JP2015508417A - Diaziridine for the treatment of neurodegenerative disorders - Google Patents

Abstract

The present invention relates to compounds of formula I and their use for the treatment of psychiatric and neurological disorders, in particular depression and psychosis of various etiologies. Compounds provided for the treatment of psychiatric and neurological disorders include those represented by general formula I, or pharmaceutically acceptable salts, hydrates thereof and the like, and such A pharmaceutical composition containing a compound: wherein R, R ′, Y are as defined herein. [Selection figure] None

Description

(Cross-reference of related applications)
This application claims priority from US Provisional Patent Application No. 61 / 591,270, filed January 26, 2012, the contents of which are hereby incorporated by reference in their entirety. It has been incorporated.

(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, in particular various 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 are symptoms such as paralysis, muscle weakness, coordination failure, sensory loss, seizures, confusion, pain and altered consciousness Can result. There are many recognized neurological disorders, some of which are fairly common, but many are rare. These are revealed by neurological experiments and can be studied and treated within the expertise of neurology and clinical neuropsychology. Interventions include preventive measures, lifestyle changes, physical or other therapies, neurorehabilitation, pain management, medication, or surgery performed by a neurosurgeon. The World Health Organization (WHO) estimated in 2006 that neurological disorders and their sequelae affect 1 billion people worldwide, and as a major factor contributing to related dysfunction and distress Established health inequality and social thumbprint / discrimination [http://www.who.int/mental_health/neurology/neurodiso/en/index.html]. A mental disorder or psychiatric disorder is a psychological or behavioral pattern that is generally associated with distress or dysfunction and is not considered part of normal development or an individual's background. Such disorders are defined by a combination of emotional, behavioral, cognitive or perceptual components, which are often associated with specific functions or areas of the brain or nervous system in social situations. obtain. The recognition and understanding of mental health status has changed across cultures over time, and there are still variations in definition, evaluation and classification, but the criteria that guide the standard are widely used. More than a third of people in most countries report that problems at some point in their lives meet the general diagnostic criteria for one or more mental disorders.

  The causes of psychiatric disorders are diverse, unknown in some cases, and theories can incorporate findings from various fields. Services are based at psychiatric hospitals or in the community, and assessments are performed by psychiatrists, clinical psychologists, and sometimes psychiatric social workers, but often for observation and interviews. Relying and executed. Clinical treatment is provided by various mental health professionals. Psychotherapy and psychotic medication are two major treatment options, such as social intervention, peer support and self-help. In a few cases, compulsory detention or forced treatment is provided, as permitted by law. Thumbprint and discrimination are added to distress and dysfunction related to mental disorders (or related to diagnosis or determination of having a mental disorder), which is a variety of societies that attempt to challenge increased understanding and social exclusion. Is connected to the movement.

  The main option for many psychiatric disorders is psychiatric medication, and there are several main groups. In addition to clinical depression, antidepressants are sometimes used to treat anxiety and various other disorders. Anti-anxiety drugs (including sedatives) are used for related problems such as anxiety disorders and insomnia. Mood stabilizers are mainly used in bipolar disorder. Antipsychotics are used for psychotic disorders, particularly for positive symptoms of schizophrenia, and also for a variety of other disorders. Psychostimulants are commonly used, especially for ADHD.

Although these drug groups have different names, there are considerable overlaps in the indications that are actually indicated, and they are also used outside approved indications for drug treatment. There are problems of adverse effects of drug treatment and adherence to them, as well as criticism of the pharmaceutical industry and conflicting interests of experts [WebMD Inc (1 July 2005). “Mental Health: Types of Mental Illness”, http://www.webmd.com/mental-health/mental-health-types-illness, retrieved April 19, 2007].
Thus, there is a certain need to design and develop new classes of drugs for the treatment of psychiatric and neurological disorders of various etiologies.

(式中：
R及びR’は、互いに独立して、水素、アルキル、ハロアルキル、アルコキシ、アミノアルキル、アルケニル、アルキニル、アリール、シクロアルキル、ヘテロシクロアルキル、ヘテロアリール、アリールアルキル、シクロアルキルアルキル、複素環式アルキル、ヘテロアリールアルキル、COR¹、COOR¹、CONHR¹、CON(R¹)₂、OR¹、NR¹R²、N(R¹)₂、SR¹、NR¹-SO₂-R²、NR¹-SO₂-NR²R³、NR¹-CO-NR²R³、-SO-R¹、-SO₂-R¹、-SO₂-NR¹R²、-NR¹COR²、-OCO-NR¹R²、-NR¹-COOR²、-O-COO-R¹、-CSR¹、-C(S)NR¹R²、-SR¹から選択され、
ここで、R及びR’の各員は、任意に置換されており、
R¹、R²、R³は、独立して、水素、アミノ、アルキル、ハロアルキル、アルコキシ、アミノアルキル、アルケニル、アルキニル、アリール、シクロアルキル、ヘテロシクロアルキル、ヘテロアリール、アリールアルキル、シクロアルキルアルキル、複素環式アルキル、ヘテロアリールアルキルから選択され、ここでR¹、R²、R³の各員は、任意に置換されており、
同じ炭素に結合したR及びR’は、それらが結合した炭素と一緒に、任意に不飽和であることができる、シクロアルキレン、ヘテロシクロアルキレンから選択された環を形成することができ、ここで言及されたシクロアルキレン、ヘテロシクロアルキレンは任意に置換され、該シクロアルキレン又はヘテロシクロアルキレンは、別の1個又は複数の環(cycle)と縮合されてよく、
Yは、水素、ハロゲン又は水素の任意の同位体であり、好ましくは水素であり、
但し、一般式Iの化合物が、2個以上のジアジリジン(1,2-ジアザシクロプロパン)環(ring)(環(cycle))を含む場合、該ジアジリジン(1,2-ジアザシクロプロパン)環(ring)(環(cycle))は全て、両方の窒素原子で置換されないことを条件とし、
並びに、但しR及びR’の両方は水素であることはできないことを条件とする。)。 (Summary of Invention)
The present invention relates to compounds of formula I, the use of these compounds for treating mental disorders and neurological disorders, in particular depression and psychosis of various etiologies. The compounds provided for the treatment of psychiatric and neurological disorders can be represented by the general formula I, or pharmaceutically acceptable derivatives, tautomers, stereoisomers, mixtures of stereoisomers, polymorphs, pro Represented by drugs, metabolites, salts or solvates, and pharmaceutical compositions containing such compounds:

(Where:
R and R ′ are independently of each other hydrogen, alkyl, haloalkyl, alkoxy, aminoalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, arylalkyl, cycloalkylalkyl, heterocyclic alkyl, Heteroarylalkyl, COR ¹ , COOR ¹ , CONHR ¹ , CON (R ¹ ) ₂ , OR ¹ , NR ¹ R ² , N (R ¹ ) ₂ , SR ¹ , NR ¹ -SO ₂ -R ² , NR ^1- SO ₂ -NR ² R ³ , NR ¹ -CO-NR ² R ³ , -SO-R ¹ , -SO ₂ -R ¹ , -SO ₂ -NR ¹ R ² , -NR ¹ COR ² , -OCO-NR ¹ R ² , -NR ¹ -COOR ² , -O-COO-R ¹ , -CSR ¹ , -C (S) NR ¹ R ² , -SR ¹
Where each member of R and R ′ is optionally substituted;
R ¹ , R ² , R ³ are independently hydrogen, amino, alkyl, haloalkyl, alkoxy, aminoalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, arylalkyl, cycloalkylalkyl, Selected from heterocyclic alkyl, heteroaryl alkyl, wherein each member of R ¹ , R ² , R ³ is optionally substituted;
R and R ′ attached to the same carbon, together with the carbon to which they are attached, can form a ring selected from cycloalkylene, heterocycloalkylene, which can be optionally unsaturated, where The mentioned cycloalkylene, heterocycloalkylene is optionally substituted, which cycloalkylene or heterocycloalkylene may be fused with one or more other cycles,
Y is hydrogen, halogen or any isotope of hydrogen, preferably hydrogen,
Provided that when the compound of general formula I contains two or more diaziridine (1,2-diazacyclopropane) rings (cycles), the diaziridine (1,2-diazacyclopropane) All rings (cycles) are subject to substitution on both nitrogen atoms,
And provided that both R and R ′ cannot be hydrogen. ).

  The compounds of formula I exhibit a high antidepressant and neuroprotective activity comparable to known antidepressants. They have low acute and chronic toxicity compared to known antidepressants, do not cause pathological changes in any of the internal, hematological and biochemical parameters and are therefore applied for a long time.

  A new class of Compound I provides the benefit of using them for the treatment of patients who are resistant to therapy with standard neuroprotective drugs, including those who are resistant to standard antidepressants.

  The present invention also includes anxiety disorder, adaptation disorder, eating disorder, personality disorder, mood disorder, physical expression disorder, personality disorder, sleep disorder, sleep disorder, psychotic disorder, eating disorder, physical expression disorder, dissociation It relates to psychotic disorders and psychiatric disorders of various etiologies, including sexual disorders, sexual disorders, sexual dysfunctions, gender identity disorders, impulse disorders, physical expression disorders, mood disorders, eating disorders, impulse control disorders. Compounds of formula I are also associated with acute stress disorder, unspecified adaptation disorder, adaptation disorder with anxiety, adaptation disorder with depressed mood, adaptation disorder with behavioral disruption, anxiety and depression Adjustment disorder, adaptation disorder with mixed emotion and behavior confusion, agoraphobia without history of panic disorder, anorexia, anorexia nervosa, antisocial personality disorder, anxiety disorder due to medical condition , Anxiety disorder, avoidance personality disorder, bipolar disorder, complete remission bipolar I disorder, partial remission bipolar I disorder, mild bipolar I disorder, moderate bipolar I disorder, psychotic Severe bipolar type I disorder with features, severe bipolar type I disorder without psychotic features, bipolar type II disorder, body dysmorphic disorder, borderline personality disorder, respiratory-related sleep disorder, short-term psychotic Disorder, bulimia nervosa, cannabis compound, diurnal Rhythm sleep disorder, conversion disorder, mood circulatory disorder, childhood disorder, cognitive disorder, delusional disorder, addiction personality disorder, divorce disorder, depression of various etiologies, especially melancholic depression, treatment resistance Depression, severe depression, and psychotic depression, dissociative amnesia, dissociative disorder, dissociative struggle, dissociative identity disorder, sexual intercourse pain, sleep disorder, sleep disorder associated with another disorder, mood Modulation disorder, eating disorder, exposure, female sexual pain due to medical condition, female sexual desire disorder due to medical condition, female orgasmic disorder, female sexual arousal disorder, fetishism, friction lover , Adolescent or adult gender identity disorder, childhood gender identity disorder, gender identity disorder, generalized anxiety disorder, acting personality disorder, sexual desire disorder, psychosis, impulse control disorder, insomnia Insomnia, intermittent, associated with another disorder Onset disorder, theft, instability or grief, complete remission major depressive disorder, partial remission major depressive disorder, male sexual pain due to medical condition, male erectile dysfunction, medical Male erectile dysfunction due to condition, male sexual desire disorder due to medical condition, male orgasmic disorder, mood disorder due to medical condition, self-love personality disorder, paroxysmal sleep, nightmare disorder, obsession Pain associated with sexual dysfunction, obsessive-compulsive personality disorder, other female sexual dysfunction due to medical condition, other male sexual dysfunction due to medical condition, both psychological factors and medical condition Disability, pain related to psychological features, panic disorder with agoraphobia, panic disorder without agoraphobia, paranoia-like personality disorder, sexual perversion, parasomnia, morbid gambling, pedophilia, personality disorder, After trauma Tres disorder, premature ejaculation, premenstrual depression, primary hypersomnia, primary insomnia, psychosis of various etiologies, especially alcohol psychosis, circulatory psychosis, regression psychosis, dementia related psychosis, Alzheimer's disease Psychosis, psychosis related to organic brain disorder, and drug-induced psychosis, psychotic disorder caused by medical condition with delusion, psychotic disorder caused by medical condition with hallucination, arson, schizophrenic emotion Disability, schizophrenic personality disorder, tension schizophrenia, destructive schizophrenia, delusional schizophrenia, remnant schizophrenia, indistinguishable schizophrenia, schizophrenia-like disorder, schizophrenia Personality disorder, sexual aversion disorder, sexual disorder, sexual dysfunction, sexual masochism, sexual sadism, shared psychotic disorder, sleep disorder caused by hypersomnia type medical condition, insomnia type medical condition Caused sleep disturbance Harm, sleep disorders caused by mixed medical conditions, sleep disorders caused by parasomnia-type medical conditions, night wonders, sleepwalking, interpersonal phobia, somatic disorder, physical expression disorder, specific phobia It can also be used for the treatment of substance-related disorders, clothes-inverted fetishism, hair loss, indistinguishable body expression disorders, suicidal ideation, suicide, unmotivation, vaginal spasticity, and sighting.

  The compounds of formula I are also associated with the treatment of neuropathies of various etiologies. For example, loss of weight sensation, acquired epileptiform aphasia, acute disseminated encephalomyelitis, adrenoleukodystrophy, agenesis of corpus callosum, agnosia, Aicardi syndrome, inability to sit still, Alexander disease, alien hand syndrome, contralateral sensory disorder, Alpers disease, alternating hemiplegia, Alzheimer's disease, amyotrophic lateral sclerosis, anencephalopathy, Angelman syndrome, hemangiomatosis, anoxia, aphasia, apraxia, arachnoid cyst, arachnoiditis, Arnold Chiari malformation, arteriovenous malformation, telangiectasia ataxia, attention deficit hyperactivity disorder, auditory processing disorder, autonomic dysfunction, back pain, Batten's disease, Behcet's disease, bell paralysis, benign essential eyelid spasm, benign skull Internal hypertension, bilateral frontal parietal cerebral gyrus, binswanger disease, blepharospasm, Bloch-Salzburger syndrome, brachial plexus injury, brain abscess, brain injury, brain Wound, brain tumor, Brown-Sekar syndrome, Canavan disease, carpal tunnel syndrome, causalgia, central pain syndrome, central pontine myelopathy, central myopathy, head disorder, cerebral aneurysm, cerebral arteriosclerosis, brain Atrophy, cerebral giantism, 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 laurie syndrome, coma, complex regional pain syndrome, pressure neuropathy, congenital facial paraparesis, basal ganglia degeneration, cranial arteritis, skull fusion, Creutzfeldt-Jakob disease, cumulative trauma Sexual disorder, Cushing syndrome, Giant cell inclusion body disease (CIBD), Cytomegalovirus infection, Dandy-Walker syndrome, Dawson's disease, Dumorsier syndrome, Degelin Krumpke paralysis, Dejerin-Sottas disease, sleep phase regression syndrome, dementia, dermatomyositis, developmental coordination disorder, diabetic neuropathy, pervasive sclerosis, Drave syndrome, autonomic dysfunction, computational impairment, writing disorder, Dyslexia, schizophrenia, empty sella syndrome, encephalitis, aneurysm, hemangiomatosis of the trigeminal region of the brain, fecal disease, epilepsy, elve palsy, extremity erythema, essential tremor, Fabry disease, Farle disease, syncope , Familial spastic paralysis, febrile seizures, Fischer syndrome, Friedreich ataxia, fibromyalgia, Fauille syndrome, Gaucher disease, Gerstmann syndrome, giant cell arteritis, giant cell inclusion body disease, globuloid cell cerebral white matter atrophy, Ectopic gray matter, Guillain-Barre syndrome, HTLV-1-related myelopathy, Hallelfolden-Spatz disease, head injury, headache, unilateral spasm, hereditary spasticity Paraplegia, hereditary polyneuropathy, ear shingles, shingles, Hirayama syndrome, global forebrain, Huntington's chorea, hydroencephalopathy, hydrocephalus, hyperadrenocorticism, hypoxia, immune-mediated brain Myelitis, inclusion body myositis, dystaxia, infantile phytanic acid accumulation, infantile lefsum disease, epilepsy, inflammatory myopathy, intracranial cyst, intracranial hypertension, Joubert syndrome, Karak syndrome, Keynes-Saire syndrome, Kennedy Disease, Kinsbrunn syndrome, Klippel file syndrome, Krabbe disease, Kugelberg-Wellander disease, Kourou disease, Lafora disease, Lambert-Eaton myasthenia syndrome, Landau-Krefner syndrome, lateral myelopathy (Walenberg syndrome), learning disability, Lee Disease, Lennox-Gastaut syndrome, Lesch-Nyhan syndrome, cerebral white matter atrophy, Lewy bodies Dementia, gyrus defect, confinement syndrome, Lou Gehrig's disease, lumbar disc disease, lumbar spinal canal stenosis, Lyme disease, Machado-Joseph disease, giant cerebral myelopathy, macroscopic syndrome, giant encephalopathy, Mercerson-Rozental syndrome , Meniere's disease, meningitis, Menkes disease, metachromatic leukotrophy, microcephaly, microcephaly, migraine, Miller-Fischer syndrome, microstroke (transient ischemic attack), sound phobia (misophonia) , Mitochondrial myopathy, Moebius syndrome, single limb atrophy, motor neuron disease, motor impairment, moyamoya disease, mucopolysaccharidosis, multiple infarct dementia, multifocal motor neuropathy, multiple sclerosis, multiple system atrophy, Muscular dystrophy, myalgic encephalomyelitis, myasthenia gravis, myelinating destructive diffuse sclerosis, infant myoclonic encephalopathy, myoclonus, myopathy, myotubular myopathy, Congenital myotosis, paroxysmal sleep, neurofibromatosis, neuroleptic malignant syndrome, neurological signs of AIDS, neurological sequelae of lupus, neuromyotonia, neuronal ceroid lipofuscinosis, neuronal cell migration disorder, Niemann-Pick disease, non-24-hour sleep-wake syndrome, nonverbal learning disorder, O'Sullivan MacLeod syndrome, occipital neuralgia, occult spinal insufficiency, Otawara syndrome, olive bridge cerebellar atrophy, ocular clonus-myoclonus syndrome, optic neuritis, Orthostatic hypotension, overuse syndrome, repetitive vision, sensory abnormalities, Parkinson's disease, congenital paramyotonia, paraneoplastic disorder, paroxymal attack, Parry-Lomberg syndrome, Pelizaeus-Merzbacher disease, periodic limb paralysis, Peripheral neuropathy, persistent plant condition, pervasive developmental disorder, light sneezing reflex, phytanic acid accumulation disease, Pick's disease Pinched nerve, pituitary tumor, polio, polypylosis, polymyositis, perforated encephalopathy, post-polio syndrome, postherpetic neuralgia (PHN), postinfectious encephalomyelitis, orthostatic hypotension, prada Villi syndrome, primary lateral sclerosis, prion disease, progressive facial unilateral atrophy, progressive multifocal leukoencephalopathy, progressive supranuclear palsy, pseudobrain tumor, rabies, type I Ramsey-Hunt syndrome, type II Ramsey Hunt Syndrome, Type III Ramsey Hunt Syndrome, Rasmussen Encephalitis, Reflex Neurovascular Dystrophy, Refsum's Disease, Repetitive Motor Injury, Restless Leg Syndrome, Retrovirus-Related Myelopathy, Rett Syndrome, Laie Syndrome, Rhythmic Movement Disorder, Lomberg syndrome, St. Vitus chorea, Sandhoff disease, schizophrenia, Schilder's disease, encephalopathy, sensory integration disorder, septal optic dysplasia, infant shake syndrome, Herpes zoster, Shy-Drager syndrome, Sjogren's syndrome, sleep apnea, sleep sickness, snatiation, sotos syndrome, spasticity, spinal cord injury, spinal cord injury, spinal cord tumor, spinal muscular atrophy, spinocerebellar ataxia, steel・ Richardson Oruszevsky Syndrome, Stiff Parson Syndrome, Stroke, Sturge-Weber Syndrome, Subacute sclerosing panencephalitis, Subcortical atherosclerotic encephalopathy, Superficial Siderosis, Sydenham chorea, Syncope, Synesthesia, Spinal cord Cavitation, tarsal tunnel syndrome, tardive dyskinesia, tardy cyst, tarrobic cyst, Tay-Sachs disease, temporal arteritis, tetanus, spinal tether syndrome, Tomzen's disease, thoracic outlet syndrome, painful tic, Todd paralysis, Tourette syndrome, toxic encephalopathy, transient ischemic attack, transmissible spongiform encephalopathy, transverse myelitis, traumatic brain injury Wound, tremor, trigeminal neuralgia, tropical spastic paraparesis, trypanosomiasis, tuberous sclerosis, Hippel-Lindau disease (VHL), birysk encephalomyelitis (VE), Wallenberg symptom group, Weldnig-Hoffmann disease, West syndrome, Whiplash, Williams syndrome, Wilson disease, Zerweger syndrome.

Many known neuroprotective drugs have been prepared using complex multi-step procedures. Furthermore, known drug treatments are not always effective in treating a wide variety of neurological or mental conditions of various etiologies. There may be problems with adverse effects of drug treatment and problems with it [WebMD Inc (July 1, 2005). “Mental Health: Types of Mental Illness”, http://www.webmd.com/mental-health/mental-health-types-illness, retrieved April 19, 2007].
Thus, there is a certain need to design and develop new classes of drugs for the treatment of psychiatric and neurological disorders of various etiologies.

  The present invention relates to compounds of formula I for the treatment of neurological and mental conditions. The invention also relates to a process for the preparation of compounds of formula I.

(Brief description of the drawings)
FIG. 1 illustrates the structure of Compound 2 determined by X-ray diffraction analysis. FIG. 2 illustrates the X-ray diffraction pattern of Compound 2. FIG. 3 illustrates the X-ray diffraction pattern of Compound 3. FIG. 4 illustrates the X-ray diffraction pattern of Compound 5.

(Detailed description of the invention)
The synthesis of compounds of formula I can be performed using a simple and convenient one-step procedure. The first synthetic method is depicted in Scheme 1:

The second method is represented below (Scheme 2):

The third method is represented in Scheme 4:

The fourth method is represented in Scheme 4:

The following compounds of formula I can be prepared using Schemes 1-4. Examples of these preferred compounds of formula I are, 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 formula I illustrate the invention. Examples of these preferred compounds of formula I are, but are not limited to:
1. 3,3-di (2-aminoethyl) -1,2-diazacyclopropane,
2. 3,3-di (2-hydroxyethyl) -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.

The following examples of the preparation of compounds of formula I illustrate the invention. Examples of these preferred compounds of formula I are, but are not limited to:
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-1,2-diazacyclopropane,
10. 3-decyl-1,2-diazacyclopropane.

The following examples of the preparation of compounds of formula I illustrate the invention. Examples of these preferred compounds of formula I are, but are not limited to:
1. 3- (phenylmethyl) -1,2-diazacyclopropane,
2. 3- (1-phenylethyl) -1,2-diazacyclopropane,
3. 3- (2-aminoethyl) -1,2-diazacyclopropane,
4. 3- (2-hydroxyethyl) -1,2-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) -1,2-diazacyclopropane,
10. 3- (2- (4-Ethylphenyl) ethyl) -1,2-diazacyclopropane.

The following examples of the preparation of compounds of formula I illustrate the invention. Examples of these preferred compounds of formula I are, but are not limited to:
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- (1-azapentamethylene) -1,2-diazacyclopropane,
5. 3,3- (2-azapentamethylene) -1,2-diazacyclopropane,
6. 3,3- (3-azapentamethylene) -1,2-diazacyclopropane,
7. 3,3- (1-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. 1,2,7,8-Tetraazadispiro [2,2,2,2] decane.

  The compounds of formula I have basic properties and are capable of forming a wide variety of different salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable salts are those that form non-toxic salts such as phosphate, acetate, oxalate, succinate, maleate, benzoate. A salt containing a pharmaceutically acceptable anion, such as an acid salt.

  The compounds of formula I and their pharmaceutically acceptable salts are also anxiety disorders, adaptation disorders, eating disorders, personality disorders, mood disorders, physical expression disorders, personality disorders, sleep disorders, sleep disorders, psychotic disorders Various, including eating disorders, somatic expression disorders, dissociative disorders, sexual disorders, sexual dysfunctions, gender identity disorders, impulse disorders, somatic expression disorders, mood disorders, eating disorders, impulse control disorders Useful for the treatment of the present invention with respect to etiological psychotic disorders and mental disorders. The compounds of formula I also have acute stress disorders, unspecified adaptation disorders, adaptation disorders with anxiety, adaptation disorders with depressed mood, adaptation disorders with behavioral disruptions, adaptation disorders with mixed anxiety and depressive mood, Adjustment disorder with mixed emotion and behavior confusion, agoraphobia with no history of panic disorder, anorexia, anorexia nervosa, antisocial personality disorder, anxiety disorder due to medical condition, anxiety Disability, avoidance personality disorder, bipolar disorder, complete remission bipolar I disorder, partial remission bipolar I disorder, mild bipolar I disorder, moderate bipolar I disorder, with psychotic features Severe bipolar type I disorder, severe bipolar type I disorder without psychotic features, bipolar type II disorder, body deformity disorder, borderline personality disorder, respiratory-related sleep disorder, short-term psychotic disorder, nerve Bulimia, cannabis compound wrinkles, circadian rhythm Sleep disorder, conversion disorder, mood circulation disorder, childhood disorder, cognitive disorder, delusional disorder, addiction personality disorder, divorce disorder, depression of various etiologies, especially melancholic depression, treatment-resistant depression , Severe depression, and psychotic depression, dissociative amnesia, dissociative disorder, dissociative struggle, dissociative identity disorder, sexual pain, dyssomnia, sleep disorder associated with another disorder, dysthymia Disorder, eating disorder, exposure, female sexual pain due to medical condition, female sexual desire disorder due to medical condition, female orgasmic disorder, female sexual arousal disorder, fetishism, friction lovers, Adolescent or adult gender identity disorder, childhood gender identity disorder, gender identity disorder, generalized anxiety disorder, acting personality disorder, hyposexual desire disorder, psychosis, impulse control disorder, insomnia, another Insomnia, intermittent explosive disorder related to disorder , Theft, instability or grief, major depressive disorder with complete remission, major depressive disorder with partial remission, male sexual pain due to medical condition, male erectile dysfunction, due to medical condition Male erectile dysfunction, male sexual desire disorder due to medical condition, male orgasmic disorder, mood disorder due to medical condition, self-love personality disorder, paroxysmal sleep, nightmare disorder, obsessive compulsive disorder, Obsessive compulsive personality disorder, other female sexual dysfunctions caused by medical conditions, other male sexual dysfunctions caused by medical conditions, painful disorders related to both psychological factors and medical conditions, psychological Pain associated with trait, panic disorder with agoraphobia, panic disorder without agoraphobia, paranoia-like personality disorder, sexual perversion, parasomnia, morbid gambling, pedophilia, personality disorder, post-traumatic stress Obstacle Harm, premature ejaculation, premenstrual depression, primary hypersomnia, primary insomnia, psychosis of various etiologies, especially alcohol psychosis, circulatory psychosis, degenerative psychosis, psychosis related to dementia, psychosis related to Alzheimer's disease , Psychosis related to organic brain disorder, and drug-induced psychosis, psychotic disorder caused by medical condition with delusion, psychotic disorder caused by medical condition with hallucination, arson, schizophrenic emotional disorder Schizophrenic personality disorder, tension schizophrenia, destructive schizophrenia, delusional schizophrenia, remnant schizophrenia, indistinguishable schizophrenia, schizophrenia-like disorder, schizophrenic personality Disability, sexual aversion disorder, sexual disorder, sexual dysfunction, sexual masochism, sexual sadism, shared psychotic disorder, sleep disorder caused by hypersomnia type medical condition, caused by insomnia type medical condition Sleep disorder, mixed Sleep disorders caused by medical conditions, sleep disorders caused by parasomnia-type medical conditions, night wonders, sleepwalking, interpersonal phobias, somaticization disorders, physical expression disorders, specific phobias, substance-related disorders It is also useful for the treatment of perversion, fetishism, hair loss, indistinguishable body expression disorder, suicidal ideation, suicide, no motivation, vaginal spasticity, and voyeurism.

  The compounds of formula I are also associated with the treatment of neuropathies of various etiologies. For example, loss of weight sensation, acquired epileptiform aphasia, acute disseminated encephalomyelitis, adrenoleukodystrophy, agenesis of corpus callosum, agnosia, Aicardi syndrome, inability to sit still, Alexander disease, alien hand syndrome, contralateral sensory disorder, Alpers disease, alternating hemiplegia, Alzheimer's disease, amyotrophic lateral sclerosis, anencephalopathy, Angelman syndrome, hemangiomatosis, anoxia, aphasia, apraxia, arachnoid cyst, arachnoiditis, Arnold Chiari malformation, arteriovenous malformation, telangiectasia ataxia, attention deficit hyperactivity disorder, auditory processing disorder, autonomic dysfunction, back pain, Batten's disease, Behcet's disease, bell paralysis, benign essential eyelid spasm, benign skull Internal hypertension, bilateral frontal parietal cerebral gyrus, binswanger disease, blepharospasm, Bloch-Salzburger syndrome, brachial plexus injury, brain abscess, brain injury, brain Wound, brain tumor, Brown-Sekar syndrome, Canavan disease, carpal tunnel syndrome, causalgia, central pain syndrome, central pontine myelopathy, central myopathy, head disorder, cerebral aneurysm, cerebral arteriosclerosis, brain Atrophy, cerebral giantism, 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 laurie syndrome, coma, complex regional pain syndrome, pressure neuropathy, congenital facial paraparesis, basal ganglia degeneration, cranial arteritis, skull fusion, Creutzfeldt-Jakob disease, cumulative trauma Sexual disorder, Cushing syndrome, Giant cell inclusion body disease (CIBD), Cytomegalovirus infection, Dandy-Walker syndrome, Dawson's disease, Dumorsier syndrome, Degelin Krumpke paralysis, Dejerin-Sottas disease, sleep phase regression syndrome, dementia, dermatomyositis, developmental coordination disorder, diabetic neuropathy, pervasive sclerosis, Drave syndrome, autonomic dysfunction, computational impairment, writing disorder, Dyslexia, schizophrenia, empty sella syndrome, encephalitis, aneurysm, hemangiomatosis of the trigeminal region of the brain, fecal disease, epilepsy, elve palsy, extremity erythema, essential tremor, Fabry disease, Farle disease, syncope , Familial spastic paralysis, febrile seizures, Fischer syndrome, Friedreich ataxia, fibromyalgia, Fauille syndrome, Gaucher disease, Gerstmann syndrome, giant cell arteritis, giant cell inclusion body disease, globuloid cell cerebral white matter atrophy, Ectopic gray matter, Guillain-Barre syndrome, HTLV-1-related myelopathy, Hallelfolden-Spatz disease, head injury, headache, unilateral spasm, hereditary spasticity Paraplegia, hereditary polyneuropathy, ear shingles, shingles, Hirayama syndrome, global forebrain, Huntington's chorea, hydroencephalopathy, hydrocephalus, hyperadrenocorticism, hypoxia, immune-mediated brain Myelitis, inclusion body myositis, dystaxia, infantile phytanic acid accumulation, infantile lefsum disease, epilepsy, inflammatory myopathy, intracranial cyst, intracranial hypertension, Joubert syndrome, Karak syndrome, Keynes-Saire syndrome, Kennedy Disease, Kinsbrunn syndrome, Klippel file syndrome, Krabbe disease, Kugelberg-Wellander disease, Kourou disease, Lafora disease, Lambert-Eaton myasthenia syndrome, Landau-Krefner syndrome, lateral myelopathy (Walenberg syndrome), learning disability, Lee Disease, Lennox-Gastaut syndrome, Lesch-Nyhan syndrome, cerebral white matter atrophy, Lewy bodies Dementia, gyrus defect, confinement syndrome, Lou Gehrig's disease, lumbar disc disease, lumbar spinal canal stenosis, Lyme disease, Machado-Joseph disease, giant cerebral myelopathy, macroscopic syndrome, giant encephalopathy, Mercerson-Rozental syndrome , Meniere's disease, meningitis, Menkes disease, metachromatic leukotrophy, microcephaly, microvision, migraine, Miller-Fischer syndrome, microstroke (transient ischemic attack), sound phobia, mitochondrial myopathy , Mobius syndrome, single-limb muscular atrophy, motor neuron disease, motor impairment, moyamoya disease, mucopolysaccharidosis, multiple infarct dementia, multifocal motor neuropathy, multiple sclerosis, multiple system atrophy, muscular dystrophy, muscle Painful encephalomyelitis, myasthenia gravis, myelinating destructive diffuse sclerosis, infant myoclonic encephalopathy, myoclonus, myopathy, myotubular myopathy, congenital muscle Stiffness, paroxysmal sleep, neurofibromatosis, neuroleptic malignant syndrome, neurological signs of AIDS, neurological sequelae of lupus, neuromyotony, neuronal ceroid lipofuscinosis, neuronal cell migration disorder, Niemann-Pick Disease, non-24-hour sleep-wake syndrome, nonverbal learning disorder, Osariban-Macleod syndrome, occipital neuralgia, latent spinal insufficiency, Otawara syndrome, olive bridge cerebellar atrophy, ocular clonus-myoclonus syndrome, optic neuritis, orthostatic low Hypertension, overuse syndrome, repetitive vision, sensory abnormalities, Parkinson's disease, congenital paramyotonia, paraneoplastic disorder, seizures, Parry-Lomberg syndrome, Pelizaeus-Merzbacher disease, periodic limb paralysis, peripheral neuropathy, persistent plant Condition, pervasive developmental disorder, light sneezing reflex, phytanic acid accumulation disease, Pick's disease, compression nerve, pituitary tumor Polio, polycerebellar encephalopathy, polymyositis, perforated encephalopathy, post-polio syndrome, postherpetic neuralgia (PHN), post-infectious encephalomyelitis, orthostatic hypotension, Prader-Villi syndrome, primary lateral sclerosis, Prion disease, progressive facial unilateral atrophy, progressive multifocal leukoencephalopathy, progressive supranuclear palsy, pseudo-brain tumor, rabies, type I Ramsey Hunt syndrome, type II Ramsey Hunt syndrome, type III Ramsey Hunt syndrome, Rasmussen encephalitis, reflex neurovascular dystrophy, refsum disease, repetitive hypermotor injury, restless leg syndrome, retrovirus-related myelopathy, Rett syndrome, Reye syndrome, rhythmic movement disorder, Romberg syndrome, St. Vitus chorea, Sandhoff disease , Schizophrenia, Schilder's disease, encephalopathy, sensory schizophrenia, septal optic dysplasia, infant shake syndrome, shingles, shy Draeger's disease Group, Sjogren's syndrome, sleep apnea, sleep disease, snatchation, Sotos syndrome, spasticity, spinal cord injury, spinal cord injury, spinal cord tumor, spinal muscular atrophy, spinocerebellar ataxia, Steel Richardson Olszewsky syndrome, Stiff person syndrome, stroke, sturge weber syndrome, subacute sclerosing panencephalitis, subcortical atherosclerotic encephalopathy, superficial siderosis, sydenam chorea, syncope, synesthesia, syringomyelia, tarsal tunnel syndrome, slow Aberrant dyskinesia, late-onset dysphrenia, tarrobic cyst, Tay-Sachs disease, temporal arteritis, tetanus, spinal tether syndrome, Tomzen's disease, thoracic outlet syndrome, painful tic, Todd's paralysis, Tourette syndrome, toxic encephalopathy , Transient ischemic attack, transmissible spongiform encephalopathy, transverse myelitis, traumatic brain injury, tremor, trigeminal neuralgia, tropical spastic dysfunction Paralysis, trypanosomiasis, tuberous sclerosis, Hippel-Lindau disease (VHL), bilisk encephalomyelitis (VE), Wallenberg symptom group, Weldnig-Hoffmann disease, West syndrome, whiplash, Williams syndrome, Wilson disease, Zellweger syndrome .

  The compounds of formula I have fairly promising antidepressant activity, antipsychotic activity, anti-amnestic activity and can be associated with the treatment of various neurological and mental conditions.

They do not have the effects of cardiotoxin and liver toxins and have no effect on rhythm, heart rate and intensity of cardiac contraction. They have no direct effect on the myocardium, do not shorten the conduction time, do not exert negative inotropic effects, do not reduce arterial pressure, and do not change the response to adrenaline. This property is very important because tricyclic antidepressants have been shown to induce orthostatic hypotension, tachycardia, shortened PQ, QRS and QT intervals, atrial appendage and ventricular arrhythmias.
Compound I can be useful in the treatment of patients who are resistant to therapy with standard neuroprotective drug therapy.

  The compositions of the invention can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. The active compounds of formula I can be formulated for oral, buccal, nasal, parenteral (eg, intravenous, intramuscular or subcutaneous) or rectal.

  In therapeutic use as a medicament for depression and anxiety, the compounds of the invention are used alone or in combination with a pharmaceutically acceptable carrier or excipient. Standard pharmaceutical formulation techniques can be used, such as those disclosed in “Remington's Pharmaceutical Sciences”, Mack Publishing, Easton, Pa. (1990). The compounds of the present invention can be administered orally or parenterally as such or in combination with conventional pharmaceutical carriers. “Carrier” means one or more compatible substances suitable for administration to a mammal. Carriers include solid or liquid fillers, diluents, hydrotopes, surfactants, and encapsulants. “Compatibility” refers to a diaziridine compound represented by Structural Formula I in a manner in which the components of the composition do not have interactions that substantially reduce the effectiveness of the composition under normal use conditions; It means that they can be mixed with each other. In order for the carrier to be suitable for administration to the mammal being treated, the carrier must be of sufficiently high purity and sufficiently low toxicity. The carrier can be inert or it can have a pharmaceutical benefit, a cosmetic benefit, or both.

  The choice of carrier depends on the route by which the compound represented by Structural Formula I is administered and the shape of the composition. The composition can be in a variety of forms, eg, suitable for systemic administration (eg, oral, rectal, nasal, sublingual, buccal, or parenteral).

  The exact amount of each component in the pharmaceutical composition will depend on various factors. The amount of diaziridine compound represented by Structural Formula I depends on the binding affinity (IC50) of the selected pharmaceutical. The amount of carrier utilized with the medicament is sufficient to provide a practical amount of the substance for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods of the invention are described in the following references: “Modern Pharmaceutics”, Chapters 9 and 10, edited by Banker and Rhodes. (1979); Lieberman et al., “Pharmaceutical Dosage Forms: Tablets” (1981); and Ansel, “Introduction to Pharmaceutical Dosage Forms”, 2nd. Edition (1976), the entirety of each of these is hereby incorporated by reference in their entirety to illustrate dosage form techniques and compositions.

  Applicable solid carriers include flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders, tablet disintegrating agents, or encapsulating agents. Can include, but is not limited to, one or more substances that can also act. In powders, the carrier can be a fine solid which can be mixed with the fine active ingredient. In tablets, the active ingredients can be mixed in suitable proportions with carriers having suitable compression properties and formed into the desired shape and size. Powders and tablets can contain up to about 99% of the active ingredient.

  Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine, a low melting wax, and an ion exchange resin. Liquid carriers can be used in preparing solutions, suspensions, emulsions, syrups, and elixirs.

  The active ingredients of the present invention can 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. . Liquid carriers include solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickeners, colorants, viscosity modifiers, stabilizers, or osmotic pressure regulators, Other suitable pharmaceutical additives can be included. Suitable examples of liquid carriers for oral and parenteral administration include water (especially containing, for example, cellulose derivatives, non-limiting additives such as, but not limited to, sodium carboxymethylcellulose solution), alcohol (Including, but not limited to, monohydric and polyhydric alcohols such as glycols) and their derivatives, and oils (eg, but not limited to fractionated coconut oil and peanut 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 can be in the form of either a liquid or solid composition. In one embodiment, the pharmaceutical composition containing the compound is in unit dosage form, such as a tablet or capsule. In such form, the composition can be subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged composition, such as a packaged powder, a vial, an ampoule, a prefilled syringe, or a sachet containing liquid. Alternatively, the unit dosage form can be, for example, a capsule or tablet itself, or it can be any suitable number of such compositions in packaged form. The therapeutically effective amount used can be varied or adjusted by the physician according to the specific condition being treated and the size, age and response pattern of the patient, and generally ranges from about 0.5 mg to about 750 mg. It is.

  Effective amounts of the compounds of the present invention are within the knowledge and opinion of the attending physician, the particular condition being treated, the age and physiological condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of the combination therapy , Depending on the route of administration, the particular pharmaceutically acceptable carrier utilized, and similar factors. The compounds of the present invention can be administered to a patient at a dose of about 0.7 to about 7000 mg per day, especially about 1.0 to about 1000 mg. For example, for a healthy adult weighing about 70 kg, the dosage is paraphrased as a daily dosage of about 0.01 to about 100 mg / kg body weight. However, the specific dose utilized can vary depending on patient requirements, the severity of the patient's condition, and the activity of the compound. The appropriate amount of determination for a particular situation can be determined clinically and is within the level of skill of those skilled in the art. These dosages are based on the rate of daily administration, but the compounds of the invention may be administered twice a day, twice a week, once a week, once a month, etc. It can also be administered at other intervals. One of ordinary skill in the art would be able to calculate a suitable effective amount for other dosing intervals.

  The exact amount of each component in the pharmaceutical composition will depend on various factors. The amount of diaziridine compound added to the pharmaceutical composition depends on the IC50 of the compound, typically expressed in nanomolar (nM) units. For example, if the pharmaceutical IC50 is 1 nM, the amount of diaziridine compound will be from about 0.001 to about 0.3%. If the pharmaceutical IC50 is 10 mM, the amount of diaziridine compound will be from about 0.01 to about 1%. If the pharmaceutical IC50 is 100 nM, the amount of diaziridine compound will be from about 0.1 to about 10%. When the IC50 of the pharmaceutical is 1000 nM, the amount of diaziridine compound will be 1-100%, preferably 5-50%. If the amount of diaziridine compound is outside the range specified above (ie, lower), the effectiveness of the treatment can be reduced. Those skilled in the art understand how to calculate and understand the IC50. The remainder of the composition, up to about 100%, can be a pharmaceutically acceptable carrier or excipient.

  A better understanding of the present invention can be obtained in view of the following examples, which are illustrated but not to be construed as limiting. For oral administration, the pharmaceutical composition may be combined with pharmaceutically acceptable excipients such as, for example, binders (e.g., polyvinylpyrrolidone or hydroxypropylmethylcellulose), lubricants (e.g., magnesium stearate, talc or silica). Can take the form of tablets or capsules, prepared by conventional means. Tablets can be manufactured by methods well known in the art using, for example, acetylphtalylcellulose acetate. Injectable formulations may be prepared in unit dosage form, eg, in ampoules or containers for repeated administration, with added preservatives.

  Specific examples of acid anhydrides used in the preparation of compounds of formula I include 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, hydroxy methane sulfonic acid, hydroxy ethane sulfonic acid, and the like, but are not limited to these Is not to be done. For additional acids, reference may be made to “Pharmaceutical Salts”, J. Pharm. Sci., 1977; 66 (1): 1-19.

(Example)
The following examples serve to further illustrate the invention and are not to be construed as limiting its scope in any way.

。
9) 3-n-プロピル-1,2-ジアザシクロプロパン；質量：M⁺＝87、沸点47〜49 (30Torr)。
10) 3-ブチル-1,2-ジアザシクロプロパン；質量：M⁺＝101。
11) 3-(2-フェニルエチル)-1,2-ジアザシクロプロパン；質量：M⁺＝149。
12) 3-(2-(ジメチルアミノ)エチル)-1,2-ジアザシクロプロパン；質量：M⁺＝116。
13) 3,3-テトラメチレン-1,2-ジアザシクロプロパン；質量：M⁺＝99、融点75℃。
14) 3,3-(2-メチルペンタメチレン)-1,2-ジアザシクロプロパン；質量：M⁺＝127。
15) 3,3-(3-メチル-3-アザペンタメチレン)-1,2-ジアザシクロプロパン；質量：M⁺＝128。
16) 3,3-(3-(ジメチルアミノ)ペンタメチレン)-1,2-ジアザシクロプロパン；質量：M⁺＝156。
17) 3,3-ジ(2-ピリジン-4-イルエチル)-1,2-ジアザシクロプロパン；質量：M⁺＝255。
18) 3,3-(2-オキサペンタメチレン)-1,2-ジアザシクロプロパン；質量：M⁺＝115、融点133℃。
19) 3-メチル-3-(アセチルアミノメチル)-1,2-ジアザシクロプロパン；質量：M⁺＝130。 Example compounds prepared according to Method AD are described below:
1) 3,3-Dimethyl-1,2-diazacyclopropane; mass: M ⁺ = 73, boiling point 106 ° C. (760 Torr), melting point 40 ° C.
2) 3,3-diethyl-1,2-diazacyclopropane; mass: M ⁺ = 101, boiling point 58 ° C. (24 Torr), melting point 56 ° C.
This structure was confirmed by an X-ray diffraction test (see FIG. 1). See Figure 2 below for spectral data.
3) 3,3-pentamethylene-1,2-diazacyclopropane (DA); mass: M ⁺ = 113, melting point 104-105 ° C.
For spectrum data, see Figure 3 below.
4) 3,3-Heptamethylene-1,2-diazacyclopropane; mass: M ⁺ = 141, melting point 40-41 ° C.
5) 3,3- (4-Methylpentamethylene) -1,2-diazacyclopropane (MP-3); mass: M ⁺ = 127, melting point 81-82 ° C.
For spectral data, see FIG. 4 below.
6) 3-ethyl-3-methyl-1,2-diazacyclopropane; mass: M ⁺ = 87, boiling point 32 ° C. (17 Torr), melting point 22 ° C.
7) 3-Hexyl-3-methyl-1,2-diazacyclopropane; M ⁺ = 142.
8) 3,3-di (2-phenylmethyl) -1,2-diazacyclopropane; mass: M ⁺ = 225, melting point 95-95.5 ° C.

.
9) 3-n-propyl-1,2-diazacyclopropane; mass: M ⁺ = 87, boiling point 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 ⁺ = 116.
13) 3,3-Tetramethylene-1,2-diazacyclopropane; mass: M ⁺ = 99, melting point 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 ⁺ = 115, melting point 133 ° C.
19) 3-Methyl-3- (acetylaminomethyl) -1,2-diazacyclopropane; mass: M ⁺ = 130.

The compounds of these examples were prepared according to general methods A, B, C or D.
Elemental analysis was performed with CHN Analyzer Perkin-Elmer 2400. All new compounds yielded satisfactory elemental analysis. The IR spectrum (ν, cm ⁻¹ ) was measured using a SPECORD-M82 spectrometer. NMR spectra of all compounds were recorded using a Bruker AM-300 spectrometer using 300 MHz for ¹ H in CDCl ₃ (δ, ppm). CDCl ₃ residual proton (7.27 ppm) and carbon (77.0 ppm) signal chemical shifts were used as internal standards. Mass spectra were measured with a Finigan MAT INCOS-50 instrument. Analytical thin layer chromatography (TLC) was performed on silica gel plates (Silufol UV-254).

液体NH₃(50ml)を、ドライアイス-Me₂CO浴により-30℃まで冷却したMeOH 250ml中の4-メチルシクロヘキサノン11.2g (0.1mol)の攪拌溶液へ添加した。95％ヒドロキシルアミン-O-スルホン酸15gの懸濁液を、30分間かけて添加し、この混合物を、-30℃で4時間攪拌した。冷却浴を取り外し、この混合物を18時間、室温で攪拌し、固形物を濾過除去し、MeOH 3×50mlで洗浄し、一緒にしたMeOH濾液を、真空中、水浴上で蒸発させ、6-メチル-1,2-ジアザスピロ[2,5]オクタン[3,3-(4-メチル(methi)ペンタメチレン-1,2-ジアザシクロプロパン)(化合物5)の5.6g(50％)を得た。融点81〜82℃。 (General method for the synthesis of compound 1,2-diazacyclopropane of formula I :)
A. The first method is shown in Scheme 1:

Liquid NH ₃ (50 ml) was added to a stirred solution of 11.2 g (0.1 mol) 4-methylcyclohexanone in 250 ml MeOH cooled to −30 ° C. with a dry ice-Me ₂ CO bath. A suspension of 15 g of 95% hydroxylamine-O-sulfonic acid was added over 30 minutes and the mixture was stirred at −30 ° C. for 4 hours. The cooling bath was removed and the mixture was stirred for 18 hours at room temperature, the solid was filtered off and washed with 3 × 50 ml MeOH, and the combined MeOH filtrates were evaporated on a water bath in vacuo to give 6-methyl 5.6 g (50%) of 1,2-diazaspiro [2,5] octane [3,3- (4-methyl (methi) pentamethylene-1,2-diazacyclopropane) (compound 5) was obtained. . Melting point 81-82 ° C.

MeOH 150ml中のペンタン-3-オン8.6g (0.1mol)の溶液へ、液体NH₃ 25mlを、-30℃で添加し、且つCl₂ 5.5gを同じ温度で通過させた。4時間後、-5℃で、スラリーからNH₄Clを濾過し；濾液を、真空中で蒸発させ、3,3-ジエチル-1,2-ジアザシクロプロパン(化合物2)の4.0g(40％)を単離した；沸点58℃ (24Torr)、融点56℃。同様に、EtOH中のC₅H₁₁COEtから、3-アミル-3-エチル-1,2-ジアザシクロプロパン、78℃ (2Torr)を調製し、リグロイン中のシクロヘキサノンから、3,3-ペンタメチレン-1,2-ジアザシクロプロパン(化合物3)、融点104〜5℃を調製した(シクロヘキサンから再結晶した)。 B. The second method is illustrated in Scheme 2.

To a solution of 8.6 g (0.1 mol) pentan-3-one in 150 ml MeOH was added 25 ml liquid NH ₃ at −30 ° C. and 5.5 g Cl ₂ was passed at the same temperature. After 4 h, NH ₄ Cl was filtered from the slurry at −5 ° C .; the filtrate was evaporated in vacuo to give 4.0 g (40% of 3,3-diethyl-1,2-diazacyclopropane (compound 2). %); Boiling point 58 ° C. (24 Torr), melting point 56 ° C. Similarly, 3-amyl-3-ethyl-1,2-diazacyclopropane, 78 ° C. (2 Torr) was prepared from C ₅ H ₁₁ COEt in EtOH, and 3,3-penta was obtained from cyclohexanone in ligroin. Methylene-1,2-diazacyclopropane (compound 3), mp 104-5 ° C., was prepared (recrystallized from cyclohexane).

式Iの化合物を、アルコール溶媒中のN-クロロケチミン及びNH₃から調製した。このように、MeOH 300ml中のシクロヘキシル-N-クロロケチミン1mol (132g)の溶液を、0℃で、NH₃により飽和させ、この混合物を、閉鎖した容器内で、一晩放置し、後処理し、3,3-ペンタメチレン-1,2-ジアザシクロプロパン(化合物3)の95g(85％)を生じた。融点104-5℃(シクロヘキサン)。3-ヘキシル-3-メチル-1,2-ジアザシクロプロパン(化合物7)を、イソ-PrOH 400ml中の2-オクチル-N-クロロケチミン162g(1mol)の溶液の、NH₃による-10℃での飽和により調製し、この混合物を、閉鎖した容器内で、50℃で5時間加熱し、後処理し、化合物7の119g(83％)を未蒸留の油状物として生じた。化合物3も、H₂O 1500ml中のシクロヘキシルアミン92g (0.93mol)及びNaHCO₃ 190gの溶液の、Cl₂ 150gによる、0〜5℃での塩素化により調製した。得られたN-ジクロロヘキシルアミンの溶液を、0〜10℃で、NH₃で飽和されたMeOH 300mlへ添加し、化合物3のメタノール性溶液(80％ヨード還元滴定)を生じた。 C. The third method is shown in Scheme 3:

The compound of formula I was prepared from N-chloroketimine and NH _{3 in} an alcohol solvent. Thus, a solution of 1 mol (132 g) of cyclohexyl-N-chloroketimine in 300 ml of MeOH is saturated with NH ₃ at 0 ° C. and the mixture is left overnight in a closed container and worked up. Yielding 95 g (85%) of 3,3-pentamethylene-1,2-diazacyclopropane (compound 3). Melting point 104-5 ° C. (cyclohexane). 3-Hexyl-3-methyl-1,2-diazacyclopropane (compound 7) was added to a solution of 162 g (1 mol) 2-octyl-N-chloroketimine in 400 ml iso-PrOH with NH ₃ at −10 ° C. This mixture was heated in a closed vessel at 50 ° C. for 5 hours and worked up to yield 119 g (83%) of compound 7 as an undistilled oil. Compound 3 was also prepared by chlorination of a solution of 92 g (0.93 mol) cyclohexylamine and 190 g NaHCO _{3 in} 1500 ml H ₂ O with 150 g Cl _{2 at} 0-5 ° C. The resulting solution of N-dichlorohexylamine was added at 0-10 ° C. to 300 ml of MeOH saturated with NH ₃ , resulting in a methanolic solution of compound 3 (80% iodo reduction titration).

ヒドロキシルアミン-O-スルホン酸(0.5mol)を、水(60ml)中アルデヒド(0.5mol)の溶液へ、-10〜-5℃で添加し、この混合物を、KIの酸性化溶液と最早反応しなくなるまで、15〜20分間攪拌した。その後、こうして得られたアルドキシム-O-スルホン酸の溶液を、-20〜-18℃で、アンモニアの水溶液(300g、47％)へ滴加した。この反応混合物を、それを通過させられる穏やかなアンモニア流と共に、0〜2℃で、8〜10時間攪拌した。その後この混合物を、0℃で一晩静置し、アンモニア流れ下で、18〜20℃で、10時間攪拌した。水性ジアジリジン溶液を、回転蒸発器を用い、ドライアイスで冷却した容器へと蒸留し、生成物を固形アルカリから3回蒸留した。3-プロピル-1,2-ジアザシクロプロパン(化合物9)の収率は22％であった；沸点47-49 (30Torr)、n_d ²⁰1.4478、IR-スペクトル：3220cm^-1;

質量スペクトル：M⁺＝87。 D. The fourth method is shown in Scheme 4.

Hydroxylamine-O-sulfonic acid (0.5 mol) was added to a solution of aldehyde (0.5 mol) in water (60 ml) at −10 to −5 ° C. and this mixture was reacted with an acidified solution of KI. Stir for 15-20 minutes until gone. The aldoxime-O-sulfonic acid solution thus obtained was then added dropwise to an aqueous ammonia solution (300 g, 47%) at −20 to −18 ° C. The reaction mixture was stirred at 0-2 ° C. for 8-10 hours with a gentle stream of ammonia passed through it. The mixture was then allowed to stand overnight at 0 ° C. and stirred at 18-20 ° C. for 10 hours under ammonia flow. The aqueous diaziridine solution was distilled using a rotary evaporator into a container cooled with dry ice and the product was distilled three times from solid alkali. The yield of 3-propyl-1,2-diazacyclopropane (compound 9) was 22%; boiling point 47-49 (30 Torr), n _d ²⁰ 1.4478, IR-spectrum: 3220 cm ^-1 ;

Mass spectrum: M ⁺ = 87.

The synthetic procedures carried out to prepare the compounds of formula I are fully explained in the following publications:
1. JJ Fuchs, US Pat. No. 6,654,472, 1966.
2. RF Chruch, AS Kende, MJ Welss, J. Am. Chem. Soc., 1965, 87, 2665.
3. HJ Abendroth, G. Henrlich, Angew. Chem., 1959, 71, 283.
4. SR Paulsen, G. Huck, Chem. Ber., 1961, 94, 968.
5. HJ Abendroth, G. Henrlich, German Patent No. 1082889, 1958; Chem. Abst .. 1963, 58, 1463a.
6. E. Schmitz, R. Ohme, Chem. Ber., 1961, 94, 2166.
7. HJ Abendroth, German Patent No. 1089878, 1960; Chem. Abst .. 1962, 57, 3289j.
8. Ch, J. Paget, Ch. S. Davis, J. Med. Chem., 1964, 7, 626.
9. HJ Abendroth, G. Henrlich, Angew. Chem., 1961, 73, 67.
10. E. Schmitz, R. Ohme, Org. Synthesis, 1965, 45, 83.
11. J. Uebel, JC 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. AN Mikhailuyk, NN Makhova, AE Bova, LI Khmel'nitskii, SS Novikov, Bull. Acad. Sci. USSR, Division Chem. Sci., 1978, 1566.
15. NN Makhova, V.Yu. Petukhova, LI Khmel'nitskii, Bull. Acad. Sci. USSR, Division Chem. Sci., 1982, 2107.
16. AN Mikhailuyk, V.Yu. Petukhova, NN Makhova, Mendeleev. Commun., 1997, 60.

  Both nitrogen atoms in the diazacyclopropane ring have been found to be chiral. However, attempts to separate enantiomeric mixtures of 1,2-unsubstituted derivatives were unsuccessful because the nitrogen inversion barrier in such compounds was very low. NH-proton dissociation and recombination may not be ruled out as a possible interconversion mechanism for NH-containing diazacyclopropanes (M. Mintas and A. Mannschreck, Tetrahedron, 1981). , 37, 867).

  The following biological examples illustrate, but limit the invention, to demonstrate the potential utility of compounds of formula I for the prevention and treatment of symptoms of depressive disorder It is not a thing.

(Biological Example)
(Example 1)
(Behavioral despair test)
animal. White male mice (25-28 g) were used to examine the biological activity.
Behavioral despair was proposed by Porsolt et al. As a model to test antidepressant activity. This suggested that immobile characteristic behaviors were induced in mice or rats that were forced to swim in a confined space where they could not escape. This behavior reflects a state of despair that can be alleviated by some drugs that are therapeutically effective in human depression.

  Male white mice (25-28 g) were treated intraperitoneally according to the procedure described below. These animals were divided into two groups and treated as follows. Group 1 mice were used as controls. They were injected intraperitoneally with distilled water 40 minutes before the experiment. The second group was treated intraperitoneally with the compound of Example 3 (3,3-pentamethylene-1,2-diazacyclopropane) at a dose of 70 mg / kg 40 minutes before this experiment.

^*p＜0.05 対照群と比較
実施例1-2、4-17の化合物は、漂流時間を〜50％短縮した。 Anti-depressant activity was assessed by estimating the immobility time as the period during which the animal remained immobile during swimming (see Table 1). Statistical data processing was performed using the “BioStat” tool for Windows.

^* p <0.05 The control group and the compounds of Comparative Examples 1-2 and 4-17 shortened the drift time by ˜50%.

(Example 2)
(Antipsychotic activity evaluated using an apomorphine verticalization model)
animal. White male mice (23-28 g) were used to examine the biological activity.
Verticalization was induced by administration of apomorphine (5 mg / kg, sc) to mice. This study described by Protais et al. (Psychopharmacologie, 1976, 50, 1-6) allows the assessment of dopaminergic antagonist activity of potential antipsychotic products. Mice administered apomorphine and placed in a cage with a vertical bar cling to the bar with their four legs and remain stationary above the cage for most of the time. Its verticalizing behavior is blocked if a dopamine agonist antagonist product is administered prior to apomorphine.

  After intraperitoneal (i.p.) administration of the test compound (Example 3, 70 mg / kg) or vehicle (control group), the mice were placed in a cylindrical barred cage with vertical bars. Ten minutes later, the animals received an apomorphine dose (5 mg / kg, s.c.). Animals are observed for 40 minutes after injection of the title compound and at each measurement, score 0 (4 legs are on the floor), score 1 (mice have 2 front legs on a stick and stand upright. Or a score of 2 (the mouse clings to its stick with its four legs).

  The effect of the product on verticalization is assessed by comparing the score obtained for each group that received the product dose with the score obtained for the control group (see Table 2).

^*p＜0.05 対照群と比較 Statistical data processing was performed using the “BioStat” tool for Windows. The effect of this product on verticalization was determined by using the Mann-Whitney U test with a probability of p <0.05, and the score obtained for each group administered product dose was obtained for the control group (solvent). And evaluate by comparing.

^* p <0.05 compared with control group

The shortening of verticalization is statistically significant, so the compound of Example 3 has promising antipsychotic activity.
The compounds of Examples 1-2 and 4-17 reduced the verticalization parameter by ˜30%.

(Example 3)
animal. White male rats (250-280 g) were used to examine the biological activity.

(Passive avoidance behavior test)
The passive avoidance behavior test is a fear-motivated test traditionally used to assess short-term or long-term memory, and was performed as described elsewhere. The instrument (Lafayette Instrument) was equipped with a light box (400 × 400 × 400 mm) and a dark box (400 × 400 × 400 mm) of the same shape with guillotine doors (60 × 60 mm). The lighting was equipped with a 60W bulb, and the dark compartment floor consisted of 2mm stainless steel bars spaced 1cm apart. Rats were gently placed in the light compartment for an acquisition trial and the door between the two compartments was then opened for 10 seconds. When the rat entered the dark compartment, the door closed automatically and an electric leg shock (0.45 mA, 5 times with 1 second impulse) was sent through the stainless steel rod. 24 hours after the acquisition trial, the mice were again placed in the light compartment for a retention trial. The time it took for the rat to enter the dark compartment after opening the door was defined as the latency for both the acquisition and retention trials.

  The latency to enter the dark compartment was recorded as a maximum of 180 seconds. If a rat did not enter the dark compartment within 180 seconds, it was excluded and assigned a latent score of 180 seconds.

  Study drug (Example 3, 70 mg / kg, i.p.) was given 30 minutes before scopolamine administration. Memory impairment was induced in mice by scopolamine (1 mg / kg, i.p.) 20 minutes before learning electric shock. The control group received solvent only.

^*p＜0.05 対照(第1群)と比較 Anti-amnestic activity was evaluated by estimating the latency to enter the dark box (see Table 3). Statistical data processing was performed using the “BioStat” tool for Windows.

^* p <0.05 compared with control (Group 1)

  The compounds of Examples 1-2 and 4-17 reduced the proportion of animals that did not enter the dark box to <30%.

(Example 4)
(Black box and white box test)
The black and white tests (also called light and dark tests) are based on the inherent propensity of rodents to avoid new bright areas and explore new environments. The relative time spent exploring each compartment is indicative of the animal's level of anxiety: avoidance of brightly illuminated areas is considered to reflect “anxiety-like” behavior. During treatment with anxiolytics, rodents spend more time in this area, which is an effect due to the reduction in intended anxiety.

  C57BL / 6J mice were treated intraperitoneally with compounds of the invention, and then the anxiolytic efficacy of the compounds of formula I was evaluated by estimating the number of times they entered the light zone (see Table 5 below). ).

(Example 5)
(Learning helplessness test)
The learning helplessness test in mice is a well-known animal model for determining the antidepressant efficacy of a compound. Basically, when an animal learns that it is powerless, if an antidepressant is administered, the animal does not learn powerlessness and begins to try to control their environment.

  C57BL / 6J mice are treated intraperitoneally with a dose of the compound of formula I corresponding to 1/3 or 1/13 of the lethal dose by intraperitoneal injection, then the antidepressant activity of the compound and the animals avoid stress Evaluation was made by estimating the latency time as a period not to be attempted (see Table 5 below).

(Example 6)
animal. White male Balb / c mice (25-28 g) were used to examine the biological activity.

(An elevated cruciform maze model of anxiety)
Anxiolytic activity was measured using an elevated cruciform maze (Pellow, 1985). The maze extends from a central platform (5 cm x 5 cm) and is elevated to a height of 100 cm from the floor, two open arms (20 cm x 5 cm x 0.2 cm) and two closed arms (20 cm x 20 cm) 5cm x 14cm). The entire maze was made of transparent Plexiglas. The mice were individually placed in the center of the maze with their faces facing the open arms, and the number of times they entered and stayed there were recorded during the 3 minute observation period. Arm entry was defined as the entry of all four legs into the arm. The percentage of open arm entry (100 × open entry / total entry) was calculated for each animal. The selective increase in parameters and the number of defecations corresponding to open arm entry reveals anxiolytic action.

  The animals were divided into two groups and treated as follows. Group 1 mice were used as controls. These were injected i.p. with distilled water (0.01 ml / body weight 10 g). The second group was treated with i.p. of the compound of Example 3 (3,3-pentamethylene-1,2-diazacyclopropane) at a dose of 70 mg / kg 40 minutes before the experiment.

^*p＜0.05 マン・ホイットニー検定に従い、対照と比較 Statistical data processing was performed using the “BioStat” tool for Windows.

^* p <0.05 Mann-Whitney test, compared to controls

  The compound of Example 3 (DA) showed a strong anxiolytic action since the time in the open arm increased more than 2-fold and this difference was statistically significant.

(Example 7)
(Test of sedation / activation of diaziridine MP-3 (the compound of Example 5, 3,3- (4-methylpentamethylene) -1,2-diazacyclopropane))
(Test method)
The sedative / activation effects of these compounds were tested in experiments in mature outbred male mice weighing 24-3 g.
In this study, an open field test was conducted (Voronina TA, Seredenin SB, 2005).

  The system “open field” is a square location with a wall of 15 cm height and dimensions of 60 × 60 cm; the chamber floor is 20 × with 16 holes at the intersection of 4 cm diameter joints Divided into 9 quadrants of 20 cm.

  Animal behavior in the open field test is assessed for 3 minutes, horizontal motor activity (number of crossed lines), vertical motor activity (number of postures), exploratory activity (when the animal puts its head in a hole> 50% (Number of holes searched), number of grooming episodes, and fecal bolus.

The animals were randomized into 6 groups:
Control-10 mice
MP-3 dose 70mg / kg-10 mice

  Compound MP-3 was administered 40 minutes prior to the experiment at a single intraperitoneal dose of 70 mg / kg in a volume of 0.1 ml per 100 g of mouse body weight. Control animals received an equal volume of distilled water (0.1 ml per 100 g mouse body weight).

^*−p＜0.005 対照群と比較、スチューデント検定 (Test results:)
The effect of compounds on horizontal motor activity of animals in open fields.
Compound MP-3 was identified to significantly increase the horizontal motor activity of animals in the open field compared to controls (Table 5).
Compound MP-3 reduced horizontal motor activity by 13.5%.

^* −p <0.005 Compared to control group, Student test

Effects of MP-3 on animal vertical motor activity in open fields.
Compound MP-3 significantly reduced the animal's vertical motor activity in the open field compared to the control. As such, compound MP-3 reduced the vertical activity of mice by 40% compared to the vertical motor activity value of control animals (Table 5).

Effect of MP-3 on animal behavior in an open field test.
The search activity in the open field test was evaluated based on the hole search behavior. MP-3 showed a significant decrease in hole exploration behavior compared to controls and was able to attenuate animal exploration activity. Compound MP-3 reduced hole exploration behavior by a factor of 1.6. The obtained data showed the sedative activity of MP-3.
Compound MP-3 reduced motor (horizontal and vertical) activity to a greater extent, and decreased exploratory activity to a lesser extent.

(Example 8)
(Test of anxiolytic (anti-panic) action of diaziridine MP-3 (3,3- (4-methylpentamethylene) -1,2-diazacyclopropane))
The anxiolytic action of the compounds was tested in experiments on white male mouse strain Balb / body weight 22-26 g.
In this study, the basic test “elevated cruciform maze” was used for the evaluation of anxiolytic drugs (Voronina TA, Seredenin SB, 2005; Pellow et al., 1985; Oliver B et al., 1991. ).

  The maze showed crossed arms (branches) with dimensions of 20x5 cm. The two opposite branches had a vertical wall 15 cm in height (dark arm) and the other open arm was open and had no wall (open light arm). This maze was elevated 20cm from the floor. The central platform was located at the intersection of the arms and the dimensions were 5 × 5 cm. The animals were transferred to the central area with their tails toward the open light arm. The total observation time for each animal was 5 minutes.

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

  Anti-anxiety drugs of various chemical structures and modes of action alleviated anxiety in mice placed in a new condition when the animals felt fear of height and light in the open arm of the maze.

  In the elevated cross maze test, the behavior of the control animals is characterized by overt anxiety, where the animals stay most of the time in the closed arm, less time in the open arm, and rarely in the central area. Visited and had a lot of intestinal motility (Table 8).

  It was established that compound MP-3 had anxiolytic activity in the basic test “elevated cruciform maze”. The anxiolytic action of these compounds, in addition to their ability to relatively increase open arm dwell time and number of entries, is the ratio between open arm dwell time and total observation time compared to controls (anti-anxiety It was shown as an increase in index) (Table 6).

*p＜0.05 対照群と比較して、有意差あり

* p <0.05 Significantly different from the control group

  After administration of MP-3, it was identified that the open arm residence time of the animals increased by 7.3 times and the number of open arm entries increased by 3.9 times compared to the control. In addition, compound MP-3 significantly increased the anti-anxiety index. Therefore, the ratio between open arm residence time and total observation time after MP-3 administration was 0.47 ± 0.05 (Table 6).

  Compound MP-3 significantly reduced fecal bolus in the labyrinth, representing a somatic-vegetative component of anxiety compared to controls (Table 6).

  Therefore, the test compound MP-3 taken at a single dose of 70 mg / kg (i / p) has anxiolytic activity in the test `` elevated cruciform maze '' and the behavioral value of anxiety (time parameter) And physical parameters) and body-plant status values

^*データは、100％とみなした対照(非-処置動物)に対する割合(％)として表した。
^**p＜0.05、対照(非-処置動物)と比較。 (Example 9)
(Toxicity test)
Toxicity to mammals was measured after intraperitoneal injection of compounds of formula I into C57BL / 6J mice. Median lethal dose (LD ₅₀ ) was calculated as described previously (see Table 5).

^* Data expressed as a percentage of control (non-treated animals) considered 100%.
^** p <0.05, compared to control (non-treated animals).

  The above examples demonstrate that the compounds of Examples 1-17 are very promising as antidepressants, antipsychotics, anti-amnestics and neuroprotectives. In summary, a new class of drugs for treating psychiatric and neurological disorders of various etiologies was investigated in the present invention.

  While certain specific forms of the invention have been illustrated and described, various modifications and combinations of the invention detailed in the text and drawings may be made without departing from the spirit and scope of the invention. It will be clear that you can. For example, references to construction materials, methods of construction, specific dimensions, shapes, utility or applicability are also not intended to be limited to any manner and may be replaced with other materials and dimensions. And remain within the spirit and scope of the present invention. For example, the compounds of general formula I described herein can be obtained by one skilled in the art according to the methods described in this patent. The substituents or their protected derivatives may be part of the starting material. Some substituent protecting groups can be removed by methods known to those skilled in the art and are readily available, for example, in ordinary organic synthesis books and texts. Accordingly, it is not intended that the invention be limited except as by the appended claims.

  As mentioned above, the compounds described herein have basic properties and are therefore subject to degradation in an acidic environment, as found in the stomach. To address this potential for degradation, the compounds can be administered in enteric coated dosage forms or enteric coated pellets in capsules. The enteric pharmaceutical formulation is such that the product passes unchanged through the patient's stomach and rapidly dissolves and releases the active ingredient as it exits the stomach and enters the small intestine. Manufactured. Such formations have been used for a long time and are conventionally in the form of tablets or pellets, where the active ingredient is in the inner part of the tablet or pellet and an acidic environment such as a film or envelope, stomach In an "enteric coating" that is insoluble but soluble in an almost neutral environment such as the small intestine.

  The compound comprises a) a core comprising the compound and a pharmaceutically acceptable excipient; b) an optional separating layer; c) an enteric layer containing an enteric polymer and optionally a pharmaceutically acceptable excipient. As well as d) an optional finishing layer: can be provided in the form of enteric coated pellets.

(core)
A preferred core for the pellets is prepared by applying a compound-containing layer to inert beads. Such inert beads are commonly used in pharmaceutical sciences and are readily purchased in all industrial countries. Suitable beads are those prepared from starch and sucrose for use in confectionery as well as pharmaceuticals. However, beads of any pharmaceutically acceptable excipient can be used including, for example, microcrystalline cellulose, vegetable gums, waxes, and the like. The main feature of inert beads is that they are inert with respect to both the drug and other excipients in the pellet and with respect to the patient who will eventually take the pellet. The size of the beads depends on the desired size of the pellet to be produced. In general, the pellets can be as small as 0.1 mm or as large as 2 mm. Suitable beads are from about 0.3 to about 0.8 mm to provide finished pellets in the desired size range of about 0.5 to about 1.5 mm in diameter. A convenient way to coat the beads with duloxetine is a “powder coating” process in which the beads are wetted with a viscous liquid or binder, duloxetine is added as a powder, and the mixture is dried. Such processes are commonly performed in the practice of the pharmaceutical industry and suitable equipment is routinely used.

  Additional solids can be added to this layer along with the compound. These solids can be added to aid flow, reduce electrostatic charge, aid in building bulk, and facilitate the coating process required to form a smooth surface. Inert materials such as talc, kaolin, and titanium dioxide, lubricants such as magnesium stearate, fine silicon dioxide, crospovidone, and lactose can be used. The amount of such materials ranges from some enough of about 1% of the product, up to about 20% of the product. Such solids must have a fine particle size of less than 50 microns to create a smooth surface.

  The compounds are prepared to adhere to beads by spraying with a pharmaceutical excipient that is viscous and adhesive when wet and forms a strong cohesive film upon drying. Pharmaceutical scientists are aware and regularly use many such substances, most of which are polymers.

  Preferred such polymers include hydroxypropyl methylcellulose, hydroxypropylcellulose and polyvinylpyrrolidone. Additional such materials include, for example, methylcellulose, carboxymethylcellulose, acacia gum and gelatin. The amount of adhesive excipient is in the range of some up to about 5% of some 1% of the product and depends largely on the amount of compound to be adhered to the beads.

(Separation layer)
An optional separation layer between the compound-containing core and the enteric layer is not required, but if there are any deleterious interactions between the compound and the enteric polymer, there are pharmaceutically useful features. is there. Other functions of the separation layer are stabilized by providing a smooth substrate for the application of the enteric layer, extending the resistance of the pellet to acidic conditions, and protecting the compound from exposure to light. Is to improve sex.

  The function of the smoothing of the separation layer is purely mechanical, its purpose is to improve the coating of the enteric layer and to avoid thin spots therein caused by ridges and irregularities on the core . Thus, a smoother and irregular core is produced, less material is required in the separation layer, and the need for the smoothing characteristics of the separation layer is that the compound is of very fine particle size and If the core is manufactured as close as possible to a true spherical shape, it can be avoided entirely.

  In some cases, the separation layer can also act as a diffusion barrier against the migration of core or enteric layer components dissolved in the moisture of the product. The separation layer can also be used as a light barrier due to its opacification by materials such as titanium dioxide, iron oxide and the like.

  In general, the separating layer is composed of a coherent or polymeric material and a finely divided solid excipient that constitutes the filler. If sugar is used in the separation layer, it constitutes part or all of the cohesive material that is applied in the form of an aqueous solution and sticks with the separation layer. In addition to or in place of sugar, polymeric materials can also be used in the separation layer. In order to increase the adhesion and aggregation of the separating layer, substances such as, for example, hydroxypropylmethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose and the like can be used in small amounts.

  In order to further increase the smoothness and fastness of the separating layer, it is reasonable to use filler excipients in the separating layer. Substances such as finely divided talc, silicon dioxide and the like are acceptable as pharmaceutical excipients without exception and are convenient in that situation for filling and smoothing the separating layer, Can be added.

  The separation layer can be applied by spraying with an aqueous solution of sugar or polymeric material, as described in the preparation of the compound-containing layer, by dusting in the filler. However, if the filler is dispersed throughout as a suspension in a solution of sugar and / or polymeric material and this suspension is sprayed onto the core and dried, the smoothness of the separating layer and The homogeneity is improved.

(Enteric layer)
The enteric layer is composed of enteric polymers that must be selected for compatibility with the compound and provide the desired pH-dependent release. Examples of enteric polymers include: (meth) acrylate copolymers, shellac, HPMCP (hydroxypropyl methylcellulose phthalate), CAP (cellulose acetate phthalate), HPMC-AS (hydroxypropylmethylcellulose succinate acetate), Polyvinyl acetate phthalate, carboxymethyl ethyl cellulose, copolymerized methacrylic acid / methacrylic acid methyl ester, such as compounds known under the trade name Eudragit L 12.5 or Eudragit L 100 (Rohm Pharma), or used to obtain enteric coatings Similar compounds. The enteric coating layer is optionally pharmaceutically acceptable such as citrate, phthalate, dibutyl succinate, or similar plasticizers such as cetanol, triacetin, those known under the trade name Citroflex (Pfizer) A plasticizer can be contained. The amount of plasticizer is usually optimized for each enteric coating polymer and is usually in the range of 1-20% of the enteric coating polymer. Dispersants such as talc, colorants and pigments can also be included in the enteric coating layer.

(Finishing layer)
A finish layer outside the enteric layer is not necessary in all cases, but often improves the elegance of the product and its handling, storage and machinability, and provides further benefits be able to. The simplest finishing layer is a small amount of an antistatic component such as less than about 1% talc or silicon dioxide, simply dusted onto the surface of the pellet. Another simple finishing layer melts on the circulating mass of pellets to further smooth the pellets, reduce static charge, prevent the tendency of the pellets to stick together, and increase surface hydrophobicity A small amount of wax, such as beeswax, that is about 1% wax.

  The more complex finish layer constitutes the last sprayed layer of the component. For example, thin layers of polymeric materials such as hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like can be applied in amounts up to some about 3%, about 1% sufficient. The polymeric material can also hold suspensions of bulking agents such as opacifiers, talc, or opaque fine colorants such as colored substances, particularly red or yellow iron oxide. Such layers are rapidly dissolved and removed in the stomach, leaving an enteric layer to protect the compound, but providing additional means for protecting the product from medicinal sophistication and mechanical damage. provide.

The following formulation examples provide guidance in the manufacture of formulations of the disclosed compounds.
(Formulation Example 1)
(Compound 10mg / capsule)

The drug layer was added to the beads in the CF granulator with a batch size of 3.6 kg.
Hydroxypropylcellulose is dissolved in a minimum amount of water and this solution is slowly sprayed onto a stirred batch of beads while simultaneously mixing the compound, lactose and crospovidone as a mixture by dusting. Add intermittently at a rate that will adhere to the beads without loss. When the drug layer is completely formed, talc is added in the same manner and the beads are dried in an oven at 55 ° C. for 1.5 hours and then classified between 20 and 42 mesh screens. The separation layer is then applied in a Wurster column (Uni-Glatt, Glatt Air Techniques, Ramsey, NJ). Hydroxypropyl methylcellulose and polyethylene glycol are dissolved in water and talc and titanium dioxide are dispersed in this solution by a homogenizer. The resulting suspension is sprayed onto the classified beads in a Wurster column.

  Enteric coating suspension is prepared by first dissolving triethyl citrate in water, cooling this solution to 15 ° C and preparing a 7 wt / vol% suspension of HPMCAS-LF in this cold solution. Prepare. Carefully and slowly add HPMCAS-LF and talc to avoid foaming or formation of polymer agglomerates. The partially formed granules are then added to a fluid bed coater equipped with a Wurster column. This batch is fluidized with air at 70 ° C. to 80 ° C. and the enteric suspension is sprayed into the batch and the spray rate and air flow are adjusted to provide adequate agitation and avoid agglomeration To do. When this addition is complete, the air flow is continued for 30 minutes to dry the batch.

  Finally, a finishing layer is made by adding beeswax to the product in a fluidized bed at 60 ° C. After cooling, hydrated silicon dioxide is added to the pellet and mixed in a Wurster column. The batch is then cooled and filled into # 3 gelatin capsules.

本化合物、乳糖、ポリビニルピロリドン、及び炭酸ナトリウムの粉末混合物を、均質化し、且つメチルセルロース及び水の溶液により、造粒した。この湿った塊を、流動床乾燥機において、入口空気温度＋50℃を使用し、30分間乾燥させた。乾燥した混合物を次に、開口部0.5mmの篩を通させた。ステアリン酸マグネシウムと混合した後、この顆粒を、打錠機において、6mmパンチを使用し、錠剤とした。錠剤の重量は、100mgであった。 (Formulation Examples 2 and 3)
(Manufacture of tablet core batch)

A powder mixture of the compound, lactose, polyvinylpyrrolidone, and sodium carbonate was homogenized and granulated with a solution of methylcellulose and water. This wet mass was dried in a fluid bed dryer for 30 minutes using inlet air temperature + 50 ° C. The dried mixture was then passed through a sieve with an opening of 0.5 mm. After mixing with magnesium stearate, the granules were tableted using a 6 mm punch in a tableting machine. The tablet weight was 100 mg.

(Sub-coating)
The tablets of Example 2 were subcoated with approximately 10% by weight of hydroxypropylmethylcellulose in aqueous solution using a perforated coating pan apparatus. The tablets of Example 3 were subcoated using dry coating techniques. Tablet granules containing anhydrous lactose (4,000 g), polyvinylpyrrolidone (PVP) (180 g), 95% ethanol (420 g) and magnesium stearate (42 g) were prepared as follows: Lactose in solution of PVP in ethanol Granulated, dried and mixed in magnesium stearate.

  The tablet granules were then dry coated around the tablet cores of Examples 2 and 3 using a Manesty Dry Cota tablet press. The resulting tablet weight of the dry coated tablet of Example 2 will be approximately 475 mg for 20 mg of the compound.

(Enteric coating)
The previously obtained subcoated tablets were then enteric coated using the same coating solution: hydroxypropylmethylcellulose phthalate (1,500 g); cetyl alcohol (105 g), methylene chloride (15,000 g), isopropanol (15,000g) and distilled water (3,150g). This coating was applied in a perforated coating pan apparatus. An amount of approximately 1 kg of coating solution was applied per 1 kg of tablet.

  While certain specific forms of the invention have been illustrated and described, various modifications and combinations of the invention detailed in the text and drawings may be made without departing from the spirit and scope of the invention. It will be clear that you can. For example, references to construction materials, construction methods, specific dimensions, shapes, utility or applicability are also not intended to be limited to any style and can be replaced with other materials and dimensions, It remains within the spirit and scope of the present invention. For example, the compounds of general formula I described herein can be obtained by one skilled in the art according to the methods described in this patent. Substituents or protected derivatives thereof may be part of the starting material. Some substituent protecting groups can be removed by methods known to those skilled in the art and are readily available, for example, in ordinary organic synthesis books and texts. Accordingly, it is not intended that the invention be limited except as by the appended claims.

The present invention also includes anxiety disorder, adaptation disorder, eating disorder, personality disorder, mood disorder, physical expression disorder, personality disorder, sleep disorder, sleep disorder, psychotic disorder, eating disorder, physical expression disorder, dissociation It relates to psychotic disorders and psychiatric disorders of various etiologies, including sexual disorders, sexual disorders, sexual dysfunctions, gender identity disorders, impulse disorders, physical expression disorders, mood disorders, eating disorders, impulse control disorders. Compounds of formula I are also associated with acute stress disorder, unspecified adaptation disorder, adaptation disorder with anxiety, adaptation disorder with depressed mood, adaptation disorder with behavioral disruption, anxiety and depression Adjustment disorder, adaptation disorder with mixed emotion and behavior confusion, agoraphobia without history of panic disorder, anorexia, anorexia nervosa, antisocial personality disorder, anxiety disorder due to medical condition , Anxiety disorder, avoidance personality disorder, bipolar disorder, complete remission bipolar I disorder, partial remission bipolar I disorder, mild bipolar I disorder, moderate bipolar I disorder, psychotic Severe bipolar type I disorder with features, severe bipolar type I disorder without psychotic features, bipolar type I disorder , body dysmorphic disorder, borderline personality disorder, respiratory-related sleep disorder, short-term psychotic Disorder, bulimia nervosa, cannabis compound, diurnal Rhythm sleep disorder, conversion disorder, mood circulatory disorder, childhood disorder, cognitive disorder, delusional disorder, addictive personality disorder, divorce disorder, depression of various etiologies, especially melancholic depression, treatment-resistant depression Illness, severe depression, and psychotic depression, dissociative amnesia, dissociative disorder, dissociative struggle, dissociative identity disorder, sexual intercourse pain, sleep disorder, sleep disorder associated with another disorder, mood modulation Sexual disorder, eating disorder, exposure, female sexual pain due to medical condition, female sexual desire disorder due to medical condition, female orgasmic disorder, female sexual arousal disorder, fetishism, friction lover Adolescent or adult gender identity disorder, childhood gender identity disorder, gender identity disorder, generalized anxiety disorder, acting personality disorder, impaired sexual desire disorder, psychosis, impulse control disorder, insomnia, Insomnia associated with another disorder, intermittent Onset disorder, theft, instability or grief, complete remission major depressive disorder, partial remission major depressive disorder, male sexual pain due to medical condition, male erectile dysfunction, medical Male erectile dysfunction due to condition, male sexual desire disorder due to medical condition, male orgasmic disorder, mood disorder due to medical condition, self-love personality disorder, paroxysmal sleep, nightmare disorder, obsession Pain associated with sexual dysfunction, obsessive-compulsive personality disorder, other female sexual dysfunction due to medical condition, other male sexual dysfunction due to medical condition, both psychological factors and medical condition Disability, pain related to psychological features, panic disorder with agoraphobia, panic disorder without agoraphobia, paranoia-like personality disorder, sexual perversion, parasomnia, morbid gambling, pedophilia, personality disorder, Post trauma Tres disorder, premature ejaculation, premenstrual depression, primary hypersomnia, primary insomnia, psychosis of various etiologies, especially alcohol psychosis, circulatory psychosis, regression psychosis, dementia related psychosis, Alzheimer's disease Psychosis, psychosis related to organic brain disorder, and drug-induced psychosis, psychotic disorder caused by medical condition with delusion, psychotic disorder caused by medical condition with hallucination, arson, schizophrenic emotion Disability, schizophrenic personality disorder, tension schizophrenia, destructive schizophrenia, delusional schizophrenia, remnant schizophrenia, indistinguishable schizophrenia, schizophrenia-like disorder, schizophrenia Personality disorder, sexual aversion disorder, sexual disorder, sexual dysfunction, sexual masochism, sexual sadism, shared psychotic disorder, sleep disorder caused by hypersomnia type medical condition, insomnia type medical condition Caused sleep disturbance , Sleep disorders caused by mixed medical conditions, sleep disorders caused by parasomnia-type medical conditions, night wonders, sleepwalking, interpersonal phobias, somatization disorders, physical expression disorders, specific phobias, It can also be used to treat substance-related disorders, clothes-inverted fetishism, hair loss, indistinguishable body expression disorders, suicidal ideation, suicide, unmotivation, vaginal spasticity, and snooping.

Claims (14)

Compounds of formula I or their pharmaceutically acceptable derivatives, tautomers, stereoisomers, stereoisomer mixtures, polymorphs, prodrugs, metabolites, salts for the treatment of psychiatric and neurological disorders Or use of solvates and pharmaceutical compositions containing such compounds:

(Where:
R and R ′ are independently of each other hydrogen, alkyl, haloalkyl, alkoxy, aminoalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, arylalkyl, cycloalkylalkyl, heterocyclic alkyl, Heteroarylalkyl, COR ¹ , COOR ¹ , CONHR ¹ , CON (R ¹ ) ₂ , OR ¹ , NR ¹ R ² , N (R ¹ ) ₂ , SR ¹ , NR ¹ -SO ₂ -R ² , NR ^1- SO ₂ -NR ² R ³ , NR ¹ -CO-NR ² R ³ , -SO-R ¹ , -SO ₂ -R ¹ , -SO ₂ -NR ¹ R ² , -NR ¹ COR ² , -OCO-NR ¹ R ² , -NR ¹ -COOR ² , -O-COO-R ¹ , -CSR ¹ , -C (S) NR ¹ R ² , -SR ¹
Where each member of R and R ′ is optionally substituted;
R ¹ , R ² , R ³ are independently hydrogen, amino, alkyl, haloalkyl, alkoxy, aminoalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, arylalkyl, cycloalkylalkyl, Selected from heterocyclic alkyl, heteroaryl alkyl, wherein each member of R ¹ , R ² , R ³ is optionally substituted;
R and R ′ attached to the same carbon, together with the carbon to which they are attached, can form a ring selected from cycloalkylene, heterocycloalkylene, which can be optionally unsaturated, where The mentioned cycloalkylene, heterocycloalkylene is optionally substituted, which cycloalkylene or heterocycloalkylene may be fused with one or more other cycles,
Y is hydrogen, halogen or any isotope of hydrogen, preferably hydrogen,
Provided that when the compound of general formula I contains two or more diaziridine (1,2-diazacyclopropane) rings (cycles), the diaziridine (1,2-diazacyclopropane) All rings (cycles) are subject to substitution on both nitrogen atoms,
And provided that both R and R ′ cannot be hydrogen. ).   A pharmaceutically acceptable salt or solvate of the compound of claim 1.   A pharmaceutical composition comprising the compound of claim 1 and one or more pharmaceutically acceptable excipients.   The pharmaceutical composition according to claims 1-3, wherein the composition comprises a tablet or capsule.   4. A pharmaceutical composition according to claims 1-3 for the treatment of psychotic disorders and mental disorders of various etiology.   Anxiety disorder, adaptation disorder, eating disorder, personality disorder, mood disorder, physical expression disorder, personality disorder, sleep disorder, sleep disorder, psychotic disorder, eating disorder, physical expression disorder, dissociative disorder, gender The pharmaceutical composition according to claims 1 to 3, for the treatment of sexual disorder, sexual dysfunction, gender identity disorder, impulse disorder, physical expression disorder, mood disorder, eating disorder, impulse control disorder.   Acute stress disorder, unspecified adaptation disorder, adaptation disorder with anxiety, adaptation disorder with depressed mood, adaptation disorder with confusion of behavior, adaptation disorder with mixed anxiety and depressive mood, emotional and behavioral Adaptation disorder with mixed confusion, agoraphobia with no history of panic disorder, anorexia, anorexia nervosa, antisocial personality disorder, anxiety disorder due to medical condition, anxiety disorder, avoidance Personality disorder, bipolar disorder, complete remission bipolar I disorder, partial remission bipolar I disorder, mild bipolar I disorder, moderate bipolar I disorder, severe bipolar with psychotic features Type I disorder, severe bipolar I disorder without psychotic features, bipolar type II disorder, body dysmorphic disorder, borderline personality disorder, respiratory-related sleep disorder, short-term psychotic disorder, bulimia nervosa, Cannabis compound sputum, circadian rhythm sleep disorder, Commutative disorder, mood circulatory disorder, childhood disorder, cognitive disorder, paranoid disorder, addiction personality disorder, divorce disorder, depression of various etiologies, especially melancholic depression, treatment-resistant depression, severe depression Disease, and psychotic depression, dissociative amnesia, dissociative disorder, dissociative fistula, dissociative identity disorder, dyspareunia, sleep disorder, sleep disorder associated with another disorder, mood modulation disorder, intake Eating disorder, exposure, female sexual pain due to medical condition, female sexual desire disorder, medical orgasmic disorder, female sexual arousal disorder, fetishism, friction adolescence, adolescence or Gender identity disorder in adults, gender identity disorder in children, gender identity disorder, generalized anxiety disorder, acting personality disorder, sexual desire disorder, psychosis, impulse control disorder, insomnia, another disorder Associated insomnia, intermittent explosive disorder, theft Unstable or grief mood, major depression with complete remission, major depression with partial remission, male sexual pain due to medical condition, male erectile dysfunction, male erection due to medical condition Disability, male sexual desire disorder due to medical condition, male orgasmic disorder, mood disorder due to medical condition, self-love personality disorder, paroxysmal sleep, nightmare disorder, obsessive compulsive disorder, obsessive-compulsive personality disorder Other female sexual dysfunctions caused by medical conditions, other male sexual dysfunctions caused by medical conditions, pain disorders related to both psychological factors and medical conditions, related to psychological characteristics Pain disorder, panic disorder with agoraphobia, panic disorder without agoraphobia, paranoia-like personality disorder, sexual perversion, parasomnia, pathological gaming, pedophilia, personality disorder, post-traumatic stress disorder, premature ejaculation, Premenstrual depression, primary hypersomnia, primary insomnia, psychosis of various etiologies, especially alcohol psychosis, circulatory psychosis, degenerative psychosis, psychosis related to dementia, psychosis related to Alzheimer's disease, organic brain Psychosis related to disability, drug-induced psychosis, psychotic disorder resulting from medical condition with delusion, psychotic disorder resulting from medical condition with hallucination, arson, schizophrenic emotional disorder, schizophrenia Personality disorder, tension-type schizophrenia, catastrophic schizophrenia, paranoid schizophrenia, remnant schizophrenia, indistinguishable schizophrenia, schizophrenia-like disorder, schizophrenic personality disorder, sexual aversion Disorder, sexual disorder, sexual dysfunction, sexual masochism, sexual sadism, shared psychotic disorder, sleep disorder caused by hypersomnia type medical condition, sleep disorder caused by insomnia type medical condition, Mixed medical Sleep disorder caused by physical condition, sleep disorder caused by parasomnia-type medical condition, night astonishment, sleepwalking, interpersonal phobia, somatization disorder, physical expression disorder, specific phobia, substance-related disorder, clothing perversion The pharmaceutical composition according to claims 1 to 3, for the treatment of sex fetishism, hair loss, indistinguishable body expression disorder, suicidal ideation, suicide, unmotivation, vaginal spasticity, and voyeurism.   4. A pharmaceutical composition according to claims 1-3 for the treatment of depression of various etiology, in particular melancholic depression, treatment-resistant depression, severe depression, and psychotic depression.   For the treatment of psychosis of various etiologies, especially alcohol psychosis, circulatory psychosis, degenerative psychosis, psychosis related to dementia, psychosis related to Alzheimer's disease, psychosis related to organic brain disorders, and drug-induced psychosis The pharmaceutical composition according to claim 1.   4. A pharmaceutical composition according to claims 1-3 for the treatment of neuropathy of various etiology.   Loss of weight sensation, acquired epilepsy-like aphasia, acute disseminated encephalomyelitis, adrenoleukodystrophy, agenesis of corpus callosum, agnosia, Aicardi syndrome, inability to sit still, Alexander disease, alien hand syndrome, contraceptive sensation, Alpers disease , Alternating hemiplegia, Alzheimer's disease, amyotrophic lateral sclerosis, anencephaly, Angelman syndrome, hemangiomatosis, anoxia, aphasia, aphasia, arachnoid cyst, arachnoiditis, Arnold-Chiari malformation , Arteriovenous malformation, telangiectasia ataxia, attention deficit hyperactivity disorder, auditory processing disorder, autonomic dysfunction, back pain, Batten's disease, Behcet's disease, Bell's palsy, benign essential blepharospasm, benign intracranial hypertension , Bilateral frontal parietal cerebral gyrus, binswanger disease, eyelid spasm, Bloch-Salzburger syndrome, brachial plexus injury, brain abscess, brain injury, brain injury, brain Ulcer, Brown-Secart syndrome, Canavan disease, carpal tunnel syndrome, causalgia, central pain syndrome, central pontine myelopathy, central myopathy, head injury, cerebral aneurysm, cerebral arteriosclerosis, cerebral atrophy , Cerebral giantosis, cerebral palsy, cerebral vasculitis, cervical spinal stenosis, Charcot-Marie-Tooth disease, Chiari malformation, chorea, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuritis (CIDP), chronic pain, Coffin-Raleigh syndrome, coma, complex regional pain syndrome, pressure neuropathy, congenital facial paraparesis, cortical basal ganglia degeneration, cranial arteritis, skull fusion, Creutzfeldt-Jakob disease, cumulative traumatic disorder , Cushing's syndrome, giant cell inclusion body disease (CIBD), cytomegalovirus infection, Dandy-Walker syndrome, Dawson's disease, Dumorsier syndrome, Dejerin Kulm Ke paralysis, Dejerin Sottas disease, sleep phase regression syndrome, dementia, dermatomyositis, developmental coordination disorder, diabetic neuropathy, pervasive sclerosis, Drave syndrome, autonomic dysfunction, computational impairment, writing disorder, Dyslexia, schizophrenia, empty sella syndrome, encephalitis, aneurysm, hemangiomatosis of the trigeminal region of the brain, fecal disease, epilepsy, elve palsy, extremity erythema, essential tremor, Fabry disease, Farle disease, syncope , Familial spastic paralysis, febrile seizures, Fischer syndrome, Friedreich ataxia, fibromyalgia, Fauille syndrome, Gaucher disease, Gerstmann syndrome, giant cell arteritis, giant cell inclusion body disease, globuloid cell cerebral white matter atrophy, Ectopic gray matter, Guillain-Barre syndrome, HTLV-1-related myelopathy, Hallelfolden-Spatz disease, head injury, headache, unilateral spasm, hereditary spastic paraplegia, Hereditary polyneurotic ataxia, herpes zoster, herpes zoster, Hirayama syndrome, global forebrain, Huntington's chorea, hydroencephalopathy, hydrocephalus, hyperadrenocorticism, hypoxia, immune-mediated encephalomyelitis, Inclusion somatomyositis, dystaxia, infantile phytanic acid accumulation disease, infantile lefsum disease, epilepsy epilepsy, inflammatory myopathy, intracranial cyst, intracranial hypertension, Joubert syndrome, Karak syndrome, Keynes-Saire syndrome, Kennedy disease, Kinsbrunn Syndrome, Klippel file syndrome, Krabbe disease, Kugelberg-Wehlander disease, Koolou disease, Lafora disease, Lambert Eaton myasthenia syndrome, Landau-Krffner syndrome, lateral myelopathy (Walenberg) syndrome, learning disorder, Lee disease, Lennox・ Gastaut syndrome, Lesch-Nyhan syndrome, cerebral white matter atrophy, Lewy body dementia, Trophic defect, confinement syndrome, Lou Gehrig's disease, lumbar disc disease, lumbar spinal canal stenosis, Lyme disease, Machado-Joseph disease, giant encephalomyelopathy, macroscopic syndrome, giant encephalopathy, Mercerson-Rozental syndrome, Meniere's disease, Meningitis, Menkes disease, metachromatic leukotrophy, microcephaly, microvision, migraine, Miller-Fischer syndrome, microstroke (transient ischemic attack), sound phobia (misophonia), mitochondrial myopathy, Mobius syndrome, single-limb muscular atrophy, motor neuron disease, motor impairment, moyamoya disease, mucopolysaccharidosis, multiple infarct dementia, multifocal motor neuropathy, multiple sclerosis, multiple system atrophy, muscular dystrophy, myalgia Encephalomyelitis, myasthenia gravis, myelin destructive diffuse sclerosis, infant myoclonic encephalopathy, myoclonus, myopathy, myotubular myopathy, congenital muscle Stiffness, paroxysmal sleep, neurofibromatosis, neuroleptic malignant syndrome, neurological signs of AIDS, neurological sequelae of lupus, neuromyotony, neuronal ceroid lipofuscinosis, neuronal cell migration disorder, Niemann-Pick Disease, non-24-hour sleep-wake syndrome, nonverbal learning disorder, Osariban-Macleod syndrome, occipital neuralgia, latent spinal insufficiency, Otawara syndrome, olive bridge cerebellar atrophy, ocular clonus-myoclonus syndrome, optic neuritis, orthostatic low Hypertension, overuse syndrome, repetitive vision, sensory abnormalities, Parkinson's disease, congenital paramyotonia, paraneoplastic disorder, paroxymal attack, Parry-Lomberg syndrome, Pelizaeus-Merzbacher disease, periodic limb paralysis, peripheral neuropathy , Persistent plant condition, pervasive developmental disorder, light sneezing reflex, phytanic acid accumulation disease, Pick's disease, God of compression (pinched nerve), pituitary tumor, polio, polycerebellar encephalopathy, polymyositis, perforated encephalopathy, post-polio syndrome, postherpetic neuralgia (PHN), postinfectious encephalomyelitis, orthostatic hypotension, Prader-Villi syndrome , Primary lateral sclerosis, prion disease, progressive facial unilateral atrophy, progressive multifocal leukoencephalopathy, progressive supranuclear palsy, pseudobrain tumor, rabies, type I Ramsey Hunt syndrome, type II Ramsey Hunt syndrome , Type III Ramsey Hunt syndrome, Rasmussen encephalitis, reflex neurovascular dystrophy, refsum disease, repetitive motor injury, restless leg syndrome, retrovirus-related myelopathy, Rett syndrome, Laie syndrome, rhythmic movement disorder, Romberg syndrome , St. Vitus chorea, Sandhoff disease, schizophrenia, Schilder's disease, encephalopathy, sensory integration disorder, septal optic dysplasia, infant shake syndrome, shingles Shy-Drager Syndrome, Sjogren's Syndrome, Sleep Apnea, Sleep Disease, snatiation, Sotos Syndrome, Spasticity, Spinal Cord Spinal Cord Injury, Spinal Cord Tumor, Spinal Muscular Atrophy, Spinocerebellar Ataxia, Steel Richardson・ Oruszevsky syndrome, Stiff-Person syndrome, stroke, Sturge-Weber syndrome, subacute sclerosing panencephalitis, subcortical arteriosclerotic encephalopathy, superficial siderosis, Sydenham chorea, syncope, synesthesia, syringomyelia, Tarsal tunnel syndrome, tardive dysmotility, tardy dysfronia, tarrobic cyst, Tay-Sachs disease, temporal arteritis, tetanus, spinal tether syndrome, Tomzen's disease, thoracic outlet syndrome, painful tic, todd paralysis, Tourette syndrome, toxic encephalopathy, transient ischemic attack, transmissible spongiform encephalopathy, transverse myelitis, traumatic brain injury, tremor , Trigeminal neuralgia, tropical spastic paraparesis, trypanosomiasis, tuberous sclerosis, Hippel-Lindau disease (VHL), bilisk encephalomyelitis (VE), Wallenberg symptom group, Weldnig Hoffmann disease, West syndrome, whiplash, Williams 4. A pharmaceutical composition according to claims 1 to 3 for the treatment of syndrome, Wilson's disease and Zerweger syndrome.   4. A pharmaceutical composition according to claims 1-3, potentially useful for the treatment of HIV or AIDS.   The pharmaceutical composition according to claims 1-3 for the treatment of Alzheimer's disease.   4. A pharmaceutical composition according to claims 1-3 for the treatment of Parkinson's disease.

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