JPH069396A - Nerve growth factor producing promotor - Google Patents
Nerve growth factor producing promotorInfo
- Publication number
- JPH069396A JPH069396A JP34993992A JP34993992A JPH069396A JP H069396 A JPH069396 A JP H069396A JP 34993992 A JP34993992 A JP 34993992A JP 34993992 A JP34993992 A JP 34993992A JP H069396 A JPH069396 A JP H069396A
- Authority
- JP
- Japan
- Prior art keywords
- opq
- ngf
- growth factor
- nerve growth
- ester
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【0001】[0001]
【産業上の利用分野】本発明は、医薬、特に老年性痴呆
症あるいはアルツハイマー病等における神経退行性疾患
の治療または予防、さらに末梢神経系疾患における神経
機能回復に有用な神経成長因子(Nerve growth facto
r)(以下NGFと略記する)の産生促進剤に関する。FIELD OF THE INVENTION The present invention relates to a drug, particularly nerve growth factor (Nerve growth) useful for treating or preventing neurodegenerative diseases such as senile dementia or Alzheimer's disease, and for recovering nerve function in peripheral nervous system diseases. facto
r) (hereinafter abbreviated as NGF) production promoter.
【0002】[0002]
【従来技術、発明が解決しようとする課題】NGFは、神
経組織の成長や機能維持に必要な栄養、成長因子の一つ
であり、末梢神経系では、知覚、交感神経の、また中枢
神経系では、大細胞性コリン作動性ニューロンの成熟、
分化、生命維持に不可欠なものと考えられている。そこ
で、NGFレベルを上昇させることにより、アルツハイマ
ー病、血管性痴呆病などの中枢機能障害、脊髄損傷、末
梢神経損傷、糖尿病性神経障害および筋萎縮性側索硬化
症などの末梢機能障害の治療が行えるものと考えられて
いる。しかしながら、NGFは、その分子量が、モノマー
で1万3千、ダイマーで 2万6千の高分子量の蛋白質であ
ることから、脳血液関門を通過することは出来ない。し
たがって、NGFを投与するよりも生体中でのNGFの産生を
促進する物質を投与し、NGFの生合成を促進し、その結
果、中枢機能障害および末梢機能障害を改善することが
好ましいと考えられる。そこでNGFの産生促進物質の探
索が試みられている。NGF産生促進活性を有する薬剤と
して、エピネフリン、ノルエピネフリンおよびドーパミ
ンなどのカテコールアミン類が見出されているが、これ
らの化合物は、ホルモン物質であることから、NGFの合
成促進のために投与することは、生体内でのホルモンの
量的バランスを崩し副作用を伴う。よって、実用上、未
だ満足できる薬剤は見い出されていない。BACKGROUND OF THE INVENTION NGF is one of the nutrients and growth factors necessary for the growth and function maintenance of nerve tissue. In the peripheral nervous system, sensory, sympathetic and central nervous systems are used. Then, maturation of large cell cholinergic neurons,
It is considered essential for differentiation and life support. Therefore, by increasing the NGF level, it is possible to treat peripheral dysfunctions such as central dysfunctions such as Alzheimer's disease and vascular dementia, spinal cord injury, peripheral nerve injury, diabetic neuropathy and amyotrophic lateral sclerosis. It is considered possible. However, NGF is a monomer whose molecular weight is
Since it is a high-molecular-weight protein with a molecular weight of 13,000 and a dimer of 26,000, it cannot cross the blood-brain barrier. Therefore, it is considered preferable to administer a substance that promotes the production of NGF in a living body rather than to administer NGF, to promote NGF biosynthesis, and as a result, to improve central and peripheral dysfunction. . Therefore, search for an NGF production promoter has been attempted. As agents having NGF production promoting activity, catecholamines such as epinephrine, norepinephrine and dopamine have been found, but since these compounds are hormonal substances, they can be administered to promote NGF synthesis. The quantitative balance of hormones in the body is disturbed and side effects are accompanied. Therefore, a practically satisfactory drug has not been found yet.
【0003】[0003]
【課題を解決するための手段、作用】本発明者らは、前
記した理由により、NGFの産生を促進する薬剤について
鋭意研究を進めたところ、オキサゾピロロキノリン類お
よびそのエステルがNGFの産生を促進する効果を示すこ
とを見出だし、本発明を完成した。すなわち、本発明は
オキサゾピロロキノリン類および/またはそのエステル
を有効成分として含有させて成るNGFの産生促進剤であ
る。オキサゾピロロキノリン類(以下OPQ類と記す)
とは、別名、5位置換2,8,10−トリカルボキシ−1H−オ
キサゾ[5,4-h]−ピロロ[2,3-f]キノリンであり、O
PQ類およびそのエステルは次の一般式で示される。[Means and Actions for Solving the Problems] For the reasons described above, the present inventors have conducted extensive research into drugs that promote NGF production. As a result, oxazopyrroloquinolines and esters thereof produce NGF. The present invention has been completed by finding out that it has a promoting effect. That is, the present invention is an NGF production promoter comprising oxazopyrroloquinoline and / or its ester as an active ingredient. Oxazopyrroloquinolines (hereinafter referred to as OPQs)
Is another name, 5-substituted 2,8,10-tricarboxy-1H-oxazo [5,4-h] -pyrrolo [2,3-f] quinoline,
PQs and their esters are represented by the following general formula.
【0004】[0004]
【化2】 [Chemical 2]
【0005】本発明において使用されるOPQ類は、ピロ
ロキノリン類またはその塩(以下PQQ類と記す)と各
種のα−アミノ酸、メチルアミンなどとを酸素の存在下
で反応させることにより、容易に製造することが可能で
ある。The OPQs used in the present invention can be easily prepared by reacting pyrroloquinolines or salts thereof (hereinafter referred to as PQQs) with various α-amino acids, methylamine and the like in the presence of oxygen. It is possible to manufacture.
【0006】本発明におけるOPQ類としては、PQQ
類とグリシン、スレオニン、トリプトファン、プロリ
ン、チロシン、セリンおよびモノメチルアミンのいずれ
か1種とから得られるOPQ(特開平3-294281号)、P
QQ類とセリンから得られるヒドロキシメチルOPQ
(特開平3-123782号)、PQQ類とバリンから得られる
1-メチルエチルOPQ(特開平3-170484号)、PQQ類
とイソロイシンから得られる1−メチルプロピルOPQ
(特開平3-170485号)、PQQ類とロイシンから得られ
る2-メチルプロピルOPQ(特開平3-170486号)、PQ
Q類とアラニンから得られるメチルOPQ(特開平3-18
8081号)、PQQ類とグルタミン酸から得られる2−カ
ルボキシエチルOPQ(特開平3−190882号)、PQQ
類とグルタミンから得られる2−カルバモイルエチルO
PQ(特開平3-188082号)、PQQ類とメチオニンから
得られる2-メチルチオエチルOPQ(特開平3-190880
号)、PQQ類とフェニルアラニンから得られるベンジ
ルOPQ(特開平3-190881号)、PQQ類とチロシンか
ら得られる4−ヒドロキシフェニルメチルOPQ(特開
平4-9387号)、PQQ類とアスパラギン酸から得られる
カルボキシメチルOPQ、PQQとアスパラギンから得
られるカルバモイルメチルOPQ、PQQ類とヒスチジ
ンから得られる4−イミダゾリルメチルOPQ、PQQ
類とをリジンから得られる4−アミノブチルOPQ、P
QQ類とアルギニンから得られる3−グアニジノプロピ
ルOPQ、PQQ類とシステインから得られるメルカプ
トメチルOPQなどがある。As the OPQs in the present invention, PQQ
OPQ (Japanese Patent Application Laid-Open No. 3-294281), P obtained from any one of glycine, threonine, tryptophan, proline, tyrosine, serine and monomethylamine
Hydroxymethyl OPQ obtained from QQs and serine
(JP-A-3-123782), obtained from PQQs and valine
1-Methylethyl OPQ (JP-A-3-170484), 1-methylpropyl OPQ obtained from PQQs and isoleucine
(JP-A-3-170485), 2-methylpropyl OPQ obtained from PQQs and leucine (JP-A-3-170486), PQ
Methyl OPQ obtained from Qs and alanine (Japanese Patent Laid-Open No. 3-18
8081), 2-carboxyethyl OPQ obtained from PQQs and glutamic acid (JP-A-3-190882), PQQ
2-carbamoylethyl O obtained from compounds and glutamine
PQ (JP-A-3-18882), 2-methylthioethyl OPQ obtained from PQQs and methionine (JP-A-3-190880)
No.), benzyl OPQ obtained from PQQs and phenylalanine (JP-A-3-90881), 4-hydroxyphenylmethyl OPQ obtained from PQQs and tyrosine (JP-A-4-9387), obtained from PQQs and aspartic acid. Carboxymethyl OPQ, PQQ and carbamoylmethyl OPQ obtained from asparagine, PQQs and 4-imidazolylmethyl OPQ obtained from histidine, PQQ
4-aminobutyl OPQ, P obtained from lysine
Examples include 3-guanidinopropyl OPQ obtained from QQs and arginine, and mercaptomethyl OPQ obtained from PQQs and cysteine.
【0007】また、それぞれのOPQ類の塩には、アル
カリ金属塩、アルカリ土類金属塩、アンモニウム塩およ
び置換アンモニウム塩などがあり、これらの塩類もNGF
産生促進剤として有効である。その代表例としては、ナ
トリウム塩、カリウム塩、マグネシウム塩、カルシウム
塩、アンモニウム塩、トリメチルアンモニウム塩、トリ
エチルアンモニウム塩、トリエタノールアンモニウム塩
などがある。また、OPQ類のエステルとは、前記の一
般式において、R1、R2、R3が、同一でも異なってもよ
く、水素原子、アルキル基、アルケニル基あるいはベン
ジル基であり、モノエステル、ジエステル、あるいはト
リエステルがある。これらのOPQ類のエステルは、O
PQ類またはその塩とアルコール類とを常法により反応
させることにより容易に製造することが可能であり、ア
ルキル基としてはメチル基およびエチル基などが、ま
た、アルケニル基としてはアリル基などがある。[0007] The OPQ salts include alkali metal salts, alkaline earth metal salts, ammonium salts and substituted ammonium salts, and these salts are also NGF.
It is effective as a production promoter. Typical examples thereof include sodium salt, potassium salt, magnesium salt, calcium salt, ammonium salt, trimethylammonium salt, triethylammonium salt and triethanolammonium salt. In addition, the ester of OPQ is a hydrogen atom, an alkyl group, an alkenyl group or a benzyl group in the above general formula, in which R 1 , R 2 and R 3 may be the same or different, and a monoester or a diester. , Or triester. The esters of these OPQs are O
It can be easily produced by reacting PQs or a salt thereof with an alcohol by an ordinary method. The alkyl group includes a methyl group and an ethyl group, and the alkenyl group includes an allyl group. .
【0008】なお、PQQまたはPQQ塩とアルコール
類とを常法により反応させ、PQQ類のエステルを得、
その後に各種のアミノ酸あるいはメチルアミンと反応さ
せることにより、目的とするOPQ類のエステルを得る
ことも可能である。The PQQ or PQQ salt is reacted with an alcohol by a conventional method to obtain an ester of PQQ,
It is also possible to obtain the desired ester of OPQs by subsequently reacting with various amino acids or methylamine.
【0009】本発明のOPQ類およびそのエステル類
は、経口または非経口のいずれの投与形態も可能であ
る。経口投与の場合は、カプセル剤、錠剤および粉剤な
どの通常の剤型で投与することができる。また、非経口
投与の場合には、注射剤および輸液剤などの剤型で投与
される。さらに徐放剤も効果的である。本発明の有効成
分を製剤化するには、界面活性剤、賦形剤、着色料、保
存料およびコーティング助剤などの添加剤が適宜使用さ
れる。また、他の薬剤との併用も可能である。また、投
与量および投与回数などは、症状、年齢、体重および投
与される剤型などによって異なり、一概に特定し得ない
が、たとえば、成人1日あたりの有効成分量として、通
常は、経口投与の場合には1〜500mg程度、非経口投与の
場合には0.1〜100mg程度とされる。これらの量を、1回
乃至数回に分けて投与することができる。The OPQs and their esters of the present invention can be administered orally or parenterally. For oral administration, it can be administered in a usual dosage form such as capsules, tablets and powders. Further, in the case of parenteral administration, it is administered in dosage forms such as injections and infusions. Further, a sustained release agent is also effective. To formulate the active ingredient of the present invention, additives such as surfactants, excipients, colorants, preservatives and coating aids are used appropriately. Further, it can be used in combination with other drugs. Further, the dose and the number of administrations vary depending on the symptoms, age, body weight, dosage form to be administered, etc., and cannot be specified unconditionally. For example, the dose of an active ingredient per day for an adult is usually orally. In the case of, the dose is about 1 to 500 mg, and in the case of parenteral administration, it is about 0.1 to 100 mg. These amounts can be administered once or in several divided doses.
【0010】[0010]
【実施例】以下に、本発明剤の有効成分であるOPQ類
およびそのエステルのNGF産生促進作用を示す実施例を
示すが、本発明は、これらの実施例に限定されるもので
はない。 実施例1 マウス結合組織由来の線維芽細胞樹立株L-M細胞を0.5%
ペプトン(Difco Laboratories社製)含有199培地(Flo
w Laboratories社製)に細胞数が2×104個/穴になるよ
うに懸濁せしめ、平底96穴マイクロプレート(Nunc社
製)に入れ、CO2インキュベーター(37℃、5%CO2−95
%空気の雰囲気下)で3日間培養した。前記の培養液を
所定の各濃度のOPQおよび0.5%牛血清アルブミン(A
mour Pharmaceutical社製)を含有する199培地、また
は、OPQ無添加の前記培地と交換し、CO2インキュベ
ーター中で培養した。培養24時間後に、培養上澄液中に
含まれるNGF量を酵素免疫測定法(KorschingとThoene
n、Proc. Natl. Acad. Sci., U.S.A., 80. 3513-3516,
1983.)で測定した。結果を表1に示す。[Examples] The following shows Examples showing the NGF production promoting action of OPQs and their esters, which are the active ingredients of the agent of the present invention, but the present invention is not limited to these Examples. Example 1 0.5% of fibroblast established LM cells derived from mouse connective tissue
Peptone (Difco Laboratories) -containing 199 medium (Flo
w Laboratories) so that the number of cells is 2 × 10 4 cells / well, put them in a flat bottom 96-well microplate (Nunc), and put them in a CO 2 incubator (37 ° C, 5% CO 2 -95).
% Under air) for 3 days. Each of the above cultures was treated with OPQ and 0.5% bovine serum albumin (A
Mour Pharmaceutical Co., Ltd.) was replaced with 199 medium or the above-mentioned medium without OPQ added, and the cells were cultured in a CO 2 incubator. After 24 hours of culture, the amount of NGF contained in the culture supernatant was measured by enzyme immunoassay (Korsching and Thoene
n, Proc. Natl. Acad. Sci., USA, 80 .3513-3516,
1983.). The results are shown in Table 1.
【0011】[0011]
【表1】 [Table 1]
【0012】NGFの測定法 ポリスチレン製の96穴マイクロプレート(住友ベークラ
イト社製 MS-3496F)に抗マウスβNGF抗体(マウス顎下
腺から調製されたβNGFを抗原にして作製されたもの)
溶液(pH8.3)を各孔に50μlずつ分注し、37℃で4時間
放置した。マイクロプレートに吸着されなかった抗体を
除去後、洗浄液で各孔を3回洗浄した。標準βNGF(東洋
紡社製)溶液あるいは、試料溶液40μlを各孔に分注
し、4℃で18時間放置した後、標準βNGFあるいは試料溶
液(上記培養上澄液)を除去し、各孔を3回洗浄した。
β−ガラクトシダーゼ標識抗βNGFモノクローナル抗体
(Boehringer Mammheim社製)溶液(40mU/ml、pH7.6)
を各孔に50μlずつ分注し、37℃で4時間放置した後、酵
素標識抗体を除去し、3回洗浄した。4-メチルウンベリ
フェリル-β-D-ガラクトシド(Sigma社製)溶液(20μg
/ml、pH7.6)を各孔に100μlずつ分注し、室温で1.5時
間反応させた後、0.2Mグリシン−水酸化ナトリウム緩衝
液(pH10.3)を各孔に100μlづつ分注して酵素反応を停
止し、生成された4−メチルウンベリフェロンの蛍光強
度をプレートリーダーで測定し、標準曲線よりNGF量を
算出し、結果を表1に示した。なお、被験化合物のNGF
産生促進活性は、被験化合物を添加しなかった無処理細
胞が産生したNGF量に対する被験化合物処理細胞が産生
したNGF量の相対値(%)で表わした。 NGF assay method Anti-mouse βNGF antibody (prepared using βNGF prepared from mouse submandibular gland as an antigen) on a polystyrene 96-well microplate (MS-3496F manufactured by Sumitomo Bakelite Co., Ltd.)
50 μl of the solution (pH 8.3) was dispensed into each hole and left at 37 ° C. for 4 hours. After removing the antibody not adsorbed on the microplate, each hole was washed 3 times with a washing solution. Standard βNGF (manufactured by Toyobo Co., Ltd.) solution or 40 μl of sample solution was dispensed into each hole, left at 4 ° C for 18 hours, then the standard βNGF or sample solution (culture supernatant above) was removed, and each hole was replaced with 3 Washed twice.
β-galactosidase-labeled anti-β NGF monoclonal antibody (Boehringer Mammheim) solution (40 mU / ml, pH 7.6)
50 μl was dispensed into each well and left at 37 ° C. for 4 hours, then the enzyme-labeled antibody was removed and the plate was washed 3 times. 4-Methylumbelliferyl-β-D-galactoside (Sigma) solution (20 μg
/ ml, pH 7.6) in 100 μl aliquots into each well and reacting at room temperature for 1.5 hours, then 0.2 M glycine-sodium hydroxide buffer (pH 10.3) in 100 μl aliquots into each well The enzymatic reaction was stopped, the fluorescence intensity of the produced 4-methylumbelliferone was measured with a plate reader, and the NGF amount was calculated from the standard curve. The results are shown in Table 1. The test compound NGF
The production promoting activity was represented by the relative value (%) of the NGF amount produced by the test compound-treated cells to the NGF amount produced by the untreated cells to which the test compound was not added.
【0013】実施例2 被験化合物としてヒドロキシメチルOPQを用いた以外
は実施例1と同様にして、ヒドロキシメチルOPQのNG
F産生促進活性を調べた。結果を表2に示す。Example 2 Hydroxymethyl OPQ NG was prepared in the same manner as in Example 1 except that hydroxymethyl OPQ was used as the test compound.
The F production promoting activity was examined. The results are shown in Table 2.
【0014】[0014]
【表2】 [Table 2]
【0015】実施例3 被験化合物としてメチルOPQを用いた以外は実施例1
と同様にして、メチルOPQのNGF産生促進活性を調べ
た。結果を表3に示す。Example 3 Example 1 except that methyl OPQ was used as the test compound.
Similarly, the NGF production promoting activity of methyl OPQ was examined. The results are shown in Table 3.
【0016】[0016]
【表3】 [Table 3]
【0017】実施例4 被験化合物として2-カルボキシエチルOPQを用いた以
外は実施例1と同様にして、2-カルボキシエチルOPQ
のNGF産生促進活性を調べた。結果を表4に示す。Example 4 2-carboxyethyl OPQ was prepared in the same manner as in Example 1 except that 2-carboxyethyl OPQ was used as the test compound.
Was investigated for its NGF production promoting activity. The results are shown in Table 4.
【0018】[0018]
【表4】 [Table 4]
【0019】実施例5 被験化合物としてベンジルOPQを用いた以外は実施例
1と同様にして、ベンジルOPQのNGF産生促進活性を
調べた。結果を表5に示す。Example 5 The NGF production promoting activity of benzyl OPQ was examined in the same manner as in Example 1 except that benzyl OPQ was used as the test compound. The results are shown in Table 5.
【0020】[0020]
【表5】 [Table 5]
【0021】実施例6 被験化合物として1−メチルプロピルOPQを用いた以
外は、実施例1と同様にして1−メチルプロピルOPQ
のNGF産生促進活性を調べた。結果を表6に示す。Example 6 1-Methylpropyl OPQ was prepared in the same manner as in Example 1 except that 1-methylpropyl OPQ was used as the test compound.
Was investigated for its NGF production promoting activity. The results are shown in Table 6.
【0022】[0022]
【表6】 [Table 6]
【0023】実施例7 被験化合物として2−メチルプロピルOPQを用いた以
外は実施例1と同様にして、2−メチルプロピルOPQ
のNGF産生促進活性を調べた。結果を表7に示す。Example 7 2-Methylpropyl OPQ was prepared in the same manner as in Example 1 except that 2-methylpropyl OPQ was used as the test compound.
Was investigated for its NGF production promoting activity. The results are shown in Table 7.
【0024】[0024]
【表7】 [Table 7]
【0025】実施例8 被験化合物として2−メチルチオエチルOPQを用いた
以外は実施例1と同様にして、2−メチルチオエチルO
PQのNGF産生促進活性を調べた。結果を表8に示す。Example 8 2-Methylthioethyl O was prepared in the same manner as in Example 1 except that 2-methylthioethyl OPQ was used as the test compound.
The NGF production promoting activity of PQ was examined. The results are shown in Table 8.
【0026】[0026]
【表8】 [Table 8]
【0027】実施例9 被験化合物として2−カルバモイルエチルOPQを用い
た以外は実施例1と同様にして、2−カルバモイルエチ
ルOPQのNGF産生促進活性を調べた。結果を表9に示
す。Example 9 The NGF production promoting activity of 2-carbamoylethyl OPQ was examined in the same manner as in Example 1 except that 2-carbamoylethyl OPQ was used as the test compound. The results are shown in Table 9.
【0028】[0028]
【表9】 [Table 9]
【0029】実施例10 被験化合物として1−メチルエチルOPQを用いた以外
は実施例1と同様にして、1−メチルエチルOPQのNGF
産生促進活性を調べた。結果を表10に示す。Example 10 1-Methylethyl OPQ NGF was prepared in the same manner as in Example 1 except that 1-methylethyl OPQ was used as the test compound.
The production promoting activity was examined. The results are shown in Table 10.
【0030】[0030]
【表10】 [Table 10]
【0031】実施例11 被験化合物として4−ヒドロキシフェニルメチルOPQ
を用いた以外は実施例1と同様にして、4−ヒドロキシ
フェニルメチルOPQのNGF産生促進活性を調べた。結
果を表11に示す。Example 11 4-hydroxyphenylmethyl OPQ as a test compound
The NGF production promoting activity of 4-hydroxyphenylmethyl OPQ was examined in the same manner as in Example 1 except that was used. The results are shown in Table 11.
【0032】[0032]
【表11】 [Table 11]
【0033】実施例12 被験化合物としてOPQの2位がメチル基のメチルエス
テル(OPQ-2-ME)を用いた以外は実施例1と同様にし
て、OPQ-2-MEのNGF産生促進活性を調べた。結果を表1
2に示す。Example 12 The NGF production promoting activity of OPQ-2-ME was measured in the same manner as in Example 1 except that a methyl ester having a methyl group at the 2-position of OPQ (OPQ-2-ME) was used as a test compound. Examined. The results are shown in Table 1.
2 shows.
【0034】[0034]
【表12】 [Table 12]
【0035】実施例13 被験化合物としてOPQの7位がメチル基のメチルエス
テル(OPQ-7-ME)を用いた以外は実施例1と同様にし
て、OPQ-7-MEのNGF産生促進活性を調べた。結果を表1
3に示す。Example 13 The NGF production promoting activity of OPQ-7-ME was measured in the same manner as in Example 1 except that a methyl ester having a methyl group at the 7-position of OPQ (OPQ-7-ME) was used as a test compound. Examined. The results are shown in Table 1.
3 shows.
【0036】[0036]
【表13】 [Table 13]
【0037】実施例14 被験化合物としてOPQの2位および7位がそれぞれメ
チル基のジメチルエステル(OPQ-2,7-DME)を用いた以
外は実施例1と同様にして、OPQ-2,7-DMEのNGF産生促進
活性を調べた。結果を表14に示す。Example 14 OPQ-2,7 was prepared in the same manner as in Example 1 except that dimethyl ester (OPQ-2,7-DME) in which the 2-position and the 7-position of OPQ were methyl groups was used as a test compound. -The NGF production promoting activity of DME was examined. The results are shown in Table 14.
【0038】[0038]
【表14】 [Table 14]
【0039】実施例15 被験化合物としてOPQの2位および9位がそれぞれメ
チル基のジメチルエステル(OPQ-2,9-DME)を用いた以
外は実施例1と同様にして、OPQ-2,9-DMEのNGF産生促進
活性を調べた。結果を表15に示す。Example 15 OPQ-2,9 was prepared in the same manner as in Example 1 except that dimethyl ester (OPQ-2,9-DME) having a methyl group at each of the 2nd and 9th positions of OPQ was used as a test compound. -The NGF production promoting activity of DME was examined. The results are shown in Table 15.
【0040】[0040]
【表15】 [Table 15]
【0041】実施例16 被験化合物としてOPQのトリメチルエステル(OPQ-TM
E)を用いた以外は実施例1と同様にして、OPQ-TMEのNG
F産生促進活性を調べた。結果を表16に示す。Example 16 Trimethyl ester of OPQ (OPQ-TM) was used as a test compound.
NG of OPQ-TME in the same manner as in Example 1 except that E) was used.
The F production promoting activity was examined. The results are shown in Table 16.
【0042】[0042]
【表16】 [Table 16]
【0043】実施例17 被験化合物としてOPQの2位がメチル基であり、か
つ、7位および9位がそれぞれエチル基であるトリアル
キルエステル(OPQ-2-M-7,9-DEE)を使用した以外は実
施例1と同様にして、OPQ-2-M-7,9-DEE)のNGF産生促進
活性を調べた。結果を表17に示す。Example 17 As a test compound, a trialkyl ester (OPQ-2-M-7,9-DEE) in which the 2-position of OPQ is a methyl group and the 7- and 9-positions are ethyl groups is used. The NGF production promoting activity of OPQ-2-M-7,9-DEE) was examined in the same manner as in Example 1 except for the above. The results are shown in Table 17.
【0044】[0044]
【表17】 [Table 17]
【0045】実施例18 NGFの産生促進剤として知られているエピネフリンを被
験化合物として使用した以外は、実施例1と同様にし、
エピネフリンのNGF産生促進活性を調べた。結果を表1
8に示す。Example 18 Example 18 was repeated except that epinephrine known as an NGF production promoter was used as a test compound,
The NGF production promoting activity of epinephrine was examined. The results are shown in Table 1.
8 shows.
【0046】[0046]
【表18】 [Table 18]
【0047】エピネフリン12.5μg/ml以上の添加でNGF
の産生促進効果が認められ、100μg/mlの添加で最大の
活性値(約500%)が得られた。一方、実施例1〜17
に示すようにOPQ類はエピネフリンに比べて低濃度で
高いNGF産生促進活性を示した。Addition of 12.5 μg / ml or more of epinephrine to NGF
The production promoting effect was observed, and the maximum activity value (about 500%) was obtained by adding 100 μg / ml. On the other hand, Examples 1 to 17
As shown in (3), OPQs showed high NGF production promoting activity at a lower concentration than epinephrine.
【0048】実施例19 SD雌性ラット(7週齢、160〜190g)を塩酸ケタミン25m
gおよびドロペリドロール0.25mgの筋肉内投与で麻酔
し、左大腿部の坐骨神経を露出させて切断し、断端の間
に約2mmの隙間を開けてシリコンチューブ(内径1mm、長
さ6mm)で繋ぎ合わせた。この断端の隙間に生理食塩水
を満たし、手術創を整復後、所定の各濃度のOPQを含
む2%アラビアゴム水溶液0.5mlを腹腔内投与した。な
お、対照としてOPQの代りに2%アラビアゴム水溶液0.
5mlを腹腔内投与した。、陽性対照として、薬剤を腹腔
内に投与することなく、坐骨神経の断端の隙間にNGFを1
mg/ml含む生理食塩水を満たした。手術4週間後に頸椎
脱臼により動物を殺し、再生した坐骨神経を採取し、こ
の再生坐骨神経の横断面の切片をつくり、ヘマトキシリ
ン−エオジン染色し、再生神経繊維の本数を数えた。結
果を表19に示す。OPQを投入することにより、再生
坐骨神経の数は大幅に増加せしめられ、NGFの直接注入
に匹敵した。Example 19 SD female rats (7 weeks old, 160 to 190 g) were treated with 25 m of ketamine hydrochloride.
anesthesia with 0.25 mg and droperidolol intramuscularly, expose and cut the sciatic nerve in the left thigh, and leave a gap of about 2 mm between the stumps and a silicon tube (1 mm inner diameter, 6 mm length) ) Together. After filling the space between the stumps with physiological saline and reducing the surgical wound, 0.5 ml of a 2% aqueous solution of gum arabic containing OPQ at each predetermined concentration was intraperitoneally administered. As a control, a 2% aqueous solution of gum arabic was used instead of OPQ.
5 ml was administered intraperitoneally. , As a positive control, 1 NGF was injected into the stump of the sciatic nerve without intraperitoneal administration of the drug.
A physiological saline solution containing mg / ml was filled. Four weeks after the operation, the animals were killed by cervical dislocation, the regenerated sciatic nerve was collected, a cross section of the regenerated sciatic nerve was cut, stained with hematoxylin-eosin, and the number of regenerated nerve fibers was counted. The results are shown in Table 19. By injecting OPQ, the number of regenerated sciatic nerves was significantly increased, which was comparable to direct injection of NGF.
【0049】[0049]
【表19】 [Table 19]
【0050】実施例20 被験化合物としてOPQトリメチルエステル(OPQ-TM
E)を用いた以外は実施例19と同様にして、OPQ-TMEの
坐骨神経の再生促進活性を調べた。結果を表20に示
す。OPQ-TMEを投入することにより、再生坐骨神経の数
は大幅に増加せしめられ、NGFの直接注入に匹敵した。Example 20 OPQ trimethyl ester (OPQ-TM) was used as a test compound.
The sciatic nerve regeneration promoting activity of OPQ-TME was examined in the same manner as in Example 19 except that E) was used. The results are shown in Table 20. By injecting OPQ-TME, the number of regenerated sciatic nerves was significantly increased, which was comparable to the direct injection of NGF.
【0051】[0051]
【表20】 [Table 20]
【0052】実施例21 Wistar雄性ラット(8〜10週齢、200〜250g)に所定の各
濃度のOPQトリメチルエステル(OPQ-TME)を0.5mlの
2%アラビアゴム水溶液に懸濁せしめ、これを腹腔内投与
した。1日おきに1日当り1回、計4回腹腔内投与し、
最終投与後2日目にラットをエーテル麻酔下で解剖し、
大脳皮質および顎下腺をそれぞれ採取して、氷冷下で次
の操作を行った。すなわち、大脳皮質および顎下腺をそ
れぞれ秤量し、20倍量のリン酸緩衝液(NaCl 8g/l、K
Cl 0.2g/l、Na2HPO4 1.15g/l、KH2PO4 0.2g/l)を加
え、超音波破砕機(BRANSON社、CELL DISRUPTOR 185)
でホモジナイズし、10,000×Gで30分間、遠心分離し、
上清液を得た。この上清液のNGF含有量を酵素免疫法で
測定した。結果を、大脳皮質および顎下腺のそれぞれの
湿重量 1mg当りのNGF量(ng)として、同時に実験した
3頭の動物の平均値±標準誤差の値で示す。また、OPQ-
TME無投与の場合に対する相対活性も示す。結果を表2
1に示す。この結果によれば、OPQ-TME投与により大脳
皮質および顎下腺のそれぞれのNGF含有量は増加せしめ
られた。特に、大脳皮質では、大幅に増加せしめられ
た。Example 21 Male Wistar rats (8-10 weeks old, 200-250 g) were supplemented with 0.5 ml of OPQ trimethyl ester (OPQ-TME) at predetermined concentrations.
It was suspended in a 2% aqueous solution of gum arabic and administered intraperitoneally. Administered intraperitoneally once every other day for a total of 4 times,
Two days after the final administration, the rat was dissected under ether anesthesia,
The cerebral cortex and the submandibular gland were collected, and the following operations were performed under ice cooling. That is, the cerebral cortex and the submandibular gland were each weighed, and 20 times the amount of phosphate buffer solution (NaCl 8 g / l, K
Cl 0.2g / l, Na 2 HPO 4 1.15g / l, KH 2 PO 4 0.2g / l) and ultrasonic crusher (BRANSON, CELL DISRUPTOR 185)
Homogenize with, centrifuge at 10,000 x G for 30 minutes,
A supernatant was obtained. The NGF content of this supernatant was measured by the enzyme immunoassay. The results are shown as the amount of NGF per 1 mg of wet weight of the cerebral cortex and submandibular gland (ng), which is the average value ± standard error of three animals simultaneously tested. Also, OPQ-
The relative activity relative to the case without TME administration is also shown. The results are shown in Table 2.
Shown in 1. According to this result, the NGF contents in the cerebral cortex and submandibular gland were increased by OPQ-TME administration. Especially in the cerebral cortex, it was significantly increased.
【0053】[0053]
【表21】 [Table 21]
【0054】[0054]
【発明の効果】OPQ類およびそのエステルが強いNGF
産生促進活性を示すことから、本発明の神経成長因子産
生促進剤は、中枢機能障害、特に、アルツハイマー痴呆
症や脳虚血病態などに対する予防及び治療薬など、ま
た、末梢機能障害、特に、脊髄損傷、末梢神経損傷、糖
尿病性神経症および筋萎縮性側索硬化症などに対する予
防及び治療薬などとして好適に利用される。EFFECT OF THE INVENTION NGF with strong OPQs and their esters
Since it shows a production promoting activity, the nerve growth factor production promoting agent of the present invention is a central dysfunction, in particular, a preventive and therapeutic drug for Alzheimer's dementia, cerebral ischemic pathology, etc., and peripheral dysfunction, in particular, spinal cord. It is preferably used as a prophylactic and therapeutic drug for injury, peripheral nerve injury, diabetic neuropathy, amyotrophic lateral sclerosis and the like.
【手続補正書】[Procedure amendment]
【提出日】平成5年2月4日[Submission date] February 4, 1993
【手続補正1】[Procedure Amendment 1]
【補正対象書類名】明細書[Document name to be amended] Statement
【補正対象項目名】0002[Name of item to be corrected] 0002
【補正方法】変更[Correction method] Change
【補正内容】[Correction content]
【0002】[0002]
【従来技術、発明が解決しようとする課題】NGFは、
神経組織の成長や機能維持に必要な栄養、成長因子の一
つであり、末梢神経系では、知覚、交感神経の、また中
枢神経系では、大細胞性コリン作動性ニューロンの成
熟、分化、生命維持に不可欠なものと考えられている。
そこで、NGFレベルを上昇させることにより、アルツ
ハイマー病、血管性痴呆病および脊髄損傷などの中枢機
能障害ならびに末梢神経損傷および糖尿病性神経損傷な
どの末梢機能障害の治療が行えるものと考えられてい
る。しかしながら、NGFは、その分子量が、モノマー
で1万3千、ダイマーで2万6千の高分子量の蛋白質で
あることから、血液脳関門を通過することは出来ない。
したがって、NGFを投与するよりも生体中でのNGF
の産生を促進する物質を投与し、NGFの生合成を促進
し、その結果、中枢機能障害および末梢機能障害を改善
することが好ましいと考えられる。そこでNGFの産生
促進物質の探索が試みられている。NGF産生促進活性
を有する薬剤として、エピネフリン、ノルエピネフリン
およびドーパミンなどのカテコールアミン類が見出され
ているが、これらの化合物は、ホルモンであることか
ら、NGFの合成促進のために投与することは、生体内
でのホルモンの量的バランスを崩し副作用を伴う。よっ
て、実用上、未だ満足できる薬剤は見出されていない。2. Description of the Related Art NGF
It is one of the nutrients and growth factors necessary for the growth and function maintenance of nervous tissue. In the peripheral nervous system, sensory and sympathetic nerves, and in the central nervous system, maturation, differentiation and life of large cell cholinergic neurons. It is considered essential for maintenance.
Therefore, by increasing the NGF level, to that Alzheimer's disease, can be performed treatment of central dysfunction and peripheral nerve injury and diabetic neuropathy loss wounds such <br/> any peripheral dysfunctions such as vascular dementia disease and spinal cord injury It is considered. However, NGF is its molecular weight, monomer over
Since it is a high-molecular-weight protein with a molecular weight of 13,000 and a dimer of 26,000, it cannot cross the blood-brain barrier.
Therefore, in vivo NGF rather than administration of NGF
It is considered preferable to administer a substance that promotes the production of NGF, promote NGF biosynthesis, and consequently improve central and peripheral dysfunction. Therefore, an attempt has been made to search for an NGF production promoting substance. As drugs having NGF production accelerating activity, epinephrine, although catecholamines such as norepinephrine and dopamine have been found, these compounds, since it is hormone, be administered for promoting synthesis of NGF is The quantitative balance of hormones in the body is disturbed and side effects are accompanied. Thus, practically, not yet satisfactory drug Heading.
【手続補正2】[Procedure Amendment 2]
【補正対象書類名】明細書[Document name to be amended] Statement
【補正対象項目名】0006[Correction target item name] 0006
【補正方法】変更[Correction method] Change
【補正内容】[Correction content]
【0006】本発明におけるOPQ類としては、PQQ
類とグリシン、スレオニン、トリプトファン、プロリ
ン、チロシン、セリンおよびモノメチルアミンのいずれ
か1種とから得られるOPQ(特開平3−294281
号)、PQQ類とセリンから得られるヒドロキシメチル
OPQ(特開平3−123782号)、PQQ類とバリ
ンから得られる1−メチルエチルOPQ(特開平3−1
70484号)、PQQ類とイソロイシンから得られる
1−メチルプロピルOPQ(特開平3−170485
号)、PQQ類とロイシンから得られる2−メチルプロ
ピルOPQ(特開平3−170486号)、PQQ類と
アラニンから得られるメチルOPQ(特開平3−188
081号)、PQQ類とグルタミン酸から得られる2−
カルボキシエチルOPQ(特開平3−190882
号)、PQQ類とグルタミンから得られる2−カルバモ
イルエチルOPQ(特開平3−188082号)、PQ
Q類とメチオニンから得られる2−メチルチオエチルO
PQ(特開平3−190880号)、PQQ類とフェニ
ルアラニンから得られるベンジルOPQ(特開平3−1
90881号)、PQQ類とチロシンから得られる4−
ヒドロキシフェニルメチルOPQ(特開平4−9387
号)、PQQ類とアスパラギン酸から得られるカルボキ
シメチルOPQ、PQQ類とアスパラギンから得られる
カルバモイルメチルOPQ、PQQ類とヒスチジンから
得られる4−イミダゾリルメチルOPQ、PQQ類とリ
ジンから得られる4−アミノブチルOPQ、PQQ類と
アルギニンから得られる3−グアニジノプロピルOP
Q、PQQ類とシステインから得られるメルカプトメチ
ルOPQなどがある。As the OPQs in the present invention, PQQ
OPQ obtained from any one of glycine, threonine, tryptophan, proline, tyrosine, serine and monomethylamine (JP-A-3-294281).
No.), hydroxymethyl OPQ obtained from PQQs and serine (JP-A-3-123782), 1-methylethyl OPQ obtained from PQQs and valine (JP-A 3-1).
70484), 1-methylpropyl OPQ obtained from PQQs and isoleucine (JP-A-3-170485).
No.), 2-methylpropyl OPQ obtained from PQQs and leucine (JP-A-3-170486), methyl OPQ obtained from PQQs and alanine (JP-A-3-188).
No. 081), obtained from PQQs and glutamic acid 2-
Carboxyethyl OPQ (JP-A-3-190882)
No.), 2-carbamoylethyl OPQ obtained from PQQs and glutamine (JP-A-3-188082), PQ
2-Methylthioethyl O obtained from Qs and methionine
PQ (JP-A-3-190880), benzyl OPQ obtained from PQQs and phenylalanine (JP-A-3-1)
90881), 4-derived from PQQs and tyrosine
Hydroxyphenylmethyl OPQ (JP-A-4-93387)
No.), carboxymethyl OPQ obtained from PQQ acids and aspartic acid, obtained carbamoylmethyl OPQ obtained from PQQ compound and asparagine, obtained from PQQ acids histidine 4-imidazolylmethyl OPQ, from PQQ compound and Li <br/> Jin 4-Aminobutyl OPQ, PQQs and 3-guanidinopropyl OP obtained from arginine
There are mercaptomethyl OPQ obtained from Q, PQQs and cysteine.
【手続補正3】[Procedure 3]
【補正対象書類名】明細書[Document name to be amended] Statement
【補正対象項目名】0047[Correction target item name] 0047
【補正方法】変更[Correction method] Change
【補正内容】[Correction content]
【0047】エピネフリン12.5μg/ml以上の添
加でNGFの産生促進効果が認められ、100μg/m
lの添加で最大の活性値(約500%)が得られた。一
方、実施例1〜17に示すようにOPQ類はエピネフリ
ンと同程度のNGF産生促進活性を示した。Addition of 12.5 μg / ml or more of epinephrine was observed to have an NGF production promoting effect.
The maximum activity value (about 500%) was obtained with the addition of 1. On the other hand, as shown in Examples 1 to 17, OPQs exhibited the same level of NGF production promoting activity as epinephrine.
【手続補正4】[Procedure amendment 4]
【補正対象書類名】明細書[Document name to be amended] Statement
【補正対象項目名】0048[Correction target item name] 0048
【補正方法】変更[Correction method] Change
【補正内容】[Correction content]
【0048】実施例19 SD雌性ラット(7週齢、160〜190g)を塩酸ケ
タミン25mgおよびドロペリドロール0.25mgの
筋肉内投与で麻酔し、左大腿部の坐骨神経を露出させて
切断し、断端の間に約2mmの隙間を開けてシリコンチ
ューブ(内径1mm、長さ6mm)で繋ぎ合わせた。こ
の断端の隙間に生理食塩水を満たし、手術創を整復後、
所定の各濃度のOPQを含む2%アラビアゴム水溶液
0.5mlを腹腔内投与した。なお、対照としてOPQ
を含まない2%アラビアゴム水溶液0.5mlを腹腔内
投与した。陽性対照として、OPQを含まない2%アラ
ビアゴム水溶液0.5mlを腹腔内投与し、かつ、坐骨
神経の断端の隙間にNGFを1mg/ml含む生理食塩
水を満たした。手術4週間後に頸椎脱臼により動物を殺
し、再生した坐骨神経を採取し、この再生坐骨神経の横
断面の切片をつくり、ヘマトキシリン−エオジン染色
し、再生神経繊維の本数を数えた。結果を表19に示
す。OPQを投与することにより、再生坐骨神経の数は
大幅に増加せしめられ、NGFの直接注入に匹敵した。Example 19 SD female rats (7 weeks old, 160 to 190 g) were anesthetized by intramuscular administration of 25 mg of ketamine hydrochloride and 0.25 mg of droperidolol, and the sciatic nerve of the left thigh was exposed and cut. Then, a gap of about 2 mm was opened between the stumps, and they were connected by a silicon tube (inner diameter 1 mm, length 6 mm). After filling the gap of this stump with physiological saline and reducing the surgical wound,
0.5 ml of a 2% aqueous solution of gum arabic containing OPQ of each predetermined concentration was intraperitoneally administered. As a control, OPQ
0.5 ml of a 2% aqueous solution of gum arabic which did not contain the drug was intraperitoneally administered. 2% ara without OPQ as a positive control
An aqueous solution of beer gum (0.5 ml) was intraperitoneally administered, and the interstitial space of the sciatic nerve was filled with a physiological saline solution containing 1 mg / ml of NGF. Four weeks after the operation, the animals were killed by cervical dislocation, the regenerated sciatic nerve was collected, a cross section of the regenerated sciatic nerve was cut, stained with hematoxylin-eosin, and the number of regenerated nerve fibers was counted. The results are shown in Table 19. By given throw the OPQ, number of reproduction sciatic nerve is allowed increased significantly, were comparable to direct injection of NGF.
【手続補正5】[Procedure Amendment 5]
【補正対象書類名】明細書[Document name to be amended] Statement
【補正対象項目名】0050[Correction target item name] 0050
【補正方法】変更[Correction method] Change
【補正内容】[Correction content]
【0050】実施例20 被験化合物としてOPQトリメチルエステル(OPQ−
TME)を用いた以外は実施例19と同様にして、OP
Q−TMEの坐骨神経の再生促進活性を調べた。結果を
表20に示す。OPQ−TMEを投与することにより、
再生坐骨神経の数は大幅に増加せしめられ、NGFの直
接注入に匹敵した。Example 20 As a test compound, OPQ trimethyl ester (OPQ-
OP was performed in the same manner as in Example 19 except that TME) was used.
The sciatic nerve regeneration promoting activity of Q-TME was examined. The results are shown in Table 20. By given throw the OPQ-TME,
The number of regenerated sciatic nerves was greatly increased, comparable to direct NGF injection.
【手続補正6】[Procedure correction 6]
【補正対象書類名】明細書[Document name to be amended] Statement
【補正対象項目名】0054[Correction target item name] 0054
【補正方法】変更[Correction method] Change
【補正内容】[Correction content]
【0054】[0054]
【発明の効果】OPQ類およびそのエステルが強いNG
F産生促進活性を示すことから、本発明の神経成長因子
産生促進剤は、中枢機能障害、特に、アルツハイマー痴
呆症や脳虚血病態および脊髄損傷などに対する予防およ
び治療薬など、また、末梢機能障害、特に、末梢神経損
傷および糖尿病性神経症などに対する予防および治療薬
などとして好適に利用される。EFFECTS OF THE INVENTION NG with strong OPQs and their esters
Since it exhibits F production promoting activity, the nerve growth factor production promoting agent of the present invention is a preventive and therapeutic drug for central dysfunction, particularly Alzheimer's dementia, cerebral ischemic pathology, spinal cord injury and the like. in addition, peripheral dysfunction, in particular, is suitably utilized as end shoot nerve damage and diabetic neuropathy disease, etc. prophylactic and therapeutic agent against.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.5 識別記号 庁内整理番号 FI 技術表示箇所 C07D 209:00 221:00 263:00) (72)発明者 浦上 貞治 東京都千代田区丸の内2丁目5番2号 三 菱瓦斯化学株式会社内─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. 5 Identification number Office reference number FI technical display location C07D 209: 00 221: 00 263: 00) (72) Inventor Sadaharu Urakami 2 Marunouchi, Chiyoda-ku, Tokyo No. 5-2 Sanryo Gas Chemical Co., Ltd.
Claims (1)
キノリン類および/またはそのエステルを有効成分とし
て含有させて成る神経成長因子産生促進剤。 【化1】 1. A nerve growth factor production promoter comprising an oxazopyrroloquinoline represented by the following general formula and / or its ester as an active ingredient. [Chemical 1]
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP34993992A JPH069396A (en) | 1992-02-20 | 1992-12-03 | Nerve growth factor producing promotor |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP4-69382 | 1992-02-20 | ||
JP6938292 | 1992-02-20 | ||
JP34993992A JPH069396A (en) | 1992-02-20 | 1992-12-03 | Nerve growth factor producing promotor |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH069396A true JPH069396A (en) | 1994-01-18 |
Family
ID=26410584
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP34993992A Pending JPH069396A (en) | 1992-02-20 | 1992-12-03 | Nerve growth factor producing promotor |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH069396A (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2007269769A (en) * | 2006-03-10 | 2007-10-18 | Ultizyme International Ltd | Inhibitor of protein-agglomerated fibrosis associated with neurodegenerative disease |
-
1992
- 1992-12-03 JP JP34993992A patent/JPH069396A/en active Pending
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2007269769A (en) * | 2006-03-10 | 2007-10-18 | Ultizyme International Ltd | Inhibitor of protein-agglomerated fibrosis associated with neurodegenerative disease |
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