Torr), η ⁰1.4478, IR-spectra: 3220 cm^"1; ^!H NMR (δ, ppm) 0.94 (t, 3H, Me), 1.43 (m, 4H, CH₂CH₂), 1.72 (br. s. 1H, NH), 2.34 (br. s. 1H, NH), 2.92 (t, 1H, CH). Mass-spectra: M⁺ = 87.

The synthetic procedures performed to prepare compounds of formula I are fully described described in following publications:

1. J.J. Fuchs, US Pat . 6655472, 1966.

2. R.F. Chruch, A.S. Kende, M.J. Weiss, J. Am. Chem. Soc, 1965, 87, 2665.

3. H.J. Abendroth, G. Henrlich, Angew. Chem., 1959, 71, 283.

4. S.R. Paulsen, G. Huck, Chem. Ber., 1961, 94, 968.

5. H.J. Abendroth, G. Henrlich, Ger. Pat. 1082889, 1958; Chem. Abst.. 1963, 58, 1463a.

6. E. Schmitz, R. Ohme, Chem. Ber., 1961 , 94, 2166.

7. H.J. Abendroth, Ger. Pat. 1089878, 1960; Chem. Abst.. 1962, 57, 3289j.

8. Ch,J. Paget, Ch.S. Davis, J. Med. Chem., 1964, 7, 626.

9. H.J. Abendroth, G. Henrlich, Angew. Chem., 1961, 73, 67.

10. E. Schmitz, R. Ohme, Org. Synthesis, 1965, 45, 83.

11. J. Uebel, J.C. Martin, J. Am. Chem. Soc, 1964, 86, 4618.

12. A. Stark, E. Schmitz, D. Habisch, Angew. Chem., 1963, 75, 725. 13. E. Schmitz, Ch. Horig, Ch. Grundemann, Chem. Ber., 1967, 100, 2101, 2093.

14. A.N. Mikhailuyk, N.N. Makhova, A.E. Bova, L.I. Khmel'nitskii, S.S. Novikov, Bull. Acad. Sci. USSR, Division Chem. Sci., 1978, 1566.

15. N.N. Makhova, V.Yu. Petukhova, L.I. Khmel'nitskii, Bull. Acad. Sci. USSR, Division Chem. Sci., 1982, 2107.

16. A.N. Mikhailuyk, V.Yu. Petukhova, N.N. Makhova, Mendeleev. Commun., 1997, 60.

It is known that both nitrogen atoms in diazacyclopropane ring are chiral.

However attempts to separate enantiomeric mixtures of 1 ,2-unsubstituted derivatives were unsuccessful since nitrogen inversion barrier in such compounds is very low. It is believed that NH-proton dissociation and recombination cannot be excluded as a possible interconversion mechanism for NH-containing diazacyclopropane (M. Mintas and A. Mannschreck, Tetrahedron, 1981, 37, 867.)

The following biological examples are illustrative to demonstrate the potential usefulness of compounds of formula I for the prevention and treatment of symptoms of depressive disorders and but not limiting the invention.

Biological examples.

Example 1.

Behavioral despair test.

Animals. White male mice (25-28 g) were used to investigate biological activity.

Behavioral despair was proposed as a model to test for antidepressant activity by Porsolt et al. It was suggested that mice or rats forced to swim in a restricted space from which they cannot escape are induced to a characteristic behavior of immobility. This behavior reflects a state of despair which can be reduced by several agents which are therapeutically effective in human depression.

The male white 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

p<0.05 compared to control

Compounds of Examples 1 -2, 4- 17 decrease time of drift for ~ 50 %. Example 2.

Antipsychotic activity assessed using apomorphine verticalisation model.

Animals. 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. 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.

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).

Statistical data processing was performed using "BioStat" tool for Windows. 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 (solvent) using a Mann and Whitney U test, with a probability p<0.05. Table 2

p<0.05 compared to control

Verticalisation reduction was statistically significant, therefore compound of Example 3 has promising antipsychotic activity.

Compounds of Examples 1-2, 4-17 decrease verticalisation parameter for ~ 30 %.

Example 3.

Animals. White male rats (250-280 g) were used to investigate biological activity.

Passive avoidance test

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. When the rat entered the dark compartment, the door automatically closed and an electrical foot shock (0.45 mA, 5 times of Is impulse) was delivered through the stainless steel rods. Twenty- four hours after this acquisition trial, the mouse was again placed in the illuminated compartment for a retention trial. The time taken for a rat to enter the dark compartment after door opening was defined as latency time for both acquisition and retention trials.

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.

Table 3

p<0.05 compared to control (group 1)

Compounds of Examples 1-2, 4- 17 decrease percentage of animals not-entering dark box to < 30 %. Example 4.

Black and white box test.

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.

The C57BL/6J mice were treated intraperitoneally with compound of the invention, then anxiolytic efficacy of compounds of formula I was assessed by estimating the number of entries to the light zone (see table 5 below).

Example 5.

Learned helplessness test.

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.

The C57BL/6J 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).

Example 6.

Animals. White male Balb/c mice (25-28 g) were used to investigate biological activity. Elevated plus-maze model of anxiety

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.

The animals were divided into two groups and treated as follows. The 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.

Statistical data processing was performed using "BioStat" tool for Windows.

Table 4

Defecation Time in open Open arm Time in close Close arm number arms, s entries arms, s entries

Control

1.6±0.4 54.0±13.3 3.5±1.2 128.3±27.6 6.3±1.2 (group 1), n=10

Example 3 (DA),

70 mg/kg, n= 10 0.63±0.4 144.6±16.4* 37.3±13.4* 4.4±1.4 (group 2)

p<0.05 compared to control according to Mann and Whitney test Compound of Example 3 (DA) showed have strong anxiolytic effect as time in open arms increased more than twice and this difference is statistically significant.

Example 7

The studies of sedative/activating effect of diaziridine MP-3 (compound of example 5, 3,3-(4-methylpentamethylene)-l,2-diazacyclopropane).

Study methods

The sedative/activating effects of the compounds were studied in experiments on mature outbred mice male mice weighted 24-3g

In the study, open field test was made (Voronina T.A., Seredenin S.B., 2005).

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:

Control - 10 mice

MP 3 in dose 70 mg/kg - 10 mice

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).

The study results:

The effect of compounds on horizontal motor activity of animals in the open field.

It is specified that compound MP-3 significantly increased horizontal motor activity of animals in the open field in comparison with control (Table 5).

Compound MP 3 decreased horizontal motor activity on 13.5%. Table 5 Effect of MP-3 on mice behavior in the open field test, Mean±SEM

- p<0,005 in comparison with control group, Student's test

The effect of MP-3 on vertical motor activity of animals in the open field.

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.

Exploratory activity in the open field test was evaluated based on hole exploratory behavior. MP-3 was able to attenuate exploratory activity of animals which showed as significant decrease of hole exploratory behavior in comparison with control. Compounds MP-3 decreased hole exploratory behavior in 1.6 times, The obtained data showed sedative activity of MP-3.

Compound MP-3 reduced motor (horizontal and vertical) activity in a greater extent and exploratory activity - in the lesser extent

Example 8.

The study of anxyolitic (anti-panic) effects of diaziridine MP-3 (3,3-(4- methylpentamethylene)-l,2-diazacyclopropane).

The anxyolitic effect of compounds was studied in experiments on linear white male mice line Balb/weighted 22-26g

In the study, the basic test "elevated plus maze" was used for evaluation of anxiolytics (Voronina T.A. Seredenin S.B., 2005; Pellow et al., 1985; Oliver B et al., 1991).

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.

The following values were registered: number of open and closed-arm entries, time spent in open and closed arms, time spent in the central area, number of fecal boluses.

Anxiolytics with various chemical structure and mode of action relieved anxiety in mice which were placed to new conditions when animals felt height and light fear in open arms of the maze.

The behavior of control animals in the test of elevated plus maze was characterized by evident anxiety and animals spent most of the time in closed arms, less time -in open arms, rarely visited the central area and had many bowel movements (Table 8).

It was established that 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).

Table 6. Effect of compound MP-3 on animal behavior in test of elevated plus maze, Mean+SEM

p< 0,05 significance of differences in comparison with control group

It was specified that after administration of MP-3, the residence time of animals in the open arms was increased in 7.3 times, and number of open-arm entries was increased in 3.9 times in comparison with control. Besides, compound MP-3 significantly increased anti-anxiety index. So after administration of MP-3, the ratio between time spent in open arms and total observation time was 0.47±0.05 (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.

So a test compounds MP-3, which were taken as single doses 70 mg/kg (i/p) had anxyolitic activity in test "elevated plus maze" and affected both behavioral (time and motor parameters) and somatic -vegetative values of anxiety.

Example 9.

Toxicity test.

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).

Table 5

**p<0.05 compared to control (non-treated animals)

The examples above demonstrate that compounds of Examples 1 - 17 are very promising as antidepressive, antipsychotic, antiamnesic drugs and neuroprotective agents. In sum, a novel class of drugs for treatment of mental and neurological disorders of different etiology was investigated in the invention.

While several particular forms of the invention have been illustrated and described, it will be apparent that various modifications and combinations of the invention detailed in the text and drawings can be made without departing from the spirit and scope of the invention. For example, references to materials of construction, methods of construction, specific dimensions, shapes, utilities or applications are also not intended to be limiting in any manner and other materials and dimensions could be substituted and remain within the spirit and scope of the invention. For example, the compounds of the general formula I described herein can be obtained by one of ordinary skill in the art according to the methods described in the patent. The substituents or their protected derivatives may be parts of staring materials. The protecting groups of some of the substituents can be removed by methods known to those of ordinary skill in the art and readily available, for example, in conventional organic synthesis books and texts. Accordingly, it is not intended that the invention is limited, except as by the appended claims.

As noted above, 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. To address this potential for degradation, 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.

The Core

A preferred core for the pellet is prepared by applying a compound-containing layer to an inert bead. Such 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. However, 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. In general, 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. Pharmaceutical scientists are aware of and conventionally use many such substances, most of them polymers.

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.

Separating Layer

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.

In some cases, 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.

In general, the separating layer is composed of coherent or polymeric materials, and finely powdered solid excipients which constitute fillers. When 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. In addition to or instead of the sugar, a polymeric material may also be used in the separating layer. For example, 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.

It is further advisable to use 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.

Enteric Layer

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. Examples of 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. 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.

Finishing 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. For example, 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. Such 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 following formulation examples provide guidance in making a formulation of the disclosed compounds. Formulation Example 1

10 mg compound/capsule

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. When the drug layer is fully formed, 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. Next, 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. Then 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.

Finally, the finishing layer is to be created by adding the beeswax to the product in the fluidized bed at 60°C. After cooling, 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.

Formulation Examples 2 and 3

Manufacture of tablet cores batch

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.

Subcoating

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.

Next 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.

Enteric coating

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.

Claims

WHAT IS CLAIMED IS:

Use of compounds of formula I to treat mental and neurological disorders.

wherein

- O-COO-R¹, -CSR¹, -C(S)NR¹R², -SR¹,

wherein each member of R and R' 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 the 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,

and with the proviso that both R and R^' cannot be hydrogens,

or pharmaceutically acceptable derivatives, tautomeric forms, stereoisomers, stereoisomeric mixtures, polymorphs, prodrugs, metabolites, salts or solvates thereof, and pharmaceutical compositions containing such compounds.

2. A pharmaceutically acceptable salt or solvate of the compound of claim 1.

3. A pharmaceutical composition comprising the compound of claim 1 and one or more pharmaceutically acceptable excipients.

4. The pharmaceutical composition of claims 1-3, wherein the composition comprises a tablet or a capsule.

5. The pharmaceutical composition of claims 1-3 for treatment of psychotic and mental disorder of different etiology.

6. The pharmaceutical composition of claims 1-3 for treatment of 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.

7. The pharmaceutical composition of claims 1-3 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 melancholic depression, resistant depression, severe depression, and psychotic depression, dissociative amnesia, dissociative disorder, dissociative fugue, dissociative identity disorder, dyspareunia, dyssomnia, dyssomnia related to another disorder, dysthymic disorder, eating disorder, exhibitionism, female dyspareunia due to medical condition, female hypoactive sexual desire disorder due to medical condition, female orgasmic disorder, female sexual arousal disorder, fetishism, frotteurism, gender identity disorder in adolescents or adults, gender identity disorder in children, gender identity disorder, generalized anxiety disorder, histrionic personality disorder, hypoactive sexual desire disorder, hypochondriasis, impulse-control disorder, insomnia, insomnia related to another disorder, intermittent explosive disorder, kleptomania, labile or saddened mood, major depressive disorder in full remission, major depressive disorder in partial remission, male dyspareunia due to medical condition, male erectile disorder, male erectile disorder due to medical condition, male hypoactive sexual desire disorder due to medical condition, male orgasmic disorder, mood disorder due to medical condition, narcissistic personality disorder, narcolepsy, nightmare disorder, obsessive compulsive disorder, obsessive-compulsive personality disorder, other female sexual dysfunction due to medical condition, other male sexual dysfunction due to medical condition, pain disorder associated with both psychological factors and medical conditions, pain disorder associated with psychological features, panic disorder with agoraphobia, panic disorder without agoraphobia, paranoid personality disorder, paraphilia,, parasomnia, pathological gambling, pedophilia, personality disorder, posttraumatic stress disorder, premature ejaculation, premenstrual associated depression, primary hypersomnia, primary insomnia, psychosis of different etiology, particularly alcohol psychosis, circular psychosis, involutional psychosis, psychosis associated with dementia, psychosis associated with Alzheimer's disease, psychosis associated with an organic brain syndrome, and drug-induced psychosis, psychotic disorder due to medical condition with delusions, psychotic disorder due to medical condition with hallucinations, pyromania, schizoaffective disorder, schizoid personality disorder, schizophrenia of catatonic type, schizophrenia of disorganized type, schizophrenia of paranoid type, schizophrenia of residual type, schizophrenia of undifferentiated type, schizophreniform disorder, schizotypal personality disorder, sexual aversion disorder, sexual disorder, sexual dysfunction, sexual masochism, sexual sadism, shared psychotic disorder, sleep disorder due to a medical condition of hypersomnia type, sleep disorder due to a medical condition of insomnia type, sleep disorder due to a medical condition of mixed type, sleep disorder due to a medical condition of parasomnia type, sleep terror disorder, sleepwalking disorder, social phobia, somatization disorder, somatoform disorder, specific phobia, substance disorder, transvestic fetishism, trichotillomania, undifferentiated somatoform disorder, suicide intention, suicide, unmotivation, vaginismus, voyeurism.

8. The pharmaceutical composition of claims 1-3 for treatment of depression of different etiology, particularly melancholic depression, resistant depression, severe depression, and psychotic depression.

9. The pharmaceutical composition of claims 1-3 for treatment of psychosis of different etiology, particularly alcohol psychosis, circular psychosis, involutional psychosis, psychosis associated with dementia, psychosis associated with Alzheimer's disease, psychosis associated with an organic brain syndrome, and drug-induced psychosis.

10. The pharmaceutical composition of claims 1-3 for treatment of neurological disorder of different etiology.

11. The pharmaceutical composition of clams 1-3 for treatment of 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, benign essential blepharospasm, benign intracranial hypertension, bilateral frontoparietal polymicrogyria, Binswanger's disease, blepharospasm, Bloch-Sulzberger syndrome, brachial plexus injury, brain abscess, brain damage, brain injury, brain tumor, Brown-Sequard syndrome, Canavan disease, carpal tunnel syndrome, causalgia, central pain syndrome, central pontine mye lino lysis, centronuclear myopathy, cephalic disorder, cerebral aneurysm, cerebral arteriosclerosis, cerebral atrophy, cerebral gigantism, cerebral palsy, cerebral vasculitis, cervical spinal stenosis, Charcot-Marie-tooth disease, chiari malformation, chorea, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic pain, Coffin-Lowry syndrome, coma, complex regional pain syndrome, compression neuropathy, congenital facial diplegia, corticobasal degeneration, cranial arteritis, craniosynostosis, Creutzfeldt- Jakob disease, cumulative trauma disorders, Cushing's syndrome, cytomegalic inclusion body disease (CIBD), cytomegalovirus infection, Dandy- Walker syndrome, Dawson disease, De Morsier's syndrome, Dejerine-Klumpke palsy, Dejerine-Sottas disease, delayed sleep phase syndrome, dementia, dermatomyositis, developmental dyspraxia, diabetic neuropathy, diffuse sclerosis, Dravet syndrome, dysautonomia, dyscalculia, dysgraphia, dyslexia, dystonia, empty sella syndrome, encephalitis, encephalocele, encephalotrigeminal angiomatosis, encopresis, epilepsy, Erb's palsy, erythromelalgia, essential tremor, Fabry's disease, Fahr's syndrome, fainting, familial spastic paralysis, febrile seizures, Fisher syndrome, Friedreich's ataxia, fibromyalgia, Foville's syndrome, Gaucher's disease, Gerstmann's syndrome, giant cell arteritis, giant cell inclusion disease, globoid cell leukodystrophy, gray matter heterotopia, Guillain-Barre syndrome, HTLV- 1 associated myelopathy, Hallervorden-Spatz disease, head injury, headache, hemifacial spasm, hereditary spastic paraplegia, heredopathia atactica polyneuritiformis, Herpes zoster oticus, Herpes zoster, Hirayama syndrome, holoprosencephaly, Huntington's disease, hydranencephaly, hydrocephalus, hypercortisolism, hypoxia, immune-mediated encephalomyelitis, inclusion body myositis, incontinentia pigmenti, infantile phytanic acid storage disease, infantile refsum disease, infantile spasms, inflammatory myopathy, intracranial cyst, intracranial hypertension, Joubert syndrome, Karak syndrome, Kearns-sayre syndrome, Kennedy disease, Kinsbourne syndrome, Klippel feil syndrome, Krabbe disease, Kugelberg-Welander disease, kuru, Lafora disease, Lambert-Eaton myasthenic syndrome, Landau-Kleffner syndrome, lateral medullary (wallenberg) syndrome, learning disabilities, Leigh's disease, Lennox-Gastaut syndrome, Lesch-Nyhan syndrome, leukodystrophy, lewy body dementia, lissencephaly, locked-in syndrome, Lou Gehrig's disease, lumbar disc disease, lumbar spinal stenosis, Lyme disease, Machado-Joseph disease, macrencephaly, macropsia, megalencephaly, Melkersson-Rosenthal syndrome, Menieres disease, meningitis, Menkes disease, metachromatic leukodystrophy, microcephaly, micropsia, migraine, Miller Fisher syndrome, mini-stroke (transient ischemic attack), misophonia, mitochondrial myopathy, Mobius syndrome, monomelic amyotrophy, motor neurone disease, motor skills disorder, moyamoya disease, mucopolysaccharidoses, multi-infarct dementia, multifocal motor neuropathy, multiple sclerosis, multiple system atrophy, muscular dystrophy, myalgic encephalomyelitis, myasthenia gravis, myelinoclastic diffuse sclerosis, myoclonic encephalopathy of infants, myoclonus, myopathy, myotubular myopathy, myotonia congenita, narcolepsy, neurofibromatosis, neuroleptic malignant syndrome, neurological manifestations of aids, neurological sequelae of lupus, neuromyotonia, neuronal ceroid lipofuscinosis, neuronal migration disorders, Niemann-Pick disease, non 24-hour sleep- wake syndrome, nonverbal learning disorder, O'Sullivan-McLeod syndrome, occipital neuralgia, occult spinal dysraphism sequence, Ohtahara syndrome, olivopontocerebellar atrophy, opsoclonus myoclonus syndrome, optic neuritis, orthostatic hypotension, overuse syndrome, palinopsia, paresthesia, Parkinson's disease, paramyotonia congenita, paraneoplastic diseases, paroxysmal attacks, Parry-Romberg syndrome, Pelizaeus- Merzbacher disease, periodic paralyses, peripheral neuropathy, persistent vegetative state, pervasive developmental disorders, photic sneeze reflex, phytanic acid storage disease, Pick's disease, pinched nerve, pituitary tumors, polio, polymicrogyria, polymyositis, porencephaly, post-polio syndrome, postherpetic neuralgia (PHN), postinfectious encephalomyelitis, postural hypotension, Prader-Willi syndrome, primary lateral sclerosis, prion diseases, progressive hemifacial atrophy, progressive multifocal leukoencephalopathy, progressive supranuclear palsy, pseudotumor cerebri, rabies, Ramsay hunt syndrome type I, Ramsay hunt syndrome type II, Ramsay hunt syndrome type III, Rasmussen's encephalitis, reflex neurovascular dystrophy, Refsum disease, repetitive stress injury, restless legs syndrome, retrovirus-associated myelopathy, Rett syndrome, Reye's syndrome, rhythmic movement disorder, Romberg syndrome, Saint Vitus dance, Sandhoff disease, schizophrenia, Schilder's disease, schizencephaly, sensory integration dysfunction, septo-optic dysplasia, shaken baby syndrome, shingles, Shy- Drager syndrome, Sjogren's syndrome, sleep apnea, sleeping sickness, snatiation, Sotos syndrome, spasticity, spina bifida, spinal cord injury, spinal cord tumors, spinal muscular atrophy, spinocerebellar ataxia, Steele-Richardson-Olszewski syndrome, Stiff-Person syndrome, stroke, Sturge-Weber syndrome, subacute sclerosing panencephalitis, subcortical arteriosclerotic encephalopathy, superficial siderosis, Sydenham's chorea, syncope, synesthesia, syringomyelia, tarsal tunnel syndrome, tardive dyskinesia, tardive dysphrenia, Tarlov cyst, Tay-Sachs disease, temporal arteritis, tetanus, tethered spinal cord syndrome, Thomsen disease, thoracic outlet syndrome, tic douloureux, Todd's paralysis, Tourette syndrome, toxic encephalopathy, transient ischemic attack, transmissible spongiform encephalopathies, transverse myelitis, traumatic brain injury, tremor, trigeminal neuralgia, tropical spastic paraparesis, trypanosomiasis, tuberous sclerosis, Von Hippel-Lindau disease (VHL), viliuisk encephalomyelitis (VE), Wallenberg's syndrome, Werdnig-Hoffman disease, West syndrome, whiplash, Williams syndrome, Wilson's disease, Zellweger syndrome.

12. The pharmaceutical composition of claims 1-3 potentially useful for treatment of HIV or AIDS.

13. The pharmaceutical composition of claims 1 -3 for treatment of Alzheimer's disease.

14. The pharmaceutical composition of claims 1-3 for treatment of Parkinson's disease.