KR19990071254A - 2-oxo-1, 3-oxazolidin-5-ylmethoxy) -quinoline-2-carboxylic acid derivative - Google Patents

Abstract

The present invention relates to 4- (3-substituted-2-oxo and 2-thioxo-1,3-oxazolidin-5-ylmethoxy) -quinoline-2-carboxylic acid derivatives of the formula 1, As a potent and specific antagonist acting on the strychinine non-susceptible glycine binding site in the < RTI ID = 0.0 > complex. ≪ / RTI > The compounds of the present invention are useful for the treatment and prevention of neurodegenerative diseases. In particular, the compounds of the present invention are useful for reducing central nervous system damage caused as a result of anemia such as stroke, hypoglycemia, ischemia, cardiac arrest, trauma, or hypoxia. In addition, the compounds of the present invention are useful for the prevention and treatment of chronic neurodegenerative diseases including epilepsy, Alzheimer's disease, Huntington's disease and Parkinson's disease. In addition, the compounds of the present invention are used as anticonvulsants, analgesics, antidepressants, antianxiety agents, and antipsychotic drugs.

(Wherein R ₁ , R ₂ , R ₃ and X are as defined in the specification)

Description

2-oxo-1, 3-oxazolidin-5-ylmethoxy) -quinoline-2-carboxylic acid derivative

The present invention relates to 4- (3-substituted-2-oxo and 2-thioxo-1,3-oxazolidin-5-ylmethoxy) -quinoline-2- carboxylic acid derivatives of the formula 1 which act as excitatory amino acid antagonists, Its preparation method and its use as a therapeutic agent for neurological diseases.

In particular, the compounds of the present invention antagonize the excitatory activity of NMDA receptors and are useful for the treatment of damage to the central nervous system resulting from anemia such as stroke, hypoglycemia, ischemia, cardiac arrest, trauma, It is especially useful for reducing.

In addition, the compounds of the present invention are useful for the prevention of chronic neurodegenerative diseases including epilepsy, Alzheimer's disease, Huntington's disease and Parkinson's disease. The compounds of the present invention are also used as anticonvulsants, analgesics, antidepressants, antianxiety agents and antipsychotic agents.

The most important excitatory neurotransmitter in mammalian central nervous system neurotransmission is L-glutamate. Almost all of the central nervous system nerve cells are excited by L-glutamate, which acts on a variety of receptor-ion channel complexes present on the surface of neurons, opening ion channels and introducing cations such as sodium or calcium To stimulate nerve cells by inducing polarization between the nerve cell membranes.

These central nervous system neurons express NMDA receptors excited by N-methyl-D-aspartate (N-methyl-D-aspartate, hereinafter abbreviated as NMDA) and non-NMDA receptors that are not excited by NMDA .

The NMDA receptor is a cell surface protein complex distributed widely in the brain or spinal cord. It is known to transmit neuronal excitability in neuronal synapses and is closely related to neuronal cell growth.

One of the characteristics of this NMDA receptor is that it is completely blocked by Mg ⁺⁺ when the cell is at rest. However, this blockage is voltage-dependent and the block is released if the cell is activated by a non-NMDA receptor or another excitable material is introduced and becomes partially depolarized. Thus, the mechanism of action of NMDA receptors plays an important role in the learning and memory process because it depends on conditions.

Another characteristic of the NMDA receptor is that if the receptor is excessively excited, the cell will die. This seems to be due to excessive accumulation of Ca ⁺⁺ in the cells. Recently, many studies have been conducted on the apoptosis caused by excitotoxicity of the NMDA receptor.

When neurons, neurons, are cultured in vitro and then treated with glutamate, the cells are swollen and cytotoxic. This excitatory toxicity is dependent on the presence of Ca ^{++. When} a large amount of Ca ⁺⁺ enters the neuron through the ion channel of the glutamate receptor, normal cell activity is destroyed and the release of glutamate is accelerated again by feedback Excitatory toxicity occurs. In this process, proteases and lipases are activated, resulting in the destruction of nerve cell membranes and the production of free radicals [JW McDold, MV Johnson, Brain Res. Reviews 15, 41 (1990). Thus, excitotoxicity caused by neurotransmitters kills neurons, and this research continues to reveal that this is a major cause of neurodegenerative diseases and stroke associated with brain cell death.

In recent years, the focus has been focused on the mechanisms by which excessive damage to the central nervous system occurs due to excessive secretion of L-glutamate by brain damage, spinal cord injury, stroke, ischemia or hypoglycemia. Studies have shown that central nervous system Lt; RTI ID = 0.0 > NMDA < / RTI > receptor antagonist.

NMDA receptor antagonists prevent many clinical disorders including ischemic and epilepsy and prevent chronic neurodegenerative diseases such as Alzheimer's disease, Huntington's disease and Parkinson's disease [G. Johnson, Annu. Rep. Med. Chem. 24, 41 (1989); G. Johnson and CF Bigge, ibid. 26 , 11 (1991); Werling et al., J. Pharmacol. Exp. Ther. 255 , 40 (1990)]. Recently, several NMDA receptor antagonists have been used to treat acute stroke and brain damage.

It has also been reported that NMDA receptor antagonists are useful for improving memory and learning, examples being 1-aminocyclopropanecarboxylic acid methyl ester, a specific glycine ligand, D- cycloserine and R - (+) - 3- Amino-1-hydroxypyrrolidin-2-one- (HA-966) [Bliss, TV P, Collingride, GL, Nature 345 , 347 (1990); GB 2231048A (1990)].

A recent report suggests that NMDA receptor antagonists have analgesic, antidepressant, antipsychotic, and anxiolytic effects [Dickenson, AH and Aydar, E., Neuroscience Lett. 121, 263 (1990); R. Trullas and P. Skolnick, Eur. J. Pharmacol. 185,1 (1990); JH Kehne, et al., Eur. J. Pharmacol. 193 , 283 (1991); PH Hutson, et al., Br. J. Pharmacol. 103 , 2037 (1991)).

Noncompetitive NMDA receptor antagonists such as ketamine, dextromethorphan, and the like are useful for the treatment of childhood growth disorders, autism, and the like. NMDA receptor antagonists are also useful as protective agents in laser neurosurgery.

The fact that NMDA receptors play an important role in the synaptic degeneration of neurons considered to be one of the causes of these diseases is more evident by recent studies on their physiological functions and the structure of subunits [Kumar KN, et al., Nature 354 , 70-73 (1991); Nakanishi, S., et al., Nature 354 , 31-37 (1991); Monyer, H., et al., Science 256 , 1217-1221 (1992)]. There are at least five distinct substrate binding sites in the NMDA receptors, including (a) a binding site that binds to the neurotransmitter L-glutamate, (b) an allosteric modulator site that binds to glycine, (c) (D) a binding site that binds to Mg ⁺⁺ and (e) a binding site that binds to the divalent cation Zn ⁺⁺ and is known to inhibit [Lynch, DR, et al., Mol. Pharmacol. 45 , 540-545 (1994); Kuryatov, A., et al., Neuron 12 , 1291-1300 (1994); Nakanishi, S., Science 256 , 1217-1221 (1992)].

Looking at the physiological actions of the subunits of NMDA receptors, NMDA receptors are activated by glutamate and glycine or their agonists. Also, the channel of associated Ca ⁺⁺ permeability is blocked by Mg ⁺⁺ in a physiologically voltage-dependent manner, and Zn ⁺⁺ , with its own regulatory site, reduces the activity of the NMDA receptor synapses [Lynch, DR, et al , Mol. Pharmacol. 45 , 540-545 (1994); Kuryatov, A., et al., Neuron 12 , 1291-1300 (1994); Nakanishi, S., Science 256 , 1217-1221 (1992)].

Over the past two decades pharmacological interest has been focused on NMDA receptors, and efficants and antagonists that rely on each of the binding sites described above have been identified as candidates for useful drugs. Among them, the most promising method for controlling NMDA receptor activity was the development of an allosteric modulator of glycine binding sites.

In 1987, Johnson and Ascher discovered a glycine binding site in the NMDA receptor, and subsequent studies have shown that the glycine binding site and the glutamate binding site of the NMDA receptor are present in the same protein and the glycine binding site of the NMDA receptor Lt; RTI ID = 0.0 > allosteric < / RTI >

Since there is a negative allosteric coupling, binding of the agonist at the glutamate recognition site reduces the affinity of glycine for the glycine recognition site, and antagonist binding at the glutamate recognition site is enhanced by the glycanside antagonist, and vice versa [ Beneveniste, M., et al. J. Physiol. 428 , 333 (1990); Leser, RA; Tong, G. and Jahr, CE, J. Neurosci. 13 , 1088 (1993); Clements, JD; Westbrook, GL, Neuron. 7 , 605 (1991).

In addition, recent in vivo microdialysis (dialysis) studies have found that a large amount of glutamate is released in the ischemic brain region in the mouse ubiquitous ischemic model, but release of glycine is scarce [Globus, MY T, et al., J. Neurochern. 57 , 470-478 (1991).

As a result of the above experiment, it can be seen that the glycine antagonist is a very potent neuronal cell protective agent that can reduce excessive excitement of neurons when the neuron, which is a neuron, is excessively excited by glutamate and causes cytotoxicity.

Glycine antagonists can prevent NMDA channels from opening by acting in a non-competitive manner with glutamate, thereby overcoming the high concentration of endogenous glutamate released in the ischemic brain regions, as opposed to competitive NMDA antagonists that compete with glutamate You do not have to. As a result, NMDA receptors are regulated by glycine antagonists rather than completely suppressed, and this regulatory action may be more physiological than receptor blockade of receptor function (as compared to channel blockers), so glycine antagonists Have fewer side effects than other antagonists. In fact, glycine antagonists can be injected directly into the brain of a rodent without side effects [Tricklebank, MD, et al., Eur. J. Pharmacol. 167 , 127 (1989); Koek, W., et al., J. Pharmacol. Exp. Ther. 245 , 969 (1989); Willets and Balster, Neuropharmacology 27,1249 (1988)].

Thus, glycine antagonist is a noncompetitive antagonist that regulates NMDA receptors rather than blocks them. As a result, NMDA receptor blockade results in less side effects than other forms of NMDA receptor antagonists, leading to the development of new central nervous system agents, It has emerged as a target substance.

Glycine antagonists are emerging candidates for central nervous system drugs because they have a broad therapeutic window between the desired effects of neuroprotection and the side effects of hyperactivity commonly found in competitive glutamate antagonists or channel blockers.

On the other hand, the biggest problem in developing glycine-ligand compounds that react with NMDA-associated glycine sites is that most of these compounds do not pass through the blood-brain barrier (BBB). As a result of intensive efforts to develop a glycine-site ligand capable of passing through the blood-brain membrane, kynurenic acid derivatives (2-carboxyquinoline), 2-carboxyindole derivatives, quinoxaline derivatives and 2- Quinolone derivatives and the like have been developed. They are also selective antagonists acting on NMDA receptors as antagonists that act upon oral administration [McOuaid, LA, et al., J. Med. Chem. 35 , 3423 (1992); Leeson, PD, et al., J. Med. Chem. 36 , 3386 (1993); Kulagowski, JJ, et al., J. Med. Chem. 37 , 1402 (1994); Cai, SX, et al., J. Med. Chem. 39 , 4682 (1996); and 39,3248 (1996); EP 489,458; EP 459,561; EP 685,466 A1; WO94 / 20470; WO93 / 10783, EP 685,466 A1 and EP 481,676 A1].

Recently, it has been discovered that the quinrenic acid derivative, which is the compound No. 1 in the following formula (2), exhibits selectivity for NMDA antagonistic activity. That is, an endogenous product of the tryptophan metabolic pathway, has selective NMDA antagonistic activity by blocking the glycine regulatory site of the NMDA receptor [Kessler, M., et al., J. Neurochem. 52, 1319 (1989); Kemp, JA, et al., Proc. Natl. Acad. Sci. USA 85 , 6547 (1988)].

In the structure activity relationship (SAR) study on most of the existing NMDA antagonists, the hydroxyl group at the C-4 position of the quinrenic acid interacts with the H-bond of the receptor and its spatial orientation Lt; RTI ID = 0.0 > binding activity. ≪ / RTI > That is, when an electron-rich substituent is appropriately introduced at the C-4 position of the kinesinic acid parent nucleotide, the binding affinity to the NMDA receptor increases.

Recently, Harrison et al. Have found that compounds 2 and 3 of the following formula 2, in which the hydroxyl group at the C-4 position of the quinolenic acid is replaced by acetic acid with a heteroatom, are more effective and selective than kynurenic acid itself (Harrison BL, et al., J. Med. Chem. 33 , 3130 (1990)). However, these compounds have a disadvantage in that they lack in vivo activity because they can not penetrate BBB well due to high polarity of carboxyl group.

Accordingly, the present inventors have made efforts to produce a quinrenic acid derivative having excellent in vivo activity, and have found that when the hydroxyl group at the C-4 position is 3-substituted-2-oxo-1,3-oxazolidin-5-ylmethoxy The present inventors have found that the kynrenic acid derivative substituted with 3-substituted-2-thioxo-1, 3-oxazolidin-5-ylmethoxy has superior in vivo activity than the conventional kynurenic acid .

It is an object of the present invention to provide a quinrenic acid derivative substituted at the C-4 position, which acts as an antagonist of an excitatory amino acid, and a process for producing the same.

In order to achieve the above object, the present invention provides a process for producing 4- (3-substituted-2-oxo-1,3-oxazolidin-5-ylmethoxy) Thioxo-1,3-oxazolidin-5-ylmethoxy) -quinoline-2-carboxylic acid derivatives, and methods by which these compounds can be readily prepared.

Hereinafter, the present invention will be described in detail.

The present invention relates to 4- (3-substituted-2-oxo and 2-thioxo-1,3-oxazolidin-5-ylmethoxy) -quinoline-2-carboxylic acid derivatives of the general formula Isomers or pharmaceutically acceptable salts thereof.

Formula 1

In Formula 1,

X represents an oxygen or sulfur atom, respectively;

R ₁ and R ₂ each represent hydrogen, alkyl, halogen, alkoxy, nitro, cyano, halogenated alkyl, hydroxy, amino, alkylamino, azido or carboxylate;

R ₃ represents an appropriately substituted aryl, alkyl, heterocycle, acyl or sulfonyl, and the like.

Suitable substituents for R < ₃ > include, but are not limited to, hydrogen, halogen, nitro, cyano, hydroxy, alkyl, aryl, amino, alkylamino, arylamino, alkoxy, aryloxy, alkylcarboxylic acid, carboxylic acid, carboxylate, guanidine, Imidate, urea, phosphorylamide, sulfonamide, alkyl halide, aryl phosphonate or carbocycle.

In the form of formula (1), preferred compounds are those wherein R ₁ and R ₂ are each hydrogen or chlorine; And R ₃ is an aryl group substituted by H, p-CH ₃ , m-CH ₃ or 4-OCH ₃ .

The alkyl group is a C ₁ -C ₁₂ alkyl group, preferably a C ₁ -C ₄ alkyl group, and includes methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl groups.

The aryl group is preferably an aryl group having from _{6 to 12} carbon atoms and includes phenyl, naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl and fluorenyl groups.

The heterocyclic group includes C ₃ -C ₇ heterocycloalkyl, C ₃ -C ₇ heterocycloalkyl (C ₁ -C ₆ ) alkyl, heteroaryl and heteroaryl (C ₁ -C ₆ ) alkyl; Suitable heterocycloalkyl groups include piperidyl, piperazinyl and morpholinyl groups; Suitable heteroaryl groups include thiophenyl, furyl, pyrrolyl, indolyl, thiazolyl, oxazolyl, benzoxazolyl, imidazolyl, oxadiazolyl, tetrazolyl, triazolyl, pyridyl, pyrimidinyl and phthalimidyl groups .

For use in medicine, the salt of the compound of formula (I) is not toxic and should be a pharmaceutically acceptable salt. A variety of salts may be used to prepare the compounds of the present invention or their non-toxic, pharmaceutically acceptable salts.

The pharmaceutically acceptable salts of the compounds of formula (I) include alkali metal salts such as lithium, sodium or potassium salts and include alkaline earth metal salts such as calcium or magnesium salts and suitable organic ligands For example, quaternary ammonium salts. Acid addition salts can be prepared by mixing solutions of the compounds of the invention with solutions of pharmaceutically acceptable non-toxic acids such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, have.

The present invention includes within its scope prodrugs of the compounds of formula (I). In general, such prodrugs are functional derivatives of the compound of formula (I) and should be readily convertible into the compound required to enter the organism and exhibit its drug efficacy. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described in the existing literature [Design of Prodrug, ed. H. Bundgaard, 1985].

If the compound according to the present invention has at least one asymmetric center, if an enantiomer can be present and the compound according to the present invention has two or more asymmetric centers, a diastereoisomer, Lt; / RTI > Such isomers and mixtures thereof are included within the scope of the present invention.

Particularly preferred compounds in the present invention include the following compounds. However, the following compounds exemplify the present invention, and the present invention is not limited to the following compounds.

1) 5,7-Dichloro-4- (2-oxo 3-m-tolyl-oxazolidin-5-ylmethoxy) quinoline-

2) 5,7-Dichloro-4- (2-oxo 3-p-tolyl-oxazolidin-5-ylmethoxy) quinoline-

3) 5,7-Dichloro-4- (3-phenyl-2-thioxo-oxazolidin-5-ylmethoxy) quinoline-

4) Synthesis of 5,7-dichloro-4- [3- (4-methoxyphenyl) -2-thioxo-oxazolidin-5-ylmethoxy] quinoline-

The pharmaceutical compositions of the present invention are preferably unit dosage forms such as tablets, capsules, powders, granules, sterile solutions or suspensions, or suppositories for oral, intravenous, parenteral or rectal administration. In order to prepare solid compositions such as tablets, the major active ingredient is mixed with a pharmaceutical carrier such as conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, di A solid preformulation composition comprising a homogeneous mixture of a compound of the invention or a pharmaceutically acceptable non-toxic salt thereof, in admixture with a suitable excipient, such as, for example, calcium phosphate or gums and other pharmaceutical diluents, . Once the preliminary solid composition is homogenized, the active ingredient is evenly dispersed throughout the composition, allowing the composition to be easily split into effective unit dosage forms containing the same amount as tablets, pills, and capsules. This preliminary solid composition is further subdivided into unit dosage forms of the type mentioned above containing from 0.1 to 500 mg of the active ingredient of the present invention. Tablets or pills of the novel compositions may be coated or synthesized to provide an advantageous dosage form when sustained release is required. For example, a tablet or pill can be comprised of an inner dosage component and an outer dosage component, wherein the outer dosage component surrounds the inner dosage component. These two components can be separated by an enteric membrane, which prevents degradation in the stomach and allows the internal components to pass through the duodenum without delay and delay the release of internal components. A variety of materials are used as such enteric coatings or coating materials, including a number of polymeric and polymeric acids and mixtures of materials such as shellac, cetyl alcohol, and cellulose acetate. The liquid form of the novel compositions of the present invention made for oral administration or administration by injection may be in the form of aqueous solutions, suitably syrups, aqueous or oily suspensions, and emulsions of edible oils such as cottonseed oil, sesame oil, coconut oil, , Elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for making aqueous suspensions include synthetic or natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin ). In the treatment of neurodegeneration an appropriate dosage is 0.01 to 250 mg / kg per day, preferably 0.05 to 100 mg / kg per day, more preferably 0.05 to 5 mg / kg per day. The present compounds may conveniently be administered by intravenous injection.

The method of preparing the compound of formula (1), which is a compound of the present invention, is shown in the following reaction formula (1).

That is, the process for preparing the compound of formula

1) a step (first step) of alkylating a compound of formula 4 with epibromohydrin to obtain an epoxide compound of formula 5;

2) a step of 1,3-cycloaddition of aryl isocyanate (RNCO) or aryl thioisocyanate (RNCS) to the compound of formula 5 to obtain a 5-membered ring carbamate of formula 6 or 7 Second step); And

3) Basic hydrolysis of the compound of formula 6 or 7 to obtain the compound of formula 1 of formula 8 or 9, which is the target compound of the present invention (step 3)

.

The manufacturing method of the present invention will be described in more detail. First, the compound of Formula 4, which is a starting material in Reaction Scheme 1, can be easily prepared by the method described in the literature [Surrey, AR; Hammer, HF, J. Am. Chem. Soc. 68 , 1244 (1946); Baker, BR; Bramhall, RR J. Med. Chem. 15 , 230 (1972)].

In the first step, the starting material of the structural formula 4 is reacted with epibromohydrin and refluxed to obtain an epoxide compound in a high yield.

Next, the second step, which is the core of the present production method, comprises: i) ringing the epoxide ring prepared in the first step into a Br anion derived from an LiBr.HMPC adduct, and ii) introducing a bicyclic carbamate anion intermediate And iii) cyclizing the N-substituted 2-oxazolidone ring. A typical 1,3-cycloaddition reaction is performed by adding a freshly prepared LiBr HMPC adduct to a solution of the epoxide compound prepared in the first step in toluene, in an appropriate isocyanate or thioisocyanate and benzene. The reaction solution is heated until the reaction is complete and an appropriate post-treatment is carried out.

Finally, the third step is a step of performing basic hydrolysis to obtain the compound of formula (1) as a final target compound, wherein the methyl ester prepared in the second step is hydrolyzed under basic conditions to produce a carboxylic acid.

Hereinafter, the present invention will be described in detail with reference to examples. The following examples illustrate the invention and are not to be construed as limiting the invention thereto.

Example 1 5,7-Dichloro-4- (2-oxo 3-m-tolyl-oxazolidin-5-ylmethoxy) quinoline-

(Step 1) 5,7-Dichloro-4- (2-methoxypropoxy) quinoline-2-carboxylic acid methyl ester

Dichloroquinolinic acid methyl ester (2.0 g, 7.35 mmol), epibromohydrin (4.03 g, 29.4 mmol), K ₂ CO ₃ (4.06 g, 29.4 mmol) and n-Bu ₄ NBr (0.20 g, 10 w / w%) were refluxed overnight. The resulting mixture was cooled to room temperature and the insoluble solids were removed by suction filtration. The filtrate was evaporated on a rotary evaporator and washed with ether (200 mL x 2). The obtained crude solid was purified by recrystallization from methanol to give the title compound as a white powder (2.10 g, yield 87%).

_{^{1 H-NMR (CDCl 3)}} δ 2.90 (dd, 1H, J A = 4.5Hz, J B = 2.6Hz, CH 2), 2.99 (t, 1H, J = 4.2 Hz, CH 2), 3.53 (m, 1H, CH), 4.05 (s , 1H, CO 2 CH 3), 4.20 (dd, 1H, J A = 12Hz, J B = 5.6 Hz, CH A2 CH B), 4.55 (dd, 1H, J A = 11.1 _{Hz, J B = 2.8 Hz,} CH A2 CH B), 7.56 (s, 1H, ArH), 7.64 (d, 1H, J = 2.2Hz, ArH), 8.72 (d, 1H, J = 2.2Hz, ArH) ; ^{MS m / e 328 [M +} ], 271 [M + -CH 2 CHOCH 2], 269 [M + -COOCH 3].

(Step 2) 5,7-Dichloro-4- (2-oxo-3-m-tolyl-oxazolidin-5-ylmethoxy) quinoline-

M-Tolylisocyanate (0.30 mL, 1.2 mmol) and freshly prepared LiBr.HMDA adduct (0.33 g, 1.0 mmol) in toluene (40 mL) were added to a solution of the epoxy compound (Dissolved in 0.05 M of benzene) was added. The resulting solution was heated under reflux for 2 hours until TLC (hexane: EtOAc = 2: 1) analysis indicated complete reaction. After general water-soluble work-up, recrystallization from methanol gave the title compound as a cyclic carbamate as white crystals (0.25 g, yield 60%).

mp 163-165 [deg.] C; _{^{1 H-NMR (CDCl 3)}} δ 2.41 (s, 3H, ArCH 3), 4.05 (s, 3H, CO 2 CH 3), 4.18-4.43 (m, 2H, NCH 2), 4.63-4.82 (m, 2H _{, OCH 2), 5.32 (m} , 1H, CO 2 CH), 7.03-7.07 (m, 1H, ArH), 7.71 (s, 1H, ArH), 7.82-8.05 (m, 3H, ArH), 7.82 (d , 1H, J = 2.2 Hz, ArH), 8.20 (d, 1H, J = 2.2 Hz, ArH).

(Step 3) 5,7-Dichloro-4- (2-oxo 3-m-tolyl-oxazolidin-5-ylmethoxy) quinoline-

The methyl ester compound (1.00 mmol) of the structural formula 4 prepared in the above step 2 was dissolved in 20 mL of methanol and treated with 20 mL of an aqueous solution of NaOH [containing 3.00 mmol of NaOH] at room temperature overnight. The mixture was concentrated under reduced pressure to a total volume of about 20 mL. The remaining solution was diluted with 50 mL of distilled water, washed three times with 50 mL of methylene chloride, and then acidified with concentrated hydrochloric acid at pH 3. The resulting precipitate was filtered, washed with a distillation shoe and dried under vacuum to give the title compound of the present invention as a white solid (yield: 42%).

mp > 160 DEG C; ^{1 H-NMR (DMSO-d} 6) δ 2.42 (s, 3H, ArCH 3), 4.18-4.43 (m, 2H, NCH 2), 4.65-4.82 (m, 2H, OCH 2), 5.31 (m, 1H _{, CO 2 CH), 7.03-7.07 (} m, 1H, ArH), 7.34-7.56 (s, 3H, ArH), 7.73 (s, 1H, ArH), 7.82 (d, 1H, J = 2.2Hz, ArH) , 8.12 (d, 1 H, J = 2.2 Hz, ArH); ^{MS m / e 402 [M +} -CO 2].

Example 2 Preparation of 5,7-dichloro-4- (2-oxo 3-p-tolyl-oxazolidin-5-ylmethoxy) quinoline-2-carboxylic acid

(Step 1) 5,7-Dichloro-4- (2-methoxypropoxy) quinoline-2-carboxylic acid methyl ester

The reaction was carried out in the same manner as in step 1 of Example 1 to give the title compound.

(Step 2) 5,7-Dichloro-4- (2-oxo-3-p-tolyl-oxazolidin-5-ylmethoxy) quinoline-2-carboxylic acid methyl ester

The reaction was carried out in the same manner as in step 2 of Example 1, except that p-tolyl isocyanate (0.15 mL, 1.2 mmol) was used to obtain the title compound as a cyclic carbamate as white crystals (0.16 g, yield 39%).

mp > 210 DEG C; _{^{1 H-NMR (CDCl 3)}} δ 2.32 (s, 3H, ArCH 3), 4.06 (s, 3H, CO 2 CH 3), 4.26 (m, 2H, J = 7.4Hz, NCH 2), 4.50 (dd, _{2H, J A = 10.2Hz, J} B = 4.0Hz, OCH 2), 5.15 (m, 1H, OCH), 7.05-7.45 (m, 4H, ArH), 7.50 (d, 1H, J = 2.2Hz, ArH ), 7.58 (s, IH, ArH), 8.14 (d, IH, J = 2.2 Hz, ArH); MS m / e 461 [M ^< ⁺ &^gt;].

(Step 3) 5,7-Dichloro-4- (2-oxo-3-p-tolyl-oxazolidin-5-ylmethoxy) quinoline-

The reaction was carried out in the same manner as in (Step 3) of Example 1 to obtain the title compound of the present invention as a white solid (yield: 67%).

mp 175-180 C; ^{1 H-NMR (DMSO-d} 6) δ 2.38 (s, 3H, ArCH 3), 4.15-4.43 (m, 2H, NCH 2), 4.72 (m, 2H, OCH 2), 5.30 (m, 1H, OCH 2H), 7.30 (d, 2H, J = 8.6 Hz, ArH), 7.58 (d, 2H, J = 8.6 Hz, ArH) ArH), 8.19 (d, 1H, J = 2.0 Hz, ArH).

Example 3 Preparation of 5,7-dichloro-4- (3-phenyl-2-thioxo-oxazolidin-5-ylmethoxy) quinoline-2-carboxylic acid

(Step 1) 5,7-Dichloro-4- (2-methoxypropoxy) quinoline-2-carboxylic acid methyl ester

The reaction was carried out in the same manner as in step 1 of Example 1 to give the title compound.

(Step 2) 5,7-Dichloro-4- (3-phenyl-2-thioxo-oxazolidin-5-ylmethoxy) quinoline-

The reaction was carried out in the same manner as in the step 2 of Example 1 except that phenyl isothiocyanate (0.15 mL, 1.2 mmol) was used to obtain the title compound as a cyclic thio carbamate as pale yellow crystals (0.15 g, yield 32%).

mp 200-201 C; _{^{1 H-NMR (CDCl 3)}} δ 3.65 (m, 2H, NCH 2), 4.06 (s, 3H, CO 2 CH 3), 4.53 (d, 2H, J = 5.5Hz, OCH 2), 5.18 (m, 1H, OCH), 6.95-7.36 (m, 5H, ArH), 7.61 (s, IH, ArH), 7.63 ArH); MS m / e 463 [M ^< ⁺ &^gt;].

(Step 3) 5,7-Dichloro-4- (3-phenyl-2-thioxo-oxazolidin-5-ylmethoxy) quinoline-

The reaction was carried out in the same manner as in step 1 of Example 1 to obtain the target compound as a target compound of the present invention as a white solid (yield: 98%).

mp > 260 DEG C; ^{1 H-NMR (DMSO-d} 6) δ 3.78 (m, 2H, NCH 2), 4.77 (m, 1H, OCH 2), 5.34 (m, 1H, OCH), 6.29-7.49 (m, 5H, ArH) , 7.75 (s, 1H, ArH), 7.95 (d, 1H, J = 2.4 Hz, ArH), 8.24 (d, 1H, J = 2.0 Hz, ArH); MS m / e 435 [M ^< ^{+ >} -COOH].

Example 4 Preparation of 5,7-dichloro-4- [3- (4-methoxyphenyl) -2-thioxo-oxazolidin-5-ylmethoxy] quinoline-2-carboxylic acid

(Step 1) 5,7-Dichloro-4- (2-methoxypropoxy) quinoline-2-carboxylic acid methyl ester

The reaction was carried out in the same manner as in step 1 of Example 1 to give the title compound.

(Step 2) 5,7-Dichloro-4- [3- (4-methoxyphenyl) -2-thioxo-oxazolidin-5-ylmethoxy] quinoline- 2-carboxylic acid methyl ester

The reaction was carried out in the same manner as in the step 2 of Example 1 except that 4-methoxyphenyl isothiocyanate (0.15 mL, 1.2 mmol) was used to obtain the title compound as a cyclic thiocarbamate as a pale yellow crystal (0.15 g, yield 30%).

mp 188-189 [deg.] C; _{^{1 H-NMR (CDCl 3)}} δ 3.67 (dd, 2H, J A = 6.9Hz, J B = 3.2Hz, NCH 2), 3.81 (s, 3H, ArOCH 3), 4.09 (s, 3H, CO 2 CH _{3), 4.55 (d, 2H} , J = 5.2Hz, OCH 2), 5.20 (m, 1H, OCH), 6.92 (d, 4H, J = 4.6Hz, ArH), 7.61 (s, 1H, ArH), 7.65 (d, 1H, J = 2.2 Hz, ArH), 8.19 (d, 1H, J = 2.2 Hz, ArH).

(Step 3) 5,7-Dichloro-4- [3- (4-methoxyphenyl) -2-thioxo-oxazolidin-5-ylmethoxy] quinoline-

The reaction was carried out in the same manner as in step 3 of Example 1 to obtain the title compound of the present invention as a white solid (yield: 83%).

mp 190-195 캜; ^{1 H-NMR (DMSO-d} 6) δ 3.75 (m, 2H, NCH 2), 3.82 (s, 3H, ArOCH 2), 4.74 (m, 2H, OCH 2), 5.31 (br m, 1H, OCH) , 6.95 (m, 4H, ArH), 7.75 (s, 1H, ArH), 7.99 (d, 1H, J = 2.0 Hz, ArH), 8.24 (d, 1H, J = 2.0 Hz, ArH); MS m / e 435 [M ^< ^{+ >} -COOH].

Ⅰ. In vitro screening for binding activity

1) Preparation of synaptic membrane

Male Sprague-Dawaur (300-400 g) was obtained from the laboratory animal laboratory of the Korea Research Institute of Chemical Technology. Experimental animals were exposed to water and standard water in an air-conditioned room (22 + 1 C (relative humidity, 60 + 5%)) with slight darkening (brightness at 8 am) during the 4-10 day preparation period prior to use. They were fed with laboratory food. The synaptic membrane for receptor binding studies is a modified method of Foster and Fagg [Eur. J. Pharmacol. 133, 291 (1987)] and Murphy et al. [Br. J. Pharmacol. 95, 932 (1988). To summarize, the male Sprague-Dawaur rat was killed, the hippocampus of the brain cortex and brain were chopped with a scalpel and homogenized 5 times with 10 volumes of 0.32 M sucrose using a Teflon-fiber homogenizer. The mixture was centrifuged for 10 minutes at 1000 x g for 10 minutes with a Beckman J2 / 21 centrifuge (roto: JA20), and the supernatant was collected and centrifuged at 20,000 x g for 20 minutes. The supernatant was removed and homogenized with a pellet homogenizer (setting 5, 30 sec).

After incubating for 30 minutes at 4 ° C, the membrane suspension was centrifuged at 39,800 x g for 25 minutes with a Beckman L8-M ultracentrifuge. The pellet was left overnight at -70 < 0 > C. The next day, the pellet was dissolved at room temperature for 10 minutes and resuspended in 20 volumes of 50 mM Tris-acetone (pH 7.1, 4 DEG C) containing 0.04% Triton X-100, incubated at 37 DEG C for 20 minutes, Lt; RTI ID = 0.0 > 3900 x g. ≪ / RTI > The pellet was centrifuged as above and washed 3 times with 20 volumes of 50 mM tri-acetate at pH 7.1 without detergent. The final pellet was suspended in 50 mM Tris-acetate and the protein concentration was measured using Bio-Rad agent (Bradford, 1976). The resuspension buffer solution was adjusted to a membrane protein concentration of 1 mg / ml and stored at -70 ° C.

2) [ ³ H] glycine binding measurement

[ ³ H] glycine binding measurements were performed as described in Baron et al. (1991). For the [ ³ H] glycine saturate binding assay, the synaptic membrane (100 μg of membrane protein) was incubated with a final volume of 0.5 ml containing 50 mM Tris-acetate buffer solution pH 7.1, 5- 500 nM [ ³ H] glycine The reaction was carried out in a borosilicated glass tube containing the mixture at a temperature of 4 ° C for 30 minutes. For drug potential measurements, the synaptic membrane (100 μg of membrane protein) was incubated in a reaction mixture containing 50 mM Tris-acetate buffer at pH 7.1, 50 nM [ ³ H] glycine and various concentrations of the experimental compound as described above .

The reaction was then terminated by the addition of 2.5 mL of ice-cold 50 mM Tris-acetate buffer, pH 7.1, and this was transferred to a Whatman GF / B glass fiber filter pre-soaked in 0.3% polyethyleneimine in the assay buffer Bound radioactivity was attached and separated by rapid filtration with a branded cell harvester (Brandel M-12R). The filter used was washed twice with 2.5 mL of cold buffer solution in 10 seconds and the radioactivity on the filter was measured with a liquid scintillation counter (Beckman LS (R)) using 3 mL of Luma gel at a counting efficiency of 50-55% 6000 TA]. Non-specific binding was measured in the presence of 1 mM glycine.

All experimental compounds were dissolved in dimethylsulfoxide (DMSO) and diluted in various concentrations for binding determination. The final concentration of DMSO in the assay mixture was 2% and it was clear that this concentration did not affect the binding of the radioligand.

The results of the percentage value (inhibition%) indicating the degree of competition with [ ³ H] glycine when the concentration of the compounds prepared in the present invention is 100 μM are shown in Table 1 below.

Compound No. Inhibition at 100 [mu] M% Example 1 71.4 Example 2 66.6 Example 3 39.2 Example 4 47.9

Ⅱ. In vivo screening for anticonvulsive activity

1) NMDA (i.c.v.) - induced convulsions experiment

Based on the method of Chugai, a dose-effect curve was obtained in which 40-160 ng of NMDA per mouse was administered iv. Lt; RTI ID = 0.0 > convulsions. ≪ / RTI > A 28-gauge needle attached to a 50-μl syringe was inserted through the 1-mm right brachymal bone on the sagittal suture and the test solution was inserted using a manipulator. Insertion volume was 5 μl per mouse. The spasm that occurred in response to NMDA occurred within 5 minutes and was characterized by 1) rough running or jumping, 2) myoclonic seizures (causing seizures and separation), and 3) (clonic seizures, loss of sense of direction and repeated movement of the limbs). The animals were i.c.v. 10 min after injection and observed seizure rate when seizure occurred. To investigate the NMDA-antagonistic properties of the experimental drug, the following procedure was performed. Experimental drug (infusion volume, 1 ml / 100 g) was administered ip. After 15 minutes of injection, mice were injected with 160 ng of NMDA at 5 μl per mouse. i.c.v. Experimental drug and NMDA solution were injected simultaneously for administration. Ten rats were used for the same dose. The dose was increased until the antagonistic NMDA reached a limit (eg, solubility, mortality) that could induce convulsions or could no longer be tested. NMDA was dissolved in a 0.9% sodium chloride solution, and AP5,5,7-dichloroquinolenic acid and 7-chloroquinolenic acid were dissolved in a minimum amount of 0.1 N sodium hydroxide to which 0.9% physiological saline had been added.

2) Permanent ligation of Middle Celebral Atery (MCA)

The middle cerebral artery ligation was performed by the method of Nagfuji et al. [Neurosci. Lett. 147, 159 (1992), Mol. Chem. Neuropathol. 26, 107 (1995), Neuro Report. 6, 1541 (1995). In summary, male Sprague Dawley rats were anesthetized with 2% halothane and maintained at 1.5% halothane oxide: oxygen (70:30) using a halothane evaporator. After laying the animal on its side, the left temporalis muscles were cut and the anatomic coagulant was used to partially separate the angular arc. Small craniofacial resection was performed using micro drills cooled with cold saline in the front of the mandibular nerve under the surgical microscope. The innervation of the olfactory nerve and the middle cerebral artery were seen through the thin dura of the brain. The middle cerebral artery near the lenticulostriate artery (LSA) of the lens nucleus was exposed and ligated using a mini clip. The middle cerebral artery and the lens nucleus artery behind the mini clip were corroded using anodic coagulant. During surgery, the temperature of the right temporalis muscles and rectum was maintained at about 37 ° C using a heating pad. The contraction of the temporalis muscle was reversed and sutured. The animal was placed in a cage and kept warm overnight using a heating lamp. Twenty-four hours after ligation of the middle cerebral artery, the animal's neck was quickly removed, the brain was quickly removed, immersed in cold salt, and sliced at 2 mm intervals from the frotal pole. The slices were freshly prepared in saline and cultured in a 2% TTC solution preheated to 37 < 0 > C. The stiffened slices were fixed in 4% formalin solution at 37 ° C for 30 minutes. The infarct area of each slice was measured with an image analyzer using a stereoscopic microscope. The infarct size in the left hemisphere was measured by subtracting the left hemisphere infarct size from the right hemisphere infarct size to exclude the effect of edema formation.

The 4- (3-substituted-2-oxo and 2-thioxo-1,3-oxazolidin-5-ylmethoxy) -quinoline-2-carboxylic acid derivatives of the present invention are useful for the inhibition of strychnine non- It is a potent and unique antagonist that acts on the glycine binding site. It has a strong antagonistic effect on the NMDA receptor and penetrates well into the central nervous system and has high solubility.

The compounds of the present invention are useful for the treatment or prevention of neurodegenerative diseases and are particularly useful for reducing the damage of the central nervous system caused by anemia such as heart attack, hypoglycemia, ischemia, arrest of heart beat, trauma, or hypoxia.

The compounds of the present invention are also useful as prophylactic and therapeutic agents for chronic neurodegenerative diseases including epilepsy, Alzheimer's disease, Huntington's disease and Parkinson's disease as well as antispasmodics, analgesics, antidepressants, antianxiety agents and antipsychotic agents have.

Claims (14)

(3-substituted-2-oxo and 2-thioxo-1,3-oxazolidin-5-ylmethoxy) -quinoline-2-carboxylic acid derivatives having the structure of the following formula 1, tautomeric isomers thereof, And pharmaceutically acceptable salts and prodrugs thereof, Formula 1 In Formula 1, X represents an oxygen or sulfur atom, respectively; R ₁ and R ₂ each represent hydrogen, alkyl, halogen, alkoxy, nitro, cyano, halogenated alkyl, hydroxy, amino, alkylamino, azido or carboxylate; R ₃ represents an appropriately substituted aryl, alkyl, heterocycle, acyl or sulfonyl, and the like. 2. A compound according to claim 1, wherein R ₁ and R ₂ are each hydrogen or chlorine and R ₃ is a substituted aryl group. 5-ylmethoxy) -quinoline-2-carboxylic acid derivative, its tautomeric isomer, its pharmaceutically acceptable salt and its prodrug _{3. A} compound according to claim 1 or 2, wherein when R3 is an aryl group, suitable substituents are selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxy, alkyl, aryl, amino, alkylamino, arylamino, alkoxy, aryloxy, alkylcarboxylic acid (3-substituted-2-oxo and 2-thiophene) which is characterized in that it is a carboxylic acid, a carboxylate, a guanidine, an imidate, a urea, a phosphorylamide, a sulfonamide, a halogenated alkyl, an arylphosphonate or a carbocycle Oxo-1, 3-oxazolidin-5-ylmethoxy) -quinoline-2-carboxylic acid derivative, its tautomeric isomer, its pharmaceutically acceptable salt and its prodrug Claim 3 wherein the substituents of the aryl group include H, p-CH _3, m-CH ₃ or 4-OCH _3, 4- (3-substituted-2-oxo and 2-thioxo, characterized in that 1, 3-oxazolidin-5-ylmethoxy) -quinoline-2-carboxylic acid derivative, a tautomeric isomer thereof, a pharmaceutically acceptable salt thereof and a prodrug The method according to claim 1, wherein the alkyl group is an alkyl group having a carbon number of _{1 to 12} , The aryl group is an aryl group having _{6 to 12} carbon atoms, The heterocyclic group is selected from the group consisting of a C ₄ -C ₇ heterocycloalkyl, a C ₃ -C ₇ heterocycloalkyl (C ₁ -C ₆ ) alkyl, a heteroaryl and a heteroaryl (C ₁ -C ₆ ) - (3-substituted-2-oxo and 2-thioxo-1,3-oxazolidin-5-ylmethoxy) -quinoline-2-carboxylic acid derivatives, tautomeric isomers, Drag 6. A compound according to claim 5, wherein the C ₁ -C ₁₂ alkyl group is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert- The aryl group having from _{6 to 14} carbon atoms includes phenyl, naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl and fluorenyl groups, Suitable heterocycloalkyl groups in the heterocyclic group include piperidyl, piperazinyl and morpholinyl groups; Suitable heteroaryl groups include thiophenyl, furyl, pyrrolyl, indolyl, thiazolyl, oxazolyl, benzoxazolyl, imidazolyl, oxadiazolyl, tetrazolyl, triazolyl, pyridyl, pyrimidinyl and phthalimidyl groups 2-oxo-1, 3-oxazolidin-5-ylmethoxy) -quinoline-2-carboxylic acid derivatives, tautomeric isomers thereof, Acceptable salts thereof and prodrugs thereof The compound of claim 1, wherein the compound is 5,7-Dichloro-4- (2-oxo 3-m-tolyl-oxazolidin-5-ylmethoxy) quinoline- 5,7-Dichloro-4- (2-oxo 3-p-tolyl-oxazolidin-5-ylmethoxy) quinoline- 5,7-dichloro-4- (3-phenyl-2-thioxo-oxazolidin-5-ylmethoxy) quinoline- 5,7-Dichloro-4- [3- (4-methoxyphenyl) -2-thioxo-oxazolidin-5-ylmethoxy] quinoline- (3-substituted-2-oxo and 2-thioxo-1,3-oxazolidin-5-ylmethoxy) -quinoline-2-carboxylic acid derivatives, tautomeric isomers thereof, Pharmaceutically acceptable salts and prodrugs thereof A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Use of a compound of claim 1, a pharmaceutically acceptable salt thereof or a prodrug thereof as an antagonist of an excitatory amino acid for an NMDA receptor. Use of a compound of claim 1, a pharmaceutically acceptable salt thereof or a prodrug thereof in the reduction of central nervous system damage resulting from anemia such as stroke, hypoglycemia, ischemia, cardiac arrest, trauma, or hypoxia. Use of the compound of claim 1, a pharmaceutically acceptable salt thereof or a prodrug thereof as a prophylactic and therapeutic agent for a neurodegenerative disease. Use of a compound of claim 1, a pharmaceutically acceptable salt thereof or a prodrug thereof for the treatment of epilepsy, stroke, Alzheimer's disease, Huntington's disease and Parkinson's disease. Use of the compound of claim 1, a pharmaceutically acceptable salt thereof or a prodrug thereof as an anticonvulsant, an analgesic, an antidepressant, an anti-anxiety agent and an antipsychotic agent. 1) a step (first step) of alkylating a compound of formula 4 with epibromohydrin to obtain an epoxide compound of formula 5; 2) a step of 1,3-cycloaddition of aryl isocyanate (RNCO) or aryl thioisocyanate (RNCS) to the compound of formula 5 to obtain a 5-membered ring carbamate of formula 6 or 7 Second step); And 3) A step of basic hydrolysis of the compound of formula 6 or 7 to obtain the compound of formula 1 of formula 8 or 9, which is the target compound of the present invention (step 3). 3-substituted-2-oxo and 2-thioxo-1,3-oxazolidin-5-ylmethoxy) -quinoline-2-carboxylic acid derivatives. Scheme 1