JPH08175992A - Agent for promoting production of nerve growth factor and condensed ring type oxazole compound - Google Patents
Agent for promoting production of nerve growth factor and condensed ring type oxazole compoundInfo
- Publication number
- JPH08175992A JPH08175992A JP6318174A JP31817494A JPH08175992A JP H08175992 A JPH08175992 A JP H08175992A JP 6318174 A JP6318174 A JP 6318174A JP 31817494 A JP31817494 A JP 31817494A JP H08175992 A JPH08175992 A JP H08175992A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- formula
- group
- alkyl
- condensed ring
- 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
Links
- -1 oxazole compound Chemical class 0.000 title claims abstract description 18
- 230000001737 promoting effect Effects 0.000 title abstract description 8
- 239000003795 chemical substances by application Substances 0.000 title abstract description 7
- 108010025020 Nerve Growth Factor Proteins 0.000 title description 23
- 102000015336 Nerve Growth Factor Human genes 0.000 title description 23
- 238000004519 manufacturing process Methods 0.000 title description 6
- 229940053128 nerve growth factor Drugs 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 14
- 230000014537 nerve growth factor production Effects 0.000 claims abstract description 9
- 239000004480 active ingredient Substances 0.000 claims abstract description 4
- 125000003118 aryl group Chemical group 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims abstract 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 abstract description 7
- 239000002904 solvent Substances 0.000 abstract description 7
- 210000005036 nerve Anatomy 0.000 abstract description 3
- 150000001413 amino acids Chemical class 0.000 abstract description 2
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 abstract description 2
- 150000003242 quaternary ammonium salts Chemical class 0.000 abstract description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 abstract 3
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 abstract 2
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- 229910052736 halogen Inorganic materials 0.000 abstract 1
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- 210000000578 peripheral nerve Anatomy 0.000 abstract 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- 238000002560 therapeutic procedure Methods 0.000 abstract 1
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- NLLBVZMLRWGOLQ-UHFFFAOYSA-N 9-ethylcarbazole-3,4-dione Chemical compound C12=CC=CC=C2N(CC)C2=C1C(=O)C(=O)C=C2 NLLBVZMLRWGOLQ-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
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- 150000002916 oxazoles Chemical class 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- 150000005206 1,2-dihydroxybenzenes Chemical class 0.000 description 1
- OQZGYMRYZAKXAF-UHFFFAOYSA-N 2-(4-methylcyclohexyl)acetic acid Chemical compound CC1CCC(CC(O)=O)CC1 OQZGYMRYZAKXAF-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- OXEUETBFKVCRNP-UHFFFAOYSA-N 9-ethyl-3-carbazolamine Chemical compound NC1=CC=C2N(CC)C3=CC=CC=C3C2=C1 OXEUETBFKVCRNP-UHFFFAOYSA-N 0.000 description 1
- 229920001342 Bakelite® Polymers 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
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- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
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- 239000000872 buffer Substances 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
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- JAUGGEIKQIHSMF-UHFFFAOYSA-N dialuminum;dimagnesium;dioxido(oxo)silane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[Mg+2].[Mg+2].[Al+3].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O.[O-][Si]([O-])=O JAUGGEIKQIHSMF-UHFFFAOYSA-N 0.000 description 1
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- 230000001225 therapeutic effect Effects 0.000 description 1
- HNJXPTMEWIVQQM-UHFFFAOYSA-M triethyl(hexadecyl)azanium;bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](CC)(CC)CC HNJXPTMEWIVQQM-UHFFFAOYSA-M 0.000 description 1
- WPPGURUIRLDHAB-UHFFFAOYSA-M triethyl(hexadecyl)azanium;chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+](CC)(CC)CC WPPGURUIRLDHAB-UHFFFAOYSA-M 0.000 description 1
- 230000001228 trophic effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- 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】本発明は神経成長因子(以下、N
GFと表わす)産生促進作用を有する縮環型オキサゾー
ル化合物及びその用途に関する。BACKGROUND OF THE INVENTION The present invention relates to nerve growth factor (hereinafter referred to as N
A condensed ring type oxazole compound having a production promoting action (denoted by GF) and its use.
【0002】[0002]
【従来技術】NGFは試験管内で神経細胞を分化させて
神経突起の生成を促したり、神経細胞を維持するほか、
動物実験においてNGFを脳内に投与すると、記憶ある
いは学習能力が高まり、また、脳虚血によってニューロ
ンが死滅するのを防ぐ効果が知られている(J. Neurosc
i., 6, 2155 (1986). Brain Res., 293, 305(1985),Sc
ience, 235,214(1986), Proc. Natl. USA, 63, 9231
(1986). Annals ofNeurology, 120 275(1986).)。2. Description of the Related Art NGF not only differentiates nerve cells in vitro to promote neurite generation and maintains nerve cells,
In animal experiments, it has been known that administration of NGF into the brain enhances memory or learning ability and also prevents death of neurons due to cerebral ischemia (J. Neurosc
i., 6, 2155 (1986). Brain Res., 293, 305 (1985), Sc
ience, 235, 214 (1986), Proc. Natl. USA, 63, 9231
(1986). Annals of Neurology, 120 275 (1986).).
【0003】また、アルツハイマー型老年性痴呆症にお
いて、記憶や思考を司る神経細胞であるマイネルト核の
コリン作動性ニューロンの多くが死滅し失われることが
多数の症例で確認されているが、この神経細胞の生存や
分化に、NGFが必須であることが多くの研究者等によ
って明らかにされている(ファルマシア,22, 147(198
6). 老年精神医学,3, 751(1986).)。実際に、ランス
−オルソン等の報告(1991 年アルツハイマー病治療の
シンポジュウム)では、アルツハイマー病で痴呆症状の
出ている患者の脳にネズミから取ったNGFを直接注入
したところ、症状が改善されたことが確認されている。
また、ハンチントン舞踏症患者の脳の線条体では、GA
BA作動性神経細胞の脱落とともにコリン作動性神経細
胞の脱落が著しく、NGFが線条体の内因性コリン作動
性神経細胞にも作用することが知られている(Science,
234, 1341 (1986).)。In many cases of Alzheimer-type senile dementia, many cholinergic neurons of the Meinert nucleus, which is a nerve cell that controls memory and thought, die and are lost. Many researchers have revealed that NGF is essential for cell survival and differentiation (Pharmacia, 22, 147 (198).
6). Geriatric Psychiatry, 3, 751 (1986).). In fact, in a report by Lance-Olson et al. (Symposium for treatment of Alzheimer's disease in 1991), direct injection of NGF taken from a rat into the brain of a patient with Alzheimer's disease causing dementia improved the condition. Has been confirmed.
In the striatum of the brain of patients with Huntington's chorea, GA
It is known that the loss of cholinergic neurons is remarkable along with the loss of BA-acting neurons, and that NGF also acts on the endogenous cholinergic neurons of the striatum (Science,
234, 1341 (1986).).
【0004】さらに、NGFは中枢神経のみならず末梢
の知覚、交感神経系の栄養因子として働き、神経の再生
に必須の因子である。すなわち、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
治療に用いることができると考えられている。Further, NGF acts as a trophic factor for not only central nerves but also peripheral sensory and sympathetic nervous systems, and is an essential factor for nerve regeneration. That is, it is considered that it can be used for the treatment of spinal cord injury, peripheral nerve injury, diabetic neuropathy, amyotrophic lateral sclerosis and the like.
【0005】しかしながら、NGFは分子量10,00
0を超える蛋白質でありNGFそのものを治療剤として
用いるには薬理的および薬剤学上の制約が大きい。これ
らの観点から、NGFの実質的、かつ効果的補充療法と
して、NGFの特定組織における産生、分泌能を誘発す
る能力を有する低分子化合物の探索は重要な意味を持
つ。このような作用を有する化合物としては、例えばカ
テコール誘導体(Furukawa.Y.,J.Bio
l.Chem.,1986,261,6039.特開昭
63−83020、特開昭63−156751、特開平
2−53767、特開平2−104568、特開平2−
149561、特開平3−99046、特開平3−83
921、特開平3−86853、特開平5−3264
6)、キノン類(特開平3−81218、特開平4−3
30010)等が知られているが、その作用は十分なも
のでなく、より高い活性を有する化合物が望まれてい
る。However, NGF has a molecular weight of 10,000.
Since it is a protein exceeding 0 and NGF itself is used as a therapeutic agent, pharmacological and pharmacological restrictions are large. From these viewpoints, as a substantial and effective replacement therapy for NGF, it is important to search for a low molecular weight compound having the ability to induce the production and secretion of NGF in a specific tissue. Examples of the compound having such an action include catechol derivatives (Furukawa.Y., J. Bio).
l. Chem. , 1986, 261, 6039. JP-A-63-83020, JP-A-63-156751, JP-A-2-53767, JP-A-2-104568, JP-A-2-
149561, JP-A-3-99046, JP-A-3-83
921, JP-A-3-86853, JP-A-5-3264
6), quinones (JP-A-3-81218, JP-A-4-3)
30010) and the like are known, but the action is not sufficient, and a compound having higher activity is desired.
【0006】[0006]
【発明が解決しようとする課題】本発明の目的は、生体
内で有用なNGF産生促進作用を有する物質を提供する
ことにある。An object of the present invention is to provide a substance having an action of promoting NGF production which is useful in vivo.
【0007】[0007]
【課題を解決するための手段】本発明者らは、鋭意研究
の結果、ある種の縮環型オキサゾール化合物が生体内で
優れたNGF産生促進作用を有することを見い出し、本
発明を完成した。Means for Solving the Problems As a result of earnest research, the inventors of the present invention have found that certain condensed ring type oxazole compounds have an excellent NGF production promoting action in vivo and completed the present invention.
【0008】すなわち本発明は、下記一般式(1)That is, the present invention provides the following general formula (1)
【0009】[0009]
【化3】 Embedded image
【0010】(式中、R1は水素原子、C1〜C6のアル
キル基、またはアリール基を表わし、環Aは置換されて
いてもよい、ベンゼン環、ナフタレン環、またはカルバ
ゾール環を表わす。)で表わされる縮環型オキサゾール
化合物を有効成分とする神経成長因子産生促進剤を提供
するものである。(In the formula, R 1 represents a hydrogen atom, a C 1 -C 6 alkyl group or an aryl group, and the ring A represents an optionally substituted benzene ring, naphthalene ring or carbazole ring. The present invention provides a nerve growth factor production-promoting agent comprising a condensed ring-type oxazole compound represented by the formula (4) as an active ingredient.
【0011】また本発明は、下記一般式(2)The present invention also relates to the following general formula (2)
【0012】[0012]
【化4】 [Chemical 4]
【0013】(式中、R1は水素原子またはC1〜C6の
アルキル基を表わし、R2、R3は各々同一又は異なって
いてもよく、水素原子、ハロゲン原子またはC1〜C6の
アルキル基を表わし、R4は水素原子または置換されて
いてもよいC1〜C6のアルキル基を表わす。)で表わさ
れる縮環型オキサゾール化合物を提供するものである。(In the formula, R 1 represents a hydrogen atom or a C 1 -C 6 alkyl group, R 2 and R 3 may be the same or different, and a hydrogen atom, a halogen atom or C 1 -C 6 In which R 4 represents a hydrogen atom or an optionally substituted C 1 to C 6 alkyl group).
【0014】上記一般式(1)において、環Aは置換さ
れていてもよい、ベンゼン環、ナフタレン環、またはカ
ルバゾール環を表わすが、その置換基としては、ハロゲ
ン原子、C1〜C6のアルコキシ基またはC1〜C6のアル
キル基を挙げることができる。また、カルバゾール環の
窒素原子は、C1〜C6のアルキル基、(CH2)nCON
(R5)2、(CH2)nCO2H、(CH2)nOR5、(C
H2)nOCOR5、(CH2)nN(R5)2、(nは1〜
4を表わし、R5は各々同一又は異なっていてもよい水
素原子またはC1〜C6のアルキル基を表わす。)を表わ
す。)で置換されていてもよい。In the above general formula (1), ring A represents an optionally substituted benzene ring, naphthalene ring or carbazole ring, and the substituent thereof is a halogen atom or a C 1 -C 6 alkoxy group. A group or a C 1 -C 6 alkyl group may be mentioned. The nitrogen atom of the carbazole ring is a C 1 to C 6 alkyl group, (CH 2 ) n CON.
(R 5 ) 2 , (CH 2 ) n CO 2 H, (CH 2 ) n OR 5 , (C
H 2) n OCOR 5, ( CH 2) n N (R 5) 2, (n is 1 to
4, R 5 represents a hydrogen atom which may be the same or different, or a C 1 -C 6 alkyl group. ) Is represented. ) May be substituted.
【0015】C1〜C6のアルキル基としては、メチル
基、エチル基、プロピル基、イソプロピル基、ブチル
基、s−ブチル基、t−ブチル基、ペンチル基、イソペン
チル基、ネオペンチル基、t−ペンチル基、ヘキシル
基、シクロペンチル基、シクロヘキシル基等を挙げるこ
とができる。その置換基としては、CON(R5)2、C
O2R5、OR5、OCOR5、N(R5)2(R5は各々同
一又は異なっていてもよい水素原子またはC1〜C6のア
ルキル基を表わす。)等を挙げることができる。アリー
ル基としては、フェニル基、ナフチル基、ビフェニル基
等が挙げられる。The C 1 -C 6 alkyl group includes a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a s-butyl group, a t-butyl group, a pentyl group, an isopentyl group, a neopentyl group and a t-group. Examples thereof include a pentyl group, a hexyl group, a cyclopentyl group and a cyclohexyl group. As the substituent, CON (R 5 ) 2 , C
O 2 R 5, OR 5, OCOR 5, N (R 5) 2 ( representing the R 5 each the same or different optionally hydrogen atom even though or C 1 -C 6 alkyl group.), And the like . Examples of the aryl group include a phenyl group, a naphthyl group, a biphenyl group and the like.
【0016】またハロゲン原子としては塩素、臭素、フ
ッ素等の原子を挙げることができる。さらに、C1〜C6
のアルコキシ基としては、メトキシ基、エトキシ基、プ
ロポキシ基、イソプロポキシ基、ブトキシ基、イソブト
キシ基、tert−ブトキシ基、ペンチルオキシ基、イ
ソペンチルオキシ基、ヘキシルオキシ基等が挙げられ
る。Further, examples of the halogen atom include atoms such as chlorine, bromine and fluorine. Furthermore, C 1 to C 6
Examples of the alkoxy group include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a tert-butoxy group, a pentyloxy group, an isopentyloxy group and a hexyloxy group.
【0017】本発明に係る一般式(1)で表わされる化
合物は、一部市販されており、あるいは、対応するo−
キノン化合物に一般式:H2NC(R1)HCO2Hで表
わされるアミノ酸を反応させることにより製造できる。
原料となるo−キノン化合物は、以下に示す方法によっ
て製造することができる。The compound represented by the general formula (1) according to the present invention is partially commercially available or the corresponding o-
It can be produced by reacting a quinone compound with an amino acid represented by the general formula: H 2 NC (R 1 ) HCO 2 H.
The o-quinone compound used as a raw material can be manufactured by the method shown below.
【0018】[0018]
【化5】 Embedded image
【0019】(式中、R2、R3およびR4は前述と同じ
意味を表わし、Xは塩素原子、臭素原子、沃素原子等の
ハロゲン原子を表わす。)(In the formula, R 2 , R 3 and R 4 have the same meanings as described above, and X represents a halogen atom such as a chlorine atom, a bromine atom or an iodine atom.)
【0020】すなわち、上記一般式(a)で表わされる
カルバゾール化合物と、塩基の存在下、ハロゲン化合物
(R2X)を反応させて得られる一般式(b)で表わさ
れる化合物をニトロ化剤で処理し、ニトロ化体(c)と
し、次いで、還元してアミノ体(d)に変換した後、直
接酸化することによりo−キノン化合物(e)が製造で
きる。That is, the compound represented by the general formula (b) obtained by reacting the carbazole compound represented by the general formula (a) with a halogen compound (R 2 X) in the presence of a base is used as a nitrating agent. The o-quinone compound (e) can be produced by treatment to give the nitrated form (c), then reduction and conversion to the amino form (d), followed by direct oxidation.
【0021】上記スキーム中で、原料となるカルバゾー
ル化合物は、一部市販されており、あるいは文献(J. C
hem, Soc., 530 (1945); Phytochem., 773 (1965); J.
Chem. Soc., 4831 (1965); Aust. J. Chem., 2053 (196
8))記載の方法により製造しうる。In the above scheme, some of the carbazole compounds used as raw materials are commercially available or are referred to in the literature (J. C.
hem, Soc., 530 (1945); Phytochem., 773 (1965); J.
Chem. Soc., 4831 (1965); Aust. J. Chem., 2053 (196
It can be produced by the method described in 8)).
【0022】本発明の縮環型オキサゾール化合物の製造
法において、縮合反応を4級アンモニウム塩の存在下で
行うことが目的物を効率良く製造する上で好ましい。4
級アンモニウム塩としては臭化セチルトリメチルアンモ
ニウム、臭化セチルトリエチルアンモニウム、塩化セチ
ルトリエチルアンモニウム等が挙げられる。用いる溶媒
としては、水、またはメタノール、エタノール、プロパ
ノール等のアルコール類、ジクロロメタン、ジクロロエ
タン等のハロゲン化炭化水素類、テトラヒドロフラン、
ジイソプロピルエーテル等のエーテル類、酢酸エチル、
酢酸ブチル等のエステル類、アセトン、エチルメチルケ
トン等のケトン類、ジメチルスルホキシド、N,N−ジ
メチルホルムアミド等の非プロトン性極性溶媒等のほ
か、反応に関与しないあらゆる溶媒が使用できる。反応
温度は約−78〜200℃が好ましい。In the method for producing a condensed ring type oxazole compound of the present invention, it is preferable to carry out the condensation reaction in the presence of a quaternary ammonium salt in order to efficiently produce the desired product. Four
Examples of the primary ammonium salt include cetyl trimethyl ammonium bromide, cetyl triethyl ammonium bromide, cetyl triethyl ammonium chloride and the like. As the solvent to be used, water or alcohols such as methanol, ethanol and propanol, halogenated hydrocarbons such as dichloromethane and dichloroethane, tetrahydrofuran,
Ethers such as diisopropyl ether, ethyl acetate,
In addition to esters such as butyl acetate, ketones such as acetone and ethyl methyl ketone, aprotic polar solvents such as dimethyl sulfoxide, N, N-dimethylformamide, and the like, any solvent that does not participate in the reaction can be used. The reaction temperature is preferably about -78 to 200 ° C.
【0023】本発明に係るNGF産生促進剤は、経口ま
たは非経口的に投与することができる。その投与剤形と
しては、例えば、散剤、顆粒剤、カプセル剤錠剤、丸
剤、シロップ剤、懸濁剤、注射剤などを例示することが
できる。これらは、患者の症状、年齢、および治療の目
的に応じて常用の賦形剤(例えば、デンプン、乳糖、結
晶セルロース、メタケイ酸アルミン酸マグネシウム、無
水ケイ酸、マンニトール等)、結合剤(例えばヒドロキ
シプロピルセルロース、ポリビニルピロリドン等)、滑
沢剤(例えば、ステアリン酸マグネシウム、タルク
等)、崩壊剤(例えば、カルボキシメチルセルロース、
カルボキシメチルセルロースカルシウム等)、コーテン
グ剤(例えば、ヒドロキシエチルセルロース)、矯味
剤、溶解剤ないし溶解補助剤(例えば、注射用蒸留水、
生理食塩水、プロピレングリコール、アルコール、脂肪
酸エステル類等)、懸濁剤(例えばポリソルベート80
等の界面活性剤)、pH調整剤(例えば、有機酸または
その金属塩等)、粘着剤(例えば、カルボキシビニルポ
リマー、多糖類等)、乳化剤(例えば界面活性剤等)、
安定化剤等を用い、通常の製造法(例えば、第12改正
日本薬局方に規定する方法)を用いて製造することがで
きる。さらに、公知の技術により持続性製剤とすること
も可能である。本発明に係る化合物のNGF産生促進剤
としての投与量は、成人を治療する場合で1〜1000
mgであり、これを1日2〜3回に分けて投与することが
好ましい。この投与量は、患者の年齢、体重および症状
によって増減することができる。The NGF production promoter according to the present invention can be administered orally or parenterally. Examples of the dosage form include powders, granules, capsule tablets, pills, syrups, suspensions, injections and the like. These are conventional excipients (for example, starch, lactose, crystalline cellulose, magnesium aluminometasilicate, silicic acid anhydride, mannitol, etc.), binders (for example, hydroxy, depending on the patient's condition, age, and therapeutic purpose). Propylcellulose, polyvinylpyrrolidone etc.), lubricants (eg magnesium stearate, talc etc.), disintegrants (eg carboxymethylcellulose, etc.)
Carboxymethyl cellulose calcium, etc.), coating agents (eg hydroxyethyl cellulose), flavoring agents, solubilizers or solubilizing agents (eg distilled water for injection,
Physiological saline, propylene glycol, alcohol, fatty acid esters, etc., suspending agent (eg polysorbate 80)
Surfactants), pH adjusters (eg organic acids or metal salts thereof), adhesives (eg carboxyvinyl polymers, polysaccharides etc.), emulsifiers (eg surfactants),
It can be produced by using a stabilizer or the like and an ordinary production method (for example, a method defined in the 12th revised Japanese Pharmacopoeia). Furthermore, it is also possible to prepare a sustained-release preparation by a known technique. The dose of the compound according to the present invention as an NGF production promoter is 1 to 1000 when treating an adult.
mg, and it is preferable to administer this in 2 to 3 divided doses per day. This dosage can be adjusted according to the age, weight and condition of the patient.
【0024】以下、本発明を参考例、合成例、試験例に
よりさらに詳しく説明する。ただし、本発明はそれらに
限定されるものではない。The present invention will be described in more detail with reference to Reference Examples, Synthesis Examples and Test Examples. However, the present invention is not limited to them.
【0025】[0025]
参考例1 Reference example 1
【0026】[0026]
【化6】 [Chemical 6]
【0027】3−アミノ−9−エチルカルバゾール
(0.16g,0.75mmol)のアセトン(75m
l)溶液にニトロソジスルホン酸カリウム(0.90
g,3.36mmol)の1/6Mのリン酸二カリウム
(19ml)溶液を加えた後、5分間攪拌した。反応液
に食塩水(200ml)を加え、酢酸エチルで抽出、水
洗後、硫酸マグネシウムで乾燥した。溶媒を留去し、残
留物をカラムクロマトグラフィーにより精製し、9−エ
チルカルバゾール−3,4−ジオン(0.06g)を得
た。1 NMR(CDCl3):δ 1.51(t,1H),
4.28(q,2H),6.26(d,J=10.2H
z,1H),7.34(m,3H),7.35(d,J
=10.2Hz,1H),8.18(m,1H). MS(m/e):225(M+).3-Amino-9-ethylcarbazole (0.16 g, 0.75 mmol) in acetone (75 m)
l) potassium nitrosodisulfonate (0.90
g, 3.36 mmol) of 1 / 6M dipotassium phosphate (19 ml) solution was added, and the mixture was stirred for 5 minutes. Brine (200 ml) was added to the reaction solution, extracted with ethyl acetate, washed with water, and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography to give 9-ethylcarbazole-3,4-dione (0.06g). 1 NMR (CDCl 3 ): δ 1.51 (t, 1H),
4.28 (q, 2H), 6.26 (d, J = 10.2H
z, 1H), 7.34 (m, 3H), 7.35 (d, J
= 10.2 Hz, 1H), 8.18 (m, 1H). MS (m / e): 225 (M + ).
【0028】合成例1Synthesis Example 1
【0029】[0029]
【化7】 [Chemical 7]
【0030】9−エチルカルバゾール−3,4−ジオン
(0.145g,0.64mmol)とグリシン(1.
24g,16.5mmol)のジクロロメタン(40m
l)溶液に臭化セチルトリメチルアンモニウム(1.6
4g,4.5mmol)を1/6Mのリン酸二ナトリウ
ム(75ml)に溶かした水溶液(360ml)を加
え、室温で24時間攪拌した。反応液は酢酸エチルで抽
出し、水洗後、硫酸マグネシウムで乾燥した。溶媒を留
去し、残留物をカラムクロマトグラフィーにより精製
し、6−エチル−1,3−オキサゾロ−[4,5−c]
カルバゾール(0.021g)を得た。1 NMR(CDCl3):δ 1.48(t,3H),
4.47(q,2H),7.35(m,1H),7.4
5(d,J=8.7Hz,1H),7.49〜7.56
(m,2H),7.86(d,J=8.7Hz,1
H),8.20(s,1H),8.33(m,1H). MS(m/e):236(M+)9-Ethylcarbazole-3,4-dione (0.145 g, 0.64 mmol) and glycine (1.
24 g, 16.5 mmol) of dichloromethane (40 m
l) In solution, cetyltrimethylammonium bromide (1.6
An aqueous solution (360 ml) prepared by dissolving 4 g, 4.5 mmol) in 1 / 6M disodium phosphate (75 ml) was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was extracted with ethyl acetate, washed with water, and dried over magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography to give 6-ethyl-1,3-oxazolo- [4,5-c].
Carbazole (0.021 g) was obtained. 1 NMR (CDCl 3 ): δ 1.48 (t, 3H),
4.47 (q, 2H), 7.35 (m, 1H), 7.4
5 (d, J = 8.7 Hz, 1H), 7.49 to 7.56
(M, 2H), 7.86 (d, J = 8.7Hz, 1
H), 8.20 (s, 1H), 8.33 (m, 1H). MS (m / e): 236 (M + ).
【0031】試験例1. ラット顎下腺に対するNGF
産生促進活性 ウィスター雄性ラット(8〜10週齢、200〜250
g)に被験化合物を1〜2回(1回/日)腹腔内投与
し、最終投与の24時間後に顎下腺を摘出した。顎下腺
を秤量した後、20倍量のリン酸緩衝液(NaCl 8g
/L、KCl 0.2g/L、 Na2HPO4 1.15g/
L、KH2PO4 0.2g/L)を加え、超音波破砕機(BR
ANSON社製、CELL DISRUPTOR 185)でホモジナイズし、
ついで遠心分離(10,000×G、30分)して上清液を得
た。この上清液のNGF含有量を以下に示す酵素免疫測
定法によって測定した。Test Example 1. NGF for rat submandibular gland
Production promoting activity Wistar male rats (8-10 weeks old, 200-250
The test compound was intraperitoneally administered to g) once or twice (once / day), and the submandibular gland was extracted 24 hours after the final administration. After weighing the submandibular gland, 20 times the amount of phosphate buffer (NaCl 8 g
/ L, KCl 0.2 g / L, Na 2 HPO 4 1.15 g /
L, KH 2 PO 4 0.2 g / L) and ultrasonic crusher (BR
Homogenized with CELL DISRUPTOR 185, manufactured by ANSON,
Then, centrifugation (10,000 × G, 30 minutes) was performed to obtain a supernatant. The NGF content of this supernatant was measured by the enzyme immunoassay method shown below.
【0032】[NGFの測定法]ポリスチレン製の96
穴プレート(住友ベークライト社製MS−3496F)
に抗マウスベータNGFポリクローナル抗体(マウス顎
下腺より調製したベータNGFを抗原として発明者らが
常法に従い作成したもの、[S. Furukawa, I. Kamo, Y.
Furukawa, S. Akazawa, E. Satoyoshi, K. Itoh and
K. Hayashi, J. Neurochem., 40, 734-744 (1983)])
の溶液(pH8.3)を各穴に50マイクロリットルづ
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、洗浄液で各穴を3回洗
浄した。標準ベータNGF(東洋紡製)溶液あるいは、
上記の遠心上清液40マイクロリットルを各穴に分注
し、4℃で18時間放置した後、標準溶液あるいは、試
料溶液を除去した。さらに各穴を3回づつ洗浄した。ベ
ータガラクトシダーゼ標識抗ベータNGFモノクローナ
ル抗体(ベーリンガーマンハイム社製)溶液(40mU
/mL、pH7.6)を各穴に50マイクロリットルづ
つ分注し、37℃で4時間放置した後、酵素標識抗体を
除去し、上記と同様にして各穴を3回づつ洗浄した。4
−メチルウンベリフェリル−ベータ−D−ガラクトシド
(シグマ社製)溶液(20マイクログラム/mL、pH
7.6)を各穴に100マイクロリットルづつ分注し、
室温で1.5時間反応させた後、0.2Nグリシン−水酸
化ナトリウム緩衝液(pH10.3)を各穴に100マ
イクロリットルづつ分注して反応を停止し、生成した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量を算出した。[Method of measuring NGF] 96 made of polystyrene
Hole plate (MS-3496F made by Sumitomo Bakelite Co., Ltd.)
Anti-mouse beta NGF polyclonal antibody (produced by the inventors according to a conventional method using beta NGF prepared from mouse submandibular gland as an antigen, [S. Furukawa, I. Kamo, Y.
Furukawa, S. Akazawa, E. Satoyoshi, K. Itoh and
K. Hayashi, J. Neurochem., 40, 734-744 (1983)])
50 microliters of the solution (pH 8.3) was dispensed into each well and left at 37 ° C. for 4 hours. After removing the antibody not adsorbed on the microplate, each well was washed three times with a washing solution. Standard beta NGF (Toyobo) solution or
40 microliters of the above-mentioned centrifugal supernatant was dispensed into each well and allowed to stand at 4 ° C. for 18 hours, after which the standard solution or sample solution was removed. Further, each hole was washed 3 times. Beta-galactosidase-labeled anti-beta NGF monoclonal antibody (Boehringer Mannheim) solution (40 mU
50 mL / mL, pH 7.6) was dispensed into each well and left at 37 ° C. for 4 hours, then the enzyme-labeled antibody was removed and each well was washed 3 times in the same manner as above. Four
-Methylumbelliferyl-beta-D-galactoside (manufactured by Sigma) solution (20 microgram / mL, pH
7.6) into each well by 100 microliters,
After reacting for 1.5 hours at room temperature, 0.2 microliters of glycine-sodium hydroxide buffer (pH 10.3) was dispensed into each well by 100 microliters to stop the reaction.
-The fluorescence intensity of methyl umbelliferone was measured with a plate reader, and the amount of NGF was calculated from the standard curve.
【0033】結果は無投薬時の顎下腺NGF含有量に対
する被験化合物投与時の顎下腺NGF含有量の倍率で表
わした。結果を表1に示す。The results were expressed as the magnification of the submandibular gland NGF content when the test compound was administered to the submandibular gland NGF content when no drug was administered. The results are shown in Table 1.
【0034】[0034]
【表1】 表1 ─────────────────────────────────── 化合物 投与量×投与回数 NGF産生促進倍率 ───────────────────────────────────ヘ゛ンソ゛オキサソ゛ール 1mg/kg×2回 5.2 2-フェニルヘ゛ンソ゛オキサソ゛ール 1mg/kg×2回 3.0 2,5-シ゛メチルヘ゛ンソ゛オキサソ゛ール 0.2mg/kg×2回 2.0 2-メチルナフトキサソ゛ール 1mg/kg×1回 3.4 合成例1の化合物 0.15mg/kg×2回 6.0 ───────────────────────────────────[Table 1] Table 1 ─────────────────────────────────── Compound dose × number of doses NGF production promotion Magnification ─────────────────────────────────── Benzooxasol 1 mg / kg × 2 times 5.2 2-Phenylbenzazosol 1 mg / kg × 2 times 3.0 2,5-Dimethylbenzazoxazole 0.2 mg / kg × 2 times 2.0 2-methylnaphthoxasole 1 mg / kg × 1 time 3.4 Compound of Synthesis Example 1 0.15 mg / kg × 2 times 6.0 ── ──────────────────────────────────
【0035】表1に示した化合物はいずれも低用量でラ
ット顎下腺のNGF含有量を増加させる活性を示した。All the compounds shown in Table 1 showed the activity of increasing the NGF content of rat submandibular gland at a low dose.
【0036】[0036]
【発明の効果】本発明に係る縮環型オキサゾール化合物
は、優れた神経成長因子産生促進作用を有し、神経成長
因子産生促進剤として有用である。また、一部の縮環型
オキサゾール化合物は新規化合物である。The fused oxazole compound according to the present invention has an excellent nerve growth factor production promoting action and is useful as a nerve growth factor production promoting agent. Moreover, some fused ring type oxazole compounds are novel compounds.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.6 識別記号 庁内整理番号 FI 技術表示箇所 C07D 263/60 (C07D 498/04 209:88 263:32) (72)発明者 近藤 聖 神奈川県大和市中央林間5−16−4─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. 6 Identification number Internal reference number FI Technical indication C07D 263/60 (C07D 498/04 209: 88 263: 32) (72) Inventor St. Kondo Kanagawa 5-16-4 Chuorinkan, Yamato-shi
Claims (2)
はアリール基を表わし、環Aは置換されていてもよい、
ベンゼン環、ナフタレン環、またはカルバゾール環を表
わす。)で表わされる縮環型オキサゾール化合物を有効
成分とする神経成長因子産生促進剤。1. A compound represented by the general formula (1): (In the formula, R 1 represents a hydrogen atom, a C 1 -C 6 alkyl group, or an aryl group, and the ring A may be substituted;
It represents a benzene ring, a naphthalene ring, or a carbazole ring. ) A nerve growth factor production promoter comprising a fused oxazole compound represented by the formula (4) as an active ingredient.
表わし、R2、R3は各々同一又は異なっていてもよく、
水素原子、ハロゲン原子またはC1〜C6のアルキル基を
表わし、R4は水素原子または置換されていてもよいC1
〜C6のアルキル基を表わす。)で表わされる縮環型オ
キサゾール化合物。2. A compound of the general formula (2) (In the formula, R 1 represents a hydrogen atom or a C 1 -C 6 alkyl group, and R 2 and R 3 may be the same or different,
Represents a hydrogen atom, a halogen atom or a C 1 -C 6 alkyl group, and R 4 represents a hydrogen atom or an optionally substituted C 1
It represents an alkyl group having -C 6. ) A condensed ring type oxazole compound represented by
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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JP6318174A JPH08175992A (en) | 1994-12-21 | 1994-12-21 | Agent for promoting production of nerve growth factor and condensed ring type oxazole compound |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP6318174A JPH08175992A (en) | 1994-12-21 | 1994-12-21 | Agent for promoting production of nerve growth factor and condensed ring type oxazole compound |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH08175992A true JPH08175992A (en) | 1996-07-09 |
Family
ID=18096298
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP6318174A Pending JPH08175992A (en) | 1994-12-21 | 1994-12-21 | Agent for promoting production of nerve growth factor and condensed ring type oxazole compound |
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JP (1) | JPH08175992A (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6066658A (en) * | 1996-09-06 | 2000-05-23 | Takeda Chemical Industries, Ltd. | Condensed 4,5,6,7-tetrahydrobenzo[C]thiophenes as enhancer for cell differentiation induction factor action |
WO2001014372A3 (en) * | 1999-08-25 | 2002-03-21 | Takeda Chemical Industries Ltd | Oxazole and thiazole derivatives as neurotrophin production/secretion promoting agent |
WO2003057215A1 (en) * | 2001-12-28 | 2003-07-17 | Takeda Chemical Industries, Ltd. | Neurotrophic factor production/secretion accelerator |
US8501713B2 (en) | 2007-08-03 | 2013-08-06 | Summit Corporation Plc | Drug combinations for the treatment of duchenne muscular dystrophy |
US8518980B2 (en) | 2006-02-10 | 2013-08-27 | Summit Corporation Plc | Treatment of Duchenne muscular dystrophy |
-
1994
- 1994-12-21 JP JP6318174A patent/JPH08175992A/en active Pending
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6066658A (en) * | 1996-09-06 | 2000-05-23 | Takeda Chemical Industries, Ltd. | Condensed 4,5,6,7-tetrahydrobenzo[C]thiophenes as enhancer for cell differentiation induction factor action |
US6242471B1 (en) | 1996-09-06 | 2001-06-05 | Takeda Chemical Industries, Ltd. | Condensed 4,5,6,7-tetrahydrobenzo[C]thiophenes as enhancer for cell differentiation induction factor action |
US6391905B1 (en) | 1996-09-06 | 2002-05-21 | Takeda Chemical Industries, Ltd. | Condensed 4,5,6,7-tetrahydrobenzo[C]thiopenes as enhancer for cell differentiation induction factor action |
US6489351B1 (en) | 1996-09-06 | 2002-12-03 | Takeda Chemical Industries, Ltd. | Condensed 4,5,6,7-tetrahydrobenzo[C]thiophenes as enhancer for cell differentation induction factor action |
WO2001014372A3 (en) * | 1999-08-25 | 2002-03-21 | Takeda Chemical Industries Ltd | Oxazole and thiazole derivatives as neurotrophin production/secretion promoting agent |
WO2003057215A1 (en) * | 2001-12-28 | 2003-07-17 | Takeda Chemical Industries, Ltd. | Neurotrophic factor production/secretion accelerator |
US8518980B2 (en) | 2006-02-10 | 2013-08-27 | Summit Corporation Plc | Treatment of Duchenne muscular dystrophy |
US8501713B2 (en) | 2007-08-03 | 2013-08-06 | Summit Corporation Plc | Drug combinations for the treatment of duchenne muscular dystrophy |
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