CN101273982A - Medicament for preventing or/and treating depression - Google Patents
Medicament for preventing or/and treating depression Download PDFInfo
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- CN101273982A CN101273982A CNA2008100891250A CN200810089125A CN101273982A CN 101273982 A CN101273982 A CN 101273982A CN A2008100891250 A CNA2008100891250 A CN A2008100891250A CN 200810089125 A CN200810089125 A CN 200810089125A CN 101273982 A CN101273982 A CN 101273982A
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
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Abstract
The invention provides a medicine for prevention and/or treatment of depression, depressive state or anxiety neurosis, or a medicine for prevention and/or treatment of these diseases with a symptom of cerebrovascular obstacles; the medicine takes the substances selected from amino alkoxy bibenzyl compounds, pharmaceutical salts thereof, ester thereof, solvate and hydrate thereof represented by the formula (1) as effective ingredients, in the formula R<1> represents hydrogen atom, halogen atom, alkoxy including 1 to 5 carbon atoms, or dialkyl amino including 2 to 6 carbon atoms; R<2> represents hydrogen atom, halogen atom, alkoxy including 1 to 5 carbon atoms; R<3> represents hydrogen atom, hydroxyl, -O-(CH2)n-COOH (n represents an integer of 1 to 5) or -O-CO(CH2)l-COOH (l represents an integer of 1 to 3); R<4> represents -N(R<5>)(R<6>)(R<5> and R<6> each independently represents hydrogen atom or alkyl including 1 to 8 carbon atoms), m represents an integer of 0 to 5.
Description
Technical field
The present invention relates to a kind of depression that prevents and/or treats, the medicine of depressive state or anxiety neurosis (the following medicine that prevents and/or treats depression that also abbreviates as), perhaps prevent and/or treat the depression that is attended by cerebrovascular disorders, be attended by the depressive state of cerebrovascular disorders or be attended by the medicine (the following medicine that prevents and/or treats vascular depression that also abbreviates as) of the anxiety neurosis of cerebrovascular disorders, wherein said medicine is to be selected from aminoalkoxy bibenzyl chemical compound, its officinal salt, its ester, their solvate and the material in the hydrate are as effective ingredient.
Background technology
Although the cardinal symptom of depression be lack cordiality, depressed; but also can see the patient and ability of thinking decline occur; or the thought disturbance that forms pessimism, feels guilty; or daily routines reduce; demoralized; mental symptoms such as sensation uneasiness, impatience, but also can find neurovegetative (with reference to the non-patent literatures 1) such as physical symptoms that causes unusually.
It is believed that depression is that if carry out suitable treatment, this disease can be eased owing to the temporary decline of the effect of brain causes.It is main effective Therapeutic Method (with reference to non-patent literature 2) that (rest) and these three kinds of methods of pharmacotherapy are instructed in psychotherapy, life.Pharmacotherapy mainly is to adopt prescription drugs such as mianserin, sulpiride, imipramine.
Up to the present, the relation of a lot of bibliographical informations have been arranged cerebrovascular disorders and depressive state, the someone proposes that the depression that these is attended by cerebrovascular disorders is called vascular depression.About the treatment of vascular depression, need carry out at the treatment of cerebrovascular disorders and carry out two aspects of antidepressant drugs treatment.It is believed that and to select for use SSRI (selective serotonin reuptake inhibithors) and SNRI (serotonin-Norepinephrine reuptake inhibithors) as effective medicine.Yet in general, vascular depression is poor for the therapeutic response of antidepressant drug, all becomes obstinate disease (with reference to non-patent literature 3) under a lot of situations.In addition, consider and for those have the vascular depression patient of organic vulnerability, when treatment, cause side effect easily, so dosage is little when the beginning administration, and progressively increases dosage (with reference to non-patent literature 4) in the concern side effect.
Verified, cilostazol is a kind of medicine of anti-platelet aggregation, for preventing that sending out again of lacunar infarction from being effective (with reference to non-patent literature 5).It is reported that cilostazol can be used for the treatment (with reference to non-patent literature 6) for the invalid vascular depression of midalcipran (a kind of known SNRI) effectively.On the other hand, do not obtain the case (with reference to non-patent literature 3) of sufficient therapeutic effect behind the known yet existence use cilostazol.In addition, up to the present cilostazol does not obtain conclusive evidence as yet for depression, intractable depression or the effective case of intractable vascular depression.
Comparing with traditional so-called tricyclic antidepressant, is easier the taking of novel antidepressant of representative with SSRI, they has been classified as first medicine of selecting (with reference to non-patent literature 7) in some medicament selection rule (algorithm).But also the someone points out that SSRI and SNRI exist and makes the patient that illeffectss such as suicidal tendency (with reference to non-patent literature 8) be arranged, so people expect safer novel antidepressant thing.
It is reported, be that the aminoalkoxy bibenzyl chemical compound with ad hoc structure of representative is to 5HT with the represented sarpogrelate hydrochloride of following formula (2)
2Receptor demonstrates the selectivity of height, and to blood pressure not influence basically, and do not have serious adverse basically, be a kind of safe medicine.So far, known that sarpogrelate hydrochloride is to having the effect of improvement (patent documentation 1) by the various microcirculation disturbance that thrombosis generates and vasoconstriction produces in the diseases such as disturbance of cerebral circulation, ischemic heart desease, peripheral circulation disorders.
But up to the present, sarpogrelate hydrochloride can be used as the medicine that prevents and/or treats depression, and is perhaps also not known as the medicine that prevents and/or treats vascular depression.
Patent documentation 1: Japanese kokai publication hei 2-304022 communique
Non-patent literature 1: the Vol.51 of officina, No.2 (2000) 2-10
Non-patent literature 2: the Vol.51 of officina, No.2 (2000) 31-40
3: the 3 times sick Hui of Japanese う つ of non-patent literature Gross can be made a copy of collection by プ ロ グ ラ system, and the 85th page, P4-04
Non-patent literature 4: Pro bed psychologic medicines 34 (5): 655-660,2005
Non-patent literature 5: the auspicious Thailand of holt: Japanese's To お け Ru Brain apoplexy リ ス Network one Brain apoplexy デ one バ Application Network I り one.Hypertens?Front?7：22-31，2004
6: the 16 times this Pro of Ri beds of non-patent literature Jing Shen Shen Longitude プ ロ グ ラ of pharmacology association system is made a copy of collection, and the 122nd page, O-19
Non-patent literature 7:Kennedy, S.H., Lam, R.W., Cohen, N.L.et al.:Clinical guidelines for treatment of depressive disorders.IV.Medications and other biological treatments.Can.J.Psychiatry, 46 (Suppl.1): 38S-58S, 2001
Non-patent literature 8: Pro beds spirit pharmacology 8:1663-1673,2005
Summary of the invention
The object of the present invention is to provide a kind of novel medicine that prevents and/or treats depression, perhaps prevent and/or treat the medicine of vascular depression.Especially, the invention provides and be selected from aminoalkoxy bibenzyl chemical compound, its officinal salt, its ester, their solvate and the new purposes of the material in the hydrate, as the medicine that prevents and/or treats depression, perhaps as the medicine that prevents and/or treats vascular depression.
For addressing the above problem, the inventor has carried out deep research.Found that aminoalkoxy bibenzyl chemical compound has antidepressant effect.Finish the present invention based on above discovery.
That is, main contents of the present invention are as follows:
[1] a kind of medicine that prevents and/or treats depression, depressive state or anxiety neurosis, this medicine is to be selected from material in following general formula (1) represented aminoalkoxy bibenzyl chemical compound, its officinal salt, its ester, their solvate and the hydrate as effective ingredient.
In the formula, R
1Expression hydrogen atom, halogen atom, have the alkoxyl of 1～5 carbon atom or have the dialkyl amido of 2～6 carbon atoms, R
2Expression hydrogen atom, halogen atom or have the alkoxyl of 1～5 carbon atom, R
3Expression hydrogen atom, hydroxyl ,-O-(CH
2)
n-COOH (in the formula, n represents 1～5 integer) or-O-CO-(CH
2)
l-COOH (in the formula, l represents 1～3 integer), R
4Expression-N (R
5) (R
6) (in the formula, R
5And R
6Represent hydrogen atom independently of one another or have the alkyl of 1～8 carbon atom) or expression (in the formula, A represents can be by the alkylidene with 3～5 carbon atoms of carboxyl substituted), m represents 0～5 integer.
[2] a kind of medicine that prevents and/or treats depression, depressive state or anxiety neurosis, this medicine is to be selected from material in following formula (2) represented aminoalkoxy bibenzyl chemical compound, its officinal salt, its ester, their solvate and the hydrate as effective ingredient.
[3] a kind of medicine that prevents and/or treats depression, depressive state or anxiety neurosis, this medicine is to be selected from material in following formula (3) represented aminoalkoxy bibenzyl chemical compound, its officinal salt, its ester, their solvate and the hydrate as effective ingredient.
[4] above-mentioned [2] described medicine that prevents and/or treats depression, depressive state or anxiety neurosis, wherein this medicine is the form of hydrochlorate.
[5] any described medicine that prevents and/or treats depression, depressive state or anxiety neurosis in above-mentioned [1]～[4], wherein said depression, depressive state or anxiety neurosis are intractable depression, intractable depressive state or intractable anxiety neurosis.
[6] any described medicine that prevents and/or treats depression, depressive state or anxiety neurosis in above-mentioned [1]～[5], wherein this medicine can share with at least a medicine that is selected from antidepressants, antianxiety drugs and the psychosis.
[7] a kind ofly prevent and/or treat the depression that is attended by cerebrovascular disorders, be attended by the depressive state of cerebrovascular disorders or be attended by the medicine of the anxiety neurosis of cerebrovascular disorders, this medicine is to be selected from material in above-mentioned general formula (1) represented aminoalkoxy bibenzyl chemical compound, its officinal salt, its ester, their solvate and the hydrate as effective ingredient.
[8] a kind ofly prevent and/or treat the depression that is attended by cerebrovascular disorders, be attended by the depressive state of cerebrovascular disorders or be attended by the medicine of the anxiety neurosis of cerebrovascular disorders, this medicine is to be selected from material in following formula (2) represented aminoalkoxy bibenzyl chemical compound, its officinal salt, its ester, their solvate and the hydrate as effective ingredient.
[9] a kind ofly prevent and/or treat the depression that is attended by cerebrovascular disorders, be attended by the depressive state of cerebrovascular disorders or be attended by the medicine of the anxiety neurosis of cerebrovascular disorders, this medicine is to be selected from material in following formula (3) represented aminoalkoxy bibenzyl chemical compound, its officinal salt, its ester, their solvate and the hydrate as effective ingredient.
[10] above-mentioned [8] describedly prevent and/or treat the depression that is attended by cerebrovascular disorders, are attended by the depressive state of cerebrovascular disorders or are attended by the medicine of the anxiety neurosis of cerebrovascular disorders, and wherein this medicine is the form of hydrochlorate.
[11] in above-mentioned [7]～[10] any one describedly prevent and/or treat the depression that is attended by cerebrovascular disorders, be attended by the depressive state of cerebrovascular disorders or be attended by the medicine of the anxiety neurosis of cerebrovascular disorders, the wherein said depression that is attended by cerebrovascular disorders, the anxiety neurosis that is attended by the depressive state of cerebrovascular disorders or is attended by cerebrovascular disorders are the intractable depression that is attended by cerebrovascular disorders, the intractable depressive state that is attended by cerebrovascular disorders or the intractable anxiety neurosis that is attended by cerebrovascular disorders.
[12] in above-mentioned [7]～[11] any one describedly prevent and/or treat the depression that is attended by cerebrovascular disorders, be attended by the depressive state of cerebrovascular disorders or be attended by the medicine of the anxiety neurosis of cerebrovascular disorders, wherein said cerebrovascular disorders is cerebral infarction, transient ischemic attack, cerebral hemorrhage, subarachnoid hemorrhage, subdural hematoma or cerebral venous occlusion disease.
[13] in above-mentioned [7]～[12] any one describedly prevent and/or treat the depression that is attended by cerebrovascular disorders, be attended by the depressive state of cerebrovascular disorders or be attended by the medicine of the anxiety neurosis of cerebrovascular disorders, wherein said cerebrovascular disorders is cerebral infarction, transient ischemic attack or cerebral venous occlusion disease.
[14] above-mentioned [12] or [13] describedly prevent and/or treat the depression that is attended by cerebrovascular disorders, are attended by the depressive state of cerebrovascular disorders or are attended by the medicine of the anxiety neurosis of cerebrovascular disorders, and wherein said cerebral infarction is cerebral thrombosis or cerebral embolism disease.
[15] in above-mentioned [7]～[14] any one describedly prevent and/or treat the depression that is attended by cerebrovascular disorders, be attended by the depressive state of cerebrovascular disorders or be attended by the medicine of the anxiety neurosis of cerebrovascular disorders, wherein said cerebrovascular disorders is the silent cerebrovascular disorders.
[16] in above-mentioned [7]～[15] any one describedly prevent and/or treat the depression that is attended by cerebrovascular disorders, be attended by the depressive state of cerebrovascular disorders or be attended by the medicine of the anxiety neurosis of cerebrovascular disorders, wherein this medicine can share with at least a medicine that is selected from antidepressants, antianxiety drugs and the psychosis.
According to the present invention, can provide a kind of medicine that prevents and/or treats the medicine of depression or prevent and/or treat vascular depression.
The specific embodiment
Below the present invention is described in detail.Of the present invention prevent and/or treat the medicine of depression or prevent and/or treat contain the material that is selected from above-mentioned general formula (1) represented aminoalkoxy bibenzyl chemical compound, its officinal salt, its ester, their solvate and the hydrate in the medicine of vascular depression as effective ingredient.
R
1The expression hydrogen atom; Halogen atoms such as chlorine atom, fluorine atom; Methoxyl group, ethyoxyl, butoxy etc. have the alkoxyl of 1～5 carbon atom; Dimethylamino, diethylamino, Methylethyl amino etc. have the dialkyl amido of 2～6 carbon atoms.R
2The expression hydrogen atom; Halogen atoms such as chlorine atom, fluorine atom; Methoxyl group, ethyoxyl, butoxy etc. have the alkoxyl of 1～5 carbon atom.R
3The expression hydrogen atom; Hydroxyl;-O-(CH
2)
2-COOH ,-O-(CH
2)
3-COOH etc.-O-(CH
2)
n-COOH (in the formula, n represents 1～5 integer);-O-CO-(CH
2)
2-COOH ,-O-CO-(CH
2)
3-COOH etc.-O-CO-(CH
2)
l-COOH (in the formula, l represents 1～3 integer).R
4Expression is amino, perhaps have the amino that 1～2 its carbon number is 1～8 alkyl, perhaps represent such as can be on the ring of azetidine-1-base, piperidines-1-base, 3-carboxyl piperidines-1-base etc. by 4～6 yuan of azacycloalkyls of carboxyl substituted such as methylamino, ethylamino, butyl amino, hexyl amino, heptyl amino, dimethylamino, diethylamino, Methylethyl amino etc.
In the chemical compound that above-mentioned general formula (1) is comprised, the chemical compound that some the present invention preferably use is shown in table-1.
Table-1
In these chemical compounds, preferably on 2 of phenyl, be combined with aminoalkoxy-OCH
2C (R
3) H-(CH
2)
m-R
4Chemical compound.In addition, R
1Be preferably hydrogen atom, have the alkoxyl of 1～5 carbon atom or have the dialkyl amido of 2～6 carbon atoms, R
2Be preferably hydrogen atom, R
4Be preferably and have the amino that at least one carbon number is 1～8 alkyl or be 4～6 yuan of azacycloalkyls such as azetidine-1-base or piperidines-1-base.M is preferably 0～2 integer.Preferred especially above-mentioned No. 15 chemical compound (in this manual, below also this chemical compound is called " M-1 " sometimes) and as No. 14 chemical compound of its succinate, in above-mentioned No. 15 chemical compound, R
1Be methoxyl group, R
2Be hydrogen atom, R
3Be hydroxyl, R
4For dimethylamino, m are 1.
" officinal salt " can be any type of salt, as long as the avirulent salt of aminoalkoxy bibenzyl compound formation that can be represented with above-mentioned general formula (1), for example, can enumerate the addition salts of mineral acids such as hydrofluoride, hydrochlorate, hydrobromate, hydriodate, sulfate, nitrate, phosphate, carbonate, bicarbonate, perchlorate; Organic acid addition salts such as formates, acetate, trifluoroacetate, propionate, oxalates, glycollate, succinate, lactate, maleate, hydroxymaleic acid salt, citraconic acid salt, fumarate, adipate, tartrate, malate, citrate, benzoate, cinnamate, Ascorbate, Salicylate, 2-acetoxy-benzoic acid salt, nicotinate .gamma.-pyridinecarboxylic acid salt; The addition salts of organic sulfonic acids such as mesylate, esilate, isethionate, benzene sulfonate, tosilate, naphthalene sulfonate, phenolsulfonate, dihydroxy benzenes sulfonic acid salt; The addition salts of acidic amino acid such as aspartate, glutamate, Glu; Alkali metal salt such as sodium salt, potassium salt; Alkali salt such as magnesium salt, calcium salt; Ammonium salt; Front three amine salt, triethylamine salt, pyridiniujm, picoline salt, hexanamine salt, N, the addition salts of N '-organic bases such as dibenzyl ethylenediamine salt; The addition salts of basic amino acid such as lysinate, arginine salt etc.
The ester of the aminoalkoxy bibenzyl chemical compound that above-mentioned general formula (1) is represented, for example, can enumerate organic acid such as this chemical compound and formic acid, acetic acid, trifluoroacetic acid, propanoic acid, oxalic acid, glycolic, succinic acid, lactic acid, maleic acid, hydroxymaleic acid, citraconic acid, fumaric acid, adipic acid, tartaric acid, malic acid, citric acid, benzoic acid, cinnamic acid, ascorbic acid, salicylic acid, 2-acetoxy-benzoic acid, nicotinic acid .gamma.-pyridinecarboxylic acid or with mineral acids such as sulphuric acid, nitric acid, phosphoric acid, carbonic acid behind dehydrating condensation and the ester that obtains.
In addition, these chemical compounds except can adopting crystalline form, in some cases, can also employing and the solvate that forms such as water or alcohol or the form of hydrate.
Wherein, (±)-1-[O-(2-(m-methoxyphenyl) ethyl) phenoxy group of preferred especially following formula (4) expression]-hydrochlorate (also this material being called " sarpogrelate hydrochloride " in this manual) of 3-(dimethylamino)-2-propyl group hydrogen succinate ester.
The represented aminoalkoxy bibenzyl chemical compound of above-mentioned general formula (1), its officinal salt with and ester be known substances, can by the method described in the Japanese kokai publication sho 58-32847 communique or based on this method come easily synthetic they.In addition, sarpogrelate hydrochloride shown in the following formula (4) is run after fame and is sold on market with " Anplag (ア Application プ ラ one グ) " (registered trade mark) by Tanabe Mitsubishi Pharmaceutical Co, in the present invention, also can directly use commercially available " Anplag (ア Application プ ラ one グ) ".
As the disease of object of the present invention, can enumerate depression, depressive state and anxiety neurosis, perhaps be attended by cerebrovascular disorders depression, be attended by the depressive state of cerebrovascular disorders and be attended by the anxiety neurosis of cerebrovascular disorders.
It is believed that depression is that if carry out suitable treatment, this disease can be eased owing to the temporary decline of the effect of brain causes.For slight relatively depression, the patient is attended by slight low-spirited symptom aspect physical symptom; For the depression of moderate, symptoms such as more intense insomnia and inappetence, mood be gloomy can appear in the patient, can go wrong when being engaged in work and housework etc.In addition, for serious depression, tangible low-spirited symptom can appear in the patient, and can see following case:the case that is attended by depressive delusion disease (often can see about the vain hope as mood, sin, poverty etc.); Be attended by the case of hypochondriacal depression; Among the Depression in women patient more than person in middle and old age, intensive lather can appear in many people, and promptly so-called agitated depression has the intensive dead idea of wishing, and the case (non-patent literature 2) of attempted suicide.In addition, find that also the patient has symptoms such as taediumvitae, the easily futile sense of generation, headache.In addition, according to the diagnostic criteria of the Americanism AMA that extensively adopts in Japan, patients with depression is meant the patient who shows major depression outbreak shown below, and so-called major depression outbreak is meant and occurs 5 states when above in the middle of following 9. (1) is in a very depressed state, (2) interest, hobby obviously go down, and (3) are lost weight or increased, and appetite weakens or strengthens, (4) insomnia or drowsiness, (5) psychomotor impatience or inhibition, (6) easy fatigue or strength go down, and (7) do not have value or guilty-feeling, (8) retardation of thinking, energy are not concentrated, or be difficult to do resolution, (9) have suicide idea and suicidal attempt (a Gutter mouth brightness man of virtue and ability:the mood branch hinder Bing , disconnected と control Treatment Gai and Shuo Pro bed と research 80 (9): 1582-1587,2003).
So-called depressive state be meant feel depressed and have a to a certain degree state of persistence.As its symptom, for example have, with feel sorrow and not regulating the spleen and stomach both or any one be that mental maladjustment, thinking process slow (being difficult to concentrate one's energy or ruminate over), the psychomotor of feature suppresses or impatient sense, the symptom of spiritual health aspect, the paranoea (hypochondria, delusion of poverty disease or delusion of culpability disease) (Pro bed psychologic medicine 34 (5): 537-542,2005) of depressibility.In addition, can also observe taediumvitae, easily futile sense, headache etc.In addition, depressive state is meant in 9 projects shown in the diagnostic criteria of above-mentioned Americanism AMA the state when 4 symptoms below the project occurring.
The present invention especially can effectively prevent treatment show be in a very depressed state, the depression or the depressive state of symptoms such as thought disturbance, feeble, impatient sense, taediumvitae, fatiguability sense, inappetence, headache and/or sleep disorder.
Anxiety is a kind of undesirable emotional state, and everyone once had such experience.But under the situation that special reasonable ground ground overanxiexty occurs not having, this state promptly is called anxiety neurosis.Anxiety neurosis can be divided into following a few class: obsession (it is characterized in that for the unplessantness displeasure that alleviates obsessive idea and caused by this obsessive idea and the impulsive behavior (compulsion) that produces); Sudden anxiety is shown effect and the panic disorder that produces repeatedly; In social environment (for example, public arena etc.), feel very intensive uneasiness, but also be accompanied by social communication's phobia of very large misery; The uneasy agoraphobe of strong sensation in specific place and environment; Live through the posttraumatic stress disorder (PTSD) that causes after the intense stimulus; The generalized anxiety disorder that continues to feel uneasiness for a long time that reason is indefinite; There are LA symptom and depressive symptom simultaneously, and intermittent Combination anxiety that has an autonomic nerve symptom and depressive disorder etc.
The present invention is especially effective for obsession, panic disorder, social communication's phobia, agoraphobe, posttraumatic stress disorder (PTSD), generalized anxiety disorder or anxiety neurosis such as Combination anxiety and depressive disorder.
The present invention is not only effective to above-mentioned depression, depressive state or anxiety neurosis, and to the depression that is attended by cerebrovascular disorders, be attended by the depressive state of cerebrovascular disorders and be attended by the anxiety neurosis of cerebrovascular disorders also effective.Be attended by the depression of cerebrovascular disorders, the anxiety neurosis that is attended by the depressive state of cerebrovascular disorders and is attended by cerebrovascular disorders is meant depression, depressive state and the anxiety neurosis that takes place after cerebrovascular disorders occurring, they are referred to as vascular depression.A principal element that causes vascular depression is direct brain injury, so vascular depression is that depression, depressive state and the anxiety neurosis that psychoreaction causes obviously is different morbid state with pathogenic factors.In addition, vascular depression is poor for the reactivity of common employed medicine in the treatment of depression, depressive state and anxiety neurosis, thereby becomes refractory disease easily.
As the cerebrovascular disorders of the inducement of vascular depression, can enumerate cerebral infarction (cerebral thrombosis, cerebral embolism disease etc.), transient ischemic attack, cerebral hemorrhage, subarachnoid hemorrhage, subdural hematoma, cerebral venous occlusion disease and silent cerebrovascular disorders etc.Herein, though the silent cerebrovascular disorders is meant the peculiar symptoms of cerebrovascular disorders such as cerebral infarction (cerebral thrombosis, cerebral embolism disease etc.), cerebral hemorrhage, subarachnoid hemorrhage, subdural hematoma or cerebral venous occlusion disease do not occur, can find in cerebrovascular, to have the disease of small hemorrhage or infraction by image-forming diagnose (CT, MRI etc.) technology.
In recent years, along with the development of image-forming diagnose technology, known clearly very that diffusivity leukodystrophy and silent lacunar infarction are along with the increase at age, its morbidity more and more common (non-patent literature 5).There is report to point out, the patient compares with non-depressed, the probability of finding diffusivity leukodystrophy and silent lacunar infarction in the depression in old age patient significantly improves (Cervilla J, Prince M, Rabe-Hesketh S:Phychol Med, Vascular disease risk factors as determinants of incident depressivesymptoms:a prospective community-based study.Phychol Med 34:635-641,2004 and Steffens DC, Helms MJ, Krishnan KR:Cerebrovascular health study.Stroke 30:2159-2166,1999).
In addition, at above-mentioned depression, depressive state and anxiety neurosis, perhaps be attended by the depression of cerebrovascular disorders, be attended by cerebrovascular disorders depressive state and be attended by in the anxiety neurosis of cerebrovascular disorders, owing to prognosis mala becomes long-term, the disease of chronicity can be classified as refractory disease, and the present invention is for this intractable depression, intractable depressive state and intractable anxiety neurosis, the perhaps intractable depression that is attended by cerebrovascular disorders, intractable depressive state that is attended by cerebrovascular disorders and the intractable anxiety neurosis that is attended by cerebrovascular disorders also are effective.
Even so-called refractory disease is meant the case of using at least 3 kinds of antidepressants also not show abundant curative effect under the condition of enough big dosage (be equivalent to imipramine every day 200 milligrams), sufficiently long time (4 to 6 week).
Therapeutic Method as described refractory disease, can adopt enhancing therapy that antidepressants and lithium, thyroxin, dopamine agonist, atypical antipsychotic etc. share or electric convulsive therapy etc., but about this therapeutic strategy, also lack at present the required sufficient amount of evidential treatment standardization clinical research (this Long of Gang is of a specified duration: the Difficult property controlled う つ disease is to ying. medical science あ ゆ body 219 (13): 955-962,2006).
When chemical compound of the present invention as the medicine that prevents and/or treats depression or when preventing and/or treating the medicine of vascular depression, those skilled in the art can suitably select medication.For example, can select any one administering modes such as non-oral administration such as subcutaneous injection, intravenous injection, intramuscular injection, lumbar injection or oral administration.Suitably determine dosage if wait according to condition such as the kind of other medicine and administration frequency or according to the character of the desired effect that reaches during with the administration simultaneously of other medicine according to conditions such as patient age, health status, body weight.In general, dosage every day of effective ingredient can be 0.5mg/kg body weight-50mg/kg body weight, is generally 1mg/kg body weight-30mg/kg body weight, can be administered once in 1st or administration on the one repeatedly.
When chemical compound of the present invention as the medicine that prevents and/or treats depression or when preventing and/or treating the medicine of vascular depression, preferably, be mixed with contain above-mentioned effective ingredient and more than a kind or 2 kinds preparation carry out administration after with the pharmaceutical composition of additive.As being suitable for peroral administration pharmaceutical composition, for example can enumerate tablet, capsule, powder, liquid preparation, elixir etc., as being suitable for para-oral pharmaceutical composition, for example can enumerate the pharmaceutical composition of the liquid form after sterilization such as liquid preparation or suspensoid.
Formulations employed is not particularly limited with the kind of additive during to the compounding pharmaceutical compositions, can select the appropriate formulations additive according to the form of various pharmaceutical compositions.Described preparation can be in solid or the liquid any one with additive, for example can use solid carrier or liquid-carrier etc.As solid carrier, for example can use common gelatin capsule.In addition, for example, effective ingredient can be made tablet with the preparation more than a kind or 2 kinds with additive or do not use preparation directly effective ingredient to be made tablet with additive or be mixed with powder after pack.In general, gross weight with respect to preparation, the effective ingredient that can contain 5 weight %-95 weight % in these capsules, tablet, the powder, the effective ingredient that preferably contains 5 weight %-90 quality %, the effective ingredient that can contain 5mg-500mg in the administration unit dosage forms preferably contains the effective ingredient of 25mg-250mg.As liquid-carrier, can use aqueous carrier (for example water etc.) or oiliness carrier (oil, Oleum Arachidis hypogaeae semen, soybean oil, mineral oil, Semen Sesami wet goods come from vegeto-animal oil or synthetic wet goods).In addition, as liquid-carrier, be preferably di-alcoholss such as normal saline, glucose or similar sucrose solution, ethylene glycol, propylene glycol, Polyethylene Glycol.Particularly, under the situation of using normal saline solution, be mixed with the effective ingredient that contains 0.5 weight %-20 weight % usually, be preferably the effective ingredient that contains 1 weight %-10 weight %.
The medicine that prevents and/or treats the medicine of depression or prevent and/or treat vascular depression of the present invention can share (following also abbreviate these medicines as combination with medication) with antidepressants, antianxiety drugs and psychosis.As the antidepressants that share, can enumerate those antidepressants that are generally used for this field, for example mianserin, sulpiride, imipramine, Clomipramine, desmethylimipramine, amitriptyline, amoxapine, trazodone, fluoxetine, fluvoxamine, paroxetine, Sertraline, citalopram etc.As the antianxiety drugs that share, can enumerate those antianxiety drugss that are generally used for this field, for example stable, flunitrazepan, brotizolam, etizolam, zolpidem, lorazepam, alprazolam, clotiazepam, tandospirone, buspirone etc.As the psychosis that share, can enumerate those psychosis that are generally used for this field, for example olanzapine, Quetiapine, risperidone, cis-N-[4-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl, droperidol, bromperidol, sulpiride, mosapramine, pimozide, zotepine etc.According to the order of severity of sex, age, body weight or the symptom of the kind of used medicine and administration object etc., serve as the dosage that described combination with medication is suitably determined on the basis with each medicine consumption clinically up to the present usually.Consider of the present inventionly to prevent and/or treat the medicine of depression or prevent and/or treat the medicine of vascular depression and the situation that other medicines share that the dosage of each medicine can reduce.
Be selected from the material in above-mentioned general formula (1), formula (2) or formula (3) represented aminoalkoxy bibenzyl chemical compound, its officinal salt, its ester, their solvate and the hydrate, can be used to make the above-mentioned medicine that prevents and/or treats depression, depressive state or anxiety neurosis, perhaps be used to make depression that above-mentioned preventing and/or treating be attended by cerebrovascular disorders, be attended by the depressive state of cerebrovascular disorders or be attended by the medicine of the anxiety neurosis of cerebrovascular disorders.
Embodiment
Further specifically describe the present invention below by embodiment, but scope of the present invention is not limited to following embodiment.
Embodiment 1
The patient following symptom occurs at X-2: mood is gloomy, and demoralized, interest care degree reduces, the futile sense of easy generation, and energy is difficult to concentrate, and morning, awakening was too early, inappetence, lose weight (minimizing 10kg), body sway etc.Duration of work is often had a rest, in X-2 retirement in March.The patient accepts diagnosis and treatment to A hospital psychiatric department in X-2 April, though it is effect improved little to have accepted Drug therapy, accepts diagnosis and treatment to B hospital spirit department of neurology November in X-2 again.Diagnostic result is a major depression sexual disorders, though taken various antidepressant drugs and used thyroid hormones medicine etc. as reinforcement therapy, effect improved little.In the own home, live all day the life of bed, thus in X August to B hospital spirit department of neurology hospitalization.
Shown in check results when being in hospital etc. are following:
Hemanalysis biochemical indicator: do not have special item.
EEG：WNL
Memory neuropsychologic examination (HDS-R (28 minutes), WAIS-R, Benton visual memory power is checked, word paired-associate according to WMS-R, FAB, Stroop Test, Trail Making Test): every check result all is in average level, so can not think that obstacle appears in memory and obstacle appears in the prefrontal lobe function.
Head mri: though find prefrontal lobe, the atrophy of side frontal lobe, have small infraction nest in the corticocerebral deep layer white matter, can not be diagnosed as vascular depression.
Head
99mTc-ECD SPECT: slight blood flow deficiency appears in prefrontal lobe, side frontal lobe.
Neurology Department diagnosis: do not have tangible anomaly, can not think dementia, degenerative disorders.
The back continuation of being admitted to hospital uses antidepressants, antianxiety drugs, psychosis etc. to carry out pharmacotherapy, but still lacks effect.The patient implements ECT treatment (9 times) October in X, though find that gloomy mood improves, still demoralized, lack active passion, effect improved not obvious.
After X end of day ECT in October 25 treatment, begin fixedly to take medicine (mianserin (mianserin) 60mg/ day, sulpiride (sulpiride) 30mg/ day, cis-N-[4-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl (perospirone) 12mg/ day, brotizolam (brotizolam) 0.25mg/ day, flunitrazepan (flunitrazepam) 1mg/ day).From X November 21, take sarpogrelate hydrochloride (ア Application プ ラ one グ (registered trade mark)) 100mg/ day (each half sheet, each 1 time sooner or later), X December 5 days, dosage increased to 200mg/ day (each 1, each 1 time sooner or later).Head mri before beginning to take medicine, the inspection situation of SPECT and do not change basically when being admitted to hospital, former frontal lobe, side frontal lobe are the small infraction nest that blood flow deficiency, atrophy, deep layer white matter place can be seen in the zone at center.
From append take Anplag after, find that the patient begins to participate in setting-up exercises to radio music activity (during 100mg dosage), go out to stay and sweep oneself dwelling house etc. (during 200mg dosage), activeness improves, and leaves hospital in 14th in the X December.
Adopt Hamilton depression evaluation criterion (HDRS; What use is structured interview SIGH-D the Japanese edition) before and after using Anplag, estimate, it must be divided into 19 fens (during beginning) → 15 minutes (after 1 week) → 13 minutes (after 5 weeks), adopt allomeric function evaluation criterion (The Global Assessment of Functioning:GAF) before and after using Anplag, to estimate, it must be divided into 38 (during beginning) → 47 (after 1 week) → 52 (after 5 weeks), all demonstrates the effect of improvement.
The above results shows, take sarpogrelate hydrochloride after, the symptom of intractable patients with depression be improved significantly, this shows that sarpogrelate hydrochloride can be used to prevent and/or treat depression, depressive state or anxiety neurosis effectively.
Industrial usability
According to the present invention, can provide a kind of novel depression, depression of preventing and/or treating The medicine of state or anxiety disorder perhaps prevents and/or treats the depression that is attended by cerebrovascular disorder Disease, be attended by the depressive state of cerebrovascular disorder and be attended by the medicine of the anxiety disorder of cerebrovascular disorder Thing.
Claims (16)
1. medicine that prevents and/or treats depression, depressive state or anxiety neurosis, this medicine is to be selected from material in following general formula (1) represented aminoalkoxy bibenzyl chemical compound, its officinal salt, its ester, their solvate and the hydrate as effective ingredient
In the formula, R
1Expression hydrogen atom, halogen atom, have the alkoxyl of 1～5 carbon atom or have the dialkyl amido of 2～6 carbon atoms, R
2Expression hydrogen atom, halogen atom or have the alkoxyl of 1～5 carbon atom, R
3Expression hydrogen atom, hydroxyl ,-O-(CH
2)
n-COOH (in the formula, n represents 1～5 integer) or-O-CO-(CH
2)
l-COOH (in the formula, l represents 1～3 integer), R
4Expression-N (R
5) (R
6) (in the formula, R
5And R
6Represent hydrogen atom independently of one another or have the alkyl of 1～8 carbon atom) or expression
(in the formula, A represents can be by the alkylidene with 3～5 carbon atoms of carboxyl substituted), m represents 0～5 integer.
2. medicine that prevents and/or treats depression, depressive state or anxiety neurosis, this medicine is to be selected from material in following formula (2) represented aminoalkoxy bibenzyl chemical compound, its officinal salt, its ester, their solvate and the hydrate as effective ingredient
3. medicine that prevents and/or treats depression, depressive state or anxiety neurosis, this medicine is to be selected from material in following formula (3) represented aminoalkoxy bibenzyl chemical compound, its officinal salt, its ester, their solvate and the hydrate as effective ingredient
4. the described medicine that prevents and/or treats depression, depressive state or anxiety neurosis of claim 2, wherein said medicine is the form of hydrochlorate.
5. any described medicine that prevents and/or treats depression, depressive state or anxiety neurosis in the claim 1～4, wherein said depression, depressive state or anxiety neurosis are intractable depression, intractable depressive state or intractable anxiety neurosis.
6. any described medicine that prevents and/or treats depression, depressive state or anxiety neurosis in the claim 1～5, wherein this medicine can share with at least a medicine that is selected from antidepressants, antianxiety drugs and the psychosis.
7. one kind prevents and/or treats the depression that is attended by cerebrovascular disorders, is attended by the depressive state of cerebrovascular disorders or is attended by the medicine of the anxiety neurosis of cerebrovascular disorders, this medicine is to be selected from material in following general formula (1) represented aminoalkoxy bibenzyl chemical compound, its officinal salt, its ester, their solvate and the hydrate as effective ingredient
In the formula, R
1Expression hydrogen atom, halogen atom, have the alkoxyl of 1～5 carbon atom or have the dialkyl amido of 2～6 carbon atoms, R
2Expression hydrogen atom, halogen atom or have the alkoxyl of 1～5 carbon atom, R
3Expression hydrogen atom, hydroxyl ,-O-(CH
2)
n-COOH (in the formula, n represents 1～5 integer) or-O-CO-(CH
2)
l-COOH (in the formula, l represents 1～3 integer), R
4Expression-N (R
5) (R
6) (in the formula, R
5And R
6Represent hydrogen atom independently of one another or have the alkyl of 1～8 carbon atom) or expression
(in the formula, A represents can be by the alkylidene with 3～5 carbon atoms of carboxyl substituted), m represents 0～5 integer.
8. one kind prevents and/or treats the depression that is attended by cerebrovascular disorders, is attended by the depressive state of cerebrovascular disorders or is attended by the medicine of the anxiety neurosis of cerebrovascular disorders, this medicine is to be selected from material in following formula (2) represented aminoalkoxy bibenzyl chemical compound, its officinal salt, its ester, their solvate and the hydrate as effective ingredient
9. one kind prevents and/or treats the depression that is attended by cerebrovascular disorders, is attended by the depressive state of cerebrovascular disorders or is attended by the medicine of the anxiety neurosis of cerebrovascular disorders, this medicine is to be selected from material in following formula (3) represented aminoalkoxy bibenzyl chemical compound, its officinal salt, its ester, their solvate and the hydrate as effective ingredient
10. claim 8 describedly prevents and/or treats the depression that is attended by cerebrovascular disorders, is attended by the depressive state of cerebrovascular disorders or is attended by the medicine of the anxiety neurosis of cerebrovascular disorders, and wherein said medicine is the form of hydrochlorate.
11. any one describedly prevents and/or treats the depression that is attended by cerebrovascular disorders, is attended by the depressive state of cerebrovascular disorders or is attended by the medicine of the anxiety neurosis of cerebrovascular disorders in the claim 7～10, the wherein said depression that is attended by cerebrovascular disorders, the anxiety neurosis that is attended by the depressive state of cerebrovascular disorders or is attended by cerebrovascular disorders are the intractable depression that is attended by cerebrovascular disorders, the intractable depressive state that is attended by cerebrovascular disorders or the intractable anxiety neurosis that is attended by cerebrovascular disorders.
12. any one describedly prevents and/or treats the depression that is attended by cerebrovascular disorders, is attended by the depressive state of cerebrovascular disorders or is attended by the medicine of the anxiety neurosis of cerebrovascular disorders in the claim 7～11, wherein said cerebrovascular disorders is cerebral infarction, transient ischemic attack, cerebral hemorrhage, subarachnoid hemorrhage, subdural hematoma or cerebral venous occlusion disease.
13. any one describedly prevents and/or treats the depression that is attended by cerebrovascular disorders, is attended by the depressive state of cerebrovascular disorders or is attended by the medicine of the anxiety neurosis of cerebrovascular disorders in the claim 7～12, wherein said cerebrovascular disorders is cerebral infarction, transient ischemic attack or cerebral venous occlusion disease.
14. claim 12 or 13 describedly prevents and/or treats the depression that is attended by cerebrovascular disorders, be attended by the depressive state of cerebrovascular disorders or be attended by the medicine of the anxiety neurosis of cerebrovascular disorders, wherein said cerebral infarction is cerebral thrombosis or cerebral embolism disease.
15. any one describedly prevents and/or treats the depression that is attended by cerebrovascular disorders, is attended by the depressive state of cerebrovascular disorders or is attended by the medicine of the anxiety neurosis of cerebrovascular disorders in the claim 7～14, wherein said cerebrovascular disorders is the silent cerebrovascular disorders.
16. any one describedly prevents and/or treats the depression that is attended by cerebrovascular disorders, is attended by the depressive state of cerebrovascular disorders or is attended by the medicine of the anxiety neurosis of cerebrovascular disorders in the claim 7～15, wherein this medicine can share with at least a medicine that is selected from antidepressants, antianxiety drugs and the psychosis.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2007093606 | 2007-03-30 | ||
| JP2007-093606 | 2007-03-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101273982A true CN101273982A (en) | 2008-10-01 |
Family
ID=39994120
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2008100891250A Pending CN101273982A (en) | 2007-03-30 | 2008-03-28 | Medicament for preventing or/and treating depression |
Country Status (3)
| Country | Link |
|---|---|
| JP (1) | JP2008273954A (en) |
| KR (1) | KR20080089279A (en) |
| CN (1) | CN101273982A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113908156A (en) * | 2016-05-25 | 2022-01-11 | 田边三菱制药株式会社 | Compositions and methods for treating negative symptoms in non-schizophrenic patients |
-
2008
- 2008-03-28 CN CNA2008100891250A patent/CN101273982A/en active Pending
- 2008-03-28 KR KR1020080029227A patent/KR20080089279A/en not_active Application Discontinuation
- 2008-03-28 JP JP2008086294A patent/JP2008273954A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113908156A (en) * | 2016-05-25 | 2022-01-11 | 田边三菱制药株式会社 | Compositions and methods for treating negative symptoms in non-schizophrenic patients |
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| Publication number | Publication date |
|---|---|
| JP2008273954A (en) | 2008-11-13 |
| KR20080089279A (en) | 2008-10-06 |
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