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WO1995002407A1 - Neuroprotecteur et nouvel ester orotique - Google Patents

Neuroprotecteur et nouvel ester orotique Download PDF

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Publication number
WO1995002407A1
WO1995002407A1 PCT/JP1994/001134 JP9401134W WO9502407A1 WO 1995002407 A1 WO1995002407 A1 WO 1995002407A1 JP 9401134 W JP9401134 W JP 9401134W WO 9502407 A1 WO9502407 A1 WO 9502407A1
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WIPO (PCT)
Prior art keywords
cerebral
orotic acid
group
pharmaceutically acceptable
acceptable salt
Prior art date
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PCT/JP1994/001134
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English (en)
Japanese (ja)
Inventor
Hiraku Akiho
Akihiko Iwai
Shin-Ichi Tsukamoto
Kazuo Koshiya
Tokio Yamaguchi
Original Assignee
Yamanouchi Pharmaceutical Co., Ltd.
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Application filed by Yamanouchi Pharmaceutical Co., Ltd. filed Critical Yamanouchi Pharmaceutical Co., Ltd.
Priority to AU70850/94A priority Critical patent/AU7085094A/en
Publication of WO1995002407A1 publication Critical patent/WO1995002407A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/557—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. orotic acid
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim

Definitions

  • the present invention relates to a neuroprotective agent, a method for treating a neuronal degenerative disease based on a neuronal protective effect, and an orotic acid, an orotic acid ester for producing a neuroprotective agent for treating a neuronal degenerative disease, or a salt thereof. It relates to the use of pharmaceutically acceptable salts, and more specifically, a drug which can be effectively used for treating stroke, especially cerebral infarction, cerebral thrombosis, cerebral hemorrhage and subarachnoid hemorrhage, and other degenerative diseases of neuronal cells.
  • orotic acid is a precursor of nucleic acid pyrimidine nucleotides, and is also one of the substances involved in protein synthesis in vivo.
  • This orotic acid is also known to play a role as a coenzyme in metabolism such as mutual transfer of sugars, production of polysaccharides, and biosynthesis of phospholipids.
  • Oroto acid also known as vitamin B 1 3, it or the like indicating a protective effect against various hepatic disorders, it has been demonstrated by the already many studies.
  • orotic acid has an anti-hypoxic effect on the liver (Japanese Patent Laid-Open No. 63-196517, Krug M., et al. , Psychopharmacology, 1977, 53, p. 73-78).
  • JP 6 3 - 1 9 6 5 1 7 discloses, although Oroto acid are described to exhibit weak antihypoxic action, "Oroto acid is vitamin B 1 3 is vitamin-like It is known that it exerts a protective effect in the case of various poisonings and disorders of the liver by assisting hepatocytes in assimilating, detoxifying and regenerating functions. " In addition, it only states that "When orotic acid is used independently, it has only a weak anti-hypoxic effect on the liver parenchyma, and an even weaker effect on the central nervous system.” No mention is made of the protective effect on nerve cells.
  • orotic acid can be used as a drug for hepatic disorders or as a nootropic drug, and its application as a neuroprotective agent Had not been tried at all.
  • the present invention has been made in view of such problems of the related art.
  • the aim is to find a novel cytoprotective effect of orotic acid, a neuroprotective agent that can treat disorders and diseases associated with damage and degeneration of nerve cells.
  • Another object of the present invention is to provide a novel orotic acid ester which has not been produced conventionally.
  • Another object of the present invention is to provide a neuroprotective agent having a wide "therapeutic time window" for cerebral ischemia, a therapeutic method based on a neuronal protective effect, and a therapeutic method.
  • An object of the present invention is to provide use of orotic acid, orotic acid ester or a pharmaceutically acceptable salt thereof for producing the neuroprotective agent of the present invention.
  • orotic acid and orotic acid ester have a neuronal protective action, which is a novel drug effect that has not been known before, and DISCLOSURE OF THE INVENTION that the inventors of the present invention have found that orotic acid esters have an excellent ability to enter the brain.
  • the nerve cell protective agent of the present invention is characterized in that a compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof is used as an active ingredient.
  • R in the formula is a hydrogen atom, C 1- (: 10 linear, branched or cyclic Represents a alkyl group. )
  • the compound (I) which is an active ingredient of the agent for protecting neurons of the present invention includes a novel oral acid ester represented by the following general formula (I) or a salt thereof, which is not described in the literature.
  • the present invention also encompasses the invention of these chemical substances, and according to the present invention, these chemical substances are also provided.
  • R represents 2-ethylbutyl group, sec-butyl group or cyclopentyl group.
  • the neuroprotective agent of the present invention is effective for treating neurodegenerative diseases.
  • neuronal protective agent refers to a neuronal protective effect by inhibiting the degeneration or necrosis of neurons in acute or subacute, or chronic phases caused by neuronal degenerative diseases. It refers to the drug that performs.
  • neurocellular degenerative disease refers to diseases caused by degeneration of neurons such as stroke, global cerebral ischemia, focal cerebral ischemia, head trauma, spinal cord injury, axonal injury, dementia, and Parkinsonism.
  • Such a protective action against neurons in animal experiments suppresses neuronal necrosis observed in a whole cerebral ischemia model or a local cerebral ischemia model by administration before or after ischemia.
  • neuroprotective agents are clinically Is used for the purpose of suppressing neuronal necrosis caused by various ischemic conditions such as stroke and cerebral arteriosclerosis, or head trauma or spinal cord injury.
  • ⁇ stroke '' includes cerebral infarction, Cerebral hemorrhage and subarachnoid hemorrhage shall be included.
  • the nerve cell protective agent of the present invention has the following formula:
  • R represents a linear, branched or cyclic alkyl group of H, C1 to C10.
  • Examples of the C 1 to C 10 linear, branched or cyclic alkyl group include, but are not particularly limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl.
  • octyl group nonyl group, decyl group, isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, isopentyl group, isohexyl group, 2-ethylbutyl group, isoheptyl group, 3- Examples thereof include an ethylpentyl group, an isooctyl group, a 4-ethylhexyl group, an isononyl group, a 5-ethylheptyl group, an isodecyl group, a 6-ethyloctyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group.
  • C1-C8 is preferable as the alkyl group of the straight chain or the branching technique, and C5-C8 is preferable as the cyclic alkyl group. Among them, a methyl group and an ethyl group are particularly preferred.
  • orotic acid itself tends to be slightly poor in solubility and in the brain In addition, it cannot be said that there is no possibility that peripheral toxicity will occur at high doses, and it is considered that the action point where orotic acid exerts a neuroprotective effect is central.
  • drugs in order for drugs to act centrally, they need to cross the blood-brain barrier of the brain and be taken up by cells in the brain.
  • the brain restricts the transfer of drugs from the blood into tissues at the blood-brain barrier, and some drugs cannot cross the blood-brain barrier at all. Therefore, it can be said that as a centrally acting drug, a drug that can easily pass through the blood-brain barrier and has a high level of translocation into the brain has good properties.
  • esterifying orotic acid it is preferable to improve the solubility and pharmacokinetics by esterifying orotic acid to increase the concentration of orotic acid in the brain and reduce the concentration of peripheral orotic acid.
  • particularly preferred orotate alkyl esters include orotate methyl ester and orotate ethyl ester.
  • orotic acid and orotic acid ester include keto enol tautomers, and any of these isomers or a mixture thereof can be used.
  • the orotic acid ester may have an optical isomer depending on its kind, and in such a case, both the D-form and the L-form can be suitably used.
  • Suitable salts of orotic acid and orotic acid ester include all suitable pharmaceutically acceptable salts, and specifically include alkali metals such as sodium and potassium, and alkali metals such as calcium and magnesium. Examples thereof include salts with inorganic metals such as lithium earth metals, and salts with organic bases such as triethylamine and methylglucamine.
  • orotic acid, orotic acid ester or a salt thereof may be in various forms.
  • hydrates, solvates, and polymorphs can be suitably used.
  • Formulations containing compound (I) or compound (I) included in compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient including a mixture with other active ingredients
  • Parenteral administration such as instillation (continuous intravenous administration) is suitable for the indications of the drug of the present invention such as acute stroke.
  • Parenteral injections include sterile aqueous and non-aqueous solutions, suspensions, and emulsions.
  • Diluents commonly used for aqueous solutions and suspensions include distilled water for injection and physiological saline, and buffers such as citrate buffer 'and phosphate buffer. Liquids can also be used.
  • non-aqueous solutions and suspending agents include surfactants such as polyoxyethylene higher fatty acid esters, polyoxyethylene sorbitan higher fatty acid esters, polyoxyethylene hydrogenated castor oil, and vegetable oils such as olive oil. Oils, solvents such as ethanol, and glycols such as propylene glycol and polyethylene glycol are used.
  • Such a composition (such as an injection) further contains lactose, glucose, sucrose, mannite, saccharides such as sorbit, xylite, amino acids such as glycine and arginine, and other conventional tonicity agents and preservatives. And may contain additives such as wetting agents, emulsifiers, dispersants, stabilizers, and solubilizing or dissolving accelerators. No.
  • Such a liquid composition can be sterilized by filtration through a bacteria retaining filter, blending of a bactericide or irradiation.
  • these compositions can be prepared as a solid sterile composition by freeze-drying or the like, and dissolved in an injectable solvent such as sterile water before use to obtain a preparation form that can be used.
  • the above additives in other formulations include starches such as corn starch and potato starch, crystalline cellulose, calcium sulfate, calcium lactate, synthetic aluminum gateate, calcium hydrogen phosphate, maleic anhydride, magnesium aluminate metasilicate , Carboxymethylcellulose calcium, magnesium stearate, talc, hydrogenated vegetable oils, fatty acid mono-, di-, triglycerides, hydroxypropylcellulose, polyvinylpyrrolidone and other commonly used carriers, excipients, lubricants, disintegrants, Binders, emulsifiers, wetting agents, preservatives, dispersants, stabilizers, solubilizing or dissolving accelerators, flavoring agents, flavoring agents, and the like can be used.
  • starches such as corn starch and potato starch, crystalline cellulose, calcium sulfate, calcium lactate, synthetic aluminum gateate, calcium hydrogen phosphate, maleic anhydride, magnesium aluminate metasilicate , Car
  • the dose of the neuroprotective agent of the present invention can be appropriately changed depending on the type of stroke (acute or subacute), administration method, prevention, or treatment.
  • the dose per dose is from lmg to 5g, preferably from 100mg to lg, and it is good to administer it 1 to 3 times a day.
  • vertebrate is not particularly limited, and includes humans and other primates, mammals (such as dogs, cats, cows, pigs, and horses), It includes fish, birds, etc., and among them, humans and other primates and mammals are preferable, and humans are more preferable.
  • orotic acid and known orotic acid esters may be commercially available, and may also be obtained by a conventionally known production method (Experimental Chemistry Course, edited by The Chemical Society of Japan, 4th edition). 2nd edition, Vol. 22, pages 43-83).
  • novel compound (H) of the present invention can also be produced according to a conventional method for producing an ester, particularly according to a conventionally known production method (Experimental Chemistry Lecture, edited by The Chemical Society of Japan, 4th edition, Vol. 22, pages 43-83). it can.
  • the typical production method is exemplified below.
  • R 1 represents the same as described above, and X represents a hydroxyl group or an activation group thereof.
  • the compound of the present invention represented by the general formula (I) comprises an orotic acid represented by the general formula (no) or an activated derivative thereof, and an alkanol represented by the general formula (W) or an activated It can be produced by reacting with a derivative.
  • Examples of the activated derivatives of orotic acid include salts of orotic acid with metals such as sodium, potassium, lithium, and magnesium, and triethylen. Salts with organic amines such as luminin, acid halides such as orotic acid sulfide, orotic acid bromide, orotic acid chloride, orotic acid anhydride, and orotic acid with monoalkyl esters of carbonic acid and p-toluenesulfonic acid Usual esters of orotic acid such as mixed acid anhydrides, orotic acid methyl ester, orotic acid ethyl ester, and orotic acid propyl ester; and orotic acid and 1-hydroxybenzotriazole or N-hydroxysuccinic acid imid
  • Activated derivatives of alkynol include alkyl halides in which X is a halogen atom such as an iodine atom, a bromine atom, and a chlorine atom, and X represents methanesulfonyl
  • Alkyl sulfonate which is an organic sulfonate residue, phosphate ester of alcohol, and the like.
  • the reaction conditions depend on the type of the raw material compounds, for example, esterification of orotic acid with alkynolic acid, orotic acid halide, active ester, esterification of mixed acid anhydride with alkynol, It depends on the reaction between the salt of orotic acid and the active derivative of arkinol and the reaction between the usual ester of orotic acid and arkinol.
  • the reaction is carried out without solvent or in dichloromethane, dichloroethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, ether, tetrahydrofuran, dioxane, acetone, acetonitrile, dimethylsulfoxide, dimethylformamide, etc.
  • the reaction is performed in an organic solvent inert to the reaction.
  • sulfuric acid p -In the presence of an acid catalyst such as toluenesulfonic acid or potassium carbonate, potassium hydroxide, sodium hydroxide, pyridine, dimethylaniline, triethylamine, 4-dimethylaminopyridine, 4-pyridinopyridine, potassium methylate, sodium
  • an acid catalyst such as toluenesulfonic acid or potassium carbonate, potassium hydroxide, sodium hydroxide, pyridine, dimethylaniline, triethylamine, 4-dimethylaminopyridine, 4-pyridinopyridine, potassium methylate, sodium
  • a base catalyst such as an alkali metal alcoholate such as methylate.
  • the reaction is advantageously carried out at room temperature to under heating or at reflux temperature.
  • the compound (IT) thus produced is isolated and purified as a free compound, a salt thereof, a hydrate thereof, a solvate thereof, or a polymorphic substance.
  • isolation and purification can be carried out by using ordinary chemical operations such as extraction, filtration, recrystallization, and various types of mouth chromatography.
  • the obtained 2-ethyl butyl orotate was analyzed by NMR, elemental analysis, and the like, and its physicochemical properties were examined. The obtained results are shown below. Show.
  • Example 2 The same operation as in Example 1 was repeated using 6 g of orotic acid methyl ester and 300 ml of 1-methylpropanol to obtain 2.38 g of orotic acid sec-butyl ester.
  • the physicochemical properties of this substance are shown below.
  • a bilateral common carotid artery occlusion reperfusion model of a murine rat was used, and as a regional cerebral ischemia model, a rat middle cerebral artery ligation model (MCA model) was used.
  • MCA model rat middle cerebral artery ligation model
  • Kirino et al. Method (Kirino T., Brain Res.239: 57-69 , 1982) i.e. c according to body weight 70 to 8 0 g male system gerbil of (purchased skilled Name: Seiwa) using a 1.
  • a midline incision was made in the anterior cervix, the bilateral common carotid arteries were exposed, occluded with a Sugita clip, and the occlusion was released 5 minutes later.
  • 37 ⁇ l e C rectal temperature measurement
  • orotic acid 30 Omg / kg (suspended in 0.5% methylcellulose solution) was intraperitoneally administered.
  • the brain was excised and frozen to make frozen sections.
  • the obtained frozen sections were stained by the Hematoxylin-Eosin method, and hippocampal CA1 neurons were observed. Histological examination was performed under an optical microscope, and the degree of neuronal damage in the hippocampal CA1 area was evaluated as follows: no damage (score 0), mild necrosis (score 11), moderate necrosis (score 1). -2) and complete necrosis (score 1-3).
  • Example 4 The same operation as in Example 4 was repeated except that a 0.5% methylcellulose solution was intraperitoneally administered as a control to the sand rat.
  • Example 4 even in the animal ischemia model, even after 24 hours from ischemia, orotic acid was It has been shown that the administration almost completely inhibits necrosis of nerve cells, and this fact is extremely remarkable. As described above, the therapeutic period of administration is remarkably wide and the neuroprotective effect is unique. Therefore, medical treatment for current ischemia, that is, after falling into ischemia, In the current medical treatment, in which medical treatment is started after a lapse of a fixed time, treatment with the neuronal protective agent of the present invention containing orotic acid as an active ingredient is expected to have a great clinical effect.
  • Orotate is rapidly degraded by carboxylesterase in the periphery (mainly in blood and liver) when administered peripherally to sand rats and rats, and provides an appropriate amount of orotate continuously to the brain. It turned out to be difficult (Examples 8 to 19 described later). For this reason, bis (nitrophenyl) phosphate (hereinafter abbreviated as “BNPPP”) was used to suppress peripheral esterase activity.
  • BNPPP bis (nitrophenyl) phosphate
  • ⁇ is a compound known as a carboxylesterase inhibitor.
  • the administration of the drug was performed by intraperitoneal administration of ⁇ ⁇ ⁇ before administration of ethyl orotate (note that ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ).
  • ethyl orotate denotes that ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ .
  • the pharmacokinetics of the combination use of orotate and orethylate will be described later (Example 20). ).
  • Example 4 drug efficacy was evaluated using a murine ischemia model.
  • BNPP 10 Omg / kg saline suspension
  • the bilateral common carotid artery was occluded 3 hours later, and released 5 minutes later c, then 1 hour, 2 hours later
  • a total of 6 doses of ethyl orotate 10 Omg / g were intraperitoneally administered 6 times.
  • Example 5 The same operation as in Example 5 was performed, except that a 0.5% methylcellulose solution was administered instead of the administration of ethyl orotate. (Results of efficacy evaluation)
  • orotic acid ester shows good translocation into the brain in a state where carboxylesterase activity is inhibited by BNPP administration, and efficiently supplies orotic acid to the brain As a result, it was found that the composition provided a suitable medicinal effect.
  • Example 6 (Latt regional cerebral ischemia model)
  • Tamura et al. (Taraura, A. et. Al., J. cerb. Blood Flow etab, 1: 53-60, 1981).
  • a male F344 (crj) rat weighing 300-350 g, a small bone window was made in the rat skull under 2% halothane anesthesia, and the left middle cerebral artery was electrocoagulated and permanently occluded.
  • Body temperature was maintained at 37 ⁇ 1 ° C (rectal temperature measurement) for 30 minutes after surgery.
  • orotic acid methyl ester was infused from the jugular vein for 24 hours with 3 kg / 10 ml of physiological saline ZkgZhr.
  • the head was decapitated, and the brain was excised to make a 2-3 mm thick section.
  • the obtained section was treated with TTC (triphenyltetrazolium chloride) saline solution.
  • Example 6 The same operation as in Example 6 was repeated, except that physiological saline was administered instead of the orotic acid methyl ester solution. Table 1 shows the obtained results.
  • Example 6 As shown in Table 1, the orotic acid methyl ester (Example 6) showed an infarct lesion associated with cerebral cortical ischemia in the 5.2 mm and 3.2 mm forehead cross-sections as compared with Comparative Example 3. It was found that the infarct area was reduced by about 60%.
  • Example 6 administration of orotic acid methyl ester has a depressing effect on the occurrence of cerebral cortical infarction in a rat middle cerebral artery occlusion model. Has been shown to be able to avoid death and allow neurons to survive.
  • the rat middle cerebral artery in which the middle cerebral artery is permanently occluded, runs in the cerebral cortex and striatum, but other blood vessels are strongly dominated by the cerebral cortex, especially in the posterior direction. is recieving. Therefore, it is considered that the supply of orotic acid methyl ester and orotic acid from other vascular routes suppressed the death of nerve cells.
  • control is almost limited to the middle cerebral artery, so that orotate methyl ester injected through the jugular vein is difficult to reach the striatum, and therefore, infarction in the striatum It is probable that nest shrinkage was not observed.
  • orotic acid ester or orotic acid is considered to have a large neuronal protective effect in human ischemic diseases by reducing the occurrence of infarct lesions.
  • orotic acid esters and orotic acid are expected to have enormous clinical effects as neuroprotective agents, in addition to the above-mentioned effects on the murine ischemia model.
  • orotic acid ester is hydrolyzed to orotic acid, if it is difficult to be hydrolyzed in the periphery, the concentration of peripheral orotic acid will decrease. If it is easily hydrolyzed, the orotic acid concentration in the brain will increase.
  • concentrations in cerebrospinal fluid (CSF) and plasma (Plasma) were evaluated as those in the brain and those at the periphery, respectively.
  • Example 7 The following procedures were performed using rats and murine rats to evaluate the pharmacokinetics of orotic acid.
  • a Wistar male rat weighing 340 to 43Og was used. Orotic acid was suspended in a 0.5% methylcellulose solution, and the obtained suspension was intraperitoneally administered once. After a certain period of time, cerebrospinal fluid (CSF) and blood were collected (under pentobarbital anesthesia), and the blood was centrifuged to obtain a plasma fraction.
  • CSF cerebrospinal fluid
  • mice Male sand rats weighing 80-90 g (purchasers: Seiwa) were used. Orotic acid was suspended in 0.5% methylcellulose solution, and the obtained suspension was single-dose intraperitoneally [ ⁇ ]. After a certain period of time, blood was collected (under pentobarbital anesthesia) and centrifuged to obtain a plasma fraction.
  • Example 7 The same operation as in 1 of Example 7 was repeated, except that the orotic acid esters shown in Table 3 were used instead of orotic acid, and the concentrations of orotic acid ester and orotic acid were measured. The results obtained are shown in Tables 3 and 4.
  • Rats similar to those described above were used.
  • a jugular vein for continuous administration was administered under pentobarbital anesthesia about 24 hours before administration of each oral acid ester.
  • Each orotate was dissolved in physiological saline and administered continuously for 4 hours.
  • the brain concentration of orotic acid in sand rats is approximately 10 to 80; zM. It is thought that it will last for a long time while displacing within the range.
  • peripheral administration of ethyl orotate can reduce peripheral orotic acid concentration and efficiently supply orotic acid to the brain.
  • peripherally administered ethyl ester is expected to undergo rapid degradation mainly by carboxylesterase mainly in the blood and liver, and cannot supply a sufficient amount of orotic acid to the brain. It is also generally known that rodents have higher esterase activity mainly in blood and liver than large animals.
  • BNPP which is an example of a carboxylesterase inhibitor
  • BNPP When BNPP is administered peripherally, it is thought that BNPP does not move into the brain but acts only in the periphery.
  • BNPP 100 mg Z2 ml saline / kg was intraperitoneally administered to rats. Then, after 2 hours, ethyl orotate
  • orotic acid when peripheral esterase activity is low, orotic acid can be more efficiently supplied to the brain.
  • orotic acid esters are particularly effective for supplying orotic acid to the brain with high efficiency, mainly in large animals having low esterase activity in blood and liver.
  • the resulting solution was aseptically filtered through a 0.2-m filter, and the filtrate (510-m1) was aseptically filled in a vial, stoppered and tightly wound to obtain a 500-ml infusion preparation. .
  • Keiic anhydride 6.3 Total 1, 2 4 O mg g Ethyl orotate 1 g
  • Ethyl orotate ester (500 g) and lactose (60.5 g) were uniformly mixed using a fluid granulation coating apparatus (Okawara Seisakusho). This was granulated by spraying 23 g of a 3.5% hydroxypropylcellulose solution. After drying, it is passed through a 20 mesh sieve, and 36 g of carboxymethyl cellulose calcium, 6.3 g of magnesium stearate, And 3.2 g of maleic anhydride were added and mixed. Using a rotary tableting machine (Hata Iron Works), using a deformable punch with a long diameter of 22 mm and a short diameter of 8 mm, 1.24 g of deformed tablets per tablet And
  • orotic acid has a neuroprotective effect, which is a novel medicinal effect of orotic acid, and a specific ester of orotic acid has excellent brain transportability
  • a cytoprotective effect on orotic acid and orotic acid ester can prevent and treat neuronal damage / degeneration-related disorders and diseases.
  • a neuroprotective agent having a wide "therapeutic time window" for cerebral ischemia can be provided.

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Abstract

Neuroprotecteur contenant un composé représenté par la formule générale (I) ou un de ses sels acceptables pharmaceutiquement en tant qu'ingrédient actif et pouvant traiter des troubles et des maladies associés à des lésions neuronales et à une dégénerescence neuronale, formule dans laquelle R représente hydrogène ou alkyle C1-10 linéaire, ramifié ou cyclique. Ce neuroprotecteur peut traiter efficacement différentes maladies associées à la dégénerescence neuronale telles que des accidents vasculaires cérébraux, les infarctus, les thromboses et les hémorragies, ainsi que les hémorragies sous-arachnoïdiennes.
PCT/JP1994/001134 1993-07-14 1994-07-12 Neuroprotecteur et nouvel ester orotique WO1995002407A1 (fr)

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AU70850/94A AU7085094A (en) 1993-07-14 1994-07-12 Neuron protective and novel orotic ester

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JP17445493 1993-07-14
JP5/174454 1993-07-14

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2221305A1 (fr) 2005-07-22 2010-08-25 Mitsubishi Tanabe Pharma Corporation Procédé pour synthétiser un composant intermédiaire afin de synthétiser un agent pharmaceutique
JP2010189283A (ja) * 2009-02-16 2010-09-02 Kao Corp アディポネクチン増加剤
JP2013132225A (ja) * 2011-12-26 2013-07-08 Kirin Holdings Co Ltd オロト酸を含有する飲料およびその製造方法
WO2015166845A1 (fr) * 2014-05-01 2015-11-05 株式会社島津製作所 Procédé pour l'évaluation de l'état de différenciation de cellules

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Abstract No. 115:270470g; & ABSTRACT OF MED.-BIOL. INF., (1), 3-8(1989). *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2221305A1 (fr) 2005-07-22 2010-08-25 Mitsubishi Tanabe Pharma Corporation Procédé pour synthétiser un composant intermédiaire afin de synthétiser un agent pharmaceutique
US7994315B2 (en) 2005-07-22 2011-08-09 Mitsubishi Tanabe Pharma Corporation Intermediate compound for synthesizing pharmaceutical agent and production method thereof
JP2010189283A (ja) * 2009-02-16 2010-09-02 Kao Corp アディポネクチン増加剤
JP2013132225A (ja) * 2011-12-26 2013-07-08 Kirin Holdings Co Ltd オロト酸を含有する飲料およびその製造方法
WO2015166845A1 (fr) * 2014-05-01 2015-11-05 株式会社島津製作所 Procédé pour l'évaluation de l'état de différenciation de cellules

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