WO1990013539A1 - Nouveaux derives de piperazine a substitution n et medicament de traitement des troubles fonctionnels du cerveau - Google Patents

Nouveaux derives de piperazine a substitution n et medicament de traitement des troubles fonctionnels du cerveau Download PDF

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Publication number
WO1990013539A1
WO1990013539A1 PCT/JP1990/000553 JP9000553W WO9013539A1 WO 1990013539 A1 WO1990013539 A1 WO 1990013539A1 JP 9000553 W JP9000553 W JP 9000553W WO 9013539 A1 WO9013539 A1 WO 9013539A1
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group
integer
hydrogen atom
substituted
formula
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PCT/JP1990/000553
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English (en)
Japanese (ja)
Inventor
Kiyoshi Yoshida
Toyokazu Hiranuma
Mitsugu Hachisu
Yuko Ishii
Takako Taniguchi
Kiyoaki Katano
Fukio Konno
Takashi Tsuruoka
Shigeharu Inoue
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Meiji Seika Kaisha, Ltd.
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Publication of WO1990013539A1 publication Critical patent/WO1990013539A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

Definitions

  • the present invention relates to a novel N-substituted piperazine derivative which has an effect of improving the dysfunction of the brain of a mammal and thus has a medical effect of ameliorating various symptoms caused by dysfunction of the brain, and a pharmaceutical use thereof. More specifically, the present invention relates to a novel N-substituted piperazine-derived conductor, and to a cerebral dysfunction improving agent containing the piperazine derivative as an active ingredient.
  • mammalian brain tissue especially human brain tissue
  • anoxia blood oxygen deficiency
  • senile dementia is caused by impaired cerebral function caused by cerebrovascular disorder and impaired energy metabolism in the brain.
  • various drugs have been developed as anti-dementia drugs.
  • the mechanism of the occurrence of senile dementia, the memory disorder caused by cerebrovascular disorders, and the mechanism of the occurrence of the memory disorder have not yet been clarified. is there.
  • Methods for finding effective pharmaceutical compounds for these diseases are not yet well established.
  • Methods to induce memory impairment (amnesia amnesia) in normal animals include drugs that inhibit the synthesis of nucleic acids and proteins, administration of anticholinergic drugs, or brain anoxia, and ischemic load. There is a way to add it.
  • An object of the present invention is to provide a novel compound having a cerebral circulation improving effect and / or a cerebral cell protecting effect, and an ameliorating effect on dysfunction of a mammal, particularly a human brain.
  • the novel N-substituted piperazine derivative represented by the following general formula (I) according to the present invention has the following medical effects:
  • the drug was found to be a drug that is expected to be effective in preventing and treating vasospasm and preventing and treating the necrosis of cells in the cerebral ischemic area, as well as preventing sclerosis of the cerebral artery. did.
  • the present invention has been completed based on these findings.
  • m is an integer of 2 or 3
  • R a and R b may be the same or different from each other, and each may be a hydrogen atom or a straight or branched chain having 1 to 6 carbon atoms.
  • Z and Y are not the same as each other, and Z is represented by the following formula:
  • R 1 is a benzyl group, A halogen-substituted benzyl group, a phenyl group, a linear or branched alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to S carbon atoms, wherein R 2 and R 3 are the same as each other; A hydrogen atom or a halogen atom, each of which may be the same or different.
  • n Ri integer der 2-4 two R 8 are rather good be the same or different from one another, each represent a hydrogen atom, Nono b Gen atoms, hydroxycarboxylic group or a C 1 - 6 is a linear or branched alkyl group or an alkoxy group having 1 to S carbon atoms), or an ⁇ -naphthyloxyalkyl group represented by the following formula:
  • Ri is found in ⁇ is a hydrogen atom or a (-C S) alkyl group or a hydroxycarboxylic ⁇ ) ⁇ Le kill group or (- C s) alkoxycarbonyl sulfonyl ⁇ ) ⁇ alkyl group or the formula
  • R 4 , R s and R s may be the same or different from each other. And each is a hydrogen atom or -C s ) alkoxy group, provided that R 4 , R s and R s are not all hydrogen at the same time.
  • R 7 is a hydrogen atom or a halogen atom
  • ⁇ - ⁇ -diphenylalkyl group represented by the following formula:
  • r is an integer of 0 to 2
  • R 4 , R s and RG have the same meanings as described above
  • R c , R d, and R e are each a hydrogen atom or —C s ) an alkoxy group or a halogen atom
  • R f is a hydrogen atom or (To C s ) alkyl group, provided that when R f is an alkyl group, 7 is zero
  • q is an integer of 1-2, and RR and R j are each a hydrogen atom, a hydroxy group, a (-C s ) alkyl group or a (C ⁇ -) alkoxy group.
  • q is 1, at least one of R, R h and R j is a hydroxy group or an alkyl group), or a substituted benzyl group or a substituted phenethyl group represented by the following formula:
  • R k ( ⁇ C S) ⁇ represented by the alkyl group Ru Der) - represented by a full E Niruarukiru group] - arsenide mud carboxymethyl - omega - Arukinore - omega -Substituted piperazine derivatives or pharmacologically acceptable acid addition salts thereof are provided.
  • Examples of the above pharmaceutically acceptable acid addition salts include, for example, pharmaceutically acceptable inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and formic acid, acetic acid, Pharmaceutically acceptable organic compounds such as propionic acid, succinic acid, glycolic acid, lactic acid, lingic acid, tartaric acid, citric acid, maleic acid, benzoic acid, salicylic acid, and methanesulfonic acid Acids, and addition salts with amino acids such as aspartic acid and glutamic acid.
  • pharmaceutically acceptable inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and formic acid
  • acetic acid Pharmaceutically acceptable organic compounds such as propionic acid, succinic acid, glycolic acid, lactic acid, lingic acid, tartaric acid, citric acid, maleic acid, benzoic acid, salicylic acid, and methanesulfonic acid
  • the novel compound of the general formula (I) according to the present invention has an effect of protecting the brain from a decrease in cerebral function in a state of oxygen deficiency and an effect of suppressing cerebral vasoconstriction.
  • Has the effect of inhibiting the incorporation of calcium ion into brain nerve cells and has the effect of protecting brain cells in the hippocampus region of the brain, which are particularly sensitive to brain anoxia, from necrosis. Therefore, the compounds of the present invention are clinically useful for treating cerebral infarction, cerebral atherosclerosis, multi-infarct dementia, etc., and also have mental disorders such as spontaneous decline, It is useful for amelioration or treatment of disability, problem behavior, and impairment of intellectual functioning.
  • Preferred embodiments of the compounds of the general formula (I) according to the present invention include 19 groups of compounds represented by the following formulas (I-1) to (I-19).
  • n is an integer of 2 to 4
  • R 1 is a benzyl group
  • R 2 and R 3 are hydrogen atoms
  • Y 1 is a hydrogen atom 2-oxopyrrolidino- A triacetyl group or a 2-oxopyrrolidino-1-carbonylmethyl group].
  • n is an integer of 2 to 4
  • Ri is a benzyl group
  • R 2 and R 3 are hydrogen atoms
  • Y 2 is
  • R 4 , R s and R s may be the same or different and are each a hydrogen atom or a methoxy group.
  • n is an integer of 2 to 4
  • R 1 is a benzyl group
  • R 2 and R 3 are hydrogen atoms
  • Y 3 is
  • R 4 , R s and R s may be the same or different and each is a hydrogen atom or a methoxy group).
  • R 7 is a hydrogen atom or a halogen in Oh Li and Y 4 are down atomic hydrogen atom or a 2-Okiso pyro Li di Bruno - 1 Asechiru group or a 2-Okiso pyro Li Gino
  • n is an integer of 2 to 4
  • R 1 is a benzyl group or a halogen-substituted benzyl group
  • R z and R 3 are each a hydrogen atom or a halogen atom.
  • R 1 is a phenyl group
  • R 2 and R 3 are each a hydrogen atom.
  • n is an integer of 2 to 4
  • R 1 is a benzyl group
  • R 2 and R 3 are each a hydrogen atom
  • Y S is an ( ⁇ C S ) alkyl group
  • n is an integer of 2 to 4
  • R 1 is a benzyl group or a halogen-substituted benzyl group or a phenyl group
  • R 2 and R 3 are each a hydrogen atom or a halogen atom.
  • n is an integer of 2 to 4
  • R 1 is an alkyl group, an alkoxy group or a benzyl group
  • R 2 and R 3 are each a hydrogen atom
  • Y 7 Is a hydrogen atom or the following formula
  • R 4 , R s and R are each a hydrogen atom or a methoxy group, provided that when R 1 is a benzyl group, Is a hydrogen atom, and Y 7 is not a hydrogen atom].
  • n is an integer of 2 or 3
  • n is an integer of 2 to 4
  • two R s are each a hydrogen atom or a halogen atom
  • Y 7 is a hydrogen atom or
  • R 4 , R s and R e are each a hydrogen atom or a methoxy group. Razine derivatives.
  • n Ri integer der of 2 ⁇ 4 R 1 is benzyl group or Ri Njiru groups der base is halogen-substituted, R 2 and R 3 and Y s Ri Ah respectively a hydrogen atom following formula
  • m is an integer of 3
  • p is an integer of 0 to 3
  • R 7 is a hydrogen atom or a halogen atom
  • Y s is a hydrogen atom or
  • R 4 , R s and RS are each a hydrogen atom or a methoxy group.
  • n is an integer of 2 to 4
  • R 1 is a benzyl group
  • R 2 and R 3 are hydrogen atoms
  • Y 7 is hydrogen Atom or
  • t is an integer of 1 to 4, and R 1, R 2 and R 3 may be the same or different and each is a hydrogen atom or a methoxy group and is a hydrogen atom, 2-oxopyrroline.
  • N-substituted pyrazine derivative represented by the following formula (15):
  • n is an integer of 2 to 4
  • R 1 is a benzyl group
  • R 2 and R 3 are each a hydrogen atom
  • Y 1 D is
  • R 4 , R s and R s are a hydrogen atom or an (() alkoxy group, or Y 1 D is
  • R c , R d and R e are each a hydrogen atom or an (-) alkoxy group, particularly a methoxy group or a halogen atom.
  • f is a hydrogen atom or (C
  • R g, f ⁇ and R j are each a hydrogen atom, hydroxycarboxylic group or ( ⁇ C e) alkyl or ( ⁇ C e) alkoxy N-substituted piperazine derivatives represented by the formula: One ⁇ one
  • n is an integer of 2 to 4, and R a and R b are each
  • R 1 is a benzyl group
  • R 2 and R 3 are each a hydrogen atom, and Y 7 is a hydrogen atom or
  • R 4 , R s and R s are each a hydrogen atom or a methoxy group.
  • Perazine derivatives are each a hydrogen atom or a methoxy group.
  • n is an integer of 2 to 4
  • R 1 is a benzyl group
  • R 2 and R 3 are each a hydrogen atom
  • Y 11 is
  • R 4 , R s and R s are water An alkoxy group, particularly a methoxy group, and R k is a (C 1 -C s ) alkyl group).
  • R 7 is a hydrogen atom or a halogen atom
  • Y 12 is
  • n is and Y a Ri integer der of 2-4 or a hydrogen atom ( ⁇ C 4) alkyl group or the formula
  • q is an integer of 1 to 2
  • R ′ is a hydrogen atom or —;
  • R are each a ⁇ ⁇ of (to ( 4 ) alkoxy group).
  • Examples of specific compounds of the ⁇ -substituted piperazine derivatives of the above formula (e-1) include the compounds listed below.
  • Examples of specific compounds of the ⁇ -substituted piperazine derivatives of the above formula (I-2) include the compounds listed below.
  • N-substituted piperazine derivatives of the above formula (1-3) examples include those listed below.
  • Examples of specific compounds of the ⁇ -substituted piperazine derivatives of the above formula (1-4) include the compounds listed below.
  • N-substituted piperazine derivative of the formula (I-5) include the compound powers of Examples 2 to 5 described below.
  • Specific examples of the compound of the above formula (I-9) include the compounds of Examples 8, 9, 32, 33, 43, and 69 described below.
  • Specific examples of the compound of the formula (1-10) include the compounds of Examples 47 and 48 described below.
  • Specific examples of the compound of the formula (1-15) include the compounds of Examples 50, 51, 58, 59 and 60 described below.
  • Examples 1, 19, 44 and 54 described below, and are particularly important compounds in the present invention.
  • the compounds of Examples 1, 19, 44 and 54 were the compound of the above formula (1-1), the compound of the formula (I-3), the compound of the formula (I-6) and the compound of the formula (I-6)
  • the compound of -7) is also redundantly included.
  • N-substituted piperazine derivatives of the general formula (I) In the chemical production of the compound, piperazine or homopirazine is used as a raw material, and an appropriate method is used depending on the type or structure of the substituent Z to be introduced into the compound and the type or structure of the substituent Y. This can be carried out by introducing groups Z and Y into the starting compound. Examples of suitable synthesis methods include the following eight methods, that is, Method A to Method H. The compound of the general formula (I) can be produced by appropriately combining two or more of these methods A to H.
  • A-method This A-method is expressed by the following equation: no (C) ffl R a
  • m is an integer of 2 or 3
  • R a and R b have the same meanings as described above
  • B is an amino protecting group which is easily removed by hydrogenolysis, such as a benzyl group or Benzyloxy carbonyl group
  • A, B, R a , R b and m are as defined above, and then reacting the compound of formula (IV) with the deprotection of the amino protecting group B For this purpose, it is subjected to a hydrogenolysis reaction in a conventional manner to produce a compound of the above formula (la).
  • the condensation reaction between the 1-N-protected piperazine or homopirazine of the formula ( ⁇ ) and the aldehyde compound of the formula ( ⁇ ) is carried out in an organic solvent inert to the starting compound and the reactant.
  • an organic solvent such as methanol, ethanol, or dioxane
  • an acid such as hydrochloric acid or acetic acid
  • the compound of formula (IV) is subjected to hydrogenolysis for deprotection, and after the reaction is completed, the product is purified by crystallization, entrapment, gel gel chromatography, etc.
  • the compound of the present invention of the type represented by the formula (la) can be obtained. Further, this can be converted into an addition salt with an acid, if necessary, to obtain an acid addition salt thereof.
  • Method B This method is another alternative suitable for the preparation of the compounds of the invention of the type represented by formula (Ia) above. That is, The B method of
  • m is an integer of 2 or 3).
  • A-CH 2 -X ⁇ (wherein, ⁇ has the same meaning as described above, and X is a leaving group) is a compound represented by the formula: Condensed into
  • the degroup X in the above formula (V) can be a halogen atom, for example, chlorine, bromine, iodine and the like.
  • the group X is an alkylsulfonyloxy group or an arylsulfonyloxy group, for example, a methansulfonyloxy group.
  • Bases acting as acid binders include inorganic bases such as potassium carbonate and sodium carbonate, and triethylamine, diisopropylethylamine, N, N-dimethylaniline and the like. Organic salt Groups can be used.
  • the above condensation reaction should be carried out in an inert solvent, preferably in dichloromethane, DMF, dioxane, benzene, DMS0, etc., at a temperature range of -20 ° C to: L00 ° C. Can be.
  • the reaction is completed in 1 to 24 hours.
  • the reaction product is purified by crystallization, precipitation, silica gel column chromatography, etc., and if necessary, converted to an addition salt with an acid.
  • a compound of formula (3 ⁇ 41) that is, a compound of formula (Ia) or an acid addition salt thereof can be obtained.
  • C method This C method is
  • A—CH 2 —X (VE) (wherein A and X have the same meanings as above) or another functional compound is condensed in the presence of a base.
  • a halide represented by XE (K) (wherein X is the same leaving group as described above, and E has the same meaning as Y in general formula (I) except that it is not a hydrogen atom)
  • the compound or other functional compound is subjected to a condensation reaction in the presence or absence of a base, thereby obtaining the following formula
  • the tombstone X in the reactant compound of formula (K) above can be a halogen atom, such as chlorine, bromine, iodine, and the like.
  • the leaving group X can be an alkylsulfonyloxy group or an arylsulfonyloxy group, for example, a methansulfonyloxy group, a trifluoromethansulfonyloxy group, a ⁇ -toluenesulfonyloxy group, or the like.
  • the above condensation reaction can be performed even in the presence of a base.
  • an inorganic base such as potassium carbonate or sodium carbonate, or an organic base such as R-triethylamine, diisopropylethylamine, ⁇ , ⁇ -dimethylaniline or the like can be used.
  • the above condensation reaction can be carried out without a solvent or in a solvent, preferably in dichloronormethane, dichloroethane, DMF, dioxane or the like. The reaction is completed in a temperature range of -30 ° C to 100 ° C for 30 minutes to 24 hours.
  • m, r ′, R, R, R 4 , R s , R s , and Z have the same meanings as described above. (See the middle row of Example 20 below).
  • the above condensation reaction can be carried out without a catalyst or in the presence of an acid or a base.
  • the acid organic acids such as formic acid, acetic acid, methanesulfonic acid and P-toluenesulfonic acid, and inorganic acids such as hydrochloric acid and sulfuric acid can be used.
  • the above reaction can be carried out in a suitable solvent, preferably in methanol, ethanol, tetrahydrofuran, dioxane or a mixed solvent thereof with water or in water.
  • a suitable solvent preferably in methanol, ethanol, tetrahydrofuran, dioxane or a mixed solvent thereof with water or in water.
  • the reducing agent used in the method F can be a reducing agent such as NaBH 4 , LiAlH 4 , LiBH 4 , NaCNBHa, or the like.
  • a catalytic reduction method can be used.
  • the desired product is obtained by carrying out the reduction reaction in a suitable solvent, preferably ether, tetrahydrofuran, dioxane, etc., at a temperature in the range of 78 to 20 ° C for 1 to 24 hours. be able to.
  • G method This G method is expressed by the following formula (Id) (Wherein q is an integer of 1 to 2, and m, R a , R b , R 4 , R s , R 6 , and Z have the same meaning as described above).
  • R is an alkyl group having 1 to 6 carbon atoms.
  • Examples of the active ester of 2-oxopiperidino-1-acetic acid include N-hydroxyconodic acid imid and N-hydroxybene in the presence of N, N-dicyclohexylcarbodiimide.
  • Esters with sodium terazole may be used.
  • esters with an alkyloxycarbonyloxy group such as an ethoxycarbonyloxy group, an isobutyloxycarbonyloxy group, and the like can also be used.
  • the above condensation reaction can be carried out without a solvent or in an anhydrous organic solvent, preferably in dichloronorethane, dichloronorethane, DMF, dioxane or the like.
  • the reaction is completed in a temperature range of -30 ° C to 100 ° C for 30 minutes to 24 hours.
  • the reaction product can be purified by crystallization, precipitation, silica gel column chromatography, etc., and can be converted to an addition salt with an acid, if necessary.
  • the compound of the general formula (I) according to the present invention has an effect of suppressing uptake of calcium ions into the inner membrane of brain nerve cells, an effect of suppressing cerebral vasoconstriction, and a mouse induced by loading hypoxic conditions under reduced pressure. It has the effect of protecting mice from cerebral anoxia and the effect of protecting hippocampal cells from gerbil hippocampal brain cells from damage caused by ischemia.Tests demonstrating these effects are described below. Shown. In addition, a test for evaluating the acute toxicity of the compound of the present invention is described.
  • tfistar system rats of the brain was a two-fraction brain cells P was used to prepare.
  • KC1 present compound 4 s Ca uptake into depolarizing stimuli in by Li occurs brain cells P 2 fraction was examined the effect of suppressing.
  • the resulting precipitate in the absence of Ca Lee Nkyubeshi ® emissions solution (132mM NaCl, 5mM KC1, 1.2raM NaH 2 P0 4, 1.3mM MgCl 2, lOmM glucose, ⁇ Pi 20mM Tris-HCl. PH7,4) in was suspended in 17, then centrifuged 10 min at 000 xg, and suspended further resulting precipitate Lee Nkyubesho down solution containing 1.2 mM CaCl 2, and centrifuged 17, at 000 X g for 10 minutes.
  • the obtained precipitate was suspended in an incubation solution containing 1.2 mM CaCl 2 , and the obtained suspension was used for the experiment as brain cell P 2 planes.
  • the above operations were all performed at 4 ° C, and the following Ca uptake experiments were performed within 4 hours after the final precipitate was obtained.
  • the reaction was stopped by adding an equal volume of an ice-cold stop solution (120 mM NaCl, 5 mM KC1, 30 mM EGTA / Tris, PH7.4) and stirring. Then, the reaction mixture was suction-filtered on a Whatman glass filter (GF / C), and the residue on the filter was washed with a 5 mM permanent washing solution (132 mM choline-Cl, 5 mM KC1, 1.2 mM NaH a P0). 4. 1.3mM Washed twice with MgCl 2 , 1.2 mM CaCl 2 , 10 mM glucose, 20 mM Tris-HCl, PH7.4).
  • the radioactivity of the residue on the filter was measured using a liquid scintillation counter.
  • the addition of the test compound to the brain cells P 2 fraction was performed plain queue base cane down start at the same time.
  • the protein concentration was measured according to the method of Lowry et al. (See “J. Biol. Chem. J 193, 265-275 (1951)) using bovine serum albumin as a standard.
  • Basilar artery click Rebusu-liquid is 0.2 g
  • the thoracic aorta was about 1 hour equilibration under static tension force of 1.5 g.
  • KC1 was cumulatively added to the Graves solution in the organ bath, and the contractile response of the arterial specimen was recorded isometrically.
  • the test compound was added to the Claves solution 10 minutes before the addition of KC1 as described above.
  • the inhibitory effect of the test compound on arterial contraction by KC1 was evaluated by comparing the contraction of the artery before the addition of the test compound with the contraction of the artery by KC1 after the addition of the test compound.
  • test compound of the present invention aqueous solution dissolved in purified water containing 1% Tween 80 so that the dose is 0. lmfi / 10 g
  • the test compound of the present invention was prepared using 6 ddY mice in one group. Was administered intraperitoneally. Thirty minutes after administration, each animal was placed in a transparent sealed container, and the pressure was reduced to 190 nmHg by a vacuum pump. The time (seconds) from the start of decompression to the death of the mouse due to respiratory arrest was measured, and the measured time was defined as the survival time (seconds).
  • the ratio of the survival time of the group to which the compound of the present invention was administered to the survival time when the mouse control group containing purified water containing 1% Tween 80 but not containing the test compound was similarly tested was determined.
  • Table 3 shows the values obtained by multiplying by 100.
  • the control ischemia test group and the sham operation group were intraperitoneally administered with 100 g of 0.5 mJ2 of purified water containing only 1% Tween80 without containing the test compound.
  • surgery was performed in the ischemic group in the same manner as in the test substance administration group.
  • the sham operation group only the surgical operation to expose the carotid artery was performed, and the wound was closed with an adhesive resin after leaving it for 5 minutes without stopping blood flow.
  • the mouse was again fixed in a dorsal position under no anesthesia, and about 30 ⁇ of physiological saline was injected from the left ventricle via a sonde. Then, about 30 mL of 10% formalin buffer was injected to kill.
  • the whole brain was removed and immersed in 10% formalin buffer. After formalin-fixed brain was embedded in paraffin, it was cut into tissue sections of about 5 layers in thickness, and brain cells were stained by Nissl staining. The number of neural pyramidal cells within a certain area (250 / ⁇ ⁇ ) of the hippocampal CA1 site in this tissue section was counted and described in Table 4. Rats that do not perform the above processing at all The brains of the normal mouse group, the control ischemic group mouse and the sham operation group mouse brain were fixed in the same manner as described above, and within a certain area of the hippocampus CA1 site of the mouse brain of each group (250 bright spots). The number of neural pyramidal cells in 2 ) was counted and shown in Table 4.
  • the number of neural pyramidal cells i.e., the number of viable cells measured as described above was measured for the brains of rats in the control ischemic group to which the test compound was not administered. Higher than cell count
  • mice Acute toxicity was tested by oral administration using mice (ddY strain, body weight 25 g, 5 animals per group). In this test, the compounds of the Examples below 4 and the compound of Example 8 LD S. Values were found to be> 500 mg / kg.
  • the compound of the formula (I) of the present invention has low toxicity, and furthermore has a function of improving cerebral circulation and a function of protecting brain cells. It is useful as a disorder improving agent, and when used clinically, cerebral infarction, cerebral atherosclerosis, head trauma, multiple sclerosis, etc., and mental disorders based on these diseases, for example, spontaneous It is expected as a medical agent that is effective for improving depression, emotional disorders, problematic behavior, intellectual dysfunction, etc. Therefore, according to the second invention, the compound of general formula (I) is effective A composition for improving cerebral dysfunction is provided, which is contained as a component and contains a pharmaceutically acceptable liquid or solid carrier.
  • the compound of the general formula (I) of the present invention is administered orally or parenterally (intramuscularly, subcutaneously, intravenously, etc.).
  • Examples of the dosage form of the composition for oral administration include tablets, capsules, powders, granules, and syrups, and the dosage form of the composition for parenteral administration. Injections and suppositories.
  • conventional carriers that is, excipients, disintegrants, binders, lubricants, coloring agents, diluents and the like are incorporated.
  • Carriers that is, excipients, for example, lactose, bud sugar, corn starch, sorbite, crystalline cellulose, etc.
  • disintegrants for example, starch, sodium alginate, gelatin powder, carbonate Calcium, calcium citrate, dextrin, etc.
  • binders for example, dimethylcellulose, polyvinyl alcohol, polyvinyl ether, methylcellulose, ethylcellulose, gum arabic, gelatin, hydroxypropyl.
  • Pill cellulose, polyvinyl pyrrolidone and the like are used as lubricants, for example, talc, magnesium stearate, polyethylene glycol, hydrogenated vegetable oil and the like.
  • a buffer, a pH adjuster, a stabilizer and the like can be added to the active ingredient compound, if necessary.
  • the dose of the compound of the general formula (I) according to the present invention is not particularly limited depending on the age, weight, disease of the patient, and the degree of the symptoms of the patient, but is usually 100 to 1500 mg per adult per day. It is about.
  • Step 3- (2-Benjirufuwe Bruno carboxymethyl) obtained in the - 1-Purono ⁇ 0 Nord 1 ⁇ 30 g (5.37 mimol) and 1.83 g (6.93 mimol) of triphenylphosphine were dissolved in 40 ⁇ of acetonitrile, and 2.68 g (8.06 mimol) of carbon tetrabromide was added to the solution under ice cooling. ) Was added little by little. After stirring for 1 hour under permanent cooling and for 2 hours at room temperature, the solvent was distilled off from the reaction solution under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: ethyl acetate-hexane (1:10)) to give the title compound as a colorless oil (1.31 g, 80%). Was.
  • the compound of the formula (I) according to the present invention has low acute toxicity and, as is clear from the above test examples, inhibits the uptake of calcium ions into nerve cells of the mammalian brain. Since it has inhibitory activity, it has the effect of protecting brain cells under ischemic conditions and suppressing cell necrosis in the cerebral ischemic area. In addition, it has the activity of suppressing cerebral vasoconstriction, and thus has the effect of improving cerebral circulation disorders.
  • the compound of formula (I) according to the present invention shows that the survival of mammals in the brain anoxic state caused by the loading of oxygen-deficient conditions under low pressure.
  • the compound of the present invention promotes the supply of oxygen to the brain and prolongs the waste of the brain by prolonging the time, thereby protecting the animal's life from brain anoxia. It may be that the consumption of oxygen and ATP is decreased or the energy metabolism and circulation of the brain are improved. Therefore, according to the present invention, it is When administered to a patient, the compound can provide a compound expected to be useful as a medicament for improving impaired brain function.

Abstract

L'invention se rapporte à de nouveaux dérivés de pipérazine à substitution N représentés par la formule (I) et à des sels de ces dérivés; où m représente un nombre entier égal à 2 ou 3; Ra et Rb peuvent être identiques ou différents entre eux et représentent chacun un hydrogène ou un alkyle; Z et Y sont différents entre eux et Z représente un phénoxyalkyle substitué, un φ,φ-diphénylalkyle substitué ou non, un φ-naphtyloxyalkyle substitué ou non ou un φ-hydroxy-φ-phénylalkyle substitué ou non, alors qu'Y représente un hydrogène, un alkyle, un hydroxyalkyle, un alkoxycarbonylalkyle, un 2-oxopyrrolidino-1-acétyle, un 2-oxopyrrolidino-1-carbonylméthyle, un benzyle à substitution alkoxy, un φ-hydroxy-φ-phénylalkyle substitué ou non, un φ,φ-diphénylalkyle substitué ou non, un benzoyle substitué, un benzoylealkyle substitué, un φ-hydroxy-φ-(phényle substitué)-alkyle substitué ou non, un benzyle à substitution hydroxy ou à substitution alkyle, un phénéthyle substitué, ou un φ-hydroxy-φ-alkyle-φ-phénylalkyle substitué ou non. Ces composés ont une toxicité aiguë réduite et une action inhibitrice de l'incorporation d'ions de calcium dans les cellules nerveuses du crâne d'un mammifère, de sorte qu'ils peuvent protéger les cellules nerveuses ischémiques pour empêcher ces cellules de provoquer une nécrose. Ces composés ont également une action inhibitrice de la constriction cérébrovasculaire, de sorte qu'ils peuvent servir à traiter les troubles de la circulation cérébrale, et ils ont en outre une action de prolongation du temps de survie d'un mammifère en état d'anoxie cérébrale dû à l'effet produit par un manque d'oxygène de pression faible. Ces composés sont par conséquent utiles comme remède pour des patients souffrant de troubles fonctionnels du cerveau.
PCT/JP1990/000553 1989-04-28 1990-04-27 Nouveaux derives de piperazine a substitution n et medicament de traitement des troubles fonctionnels du cerveau WO1990013539A1 (fr)

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JP1/107784 1989-04-28
JP10778489 1989-04-28

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0623605A2 (fr) * 1993-05-06 1994-11-09 Bayer Ag Piperazines substituées comme agents antirétroviraux
WO1998002151A2 (fr) * 1996-07-12 1998-01-22 Leukosite, Inc. Antagonistes des recepteurs de la chemokine et procedes d'utilisation de ces derniers
WO1998037077A1 (fr) * 1997-02-24 1998-08-27 Zymogenetics, Inc. Mimetiques de calcitonine
WO2000039110A1 (fr) * 1998-12-24 2000-07-06 Astrazeneca Ab Derives homopiperazine en tant qu'inhibiteurs selectifs de l'emopamile
US6288084B1 (en) 1998-09-04 2001-09-11 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6323206B1 (en) 1996-07-12 2001-11-27 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
WO2003068236A1 (fr) * 2002-02-18 2003-08-21 Glaxo Group Limited Derives de piperidine et de piperazine possedant une affinite pour les recepteurs de type 5ht-1
US6737425B1 (en) 1998-07-21 2004-05-18 Eisai Co., Ltd. N,N-substituted cyclic amine derivatives
WO2014156196A1 (fr) * 2013-03-29 2014-10-02 一般社団法人ファルマバレープロジェクト支援機構 Agent thérapeutique pour le diabète de type 2
JP2021522297A (ja) * 2018-05-04 2021-08-30 コリア リサーチ インスティチュート オブ バイオサイエンス アンド バイオテクノロジーＫｏｒｅａ Ｒｅｓｅａｒｃｈ Ｉｎｓｔｉｔｕｔｅ Ｏｆ Ｂｉｏｓｃｉｅｎｃｅ Ａｎｄ Ｂｉｏｔｅｃｈｎｏｌｏｇｙ 癌細胞の遊走及び浸潤抑制を介した癌転移抑制剤

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JPS58124776A (ja) * 1982-01-21 1983-07-25 Nippon Chemiphar Co Ltd 新規ピペラジン誘導体およびその製造法ならびにこれを含有する脳循環改善剤
JPS58210076A (ja) * 1982-05-25 1983-12-07 フオルドナル・エセ・ア ピペラジン誘導体
JPS5920275A (ja) * 1982-06-29 1984-02-01 ギスト・ブロカデス・ナ−ムロ−ゼ・フエンノ−トチヤツプ ピペラジン誘導体、その製造法並びにこれらを含有する薬剤処方物
JPS59101475A (ja) * 1982-12-02 1984-06-12 Nippon Chemiphar Co Ltd 新規ピペラジン誘導体およびその製造法ならびにこれを含有する脳循環改善剤
JPS59134785A (ja) * 1982-12-28 1984-08-02 リヒタ−・ゲデオン・ベジエセテイ・ジヤ−ル　ア−ル・テ−・ ベンズヒドリルピペラジン誘導体
JPH01104041A (ja) * 1987-07-15 1989-04-21 Shionogi & Co Ltd Ｎ−［（２−オキソ−１−ピロリジニル）アセチル］ピペラジン誘導体、その製造方法および老人性痴呆症薬

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Publication number Priority date Publication date Assignee Title
JPS50121285A (fr) * 1974-03-12 1975-09-23
JPS5557572A (en) * 1978-10-20 1980-04-28 Ferrosan Ab Diphenylbutyllpiperazinecarboxamide and carbothioamide*its acid addition salt*its manufacture and medical composition containing it
JPS58124776A (ja) * 1982-01-21 1983-07-25 Nippon Chemiphar Co Ltd 新規ピペラジン誘導体およびその製造法ならびにこれを含有する脳循環改善剤
JPS58210076A (ja) * 1982-05-25 1983-12-07 フオルドナル・エセ・ア ピペラジン誘導体
JPS5920275A (ja) * 1982-06-29 1984-02-01 ギスト・ブロカデス・ナ−ムロ−ゼ・フエンノ−トチヤツプ ピペラジン誘導体、その製造法並びにこれらを含有する薬剤処方物
JPS59101475A (ja) * 1982-12-02 1984-06-12 Nippon Chemiphar Co Ltd 新規ピペラジン誘導体およびその製造法ならびにこれを含有する脳循環改善剤
JPS59134785A (ja) * 1982-12-28 1984-08-02 リヒタ−・ゲデオン・ベジエセテイ・ジヤ−ル　ア−ル・テ−・ ベンズヒドリルピペラジン誘導体
JPH01104041A (ja) * 1987-07-15 1989-04-21 Shionogi & Co Ltd Ｎ−［（２−オキソ−１−ピロリジニル）アセチル］ピペラジン誘導体、その製造方法および老人性痴呆症薬

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0623605A3 (fr) * 1993-05-06 1995-03-01 Bayer Ag Piperazines substituées comme agents antirétroviralin.
EP0623605A2 (fr) * 1993-05-06 1994-11-09 Bayer Ag Piperazines substituées comme agents antirétroviraux
US6323206B1 (en) 1996-07-12 2001-11-27 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
WO1998002151A2 (fr) * 1996-07-12 1998-01-22 Leukosite, Inc. Antagonistes des recepteurs de la chemokine et procedes d'utilisation de ces derniers
WO1998002151A3 (fr) * 1996-07-12 1998-06-25 Leukosite Inc Antagonistes des recepteurs de la chemokine et procedes d'utilisation de ces derniers
US6281212B1 (en) 1996-07-12 2001-08-28 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
WO1998037077A1 (fr) * 1997-02-24 1998-08-27 Zymogenetics, Inc. Mimetiques de calcitonine
US6124299A (en) * 1997-02-24 2000-09-26 Zymogenetics, Inc. Calcitonin mimetics
US6395740B1 (en) 1997-02-24 2002-05-28 Zymogenetics, Inc. Calcitonin mimetics
US6737425B1 (en) 1998-07-21 2004-05-18 Eisai Co., Ltd. N,N-substituted cyclic amine derivatives
US6288084B1 (en) 1998-09-04 2001-09-11 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6288083B1 (en) 1998-09-04 2001-09-11 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
WO2000039110A1 (fr) * 1998-12-24 2000-07-06 Astrazeneca Ab Derives homopiperazine en tant qu'inhibiteurs selectifs de l'emopamile
WO2003068236A1 (fr) * 2002-02-18 2003-08-21 Glaxo Group Limited Derives de piperidine et de piperazine possedant une affinite pour les recepteurs de type 5ht-1
WO2014156196A1 (fr) * 2013-03-29 2014-10-02 一般社団法人ファルマバレープロジェクト支援機構 Agent thérapeutique pour le diabète de type 2
JPWO2014156196A1 (ja) * 2013-03-29 2017-02-16 国立大学法人 熊本大学 ２型糖尿病治療剤
JP2021522297A (ja) * 2018-05-04 2021-08-30 コリア リサーチ インスティチュート オブ バイオサイエンス アンド バイオテクノロジーＫｏｒｅａ Ｒｅｓｅａｒｃｈ Ｉｎｓｔｉｔｕｔｅ Ｏｆ Ｂｉｏｓｃｉｅｎｃｅ Ａｎｄ Ｂｉｏｔｅｃｈｎｏｌｏｇｙ 癌細胞の遊走及び浸潤抑制を介した癌転移抑制剤
JP7111390B2 (ja) 2018-05-04 2022-08-02 ブイエスファーマテック 癌細胞の遊走及び浸潤抑制を介した癌転移抑制剤

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