JP2009292782A - Agent for promoting neurogenesis and/or neurotization - Google Patents
Agent for promoting neurogenesis and/or neurotization Download PDFInfo
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Abstract
Description
本発明は、神経新生作用、神経再生作用、神経新生促進作用、及び神経再生促進作用からなる群から選ばれる１又は２以上の作用を有する剤、並びにその医薬組成物に関する。 The present invention relates to an agent having one or more actions selected from the group consisting of a neurogenesis action, a nerve regeneration action, a neurogenesis promotion action, and a nerve regeneration promotion action, and a pharmaceutical composition thereof.
脳や脊髄の外傷、脳血管障害、神経変性疾患などで、神経の軸索が損傷したり、神経が脱落したりすると、治癒することは困難である。神経系、特に中枢神経系では、一旦軸索が損傷したり、神経細胞死が生じたりした場合、神経が再生もしくは新生しないと考えられてきた。近年、中枢神経系でも神経を再生もしくは新生させることの可能性があることが明らかとされつつある。しかし、神経新生もしくは神経再生を、医療技術として使用する為の満足いく治療方法は現在無い。従って、安全性の高い神経新生及び／又は神経再生促進剤の開発が望まれている。 It is difficult to heal if nerve axons are damaged or nerves fall off due to trauma of the brain or spinal cord, cerebrovascular disorder, neurodegenerative disease, and the like. In the nervous system, particularly the central nervous system, it has been considered that once axons are damaged or nerve cell death occurs, nerves do not regenerate or regenerate. In recent years, it has been clarified that there is a possibility of regenerating or regenerating nerves in the central nervous system. However, there is currently no satisfactory treatment method for using neurogenesis or nerve regeneration as a medical technique. Therefore, development of a highly safe neurogenesis and / or nerve regeneration promoter is desired.
一方、一般式（Ｉ）で示される化合物は、Ｒｈｏキナーゼ、ミオシン軽鎖リン酸化酵素、プロテインキナーゼＣといったキナーゼ阻害活性を有し、血管平滑筋弛緩作用、血流増加作用、血圧低下作用、脳、心臓保護作用等を示し、血管拡張剤（特に、狭心症治療剤）、高血圧治療剤、脳、心臓保護剤、動脈硬化症治療剤等において有効な物質であることは、既に公知である（例えば、特許文献１、特許文献２、特許文献３、特許文献４、特許文献５、特許文献６、特許文献７、特許文献８、特許文献９、非特許文献１、非特許文献２、非特許文献３、又は非特許文献４参照）。しかし、一般式（Ｉ）で示される化合物が、神経の新生及び／又は再生に有用である旨、或いはそれを示唆する記載は認められない。
本発明は、神経を新生及び／又は再生する医薬を提供することを目的とするものである。 An object of the present invention is to provide a medicine for regenerating and / or regenerating nerves.
本発明者は、上記課題を解決するために鋭意研究を重ねた結果、一般式（Ｉ）で示される化合物、又はその酸付加塩、もしくはそれらの水和物が、上記血管平滑筋弛緩作用、血流増加作用、血圧低下作用、脳、心臓保護作用など、従来知られている作用からは全く予期できない神経の新生及び／又は再生に有効であることを見出し、本発明を完成するに至った。
すなわち、本発明は以下に関する。
（１）下記一般式（Ｉ）
As a result of intensive studies in order to solve the above problems, the present inventor has found that the compound represented by the general formula (I), or an acid addition salt thereof, or a hydrate thereof has the above-mentioned vascular smooth muscle relaxing action, The present invention has been completed by finding that it is effective for neurogenesis and / or regeneration, which is totally unexpected from conventionally known actions such as blood flow increasing action, blood pressure lowering action, brain and cardioprotective action. .
That is, the present invention relates to the following.
(1) The following general formula (I)
（式中、Ｒ１は水素原子、又は水酸基を表す）で示される化合物、又はその酸付加塩、もしくはそれらの水和物を有効成分とする神経新生作用、神経再生作用、神経新生促進作用、及び神経再生促進作用からなる群から選ばれる１又は２以上の作用を有する剤。 (Wherein R 1 represents a hydrogen atom or a hydroxyl group), or a neurogenesis action, a nerve regeneration action, a neurogenesis promotion action containing an acid addition salt thereof or a hydrate thereof as an active ingredient, And an agent having one or more actions selected from the group consisting of a nerve regeneration promoting action.
（２）幹細胞、神経前駆細胞、又は神経細胞からなる群から選ばれる細胞を神経細胞として有効に機能させる為の剤であって、該前駆細胞の生着段階、分化段階、及び増殖段階からなる群から選ばれる１つ以上の段階の進行又は進行の促進をするか、或いは機能発現を促進することを特徴とする上記（１）記載の剤。
（３）幹細胞が、胚性幹細胞、骨髄幹細胞、又は神経幹細胞である上記（２）記載の剤。
（４）幹細胞、神経前駆細胞、又は神経細胞が、内在性細胞である上記（２）記載の剤。
（５）幹細胞、神経前駆細胞、又は神経細胞が、移植細胞である上記（２）記載の剤。
（６）神経が、中枢神経である上記（１）〜（５）のいずれかに記載の剤。
（７）神経が、末梢神経である上記（１）〜（５）のいずれかに記載の剤。
（８）機能発現の促進が、神経細胞の神経突起成長促進、又は退縮抑制である上記（２）記載の剤。
（９）上記（１）〜（８）のいずれかに記載の剤を含有する中枢及び／又は末梢神経系疾患の予防及び／又は治療剤。
(2) An agent for effectively functioning as a neural cell a cell selected from the group consisting of a stem cell, a neural progenitor cell, or a neural cell, comprising an engraftment stage, a differentiation stage, and a proliferation stage of the progenitor cell The agent according to (1) above, wherein the progression of one or more stages selected from the group or promotion of progression, or promotion of function expression is promoted.
(3) The agent according to (2) above, wherein the stem cells are embryonic stem cells, bone marrow stem cells, or neural stem cells.
(4) The agent according to (2) above, wherein the stem cell, neural progenitor cell, or neural cell is an endogenous cell.
(5) The agent according to (2) above, wherein the stem cell, neural progenitor cell, or neural cell is a transplanted cell.
(6) The agent according to any one of (1) to (5), wherein the nerve is a central nerve.
(7) The agent according to any one of (1) to (5), wherein the nerve is a peripheral nerve.
(8) The agent according to (2) above, wherein the functional expression is promoted by neurite growth promotion or regression inhibition of nerve cells.
(9) A preventive and / or therapeutic agent for central and / or peripheral nervous system diseases comprising the agent according to any one of (1) to (8) above.
（１０）中枢及び／又は末梢神経系疾患が、神経変性疾患、認知又は記憶障害、血管障害、或いは外傷である上記（９）記載の予防及び／又は治療剤。
（１１）神経変性疾患が、アルツハイマー病、パーキンソン病、筋萎縮性側索硬化症、又はハンチントン病である上記（１０）記載の予防及び／又は治療剤。
（１２）少なくとも下記の（ａ）に記載の化合物と（ｂ）に記載の薬とを組み合わせてなる神経新生及び／又は神経再生促進剤；
（ａ）一般式（Ｉ）（式中、Ｒ１は水素原子、又は水酸基を表す）で示される化合物、又はその酸付加塩、もしくはそれらの水和物、
（ｂ）神経成長因子、脳機能賦活薬、抗うつ薬、及び抗不安薬からなる群から選ばれる少なくとも１つ以上の薬。
（１３）神経再生剤である、上記（６）に記載の剤。
（１４）神経再生促進剤である、上記（７）に記載の剤。
（１５）神経新生剤、又は神経新生促進剤である、上記（１）〜（５）のいずれかに記載の剤。
(10) The preventive and / or therapeutic agent according to (9) above, wherein the central and / or peripheral nervous system disease is a neurodegenerative disease, cognitive or memory disorder, vascular disorder, or trauma.
(11) The preventive and / or therapeutic agent according to the above (10), wherein the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, or Huntington's disease.
(12) A neurogenesis and / or nerve regeneration-promoting agent comprising a combination of at least the compound described in (a) below and the drug described in (b);
(A) a compound represented by the general formula (I) (wherein R 1 represents a hydrogen atom or a hydroxyl group), or an acid addition salt thereof, or a hydrate thereof;
(B) At least one or more drugs selected from the group consisting of nerve growth factors, brain function activators, antidepressants, and anxiolytics.
(13) The agent according to (6) above, which is a nerve regeneration agent.
(14) The agent according to (7) above, which is a nerve regeneration promoter.
(15) The agent according to any one of (1) to (5), which is a neurogenesis agent or a neurogenesis promoter.
本発明によれば、神経新生作用、神経再生作用、神経新生促進作用、及び神経再生促進作用からなる群から選ばれる１又は２以上の作用を有する剤、並びにその医薬組成物が提供できる。 According to the present invention, an agent having one or more actions selected from the group consisting of a neurogenesis action, a nerve regeneration action, a neurogenesis promotion action, and a nerve regeneration promotion action, and a pharmaceutical composition thereof can be provided.
以下、本願発明について具体的に説明する。
本発明における神経としては、神経細胞体、中枢神経、末梢神経等が挙げられる。
本発明における神経新生としては、例えば、神経細胞以外の細胞、又は別の機能を有する神経細胞（これらを前駆細胞と呼ぶことがある）が所望の機能を有する神経細胞に変わり、最終的に「所望の神経細胞としての所望の機能を果たす」状態にまで成熟することが挙げられる。神経細胞以外の細胞としては、所望の神経細胞に変化し得る細胞であれば何ら限定されないが、例えば、幹細胞、又は神経前駆細胞等が挙げられる。幹細胞としては、例えば、胚性幹細胞、骨髄幹細胞、又は神経幹細胞等が挙げられる。
Hereinafter, the present invention will be specifically described.
Examples of nerves in the present invention include nerve cell bodies, central nerves, and peripheral nerves.
As the neurogenesis in the present invention, for example, a cell other than a nerve cell or a nerve cell having another function (sometimes referred to as a progenitor cell) is changed to a nerve cell having a desired function. Maturation to a state of “performing a desired function as a desired nerve cell”. The cell other than the nerve cell is not limited as long as it can be changed into a desired nerve cell, and examples thereof include a stem cell or a neural progenitor cell. Examples of stem cells include embryonic stem cells, bone marrow stem cells, or neural stem cells.
幹細胞、神経前駆細胞、又は神経細胞からなる群から選ばれる細胞としては、内在性細胞であってもよいし、移植細胞等の外来性細胞であってもよいが、移植細胞であることが好ましい。
例えば、他から神経細胞以外の細胞を移植した場合における神経新生を考えてみると、該細胞が生着し、移植細胞が神経細胞に分化し、分化した神経細胞が増殖できるのであれば増殖し、最終的に「神経細胞としての機能を果たす」状態になることが挙げられる。
本発明における神経新生促進としては、例えば、前記神経新生の速度を促進する作用等が挙げられる。
本発明における神経再生としては、例えば、軸索が損傷した場合、軸索を再生して最終的に「神経細胞としての機能を果たす」状態になることが挙げられる。
本発明における神経再生促進としては、例えば、前記神経再生の速度を促進する作用等が挙げられる。
本発明における神経細胞の機能発現の促進としては、「神経細胞としての機能を果たす」状態になることを促進することが挙げられ、例えば、神経細胞の神経突起成長促進、又は神経突起退縮抑制等が挙げられる。
本発明における神経新生作用、神経再生作用、神経新生促進作用、及び神経再生促進作用からなる群から選ばれる１又は２以上の作用を有する化合物としては、例えば、前記一般式（Ｉ）で示される化合物が挙げられる。
The cells selected from the group consisting of stem cells, neural progenitor cells, or neural cells may be endogenous cells or foreign cells such as transplanted cells, preferably transplanted cells. .
For example, considering neurogenesis when cells other than neurons are transplanted from other sources, if the cells engraft, the transplanted cells differentiate into neurons, and the differentiated neurons can proliferate, they will proliferate. Finally, it can be said that it “behaves as a nerve cell”.
Examples of the promotion of neurogenesis in the present invention include an action of promoting the speed of neurogenesis.
Examples of nerve regeneration in the present invention include, for example, when an axon is damaged, the axon is regenerated and finally becomes a “function as a nerve cell”.
Examples of the nerve regeneration promotion in the present invention include an action for promoting the speed of the nerve regeneration.
Examples of the promotion of the expression of the function of the nerve cell in the present invention include the promotion of the state of “functioning as a nerve cell”, such as promotion of neurite growth or suppression of neurite retraction of the nerve cell. Is mentioned.
Examples of the compound having one or more actions selected from the group consisting of a neurogenesis action, a nerve regeneration action, a neurogenesis promotion action, and a nerve regeneration promotion action in the present invention include those represented by the general formula (I). Compounds.
本発明における神経新生作用、神経再生作用、神経新生促進作用、及び神経再生促進作用からなる群から選ばれる１又は２以上の作用を有する医薬組成物としては、少なくとも本発明における神経新生作用、神経再生作用、神経新生促進作用、及び神経再生促進作用からなる群から選ばれる１又は２以上の作用を有する化合物を有効成分として含有していれればよい。
少なくとも下記の（ａ）に記載の化合物と（ｂ）に記載の薬とを組み合わせてなる神経新生及び／又は神経再生促進剤も、本発明の範囲に含まれる。
（ａ）一般式（Ｉ）（式中、Ｒ１は水素原子、又は水酸基を表す）で示される化合物、又はその酸付加塩、もしくはそれらの水和物、
（ｂ）神経成長因子、脳機能賦活薬、抗うつ薬、及び抗不安薬からなる群から選ばれる少なくとも１つ以上の薬。
As the pharmaceutical composition having one or more actions selected from the group consisting of neurogenesis action, nerve regeneration action, neurogenesis promotion action and nerve regeneration promotion action in the present invention, at least the neurogenesis action and nerve in the present invention A compound having one or more actions selected from the group consisting of a regeneration action, a neurogenesis promotion action, and a nerve regeneration promotion action may be contained as an active ingredient.
A neurogenesis and / or nerve regeneration promoter comprising at least the compound described in (a) below and the drug described in (b) is also included in the scope of the present invention.
(A) a compound represented by the general formula (I) (wherein R 1 represents a hydrogen atom or a hydroxyl group), or an acid addition salt thereof, or a hydrate thereof;
(B) At least one or more drugs selected from the group consisting of nerve growth factors, brain function activators, antidepressants, and anxiolytics.
神経成長因子、脳機能賦活薬、抗うつ薬、抗不安薬としては、公知のものを用いることができるが、当該作用を有する化合物／薬であれば特に限定されない。
本発明における神経新生作用、神経再生作用、神経新生促進作用、及び神経再生促進作用からなる群から選ばれる１又は２以上の作用を有する化合物が有効に作用する適応症としては、中枢及び／又は末梢神経系疾患が挙げられ、中枢神経系疾患が好ましい適応症である。また、末梢神経系疾患が好ましい別の態様もある。
中枢及び／又は末梢神経系疾患としては、神経変性疾患、認知又は記憶障害、血管障害、或いは外傷等が挙げられる。
As a nerve growth factor, a brain function activator, an antidepressant, and an anxiolytic agent, known ones can be used, but are not particularly limited as long as they are compounds / drugs having the action.
Indications in which the compound having one or more actions selected from the group consisting of neurogenesis action, nerve regeneration action, neurogenesis promotion action, and nerve regeneration promotion action according to the present invention act effectively include central and / or Peripheral nervous system diseases are mentioned, and central nervous system diseases are preferred indications. There is also another embodiment in which peripheral nervous system diseases are preferred.
Examples of central and / or peripheral nervous system diseases include neurodegenerative diseases, cognitive or memory disorders, vascular disorders, or trauma.
神経変性疾患としては、アルツハイマー病、パーキンソン病、筋萎縮性側索硬化症、又はハンチントン病等が挙げられる。
本発明の一般式（Ｉ）で示される化合物は、公知の方法、例えば、Chem. Pharam. Bull., 40, (3) 770-773 (1992)、特開昭６１−１５２６５８号公報等に記載されている方法に従って合成することができる。また、その酸付加塩は、薬学上許容される非毒性の塩が好ましく、例えば塩酸、臭化水素酸、リン酸、硫酸等の無機酸、および酢酸、クエン酸、酒石酸、乳酸、コハク酸、フマル酸、マレイン酸、メタンスルホン酸等の有機酸の塩を挙げることができる。
Examples of neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, or Huntington's disease.
The compound represented by the general formula (I) of the present invention is described in a known method such as Chem. Pharam. Bull., 40, (3) 770-773 (1992), JP-A 61-152658. Can be synthesized according to the methods described. The acid addition salt is preferably a pharmaceutically acceptable non-toxic salt, for example, an inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and acetic acid, citric acid, tartaric acid, lactic acid, succinic acid, Mention may be made of organic acid salts such as fumaric acid, maleic acid and methanesulfonic acid.
本発明の、神経新生及び／又は神経再生促進剤を、投与に適した形の製剤として調整するのに際しては、上述の一般式（Ｉ）で示される化合物またはその酸付加塩もしくは水和物と、公知の医薬上許容される担体とを混合すればよい。この担体としては、例えば、ゼラチン；乳糖、グルコース等の糖類；小麦、米、とうもろこし澱粉等の澱粉類；ステアリン酸等の脂肪酸；ステアリン酸カルシウム、ステアリン酸マグネシウム等の脂肪酸塩；タルク；植物油；ステアリンアルコール、ベンジルアルコール等のアルコール；ガム；ポリアルキレングリコール等が挙げられる。
また、液状担体としては、一般に水、生理食塩液、デキストロースまたは類似の糖溶液、エチレングリコール、プロピレングリコール、ポリエチレングリコール、ポリプロピレンルリコール等のグルコール類が挙げられる。カプセル剤となす場合には、通常ゼラチンを用いてカプセルを調整することが好ましい。
以上のような担体と一般式（Ｉ）で示される化合物またはその酸付加塩もしくは水和物よりなる本発明の神経新生及び／又は神経再生促進剤中には、通常0.01重量％以上、また80重量％以下、好ましくは60重量％以下の有効成分を含む例が挙げられる。
In preparing the neurogenesis and / or nerve regeneration-promoting agent of the present invention as a preparation suitable for administration, the compound represented by the above general formula (I) or an acid addition salt or hydrate thereof is used. A known pharmaceutically acceptable carrier may be mixed. Examples of the carrier include gelatin; sugars such as lactose and glucose; starches such as wheat, rice and corn starch; fatty acids such as stearic acid; fatty acid salts such as calcium stearate and magnesium stearate; talc; vegetable oil; stearic alcohol And alcohol such as benzyl alcohol; gum; polyalkylene glycol and the like.
Examples of the liquid carrier generally include water, physiological saline, dextrose or a similar sugar solution, and glycols such as ethylene glycol, propylene glycol, polyethylene glycol, and polypropylene glycol. When preparing capsules, it is usually preferable to prepare capsules using gelatin.
In the neurogenesis and / or nerve regeneration-promoting agent of the present invention comprising the above carrier and the compound represented by the general formula (I) or acid addition salt or hydrate thereof, usually 0.01% by weight or more, and 80 Examples include active ingredients of not more than wt%, preferably not more than 60 wt%.
投与方法は、経口投与や非経口投与が挙げられる。経口投与に適した剤形としては、錠剤、カプセル剤、粉剤、顆粒剤、液剤、エリキシル剤等が挙げられ、非経口投与に適した剤形としては、液剤が挙げられる。
非経口的に筋肉内注射、静脈内注射、皮下注射で投与する場合、一般式（Ｉ）で示される化合物またはその酸付加塩もしくは水和物を等張にするために、食塩または、グルコース等の他の溶質を添加した無菌溶液として投与される。
注射により投与する場合には、滅菌水、塩酸リドカイン溶液（筋肉内注射用）、生理食塩液、ブドウ糖、静脈内注射用溶液、電解質溶液（静脈内注射用）等で溶解することも好ましい。このようにして溶解した場合には、通常0.01重量％以上、また20重量％以下、好ましくは0.1重量％以上、また10重量％以下の有効成分を含むように調整されることがある。経口投与の液剤の場合、0.01-20重量％の有効成分を含む懸濁液またはシロップが好ましい例として挙げられる。この場合における担体としては、香料、シロップ、製剤的ミセル体等の水様賦形剤が挙げられる。
Examples of the administration method include oral administration and parenteral administration. Examples of dosage forms suitable for oral administration include tablets, capsules, powders, granules, solutions, elixirs, and the like, and dosage forms suitable for parenteral administration include solutions.
When administered parenterally by intramuscular injection, intravenous injection, or subcutaneous injection, sodium chloride, glucose or the like is used to make the compound represented by the general formula (I) or an acid addition salt or hydrate thereof isotonic. It is administered as a sterile solution with the addition of other solutes.
When administering by injection, it is also preferable to dissolve in sterile water, lidocaine hydrochloride solution (for intramuscular injection), physiological saline, glucose, intravenous injection solution, electrolyte solution (for intravenous injection) and the like. When dissolved in this manner, it may be adjusted so as to contain an active ingredient of usually 0.01% by weight or more and 20% by weight or less, preferably 0.1% by weight or more and 10% by weight or less. In the case of a solution for oral administration, a preferred example is a suspension or syrup containing 0.01 to 20% by weight of the active ingredient. Examples of the carrier in this case include aqueous excipients such as fragrances, syrups, and pharmaceutical micelles.
本発明の神経新生及び／又は神経再生促進剤の投与量は、被投与者の年齢、健康状態、体重、症状の程度、同時処置があるならばその種類、処置頻度、所望の効果の性質、あるいは投与経路や投与計画などによって異なるが、一般には、非経口投与で0.01-20mg/kg・日、経口投与で0.02-100mg/kg・日が挙げられる。 The dose of the neurogenesis and / or nerve regeneration-promoting agent of the present invention is the age, health status, body weight, degree of symptom, type of treatment if there is simultaneous treatment, frequency of treatment, nature of desired effect, Or, depending on the route of administration and administration schedule, generally, it is 0.01-20 mg / kg · day for parenteral administration and 0.02-100 mg / kg · day for oral administration.
本発明を実施例に基づいて説明するが、本発明の範囲は以下の例に限定されることはない。 The present invention will be described based on examples, but the scope of the present invention is not limited to the following examples.
［実施例１］N1E-115神経芽細胞腫細胞における神経突起退縮に対する作用
N1E-115神経芽細胞腫細胞を増殖培地（10% Fetal Bovine Serum 添加 Dulbecco’s Modified Eagle Medium (DMEM)）で培養した。N1E-115神経芽細胞腫細胞の培地を増殖培地から分化培地（DMEM）に交換し、２４時間培養した。一般式（Ｉ）（式中Ｒ１は水素原子または水酸基）で示される化合物を、最終濃度 0.1, 0.3, 1, 3, 10 mM で添加し、30分間プレインキュベートした。リゾフォスファチジン酸（LPA）を最終濃度 1 mM で添加し、室温で10分間放置した。Basal control では、LPA の代わりに生理食塩液を添加し、Positive control では、一般式（Ｉ）（式中Ｒ１は水素原子または水酸基）で示される化合物の代わりに生理食塩液を添加した。Glutaraldehyde で細胞を固定し、位相差顕微鏡下、任意の５視野を撮影した。神経突起の消失した完全に丸い細胞（rounded cells: RC）数と総細胞数を数えた。
[Example 1] Effect on neurite retraction in N1E-115 neuroblastoma cells
N1E-115 neuroblastoma cells were cultured in a growth medium (Dublbecco's Modified Eagle Medium (DMEM) supplemented with 10% Fetal Bovine Serum). The medium of N1E-115 neuroblastoma cells was changed from the growth medium to the differentiation medium (DMEM) and cultured for 24 hours. A compound represented by the general formula (I) (wherein R 1 is a hydrogen atom or a hydroxyl group) was added at a final concentration of 0.1, 0.3, 1, 3, 10 mM and preincubated for 30 minutes. Lysophosphatidic acid (LPA) was added at a final concentration of 1 mM and left at room temperature for 10 minutes. In Basal control, physiological saline was added instead of LPA, and in Positive control, physiological saline was added instead of the compound represented by the general formula (I) (wherein R 1 is a hydrogen atom or a hydroxyl group). Cells were fixed with Glutaraldehyde, and arbitrary 5 fields of view were photographed under a phase contrast microscope. The number of completely rounded cells (RC) in which neurites disappeared and the total number of cells were counted.
神経突起退縮の阻害率は、
阻害率（％）＝１００−｛（化合物投与時のRC数―Basal controlのRC数）／（Positive controlのRC数―Basal controlのRC数）｝ｘ１００
で算出し、ＩＣ５０値を求めた。
一般式（Ｉ）（式中Ｒ１は水素原子または水酸基）で示される化合物は、用量依存的に神経突起退縮を阻害した。ＩＣ５０値を以下に示す。
化合物（一般式Ｉ） ｎ数 神経突起退縮阻害作用（ＩＣ５０）
Ｒ１＝Ｈ （ｎ＝４） １．７ mＭ
Ｒ１＝ＯＨ （ｎ＝４） １．６ mＭ
The inhibition rate of neurite regression is
Inhibition rate (%) = 100 − {(RC number at compound administration−RC number of Basal control) / (RC number of Positive control−RC number of Basal control)} × 100
To obtain an IC50 value.
The compound represented by the general formula (I) (wherein R 1 is a hydrogen atom or a hydroxyl group) inhibited neurite retraction in a dose-dependent manner. IC50 values are shown below.
Compound (general formula I) n number Neurite retraction inhibitory action (IC50)
R 1 = H (n = 4) 1.7 mM
R 1 = OH (n = 4) 1.6 mM
［実施例２］急性毒性試験
本発明の化合物の急性毒性試験を、ラット（Jcl:Wistar,５週齢）およびマウス（Slc:ddY,５週齢）を用いて実施した結果、低毒性であることが確認された。その結果を以下に示す。
化合物 動物種 投与経路 性別 成績
（一般式Ｉ） ＬＤ５０（mg/kg）
Ｒ１＝Ｈ ラット 静脈内 オス ５９．９
メス ６３．９
経口 オス ３３５．０
メス ３４８．０
皮下 オス １２３．２
メス １２８．３
Ｒ１＝Ｈ マウス 静脈内 オス ６３．７
Ｒ１＝ＯＨ マウス 静脈内 オス １１９．３
[Example 2] Acute toxicity test An acute toxicity test of the compound of the present invention was carried out using rats (Jcl: Wistar, 5 weeks old) and mice (Slc: ddY, 5 weeks old). It was confirmed. The results are shown below.
Compound Animal species Route of administration Sex Results (general formula I) LD50 (mg / kg)
R 1 = H rat intravenous male 59.9
Female 63.9
Oral male 335.0
Female 348.0
Subcutaneous male 123.2
Female 128.3
R 1 = H mouse intravenous male 63.7
R 1 = OH mouse intravenous male 119.3
［実施例３］製剤例（無菌注射剤）
下記の成分を注射用蒸留水に溶解し、その後、注射用蒸留水を添加し、必要な最終重量とし、この溶液２ｍｌをアンプルに密封し、加熱滅菌した。
成分 量
１０ｍｇ製剤 一般式（Ｉ）塩酸塩 １０ｍｇ
（式中Ｒ１は水素原子）
塩化ナトリウム１６ｍｇ
蒸留水 適量
全量２ｍｌとした
３０ｍｇ製剤 一般式（Ｉ）塩酸塩 ３０ｍｇ
（式中Ｒ１は水素原子）
塩化ナトリウム １６ｍｇ
蒸留水 適量
全量２ｍｌとした
６０ｍｇ製剤 一般式（Ｉ）塩酸塩 ６０ｍｇ
（式中Ｒ１は水素原子）
塩化ナトリウム １６ｍｇ
蒸留水 適量
全量２ｍｌとした
１０ｍｇ製剤 一般式（Ｉ）塩酸塩 １０ｍｇ
（式中Ｒ１は水酸基）
塩化ナトリウム １６ｍｇ
蒸留水 適量
全量２ｍｌとした
３０ｍｇ製剤 一般式（Ｉ）塩酸塩 ３０ｍｇ
（式中Ｒ１は水酸基）
塩化ナトリウム １６ｍｇ
蒸留水 適量
全量２ｍｌとした
６０ｍｇ製剤 一般式（Ｉ）塩酸塩 ６０ｍｇ
（式中Ｒ１は水酸基）
塩化ナトリウム １６ｍｇ
蒸留水 適量
全量２ｍｌとした
[Example 3] Formulation example (sterile injection)
The following components were dissolved in water for injection, and then water for injection was added to the required final weight, and 2 ml of this solution was sealed in an ampoule and sterilized by heating.
Ingredient Amount 10 mg Formulation General Formula (I) Hydrochloride 10 mg
(Wherein R 1 is a hydrogen atom)
Sodium chloride 16mg
Appropriate amount of distilled water
The total volume was 2 ml
30 mg formulation General formula (I) hydrochloride 30 mg
(Wherein R 1 is a hydrogen atom)
Sodium chloride 16mg
Appropriate amount of distilled water
The total volume was 2 ml
60 mg preparation General formula (I) hydrochloride 60 mg
(Wherein R 1 is a hydrogen atom)
Sodium chloride 16mg
Appropriate amount of distilled water
The total volume was 2 ml
10 mg formulation General formula (I) hydrochloride 10 mg
(Wherein R 1 is a hydroxyl group)
Sodium chloride 16mg
Appropriate amount of distilled water
The total volume was 2 ml
30 mg formulation General formula (I) hydrochloride 30 mg
(Wherein R 1 is a hydroxyl group)
Sodium chloride 16mg
Appropriate amount of distilled water
The total volume was 2 ml
60 mg preparation General formula (I) hydrochloride 60 mg
(Wherein R 1 is a hydroxyl group)
Sodium chloride 16mg
Appropriate amount of distilled water
The total volume was 2 ml
［実施例４］製剤例（錠剤）
下記の成分を含む錠剤を常法により調整した。
成分 量
１０ｍｇ製剤 一般式（Ｉ）塩酸塩 １０．０ｍｇ
（式中Ｒ１は水素原子）
結晶セルロース ２５．０ｍｇ
乳糖 １０８．５ｍｇ
ステアリン酸マグネシウム １．５ｍｇ
カルボキシメチルセルロースカルシウム ５．０ｍｇ
合計 １５０．０ｍｇ
２０ｍｇ製剤 一般式（Ｉ）塩酸塩 ２０．０ｍｇ
（式中Ｒ１は水素原子）
結晶セルロース ２５．０ｍｇ
乳糖 ９８．５ｍｇ
ステアリン酸マグネシウム １．５ｍｇ
カルボキシメチルセルロースカルシウム ５．０ｍｇ
合計 １５０．０ｍｇ
１０ｍｇ製剤 一般式（Ｉ）塩酸塩 １０．０ｍｇ
（式中Ｒ１は水酸基）
結晶セルロース ２５．０ｍｇ
乳糖 １０８．５ｍｇ
ステアリン酸マグネシウム １．５ｍｇ
カルボキシメチルセルロースカルシウム ５．０ｍｇ
合計 １５０．０ｍｇ
２０ｍｇ製剤 一般式（Ｉ）塩酸塩 ２０．０ｍｇ
（式中Ｒ１は水酸基）
結晶セルロース ２５．０ｍｇ
乳糖 ９８．５ｍｇ
ステアリン酸マグネシウム １．５ｍｇ
カルボキシメチルセルロースカルシウム ５．０ｍｇ
合計 １５０．０ｍｇ
[Example 4] Formulation example (tablet)
A tablet containing the following components was prepared by a conventional method.
Ingredient Amount 10 mg Formulation General Formula (I) Hydrochloride 10.0 mg
(Wherein R 1 is a hydrogen atom)
Crystalline cellulose 25.0mg
Lactose 108.5mg
Magnesium stearate 1.5mg
Carboxymethylcellulose calcium 5.0mg
Total 150.0mg
20 mg preparation General formula (I) hydrochloride 20.0 mg
(Wherein R 1 is a hydrogen atom)
Crystalline cellulose 25.0mg
Lactose 98.5mg
Magnesium stearate 1.5mg
Carboxymethylcellulose calcium 5.0mg
Total 150.0mg
10 mg formulation General formula (I) hydrochloride 10.0 mg
(Wherein R 1 is a hydroxyl group)
Crystalline cellulose 25.0mg
Lactose 108.5mg
Magnesium stearate 1.5mg
Carboxymethylcellulose calcium 5.0mg
Total 150.0mg
20 mg preparation General formula (I) hydrochloride 20.0 mg
(Wherein R 1 is a hydroxyl group)
Crystalline cellulose 25.0mg
Lactose 98.5mg
Magnesium stearate 1.5mg
Carboxymethylcellulose calcium 5.0mg
Total 150.0mg
本発明により優れた神経新生剤、神経再生剤、神経新生促進剤、及び神経再生促進剤からなる群から選ばれる剤、並びにその医薬組成物の提供が可能となった。本発明の剤は、中枢及び／又は末梢神経系疾患の予防及び／又は治療に有用である。 The present invention makes it possible to provide an agent selected from the group consisting of an excellent neurogenesis agent, nerve regeneration agent, neurogenesis promoter, and nerve regeneration promoter, and a pharmaceutical composition thereof. The agent of the present invention is useful for the prevention and / or treatment of central and / or peripheral nervous system diseases.
Claims (12)
（ａ）一般式（Ｉ）（式中、Ｒ１は水素原子、又は水酸基を表す）で示される化合物、又はその酸付加塩、もしくはそれらの水和物、
（ｂ）神経成長因子、脳機能賦活薬、抗うつ薬、及び抗不安薬からなる群から選ばれる少なくとも１つ以上の薬。 A neurogenesis and / or nerve regeneration promoter comprising a combination of at least the compound described in (a) below and the drug described in (b);
(A) a compound represented by the general formula (I) (wherein R 1 represents a hydrogen atom or a hydroxyl group), or an acid addition salt thereof, or a hydrate thereof;
(B) At least one or more drugs selected from the group consisting of nerve growth factors, brain function activators, antidepressants, and anxiolytics.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2008149241A JP2009292782A (en) | 2008-06-06 | 2008-06-06 | Agent for promoting neurogenesis and/or neurotization |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2008149241A JP2009292782A (en) | 2008-06-06 | 2008-06-06 | Agent for promoting neurogenesis and/or neurotization |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JP2009292782A true JP2009292782A (en) | 2009-12-17 |
Family
ID=41541321
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2008149241A Withdrawn JP2009292782A (en) | 2008-06-06 | 2008-06-06 | Agent for promoting neurogenesis and/or neurotization |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2009292782A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013135596A1 (en) * | 2012-03-12 | 2013-09-19 | Georg-August-Universität Göttingen Stiftung Öffentlichen Rechts, Universitätsmedizin | Rho kinase inhibitors for use in treating amyotrophic lateral sclerosis |
| JP2015528486A (en) * | 2012-10-01 | 2015-09-28 | エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ | Benzimidazoles as CNS activators |
| JP2016531143A (en) * | 2013-09-12 | 2016-10-06 | エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ | Indole-carboxamide derivatives |
| US11318126B2 (en) | 2016-08-31 | 2022-05-03 | Kyoto University | Composition for activating neurogenesis |
-
2008
- 2008-06-06 JP JP2008149241A patent/JP2009292782A/en not_active Withdrawn
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013135596A1 (en) * | 2012-03-12 | 2013-09-19 | Georg-August-Universität Göttingen Stiftung Öffentlichen Rechts, Universitätsmedizin | Rho kinase inhibitors for use in treating amyotrophic lateral sclerosis |
| US9980972B2 (en) | 2012-03-12 | 2018-05-29 | Georg-August-Universität Göttingen Stiftung Öffentlichen Rechts, Universitätsmedizin | Rho kinase inhibitors for use in treating familial amyotrophic lateral sclerosis |
| JP2015528486A (en) * | 2012-10-01 | 2015-09-28 | エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ | Benzimidazoles as CNS activators |
| JP2016531143A (en) * | 2013-09-12 | 2016-10-06 | エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ | Indole-carboxamide derivatives |
| US11318126B2 (en) | 2016-08-31 | 2022-05-03 | Kyoto University | Composition for activating neurogenesis |
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