KR20140025835A - Pharmaceutical composition for preventing or treating bone disease comprising quinoline derivatives - Google Patents

Abstract

The present invention relates to a pharmaceutical composition comprising quinoline derivatives or a pharmaceutically acceptable salt thereof for preventing or treating bone diseases. More specifically, the composition of the present invention can be used as a pharmaceutical composition for preventing or treating the bone diseases such as fracture and osteoporosis since the composition has an effect of promoting differentiation and activation of osteoblast.

Description

[0001] The present invention relates to a pharmaceutical composition for preventing or treating osteoporosis comprising quinoline derivatives,

The present invention relates to quinoline derivatives which can be usefully used for the prevention or treatment of bone diseases.

Bone tissue constitutes the cartilage and skeletal system. It plays a role of support and muscle attachment by mechanical function, protects organism and bone marrow, and preserve calcium and phosphorus to maintain homeostasis. It is a very dynamic tissue that maintains homeostasis by breaking down little by little every day and forming new bone in proportion to the amount disintegrated. Specifically, the bone is repeatedly cycled for about 120 to 150 days including osteoclast-induced bone resorption, osteoblast-induced osteogenesis and dormancy. In healthy adults, bone resorption and bone formation are strictly controlled, and the total bone mass remains almost unchanged.

The osteocyte is formed from mesenchymal stem cells. Mineralization such as calcium formation by osteoblast differentiation not only maintains bone strength, but also plays an important role in the homeostasis of calcium and hormone metabolism throughout the body. Calcium formation by osteoblast differentiation is regulated by vitamin D and parathyroid hormone. Bone morphogenesis by osteoblast differentiation induces bone morphogenetic protein (BMP), Wnt, MAP Related to the differentiation of osteoblasts by the cross-talk of various signal transduction systems such as kinase, calcineurin-calmodulin kinase, NF-κB and AP-1. phosphatase, ALP) are synthesized in the early stage of differentiation and then osteopontin, osteocalcin, type I collagen, etc. associated with mineralization are synthesized (Pittenger, MF, Mackay, AM, Beck, SC; Jaiswal, RK; Douglas, R .; Mosca, JD; Moorman, MA, Simmonetti, DW; Craig, S.; Marshak, DR Multilineage Potential of Adult Human Mesenchymal Stem Cells. Science 1999, 284, 143-147). That is, the compounds that promote the activity of alkaline phosphatase may promote the differentiation of osteocytes and may be targets of therapeutic agents for bone diseases.

Osteoporosis, a typical example of bone disease, is a disease caused by weakening of bone density due to breakage of equilibrium between bone formation and bone resorption. Currently, about 10 million people already suffer from osteoporosis disease in the US and 18 million people are at risk of osteoporosis. In addition, one in two women and one in eight men experience lifelong fractures associated with osteoporosis, and over two million Americans already have osteoporosis. In the United States, direct spending on osteoporosis-related illnesses and fractures is about $ 14 billion annually, and about 400 million people in the country are at risk for osteoporosis. It is estimated that this will increase further as the society becomes more aged, and it is expected that social spending and psychological and economic expenditure of family members will be large.

In order to treat the above-mentioned bone diseases, it is necessary to control the balance between osteoclasts and osteoblasts. Therefore, bone resorption inhibitors and bone formation stimulators are widely used as therapeutic agents. Although bone resorption stimulants have been actively studied, bone mineral density enhancement due to osteogenic stimuli does not necessarily mean reduction of fracture. Therefore, more research is needed to be widely used for clinical use. In addition, as an agent for stimulating osteogenesis, an accelerator for activating osteoblast and an inhibitor for inhibiting bone resorption of osteoclast generally need to be administered to a patient for a long period of time. The research on this subject is urgently needed.

In view of the fact that most of the osteoporosis treatment agents currently in use are bone resorption inhibitors, the inventors of the present invention have made efforts to find a compound that promotes osteoblast differentiation with an interest in osteoblast osteogenesis. As a result, The present inventors confirmed that they have a preventive and therapeutic effect on bone diseases by promoting differentiation and completed the invention.

The present invention provides a pharmaceutical composition for preventing or treating a bone disease comprising a quinoline derivative or a pharmaceutically acceptable salt thereof.

In one aspect, the present invention provides a pharmaceutical composition for preventing or treating bone diseases, comprising a quinoline derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

In the above formula

R ₁ is hydrogen; C ₁ -C ₄ alkyl; C ₁ -C ₄ haloalkyl; Phenyl; Or pyridinyl,

R ₂ is hydrogen; Or halogen,

R ₃ is hydrogen; Or C ₁ -C ₄ alkyl, and

R ₄ is hydrogen; C ₁ -C ₄ alkyl; C ₁ -C ₄ haloalkyl; Phenylsulfonyl unsubstituted or substituted by C ₁ -C ₄ haloalkoxy; One or two C ₁ -C ₄ Phenylamido substituted with alkoxy or halogen; Or 3-carboxy-cyclobutanecarbonyl.

Preferably, R ₁ is hydrogen, methyl, trifluoromethyl, phenyl, or pyridin-4-yl.

Preferably, R < ₂ > is hydrogen or chloro.

Preferably, R ₃ is hydrogen or methyl.

Preferably, R ₄ is selected from the group consisting of hydrogen, methyl, 2-chloroethyl, phenylsulfonyl, 2-trifluoromethoxy-phenylsulfonyl, 2-methoxy- phenylamido, 2,4- difluoro-phenyl Amido, or 3-carboxy-cyclobutanecarbonyl.

Representative examples of the quinoline derivative represented by the above formula (1) are as follows:

1) 4- (4-Methylpiperazin-1-yl) -2- (pyridin-4-yl) quinoline,

2) 2-methyl-4- (4- (phenylsulfonyl) piperazin-1-yl) quinoline,

3) 4- (4-methylpiperazin-1-yl) -2-phenylquinoline,

4) 2- (4- (2-methylquinolin-4-yl) piperazine-1-carbonyl) cyclobutanecarboxylic acid,

5) 4- (4- (2- (Trifluoromethoxy) phenylsulfonyl) piperazin-1-yl) -2- (trifluoromethyl) quinoline,

6) Synthesis of 4- (7-chloroquinolin-4-yl) -N- (2-methoxyphenyl) piperazine-

7) Synthesis of 4- (7-chloroquinolin-4-yl) -N- (2,5-difluorophenyl) piperazine-

8) 7-Chloro-4- (4- (2-chloroethyl) piperazin-1-yl) quinoline,

9) 7-Chloro-4- (4-methylpiperazin-1-yl) quinoline and

10) 6-Methyl-4- (piperazin-1-yl) -2- (trifluoromethyl) quinoline.

The quinoline derivative represented by the above formula (1) of the present invention can be isolated from a natural source, prepared by chemical modification obtained from a natural source, or chemically synthesized by a person skilled in the art by a known production method, And the like. In a specific example of the present invention, 10 quinoline compounds were commercially purchased and used.

The quinoline derivatives of the present invention can be used in the form of pharmaceutically acceptable salts. The compounds of the present invention may also be used alone or in combination with other pharmaceutically active compounds or as a set.

As used herein, the term "pharmaceutically acceptable salts" refers to salts prepared according to methods conventional in the art, and such methods of preparation are known to those skilled in the art. In particular, the pharmaceutically acceptable salts include, but are not limited to, salts derived from inorganic and organic acids and bases which are pharmacologically or physiologically acceptable. Examples of suitable acids include hydrochloric acid, bromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, formic acid , Benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like. Salts derived from suitable bases may include alkali metals such as sodium, or potassium, alkaline earth metals such as magnesium.

The composition of the present invention can be used without limitation in bone related diseases in which osteoclast activation is required.

As used herein, the term "bone disease" means a condition or disease in which an increase in bone mass is required or required in order to promote the activity of osteoblasts, and includes bone loss diseases. The term "lowering bone disease" refers to a condition or disease in which a decrease in bone mass accompanied by a symptom such as a decrease in bone density, a deterioration in a bone tissue or the like occurs, and includes, for example, osteoporosis, Paget's disease, periodontal disease, Rheumatoid arthritis, < / RTI >

Preferably, the composition of the present invention can be used for preventive treatment of osteoporosis or osteopenia. Specifically, the term "osteoporosis" as used herein means a condition in which bone mass is decreased and fracture is likely to occur due to a qualitative change, and "osteopenia" means an initial symptom of osteoporosis. In general, osteopenia is classified as -1.0 to -2.5 based on the bone mineral density (T value), and osteoporosis is classified as -2.5 or more.

As used herein, the term "prevention or treatment of bone disease" includes prevention and complete or partial treatment of the bone disease. It also includes reduction or amelioration of symptoms of bone disease, relief of the symptoms of pain, reduction in the incidence of bone disease, or any other change in the patient that increases the outcome of the treatment.

Preferably, the composition of the present invention is characterized by promoting osteoblast differentiation or activity. As used herein, the term "osteoblast" refers to a cell that plays a role in enhancing bone mineral density by making bone cells from cells differentiated from mesenchymal stem cells.

In a specific example, the quinoline derivative of the present invention was treated with mesenchymal stem cell C2C12, and the activity of ALP (alkaline phosphatase), which is a differentiation marker in the early stage of osteoblast differentiation, was remarkably increased One).

As used herein, the term "ALP (alkaline phosphatase) " refers to an alkaline phosphatase and is widely distributed in the cytoplasm of each tissue cell. Among them, ALP, which is present in bone, is a differentiation marker of osteoblast. When the activity of ALP increases, osteoblast differentiates or activates. In healthy persons, the positive index of ALP is 220 ± 30, and when it is lowered, chronic myelogenous leukemia and leukemia may occur. In case of elevation, bone marrow fibrosis, osteosclerosis or leukemia may appear.

The quinoline derivatives of the present invention can promote the differentiation and activity of osteoblast ultimately through the increase of ALP activity of bone, thus effectively preventing and treating bone diseases.

Preferably, the pharmaceutical composition of the present invention may contain 0.01 to 1% by weight of the quinoline derivative.

The pharmaceutical composition for preventing or treating bone diseases of the present invention may contain a pharmaceutically acceptable carrier, excipient or diluent in addition to the above-described effective ingredient. Examples of the carrier, excipient and diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, Cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

The pharmaceutical compositions of the present invention may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols or the like, oral preparations, suppositories or sterilized injection solutions according to a conventional method have. In detail, when formulating, it can be prepared by using diluents or excipients such as fillers, weighing agents, binders, humectants, disintegrants, surfactants and the like which are generally used. Solid formulations for oral administration include, but are not limited to, tablets, pills, powders, granules, capsules, and the like. Such a solid preparation may be prepared by mixing at least one excipient, for example, starch, calcium carbonate, sucrose, lactose, gelatin, and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid preparations for oral administration, liquid paraffin, and various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations and suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, and the like. Examples of the suppository base include withexol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like.

The pharmaceutical composition of the present invention may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically) depending on the intended method, and the dose may vary depending on the condition and the weight of the patient, The mode of administration, the route of administration, and the time, but may be appropriately selected by those skilled in the art.

The pharmaceutical composition comprising the quinoline derivative according to the present invention promotes osteoblast differentiation and mineralization to promote osteogenesis and thus can be effectively used as a preventive and therapeutic agent for bone diseases including osteoporosis.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are for further illustrating the present invention, and the scope of the present invention is not limited by these examples.

Example  1: alkaline of osteoblast Phosphatase (ALP)  Activity analysis

In order to examine the effect of promoting osteogenesis of the quinoline derivative compounds of the present invention, bone morphogenetic protein-2 (BMP-2), a substance inducing osteoblast differentiation, was administered to C2C12 (American Cell Line, ATCC) After treatment of the compounds of the present invention, the activity of alkaline phosphatase (ALP), an osteoblast differentiation marker, was measured.

All the compounds used in the experiment were purchased from Maybridge, USA.

The mesenchymal stem cell C2C12 cells were cultured in DMEM medium (Hyclone) containing 10% FBS, and the medium was changed every 3 days. For the differentiation, the cells were placed at 4 × 10 ³ cells / well in each well of a 96-well plate, and after 24 hours, the cells were replaced with DMEM medium (Hyclone) containing 5% FBS BMP-2 (100 ng / ml, R & D Systems). At this time, 3 μM of the quinoline derivative compound of the present invention was treated together and incubated for 3 days, and ALP activity was measured. For the control group, 0.1% DMSO was treated.

The cultured cells were washed with PBS solution, and 100 쨉 l per well of a cell disruption solution (10 mM Tris, pH 7.5, 0.5 mM MgCl ₂ , 0.1% Triton X-100) was added, , And the supernatant was obtained by centrifugation. Thereafter, the activity provided by Wako Co. was measured, and the results are shown in Table 1 below.

compound ALP activity (% for control) One

341% 2

299% 3

290% 4

258% 5

228% 6

209% 7

206%




8

179% 9

112% 10

110%

As a result, as shown in Table 1, it was confirmed that quinoline derivative compounds according to the present invention effectively activate alkaline phosphatase (ALP), which is an activation marker of osteoblasts, as compared with the control group. This means that the quinoline derivative compounds according to the present invention promote the activity of osteoblasts and thus can be useful for bone diseases such as osteoporosis.

Claims (9)

A pharmaceutical composition for preventing or treating bone diseases, comprising a quinoline derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]

In the above formula
R ₁ is hydrogen; C ₁ -C ₄ alkyl; C ₁ -C ₄ haloalkyl; Phenyl; Or pyridinyl,
R ₂ is hydrogen; Or halogen,
R ₃ is hydrogen; Or C ₁ -C ₄ alkyl, and
R ₄ is hydrogen; C ₁ -C ₄ alkyl; C ₁ -C ₄ haloalkyl; Phenylsulfonyl unsubstituted or substituted by C ₁ -C ₄ haloalkoxy; One or two C ₁ -C ₄ Phenylamido substituted with alkoxy or halogen; Or 3-carboxy-cyclobutanecarbonyl.
The composition of claim 1, wherein R ₁ is hydrogen, methyl, trifluoromethyl, phenyl, or pyridin-4-yl.
2. The composition of claim 1 wherein R < ₂ > is hydrogen or chloro.
2. A composition according to claim 1, wherein R < ₃ > is hydrogen or methyl.
3. A compound according to claim 1 wherein R < ₄ > is hydrogen, methyl, 2-chloroethyl, phenylsulfonyl, 2-trifluoromethoxy-phenylsulfonyl, 2- Phenyl amido, or 3-carboxy-cyclobutanecarbonyl.
The method according to claim 1, wherein the quinoline derivative
1) 4- (4-methylpiperazin-1-yl) -2- (pyridin-4-yl) quinoline;
2) 2-methyl-4- (4- (phenylsulfonyl) piperazin-1-yl) quinoline;
3) 4- (4-methylpiperazin-1-yl) -2-phenylquinoline;
4) 2- (4- (2-methylquinolin-4-yl) piperazine-1-carbonyl) cyclobutanecarboxylic acid;
5) 4- (4- (2- (Trifluoromethoxy) phenylsulfonyl) piperazin-1-yl) -2- (trifluoromethyl) quinoline;
6) 4- (7-chloroquinolin-4-yl) -N- (2-methoxyphenyl) piperazine-1-carboxamide;
7) 4- (7-chloroquinolin-4-yl) -N- (2,5-difluorophenyl) piperazine-1-carboxamide;
8) 7-Chloro-4- (4- (2-chloroethyl) piperazin-1-yl) quinoline;
9) 7-Chloro-4- (4-methylpiperazin-1-yl) quinoline; And
10) 6-Methyl-4- (piperazin-1-yl) -2- (trifluoromethyl) quinoline.
The composition according to claim 1, wherein the bone disease is at least one selected from the group consisting of osteoporosis, Paget's disease, periodontal disease, bone growth disorder, bone metastatic cancer and rheumatoid arthritis.
The composition of claim 1, wherein the quinoline derivative promotes osteoblast differentiation or activity.
The composition according to claim 1, which contains 0.01 to 1% by weight of the quinoline derivative.