KR100274004B1 - 4-(3-substituted-propyloxy)-quinoline-2-carboxylic acid derivatives acting as nmda receptor antagonists - Google Patents

Abstract

PURPOSE: Provided are the novel NMDA receptor antagonist, 4-(3-substituted-propyloxy)-quinoline-2-carboxylic acid derivatives and the preparation method thereof. CONSTITUTION: The derivatives are represented as shown in the chemical formula 1, where A represents carbamate, amide, thiourea, sulfonylurea, acylthiourea, thiocarbamate, amidine, guanidine, imidate, thioimidate, phosphorylamide, sulfonamide, sulfonthiourea or amines and R represents alkyl (C1¯C20), aryl (C6¯C12), aralkyl, heterocycles, carbocycles (C3¯C14), fused bicyclic, hydrogen or cyano groups. The synthetic process comprises the steps of alkylating 5,7-dichlorokynurenic acid methylester with 1,3-dibromopropane; substitution of the bromine with NaN3 to make azidomine; reducing the resultant to amine compound with Pd-catalyst; converting to amide with the corresponding isocyanate, thioisocyanate or acid chloride and finally hydrolysing the ester group in the parent moiety to make the compound of formula 1. They are strong and unique antagonist acting on the coupling position of the strychnine non-susceptive glycine in the NMDA receptor complex and penetrate effectively into central nervous system. They are effective in the treatment of neurodegeneration, especially useful for the CNS damages effected by the diseases such as heart attack, low blood sugar, local anemia and heart beat halt arising from the low oxygen concentration caused by the external wounds or anemia.

Description

4- (3-substituted-propyloxy) -quinoline-2-carboxylic acid derivatives acting as NMDA receptor antagonists}

The present invention relates to 4- (3-substituted-propyloxy) -quinoline-2-carboxylic acid derivatives of formula (I) which act as antagonists of excitatory amino acids, methods for their preparation and their use as therapeutic agents for neurological diseases.

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

In addition, the compounds of the present invention are useful for preventing 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, anti-anxiety agents and antischizophrenia.

L-glutamate is the most important excitatory neurotransmitter in mammalian central nervous system neurotransmission. Nearly all central nervous system neurons are excited by L-glutamate, which acts on several receptor-ion channel complexes on the surface of neurons to open ion channels and induce cations such as sodium or calcium. To excite nerve cells by inducing polarization between nerve cell membranes.

These CNS neurons are non-NMDA not excited by NMDA receptors and NMDA excited by glutamate analogue N-methyl-D-aspartate (abbreviated as "NMDA"). It contains a receptor.

NMDA receptors are cell surface protein complexes that are widely distributed in the brain or spinal cord and are known to transmit neuronal excitability at the synapse of neurons and to be closely involved in neuronal growth.

One of the characteristics of this NMDA receptor is that its activity is completely blocked by Mg ⁺⁺ when the cells are at rest. However, this blockade is voltage-dependent and the block is released when the cell is activated by non-NMDA receptors or when other excitatory substances are partially nonpolarized. As such, the mechanism of action of NMDA receptors depends on conditions and plays an important role in learning and memory processes.

Another property of NMDA receptors is that the cells die when the receptor is overly excited. This may be due to excessive accumulation of Ca ⁺⁺ in cells. Recently, many studies have been conducted on cell death by excitatory toxicity of NMDA receptors.

After culturing neurons in vitro, glutamate treatment causes cells to swell and cytotoxicity. This excitatory toxicity is dependent on the presence of Ca ^{++. When} a large amount of Ca ⁺⁺ enters neurons through the ion channel of glutamate receptors, normal cell activity is destroyed and the release of glutamate is accelerated by feedback. Excitatory toxicity occurs. In this process, proteases and lipases are activated to destroy the membranes of neurons and produce free radicals that kill the cells [JW Mcdold, MV Johnson, Brain Res. Reviews 15, 41 (1990)]. As such, excitatory toxicity caused by neurotransmitters kills neurons, and research has been found to be an important cause of neurodegenerative diseases and stroke associated with brain cell death.

Recently, research has focused on the mechanism by which L-glutamate is excessively secreted by brain injury, spinal cord injury, stroke, ischemia, or hypoglycemia resulting in permanent damage to the central nervous system. It has been found that the damage caused by is prevented by NMDA receptor antagonists.

NMDA receptor antagonists prevent many clinical diseases, including ischemic symptoms 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). Accordingly, several NMDA receptor antagonists have recently been used to treat acute stroke or brain damage.

There are also reports that NMDA receptor antagonists are useful for improving memory and learning, such as 1-aminocyclopropanecarboxylic acid methyl esters, D-cycloserine and R-(+)-3-, which are specific glycine site ligands. Amino-1-hydroxypyrrolidin-2-one- (HA-966) [Bliss, TV P, Collingride, GL, Nature 345 , 347 (1990); GB 2231048A (1990).

Recent reports suggest that NMDA receptor antagonists have analgesic, antidepressant, antipsychotic and anti-anxiety 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).

Non-competitive NMDA receptor antagonists such as ketamine and dextrometopan are useful for the treatment of growth disorders, autism and the like in children. 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, which is thought to be one of the causes of these diseases, is more evident by recent studies on their physiological function and subunit structure. 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). The NMDA receptor has at least five distinct substrate binding sites, including (a) a binding site for binding to the neurotransmitter L-glutamate, (b) an allosteric modulator site for binding to glycine, and (c) in the channel Sites that bind fencyclidine and related compounds, (d) binding sites that bind Mg ⁺⁺ , and (e) binding sites that bind to the divalent cation Zn ⁺⁺ and exhibit inhibitory activity [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 action of subunits of NMDA receptors, the NMDA receptors are activated by glutamate and glycine or their agonists. In addition, the associated Ca ⁺⁺ permeable channel is physiologically blocked by Mg ⁺⁺ in a voltage-dependent manner, and Zn ⁺⁺ with its own regulatory site reduces the activity of synapses of NMDA receptors [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).

Pharmacological interest has focused on the NMDA receptors over the past two decades, and agonists and antagonists that depend on each of the binding sites described above have been explored as candidates for useful drugs. Among them, the most promising method for regulating NMDA receptor activity was the development of an allosteric modulator of glycine binding site.

In 1987, Johnson and Ascher discovered glycine binding sites in NMDA receptors. Subsequent studies have revealed that glycine binding sites and glutamate binding sites in NMDA receptors are present in the same protein and glycine binding sites in NMDA receptors. It was found that there is a negative allosteric coupling between and glutamate binding sites.

Since the presence of negative allosteric coupling, binding of agonists at glutamate recognition sites reduces glycine affinity for glycine recognition sites, and antagonist binding at glutamate recognition sites is enhanced by glycine site antagonists 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 microdialixis (dialysis) studies have found that large amounts of glutamate are released in the ischemic brain region but little release of glycine in the rat ubiquitous ischemic model [Globus, MY T, et. al., J. Neurochern. 57 , 470-478 (1991).

As a result of the experiment, it can be seen that the glycine antagonist is a very powerful neuroprotective drug that can reduce excessive excitability of neurons when neurons, neurons, are excessively excited by glutamate to cause cytotoxicity.

Glycine antagonists act non-competitively with glutamate to prevent the NMDA channels from opening, thus overcoming the high concentrations of endogenous glutamate released in the ischemic brain region, unlike competitive NMDA antagonists that compete competitively with glutamate. There is no need to do it. Thus, NMDA receptors are regulated rather than completely inhibited by glycine site antagonists, and these regulatory actions may be much more physiological than receptor blockade where receptor function is completely inhibited (compared to channel blockers), thus glycine antagonists Has fewer side effects than other antagonists. In fact, glycine antagonists can be injected directly into the brains of rodents 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).

As such, glycine site antagonists are noncompetitive antagonists that regulate rather than block NMDA receptors, and thus have fewer side effects from NMDA receptor blockade than other forms of NMDA receptor antagonists. It has emerged as a target substance.

Glycine site antagonists have emerged as central nervous system agonist candidates because they have a wide therapeutic window between the desirable 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 was that most of these compounds did not pass through the blood-brain barrier (abbreviated as "BBB"). . As a result of our efforts to develop glycine-site ligands that can cross the blood-brain-membrane, we have shown that kynureric acid derivatives (2-carboxyquinoline), 2-carboxyindole derivatives, quinoxaline derivatives and 2- Quinolone derivatives and the like have been developed. These are selective noncompetitive antagonists that act on NMDA receptors and are also active 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; WO 94/20470; WO 93/10783, EP 685,466 A1 and EP 481,676 A1.

Recently, it has been discovered that the chineurenic acid derivative, compound No. 1 in Formula 2, exhibits selectivity for NMDA antagonistic activity. That is, the endogenous product of the tryptophan metabolic pathway is a blockade of the glycine regulatory sites of the NMDA receptor and thus has selective NMDA antagonistic activity [Kessler, M., et al., J. Neurochem. 52 , 1319 (1989); Kemp, JA, et al., Proc. Natl. Acad. Sci. USA 85 , 6547 (1988).

In most existing Structure Activity Relationship (SAR) studies of NMDA antagonists, the hydroxyl groups at the C-4 position of the chineurenic acid interact with the H-binding of the receptor and their spatial orientation It has been found to be very important for binding activity. In other words, when the electron-rich substituent is appropriately introduced at the C-4 position of the kynurenic acid mother nucleus, binding affinity to the NMDA receptor is increased.

In particular, Harrison et al. Recently found that compounds 2 and 3 of the following Chemical Formula 2, in which the hydroxyl group at the C-4 position of the kynurenic acid are substituted with heteroatoms linked with heteroatoms, are more effective and selectable than the kynurenic acid itself. Was found in Harrison BL, et al., J. Med. Chem. 33 , 3130 (1990). However, these compounds do not penetrate BBB due to the high polarity of the carboxyl group, and thus have a disadvantage of lacking in vivo activity.

Accordingly, the inventors of the present invention have been trying to prepare an excellent in vivo activity of the kynurenic acid derivatives. The present invention was completed by finding that not only the in vivo activity is excellent but also the in vitro NMDA receptor antagonist activity in micromolar units.

It is an object of the present invention to provide a chineurenic acid derivative substituted with a C-4 position which acts as an antagonist of an excitatory amino acid and a method for preparing the same.

In order to achieve the above object, the present invention provides a 4- (3-substituted-propyloxy) -quinoline-2-carboxylic acid derivative and a method for easily preparing these compounds.

Hereinafter, the present invention will be described in detail.

The present invention relates to 4- (3-substituted-propyloxy) -quinoline-2-carboxylic acid derivatives of the general formula (1), including tautomeric isomers or pharmaceutically acceptable salts thereof.

Formula 1

In Chemical Formula 1,

A is carbamate, amide, urea, thiourea, acylurea, sulfonylurea, acylthiourea, thiocarbamate, amidine, guanidine, imidate, thiimidate, phosphorylamide, sulfonamide, sulfonylthiourea Or amine;

R is alkyl (C ₁ -C ₂₀ ), aryl (C ₆ -C ₁₂ ), aralkyl, heterocycle, carbocycle (C ₃ -C ₁₄ ), soluble bicyclic, hydrogen or cyano group Indicates.

In the form of Formula 1, preferred compounds are those where A is carbamate, amide, urea, thiourea, acylurea, sulfonylurea or acylthiourea and R is aryl, aralkyl or carbocycle.

In the above, the alkyl group is a C ₁ -C ₂₀ alkyl group and the C ₁ -C ₄ alkyl group is preferable and includes methyl, ethyl, propyl, isopropyl, butyl, secondary-butyl and tert-butyl groups.

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

Heterocyclic groups include 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, isoxazolyl, benzooxazolyl, imidazolyl, tetrazolyl, triazolyl, pyridyl, pyrimidinyl and phthalimidyl groups Include.

For use in medicine, the salts of the compounds of formula 1 should be non-toxic and pharmaceutically acceptable salts. Various salts may be used to prepare the compounds of the invention or their toxic and pharmaceutically acceptable salts.

Pharmaceutically acceptable salts of compounds of formula 1 include alkali metal salts such as lithium, sodium, or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, and suitable organic ligands. Salts formed, for example, quaternary ammonium salts. Acid addition salts can be prepared by mixing a solution of a compound of the invention with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. have.

The present invention includes prodrugs of compounds of formula 1 within the scope of the present invention. In general, such prodrugs are functional derivatives of the compound of formula (I), and should be able to be readily changed to the compound required to enter the body and exhibit 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 corresponding to the present invention has at least one asymmetric center, an enantiomer may be present, and if the compound corresponding to the present invention has two or more asymmetric centers, the diastereoisomer May be present. 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 are illustrative of the present invention and the present invention is not limited to the following compounds.

1) 4- [3- (3-benzyl-oxy-carbonylamino) propoxy] -5,7-dichloroquinoline-2-carboxylic acid,

2) 4- [3- (3-n-butyrylamido) propoxy] -5,7-dichloroquinoline-2-carboxylic acid,

3) 4- [3- (3-t-butoxycarbonylamino) propoxy] -5,7-dichloroquinoline-2-carboxylic acid,

4) 4- [3- (3-phenylacetylamido) propoxy] -5,7-dichloroquinoline-2-carboxylic acid,

5) 4- [3- (3-p-tosylureido) propoxy] -5,7-dichloroquinoline-2-carboxylic acid,

6) 4- [3- (3-phenylureido) propoxy] -5,7-dichloroquinoline-2-carboxylic acid,

7) 4- [3- (3-benzylureido) propoxy] -5,7-dichloroquinoline-2-carboxylic acid,

8) 4- [3- (3-benzoylureido) propoxy] -5,7-dichloroquinoline-2-carboxylic acid,

9) 4- [3- (3-phenylthioureido) propoxy] -5,7-dichloroquinoline-2-carboxylic acid,

10) 4- {3- [3- (4-methoxyphenyl) thioureido] propoxy} -5,7-dichloroquinoline-2-carboxylic acid,

11) 4- [3- (3-benzoylthioureido) propoxy] -5,7-dichloroquinoline-2-carboxylic acid,

12) 4- {3- [3- (4-phenoxyphenyl) thioureido] propoxy} -5,7-dichloroquinoline-2-carboxylic acid

The pharmaceutical compositions of the invention are preferably in unit dosage form such as tablets, capsules, powders, granules, sterile solutions or suspensions, or suppositories for oral, intravenous, parenteral or rectal administration. To prepare solid compositions such as tablets, the main active ingredient is a pharmaceutical carrier, e.g., the conventional tableting ingredients cornstarch, 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 calcium phosphate or gums and other pharmaceutical diluents such as water Form. The homogeneous preliminary solid composition allows the active ingredient to be dispersed evenly throughout the composition so that the composition can be easily divided into effective unit dosage forms containing the same amount such as tablets, pills and capsules. This preliminary solid composition is further subdivided into unit dosage forms of the abovementioned type comprising from 0.1 to 500 mg of the active ingredient of the 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 may be composed of an internal dosage ingredient and an external dosage ingredient, in which the external dosage ingredient surrounds the internal dosage ingredient. The two components can be separated by an enteric membrane, which prevents the digestion of the stomach and allows the internal components to pass through the duodenum or delay the release of the internal components intact. A variety of materials are used as such enteric membranes or coating materials, which include a plurality of polymeric acids and mixtures of polymeric acids and materials such as shellac, cetyl alcohol, cellulose acetate. The liquid form of the novel compositions of the present invention prepared for oral or injectable administration is an emulsion consisting of an aqueous solution, a properly flavored syrup, an aqueous or oily suspension and an edible oil such as cottonseed oil, sesame oil, coconut oil or peanut 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, a suitable dosage is 0.01-250 mg / kg per day, preferably 0.05-100 mg / kg per day, more preferably 0.05-5 mg / kg per day. The compound may be conveniently administered by intravenous injection.

The method for preparing a compound of Formula 1, which is a compound of the present invention, is shown in Scheme 1 below.

The compound of formula 1 in Scheme 1 is the same as the compound of formula 1,

Y represents O, S, NH or H ₂ ,

R ₂ can be represented by -ZR,

Z represents NH, O, S, CH ₂ , acylamino or sulfoneamino and the like,

R is the same as R in the formula (1).

That is, the preparation process of the compound of Formula 1 of the present invention

1) alkylating the compound of formula 4 with 1,3-dibromopropane to obtain a bromide compound of formula 5 (first step);

2) reacting the compound of formula 5 prepared in step 1 with NaN ₃ to substitute bromine to obtain an azido compound of formula 6 (second step);

3) Catalytic hydrogenation of the azido compound prepared in the second step to obtain a compound of formula 7, which is reacted with an appropriate isocyanate (R ₂ NCO), thioisocyanate (R ₂ NCS) or acid chloride (R ₂ COCl) Obtaining a compound of formula 8 (third step) and

4) basic hydrolysis of the compound of formula 8 to obtain a compound of formula 1 which is the target compound of the present invention

Is made of.

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 Scheme 1, can be easily prepared by the method described in the existing 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 5,7-dichloroquinernic acid methyl ester of formula 4 is reacted with 1,3-dibromopropane, K ₂ CO ₃ , n-Bu ₄ NBr and the like to react the C-4 position of the kynurenic acid. As the step of alkylation, acetone is used as the reaction solvent.

In the second step, the compound prepared in the first step is reacted with NaN ₃ to substitute bromine to obtain an azido compound. The solvent used may include DMF, DMSO, or toluene.

The third step is hydrogenation of the azide compound in the presence of a Pd-C catalyst, followed by reaction with an appropriate isocyanate, thioisocyanate or acid chloride to suit the type of substituent to be substituted for the propyloxy group to form a propyloxy group with the desired substituents. This is the step.

In the fourth step, a conventional basic hydrolysis of the compound prepared in the third step is carried out to obtain a compound of Formula 1, which is a final target compound. The methyl ester prepared in the third step is hydrolyzed under basic conditions to prepare a carboxylic acid. It's a step.

Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are merely to illustrate the invention and the present invention is not limited by the examples.

Example 1 4- [3- (3-benzyl-oxy-carbonylamino) propoxy] -5,7-dichloroquinoline-2-carboxylic acid

(Step 1) 4- (3-Bromopropoxy) -5,7-dichloroquinoline-2-carboxylic acid methyl ester

5,7-dichloroquinernic acid methyl ester (0.54 g, 0.2 mmol), 1,3-dibromopropane (1.20 g, 6.0 mmol), K ₂ CO ₃ (0.55 g, 4.0 mmol) and n-Bu ₄ The suspension in NBr (108 mg, 20 w / w%) in 50 mL of acetone was refluxed overnight. The resulting mixture was cooled to rt and filtered, then the filtrate was evaporated and recrystallized with methanol to give the title compound as a white powder (0.42 g, 54% yield).

mp 144-145 ° C .; ¹ H-NMR (CDCl ₃ ) δ 2.50 (m, 2H, CH ₂ ), 3.74 (t, 2H, J = 6.2 Hz, CH ₂ Br), 4.07 (s, 3H, CO ₂ CH ₃ ), 4.41 (t , 2H, J = 6.4 Hz, OCH ₂ ), 7.59 (m, 2H, ArH), 8.15 (d, 1H, J = 2.2 Hz, ArH); MS m / e 393 [M ⁺ ], 334 [M ⁺ -CO ₂ CH ₃ ].

(Step 2) 4- (3-azidopropoxy) -5,7-dichloroquinoline-2-carboxylic acid methyl ester

The suspension obtained by dissolving the title compound of (Step 1), a bromide compound (0.39 g, 1.0 mmol) and sodium azide (NaN ₃ ; 2.65 g, 4.0 mmol) in 5 mL of DMF, was heated at 50 ° C. under a nitrogen atmosphere for 1 hour. Heated. The mixture was cooled to room temperature and the solvent was removed in vacuo, then the residue was washed with water (10 mL × 2) and ether (10 mL × 2) and dried to give the title compound azido compound (0.33 g, Yield 92%).

mp 132-133 ° C .; ¹ H-NMR (CDCl ₃ ) δ 2.21 (m, 2H, CH ₂ ), 3.06 (t, 2H, J = 6.6 Hz, OCH ₂ ), 4.06 (s, 3H, CO ₂ CH ₃ ), 4.33 (t, 2H, J = 5.8 Hz, OCH ₂ ), 7.57 (s, 1H, ArH), 7.60 (d, 1H, J = 2.2 Hz, ArH), 8.14 (d, 1H, J = 2.2 Hz, ArH).

(Step 3) 4- [3- (3-benzyl-oxy-carbonylamino) propoxy] -5,7-dichloroquinoline-2-carboxylic acid methyl ester

The azido compound (1.0 mmol), which is the title compound of (Step 2), was dissolved in 100 mL of ethyl acetate and then hydrogenated using 10% Pd / C catalyst amount. After the reaction was completed, the Pd / C catalyst used was removed by suction filtration on a celite pad using methanol / methylene chloride 1: 1 mixed solvent as eluent. The filtrate was evaporated under reduced pressure to yield the corresponding amine compound quantitatively as a colorless solid.

Without further purification, the crude amine prepared above was dissolved in 15 mL of dry methylene chloride under nitrogen atmosphere, then benzyloxy acid chloride (1.2 mmol) and triethylamine (1.2 mmol) were dissolved in 5 mL of dry methylene chloride. After dilution it was added using cannula. The mixture was stirred at room temperature until the first amine compound disappeared. The mixture was then diluted with methylene chloride (100 mL), washed with water (100 mL × 2) and dried over magnesium sulfate. The solvent was removed under reduced pressure to give the crude product, which was purified by flash column chromatography (EtOAc: hexanes) to give the title compound as a white solid (0.32 g, yield 70%).

¹ H-NMR (CDCl ₃ ) δ 2.18 (m, 2H, CH ₂ ), 3.52 (m, 2H, NHCH ₂ ), 4.03 (s, 3H, CO ₂ CH ₃ ), 4.27 (m, 2H, OCH ₂ ) , 5.07 (s, 2H, ArCH ₂ ), 5.14 (br s, 1H, NH), 7.25-7.40 (br s, 5H, ArH), 7.48 (s, 1H, ArH), 7.56 (d, 1H, J = 2.2 Hz, ArH), 8.11 (d, 1H, J = 2.2 Hz, ArH).

(Step 4) 4- [3- (3-benzyl-oxy-carbonylamino) propoxy] -5,7-dichloroquinoline-2-carboxylic acid

Methyl ester (1.0 mmol) and NaOH (2.0 mmol), which are the title compounds of (Step 3), were added to a 1: 1 solvent of THF and water, followed by stirring at room temperature until the methyl ester disappeared. The reaction mixture was washed with ether and the aqueous layer was acidified with 1N hydrochloric acid at pH 3. The precipitate was collected by filtration (or extraction with dichloromethane) and dried in vacuo to afford the title compound as a white solid (0.27 g, yield 60%).

¹ H-NMR (DMSO-d ₆ ) δ 2.10 (br s, 2H, CH ₂ ), 4.32 (br s, 2H, OCH ₂ ), 5.09 (s, 2H, PhCH ₂ ), 7.27-7.48 (br s, 5H, ArH), 7.53 (br s, 1H, NH), 7.68 (br s, 2H, ArH), 7.68 (d, 1H, J = 2.2 Hz, ArH), 8.39 (d, 1H, J = 2.2 Hz, ArH).

<Example 2> 4- [3- (3-n-butyrylamido) propoxy] -5,7-dichloroquinoline-2-carboxylic acid

(Step 1) 4- (3-Bromopropoxy) -5,7-dichloroquinoline-2-carboxylic acid methyl ester

The title compound was prepared in the same manner as in (Step 1) of <Example 1>.

(Step 2) 4- (3-azidopropoxy) -5,7-dichloroquinoline-2-carboxylic acid methyl ester

The title compound was prepared in the same manner as in (Step 2) of <Example 1>.

(Step 3) 4- [3- (3-n-butyrylamido) propoxy] -5,7-dichloroquinoline-2-carboxylic acid methyl ester

The title compound was prepared in the same manner as in (Step 3) of <Example 1>, except that butyric acid chloride was used instead of benzyloxy acid chloride (0.17 g, yield 40%). ).

mp 120-123 ° C .; ¹ H-NMR (CDCl ₃ ) δ 0.89 (t, 3H, J = 7.2 Hz, CH ₃ ), 1.32 (m, 2H, CH ₂ ), 1.55 (m, 2H, CH ₂ ), 2.18 (m, 2H, CH ₂ ), 3.48 (m, 2H, NHCH ₂ ), 3.99-4.05 (m, 2H, OCH ₂ ), 4.05 (s, 3H, CO ₂ CH ₃ ), 4.29 (t, 2H, J = 5.4 Hz, OCH ₂ ), 4.96 (br s, 1H, NH), 7.53 (s, 1H, ArH), 7.59 (d, 1H, J = 2.2 Hz, ArH), 8.13 (d, 1H, J = 2.2 Hz, ArH).

(Step 4) 4- [3- (3-n-butyrylamido) propoxy] -5,7-dichloroquinoline-2-carboxylic acid

Using the title compound of (step 3), the reaction was carried out in the same manner as in (Step 4) of <Example 1>, to thereby obtain the title compound as a white solid (0.16 g, 98% yield).

mp 140-142 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ 0.95 (t, 3H, J = 7.4 Hz, CH ₃ ), 1.34-1.61 (m, 4H, CH ₂ ), 2.09 (m, 2H, CH ₂ ), 3.99 ( t, 2H, J = 7.0 Hz, OCH ₂ ), 4.40 (t, 2H, J = 5.6 Hz, OCH ₂ ), 7.30 (m, 1H, NH), 7.64 (s, 1H, ArH), 7.94 (d, 1H, J = 2.0 Hz, ArH), 8.19 (d, 1H, J = 2.0 Hz, ArH).

Example 3 4- [3- (3-t-butoxycarbonylamino) propoxy] -5,7-dichloroquinoline-2-carboxylic acid

(Step 1) 4- (3-Bromopropoxy) -5,7-dichloroquinoline-2-carboxylic acid methyl ester

The title compound was prepared in the same manner as in (Step 1) of <Example 1>.

(Step 2) 4- (3-azidopropoxy) -5,7-dichloroquinoline-2-carboxylic acid methyl ester

The title compound was prepared in the same manner as in (Step 2) of <Example 1>.

(Step 3) 4- [3- (3-t-butoxycarbonylamino) propoxy] -5,7-dichloroquinoline-2-carboxyl acid methyl ester

The title compound was prepared in the same manner as in (Step 3) of <Example 1>, except that butoxy acid chloride was used instead of benzyloxy acid chloride (0.13 g, yield 30%). ).

¹ H-NMR (CDCl ₃ ) δ 1.42 (s, 9H, CH ₃ ), 2.17 (m, 2H, CH ₂ ), 3.45 (m, 2H, NCH ₂ ), 4.06 (s, 3H, CO ₂ CH ₃ ) , 4.29 (t, 2H, J = 6.0 Hz, OCH ₂ ), 5.26 (br s, 1H, NH), 7.52 (s, 1H, ArH), 7.60 (d, 1H, J = 2.0 Hz, ArH), 8.15 (d, 1H, J = 2.0 Hz, ArH); MS m / e 429 [M ⁺ ], 372 [M ⁺ -t-butyl], 356 [M ⁺ -O-butyl]

(Step 4) 4- [3- (3-t-butoxycarbonylamino) propoxy] -5,7-dichloroquinoline-2-carboxyl acid

Using the title compound of (step 3), the title compound was prepared in the same manner as in (Step 4) of <Example 1>, to obtain the title compound as a white solid (0.15 g, 60% yield).

mp 120-124 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ 1.44 (s, 9H, CH ₃ ), 2.06 (m, 2H, CH ₂ ), 3.32 (m, 2H, NCH ₂ ), 4.30 (br m, 2H, OCH ₂ ), 7.05 (br m, 1H, NH), 7.64 (s, 1H, ArH), 7.94 (d, 1H, J = 2.0 Hz, ArH), 8.19 (d, 1H, J = 2.0 Hz, ArH).

Example 4 4- [3- (3-phenylacetylamido) propoxy] -5,7-dichloroquinoline-2-carboxyl acid

(Step 1) 4- (3-Bromopropoxy) -5,7-dichloroquinoline-2-carboxylic acid methyl ester

The title compound was prepared in the same manner as in (Step 1) of <Example 1>.

(Step 2) 4- (3-azidopropoxy) -5,7-dichloroquinoline-2-carboxylic acid methyl ester

The title compound was prepared in the same manner as in (Step 2) of <Example 1>.

(Step 3) 4- [3- (3-phenylacetylamido) propoxy] -5,7-dichloroquinoline-2-carboxylic acid methyl ester

The title compound was prepared in the same manner as in (Step 3) of <Example 1>, except that benzyl acid chloride was used instead of benzyloxy acid chloride (0.15 g, yield 26%). ).

mp 171-173 ° C .; ¹ H-NMR (CDCl ₃ ) δ 2.13 (m, 2H, CH ₂ ), 3.51 (m, 2H, CH ₂ ), 3.56 (s, 2H, PhCH ₂ ), 4.06 (s, 3H, CO ₂ CH ₃ ) , 4.19 (t, 2H, J = 5.6 Hz, OCH ₂ ), 5.63 (br s, 1H, NH), 7.16-7.25 (m, 5H, ArH), 7.47 (s, 1H, ArH), 7.57 (d, 1H, J = 2.2 Hz, ArH), 8.13 (d, 1H, J = 2.2 Hz, ArH); MS m / e 447 [M ⁺ ], 415 [M ⁺ -OCH ₃ ].

(Step 4) 4- [3- (3-phenylacetylamido) propoxy] -5,7-dichloroquinoline-2-carboxylic acid

Using the title compound of (step 3), the reaction was carried out in the same manner as in (Step 4) of <Example 1>, to thereby obtain the title compound as a white solid (0.056 g, 39% yield).

mp 110-113 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ 2.10 (m, 2H, CH ₂ ), 3.42 (m, 2H, CH ₂ ), 3.48 (s, 2H, PhCH ₂ ), 7.28-7.35 (m, 5H, ArH ), 8.06 (d, 1H, J = 2.2 Hz, ArH), 8.19 (d, 1H, J = 2.2 Hz, ArH), 8.26 (br m, 1H, NH); MS m / e 432 [M ⁺ ], 388 [M ⁺ -CO ₂ ], 339 [M ⁺ -pHCH ₂ ].

Example 5 4- [3- (3-p-tosylureido) propoxy] -5,7-dichloroquinoline-2-carboxylic acid

(Step 1) 4- (3-Bromopropoxy) -5,7-dichloroquinoline-2-carboxylic acid methyl ester

The title compound was prepared in the same manner as in (Step 1) of <Example 1>.

(Step 2) 4- (3-azidopropoxy) -5,7-dichloroquinoline-2-carboxylic acid methyl ester

The title compound was prepared in the same manner as in (Step 2) of <Example 1>.

(Step 3) 4- [3- (3-p-tosylureido) propoxy] -5,7-dichloroquinoline-2-carboxylic acid methyl ester

The title compound was prepared in the same manner as in (Step 3) of <Example 1>, except that p-tosyl isocyanate was used instead of benzyloxy acid chloride (0.27 g, Yield 40). %).

mp 176-180 ° C .; ¹ H-NMR (CDCl ₃ ) δ 2.16 (m, 2H, CH ₂ ), 2.38 (s, 3H, PhCH ₃ ), 3.55 (m, 2H, NHCH ₂ ), 4.06 (s, 3H, CO ₂ CH ₃ ) , 4.13 (t, 2H, J = 5.4 Hz, OCH ₂ ), 6.83 (br s, 1H, NH), 7.26 (d, 1H, J = 7.8 Hz, ArH), 7.36 (s, 1H, NH), 7.52 (d, 1H, J = 2.0 Hz, ArH), 7.76 (d, 1H, J = 7.8 Hz, ArH), 8.04 (d, 1H, J = 2.0 Hz, ArH).

(Step 4) 4- [3- (3-p-tosylureido) propoxy] -5,7-dichloroquinoline-2-carboxylic acid

Using the title compound of (step 3) above, the title compound was prepared in the same manner as in (Step 4) of <Example 1>, to obtain the title compound as a white solid (0.16 g, 70% yield).

mp 155-160 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ 1.93 (m, 2H, CH ₂ ), 2.34 (s, 3H, PhCH ₃ ), 3.25 (m, 2H, NHCH ₂ ), 4.18 (t, 2H, J = 5.4 Hz, OCH ₂ ), 6.72 (t, 2H, J = 4.6 Hz, NH), 7.35 (d, 2H, J = 8.8 Hz, ArH), 7.48 (s, 1H, ArH), 7.75 (d, 2H, J = 8.8 Hz, ArH), 7.72 (d, 1H, J = 2.2 Hz, ArH), 8.08 (d, 1H, J = 2.2 Hz, ArH).

Example 6 4- [3- (3-phenylureido) propoxy] -5,7-dichloroquinoline-2-carboxylic acid

(Step 1) 4- (3-Bromopropoxy) -5,7-dichloroquinoline-2-carboxylic acid methyl ester

The title compound was prepared in the same manner as in (Step 1) of <Example 1>.

(Step 2) 4- (3-azidopropoxy) -5,7-dichloroquinoline-2-carboxylic acid methyl ester

The title compound was prepared in the same manner as in (Step 2) of <Example 1>.

(Step 3) 4- [3- (3-phenylureido) propoxy] -5,7-dichloroquinoline-2-carboxylic acid methyl ester

The title compound was prepared in the same manner as in (Step 3) of <Example 1>, except that phenylisocyanate was used instead of benzyloxy acid chloride (0.17 g, 50% yield). .

mp 208-209 ° C; ¹ H-NMR (CDCl ₃ ) δ 2.18 (m, 2H, CH ₂ ), 3.68 (m, 2H, NCH ₂ ), 4.04 (s, 3H, CO ₂ CH ₃ ), 4.19 (t, 2H, J = 5.2 Hz, OCH ₂ ), 5.98 (m, 1H, NH), 7.02 (m, 1H, ArH), 7.06 (br s, 1H, NH), 7.18-7.32 (m, 5H, ArH), 7.48 (d, 1H , J = 2.0 Hz, ArH), 8.01 (d, 1H, J = 2.0 Hz, ArH); MS m / e 357 [M ⁺ -PhNH], 296 [M ⁺ -PhNH, OCH ₃ ].

(Step 4) 4- [3- (3-phenylureido) propoxy] -5,7-dichloroquinoline-2-carboxylic acid

Using the title compound of (step 3), the title compound was prepared in the same manner as in (Step 4) of <Example 1>, to obtain a title compound as a white solid (0.10 g, 63% yield).

mp 162-164 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ 2.14 (m, 2H, CH ₂ ), 4.45 (t, 2H, J = 5.0 Hz, OCH ₂ ), 6.49 (br m, 2H, NH), 6.92-6.98 ( m, 1H, ArH), 7.24-7.32 (m, 2H, ArH), 7.43-7.47 (m, 2H, ArH), 7.67 (s, 1H, ArH), 7.94 (d, 1H, J = 2.0 Hz, ArH ), 8.19 (d, 1H, J = 2.0 Hz, ArH), 8.59 (br s, 1H, NH).

Example 7 4- [3- (3-benzyl ureido) propoxy] -5,7-dichloroquinoline-2-carboxylic acid

(Step 1) 4- (3-Bromopropoxy) -5,7-dichloroquinoline-2-carboxylic acid methyl ester

The title compound was prepared in the same manner as in (Step 1) of <Example 1>.

(Step 2) 4- (3-azidopropoxy) -5,7-dichloroquinoline-2-carboxylic acid methyl ester

The title compound was prepared in the same manner as in (Step 2) of <Example 1>.

(Step 3) 4- [3- (3-benzylureido) propoxy] -5,7-dichloroquinoline-2-carboxylic acid methyl ester

The title compound was prepared in the same manner as in (Step 3) of <Example 1>, except that benzyl isocyanate was used instead of benzyloxy acid chloride (0.20 g, 45% yield). .

mp 195-197 ° C .; ¹ H-NMR (CDCl ₃ ) δ 2.15 (dt, 2H, J _A = 12 Hz, J _B = 2.6 Hz, CH ₂ ), 3.55 (m, 2H, NHCH ₂ ), 4.02 (s, 3H, CO ₂ CH ₃ ), 4.19 (t, 2H, J = 5.8 Hz, OCH ₂ ), 4.34 (d, 2H, J = 5.6 Hz, PhCH ₂ ), 4.96 (t, 1H, J = 6.4 Hz, NH), 5.14 (t, 1H, J = 5.6 Hz, NH), 7.15 -7.27 (m, 5H, ArH), 7.34 (s, 1H, ArH), 7.50 (d, 1H, J = 2.2 Hz, ArH), 8.05 (d, 1H, J = 2.2 Hz, ArH); MS m / e 355 [M ⁺ -BzNH].

(Step 4) 4- [3- (3-benzylureido) propoxy] -5,7-dichloroquinoline-2-carboxylic acid

Using the title compound of (step 3) above, the title compound was prepared in the same manner as in (Step 4) of <Example 1>, to give the title compound as a white solid (0.12 g, 63% yield).

mp 157-160 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ 2.18 (m, 2H, CH ₂ ), 4.28 (d, 2H, J = 6.2 Hz, PhCH ₂ ), 4.39 (m, 2H, OCH ₂ ), 6.24 (m, 1H, NH), 6.41 (m, 1H, NH), 7.27-7.41 (m, 5H, ArH), 7.65 (s, 1H, ArH), 7.90 (d, 1H, J = 2.2 Hz, ArH), 8.19 ( d, 1H, J = 2.2 Hz, ArH); MS m / e 355 [M ⁺ -BzNH].

<Example 8> 4- [3- (3-benzoylureido) propoxy] -5,7-dichloroquinoline-2-carboxylic acid

(Step 1) 4- (3-Bromopropoxy) -5,7-dichloroquinoline-2-carboxylic acid methyl ester

The title compound was prepared in the same manner as in (Step 1) of <Example 1>.

(Step 2) 4- (3-azidopropoxy) -5,7-dichloroquinoline-2-carboxylic acid methyl ester

The title compound was prepared in the same manner as in (Step 2) of <Example 1>.

(Step 3) 4- [3- (3-benzoylureido) propoxy] -5,7-dichloroquinoline-2-carboxylic acid methyl ester

The title compound was prepared in the same manner as in (Step 3) of <Example 1>, except that benzoylisocyanate was used instead of benzyloxy acid chloride (0.14 g, 38% yield). .

mp 193-195 ° C .; ¹ H-NMR (CDCl ₃ ) δ 2.32 (m, 2H, CH ₂ ), 3.74 (m, 2H, NHCH ₂ ), 4.09 (s, 3H, CO ₂ CH ₃ ), 4.48 (m, 2H, OCH ₂ ) 7.42-7.87 (m, 7H, ArH), 8.17 (d, 1H, J = 2.2 Hz, ArH), 8.49 (br s, 1H, NH), 8.83 (br s, 1H, NH); MS m / e 298 [M ⁺ -PhCO, CO ₂ CH ₃ ].

(Step 4) 4- [3- (3-benzoylureido) propoxy] -5,7-dichloroquinoline-2-carboxylic acid

Using the title compound of (step 3) above, the reaction was carried out in the same manner as in (Step 4) of <Example 1>, to thereby obtain the title compound as a white solid (0.14 g, 100% yield).

mp 218-220 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ 2.21 (m, 2H, CH ₂ ), 3.58 (m, 2H, NHCH ₂ ), 4.43 (m, 2H, OCH ₂ ), 7.52-7.65 (m, 4H, ArH ), 7.85-7.99 (m, 3H, ArH), 8.14 (m, 1H, ArH), 8.83 (br s, 1H, NH).

Example 9 4- [3- (3-phenylthioureido) propoxy] -5,7-dichloroquinoline-2-carboxyl acid

(Step 1) 4- (3-Bromopropoxy) -5,7-dichloroquinoline-2-carboxylic acid methyl ester

The title compound was prepared in the same manner as in (Step 1) of <Example 1>.

(Step 2) 4- (3-azidopropoxy) -5,7-dichloroquinoline-2-carboxylic acid methyl ester

The title compound was prepared in the same manner as in (Step 2) of <Example 1>.

(Step 3) 4- [3- (3-phenylthioureido) propoxy] -5,7-dichloroquinoline-2-carboxylic acid methyl ester

The title compound was prepared in the same manner as in (Step 3) of <Example 1>, except that phenylthioisocyanate was used instead of benzyloxy acid chloride (0.18 g, yield 39%). ).

mp 176-178 ° C; ¹ H-NMR (CDCl ₃ ) δ 2.27 (m, 2H, CH ₂ ), 3.85 (br m, 2H, NHCH ₂ ), 4.04 (s, 3H, CO ₂ CH ₃ ), 4.44 (t, 2H, J = 5.6 Hz, OCH ₂ ), 7.13-7.22 (m, 1H, ArH), 7.32-7.65 (m, 4H, ArH), 7.64 (s, 1H, ArH), 7.93 (d, 1H, J = 2.0 Hz, ArH ), 8.00 (br s, 1H, NH), 8.20 (d, 1H, J = 2.0 Hz, ArH), 9.58 (br s, 1H, NH); MS m / e 371 [M ⁺ -PhNH], 328 [M ⁺ -NH (CS) NHPh].

(Step 4) 4- [3- (3-phenylthioureido) propoxy] -5,7-dichloroquinoline-2-carboxylic acid

Using the title compound of (step 3) above, the title compound was prepared in the same manner as in (Step 4) of <Example 1>, to obtain a title compound as a white solid (0.16 g, 94% yield).

mp 154-155 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ 2.16 (m, 2H, CH ₂ ), 3.80 (m, 2H, NHCH ₂ ), 4.31 (m, 2H, OCH ₂ ), 7.03-7.09 (m, 1H, ArH ), 7.24- 7.32 (m, 2H, ArH), 7.42-7.49 (s, 2H, ArH), 7.51 (s, 1H, ArH), 7.75 (br s, 1H, ArH), 8.03 (br s, 1H, ArH), 8.27 (br s, 1 H, NH), 9.78 (br s, 1 H, NH).

Example 10 4- {3- [3- (4-methoxyphenyl) thioureido] propoxy} -5,7-dichloroquinoline-2-carboxylic acid

(Step 1) 4- (3-Bromopropoxy) -5,7-dichloroquinoline-2-carboxylic acid methyl ester

The title compound was prepared in the same manner as in (Step 1) of <Example 1>.

(Step 2) 4- (3-azidopropoxy) -5,7-dichloroquinoline-2-carboxylic acid methyl ester

The title compound was prepared in the same manner as in (Step 2) of <Example 1>.

(Step 3) 4- {3- [3- (4-methoxyphenyl) thioureido] propoxy} -5,7-dichloroquinoline-2-carboxylic acid methyl ester

The reaction was carried out in the same manner as in (Step 3) of <Example 1>, except that 4-methoxyphenylthioisocyanate was used instead of benzyloxy acid chloride, to obtain the title compound as a white solid (0.18 g , Yield 38%).

mp 177-179 ° C .; ¹ H-NMR (CDCl ₃ ) δ 2.29 (dt, 2H, J _A = 12.8 Hz, J _B = 6.4 Hz, CH ₂ ), 3.69 (s, 3H, ArOCH ₃ ), 3.93 (m, 2H, NHCH ₂ ) , 4.05 (s, 3H, CO ₂ CH ₃ ), 4.26 (t, 2H, J = 5.8 Hz, OCH ₂ ), 6.10 (m, 1H, NH), 6.73 (d, 2H, J = 6.6 Hz, ArH) , 7.03 (d, 2H, J = 6.6 Hz, ArH), 7.49 (s, 1H, ArH), 7.52 (d, 1H, J = 2.2 Hz, ArH), 8.12 (d, 1H, J = 2.2 Hz, ArH ).

(Step 4) 4- {3- [3- (4-methoxyphenyl) thioureido] propoxy} -5,7-dichloroquinoline-2-carboxylic acid

Using the title compound of (step 3) above, the reaction was carried out in the same manner as in (Step 4) of <Example 1>, to thereby obtain the title compound as a white solid (0.10 g, 59% yield).

mp 125-130 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ 2.17 (m, 2H, CH ₂ ), 3.73 (s, 5H, ArOCH ₃ , NHCH ₂ ), 4.33 (m, 2H, OCH ₂ ), 6.88 (d, 2H, J = 8.8 Hz, ArH), 7.20 (d, 2H, J = 8.8 Hz, ArH), 7.57 (s, 1H, ArH), 7.84 (d, 1H, J = 2.2 Hz, ArH), 8.10 (d, 1H , J = 2.2 Hz, ArH).

Example 11 4- [3- (3-benzoylthioureido) propoxy] -5,7-dichloroquinoline-2-carboxylic acid

(Step 1) 4- (3-Bromopropoxy) -5,7-dichloroquinoline-2-carboxylic acid methyl ester

The title compound was prepared in the same manner as in (Step 1) of <Example 1>.

(Step 2) 4- (3-azidopropoxy) -5,7-dichloroquinoline-2-carboxylic acid methyl ester

The title compound was prepared in the same manner as in (Step 2) of <Example 1>.

(Step 3) 4- [3- (3-benzoylthioureido) propoxy] -5,7-dichloroquinoline-2-carboxylic acid methyl ester

The title compound was prepared in the same manner as in (Step 3) of <Example 1>, except that benzoylthioisocyanate was used instead of benzyloxy acid chloride (0.24 g, 50% yield). ).

mp 204-205 ° C; ¹ H-NMR (CDCl ₃ ) δ 2.43 (m, 2H, CH ₂ ), 4.08 (s, 3H, CO ₂ CH ₃ ), 4.39 (m, 2H, OCH ₂ ), 7.45-7.64 (m, 5H, ArH ), 7.78 (d, 1H, J = 2.2 Hz, ArH), 7.82 (s, 1H, NH), 8.25 (d, 1H, J = 2.2 Hz, ArH), 8.98 (s, 1H, NH); MS m / e 298 [M ⁺ ], 461 [M ⁺ -C0 ₂ CH ₃ ].

(Step 4) 4- [3- (3-benzoylthioureido) propoxy] -5,7-dichloroquinoline-2-carboxylic acid

Using the title compound of (step 3), the reaction was carried out in the same manner as in (Step 4) of <Example 1>, to thereby obtain the title compound as a white solid (0.21 g, 91% yield).

mp> 160 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ 2.26 (m, 2H, CH ₂ ), 3.96 (m, 2H, NHCH ₂ ), 4.42 (m, 2H, OCH ₂ ), 7.43-7.67 (m, 4H, ArH ), 7.55-7.92 (m, 4H, ArH), 8.09 (d, 1H, J = 2.2 Hz, ArH), 10.95 (m, 1H, NH), 11.24 (s, 1H, NH).

Example 12 4- {3- [3- (4-phenoxyphenyl) thioureido] propoxy} -5,7-dichloroquinoline-2-carboxylic acid

(Step 1) 4- (3-Bromopropoxy) -5,7-dichloroquinoline-2-carboxylic acid methyl ester

The title compound was prepared in the same manner as in (Step 1) of <Example 1>.

(Step 2) 4- (3-azidopropoxy) -5,7-dichloroquinoline-2-carboxylic acid methyl ester

The title compound was prepared in the same manner as in (Step 2) of <Example 1>.

(Step 3) 4- {3- [3- (4-phenoxyphenyl) thioureido] propoxy} -5,7-dichloroquinoline-2-carboxylic acid methyl ester

Except for using 4-phenoxyphenylthioisocyanate instead of benzyloxy acid chloride, the reaction was carried out in the same manner as in (Step 3) of <Example 1>, to obtain the title compound as a pale yellow solid (0.24 g, yield 50%).

mp 80-81 ° C .; ¹ H-NMR (CDCl ₃ ) δ 2.36 (m, 2H, CH ₂ ), 3.98 (m, 2H, SCH ₃ ), 4.09 (s, 3H, CO ₂ CH ₃ ), 4.34 (t, 2H, J = 5.8 Hz, OCH ₂ ), 6.95 (s, 1H, NH), 6.96-7.04 (m, 4H, ArH), 7.15-7.22 (m, 3H, ArH), 7.35-7.43 (m, 2H, ArH), 7.56 ( s, 1H, ArH), 7.60 (d, 1H, J = 2.2 Hz, ArH), 8.18 (d, 1H, J = 2.2 Hz, ArH); MS m / e 521 [M ⁺ -OCH ₃ ], 461 [M ⁺ -NHPh-O-Ph].

(Step 4) 4- {3- [3- (4-phenoxyphenyl) thioureido] propoxy} -5,7-dichloroquinoline-2-carboxylic acid

Using the title compound of (step 3), the reaction was carried out in the same manner as in (Step 4) of <Example 1>, to obtain the title compound as a white solid (0.22 g, yield 60%).

mp> 160 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ 2.19 (br s, 2H, CH ₂ ), 3.97 (br s, 2H, SCH ₃ ), 4.31 (br s, 2H, OCH ₂ ), 6.98-7.07 (m, 4H, ArH), 7.18-7.21 (m, 1H, ArH), 7.41-7.65 (m, 6H, ArH), 8.06 (d, 1H, J = 2.2 Hz, ArH), 9.24 (br s, 1H, NH) , 10.71 (br s, 1 H, NH); MS m / e 284 [M ⁺ -(CH ₂ ) ₃ C (S) NH-Ph-O-Ph], 227.

I. In vitro screening for binding activity

1) Preparation of Synaptic Membrane

Male Sprague-Dawley rats (300-400 g) were obtained from a laboratory animal laboratory at Korea Research Institute of Chemical Technology. Laboratory animals were treated with water and standard in an air-conditioned room (22 + 1 ° C .; relative humidity, 60 + 5%) in a slightly darkened condition (brightness at 8 am) during the preparation period of 4-10 days prior to use. The laboratory food was fed and bred. Synaptic membranes for receptor binding studies are modified methods of Foster and Fagg [Eur. J. Pharmacol. 133, 291 (1987) and the modified method by Murphy et al. [Br. J. Pharmacol. 95, 932 (1988). In summary, male Sprague-Dawley rats were killed, brain cortex and hippocampus (chopocampus) were chopped with a scalpel and homogenized five times with 10 volumes of 0.32 M sucrose using a Teflon-fiber equalizer. Centrifuged for 10 minutes at 1000x g for 10 minutes with a Beckman J2 / 21 centrifuge (roto: JA20), and the supernatant was collected and centrifuged for 20 minutes at 20,000x g. The supernatant was removed and homogenized with a pellet homogenizer (5 times setting, 30 seconds).

After incubation at 4 ° C. for 30 minutes, the membrane suspension was centrifuged at 39,800 × g for 25 minutes with a Beckman L8-M ultracentrifuge. The pellet was left overnight at -70 ° C. The next day the pellet is dissolved at room temperature for 10 minutes and then resuspended in 20 volumes of 50 mM tris-acetone (pH 7.1, 4 ° C.) containing 0.04% Triton X-100, incubated at 37 ° C. for 20 minutes and 20 minutes. Centrifuge as above at 39,800 × g. The pellet was washed three times by centrifugation as above 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 protein concentration was measured using Bio-Rad agent (Bradford, 1976). The resuspension buffer 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 [ ³ H] glycine saturation binding assay, reaction of the synaptic membrane (100 μg membrane protein) with a final volume of 0.5 ml containing 50 mM tris-acetate buffer solution at pH 7.1, 5-500 nM of [ ³ H] glycine The reaction was carried out at a temperature of 4 ° C. for 30 minutes in a borosilicated glass tube containing the mixture. For drug potential measurements, the synaptic membrane (100 μg of membrane protein) was reacted as above in a reaction mixture containing 50 mM tris-acetate buffer, pH 7.1, 50 nM of [ ³ H] glycine, and various concentrations of experimental compounds. I was.

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

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

Compounds prepared in the present invention exhibit IC ₅₀ (μM), the concentration required to reduce [ ³ H] glycine binding by 50%, and compete with [ ³ H] glycine when the concentration of the compound of the present invention is 100 μM. The results of the percentage values (% inhibition) are shown in Table 1 below.

compound IC ₅₀ (μM) Suppression% Example 1 〉 100 24 Example 2 〉 100 11 Example 3 50.6 52 Example 4 〉 100 26 Example 5 〉 100 35 Example 6 - 56 Example 7 〉 100 41 Example 8 24.3 81 Example 9 6.04 84 Example 10 20.2 71 Example 11 3.95 90 Example 12 23.5 -

II. In vivo screening for anticonvulsive activity

1) NMDA (i.c.v.)-Induced spasm experiment

Based on the method of Chugai, 40-160 ng of NMDA per mouse was calculated using i.c.v. Obtained for induced spasms after administration. A 28 gauge injection needle attached to a 50 μl syringe was inserted through the bregma 1 mm right cartilage on the parietal suture and the test solution was inserted using a manipulator. The insertion volume was 5 μl per rat. Convulsions in response to NMDA occurred within 5 minutes, 1) rough running or jumping, 2) myoclonic seizures; (clonic seizures; loss of direction and repetitive movements of the limbs at the same time). Animals are i.c.v. Observation was performed for 10 minutes after injection and the seizure seen when myoclonus occurred. In order to investigate the NMDA-antagonist properties of the experimental drug, the following procedure was performed. The experimental drug (injection dose, 1 ml / 100 g) was i.p. 15 min after injection, 160 μl of NMDA was injected at 5 μl per horse. i.c.v. The experimental drug and NMDA solution were injected at the same time for investigation by administration. Ten rats were used for the same dose. The dose was increased until antagonistic NMDA reached a limit (eg solubility, lethality) that induces convulsions or can no longer be tested. NMDA was dissolved in 0.9% sodium chloride solution, and AP5,5,7-dichloroquinernic acid and 7-chloroquinernic acid were dissolved in a minimum amount of 0.1 N sodium hydroxide with 0.9% physiological saline.

2) Permanent Ligation of the Middle Celebral Atery (MCA)

Midbrain artery ligation is performed by 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% halotan and then maintained at 1.5% halotan in nitrous oxide: oxygen (70:30) using a halotan evaporator. After the animal was lying on its side, the left temporal muscles were cut and partially separated from the iliac arc with bipolar coagulant. Small bilateral incisions were performed using a micro-drill cooled with cold saline in front of the hole of the mandible nerve under the surgical microscope. The medial end of the olfactory nerve and the middle cerebral artery were seen through the thin brain dura. The midbrain artery close to the lenticulostriate artery (LSA) was exposed and ligated using a miniclip. The midbrain artery and the lenticular striatum behind the miniclip were corroded with bipolar coagulant. During surgery, the temperature of the right temporal muscles and rectum was maintained at about 37 ° C. using a heating pad. The contracted temporal nerves were returned to place and sutured. The animals were placed in cages and kept warm using a heating lamp overnight. Twenty four hours after midbrain artery ligation, the animal's neck was cut quickly, soaked in cold saline, and sliced at 2 mm intervals from the frotal pole. The slices were freshly prepared in salt and incubated in 2% TTC solution preheated to 37 ° C. Slices chopped for 30 minutes at 37 ° C. were fixed with 4% formalin solution. An infarct region of each slice was measured with an image analyzer using a stereomicroscope. Infarct size in the left hemisphere was measured by subtracting the left hemisphere infarct size from the right hemisphere infarct size to rule out the effect of edema formation.

As a result of the experiment, the 3-phenylureido compound of Example 6 among the compounds of the present invention showed the best animal test result ( in vivo anticonvulsive effect).

The 4- (3-substituted-propyloxy) -quinoline-2-carboxylic acid derivative of the present invention is a potent and unique antagonist that acts on the strikinin non-sensitive glycine binding site in the NMDA receptor complex, which is a potent antagonist against the NMDA receptor. It 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 damage to the central nervous system caused by anemia or hypoxia such as heart attack, hypoglycemia, ischemia, cardiac arrest, trauma.

In addition, the compounds of the present invention are not only used for the prevention and treatment of chronic neurodegenerative diseases including epilepsy, Alzheimer's disease, Huntington's disease and Parkinson's disease, but also have an effect as antispasmodic, analgesic, antidepressant, anti-anxiety and antischizophrenic agents. have.

Claims (12)

4- (3-substituted-propyloxy) -quinoline-2-carboxylic acid derivative having the structure of Formula 1, tautomeric isomers thereof and pharmaceutically acceptable salts thereof. Formula 1 In Chemical Formula 1, A is carbamate, amide, urea, thiourea, acylurea, sulfonylurea, acylthiourea, thiocarbamate, amidine, guanidine, imidate, thiimidate, phosphorylamide, sulfonamide, sulfonylthiourea Or amine; R is alkyl (C ₁ -C ₂₀ ), aryl (C ₆ -C ₁₂ ), aralkyl, heterocycle, carbocycle (C ₃ -C ₁₄ ), soluble bicyclic, hydrogen or cyano group Indicates. The alkyl group is an alkyl group having _{1 to 20} carbon atoms, The aryl group is an aryl group having a carbon number of C ₆ ~C _12, Heterocyclic groups are characterized in that C ₃ -C ₇ heterocycloalkyl, C ₃ -C ₇ heterocycloalkyl (C ₁ -C ₆ ) alkyl, heteroaryl and heteroaryl (C ₁ -C ₆ ) alkyl -(3-substituted-propyloxy) -quinoline-2-carboxylic acid derivatives, tautomeric isomers thereof and pharmaceutically acceptable salts thereof. The C1-C20 alkyl group of claim 2, wherein the C ₁ -C ₂₀ alkyl group comprises methyl, ethyl, propyl, isopropyl, butyl, secondary-butyl and tert-butyl groups, Aryl groups having _{6 to 14} carbon atoms include 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 are thiophenyl, furyl, pyrrolyl, indolyl, thiazolyl, oxazolyl, isoxazolyl, benzooxazolyl, imidazolyl, tetrazolyl, triazolyl, pyridyl, pyrimidinyl and phthalimidyl groups 4- (3-substituted-propyloxy) -quinoline-2-carboxylic acid derivative, tautomer isomer thereof and pharmaceutically acceptable salt thereof. The 4- (3-substituted-propyloxy) -quinoline-2-carboxylic acid derivative according to claim 1, wherein A is carbamate, amide, urea, thiourea, acylurea, sulfonylurea or acylthiourea. , Tautomer isomers thereof and pharmaceutically acceptable salts thereof. The 4- (3-substituted-propyloxy) -quinoline-2-carboxylic acid derivative, tautomer isomer thereof and pharmaceutically acceptable salt thereof, according to claim 1, wherein R is aryl, aralkyl or carbocycle. . The compound of claim 1 wherein the compound is 4- [3- (3-benzyl-oxy-carbonylamino) propoxy] -5,7-dichloroquinoline-2-carboxylic acid, 4- [3- (3-n-butyrylamido) propoxy] -5,7-dichloroquinoline-2-carboxylic acid, 4- [3- (3-t-butoxycarbonylamino) propoxy] -5,7-dichloroquinoline-2-carboxylic acid, 4- [3- (3-phenylacetylamido) propoxy] -5,7-dichloroquinoline-2-carboxylic acid, 4- [3- (3-p-tosylureido) propoxy] -5,7-dichloroquinoline-2-carboxylic acid, 4- [3- (3-phenylureido) propoxy] -5,7-dichloroquinoline-2-carboxylic acid, 4- [3- (3-benzylureido) propoxy] -5,7-dichloroquinoline-2-carboxylic acid, 4- [3- (3-benzoylureido) propoxy] -5,7-dichloroquinoline-2-carboxylic acid, 4- [3- (3-phenylthioureido) propoxy] -5,7-dichloroquinoline-2-carboxylic acid, 4- {3- [3- (4-methoxyphenyl) thioureido] propoxy} -5,7-dichloroquinoline-2-carboxylic acid, 4- [3- (3-benzoylthioureido) propoxy] -5,7-dichloroquinoline-2-carboxylic acid and 4- {3- [3- (4-phenoxyphenyl) thioureido] propoxy} -5,7-dichloroquinoline-2-carboxylic acid 4- (3-substituted-propyloxy) -quinoline-2-carboxylic acid derivative, tautomer isomer thereof and pharmaceutically acceptable salt thereof. An antagonist of excitatory amino acids to the NMDA receptor containing the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. A therapeutic agent for damage to the central nervous system caused as a result of anemia or hypoxia such as stroke, hypoglycemia, ischemia, cardiac arrest, trauma containing the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. A prophylactic and therapeutic agent for neurodegenerative diseases containing the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. A therapeutic agent for epilepsy, cerebral hemorrhage, Alzheimer's disease, Huntington's disease and Parkinson's disease containing the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. An anticonvulsant, analgesic, antidepressant, anti-anxiety and antischizophrenic agent comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 1) alkylating the compound of formula 4 with 1,3-dibromopropane to obtain a bromide compound of formula 5 (first step); 2) reacting the compound of formula 5 prepared in step 1 with NaN ₃ to substitute bromine to obtain an azido compound of formula 6 (second step); 3) Catalytic hydrogenation of the azido compound prepared in the second step to obtain a compound of formula 7, which is reacted with an appropriate isocyanate (R ₂ NCO), thioisocyanate (R ₂ NCS) or acid chloride (R ₂ COCl) Obtaining a compound of formula 8 (third step) and 4) basic hydrolysis of the compound of formula 8 to obtain a compound of formula 1 which is the target compound of the present invention A process for producing the 4- (3-substituted-propyloxy) -quinoline-2-carboxylic acid derivative of the present invention, comprising: Scheme 1 The compound of formula 1 in Scheme 1 is the same as the compound of formula 1, Y represents O, S, NH or H ₂ , R ₂ can be represented by -ZR, Z represents NH, O, S, CH ₂ , acylamino or sulfoneamino and the like, R is the same as R in the formula (1).