KR100838692B1 - 7-(3',4'-dialkoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine compounds, process for preparing thereof, and pharmaceutical composition for treating or preventing asthma, chronic obstructive pulmonary disease, arthritis, atopic dermatitis, tumor and degenerative brain diseases comprising the same - Google Patents

Abstract

A novel 7-(3',4'-dialkoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine compound is provided to show excellent inhibitory activity and high enzyme selectivity on PDE-4 enzyme, thereby being used in order to prevent and treat inflammation related diseases, arthritis, atopic dermatitis, tumor, and brain diseases. A 7-(3',4'-dialkoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine compound is represented by a formula(1), wherein each R1 and R2 is independently H, linear or branched saturated or unsaturated C1-7 alkyl, linear or branched saturated or unsaturated C1-7 alkyl including O, N or S, C3-7 cycloalkyl, C3-7 cycloalkyl including O, N or S, (C3-7)cycloalkyl(C1-7)alkyl, 3 to 7-membered saturated or unsaturated heterocycloalkyl including O, N or S in a hetero-ring, phenyl or benzyl, or R1 and R2 may be linked to each other by C1-3 alkylene or C1-3 alkylene including halogen; each R3 and R4 is independently H, formyl, halogen, linear or branched saturated or unsaturated C1-7 alkyl. C1-7 alkoxy, C3-7 cycloalkyl, (C1-7)alkoxy(C1-7)alkyl, C1-7 alkyl ketone, hydroxy(C1-7)alkyl, (C3-7)cycloalkyl(C1-7)alkyl, (C3-7)cycloalkyl(C1-7)alkoxy, C1-7 alkyl carboxyl, carboxy(C1-10)alkylester, carboxyl(C1-10)alkylamide, amino, mono or di(C1-7)alkylamino, mono or di(C1-7)alkylaminocarbonyl, (C3-7)cycloalkylamino, morpholine, morpholine oxide, thio- morpholine, piperidine, piperazine, piperazine oxide, piperidine, piperidine oxide, pyrrolidine, cyano, nitro, carboxyl, guanidine, urea, phenoxy, benzyloxy or aryl represented by Ar; and R5 is H, linear or branched saturated or unsaturated C1-7 alkyl, C3-7 cycloalkyl, (C1-7)alkoxy(C1-7)alkyl, (C3-7)cycloalkyl(C1-7)alkyl, (C3-7)cycloalkyl(C1-7)alkoxy, mono or di(C1-7)alkylamino, carbonyl, cyano, C1-7 alkoxycarbonyl, aminocarbonyl, C1-7 alkylcarbonyl, (C6-10)ar(C1-7)alkylcarbonyl or C6-10 arylcarbonyl. A method for preparing the compound of the formula(1) comprises the steps of: (a) after reacting a 3-amino-5-substituted pyrazole compound represented by a formula(4) with a 3-(dimethylamino)-1-(3,4-dialkoxyphenyl)prophenone compound represented by a formula(5) or a 3-(3,4-dialkoxyphenyl)cinnamic aldehyde compound represented by a formula(6) in the presence of an acetic acid, reducing a reaction producing with NaBH4 to prepare a compound represented by the formula(1); and (b) subjecting the compound of a formula(10) to nucleophilic substitution. A pharmaceutical composition for treating or preventing asthma, chronic obstructive pulmonary disease, arthritis, atopic dermatitis, tumor and degenerative brain diseases comprises the compound of the formula(1) or a pharmaceutically acceptable salt thereof.

Description

7- (3 ', 4'-dialkoxyphenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidine compound, preparation method thereof and asthma and chronic obstructive pulmonary disease comprising the same Pharmaceutical composition for the treatment and prevention of inflammation-related diseases, including arthritis, atopic dermatitis, cancer and brain diseases, including: {7- (3 ', 4'-dialkoxyphenyl) -4,5,6,7-tetrahydropyrazolo [1,5 -a] pyrimidine Compounds, Process For Preparing Thereof, And Pharmaceutical Composition For Treating Or Preventing Asthma, Chronic Obstructive Pulmonary Disease, Arthritis, Atopic Dermatitis, Tumor And Degenerative Brain Diseases Comprising The Same}

The present invention provides a novel 7- (3 ′, 4′-dialkoxyphenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidine compound or a pharmaceutically acceptable salt thereof, Methods for the preparation and treatment of inflammation-related diseases including asthma and chronic obstructive pulmonary diseases, arthritis, atopic dermatitis, cancers including leukemia and Alzheimer's, depression or memory, including as an active ingredient And pharmaceutical compositions for prevention.

PDE-4 inhibitors on which the present invention is based, various compounds have been studied for the development of treatment for asthma and chronic obstructive pulmonary disease [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]. 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 is a compound that has ceased development as an asthma treatment agent due to the low therapeutic effect on asthma and clinical trials for Chronic 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) has a high PDE-4 inhibitory effect (IC ₅₀ = 0.8 nM) and has been shown to be effective against asthma and COPD in animal studies (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 license for asthma was canceled in 2005 in Europe.

PDE-4 inhibitors treat arthritis in addition to the inflammatory-related lung diseases such as asthma and chronic obstructive pulmonary disease (USP 2003/0092706 A1), atopic dermatitis, leukemia, various cancers (Miles D. Houslay, Peter Schafer and Kam YJ Zhang, Drug Discovery Today , 2005 , 10 (22), 1503-1519) and depression treatment (USP 4,178,449, 11 December 1979), Alzheimer's and other brain diseases treatment effects (Sophie L. Rovner, C & EN , 38, 2005 February 21, is also known.

7- (3 ′, 4′-dialkoxyphenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidine derivatives similar to the compounds of formula 1 to be provided herein are No synthesis has been reported and 7- (3 ′, 4′-alkoxyphenyl) -4 has been reported in the field of prevention and treatment of various cancers and brain diseases including asthma and chronic obstructive pulmonary disease, arthritis, atopic dermatitis, leukemia. The application of, 5,6,7-tetrahydropyrazolo [1,5-a] pyrimidine compounds has not been studied at all.

Accordingly, the present inventors have shown excellent in vitro and in vivo effects for the development of therapeutic agents for inflammation-related diseases, arthritis, atopic dermatitis, cancer and brain diseases, including asthma and chronic obstructive pulmonary disease, based on PDE-4 inhibition. New 7- (3 ′, 4′-dialkoxyphenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidine to overcome related side effects such as vomiting and headaches Compounds were prepared, and the compounds according to the present invention showed excellent inhibitory activity and high enzyme selectivity against PDE-4 enzyme as a result of biochemical and pharmacological tests.

Accordingly, an object of the present invention is to provide a novel 7- (3 ′, 4′-dialkoxyphenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidine compound and its pharmaceutically To provide an acceptable salt, as another object a novel 7- (3 ', 4'- dialkoxyphenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a ] Methods for preparing pyrimidine compounds and inflammation-related diseases including asthma and chronic obstructive pulmonary diseases containing them as an active ingredient, arthritis, atopic dermatitis, cancer and Alzheimer's including leukemia, depression or memory loss, etc. It provides a pharmaceutical composition for the treatment and prevention of brain diseases.

The present invention provides a novel 7- (3 ′, 4′-dialkoxyphenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidine compound represented by the following general formula (1) Pharmaceutically acceptable salts, preparation methods thereof, and inflammation-related diseases including asthma and chronic obstructive pulmonary diseases, comprising arthritis, atopic dermatitis, and leukemia, including Alzheimer's disease It relates to a pharmaceutical composition for the treatment and prevention of brain diseases such as depression, memory loss or memory.

[Formula 1]

[In Formula 1,

R ₁ and R ₂ may be the same as or different from each other, and independently from each other, a saturated or unsaturated (C ₁ -C ₇ ) alkyl, oxygen, nitrogen or sulfur saturated or unsaturated saturated or unsaturated (C ₁ -C ₇ ) alkyl ₁ -C ₇ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, ₃ -membered containing (C ₃ -C ₇ ) cycloalkyl containing oxygen, nitrogen or sulfur, (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₇ ) alkyl, oxygen, nitrogen or sulfur in the heterocycle 3- to 7-membered saturated or unsaturated heterocycloalkyl (C ₁ -C ₇ ) alkyl, phenyl or benzyl containing from 7 to 7 membered saturated or unsaturated heterocycloalkyl, oxygen, nitrogen or sulfur in the heterocycle, or R ₁ and R ₂ are (C ₁ - C ₃₎ comprises an alkylene, or a halogen (C ₁ - C ₃₎ can be coupled to the alkylene and;

R ₃ and R ₄ independently of one another are hydrogen, formyl, halogen, straight or branched saturated or unsaturated (C ₁ -C ₇ ) alkyl, (C ₁ -C ₇ ) alkoxy, (C ₃ -C ₇ ) cycloalkyl , (C ₁ -C ₇ ) alkoxy (C ₁ -C ₇ ) alkyl, (C ₁ -C ₇ ) alkylketone, hydroxy (C ₁ -C ₇ ) alkyl, (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₇ ) alkyl, (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₇ ) alkoxy, (C ₁ -C ₇ ) alkylcarboxylic acid, carboxyl (C ₁ -C ₁₀ ) alkylester, car Compound (C ₁ -C ₁₀ ) alkylamides, amino, mono or di (C ₁ -C ₇ ) alkylamino, mono or di (C ₁ -C ₇ ) alkylaminocarbonyl, (C ₃ -C ₇ ) cycloalkyl Amino, morpholine, morpholine oxide, thiomorpholine, piperidine, piperazine, piperazine oxide, piperidine, piperidine oxide, pyrrolidine, cyano, nitro, carboxylic acid, guanidine, Aryl groups represented by urea, phenoxy, benzyloxy or Ar below;

A is N or NO; B is CH or N; D is CH or N; E is S, O or NH; F is CH or N; G is CH or N; H is S, O or NH; I is CH or N; J is CH, N or NO;

m and n independently of each other represent an integer of 0 to 4;

X may be the same or different from each other, and independently from each other, straight or branched saturated or unsaturated (C ₁ -C ₇ ) alkyl, (C ₁ -C ₇ ) alkoxy, (C ₁ -C ₇ ) alkylthio, thiol, (C ₆ -C ₁₀ ) arylthio, (C ₆ -C ₁₀ ) ar (C ₁ -C ₇ ) alkyloxy, (C ₁ -C ₇ ) alkylsulfinyl, (C ₆ -C ₁₀ ) arylsulfinyl, (C ₁ -C ₇ ) alkylsulfonyl, (C ₆ -C ₁₀ ) arylsulfonyl, (C ₁ -C ₇ ) alkoxy (C ₁ -C ₇ ) alkyl, (C ₁ -C ₇ ) alkoxycarbonyl, (C ₁ -C ₇ ) alkoxycarbonyl (C ₁ -C ₇ ) alkoxy, (C ₁ -C ₇ ) alkoxycarbonyl (C ₁ -C ₇ ) alkylamino, (C ₁ -C ₇ ) alkoxycarbonyl ( C ₁ -C ₇ ) alkylaminocarbonyl, (C ₁ -C ₇ ) alkylcarbonyloxy, hydroxy, halogen, cyano, nitro, amino, mono or di (C ₁ -C ₇ ) alkylamino, mono or Di (C ₆ -C ₁₀ ) arylamino, mono or di (C ₁ -C ₇ ) alkylaminocarbonyl, mono or dibenzylamino, mono or di (C ₁ -C ₇ ) alkylamino (C ₁ -C ₇ ) Alkoxy, (C ₃ -C ₇ ) cycloalkylamino, (C ₁ -C ₇ ) alkylcarbonylamino, (C ₁ -C ₇ ) alkylsulfinylamino, (C ₁ -C ₇ ) alkylsulfonylamino, (C ₆ -C ₁₀ ) arylsulfinylamino, (C ₆ -C ₁₀ ) arylsulfonylamino, benzylsulfinylamino, benzylsulfonylamino, aminosulfonylamino, (C ₁ -C ₇ ) alkylaminosul 3- to 7-membered saturated or unsaturated heterocycloalkyl, morpholin, which comprises at least one of a phenylamino, a (C ₆ -C ₁₀ ) arylaminosulfonylamino, aminocarbonyl, oxygen, nitrogen or sulfur in a heterocycle, Mo morpholine oxide, piperazine, piperacillin jinok oxide, (C ₁ - C ₇₎ alkyl piperazine, (C ₁ - C ₇₎ alkyl piperacillin jinok oxide, guanidine, urea, hydrazine, (C ₁ - C ₇₎ Alkylhydrazine, di (C ₁ -C ₇ ) alkylhydrazine, (C ₆ -C ₁₀ ) arylhydrazine, benzylhydrazine, dibenzylhydrazine, hydroxylamine, (C ₁ -C ₇ ) alkylhydroxylamine, (C ₆ -C ₁₀ ) arylhydroxy Silamine, oxime, (C ₁ -C ₇ ) alkyl oxime, (C ₆ -C ₁₀ ) aryl oxime, (C ₁ -C ₇ ) alkylguanidine, urea, (C ₁ -C ₇ ) alkylurea, phenyl, phenoxy C, benzyl, benzyloxy, thiobenzyl, carboxylic acid, carboxyl (C ₁ -C ₇ ) alkylamino, carboxyl (C ₁ -C ₁₀ ) alkylaminocarbonyl, (C ₁ -C ₇ ) alkylcarbonyl , (C ₁ -C ₇ ) alkylketone or benzoyl;

을 나타내 며, R₅의 알킬, 알콕시 및 알킬카보닐은 할로겐이 더 치환될 수 있으며;R ₅ is hydrogen, straight or branched saturated or unsaturated (C ₁ -C ₇ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, (C ₁ -C ₇ ) alkoxy (C ₁ -C ₇ ) alkyl, (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₇ ) alkyl, (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₇ ) alkoxy, mono or di (C ₁ -C ₇ ) alkylaminocarbonyl, cya Furnace, (C ₁ -C ₇ ) alkoxycarbonyl, aminocarbonyl, (C ₁ -C ₇ ) alkylcarbonyl, (C ₆ -C ₁₀ ) ar (C ₁ -C ₇ ) alkylcarbonyl or (C ₆ C ₁₀ ) arylcarbonyl or

Alkyl, alkoxy and alkylcarbonyl of R ₅ may be further substituted by halogen;

R ₁₁ and R ₁₂ independently of one another represent hydrogen, (C ₁ -C ₇ ) alkyl, (C ₁ -C ₇ ) alkylcarbonyl or (C ₁ -C ₇ ) alkoxycarbonyl;

Provided that R ₁ , R ₂ , R ₃ , R ₄ and (C ₁ -C ₇ ) alkyl, (C ₁ -C ₇ ) alkoxy, (C ₃ -C ₇ ) cycloalkyl, (C ₃ -C ₇ ) Cycloalkyl (C ₁ -C ₇ ) alkyl, heterocycloalkyl, phenyl or benzyl is a (C ₁ -C ₇ ) alkoxy, halogen, nitro, cyano, hydroxy, amino, mono or di (C ₁ -C ₇ ) Alkylamino, (C ₁ -C ₁₀ ) alkoxycarbonyl, carboxyl (C ₁ -C ₁₀ ) alkylamide, guanidine, (C ₁ -C ₇ ) alkylguanidine, urea, (C ₁ -C ₇ ) alkylurea , (C ₁ -C ₇ ) alkylcarbonylamino or carboxylic acid.]

7- (3 ′, 4′-dialkoxyphenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidine compounds of formula 1 according to the present invention are novel compounds, It has excellent activity and selectivity against -4 enzymes such as inflammation-related diseases including asthma and chronic obstructive pulmonary disease, arthritis, atopic dermatitis, cancer and Alzheimer's including leukemia, depression or memory loss It is useful as a treatment and prevention of brain diseases

7- (3 ′, 4′-dialkoxyphenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidine compound represented by Formula 1 according to the present invention or a pharmaceutical thereof Specific examples of the salts that are acceptable as R ₁ and R ₂ may be the same or different from each other, and independently from each other hydrogen, straight or crushed, saturated or unsaturated (C ₁ -C ₇ ) alkyl, straight or crushed containing halogen Unsaturated (C ₁ -C ₇ ) alkyl, (C ₃ -C ₇ ) cycloalkyl or It is characterized by being substituted with (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₇ ) alkyl.

Preferred compounds represented by the formula (1) according to the present invention include R ₁ is R ₁ is straight or branched or saturated (C ₁ -C ₇ ) alkyl or halogen containing straight chain or branched unsaturated (C ₁ -C ₇ ) alkyl; R ₂ is straight or branched saturated or unsaturated (C ₁ -C ₇ ) alkyl, cyclopropyl, cyclopentyl or cyclopropylmethyl; R ₃ and R ₄ are each independently an aryl group selected from the following structures:

을 나타내며, R₅의 알킬, 알콕시 및 알킬카보닐은 할로겐이 더 치환될 수 있으며; R₁₁ 및 R₁₂는 서로 독립적으로 수소, (C₁ - C₇)알킬, (C₁ - C₇)알킬카보닐 또는 (C₁ - C₇)알콕시카보닐인 화합물이다.A is N or NO; X is straight chain or branched saturated or unsaturated (C ₁ -C ₇ ) alkyl, straight chain or branched unsaturated (C ₁ -C ₇ ) alkyl including halogen, (C ₁ -C ₇ ) alkoxy, (C ₁ -C ₇ ) alkylthio, (C ₆ -C ₁₀ ) ar (C ₁ -C ₇ ) alkyloxy, (C ₁ -C ₇ ) alkoxycarbonyl, (C ₁ -C ₇ ) alkylcarbonyloxy, hydroxy, halogen , Cyano, nitro, mono or di (C ₁ -C ₇ ) alkyl aminocarbonyl, (C ₁ -C ₇ ) alkylcarbonylamino, aminocarbonyl, phenyl, phenoxy, benzyl, benzyloxy, thiobenzyl or Carboxylic acid; m and n are independently of each other an integer from 0 to 3; R ₅ is hydrogen, straight or branched saturated or unsaturated (C ₁ -C ₇ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, (C ₁ -C ₇ ) alkoxy (C ₁ -C ₇ ) alkyl, (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₇ ) alkyl, (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₇ ) alkoxy, mono or di (C ₁ -C ₇ ) alkylaminocarbonyl, cya Furnace, (C ₁ -C ₇ ) alkoxycarbonyl, aminocarbonyl, (C ₁ -C ₇ ) alkylcarbonyl, (C ₆ -C ₁₀ ) ar (C ₁ -C ₇ ) alkylcarbonyl, (C ₆ C ₁₀ ) arylcarbonyl or

Alkyl, alkoxy and alkylcarbonyl of R ₅ may be further substituted by halogen; R ₁₁ and R ₁₂ are independently of each other hydrogen, (C ₁ -C ₇ ) alkyl, (C ₁ -C ₇ ) alkylcarbonyl or (C ₁ -C ₇ ) alkoxycarbonyl.

Particularly preferred ranges of compounds include compounds represented by the following formula (2).

[Formula 2]

[Wherein, R ₃ And R ₄ are independently of each other an aryl group selected from the following structures:

A is N or NO;

m and n independently of each other represent an integer of 0 to 3;

X may be the same or different from each other, and independently from each other, straight or branched saturated or unsaturated (C ₁ -C ₇ ) alkyl, linear or branched unsaturated (C ₁ -C ₇ ) alkyl including halogen, (C ₁ -C ₇ ) alkoxy, (C ₁ -C ₇ ) alkylthio, (C ₁ -C ₇ ) alkoxycarbonyl, (C ₁ -C ₇ ) alkylcarbonyloxy, (C ₆ -C ₁₀ ) ar (C ₁ C ₇ ) alkyloxy, halogen, cyano, nitro, hydroxy, amino, aminocarbonyl or carboxylic acid;

을 나타내며, R₅의 알킬, 알콕시 및 알킬카보닐은 할로겐이 더 치환될 수 있으며; R₁₁ 및 R₁₂는 서로 독립적으로 수소, (C₁ - C₇)알킬, (C₁ - C₇)알킬카보닐 또는 (C₁ - C₇)알콕시카보닐이다.]R ₅ is hydrogen, straight or branched saturated or unsaturated (C ₁ -C ₇ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, (C ₁ -C ₇ ) alkoxy (C ₁ -C ₇ ) alkyl, (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₇ ) alkyl, (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₇ ) alkoxy, mono or di (C ₁ -C ₇ ) alkylaminocarbonyl, cya Furnace, (C ₁ -C ₇ ) alkoxycarbonyl, aminocarbonyl, (C ₁ -C ₇ ) alkylcarbonyl, (C ₆ -C ₁₀ ) ar (C ₁ -C ₇ ) alkylcarbonyl, (C ₆ C ₁₀ ) arylcarbonyl or

Alkyl, alkoxy and alkylcarbonyl of R ₅ may be further substituted by halogen; R ₁₁ and R ₁₂ independently of one another are hydrogen, (C ₁ -C ₇ ) alkyl, (C ₁ -C ₇ ) alkylcarbonyl or (C ₁ -C ₇ ) alkoxycarbonyl.]

Most preferred compounds according to the present invention is a compound of Formula 2 R ₃ and R ₄ are independently of each other As an aryl group chosen from the following structures,

A is N or NO;

m and n independently of each other represent an integer of 0 or 1;

X may be the same or different from each other, and independently from each other (C ₁ -C ₇ ) alkoxy, hydroxy, (C ₁ -C ₇ ) alkoxycarbonyl, (C ₁ -C ₇ ) alkylcarbonyloxy or (C ₆ -C ₁₀ ) ar (C ₁ -C ₇ ) alkyloxy;

을 나타내며, R₅의 알킬, 알콕시 및 알킬카보닐은 할로겐이 더 치환될 수 있으며; R₁₁ 및 R₁₂는 서로 독립적으로 수소, (C₁ - C₇)알킬, (C₁ - C₇)알킬카보닐 또는 (C₁ - C₇)알콕시카보닐인 경우이다.R ₅ is hydrogen, straight or branched saturated or unsaturated (C ₁ -C ₇ ) alkyl, cyano, (C ₁ -C ₇ ) alkoxycarbonyl, aminocarbonyl, (C ₁ -C ₇ ) alkylcarbonyl or

Alkyl, alkoxy and alkylcarbonyl of R ₅ may be further substituted by halogen; R ₁₁ and R ₁₂ are each independently hydrogen, (C ₁ -C ₇ ) alkyl, (C ₁ -C ₇ ) alkylcarbonyl or (C ₁ -C ₇ ) alkoxycarbonyl.

Representative compounds of Formula 1 include the following compounds.

Scheme 1 is illustrated as a method of preparing the compound of Formula 1 according to the present invention, and the following preparation method does not limit the method of preparing the compound of Formula 1 according to the present invention. It will be apparent to and unless defined otherwise, the definitions of substituents in the following schemes are the same as in Formula 1.

As shown in Scheme 1, 3-amino-5-substituted pyrazole compound (4) and 3- (dimethylamino) -1- (3,4-dialkoxyphenyl) propenone compound (5) were acetic acid In the presence of the compound to prepare 7- (3,4-dialkoxyphenyl) -pyrazolo [1,5-a] pyrimidine compound represented by the formula (9) or 3-amino-5-substituted pyrazole compound (4) Is reacted with 3- (3,4-dialkoxyphenyl) cinnaaldehyde compound (6) in the presence of an acetic acid or other solvent and a base to give 7- (3,4-dialkoxyphenyl) -pyrazolo [ 1,5-a] pyrimidine compounds can be prepared. In this case, Y represents halogen or alkoxy. The 7- (3,4-dialkoxyphenyl) -pyrazolo [1,5-a] pyrimidine compound (9) prepared above was reduced to NaBH ₄ or the like in a solvent such as alcohol to give tetrahydropyrazolo [10]. 1,5-a] pyrimidine compound was prepared, and various substituents were substituted by nucleophilic substitution reaction in the amine group of tetrahydropyrazolo [1,5-a] pyrimidine compound (10) to 7- (3 ′, 4′-dialkoxyphenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidine compounds may be prepared.

Scheme 1

[In the formula, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are the same as defined in Formula 1.]

7 represented by the formula (1) according to the present invention from 3-amino-5-substituted pyrazole compound (4) and 3- (dimethylamino) -1- (3,4-dialkoxyphenyl) propenone compound (5) In preparing-(3 ', 4'-dialkoxyphenyl)-[1,2,4] triazolo [1,5-a] pyrimidine compounds, bases and alcohols such as piperidine may be used (KM Al-Zaydi, MAA Al-Shiekh, EAA Hafez, J. Chem.Res.Synop, 2000 , 1 , 13-15.EI Al-Afaleq, Synth Commun, 2000 , 30 (11), 1985-1999), acetic acid It is more preferable to use it as a solvent.

3-amino-5-substituted pyrazole compound (4), which is a substance used for preparing the compound of Formula 1, is prepared by reacting α -cyanomethylphenylketone compound (7) with hydrazine, as shown in Scheme 2. The aminopropene compound (5) can be prepared by reacting the catechol ketone compound (8) with an acetal of dimethylformamide. In addition, 6a, which is a representative compound of Compound 6, may be prepared by using POCl ₃ / DMF in Compound 8, and Compound 6b may be obtained by substituting alcohol for Compound 6a.

Scheme 2

In the step of preparing the 3-amino-5-substituted pyrazole compound (4) from the α -cyanomethylphenyl ketone compound (7) and hydrazine, alcohol is mainly used as the solvent, and the catechol ketone compound (8) and The reaction for preparing the aminopropene compound (5) from the acetal of dimethylformamide can be synthesized by similar methods as known in the literature (F. Al-Omran, N. Al-Awadhi, MM Abdel Khalik, K. Kaul). , AA El-Khair, and MH Elnadgi, J. Chem. Res , Synop , 1997 , 3 , 84-85 ), where DMF-acetal is a reactant and a solvent.

In addition, the α -cyanomethylphenyl ketone compound (7) may be prepared according to the method exemplified in British Patent Publication No. 2,127,410, but is not limited thereto, and may be synthesized by other methods.

7- (3 ′, 4′-dialkoxyphenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidine compounds represented by Formula 1 prepared according to the present invention are biochemical As a result of the pharmacological test, side effects such as vomiting are expected to be insignificant due to excellent inhibitory activity and high selectivity for PDE-4 enzyme and low HARBS affinity.

The compound represented by Formula 1 according to the present invention is an inflammation-related disease including bronchial asthma and chronic obstructive pulmonary disease, arthritis, atopic dermatitis, cancer treatment agents including leukemia and Alzheimer's, depression or memory reduction, etc. Suitable for use as a pharmaceutical composition for the treatment and prevention of diseases, the compound of formula 1 may include those formed with both organic and inorganic acids or bases as salts of the compound of formula 1 suitable for use in medicine. 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-methoxycin Methyl, methoxy, halogen, or phenyl substituted cinnamic acid, including namic acid and α-phenyl cinnamic acid), ascorbic acid, oleic acid, naphthoic acid, hydroxynaphthoic acid (eg, 1- or 3-hydroxy- 2-naphthoic acid), naphthalate Leneacrylic 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. In addition, certain compounds are expected to show 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 disorder or condition to be treated, may be oral, intravenous or inhaled. Can be.

It is possible to administer the compound of formula 1 according to the invention 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 7- (3 ′, 4′-dialkoxyphenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidine compound according to the present invention is a novel compound having a new chemical structure As such, it has good activity for PDE-4 enzymes and high selectivity for other PDE enzymes. Therefore, it can be used as a therapeutic agent for inflammation-related diseases including asthma and chronic obstructive pulmonary disease, as well as vomiting-related side effects, which are the most serious problems of PDE-4 inhibitors, are greatly improved, and inflammation including asthma and chronic obstructive pulmonary diseases. In addition to related diseases, it can be used as a preventive and therapeutic agent for brain diseases such as arthritis, atopic dermatitis, leukemia and cancers including Alzheimer's disease, depression or memory based on PDE-4 inhibition.

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.

[Production Example 1]

Preparation of the compound of formula 9 by reaction of 3-amino-5-substituted pyrazole compound (4) with 3- (dimethylamino) -1- (3,4-dialkoxyphenyl) propenone compound (5)

1.31 mmol of 3-amino-5-substituted pyrazole compound (4) and 3- (dimethylamino) -1- (3,4-diakoxyphenyl) propenone compound (3- (dimethylamino) -1- ( 1.31 mmol of 3,4-dialkoxy phenyl) prop-2-en-1-one) (5) was added thereto, followed by stirring at room temperature. NaHCO ₃ saturated aqueous solution was added to the reaction solution, extracted three times with ethyl acetate, and the organic layer was washed twice with brine. After drying over MgSO ₄ , the solvent was removed under reduced pressure. The organic layer was dried over MgSO _4, and then the solvent was removed under reduced pressure. The mixture was separated by silica gel column chromatography to obtain the target compound of formula (9).

[Production Example 2]

Preparation of the compound of formula 9 by reaction of 3-amino-5-substituted pyrazole compound (4) with 3- (3,4-dialkoxyphenyl) cinnamaldehyde compound (6)

1.31 mmol of 3-amino-5-substituted pyrazole compound (4) and 3- (3,4-dialkoxyphenyl) cinnamaldehyde (3- (3,4-dialkoxyphenyl) cinnamic aldehyde) compound (6) 1.31 After adding mmol, the mixture was stirred at room temperature. NaHCO ₃ saturated aqueous solution was added to the reaction solution, extracted three times with ethyl acetate, and the organic layer was washed twice with brine. After drying over MgSO ₄ , the solvent was removed under reduced pressure. The organic layer was dried over MgSO _4, and then the solvent was removed under reduced pressure. The mixture was separated by silica gel column chromatography to obtain the target compound of formula (9).

[ Example Representative Method of Preparation of Compound of Formula 1

After dissolving 0.73 mmol of 7- (3 ′, 4′-diakoxyphenyl) -pyrazolo [1,5-a] pyrimidine compound (9) in dichloromethane, methanol was added and NaBH ₄ 3.7 mmol was added slowly, followed by room temperature. After stirring for an appropriate period of time and warmed to reflux to obtain a compound of formula (10). After substituting various substituents through the nucleophilic substitution reaction of the amine group of the compound of Formula 10, saturated aqueous NH ₄ Cl solution was added to the reaction solution, extracted three times with ethyl acetate, and the organic layer was washed twice with brine. After drying over MgSO ₄ , the solvent was removed under reduced pressure. The mixture was separated by silica gel column chromatography to obtain the target compound of formula (1). The structure of each compound of Formula 1 and ¹ H NMR are shown in Table 1 below.

[Production Example 1]

7- (3- ( cyclopropylmethoxy )-4-( difluoromethoxy ) phenyl )-2-( pyridin -3- yl ) Preparation of pyrazolo [1,5-a] pyrimidine

Dissolve 1- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -3- (dimethylamino) prop-2-en-1-one (0.54 g, 1.31 mmol) in acetic acid and 3-amino-5-pyridin -3-yl-2H-pyrazole (0.21 g, 1.31 mmol) was added thereto, followed by stirring at room temperature for 12 hours. Saturated NaHCO ₃ (aq) was added to the reaction solution, which was extracted three times with ethyl acetate and washed twice with brine. After drying over MgSO ₄ , the solvent was removed under reduced pressure. The mixture was separated by column chromatography (methylene chloride / methanol, 100/1) to give the title compound 7- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -2- (pyridin-3-yl) pyrazolo [1 , 5-a] pyrimidine (0.19 g, 36.2%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.19 (1H, s, Ar), 8.61 (1H, m, Ar), 8.49 (1H, m, Ar), 8.20 (1H, m, Ar), 8.00 (1H , m, Ar), 7.60 (1H, m, Ar), 7.33 (2H, m, Ar), 7.08 (1H, m, Ar), 6.91 (1H, m, Ar), 6.79 (1H, t, J = 75 Hz, -CHF ₂ ), 4.00 (2H, d, J = 6.90 Hz, -OCH _2- ), 1.39 (1H, m, -CH-), 0.68 (2H, q, J = 6.22 Hz, -CH ₂ 0.40 (2H, q, J = 5.04 Hz, -CH _2- ).

[ Example  One]

7- (3- ( cyclopropylmethoxy )-4-( difluoromethoxy ) phenyl ) -4,5,6,7- tetrahydro  Preparation of 2- (pyridin-3-yl) pyrazolo [1,5-a] pyrimidine (Compound 103)

7- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -2- (pyridin-3-yl) pyrazolo [1,5-a] pyrimidine (0.3 g, 0.73 mmol) obtained in Preparation Example 1 was diluted with dichloromethane 0.5. It was dissolved in ml and then added to 5 ml of methanol. NaBH ₄ (0.14 g, 3.7 mmol) was slowly added thereto, stirred at room temperature for 2 hours, and warmed to reflux for 24 hours. Saturated NH ₄ Cl (aq) was added to the reaction mixture, which was extracted three times with ethyl acetate and washed twice with brine. After drying over MgSO ₄ , the solvent was removed under reduced pressure. The mixture was separated by column chromatography (methylene chloride / methanol, 50/1), and the title compound 7- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4,5,6,7-tetrahydro-2- (pyridin-3-yl) pyrazolo [1,5-a] pyrimidine (Compound 103) (0.16 g, 53.3%) was obtained.

Example 2

ethyl  7- (3- ( cyclopropylmethoxy )-4-( difluoromethoxy ) phenyl ) -6,7- dihydro -2-( pyridin Preparation of -3-yl) pyrazolo [1,5-a] pyrimidine-4 (5H) -carboxylate (Compound 104)

7- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4,5,6,7-tetrahydro-2- (pyridin-3-yl) pyrazolo [1,5-a] prepared in Example 1 Pyrimidine (Compound 103) (20 mg, 0.048 mmol) was dissolved in 5 ml of acetone and K ₂ CO ₃ (40 mg, 0.29 mmol) was added. Ethyl chloroformate (21 mg, 0.19 mmol) was slowly added while stirring the reaction solution, and the mixture was refluxed for 24 hours. Saturated NaHCO ₃ (aq) was added to the reaction solution, which was extracted three times with ethyl acetate and washed twice with brine. After drying over MgSO ₄ , the solvent was removed under reduced pressure. The mixture was separated by column chromatography (methylene chloride / methanol, 100/1), and the title compound ethyl 7- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -6,7-dihydro-2- (pyridin- 3-yl) pyrazolo [1,5-a] pyrimidine-4 (5H) -carboxylate (Compound 104) (21 mg, 89.5%) was obtained.

[ Example  3]

3- [7- (3- ( cyclopropylmethoxy )-4-( difluoromethoxy ) phenyl ) -4,5,6,7- tetrahydro -4-( ethoxycarbonyl )- pyrazolo [1,5-a] pyrimidine-2- yl ]- pyridine Preparation of -N-oxide (Compound 106)

Ethyl 7- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -6,7-dihydro-2- (pyridin-3-yl) pyrazolo [1,5-a] pyrimidine- prepared in Example 2 4 (5H) -carboxylate (Compound 104) (3.3 mg, 0.007 mmol) was dissolved in 0.5 ml of dichloromethane, and 60% mcpba (3.8 mg, 0.014 mmol) was slowly added thereto, followed by stirring for 1 hour. Saturated NaHCO ₃ (aq) was added to the reaction solution, which was extracted three times with ethyl acetate and washed twice with brine. After drying over MgSO ₄ , the solvent was removed under reduced pressure. The mixture was separated by column chromatography (methylene chloride / methanol, 20/1) to obtain the title compound 3- [7- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -4,5,6,7-tetrahydro 4- (ethoxycarbonyl) -pyrazolo [1,5-a] pyrimidine-2-yl] -pyridine-N-oxide (Compound 106) (2.3 mg, 69%) was obtained.

TABLE 1

Inhibition of PDE-4 Activity

Inhibitory 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 the above examples. Each compound was added at a concentration of 1-50 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 for the PDE-4 enzymes of the compounds are shown in Table 2 below.

TABLE 2

The IC ₅₀ values for the PDE-4 enzymes of the compounds according to the invention were mostly in the level of 0.028 to 0.240 μM, in particular for the compound 103 showed an IC ₅₀ value of 0.028 μM, and for the compounds 117 and 119 respectively 0.041 And an IC ₅₀ value of 0.048 μM.

Claims (9)

Novel 7- (3 ′, 4′-dialkoxyphenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidine compounds represented by Formula 1 below or their pharmaceutically acceptable Salt. [Formula 1]

[In Formula 1, R ₁ and R ₂ may be the same as or different from each other, and independently from each other, a saturated or unsaturated (C ₁ -C ₇ ) alkyl, oxygen, nitrogen or sulfur saturated or unsaturated saturated or unsaturated (C ₁ -C ₇ ) alkyl ₁ -C ₇ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, ₃ -membered to include (C ₃ -C ₇ ) cycloalkyl containing oxygen, nitrogen or sulfur, (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₇ ) alkyl, oxygen, nitrogen or sulfur in the heterocycle 3- to 7-membered saturated or unsaturated heterocycloalkyl (C ₁ -C ₇ ) alkyl, phenyl or benzyl containing 7 membered saturated or unsaturated heterocycloalkyl, oxygen, nitrogen or sulfur in the heterocycle, or R ₁ and R ₂ is (C ₁ - C ₃₎ comprises an alkylene, or a halogen (C ₁ - C ₃₎ can be coupled to the alkylene and; R ₃ and R ₄ independently of one another are hydrogen, formyl, halogen, straight or branched saturated or unsaturated (C ₁ -C ₇ ) alkyl, (C ₁ -C ₇ ) alkoxy, (C ₃ -C ₇ ) cycloalkyl , (C ₁ -C ₇ ) alkoxy (C ₁ -C ₇ ) alkyl, (C ₁ -C ₇ ) alkylketone, hydroxy (C ₁ -C ₇ ) alkyl, (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₇ ) alkyl, (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₇ ) alkoxy, (C ₁ -C ₇ ) alkylcarboxylic acid, carboxyl (C ₁ -C ₁₀ ) alkylester, car Compound (C ₁ -C ₁₀ ) alkylamides, amino, mono or di (C ₁ -C ₇ ) alkylamino, mono or di (C ₁ -C ₇ ) alkylaminocarbonyl, (C ₃ -C ₇ ) cycloalkyl Amino, morpholine, morpholine oxide, thiomorpholine, piperidine, piperazine, piperazine oxide, piperidine, piperidine oxide, pyrrolidine, cyano, nitro, carboxylic acid, guanidine, Aryl groups represented by urea, phenoxy, benzyloxy or Ar below;

A is N or NO; B is CH or N; D is CH or N; E is S, O or NH; F is CH or N; G is CH or N; H is S, O or NH; I is CH or N; J is CH, N or NO; m and n independently of each other represent an integer of 0 to 4; X may be the same or different from each other, and independently from each other, straight or branched saturated or unsaturated (C ₁ -C ₇ ) alkyl, (C ₁ -C ₇ ) alkoxy, (C ₁ -C ₇ ) alkylthio, thiol, (C ₆ -C ₁₀ ) arylthio, (C ₆ -C ₁₀ ) ar (C ₁ -C ₇ ) alkyloxy, (C ₁ -C ₇ ) alkylsulfinyl, (C ₆ -C ₁₀ ) arylsulfinyl, (C ₁ -C ₇ ) alkylsulfonyl, (C ₆ -C ₁₀ ) arylsulfonyl, (C ₁ -C ₇ ) alkoxy (C ₁ -C ₇ ) alkyl, (C ₁ -C ₇ ) alkoxycarbonyl, (C ₁ -C ₇ ) alkoxycarbonyl (C ₁ -C ₇ ) alkoxy, (C ₁ -C ₇ ) alkoxycarbonyl (C ₁ -C ₇ ) alkylamino, (C ₁ -C ₇ ) alkoxycarbonyl ( C ₁ -C ₇ ) alkylaminocarbonyl, (C ₁ -C ₇ ) alkylcarbonyloxy, hydroxy, halogen, cyano, nitro, amino, mono or di (C ₁ -C ₇ ) alkylamino, mono or Di (C ₆ -C ₁₀ ) arylamino, mono or di (C ₁ -C ₇ ) alkylaminocarbonyl, mono or dibenzylamino, mono or di (C ₁ -C ₇ ) alkylamino (C ₁ -C ₇ ) Alkoxy, (C ₃ -C ₇ ) cycloalkylamino, (C ₁ -C ₇ ) alkylcarbonylamino, (C ₁ -C ₇ ) alkylsulfinylamino, (C ₁ -C ₇ ) alkylsulfonylamino, (C ₆ -C ₁₀ ) arylsulfinylamino, (C ₆ -C ₁₀ ) arylsulfonylamino, benzylsulfinylamino, benzylsulfonylamino, aminosulfonylamino, (C ₁ -C ₇ ) alkylaminosulfonyl 3- to 7-membered saturated or unsaturated heterocycloalkyl, morpholin, parent, containing one or more amino, (C ₆ -C ₁₀ ) arylaminosulfonylamino, aminocarbonyl, oxygen, nitrogen or sulfur in the heterocycle Foreign-oxide, piperazine, piperacillin jinok oxide, (C ₁ - C ₇₎ alkyl piperazine, (C ₁ - C ₇₎ alkyl piperacillin jinok oxide, guanidine, urea, hydrazine, (C ₁ - C ₇₎ alkyl Hydrazine, di (C ₁ -C ₇ ) alkylhydrazine, (C ₆ -C ₁₀ ) arylhydrazine, benzylhydrazine, dibenzylhydrazine, hydroxylamine, (C ₁ -C ₇ ) alkylhydroxylamine, (C _6- C ₁₀₎ aryl hydroxide Amine, oxime, (C ₁ - C ₇₎ alkyl-oxime, (C ₆ - C ₁₀₎ aryl oxime, (C ₁ - C ₇₎ alkyl guanidine, urea, (C ₁ - C ₇₎ alkyl urea, phenyl, phenoxy Benzyl, benzyloxy, thiobenzyl, carboxylic acid, carboxyl (C ₁ -C ₇ ) alkylamino, carboxyl (C ₁ -C ₁₀ ) alkylaminocarbonyl, (C ₁ -C ₇ ) alkylcarbonyl, (C ₁ -C ₇ ) alkylketone or benzoyl; R ₅ is hydrogen, straight or branched saturated or unsaturated (C ₁ -C ₇ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, (C ₁ -C ₇ ) alkoxy (C ₁ -C ₇ ) alkyl, (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₇ ) alkyl, (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₇ ) alkoxy, mono or di (C ₁ -C ₇ ) alkylaminocarbonyl, cya Furnace, (C ₁ -C ₇ ) alkoxycarbonyl, aminocarbonyl, (C ₁ -C ₇ ) alkylcarbonyl, (C ₆ -C ₁₀ ) ar (C ₁ -C ₇ ) alkylcarbonyl or (C ₆ C ₁₀ ) arylcarbonyl or

Alkyl, alkoxy and alkylcarbonyl of R ₅ may be further substituted by halogen; R ₁₁ and R ₁₂ independently of one another represent hydrogen, (C ₁ -C ₇ ) alkyl, (C ₁ -C ₇ ) alkylcarbonyl or (C ₁ -C ₇ ) alkoxycarbonyl; Provided that R ₁ , R ₂ , R ₃ , R ₄ and (C ₁ -C ₇ ) alkyl, (C ₁ -C ₇ ) alkoxy, (C ₃ -C ₇ ) cycloalkyl, (C ₃ -C ₇ ) Cycloalkyl (C ₁ -C ₇ ) alkyl, heterocycloalkyl, phenyl or benzyl is a (C ₁ -C ₇ ) alkoxy, halogen, nitro, cyano, hydroxy, amino, mono or di (C ₁ -C ₇ ) Alkylamino, (C ₁ -C ₁₀ ) alkoxycarbonyl, carboxyl (C ₁ -C ₁₀ ) alkylamide, guanidine, (C ₁ -C ₇ ) alkylguanidine, urea, (C ₁ -C ₇ ) alkylurea , (C ₁ -C ₇ ) alkylcarbonylamino or carboxylic acid.] The method of claim 1, R ₁ and R ₂ may be the same or different from each other, and independently from each other hydrogen or straight, or saturated or saturated (C ₁ -C ₇ ) alkyl, oxygen, nitrogen or sulfur, or saturated or straight chain or Unsaturated (C ₁ -C ₇ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, (C ₃ -C ₇ ) cycloalkyl containing oxygen, nitrogen or sulfur, (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₇ ) heterocycle of 3 to 7 membered saturated or unsaturated heterocycloalkyl, oxygen, nitrogen or sulfur containing alkyl, oxygen, nitrogen or sulfur in the heterocycle 3- to 7-membered saturated or unsaturated heterocycloalkyl (C ₁ -C ₇ ) alkyl, phenyl or benzyl, or R ₁ and R ₂ comprise (C ₁ -C ₃ ) alkylene or halogen May be linked with (C ₁ -C ₃ ) alkylene; R ₃ and R ₄ are each independently an aryl group selected from the following structures:

A is N or NO; m and n independently of each other represent an integer of 0 to 4; X may be the same or different from each other, and independently from each other, straight or branched, saturated or unsaturated (C ₁ -C ₇ ) alkyl, (C ₁ -C ₇ ) alkoxy, (C ₁ -C ₇ ) alkylthio, (C ₆ -C ₁₀ ) Ar (C ₁ -C ₇ ) alkyloxy, (C ₁ -C ₇ ) alkoxy (C ₁ -C ₇ ) alkyl, (C ₁ -C ₇ ) alkoxycarbonyl, (C ₁ -C ₇ ) Alkoxycarbonyl (C ₁ -C ₇ ) alkoxy, (C ₁ -C ₇ ) alkoxycarbonyl (C ₁ -C ₇ ) alkylamino, (C ₁ -C ₇ ) alkoxycarbonyl (C ₁ -C ₇ ) Alkylaminocarbonyl, (C ₁ -C ₇ ) alkylcarbonyloxy, hydroxy, halogen, cyano, nitro, amino, mono or di (C ₁ -C ₇ ) alkylamino, mono or di (C ₁ -C ₇ ) alkylaminocarbonyl, (C ₃ -C ₇ ) cycloalkylamino, (C ₁ -C ₇ ) alkylcarbonylamino, aminocarbonyl, morpholine, morpholine oxide, piperazine, piperazine oxide, guanidine, (C ₁ - C ₇₎ alkyl guanidine, urea, (C ₁ - C ₇₎ alkyl urea, phenyl, phenoxy, benzyl, benzyl When, benzyl thioether, carboxylic acid, a carboxylic acid (C ₁ - C ₇₎ alkylamino, (C ₁ - C ₇₎ alkyl represents a carbonyl or benzoyl; R ₅ is hydrogen, straight or branched saturated or unsaturated (C ₁ -C ₇ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, (C ₁ -C ₇ ) alkoxy (C ₁ -C ₇ ) alkyl, (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₇ ) alkyl, (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₇ ) alkoxy, mono or di (C ₁ -C ₇ ) alkylaminocarbonyl, cya Furnace, (C ₁ -C ₇ ) alkoxycarbonyl, aminocarbonyl, (C ₁ -C ₇ ) alkylcarbonyl, (C ₆ -C ₁₀ ) ar (C ₁ -C ₇ ) alkylcarbonyl or (C ₆ C ₁₀ ) arylcarbonyl or

Alkyl, alkoxy and alkylcarbonyl of R ₅ may be further substituted by halogen; R ₁₁ and R ₁₂ independently of one another represent hydrogen, (C ₁ -C ₇ ) alkyl, (C ₁ -C ₇ ) alkylcarbonyl or (C ₁ -C ₇ ) alkoxycarbonyl; Provided that R ₁ , R ₂ , R ₃ , R ₄ and (C ₁ -C ₇ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₇₎ 7- (3 ′, 4′-di), wherein alkyl, phenyl or benzyl may be substituted with (C ₁ -C ₇ ) alkoxy, halogen, nitro, cyano, hydroxy, amino or carboxylic acid Alkoxyphenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidine compound or a pharmaceutically acceptable salt thereof. The method of claim 2, R ₁ is straight or branched saturated or unsaturated (C ₁ -C ₇ ) alkyl or straight chain or branched unsaturated (C ₁ -C ₇ ) alkyl including halogen; R ₂ is straight or branched saturated or unsaturated (C ₁ -C ₇ ) alkyl, cyclopropyl, cyclopentyl or cyclopropylmethyl; R ₃ and R ₄ are each independently an aryl group selected from the following structures:

A is N or NO; X is straight chain or branched saturated or unsaturated (C ₁ -C ₇ ) alkyl, straight chain or branched unsaturated (C ₁ -C ₇ ) alkyl including halogen, (C ₁ -C ₇ ) alkoxy, (C ₁ -C ₇ ) alkylthio, (C ₆ -C ₁₀ ) ar (C ₁ -C ₇ ) alkyloxy, (C ₁ -C ₇ ) alkoxycarbonyl, (C ₁ -C ₇ ) alkylcarbonyloxy, hydroxy, halogen , Cyano, nitro, mono or di (C ₁ -C ₇ ) alkylaminocarbonyl, (C ₁ -C ₇ ) alkylcarbonylamino, aminocarbonyl, phenyl, phenoxy, benzyl, benzyloxy, thiobenzyl or Carboxylic acid; m and n are independently of each other an integer from 0 to 3; R ₅ is hydrogen, straight or branched saturated or unsaturated (C ₁ -C ₇ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, (C ₁ -C ₇ ) alkoxy (C ₁ -C ₇ ) alkyl, (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₇ ) alkyl, (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₇ ) alkoxy, mono or di (C ₁ -C ₇ ) alkylaminocarbonyl, c Ano, (C ₁ -C ₇ ) alkoxycarbonyl, aminocarbonyl, (C ₁ -C ₇ ) alkylcarbonyl, (C ₆ -C ₁₀ ) ar (C ₁ -C ₇ ) alkylcarbonyl, (C ₆ C ₁₀ ) arylcarbonyl or

Alkyl, alkoxy and alkylcarbonyl of R ₅ may be further substituted by halogen; R ₁₁ and R ₁₂ independently of one another represent hydrogen, (C ₁ -C ₇ ) alkyl, (C ₁ -C ₇ ) alkylcarbonyl or (C ₁ -C ₇ ) alkoxycarbonyl. 3 ′, 4′-dialkoxyphenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidine compound or a pharmaceutically acceptable salt thereof. The method of claim 2, 7- (3 ′, 4′-dialkoxyphenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidine compound or a pharmaceutical thereof, which is represented by the following Chemical Formula 2 Acceptable salts. [Formula 2]

[Wherein, R ₃ and R ₄ are each independently an aryl group selected from the following structure,

A is N or NO; m and n independently of each other represent an integer of 0 to 3; X may be the same or different from each other, and independently from each other, straight or branched saturated or unsaturated (C ₁ -C ₇ ) alkyl, linear or branched unsaturated (C ₁ -C ₇ ) alkyl including halogen, (C ₁ -C ₇ ) alkoxy, (C ₁ -C ₇ ) alkylthio, (C ₁ -C ₇ ) alkoxycarbonyl, (C ₁ -C ₇ ) alkylcarbonyloxy, (C ₆ -C ₁₀ ) ar (C ₁ C ₇ ) alkyloxy, halogen, cyano, nitro, hydroxy, amino, aminocarbonyl or carboxylic acid; R ₅ is hydrogen, straight or branched saturated or unsaturated (C ₁ -C ₇ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, (C ₁ -C ₇ ) alkoxy (C ₁ -C ₇ ) alkyl, (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₇ ) alkyl, (C ₃ -C ₇ ) cycloalkyl (C ₁ -C ₇ ) alkoxy, mono or di (C ₁ -C ₇ ) alkylaminocarbonyl, cya Furnace, (C ₁ -C ₇ ) alkoxycarbonyl, aminocarbonyl, (C ₁ -C ₇ ) alkylcarbonyl, (C ₆ -C ₁₀ ) ar (C ₁ -C ₇ ) alkylcarbonyl, (C ₆ -C ₁₀ ) arylcarbonyl or

Alkyl, alkoxy and alkylcarbonyl of R ₅ may be further substituted by halogen; R ₁₁ and R ₁₂ independently of one another are hydrogen, (C ₁ -C ₇ ) alkyl, (C ₁ -C ₇ ) alkylcarbonyl or (C ₁ -C ₇ ) alkoxycarbonyl.] The method of claim 4, wherein R ₃ and R ₄ are each independently an aryl group selected from the following structures:

A is N or NO; m and n independently of each other represent an integer of 0 or 1; X may be the same or different from each other, and independently from each other (C ₁ -C ₇ ) alkoxy, hydroxy, (C ₁ -C ₇ ) alkoxycarbonyl, (C ₁ -C ₇ ) alkylcarbonyloxy or (C ₆ -C ₁₀ ) ar (C ₁ -C ₇ ) alkyloxy; R ₅ is hydrogen, straight or branched saturated or unsaturated (C ₁ -C ₇ ) alkyl, cyano, (C ₁ -C ₇ ) alkoxycarbonyl, aminocarbonyl, (C ₁ -C ₇ ) alkylcarbonyl or

Alkyl, alkoxy and alkylcarbonyl of R ₅ may be further substituted by halogen; R ₁₁ and R ₁₂ independently of one another are hydrogen, (C ₁ -C ₇ ) alkyl, (C ₁ -C ₇ ) alkylcarbonyl or (C ₁ -C ₇ ) alkoxycarbonyl ′, 4′-dialkoxyphenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidine compound or a pharmaceutically acceptable salt thereof. The method of claim 5, 7- (3 ', 4'-dialkoxyphenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidine compound or a pharmaceutical thereof, characterized in that it is selected from the following compounds: Acceptable salts.

3-amino-5-substituted pyrazole compound (4) and 3- (dimethylamino) -1- (3,4-dialkoxyphenyl) propenone compound (5) or 3- (3,4-dialkoxy Phenyl) cinnaaldehyde compound (6) is reacted in the presence of acetic acid and then reduced to NaBH ₄ to prepare a compound of formula (10), and nucleophilic substitution from the compound of formula 10 to prepare a compound of formula (1) A process for producing a 7- (3 ′, 4′-dialkoxyphenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidine compound. [Formula 1]

[Formula 4]

[Formula 5]

[Formula 6]

[Formula 10]

[Wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are the same as defined in claim 1 and Y is halogen or (C ₁ -C ₇ ) alkoxy.] 7- (3 ′, 4′-dialkoxyphenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidine compound represented by Formula 1 according to claim 1 or a pharmaceutical thereof Pharmaceutical compositions for the treatment or prevention of bronchial inflammation-related diseases, including asthma or chronic obstructive pulmonary disease, characterized in that it contains an acceptable salt as an active ingredient. 7- (3 ′, 4′-dialkoxyphenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidine compound represented by Formula 1 according to claim 1 or a pharmaceutical thereof A pharmaceutical composition for the treatment or prevention of arthritis, atopic dermatitis, leukemia, cancer and Alzheimer's, depression and memory disorders, including a salt that is acceptable as an active ingredient.