TWI519524B - Novel quinazoline-2,4-dione derivatives and a pharmaceutical composition for preventing or treating of neurological brain disease - Google Patents

Description

Novel quinazoline-2,4-dione derivatives and pharmaceutical compositions for preventing or treating neurological brain diseases

The present invention relates to a novel quinazoline-2,4-dione derivative of formula (I) Wherein R ₁ is hydrogen or alkyl; each R ₂ and R ₃ are each independently selected from hydrogen, alkyl, -COR ₆ , -SO ₂ R ₇ , or substituted or unsubstituted phenyl or benzyl, wherein R ₆ is alkyl, alkoxy, phenyl, phenoxy or benzyloxy, which are unsubstituted or substituted by halogen, hydroxy, methoxy, ethoxy or nitro, respectively, and R ₇ is not Substituted or substituted lower alkyl or aryl; A is -(CH ₂ ) _n - or -CH ₂ CH=CHCH ₂ -, wherein n is an integer selected from 2 to 4; R ₄ is hydrogen and R ₅ is hydrogen or benzhydryl, which is unsubstituted or substituted with one or more halogen, hydroxy, alkoxy or nitro groups, or when R ₄ and R ₅ together with N form a ring, R ₄ and R ₅ form a divalent group of the formula: Wherein R ₈ is hydrogen or alkyl; each l and m are each independently selected from an integer from 2 to 4; and p is an integer of 0 or 1, or a pharmaceutically acceptable salt thereof, and comprises a compound of formula (I) as an activity A pharmaceutical composition of ingredients for the prevention or treatment of neurological brain diseases.

The development of neurological brain diseases causes nerve cells to die in a short period of time or for a long period of time, and finally causes fatal brain function loss. Stroke is one of the most common cerebrovascular diseases. Because of the significant increase in patients with intracranial neuropathy in the 40- to 50-year-old population, it has been found to be not only a personal problem but also a national problem.

There are two types of stroke: cerebral infarction and cerebral hemorrhage. Cerebral infarction is caused by blood clots and the like blocked by blood supplied to the brain tissue, resulting in necrosis of brain tissue. The cerebral hemorrhage is caused by blood loss due to rupture of the cerebral blood vessels. Although the causes of cerebral infarction and cerebral hemorrhage are different, the symptoms are often similar.

The current standard method for treating the acute phase of infarction is thrombolytic therapy. The period of time from the onset of cerebral infarction to the time of initiation of treatment is very important, and it is known that when a thrombolytic agent is administered within 3 hours after the onset of a cerebral infarction, the functional state of the patient can be improved.

Many researchers have investigated the causes of brain cell necrosis due to ischemia, and believe that the main pathways are toxicity induced by excessive neurotransmitters, oxidative toxicity due to stress, zinc toxicity, apoptosis, and the like.

Glutamine is one of the toxic substances that can be stimulated and is an stimulating neurotransmitter of the central nervous system that reacts with NMDA (N-methyl-D-aspartate) receptors. When the ischemia causes excessive production of glutamate, nerve cell death is induced. Recent reports indicate that such stimulating toxicity may be the primary mechanism of neuronal cell death caused by ischemic stroke and epilepsy. If the oxygen-glucose supplied to the nerve tissue is reduced after ischemia, the glutamate, which is an stimulating neurotransmitter, accumulates at the junction between the neurons. Excessive activity of the NMDA glutamate receptor is then predominantly responsible for neuronal cell death. Therefore, an antagonist of NMDA glutamate receptor can be used to suppress neuronal cell death due to ischemic stroke.

Free radicals are also one of the main mechanisms of nerve cell death. In the nerve cells, free radicals are increased due to ischemia, etc., and membrane lipids are induced to be destroyed by lipid peroxidation, nucleic acids are damaged by oxygen radicals, proteins are denatured, and the like. The result is fatal damage to the underlying factors required for cell survival. Many researchers have pointed out that ischemia causes reactive oxygen species in the brain, such as reactive oxygen species, Parkinson's disease, Huntington's disease and Alzheimer's disease, catalase (enzymes that scavenge free radicals), Cu /Zn superoxide dismutase (SOD) activity and increase in Fe ²⁺ .

As mentioned above, although many mechanisms have been disclosed to treat intracranial neuropathy, there is still a need to develop novel drugs in terms of efficacy and toxicity.

The present inventors have found that a natural substance released from living Eisenia Andrei and Eisenia fetida can produce electrical stimulation in the study of folklore therapy for long-term use in the East. We have found that certain compounds of these substances are effective in protecting the intracranial nerves. Many derivative compounds, including novel compounds isolated from natural products, can be synthesized based on this discovery. It is known that the quinazoline-2,4-dione derivative compounds of the formula (I) and salts thereof have a superior effect on protecting nerve cell activity, and we have thus completed the present invention.

[Object of the Invention]

An object of the present invention is to provide a compound of the formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the compound as an active ingredient for preventing or treating a neurological brain disease.

The present invention provides a novel quinazoline-2,4-dione derivative of formula (I) Wherein R ₁ is hydrogen or alkyl; each R ₂ and R _{3 are} independently selected from hydrogen, alkyl, -COR ₆ , -SO ₂ R ₇ , or substituted or unsubstituted phenyl or benzyl, wherein R ₆ is alkyl, alkoxy, phenyl, phenoxy or benzyloxy, which are unsubstituted or substituted by halogen, hydroxy, methoxy, ethoxy or nitro, respectively, and R ₇ is not Substituted or substituted lower alkyl or aryl; A is -(CH ₂ ) _n - or -CH ₂ CH=CHCH ₂ -, wherein n is an integer selected from 2 to 4; R ₄ is hydrogen and R ₅ is hydrogen or benzhydryl, which is unsubstituted or substituted with one or more halogen, hydroxy, alkoxy or nitro groups in the phenyl ring, or when R ₄ and R ₅ together form a ring with N , R ₄ and R ₅ form a divalent group as follows: Wherein R ₈ is hydrogen or an alkyl group; each of l and m is independently selected from an integer of from 2 to 4; and p is an integer of 0 or 1, or a pharmaceutically acceptable salt thereof.

The term "alkyl" as used herein, refers to an alkyl group having from 1 to 6 carbon atoms, for example, a fatty hydrocarbon chain, including straight chain, branched chain or cyclic forms such as methyl, ethyl or n-propyl. , isopropyl, n-butyl, t-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylpentyl, hexyl and cyclohexyl.

The term "lower alkyl" refers to a straight or branched chain hydrocarbon having from 1 to 4 carbon atoms.

The term "alkoxy" refers to -O-alkyl, wherein "alkyl" refers to a straight or branched chain hydrocarbon having from 1 to 4 carbon atoms.

The compound of the formula (I) can be used in the form of a pharmaceutically acceptable salt thereof, and the pharmaceutically acceptable salt comprises an acid addition salt or an alkali metal salt as known in the art.

A typical example of the formula (I) according to the present invention is as follows: 3-{3-[4-(3-aminopropylamino)butylamino]propyl}-1H-quinazoline-2,4- Diketone; 3-(3-{4-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butylamino }propyl)-1H-quinazoline-2,4-dione; N-[3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl) Propyl]-N-{4-[3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide ;N-(4-{Ethyl-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]amino}butyl) -N-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]acetamide; [3-(2,4-two-side) Oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl]-{4-[3-(2,4-di-oxy-1,4-dihydro-2H-quinaline Ethyl oxazol-3-yl)propylamino]butyl}carbamate; N-[3-(2,4-di-oxy-1,4-dihydro-2H-quinazoline-3- Propyl]-N-(4-{[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]methylamino} Butyl)acetamide; 3-{4-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl }-1H-quinazoline-2,4-dione; N-(3-{4-[3-(2,4-di-oxo-1,4- Hydrogen-2H-quinazolin-3-yl)propylamino]butylamino}propyl)-4-hydroxybenzamide; 3-{3-[4-({N-[3-( 2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-benzyl}amino)butylamino]propyl}-1H- Quinazoline-2,4-dione; N-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{ 4-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}benzamide; [3-(2 , 4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl]-{4-[3-(2,4-di-oxo-1,4-di Hydrogen-2H-quinazolin-3-yl)propylamino]butyl}aminecarboxylic acid tert-butyl ester; N-[3-(2,4-di-oxy-1,4-dihydro-2H) -quinazolin-3-yl)propyl]-N-{4-[3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl Amino]butyl}methanesulfonamide; N-(4-{benzyl-[3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl) -propyl]amino}butyl)-N-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]acetamide; (4-{Ethyl-[3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl]amino}butyl)-[3 -(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl]amino acid B ;3-{[3-(4-{N-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-benzene Methylamino}butyl)-N-benzylamino]propyl}-1H-quinazoline-2,4-dione; [3-(2,4-di- oxo-1,4 -dihydro-2H-quinazolin-3-yl)propyl]-(4-{[3-(2,4-di-oxo-1,4-dihydro-2H-quinazoline-3- Ethyl]propyloxycarbonylamino}butyl) urethane; (4-{t-butoxycarbonyl-[3-(2,4-di- oxy-1,4-dihydro) -2H-quinazolin-3-yl)propyl]amino}butyl)-[3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl) Propyl] butyl methacrylate; N-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-( 4-{[3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl]methanesulfonylamino}butyl)methanesulfonamide ;N-[3-(ethenyl-{4-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]] Amino]propyl)-4-hydroxybenzamide; N-[3-(4-{ethylindolyl-[3-(2,4-di-oxo-1,4-dihydro-) 2H-quinazolin-3-yl)propyl]amino}butylamino)propyl]-4-hydroxybenzamide; N-{3-[ethyl fluorenyl-(4-{ethyl fluorenyl) -[3-(2,4-di-oxy-1,4-dihydro-2H-quinazoline-3 -yl)propyl]amino}butyl)amino]propyl}-4-hydroxybenzamide; N-[4-(2,4-di-oxy-1,4-dihydro-2H -quinazolin-3-yl)butyl]-N-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]acetamidine Amine; 3-(2-{3-[2-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)ethylamino]propylamino} Ethyl)-1H-quinazoline-2,4-dione; 3-(3-{3-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazoline) 3-yl)propylamino]propylamino}propyl)-1H-quinazoline-2,4-dione; 3-(3-{4-[3-(2,4-two-side) Oxy-1,4-dihydro-2H-quinazolin-3-yl)propylamino]-2-butenylamino}propyl)-1H-quinazoline-2,4-dione (4-{Tertibutoxycarbonyl-[3-(1-methyl-2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl] Amino}butyl)-[3-(1-methyl-2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]aminecarboxylic acid tert-butyl Ester; 1-methyl-3-(3-{4-[3-(1-methyl-2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl) Propylamino]butylamino}propyl)-1H-quinazoline-2,4-dione; 3-(3-{4-[3-(1,3-di- oxy-1) 3-Dihydro-isoindol-2-yl)propylamino]butylamino}propyl)-1H-quinazoline-2 , 4-dione; 3-(3-{2-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]B Amino) propyl)-1H-quinazoline-2,4-dione; [3-(2,4-di-oxy-1,4-dihydro-2H-quinazoline-3- Propyl]-(4-{[3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl]hexylamino}butyl) Tert-butyl carbamic acid; 3-[3-(4-{N-[3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl) ]-N-hexylamino}butylamino)propyl]-1H-quinazoline-2,4-dione; (4-{t-butoxycarbonyl-[3-(1-hexyl-2) , 4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl]amino}butyl)-[3-(1-hexyl-2,4-dihydroxyloxy) Tert-butyl 3-1,4-dihydro-2H-quinazolin-3-yl)propyl]amine; 1-hexyl-3-(3-{4-[3-(1-hexyl-2) ,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butylamino}propyl)-1H-quinazoline-2,4-di Ketone; [3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-(4-{[3-(2,4-two-side) Oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl]heptanoylamino}butyl)aminecarboxylic acid tert-butyl ester; [3-(2,4-di-side oxygen) 1,4-1,4-dihydro-2H-quinazolin-3-yl)propyl]-{4-[3-(2 , 4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}heptanylamine; N-[3-(2,4-di-oxo) 1,4-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-di-oxo-1,4-dihydro-2H- Quinazolin-3-yl)propylamino]butyl}-2,2,2-trifluoroacetamide; N-[3-(2,4-di-oxo-1,4-dihydrol) -2H-quinazolin-3-yl)propyl]-N-{4-[[3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl) )propyl]-(2,2,2-trifluoroethyl)amino]butyl}-2,2,2-trifluoroacetamide; N-[3-(2,4-di-oxo) 1,4-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-di-oxo-1,4-dihydro-2H- Quinazolin-3-yl)propylamino]butyl}-2-methoxyacetamide; [3-(2,4-di-oxy-1,4-dihydro-2H-quinazoline) Benz-3-yl)propyl]-{4-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl Benzyl methacrylate; N-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[ 3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}-4-methylbenzenesulfonamide; N-[ 3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-(4-{[3-(2,4-di-oxo) Base-1,4- Hydrogen-2H-quinazolin-3-yl)propyl]-4-methylbenzenesulfonylamino}butyl)-4-methylbenzenesulfonamide; or 3-(3-{4-[ 3-(2,5-Di-oxy-pyrrolidin-1-yl)propylamino]butylamino}propyl)-1H-quinazoline-2,4-dione.

The compound of formula (I) can be prepared by the reaction illustrated in the following reaction schemes I to III. It is therefore another object of the present invention to provide such a process.

However, the following reaction schemes only illustrate the most common method of the present invention. The method of preparing the compound of the formula (I) according to the present invention is not limited to the reaction diagrams exemplified below. The compounds of formula (I) can be prepared in a variety of different processes known in the art.

The benzoic acid-derived compound (IV) having alkoxycarbonylamino substituent at position 2 is reacted with an amine compound (V), wherein A is appropriately selected to form a ring in the presence or absence of a solvent, and A quinazoline 2,4-dione derivative of the quinazoline 2,4-dione backbone structure of the monoamine compound (IX) wherein R ₄ and R ₅ are hydrogen. Alternatively, by increasing the stoichiometry of the compound (IV), a quinazoline 2,4-dione derivative of the compound (IX) wherein R ₄ and R ₅ together with the N atom form a cyclic quinazoline-2 can be obtained. , 4-dione. The ring fusion reaction or ring-closing reaction carried out in the absence of a solvent should be carried out at a temperature sufficient to melt the two reactants.

In the above reaction scheme, A, l, m and p are the same as defined above. R ₄ and R ₅ represent hydrogen, or when R ₄ and R ₅ together with N form a ring, R ₄ and R ₅ form a divalent group as follows: And Alk represents an alkyl group. L represents a leaving group, preferably a hydroxyl group, an alkoxy group or a halogen.

The quinazoline-2,4-dione derivative of the compound (IX) wherein R ₄ and R are obtained by reacting the compound (VI) with the compound (VII) or (VIII) having a substituent of R ₄ and R _{5 5 A} terminal primary amine is suitably introduced, wherein the reaction can be carried out in the presence of a solvent, the condensing reaction can be carried out without a solvent, or if X is a hydroxyl group, a condensation reaction can be carried out.

This condensation reaction can be carried out using DCC (dicyclohexylcarbodiimide) or EDC (1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide). Alternatively, the compound (IX) can be obtained by converting a carboxyl group into a more reactive group such as an acid anhydride or an acid chloride, followed by reacting with the compound (VI).

In the above reaction scheme, A, R ₄ , R ₅ , l, m and p are the same as defined above. R _{5 is} not H, X represents hydroxy, halogen, alkoxy or -OR ₅ , each Y and Y' is hydroxy, halogen, alkoxy or when Y and Y' form a ring, Y and Y' form -O -.

When at least one hydrogen in the compound of the formula (IX) is substituted by R ₂ and/or R ₃ , a quinazoline-2,4-dione derivative of the compound (I) wherein R ₂ and R _{3 are} suitably introduced into the amine Position, R ₁ is hydrogen, and at least one of R ₂ and R _{3 is} not hydrogen. To obtain the formula wherein R ₂ and R ₃ are the same groups substituted compound, R ₂ may be introduced at the same time and R ₃ substituents.

To obtain a compound wherein R ₂ and R ₃ are different substituents, the R ₂ substituent may be introduced first to the compound (IX) to obtain a quinazoline-2,4-dione derivative of the compound (I). Wherein R ₁ and R ₃ are hydrogen, and then an R ₃ substituent is introduced in the presence of an organic solvent and a base. On the other hand, R ₃ substituent can be first introduced into the compound (IX) to the base, and then introducing a substituent to R ₂ substituted by R ₃ of the compound, to give quinoline compounds (I) of the 2,4-dione a derivative wherein R ₂ and R ₃ are suitably substituted, and R ₁ is hydrogen.

Further, after the desired substituent is introduced into the secondary amine position of the compound (IX), it may be alkylated by the alkylating agent at the position -1 of the quinazoline ring in the presence of a base, or may be removed after the alkylation reaction. In addition to the protecting group, a quinazoline-2,4-dione derivative of the compound (I) wherein R ₁ is an alkyl group and introduced with a desired substituent is obtained. As the above alkylating agent, an alkyl halide, a dialkyl sulfate or an alkyl sulfonate can be used.

In the above reaction scheme, A, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , l, m and p are the same as defined above, and R _{5 is} not H. More specific reaction conditions are illustrated in the following Examples 1 to 42.

On the other hand, the compound of the formula (I) of the present invention which is prepared according to the above process can be further isolated and purified by a conventional post-treatment method, or can be made into a corresponding pharmaceutically acceptable salt by a conventional method. It is known to those skilled in the art that the salt should be pharmaceutically acceptable and non-toxic. Several salts are useful in the manufacture of the compounds of the invention and their non-toxic pharmaceutically acceptable salts.

Pharmaceutically acceptable salts of the compounds of the invention include acid addition salts or alkali metal salts. Such acid addition salts can be, but are not limited to, salts formed with the following acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, acetic acid, benzenesulfonic acid, methanesulfonic acid, phosphoric acid, nitric acid, formic acid, C. Acid, succinic acid, glycolic acid, lactic acid, malic acid, orotic acid, nicotinic acid, adipic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, benzoic acid, salicylic acid, fumaric acid, camphorsulfonic acid (camsylic acid) or a carboxylic acid, and such alkali metal salts may be, but are not limited to, salts of sodium, potassium, lithium, magnesium or calcium.

Further, the present invention provides a pharmaceutical composition suitable for preventing or treating the above-mentioned neurological brain disease, which is a combination of a quinazoline-2,4-dione derivative compound of the formula (I) and a pharmaceutically acceptable salt thereof, And pharmaceutically acceptable carrier.

The compounds of the formula (I) of the present invention are useful for treating diseases caused by normal or abnormal deterioration of the neurological brain system or for protecting their nerve cells, which are confirmed by the results of the following examples.

The present invention provides a pharmaceutical composition comprising as an active ingredient A compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier for the prevention or treatment of neurological brain disorders, degenerative neurological brain disorders or neurological dysfunction. More specifically, the pharmaceutical composition of the present invention is suitable for preventing or treating diseases selected from the group consisting of neurological dysfunction, memory loss, insufficient cerebral vascular function, local brain injury, focal brain trauma, extensive brain trauma, and spinal cord. Injury, cerebral ischemia, cerebral hemorrhage, ischemic stroke, hemorrhagic stroke, dementia, cerebral infarction, embolic obstruction, thrombotic obstruction, acute ischemic reperfusion, transient ischemic attack, perinatal hypoxia - Ischemic injury, cardiac arrest, intracranial hemorrhage, subarachnoid hemorrhage, cerebral aneurysm, William's cerebellar aneurysm, acute pediatric hemiplegia syndrome, infant whipping syndrome, Alzheimer's disease, Pick's Disease , extensive Diffuse Lewy body disease, progressive supranuclear nerve palsy (Steel-Richardson syndrome), multiple systemic degeneration (Hi-De's syndrome) -Drager syndrome)), chronic epilepsy associated with neurodegeneration, motor neuron disease, amyotrophic lateral sclerosis, primary lateral sclerosis, degenerative motor disorders , cortical basal ganglia degeneration, subacute sclerosing encephalitis, Huntington's disease, Parkinson's disease, nucleus globulin disease, primary progressive aphasia, spinal muscular atrophy, and spinal cord musculoskeletal atrophy Kennedy's Disease), Multiple Sclerosis, Tay-Sach's Disease, Spastic Hemiplegia, Prion Protein Disease, Creutzfeldt-Jakob Disease, Epilepsy, Plexus Or neuropathy; and improve memory.

The pharmaceutical compositions of the present invention can be prepared by combining a compound of the present invention with a pharmaceutically acceptable solid or liquid inactive carrier, and can be formulated into a pharmaceutically acceptable form suitable for administration. The above formulations may be formulated as immediate release or sustained release, as is known to those skilled in the art. The pharmaceutical composition can be formulated into oral tablets, pills, granules, powders, capsules, suspensions, syrups, elixirs, solutions, emulsions or injections for intravenous or parenteral administration. The pharmaceutical composition can be formulated into a suppository tablet, a capsule, a powder, a microcapsule, a sterile solution or a suspension for rectal administration.

The above pharmaceutically acceptable carriers may include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia, alginate, gelatin, phosphoric acid. Calcium, calcium citrate, cellulose, methyl-cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate or mineral oil. Further, the above pharmaceutically acceptable carrier may include a diluent or an additive such as a filler, a extender, a binder, a wetting agent, a disintegrant, a surfactant, and the like.

The solid preparation for oral administration may be in the form of tablets, pills, powders, granules, capsules and the like, and may include at least one additive such as, for example, starch, calcium carbonate, sucrose, lactose and gelatin, or a lubricant, Such as: magnesium stearate, talc and so on. The liquid for oral administration may be in the form of a suspension, a solution, an emulsion, a syrup or the like, and may include a diluent such as water and liquid paraffin, a wetting agent, a sweetener, a fragrance or a preservative. The parenteral dosage formulation can be in the form of a sterile solution, a non-aqueous solvent, a suspension, an emulsion, a lyophilizate or a suppository. Non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oils (eg, olive oil), injectable esters (eg, ethyl oleate, etc.). Witepsol, macrogol, Tween 61, cocoa butter, lauric oil, glycerin gelatin or the like can be used as a carrier for the suppository.

The desired dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof contained in the pharmaceutical composition of the present invention varies depending on the condition, body weight, age and sex of the individual, the severity of the disease, the type of the drug, the route of administration and the time period. And can be selected by the person skilled in the art. For example, it is generally recommended that the compound of the formula (I) or a pharmaceutically acceptable salt thereof is administered in an amount of from 0.01 to 500 mg/kg body weight/day, preferably from 0.1 to 100 mg/kg body weight/day, but is not limited by this range. A single dose can be administered or divided into several doses per day or week.

Further, the pharmaceutical composition of the present invention may comprise, based on the total weight of the composition, from 0.001 to 50% by weight, preferably from 0.1 to 50% by weight, of the compound of the formula (I) or a pharmaceutically acceptable salt thereof, but not Range limit.

[Advantageous effect]

a quinazoline-2,4-dione derivative of the present invention, a pharmaceutically acceptable salt thereof, and a composition comprising the quinazoline-2,4-dione derivative and a pharmaceutically acceptable salt thereof, It inhibits brain cell death, protects nerve cells, protects against oxidation, fights mites and relaxes blood vessels. It is therefore suitable for preventing or treating various diseases such as stroke, Alzheimer's disease and epilepsy, and enhancing memory.

[Specific embodiment of carrying out the invention]

The invention will be more clearly described with reference to the following examples, which are intended to be illustrative only and not intended to be limiting.

Example 1 3-{3-[4-(3-Aminopropylamino)butylamino]propyl}-1H-quinazoline-2,4-dione (Compound 1) 1) Preparation method of 2-ethoxycarbonylaminobenzoic acid ethyl ester:

Ethyl 2-aminobenzoate (20 g, 0.12 mol) was dissolved in 140 mL of xylene, and ethyl chloroformate (13.8 mL, 0.15 mol) was added. After reacting for 3 hours under reflux, the solvent was distilled off under reduced pressure. 30 mL of petroleum ether was added to the residue and cooled. The title compound was obtained as a white solid (26 g, 90.5%).

¹ H NMR{CDCl ₃ ): 10.51 (s, 1H), 8.43 (dd, 1H), 8.01 (dd, 1H), 7.51 (t, 1H), 7.01 (t, 1H), 4.37 (q, 2H), 4.22(q, 2H), 1.40(t, 3H), 1.32(t, 3H);

2) 3-{3-[4-(3-Aminopropylamino)butylamino]propyl}-1H-quinazoline-2,4-dione Preparation:

Ethyl 2-ethoxycarbonylaminobenzoate (8.0 g, 33.7 mmol) and N,N'-bis-(3-aminopropyl)butane-1,4-diamine (8.87 g, 43.8) Mmmol) heat melting. After stirring at 125 to 135 ° C for 4 hours, isopropyl alcohol was added thereto, and concentrated hydrochloric acid was added to form a solid.

The solid obtained by filtration was dissolved in water and neutralized with an aqueous sodium hydroxide solution. After the water was evaporated under reduced pressure, the residue was purified mjjjjjjjj

HNMR (D ₂ O): 7.48 (dd, 1H), 7.30 (t, 1H), 6.83 (m, 2H), 3.73 (t, 2H), 2.59 (t, 2H), 2.52 (t, 2H), 2.46 (t, 6H), 1.66 (m, 2H), 1.56 (m, 2H), 1.37 (m, 4H);

Example 2

3-(3-{4-[3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butylamino}propyl )-1H-quinazoline-2,4-dione (compound 2)

(Process 1)

Ethyl 2-ethoxycarbonylaminobenzoate (4.9 g, 20.6 mmol) and N,N'-bis-(3-aminopropyl)butane-1,4-diamine (2.1 g, 10.3) Mmmol) heat melting. After stirring for 5 hours at 125 to 135 ° C, 25 mL of isopropyl alcohol was added to give a solid.

¹ H NMR (CDCl ₃ ): 8.05 (d, 2H), 7.62 (t, 2H), 7.22 (t, 2H), 7.15 (d, 2H), 4.11 (t, 4H), 2.62 (m, 8H), 1.94 (m, 4H), 1.55 (s, 4H);

(Process 2)

3-{3-[4-(3-Aminopropylamino)butylamino]propyl}-1H-quinazoline-2,4-dione (2.1 g, 6.0 mmol) and 2- Ethyl ethoxycarbonylaminobenzoate (1.6 g, 6.6 mmol) was melted at 125 to 135 °C. After 5 hours, 20 mL of isopropanol was added to give a solid, which was filtered and dried under reduced pressure to give the title compound as a white solid (2.2 g, 74%).

Example 3 N-[3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-di Hydroxyl-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride (Compound 3)

Take 3-(3-{4-[3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butylamino}propyl After the -1H-quinazoline-2,4-dione (3 g, 6.1 mmol) was dissolved in 60 mL of pyridine, acetic anhydride (0.7 mL, 7.3 mmol) was added. After 2 hours, pyridine was distilled off under reduced pressure. Dichloromethane and water were added to the residual residue, and the formed solid was removed by filtration, and the solution was separated. Concentrated hydrochloric acid was added to the aqueous layer to adjust the pH to 2 to 3. After the water was evaporated under reduced pressure, the residue was purified mjjjjjjjj

¹ H NMR (MeOD): 7.97 (m, 2H), 7.61 (m, 2H), 7.17 (m, 4H), 4.14 (m, 2H), 4.02 (m, 2H), 3.47 (m, 4H), 3.07 (m, 4H), 2.12 (m, 5H), 1.96 (m, 2H), 1.73 (m, 4H);

1.0 g of the compound of the above Example 3 was treated with an ion exchange resin to obtain a compound of a basic type, N-[3-(2,4-di-oxy-1,4-dihydro-2H-quinazoline-3- Propyl]-N-{4-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}B Guanidine (0.65 g). ¹ HN MR(MeOD): 7.89 (m, 2H), 7.53 (m, 2H), 7.15-7.01 (m, 4H), 3.97 (m, 4H), 3.40 (t, 2H), 3.32 (q, 2H) , 2.54 (m, 4H), 2.05 (d, 3H), 1.94-1.83 (m, 4H), 1.61-1.44 (m, 4H);

Example 4 N-(4-{Ethyl-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]amino}butyl)- N-[3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl]acetamide (Compound 4)

Take 3-(3-{4-[3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butylamino}propyl After the -1H-quinazoline-2,4-dione (2 g, 4.1 mmol) was dissolved in 50 mL of pyridine, acetic anhydride (1.0 mL, 10.2 mmol) was added. After 2 hours, the title compound (2.1 g, 90%) was obtained.

¹ H NMR (DMSO-d ₆ ): 11.40 (s, 2H), 7.91 (m, 2H), 7.63 (m, 2H), 7.17 (m, 4H), 3.86 (m, 4H), 3.27 (m, 8H) , 1.95 (m, 6H), 1.80 (m, 4H), 1.43 (m, 4H);

Example 5 [3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-{4-[3-(2,4-di-oxyl- Hydrate of ethyl 1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}aminecarboxylate (Compound 5)

Take 3-(3-{4-[3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butylamino}propyl The -1H-quinazoline-2,4-dione (2 g, 4.1 mmol) was dissolved in 20 mL of hexamethylphosphonamide, and cooled, and ethyl chloroformate (0.4 mL, 4.1 mmol) was added. After 2 hours, the title compound was crystalljjjjjjjjj

¹ H NMR (MeOD): 8.00 (t, 2H), 7.63 (q, 2H), 7.21 (q, 2H), 7.14 (m, 2H), 4.15 (t, 2H), 4.09 (q, 2H), 4.02 (t, 2H), 3.36 (m, 4H), 3.05 (m, 4H), 2.10 (m, 2H), 1.95 (m, 2H), 1.71 (t, 4H), 1.21 (bs, 3H);

Example 6 N-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-(4-{[3-(2,4- Bilateral oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl]methylamino}butyl)acetamide (Compound 6)

Take N-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4- Bis-oxy-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride (2 g, 3.5 mmol) was dissolved in 80 mL of dichloromethane. 10 mL of methanol. Triethylamine (0.45 g, 4.5 mmol) and trioxane (0.14 g, 4.5 mmol) were added thereto, and the mixture was stirred at room temperature for 2 hr. After concentrating the solvent, 40 mL of methanol and sodium borohydride (0.76 g, 20.2 mmol) were added and stirred for 15 hours. Methanol was evaporated under reduced pressure and the residue was purified mjjjjjjjj

¹ H NMR (MeOD): 7.98 (m, 2H), 7.60 (m, 2H), 7.19 (m, 2H), 7.11 (m, 2H), 4.02 (m, 4H), 3.46-3.36 (m, 4H) , 2.69-2.52 (m, 4H), 2.41, 2.34 (s, 3H), 2.10 (d, 3H), 1.98-1.90 (m, 4H), 1.63-1.51 (m, 4H)

Example 7 3-{4-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}-1H-quinazoline- 2,4-dione (compound 7)

Ethyl 2-ethoxycarbonylaminobenzoate (7 g, 29.5 mmol) and 2.1 g (14.8 mmol) of N-(3-aminopropyl)butane-1,4-diamine were dissolved at 140 °C. After 3 hours, 50 mL of isopropanol was added thereto to form a solid, which was filtered and dried under reduced pressure. The title compound was obtained as a yellow solid (3.2 g, 50%).

¹ H NMR (DMSO-d ₆ ): 7.91 (m, 2H), 7.63 (m, 2H), 7.18 (m, 4H), 3.90 (m, 4H), 2.50 (m, 4H), 1.69 (m, 2H) ), 1.58 (m, 2H), 1.39 (m, 2H);

Example 8 N-(3-{4-[3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butylamino}propyl -4-hydroxybenzimidamide dihydrochloride (Compound 8)

4-Hydroxybenzoic acid (1.13 g, 8.2 mmol), 1-hydroxybenzotriazole (1.27 g, 9.4 mmol), 1,3-dicyclohexylcarbodiimide (1.94 g, 9.4 mmol) and N, N'-Diisopropylethylamine (1.64 mL, 9.4 mmol) was added to 20 mL of dimethylhydrazine and stirred for 15 min. Addition of 3-{3-[4-(3-aminopropylamino)butylamino]propyl}-1H-quinazoline-2,4-dione (2.18 g, 6.3 mmol) A 10 mL solution of dimethyl sulfoxide was heated and stirred at 50 °C. After 5 hours, dimethyl sulfoxide was removed and the residual solution was dissolved in methanol containing concentrated hydrochloric acid. After the methanol was removed, the residue was purified mjjjjjjjj

¹ H NMR (D ₂ O): 7.91 (d, 1H), 7.74 (t, 1H), 7.63 (d, 2H), 7.33 (t, 1H), 7.16 (d, 1H), 6.87 (d, 2H) , 4.07 (t, 2H), 3.53 (t, 2H), 3.20 (m, 8H), 2.11 (m, 4H), 1.91 (s, 4H);

Example 9 3-{3-[4-({N-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-phenyl Amino)butylamino]propyl}-1H-quinazoline-2,4-dione (compound 9)

Take 3-(3-{4-[3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butylamino}propyl The -1H-quinazoline-2,4-dione (2 g, 4.1 mmol) was dissolved in 60 mL of tetrahydrofuran and 60 mL of aqueous sodium hydroxide (0.3 g, 8.1 mol) and cooled. To the solution was added benzyl bromide (0.48 mL, 4.1 mmol). After 15 hours, the solid formed was filtered, and the residue was evaporated,jjjjjjjj

¹ H NMR (CDCl ₃ ): 7.91 (dd, 2H), 7.48 (m, 4H), 7.29-7.04 (m, 7H), 4.13 (t, 2H), 3.92 (t, 2H), 3.57 (s, 2H) ), 3.13 (t, 2H), 3.04 (t, 2H), 2.51 (m, 4H), 2.30 (m, 2H), 2.00 (m, 2H), 1.78 (m, 2H), 1.63 (m, 2H) ;

Example 10

N-[3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-di Hydroxyl-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}benzamide hydrochloride (Compound 10)

According to Example 5 above, but benzamidine chloride (0.69 g, 4.9 mmol) was used instead of ethyl chloroformate. The title compound was obtained as a white solid (0.2 g, 7.%).

¹ H NMR (DMSO-d ₆ ): 7.94-7.84 (m, 2H), 7.65 (m, 2H), 7.38 (m, 2H), 7.22-7.01 (m, 7H), 3.96-3.72 (m, 4H) , 3.48-3.16 (m, 4H), 2.89-2.64 (m, 4H), 1.96-1.82 (m, 4H), 1.62-1.34 (m, 4H);

Example 11 [3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-{4-[3-(2,4-di-oxyl- 1,4-Dihydro-2H-quinazolin-3-yl)propylamino]butyl}aminocarboxylic acid tert-butyl ester (Compound 11)

Take 3-(3-{4-[3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butylamino}propyl The -1H-quinazoline-2,4-dione (2 g, 4.1 mmol) was dissolved in 20 ml of pyridine and then cooled. 0.93 g of di-tert-butyl dicarbonate (4.3 mmol) was added thereto. After 3 hours, pyridine was purified eluting EtOAcqqqqqqqq

¹ H NMR (MeOD): 7.99 (m, 2H), 7.60 (m, 2H), 7.22-7.09 (m, 4H), 4.04 (m, 4H), 3.25 (t, 4H), 2.59 (m, 4H) , 1.90 (m, 4H), 1.60-1.48 (m, 4H), 1.40 (s, 9H);

Example 12 N-[3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-di Hydroxyl-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}methanesulfonamide hydrochloride (Compound 12)

Take 3-(3-{4-[3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butylamino}propyl The base-1H-quinazoline-2,4-dione (2 g, 4.1 mmol) was dissolved in 10 mL of hexamethylphosphoniumamine. After adding 30 mL of dichloromethane and cooling, methanesulfonium chloride (0.5 g, 4.3 mmol) was added thereto. After 2 hours, methylene chloride was evaporated under reduced pressure.

¹ H NMR (DMSO-d ₆ ): 7.93 (m, 2H), 7.64 (m, 2H), 7.20 (m, 4H), 3.97 (t, 2H), 3.91 (t, 2H), 3.17 (m, 4H) ), 2.90 (s, 3H), 2.89 (m, 4H), 1.97 (m, 2H), 1.85 (m, 2H), 1.61 (s, 4H);

Example 13 N-(4-{Benzyl-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]amino}butyl)- N-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]acetamide (Compound 13)

Take 3-(3-[4-({N-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-benzene Methyl}amino)butylamino]propyl)-1H-quinazoline-2,4-dione (0.28 g, 0.48 mmol) was dissolved in 5 mL dichloromethane. Triethylamine (0.13 mL, 0.96 mmol) and acetic anhydride (0.06 mL, 0.58 mmol) were added and stirred for 1 hour. The organic layer was separated by adding water and dried over magnesium sulfate. After filtration and concentrating, the residue was purified mjjjjjjjj

¹ H NMR (MeOD): 7.96 (t, 2H), 7.58 (m, 2H), 7.32 (d, 2H), 7.25-7.06 (m, 7H), 4.01 (m, 4H), 3.64, 3.59 (s, 2H), 3.41 (m, 2H), 3.29 (m, 2H), 2.54 (m, 4H), 2.09, 2.04 (s, 3H), 1.98-1.85 (m, 4H), 1.63-1.49 (m, 4H) ;

Example 14 (4-{Ethyl-[3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl]amino}butyl)-[3 -(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl] urethane (Compound 14)

According to the above example 4, but using N.-[3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4- [3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride 3 g (5.3 mmol) And 0.6 mL (6.3 mmol) of ethyl chloroformate in place of 3-(3-{4-[3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl) Propylamino]butylamino}propyl)-1H-quinazoline-2,4-dione and acetic anhydride. The title compound was obtained as a white solid (l.

¹ H NMR (CDCl ₃ ): 10.40 (d, 2H), 8.06 (m, 2H), 7.56 (m, 2H), 7.17 (m, 4H), 4.10 (m, 6H), 3.50-3.30 (m, 8H) ), 2.10 (s, 3H), 1.97 (m, 4H), 1.55 (d, 4H), 1.21 (m, 3H);

Example 15 3-[3-(4-{N-[3-(2,4-Di-Ethyl-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-benzyl Amino}butyl)-N-benzylamino]propyl-1H-quinazoline-2,4-dione (compound 15)

The title compound (0.4 g, 15%) was obtained.

¹ H NMR (DMSO-d ₆ ): 7.88 (d, 2H), 7.61 (t, 2H), 7.27-7.13 (m, 14H), 3.88 (t, 4H), 3.46 (s, 4H), 2.39 (t) , 4H), 2.29 (s, 4H), 1.72 (m, 4H), 1, 36 (s, 4H);

Example 16 [3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl]-(4-{[3-(2,4-di-oxy) -1,4-Dihydro-2H-quinazolin-3-yl)propyl]ethoxycarbonylamino}butyl) urethane (Compound 16)

Take 3-(3-{4-[3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butylamino}propyl The -1H-quinazoline-2,4-dione (2 g, 4.1 mmol) was dissolved in 40 mL of pyridine, and ethyl chloroformate (0.46 mL, 4.9 mmol) was added. After 2 hours, the pyridine was removed under reduced pressure and dichloromethane and water were added to residue. After separation of the layers, methylene chloride was evaporated.

¹ H NMR (CDCl ₃ ): 8.09 (d, 2H), 7.58 (t, 2H), 7.20 (t, 2H), 7.12 (d, 2H), 4.09 (m, 8H), 3.35-3.25 (m, 8H) ), 1.96 (m, 4H), 1.52 (s, 4H), 1.21 (t, 6H);

Example 17 (4-{Tertibutoxycarbonyl-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]amino}butyl) -[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]aminocarboxylic acid tert-butyl ester (Compound 17)

The title compound was obtained as a white solid (0.3 g, 11%).

¹ H NMR (CDCl ₃ ): 10.08 (bs, 2H), 8.09 (d, 2H), 7.56 (t, 2H), 7.19 (t, 2H), 7.12 (d, 2H), 4.05 (m, 4H), 3.30-3.20 (m, 8H), 1.94 (t, 4H), 1.51 (s, 4H), 142 (s, 18H);

Example 18 N-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-(4-{[3-(2,4- Bilateral oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl]methanesulfonylamino}butyl)methanesulfonamide (Compound 18)

The title compound was obtained as a white solid (0.24 g, 9.1%).

¹ H NMR (DMSO-d ₆ ): 11.36 (s, 2H), 7.90 (d, 2H), 7.62 (t, 2H), 7.16 (m, 4H), 3.90 (t, 4H), 3.21-3.13 (m) , 8H), 2.88 (s, 6H), 1.84 (m, 4H), 1.56 (s, 4H);

Example 19 N-[3-(Ethyl-{4-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl }Amino)propyl]-4-hydroxybenzamide (Compound 19)

Take N-(3-{4-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butylamino}propyl 4-Hydroxybenzamide (1.27 g, 2.72 mmol) was dissolved in 10 mL of pyridine, and acetic anhydride (0.4 mL, 4.07 mmol) was added. After 2 hours, pyridine was distilled off under reduced pressure, and dichloromethane and water were added. The organic layer was separated and excluded. After concentrating under reduced pressure, the residue was purified mjjjjjjjjjj

¹ H NMR (MeOD): 8.00 (d, 1H), 7.70 (d, 2H), 7.63 (t, 1H), 7.21. (t, 1H), 7.16 (d, 1H), 6.80 (d, 2H), 4.09 (t, 2H), 3.39 (m, 6H), 2.77 (m, 4H), 2.12, 2.09 (s, 3H), 1.99-1.82 (m, 4H), 1.59 (m, 4H);

Example 20 N-[3-(4-{Ethyl-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]amino} Amino) propyl]-4-hydroxybenzamide (Compound 20)

An oil of the title compound (0.06 g, 4.0%) was obtained from the title compound.

¹ H NMR (MeOD): 7.99 (m, 1H), 7.70 (d, 2H), 7.61 (m, 1H), 7.17 (m, 2H), 6.80 (d, 2H), 4.01 (m, 2H), 3.42 (m, 6H), 2.87 (m, 4H), 2.10 (s, 3H), 1.97-1.90 (m, 4H), 1.64 (m, 4H);

real Example 21 N-{3-[Ethyl-(4-{ethylindolyl-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl) Amino}butyl)amino]propyl}-4-hydroxybenzamide (Compound 21)

The title compound was obtained as a white solid (0.53 g, 35.4%).

¹ H NMR (MeOD): 7.98 (t, 1H), 7.70 (dd, 2H), 7.60 (m, 1H), 7.15 (m, 2H), 6.80 (dd, 2H), 3.99 (m, 2H), 3.42 -3.30 (m, 10H), 2.09 (t, 3H), 2.07 (t, 3H), 1.92-178 (m, 4H), 1.55 (m, 4H);

Example 22 N-[4-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)butyl]-N-[3-(2,4-di-oxyl) -1,4-dihydro-2H-quinazolin-3-yl)propyl]acetamide (Compound 22)

According to the above Example 4, 3-{4-[3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl} was used instead. -1H-quinazoline-2,4-dione (1 g, 2.3 mmol) instead of 3-(3-4-[3-(2,4-di-oxy-1,4-dihydro-2H-quine) Oxazolin-3-yl)propylamino]butylaminopropyl)-1H-quinazoline-2,4-dione. The title compound was obtained as a white solid (yield: <RTIgt;

¹ H NMR (MeOD): 7.98 (m, 2H), 7.60 (m, 2H), 7.16 (m, 4H), 4.02 (m, 4H), 3.42 (m, 4H), 2.09 (d, 3H), 1.95 (m, 2H), 1.64 (m, 4H);

Example 23 3-(2-{3-[2-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)ethylamino]propylamino}ethyl )-1H-quinazoline-2,4-dione (compound 23)

In the above example 7, instead of N-(3-aminopropyl)butane-1, N,N'-bis(2-aminoethyl)-1,3-propanediamine 2.4 g (14.8 mmol) was used instead. , 4-diamine. The title compound was obtained as a yellow solid (3.7 g, 55%).

¹ H NMR (DMSO-d ₆ ): 7.88 (d, 2H), 7.59 (t, 2H), 7.14 (m, 4H), 3.92 (t, 4H), 2.65 (t, 4H), 2.47 (m, 4H) ), 1.43 (m, 2H);

Example 24 3-(3-{3-[3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propylamino]propylamino}propyl )-1H-quinazoline-2,4-dione (compound 24)

According to the above Example 7, 2.8 g (14.8 mmol) of N,N'-bis(3-aminopropyl)-1,3-propanediamine was used instead of N-(3-aminopropyl)butane-1. , 4-diamine. The title compound was obtained as a white solid (2.9 g, 41%).

¹ H NMR (DMSO-d ₆ ): 7.91 (d, 2H), 7.63 (t, 2H), 7.17 (m, 4H), 3.92 (t, 4H), 2.49 (t, 8H), 1.70 (m, 4H) ), 1.49 (m, 2H);

Example 25 3-(3-{4-[3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propylamino]-2-butenylamine Propyl)-1H-quinazoline-2,4-dione (compound 25)

According to the above example 7, instead of N-(3-aminopropyl), N,N'-bis(3-aminopropyl)-2-butene-1,4-diamine 2.96 g (14.8 mmol) was used instead. Butane-1,4-diamine. The title compound was obtained as a white solid (4.5 g, 62%).

¹ H NMR (DMSO-d ₆ ): 7.91 (d, 2H), 7.62 (t, 2H), 7.17 (m, 4H), 5.51 (s, 2H), 3.91 (t, 4H), 3.06 (s, 4H) ), 2.47 (m, 4H), 1.68 (m, 4H);

Example 26 (4-{Tertibutoxycarbonyl-[3-(1-methyl-2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]amine Tert-butyl)-[3-(1-methyl-2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl]aminecarboxylic acid tert-butyl ester (Compound 26)

Take (4-{t-butoxycarbonyl-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]amino}butyl -[3-(2,4-Di-Ethylene-1,4-dihydro-2H-quinazolin-3-yl)propyl]aminecarboxylic acid tert-butyl ester (2 g, 2.9 mmol) dissolved in 10 mL It was cooled in tetrahydrofuran and 10 mL of dichloromethane. Sodium hydride (0.2 g, 8.3 mmol) and methyl iodide (0.6 mL, 9.6 mmol) were added and stirred for 2 hr. After concentrating the solvent under reduced pressure, EtOAc m.

¹ H NMR (CDCl ₃ ): 8.21 (d, 2H), 7.66 (t, 2H), 7.24 (t, 2H), 7.18 (d, 2H), 4.09 (t, 4H), 3.59 (s, 6H), 3.26-3.19(m,8H), 1.91(m,4H), 1.48(s,4H), 1.40(s,18H);

Example 27 1-methyl-3-(3-{4-[3-(1-methyl-2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl Amino]butylamino}propyl)-1H-quinazoline-2,4-dione dihydrochloride (Compound 27)

Take (4-{t-butoxycarbonyl-[3-(1-methyl-2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl] Amino}butyl)-[3-(1-methyl-2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]aminecarboxylic acid tert-butyl The ester (1.8 g, 2.5 mmol) was dissolved in 20 mL of methanol, concentrated hydrochloric acid was added and stirred. The title compound was obtained as a white solid (1.3 g, 88%).

¹ H NMR (D ₂ O): 7.81 (d, 2H), 7.71 (t, 2H), 7.25 (t, 2H), 7.19 (d, 2H), 4.04 (t, 4H), 3.34 (s, 6H) , 3.13 (m, 8H), 2.10 (m, 4H), 1.89 (s, 4H);

Example 28 3-(3-{4-[3-(1,3-Di-Ethylene-1,3-dihydro-isoindol-2-yl)propylamino]butylamino}propyl)- 1H-quinazoline-2,4-dione dihydrochloride (Compound 28)

3-{3-[4-(3-Aminopropylamino)butylamino]propyl}-1H-quinazoline-2,4-dione (1.06 g, 3.1 mmol) and citric acid Diethyl ester (0.68 g, 3.1 mmol) was heated and stirred at 125 to 130 °C. After 3 hours, 25 mL of isopropanol and concentrated hydrochloric acid were added thereto to form a solid. The resulting solid was purified by EtOAc EtOAcjjjjjj

¹ H NMR (D ₂ O): 7.77 (d, 1H), 7.71 (m, 4H), 7.61 (m, 1H), 7.19 (t, 1H), 6.99 (d, 1H), 3.98 (t, 2H) , 3.71 (t, 2H), 3.10 (m, 8H), 2.06 (m, 4H), 1.81 (s, 4H);

Example 29 3-(3-{2-[3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propylamino]ethylamino}propyl )-1H-quinazoline-2,4-dione dihydrochloride (Compound 29)

According to the above example 7, N,N'-bis(3-aminopropyl)ethylenediamine (2.5 g, 14.3 mmol) was used instead of N-(3-aminopropyl)butane-1,4-di amine. The title compound was obtained as a white solid (1. 5 g, 9.5%).

¹ H NMR (D ₂ O): 7.91 (d, 2H), 7.64 (m, 2H), 7.25 (m, 2H), 7.07 (d, 2H), 4.07 (t, 4H), 3.48 (s, 4H) , 3.21 (t, 4H), 2.12 (m, 4H);

Example 30 [3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl]-(4-{[3-(2,4-di-oxy) -1,4-Dihydro-2H-quinazolin-3-yl)propyl]hexylamino}butyl)carbamic acid tert-butyl ester (Compound 30)

Taking [3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl]-{4-[3-(2,4-di-oxyl) -1,4-Dihydro-2H-quinazolin-3-yl)propylamino]butyl}aminocarboxylic acid tert-butyl ester (2 g, 3.4 mmol) was dissolved in 40 mL of tetrahydrofuran. Sodium hydride (0.16 g, 6.7 mmol) and 1-bromohexane (0.67 g, 4.0 mmol) were added and stirred under reflux. The solvent was concentrated under reduced pressure.

¹ H NMR (MeOD): 7.99 (m, 2H), 7.61 (m, 2H), 7.20 (m, 2H), 7.12 (dd, 2H), 4.04 (m, 4H), 3.26 (m, 4H), 2.74 (m, 6H), 1.93 (m, 4H), 1.54 (m, 6H), 1.40 (s, 9H), 1.29 (s, 6H), 088 (t, 3H);

Example 31 3-[3-(4-{N-[3-(2,4-Di-Sideoxy-1,4-Dihydro-2H-quinazolin-3-yl)propyl]-N-hexylamino) }butylamino)propyl]-1H-quinazoline-2,4-dione dihydrochloride (compound 31)

Taking [3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-(4-{[3-(2,4-di-oxo) Tert-butyl 1,4-dihydro-2H-quinazolin-3-yl)propyl]hexylamino}butyl) carboxylic acid tert-butyl ester 0.4 g (0.6 mmol) was removed according to the same procedure as in Example 27 above. The protecting group was isolated by chromatography to give white crystals (lj,

¹ H NMR (MeOD): 7.97 (m, 2H), 7.60 (m, 2H), 7.20 (m, 2H), 7.11 (t, 2H), 4.13 (t, 2H), 4.04 (t, 2H), 3.04 (m, 4H), 2.75 (t, 2H), 2.67 (m, 4H), 2.10 (m, 2H), 1.91 (m, 2H), 1.79 (m, 2H), 1.70 (m, 2H), 1.55 ( m, 2H), 1.30 (m, 6H), 0.88 (t, 3H);

Example 32 (4-{Tertibutoxycarbonyl-[3-(1-hexyl-2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]amino group }butyl)-[3-(1-hexyl-2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]aminecarboxylic acid tert-butyl ester (compound) 32)

Take (4-{t-butoxycarbonyl-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]amino}butyl -[3-(2,4-Di-Ethyl-1,4-dihydro-2H-oxazolin-3-yl)propyl]- carboxylic acid tert-butyl ester (3 g, 4.3 mmol) dissolved in 120 mL Acetonitrile. Potassium carbonate (3.45 g, 25.0 mmol) and 1-bromohexane (3.5 g, 21.1 mmol) were added thereto, and stirred under reflux for 3 hours. The solvent was concentrated under reduced pressure and EtOAcqqqqqm

¹ H NMR (CDCl ₃ ): 8.13 (d, 2H), 7.57 (t, 2H), 7.14 (t, 2H), 7.09 (d, 2H), 4.01 (m, 8H), 3.13 (m, 8H), 1.84 (m, 4H), 1.64 (m, 4H), 1.36 (s, 18H), 1.41-1.25 (m, 16H), 0.82 (t, 6H);

Example 33 1-hexyl-3-(3-{4-[3-(1-hexyl-2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino) Butylamino}propyl)-1H-quinazoline-2,4-dione dihydrochloride (Compound 33)

Take (4-{t-butoxycarbonyl-[3-(1-hexyl-2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]amine Benzyl)-[3-(1-hexyl-2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]aminecarboxylic acid tert-butyl ester ( The title compound was obtained as a white solid (l.

¹ H NMR (MeOD): 8.15 (d, 2H), 7.78 (m, 2H), 7.43 (d, 2H), 7.30 (t, 2H), 4.17 (m, 8H), 3.09 (t, 8H), 2.12 (m, 4H), 1.84 (s, 4H), 1.72 (m, 4H), 1.45-1.35 (m, 12H), 0.91 (t, 6H);

Example 34 [3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl]-(4-{[3-(2,4-di-oxy) -1,4-Dihydro-2H-quinazolin-3-yl)propyl]heptanoylamino}butyl)aminecarboxylic acid tert-butyl ester (Compound 34)

Taking [3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl]-{4-[3-(2,4-di-oxyl) -1,4-Dihydro-2H-quinazolin-3-yl)propylamino]butyl}aminecarboxylic acid tert-butyl ester (0.4 g, 0.7 mmol) with heptanoic anhydride (0.2 g, 0.8 mmol) The reaction was carried out in place of the acetic anhydride of the above Example 4. The title compound was obtained as a white solid (0.37 g, 88%).

¹ H NMR (CDCl ₃ ): 8.10 (m, 2H), 7.58 (m, 2H), 7.26-7.10 (m, 4H), 4.08 (m, 4H), 349-3.23 (m, 8H), 2.28 (t) , 2H), 1.95 (m, 4H), 1.66-1.50 (m, 6H), 1.43 (d, 9H), 1.27 (m, 6H), 0.87 (m, 3H);

Example 35 [3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-{4-[3-(2,4-di-oxyl- 1,4-Dihydro-2H-quinazolin-3-yl)propylamino]butyl}heptylamine hydrochloride (Compound 35)

Use [3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-(4-{[3-(2,4-two side) instead Oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl]heptanylamino}butyl) carboxylic acid tert-butyl ester (0.36 g, 0.5 mmol) according to Example 31 above The title compound was obtained as a white solid (0.2 g, 61%).

¹ H NMR (MeOD): 8.01 (m, 2H), 7.63 (m, 2H), 7.23 - 7.13 (m, 4H), 4.14 (t, 2H), 4.05 (m, 2H), 3.45 (m, 4H) , 3.02 (m, 4H), 2.35 (m, 2H), 2.10 - 1.95 (m, 4H), 1.76-1.55 (m, 6H), 1.27 (m, 6H), 0.87 (m, 3H);

Example 36 N-[3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-di Hydroxyl-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}-2,2,2-trifluoroacetamide hydrochloride (Compound 36)

The title compound was obtained as a yellow solid (0.6 g, 15.8%) from EtOAc.

¹ H NMR (MeOD): 8.00 (m, 2H), 7.63 (m, 2H), 7.25-7.13 (m, 4H), 4.14 (m, 2H), 4.06 (m, 2H), 3.54 (m, 4H) , 3.01 (m, 4H), 2.07 (m, 4H), 1.74 (m, 4H);

Example 37 N-[3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[[3-(2,4- Bis-oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl]-(2,2,2-trifluoroethyl)amino]butyl}-2,2, 2-trifluoroacetamide (Compound 37)

The title compound was obtained as a white solid (1.1 g, 26.4%).

¹ H NMR (MeOD): 8.01 (m, 2H), 7.62 (m, 2H), 7.23 - 7.12 (m, 4H), 4.03 (m, 4H), 3.50 (m, 8H), 2.01 (m, 4H) , 1.65 (m, 4H);

Example 38 N-[3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-di Hydroxyl-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}-2-methoxyacetamide hydrochloride (Compound 38)

Instead of ethyl chloroformate, 0.5 g (1.0 mmol) of the starting material of the above Example 5 and methoxyethyl hydrazine chloride (0.12 g, 1.1 mmol) were used instead. The title compound was obtained as a white solid (0.1 g, 16.4%).

¹ H NMR (MeOD): 800 (m, 2H), 7.63 (m, 2H), 7.23-7.12 (m, 4H), 4.14 (m, 4H), 4.05 (m, 2H), 3.48-3.32 (m, 7H), 3.01 (m, 4H), 2.12-2.01 (m, 4H), 1.70 (m, 4H);

Example 39 [3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-{4-[3-(2,4-di-oxyl- Benzyl 1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}amine carboxylic acid hydrochloride (Compound 39)

The title compound was obtained as a yellow solid (0.34 g, 8.4%).

¹ H NMR (MeOD): 8.00 (m, 2H), 7.63 (m, 2H), 7.33-7.19 (m, 7H), 7.13 (t, 2H), 5.08 (s, 2H), 4.13 (t, 2H) , 4.00 (m, 2H), 3.41 (m, 4H), 3.00-2.92 (m, 4H), 2.06 (m, 2H), 1.96 (m, 2H), 1.69 (bs, 4H);

Example 40 N-[3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-di oxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}-4-methylbenzenesulfonamide (Compound 40)

Instead of the methanesulfonium chloride of the above Example 12, 1.4 g (7.3 mmol) of p-toluenesulfonium chloride was used instead. The title compound was obtained as a white solid (0.3 g, 8%).

¹ H NMR (MeOD): 7.95 (d, 2H), 7.66 (d, 2H), 7.58 (m, 2H), 7.33 (d, 2H), 7.18-7.08 (m, 4H), 4.02 (m, 4H) , 3.32 (t, 2H), 3.15 (t, 2H), 2.55 (q, 4H), 2.39 (s, 3H), 1.89 (m, 4H), 1.63 (m, 2H), 1.52 (m, 2H);

Example 41 N-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-(4-{[3-(2,4- Bilateral oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl]-4-methylbenzenesulfonylamino}butyl)-4-methylbenzenesulfonamide Compound 41)

The title compound was obtained as a white solid (1.27 g, 26%).

¹ H NMR (DMSO-d ₆ ): 11.40 (s, 2H), 7.90 (d, 2H), 7, 62 (m, 6H), 7.32 (d, 4H), 7.17 (m, 4H), 3.86 (t) , 4H), 3.08 (m, 8H), 2.35 (s, 6H), 1.75 (m, 4H), 1.42 (s, 4H);

Example 42 3-(3-{4-[3-(2,5-di-oxy-pyrrolidin-1-yl)propylamino]butylamino}propyl)-1H-quinazoline-2, 4-dione dihydrochloride (compound 42)

1.5 g (4.3 mmol) of the starting material of the above Example 28 and succinic anhydride (0.43 g, 4.33 mmol) were used instead of diethyl phthalate. The title compound was obtained as a yellow solid (0.23 g, 11%).

¹ H NMR (MeOD): 8.05 (d, 1H), 7.67 (m, 1H), 7.25 (t, 1H), 7.20 (d, 1H), 4.16 (t, 2H), 3.61 (t, 2H), 3.07 (m, 8H), 2.72 (s, 4H), 2.12 (m, 2H), 1.97 (m, 2H), 1.82 (m, 4H);

The following experimental examples will illustrate the compounds of the above formula (I) having excellent effects as neuroprotective agents in more detail using the compounds prepared in the above examples.

The following examples are provided to aid the understanding of the invention and should not be construed as limiting the scope of the claims described below.

<Experimental Example 1> Anti-stroke effect test in middle cerebral artery occlusion (MCAO) mode

Male SD rats weighing 290 to 300 g were used as experimental animals, and 8 rats were used in each experimental group. Surgery was performed using the method of Nagasawa et al. (Nagasawa, H. and Gogure, K. 1989, Stroke, 20: 1037-1043).

The rats were anesthetized with K-tart, and when the operation was performed, the body temperature was maintained by a hot plate. Cut the brain area along the midline of the neck, separate the left common carotid artery, the internal carotid artery, and the external carotid artery, taking care to avoid injuring the vagus nerve. The common carotid artery and the external carotid artery were ligated, and a probe was inserted from the branch points of the internal carotid artery and the external carotid artery to the internal carotid artery. The base of the occluded midbrain artery is then ligated just above the insertion point. The probe was prepared by heating the end with a 4-0 nylon surgical suture (Dafilon, B. Braun, Germany) and then cutting it to 30 mm. A mixture of hydrazine (Xantopren VL plus, Heraeus Kulzer, Germany) and a hardener (Optosyl-Xantopren VL plus, Heraeus Kulzer, Germany) was applied at a thickness of 0.3 to 0.4 mm at a distance of 7 to 9 mm from the end of the probe. After the probe was inserted, the animal was awakened from anesthesia, and the individual with a neurological defect (turning to the right) was included in the ischemic treatment group.

After 3 hours of ischemia, the inserted probe was removed and blood circulation was resumed and reperfused. After 24 hours, the brain was cut and then tissue stained.

Compound 3 was administered orally or intravenously at a specified time interval before or after insertion of the probe. TTC (2,3,5-triphenyltetrazolium chloride) staining was performed to assess ischemic injury to brain tissue. The original head of the removed brain was continuously cut into 2 mm sections using a brain tissue section table (ASI instrument, Warren, MI, USA). The sections were placed in a 2% TTC solution and incubated at 37 ° C for 60 minutes for staining. Brain sections stained with TTC were fixed in 10% formalin buffer and photographed on the front of each section with a digital camera. The infarct area (cm ² ) which was not stained dark red was measured for each image obtained by an image analyzer, and the total infarct volume (cm ³ ) was calculated by multiplying the slice thickness.

As a result, when the compound 3 was orally administered (100 mg/kg) 1 hour before the stroke induction and immediately before the induction, the percentage of the inhibitory effect on the volume of the cerebral infarction was 22.3% and 69.8%, respectively, as compared with the negative control group. When Citicoline (2 g/kg) was administered as a positive control group, 51.1 and 37.8% were observed, respectively (Table 1 and Figure 1).

In this experiment, the probe was removed after induction of stroke to restore circulation and reperfusion. Compound 3 was then administered at a 5 mg/kg dose at separate time points, and an inhibitory effect of 62.7% was observed for necrotic volume even when administered 12 hours after reperfusion. On the other hand, when MK-801 was administered as a positive control group, the highest effect occurred 30 minutes after reperfusion (Table 2). Therefore, Compound 3 has a significant effect on the prevention and treatment of stroke, and can also be used in patients who have been delayed in treatment after stroke.

* Negative control group infarct volume 0.45 ± 0.03

* Negative control group infarct volume 0.43 ± 0.02

<Experimental Example 2> Inhibition of stimulating neurotoxicity in a mixed culture of nerve cells and glial cells

Neurons were isolated and cultured according to the method of Choi (Choi, DW 1985, Neurosci. Lett., 58: 293-297). That is, embryonic ICR mice from the 14th day of pregnancy were isolated from the cortical layer, and then a single cell was obtained from the tissue using a pipette. The cells were dispensed into a 24-well plate (Falcon) at a density of 2 × 10 ⁵ /well, and the glial cells of the cerebral cortex were cultured in an incubator at 37 ° C for 3 weeks using 5% CO ₂ . The medium was supplemented with MEM (Minimum Essential Medium, Sigma), 2 mM branamine, 21 mM glucose, 26.5 mM bicarbonate, 10% fetal bovine serum (FBS). Three to five days after aliquoting, treatment with 10 μM Ara-C (arabinoside) to inhibit glial cell proliferation. And 12 to 15 days after the aliquot, 100 μM NMDA and 1 μg/mL or 2 μg/mL of each sample (compound) were treated for 20 minutes to induce nerve cells to die due to excitable toxicity. Due to nerve cell death, the accumulation of lactate dehydrogenase (LDH) is proportional to the number of dead cells. After 24 hours of drug treatment, the amount of dehydrogenase (LDH) released to the outside of the cells was measured using an LDA assay kit (CytoTox 96, Promega). After the reaction was completed, the change in absorbance with LDH content was measured using a microplate luminometer.

The inhibitory effect on cell death compared with the negative control group is shown in Table 3, which shows a remarkable effect.

ND: not detected

<Experimental Example 3> Inhibition effect of SH-SY5Y cells on H ₂ O ₂ -mediated cytotoxicity

The SH-SY5Y cells, which were human-targeted as a neural cell strain, were cultured in a 96-well plate at a concentration of 3 × 10 ⁴ cells, and the samples were processed. After 30 minutes, it was treated with 200 μM hydrogen peroxide to induce toxicity for 24 hours. After the reaction was completed, the cell viability was measured by MTT assay.

As a result, it was found that the survival rate of SH-SY5Y cells was positively correlated with the concentration of Compound 4, and showed a protective effect of about 35% on the cells at a concentration of 100 μg/ml (Table 4).

<Experimental Example 4> Inhibition effect of SH-SY5Y cells on ZnSO ₄ -mediated cytotoxicity

SH-SY5Y cells were cultured in a 96-well plate at a concentration of 3 × 10 ⁴ cells, and treated with a compound (50 μg/ml). After 30 minutes, the cells were treated with 600 μM zinc sulfate to induce toxicity for 24 hours, and cell viability was measured by MTT assay. The results showed an inhibitory effect on toxicity of 9.1 to 21.7% (Table 5).

<Experimental Example 5> Inhibition effect of brain cells on ROS production

Oxidative pressure was measured using DCF-DA, which is a fluorescent probe, to test the inhibitory effect on the production of reactive oxygen species (ROS). Brain cells were obtained from the mouse cerebral cortex to prepare a cell solution of 2 x 10 ⁶ cells/ml. Each brain cell was treated with 11 μM DCF-DA and reacted in a 5% CO ₂ incubator at 37 ° C for 1 hour. After washing twice, it was treated with Compound 3 at a concentration of 125 μg/ml and 250 μg/ml. At the same time, it was treated with 300 μM NMDA and cultured at 37 ° C for 24 hours in a 5% CO ₂ incubator. After completion of the reaction, fluorescence of reactive oxygen in the reaction solution was measured by a fluorescence photometer (excitation light 480 nm / emission light 535 nm). As a result, Compound 3 inhibited the oxidative stress induced by NMDA of nerve cells in a dose-dependent manner (Fig. 2).

The ROS inhibitory effect of the compound was expressed as a dose at which 50% of reactive oxygen production was inhibited relative to the control group. An increase in the activity of superoxide dismutase (SOD), an enzyme that plays an important angular role in the production of reactive oxygen, has been observed and indicates its rate of increase relative to the control group. The activity of superoxide dismutase (SOD) was determined using a kit from Sigma. As a result, most of the compounds showed lower doses of ID ₅₀ than MK-801, which is a positive control group. This means that it has an excellent effect at a dose lower than MK-801.

The antagonism of the compound against the NMDA receptor was examined in Experimental Examples 2 to 5, and it was confirmed that the compound of the present invention can be used not only as a drug for treating ischemic stroke, but also for preventing and treating degenerative brain diseases associated with the receptor, such as : Epilepsy, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Huntington's disease, Alzheimer's disease and traumatic brain injury or spinal injury. It can also be used to improve memory.

<Experimental Example 6> Anti-caries effect experiment

Experiments were performed according to the method of Ali et al. (Ali, A. et al. 2006, Pharmacological Reports, 58: 242-245). The compound at a dose of 10 mg/kg was administered intraperitoneally to discriminate the anticonvulsant effect, and the effect was observed (Table 8). The study of activity was performed in accordance with NIH's Anti-epileptic Drug Development Program (ADD) during the development of anticonvulsant drugs. One of the first steps in the program to evaluate anti-caries activity was the pentylenetetrazol (PTZ) test. After administration of the test drug, PTZ at a dose of 80 mg/kg was administered subcutaneously and observed for at least 30 minutes. After administration of the test drug at 10 mg/kg, the time to start the blockage was estimated until the time period during which the blockage completely disappeared and the mortality rate was evaluated. When PTZ was administered, at least one of the four experimental animals was evaluated for its anticonvulsant effect when no clonic spasm occurred within 5 seconds.

Each value represents the mean value (n=6) (negative control group, n=23)

*: Statistically significant (95% confidence) compared to the control group

**: Statistically significant compared to the control group (99% confidence)

N. D.: not detected

<Experimental Example 7> Relaxation effect on rat thoracic artery

Male SD rats (250 to 300 g) were anesthetized by inhalation of ether, and the thoracic artery was removed and placed in Krebs buffer (mM; NaCl 118, NaHCO ₃ 27.3, KCl 4.8, MgSO ₄ 1.2, KH ₂ PO ₄ 1.0, CaCl ₂ 1.25, glucose 11.1). A 2 mm aneurysm was made under a dissecting microscope and cultured in an organ bath to measure vascular tone. The organ bath was filled with Krebs buffer and saturated with 95% O ₂ , 5% CO ₂ to maintain dissolved oxygen and physiological pH. The change in tension was measured using a tensiometer (Hugo-sachs, model K30) and recorded with a physiological recorder (Coulbourn wave spirograph). Gradually increase the length of the blood vessel until the base tension reaches 1.0 g for 90 minutes. The equilibrated blood vessels were contracted with dehydroxyephrine (0.5 μM). When the shrink wrinkles reached equilibrium, the compound was added and then the relaxation effect was observed.

The results of the addition of Compound 3 at doses of 50 μg/mL, 100 μg/mL, and 200 μg/mL are shown in Table 9, and Compound 3 showed a relaxation in the rat thoracic artery causing contraction of phenylephrine in a dose-dependent manner (Table 9). The results of administration of each compound at a dose of 67 μg/mL are shown in Table 10, and it was inferred from this that the vasodilation in the body increased blood flow, thereby delaying cell death and inducing regeneration of dead cells.

Each value represents the mean value ± standard deviation (n = 3).

Each value represents the measured average (n=3).

ND: not detected

Most compounds showed superior relaxation effects on vascular muscles compared to the control group.

[Industrial availability]

As described in the above examples, the compound of the present invention exhibits an anti-stroke effect, an antagonistic effect on NMDA receptors, an inhibitory effect on the toxicity of nerve cells on H ₂ O ₂ and ZnSO ₄ toxicity, an antioxidant effect on nerve cells, and an anti-caries effect. And the relaxation effect on the thoracic artery. Therefore, it can be used as a medicine for the prevention and treatment of various diseases such as stroke, nervous system function, memory loss, cerebrovascular dysfunction, brain and spinal cord injury, cerebral ischemia, dementia, Alzheimer's Symptoms, Parkinson's disease and epilepsy.

Figure 1 shows the anti-stroke effect of Compound 3 in the middle cerebral artery occlusion (MCAO) mode. The red (colored area) represents the normal brain area, and the white (colorless area) represents the occlusion area. 100 mg/kg of Compound 3 and 2000 mg/kg of citicoline (8 mice in each experimental group) were administered 1 hour before the induction of stroke and immediately before induction.

Fig. 2 shows the inhibitory effect of Compound 3 on oxidative stress induced by NMDA in mouse brain cells. The "normal control group" was normal cells that did not receive any treatment, and the "negative control group" was brain cells treated with 300 μM NMDA. Treatment was carried out at 125 μg/mL and 250 μg/mL of Compound 3 (compound treatment group). Marks #, *, and ** indicate that when ANOVA and Student-t tests were performed, significant differences of P < 0.05 were observed compared with their respective control groups (#; comparing normal control group with negative control group; and * and **; Comparative compound treatment group and negative control group).

Since the picture in this case is experimental data, it is not a representative figure of this case. Therefore, there is no designated representative map in this case.

Claims (16)

A quinazoline-2,4-dione compound of the formula (I) or a pharmaceutically acceptable salt thereof, Wherein R ₁ is hydrogen or C _1-6 alkyl; each R ₂ and R _{3 are} independently selected from hydrogen, C _1-6 alkyl, -COR ₆ , -SO ₂ R ₇ , phenyl or benzyl, wherein R ₆ is C _1-6 alkyl, C _1-4 alkoxy, phenyl, phenoxy or benzyloxy, which are respectively unsubstituted or halogen, hydroxy, methoxy, ethoxy or nitro Substituted, and R ₇ is C _1-4 alkyl or unsubstituted or substituted by C _1-6 alkyl; A is -(CH ₂ ) _n - or -CH ₂ CH=CHCH ₂ -, wherein n is an integer selected from 2 to 4; R ₄ and R ₅ together with N form a ring, and form a divalent group as follows: Wherein R ₈ is hydrogen or C _1-6 alkyl; each l and m are independently selected from an integer from 2 to 4; and p is an integer of 0 or 1. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R ₁ is hydrogen; each R ₂ and R _{3 are} independently selected from the group consisting of hydrogen, C _1-6 alkyl, -COR ₆ , -SO ₂ R ₇ , phenyl or benzyl, wherein R ₆ is C _1-6 alkyl, C _1-4 alkoxy, phenyl, phenoxy or benzyloxy, respectively unsubstituted or halogen, hydroxy , methoxy, ethoxy or nitro substituted, and R ₇ is C _1-4 alkyl or unsubstituted or substituted by C _1-6 alkyl; A is -(CH ₂ ) _n - or -CH ₂ CH=CHCH ₂ -, wherein n is an integer selected from 2 to 4; R ₄ and R ₅ together with N form a ring and form a divalent group as follows: Wherein R ₈ is hydrogen or C _1-6 alkyl; each l and m are independently selected from an integer from 2 to 4; and p is an integer of 0 or 1. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of 3-(3-{4-[3-(2,4-di-oxy)- 1,4-Dihydro-2H-quinazolin-3-yl)propylamino]butylamino}propyl)-1H-quinazoline-2,4-dione; N-[3-( 2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-di-oxy-1, 4-Dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamidamine; N-(4-{ethylindolyl-[3-(2,4-di-oxy)- 1,4-Dihydro-2H-quinazolin-3-yl)propyl]amino}butyl)-N-[3-(2,4-di-oxo-1,4-dihydro-2H -quinazolin-3-yl)propyl]acetamide; [3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl]- {4-[3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}aminecarboxylic acid ethyl ester; N-[3 -(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-(4-{[3-(2,4-di-oxyl) -1,4-dihydro-2H-quinazolin-3-yl)propyl]methylamino}butyl)acetamidine; 3-{4-[3-(2,4-di-oxyl) -1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}-1H-quinazoline-2,4-dione; 3-{3-[4-({ N-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-benzyl}amino)butylamino] Propyl}-1H-quinazoline-2,4-dione; N-[3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)-propyl ]-N-{4-[3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}benzamide [3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl]-{4-[3-(2,4-di-oxyl) -1,4-Dihydro-2H-quinazolin-3-yl)propylamino]butyl}aminocarboxylic acid tert-butyl ester; N-[3-(2,4-di- oxy-1, 4-Dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazoline- 3-yl)propylamino]butyl}methanesulfonamide; N-(4-{benzyl-[3-(2,4-di-oxo-1,4-dihydro-2H) -quinazolin-3-yl)propyl]amino}butyl)-N-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl Propyl]acetamide; (4-{ethylindolyl-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]amine } butyl)-[3-(2,4-di-oxy-1,4-dihydrol -2H-quinazolin-3-yl)propyl] urethane; 3-{[3-(4-{N-[3-(2,4-di- oxo-1,4-dihydro) -2H-quinazolin-3-yl)propyl]-N-benzylamino}butyl]-N-benzylamino]propyl}-1H-quinazoline-2,4-di Ketone; [3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-(4-{[3-(2,4-two-side) Ethyloxy-1,4-dihydro-2H-quinazolin-3-yl)propyl]ethoxycarbonylamino}butyl) urethane; (4-{t-butoxycarbonyl-[ 3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl]amino}butyl)-[3-(2,4-dihydroxyl) Tert-butyl 3- 1,4-dihydro-2H-quinazolin-3-yl)propyl]amine; N-[3-(2,4-di-oxy-1,4-dihydro) -2H-quinazolin-3-yl)propyl]-N-(4-{[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl) )propyl]methanesulfonylamino}butyl)methanesulfonamide; N-[4-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl) Butyl]-N-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]acetamide; 3-(2-{ 3-[2-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)ethylamino]propylamino}ethyl)-1H-quinazole Porphyrin-2,4-dione; 3-(3-{3-[3-(2,4-di-oxo-1,4-dihydrol) -2H-quinazolin-3-yl)propylamino]propylamino}propyl)-1H-quinazoline-2,4-dione; 3-(3-{4-[3-( 2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propylamino]-2-butenylamino}propyl)-1H-quinazoline- 2,4-dione; (4-{t-butoxycarbonyl-[3-(1-methyl-2,4-di-oxy-1,4- Dihydro-2H-quinazolin-3-yl)propyl]amino}butyl)-[3-(1-methyl-2,4-di-oxo-1,4-dihydro-2H- Tert-butyl quinazolin-3-yl)propyl]amine; 1-methyl-3-(3-{4-[3-(1-methyl-2,4-di-oxyl-1) ,4-dihydro-2H-quinazolin-3-yl)propylamino]butylamino}propyl)-1H-quinazoline-2,4-dione; 3-(3-{2 -[3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propylamino]ethylamino}propyl]-1H-quinazoline -2,4-dione; [3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-(4-{[3-( 2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl]hexylamino}butyl) carboxylic acid tert-butyl ester; 3-[3-(4 -{N-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-hexylamino}butylamino)propyl -1H-quinazoline-2,4-dione; (4-{t-butoxycarbonyl-[3-(1-hexyl-2,4-di-oxo-1,4-dihydro) -2H-quinazolin-3-yl)propyl]amino}butyl)-[3-(1-hexyl-2,4-di-oxy-1,4-dihydro-2H-quinazoline 3-butyl)propyl]aminecarboxylic acid tert-butyl ester; 1-hexyl-3-(3-{4-[3-(1-hexyl-2,4-di-oxo-1,4-dihydrol) -2H-quinazolin-3-yl)propylamino]butylamino}propyl -1H-quinazoline-2,4-dione; [3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-( 4-{[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]heptanylamino}butyl)aminecarboxylic acid tert-butyl ester; [3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-{4-[3-(2,4-di-oxyl- 1,4-Dihydro-2H-quinazolin-3-yl)propylamino]butyl}heptanylamine; N-[3-(2,4-di-oxo-1,4-dihydrogen) -2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl) Propylamino]butyl}-2,2,2-trifluoroacetamide; N-[3-(2,4-di-oxy-1,4-dihydro-2H-quinazoline-3 -yl)propyl]-N-{4-[[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-(2, 2,2-trifluoroethyl)amino]butyl}-2,2,2-trifluoroacetamide; N-[3-(2,4-di-oxo-1,4-dihydrogen) -2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl) Propylamino]butyl}-2-methoxyacetamide; [3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl ]-{4-[3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}aminecarboxylic acid benzyl ester; N-[3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-di oxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}-4-methylbenzenesulfonamide; and N-[3-(2,4- Bilateral oxy- 1,4-Dihydro-2H-quinazolin-3-yl)propyl]-N-(4-{[3-(2,4-di-oxo-1,4-dihydro-2H-quinaline Oxazolin-3-yl)propyl]-4-methylbenzenesulfonylamino}butyl)-4-methylbenzenesulfonamide. Such as the compound of claim 1 or a pharmaceutically acceptable salt thereof, Wherein the compound is N-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2 , 4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 3-{4-[3-(2,4-di-oxy-1,4-dihydro-2H-quinazoline) Polin-3-yl)propylamino]butyl}-1H-quinazoline-2,4-dione. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 3-{3-[4-({N-[3-(2,4-di-oxy-1,4-) Dihydro-2H-quinazolin-3-yl)propyl]-N-benzyl}amino)butylamino]propyl}-1H-quinazoline-2,4-dione. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 3-(2-{3-[2-(2,4-di-oxo-1,4-dihydro-2H) -quinazolin-3-yl)ethylamino]propylamino}ethyl)-1H-quinazoline-2,4-dione. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is [3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl) )propyl]-(4-{[3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propyl]hexylamino}butyl)amine Tert-butyl formate. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is [3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl) )propyl]-{4-[3-(2,4-di-oxy-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}aminecarboxylic acid benzoate Base ester. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is N-[3-(2,4-di-oxy-1,4-dihydro-2H-quinoline Oxazolin-3-yl)propyl]-N-{4-[3-(2,4-di-oxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino ]butyl}-4-methylbenzenesulfonamide. A process for the preparation of a compound of formula (IX) comprising the step of reacting a compound of formula (IV) with an amine compound of formula (V) in the presence or absence of a solvent to provide a compound of formula (IX): Wherein A, l , m and p are as defined in the first paragraph of the patent application; R ₄ and R ₅ represent hydrogen, or when R ₄ and R ₅ together with N form a ring, R ₄ and R ₅ form the following two Price group: Alk represents a C _1-6 alkyl group; and L represents a leaving group. A process for the preparation of a compound of the formula (IX) according to claim 11, wherein the compound of the formula (IV) is ethyl 2-ethoxycarbonylaminobenzoate, which is a 2-amino group of the formula (II). Ethyl benzoate is reacted with ethyl chloroformate of formula (III) in an organic solvent. A process for the preparation of a compound of formula (IX) which comprises the steps of reacting a primary amine compound of formula (VI) with a compound of formula (VIII) to give a compound of formula (IX) in the presence or absence of a solvent: Wherein A, R ₄ , R ₅ , l , m and p are as defined in the first paragraph of the patent application; each Y and Y' is a hydroxyl group, a halogen or a C _1-4 alkoxy group, or when Y and Y' are formed In the ring, Y and Y' form -O-. A method of preparing a compound of formula (Ia), which comprises an amine compound of R _2, R _3, or R ₂ and R ₃ substituents of formula (IX) in at least two and a hydrogen to obtain a compound of formula (Ia) wherein R ₂ and The step of at least one of R ₃ not being hydrogen: Wherein R ₂ , R ₃ , R ₄ , R ₅ , A, l , m and p are as defined in the first item of the patent application. A process for the preparation of a compound of formula (I), wherein R ₁ is C _1-6 alkyl, the process comprising reacting a compound of formula (Ia) with an alkylating agent and, if desired, removing the protection a step of obtaining a compound of the formula (I) wherein R ₁ is a C _1-6 alkyl group, Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , A, l , m and p are as defined in the first item of the patent application, but the limitation is that R _{1 is} not hydrogen. A method used to protect nerve cells, improve memory, or prevent or treat God A pharmaceutical composition for menstrual brain disease, degenerative neurological brain disease, stroke, Alzheimer's disease or epilepsy, which comprises a compound of any one of claims 1 to 10 or a pharmaceutically acceptable substance thereof Accept salt as the active ingredient.