JP2008273954A - Agent for preventing and/or treating melancholia - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an agent for preventing and/or treating melancholia, melancholic state or anxiety disorders, or an agent for preventing and/or treating a melancholia accompanied with cerebrovascular disorders, a melancholic state accompanied with cerebrovascular disorders or an anxiety disorder accompanied with cerebrovascular disorders. <P>SOLUTION: The agent for preventing and/or treating melancholia, melancholic state or anxiety disorders, or the agent for preventing and/or treating the melancholia accompanied with cerebrovascular disorders, the melancholic state accompanied with cerebrovascular disorders or the anxiety disorder accompanied with cerebrovascular disorders; contains, as an effective component, a substance selected from the group consisting of aminoalkoxybibenzyls expressed by formula (1), their pharmaceutically permissible salts, esters, solvates and hydrates. In the formula, R<SP>3</SP>expresses a hydrogen atom, a hydroxy group, -O-(CH<SB>2</SB>)<SB>n</SB>-COOH, in which n expresses an integer of 1-5, or O-CO-(CH<SB>2</SB>)<SB>l</SB>-COOH, in which l expresses an integer of 1-3, R<SP>4</SP>expresses -N(R<SP>5</SP>)(R<SP>6</SP>) or the like, and m expresses an integer of 0-5. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to an aminoalkoxybibenzyl, a pharmaceutically acceptable salt thereof, an ester thereof, and a substance selected from the group consisting of a solvate and a hydrate thereof as an active ingredient. Agents for the prevention and / or treatment of anxiety disorders (hereinafter also simply referred to as depression prevention and / or treatment agents) or depression with cerebrovascular disorders, depression with cerebrovascular disorders or anxiety disorders with cerebrovascular disorders The present invention relates to a preventive and / or therapeutic agent (hereinafter also simply referred to as a prophylactic and / or therapeutic agent for vascular depression).

  The main symptom of depression is stagnation of vital feelings, but mental illness such as reduced thinking ability, pessimistic and self-responsible thinking disorder, diminished daily activity, reduced motivation, anxiety / irritability, Furthermore, physical symptoms due to abnormalities in the autonomic nervous system are also seen (see Non-Patent Document 1).

  Depression is thought to be caused by a temporary decrease in brain function, and is a disease that results in remission if treated appropriately. As effective treatment methods, there are mainly three approaches of psychotherapy, life guidance (rest), and pharmacotherapy (see Non-Patent Document 2). As drug therapy, mianserin, sulpiride, imipramine and the like are mainly prescribed.

  Many relations between cerebrovascular disorders and depression have been reported so far, and depression accompanied with these cerebrovascular disorders has been proposed as vascular depression. Treatment of vascular depression involves both treatment for cerebrovascular disorders and antidepressant treatment. SSRIs (selective serotonin reuptake inhibitors) and SNRIs (serotonin noradorenaline reuptake inhibitors) are considered to be potential therapeutic choices. However, vascular depression generally has a poor therapeutic response to antidepressants and is often intractable (see Non-Patent Document 3). In addition, it is desirable to start with a small dose and gradually increase it while paying attention to the side effects, considering that side effects are likely to occur in patients with vascular depression having organic vulnerability (see Non-Patent Document 4).

  Cilostazol is an antiplatelet drug and has been demonstrated to be effective in preventing recurrence of lacunar infarction (see Non-Patent Document 5). There is a report that cilostazol showed an effect on vascular depression in which milnacipran known as SNRI was ineffective (see Non-Patent Document 6). On the other hand, it is known that there are cases where a sufficient therapeutic effect cannot be obtained (see Non-Patent Document 3). In addition, no effective cases have been confirmed for cases of depression, refractory depression, or refractory vascular depression.

  New antidepressants, including SSRIs, are considered easier to use than traditional so-called tricyclic antidepressants, and are already the first choice in some drug selection algorithms (non-patented) Reference 7). However, SSRI and SNRI may point out harmful effects such as suicide attempts (see Non-Patent Document 8), and a safer new antidepressant is desired.

  Following formula (2):

It has been reported that aminoalkoxybibenzyls having a specific structure typified by sarpogrelate hydrochloride represented by the formula show high selectivity for the 5HT ₂ receptor and hardly affect blood pressure, and there are also serious side effects. There is almost no drug that shows high safety. Sarpogrelate hydrochloride has been known to be effective in improving various microcirculatory disorders based on thrombus formation and vasoconstriction in diseases such as cerebral circulation disorder, ischemic heart disease and peripheral circulation disorder (patents) Reference 1).

  However, it has not been conventionally known that sarpogrelate hydrochloride is useful as a prophylactic and / or therapeutic agent for depression or as a prophylactic and / or therapeutic agent for vascular depression.

Japanese Patent Laid-Open No. 2-304022 Pharmacy Vol. 51, no. 2 (2000) 2-10 Pharmacy Vol. 51, no. 2 (2000) 31-40 The 3rd Annual Meeting of the Japanese Society for Depression Research, Abstracts, page 85, P4-04 Clinical Psychiatry 34 (5): 655-660, 2005 Yoshiyasu Kobayashi: Stroke risk in Japanese -From the Stroke Data Bank-. Hypertens Front 7: 22-31,2004 16th Annual Meeting of Japanese Society of Clinical Neuropsychopharmacology, Abstracts, page 122, O-19 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 Clinical psychopharmacology 8: 1663-16733,2005

  An object of the present invention is to provide a novel preventive and / or therapeutic agent for depression or a preventive and / or therapeutic agent for vascular depression. In particular, the prevention and / or prevention of depression as a novel use of a substance selected from the group consisting of aminoalkoxybibenzyls, pharmaceutically acceptable salts thereof, esters thereof, and solvates and hydrates thereof. The object is to provide a therapeutic agent or a prophylactic and / or therapeutic agent for vascular depression.

  As a result of intensive studies to solve the above problems, the present inventors have found that aminoalkoxybibenzyls have an antidepressant action. The present invention has been completed based on the above findings.

〔式中、Ｒ^１は水素原子、ハロゲン原子、Ｃ_１〜Ｃ_５のアルコキシ基、又はＣ_２〜Ｃ_６のジアルキルアミノ基を表わし、Ｒ^２は水素原子、ハロゲン原子又はＣ_１〜Ｃ_５のアルコキシ基を表わし、Ｒ^３は水素原子、ヒドロキシル基、−Ｏ−（ＣＨ_２）_ｎ−ＣＯＯＨ（式中、ｎは１〜５の整数を表わす。）、又は−Ｏ−ＣＯ−（ＣＨ_２）_l−ＣＯＯＨ（式中、ｌは１〜３の整数を表わす。）を表わし、Ｒ^４は−Ｎ（Ｒ^５）（Ｒ^６）（式中、Ｒ^５及びＲ^６はそれぞれ独立して水素原子又はＣ_１〜Ｃ_８のアルキル基を表わす。）又は

（式中、Ａはカルボキシル基で置換されていてもよいＣ_３〜Ｃ_５のアルキレン基を表わす。）を表わし、ｍは０〜５の整数を表わす。〕
［２］ 下記式（２）で表わされるアミノアルコキシビベンジル類、その薬学上許容し得る塩、そのエステル、並びにそれらの溶媒和物及びそれらの水和物よりなる群から選ばれる物質を有効成分とするうつ病、うつ状態又は不安障害の予防及び／又は治療剤。

［３］ 下記式（３）で表わされるアミノアルコキシビベンジル類、その薬学上許容し得る塩、そのエステル、並びにそれらの溶媒和物及びそれらの水和物よりなる群から選ばれる物質を有効成分とするうつ病、うつ状態又は不安障害の予防及び／又は治療剤。

［４］ 塩酸塩の形態である［２］に記載のうつ病、うつ状態又は不安障害の予防及び／又は治療剤。
［５］ うつ病、うつ状態又は不安障害が難治性のうつ病、難治性のうつ状態又は難治性の不安障害である［１］〜［４］のいずれか１項に記載のうつ病、うつ状態又は不安障害の予防及び／又は治療剤。
［６］ 抗うつ薬、抗不安薬及び抗精神病薬からなる群から選択される少なくとも１種と併用して用いられる［１］〜［５］のいずれか１項に記載のうつ病、うつ状態又は不安障害の予防及び／又は治療剤。
［７］ 上記一般式（１）で表わされるアミノアルコキシビベンジル類、その薬学上許容し得る塩、そのエステル、並びにそれらの溶媒和物及びそれらの水和物よりなる群から選ばれる物質を有効成分とする脳血管障害を伴ううつ病、脳血管障害を伴ううつ状態又は脳血管障害を伴う不安障害の予防及び／又は治療剤。
［８］ 上記式（２）で表わされるアミノアルコキシビベンジル類、その薬学上許容し得る塩、そのエステル、並びにそれらの溶媒和物及びそれらの水和物よりなる群から選ばれる物質を有効成分とする脳血管障害を伴ううつ病、脳血管障害を伴ううつ状態又は脳血管障害を伴う不安障害の予防及び／又は治療剤。
［９］ 上記式（３）で表わされるアミノアルコキシビベンジル類、その薬学上許容し得る塩、そのエステル、並びにそれらの溶媒和物及びそれらの水和物よりなる群から選ばれる物質を有効成分とする脳血管障害を伴ううつ病、脳血管障害を伴ううつ状態又は脳血管障害を伴う不安障害の予防及び／又は治療剤。
［１０］ 塩酸塩の形態である［８］に記載の脳血管障害を伴ううつ病、脳血管障害を伴ううつ状態又は脳血管障害を伴う不安障害の予防及び／又は治療剤。
［１１］ 脳血管障害を伴ううつ病、脳血管障害を伴ううつ状態又は脳血管障害を伴う不安障害が難治性の脳血管障害を伴ううつ病、難治性の脳血管障害を伴ううつ状態又は難治性の脳血管障害を伴う不安障害である［７］〜［１０］のいずれか１項に記載の脳血管障害を伴ううつ病、脳血管障害を伴ううつ状態又は脳血管障害を伴う不安障害の予防及び／又は治療剤。
［１２］ 脳血管障害が脳梗塞、一過性脳虚血発作、脳出血、くも膜下出血、硬膜下血腫又は脳静脈閉塞症である［７］〜［１１］のいずれか１項に記載の脳血管障害を伴ううつ病、脳血管障害を伴ううつ状態又は脳血管障害を伴う不安障害の予防及び／又は治療剤。
［１３］ 脳血管障害が脳梗塞、一過性脳虚血発作又は脳静脈閉塞症である［７］〜［１２］のいずれか１項に記載の脳血管障害を伴ううつ病、脳血管障害を伴ううつ状態又は脳血管障害を伴う不安障害の予防及び／又は治療剤。
［１４］ 脳梗塞が脳血栓症又は脳塞栓症である［１２］又は［１３］に記載の脳血管障害を伴ううつ病、脳血管障害を伴ううつ状態又は脳血管障害を伴う不安障害の予防及び／又は治療剤。
［１５］ 脳血管障害が無症候性の脳血管障害である［７］〜［１４］のいずれか１項に記載の脳血管障害を伴ううつ病、脳血管障害を伴ううつ状態又は脳血管障害を伴う不安障害の予防及び／又は治療剤。
［１６］ 抗うつ薬、抗不安薬及び抗精神病薬からなる群から選択される少なくとも１種と併用して用いられる［７］〜［１５］のいずれか１項に記載の脳血管障害を伴ううつ病、脳血管障害を伴ううつ状態又は脳血管障害を伴う不安障害の予防及び／又は治療剤。 That is, the gist of the present invention is as follows.
[1] A substance selected from the group consisting of aminoalkoxybibenzyls represented by the following general formula (1), pharmaceutically acceptable salts, esters, solvates and hydrates thereof is effective. A preventive and / or therapeutic agent for depression, depression or anxiety disorder as a component.

[Wherein, R ¹ represents a hydrogen atom, a halogen atom, a C _{1 to} C ₅ alkoxy group, or a C _{2 to} C ₆ dialkylamino group, and R ² represents a hydrogen atom, a halogen atom, or C _{1 to} C ₅ . Represents an alkoxy group, R ³ represents a hydrogen atom, a hydroxyl group, —O— (CH ₂ ) _n —COOH (wherein n represents an integer of 1 to 5), or —O—CO— (CH ₂ ). _l- COOH (wherein, l represents an integer of 1 to 3), R ⁴ represents —N (R ⁵ ) (R ⁶ ) (wherein R ⁵ and R ⁶ are each independently a hydrogen atom; or an alkyl group of _C 1 _{~C 8.)} or

(Wherein, A represents a C _{3 to} C ₅ alkylene group which may be substituted with a carboxyl group), and m represents an integer of 0 to 5. ]
[2] A substance selected from the group consisting of aminoalkoxybibenzyls represented by the following formula (2), pharmaceutically acceptable salts, esters thereof, solvates and hydrates thereof as an active ingredient An agent for the prevention and / or treatment of depression, depression or anxiety disorders.

[3] A substance selected from the group consisting of aminoalkoxybibenzyls represented by the following formula (3), pharmaceutically acceptable salts, esters thereof, solvates and hydrates thereof as an active ingredient An agent for the prevention and / or treatment of depression, depression or anxiety disorders.

[4] The prophylactic and / or therapeutic agent for depression, depression or anxiety disorder according to [2], which is in the form of hydrochloride.
[5] Depression, depression according to any one of [1] to [4], wherein depression, depression or anxiety disorder is refractory depression, refractory depression or refractory anxiety disorder A preventive and / or therapeutic agent for a condition or anxiety disorder.
[6] Depression, depression state according to any one of [1] to [5], used in combination with at least one selected from the group consisting of antidepressants, anxiolytics and antipsychotics Or a preventive and / or therapeutic agent for anxiety disorders.
[7] A substance selected from the group consisting of aminoalkoxybibenzyls represented by the above general formula (1), pharmaceutically acceptable salts, esters thereof, solvates and hydrates thereof is effective. A prophylactic and / or therapeutic agent for depression associated with cerebrovascular disorder, depressive state associated with cerebrovascular disorder, or anxiety disorder associated with cerebrovascular disorder as a component.
[8] A substance selected from the group consisting of aminoalkoxybibenzyls represented by the above formula (2), pharmaceutically acceptable salts, esters thereof, solvates and hydrates thereof as an active ingredient A prophylactic and / or therapeutic agent for depression associated with cerebrovascular disorder, depression associated with cerebrovascular disorder, or anxiety disorder associated with cerebrovascular disorder.
[9] A substance selected from the group consisting of aminoalkoxybibenzyls represented by the above formula (3), pharmaceutically acceptable salts, esters thereof, solvates and hydrates thereof as an active ingredient A prophylactic and / or therapeutic agent for depression associated with cerebrovascular disorder, depression associated with cerebrovascular disorder, or anxiety disorder associated with cerebrovascular disorder.
[10] The prophylactic and / or therapeutic agent for depression with cerebrovascular disorder, depression with cerebrovascular disorder or anxiety disorder with cerebrovascular disorder according to [8], which is in the form of hydrochloride.
[11] Depression with cerebrovascular disorder, depression with cerebrovascular disorder, or anxiety disorder with cerebrovascular disorder is intractable, depression with intractable cerebrovascular disorder, depression with intractable cerebrovascular disorder or intractable The depression according to any one of [7] to [10], a depression state accompanied by cerebrovascular disorder, or an anxiety disorder accompanied by cerebrovascular disorder Prophylactic and / or therapeutic agent.
[12] The cerebral vascular disorder is cerebral infarction, transient cerebral ischemic attack, cerebral hemorrhage, subarachnoid hemorrhage, subdural hematoma or cerebral vein occlusion [1] A prophylactic and / or therapeutic agent for depression with cerebrovascular disorder, depression with cerebrovascular disorder or anxiety disorder with cerebrovascular disorder.
[13] Depression or cerebrovascular disorder with cerebrovascular disorder according to any one of [7] to [12], wherein the cerebrovascular disorder is cerebral infarction, transient cerebral ischemic attack or cerebral venous occlusion A prophylactic and / or therapeutic agent for an anxiety disorder associated with depression or cerebrovascular disorder.
[14] Prevention of depression with cerebrovascular disorder, depression with cerebrovascular disorder or anxiety disorder with cerebrovascular disorder according to [12] or [13], wherein the cerebral infarction is cerebral thrombosis or cerebral embolism / Or therapeutic agent.
[15] Depression with cerebrovascular disorder, depression state with cerebrovascular disorder or cerebrovascular disorder according to any one of [7] to [14], wherein the cerebrovascular disorder is asymptomatic cerebrovascular disorder A prophylactic and / or therapeutic agent for anxiety disorders involving
[16] The cerebrovascular disorder according to any one of [7] to [15], which is used in combination with at least one selected from the group consisting of an antidepressant, an anxiolytic and an antipsychotic A prophylactic and / or therapeutic agent for depression, a depression state associated with cerebrovascular disorder, or an anxiety disorder associated with cerebrovascular disorder.

  According to the present invention, a prophylactic and / or therapeutic agent for depression or a prophylactic and / or therapeutic agent for vascular depression can be provided.

  Hereinafter, the present invention will be described in detail. The agent for preventing and / or treating depression or the agent for preventing and / or treating vascular depression according to the present invention includes aminoalkoxybibenzyls represented by the above general formula (1), pharmaceutically acceptable salts thereof, Substances selected from the group consisting of esters and solvates and hydrates thereof are included as active ingredients.

R ¹ represents a hydrogen atom; a halogen atom such as a chlorine atom or a fluorine atom; a C _{1 to} C ₅ alkoxy group such as a methoxy group, an ethoxy group, or a butoxy group; a C ₂ such as a dimethylamino group, a diethylamino group, or a methylethylamino group. It shows a dialkylamino group -C _6. R ² represents a hydrogen atom; a halogen atom such as a chlorine atom or a fluorine atom; a C _{1 to} C ₅ alkoxy group such as a methoxy group, an ethoxy group, or a butoxy group. R ³ is a hydrogen atom; a hydroxyl _{group; -O- (CH 2) 2 -COOH} , -O- (CH 2) 3 -COOH, etc. -O- (CH ₂₎ in _n -COOH (wherein, n is 1 to 5 represents an integer of); - O-CO- (CH 2) 2 -COOH, -O-CO- (CH 2) 3 -O-CO- (CH 2 -COOH, etc.) in _l -COOH (wherein, l represents an integer of 1 to 3). R ⁴ represents an amino group or an alkyl group having 1 to 8 carbon atoms such as a methylamino group, an ethylamino group, a butylamino group, a hexylamino group, a heptylamino group, a dimethylamino group, a diethylamino group, or a methylethylamino group. A 4- to 6-membered polymethyleneamino group which represents an amino group having ˜2 or a ring such as a trimethyleneamino group, a pentamethyleneamino group or a 3-carboxypentamethyleneamino group may be substituted with a carboxyl group Represents.

  Among the compounds included in the general formula (1), some of the compounds preferably used in the present invention are shown in Table-1.

Among these, a compound in which an aminoalkoxy group; —OCH ₂ C (R ³ ) H— (CH ₂ ) m —R ⁴ is bonded to the 2-position of the phenyl group is preferable. R ¹ is preferably a hydrogen atom, a C ₁ -C ₅ alkoxy group, or a C ₂ -C ₆ dialkylamino group, R ² is preferably a hydrogen atom, and R ⁴ is at least one C ₁ -C _8. It is preferably a 4-6 membered polymethyleneamino group having an alkyl group or a trimethylene group or a pentamethylene group, and m is preferably an integer of 0-2. Particularly preferred is ^{No. 1 wherein} R ¹ is a methoxy group, R ² is a hydrogen atom, R ³ is a hydroxyl group, R ⁴ is a dimethylamino group, and m is 1. No. 15 (hereinafter, this compound may be referred to as “M-1”) and its succinic acid ester No. 15 14 compounds.

  The “pharmaceutically acceptable salt” may be any non-toxic salt formed with the aminoalkoxybenzyls represented by the general formula (1). For example, hydrofluoric acid Salts, hydrochlorides, hydrobromides, hydroiodides, sulfates, nitrates, phosphates, carbonates, bicarbonates, perchlorates and other inorganic acid addition salts; formates, acetates , Trifluoroacetate, propionate, oxalate, glycolate, succinate, lactate, maleate, hydroxy maleate, methyl maleate, fumarate, adipate, tartrate, Malate, citrate, benzoate, cinnamate, ascorbate, salicylate, 2-acetoxybenzoate, nicotinate, isonicotinate and other organic acid addition salts; methanesulfonic acid Salt, ethanesulfo Acid, isethionate, benzenesulfonate, p-toluenesulfonate, naphthalenesulfonate, hydroxybenzenesulfonate, dihydroxybenzenesulfonate, and other organic sulfonic acid addition salts; aspartate, glutamate Addition salts of acidic amino acids such as; alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as magnesium salts and calcium salts; ammonium salts; trimethylamine salts, triethylamine salts, pyridine salts, picoline salts, dicyclohexylamine salts And addition bases of organic bases such as N, N′-dibenzylethylenediamine salts; addition salts of basic amino acids such as lysine salts and arginine salts.

  Examples of the esters of aminoalkoxybenzyls represented by the general formula (1) include formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, glycolic acid, succinic acid, lactic acid, maleic acid, hydroxymaleic acid, and methylmaleic acid. , Fumaric acid, adipic acid, tartaric acid, malic acid, citric acid, benzoic acid, cinnamic acid, ascorbic acid, salicylic acid, 2-acetoxybenzoic acid, nicotinic acid, isonicotinic acid and other organic acids, sulfuric acid, nitric acid, phosphoric acid And esters obtained by dehydration condensation with inorganic acids such as carbonic acid.

  In addition to the crystalline form, these compounds may be solvates or hydrates with water or alcohol depending on the case.

  Among these, (±) -1- [O- [2- (m-methoxyphenyl) ethyl] phenoxy] -3- (dimethylamino) -2-propyl represented by the following formula (4) is particularly preferable. Hydrogen succinate hydrochloride (hereinafter, this substance is also referred to as “sarpogrelate hydrochloride”).

  The aminoalkoxybibenzyls represented by the general formula (1), pharmaceutically acceptable salts and esters thereof are known and can be easily prepared by the method described in JP-A-58-32847 or a method analogous thereto. Can be synthesized. The sarpogrelate hydrochloride represented by the above formula (4) is commercially available as “Amprag (registered trademark)” by Mitsubishi Tanabe Pharma Corporation, and in the present invention, the commercially available “amplag” can be used as it is. is there.

  Diseases targeted by the present invention include depression, depression and anxiety disorders or depression with cerebrovascular disorders, depression with cerebrovascular disorders and anxiety disorders with cerebrovascular disorders.

  Depression is thought to be caused by a temporary decrease in brain function, and is a disease that results in remission if treated appropriately. In relatively mild depression, physical symptoms are accompanied by mild decline in motivation, but in moderate depression, symptoms such as insomnia, loss of appetite, and depression are relatively strong, which hinders work and housework. coming out. Also, in severe depression, there is a marked decrease in motivation and examples with depressive delusions (common delusions such as morale, crime and poverty), depression with melancholic, and older women There are cases of so-called abrupt depression, strong anxiety that is common in depression, examples of strong thoughts of death, and examples of attempted suicide (Non-patent Document 2). Other symptoms include fatigue, easy labor, and headaches. In addition, as a diagnostic standard of the American Psychiatric Association, which is also widely used in Japan, it refers to patients who have the following major depressive episodes, and major depressive episodes include five or more of the following nine items: Refers to the recognized state. (1) Depressive mood, (2) Significant decrease in interest, joy, (3) Weight loss or increase, loss or increase in appetite, (4) Insomnia or hypersomnia, (5) Psychomotor agitation or arrest, (6 ) Fatigue or decline in spirit, (7) Valuelessness or guilt, (8) Decrease in thinking or concentration or difficulty in making decisions, (9) Suicidal ideation or suicide attempt (Takehiko Higuchi: The pathology of mood disorders, Diagnosis and Treatment Overview, Clinical and Research 80 (9): 1582-1587, 2003).

  Depressed state means that the state is depressive and persistent to some extent. Symptoms include mood disorders characterized by sadness and / or anxiety, congestion of thought processes (concentration difficulties and repeated thoughts), psychomotor suppression or agitation, psychosomatic symptoms, depressive delusions ( Psychosis, poverty delusion or guilt delusion) (Clinical Psychiatry 34 (5): 537-542, 2005). In addition, fatigue, easy labor, and headaches are observed. In addition, it refers to a condition in which symptom of 4 items or less is observed among 9 items shown in the diagnostic criteria of the American Psychiatric Association.

  The present invention is particularly effective for the prevention and treatment of depression or depression that show symptoms such as depressed mood, thought disorder, decreased power, agitation, malaise, fatigue, loss of appetite, headache and / or sleep disorders. It is.

  Anxiety is an unpleasant emotional state that everyone experiences. However, there may be excessive anxiety for no particular reason, and such a condition can be referred to as an anxiety disorder. Anxiety disorders are obsessive-compulsive disorders characterized by obsessions and urges to reduce discomfort due to obsessions (compulsive acts), panic disorders in which anxiety occurs as a sudden attack, social situations (for example, public) ) Is a very anxious and very painful social phobia, square phobia with strong anxiety in certain places and environments, post-traumatic stress disorder (PTSD) that develops after experiencing intense stress, It is classified into generalized anxiety disorder with unexplained anxiety that lasts for a long time, mixed anxiety-depressive disorder with mild anxiety and depressive symptoms, and intermittent presence of autonomic symptoms.

  The present invention is particularly effective for anxiety disorders such as obsessive-compulsive disorder, panic disorder, social phobia, agoraphobia, posttraumatic stress disorder (PTSD), generalized anxiety disorder or mixed anxiety depression disorder.

In addition to the depression, depression and anxiety disorders described above, the present invention is also considered to be effective for depression with cerebrovascular disorders, depression with cerebrovascular disorders and anxiety disorders with cerebrovascular disorders. . Depression with cerebrovascular disorder, depression with cerebrovascular disorder and anxiety disorder with cerebrovascular disorder are depression, depression and anxiety disorder that occur after cerebrovascular disorder, and are collectively referred to as vascular depression Called sick. The cause of vascular depression is direct brain damage, and the pathological condition is clearly different from depression, depression and anxiety disorders that are thought to be caused by psychological reactions. In addition, it is poor in responsiveness to drugs usually used for the treatment of depression, depressive state and anxiety disorder, and is easily intractable.
Cerebrovascular disorders that cause vascular depression include cerebral infarction (cerebral thrombosis, cerebral embolism, etc.), transient cerebral ischemic attack, cerebral hemorrhage, subarachnoid hemorrhage, subdural hematoma, cerebral venous occlusion and Asymptomatic cerebrovascular disorder and the like. Here, asymptomatic cerebrovascular disorder is cerebral infarction (cerebral thrombosis, cerebral embolism, etc.), cerebral hemorrhage, subarachnoid hemorrhage, subdural hematoma or cerebral venous occlusion Although it does not appear, it means that microscopic bleeding or infarction is found in the cerebral blood vessel by image diagnosis (CT, MRI, etc.).

  In recent years, it has become clear that diffuse white matter lesions and asymptomatic lacunar infarctions are frequently observed with aging due to advances in diagnostic imaging (Non-patent Document 5). In elderly depression, these findings have been reported to be significantly higher than in non-depression (Cervilla J, Prince M, Rabe-Hesketh S: Phychol Med, Vascular disease risk factors as determinants of incident depressive symptoms: 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, among the above depression, depression and anxiety disorder or depression with cerebrovascular disorder, depression with cerebrovascular disorder and anxiety disorder with cerebrovascular disorder, those with poor prognosis, prolonged or chronic Can be classified as refractory, and the present invention relates to such refractory depression, refractory depression and depression with refractory anxiety disorder or refractory cerebrovascular disorder, refractory cerebrovascular It is also useful for depressive states with disabilities and anxiety disorders with intractable cerebrovascular disorders.

  Refractory refers to a case where a sufficient therapeutic effect does not appear even if a sufficient amount (200 mg / day equivalent to imipramine) is used for a sufficient period (4-6 weeks) of at least three types of antidepressants.

  Intractable therapies such as lithium, thyroid hormone, dopamine agonists, atypical antipsychotics, and other anti-depressants are used, such as augmentation therapy and electroconvulsive therapy. There is not yet a sufficient number of clinical studies to standardize treatment based on it (Nagahisa Okamoto: Addressing depressive depression. History of medicine 219 (13): 955-962, 2006).

  The administration method when the compound of the present invention is used as a prophylactic and / or therapeutic agent for depression or a prophylactic and / or therapeutic agent for vascular depression can be appropriately selected by those skilled in the art. For example, it is possible to select any administration route of parenteral administration such as subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, or oral administration. The dosage can be appropriately determined depending on conditions such as the age, health condition, and weight of the patient, the conditions such as the type and frequency of administration, or the nature of the desired effect, if there are drugs to be administered simultaneously. In general, the daily dose of the active ingredient is 0.5 to 50 mg / kg body weight, usually 1 to 30 mg / kg body weight, and can be administered once or more per day.

  When the compound of the present invention is used as a prophylactic and / or therapeutic agent for depression or a prophylactic and / or therapeutic agent for vascular depression, it contains the above-mentioned active ingredient and one or more pharmaceutical additives. It is preferred to prepare and administer a pharmaceutical composition. Examples of the pharmaceutical composition suitable for oral administration include tablets, capsules, powders, solutions, elixirs, and the like. Examples of the pharmaceutical composition suitable for parenteral administration include solutions or suspensions. An example is a sterilized liquid pharmaceutical composition such as an agent.

  The type of pharmaceutical additive used for preparing the pharmaceutical composition is not particularly limited, and it is possible to select an appropriate pharmaceutical additive depending on the form of various pharmaceutical compositions. The pharmaceutical additive may be either solid or liquid, and for example, a solid carrier or a liquid carrier can be used. As an example of the solid carrier, a normal gelatin type capsule can be used. Also, for example, the active ingredient can be tableted with or without one or more formulation additives, or can be prepared and packaged as a powder. These capsules, tablets, and powders can generally contain 5 to 95% by weight, preferably 5 to 90% by weight, of the active ingredient relative to the total weight of the preparation, and the dosage unit form is 5 to 500 mg, Preferably it contains 25 to 250 mg of active ingredient. As the liquid carrier, an aqueous carrier (such as water) or an oily carrier (such as oil of animal or vegetable origin such as petroleum, peanut oil, soybean oil, mineral oil, sesame oil, or synthetic oil) is used. In general, physiological saline, dextrol or similar sucrose solution, glycols such as ethylene glycol, propylene glycol, polyethylene glycol and the like are preferable as the liquid carrier, and in the case of an injection solution using physiological saline, it is usually 0.00. It can be prepared to contain 5-20% by weight, preferably 1-10% by weight of the active ingredient.

  The agent for preventing and / or treating depression or the agent for preventing and / or treating vascular depression of the present invention can be used in combination with an antidepressant, an anxiolytic agent and an antipsychotic agent (hereinafter referred to as these agents). Simply referred to as concomitant drugs). Examples of the antidepressant used in combination include those usually used in the art, such as mianserin, sulpiride, imipramine, clomipramine, desipramine, amitriptyline, amoxapine, trazodone, fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram and the like. Is used. Examples of the anti-anxiety drugs used in combination include those commonly used in the art, such as diazepam, flunitrazepam, brotizolam, etizolam, zolpidem, lorazepam, alprazolam, clothiazepam, tandospirone, and buspirone. Examples of the antipsychotic drug used in combination include those usually used in the art, such as olanzapine, quetiapine, risperidone, perospirone, haloperidol, bronperidol, sulpiride, mosapramine, pimozide, zotepine and the like. The dose of the concomitant drug is usually based on the amount conventionally used clinically for each drug, depending on the type of drug used, sex, age, weight, or severity of symptoms. Is determined as appropriate. In consideration of the combined use of the prophylactic and / or therapeutic agent for depression of the present invention or the prophylactic and / or therapeutic agent for vascular depression with other drugs, the dose of each drug may be reduced.

  It comprises aminoalkoxybibenzyls represented by the above general formula (1), formula (2) or formula (3), pharmaceutically acceptable salts, esters thereof, and solvates and hydrates thereof. The substance selected from the group is for the prevention and / or treatment of the above depression, depression or anxiety disorder or depression with cerebrovascular disorder, depression with cerebrovascular disorder or anxiety disorder with cerebrovascular disorder and It can be used for the manufacture of a therapeutic agent.

  Hereinafter, the present invention will be described more specifically with reference to examples. However, the scope of the present invention is not limited to the following examples.

Example 1
X-2 years, appearance of depression, decreased motivation / interest, ease of labor, difficulty concentrating, waking up early in the morning, loss of appetite, weight loss (10 kg loss), body wobble, etc. Work tends to be off and retires in March X-2. X-2 Apr. Visited Psychiatry A Hospital and received medication, but the improvement was poor. In the diagnosis of major depressive disorder, various antidepressants, thyroid hormones, etc. were used as augmentation therapy, but the improvement was poor, and since I was living at home almost all day, X year 8 Month B Hospital was admitted to the Department of Psychiatry and Neurology.

The results of hospitalization tests are as follows.
Blood count / biogenesis: No special notes
EEG: WNL
Inscription / neuropsychological examination (HDS-R (28 points), WAIS-R, Benton visual inscription examination, WMS-R than linguistic versus federation, FAB, Troop Test, Trail Making Test): All At the average level, it cannot be said that there is an obstacle in memorization ability and frontal lobe function.
Head MRI: Frontal / temporal lobe atrophy and microinfarct lesions in deep white matter of the cerebrum, but cannot be identified as vascular depression.
Head ^99m Tc-ECD SPECT: There is a slight decrease in blood flow in the frontal and temporal lobes.
Neurology visit: It is not a dementia or degenerative disease without clear findings.

  Continued pharmacotherapy using antidepressants, anti-anxiety drugs, antipsychotics, etc. even after hospitalization, but the effect was poor, and ECT (9 times) was performed in October X, and depression was improved.・ Decrease in activity was poor.

  Drugs used (Mianserin 60 mg / day, sulpiride 30 mg / day, perospirone 12 mg / day, brotizolam 0.25 mg / day, flunitrazepam (flunitrazepam) 1 mg / day) was fixed, and started on November 21, X at sarpogrelate hydrochloride (sarpogrelate hydrochloride: Amprag (registered trademark)) 100 mg / day (half tablet twice a day in the morning and evening). The dose was increased to 200 mg / day (one tablet twice in the morning and evening). The findings of head MRI and SPECT before the start were almost unchanged from the time of admission, and decreased blood flow, atrophy, and deep white matter microinfarct lesions were observed mainly in the frontal and temporal lobes.

  Participated in radio exercises after the addition of Amprag (at the time of 100 mg administration), and stayed out and stayed at home to clean up the house (at the time of 200 mg administration), and was discharged on December 14, X.

  The score on the Hamilton Depression Rating Scale (HDRS; Japanese for the structured interview using the Japanese version of SIG-D) before and after the use of Amprag was 19 points (at the start) → 15 points (after 1 week) → 13 points (after 5 weeks) The Global Assessment of Functioning (GAF) showed an improvement of 38 (at the start) → 47 (after 1 week) → 52 (after 5 weeks).

  From this result, it was clear that administration of sarpogrelate hydrochloride significantly improved the symptoms of patients with intractable depression, and that sarpogrelate hydrochloride is effective for depression, depression or anxiety disorder became.

  According to the present invention, a novel agent for preventing and / or treating depression, depression or anxiety disorder or depression with novel cerebrovascular disorder, depression with cerebrovascular disorder and prevention of anxiety disorder with cerebrovascular disorder And / or a therapeutic agent can be provided.

Claims (16)

A substance selected from the group consisting of aminoalkoxybibenzyls represented by the following general formula (1), pharmaceutically acceptable salts, esters thereof, and solvates and hydrates thereof is an active ingredient. A preventive and / or therapeutic agent for depression, depression or anxiety disorder.

[Wherein, R ¹ represents a hydrogen atom, a halogen atom, a C _{1 to} C ₅ alkoxy group, or a C _{2 to} C ₆ dialkylamino group, and R ² represents a hydrogen atom, a halogen atom, or C _{1 to} C ₅ . Represents an alkoxy group, R ³ represents a hydrogen atom, a hydroxyl group, —O— (CH ₂ ) _n —COOH (wherein n represents an integer of 1 to 5), or —O—CO— (CH ₂ ). _l- COOH (wherein, l represents an integer of 1 to 3), R ⁴ represents —N (R ⁵ ) (R ⁶ ) (wherein R ⁵ and R ⁶ are each independently a hydrogen atom; or an alkyl group of _C 1 _{~C 8.)} or

(Wherein, A represents a C _{3 to} C ₅ alkylene group which may be substituted with a carboxyl group), and m represents an integer of 0 to 5. ] Depression comprising an aminoalkoxybibenzyl compound represented by the following formula (2), a pharmaceutically acceptable salt thereof, an ester thereof, and a substance selected from the group consisting of solvates and hydrates thereof as an active ingredient A preventive and / or therapeutic agent for illness, depression or anxiety disorder.

Depression comprising an aminoalkoxybibenzyl compound represented by the following formula (3), a pharmaceutically acceptable salt thereof, an ester thereof, and a solvate and a hydrate thereof as an active ingredient A preventive and / or therapeutic agent for illness, depression or anxiety disorder.

  The prophylactic and / or therapeutic agent for depression, depression or anxiety disorder according to claim 2, which is in the form of hydrochloride.   The depression, depression state or anxiety disorder according to any one of claims 1 to 4, wherein the depression, depression state or anxiety disorder is refractory depression, refractory depression state or refractory anxiety disorder Prophylactic and / or therapeutic agent.   The prevention of depression, depression or anxiety disorder according to any one of claims 1 to 5, which is used in combination with at least one selected from the group consisting of an antidepressant, an anxiolytic and an antipsychotic. And / or therapeutic agent. A substance selected from the group consisting of aminoalkoxybibenzyls represented by the following general formula (1), pharmaceutically acceptable salts, esters thereof, and solvates and hydrates thereof is an active ingredient. A prophylactic and / or therapeutic agent for depression with cerebrovascular disorder, depression with cerebrovascular disorder or anxiety disorder with cerebrovascular disorder.

[Wherein, R ¹ represents a hydrogen atom, a halogen atom, a C _{1 to} C ₅ alkoxy group, or a C _{2 to} C ₆ dialkylamino group, and R ² represents a hydrogen atom, a halogen atom, or C _{1 to} C ₅ . Represents an alkoxy group, R ³ represents a hydrogen atom, a hydroxyl group, —O— (CH ₂ ) _n —COOH (wherein n represents an integer of 1 to 5), or —O—CO— (CH ₂ ). _l- COOH (wherein, l represents an integer of 1 to 3), R ⁴ represents —N (R ⁵ ) (R ⁶ ) (wherein R ⁵ and R ⁶ are each independently a hydrogen atom; or an alkyl group of _C 1 _{~C 8.)} or

(Wherein, A represents a C _{3 to} C ₅ alkylene group which may be substituted with a carboxyl group), and m represents an integer of 0 to 5. ] A brain comprising as an active ingredient a substance selected from the group consisting of aminoalkoxybibenzyls represented by the following formula (2), pharmaceutically acceptable salts, esters thereof, and solvates and hydrates thereof: A prophylactic and / or therapeutic agent for depression with vascular disorder, depression with cerebrovascular disorder or anxiety disorder with cerebrovascular disorder.

A brain comprising as an active ingredient a substance selected from the group consisting of aminoalkoxybibenzyls represented by the following formula (3), pharmaceutically acceptable salts, esters thereof, and solvates and hydrates thereof: A prophylactic and / or therapeutic agent for depression with vascular disorder, depression with cerebrovascular disorder or anxiety disorder with cerebrovascular disorder.

  The prophylactic and / or therapeutic agent for depression with cerebrovascular disorder, depression with cerebrovascular disorder or anxiety disorder with cerebrovascular disorder according to claim 8, which is in the form of hydrochloride.   Depression with cerebrovascular disorder, depression with cerebrovascular disorder, or anxiety disorder with cerebrovascular disorder, depression with cerebrovascular disorder, depression with refractory cerebrovascular disorder, or refractory brain The prevention and / or treatment of an anxiety disorder accompanied by a cerebrovascular disorder according to any one of claims 7 to 10, wherein the depression is accompanied by a cerebrovascular disorder, a depression state accompanied by a cerebrovascular disorder or a cerebrovascular disorder. Agent.   The cerebral vascular disorder is cerebral infarction, transient cerebral ischemic attack, cerebral hemorrhage, subarachnoid hemorrhage, subdural hematoma, or cerebral venous occlusion. A prophylactic and / or therapeutic agent for depression, a depression state associated with cerebrovascular disorder, or an anxiety disorder associated with cerebrovascular disorder.   The cerebrovascular disorder is cerebral infarction, transient cerebral ischemic attack or cerebral venous occlusion, depression according to any one of claims 7 to 12, depression state associated with cerebrovascular disorder, or A prophylactic and / or therapeutic agent for anxiety disorders associated with cerebrovascular disorders.   The cerebral infarction is cerebral thrombosis or cerebral embolism, The prophylactic and / or therapeutic agent for depression with cerebrovascular disorder, depression with cerebrovascular disorder or anxiety disorder with cerebrovascular disorder according to claim 12 or 13.   The cerebrovascular disorder is an asymptomatic cerebrovascular disorder. Depression with cerebrovascular disorder according to any one of claims 7 to 14, depression state with cerebrovascular disorder, or anxiety disorder with cerebrovascular disorder. Prophylactic and / or therapeutic agent.   The depression and cerebrovascular disease with cerebrovascular disorder according to any one of claims 7 to 15, which is used in combination with at least one selected from the group consisting of an antidepressant drug, an anxiolytic drug and an antipsychotic drug. A prophylactic and / or therapeutic agent for a depression state accompanied by a disorder or an anxiety disorder associated with a cerebrovascular disorder.