WO1998038989A1 - Preparations contenant des antagonistes d'acide amine excitateur exempts d'effets secondaires - Google Patents

Preparations contenant des antagonistes d'acide amine excitateur exempts d'effets secondaires Download PDF

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Publication number
WO1998038989A1
WO1998038989A1 PCT/JP1998/000844 JP9800844W WO9838989A1 WO 1998038989 A1 WO1998038989 A1 WO 1998038989A1 JP 9800844 W JP9800844 W JP 9800844W WO 9838989 A1 WO9838989 A1 WO 9838989A1
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Prior art keywords
amino acid
optionally substituted
hydrogen
acid
benzoyl
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PCT/JP1998/000844
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English (en)
Japanese (ja)
Inventor
Takayoshi Yoshikawa
Koji Takahashi
Ikuo Kato
Akira Kato
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Shionogi & Co., Ltd.
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Priority to JP53835298A priority Critical patent/JP4204073B2/ja
Priority to AU61186/98A priority patent/AU6118698A/en
Publication of WO1998038989A1 publication Critical patent/WO1998038989A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a pharmaceutical preparation containing an excitatory amino acid antagonist, and more particularly to a preparation with reduced side effects of the antagonist. More specifically, the present invention relates to a pharmaceutical preparation containing an N-amino acid or dicarboxylic acid to reduce side effects such as nephrotoxicity which may occur when an excitatory amino acid is administered.
  • Excitatory amino acids such as glutamate and diaspartate are important for neuronal activation as neurotransmitters in the central nervous system.
  • excitatory amino acids such as glutamate and diaspartate are important for neuronal activation as neurotransmitters in the central nervous system.
  • the extracellular accumulation of these excitatory amino acids induces excessive stimulation of nerve cells, causing various neurological disorders such as Parkinson's disease, senile dementia, Huntington's chorea, and epilepsy.
  • the above-mentioned Dalmes mate receptors are classified into an ion channel type and a metabolic type, and the ion channel type is further classified into three types based on selectivity for agonists. These are the N-methyl-D-aspartate (NMDA) receptor, the 2-amino-3- (3-hydroxy-5-methylisoxazole-4-yl) propanoate (AMP A) receptor, respectively. And called kainate receptors. ,
  • the NMDA receptor is selectively activated by agonists such as NMDA and ibotenic acid. This intense stimulation of the NMDA receptor causes a large amount of calcium ions to enter neuronal cells, which is thought to be one of the causes of neuronal cell death.
  • agonists such as NMDA and ibotenic acid.
  • This intense stimulation of the NMDA receptor causes a large amount of calcium ions to enter neuronal cells, which is thought to be one of the causes of neuronal cell death.
  • D-AP5 2-amino-5-phosphovaleric acid
  • CPP 3- [2-carboxypiperazine-4-yl] propyl-1-monophosphate
  • the NMDA receptor has an aosteric site (glycine binding site) to which glycine binds, in addition to the site that recognizes the agonist. It is known that binding of daricin to this glycine binding site significantly enhances NMDA receptor function. Recently, there has been interest in the development of antagonists or modulators of the glycine binding site, which allosterically act on the NMDA receptor as described above. 5,7-Dichlorokynurenic acid and the like are known as an antagonist to such a glycine binding site.
  • the AMPA receptor is selectively activated by agonists such as AMPA, glutamate and quisqualate.
  • agonists such as AMPA, glutamate and quisqualate.
  • 6, Quinoxaline (1,2) such as 7-dichro-8-nitro-1,4-dihydroxyquinoxaline-2,3-dione (ACEA 1021) 4_Benzodazepine
  • Japanese Patent Application Laid-Open No. 7-324084 discloses that a strong treatment for both the AMP A receptor and the glycine binding site of the NMD A receptor, and a more excellent treatment for the diseases and symptoms. A series of quinoxaline derivatives with effects have been described.
  • excitatory amino acid agonists have not yet been put to practical use as pharmaceuticals due to problems such as side effects.
  • excitatory amino acid antagonist having a quinoxaline skeleton is triggered by the renal cell death phenomenon caused by crystal precipitation in the renal tubule due to low solubility near neutrality, as reported, for example, for NBQX. It is known that renal toxicity develops as a result (J. Cerb Blood Flow Metab., Vol. 14, No. 2 (1994)).
  • references that disclose excitatory amino acid antagonists in addition to those described above include WO9532205, WO9609295, WO9608493, and WO 9 6 1 5 1 2 7 No., WO 9 6 10 0 2 3 No., W ⁇ 9 6 1 4 3 18 No. 6, W09 6 2 8 4 4 5 No., WO 9 6 1 9 4 7 6 No., W09 6 1 2 7 2 4, W09 6 1 2 7 No. 25, WO 964 065 1, WO 964 065, WO 9640 1 41, WO 9 07 8 55, WO 9 0 3 0 No.
  • the present inventors have conducted intensive studies in view of the above problems, and as a result, have found that when administering an excitatory amino acid antagonist, side effects such as nephrotoxicity can be reduced by using N-acyl amino acid or dicarboxylic acid in combination.
  • the present invention provides an excitatory amino acid antagonist-containing preparation (hereinafter referred to as the preparation of the present invention), which comprises an N-acylamino acid or a dicarboxylic acid.
  • the present invention provides a kit for preparing the preparation of the present invention, a method for reducing the side effects of an excitatory amino acid antagonist, and the like.
  • a preparation containing an excitatory amino acid antagonist which comprises an N-acyl amino acid or a dicarboxylic acid.
  • N-acyl amino acid has the formula:
  • Ra is hydrogen or an amino group
  • A represents an amino acid residue linked to an adjacent carbonyl group via an amino group in the molecule
  • R b and R c each independently represent an ⁇ -amino acid substituent at the ⁇ -amino acid).
  • RR 2 and R 3 are each independently hydrogen, hydroxy, halogen, nitro, cyano, optionally substituted amino, optionally substituted lower alkyl, or optionally substituted Lower cycloalkyl, optionally substituted lower alkoxy, optionally substituted lower alkyl rubonyl, lower alkyl optionally substituted rubamoyl, lower alkyl optionally substituted rubamoylamino, lower sulfamoyl optionally substituted by alkyl, which may also have sulfamoylamino substituted by lower alkyl, sulfonyl optionally substituted;
  • R 4 is hydrogen, hydroxy, optionally substituted lower alk kill, substituted Lower alkoxy which may be substituted, or lower cyclo which may be substituted
  • Y represents hydrogen, halogen, nitro, cyano, optionally substituted lower alkoxy, optionally substituted amino, or optionally substituted heterocycle, and R 1 and R 2 , R 2 and Y, R
  • R 1 is hydrogen or nitro
  • R 2 is hydrogen, nitro, halogen, or methyl halide
  • R 3 is hydrogen
  • R 4 is hydrogen or optionally substituted lower alkyl
  • ⁇ is hydrogen, halogen
  • the compound represented by the formula (I) is 6— (1,4 dihydro —4—oxo —1 monopyridyl) -17-nitro—2,3 (1H, 4H) —quinoxalinedione
  • N-acyl amino acid is N-benzoyl-i3-alanine or N-benzoyl 5-aminovaleric acid
  • the excitatory amino acid antagonist is a quinoxaline derivative
  • a method for reducing the side effects of an stimulating amino acid antagonist comprising using an N-acyl amino acid or a dicarboxylic acid in combination.
  • the excitatory amino acid antagonist which can be contained in the preparation of the present invention is, as described above, an effective amino acid for preventing and treating various diseases caused by extracellular accumulation of excitatory amino acids in the brain. It broadly means a drug that may cause some side effects, for example, nephrotoxicity, hepatotoxicity, dysuria, etc., and includes various angiogonists disclosed in the above-mentioned prior literature. Among them, quinoxaline derivatives are particularly preferred as the angiogonist particularly effective in reducing the side effects according to the present invention, and typically, 1,4-dihydroquinoxaline-12,3-dione such as the compound (I) is mentioned. Derivatives are exemplified. However, various excitatory amino acids having other chemical structures can be applied to the present invention. Excitatory amino acid agonites applicable to the present invention are exemplified in Tables 4-6 at the end of this specification.
  • halogen in the compound (I) examples include chlorine, fluorine, bromine, and iodine.
  • Lower alkyl means a straight or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, or hexyl. is there.
  • Lower cycloalkyl means cycloalkyl, preferably having from 3 to 6 carbon atoms, and is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • the lower alkoxy means the alkoxy derived from the lower alkyl, and is, for example, methoxy, ethoxy, propoxy, or butoxy.
  • each of the substituents is a lower alkyl (eg, methyl, ethyl, propyl, butyl, pentyl, hexyl, etc.) , Lower alkylcarbonyl, lower alkoxycarbonyl, lower alkoxycarbonylmethyl, halogen (F, C 1, Br), methyl halide (eg, CF 3 ), optionally substituted amino (eg, dimethylamino, Jechiruamino, Benzoiruamino etc.), Shiano, nitro, carboxy, Okiso, carboxymethyl, CHO, PO (OH) 2, OP_ ⁇ ( ⁇ _H) 2, PO (OCH 2 CH 3) 2, S_ ⁇ 3 H, SO 2 CH 3, S 0 2 CF 3 , optionally substituted phenyl (phenyl, p-nitrophenyl, p_methylphenyl, m-
  • the heterocycle in Y means a 5- to 7-membered aromatic or non-aromatic ring containing 1 to 4 identical or different heteroatoms selected from ⁇ , S and N atoms, but has pharmacological activity
  • a 5- or 6-membered ring containing an N atom is preferable, and examples thereof include a pyridine ring, an imidazole ring, a triazole ring, a pyrrolyl ring, a piperidine ring and the like.
  • substituent in the hetero ring examples include oxo, thioxo, halogen, nitro, cyano, amino, and acylamino (eg, acetylamino, benzoylamino, pyridylcarbonylamino), acylaminomethyl, di-lower alkylamino, carboxy, lower alkyl, Lower alkyl halides (eg, trifluoromethyl), Carboxy-lower alkyl, lower-alkoxy, halogenated lower-alkoxy (eg, trifluoromethoxy), lower-alkoxycarbonyl, lower-alkoxycarbonylmethyl, power optionally substituted by lower-alkyl Rubamoiruamino, which may be sul Hue carbamoyl ⁇ amino substituted by lower alkyl, S 0 3 H, SO 2 NH 2, NHC S NH 2, NHC SH, NH S_ ⁇ 2 NH, NH S_ ⁇ 2 CF 3, substituted (E
  • R 2 and Y, R 3 and ⁇ , or R 3 and R 4 together, form the same carbocyclic ring selected from 0, S and ⁇ atoms together with adjacent atoms.
  • a thiazolyl ring an imidazoline ring, an imidazolidine ring, an oxazolidine ring, a pyridine ring, a pyran ring, a thiopyran ring, a piperidine ring, a pyrazine ring, a morpholino ring, and a triazole ring. These may have the same substituents as in the case of the heterocyclic ring in the above.
  • the excitatory amino acid antagonist of the present invention may be a pharmaceutically acceptable salt, such as a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, or acetic acid, tartaric acid, or fumaric acid.
  • Salts with organic acids such as acids and sulfonic acids, or salts with inorganic bases such as sodium hydroxide and potassium hydroxide (ie sodium salts, potassium salts, etc.), or organic salts such as tris (hydroxymethyl) amino methane and choline
  • examples thereof include salts with bases, and may be hydrates such as monohydrate and dihydrate.
  • ⁇ -acyl amino acid It broadly refers to compounds that can reduce their side effects, especially nephrotoxicity, without adversely affecting the main effects of excitatory amino acid antagonists.
  • the acyl group may be either an aromatic acyl or an aliphatic acyl.
  • the aromatic acylamino acid is preferably an N-benzoyl derivative represented by the above formula II (hereinafter, also referred to as compound (II)).
  • the aliphatic acyl amino acid is preferably a dipeptide, for example, a dipeptide represented by the above formula III (hereinafter, also referred to as compound (III)).
  • Ra is preferably a p-amino group.
  • the amino acid in the amino acid residue represented by A means a natural or synthetic amino acid, the position of the amino group is not particularly limited, and may be a racemic form or an optically active form (D form or L form).
  • Natural amino acids include glycine, alanine, valine, leucine, isoleucine, proline, fenylalanine, tributofan, methionine, serine, threonine, cystine, tyrosine, asparagine, dalsuimin, aspartic acid, lysine, arginine, histidine Although glycine, alanine, phenylalanine, valine, lysine and the like are preferable.
  • A is a synthetic amino acid residue
  • an amino acid group represented by _NH—Xa—C ⁇ OH wherein Xa represents a lower alkylene which may be substituted.
  • the lower alkylene represented by Xa is preferably a linear or branched alkylene having 1 to 6 carbon atoms, and examples of the substituent include lower alkyl (methyl, isopropyl, etc.) and lower alkylthio (methylthio, etc.). ), Phenyl, benzyl, phenylthio, benzoylamino and the like.
  • Preferred examples of X a include unsubstituted ethylene and butylene.
  • the compound (II) include N-benzoyl-alanine, N-benzoyl-4-aminobutyric acid, N-benzoyl_5-aminovaleric acid, N-benzoyl-16-aminocaproic acid, and N-benzoyl- ⁇ - Aranin, Nyu- Benzoirubari down, Nyu- benzo I Rume Chio Nin, New alpha, epsilon - dibenzo I le lysine, Nyu- Benzoiru one Fuenirudarishin, Nyu- Benzoirufue two Ruaranin, Nyu- Benzoirugurishi N-benzoyl-3-alanine, N-benzoylglycine, p-aminohippuric acid, N-benzoylyl 5-aminovaleric acid and the like are preferred. is there. is there.
  • the two amino acids forming the dipeptide compound (III) are the same or different ⁇ -amino acids selected from the aforementioned natural or synthetic amino acids, and include tributofan, fenylalanine, glycine, alanine, Leucine, arginine and the like are exemplified. Therefore, examples of R b and R c include indolylmethyl, benzyl, hydrogen, methyl, isobutyl, and guanidinopropyl.
  • the compound (m) is preferably L-tributofan-L-alanine.
  • the dicarboxylic acid is preferably an aliphatic carboxylic acid, and examples thereof include a compound represented by the above formula: HOOC-Xb-Xc-COOH (IV) (hereinafter, also referred to as compound (IV)).
  • the alkylene in X c is preferably a linear or branched alkylene having preferably 1 to 10 carbon atoms, more preferably 3 to 10 carbon atoms, such as lower alkyl (methyl, isopropyl). ), Lower alkylthio (eg, methylthio), phenyl, benzyl, phenylthio, benzoylamino and the like.
  • ⁇ -ketoglutaric acid is exemplified.
  • the content ratio of the above-mentioned additive, that is, amino acid or dicarboxylic acid, in the preparation of the present invention can be appropriately set depending on the kind and content of the excitatory amino acid antagonist as an active ingredient or the kind and degree of expected side effects.
  • the molar ratio is about 0.1 to 200 equivalents, preferably about 0.1 to 10 equivalents, more preferably 1 to 10 equivalents to the excitatory amino acid antagonist. In ratio, it is about 0.5 to 100 equivalents, preferably about 1 to 0.5 equivalents.
  • the administration method of the preparation of the present invention may be in accordance with the administration method of the excitatory amino acid antagonist, and may be oral or parenteral administration, preferably parenteral administration, more preferably injection, particularly intravenous drip infusion. Administration.
  • the present invention The preparation may be in the form of an injection containing the above-mentioned active ingredient (excitatory amino acid antagonist) and an additive (N-acylamino acid or dicarboxylic acid) for reducing side effects, or may be an injection thereof. It may be a solid preparation for preparing a liquid at the time of use, for example, a lyophilized preparation. Further, the freeze-dried preparation may contain the active ingredient and the additive in a mixed or two-layered state.
  • One embodiment of the present invention may be a kit for use at the time of use in which the active ingredient and the additive are separately freeze-dried and combined into one set.
  • the composition of the kit may further include an aqueous solution for re-dissolving these components.
  • the content of the excitatory amino acid antagonist per single administration contained in the preparation of the present invention may be appropriately determined depending on the type of the anginaist, the target disease, and the like. For example, about 1 to: L0000 mg And preferably about 10-50 mg.
  • the dose of the excitatory amino acid antagonist contained in the preparation of the present invention may be appropriately set depending on the antagonist and the type of the target disease, and the like. It ranges from 1 to 1000 mg, preferably from 10 to 500 mg, and for parenteral administration, from about 1 to 500 mg. Dosage may be administered once or several times a day, or may be continuous.
  • the preparation of the present invention further comprises additives not required for reducing the side effects of the excitatory amino acid agonite, but for other purposes, for example, stabilizers, pH regulators, isotonic agents And the like may be arbitrarily contained.
  • the stabilizer examples include human serum albumin, aprotinin, L-ascorbic acid, sodium pyrosulfite, ⁇ -tocopherol and the like.
  • pH regulator examples include hydrochloric acid, citrate, acetate, phosphate, sodium hydroxide, sodium carbonate and the like.
  • tonicity agent examples include salt, glucose, mannitol and the like.
  • one of the methods of using the preparation of the present invention or the kit for preparation at the time of use is to combine an excitatory amino acid antagonist with a cis-amino acid or a dicarboxylic acid. This is a method for simultaneous administration as a formulation. As another method, two preparations containing the two preparations separately may be administered simultaneously or at a different time.
  • N-Benzoru] 3-Aranine (Tokyo Kasei) was suspended in physiological saline, and INNAOH was added to obtain a solution with a concentration of 40 mg / m 1, H9.7 (hereinafter referred to as solution A). Produced. By dissolving Compound S in this solution at a concentration of 10 mg / m 1, a solution for injection of Compound S with reduced side effects can be obtained.
  • solution B After suspending N-benzoyl-5-aminovaleric acid (Tokyo Kasei) in physiological saline, add 1 N Na ⁇ H to a concentration of 4 Omg / m and adjust the pH 9.7 solution (hereinafter referred to as solution B). ). By dissolving Compound S in this solution to a concentration of 1 OmgZml, an injection solution of Compound S with reduced side effects can be obtained.
  • solution C a dosing solution having a concentration of 1 O mgZm 1
  • the rat was lightly anesthetized with ether, and the solution C was used as compound S from the femoral vein 12.
  • the dose was 5 mg / kg. Radioactivity in the kidney was measured 15 minutes and 60 minutes after the administration.
  • Example 1 After the rat is anesthetized in the same manner as in (1) above, the above solution C containing compound S and ⁇ -benzoyl- ⁇ -alanine (N-benzoytri / 3-alanine) prepared in Example 1 are contained from the femoral vein. Solution A was co-administered. Each dose is 12.5 mg / kg for compound S and 5 O mg / kg for N_benzoyl- ⁇ -alanine. After the administration, the radioactivity was measured in the same manner as in (1) above.
  • Compound S was dissolved in an isotonic carbonate buffer having ⁇ 9.7 to prepare a dosing solution having a concentration of S mg Zm 1.
  • Five rats SD male male, body weight: 248.5-30.4.4 g were used, and the administration solution was repeatedly administered from the rat tail vein once a day for 3 days. The dose was administered such that Compound S was 25 mg / kg.
  • the kidneys were visually observed and then weighed, and H-E stained specimens were prepared according to a conventional method and observed under a light microscope.
  • an administration solution (5 mg / ml) of the compound S was prepared.
  • N-benzoyl / 3 / 3-alanine was dissolved in 0.5 N Na ⁇ H solution while heating at 50 to 60 ° C to prepare a 100 mg / m 1 solution.
  • the solution was diluted with physiological saline to prepare an administration solution having a concentration of 1 O mg / m 1 and a pH of 9.7.
  • five rats of the same species as in (1) above were used, and N-benzoyl / 3/3
  • the drug was administered via the rat tail vein, and one minute later, the compound S-containing solution was also administered via the tail vein, and both drugs were administered once a day for 3 days.
  • the dose was 25 mg / kg for both drugs.
  • blood was collected in the same manner as in (1) above, creatinine and urea nitrogen in plasma were measured, and the state of kidney tissues was observed.
  • an N-benzilol / 3-alanine administration solution (ZO mg Zml, 40 mg / m 1) was prepared, and the test was performed by changing the dose. Table 2 shows the results.
  • Tubular dilatation 5/5 2/5 1/5 0/5 Emptying of proximal tubule epithelium 5/5 2/5 1/5 2/5 Granular cast 2/5 0/5 0/5 0/5 Assembly Crystal in lumen 5/5 0/5 1/5 0/5 Regeneration of collecting duct epithelium 5/5 2/5 1/5 0/5 Hyperplasia of renal pelvis epithelium 3/5 1/5 1/5 1 / 5 Increase in kidney weight 2/5 1/5 1/5 0/5
  • solution D 14 C-labeled compound S was dissolved in an isotonic carbonate buffer at pH 9.7 to prepare a dosing solution with a concentration of 6.25 mg / m1 (hereinafter referred to as solution D). I do.
  • the same rat used in Test Example 1 was fixed in a Bollman cage, and solution D was applied from the tail vein at a rate of 4 ml / kg so that the concentration of compound S was 25 mgZkg / hr. The administration was continued for 1 hour. One hour after the end of the administration, the rats were bled to death and the radioactivity in the kidney was measured.
  • Hydrogen Nitro hydrogen Hydrogen 1 2nd position is methyl hydrogen 2 hydrogen Hydrogen 1 3 position is chlorine hydrogen Nitro hydrogen hydrogen 1 3 position is hydrogen hydrogen Nitro hydrogen Hydrogen 4 All fluorine hydrogen Nitro hydrogen Hydrogen 2 Chlorine hydrogen at 3 and 5 position Nitrogen Hydrogen Lower alkyl 1 3-position is Nitrogen Hydrogen Lower 7-alkyl substitution Hydrogen Hydrogen 0

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Abstract

On décrit des préparations comprenant des antagonistes d'acide aminé excitateur exempts d'effets secondaires, qui se caractérisent par le fait de contenir des acides n-acylamino ou des acides dicarboxyliques et d'être des préparations médicinales sûres, exemptes notamment de la néphrotoxicité propre aux antagonistes d'acide aminé excitateur.
PCT/JP1998/000844 1997-03-04 1998-03-02 Preparations contenant des antagonistes d'acide amine excitateur exempts d'effets secondaires WO1998038989A1 (fr)

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Application Number Priority Date Filing Date Title
JP53835298A JP4204073B2 (ja) 1997-03-04 1998-03-02 副作用が軽減された興奮性アミノ酸アンタゴニスト含有製剤
AU61186/98A AU6118698A (en) 1997-03-04 1998-03-02 Preparations containing excitatory amino acid antagonists relieved in side effects

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JP4893197 1997-03-04
JP9/48931 1997-03-04

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Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
NORDHOLM L., ET AL.: "THE NBOX STORY.", EXCITATORY AMINOACIDS. CLINICAL RESULTS WITH ANTAGONISTS, XX, XX, 1 January 1997 (1997-01-01), XX, pages 89 - 97 + 129, XP002911683 *

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