KR100689961B1 - 4-3,4-dialkoxyphenyl-2-amino-thiazole compounds, process for preparing thereof, and pharmaceutical composition for treating asthma, COPD and alzheimer comprising the same - Google Patents

Abstract

The present invention provides a novel 4- (3,4-dialkoxyphenyl) -2-aminothiazole compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof, a method for preparing the same, and a compound containing the same as an active ingredient The present invention relates to a pharmaceutical composition for the treatment of inflammation-related diseases including asthma and chronic obstructive pulmonary diseases, and the treatment and prevention of central nervous system diseases including Alzheimer's disease.

[Formula 1]

 4- (3,4-dialkoxyphenyl) -2-aminothiazole, PDE-4, asthma, chronic obstructive pulmonary disease, inflammatory diseases, central nervous system disease, Alzheimer's disease.

Description

4- (3,4-dialkoxyphenyl) -2-aminothiazole compound, method for preparing the same, and a composition for treating asthma, an inflammation-related disease including chronic obstructive pulmonary disease and a central nervous system disease including Alzheimer's disease { 4- (3,4-dialkoxyphenyl) -2-amino-thiazole compounds, process for preparing girls, and pharmaceutical composition for treating asthma, COPD and alzheimer comprising the same}

The present invention relates to a 4- (3,4-dialkoxyphenyl) -2-aminothiazole compound, a pharmaceutically acceptable salt thereof, a method for preparing the same, and a chronic obstructive pulmonary disease including the same. It relates to a composition for treating inflammation-related diseases, including.

Various compounds have been studied for the development of a therapeutic agent for asthma and chronic obstructive pulmonary disease based on PDE-4 inhibition on which the present invention is based [Peter Norman, Expert Opin. Ther. Patents. 2002 , 12 (1) , pp 93-111], among which the most representative compounds are Rolipram [EP 0660711, July 5, 1995], Cilomilast [USP 6,013,827, January 11, 2000] and Roflumilast [USP 5,712,298] January 27, 1998]. In addition, PDE-4 inhibitors have been suggested to improve the memory, cognition enhancing effects and the Alzheimer's treatment of the nervous system. Rolipram, the first of these compounds to enter the clinic, was stopped due to side effects such as weak clinical effects and vomiting. In addition, Cilomilast, a clinical trial, has ceased development as an asthma treatment due to its low therapeutic effect on asthma, and is a compound in progress for clinical obstructive pulmonary disease (COPD) [Peter Norman, Expert Opin. Ther. Patents 2002 , 12 (1) , 93-111; Compton C., Edelson JD., Cedar E ,. Am. J. Respir. Crit. Care Med. 2001 , 163 , A909. Roflumilast (Zheng Huang, Yves Ducharme, Dwight Macdonald and Annette Robichaud, Current Opinion in Chemical Biology 2001 , 5, 432-438) developed by Altana, Germany, has the highest PDE-4 inhibitory effect. (IC 50 = 0.8 nM) Animal testing is also known to be effective against asthma and COPD. Armin Hatzelman and Christian Schudt, The Journal of Pharmacology and Experimental Therapeutics 2001 , 297 (1) , 267-279; Daniela S. Bundschuh, Manfrid Eltze, Johannes Barsig, Lutz Wollin, Armin Hatzelmann, and Rolf Beume, The Journal of Pharmacology and Experimental Therapeutics 2001 , 297 (1 ), 280-290]. The compound has completed a clinical trial and has submitted a new drug application in Europe in February 2004 for the treatment of asthma.

As mentioned above, the development of drugs for the treatment of inflammation-related diseases including asthma and chronic obstructive pulmonary disease based on PDE-4 inhibition is often stopped due to low clinical effects and vomiting-related side effects. As a result, there is a need for development of a therapeutic agent having excellent clinical therapeutic effects and safety. In other words, high selectivity to PDE-4 isozyme (compared to PDE-3, PDE-5 and PDE-7) and low binding to HARBS (High Affinity Rolipram Binding Site) are required to overcome vomiting-related side effects. Problems in which good therapeutic effect should be maintained must be overcome.

Therefore, the present inventors have excellent in vitro and in vivo effects as a compound of a novel structure for the development of a therapeutic agent for asthma and inflammation-related diseases, and have high affinity for PDE-4 enzyme and low affinity for HARBS to overcome the side effects related to vomiting. To develop a PDE-4 inhibitor, a novel 4- (3,4-dialkoxyphenyl) -2-aminothiazole derivative was prepared, and the compounds according to the present invention were biochemical and pharmacologically tested for PDE-4 enzyme. It was confirmed to exhibit good inhibitory activity, high selectivity and low HARBS affinity.

Accordingly, it is an object of the present invention to provide novel 4- (3,4-dialkoxyphenyl) -2-aminothiazole compounds of formula (1) and their pharmaceutically acceptable salts, and as yet another object Method for preparing a novel 4- (3,4-dialkoxyphenyl) -2-aminothiazole compound according to the present invention, including Alzheimer's disease and inflammation-related diseases including asthma and chronic obstructive pulmonary disease It is to provide a therapeutic composition for diseases of the central nervous system.

The present invention provides a novel 4- (3,4-dialkoxyphenyl) -2-aminothiazole compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof, a method for preparing the same, and a bronchial asthma and Alzheimer's agent comprising the same It relates to a composition.

[Formula 1]

In Formula 1, A is N or NO, and R ₁ and R ₂ may be the same or different from each other, and each independently substituted with a hydrogen atom, a straight chain or a saturated or unsaturated (C ₁ -C ₇ ) alkyl, or halogen. Straight or branched saturated or unsaturated (C ₁ -C ₇ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, (C ₄ -C ₁₀ ) cycloalkylalkyl group, phenyl, benzyl or R ₁ and R ₂ are interconnected It is (C ₁ - C ₃₎ alkylene group substituted by halogen or (C ₁ - C ₃₎ alkylene group, and can be connected; R ₃ represents a hydrogen atom, a halogen atom, straight or branched saturated and unsaturated (C ₁ -C ₇ ) alkyl, amino, mono or di (C ₁ -C ₇ ) alkylamino, phenyl, benzyl; R ₄ is a hydrogen atom, straight or branched saturated or unsaturated (C ₁ -C ₇ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, (C ₁ -C ₃ ) alkoxycarbonyl, (C ₁ -C ₃ ) Alkoxy carbonyl (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkylsulfonyl, benzenesulfonyl; X may be the same or different from each other and is a hydrogen atom, crushed or straight-chain saturated or unsaturated (C ₁ -C ₇ ) alkyl, straight or crushed saturated or unsaturated (C ₁ -C ₇ ) alkyl, hydroxy, hydroxy Alkyl, aminoalkyl, mono- or di (C ₁ -C ₇ ) alkylaminoalkyl, (C ₁ -C ₇ ) alkoxy, (C ₁ -C ₇ ) alkoxyalkyl, halogen, cyano, nitro, amino, mono- Or di (C ₁ -C ₇ ) alkyl amino, (C ₁ -C ₆ ) alkylguanidine, (C ₁ -C ₆ ) alkoxycarbonylamino, (C ₁ -C ₇ ) alkylcarboxyamino, (C _1- C ₇ ) alkylsulfonamino, (C ₁ -C ₆ ) alkoxycarbonylaminoalkyl, N -alkoxycarbonylaminoacetate, N -benzyloxycarbonylaminoacetate, carboxylic acid, aminocarbonyl, mono or di (C ₁ -C ₇ ) alkylaminocarbonyl, (C ₁ -C ₇ ) alkoxycarbonyl, (C ₁ -C ₇ ) alkylcarbonyl, arylcarbonyl, (C ₁ -C ₇ ) alkylcarboxylate, (C ₁ - C ₇₎ Al When (C ₁ - C ₄₎ alkyl carboxylate, denotes an aryl carboxylate; n is an integer from 0 to 4; R ₄ is and Ar is selected interconnecting comprises a heterocyclic compound containing a C ₃ -C ₈ saturated or unsaturated cycloalkyl compound, or each of one or two oxygen, nitrogen and sulfur atom in the ring of C ₃ -C ₈ . However, the phenyl group or benzyl group of R ₁ to R ₃ may be substituted with (C ₁ -C ₇ ) alkoxy, halogen, nitro, cyano, hydroxy, carboxyl or amino groups, respectively.

또는

이며, A는 N 또는 NO이고, R₁과 R₂는 서로 동일하거나 상이할 수 있으며, 각각 수소원자, 직쇄 또는 분쇄의 포화 또는 불포화 (C₁ - C₇)알킬, 할로겐으로 치환된 직쇄 또는 분쇄의 포화 또는 불포화 (C₁ - C₇)알킬, (C₃ - C₇)시클로알킬기, (C₃ - C₈)시클로알킬메틸 또는 알릴기이며; R₃는 수소, 직쇄 또는 분쇄의 포화(C₁ - C₇)알킬, 페닐, 할로겐을 나타내며; X는 서로 동일하거나 상이할 수 있으며, 수소원자, 분쇄 또는 직쇄의 포화 또는 불포화 (C₁ - C₇)알킬, 할로겐으로 치환된 직쇄 또는 분쇄의 포화 또는 불포화 (C₁ - C₇)알킬, 히드록시, 히드록시알킬, (C₁ - C₇)알콕시, 할로겐, 카르복실산, (C₁ - C₇)알킬카르복실레이트, 아릴카르복실레이트를 나타내며; n은 0 내지 4의 정수이이다. 단, 상기 R₃에 서 페닐, 벤질기는 (C₁ - C₇)알콕시, 할로겐, 니트로, 시아노, 히드록시, 카르복실 또는 아미노기로 각각 치환될 수 있다.Among the novel 4- (3,4-dialkoxyphenyl) -2-aminothiazole compounds represented by the general formula (1) according to the present invention, Ar is hydrogen,

or

And A is N or NO, and R ₁ and R ₂ may be the same or different from each other, and each hydrogen atom, straight or branched saturated or unsaturated (C ₁ -C ₇ ) alkyl, halogen or straight chain substituted with halogen Saturated or unsaturated (C ₁ -C ₇ ) alkyl, (C ₃ -C ₇ ) cycloalkyl group, (C ₃ -C ₈ ) cycloalkylmethyl or allyl group; R ₃ represents hydrogen, straight or branched saturated (C ₁ -C ₇ ) alkyl, phenyl, halogen; X may be the same or different from each other, and is a hydrogen atom, a crushed or straight chain saturated or unsaturated (C ₁ -C ₇ ) alkyl, a linear or branched saturated or unsaturated (C ₁ -C ₇ ) alkyl, substituted with a halogen Hydroxy, hydroxyalkyl, (C ₁ -C ₇ ) alkoxy, halogen, carboxylic acid, (C ₁ -C ₇ ) alkylcarboxylate, arylcarboxylate; n is an integer from 0 to 4. However, the phenyl and benzyl groups in R ₃ may be substituted with (C ₁ -C ₇ ) alkoxy, halogen, nitro, cyano, hydroxy, carboxyl or amino groups, respectively.

Preferred Formula 1 compounds according to the invention may be the same or different from each other, wherein R ₁ and R ₂ are each methyl, difluoromethyl, cyclopentyl, cyclopropylmethyl; R ₃ and R ₄ each represent hydrogen; X may be the same or different from each other and is a hydrogen atom, a saturated or unsaturated (C ₁ -C ₇ ) alkyl of straight or branched chain, a saturated or unsaturated (C ₁ -C ₇ ) alkoxy of a straight chain or branched chain, alkoxy, hydroxy, halogen, carbo Acids, (C ₁ -C ₇ ) alkylcarboxylates, arylcarboxylates; n is an integer of 1-2.

The preparation method according to the present invention is illustrated in Scheme 1, and the following preparation method does not limit the method of preparing the compound of formula 1 according to the present invention, and modifications of the following preparation method will be apparent to those skilled in the art, and are mentioned otherwise. Unless otherwise specified, the definition of the substituent in the following scheme is the same as defined in the formula (1).

Scheme 1

In the method for preparing the compound of Formula 1 according to the present invention, as shown in Scheme 1, a monobromo compound 3 is first synthesized by a bromination reaction of an acetophenone compound represented by Formula 2, and then a thiourea represented by Formula 4 As the reaction with the compound, a desired compound of formula (1) can be synthesized.

As a solvent that can be used in the bromination reaction for preparing the compound of Formula 3 according to Scheme 1, an organic solvent may be used, and chloroform and methylene chloride are preferable, and an appropriate amount of acetic acid is mixed to dissolve dialkoxy acetophenone compound 2 . Thereafter, 1 equivalent of N -bromine succinimide is added to proceed with the reaction. If sulfuric acid is not used as a catalyst, the bromination reaction is not very slow or complete. Therefore, it is preferable to proceed with the reaction due to the presence of a small amount of concentrated sulfuric acid catalyst in the bromination step. The reaction can synthesize Compound 3 using bromine gas, but the use of N -brosuccinimide is more preferred for mono bromination yield.

Compound 3 prepared by the bromination reaction and various thiourea compound 4 may be synthesized by using an organic salt in an acetone solvent, the dialkoxyphenyl thiazole compound of the formula (1). Any organic solvent may be used as the solvent, but dimethylformamide, dichloromethane, acetone, and the like are more preferable in terms of yield.

Various derivatives of Compound 4 related to this patent are known from Chemical & Pharmaceutical Bulletin, 1985 , 33 (10 ), 4409-4421. Journal of Heterocyclic Chemistry, 1986 , 23 (1) , 113-118.].

Meanwhile, the 4- (3,4-dialkoxyphenyl) -2-aminothiazole compound represented by Chemical Formula 1 prepared according to the present invention has excellent activity and enzyme selectivity with respect to the PDE-4 enzyme and has low HARBS affinity. Side effects such as vomiting are expected to be minimal.

Compound represented by the formula (1) according to the present invention as a pharmaceutical composition for the treatment of inflammation-related diseases including bronchial asthma and chronic obstructive pulmonary disease and the treatment, prevention of diseases of the central nervous system including Alzheimer's Salts of the compounds of formula (I) which are suitable for use and suitable for use in the medicament may include those formed with both organic and inorganic acids or bases. Pharmaceutically acceptable acid addition salts include hydrochloric acid, bromic acid, sulfuric acid, citric acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, trifluoroacetic acid, triphenylacetic acid, phenylacetic acid, substituted phenylacetic acid, for example methoxy Phenylacetic acid, sulfamic acid, sulfanilic acid, succinic acid, oxalic acid, fumaric acid, maleic acid, malic acid, glutamic acid, aspartic acid, oxaloacetic acid, methanesulfonic acid, ethanesulfonic acid, arylsulfonic acid (e.g. p-toluenesulfonic acid , Benzenesulfonic acid, naphthalenesulfonic acid or naphthalenedisulfonic acid), salicylic acid, glutaric acid, gluconic acid, tricavalylic acid, mandelic acid, cinnamic acid, substituted cinnamic acid (e.g. 4-methyl and 4-methoxy Methyl, methoxy, halo or phenyl substituted cinnamic acid, including cinnamic acid and α-phenyl cinnamic acid, ascorbic acid, oleic acid, naphthoic acid, hydroxynaphthoic acid (eg, 1- or 3-hydroxy) -2-naphthoic acid), naph Taleneacrylic acid (eg, naphthalene-2-acrylic acid), benzoic acid, 4-methoxybenzoic acid, 2 or 4-hydroxybenzoic acid, 4-chlorobenzoic acid, 4-phenylbenzoic acid, benzeneacrylic acid (eg, 1,4 Benzenediacrylic acid) and isetionic acid. Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts and organic bases such as dicyclohexylamine and N -methyl- D -Salts with glucamine.

The compounds according to the invention also have the potential of combining long lasting effects and rapid onset of action. Certain compounds also exhibit improved therapeutic indicators in animal models compared to existing long-lasting PDE-4 inhibitors. In addition, the compounds of the present invention may be suitable for once to three times daily administration.

The amount of the compound of formula (1) or a pharmaceutically acceptable salt thereof used to achieve a therapeutic effect, as well as the particular compound, the method of administration, the subject to be treated, and the tablet disorder or disease to be treated, may range from 0.0005 mg to 10 mg. mg, preferably orally, or inhaled at a dose of 0.005 mg to 5 mg. Dosage ranges for adults are generally from 0.0005 mg to 100 mg per day, preferably from 0.01 mg to 5 mg per day.

It is possible to administer Compound (1) or a pharmaceutically acceptable salt thereof alone, but preferably in a pharmaceutical formulation. Accordingly, the present invention is also preferably provided as a pharmaceutical formulation comprising Formula 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient, and any one or more therapeutic ingredients.

The present invention as described above will be described in more detail based on the following examples, but the present invention is not limited thereto.

Example 1

Representative Method of Preparation of Compound of Formula 1

Preparation of [4- (3-Cyclopropylmethoxy-4-difluoromethoxyphenyl) thiazol-2-yl]-(4-trifluoromethylphenyl) amine (Compound 68)

Dissolve 50 mg (0.15 mmol) of 2-Bromo-1- (3-cyclopropylmethoxy-4-difluoromethoxy-phenyl) -ethanone in 2 ml of acetone, and then add 37 mg (0.17 mmol) of (4-trifluoromethyl-phenyl) -thiourea. It was. Triethylamine 0.04 ml was added dropwise and stirred at room temperature for 20 minutes. The solvent was evaporated under reduced pressure and purified by column chromatography under hexane: ethylacetate = 5: 1 to obtain 57 mg (yield 84%) of the title compound (68).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.72-7.17 (m, 7H), 6.90 (s, 1H), 6.65 (t, 1H), 3.96 (d, 2H), 1.30 (m, 1H), 0.65 ( m, 2H), 0.35 (m, 2H).

The structure and ¹ H NMR of the compounds synthesized in the same manner as shown in Table 1 below.

TABLE 1

Example 2

Inhibition of PDE-4 Activity

The activity inhibition activity of PDE-4d was performed by modifying the method of Kate et al. (Kate, et al., JBC , 271 : 796 (1996)). PDE-4d used human PDE-4d prepared by genetic recombination technology.

The PDE4d gene was cloned into the GST fusion expression vector pGEX4T3 (APBiotech), and then transformed into E. coli BL21, DE3. After incubating the strain at 37 ° C. in LB medium, the temperature was lowered to 18 ° C. when 0.3-0.5 OD was induced to induce PDE4d expression with 0.5 mM IPTG. After 15 hours of expression induction, PDE4d-expressing cells were obtained, and the cells were suspended in a buffer solution (50 mM Tris, pH 8.0, 0.4 M NaCl, 5 mM DTT), disrupted, and purified by centrifugation. The columns used for purification are Q-Sepharose (APBiotech), Glutanion-Sepharose (APBiotech), and Superdex 200 gel filtration chromatography (APBiotech) in this order.

In order to measure the ability to inhibit PDE4d activity of each compound, 1 nM of PDE4d and 250 nM of cAMP (Sigma) as a substrate were added to the reaction buffer (50 mM Tris-HCl, pH 7.5) and 4 mM MgCl ₂ , and obtained in Example 1 above. Each compound was added at a concentration of 1 to 50 uM and then reacted at 34 ° C. for 45 minutes. The reaction total was 60 µl. At this time, cAMP was used by mixing a ratio of [ ³ H] cAMP (Amersham, 1 μCi / μl) and cAMP (hot: cold, that is, isotope: non-isotope) at 1: 200. The reaction was then stopped by heating at 95 ° C. for 2 minutes, then cooled for 3 minutes and 30 μl of 1 mg / ml Snake Venome (sigma V0376) was added. Subsequently, after 30 minutes of reaction at 34 ° C, 30 μl of the reaction solution was poured into 250 μl of DOWEX 1 × 2-100 ion exchange resin (Aldrich, pre-mixed at a ratio of 1 to 1.6 of distilled water) and stirred vigorously for 2 minutes. Then, the resin was allowed to settle, and 130 μl of the supernatant was added to 2 ml of scintillation cocktail (Packard), mixed well, and measured by beta-counter. The concentration of each test compound that inhibited 50% of the enzyme activity compared to the enzyme activity of the control group without the addition of the compound of Formula 1 was determined as IC ₅₀ . IC ₅₀ values of the compounds are shown in Table 2 below.

TABLE 2

PDE-4 Enzyme Selectivity Assay

In order to measure the enzyme selectivity against PDE4d, the enzyme activity inhibitory effect of each test compound against PDE-3a, PDE-5a, and PDE-7a was measured. PDE3a and PDE7a, which used cAMP as a substrate, measured the degree of activity inhibition using the Amplified Luminescent Proximity Homogeneous Assay (Alpha) Screen method. Activity inhibition efficacy was measured. PDE3a, PDE5a and PDE7a all used human enzymes prepared by genetic recombination techniques.

In order to measure the inhibitory activity of PDE3a and PDE7a of each test compound, first put each compound (final DMSO 1%) at the concentration to be tested in a 96 well half area white plate and follow the same conditions as the conditions for measuring PDE4d enzyme activity described above. Enzyme reaction at When measuring enzyme activity using Alpha Screen, the concentrations of PDE3a and PDE7a should be 10nM and 80nM, respectively, and were carried out according to the method proposed in the Alphascreen cAMP assay kit (Perkin Elmer life science). Briefly, after the enzymatic reaction between PDE3a and PDE7a is terminated, a final 10 nM biotinylated-cAMP and 20ul / mL donor beads are added to the reaction mixture. The donor bead is sensitive to light, so be careful not to expose it to light and let it react for 30 minutes at room temperature. Then add acceptor beads to a final 20ul / ml. After reacting for 45 minutes at room temperature, the reaction was further reacted for 20 minutes in the Fusion Alpha-FP device, and the emission at 520-620 nm was measured.

 In the enzymatic reaction of PDE3a and PDE7a, the signal increase and decrease is caused by the mutual competition between the remaining cAMP and the newly added biotinylated-cAMP, which is not used as a substrate. The signal is reduced.

PDE5a, which uses cGMP as an enzyme substrate, measured the enzyme inhibitory ability of each test compound according to the experimental method presented by IMAP ^TM Phosphodiesterase Assay Kit (Molecular Device), which measures enzyme activity by fluorescence polarization (FP) method. First, add each test compound (final DMSO 5%) at the concentration to be tested in 96 well black plate, and add FL-cGMP (Fluorescence-labeled derivatives of cGMP) and final 200 nM PDE5a. After reacting for 45 minutes at 30 degrees, add the IMAP binding reagent provided by the kit. After reacting at room temperature for 60 minutes, FP obtained by 485 nm exitation and 535 nm emission was measured. The higher the enzyme activity of PDE5a, the higher the FP signal. The inhibition of enzymatic activity of PDE5a by each test compound can be determined by measuring the decreased FP signal.

In vivo experiment

For in vivo animal experiments, 8 to 9 week old male C57BL / 6J mice weighing 20-25 g were used as experimental animals. For sensitization and challenge of airway and lung by ovalbumin (OVA), OVA mixed with Al (OH) ₃ was firstly sensitized by intraperitoneal administration to mice. 2nd sensitization. Six days after the second sensitization, 5% OVA was inhaled through the nebulizer for three days. Drug administration to sensitized mice was administered orally (po) three times each 1 hour prior to inhalation of the OVA. 0.5% CMC was administered as a control. To observe the activity and cell composition of the mouse tracheal alveolar lavage fluid, the mice were anesthetized after 62 hours, inoculated with OVA, the cervical thorax was opened, the tube was inserted into the trachea using a tube containing 0.8 ml of PBS, and then PBS was injected. After massaging the chest for about 30 seconds, a cell suspension was obtained from the lungs. The obtained cells were centrifuged at 400xg, and the supernatant was used for measuring the eosinophil peroxidase activity (EPO activity), and pellets were used for cell composition investigation. To measure the activity of basophils, 100 ul of cell suspension was reacted with 0.1 mM OPD, 0.05 M Tris-HCl (pH 8.0), Triton X-100 and 1 mM H ₂ O _2, and the absorbance was measured at 492 nm. . For staining of basophils, cell pellets were resuspended in PBS and centrifuged at 150xg for 5 minutes to ensure that the cells adhered to the slides. The attached cells were subjected to Diff-Quick staining to observe the number of cells under a microscope. Airway hyper-responsiveness (AHR) analysis was performed using a whole body plethysmographer in living animals. 48 hours after OVA inhalation, Methacholine (Mch) was inhaled with nebulizer, and airway reactivity by Mch was measured using whole body plethysmography to compare enhanced pause (Penh) values for respiratory ability of airways.

As can be seen in Table 2, among the compounds of Formula 1 exhibiting PDE-4 inhibitory activity, the activity varies depending on R ₁ and R ₂ but does not show a constant trend (Compound 7 and Compound 62, Compound 9 and Compound) 63) The PDE-4 inhibitory activity of the compounds substituted with both R ₄ and Ar is reduced (compounds 32, 33, 34, 35). When R ₄ of Formula 1 is hydrogen and Ar is a phenyl derivative, the activity is excellent, and among them, hydroxy (compound 70) or halogen (compound 18, 19, 23) derivative is the most excellent. In the case of the compound 82 and the compound 88 in which the hydroxy group and the halogen group were substituted at the same time, the activity was slightly decreased compared to the case in which the hydroxy group and the halogen group were substituted alone.

TABLE 3

As shown in Table 3 above, all the compounds tested for PDE-4 of the active compounds showed a selectivity of 250 times or more, and in particular, the selectivity for PDE-7a was 3,000 times higher for all of the compounds 18, 19, and 70. It can be seen that it has very good selectivity.

The compounds of formula 1 according to the present invention are novel compounds having excellent activity against PDE-4 enzymes and high selectivity for other PDE enzymes, thus causing diseases of the central nervous system including bronchial asthma, COPD treatment, and Alzheimer's disease in animal experiments. It is expected to have an excellent effect on the treatment of pneumonia and no side effects.

Claims (10)

The novel 4- (3,4-dialkoxyphenyl) -2-aminothiazole compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof. [Formula 1]

In Chemical Formula 1, R ₁ and R ₂ may be the same as or different from each other, and each independently a straight or branched saturated or unsaturated (C ₁ -C ₇ ) alkyl, substituted or substituted with halogen, a straight or branched saturated or unsaturated ( C ₁ -C ₇ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, (C ₄ -C ₁₀ ) cycloalkyl (C ₁ -C ₇ ) alkyl group, allyl group; R ₃ represents a hydrogen atom, phenyl; R ₄ represents a hydrogen atom; X may be the same or different from each other, and hydroxy, hydroxy (C ₁ -C ₆ ) alkyl, amino (C ₁ -C ₇ ) alkyl, mono- or di (C ₁ -C ₇ ) alkylamino (C ₁ C ₇ ) alkyl, chloro (Cl), fluorine (F), cyano, (C ₁ -C ₇ ) alkylsulfonamino, N -alkoxycarbonylaminoacetate, N -benzyloxycarbonylaminoacetate, mono or di (C ₁ -C ₇ ) alkylaminocarbonyl, (C ₁ -C ₇ ) alkylcarbonyl, (C ₁ -C ₇ ) alkylcarboxylate, (C ₁ -C ₇ ) alkoxy (C ₁ -C ₄ ) Alkylcarboxylates; n is an integer from 0 to 4; Ar is

or

Hydroxy (C ₁ -C ₆ ) alkyl, amino (C ₁ -C ₇ ) alkyl, mono- or di (C ₁ -C ₇ ) alkylamino (C ₁ -C ₇ ) alkyl, cyano, (C ₁ -C ₇ ) alkylsulfonamino, N-alkoxycarbonylaminoacetate, N-benzyloxycarbonylaminoacetate, mono or di (C ₁ -C ₇ ) alkylaminocarbonyl, (C ₁ -C ₇ ) alkylcar Carbonyl, (C ₁ -C ₇ ) alkylcarboxylate, (C ₁ -C ₇ ) alkoxy (C ₁ -C ₄ ) alkylcarboxylate. However, the phenyl group of R ₃ may be each substituted with a (C ₁ -C ₇ ) alkoxy, halogen, nitro, cyano, hydroxy, carboxyl or amino group. The method of claim 1, Ar is

or

R ₁ and R ₂ may be the same as or different from each other, and straight or branched saturated or unsaturated (C ₁ -C ₇ ) alkyl, halogen or linear substituted or branched saturated or unsaturated (C ₁ -C _{7), respectively.} ) Alkyl, (C ₃ -C ₇ ) cycloalkyl group, (C ₃ -C ₈ ) cycloalkylmethyl or allyl group; R ₃ represents hydrogen, phenyl; X may be the same or different from each other, and hydroxy, hydroxy (C ₁ -C ₆ ) alkyl, amino (C ₁ -C ₇ ) alkyl, mono- or di (C ₁ -C ₇ ) alkylamino (C ₁ C ₇ ) alkyl, chloro (Cl), fluorine (F), cyano, (C ₁ -C ₇ ) alkylsulfonamino, N-alkoxycarbonylaminoacetate, N-benzyloxycarbonylaminoacetate, mono or di (C ₁ -C ₇ ) alkylaminocarbonyl, (C ₁ -C ₇ ) alkylcarbonyl, (C ₁ -C ₇ ) alkylcarboxylate, (C ₁ -C ₇ ) alkoxy (C ₁ -C ₄ ) Alkylcarboxylates; n is an integer of 0-4. The method of claim 2, R ₁ and R ₂ may be the same as or different from each other, and 4- (3,4-dialkoxyphenyl) -2-aminothiazole compound, each of which is methyl, difluoromethyl, cyclopentyl or cyclopropylmethyl Or a pharmaceutically acceptable salt thereof. The method of claim 3, Ar is

or

R ₃ and R ₄ each represent hydrogen; X may be the same or different from each other and represents hydroxy, chloro (Cl), fluorine (F), (C ₁ -C ₇ ) alkylcarboxylate; n is an integer of 1 to 2 4- (3,4-dialkoxyphenyl) -2-aminothiazole compound or a pharmaceutically acceptable salt thereof. The method of claim 1, 4- (3,4-dialkoxyphenyl) -2-aminothiazole compound or a pharmaceutically acceptable salt thereof, characterized in that it is selected from the following compounds:

A process for preparing the compound of formula 1 according to claim 1 by reacting a brominated dialkoxybenzophenone of formula 3 with a thiourea compound of formula 4. Scheme 1

A pharmaceutical for the treatment and prevention of bronchial inflammation-related diseases, which comprises a 4- (3,4-dialkoxyphenyl) -2-aminothiazole compound derivative represented by Formula 1 according to claim 1 as an active ingredient. Composition. The method of claim 7, wherein Pharmaceutical compositions for the treatment and prevention of inflammatory diseases associated with asthma and chronic obstructive pulmonary disease. A pharmaceutical composition for treating and preventing Alzheimer's, comprising a 4- (3,4-dialkoxyphenyl) -2-aminothiazole compound derivative represented by Formula 1 as an active ingredient. The method of claim 1, R ₁ is a straight chain saturated or unsaturated or of crushing (C ₁ - C ₇₎ of a saturated straight or branched chain optionally substituted by alkyl or halogen, or an unsaturated (C ₁ - C ₇₎ alkyl; R ₂ is straight or branched saturated or unsaturated (C ₁ -C ₇ ) alkyl, substituted by halogen straight or branched saturated or unsaturated (C ₁ -C ₇ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, ( C ₄ -C ₁₀ ) cycloalkyl (C ₁ -C ₇ ) alkyl group or allyl group; R ₃ is hydrogen or phenyl; R ₄ is hydrogen; Ar is

or

Is; X may be the same or different from each other, and hydroxy, hydroxy (C ₁ -C ₆ ) alkyl, amino (C ₁ -C ₇ ) alkyl, mono- or di (C ₁ -C ₇ ) alkylamino (C ₁ C ₇ ) alkyl, chloro (Cl), fluorine (F), cyano, (C ₁ -C ₇ ) alkylsulfonamino, N-alkoxycarbonylaminoacetate, N-benzyloxycarbonylaminoacetate, mono or di (C ₁ -C ₇ ) alkylaminocarbonyl, (C ₁ -C ₇ ) alkylcarbonyl, (C ₁ -C ₇ ) alkylcarboxylate or (C ₁ -C ₇ ) alkoxy (C ₁ -C ₄ ) Alkylcarboxylates; n is an integer of 0 to 3 4- (3,4-dialkoxyphenyl) -2-aminothiazole compound or a pharmaceutically acceptable salt thereof.