KR20110029653A - Compounds having inhibitory activity against phosphodiesterase and use thereof - Google Patents

Abstract

PURPOSE: A compound with an activity of suppressing phosphodiesterasse is provided to be used as a pharmaceutical composition for preventing or treating central nervous system diseases. CONSTITUTION: A compound with an activity of suppressing phosphodiesterase is denoted by chemical formula 1. A pharmaceutical composition for preventing or treating central nervous system diseases contains a compound of chemical formula 2, pharmaceutically acceptable salt, hydrate, or solvent thereof as an active ingredient. The central nervous system diseases are mild cognitive impairment, Lewy body dementia, vascular dementais, stroke, AIDS dementia complex, schizophrenia, manic-depressive insanity, or Huntington's disease.

Description

Compound having phosphodiesterase inhibitory activity and use thereof {Compounds having inhibitory activity against phosphodiesterase and use thereof}

The present invention relates to a compound having a phosphodiesterase inhibitory activity and its use. Specifically, the compound has a phosphodiesterase inhibitory activity and thus may be usefully used as a pharmaceutical composition for preventing or treating central nervous system diseases.

The cyclic nucleotides cAMP and cGMP are used as secondary signal transduction agents in intracellular signal transduction systems. The cAMP and cGMP are synthesized from AMP and GMP by nucleotide cyclase (adenyl cyclase or guanyl cyclase), respectively.

External signals such as neurotransmitters, hormones, light, and odors change the activity of cyclase through G-protein-coupled receptors, and regulate the amount of cyclic nucleotides (cAMP, cGMP) to deliver signals inside the cell. . Cyclic nucleotides, the second intracellular signal transmitters generated as described above, regulate the functions of various proteins in the cell. In other words, the increase of cAMP induces the activity of protein kinase A (PKA), a cAMP (cGMP) dependent kinase, which regulates the activity and function of proteins such as ion channels, enzymes and various transcription factors through phosphorylation. do. In addition, guanylcyclases each have a different activation process depending on their form.

On the other hand, cyclic nucleotide phosphodiesterases (phosphodiesterases, PDEs) are enzymes involved in the reaction of hydrolyzing the cAMP and cGMP to form adenosine monophosphate (AMP) and guanosine monophosphate (GMP). The PDEs consist of a catalytic activity domain at the carboxyl end and a regulatory domain at the amino end, and it is known that 11 PDE protein groups are made from more than 20 different genes (lugnier, C., Pharmacol Ther. 2006). Mar 109 (3): 366-98). These 11 PDE protein groups can be classified according to specific amino acid sequence, catalytic regulatory action, sensitivity to low molecular inhibitors, and the like. The 11 kinds of PDE protein groups are variously expressed in each organ of the body, including the central nervous system, and each protein is expressed in different tissues to perform different physiological functions.

In particular, PDE 10 is mainly expressed in the brain, specifically in the nucleus location and the tail putamen. Intermediate expression sites are in the thalamus, hippocampus, frontal cortex and olfactory nodules (Menniti et al., 2001). All these brain regions are involved in the physiological mechanism of schizophrenia (Lapiz et al. 2003), so the location of enzymes plays a predominant role in the pathogenesis of psychosis.

The PDE 10 has, in particular, a higher affinity for cAMP (Km = 0.05 μM) than cGMP (KM = 3 μM) and hydrolyses both cAMP and cGMP (Sonderling et al., 1999). Psychotic patients have been found to have dysfunction in cGMP and cAMP levels and downstream substrates thereof (Kaiya, 1992; Muly, 2002; Garver et al., 1982). Thus, since PDE 10 hydrolyses both cAMP and cGMP, inhibition of PDE 10 can also lead to an increase in cAMP and cGMP.

As such, inhibition of PDE is associated with facilitating neurotransmission and is useful for the prevention or treatment of various central nervous system diseases, and therefore, the development of PDE inhibitors is urgently required.

Accordingly, the present inventors are searching for a compound that can effectively treat central nervous system diseases, and find a compound having an activity that can effectively inhibit phosphodiesterase, and the compound is used for the prevention or treatment of central nervous system diseases. The present invention has been completed.

Accordingly, an object of the present invention is to provide a compound of formula 1, a pharmaceutically acceptable salt, hydrate or solvate thereof.

<Formula 1>

In addition, the present invention provides a pharmaceutical composition for the prevention or treatment of central nervous system diseases containing at least one selected from the group consisting of a compound of formula (2), a pharmaceutically acceptable salt, hydrate and solvate thereof as an active ingredient For the purpose of

<Formula 2>

In order to solve the above problems, the present invention provides a compound of Formula 1, a pharmaceutically acceptable salt, hydrate or solvate thereof.

<Formula 1>

In addition, the present invention provides a pharmaceutical composition for preventing or treating central nervous system diseases containing at least one selected from the group consisting of a compound represented by the following formula (2), a pharmaceutically acceptable salt, hydrate, and solvate thereof as an active ingredient. .

<Formula 2>

The present invention is described in more detail below.

Pharmaceutically acceptable salts herein include, but are not limited to, acid addition salts formed with pharmaceutically acceptable free acids. Inorganic acids and organic acids can be used as the free acid. Hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, etc. may be used as the inorganic acid, and citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, gluconic acid, methanesulfonic acid, glyconic acid, succinic acid, 4-toluenesulfonic acid , Gluturonic acid, embonic acid, glutamic acid, or aspartic acid and the like may be used and may also be a pharmaceutically acceptable metal salt, especially an alkali metal salt, formed due to a base. Examples of these are sodium salts and potassium salts.

Hydrate in the present invention means that the compound of the present invention is formed by binding to water molecules.

Solvate in the present invention means the physical association of a compound of the invention with one or more solvent molecules. Such physical association may include hydrogen bonding. In certain cases, solvates may be separable, for example when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. The solvates include both solution-phase and separable solvates.

In the present invention, a functional group means a part in a molecule to exhibit physical, chemical, and biological properties, and a substituent means that a functional group is changed from one functional group to another to improve the physical, chemical, and biological properties of the compound.

The novel compounds in the present invention include compounds of the formula (1) below, pharmaceutically acceptable salts, hydrates or solvates thereof.

In the above formula

A1, A2 and A3 are each independently a functional group selected from the group consisting of hydrogen, C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C5 cycloalkoxy, C1 to C5 cyclic methoxy and halogen;

R 1 is selected from the group consisting of hydrogen, a C 1 to C 5 alkyl group substituted or unsubstituted with a hydroxy group, CH—R 6 and CH ₂ —O—R 7;

R6 and R7 are each independently C3 to C6 monocyclic, C8 to C10 bicyclic, nitrogen, oxygen and sulfur, including at least one selected from the group consisting of C3 to C6 heteromonocyclic, nitrogen, oxygen And C8 to C10 heterobicyclic, C5 to C6 monocyclic aromatic, C8 to C10 bicyclic aromatic, nitrogen, oxygen and sulfur, including at least one selected from the group consisting of sulfur. A functional group selected from the group consisting of C5 to C6 heteromonocyclic aromatic and C8 to C10 heterobicyclic aromatic including at least one selected from the group consisting of nitrogen and oxygen;

R2 is a group consisting of C3 to C6 monocyclic, C8 to C10 bicyclic, nitrogen, oxygen and sulfur containing at least one kind selected from the group consisting of C3 to C6 heteromonocyclic, nitrogen, oxygen and sulfur C5 including at least one selected from the group consisting of C8 to C10 heterobicyclic, C5 to C6 monocyclic aromatic, C8 to C10 bicyclic aromatic, nitrogen, oxygen and sulfur A functional group selected from the group consisting of C8 to C10 heterobicyclic aromatic including at least one selected from the group consisting of nitrogen, oxygen and sulfur;

n is 1 or 2, and when n is 2, it is unsubstituted or substituted with 1 or 2 oxo groups.

Preferably in Formula 1

A 1, A 2 and A 3 are each independently hydrogen or alkoxy of C 1 to C 6;

R 1 is selected from the group consisting of hydrogen, a C 1 to C 5 alkyl group substituted with a hydroxy group, CH—R 6 and CH ₂ —O—R 7;

R6 and R7 are each independently C3 to C6 heteromonocyclic including at least one selected from the group consisting of nitrogen, oxygen and sulfur, or C8 to C10 containing at least one selected from the group consisting of nitrogen, oxygen and sulfur A functional group selected from the group consisting of heterobicyclic aromatic

R2 is C5 to C6 monocyclic aromatic, C8 to C10 bicyclic aromatic, C5 to C6 heteromonocyclic aromatic and nitrogen, oxygen and sulfur containing at least one selected from the group consisting of It is a functional group selected from the group consisting of C8 to C10 heterobicyclic aromatic containing at least one selected from the group consisting of;

n is 1 or 2, and when n is 2, it may be unsubstituted or substituted with one oxo group.

More preferably in Formula 1

R6 and R7 may each independently include an oxo group as a substituent, wherein R2 is C1 to C5 alkyl, C3 to C6 cycloalkyl, C1 to C4 alkoxy, amine, nitro, halogen, sulfone, sulfoxide, sulfone It may include at least one substituent selected from the group consisting of amides, amides and esters.

Most preferably, the compound represented by Chemical Formula 1 is 8-((3- (3,4-dimethoxyphenyl) -1H-pyrazol-1-yl) methyl) quinoline; 5-((3- (3,4-dimethoxyphenyl) -1H-pyrazol-1-yl) methyl) quinoxaline; 3- (3,4-dimethoxyphenyl) -1- (naphthalen-2-ylmethyl) -1H-pyrazole; 2- (3- (3,4-dimethoxyphenyl) -1H-pyrazol-1-yl) -1- (naphthalen-2-yl) ethanol; 1-benzyl-3- (3,4-dimethoxyphenyl) -1H-pyrazole; 3- (3,4-dimethoxyphenyl) -1-phenethyl-1H-pyrazole; 3- (3,4-dimethoxyphenyl) -1- (4-methoxybenzyl) -1H-pyrazole; 3- (3,5-dimethoxyphenyl) -1- (4-methoxybenzyl) -1H-pyrazole; 3- (3,5-dimethoxyphenyl) -1- (naphthalen-2-ylmethyl) -1H-pyrazole; 3- (3,5-dimethoxyphenyl) -1- (2- (naphthalen-1-yl) ethyl) -1H-pyrazole; 6-((3- (3,5-dimethoxyphenyl) -1- (4-methoxybenzyl) -1H-pyrazol-4-yl) methoxy) quinoline; 3- (3,4-dimethoxyphenyl) -1- (2- (naphthalen-1-yl) ethyl) -1H-pyrazole; (3- (3,5-dimethoxyphenyl) -1- (4-methoxybenzyl) -1H-pyrazol-4-yl) methanol and (E) -5-((3- (3,4- Dimethoxyphenyl) -1- (4-methoxybenzyl) -1H-pyrazol-4-yl) methylene) thiazolidine-2,4-dione.

Meanwhile, the pharmaceutical composition for preventing or treating CNS diseases of the present invention contains at least one selected from the group consisting of a compound of Formula 2, a pharmaceutically acceptable salt, hydrate, and solvate thereof as an active ingredient.

In the above formula

A1, A2 and A3 are each independently hydrogen, C1 to C6 alkyl, C1 to C8 alkoxy, C1 to C8 alkoxy substituted with halogen, C1 to C8 alkoxy substituted with C1 to C8 monocyclic, C5 C1 to C8 alkoxy substituted with monocyclic aromatic of C6 to C6, C1 to C8 alkoxy, halogen, nitro group and hydroxy groups substituted with alkyl esters of C1 to C5;

R 1 is selected from the group consisting of hydrogen, a C 1 to C 5 alkyl group substituted or unsubstituted with a hydroxy group, CH—R 6 and CH ₂ —O—R 7;

R6 and R7 are each independently C3 to C6 monocyclic, C8 to C10 bicyclic, nitrogen, oxygen and sulfur, including at least one selected from the group consisting of C3 to C6 heteromonocyclic, nitrogen, oxygen And C8 to C10 heterobicyclic, C5 to C6 monocyclic aromatic, C8 to C10 bicyclic aromatic, nitrogen, oxygen and sulfur, including one or more selected from the group consisting of sulfur. A functional group selected from the group consisting of C5 to C6 heteromonocyclic aromatic and C8 to C10 heterobicyclic aromatic including at least one selected from the group consisting of nitrogen and oxygen;

R2 is C3 to C6 monocyclic, C8 to C6, linked directly or linked to a linker selected from the group consisting of C1 to C3 alkyl, ether, ester, amine and thioether, substituted or substituted with one to three oxo groups C8 to C10 hetero containing at least one selected from the group consisting of C3 to C6 heteromonocyclic, nitrogen, oxygen and sulfur containing at least one selected from the group consisting of C10 bicyclic, nitrogen, oxygen and sulfur C5 to C6 heteromonocyclic aromatic and nitrogen, oxygen, including at least one selected from the group consisting of bicyclic, C5 to C6 monocyclic aromatic, C8 to C10 bicyclic aromatic, nitrogen, oxygen and sulfur And in the group consisting of C8 to C10 heterobicyclic aromatic containing at least one selected from the group consisting of sulfur Is a functional group selected.

Preferably in Formula 2

R 1 is selected from the group consisting of hydrogen, a C 1 to C 5 alkyl group substituted with a hydroxy group, CH—R 6 and CH ₂ —O—R 7;

R6 and R7 are each independently selected from the group consisting of at least one selected from the group consisting of nitrogen, oxygen and sulfur C3 to C6 heteromonocyclic or C8 to C10 containing at least one selected from the group consisting of nitrogen, oxygen and sulfur A functional group selected from the group consisting of heterobicyclic aromatics;

R2 is C5 to C6 monocyclic aromatic, C8 to C10 bicyclic aromatic, nitrogen, oxygen and sulfur, which are directly linked or substituted with 1 to 3 oxo groups or unsubstituted C1 to C3 alkyl group by linker C5 to C6 heteromonocyclic aromatic containing at least one selected from the group consisting of C8 to C10 heterobicyclic aromatic containing at least one selected from the group consisting of a function selected from the group consisting of It may be a flag.

More preferably in Formula 2

R 6 and R 7 are each independently an oxo group, substituted or unsubstituted C 1 to C 5 alkyl ester, C 1 to C 5 alkyl, C 1 to C 5 alkyne, C 1 to C 5 alkyl sulfonyl and C 1 to C 5 alkyl acetate It may include one or more substituents selected from the group consisting of;

 R2 may comprise at least one substituent selected from the group consisting of C1 to C5 alkyl, C3 to C6 cycloalkyl, C1 to C4 alkoxy, amine, nitro, halogen, sulfone, sulfoxide, sulfonamide, amide and ester have.

Most preferably, the compound represented by Chemical Formula 2 is 8-((3- (3,4-dimethoxyphenyl) -1H-pyrazol-1-yl) methyl) quinoline (hereinafter referred to as Compound 1); 5-((3- (3,4-dimethoxyphenyl) -1H-pyrazol-1-yl) methyl) quinoxaline (hereinafter referred to as compound 2); 3- (3,4-dimethoxyphenyl) -1- (naphthalen-2-ylmethyl) -1H-pyrazole (hereinafter referred to as compound 3); 2- (3- (3,4-dimethoxyphenyl) -1H-pyrazol-1-yl) -1- (naphthalen-2-yl) ethanol (hereinafter referred to as compound 4); 1-benzyl-3- (3,4-dimethoxyphenyl) -1H-pyrazole (hereinafter referred to as compound 5); 3- (3,4-dimethoxyphenyl) -1-phenethyl-1H-pyrazole (hereinafter referred to as compound 6); 3- (3,4-dimethoxyphenyl) -1- (4-methoxybenzyl) -1H-pyrazole (hereinafter referred to as compound 7); 3- (3,5-dimethoxyphenyl) -1- (4-methoxybenzyl) -1H-pyrazole (hereinafter referred to as compound 8); 3- (3,5-dimethoxyphenyl) -1- (naphthalen-2-ylmethyl) -1H-pyrazole (hereinafter referred to as compound 9); 3- (3,5-dimethoxyphenyl) -1- (2- (naphthalen-1-yl) ethyl) -1H-pyrazole (hereinafter referred to as compound 10); 6-((3- (3,5-dimethoxyphenyl) -1- (4-methoxybenzyl) -1H-pyrazol-4-yl) methoxy) quinoline (hereinafter referred to as compound 111); 3- (3,4-dimethoxyphenyl) -1- (2- (naphthalen-1-yl) ethyl) -1H-pyrazole (hereinafter referred to as compound 12); (3- (3,5-dimethoxyphenyl) -1- (4-methoxy benzyl) -1H-pyrazol-4-yl) methanol (hereinafter referred to as compound 13); (E) -5-((3- (3,4-dimethoxyphenyl) -1- (4-methoxybenzyl) -1H-pyrazol-4-yl) methylene) thiazolidine-2,4 Diones (hereinafter referred to as compound 14); (E) -5-((3- (4-ethoxy-3-isopropylphenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) -1-methylimidazolidine-2,4 Diones (hereinafter referred to as compound 15); (Z) -3- (methylsulfonyl) -5-((3- (3-nitrophenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) thiazolidine-2,4-da Ions (hereinafter referred to as compound 16); (Z) -5-((3- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -1- (pyridin-2-yl) -1H-pyrazol-4-yl) Methylene) -2-thiazolidine-2,4-dione (hereinafter referred to as compound 17); (Z) -5-((3- (3,4-bis (difluoromethoxy) phenyl) -1- (pyridin-2-yl) -1H-pyrazol-4-yl) methylene) thiazolidine -2,4-dione (hereinafter referred to as compound 18); (Z) -5-((3- (3,5-dimethoxyphenyl) -1- (pyridin-2-yl) -1H-pyrazol-4-yl) methylene) thiazolidine-2,4 Diones (hereinafter referred to as compound 19); (Z) -5-((3- (3,5-Dibromo-4- (difluoromethoxy) phenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) -3- (propo -2-pinyl) thiazolidine-2,4-dione (hereinafter referred to as compound 20); (Z) -5-((3- (3,5-Dibromo-4- (difluoromethoxy) phenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) thiazolidine-2 , 4-dione (hereinafter referred to as compound 21); (Z) -5-((3- (3,5-Dibromo-4-ethoxyphenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) -3- (prop-2-ynyl Thiazolidine-2,4-dione (hereinafter referred to as compound 22); (Z) -5-((3- (3,5-Dibromo-4-propoxyphenyl) -1- (pyridin-2-yl) -1H-pyrazole-4-yl) methylene) thiazolidine -2,4-dione (hereinafter referred to as compound 23); (Z) -5-((3- (3,5-Diisopropyl-4-propoxyphenyl) -1- (4-nitrophenyl) -1H-pyrazol-4-yl) methylene) thiazolidine -2,4-dione (hereinafter referred to as compound 24); (Z) -5-((3- (3,5-di-t-butyl-4-hydroxyphenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) thiazolidine-2, 4-dione (hereinafter referred to as compound 25); (Z) -5-((3- (3,5-bis (benzyloxy) phenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) -3- (methylsulfonyl) thiazolidine -2,4-dione (hereinafter referred to as compound 26); (Z) -5-((3- (3,5-bis (cyclopentyloxy) phenyl) -1- (pyridin-2-yl) -1H-pyrazol-4-yl) methylene) thiazolidine- 2,4-dione (hereinafter referred to as compound 27); (Z) -5-((3- (3-bromo-4- (cyclopropylmethoxy) phenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) -3-methylthiazolidine -2,4-dione (hereinafter referred to as compound 28); (Z) -5-((3- (3-bromo-4-ethoxyphenyl) -1- (pyridin-2-yl) -1H-pyrazol-4-yl) methylene) -3- (methylsul Fonyl) thiazolidine-2,4-dione (hereinafter referred to as compound 29); (Z) -5-((3- (3-bromo-4-ethoxyphenyl) -1- (pyridin-2-yl) -1H-pyrazol-4-yl) methylene) thiazolidine-2 , 4-dione (hereinafter referred to as compound 30); (Z) -5-((3- (3-bromo-4-ethoxyphenyl) -1- (pyrimidin-2-yl) -1H-pyrazol-4-yl) methylene) thiazolidine- 2,4-dione (hereinafter referred to as compound 31); (Z) -5-((3- (3-isopropyl-4-propoxyphenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) thiazolidine-2,4-dione ( Compound 32 in the following); (Z) -5-((3- (3-chloro-4-propoxyphenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) -3- (methylsulfonyl) thiazolidine- 2,4-dione (hereinafter referred to as compound 33); (Z) -5-((3- (3-t-butyl-4-propoxyphenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) thiazolidine-2,4-dione (Hereinafter referred to as compound 34); (Z) -Ethyl 2- (2,6-di-t-butyl-4- (4-((2,4-dioxothiazolidine-5-ylidene) methyl) -1-phenyl-1H- Pyrazol-3-yl) phenoxy) acetate (hereinafter referred to as compound 35); (Z) -ethyl 2- (5-((3- (3,5-dibromo-4- (difluoromethoxy) phenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) -2 , 4-dioxothiazolidin-3-yl) acetate (hereinafter referred to as compound 36); (Z) -Ethyl 2- (5-((3- (3-bromo-4- (cyclopropylmethoxy) phenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) -dioxothio Azolidin-3-yl) acetate (hereinafter referred to as compound 37); (Z) -ethyl 2- (5-((3- (3-bromo-4-methoxyphenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) -2,4-dioxothio Azolidin-3-yl) acetate (hereinafter referred to as compound 38); (Z) -Ethyl 2- (5-((3- (4- (allyloxy) -3,5-dibromophenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) -dioxothio Azolidin-3-yl) acetate (hereinafter referred to as compound 39) and (Z) -ethyl 4- (5-((3- (3- (cyclopentyloxy) -4-methoxyphenyl) -1- Phenyl-1H-pyrazol-4-yl) methylene) -4-oxo-2-thioxothiazolidin-3-yl) butanoate (hereinafter referred to as compound 40) have.

Compounds used as the active ingredient of the pharmaceutical composition of the present invention is very excellent in phosphodiesterase inhibitory activity (see <Experimental Example 1>). The phosphodiesterase may be preferably phosphodiesterase 10 (PDE 10). The PDE 10 is expressed in high concentrations in specific regional neurons of the brain associated with various neurological and mental diseases, and plays an important role in signal transmission in the central nervous system. Specifically, when the PDE 10 is overexpressed, hydrolysis of cAMP and cGMP may cause central nervous system disease. Therefore, the compound used as an active ingredient of the pharmaceutical composition of the present invention has an activity of inhibiting PDE10, and thus may be usefully used for the prevention or treatment of central nervous system diseases.

The central nervous system disease affects a broad population at different depths. In general, the main features of this kind of disease include severe impairment of cognition or memory, which shows a marked drop in function from previous levels. For example, dementia is characterized by several cognitive impairments, including severe memory deficiency, and may exist alone or be the source of various diseases, including, for example, Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. . Other central nervous system diseases include delirium or cognitive confusion that occurs over a short period of time, and forgetfulness disease that occurs in the absence of other central nervous system damage, or discrete memory damage.

Thus, the central nervous system disease is not limited thereto but preferably age-associated memory impairment, mild cognitive impairment, elderly dementia (early onset Alzheimer's disease), senile dementia (Alzheimer's form). Dementia), Lewy body dementia, vascular dementia, Alzheimer's disease, stroke, AIDS dementia complex, attention deficit disorder, attention deficit hyperactivity disorder, dyslexia, mental Schizophrenia, schizophreniform disorder, obesity, insulin-independent diabetes, mood swings and schizoaffective disorder, Parkinson's disease, and Huntington's disease Can be.

The pharmaceutical composition can be applied directly to animals, including humans, preferably to mammals, more preferably to humans. In this case, the compound of Formula 2, pharmaceutically acceptable salts, hydrates and solvates thereof in the composition, and the content of the compound according to the mode of use and the method of use of the composition can be appropriately adjusted to the desired content have.

The compound of Formula 2, pharmaceutically acceptable salts, hydrates and solvates thereof may be used alone in a composition for the prevention or treatment of diseases, and additionally include other pharmacologically acceptable carriers, excipients, diluents or accessory ingredients. It may include.

Examples of the pharmaceutically acceptable carrier, excipient or diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, propylhydroxybenzoate, talc, magnesium stearate and mineral oil , Dextrin, calcium carbonate, propylene glycol, liquid paraffin, and one or more selected from the group consisting of physiological saline, but is not limited thereto, and all common carriers, excipients or diluents can be used. In addition, the pharmaceutical compositions are conventional fillers, extenders, binders, disintegrants, anti-coagulants, lubricants, wetting agents, pH adjusting agents, nutrients, vitamins, electrolytes, alginic acid and salts thereof, pectic acid and salts thereof, protective colloids, glycerin , Fragrances, emulsifiers or preservatives may be further included.

In addition, the pharmaceutical composition of the present invention may further include a substance used as a known central nervous system disease treatment agent in addition to the active ingredient.

The method of administering the composition may be oral or parenteral, and for example, may be administered through various routes including oral, transdermal, subcutaneous, intravenous or intramuscular. In addition, the formulation of the composition may vary depending on the method of use and is formulated using methods well known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal. Can be. Generally, solid preparations for oral administration include tablets, pills, soft or hard capsules (CAPSULES), pills (PILLS), powders (POWDERS) and granules (GRANULES), and the like. Excipients, for example, may be prepared by mixing starch, calcium carbonate, sucrose or lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Oral liquid preparations include suspending agents (SUSTESIONS), liquid solutions, emulsions (EMULSIONS) and syrups (SYRUPS) .Such as simple diluents such as water and liquid paraffin, various excipients such as wetting agents, Sweeteners, fragrances, preservatives and the like can be included. Forms for parenteral administration are CREAM, LOTIONS, ONITMENTS, PLASTERS, LIQUIDS AND SOULTIONS, AEROSOLS, FRUIDEXTRACTS, Elixir (ELIXIR), INFUSIONS, SACHET, PATCH or INJECTIONS. Furthermore, the compositions of the present invention can be formulated using suitable methods known in the art or using methods disclosed in Remington's Pharmaceutical Science (Recent), Mack Publishing Company, Easton PA. have.

The dosage of the composition can be determined in consideration of the method of administration, the age, sex of the person, the severity, the condition of the patient, the absorption of the active ingredient in the body, the inactivation rate and the drug used in combination, and may be administered once or in several divided doses. Can be.

Meanwhile, in the present invention, the compound may be prepared using various synthetic methods known in the art, and may be synthesized using the method described in the international patent application (International Patent Application Publication No. WO06 / 101307). Include by reference.

Preferably, the compound represented by Formula 1 of the present invention may be prepared through the following Scheme 1.

The acetophenone and N, N-dimethylformaldehyde dimethyl acetal are condensed to obtain alpha, beta unsaturated ketones. This is condensed with hydrazine using an alcohol (C1 to C5 primary, secondary alcohol, more preferably methanol, ethanol, propanol, etc.) solvent to synthesize pyrazole. The synthesized pyrazole is prepared under an inorganic or organic base (sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, cesium carbonate, calcium carbonate, triethyl amine, trimethyl amine, pyridine, diethyl propyl as organic base). Condensation with haloalkyl to give the compounds represented by Example 1. The compound may then introduce an aldehyde group using phosphooxychloride and anhydrous dimethylformamide, if necessary, and then introduce a substituent R1 using a reduction or condensation reaction.

More preferably, the compound 1 may be prepared through the following process. Specifically, alpha, beta unsaturated ketone is obtained through condensation reaction using 3,4-dimethoxy acetophenone and N, N-dimethylformaldehyde dimethyl acetal as a solvent. Compound 1 may be obtained by condensing pyrazole by condensation with hydrazine using ethanol as a solvent, followed by condensation with 8-bromomethylquinoline using trimethyl amine.

In addition, the compounds 2 to 10, 12 may be prepared through the manufacturing process of the compound 1. Specifically, acetophenone may be 3,4-dimethoxy acetophenone or 3,5-dimethoxyacetophenone depending on the compound, 5-bromomethyl quinoxaline, 2-bromomethyl naphthalene. Linker using one selected from 2-chloromethyl naphthalene, 2-bromo-2'-acetophenone, benzyl bromide, phenethylchloride, 4-methoxybenzylbromide, 1- (2-bromoethyl) naphthalene R2 can be introduced.

Compound 13 may also be prepared through Scheme 2 below.

It can be prepared by condensing acetophenone and alkyl hydrazine under acetic acid catalyst to obtain hydrazone, and simultaneously introducing cyclization and aldehyde with phosphooxychloride and anhydrous dimethylformamide and then reducing with NaBH4.

Compound 11 may also be prepared by the following procedure. Specifically, an aldehyde group is introduced into compound 8 by using phosphooxychloride and anhydrous dimethylformamide, and then reduced using NaBH 4 to obtain an alcohol as shown in Scheme 2, and then compound 11 is condensed with 6-hydroxyquinoline. It can manufacture.

In addition, compound 14 may be prepared through Scheme 3, using the intermediate aldehyde obtained in Scheme 2 as a starting material.

As described above, the compound of the present invention has an activity capable of effectively inhibiting phosphodiesterase, and thus can be effectively used for the prevention or treatment of central nervous system diseases.

Hereinafter, the present invention will be described in detail by way of examples.

However, the following examples are illustrative of the present invention, and the present invention is not limited to the following examples.

< Example  1>

8-((3- (3,4- Dimethoxyphenyl ) -1H- Pyrazole -1 day) methyl Synthesis of Quinoline (Compound 1)

Step 1: 1- (3,4- Dimethoxyphenyl ) -3- ( Dimethylamino ) Prof 2-en-1-one synthesis

A mixture of 10.0 g of 3,4-dimethoxybenzophenone and 20 mL of N, N-dimethylformamide dimethyl acetal was refluxed under reflux for 24 hours, concentrated under reduced pressure, and then 13.0 g of 1- (3,4-dimethoxyphenyl ) -3- (dimethylamino) prop-2-en-1-one was obtained in 99% or more yield.

The NMR analysis of the 1- (3,4-dimethoxyphenyl) -3- (dimethylamino) prop-2-en-1-one synthesized as above is described as follows.

NMR δ, 7.80 (d, 1H), 7.60 (s, 1H), 7.50 (d, 1H), 6.90 (d, 1H), 5.95 (d, 1H), 3.98 (s, 3H), 3.95 (s, 3H ), 3.0 (br, 6H)

Step 2: 3- (3,4- Dimethoxyphenyl ) -1H- Pyrazole  synthesis

The 1- (3,4-dimethoxyphenyl) -3- (dimethylamino) prop-2-en-1-one obtained in step 1 was dissolved in ethanol and heated. 17 mL of hydrazine was slowly added dropwise to the heated solution, and the mixture was stirred under reflux for 3 hours, concentrated under reduced pressure to remove the solvent, and the resulting white solid was separated by filtration through a filter paper. The separated solid product was dissolved in dichloromethane, dried over anhydrous sodium sulfate, and the filtered solution was concentrated and dried under reduced pressure to obtain 11.0 g of 3- (3,4-dimethoxyphenyl) -1H-pyrazole product as 98%. Obtained in the yield.

The NMR analysis of the 3- (3,4-dimethoxyphenyl) -1H-pyrazole synthesized as described above is described as follows.

NMR δ, 7.60 (s, 1H), 7.30 (m, 2H), 6.91 (d, 1H), 6.59 (s, 1H), 3.98 (s, 3H), 3.95 (s, 3H)

Step 3: 8-((3- (3,4- Dimethoxyphenyl ) -1H- Pyrazole -1 day) methyl Quinoline Synthesis

Method 1 . The 1- (3,4-dimethoxyphenyl) -3- (dimethylamino) prop-2-en-1-one obtained in step 1 was dissolved in ethanol and heated. After the addition of 8- hydrazinequinoline to the heated solution, the mixture was stirred under reflux for 3 hours, concentrated under reduced pressure to remove the solvent, and the resulting white solid was separated by filtration through a filter paper. The separated solid product was dissolved in dichloromethane again, dried over anhydrous sodium sulfate, and the filtered solution was concentrated and dried under reduced pressure to obtain 8-((3- (3,4-dimethoxyphenyl) -1H-pyrazole-1 -Yl) methyl) quinoline product was obtained in a yield of 70%.

Method 2 . 50 mg of 3- (3,4-dimethoxyphenyl) -1H-pyrazole obtained in step 2 was added to DMF (N, N-dimethyl formamide). After dissolving in 2mL, 81.5mg of 8-bromomethylquinoline and 0.052mL of triethyl amine were added, followed by stirring at room temperature for 10 hours. The stirred solution was diluted with dichloromethane, washed with distilled water and dried under reduced pressure with anhydrous sodium sulfate. Gradient flash column chromatography from 100% hexane to 100% ethyl acetate using silica as a stationary phase and ethyl acetate and hexane as mobile phase gave 8-((3- (3,4- Dimethoxyphenyl) -1H-pyrazol-1-yl) methyl) quinoline product was obtained in 80% yield.

The NMR analysis of 8-((3- (3,4-dimethoxyphenyl) -1H-pyrazol-1-yl) methyl) quinoline synthesized as above is described as follows.

NMR δ, 8.98 (dd, 1H, J = 4.5, 1.8 Hz), 8.18 (dd, 1H, J = 8.4, 1.5 Hz), 7.77 (d, 1H, J = 7.2, Hz), 7.59 (d, 1H, J = 2.4, Hz), 7.50 ~ 7.33 (m, 5H), 6.90 (d, 1H, J = 8.7, Hz), 6.52 (d, 1H, J = 2.4Hz), 6.09 (s, 2H), 3.96 ( s, 3H), 3.91 (s, 3H)

< Example  2>

5-((3- (3,4- Dimethoxyphenyl ) -1H- Pyrazole -1 day) methyl ) Quinoxaline  (Compound 2) Synthesis

5-((3- (3,4-dimethoxyphenyl) -1H-pyrazol-1-yl) methyl) quinoxaline by condensing 5-bromomethyl quinoxaline in the same manner as in <Example 1> Was synthesized.

The NMR analysis of the 5-((3- (3,4-dimethoxyphenyl) -1H-pyrazol-1-yl) methyl) quinoxaline synthesized as above is described as follows.

NMR δ, 8.90 (s, 2H), 8.06 (d, 1H, J = 8.4 Hz), 7.72 (dd, 1H, J = 8.7, 7.2 Hz), 7.57 (d, 1H, J = 2.4, Hz), 7.48 (d, 1H, J = 6.9Hz), 7.42 (d, 1H, J = 2.1Hz) 7.33 (dd, 1H, J = 8.4,2.1Hz), 6.95 (d, 1H, J = 8.4Hz), 6.53 ( d, 1H, J = 2.4Hz), 6.06 (s, 1H), 3.96 (s, 3H), 3.91 (s, 3H)

< Example  3>

3- (3,4- Dimethoxyphenyl ) -1- (naphthalene-2- Yl methyl ) -1H- Pyrazole  (Compound 3) Synthesis

In the same manner as in <Example 1>, 2-bromomethyl naphthalene was condensed to synthesize 3- (3,4-dimethoxyphenyl) -1- (naphthalen-2-ylmethyl) -1H-pyrazole. .

The NMR analysis of the 3- (3,4-dimethoxyphenyl) -1- (naphthalen-2-ylmethyl) -1H-pyrazole synthesized as described above is described as follows.

NMR δ, 7.90-7.81 (m, 2H), 7.72 (s, 1H), 7.54-7.43 (m, 3H), 7.41-7.35 (m, 3H), 6.92 (d, 1H), 6.58 (s, 1H) , 5.48 (s, 2H), 3.96 (s, 3H), 3.91 (s, 3H)

< Example  4>

2- (3- (3,4- Dimethoxyphenyl ) -1H- Pyrazole Synthesis of -1-yl) -1- (naphthalen-2-yl) ethanol (Compound 4)

2-bromo-2'-acetophenone is condensed in the same manner as in <Example 1> to give 2- (3- (3,4-dimethoxyphenyl) -1H-pyrazol-1-yl) -1 -(Naphthalen-2-yl) ethanol was synthesized.

The NMR analysis of 2- (3- (3,4-dimethoxyphenyl) -1H-pyrazol-1-yl) -1- (naphthalen-2-yl) ethanol synthesized as described above is described as follows. It was.

NMR δ, 8.75 (s, 1H), 8.10-7.90 (m, 4H,), 7.72 (s, 1H), 7.65 (m, 2H), 7.42 (s, 1H), 7.35 (d, 1H) 6.97 (d , 1H), 6.68 (s, 1H), 5.95 (s, 2H), 3.87 (s, 3H), 3.85 (s, 3H)

< Example  5>

1-benzyl-3- (3,4- Dimethoxyphenyl ) -1H- Pyrazole  (Compound 5) Synthesis

Benzyl bromide was condensed in the same manner as in <Example 1> to synthesize 1-benzyl-3- (3,4-dimethoxyphenyl) -1H-pyrazole.

The results of NMR analysis of 1-benzyl-3- (3,4-dimethoxyphenyl) -1H-pyrazole synthesized as described above are described as follows.

NMR δ, 7.42 (d, 1H, J = 2.1 Hz), 7.75-7.60 (m, 5H,), 7.52 (m, 2H), 6.89 (d, 1H, J = 3.9 Hz), 6.51 (d, 1H, J = 2.4 Hz), 5.35 (s, 2H), 3.96 (s, 3H), 3.90 (s, 3H)

< Example  6>

3- (3,4- Dimethoxyphenyl )-One- Phenethyl -1H- Pyrazole  (Compound 6) Synthesis

Phenethyl chloride was condensed in the same manner as in <Example 1> to synthesize 3- (3,4-dimethoxyphenyl) -1-phenethyl-1H-pyrazole.

The NMR analysis of the 3- (3,4-dimethoxyphenyl) -1-phenethyl-1H-pyrazole synthesized as described above is described as follows.

NMR δ, 7.8 (d, 1H), 7.1-7.8 (m, 8H), 6.94 (d, 1H), 6.50 (d, 1H), 4.2 (d, 2H), 3.94 (s, 6H), 3.80 (d , 2H)

< Example  7>

3- (3,4- Dimethoxyphenyl ) -1- (4-methoxybenzyl) -1H- Pyrazole  (Compound 7) Synthesis

4-methoxybenzylbromide was condensed in the same manner as in <Example 1> to synthesize 3- (3,4-dimethoxyphenyl) -1- (4-methoxybenzyl) -1H-pyrazole.

The NMR analysis of the 3- (3,4-dimethoxyphenyl) -1- (4-methoxybenzyl) -1H-pyrazole synthesized as described above is described as follows.

NMR δ, 9.95 (s, 1H), 7.83 (s, 1H), 7.40-7.33 (m, 3H), 6.98-6.86 (m, 3H), 5.31 (s, 2H), 3.94 (s, 3H), 3.90 (s, 3H), 3.80 (s, 3H)

< Example  8>

3- (3,5- Dimethoxyphenyl ) -1- (4-methoxybenzyl) -1H- Pyrazole  (Compound 8) Synthesis

Using 3,5-dimethoxy acetophenone in the same manner as in <Example 1>, 4-methoxybenzyl bromide is condensed to 3- (3,5-dimethoxyphenyl) -1- (4-methoxy Toxybenzyl) -1H-pyrazole was synthesized.

The NMR analysis of the 3- (3,5-dimethoxyphenyl) -1- (4-methoxybenzyl) -1H-pyrazole synthesized as described above is described as follows.

NMR δ, 7.3-7.2 (m, 3H), 7.0 (d, 2H), 6.88 (d, 2H), 6.55 (d, 1H), 6.41 (t, 1H), 5.28 (s, 2H), 3.85 (s , 6H), 3.80 (s, 3H)

< Example  9>

3- (3,5- Dimethoxyphenyl ) -1- (naphthalene-2- Yl methyl ) -1H- Pyrazole  (Compound 9) Synthesis

3- (3,5-dimethoxyphenyl) -1- (naphthalene-) by condensing 2-bromomethyl naphthalene using 3,5-dimethoxy acetophenone in the same manner as in <Example 1> 2-ylmethyl) -1H-pyrazole was synthesized.

The NMR analysis of the 3- (3,5-dimethoxyphenyl) -1- (naphthalen-2-ylmethyl) -1H-pyrazole synthesized as described above is described as follows.

NMR δ, 7.85 (m, 2H), 7.70 (s, 1H), 7.48 (m, 2H), 7.39 (m, 2H), 7.05 (m, 2H), 6.58 (d, 1H), 6.43 (t, 1H) ), 3.84 (s, 6 H)

< Example  10>

3- (3,5- Dimethoxyphenyl ) -1- (2- (naphthalen-1-yl) ethyl) -1H- Pyrazole  (Compound 10) Synthesis

Using 3,5-dimethoxy acetophenone in the same manner as in <Example 1>, and condensation of 1- (2-bromoethyl) naphthalene to 3- (3,5-dimethoxyphenyl) -1 -(2- (naphthalen-1-yl) ethyl) -1H-pyrazole was synthesized.

The NMR analysis of the 3- (3,5-dimethoxyphenyl) -1- (2- (naphthalen-1-yl) ethyl) -1H-pyrazole synthesized as described above is described as follows.

NMR δ, 8.09 (d, 1H), 7.92 (d, 1H), 7.75 (d, 1H), 7.60-7.48 (m, 2H), 7.38 (t, 1H), 7.24 (t, 1H), 7.08 (dd , 1H), 7.01 (m, 2H), 6.44 (d, 1H), 6.40 (d, 1H), 4.50 (t, 2H), 3.88 (s, 6H), 3.65 (t, 2H)

< Example  11>

6-((3- (3,5- Dimethoxyphenyl ) -1- (4-methoxybenzyl) -1H- Pyrazole -4- days) Methoxy Synthesis of Quinoline (Compound 11)

The compound prepared in <Example 8> synthesized in the same manner as in <Example 1> was used as a starting material. Phosphooxychloride (0.45 mL) was added to 2 mL of anhydrous dimethylformamide (DMF) and then stirred at 0 ° C. for 1 hour. 0.5 equivalent of 3- (3,5-dimethoxyphenyl) -1- (4-methoxybenzyl) -1H-pyrazole prepared in <Example 8> dissolved in 5 mL of anhydrous DMF was slowly added dropwise. Stir at 80 ° C. for 6 hours. After cooling to 0 ° C., the pH was adjusted to 7-8 with 30% aqueous sodium hydroxide solution, the resulting solid was filtered, washed with water and dried to obtain 6-((3- (3,5-dimethoxyphenyl)) in 80% yield. -1- (4-methoxybenzyl) -1H-pyrazol-4-yl) methoxy) quinoline was synthesized.

NMR analysis of 6-((3- (3,5-dimethoxyphenyl) -1- (4-methoxybenzyl) -1H-pyrazol-4-yl) methoxy) quinoline synthesized as above It was described as follows.

NMR δ, 8.7 (br, 1H), 8.69 (d, 1H), 7.93 (d, 1H), 7.2-7.4 (m, 6H), 6.81 (d, 2H), 6.58 (d, 1H), 6.43 (d , 2H), 6.32 (d, 2H), 5.31 (s, 2H), 4.46 (s, 2H), 3.78 (s, 3H), 3.71 (s, 3H), 3.22 (s, 3H)

< Example  12>

3- (3,4- Dimethoxyphenyl ) -1- (2- (naphthalen-1-yl) ethyl) -1H- Pyrazole  (Compound 12) Synthesis

Condensation of 1- (2-bromoethyl) naphthalene in the same manner as in <Example 1> to 3- (3,4-dimethoxyphenyl) -1- (2- (naphthalen-1-yl) ethyl) -1H-pyrazole was synthesized.

The NMR analysis of the 3- (3,4-dimethoxyphenyl) -1- (2- (naphthalen-1-yl) ethyl) -1H-pyrazole synthesized as described above is described as follows.

NMR δ, 8.09 (d, 1H), 7.89 (d, 1H), 7.75 (d, 1H), 7.58-7.48 (m, 2H), 7.42 (s, 1H), 7.40-7.30 (m, 3H), 7.2 (m, 1H), 7.08 (d, 1H), 7.01 (m, 2H), 6.92 (dd, 1H), 6.38 (d, 1H), 4.50 (t, 2H), 4.00 (s, 3H), 3.92 ( s, 3H), 3.65 (t, 2H)

< Example  13>

(3- (3,5- Dimethoxyphenyl ) -1- (4-methoxybenzyl) -1H- Pyrazole 4-yl) methanol (compound 13) synthesis

(3- (3,5-dimethoxyphenyl) -1- (4-methoxybenzyl) -1H-pyrazol-4-yl) methanol is a known international patent application (International Patent Application Publication No. WO06 / 101307).

Step 1 . (3,5- Dimethoxy 4- of acetophenone Methoxybenzylhydrazone

After dissolving (3,5-dimethoxy) acetophenone (1,00 g) in 20 mL of absolute ethanol, 1 equivalent of 4-methoxybenzylhydrazine and a catalytic amount of acetic acid were mixed and stirred at room temperature for 3 hours. After diluting with 20 mL of ethyl acetate and washing with water and saturated sodium chloride solution, the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Obtained in yield.

Step 2 . 3- (3,5- Dimethoxyphenyl ) -1H- Parasol -4- Carboxyaldehyde

Phosphooxychloride (0.45 mL) was added to 2 mL of anhydrous dimethylformamide (DMF) and then stirred at 0 ° C. for 1 hour. 0.5 equivalent of Hydrazone of (3,5-dimethoxy) acetophenone dissolved in 5 mL of anhydrous DMF was slowly added dropwise and stirred at 70-80 ° C. for 6 hours. After cooling to 0 ° C., pH 7-8 was adjusted with 30% aqueous sodium hydroxide solution, the resulting solids were filtered, washed with water and dried to yield 3- (3,5-dimethoxyphenyl) -1H-parasol- in 70% yield. 4-carboxyaldehyde was obtained.

Step 3 . (3- (3,5- Dimethoxyphenyl ) -1- (4-methoxybenzyl) -1H- Pyrazole -4-yl) methanol

3- (3,5-dimethoxyphenyl) -1H-parazol-4-carboxyaldehyde (1.0 g) was dissolved in ethanol, and then 1.5 equivalents of NaBH ₄ was added and stirred at room temperature for 4 hours.

Ethanol was removed by concentration under reduced pressure, and then dissolved in ethyl acetate and washed with water. After drying over anhydrous sodium sulfate, the reaction mixture was concentrated under reduced pressure to obtain (3- (3,5-dimethoxyphenyl) -1- (4-methoxybenzyl) -1H-pyrazol-4-yl) methanol in a yield of 90%. Synthesized.

More specifically, the NMR analysis results of (3- (3,5-dimethoxyphenyl) -1- (4-methoxybenzyl) -1H-pyrazol-4-yl) methanol synthesized as described above are as follows. Described.

NMR δ, 7.38 (d, 1H), 7.23 (d, 2H), 6.88 (d, 2H), 6.65 (d, 1H), 6.48 (t, 2H), 5.26 (s, 2H), 4.62 (s, 2H ), 3.86 (s, 3H), 3.83 (s, 3H), 3.79 (s, 3H)

< Example  14>

(E) -5-((3- (3,4- Dimethoxyphenyl ) -1- (4-methoxybenzyl) -1H- Pyrazole -4-yl) methylene) Thiazolidine -2,4- Dion  (Compound 14) Synthesis

(E) -5-((3- (3,4-dimethoxyphenyl) -1- (4-methoxybenzyl) -1H-pyrazol-4-yl) methylene) thiazolidine-2,4 Dion was synthesized on the basis of known literature, International Patent Application (International Patent Application Publication No. WO06 / 101307). Specifically, 3- (3,4-dimethoxyphenyl) -1H-parazol-4-carboxyaldehyde obtained through the same process as in <Example 13> using 3,4-dimethoxy acetophenone The starting material was synthesized through the following procedure.

The aldehyde (0.5 g) and 1 equivalent of tazolidine-2,4-dione were dissolved in anhydrous toluene, followed by addition of acetic acid (3.7 ul) and piperidine (7.8 uL) as a catalyst. It was refluxed while removing water with a Stark trap. After cooling to room temperature, the mixture was stirred for 6 hours and the resulting solid was filtered and washed with diethyl ether to obtain (E) -5-((3- (3,4-dimethoxyphenyl) -1- ( 4-methoxybenzyl) -1H-pyrazol-4-yl) methylene) thiazolidine-2,4-dione was obtained.

(E) -5-((3- (3,4-dimethoxyphenyl) -1- (4-methoxybenzyl) -1H-pyrazol-4-yl) methylene) thiazole synthesized as above The results of NMR analysis of din-2,4-dione are described as follows.

NMR δ, 7.82 (s, 1H), 7.58 (s, 1H), 7.35 ~ 7.21 (m, 4H), 7.18 ~ 7.03 (m, 1H), 6.98 ~ 6.92 (t, 2H), 5.32 (s, 2H) , 3.90 (s, 1H), 3.82 (s, 1H)

Compounds having phosphodiesterase inhibitory activity as described above are described in a total of 17 novel compounds synthesized in the present invention and in international patent application (International Patent Application Publication No. WO06 / 101307) which is known as follows. Compound. In particular, the compounds described in International Patent Application (International Patent Application Publication No. WO06 / 101307), which are known documents, are summarized as follows.

Compound 15: (E) -5-((3- (4-ethoxy-3-isopropylphenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) -1-methylimidazolidine- 2,4-dione

M + 1: 432

Compound 16: (Z) -3- (methylsulfonyl) -5-((3- (3-nitrophenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) thiazolidine-2, 4-dione

M + 1: 587

Compound 17: (Z) -5-((3- (2,5-dichlorophenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) thiazolidine-2,4-dione

NMR δ, 7.19 (s, 1H), 7.41-7.75 (m, 6H), 8.01 (d, 2H), 8.76 (s, 1H), 12.54 (br, 1H)

Compound 18: (Z) -5-((3- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -1- (pyridin-2-yl) -1H-pyrazole-4 -Yl) methylene) -2-thiazolidine-2,4-dione

M + 1: 484

Compound 19: (Z) -5-((3- (3,4-bis (difluoromethoxy) phenyl) -1- (pyridin-2-yl) -1H-pyrazol-4-yl) methylene) thi Azolidine-2,4-dione

M + 1: 481

Compound 20: (Z) -5-((3- (3,5-Dibromo-4- (difluoromethoxy) phenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) -3- (Propo-2-pinyl) thiazolidine-2,4-dione

NMR δ, 1.52 (t, 1H), 4.52 (d, 2H), 6.32-7.06 (m, 1H), 7.43-7.89 (m, 8H), 8.19 (s, 1H)

Compound 21: (Z) -5-((3- (3,5-Dibromo-4- (difluoromethoxy) phenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) thiazoli Dean-2,4-dione

NMR δ, 6.48-6.97 (m, 1H), 7.42-7.57 (m, 3H), 7.66 (s, 1H), 7.78-7.81 (m, 2H), 7.90 (s, 2H), 8.23 (s, 1H) .

Compound 22: (Z) -5-((3- (3,5-Dibromo-4-ethoxyphenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) -3- (prop- 2-personal) thiazolidine-2,4-dione

NMR δ, 1.55 (t, 3H), 2.30 (t, 1H), 4.18 (q, 2H), 4.52 (d, 2H), 7.42-7.88 (m, 8H), 8.18 (s, 1H)

Compound 23: (Z) -5-((3- (3,5-Dibromo-4-propoxyphenyl) -1- (pyridin-2-yl) -1H-pyrazole-4-yl) methylene) Azolidine-2,4-dione

M + 1: 564

Compound 24: (Z) -5-((3- (3,5-Diisopropyl-4-propoxyphenyl) -1- (4-nitrophenyl) -1H-pyrazol-4-yl) methylene) thi Azolidine-2,4-dione

NMR δ, 1.09 (t, 3H), 1.26 (d, 12H), 1.82-1.88 (m, 2H), 3.65-3.95 (m, 2H), 7.40-8.80 (m, 8H), 8.70 (s, 1H) , 12.90 (br, 1H)

Compound 25: (Z) -5-((3- (3,5-di-t-butyl-4-hydroxyphenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) thiazolidine -2,4-dione

NMR δ, 1.27 (s, 18H), 6.92-7.20 (m, 1H), 7.17-7.28 (m, 2H), 7.39 (t, 2H), 7.50 (s, 1H), 7.82 (d, 2H), 8.48 (s, 1H), 12.31 (br, 1H)

Compound 26: (Z) -5-((3- (3,5-bis (benzyloxy) phenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) -3- (methylsulfonyl) thio Azolidine-2,4-dione

M + 1: 639

Compound 27: (Z) -5-((3- (3,5-bis (cyclopentyloxy) phenyl) -1- (pyridin-2-yl) -1H-pyrazol-4-yl) methylene) thia Zolidine-2,4-dione

M + 1: 518

Compound 28: (Z) -5-((3- (3-bromo-4- (cyclopropylmethoxy) phenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) -3-methylthio Azolidine-2,4-dione

NMR δ, 0.43-0.48 (m, 2H), 0.64-0.73 (m, 2H), 1.26-1.40 (m, 1H), 3.97 (d, 2H), 6.97-8.18 (m, 10H)

Compound 29: (Z) -5-((3- (3-bromo-4-ethoxyphenyl) -1- (pyridin-2-yl) -1H-pyrazol-4-yl) methylene) -3- (Methylsulfonyl) thiazolidine-2,4-dione

M + 1: 550

Compound 30: (Z) -5-((3- (3-bromo-4-ethoxyphenyl) -1- (pyridin-2-yl) -1H-pyrazol-4-yl) methylene) thiazoli Dean-2,4-dione

M + 1: 472

Compound 31: (Z) -5-((3- (3-bromo-4-ethoxyphenyl) -1- (pyrimidin-2-yl) -1H-pyrazol-4-yl) methylene) thia Zolidine-2,4-dione

M + 1: 473

Compound 32: (Z) -5-((3- (3-isopropyl-4-propoxyphenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) thiazolidine-2,4- Dion

NMR δ, 1.04 (t, 3H, J = 7.4 Hz), 1.23 (d, 6H, J = 6.8 Hz), 1.62-1.84 (m, 2H), 3.91-4.09 (m, 2H), 7.42-8.04 (m , 10H), 8.75 (s, 1H)

Compound 33: (Z) -5-((3- (3-chloro-4-propoxyphenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) -3- (methylsulfonyl) thia Zolidine-2,4-dione

M + 1: 519

Compound 34: (Z) -5-((3- (3-t-butyl-4-propoxyphenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) thiazolidine-2,4 Dion

NMR δ, 1.08 (t, 3H, J = 7.5 Hz), 1.41 (s, 9H), 1.85 (m, 2H), 4.06 (t, 2H, J = 5.7 Hz), 7.13-8.03 (m 9H), 8.67 (s, 1H), 12.52 (br, 1H)

Compound 35: (Z) -ethyl 2- (2,6-di-t-butyl-4- (4-((2,4-dioxothiazolidine-5-ylidene) methyl) -1-phenyl -1H-pyrazol-3-yl) phenoxy) acetate

NMR δ, 1.26 (t, 3H), 1.24 (d, 12H), 3.68-3.80 (m, 2H), 3.84 (q, 4H), 7.37-7.56 (m, 7H), 7.80 (s, 1H), 8.18 (s, 1H)

Compound 36: (Z) -ethyl 2- (5-((3- (3,5-dibromo-4- (difluoromethoxy) phenyl) -1-phenyl-1H-pyrazol-4-yl) methylene ) -2,4-dioxothiazolidin-3-yl) acetate

M + 1: 658

Compound 37: (Z) -ethyl 2- (5-((3- (3-bromo-4- (cyclopropylmethoxy) phenyl) -1-phenyl-1H-pyrazol-4-yl) methylene)- Dioxothiazolidin-3-yl) acetate

M + 1: 583

Compound 38: (Z) -ethyl 2- (5-((3- (3-bromo-4-methoxyphenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) -2,4- Dioxothiazolidin-3-yl) acetate

M + 1: 543

Compound 39: (Z) -ethyl 2- (5-((3- (4- (allyloxy) -3,5-dibromophenyl) -1-phenyl-1H-pyrazol-4-yl) methylene)- Dioxothiazolidin-3-yl) acetate

M + 1: 648

Compound 40: (Z) -ethyl 4- (5-((3- (3- (cyclopentyloxy) -4-methoxyphenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) -4 -Oxo-2-thioxothiazolidin-3-yl) butannoate

M + 1: 593

< Experimental Example  1>

Of the compounds of the present invention Phosphodiesterase  Inhibitory activity

In order to confirm whether the compound of the present invention has phosphodiesterase inhibitory activity, a PDE10a IC ₅₀ assay experiment was conducted (Kotomi Fujishige et.al. journal of Bio.Chem., Vol. 274, 1999, 18438). ). Specifically, the experiment is a test for determining whether the compound of the present invention inhibits phosphodiesterase 10a (PDE10a: NCBI Registration No .: NP_001124162) and the entire experiment can be largely separated into an enzyme reaction process and a detection process.

For the enzymatic reaction, the compound of the present invention, 250nM cAMP, 8nM PDE10a and the reaction buffer (50mM Tris-HCl (pH7.5), 4mM MgCl ₂ ) were mixed and reacted at 30 ° C. for 1 hour, followed by enzymatic reaction. Heated at 95 ° C. for 2 minutes to stop.

Next, 10ul of the total reaction solution was transferred to a 96-well plate for detection, and biotinylated cAMP (1 unit biotinylated-cAMP) and donor beads (1 unit donor bead) were added and reacted at room temperature for 30 minutes. Receptor beads (1 unit acceptor bead) was added and further reacted for 45 minutes at room temperature. Signals were detected using Fusion alpha FP instrument (Packard Bioscience). (excitation 680nm, emission 520-620nm).

The measurement results are described as follows.

Phosphodiesterase inhibitory activity of the compounds of the present invention in uM compound IC ₅₀ compound IC ₅₀ compound IC ₅₀ compound IC ₅₀ One 8.7 11 22 21 0.34 31 0.16 2 15.5 12 22 22 3.5 32 0.32 3 18 13 42 23 0.32 33 > 10 4 22 14 1.2 24 0.62 34 0.17 5 > 50 15 > 10 25 0.89 35 0.60 6 12.5 16 0.20 26 0.03 36 0.46 7 11.5 17 3.35 27 0.42 37 2.65 8 > 50 18 0.60 28 3.6 38 1.85 9 50 19 1.0 29 0.40 39 2.05 10 > 50 20 0.73 30 1.55 40 1.45

Claims (11)

A compound of Formula 1, a pharmaceutically acceptable salt, hydrate or solvate thereof; <Formula 1>

In the above formula; A1, A2 and A3 are each independently a functional group selected from the group consisting of hydrogen, C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C5 cycloalkoxy, C1 to C5 cyclic methoxy and halogen; R 1 is selected from the group consisting of hydrogen, a C 1 to C 5 alkyl group substituted or unsubstituted with a hydroxy group, CH—R 6 and CH ₂ —O—R 7; R6 and R7 are each independently C3 to C6 monocyclic, C8 to C10 bicyclic, nitrogen, oxygen and sulfur, including at least one selected from the group consisting of C3 to C6 heteromonocyclic, nitrogen, oxygen And C8 to C10 heterobicyclic, C5 to C6 monocyclic aromatic, C8 to C10 bicyclic aromatic, nitrogen, oxygen and sulfur, including at least one selected from the group consisting of sulfur. A functional group selected from the group consisting of C5 to C6 heteromonocyclic aromatic and C8 to C10 heterobicyclic aromatic including at least one selected from the group consisting of nitrogen and oxygen; R2 is a group consisting of C3 to C6 monocyclic, C8 to C10 bicyclic, nitrogen, oxygen and sulfur containing at least one kind selected from the group consisting of C3 to C6 heteromonocyclic, nitrogen, oxygen and sulfur C5 including at least one selected from the group consisting of C8 to C10 heterobicyclic, C5 to C6 monocyclic aromatic, C8 to C10 bicyclic aromatic, nitrogen, oxygen and sulfur A functional group selected from the group consisting of C8 to C10 heterobicyclic aromatic including at least one selected from the group consisting of nitrogen, oxygen and sulfur; n is 1 or 2, and when n is 2, it is unsubstituted or substituted with 1 or 2 oxo groups. According to claim 1, in Formula 1; A 1, A 2 and A 3 are each independently hydrogen or alkoxy of C 1 to C 6; R 1 is selected from the group consisting of hydrogen, a C 1 to C 5 alkyl group substituted with a hydroxy group, CH—R 6 and CH ₂ —O—R 7; R6 and R7 are each independently C3 to C6 heteromonocyclic including at least one selected from the group consisting of nitrogen, oxygen and sulfur, or C8 to C10 containing at least one selected from the group consisting of nitrogen, oxygen and sulfur A functional group selected from the group consisting of heterobicyclic aromatic R2 is C5 to C6 monocyclic aromatic, C8 to C10 bicyclic aromatic, C5 to C6 heteromonocyclic aromatic and nitrogen, oxygen and sulfur containing at least one selected from the group consisting of It is a functional group selected from the group consisting of C8 to C10 heterobicyclic aromatic containing at least one selected from the group consisting of; n is 1 or 2, and when n is 2, a compound substituted with one oxo group or unsubstituted, a pharmaceutically acceptable salt, hydrate or solvate thereof. According to claim 1 or 2, in Formula 1; R 6 and R 7 each independently include an oxo group as a substituent, a pharmaceutically acceptable salt, hydrate or solvate thereof. According to claim 1 or 2, in Formula 1; R2 comprises at least one substituent selected from the group consisting of C1 to C5 alkyl, C3 to C6 cycloalkyl, C1 to C4 alkoxy, amine, nitro, halogen, sulfone, sulfoxide, sulfonamide, amide and ester Phosphorus compounds, pharmaceutically acceptable salts, hydrates or solvates thereof. The compound of claim 1, wherein the compound of Formula 1 is selected from the group consisting of 8-((3- (3,4-dimethoxyphenyl) -1H-pyrazol-1-yl) methyl) quinoline; 5-((3- (3,4-dimethoxyphenyl) -1H-pyrazol-1-yl) methyl) quinoxaline; 3- (3,4-dimethoxyphenyl) -1- (naphthalen-2-ylmethyl) -1H-pyrazole; 2- (3- (3,4-dimethoxyphenyl) -1H-pyrazol-1-yl) -1- (naphthalen-2-yl) ethanol; 1-benzyl-3- (3,4-dimethoxyphenyl) -1H-pyrazole; 3- (3,4-dimethoxyphenyl) -1-phenethyl-1H-pyrazole; 3- (3,4-dimethoxyphenyl) -1- (4-methoxybenzyl) -1H-pyrazole; 3- (3,5-dimethoxyphenyl) -1- (4-methoxybenzyl) -1H-pyrazole; 3- (3,5-dimethoxyphenyl) -1- (naphthalen-2-ylmethyl) -1H-pyrazole; 3- (3,5-dimethoxyphenyl) -1- (2- (naphthalen-1-yl) ethyl) -1H-pyrazole; 6-((3- (3,5-dimethoxyphenyl) -1- (4-methoxybenzyl) -1H-pyrazol-4-yl) methoxy) quinoline; 3- (3,4-dimethoxyphenyl) -1- (2- (naphthalen-1-yl) ethyl) -1H-pyrazole; (3- (3,5-dimethoxyphenyl) -1- (4-methoxybenzyl) -1H-pyrazol-4-yl) methanol and (E) -5-((3- (3,4- Dimethoxyphenyl) -1- (4-methoxybenzyl) -1H-pyrazol-4-yl) methylene) thiazolidine-2,4-dione, a pharmaceutically acceptable compound thereof Salts, hydrates or solvates. A pharmaceutical composition for preventing or treating central nervous system diseases containing at least one compound selected from the group consisting of a compound of Formula 2, a pharmaceutically acceptable salt, hydrate and solvate thereof as an active ingredient; <Formula 2>

In the above formula; A1, A2 and A3 are each independently hydrogen, C1 to C6 alkyl, C1 to C8 alkoxy, C1 to C8 alkoxy substituted with halogen, C1 to C8 alkoxy substituted with C1 to C8 monocyclic, C5 C1 to C8 alkoxy substituted with monocyclic aromatic of C6 to C6, C1 to C8 alkoxy, halogen, nitro group and hydroxy groups substituted with alkyl esters of C1 to C5; R 1 is selected from the group consisting of hydrogen, a C 1 to C 5 alkyl group substituted or unsubstituted with a hydroxy group, CH—R 6 and CH ₂ —O—R 7; R6 and R7 are each independently C3 to C6 monocyclic, C8 to C10 bicyclic, nitrogen, oxygen and sulfur, including at least one selected from the group consisting of C3 to C6 heteromonocyclic, nitrogen, oxygen And C8 to C10 heterobicyclic, C5 to C6 monocyclic aromatic, C8 to C10 bicyclic aromatic, nitrogen, oxygen and sulfur, including one or more selected from the group consisting of sulfur. A functional group selected from the group consisting of C8 to C6 heteromonocyclic aromatic and C8 to C10 heterobicyclic aromatic including at least one selected from the group consisting of nitrogen, oxygen and sulfur; R2 is C3 to C6 monocyclic, C8 to C6, linked directly or linked to a linker selected from the group consisting of C1 to C3 alkyl, ether, ester, amine and thioether, substituted or substituted with one to three oxo groups C8 to C10 hetero containing at least one selected from the group consisting of C3 to C6 heteromonocyclic, nitrogen, oxygen and sulfur containing at least one selected from the group consisting of C10 bicyclic, nitrogen, oxygen and sulfur C5 to C6 heteromonocyclic aromatic and nitrogen, oxygen, including at least one selected from the group consisting of bicyclic, C5 to C6 monocyclic aromatic, C8 to C10 bicyclic aromatic, nitrogen, oxygen and sulfur And in the group consisting of C8 to C10 heterobicyclic aromatic containing at least one selected from the group consisting of sulfur Selected functional group. According to claim 6, in Formula 2; R 1 is selected from the group consisting of hydrogen, a C 1 to C 5 alkyl group substituted with a hydroxy group, CH—R 6 and CH ₂ —O—R 7; R6 and R7 are each independently selected from the group consisting of at least one selected from the group consisting of nitrogen, oxygen and sulfur C3 to C6 heteromonocyclic or C8 to C10 containing at least one selected from the group consisting of nitrogen, oxygen and sulfur A functional group selected from the group consisting of heterobicyclic aromatics; R2 is C5 to C6 monocyclic aromatic, C8 to C10 bicyclic aromatic, nitrogen, oxygen and sulfur, which are directly linked or substituted with 1 to 3 oxo groups or unsubstituted C1 to C3 alkyl group by linker A functional group selected from the group consisting of C5 to C6 heteromonocyclic aromatic containing at least one selected from the group consisting of and C8 to C10 heterobicyclic aromatic containing at least one selected from the group consisting of nitrogen, oxygen and sulfur Pharmaceutical composition for the prevention or treatment of phosphorus central nervous system diseases. According to claim 6 or 7, wherein in the formula (2); R6 and R7 are each independently composed of an oxo group, C1 to C5 alkyl, C1 to C5 alkyne, C1 to C5 alkyl sulfonyl and C1 to C5 alkyl acetate, unsubstituted or substituted with alkyl esters of C1 to C5. A pharmaceutical composition for preventing or treating central nervous system diseases comprising at least one substituent selected from the group. According to claim 6 or 7, wherein in the formula (2); R2 comprises at least one substituent selected from the group consisting of C1 to C5 alkyl, C3 to C6 cycloalkyl, C1 to C4 alkoxy, amine, nitro, halogen, sulfone, sulfoxide, sulfonamide, amide and ester Pharmaceutical composition for the prevention or treatment of phosphorus central nervous system diseases. The compound of claim 6, wherein the compound of Formula 2 is selected from 8-((3- (3,4-dimethoxyphenyl) -1H-pyrazol-1-yl) methyl) quinoline; 5-((3- (3,4-dimethoxyphenyl) -1H-pyrazol-1-yl) methyl) quinoxaline; 3- (3,4-dimethoxyphenyl) -1- (naphthalen-2-ylmethyl) -1H-pyrazole; 2- (3- (3,4-dimethoxyphenyl) -1H-pyrazol-1-yl) -1- (naphthalen-2-yl) ethanol; 1-benzyl-3- (3,4-dimethoxyphenyl) -1H-pyrazole; 3- (3,4-dimethoxyphenyl) -1-phenethyl-1H-pyrazole; 3- (3,4-dimethoxyphenyl) -1- (4-methoxybenzyl) -1H-pyrazole; 3- (3,5-dimethoxyphenyl) -1- (4-methoxybenzyl) -1H-pyrazole; 3- (3,5-dimethoxyphenyl) -1- (naphthalen-2-ylmethyl) -1H-pyrazole; 3- (3,5-dimethoxyphenyl) -1- (2- (naphthalen-1-yl) ethyl) -1H-pyrazole; 6-((3- (3,5-dimethoxyphenyl) -1- (4-methoxybenzyl) -1H-pyrazol-4-yl) methoxy) quinoline; 3- (3,4-dimethoxyphenyl) -1- (2- (naphthalen-1-yl) ethyl) -1H-pyrazole; (3- (3,5-dimethoxyphenyl) -1- (4-methoxybenzyl) -1H-pyrazol-4-yl) methanol; (E) -5-((3- (3,4-dimethoxyphenyl) -1- (4-methoxybenzyl) -1H-pyrazol-4-yl) methylene) thiazolidine-2,4 -Dione; (E) -5-((3- (4-ethoxy-3-isopropylphenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) -1-methylimidazolidine-2,4 -Dione; (Z) -3- (methylsulfonyl) -5-((3- (3-nitrophenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) thiazolidine-2,4-da ion; (Z) -5-((3- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -1- (pyridin-2-yl) -1H-pyrazol-4-yl) Methylene) -2-thiazolidine-2,4-dione; (Z) -5-((3- (3,4-bis (difluoromethoxy) phenyl) -1- (pyridin-2-yl) -1H-pyrazol-4-yl) methylene) thiazolidine -2,4-dione; (Z) -5-((3- (3,5-dimethoxyphenyl) -1- (pyridin-2-yl) -1H-pyrazol-4-yl) methylene) thiazolidine-2,4 -Dione; (Z) -5-((3- (3,5-Dibromo-4- (difluoromethoxy)) phenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) -3- (pro Po-2-pinyl) thiazolidine-2,4-dione; (Z) -5-((3- (3,5-Dibromo-4- (difluoromethoxy) phenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) thiazolidine-2 , 4-dione; (Z) -5-((3- (3,5-Dibromo-4-ethoxyphenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) -3- (prop-2-ynyl Thiazolidine-2,4-dione; (Z) -5-((3- (3,5-Dibromo-4-propoxyphenyl) -1- (pyridin-2-yl) -1H-pyrazole-4-yl) methylene) thiazolidine -2,4-dione; (Z) -5-((3- (3,5-Diisopropyl-4-propoxyphenyl) -1- (4-nitrophenyl) -1H-pyrazol-4-yl) methylene) thiazolidine -2,4-dione; (Z) -5-((3- (3,5-di-t-butyl-4-hydroxyphenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) thiazolidine-2, 4-dione; (Z) -5-((3- (3,5-bis (benzyloxy) phenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) -3- (methylsulfonyl) thiazolidine -2,4-dione; (Z) -5-((3- (3,5-bis (cyclopentyloxy) phenyl) -1- (pyridin-2-yl) -1H-pyrazol-4-yl) methylene) thiazolidine- 2,4-dione; (Z) -5-((3- (3-bromo-4- (cyclopropylmethoxy) phenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) -3-methylthiazolidine -2,4-dione; (Z) -5-((3- (3-bromo-4-ethoxyphenyl) -1- (pyridin-2-yl) -1H-pyrazol-4-yl) methylene) -3- (methylsul Fonyl) thiazolidine-2,4-dione; (Z) -5-((3- (3-bromo-4-ethoxyphenyl) -1- (pyridin-2-yl) -1H-pyrazol-4-yl) methylene) thiazolidine-2 , 4-dione; (Z) -5-((3- (3-bromo-4-ethoxyphenyl) -1- (pyrimidin-2-yl) -1H-pyrazol-4-yl) methylene) thiazolidine- 2,4-dione; (Z) -5-((3- (3-isopropyl-4-propoxyphenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) thiazolidine-2,4-dione; (Z) -5-((3- (3-chloro-4-propoxyphenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) -3- (methylsulfonyl) thiazolidine- 2,4-dione; (Z) -5-((3- (3-t-butyl-4-propoxyphenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) thiazolidine-2,4-dione ; (Z) -Ethyl 2- (2,6-di-t-butyl-4- (4-((2,4-dioxothiazolidine-5-ylidene) methyl) -1-phenyl-1H- Pyrazol-3-yl) phenoxy) acetate; (Z) -ethyl 2- (5-((3- (3,5-dibromo-4- (difluoromethoxy) phenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) -2 , 4-dioxothiazolidin-3-yl) acetate; (Z) -Ethyl 2- (5-((3- (3-bromo-4- (cyclopropylmethoxy) phenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) -dioxothio Azolidin-3-yl) acetate; (Z) -ethyl 2- (5-((3- (3-bromo-4-methoxyphenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) -2,4-dioxothio Azolidin-3-yl) acetate; (Z) -Ethyl 2- (5-((3- (4- (allyloxy) -3,5-dibromophenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) -dioxothio Azolidin-3-yl) acetate and (Z) -ethyl 4- (5-((3- (3- (cyclopentyloxy) -4-methoxyphenyl) -1-phenyl-1H-pyrazole-4 -Yl) methylene) -4-oxo-2-thioxothiazolidin-3-yl) butannoate is a compound selected for the prevention or treatment of central nervous system diseases. The system of claim 6, wherein the central nervous system disease is age-associated memory impairment, mild cognitive impairment, elderly dementia (early onset Alzheimer's disease), senile dementia (Alzheimer's type of dementia) ), Lewy body dementia, vascular dementia, Alzheimer's disease, stroke, AIDS dementia complex, attention deficit disorder, attention deficit hyperactivity disorder, dyslexia, schizophrenia ( schizophrenia, schizophreniform disorder, obesity, insulin-independent diabetes, mood swings, schizoaffective disorder, Parkinson's disease, and Huntington's disease Pharmaceutical compositions for the prevention or treatment of diseases of the nervous system.