KR20010112372A - Method for the treatment of neurological or neuropsychiatric disorders - Google Patents

Abstract

A method for the treatment and / or prophylaxis of neuropathic or psychiatric neurological disorders associated with modified dopamine function comprising administering a compound of formula (I) or formula (II) to a patient in need thereof.

[Formula 1]

[Formula 2]

Description

METHODS FOR THE TREATMENT OF NEUROLOGICAL OR NEUROPSYCHIATRIC DISORDERS}

The pineal body, located within the thalamus in the center of the brain, synthesizes and secretes melatonin in the general circulation only during the night, regardless of which species's behavioral pattern is nocturnal or traveling. The nocturnal melatonin secretion rhythm of the pineal gland in mammals is formed by a biological clock located in the suprachiasmatic nuclei (abbreviated as SCN) in front of the hypothalamus. After traversing the pathway through the brain, the afferent path of the pineal nerve derived from the upper cervical ganglion ends in sympathetic control on the pineal cell. In humans, the only natural phenomenon currently known to inhibit melatonin secretion is bright light. Melatonin secretion is strongly resistant to changes caused by many powerful stimuli. The stability of the melatonin rhythm makes melatonin an ideal candidate as a biological time-regulating hormone, which is apparently a rhythm in photosensitive seasonal breeding mammals and has been assumed as a daily rhythm in non-seasonal breeders.

Daily injections of melatonin cause rats residing in constant cancer or constant light to enter the free-running motor activity rhythm and affect the speed and direction of reloading to switch to the light-arm cycle, disrupting the 24-hour cycle system Reorganize and rearrange elements. This riding effect is dependent on the integration of the SCN biological clock, a structure comprising highly affinity melatonin receptors. In addition to these effects on the motor activity pattern of exogenous melatonin, there is an unconfirmed report that melatonin injection, pineal extract and pineal ablation affect the amount of motor activity. Although these reports have not been confirmed, they raise the possibility of a more direct action on the motor system itself rather than indirect effects through the SCN. This suggests that the decrease in spontaneous locomotor activity in mice is associated with melatonin peripheral (Chuang, JI and Ling, MT J. Pineal Res., 17 , 11, 1994) and in vaginal (Bradbury, AJ et al . , 327, 1985)), as well as melatonin blockade of L-dopa-induced locomotion (Cotzias, GC, et al. Science, 173 , 450, 1971) and melatonin regulation of apomorphine-induced rotational behavior (Burton). , S. et al. Experientia, 47 , 466, 1991). Contrary to this background, early reports on the alleviation of Parkinson's disease by high doses of melatonin appear to be possible (Anton-Tay, F. Proc. 4th Int. Cong. Endo., V273, 18, 1972). In view of the role of dopamine in Parkinson's disease and other motor disorders, a common link between these disorders is the change in dopamine function.

Clinical studies on the role of melatonin in neuropsychiatric disorders are limited in number and inconsistent in the hypothesized role of this hormone and in the reported findings. It has been suggested by McIsaac that melatonin is involved in the promotion of many symptoms of schizophrenia (McIsaac, WM et al. Post Grad. Med., 30 , 111, 1961). This hypothesis is consistent with the conjecture that the pineal gland excessively acts on this disorder (Miles, A. and Philbrick, DRS Biol. Psychiatry, 23 , 405, 1988). However, in other clinical studies, nocturnal melatonin secretion is reduced in chronic schizophrenia (Ferrier, IN et al. Clin. Endocrinology, 17 , 181, 1982; Fanget, F. et al. Biol. Psychiatry, 25 , 499, 1989 And some have found that the negative symptoms of this disease are consistent with Parkinson's disease (Hoen, MM et al. J. Neurol. Neurosurg. & Psychiatry, 39 , 941, 1976) .Melatonin is associated with schizophrenia from the onset of puberty. Point out that it provides a protective effect on the development of negative symptoms of Parkinson's disease (Sandyk, R. & Kay, SR, Int. J. Neurosci., 55 , 1, 1990). This hypothesis is further supported by the discovery of the association with pineal deficiency in schizophrenia (Horobin, D. Lancet Vol 1 , p. 529, 1979). Additional confusion has arisen regarding the role of melatonin in the pathogenesis of schizophrenia, as a result of experiments in which bovine pineal extract was administered to patients with this disorder resulting in biochemical abnormal reversal and clinical improvement (Altschule, MD New Eng. J. Med. , 257, 919, 1957; Kitay, JI & Altschule, MD In: The Pineal Gland: A Review of the Physiologic Literature, p. 280, 1954). However, further review of these studies did not yield clinically meaningful results (Eldred, SH New, Eng. J. Med., 263 , 1330, 1960).

Psychopharmacology of psychosis did not help identify the role of melatonin in these disorders. Administration of β-adrenergic agonists, sometimes used as antipsychotic drugs, reduces plasma concentrations of melatonin (Hanssen, T. et al. Arch. Gen. Psychiatry, 37 , 685, 1980), while chloropromazine reduces melatonin Increase (Smith, JA et al. J. Pharm. Pharmacol. (Comm.) 31 , 246, 1979). However, since other antipsychotics do not increase melatonin levels (Smith, JA et al. J. Pharm. Pharmacol. (Comm.) 31 , 246, 1979), melatonin potency functions change in schizophrenia and the melatonin potency system The hypothesis that effective treatment could work through (Smith, JA et al. Clin. Endocrin. 14 , 75, 1981) has not received much support.

The situation became more ambiguous when the results obtained from studies in which melatonin was administered to patients with Parkinson's disease were reviewed. The daily dose of 1000-1200 mg of melatonin per day was 20-36% improvement in clinical status (Anton-Tay, F. Proc. 4th Int. Cong. Endo. V273 , p. 18 , 1972) and tremor. Has been reported to result in a significant reduction of (Cotzias, GC Ann. Rev. Med. 22, 305, 1971). However, repeating this study with similar amounts of the same period of time did not improve the major symptoms of Parkinson's disease (Papavasiliou, PS, JAMA 221, 88, 1972). In addition, decreased pineal gland secretion activity in the disease (Sandyk, R. Int. J. Neurosci. 50 , 83, 1990; Sandyk, R. Int. J. Neurosci. 51 , 73, 1990) and melatonin itself were Parkinson's own It has been claimed that it may be useful to alleviate seed symptoms (Anton-Tay, F. Proc. 4th Int. Cong. Endo. V273 , p . 18,1972). A review of the findings from other studies investigating the relationship between agonist treatment and melatonin potency activity (Papavasiliou, PS, JAMA 221, 88, 1972) found that Parkinson's disease was not derived from the etiology of the melatonin potency system. Reached. Subsequent studies (Vaughan, GM et al, In: Pineal Function, p. 19, 1981) could not reveal major changes in melatonin rhythm or any changes in plasma melatonin concentrations after dopamine agonist treatment. Attempts to stop gradual degeneration of Parkinson's disease by providing antioxidant properties of melatonin (Hardeland, R. et al. Neurosci. Biobehav. Rev., 17 , 347, 1993) and providing antioxidants (Jenner, P. et. al , In: The Assessment and Therapy of Parkinsonism, p. 17, 1990), keeping in mind any attempt to explain Parkinson's disease on the basis of the pathological function of the pineal gland.

It is believed that the role of melatonin over clinical appetite is of minimal importance. Plasma melatonin concentrations were significantly decreased in the subgroup of anorexia nervosa (Kennedy, SH et al, Arch. Gen Psych. 46 , 73, 1989), rather than the pathological aspects of anorexia nervosa or anorexia nervosa. Due to depression (Mortola, JF et al, J. Clin. Endocrin. Metab. 77 , 1540, 1993). Changes in the melatonin secretion cycle are detected in about one third of patients with anorexia nervosa or anorexia nervosa (Ferrari, E. et al, Biol. Psychiatry, 27 , 1007, 1990). However, the increase in melatonin is thought to be due to chronic malnutrition or sustained physical activity, and the explanation that the pathology of the melatonin potency system plays an important role in this disorder is poorly supported.

The present invention relates generally to methods for the treatment and / or prevention of neuropathic or neuropsychiatric disorders, in particular neuropathological or neuropsychiatric disorders associated with modified dopamine function.

FIG. 1 is a graph showing the effect of constant light exposure on weight control in rats receiving intracranial injection of 6-OHDA to induce experimental anorexia and weight loss. Injections were administered on the day labeled “I” and body weight. Are shown for cumulative changes of each day in each group (LL = 24 hour light exposure; LD = 12 hour light, 12 hour dark cycle).

FIG. 2A is a graph showing the effect of constant light exposure on overall migration during the 10 minute test period of several of the infrared active rooms in rats receiving intracranial injection of 6-OHDA. Measurements were performed during the light and dark phases of the light cycle. (LL = 24 hours light exposure; LD = 12 hours light, 12 hours dark cycle).

FIG. 2B is a graph showing the effect of constant light exposure on migration during a 10 minute test period in an infrared active room within 4 days after rats received an intracranial injection of 6-OHDA, with measurements performed during the light and dark phases of the light cycle. (LL = 24 hour light exposure; LD = 12 hour light, 12 hour dark cycle).

FIG. 3 is a graph showing the effect of constant light exposure on the light cycle of the light cycle and the ability to clench limbs during several measurement phases during the cancer phase after rats received 6-OHDA intracranial injection (LL = 24 hour light) Exposure; LD = 12 hours light, 12 hours dark cycle).

FIG. 4 is a graph showing the effect of constant light exposure on the ability of rats to descend during several measurement steps during the light cycle and the cancer phase of the light cycle after receiving an intracranial injection of 6-OHDA (LL = 24 hour light exposure; LD = 12 hours light, 12 hours cancer cycle).

FIG. 5 is a graph showing the effect of constant light exposure on the ability of a rat to walk during several measurement steps during the light and cancer phases of the light cycle after receiving an intracranial injection of 6-OHDA (LL = 24 hour light exposure; LD = 12 hours light, 12 hours cancer cycle).

FIG. 6 is a graph showing the effect of constant light (LL) compared to a 12 hour light / 12 hour cancer (L / D) cycle for a 3 hour food and water intake test after 6 days of intracerebral 6-OHDA injection in animals. to be.

FIG. 7 is a graph showing the effect of pineal ablation on weight control in rats receiving intracranial injection of 6-OHDA to induce experimental anorexia and weight loss. Injections were administered on the day marked “I” and body weight was Daily cumulative changes in each group were indicated (PX = pineal excision animal and SHAM = control animals without pineal extraction).

FIG. 8A is a graph showing the effect of pineal ablation on total migration during a 10-minute examination period of several infrared-activated chambers in rats receiving intracranial injection of 6-OHDA. Measurements were performed during the light and dark phases of the light cycle. PX = pineal resected animal and SHAM = animal undergoing control surgery without pineal extraction).

8B is a graph showing the effect of pineal ablation on migration during the 10 minute test period in an infrared active room within 4 days after rats received an intracranial injection of 6-OHDA, with measurements taken during the light and dark phases of the light cycle. (PX = pineal resected animal and SHAM = animal that had control surgery without pineal extraction).

9 is a graph showing the effect of pineal ablation on the ability of the rat to pinch limbs during several measurement stages after receiving an intracranial injection of 6-OHDA, with measurements performed during the light and dark phases of the light cycle (PX = Pineal resected animal and SHAM = animal with control surgery without pineal extraction).

FIG. 10 is a graph showing the effect of pineal ablation on the ability of rats to descend during several measurement steps after receiving an intracranial injection of 6-OHDA. Measurements were performed during the light and cancer phases of the light cycle (PX = pineal sectioned animal). And SHAM = animals undergoing control surgery without pineal extraction).

FIG. 11 is a graph showing the effect of pineal ablation on the ability of rats to walk during several measurement stages after receiving an intracranial injection of 6-OHDA, where measurements were performed during the light and cancer phases of the light cycle (PX = pineal ablation animal) And SHAM = controlled animals without pineal extraction).

FIG. 12 is a graph showing the effect of pineal resection in animals that received control intra-brain 6-OHDA injections and received control surgery without pineal extraction for a 3 hour food and water intake test after 6 days. Then during the first three hour period.

FIG. 13 is a graph showing the effect of pineal ablation on the tendency of rats to walk into the central square of an infrared open field after receiving an intracranial injection of 6-OHDA, where measurements are performed during the light phase of the light cycle. (PX = pineal resected animal and SHAM = animal undergoing control surgery without pineal extraction).

14 is a graph showing the effect of melatonin intraventricular implants on weight control in rats receiving intracranial injection of 6-OHDA to induce experimental anorexia and weight loss. Dosage and body weight were indicated for daily cumulative changes in each group (Mel = melatonin and Nyl = nylon).

FIG. 15A is a graph showing the effect of melatonin intraventricular implants on migration during the 10 minute test period in an infrared active room in rats within 5 days after receiving an intracranial injection of 6-OHDA. Was performed during the stage (Mel = melatonin and Nyl = nylon).

FIG. 15B is a graph showing the effect of melatonin intraventricular implants on changes in migration during the 10 minute test period in an infrared active room within 5 days after rats received an intracranial injection of 6-OHDA. Was carried out during the light phase of (Mel = melatonin and Nyl = nylon).

FIG. 16 is a graph showing the effect of melatonin's intraventricular implant on the ability of rats to clench limbs during the night measurement phase test during the cancer phase of the light cycle after rats received 6-OHDA intra brain injection (Mel = melatonin Nyl = nylon).

17 is a graph showing the effect of melatonin's intraventricular implant on the ability of rats to descend during the night measurement phase test during the cancer phase of the light cycle after receiving an intracranial injection of 6-OHDA (Mel = melatonin and Nyl = nylon). .

FIG. 18 is a graph showing the effect of melatonin's intraventricular implant on the ability of rats to walk during the night measurement phase test during the cancer phase of the light cycle after receiving an intracranial injection of 6-OHDA (Mel = melatonin and Nyl = nylon). .

FIG. 19 is a graph showing the effect of pineal resection on weight control in rats receiving intraperitoneal injection of MPTP to induce experimental anorexia and weight loss. The daily cumulative change in the group was indicated (PX = pineal resected animal and SHAM = control animal without pineal extraction).

FIG. 20 is a graph showing the effect of pineal ablation on overall migration during the 10 minute test period of several of the infrared active rooms at 1 and 48 hours after rats received an intraperitoneal injection of MPTP, with measurements taken during the light phase of the light cycle. (PX = pineal resected animal and SHAM = animal undergoing control surgery without pineal extraction).

FIG. 21A is a graph showing the effect of pineal ablation on migration during the 10 minute test period in an infrared active room at 1 hour after rats received an intraperitoneal injection of MPTP, with measurements taken during the light phase of the light cycle (PX = Pineal resected animal and SHAM = controlled animal without pineal extraction).

FIG. 21B is a graph showing the effect of pineal ablation on migration during the 10 minute test period in the infrared active room during recovery at 48 hours after rats received an intraperitoneal injection of MPTP. Measurements were performed during the light phase of the light cycle. (PX = pineal resected animal and SHAM = animal that had control surgery without pineal extraction).

FIG. 22A is a graph showing the effect of melatonin intraventricular implants on weight control in rats receiving intraperitoneal injection of MPTP to induce experimental anorexia and weight loss. Injections were administered on the day labeled “inj”. And body weight was expressed for daily cumulative changes in each group (Mel = melatonin and Nyl = nylon).

FIG. 22B is a graph showing the effect of melatonin intraventricular implants on body weight change in rats receiving intraperitoneal injection of MPTP to induce experimental anorexia and weight loss. Injections were administered on days marked “inj”. And body weight was expressed for daily cumulative changes in each group (Mel = melatonin and Nyl = nylon).

FIG. 23A is a graph showing the effect of melatonin intraventricular implants on total migration during the 10 minutes of IR activity in rats within 5 days after receiving an intracranial injection of MPTP, with measurements taken during the light and cancer phases of the light cycle. (Mel = melatonin and Nyl = nylon).

FIG. 23B is a graph showing the effect of melatonin's intraventricular implant on migration during the cancer phase of the light cycle during the 10 minute test period in an infrared active room within 4 days after rats received an intracranial injection of MPTP (Mel = melatonin Nyl = nylon).

24 is a graph showing the effect of melatonin's intraventricular implant on the ability of rats to descend during the cancer phase of the light cycle within 4 days after receiving an intracranial injection of MPTP (Mel = melatonin and Nyl = nylon).

FIG. 25 is a graph showing the effect of bright light treatment and oral atenolol (50 mg daily) on the ability to walk 6 meters of Parkinson's disease patients before and after two weeks of treatment.

FIG. 26 is a graph showing the effect of bright light therapy and oral atenolol (50 mg daily) on the ability of their toes to touch their inner knees in Parkinson's disease patients. Measurements were performed before and after 2 weeks of treatment. It was stopped after five weeks.

We have found a specific mechanism by which melatonin can exacerbate many disorders associated with ataxia and motor function. This finding is designed to provide a reasonable basis for the treatment of neuropathic or neuropsychiatric disorders and to block and / or inhibit the activity of melatonin.

Many melatonin antagonists have been reported in the literature. For example, US Pat. Nos. 4,880,826 and 5,616,614 report two different chemical classes of melatonin antagonists, the compounds of formula (I) and formula (II), respectively.

In structural formula (Ⅰ),

X is -NO ₂ , -N ₂ ,

Y is -H, I.

In structural formula (II),

R represents a hydrogen atom or an -OR ₄ group, wherein R ₄ represents a hydrogen atom or a substituted or unsubstituted group selected from alkyl, cycloalkyl, cycloalkylalkyl, phenyl, phenylalkyl and diphenylalkyl,

R ₁ represents a hydrogen atom or a -CO-OR ₅ group wherein R ₅ represents a hydrogen atom or a substituted or unsubstituted alkyl group,

R ₂ represents a hydrogen atom or —R ′ ₂ group, wherein R ′ ₂ represents an alkyl or substituted alkyl radical,

R ₃ represents —C (═O) — (CH ₂ ) _n —R ₆ , wherein n represents 0 or an integer from 1 to 3 and R ₆ represents a hydrogen atom or an alkyl, substituted alkyl, alkene, substituted alkene, Cycloalkyl or substituted cycloalkyl group, or substituted or unsubstituted heterocyclic group selected from pyrrolidine, piperidine, piperazine, homopiperidine, homopiperazine, morpholine and thiomorpholine; or

-C (= X) -NH- (CH ₂ ) _n -R ₇ , wherein X represents an oxygen or sulfur atom, n 'represents an integer of 0 or 1 to 3, and R ₇ represents alkyl, substituted alkyl , Cycloalkyl, substituted cycloalkyl, phenyl or substituted phenyl group,

if,

R represents an alkoxy group, or

R represents a hydrogen atom and R ₃ represents a -CO-R ₈ group, wherein R ₈ is a hydrogen atom, a methyl group or a methyl or propyl group substituted with a halogen, or

R ₃ represents —C (═X) —NH— (CH ₂ ) _n —R ₇ , wherein X, n ′ and R ₇ are as defined above,

R ₁ may not be a hydrogen atom,

Addition salts with their optical isomers and their pharmaceutically acceptable bases, unless defined otherwise,

The term "substituted" means that the group concerned can be substituted with one or more radicals selected from halogen, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, phenyl and phenylalkyl, wherein the phenyl ring It is possible for itself to be substituted with one or more halogen, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, hydroxyl or trifluoromethyl radicals,

The term "alkyl" means a group containing 1 to 6 carbon atoms in a branched or unbranched chain,

The term "alkene" means a group containing 1 to 6 carbon atoms in a branched or unbranched chain,

The term "cycloalkyl" refers to a saturated or unsaturated, mono- or bicyclic group containing 3 to 10 carbon atoms.

It has been found that the compounds of structures (I) and (II) are agents which are active in the treatment and / or prevention of neuropathic or neuropsychiatric disorders associated with modified dopamine function.

According to one aspect of the present invention there is provided a method of treating and / or preventing a neuropathic or neuropsychiatric disorder associated with modified dopamine function, comprising administration of a compound of formula (I).

[Formula 1]

Wherein X is NO ₂ or -N ₂ and Y is H or I.

In another aspect, the present invention provides a method of treating and / or preventing a neuropathic or neuropsychiatric disorder associated with modified dopamine function, comprising the administration of a compound of formula (II) or an optical isomer thereof and an addition salt thereof. do.

[Formula 2]

From here,

R represents a hydrogen atom or an -OR ₄ group, wherein R ₄ represents a hydrogen atom or a substituted or unsubstituted group selected from alkyl, cycloalkyl, cycloalkylalkyl, phenyl, phenylalkyl and diphenylalkyl,

R ₁ represents a hydrogen atom or a -CO-OR ₅ group wherein R ₅ represents a hydrogen atom or a substituted or unsubstituted alkyl group,

R ₂ represents a hydrogen atom or —R ′ ₂ group, wherein R ′ ₂ represents an alkyl or substituted alkyl radical,

R ₃ represents —C (═O) — (CH ₂ ) _n —R ₆ , wherein n represents 0 or an integer from 1 to 3 and R ₆ represents a hydrogen atom or an alkyl, substituted alkyl, alkene, substituted alkene, Cycloalkyl or substituted cycloalkyl group, or substituted or unsubstituted heterocyclic group selected from pyrrolidine, piperidine, piperazine, homopiperidine, homopiperazine, morpholine and thiomorpholine; or

-C (= X) -NH- (CH ₂ ) _n -R ₇ , wherein X represents an oxygen or sulfur atom, n 'represents an integer of 0 or 1 to 3, and R ₇ represents alkyl, substituted alkyl , Cycloalkyl, substituted cycloalkyl, phenyl or substituted phenyl group,

if,

R represents an alkoxy group, or

R represents a hydrogen atom and R ₃ represents a -CO-R ₈ group, wherein R ₈ is a hydrogen atom, a methyl group or a methyl or propyl group substituted with a halogen, or

R ₃ represents —C (═X) —NH— (CH ₂ ) _n —R ₇ , wherein X, n ′ and R ₇ are as defined above,

R ₁ may not be a hydrogen atom.

Throughout this specification and the appended claims, unless the context otherwise requires, the term "comprises" and modified terms such as "comprising" include the integers or steps or groups of integers or steps mentioned. It will be understood that it is meant to mean and not exclude other integers or steps or groups of integers or steps.

Neuropathic or neuropsychiatric disorders associated with altered dopamine function include Huntington's chorea, periodic limb motor symptoms, restless leg symptoms (akathesia), Tourettet's syndrome, and Sundowner symptoms ( Sundowner's syndrome, schizophrenia, Pick's disease, Punch drunk syndrome, progressive subnuclear palsy, Korsakow's syndrome, complex sclerosis or Parkinson's disease Same movement disorder; Parkinson's syndrome, malignant symptoms, acute dystonia, stroke, trans-ischaemic attack, tardive dyskinesia or complex symptom atrophy induced by neuroleptic syndrome (of Parkinson's syndrome) Drug-induced movement disorders such as; Food intake disorders such as cachexia or anorexia; And cognitive impairment such as Alzheimer's disease or dementia, for example pseudo dementia, hydrocephalic dementia, subcortical dementia, or Huntington's chorea or Parkinson's disease; May include psychiatric disorders characterized by anxiety such as panic disorders, agoraphobia, obsessive-neural disorders, posttraumatic stress disorders, acute stress disorders, general anxiety disorders and other medical disorders such as depression. .

Preferably, the method according to the invention treats Parkinson's disease, schizophrenia, restless leg symptom, general motor disorder, general anxiety disorder, or treatment of one or more, preferably two or more Parkinson's syndromes associated with movement disorders. Used for The recognized symptoms or characteristics of Parkinson's disease are bradykinesia (slowness of exercise), stiffness and tremor.

As used herein, the terms "Parkinson's disease", "Parkinson's disease" and "Parkinson's syndrome" refer to drug induction, such as specific Parkinson's disease, post-encephaletic Parkinson's disease, and neuroleptic-induced Parkinson's syndrome. It will be understood to include various forms of symptoms, including Parkinson's disease, and Parkinson's syndrome after ischemia.

When dopamine-containing neurons in the brain degenerate, there are two immediate consequences. One is the disruption of normal synaptic transmission, which is ultimately characterized by depletion of functional dopamine (accompanied by changes in receptor numbers, affinity, etc.), which affects normal synaptic connectivity with neighboring neurons due to reduced neurotransmission. Several neurological and neuropsychiatric disorders, such as Parkinson's syndrome, are currently thought to be due to brain depletion of dopamine. However, in the present invention, increased brain dopamine is used as a biological marker for pointing to mechanisms underlying motor impairment and alleviation of related anxiety and depressive states. Thus, from this perspective, modified dopamine function associated with neuropathic or neuropsychiatric disorders is generally characterized as a change in dopamine function.

Compounds of formula (I) or (II) may be administered in connection with external therapies that block and / or inhibit melatonin, its precursors and / or metabolites thereof, including, for example, phototherapy, and / or melatonin Antagonists such as other agents that block and / or inhibit melatonin, its precursors and / or its metabolites, such as β-adrenergic agonists such as propranolol or atenolol, calcium channel blockers or melanocyte stimulating hormones (MSH) Administration and / or surgical removal or destruction of the pineal gland (pineal resection). Melatonin antagonists can include melatonin homologues or metabolites or other indoleamines, neurotransmitters, neuromodulators, neurohormones or neuropeptides that have affinity for melatonin receptors and thus inhibit normal melanotin agonistic function. Compounds of formula (I) or (II) are, for example, neuropathic or neuropsychiatric, such as domperidone, haloperidol, pimozide, clozapine, sulfide, metallopromide, spiroperidol or dopamine neurotransmitter inhibitors. It may be administered in conjunction with drugs used for the treatment of the disorder.

Among the pharmaceutically acceptable bases that can be used to form addition salts with the compounds of the invention include, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide or aluminum hydroxide, alkali metal or alkaline earth metal carbonates and triethylamine, benzylamine, di Organic bases such as ethanolamine, tert-butylamine, dicyclohexylamine, arginine, and the like, and the like, but are not limited thereto.

Compounds of formula (I) wherein X = NO ₂ and Y = H (known as ML-23) are particularly preferred compounds. R = H, R ₁ = H, R ₂ = H, R ₃ =-(C = O)-(CH ₂ ) _n -R ₆ , where n = O and R ₆ is a cyclobutyl group The compound of is known as S20928.

Administration of the compounds of formula (I) or (II) is associated with the removal or destruction of sites with increased dopamine function in the brain and / or atypically such as, for example, dopamine receptor blockers (antagonists), in particular clozapine. Drug therapy that modifies dopamine function, such as known neuroleptics, and / or in combination with drug therapy with β-adrenergic potency receptor antagonists such as athenol.

Typical concentrations at which melatonin can be blocked and / or inhibited can be:

(Iii) the concentration of the signal from the brain to the pineal body where secretion occurs;

(Ii) the concentration at which synthesis occurs in the pineal body; And

(Iii) the receptor concentration of the receptor.

Thus, the treatment is not only melatonin itself, but also precursors used in the production of melatonin, for example tryptophan hydroxylase, aromatic amino acid decarboxylase, for example tryptophan, 5-hydroxy tryptophan, serotonin or N-acetyl serotonin. Enzymes or other catalysts, such as N-acetyltransferase and hydroxyindole-O-methyltransferase, can be included to block and / or inhibit metabolites resulting from degradation of melatonin. An example of a product resulting from the degradation of melatonin is 6-hydroxy melatonin sulfate.

The invention also extends to the use of a compound of formula (I) or (II) as defined above in the manufacture of a medicament for the treatment and / or prophylaxis of neuropathic or neuropsychiatric disorders associated with modified dopamine function. .

The patient can be human or livestock or wild animals, especially those of economic importance.

An “effective amount” of the agent is an amount sufficient to alleviate and / or inhibit a neuropathic or neuropsychiatric disorder.

The daily dose when the compound of the present invention is administered to a human can be determined depending on the participating physician, along with the dose that generally varies depending on the severity of the patient's symptoms as well as the age, weight and response of the individual patient. In general, a suitable dose of a compound of the present invention may be in the range of 0.01 to 50 mg / kg body weight per day, with a preferred range of 0.5 to 10 mg / kg body weight per day. The desired dose is preferably administered in 2, 3, 4, 5, 6 or more sub doses at appropriate intervals throughout the day. Sub doses may be administered in unit dosage forms comprising 1 to 500 mg, preferably 10 to 1000 mg, of active ingredient per unit dosage form.

The drug is intended for oral, implant, rectal, inhaled or sprayed (through mouth or nose), topical (including oral and sublingual), vaginal and injection (subcutaneous, intramuscular, intravenous, intrasternal and skin) for treatment. Can be administered by any suitable route, including). Preferred routes will vary depending on the condition and age of the patient and the drug selected.

The agent may be administered in the form of a composition together with one or more pharmaceutically acceptable carriers, diluents, adjuvants and / or excipients.

Thus, according to another aspect of the invention, a pharmaceutically or veterinary acceptable carrier, diluent, adjuvant and / or for the treatment and / or prevention of neuropathic or neuropsychiatric disorders associated with modified dopamine function A pharmaceutical or veterinary composition is provided that includes an excipient and an agent that blocks and / or inhibits melatonin, its precursors, and / or metabolites thereof.

Carriers, diluents, adjuvants and / or excipients should be pharmaceutically "acceptable" in the sense of being incompatible with the other ingredients of the composition and not harmful to the individual. The compositions may be used for oral, implant, rectal, inhalation or spraying (through the mouth or nose), topical (including the oral and sublingual), vaginal and injection (including subcutaneous, intramuscular, intravenous and intradermal). Including suitable ones. The compositions may conveniently be presented in unit dosage form and may be prepared by methods known in the art of pharmacy. Such methods include combining a medicament with a carrier which constitutes one or more accessory ingredients. In general, the composition is prepared by uniformly and directly combining the medicament with a liquid carrier, diluent, adjuvant and / or excipient or finely ground solid carrier or both, into a product form as required.

Compositions of the invention suitable for oral administration may be presented as powders or granules; As a solution or a suspension in an aqueous or non-aqueous liquid; Or as an oil-in-water emulsion or water-in-oil emulsion, a predetermined amount of medicament may be provided as divided units such as capsules, sachets or tablets. The medicament may also be provided as a bolus, electuary or paste.

Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared in a suitable machine with a binder (eg pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethyl cellulose), fillers (eg lactose, microcrystalline cellulose or calcium hydrogen phosphate), bow With turbidity agents (eg magnesium stearate, talc or silica), inert diluents, preservatives, disintegrants (eg sodium starch glycolate, crosslinked povidone, crosslinked carboxymethyl cellulose), surfactants or dispersants It may be prepared by compressing a medicament in a fluid form such as optionally mixed powders or granules. Molded tablets may be made by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. Tablets may be coated or etched and may be formulated to provide slow release or controlled release of the medicament, for example using hydroxypropylmethyl cellulose in various ratios therein to provide the desired release form. have. Tablets may optionally be enteric coated to provide release in a portion of the intestine rather than the stomach.

Liquids for oral administration may be provided, for example, in the form of liquids, syrups or suspensions, or in dried products which are constituted with water or other suitable carrier prior to use. Such solutions include suspending agents (eg, sorbitol syrup, cellulose derivatives or cured edible fats); Emulsifiers (eg lecithin or acacia); Non-aqueous carriers (eg, almond oil, oily esters, ethyl alcohol or fractionally distilled vegetable oils); And pharmaceutically acceptable additives such as preservatives (eg, methyl or propyl-p-hydroxybenzoate or sorbic acid).

Compositions suitable for topical administration in the mouth include lozenges comprising the agent in an aromatic base, usually sugar and acacia or tragacanta rubber; Pastilles comprising the agent in an inert base such as gelatin and glycerin or sugar and acacia rubber; And mouthwashes comprising a medicament in a suitable liquid carrier.

For topical application to the skin, the agent may be in the form of a cream, ointment, jelly, solution or suspension.

For topical application to the eye, the agent may be in the form of a solution or suspension in a suitable sterile water-soluble or non-aqueous carrier. For example, additives such as buffers, phenylmercuric acetate or nitrate, preservatives including fungicides and fungicides such as benzalkonium chloride or chlorhexidine, and viscous agents such as hypromellose may also be included.

The agent may also be formulated in a depot formulation. Such sustained action formulations may be administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the medicament may be formulated with a suitable polymer or hydrophobic material (eg, an acceptable oil or ion exchange resin) or as a derivative that is almost insoluble, such as a salt that is almost insoluble. Preferably, the medicament is a polymer such as microspheres suitable for sustained or pulsating release in the central nervous system where dopamine is present, for example in the substantial nigra, globus pallius or nucleus caudatas. Administered in the form of implants.

Compositions for rectal administration may be provided as suppositories or oleaginous enema with solid non-irritating excipients that are solid at ordinary temperatures but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such excipients include cocoa butter or salicylates.

For intranasal and pulmonary administration, the medicament may be formulated as a powder mixture with a liquid or suspension administered via a suitable metered or unit dose device, or with a suitable carrier administered with a suitable delivery device.

Suitable compositions for vaginal administration may be provided as pessaries, tampons, creams, gels, pastas, foams or spray formulations comprising a suitable carrier known in the art with the agent.

Suitable compositions for injection administration include aqueous and non-aqueous isotonic sterile injectable solutions, which may include antioxidants, buffers, bacteriostatics and solutes to isotonic the composition with the blood of the intended individual; And aqueous and non-aqueous sterile suspending agents which may include suspending agents and viscous agents. The compositions may be presented in unit or multiple dose sealed containers, such as ampoules and vials, in a lyophilized state where only adding a sterile liquid carrier, such as water for injection, is required immediately before use. Can be stored. Instant injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the kind previously described.

Preferred unit dose compositions are those comprising a daily dose or unit of a medicament as described above, a daily subdose, or an appropriate divided amount thereof.

The medicaments may be provided for use in the form of a veterinary composition, which may be prepared, for example, by methods conventional in the art. Examples of such veterinary compositions include those suitable for:

(a) oral administration, external use, such as drunks (eg, aqueous or non-aqueous solutions or suspensions); Tablets or pills; Powders, granules or pellets for mixing with food ingredients; Pasta for application to the tongue;

(b) injection administration, for example by subcutaneous, intramuscular or intravenous injection, for example as a sterile solution or suspension; Or injection administration by intramammary injection, where (suitably) the suspension or solution is introduced into the mammary gland via the nipple;

(c) topical application, for example as a cream, ointment or spray applied to the skin; or

(d) Vaginal as pessary, cream or foam.

In addition to the components particularly mentioned above, it will be appreciated that the compositions of the present invention may include other agents conventional in the art with respect to the form of the composition in question, for example those suitable for oral administration are binders, sweeteners , Agents such as viscous agents, fragrances, disintegrants, coatings, preservatives, lubricants and / or time lasting agents.

Suitable sweeteners include sugar, lactose, glucose, aspartame or saccharin. Suitable disintegrants include corn starch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar. Suitable fragrances include peppermint oil, oil of wintergreen, cherry, orange or raspberry flavors. Suitable coatings include polymers or copolymers of acrylic acid and / or methacrylic acid and / or esters, waxes, fatty alcohols, zein, shellac or gluten thereof. Suitable preservatives include benzoic acid, vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propyl paraben or bisulfite sodium. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc. Suitable time lasting agents include glyceryl monostearate or glyceryl distearate.

The invention will be explained with reference to the following examples. These examples will not be construed as limiting the invention in any way.

Experiment method

Lesions of the brain dopamine system in mammalian species serve as models of various neuropsychiatric disorders. When lesions occur at various levels along the upward dopamine pathway in the brains of experimental animals, there are dopamine functional modifications that involve both acute and continuous changes in emotion, exercise, and dietary behavior, each of which causes specific biochemical sequelae. .

For example, modifications of central catecholamine function, particularly of the upstream noradrenaline and dopamine potency systems that stimulate the striatum, have been shown to be responsible for latent schizophrenia (Stein, L & CD, Science, 171 , 1032). , 1971). Experimental accompaniments of movement disorders can be formed in some species by lesioning the up-dopamine system at any anatomical location that extends from the medullotic midbrain cell bodies to the caudate / putamen nucleus. Depending on the species employed, this can lead to loss of appetite and weight, laxity, oral reflexes, and further progress and eventually death. The pathology of the upward dopamine system is more subtly associated with anorexia nervosa and depression on several backgrounds.

Other recent and early studies reveal many similarities between the clinical symptoms of anorexia nervosa and the experimental models with modified dopamine function employed by the inventors. These similarities include iii) food interactions; Ii) increased activity in the presence of severe energy storage depletion and weakness; Iii) increased motivation for food with food intake and weight loss; Viii) hypothermia; And iii) similarities between modified dopamine function, especially 6-OHDA induced anorexia and what appears after amphetamine administration.

Neurotoxic 6-hydroxydopamine (abbreviated herein as "6-OHDA") at appropriate concentrations results in specific and permanent lesions of brain monoamines. Intracranial injection of this compound was used in the Examples to form a model of motor disorders such as Parkinson's disease and schizophrenia. Bilateral lesions of the nigrostriatal pathway cause vegetative and involuntary asynchronous symptoms characterized by a lack of spontaneous movement, acute posture and weight loss accompanied by severe adipasia and aphagia. do. As a result test, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (hereinafter abbreviated as "MPTP") also known to cause Parkinson's syndrome by a mechanism similar to that of 6-OHDA Was administered as the second animal model.

In humans, MPTP was synthesized as a paraquat-like herbicide and workers exposed to high doses showed irreversible Parkinson's syndrome no different from the specific form of the disease. In addition, MPTP was used to "break" morphine in the illegal drug market and gave increased effects (eg euphoria). This use resulted in the first patient who was misdiagnosed as schizophrenia and continued antipsychotic treatment for three months. Many addicts who were exposed to MPTP had Parkinson's symptoms.

In this embodiment, reference will be made to the accompanying drawings.

Example 1

Natural secretion of melatonin can be included in the manifestation of motor damage. One way to inhibit endogenous melatonin secretion is to place animals in an environment that is exposed to bright, constant light. One group of animals was placed in an environment with constant light (minimum intensity = 150 lux) for 2 weeks after insertion of the PLH tubing as described below:

After several days of control observations, all animals were injected on both sides with 2 μl of 8 μg / μl solution of 6-OHDA. Body weight was measured daily immediately after the start of the light cycle and motor performance was measured by evaluating the performance of the animal against three tests commonly used to evaluate motor function in the open field. Public field activity was measured in PVC boxes with infrared sensors. The number of disconnected beams was recorded during the 10 minute inspection period. The three reflexes employed are the incubation period with which the limb is 25 cm above the surface of the examination area, the incubation period when the rear torso is raised or descended from the raised hem when the rear torso is lifted 30 cm above the surface of the examination area, and the incubation period going out of the previous area. . All tests had an optimal latency latency of 30 seconds and were based on extensive validation, use and experience.

Tubing animals of the second group were placed in a 12 hour light / 12 hour dark cycle. After 20 days of controlled observation of body weight and motor function, animals received 6-OHDA injections as described in Example 3 below. Body weights were measured daily for 24 days after 6-OHDA and athletic performance was measured at 2, 4, 14 and 15 days.

1 shows that daily cumulative changes in body weight in animals received in L / L or L / D state are similar to control observations prior to 6-OHDA injection during the first 22 days. After this period, these animals received L / D status showed a progressively more severe reduction in body weight than animals in L / L status (p = .001). Recovery began on day 10 after 6-OHDA injection in L / L animals, while weight loss was still present on day 44 in L / D animals.

Motor activity for all tests of motor function was significantly different between the two groups. In FIG. 2A, damage in the open area was significantly less severe in 6-OHDA injected L / L animals than in animals received in L / D state (p = .05). As shown in FIG. 2A, L / L animals performed significantly better than L / D animals when tested during the recovery phase of the experiment (p = .035).

The incubation period with the extremities (FIG. 3) showed a slight severe damage to this reflex by animals received in the L / D state, while only slightly increased in 6-OHDA animals when received in the L / L state. The performance of L / L animals was significantly better than L / D animals (p = .000). The incubation period was similarly affected in L / L animals showing severe damage while animals in the L / D state were severely damaged (FIG. 4; p = .00? 9). Gait incubation was minimally affected by exposure to L / L status but showed a significant trend in a predetermined direction by L / L animals (FIG. 5; p = .089).

Animals received in L / L state lived longer than animals in L / D state. As shown in FIG. 6, the food intake of the animals in the L / L group was significantly higher than that of the animals in the L / D state in the 3 hour test (p = .025), while the water intake was similar in both groups. It was.

Example 2

To remove the underlying source of endogenous melatonin, the pineal gland was surgically removed under anesthesia. SHAM rats were used as a control group that underwent anesthesia, incision, skull resection, sinus perforation, and bleeding, but did not damage the pineal gland. Body weight was measured daily during the experiment and motor reflex control was measured at 2, 4, 14 and 15 days. 6-OHDA injections were administered as in Example 3 except that the injections were made accurately without implanting permanent cannula on the designated day.

As shown in FIG. 7, the body weight of PX animals was similar to SHAM animals until they received an intracranial injection of 6-OHDA. The two groups then lost weight at a comparable rate in the first two days after injection, but then PX animals gained their weight from 23 to 30 days, while SHAM continued to decline during that period and the difference was significant ( p = .05). 8A shows that the open field performance of PX animals is significantly better than that of the corresponding SHAM (p = .45). PX animals also showed a significant trend toward better performance during the test period than SHAM animals (FIG. 8B; p = .063).

As shown in FIG. 13, the tendency of the animal to reluctant to move to the central square of the thymmotaxis or the open field was also reduced by pineal resection. Pineal ablation reduced associated anxiety compared to the SHAM control, resulting in significantly increased exercise (p = .019).

Example 3

In order to obtain sustained central secretion of melatonin, Regulin® pellets were implanted into the left ventricle of rats during cannulation of the posterior, lateral hypothalamus (PLH). Control rats were implanted with inert nylon pellets of the same dimensions. This method of melatonin was chosen based on the study that peripheral injections result in moderately impaired motor function, since injection of bolus does not approximate the low and sustained secretion properties of natural secretion. Animals were plugged in and tested as described in Example 1.

As shown in FIG. 14, the nylon pellet-grafted animals showed a gradual weight loss and the spontaneous recovery began on the first 4 days after 6-OHDA injection, similar to that shown in the melatonin-grafted animals. However, melatonin-transplanted animals showed a more severe reduction in body weight each day from day 16 to end of the experiment, and this damage was significantly greater than that of nylon-grafted animals at day 4 (p = .0143).

As shown in FIGS. 15A and 15B, the overall changes seen during open field performance and testing were significantly worse in animals implanted with melatonin (p = .0022). Melatonin-grafted animals showed a decrease in public field outcomes, which was more than twice that of inactive nylon-grafted animals. The results on the trimotor test of melatonin-transplanted animals were slower than nylon-transplanted animals, although not significant (FIGS. 16-18).

Example 4

In this study, the animals were resected and had SHAM surgery. Four to eight weeks after pineal resection, all animals received an intraperitoneal injection of MPTP as described in Example 5. Body weights were measured 7 days before and 4 days after MPTP. The performance of all motor tests was measured at 1 hour and 48 hours after MPTP administration.

As shown in FIGS. 19A and 19B, PX animals were weighted to slightly higher levels than for SHAM animals. Moreover, they lost slightly less body weight than the corresponding SHAM after MPTP injection, but the difference is not significant.

20 shows that pineal excision animals 1 hour after MPTP administration are more active than SHAM controls (p = .0051). Test modalities were significantly better in PX animals at the open site (FIG. 21A; p = .354) and Px animals recovered faster than SHAM (FIG. 21B; p = .0114).

Example 5

Rats were implanted with melatonin pellets or inert nylon in the brain as shown in Example 3, the only difference being that they were not implanted into the hypothalamic cannula. After evaluating the control outcomes, all animals received an intraperitoneal injection of MPTP on day 4 (7 mg / kg / i.p.). Given that the effects of MPTP are less persistent and more traumatic than 6-OHDA, this provided an opportunity to study the phenomenon of recovery. Body weight was measured daily and athletic performance was measured 1 hour, 2 days after injection.

As shown in FIG. 22A, animals grafted with melatonin did not gain much weight during the observation period compared to animals transplanted with inert nylon. Differences in the rate of weight gain were reduced after MPTP injection and this difference is significant as shown in FIG. 22B (p = .0201). As shown in FIGS. 23A and 23B, transplantation of melatonin pellets increased motor impairment seen after MPTP compared to nylon transplanted animals (overall behavioral pattern, p = .0344; behavioral trend at night, p = 0.0638). As shown in FIG. 24, melatonin-transplanted animals showed a significant decrease in their ability to walk when evaluated over night (p = .0238).

Example 6

One patient diagnosed with Parkinson's disease three years ago occurs twice a day for 1 hour of bright light therapy (1500 lux), one before going to bed and one to antagonize melatonin secretion. Exposed immediately. The patient was also prescribed 50 mg of atenolol, a β-adrenergic agonist, before going to sleep. The patient's exercise test and performance on body weight were measured before and two weeks after the start of treatment.

As shown in FIG. 25, the time taken to walk and return to the 3 meter path ranged from 31.3 seconds before treatment to 13.5 seconds after treatment. Similarly, the time taken to lift the foot to the knee and return it 10 times to the floor was 44 seconds on both sides from 58 seconds (R) and 65 seconds (L) before treatment and two weeks after treatment. Similarly, on other motor tests the patient showed improvement after treatment and memory loss and mental state improved, which allowed to reduce the daily dose of 1-wave. Progress and stiffness have also improved. The patient was also shown to be thin with poor appetite during the course of the disease and could not gain weight, but after 2 weeks of treatment he gained 3 kg in weight. Increased exercise increased patient daily activity and improved quality of life.

At least 10 years ago, a second patient diagnosed with Parkinson's disease had the same test as the first. The effect of bright light therapy (1000 lux) for 1 hour in the morning and 1 hour at night with 50 mg of atenolol before bedtime is shown in FIG. 26 on the ability to perform leg exercise.

The incubation period required to touch the knee with the foot and return it to the floor 10 times improved dramatically after 5 weeks of treatment. The behavior worsened when the patient withdrew from treatment for five weeks.

Example 7

Compound ML-23 was tested using a 12 hour light / 12 hour dark cycle on the 6-OHDA model described in Example 1. Briefly, animals received 13 days of controlled observation and at day 14 6-OHDA was injected. Animals in the treatment group were treated with melatonin antagonist (ML-23 (3 mg per ml) in DMSO) once per 6-OHDA injection day, then twice daily for 3 days (3 mg / kg / ml, intraperitoneal injection (ip ))

ML-23 prevented the development of severe motor damage typically seen in 6-OHDA treated rats. ML-23 prevented the severe weight loss characteristic of 6-OHDA treated animals. Three of the seven animals in the 6-OHDA / carrier group died 6 days after treatment, while all rats treated with ML-23 recovered and were able to control their weight. Horizontal and vertical movement, especially night movement, was significantly improved by the therapy of ML-23 employed. The incubation period to perform the exercise test (latency to crouch the limb, incubation to walk, and incubation to move) was also improved during the post-treatment examination and recovery period with ML-23. In summary, all animals that received ML-23 injections and then 6-OHDA injections performed better than animals that received carriers followed by 6-OHDA injection treatments.

Example 8

As described in Examples 1 and 7, a second melatonin antagonist, S-20928, was tested in the 6-OHDA model. At a dose of 1 mg / kg ip, S-20928 can restore the most restorative outcome of DA degeneration in any preclinical PD model; that is, body weight (Dunnett, SB, et al, Trends Neurosci. 6, p.266). -70, 1983; Dunnett, SB, and Bjorklund, A., Appetite, 5, p. 263-65, 1984). In doing so, S-20928 also reduces disease morbidity and increases survival time.

Those skilled in the art will appreciate that the invention described herein is easy to change and modify other than those specifically described. It will be understood that the present invention includes all such changes and modifications. The invention also includes all steps, aspects, compositions and compounds mentioned or indicated individually or collectively herein, and all combinations of any two or more of the above steps or aspects.

Claims (18)

A method of treating and / or preventing neuropathic or neuropsychiatric disorders associated with modified dopamine function, comprising administering a compound of formula (I). [Formula 1] Wherein X is NO ₂ or -N ₂ and Y is H or I. The method of claim 1 wherein X is NO ₂ and Y is H. 10. A method of treating and / or preventing neuropathic or neuropsychiatric disorders associated with modified dopamine function, comprising the administration of a compound of formula (II), optical isomers thereof, and addition salts thereof. [Formula 2] From here, R represents a hydrogen atom or an -OR ₄ group, wherein R ₄ represents a hydrogen atom or a substituted or unsubstituted group selected from alkyl, cycloalkyl, cycloalkylalkyl, phenyl, phenylalkyl and diphenylalkyl, R ₁ represents a hydrogen atom or a -CO-OR ₅ group wherein R ₅ represents a hydrogen atom or a substituted or unsubstituted alkyl group, R ₂ represents a hydrogen atom or —R ′ ₂ group, wherein R ′ ₂ represents an alkyl or substituted alkyl radical, R ₃ represents —C (═O) — (CH ₂ ) _n —R ₆ , wherein n represents 0 or an integer from 1 to 3 and R ₆ represents a hydrogen atom or an alkyl, substituted alkyl, alkene, substituted alkene, Cycloalkyl or substituted cycloalkyl group, or substituted or unsubstituted heterocyclic group selected from pyrrolidine, piperidine, piperazine, homopiperidine, homopiperazine, morpholine and thiomorpholine; or -C (= X) -NH- (CH ₂ ) _n -R ₇ , wherein X represents an oxygen or sulfur atom, n 'represents an integer of 0 or 1 to 3, and R ₇ represents alkyl, substituted alkyl , Cycloalkyl, substituted cycloalkyl, phenyl or substituted phenyl group, if, R represents an alkoxy group, or R represents a hydrogen atom and R ₃ represents a -CO-R ₈ group, wherein R ₈ is a hydrogen atom, a methyl group or a methyl or propyl group substituted with a halogen, or R ₃ represents —C (═X) —NH— (CH ₂ ) _n —R ₇ , wherein X, n ′ and R ₇ are as defined above, R ₁ may not be a hydrogen atom. The method of claim 1, wherein said neuropathic or neuropsychiatric disorders associated with modified dopamine function are selected from psychiatric disorders and motor disorders characterized by anxiety. 5. The method of claim 4, wherein said neuropathic or neuropsychiatric disorder associated with modified dopamine function is Huntington's chorea, periodic limb motor symptoms, restless leg symptoms (akathesia), Tourette's syndrome , Sundowner's syndrome, schizophrenia, Pick's disease, Punch drunk syndrome, progressive subnuclear palsy, Korsakow's syndrome, Multiple sclerosis, Parkinson's disease, malignant syndrome, acute dystonia, stroke, trans-ischaemic attack, tardive dyskinesia, and multiple Exercise disorder method selected from symptom atrophy (addition of Parkinson's syndrome). 6. The method of claim 5, wherein the movement disorder is selected from Parkinson's disease, schizophrenia, restless leg symptoms and a general motor disorder. 6. The method of claim 5, wherein the movement disorder is Parkinson's disease. 6. The method of claim 5, wherein said neuropathic or neuropsychiatric disorder associated with modified dopamine function is panic disorder, agoraphobia, obsessive-nerve disorder, post traumatic stress disorder, acute stress disorder, general anxiety disorder. And anxiety disorder methods caused by depression. The method of claim 8, wherein said neuropathic or neuropsychiatric disorder is common. The method of claim 1, wherein said neuropathic or neuropsychiatric disorder associated with modified dopamine function is cachexia anorexia cachexia or anorexia nervosa. 4. The method of any one of claims 1 to 3, wherein said neuropathic or neuropsychiatric disorder associated with modified dopamine function is Alzheimer's disease or dementia. The method of claim 1, wherein the patient further receives an external therapy that blocks and / or inhibits melatonin, its precursors, and / or metabolites thereof. The method of claim 10, wherein said external therapy comprises phototherapy. 4. The method of any one of claims 1 to 3, further comprising administering a drug that modifies dopamine function to the patient and optionally phototherapy. Use of a compound of formula (I) in the manufacture of a medicament for the treatment and / or prevention of neuropathic or neuropsychiatric disorders associated with modified dopamine function. [Formula 1] Wherein X is NO ₂ or -N ₂ and Y is H or I. Use of the compounds of formula (II), their optical isomers and addition salts thereof in the manufacture of a medicament for the treatment and / or prevention of neuropathic or neuropsychiatric disorders associated with modified dopamine function. [Formula 2] From here, R represents a hydrogen atom or an -OR ₄ group, wherein R ₄ represents a hydrogen atom or a substituted or unsubstituted group selected from alkyl, cycloalkyl, cycloalkylalkyl, phenyl, phenylalkyl and diphenylalkyl, R ₁ represents a hydrogen atom or a -CO-OR ₅ group wherein R ₅ represents a hydrogen atom or a substituted or unsubstituted alkyl group, R ₂ represents a hydrogen atom or —R ′ ₂ group, wherein R ′ ₂ represents an alkyl or substituted alkyl radical, R ₃ represents —C (═O) — (CH ₂ ) _n —R ₆ , wherein n represents 0 or an integer from 1 to 3 and R ₆ represents a hydrogen atom or an alkyl, substituted alkyl, alkene, substituted alkene, Cycloalkyl or substituted cycloalkyl group, or substituted or unsubstituted heterocyclic group selected from pyrrolidine, piperidine, piperazine, homopiperidine, homopiperazine, morpholine and thiomorpholine; or -C (= X) -NH- (CH ₂ ) _n -R ₇ , where X represents an oxygen or sulfur atom, n 'represents an integer of 0 or 1 to 3 and R ₇ represents alkyl, substituted alkyl , Cycloalkyl, substituted cycloalkyl, phenyl or substituted phenyl group, if, R represents an alkoxy group, or R represents a hydrogen atom and R ₃ represents a -CO-R ₈ group, wherein R ₈ is a hydrogen atom, a methyl group or a methyl or propyl group substituted with a halogen, or R ₃ represents —C (═X) —NH— (CH ₂ ) _n —R ₇ , wherein X, n ′ and R ₇ are as defined above, R ₁ may not be a hydrogen atom. To treat and / or prevent neuropathic or neuropsychiatric disorders associated with modified dopamine function, comprising a compound of formula (I) together with a pharmaceutically or veterinary acceptable carrier, diluent, adjuvant and / or excipient. Pharmaceutical or veterinary composition for. [Formula 1] Wherein X is NO ₂ or -N ₂ and Y is H or I. Neuropathic or neurological associated with modified dopamine function, including compounds of formula (II), their optical isomers, and addition salts thereof, together with pharmaceutically or veterinary acceptable carriers, diluents, adjuvants and / or excipients Pharmaceutical or veterinary compositions for the treatment and / or prevention of psychotic disorders. [Formula 2] From here, R represents a hydrogen atom or an -OR ₄ group, wherein R ₄ represents a hydrogen atom or a substituted or unsubstituted group selected from alkyl, cycloalkyl, cycloalkylalkyl, phenyl, phenylalkyl and diphenylalkyl, R ₁ represents a hydrogen atom or a -CO-OR ₅ group wherein R ₅ represents a hydrogen atom or a substituted or unsubstituted alkyl group, R ₂ represents a hydrogen atom or —R ′ ₂ group, wherein R ′ ₂ represents an alkyl or substituted alkyl radical, R ₃ represents —C (═O) — (CH ₂ ) _n —R ₆ , wherein n represents 0 or an integer from 1 to 3 and R ₆ represents a hydrogen atom or an alkyl, substituted alkyl, alkene, substituted alkene, Cycloalkyl or substituted cycloalkyl group, or substituted or unsubstituted heterocyclic group selected from pyrrolidine, piperidine, piperazine, homopiperidine, homopiperazine, morpholine and thiomorpholine; or -C (= X) -NH- (CH ₂ ) _n -R ₇ , wherein X represents an oxygen or sulfur atom, n 'represents an integer of 0 or 1 to 3, and R ₇ represents alkyl, substituted alkyl , Cycloalkyl, substituted cycloalkyl, phenyl or substituted phenyl group, if, R represents an alkoxy group, or R represents a hydrogen atom and R ₃ represents a -CO-R ₈ group, wherein R ₈ is a hydrogen atom, a methyl group or a methyl or propyl group substituted with a halogen, or R ₃ represents —C (═X) —NH— (CH ₂ ) _n —R ₇ , wherein X, n ′ and R ₇ are as defined above, R ₁ may not be a hydrogen atom.