WO1998024773A1 - Derives de phenazine - Google Patents

Derives de phenazine Download PDF

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Publication number
WO1998024773A1
WO1998024773A1 PCT/JP1997/003675 JP9703675W WO9824773A1 WO 1998024773 A1 WO1998024773 A1 WO 1998024773A1 JP 9703675 W JP9703675 W JP 9703675W WO 9824773 A1 WO9824773 A1 WO 9824773A1
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Prior art keywords
group
aryl
aralkyl
general formula
hydrogen atom
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PCT/JP1997/003675
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English (en)
Japanese (ja)
Inventor
Toshihiro Takahashi
Yutaka Nomura
Haruo Seto
Kazuo Shin-Ya
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Nippon Chemiphar Co., Ltd.
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Publication of WO1998024773A1 publication Critical patent/WO1998024773A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/46—Phenazines

Definitions

  • the present invention contains a phenazine derivative represented by the following general formula (I) or (II) and a phenazine derivative represented by the following general formula (I), (II) or (III) as effective components. It relates to an inhibitor of glucumic acid toxicity. [Background technology]
  • the substance that suppresses glutamate toxicity to nerve cells can be used as a brain metabolism activator, a brain metabolism improving agent, and the like.
  • JP-A-6-135982 discloses that a strain produced from a strain of the genus Streptomyces (HR04 strain) has the following formula (A):
  • JP-B-50-12000, JP-B-53-31237 and JP-B-8-259409 disclose phenazine-1-carboxylic acid in pseudomonas. It is described that it is an antibiotic produced by a strain belonging to the genus, and that it can be used as a herbicide, an algicide, a control agent for snow rot, etc. by utilizing its antibacterial action.
  • R H, SCH 2 CH (NHCOCH 3 ) C0 2 H
  • the present inventors have conducted intensive studies on a compound having an inhibitory effect on glucumic acid toxicity, and as a result, it was found that the guanazine derivatives of the following general formulas (I), (II) and (III) are superior
  • the present inventors have found that they have a toxicity suppressing effect and completed the present invention. That is, the present invention provides the following general formula (I):
  • R 1 represents a linear or branched alkyl group, an aralkyl group or an aryl group
  • R 2 and R 3 are the same or different and are a hydrogen atom, an aryl group, a nitro group, a cyano group, an alkylsulfonyl group, an aryl group.
  • R 4 represents a linear, branched or cyclic alkyl group, an aralkyl group or an aryl group
  • R 2fl , R 5 and R 5 are the same or different and are a hydrogen atom, a linear or branched alkyl group Alkenyl group, alkynyl group, aralkyl group, aryl group, hydroxyl group, alkoxy group, aryloxy group, aralkyloxy group, alkoxyalkyl group, halogen atom, nitro group, cyano group, alkylsulfonyl group, arylsulfonyl group , an alkylcarbonyl group, Arirukarubo group, ⁇ Lal kill carbonyl group, a haloalkyl group, a haloalkoxy group, an alkoxycarbonyl group, a carboxyl group, a formyl group, N (R 7) (R 8) or S0 2 N (R ).
  • R 7 and R 8 are the same or different hydrogen atom, an alkyl group, Ararukiru group, a Ariru group And R 9 and R in the same or different hydrogen atom, an alkyl group, Ararukiru group, represents a Ariru group.
  • the present invention also relates to an inhibitor of glucumic acid toxicity, which comprises, as an active ingredient, a phenazine derivative represented by the above general formula (I) or (II). Furthermore, the present invention provides the following general formula (III):
  • R 11 represents a linear, branched or cyclic alkyl group, an aralkyl group or an aryl group
  • R 12 and R 13 are the same or different and are a hydrogen atom, a linear or branched alkyl group.
  • R 14 and R 15 are the same or different and represent a hydrogen atom, an alkyl group, an aralkyl group, or an aryl group
  • R 16 and R 17 are the same or different and are a hydrogen atom, an alkyl group, an aralkyl group, or an aryl group.
  • the present invention relates to an inhibitor of glucumic acid toxicity, which comprises a phenazine derivative represented by the following formula:
  • R 1 represents a straight-chain or straight-chain having 1 to 8 carbon atoms such as methyl, ethyl, propyl, i-propyl, butyl, i-butyl, tert-butyl and the like.
  • R 2 and R 3 are the same or different, and include an alkylsulfonyl group having 1 to 8 carbon atoms such as a hydrogen atom, a phenyl group, an aryl group such as a naphthyl group, a nitro group, a cyano group, a methanesulfonyl group, and a benzenesulfonyl group.
  • Groups such as arylsulfonyl, benzyl, etc., arylcarbonyl, benzylcarbonyl, etc., chloromethyl, trifluoromethyl, etc., chlorine, bromine, fluorine, etc.
  • halogen atoms such as a haloalkyl group having 1 to 3 carbon atoms having 1 to 3 halogen atoms or a chlorine atom such as 2-chloroethoxy group, trifluoromethoxy group, etc., a bromine atom, a fluorine atom, etc.
  • R 4 is a straight chain having 1 to 8 carbon atoms such as a methyl group, an ethyl group, a propyl group, an i-butyl group, a butyl group, an i-butyl group and a tert-butyl group.
  • a 3- to 8-membered cyclic alkyl group such as a branched alkyl group or a cyclohexyl group; an aralkyl group such as a benzyl group or a phenethyl group; or an aryl group such as a phenyl group or a naphthyl group.
  • R 20 , R 5 and R 6 are the same or different and have 1 carbon atom such as hydrogen atom, methyl group, ethyl group, propyl group, i-propyl group, butyl group, i-butyl group, tert-butyl group, etc.
  • a C8-C8 alkynyl group such as a C8-C8 straight-chain or branched-chain alkyl group, vinyl group, aryl group, 3-methyl-2-butenyl group, and propynyl group;
  • An aralkyl group such as a benzyl group or a phenyl group, an aralkyl group such as a phenyl group or a naphthyl group, an alkoxy group having 1 to 8 carbon atoms such as a hydroxyl group, a methoxy group or an ethoxy group, and an aryloxy group such as a phenyloxy group;
  • C1-C8 alkoxy-substituted C1-C8 alkyl groups such as aralkyloxy groups such as benzyloxy group, methoxymethyl group and methoxethyl group; halogens such as chlorine atom, bromine atom and fluorine atom C2-8 alkylcarbon
  • arylsulfonyl, acetyl, propionyl, etc. having 1-8 carbon atoms such as nitro, cyano, methanesulfonyl, etc. 1 to 3 halogen atoms such as an arylcarbonyl group such as a benzoyl group, an aralkylcarbonyl group such as a benzylcarbonyl group, a chloromethyl group, and a trifluoromethyl group; a bromine atom; and a fluorine atom.
  • a haloalkyl group having 1 to 8 carbon atoms having 1 to 8 carbon atoms having 1 to 3 halogen atoms such as a chlorine atom, a bromine atom, a fluorine atom such as haloalkoxy groups, main butoxycarbonyl alkoxycarbonyl group having a carbon number 2-8 such groups, carboxyl groups, formyl groups, N (R 7) (R 8) Or S 0 2 N (R 9 ) (R 10 ).
  • R 7 and R 8 are the same or different and are a hydrogen atom, a methyl group, an ethyl group, a propyl group, an i-propyl group, a butyl group, an i-butyl group, etc. Examples thereof include an aralkyl group such as a chain alkyl group, a benzyl group and a phenyl group, or an aryl group such as a phenyl group and a naphthyl group.
  • R 9 and R 1 (where 1 is the same or different, and is a straight-chain alkyl group having 1 to 8 carbon atoms such as a hydrogen atom, a methyl group, an ethyl group, a propyl group, an i-propyl group, a butyl group, and an i-butyl group).
  • an aralkyl group such as a branched alkyl group, a benzyl group and a phenyl group, or an aryl group such as a phenyl group and a naphthyl group.
  • R 11 of the above general formula (III) is R 4 of the above general formula (II)
  • RM and R 15 of the above general formula (III) are R 7 or R 8 of the above general formula (II)
  • R 16 and R 17 in formula (III) include the same atoms or groups as R 9 or R 1Q in formula (II).
  • R 12 and R 13 in the general formula (III) are each an atom or a group obtained by removing an alkenyl group from R 5 or R 6 in the general formula (II).
  • R 12 and R 13 are not hydrogen atoms at the same time.
  • R 2 and R 3 in the above general formula (I), R 2 , R 5 and R 6 in the above general formula (II) and R 12 and R 13 in the above general formula (III) may be plural. .
  • R 2 and R 3 in the above general formula (I), R 5 and R 6 in the above general formula (II) and R 12 and R 13 in the above general formula (III) represent a cyano group, a nitro group, a benzoyl group or the like.
  • the electron-withdrawing group is preferably
  • Ararukiru groups and ⁇ Li in R 15 - group, Ararukiru group and ⁇ Li in R 16 and R 17 - aromatic Le groups are, for example, methyl group, Echiru group, propyl group A lower alkyl group having 1 to 6 carbon atoms, a lower alkoxy group having 1 to 6 carbon atoms such as a methoxy group, an ethoxy group, a propoxy group, a chlorine atom, a halogen atom such as a fluorine atom, a trifluoromethyl group, etc.
  • the linear or branched alkyl group represented by I 1 in the general formula (I), R 4 in the general formula (II) and R 11 in the general formula (III) is an amino group (NH 2 ) or an ethylamino group.
  • C1 to C6 alkylamino groups C1 to C6 alkylamino groups, aralkylamino groups such as pendylamino groups (the alkyl moiety has 1 to 4 carbon atoms), dimethylamino groups, and di (C1-6 alkyl) amino groups such as getylamino groups And a cyclic amino group such as a piperidino group and a morpholino group; and a diaralkylamino group (having 1 to 4 carbon atoms in the alkyl portion) such as a dipendylamino group.
  • the phenazine derivative represented by the general formula (I) of the present invention can be produced, for example, by the following synthetic route.
  • the compound of the general formula (b) is prepared by adding the compound of the general formula (a) to sodium hydrosulfite in a solvent that does not participate in a reaction such as a mixed solvent of ethanol and water. Or the like, by subjecting it to a reduction reaction in the presence of a reducing agent such as
  • the compound of the general formula (a) as a raw material is the same as the synthetic method described in, for example, J. Chem. Soc., Perkin Trans. 1 (11) p. 1354 (1974), U.S. Pat. It can be obtained using a method.
  • the compound of the general formula (b) can be prepared by reacting the compound of the general formula (c) with an alcohol represented by the formula (C) in the presence of an acid catalyst such as concentrated sulfuric acid, or the compound of the general formula (c) be obtained by reacting an alcohol represented by R 1 0 Eta the presence of 1-Echiru one 3- (3-dimethylaminopropyl ⁇ amino propyl) Karupojiimi de hydrochloride / 4-dimethyl ⁇ amino bi condensing agent such as lysine Can be.
  • the compound of the general formula (c) as a raw material is, for example, J. Chem. Soc. Chem. Commun., 1423 (1970), J. Med. Chem., 30, 843 (1987), Synth. Commun., 17, 1171 (1987), Ann. Chim., [13], 1, 115 (1956).
  • the compound of the general formula (b) can be obtained by oxidizing the compound of the general formula (d) by air oxidation or the like.
  • the compound of the general formula (d) as a raw material can be obtained by a method similar to the synthesis method described in, for example, He1 v. Chim. Acta, 52, 322 (1969).
  • phenazine derivative represented by the general formula (II) or the general formula (III) can also be obtained by using the same method as the synthetic route of the phenazine derivative represented by the general formula (I).
  • the phenazine derivatives represented by the above general formulas (I), (II) and (III) can be optionally used as pharmacologically acceptable salts, such as hydrochloride, hydrobromide and the like. And organic acid salts such as fumarate and acetate.
  • Table 1 shows examples of representative compounds of the phenazine derivatives represented by the general formula (I).
  • Table 2 shows typical examples of the phenazine derivatives represented by the general formula (II) (excluding those described in Table 1).
  • No Table 3 shows examples of typical compounds (excluding those described in Tables 1 and 2) of the phenazine derivatives represented by the general formula (III).
  • phenazine derivatives represented by the above general formulas (I), (II) and (III) are derived from nerve cells (N18-RE-105 cells) and rat fetuses. Excellent cell-protecting activity was demonstrated in the test for inhibition of glumic acid toxicity on primary hippocampal cells and in the test for inhibition of BSO toxicity on nerve cells (N18-RE-105 cells).
  • the phenazine derivatives represented by the general formulas (I), (II) and (III) are also useful as an active ingredient of a therapeutic drug for cerebrovascular disorders such as cerebral infarction and cerebrovascular dementia.
  • the phenazine derivatives of the general formulas (I), (II) and (III) were excellent in an experiment for suppressing lipid peroxide production using rat whole brain homogenate. It showed an inhibitory effect on lipid peroxide production.
  • the phenazine derivatives represented by the above general formulas (I), (II) and (III) are also useful as therapeutic agents for these diseases.
  • Inhibitors of glutamate toxicity containing the phenazine derivatives represented by the above general formulas (I), (II) and (III) as active ingredients can be used as oral preparations such as tablets, capsules and granules or as injections, It can be used as a parenteral administration agent such as suppositories.
  • These preparations include excipients such as glucose and lactose that are used in the usual production of pharmaceutical preparations, starch, disintegrants such as calcium carboxymethylcellulose (CMC-Ca), hydroxypropylcellulose (HPC), and polyvinylpyrrolidone. Binders such as (PVP), lubricants such as talc and magnesium stearate, diluents, and pigments are used.
  • excipients such as glucose and lactose that are used in the usual production of pharmaceutical preparations, starch, disintegrants such as calcium carboxymethylcellulose (CMC-Ca), hydroxypropylcellulose (HPC), and polyvinylpyrrolidone.
  • Binders such as (PVP), lubricants such as talc and magnesium stearate, diluents, and pigments are used.
  • the dosage of the phenazine derivatives represented by the above general formulas (I), (II) and (III) is about 0.001 mg to 10 Omg per day for an injection, and For administration, the dose is about 0.01 mg to 1.0 g per day, but it can be increased or decreased depending on age, symptoms, and the like. -Next, the present invention will be described in more detail with reference examples and examples. [Reference Example 1]
  • N- (4-benzoyl-2-nitrophenyl) anthranilic acid Anthranilic acid (1.37 g, 10 mmol), 4-chloro-3-nitrobenzophenone (2.88 g, llmmol), powder A mixture of anhydrous potassium carbonate (2.77 g, 20 mmo 1), copper powder (5 Omg), and isoamyl alcohol (25 ml) was heated to reflux for 1 hour with stirring. After cooling to room temperature, water (30 ml) and ether (30 ml) were added to the reaction mixture, and the mixture was stirred for 15 minutes. The insoluble red-brown solid was collected by filtration and washed with water and ether.
  • the reddish-brown solid was mainly the potassium salt of the desired product, which was collected, suspended in water (40 ml), and 2N hydrochloric acid was added until the pH of the solution reached about 2. After stirring vigorously at room temperature for 1 hour, the crystals were collected by filtration and washed several times with water and ether. The crystals were dried under reduced pressure at 60 ° C. for 3 hours to obtain 2.34 g (65%) of the title compound as yellow-orange crystals.
  • the solvent was distilled off under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was separated.
  • the organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline. After drying over anhydrous sodium sulfate and evaporating the solvent under reduced pressure, the residue was recrystallized from ethanol (18 Oml) to obtain 8.88 g (82%) of the title compound as yellow crystals. In addition, 0.31 g (3%) of a secondary crystal was obtained from the mother liquor.
  • LDH release rate [LDH activity in medium / (intracellular + LDH activity in medium)] xl OO
  • Rats 18 days of gestation were anesthetized with sodium pentobarbi and the abdomen was disinfected with 83% ethanol, and the fetus was removed. The whole brain was removed from the fetus under a stereoscopic microscope, and the hippocampus region was further cut out. The hippocampus was further cut into small pieces using a scalpel. As described above, the hippocampus was removed from the fetus and the chopping operation was performed in a Hanks buffer (4 ° C) from which Ca 2 + and Mg 2 + had been removed. Small pieces of hippocampus were treated in 0.25% trypsin-0.01% DNase I solution at 37 ° C for 30 minutes.
  • the cytoprotective effect of the test substance was determined by measuring the activities of lactate dehydrogenase which had flowed out of dead cells and extracellular lactate dehydrogenase, respectively.
  • ⁇ ⁇ Suppression test of lipid peroxide production in rat whole brain homogenate Whole brain was taken out from a rat bred on a vitamin E-deficient diet for 1 week and frozen in liquid nitrogen. The frozen whole brain was crushed and powdered, and then homogenized with a dounce homogenizer. Then, the mixture was centrifuged at 180 g for 10 minutes, and the supernatant was recovered. This was used as a whole brain homogenate in the test. Lipid peroxidation was initiated by stimulation with iron-ascorbic acid, and the amount of lipid peroxide produced was quantified by the thiobarbituric acid (TBA) method.
  • TSA thiobarbituric acid
  • Table 4 shows that the compound of the present invention has an excellent cytoprotective effect on glucamic acid toxicity in nerve cells (N18-RE-105 cells) and rat hippocampal primary hippocampal cells. Moreover, whereas c revealed to have excellent cell protecting action against B SO toxicity definitive in neurons (N 18 -RE- 105 cells), the compound obtained in Reference Example 2 (7- N-ziryl 1-phenazine carboxylic acid), a known compound (11-phenazine carboxylic acid), the compound obtained in Reference Example 3 (11-phenazine carboxylic acid ethyl) and a known antioxidant (2) Carabene and ebselen had weak cytoprotective effects on glutamate and BSO toxicity to neurons.
  • the compound of the present invention has an excellent lipid peroxide production inhibitory action in an experiment of suppressing lipid peroxide production using rat whole brain homogenate.
  • a d dY male mouse weighing 23 to 27 g was intravenously administered with 5 mg of the compound of the present invention (7-benzoyl-1-ethyl phenazinecarboxylate) obtained in Example 1, but no deaths were observed.
  • the compound of the present invention (7-benzoyl-1-ethyl phenazinecarboxylate) obtained in Example 1, but no deaths were observed.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des dérivés de phénazine représentés par la formule générale (I) dans laquelle R1 représente alkyle, aralkyle, ou aryle linéaire ou ramifié; et R2 ainsi que R3 sont identiques ou différents et représentent chacun hydrogène, aryle, nitro, cyano, alkylsulfonyle, arylsulfonyle, arylcarbonyle, aralkylcarbonyle, haloalkyle, ou haloalcoxy, à l'exclusion du cas où à la fois R2 et R3 représentent hydrogène. Les dérivés de phénazine présentent un excellent effet d'inhibition de la toxicité de l'acide glutamique.
PCT/JP1997/003675 1996-12-03 1997-10-14 Derives de phenazine WO1998024773A1 (fr)

Applications Claiming Priority (2)

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JP8/337493 1996-12-03
JP33749396 1996-12-03

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WO1998024773A1 true WO1998024773A1 (fr) 1998-06-11

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104957152A (zh) * 2014-09-30 2015-10-07 四川利尔作物科学有限公司 杀菌组合物及其应用
CN105418518A (zh) * 2014-09-18 2016-03-23 沈阳中化农药化工研发有限公司 一种吩嗪羧酸酯类化合物及其用途

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08198888A (ja) * 1995-01-25 1996-08-06 Nippon Chemiphar Co Ltd ジヒドロフェナジン誘導体
JPH09295976A (ja) * 1996-05-01 1997-11-18 Kirin Brewery Co Ltd 神経保護作用物質ｃｕ３９、その製造法および使用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08198888A (ja) * 1995-01-25 1996-08-06 Nippon Chemiphar Co Ltd ジヒドロフェナジン誘導体
JPH09295976A (ja) * 1996-05-01 1997-11-18 Kirin Brewery Co Ltd 神経保護作用物質ｃｕ３９、その製造法および使用

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105418518A (zh) * 2014-09-18 2016-03-23 沈阳中化农药化工研发有限公司 一种吩嗪羧酸酯类化合物及其用途
CN104957152A (zh) * 2014-09-30 2015-10-07 四川利尔作物科学有限公司 杀菌组合物及其应用
CN104957152B (zh) * 2014-09-30 2017-03-15 四川利尔作物科学有限公司 杀菌组合物及其应用

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