KR101676158B1 - A novel 6-amino-5-(substituted)pyrimidine-2,4(1H,3H)-dione derivatives, a method for preparing the same and use thereof - Google Patents

Abstract

The present invention relates to a novel 6-amino-5- (substituted) pyrimidine-2,4 (1H, 3H) -dione derivative or a pharmaceutically acceptable salt thereof, a process for preparing the same, A pharmaceutical composition for preventing or treating osteogenic differentiation, and a composition for inducing bone differentiation of stem cells.
Since the pharmaceutical composition comprising the 6-amino-5-substituted pyrimidine-2,4 (1H, 3H) -dione derivative according to the present invention promotes osteoblast differentiation and mineralization to promote osteogenesis, And can be usefully used as a prophylactic and therapeutic agent for bone diseases including osteoporosis. In addition, since the BMP-2 pathway can be activated, bone differentiation of the stem cells induced thereby can be promoted.

Description

Novel 6-amino-5- (substituted) pyrimidine-2,4 (1H, 3H) -dione derivatives, 1H, 3H) -dione derivatives, a method for preparing the same and use thereof,

The present invention relates to a novel 6-amino-5- (substituted) pyrimidine-2,4 (1H, 3H) -dione derivative or a pharmaceutically acceptable salt thereof, a process for preparing the same, A pharmaceutical composition for preventing or treating osteogenic differentiation, and a composition for inducing bone differentiation of stem cells.

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 tightly controlled, with little change in total bone mass.

Osteoblasts are formed from mesenchymal stem cells. Mineralization, such as calcium formation by osteoblasts, 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 osteoblasts is regulated by vitamin D and parathyroid hormone, and bone formation by osteoblasts is induced by intracellular bone morphogenetic protein (BMP), Wnt, MAP kinase, calcineurin Alkaline phosphatase (ALP), which is involved in osteoblast differentiation by cross-talk between various signaling systems such as calcineurin-calmodulin kinase, NF-κB and AP-1, (Pittenger, MF, Mackay, AM, Beck, SC, Jaiswal, M., et al., J. Clin. Biochem. Soc. 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).

Osteoporosis, a typical example of bone disease, is a disease caused by weakening bone mineral density by breaking the equilibrium of bone formation and bone resorption. Currently, about 10 million people already suffer from osteoporosis in the US and 18 million people are at risk for 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 general, the substances used as therapeutic agents for osteoporosis have considerable toxicity, and since they do not selectively activate only osteoblasts, it is necessary to develop more efficient and less toxic therapeutic agents for prevention or treatment of osteoporosis.

As an agent for stimulating osteogenesis, an accelerator for activating osteoblast and an inhibitor for inhibiting bone resorption of osteoclast are generally preferable because they are long-term to be administered to a patient because of the characteristics of the disease, so that they can be administered orally Research on this is urgently needed. However, chemotherapeutic agents for osteoporosis, which are classified as metabolic antagonists, alkylating agents, mitotic inhibitors, hormones, etc., exhibit drug resistance, and even if they show an initial successful response, they eventually fail treatment.

Therefore, there is a need to find a therapeutic agent for osteoporosis that targets a new point of action that can reduce the side effects of drugs, and the target of this novel drug discovery may be related to proteins involved in bone formation. For example, activation of BMP-2 has been reported to selectively activate only osteoblasts ( J. Med . Chem. , 2012, 55: 8248-8259) To promote osteogenesis, thereby preventing or treating osteoporosis.

Accordingly, the present inventors have made intensive studies to discover new compounds having chemical structural formula that can promote osteoblast bone formation through BMP-2 pathway activation. As a result, it has been found that novel compounds having carbamoyl, imino or alkanoyl substitution Amino-5- (substituted) pyrimidine-2,4 (1H, 3H) -dione derivatives were synthesized and these compounds effectively inhibited BMP-2 induced bone formation, And completed the present invention.

One object of the present invention is to provide novel 6-amino-5- (substituted) pyrimidine-2,4 (1H, 3H) -dione derivatives or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a process for producing the above compound.

It is still another object of the present invention to provide a pharmaceutical composition for preventing or treating bone diseases comprising the above compound or a pharmaceutically acceptable salt thereof as an active ingredient.

It is a further object of the present invention to provide a method of preventing or treating bone disease in a subject, comprising administering the pharmaceutical composition to a subject in need thereof.

It is still another object of the present invention to provide a composition for promoting bone differentiation of stem cells comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

In order to solve the above-mentioned problems, the present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

In this formula,

L is - (C = O) -NH-, -C = N- or - (C = O) -;

R ₁ is hydrogen, C _{1 -6} alkyl, C _{3 -8-cycloalkyl,} hydroxy, C _{1 -6} alkoxy, C _{1 -6} alkoxy -C _1-6 alkyl, C _{1 -6} alkyl, cyano, -NR _{6 R 7, - (C = O} ) -NR 8 R 9, or unsubstituted or substituted C _{5 -14} aryl, C _{5 -14} heteroaryl, C _{5 -14} aryl -C _{1 -6} alkyl, or C _{5 -14} aryl -C _{1 -6} alkoxy;

R ₂ is hydrogen or C _{1 -6} alkyl;

R ₃ is hydrogen, C _{1 -6} alkyl or unsubstituted or substituted C _{5 -14} aryl group;

R ₄ and R ₅ are each independently selected from the group consisting of hydrogen, C _{1 -6} alkenyl, - (C═O) -R ₁₀ , - (C═O) -NHR ₁₁ , - (C═S) -NHR ₁₂ , Or a substituted or unsubstituted C ₅ -C ₁₄ aryl-C _{1 -6} alkyl, C _{5 -14} aryl-C _{1 -6} alkenyl, or R ₄ and R ₅ together form a double bond to form ═C-NR ₁₃ R ₁₄ ; And

R ₆ to R ₁₄ are each independently hydrogen, C _{1 -6} alkyl, or unsubstituted or substituted C _{5 -14} aryl,

The substituted C _{5 -14} aryl, C _{5 -14} heteroaryl, C _{5 -14} aryl -C _{1 -6} alkyl, or C _{5 -14} aryl -C _1-6 alkoxy, halogen, hydroxy, nitro, C _{1 - 6} may be substituted with one or more substituents selected from alkyl, the group consisting of alkyl and C _{1 -6} alkoxy, C _{1 -6} perfluoroalkyl.

For example, when L is - (C = O) -NH-, R ₁ is C _{1 -6} alkyl, C _{3 -8} cycloalkyl, or unsubstituted or substituted C _{5 -14} aryl; R ₂ is C _{1 -6} alkyl; R ₃ is C _{1 -6} alkyl or C _{5 -14} aryl; And R ₄ and R ₅ are each independently hydrogen or unsubstituted or substituted C _{5 -14} aryl-C _{1 -6} alkyl, said substituted C _{5 -14} aryl or C _{5 -14} aryl-C _{1 -14} aryl _-6 alkyl may be substituted with one or more substituents selected from halogen, nitro, C _{1 -6} alkyl and C _{1 -6} alkoxy group consisting of.

Preferably, when L is - (C = O) -NH-, R ₁ is selected from butyl, phenyl, Cyclohexyl; R ₂ is methyl; R < ₃ > is methyl or phenyl; R ₄ is hydrogen; And R < ₅ > may be hydrogen, benzyl or methyl benzyl.

For example, when L is -C = N-, R ₁ is hydroxy, C _{1 -6} alkoxy, C _{1 -6} alkoxy -C _{1 -6} alkyl, C _{1 -6} alkyl, _{cyano, -NR 6 R 7, - (} C = O) -NR 8 R 9, or unsubstituted or substituted C _{5 -14} aryl, C _{5 -14} heteroaryl, C _{5 -14} aryl -C _{1 -6} alkyl, or C _{5 -14} aryl -C _{1 -6} alkoxy; R ₂ is C _{1 -6} alkyl; R ₃ is C _{1 -6} alkyl; R ₄ and R ₅ are each independently selected from the group consisting of hydrogen, C _{1 -6} alkenyl, - (C═O) -R ₁₀ , - (C═O) -NHR ₁₁ , - (C═S) -NHR ₁₂ , Or a substituted or unsubstituted C ₅ -C ₁₄ aryl-C _{1 -6} alkyl, C _{5 -14} aryl-C _{1 -6} alkenyl, or R ₄ and R ₅ together form a double bond to form ═C-NR ₁₃ R ₁₄ ; And R ₆ to R ₁₄ are each independently hydrogen, C _{1 -6} alkyl, or C _{5 -14} aryl, wherein said substituted C _5-14 aryl or C _{5 -14} aryl-C _{1 -6} alkyl is _optionally substituted with one in more halogen or C _{1 -6} perfluoroalkyl group it may be substituted with an alkyl.

Preferably, when L is -C = N-, R ₁ is selected from the group consisting of hydroxy, methoxy, methoxyethyl, cyanomethyl, dimethylamine, phenylamine, chlorophenylamine, benzyl, benzyloxy, phenyl, indazolyl or phenylcarbamoyl; R ₂ is methyl; R ₃ is methyl; R ₄ is hydrogen; And R < ₅ > are hydrogen, benzyl, perfluoromethylbenzyl, phenylpropenyl, Propenyl, Difluorophenyl, tert-butylcarbamoyl, phenylcarbamothioyl, benzoyl, or R ₄ and R ₅ together form a double bond to form = C-NMe ₂ ;

For example, wherein L is - (C = O) - one time, R ₁ is hydrogen, or unsubstituted or substituted C _{5 -14} aryl or C _{5 -14} aryl -C _{1 -6} alkyl; R ₂ is C _{1 -6} alkyl; R ₃ is C _{1 -6} alkyl; And R ₄ and R ₅ are each independently hydrogen or C _{5 -14} aryl-C _{1 -6} alkyl, and said substituted C _{5 -14} aryl may be substituted with halogen.

Preferably, when L is - (C = O) -, R ₁ is hydrogen, bromophenyl, fluorophenyl or benzyl; R ₂ is methyl; R ₃ is methyl; R ₄ is hydrogen; And R < ₅ > may be hydrogen, or benzyl.

Preferably, the compound represented by the formula (1)

1) 6-Amino-N- (2-chlorophenyl) -1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-

2) 6-Amino-N- (4-chlorophenyl) -1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-

3) 6- (Benzylamino) -N- (2-chlorophenyl) -1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide,

4) N- (4-Chlorophenyl) -1,3-dimethyl-6- (4-methylbenzylamino) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine- Copy Mid,

5) 6-Amino-N- (4-chlorophenyl) -3-methyl-2,4-dioxo-1-phenyl-1,2,3,4-tetrahydropyrimidine-

6) 6-Amino-N- (2,6-dimethylphenyl) -3-methyl-2,4-dioxo-1-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide ,

7) 6-Amino-N- (4-methoxyphenyl) -3-methyl-2,4-dioxo-1-phenyl-1,2,3,4-tetrahydropyrimidine-

8) 6-Amino-N- (2-bromophenyl) -3-methyl-2,4-dioxo-1-phenyl-1,2,3,4-tetrahydropyrimidine-

9) 6- (Benzylamino) -N- (4-chlorophenyl) -1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide,

10) 6-Amino-N-cyclohexyl-3-methyl-2,4-dioxo-1-phenyl-1,2,3,4-tetrahydropyrimidine-

11) 6-Amino-N- (2-methoxyphenyl) -3-methyl-2,4-dioxo-1-phenyl-1,2,3,4-tetrahydropyrimidine-

12) 6-Amino-3-methyl-2,4-dioxo-N, 1-diphenyl-1,2,3,4-tetrahydropyrimidine-

13) Synthesis of 6-amino-N- (4-fluorophenyl) -3-methyl-2,4-dioxo-1-phenyl-1,2,3,4-tetrahydropyrimidine-

14) 6-Amino-3-methyl-2,4-dioxo-1-phenyl-N-p-tolyl-1,2,3,4-tetrahydropyrimidine-

15) Synthesis of 6-amino-N- (2-ethylphenyl) -3-methyl-2,4-dioxo-1-phenyl-1,2,3,4-tetrahydropyrimidine-

16) 6-Amino-N-butyl-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide,

17) 6-Amino-N- (2-methoxyphenyl) -1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-

18) 6-Amino-N- (2-bromophenyl) -1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-

19) 6-Amino-N- (4-fluorophenyl) -1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-

20) 6-Amino-N- (4-ethylphenyl) -1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-

21) Synthesis of 6-amino-N- (4-ethylphenyl) -3-methyl-2,4-dioxo-1-phenyl-1,2,3,4-tetrahydropyrimidine-

22) 6-Amino-N- (2-fluorophenyl) -1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-

23) 6-Amino-3-methyl-N- (4-nitrophenyl) -2,4-dioxo-1-phenyl-1,2,3,4-tetrahydropyrimidine-

24) 6-Amino-N- (2-chlorophenyl) -3-methyl-2,4-dioxo-1-phenyl-1,2,3,4-tetrahydropyrimidine-

25) 6-Amino-N- (2-fluorophenyl) -3-methyl-2,4-dioxo-1-phenyl-1,2,3,4-tetrahydropyrimidine-

26) (E) -6-Amino-5 - ((2- (4-chlorophenyl) hydrazano) methyl) -1,3-dimethylpyrimidine-

27) (E) -6-Amino-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde oxime,

28) (E) -6-Amino-5 - ((2,2-dimethylhydrazano) methyl) -1,3-dimethylpyrimidine-

29) (E) -6-Amino-1,3-dimethyl-5 - ((2-phenylhydrazano) methyl) pyrimidine-

30) (E) -N- (5 - ((2,2-Dimethylhydrazano) methyl) -1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine Yl) benzamide,

31) (E) -6- (Benzylamino) -5 - ((2,2- dimethylhydrazano) methyl) -1,3-dimethylpyrimidine-

32) (E) -6-Amino-1, 3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde O-

33) (E) -6-Amino-5 - ((benzylimino) methyl) -1,3-dimethylpyrimidine-2,4 (1H, 3H)

34) Synthesis of (E) -5 - ((1H-indazol-6-ylimino) methyl) -6-amino-1,3-dimethylpyrimidine-

35) (E) -2 - ((6-Amino-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5- yl) methyleneamino) acetonitrile,

36) (E) -6-Amino-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde O-

37) (E) -N'- (5 - ((E) - (Benzyloxyimino) methyl) -1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine Yl) -N, N-dimethylformamide < / RTI > amide,

38) (E) -6- (cinnamylamino) -1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde O-

39) (E) -6- (Benzylamino) -1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde O-

40) (E) -1,3-Dimethyl-2,4-dioxo-6- (4- (trifluoromethyl) benzylamino) -1,2,3,4-tetrahydropyrimidine- Aldehyde O-benzyloxime,

41) (E) -6-Amino-5 - ((2-methoxyethylimino) methyl) -1,3-dimethylpyrimidine-2,4 (1H, 3H)

42) (E) -1- (5 - ((Benzylimino) methyl) -1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin- -3-tert-butylurea,

43) (E) -1- (5 - ((Benzylimino) methyl) -1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin- -3-phenylthiourea,

44) Synthesis of (E) -1 - ((6-amino-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin- Urea,

45) (E) -6-Amino-1,3-dimethyl-5 - ((phenylimino) methyl) pyrimidine-2,4 (1H, 3H)

46) (E) -1- (5 - ((Benzyloxyimino) methyl) -1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin- -3-tert-butylurea,

47) (E) -6- (Benzylamino) -1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde O-

48) (E) -6- (Allylamino) -1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde O-

49) (E) -6- (3,5-Difluorobenzylamino) -1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde O-methyloxime,

50) (E) -6- (Benzylamino) -1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde O-

51) 6-Amino-1,3-dimethyl-5- (2-phenylacetyl) pyrimidine-2,4 (1H, 3H)

52) 6-Amino-5- (2-bromobenzoyl) -1,3-dimethylpyrimidine-2,4 (1H, 3H)

53) 6-Amino-5- (2-fluorobenzoyl) -1,3-dimethylpyrimidine-2,4 (1H, 3H)

54) 6- (Benzylamino) -1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde.

In the specific examples of the present invention, the above-mentioned 54 kinds of compounds were synthesized, and their substituent structures are summarized in Tables 1 to 3.

The compounds of the present invention may exist in the form of a salt, particularly a pharmaceutically acceptable salt. Salts include, without limitation, salts commonly used in the art, such as acid addition salts formed by pharmaceutically acceptable free acids. The term "pharmaceutically acceptable salt" of the present invention means a concentration that has a relatively non-toxic and harmless effective action in a patient, wherein the adverse effect due to the salt is an adverse effect of the compound &Quot; means all organic or inorganic addition salts.

The acid addition salt is prepared by a conventional method, for example, by dissolving the compound in an excess amount of an acid aqueous solution and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. The same molar amount of the compound and the acid or alcohol (e.g., glycol monomethyl ether) in water may be heated and then the mixture may be evaporated to dryness, or the precipitated salt may be subjected to suction filtration.

As the free acid, organic acids and inorganic acids can be used. As the inorganic acids, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid and the like can be used. Examples of the organic acids include methanesulfonic acid, p- toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycollic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid and the like can be used , But are not limited to these.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal salt or the alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the non-soluble salt salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically acceptable to produce sodium, potassium, or calcium salt, but not limited thereto. The corresponding silver salt can also be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

Pharmaceutically acceptable salts of the compounds of this invention include, unless otherwise indicated, salts of acidic or basic groups that may be present in the compounds of formula (I). For example, pharmaceutically acceptable salts may include sodium, calcium and potassium salts of hydroxy groups, and the other pharmaceutically acceptable salts of amino groups include hydrobromides, sulphates, sulphates, phosphates, hydrogen phosphates (Hydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts and the like, ≪ / RTI >

(1H, 3H) -dione derivatives of the present invention such as 6-amino-5- (carbamoyl) pyrimidine-2,4 (1H, 3H) -dione derivative or 6-amino-5- (alkanoyl) pyrimidine-2,4 As a pharmaceutically acceptable salt of the dione derivative compound, BMP-2 (equivalent to the 6-amino-5- (substituted) pyrimidine-2,4 Any salt of a compound that exhibits the osteogenic stimulatory effect of osteoblast through pathway activation can be used without limitation.

In addition, the compound represented by Formula 1 according to the present invention includes not only pharmaceutically acceptable salts thereof but also solvates such as possible hydrates which can be prepared therefrom. The solvate of the compound represented by the formula (1) can be prepared from the compound represented by the formula (1) using methods known in the art.

In addition, the compound represented by Formula 1 according to the present invention may be prepared in crystalline form or amorphous form, and may be optionally hydrated or solvated when prepared in crystalline form. In the present invention, compounds containing various amounts of water as well as stoichiometric hydrates of the compound represented by the formula (1) may be included. Solvates of the compounds of formula (I) according to the present invention include both stoichiometric solvates and non-stoichiometric solvates.

In another embodiment, the present invention provides a process for preparing a compound of formula (I), comprising reacting a 6-amino-pyrimidine-2,4 (1H, 3H) -dione derivative represented by the following formula 2 with an isocyanate derivative in the presence of microwave. Amino-5- (substituted) pyrimidine-2,4 (1H, 3H) -dione derivative represented by the following formula 1:

[Formula 1-1]

(2)

Wherein R ₁ to R ₅ are as defined above.

The reaction can be represented by the following reaction formula (1).

[Reaction Scheme 1]

In the above reaction formulas, R ₁ to R ₅ are as defined above.

Preferably, the isocyanate derivative is used in an amount of 1.0 to 1.5 molar equivalents relative to the 6-amino-pyrimidine-2,4 (1H, 3H) -dione derivative. More preferably 1.0 to 1.1 molar equivalents, but not limited thereto.

At this time, nitrobenzene can be used as a solvent, but it is not limited thereto.

For example, the reaction may be carried out using a microwave reactor at 180 to 250 ° C for 15 to 50 minutes, but is not limited thereto.

In another embodiment, the present invention relates to a process for the preparation of 6-amino-pyrimidine-2,4 (1H, 3H) -dione derivative represented by the following formula 2 by reaction with phosphoryl chloride, -1,2,3,4-tetrahydropyrimidine-5-carbaldehyde derivative; And the 6-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde derivative is reacted with a primary amine derivative to obtain 6-amino-5- (iminomethyl) Amino-5- (substituted) pyrimidine-2,4 (1H, 3H) -dione derivative represented by the general formula (1-2) Lt; / RTI > derivative of formula < RTI ID = 0.0 >

[Formula 1-2]

(2)

Wherein R ₁ to R ₅ are as defined above.

The reaction can be represented by the following reaction formula (2).

[Reaction Scheme 2]

In the above reaction formulas, R ₁ to R ₅ are as defined above.

Preferably, in the first step, the phosphoryl chloride can be used in an amount of 1.0 to 1.5 molar equivalents relative to the 6-amino-pyrimidine-2,4 (1H, 3H) -dione derivative. More preferably 1.0 to 1.1 molar equivalents, but not limited thereto.

Preferably, the first step may be carried out in a dimethylformamide solvent. At this time, the dimethylformamide is not a simple solvent but may participate in an actual reaction.

For example, the first step is a step of dropwise adding phosphoryl chloride to a solution of 6-amino-pyrimidine-2,4 (1H, 3H) -dione derivative in dimethylformamide; B) stirring the mixed solution of step a) at 18 to 35 DEG C for 30 minutes to 5 hours; C) adjusting the pH of the reaction solution of step b) to 9 to 11; And d-crystallizing with hexane and ethyl acetate.

Preferably, in the second step, the primary amine derivative is used in an amount of 1.0 to 1.5 molar equivalents relative to the 6-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde derivative . More preferably 1.0 to 1.1 molar equivalents, but not limited thereto.

For example, the second step can be carried out in a C _{1 -4} lower alcohol solvent, preferably in ethanol, but is not limited thereto.

For example, the second step may be performed at 50 to 70 ° C for 6 minutes to 12 hours, but is not limited thereto.

Preferably, the process for the production of the 6-amino-5- (imino) pyrimidine-2,4 (1H, 3H) -dione derivative of the present invention is characterized in that the first or second step comprises filtering, Or a combination thereof. The filtration, drying, washing and purification steps can be carried out by using methods known in the art without limitation.

In another embodiment, the present invention provides a process for the preparation of a compound of formula (I), comprising reacting a 6-amino-pyrimidine-2,4 (1H, 3H) -dione derivative represented by the following formula 2 with an acyl chloride derivative in the presence of pyridine Amino-5- (substituted) pyrimidine-2,4 (1H, 3H) -dione derivative represented by formula

[Formula 1-3]

(2)

Wherein R ₁ to R ₅ are as defined above.

The reaction can be represented by the following reaction formula (3).

[Reaction Scheme 3]

In the above reaction formulas, R ₁ to R ₅ are as defined above.

Preferably, the acyl chloride derivative can be used in an amount of 1.0 to 1.5 molar equivalents relative to the 6-amino-pyrimidine-2,4 (1H, 3H) -dione derivative. More preferably 1.0 to 1.1 molar equivalents, but not limited thereto.

For example, the reaction may be carried out in a dioxane solvent, but is not limited thereto.

For example, the reaction can be carried out at 18 to 35 ° C for 30 minutes to 5 hours, but is not limited thereto.

Preferably, the process for preparing the 6-amino-5- (alkanoyl) pyrimidine-2,4 (1H, 3H) -dione derivative of the present invention further comprises filtration, drying, washing, can do. The filtration, drying, washing and purification steps can be carried out by using methods known in the art without limitation.

In another aspect, the present invention provides a pharmaceutical composition for preventing or treating bone diseases, comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:

[Chemical Formula 1]

Wherein L and R < ₁ > to R < ₅ > are as defined above.

The present invention also provides a method of preventing or treating bone disease in a subject, comprising administering the pharmaceutical composition to a subject in need thereof.

The compound represented by Formula 1 of the present invention is a compound capable of promoting osteoblast osteogenesis by activating the BMP-2 pathway. Accordingly, the pharmaceutical composition of the present invention comprising the compound of Formula 1 as an active ingredient can be used without limitation in bone related diseases in which osteoclast activation is required.

As used herein, the term "bone disease" refers to a condition or disease in which bone mass increase is required or required in order to promote the activity of osteoblasts. 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. Examples of such a condition include osteoporosis, osteopenia, Paget's disease, periodontal disease, Cancer, and rheumatoid arthritis.

Preferably, the composition of the present invention can be used for preventive treatment of osteoporosis or osteopenia. Specifically, the term "osteoporosis" used in the present invention 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 bone diseases. 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.

As used herein, the term "individual" refers to all animals, including humans, who have developed or are capable of developing bone disease. The composition of the present invention can be administered to an individual to effectively prevent or treat the bone disease. The composition of the present invention may be administered in combination with a conventional bone disease therapeutic agent.

As used herein, the term "administering" means introducing a given substance into a patient in an appropriate manner, and the administration route of the composition of the present invention may be administered via any conventional route so long as it can reach the target tissue have. But are not limited to, intraperitoneal, intravenous, intramuscular, subcutaneous, intradermal, oral, topical, intranasal, intrathecal, rectal.

The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. The term "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment and not causing side effects, and the effective dosage level will vary depending on the sex, Including, but not limited to, age, weight, health status, type of disease, severity, activity of the drug, sensitivity to the drug, method of administration, time of administration, route of administration, and rate of release, Can be readily determined by those skilled in the art according to well known factors. Generally, the active substance may be administered at a dose of from about 0.01 mg / kg / day to 1000 mg / kg / day. When administered orally, a dose of 50 to 500 mg / kg may be appropriate, and may be administered at least once a day.

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

In one specific embodiment, the 6-amino-5- (substituted) pyrimidine-2,4 (1H, 3H) -dione derivative of the present invention is treated with C2C12 mesenchymal cells, The activity of ALP (alkaline phosphatase) was markedly increased (Table 1).

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 these, ALP present in bone is a marker of osteoblast differentiation and / or activity, and ALP level is increased when osteoblast is differentiated or activated. 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 6-amino-5- (substituted) pyrimidine-2,4 (1H, 3H) -dione derivatives of the present invention can ultimately promote osteoblast differentiation and activity through increased bone ALP activity, The disease can be effectively prevented and treated.

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. As used herein, the term "pharmaceutically acceptable" means that the composition is free of toxicity to an individual such as a cell or human being exposed to the composition. Such carriers may be used without limitation as long as they are known in the art such as buffers, preservatives, wetting agents, solubilizers, isotonic agents, stabilizers, bases, excipients and lubricants. Examples of carriers, excipients and diluents that can be included in the pharmaceutical composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium Silicates, cellulose, methylcellulose, microcrystalline 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 solutions, suspensions, emulsions, freeze-dried 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 composition of the present invention may also be administered by any device capable of moving the active substance to the target cell. Examples of preferable parenteral administration methods and formulations include intravenous injection, subcutaneous injection, intradermal injection, intramuscular injection, drip injection and the like. The injectable solution may be a non-aqueous solvent such as an aqueous solvent such as a physiological saline solution or a ring gel solution, a vegetable oil, a higher fatty acid ester (e.g., oleic acid), an alcohol (e.g., ethanol, benzyl alcohol, propylene glycol, glycerin, etc.) (For example, ascorbic acid, sodium hydrogen sulfite, sodium pyrophosphate, BHA, tocopherol, EDTA and the like), an emulsifier, a buffer for pH control, a microbial growth inhibitor And a pharmaceutical carrier such as a preservative (e.g., mercury nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.).

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.

In another aspect, the present invention provides a composition for stimulating bone marrow differentiation comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:

[Chemical Formula 1]

Wherein L and R < ₁ > to R < ₅ > are as defined in claim 1.

For example, the stem cells may be undifferentiated cells capable of differentiating into bone cells. The stem cells include, but are not limited to, adult stem cells, embryonic stem cells, decellularized stem cells, and induced pluripotent stem cells. Preferably, the stem cells may be mesenchymal stem cells, but are not limited thereto.

Preferably, the promotion of bone differentiation by the compounds of the present invention can be achieved by activating the BMP-2 pathway. In a specific example of the present invention, when human myoblast C2C12 is cultured in the bone differentiation induction medium supplemented with BMP-2 to induce differentiation into osteoblasts, when the compound of the present invention is further added thereto, (Fig. 1). Therefore, the compound of the present invention can be added to the osteogenic induction medium of stem cells to promote differentiation into osteoblasts.

Since the pharmaceutical composition comprising the 6-amino-5-substituted pyrimidine-2,4 (1H, 3H) -dione derivative according to the present invention promotes osteoblast differentiation and mineralization to promote osteogenesis, And can be usefully used as a prophylactic and therapeutic agent for bone diseases including osteoporosis. In addition, since the BMP-2 pathway can be activated, bone differentiation of the stem cells induced thereby can be promoted.

Brief Description of the Drawings Fig. 1 is a graph showing the effect of Compound 1 according to an embodiment of the present invention on the osteoblast differentiation promoting effect of human myobacterium C2C12 cell line. Fig. In the experimental group, Compound 1 of the present invention was added to the bone differentiation induction medium containing BMP2 at a concentration of 2.5 μM and cultured. The positive control group was cultured in a medium containing only BMP2 to induce bone differentiation, and the negative control group was cultured in a medium not containing both BMP2 and the compound of the present invention.

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: 6-Amino-3- methyl -2,4- Dioxo -N, 1- Diphenyl -1,2,3,4- Tetrahydropyrimidine -5- Carboxamide (Compound 12)  synthesis

(1H, 3H) -dione (217.2 mg, 1.0 mmol) and phenyl isocyanate (142.9 mg, 1.2 mmol) were added to a microwave reaction vessel at room temperature, (1 ml). The reaction mixture was reacted at 210 캜 under microwave conditions for 10 to 20 minutes. After completion of the reaction, the reaction mixture was transferred to a round bottom flask and distilled under reduced pressure. Purification of the concentrated reaction mixture by silica gel column chromatography using hexane and ethyl acetate gave the title compound 6-amino-3-methyl-2,4-dioxo-N, Tetrahydropyrimidine-5-carboxamide (282.5 mg, 84%).

^{1 H NMR (200, DMSO)} : 12.16 (s, 1H), 10.57 (s, 1H), 7.57-7.64 (m, 5H), 7.43-7.48 (m, 2H), 7.32 (t, 2H, J = 7.9 Hz), 7.06 (t, IH, J = 7.3Hz), 6.77 (s, IH), 3.23 (s, 3H).

Example  2: (E) -6-Amino-5 - (( Benzylimino ) methyl ) -1,3-dimethylpyrimidine-2,4 (1H, 3H) -di orderliness Synthesis of compound 33)

2.1. 6-Amino-1, 3-dimethyl- Dioxo -1,2,3,4- Tetrahydropyrimidine -5- Car Synthesis of benzaldehyde

(465.3 mg, 3.0 mmol) was dissolved in dimethylformamide (4 ml), and the mixture was cooled to 0 ° C and stirred for 10 minutes. To the reaction mixture was added dropwise a solution of 6-amino-1,3-dimethylpyrimidine- Respectively. Phosphoryl chloride (POCl ₃ , 505.9 mg, 3.3 mmol) was added dropwise to the reaction mixture and stirred at room temperature for 2 hours. Water (5 ml) was then added and adjusted to pH 10 with 1 N saturated solution of potassium hydroxide. The resulting solid was filtered through a vacuum filter and then crystallized with hexane and ethyl acetate to obtain the title compound 6-amino-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine 5-carbaldehyde (219.8 mg, 1.2 mmol).

¹ H NMR (200, DMSO): 10.35 (s, IH), 8.56 (s, 2H), 3.16 (s, 3H), 3.01 (s, 3H).

2.2. (E) -6-amino-5 - (( Benzylimino ) methyl ) -1,3-dimethylpyrimidine-2,4 (1H, 3H) - Dion's  synthesis

Amino-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde (183.2 mg, 1.0 mmol ) Was dissolved in ethanol (4 ml) and stirred. Benzylamine (128.6 mg, 1.2 mmol) was added to the reaction mixture, and the mixture was stirred at 60 占 폚 for 8 hours. The reaction mixture was then cooled to room temperature and distilled under reduced pressure. The concentrated reaction mixture was extracted with ethyl acetate and water, and the organic layer recovered with magnesium sulfate was dried and distilled under reduced pressure. The reaction mixture was purified by silica gel column chromatography using hexane and ethyl acetate to give the title compound (E) -6-amino-5 - ((benzylimino) methyl) -1,3-dimethylpyrimidine- 1H, 3H) -dione (190.6 mg, 0.7 mmol).

¹ H NMR (200, DMSO): 11.17 (s, br, IH), 8.59 (s, IH), 7.96 (s, br, IH), 7.25-7. 3.36 (s, 3 H), 3.30 (s, 3 H).

Example  3: 6-Amino-1, 3-dimethyl-5- (2- Phenylacetyl ) Pyrimidine-2,4 (1H, 3H) - (Compound 51)  synthesis

(155.2 mg, 1.0 mmol) and pyridine (87.0 mg, 1.1 mmol) were dissolved in dioxane (4 ml), and a solution of 10 Lt; / RTI > Then, 2-phenylacetyl chloride (154.6 mg, 1.0 mmol) was added thereto, followed by stirring at room temperature for 1 hour, and the reaction was terminated. After the reaction was completed, the reaction mixture was extracted with ethyl acetate and water, and the aqueous layer was extracted again with ethyl acetate. The recovered organic layers were combined, washed with saturated sodium chloride solution, and distilled under reduced pressure. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography using ethyl acetate and hexane to obtain the title compound 6-amino-1,3-dimethyl-5- (2-phenylacetyl) pyrimidine- Dione (229.6 mg, 0.84 mmol).

¹ H NMR (200, DMSO): 11.14 (s, br, IH), 8.24 (s, br, IH), 7.11-7.31 (m, 5H), 4.32 (s, 2H) 3.17 (s, 3 H).

Example 1 (Compound 1 to 25; Table 1), Example 2 (Compound 26 to 50; Table 2), or Example 3 (Compound 51 to 54; Table 1), except that appropriate reactants were selected and used in combination. 3). ≪ / RTI > The structures of the synthesized compounds are shown in Tables 1 to 3. The results of ¹ H NMR spectroscopic analysis for each compound are shown in Table 4. ^{The 1} H NMR spectrum was recorded by Bruker 200 MHz NMR or 300 MHz NMR and the chemical shift ( δ ) was recorded in ppm relative to TMS as an internal standard. All specimens were dissolved in DMSO- d ₆ and CDCl ₃ unless otherwise specified.

[Table 1-1]

[Table 1-2]

[Table 1-3]

[Table 2-1]

[Table 2-2]

[Table 2-3]

[Table 3]

[Table 4-1]

[Table 4-2]

[Table 4-3]

[Table 4-4]

[Table 4-5]

[Table 4-6]

Experimental Example  One: Osteoblast  Promoting differentiation

Human myoblast C2C12 cells were cultured in a cell incubator maintained at 37 ° C with 5% CO ₂ using DMEM (Dulbecco's modified Eagle's medium, Welgene Cat: 001-05) containing 5% FBS and 1% penicillin sheetreptomycin Lt; / RTI > Specifically, the 48-C2C12 cells in the well plates at 2 × 10 ⁴ cells / well seeded in a density of, adding a DMEM medium containing 5% FBS and 1% penicillin sheet repto mitomycin, 5% CO _2, 37 ℃ Lt; / RTI > and maintained in a cell incubator. After 24 hours, the cells were exchanged with fresh culture medium and treated with BMP2 (Peprotech, Cat: 120-02) at a concentration of 300 ng / ml or 500 ng / ml. As the experimental group, the compound of the present invention was further added to the cells treated with 300 ng / ml BMP2 at a concentration of 2.5 μM. BMP2 and the compound of the present invention were treated with the same conditions as above, and the cells were cultured for 5 days to be differentiated. Then, using an alkaline phosphate detection kit (Millipore, Cat: SCR004) And the degree of differentiation of osteoclast cells of C2C12 cells was confirmed. The results are shown in Fig. As shown in FIG. 1, no differentiation into osteoblasts was observed in BMP2 and the control group in which the compound of the present invention was not treated, and it was confirmed that a small amount of osteoblasts were present in the positive control group cultured with BMP2, Therefore, it was confirmed that a significantly increased amount of osteoblast was present when the compound of the present invention was further contained. That is, this indicates that the compound of the present invention is excellent in the ability to promote differentiation into osteoblasts under conditions that induce differentiation into osteoblasts.

Manufacturing example  1: Preparation of tablets by direct pressurization

5.0 mg of the compound of the present invention as an active ingredient was sieved, mixed with 14.1 mg of lactose, 0.8 mg of crospovidone USNF and 0.1 mg of magnesium stearate, and pressed to prepare tablets.

Manufacturing example  2: Preparation of tablets by wet granulation

5.0 mg of the compound of the present invention as an active ingredient was sieved and then mixed with 16.0 mg of lactose and 4.0 mg of starch. 0.3 mg of polysorbate 80 was dissolved in purified water, which was then added to the mixture and atomized. The formed microspheres were dried and sieved, mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate, and pressed to prepare tablets.

Manufacturing example  3: Preparation of powders and capsules

5.0 mg of the compound of the present invention was sieved as an active ingredient and mixed with 14.8 mg of lactose, 10.0 mg of polyvinylpyrrolidone and 0.2 mg of magnesium stearate. The mixture was filtered through a hard No. 5 < / RTI > gelatin capsules.

Manufacturing example  4: Preparation of injection

Injections were prepared so as to contain 180 mg of mannitol, 26 mg of Na ₂ HPO ₄ .12H ₂ O and 2974 mg of distilled water in addition to 100 mg of the compound of the present invention as an active ingredient.

Claims (27)

delete 1. A compound represented by the following formula (1): < EMI ID =
[Chemical Formula 1]

In this formula,
L is - (C = O) -NH-,
R ₁ is substituted C _5-14 aryl;
R ₂ is C _1-6 alkyl;
R ₃ is C _1-6 alkyl or C _5-14 aryl; And
R ₄ and R ₅ are each independently hydrogen or unsubstituted or substituted C _5-14 aryl-C _1-6 alkyl,
_Wherein said substituted C _5-14 aryl or C _5-14 aryl-C _1-6 alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, C _1-6 alkyl and C _1-6 alkoxy,
When R ₂ and R ₃ are methyl and R ₄ and R ₅ are hydrogen, then R ₁ is not 4-chlorophenyl, 2-bromophenyl, 4-methoxyphenyl, or 2-ethylphenyl.
3. The method of claim 2,
R ₁ is selected from the group consisting of fluorophenyl, chlorophenyl, bromophenyl, methylphenyl, ethylphenyl, dimethylphenyl, methoxyphenyl, or nitrophenyl;
R ₂ is methyl;
R < ₃ > is methyl or phenyl;
R ₄ is hydrogen; And
R < ₅ > is hydrogen, benzyl or methylbenzyl,
When R ₂ and R ₃ are methyl and R ₄ and R ₅ are hydrogen, then R ₁ is not 4-chlorophenyl, 2-bromophenyl, 4-methoxyphenyl, or 2-ethylphenyl. A pharmaceutically acceptable salt.
1. A compound represented by the following formula (1): < EMI ID =
[Chemical Formula 1]

In this formula,
L is -CH = N-,
R ₁ is C _1-6 alkoxy-C _1-6 alkyl, C _1-6 cyanoalkyl, -NR ₆ R ₇ , - (C = O) -NR ₈ R ₉ , C _5-14 heteroaryl, C _{5 -14} aryl-C _1-6 alkyl or C _5-14 aryl-C _1-6 alkoxy;
R ₂ is C _1-6 alkyl;
R ₃ is C _1-6 alkyl;
R ₄ is hydrogen; And
R ₅ is hydrogen, C _2-6 alkenyl, - (C = O) -R 10, - (C = O) -NHR 11, - (C = S) -NHR 12, or unsubstituted or substituted C _{5 -14} aryl-C _1-6 alkyl, C _5-14 aryl-C _2-6 alkenyl, or R ₄ and R ₅ together form a double bond to form = CH-NR ₁₃ R ₁₄ ; And
R ₆ to R ₁₄ are each independently hydrogen, C _1-6 alkyl, or C _5-14 aryl,
_Wherein said substituted C _5-14 aryl or C _5-14 aryl-C _1-6 alkyl is _optionally substituted by one or more halogen or C _1-6 perfluoroalkyl,
R ₂ and R ₃ are methyl, R ₄ and R ₅ are hydrogen, R ₁ is not benzyl, or phenylethyl, or a pharmaceutically acceptable salt thereof.
5. The method of claim 4,
R ₁ is methoxyethyl, cyanomethyl, dimethylamine, phenylamine, chlorophenylamine, benzyl, benzyloxy, phenyl, indazolyl or phenylcarbamoyl;
R ₂ is methyl;
R ₃ is methyl;
R ₄ is hydrogen; And
R < ₅ > is hydrogen, benzyl, perfluoromethylbenzyl, phenylpropenyl, Propenyl, Difluorophenyl, tert-butylcarbamoyl, phenylcarbamoyl, benzoyl,
R ₄ and R ₅ together form a double bond to form = CH-NMe ₂ ,
R ₂ and R ₃ are methyl, R ₄ and R ₅ are hydrogen, R ₁ is not phenyl or benzyl, or a pharmaceutically acceptable salt thereof.
1. A compound represented by the following formula (1): < EMI ID =
[Chemical Formula 1]

In this formula,
L is - (C = O) -,
R ₁ is substituted C _5-14 aryl or C _5-14 aryl-C _1-6 alkyl;
R ₂ is C _1-6 alkyl;
R ₃ is C _1-6 alkyl; And
R ₄ and R ₅ are each independently hydrogen or C _5-14 aryl-C _1-6 alkyl,
_Wherein said substituted C _5-14 aryl is substituted with halogen; or a pharmaceutically acceptable salt thereof.
The method according to claim 6,
R ₁ is bromophenyl, fluorophenyl or benzyl;
R ₂ is methyl;
R ₃ is methyl;
R ₄ is hydrogen; And
R < ₅ > is hydrogen, or benzyl; or a pharmaceutically acceptable salt thereof.
A compound selected from the group consisting of or a pharmaceutically acceptable salt thereof:
1) 6-Amino-N- (2-chlorophenyl) -1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-
3) 6- (Benzylamino) -N- (2-chlorophenyl) -1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide,
4) N- (4-Chlorophenyl) -1,3-dimethyl-6- (4-methylbenzylamino) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine- Copy Mid,
5) 6-Amino-N- (4-chlorophenyl) -3-methyl-2,4-dioxo-1-phenyl-1,2,3,4-tetrahydropyrimidine-
6) 6-Amino-N- (2,6-dimethylphenyl) -3-methyl-2,4-dioxo-1-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide ,
7) 6-Amino-N- (4-methoxyphenyl) -3-methyl-2,4-dioxo-1-phenyl-1,2,3,4-tetrahydropyrimidine-
8) 6-Amino-N- (2-bromophenyl) -3-methyl-2,4-dioxo-1-phenyl-1,2,3,4-tetrahydropyrimidine-
9) 6- (Benzylamino) -N- (4-chlorophenyl) -1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide,
11) 6-Amino-N- (2-methoxyphenyl) -3-methyl-2,4-dioxo-1-phenyl-1,2,3,4-tetrahydropyrimidine-
13) Synthesis of 6-amino-N- (4-fluorophenyl) -3-methyl-2,4-dioxo-1-phenyl-1,2,3,4-tetrahydropyrimidine-
14) 6-Amino-3-methyl-2,4-dioxo-1-phenyl-Np-tolyl-1,2,3,4-tetrahydropyrimidine-
15) Synthesis of 6-amino-N- (2-ethylphenyl) -3-methyl-2,4-dioxo-1-phenyl-1,2,3,4-tetrahydropyrimidine-
17) 6-Amino-N- (2-methoxyphenyl) -1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-
19) 6-Amino-N- (4-fluorophenyl) -1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-
20) 6-Amino-N- (4-ethylphenyl) -1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-
21) Synthesis of 6-amino-N- (4-ethylphenyl) -3-methyl-2,4-dioxo-1-phenyl-1,2,3,4-tetrahydropyrimidine-
22) 6-Amino-N- (2-fluorophenyl) -1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-
23) 6-Amino-3-methyl-N- (4-nitrophenyl) -2,4-dioxo-1-phenyl-1,2,3,4-tetrahydropyrimidine-
24) 6-Amino-N- (2-chlorophenyl) -3-methyl-2,4-dioxo-1-phenyl-1,2,3,4-tetrahydropyrimidine-
25) 6-Amino-N- (2-fluorophenyl) -3-methyl-2,4-dioxo-1-phenyl-1,2,3,4-tetrahydropyrimidine-
28) (E) -6-Amino-5 - ((2,2-dimethylhydrazano) methyl) -1,3-dimethylpyrimidine-
29) (E) -6-Amino-1,3-dimethyl-5 - ((2-phenylhydrazano) methyl) pyrimidine-
30) (E) -N- (5 - ((2,2-Dimethylhydrazano) methyl) -1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine Yl) benzamide,
31) (E) -6- (Benzylamino) -5 - ((2,2- dimethylhydrazano) methyl) -1,3-dimethylpyrimidine-
32) (E) -6-Amino-1, 3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde O-
34) Synthesis of (E) -5 - ((1H-indazol-6-ylimino) methyl) -6-amino-1,3-dimethylpyrimidine-
35) (E) -2 - ((6-Amino-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5- yl) methyleneamino) acetonitrile,
37) (E) -N'- (5 - ((E) - (Benzyloxyimino) methyl) -1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine Yl) -N, N-dimethylformamide < / RTI > amide,
38) (E) -6- (cinnamylamino) -1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde O-
39) (E) -6- (Benzylamino) -1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde O-
40) (E) -1,3-Dimethyl-2,4-dioxo-6- (4- (trifluoromethyl) benzylamino) -1,2,3,4-tetrahydropyrimidine- Aldehyde O-benzyloxime,
41) (E) -6-Amino-5 - ((2-methoxyethylimino) methyl) -1,3-dimethylpyrimidine-2,4 (1H, 3H)
42) (E) -1- (5 - ((Benzylimino) methyl) -1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin- -3-tert-butylurea,
43) (E) -1- (5 - ((Benzylimino) methyl) -1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin- -3-phenylthiourea,
44) Synthesis of (E) -1 - ((6-amino-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin- Urea,
46) (E) -1- (5 - ((Benzyloxyimino) methyl) -1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin- -3-tert-butylurea,
50) (E) -6- (Benzylamino) -1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde O-
51) 6-Amino-1,3-dimethyl-5- (2-phenylacetyl) pyrimidine-2,4 (1H, 3H)
52) 6-Amino-5- (2-bromobenzoyl) -1,3-dimethylpyrimidine-2,4 (1H, 3H)
53) 6-Amino-5- (2-fluorobenzoyl) -1,3-dimethylpyrimidine-2,4 (1H, 3H) -dione.
Amino-pyrimidine-2,4 (1H, 3H) -dione derivative represented by the following formula (2) with an isocyanate derivative in the presence of microwave.
Preparation of 6-amino-5- (substituted) pyrimidine-2,4 (1H, 3H) -dione derivative represented by Formula 1-1:
[Formula 1-1]

(2)

Wherein R ₁ to R ₅ are as defined in claim 2.
10. The method of claim 9,
Lt; RTI ID = 0.0 > nitrobenzene < / RTI > solvent.
10. The method of claim 9,
Is carried out using a microwave reactor at 180 to 250 DEG C for 15 to 50 minutes.
Amino-pyrimidine-2,4 (1H, 3H) -dione derivative represented by the following formula 2 is reacted with phosphoryl chloride to obtain 6-amino-2,4-dioxo-1,2,3,4- A first step of preparing a tetrahydropyrimidine-5-carbaldehyde derivative; And
The 6-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde derivative is reacted with a primary amine derivative to give 6-amino-5- (iminomethyl) -2,4 (1H, 3H) -dione derivative. ≪ RTI ID = 0.0 >
Preparation of 6-amino-5- (substituted) pyrimidine-2,4 (1H, 3H) -dione derivatives of formula 1-2:
[Formula 1-2]

(2)

Wherein R ₁ to R ₅ are as defined in claim 4.
13. The method of claim 12,
Wherein the first step is carried out in a dimethylformamide solvent.
13. The method of claim 12,
In the first step,
A step of dropwise adding phosphoryl chloride to a solution of 6-amino-pyrimidine-2,4 (1H, 3H) -dione derivative in dimethylformamide;
B) stirring the mixed solution of step a) at 18 to 35 DEG C for 30 minutes to 5 hours;
C) adjusting the pH of the reaction solution of step b) to 9 to 11; And
≪ / RTI > and crystallizing with hexane and ethyl acetate.
13. The method of claim 12,
Wherein the primary amine derivative is used in 1.0 to 1.5 molar equivalents relative to the 6-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde derivative in the second step. Way.
13. The method of claim 12,
And the second step is carried out in a C _{1 -4} lower alcohol solvent.
13. The method of claim 12,
And the second step is carried out at 50 to 70 DEG C for 6 minutes to 12 hours.
Amino-pyrimidine-2,4 (1H, 3H) -dione derivative represented by the following formula (2) with an acyl chloride derivative in the presence of pyridine.
Preparation of 6-amino-5- (substituted) pyrimidine-2,4 (1H, 3H) -dione derivatives of formula 1-3
[Formula 1-3]

(2)

Wherein R ₁ to R ₅ are as defined in claim 6.
19. The method of claim 18,
Lt; RTI ID = 0.0 > dioxane < / RTI > solvent.
19. The method of claim 18,
Lt; RTI ID = 0.0 > 18-35 C < / RTI > for 30 minutes to 5 hours.
19. The method of claim 18,
Filtration, drying, washing, purification, or a combination thereof.
1. A pharmaceutical composition for preventing or treating bone diseases comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:
[Chemical Formula 1]

In this formula,
L is - (C = O) -NH-,
R < ₁ > is phenyl substituted with halogen,
R ₂ and R ₃ are each independently C _1-6 alkyl,
R ₄ and R ₅ are hydrogen.
23. The method of claim 22,
Wherein the bone disease is at least one selected from the group consisting of osteoporosis, osteopenia, Paget's disease, periodontal disease, bone growth disorder, bone metastatic cancer and rheumatoid arthritis.
23. The method of claim 22,
Wherein said compound or a pharmaceutically acceptable salt thereof promotes differentiation into osteoblasts or its activity.
A composition for promoting bone differentiation of stem cells comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:
[Chemical Formula 1]

In this formula,
L is - (C = O) -NH-,
R1 is phenyl substituted with halogen,
R2 and R3 are independently C1-6 alkyl,
R4 and R5 are hydrogen.
26. The method of claim 25,
Wherein the stem cell is a mesenchymal stem cell.
26. The method of claim 25,
Wherein the differentiation promotion is achieved by BMP-2 pathway activation.

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