KR20150010195A - Novel Adenine Derivatives and the Use Thereof - Google Patents

Abstract

The present invention relates to a novel adenine derivative and a pharmaceutical use thereof and, more specifically, to a novel adenine derivative having a structure of chemical formula 1 or a pharmaceutically acceptable salt thereof, and to a composition containing the same for preventing or treating degenerative brain disease. The novel adenine derivative and the pharmaceutically acceptable salt thereof according to the present invention are adenosine A3 receptor agonists, and have an action of inhibiting the migration (or infiltration) of inflammatory cells (microglia, macrophages, neutrophils, etc.), to disease areas and the activities thereof. In addition, the adenine derivative according to the present invention was verified to suppress and treat brain injury more remarkably when compared with the known adenosine A3 receptor agonists in a cerebral ischemia experimental model, exhibit a significant effect by drug administration 10 hours after cerebral infarction, and allow long-term survival in spite of brain injury due to cerebral ischemia, and thus can be useful as an agent for treating and preventing degenerative brain disease including stroke.

Description

Novel Adenine Derivatives and the Use Thereof}

The present invention relates to a novel adenine derivative and its pharmaceutical use, and more particularly to a novel adenine derivative having a structural formula (1) or a pharmaceutically acceptable salt thereof and a method for preventing or treating a degenerative brain disease ≪ / RTI >

Stroke is a disorder causing cerebral blood flow abnormality. It is a very high mortality worldwide, and it is a disease that greatly lowers the quality of life. There is a steady increase in the interest in stroke worldwide. In Korea, stroke patients have been on the rise since the early 1980s due to the improvement of living standards.

Stroke is distinguished from hemorrhagic stroke, characterized by brain tissue damage due to rupture of the brain, and ischemic stroke, when tissue necrosis occurs only in one part of the whole body due to obstruction of blood supply. Such a stroke is a disease in which cell damage occurs through various intracellular signal transduction pathways, and brain damage is caused by the same cell damage mechanism as many degenerative brain diseases. Thus, the prevention, control, and development of stroke for the mechanism of death of brain cells can be used for various brain diseases such as Parkinson's disease, head trauma, spinal cord injury, Alzheimer's disease, And the application range is very vast.

Stroke is the second most common cause of death following cancer. According to the American Heart Association (AHA) report in 2008, the annual cost of stroke is $ 65.5 billion for the treatment and management of strokes, but the stroke drug market is only $ 1.3 billion. It is expected that the market value of stroke treatment drugs that are proven effective within 5 ~ 10 years from the above will form a market value of more than $ 22 billion. Domestic market will be KRW 2,155.4 billion in 2015 from KRW 646 billion in 2005 .

In addition, in view of the recent trend of the rapid increase of the elderly population due to the aging trend of the modern society, the increase of the survival period after the occurrence of the stroke is becoming a big social problem. Therefore, it is expected that the future demand for symptom relief and development of therapeutic drug for stroke will be increased, and the market will be expanded by the factors due to unbalanced dietary habits, environmental factors and stress.

Therefore, in order to reduce the clinical severity and socioeconomic loss of stroke, research on the development of therapeutic agents for the stroke has been progressing actively. Brain tissue damage after stroke is caused by the loss of intracellular energy sources (eg, ATP, etc.) due to mitochondrial dysfunction and by inflammatory responses due to excitatory neurotoxicity, radical production, and activation of inflammatory cells. In this regard, many researchers have tried to reduce ischemic brain damage by developing NMDA receptor blockers, but there are no cases of clinical trials that are toxic. Thus, MK-801, an NMDA receptor blocker, significantly reduced ischemic brain injury, but neuroprotective effect was confirmed only after administration within 1 hour after ischemia. (Margaill I, Parmentier S, Callebert J, Allix M, Boulu RG, Plotkine M. Short therapeutic window for MK-801 in transient focal cerebral ischemia in normotensive rats J Cereb Blood Flow Metab. 1996; In addition, since oxidative stress has a great effect on apoptosis or loss of function, studies on the therapeutic effect of ischemic stroke using antioxidants have been actively conducted. In Japan, Edaravone is used as a therapeutic agent for stroke (Firuzi O, Miri R, Tavakkoli M, Saso L. Antioxidant therapy: current status and future prospects.Curr Med Chem. 2011; 18 (25): 3871-88.).

As mentioned earlier, the development of therapeutic agents for stroke is still insufficient, and tissue plasminogen activator (t-PA) is mainly used as a treatment approved by the FDA for the treatment of clinically acceptable strokes. During the time it takes for the patient to arrive at the hospital emergency room after stroke, the neurons undergo primary damage due to excitatory neurotoxicity due to excessive glutamate release and are exposed to excessive production of oxygen and nitrogen radicals over time, And secondary damage occurs. Primary ischemic damage occurs within a very short time and is difficult to treat. Thus, attempts are being made to prevent secondary damage, and development of drugs that inhibit inflammation, or have antioxidant and antiinflammatory properties is being attempted.

Recently, the importance of inflammation in cerebral damage due to brain ischemia has been reported (Guann-Juh Chen, Brandon K. Harvey, Hui Shen, Jenny Chou, Adrienne Victor, and Yun Wang. Activation of Adenosine A3 Receptors Reduces Ischemic Brain Injury in Rodents J Neurosci Res 2006 Dec; 84 (8): 1848-55.; Choi YK, Cho GS, Hwang S, Kim BW, Lim JH, Lee JC, Kim HC, Kim WK & Kim YS, Methyleugenol 2010 Aug; 44 (8): 925-35.; Choi, IH, Lim, JH, Hwang S, Lee JC, Cho GS, Kim WK, Anti-ischemic and anti-inflammatory activity of (S) -cis-verbenol. Free Radic Res. 2010 May; 44 (5): 541-51.). In addition, it has been reported that the anti-inflammatory response of cannabinoid B2 receptor inhibits the damage of ischemic brain tissue (Choi, YC, Anthony Jalin AM, Lee DA, Prather PL, Kim WK. Activation of cannabinoid CB2 receptor- mediated AMPK / CREB pathway reducing cerebral ischemic injury. Am J Pathol. 2013 Mar; 182 (3): 928-39.). Recently, it has been reported that the use of Adenosine A3 receptor agonist, which is known to have antiinflammatory effect, can prevent ischemic brain damage, and it has been reported that the protective effect against lung and heart damage, anti-inflammatory / inflammatory action, Cl-IB-MECA [Zhi-Dong Ge, Jason N. Peart, Laura M. Kreckler, Tina C. Wan, Marlene A. Jacobson, Garrett J. Gross and John A. Auchampach. 2-Chloro-N6- (3-iodobenzyl) adenosine-5-Nmethylcarboxamide] Reduces Ischemia / Reperfusion Injury in Mice by Activating the A3 Adenosine Receptor J Pharmacol Exp Ther 2006 Dec; 319 (3): 1200-10; Morello, Antonello Petrella, Michela Festa, Ada Popolo, Mario Monaco, Emilia Vuttariello, Gennaro Chiappetta, Luca Parente and Aldo Pinto. Cl-IB-MECA inhibits human thyroid cancer cell proliferation independently of A3 adenosine receptor activation. ; 7 (2): 278-84 .; Leo M. Gazoni, MD, Dustin M. Walters, MD, Eric B. Unger, BS, Joel Linden, PhD, Irving L. Kron, MD, and Victor E. Laubach, PhD Activation of A1, A2A, or A3 adenosine receptors attenuates lung ischemia-reperfusion injury J Thorac Cardiovasc Surg. 2010 Aug; 140 (2): 440-6. ; Dr. Daniel P. Mulloy, MD, Ashish K. Sharma, MBBS, PhD, Lucas G. Fernandez, MD, Yunge Zhao, MD, PhD, Christine L. Lau, MD, Irving L. Kron, MD, and Victor E. Laubach, PhD . Adenosine A3 Receptor Activation Attenuates Lung Ischemia-Reperfusion Injury. Ann Thorac Surg. May 201 (5): 1762-7. ; Bella Chanyshev, Asher Shainberg, Ahuva Isak, Alexandra Litinsky, Yelena Chepurko, Dilip K. Tosh, Khai Phan, Zhan-Guo Gao, Edith Hochhauser, Kenneth A. Jacobson. Anti-ischemic effects of multivalent dendrimeric A3 adenosine receptor agonists in cultured cardiomyocytes and in the isolated rat heart. Pharmacol Res. 2012 Mar; 65 (3): 338-46 .; Choi IJ, Lee JC, Ju C, Hwang S, Cho GS, Lee HW, Choi WJ, Jeong LS, Kim WK. A3 adenosine receptor agonist reduces brain ischemic injury and inhibits inflammatory cell migration in rats. Am J Pathol. 2011 Oct; 179 (4): 2042-52.).

Accordingly, the present inventor has made intensive efforts to provide a new degenerative brain disease, inflammation or cancer epidemic or therapeutic agent, and as a result, it has been found that a novel adenine derivative and a pharmaceutically acceptable salt thereof, Time-dependent infarct volume, edema rate, and neurobehavioral test. In addition, the present inventors confirmed that the long-term survival survival rate and the permanent MCAO condition were significantly superior to each other, and completed the present invention.

The information described in the Background section is intended only to improve the understanding of the background of the present invention and thus does not include information forming a prior art already known to those skilled in the art .

It is an object of the present invention to provide novel adenine derivatives which can act as adenosine A3 receptor agonists and their pharmaceutically acceptable salts.

Another object of the present invention is to provide a pharmaceutical composition comprising the above-mentioned adenine derivative or a pharmaceutically acceptable salt thereof, which exhibits an excellent effect of preventing or treating degenerative brain diseases.

In order to achieve the above object, the present invention largely provides a novel adenine derivative, its use and preparation method.

Specifically, the present invention provides an adenine derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

Wherein R ₁ and R ₂ are each independently a hydrogen atom, an alkyl group, an m-halo-benzyl group, an m-amino-benzyl group, or an aromatic ring;

R ₃ is a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogen atom;

또는

이고;R ₄ is

or

ego;

R ₅ and R ₆ are each independently a hydrogen atom or an alkyl group.

The present invention also provides a pharmaceutical composition for treating or preventing degenerative brain diseases containing the above-mentioned adenine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides a method for treating or preventing a degenerative brain disease comprising administering the adenine derivative or a pharmaceutically acceptable salt thereof.

The present invention also provides the use of the adenine derivative or a pharmaceutically acceptable salt thereof for the treatment or prevention of degenerative brain diseases.

The present invention also provides the use of the adenine derivative or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment or prevention of degenerative brain diseases.

The present invention also provides a health functional food for the improvement or prevention of a degenerative brain disease containing the above-mentioned adenine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides a pharmaceutical composition for treating or preventing pulmonary disease, heart disease, cancer or inflammation containing an adenine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides a method for treating or preventing pulmonary disease, heart disease, cancer or inflammation comprising administering the adenine derivative or a pharmaceutically acceptable salt thereof.

The present invention also provides the use of the adenine derivative or a pharmaceutically acceptable salt thereof for the treatment or prevention of pulmonary diseases, heart diseases, cancer or inflammation.

The present invention also provides the use of the adenine derivative or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment or prevention of pulmonary diseases, heart diseases, cancer or inflammation.

The present invention also provides a health functional food for improving or preventing lung disease, heart disease, cancer or inflammation containing the above-mentioned adenine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides a process for preparing an adenine derivative represented by the following formula (2), comprising the steps of:

(2)

(a) The purine-based compound represented by the formula (4) is reacted with the starting compound, (2R, 3R, 4S, 5R) -2-acetoxy-5- (benzoyloxymethyl) tetrahydrofuran- , ≪ / RTI >

[Chemical Formula 4]

Wherein R ₃ is a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogen atom, and X is a halogen atom;

(b) reacting the intermediate compound prepared in step (a) with R ₁ -NY-R ₂ ,

Wherein R ₁ and R ₂ are each independently a hydrogen atom, an alkyl group, an m-halo-benzyl group, an m-amino-benzyl group or an aromatic ring and Y is a halogen atom;

(c) acetonizing the intermediate compound prepared in step (b);

(d) reacting the intermediate compound prepared in step (c) with R ₅ -NH-R ₆ ,

Wherein R ₅ and R ₅ are each independently a hydrogen atom or an alkyl group; And

(e) carrying out ring-opening reaction of the furan ring of the intermediate compound prepared in step (d) to prepare a compound of formula (2).

(S) -2 - ((R) -1- (2-Chloro-6- (3-iodobenzylamino) -9H-purin-9-yl) -2 -Hydroxyethoxy) -3-hydroxy-N-methylpropanamide < / RTI >

(a) A solution of 2,6-dichloropurine in (2R, 3R, 4S, 5R) -2-acetoxy-5- (benzoyloxymethyl) tetrahydrofuran- (2R, 3S, 4S, 5R) -2- (benzoyloxymethyl) -5- (2,6- dichloro-9H- purin-9- yl) tetrahydrofuran- Acetate;

(b) Synthesis of (2R, 3S, 4S, 5R) -2- (benzoyloxymethyl) -5- (2,6- dichloro- 9H- purin-9- yl) tetrahydrofuran- Dibenzoate was reacted with 3-iodobenzylamine hydrochloride to give (2R, 3S, 4S, 5R) -2- (benzoyloxymethyl) -5- 9H-purin-9-yl) tetrahydrofuran-3,4-diyl dibenzoate;

(c) Synthesis of (2R, 3S, 4S, 5R) -2- (benzoyloxymethyl) -5- (2-chloro-6- Furan-3,4-diyl dibenzoate was dissolved in methanolic ammonia and then concentrated under reduced pressure to give a triol intermediate. ((3aR, 4R, 6R, 6aR) -6- (3-fluorobenzylamino) -9H-purin-9-yl) -2,2-dimethyltetrahydrofuro [3,4- d] [1,3] dioxol- 4-yl) methanol;

(d) By reacting the above ((3aR, 4R, 6R, 6aR) -6- (2-Chloro-6- (3-iodobenzylamino) -9H- purin-9- yl) -2,2-dimethyltetrahydro (2S, 5R) -5- (2-chloro-6- (3 < RTI ID = 0.0 & - iodobenzylamino) -9H-purin-9-yl) -3,4-dihydroxy-N-methyltetrahydrofuran-2-carboxamide; And

(e) Synthesis of (2S, 5R) -5- (2-chloro-6- (3-iodobenzylamino) -9H- purin-9- yl) -3,4-dihydroxy-N-methyltetrahydro (R) -1- (2-chloro-6- (3-iodobenzylamino) -9H-purine-9 -Yl) -2-hydroxyethoxy) -3-hydroxy-N-methylpropanamide.

The present invention also provides a process for preparing an adenine derivative represented by the following formula (2), comprising the steps of:

(2)

(a) Synthesis of (2R, 5R) -2- (6-chloro-9H-purin-9-yl) -5- (hydroxymethyl) tetrahydrofuran- ;

(b) blocking the CH ₂ OH group of the furan ring of the intermediate compound prepared in step (a) with a protecting group, followed by reacting R ₁ -NY-R ₂ ,

Wherein R ₁ and R ₂ are each independently a hydrogen atom, an alkyl group, an m-halo-benzyl group, an m-amino-benzyl group or an aromatic ring and Y is a halogen atom;

(c) deacetonatizing the intermediate compound produced in step (b), and blocking the diol group of the furan ring of the deacetonized intermediate compound with a protecting group, respectively;

(d) removing the protecting group of the CH ₂ OH group of the furan ring of the intermediate compound prepared in the step (c);

(e) reacting the intermediate compound prepared in step (d) with R ₅ -NH-R ₆ ,

Wherein R ₅ and R ₆ are each independently a hydrogen atom or an alkyl group; And

(f) removing the protecting group of the diol group of the furan ring of the intermediate compound prepared in the step (e) and performing a ring-opening reaction of the furan ring to prepare a compound of the formula (2).

The present invention also relates to a process for the preparation of (S) -3-hydroxy-2 - ((R) -2-hydroxy- 1- (6- (3-iodobenzylamino) 9-yl) ethoxy) -N-methylpropanamide: < EMI ID =

(a) Synthesis of (2R, 5R) -2- (6-chloro-9H-purin-9-yl) -5- (hydroxymethyl) tetrahydrofuran- ((3aR, 4R, 6R, 6aR) -6- (6-Chloro-9H-purin-9- yl) -2,2- dimethyltetrahydrofuro [3,4d] [1,3] dioxane Sol-4-yl) methanol;

(b) A mixture of (3aR, 4R, 6R, 6aR) -6- (6-chloro-9H- purin-9- yl) -2,2-dimethyltetrahydrofuro [3,4d] Benzoyl chloride was added dropwise to a solution of (3aR, 4R, 6R, 6aR) -6- (6-chloro-9H-purin-9-yl) -2,2- Lt; / RTI > [3,4-d] [1,3] dioxol-4-yl) methyl benzoate;

(c) A mixture of (3aR, 4R, 6R, 6aR) -6- (6-Chloro-9H- purin-9- yl) -2,2- dimethyltetrahydrofuro [3,4- d] [1 (3R, 4R, 6R, 6aR) -6- (6- (3-iodobenzylamino) -9H -Purin-9-yl) -2,2-dimethyltetrahydrofuro [3,4-d] [1,3] dioxol-4-yl) methyl benzoate;

(d) A mixture of (3aR, 4R, 6R, 6aR) -6- (6- (3-iodobenzylamino) -9H- purin-9- yl) -2,2- dimethyltetrahydrofuro [ 4-d] [1,3] dioxol-4-yl) methyl benzoate was heated to reflux and concentrated under reduced pressure to give a diol intermediate, followed by addition of tetrabutyldimethylsilyl triflate ((2R, -9H-purin-9-yl) tetrahydrofuran-2-carboxamide < / RTI > Yl) methyl benzoate;

((2R, 3R, 4R, 5R) -3,4-bis (tert-butyldimethylsilyloxy) -5- (6- (3- iodobenzylamino) -9H- purin- Yl) methylbenzoate was dissolved in methanol and then sodium methoxide / methanol was added to the solution to obtain ((2R, 3R, 4R, 5R) -3,4-bis (tert- butyldimethylsilyloxy) (6- (3-iodobenzylamino) -9H-purin-9-yl) tetrahydrofuran-2-yl) methanol;

((2R, 3R, 4R, 5R) -3,4-bis (tert-butyldimethylsilyloxy) -5- (6- (3- iodobenzylamino) -9H- purin- Yl) methanol was subjected to ethyl esterification and then methylamine was added thereto to obtain (2S, 5R) -3,4-bis (tert-butyldimethylsilyloxy) -5- -9H-purin-9-yl) -N-methyltetrahydrofuran-2-carboxamide;

(g) Synthesis of (2S, 5R) -3,4-bis (tert-butyldimethylsilyloxy) -5- (6- (3- iodobenzylamino) -9H- purin- Methyl-tetrahydrofuran-2-carboxamide ethertylammonium fluoride was added dropwise to obtain 3,4-dihydroxy-5- (6- (3-iodobenzylamino) -9H-purin- To obtain N-methyltetrahydrofuran-2-carboxamide; And

(h) Preparation of the furan ring of the above 3,4-dihydroxy-5- (6- (3-iodobenzylamino) -9H-purin-9-yl) -N-methyltetrahydrofuran- (R) -2-hydroxy-1- (6- (3-iodobenzylamino) -9H-purin-9-yl) Methoxy) -N-methylpropanamide. ≪ / RTI >

The present invention also provides a process for preparing an adenine derivative represented by the following formula (3), comprising the steps of:

(3)

(a) The purine-based compound represented by the formula (4) is reacted with the starting compound, (2R, 3R, 4S, 5R) -2-acetoxy-5- (benzoyloxymethyl) tetrahydrofuran- , ≪ / RTI >

[Chemical Formula 4]

Wherein R ₃ is a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogen atom, and X is a halogen atom;

(b) reacting the intermediate compound prepared in step (a) with R ₁ -NY-R ₂ ,

Wherein R ₁ and R ₂ are each independently a hydrogen atom, an alkyl group, an m-halo-benzyl group, an m-amino-benzyl group or an aromatic ring and Y is a halogen atom;

(c) removing the benzyl group on the furan ring of the intermediate compound prepared in the step (b) and carrying out a ring-opening reaction of the furan ring to prepare a compound of the formula (3).

The novel adenine derivatives and pharmaceutically acceptable salts thereof according to the present invention are useful as adenosine A3 receptor agonists for the treatment of inflammatory cells (microglia, macrophages and neutrophil, etc.) (Migration, migration, or infiltration) and inhibition of activity. In addition, the adenine derivative according to the present invention has an effect of inhibiting and treating brain damage to a remarkable extent as compared with the conventionally known adenosine A3 receptor agonist in the experimental model of cerebral ischemia, and a significant effect is also shown in administration of the drug after 10 hours after cerebral infarction , It is confirmed that it enables long-term survival even in cerebral damage caused by cerebral ischemia. Therefore, it can be utilized as a therapeutic and preventive agent for degenerative brain diseases including stroke.

Fig. 1 shows the results of oral administration of a novel adenine derivative at a dose of 2 mg / kg twice over 3 hours and 8 hours after cerebral ischemia, showing the degree of brain damage reduction. Fig. FIG. 1B is a graph showing the infarct volume of each group, FIG. 1C is a graph showing the edema rate of each group, and FIG. 1D is a graph showing the neurobehavioral test results of the respective groups. Compared with the Cl-IB-MECA treated group used as a control group, it was possible to observe remarkably good brain tissue protection effect in all the measures of the new adenine derivative treatment group.
FIG. 2 shows the degree of decrease in brain damage when the new adenine derivative was intravenously administered at a dose of 2 mg / kg twice at 3 hours and 8 hours after the cerebral ischemia, and Fig. FIG. 2B is a graph showing the infarct volume of each group, FIG. 2C is a graph showing the edema rate of each group, and FIG. 2D is a graph showing the neurobehavioral test results of the respective groups. Compared with the Cl-IB-MECA treated group used as a control group, it was possible to observe remarkably good brain tissue protection effect in all the measures of the new adenine derivative treatment group.
FIG. 3 is a photograph showing the brain-slice reduction of each group when the new adenine derivative is intravenously administered at a dose of 10 mg / kg. FIG. 3 (b) is a photograph showing the coronary brain slice of each group. FIG. 3C is a graph showing the edema rate of each group, and FIG. 3D is a graph showing the neurobehavioral test results of the respective groups.
Fig. 4 shows the results of brain injury reduction when the new adenine derivative was intravenously administered at a dose of 2 mg / kg twice at 6 hours and 12 hours after cerebral ischemia. Fig. 4 FIG. 4B is a graph showing the infarct volume of each group, FIG. 4C is a graph showing the edema rate of each group, and FIG. 4D is a graph showing the neurobehavioral test results of the respective groups.
FIG. 5 shows the degree of decrease in brain damage when the new adenine derivative was intravenously administered at a dose of 2 mg / kg twice at 10 hours and 18 hours after the cerebral ischemia, and FIG. FIG. 4B is a graph showing the infarct volume of each group, FIG. 4C is a graph showing the edema rate of each group, and FIG. 4D is a graph showing the neurobehavioral test results of the respective groups.
FIG. 6 shows that the novel adenine derivative was administered intravenously at 3 hours and 8 hours after brain ischemia, followed by oral administration at intervals of 12 hours, followed by discontinuation of administration of the drug, and reduction of brain damage after 32 days FIG. 6A is a photograph of a coronary brain slice photographed by a slice on day 32, and FIG. 6B is a graph showing a mortality rate of a mouse for 32 days.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In general, the nomenclature used herein is well known and commonly used in the art.

The definitions of the main terms used in the description of the present invention and the like are as follows.

The term "degenerative brain disease" in the present invention means that the degenerative brain disease is selected from the group consisting of stroke, stroke, dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis and proximal lateral sclerosis amyotrophic lateral sclerosis), and the brain disease is the most important in the transmission of information in the brain nervous system, the death of brain cells, the formation of synapses or functional problems that transmit information between brain cells and neurons, the ideal of electrical activity of the brain It means disease caused by symptoms or reduction. In the present invention, the degenerative brain disease is more preferably characterized by including stroke, more preferably ischemic stroke disease.

The term "inflammatory disease" in the present invention includes acute and chronic inflammatory diseases such as pernicious inflammation, exudative inflammation, pyruvic inflammation, hemorrhagic inflammation or proliferative inflammation.

The term " agonist " in the present invention is a substance that specifically binds to a receptor to change its higher order structure and imparts chemical information to the cell, which is also referred to as an agonist.

Hereinafter, the present invention will be specifically described.

In one aspect, the present invention relates to an adenine derivative represented by the following general formula (1) or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

Wherein R ₁ and R ₂ are each independently a hydrogen atom, an alkyl group, an m-halo-benzyl group, an m-amino-benzyl group, or an aromatic ring;

R ₃ is a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogen atom;

또는

이고;R ₄ is

or

ego;

R ₅ and R ₆ are each independently a hydrogen atom or an alkyl group.

The novel adenine derivatives according to the present invention can be used in the form of pharmaceutically acceptable salts, and the pharmaceutically acceptable salts include acid addition salts formed by pharmaceutically acceptable free acids. An acid addition salt such as methanesulfonate, ethanesulfonate, fumarate, succinate, hydrochloride, citrate, malate, tartrate and (less preferably) hydrobromide. Salts formed with hydrochloric acid, phosphoric acid and sulfuric acid are also suitable. Suitable salts also include basic salts such as alkali metal salts such as sodium; Alkaline earth metal salts such as calcium or magnesium; Organic amine salts such as triethylamine, morpholine, N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine, N, N-dibenzylethylamine, tris- (2- Hydroxyethyl) amine, N-methyl d-glucamine and lysine. Depending on the number of charged groups and the valence of the cation or anion, there can be one or more cations or anions. A preferred pharmaceutically acceptable salt is a sodium salt. However, in order to facilitate release of the salt during manufacture, a salt that is less soluble with respect to the selected solvent may be preferred depending on the pharmaceutical availability.

In addition, the novel adenine derivative according to the present invention can be used in the form of a prodrug, a hydrate, a solvate, an isomer or a pharmaceutically acceptable salt thereof in order to enhance in vivo absorption or increase solubility. Prodrugs, hydrates, solvates, isomers and pharmaceutically acceptable salts thereof are also within the scope of the present invention.

The adenine derivatives of the present invention may exist in solvated forms, such as hydrated forms and unsolvated forms, and solvates of the adenine derivative compounds according to the present invention include all solvated forms with pharmaceutical activity .

The adenine derivatives of the present invention may be administered in the form of prodrugs which are degraded in the human or animal body to provide the compounds of the present invention. A prodrug may be formed when it contains a suitable group or substituent which can be used to alter or improve the physical and / or pharmacokinetic profile of the parent compound and which parent compound can be derivatized to form a prodrug. Examples of prodrugs include in vivo hydrolysable esters of the compounds according to the invention and their pharmaceutically acceptable salts.

Various forms of prodrugs are known in the art including, for example:

a) Hans Bundarrd, Design of Prodrugs, p. 1 © 1985 Elsevier Science Publishers. And WIDDER, Kenneth J. and GREEN, Ralph., Drug and enzyme targeting. Methods in Enzymol. Volume 112. ⓒ 1985 Academic Press, Inc.];

b) Krogsgaard-Larsen, P .; Bundgaard, H. A Textbook of Drug Design and Development, p. 113 © 1991 Harwood Academic Publishers];

c. Bundgaard. (C) Means to enhance penetration: (1) Prodrugs as a means to improve the delivery of peptide drugs. Adv Drug Deliv Rev. 1992; 8 (1): 1-38.];

d) Nielsen NM, Bundgaard H. Glycolamide esters as biolabile prodrugs of carboxylic acid agents: synthesis, stability, bioconversion, and physicochemical properties. J Pharm Sci. 1988 Apr; 77 (4): 285-98.); And

e) [Kakeya N, Nishimura K, Yoshima A, Nakamura S, Nishizawa S, Tamaki S, Matsui H, Kawamura T, Kasai M, Kitao K. Studies on prodrugs of cephalosporins. I. Synthesis and biological properties of glycyloxybenzoyloxymethyl and glycylaminobenzoyloxymethyl esters of 7 beta- [2- (2-aminothiazol-4-yl) - (Z) -2-methoxyiminoacetamido] -3-methyl-3-cephem-4-carboxylic acid. Chem Pharm Bull (Tokyo). 1984 Feb; 32 (2): 692-8.)

And the like can be referred to.

In addition, it is understood that all optical and diastereomeric and racemic mixtures having A3 adenosine receptor agonist activity are also included in the scope of the present invention. Methods of making optically active forms (e.g., recrystallization techniques, chiral synthesis, resolution by enzymes, separation of racemates by biotransformation or chromatographic separation) and methods of measuring antimicrobial activity are known in the art .

Although the compounds of formula (I) or salts thereof in the present invention may exhibit tautomeric tautomerism, even though the formulas or schemes herein depict only a single possible tautomeric form, the invention encompasses the A3 adenosine receptor But are not limited to only one tautomeric form that has an agonist activity and is merely a tautomeric form used within a formula or reaction formula.

Certain compounds of the invention may also exhibit polymorphism, and any phe- nozymes having an A3 adenosine receptor agonist activity are also encompassed by the present invention.

In the present invention, preferably, R ₁ and R ₂ are each independently a hydrogen atom or m-iodobenzyl.

In the present invention, preferably, R ₃ may be a hydrogen atom or a chlorine atom.

In the present invention, R ₅ and R ₆ may each independently be a hydrogen atom or a methyl group.

In the present invention, representative examples of the adenine derivative represented by the above formula (1) or a pharmaceutically acceptable salt thereof are as follows:

(R) -1- (2-chloro-6- (3-iodobenzylamino) -9H-purin-9-yl) -2-hydroxyethoxy) -3- -N-methylpropanamide;

(R) -2- (1- (2-Chloro-6- (3-iodobenzylamino) -9H-purin-9-yl) -2-hydroxyethoxy) propane-1,3-diol;

(R) -2-hydroxy-1- (6- (3-iodobenzylamino) -9H-purin-9-yl) ethoxy) -N-methyl Propanamide; And

(R) -2- (2-hydroxy-1- (6- (3-iodobenzylamino) -9H-purin-9-yl) ethoxy) propane-1,3-diol.

The novel adenine derivative compound according to the present invention can be prepared by various methods known in the art depending on the kind of the substituent. For example, the adenine derivative compound can be prepared according to the method illustrated in the following reaction formula. Since the preparation method shown in the following reaction scheme is merely an example and it can be easily modified by a person skilled in the art according to a specific substituent, the method illustrated in the following reaction formula does not limit the method for preparing the adenine derivative compound according to the present invention, Unless otherwise indicated, the definitions of the substituents in the following reactions are the same as those in the above formula (1).

First, the compound of formula (1) may be an adenine derivative represented by the following formula (2), and the adenine derivative represented by the formula (2) may be prepared as follows:

(2)

.

.

That is, the adenine derivative of formula (2) can be prepared by the following steps:

(a) The purine-based compound represented by the formula (4) is reacted with the starting compound, (2R, 3R, 4S, 5R) -2-acetoxy-5- (benzoyloxymethyl) tetrahydrofuran- , ≪ / RTI >

[Chemical Formula 4]

Wherein R ₃ is a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogen atom, and X is a halogen atom;

(b) reacting the intermediate compound prepared in step (a) with R ₁ -NY-R ₂ ,

Wherein R ₁ and R ₂ are each independently a hydrogen atom, an alkyl group, an m-halo-benzyl group, an m-amino-benzyl group or an aromatic ring and Y is a halogen atom;

(c) acetonizing the intermediate compound prepared in step (b);

(d) reacting the intermediate compound prepared in step (c) with R ₅ -NH-R ₆ ,

Wherein R ₅ and R ₅ are each independently a hydrogen atom or an alkyl group; And

(e) carrying out ring-opening reaction of the furan ring of the intermediate compound prepared in step (d) to prepare a compound of formula (2).

(S) -2 - ((R) -1- (2-Chloro-6- (3-iodobenzylamino) -9H-purine -9-yl) -2-hydroxyethoxy) -3-hydroxy-N-methylpropanamide, the reaction scheme of which is as follows:

[Reaction Scheme 1]

(R) -1- (2-chloro-6- (3-iodobenzylamino) -9H-purin-9-yl) -2-hydroxyethoxy) -3 -Hydroxy-N-methylpropanamide can be prepared by a process comprising the following steps:

(a) A solution of 2,6-dichloropurine in (2R, 3R, 4S, 5R) -2-acetoxy-5- (benzoyloxymethyl) tetrahydrofuran- (2R, 3S, 4S, 5R) -2- (benzoyloxymethyl) -5- (2,6- dichloro-9H- purin-9- yl) tetrahydrofuran- Acetate;

(b) Synthesis of (2R, 3S, 4S, 5R) -2- (benzoyloxymethyl) -5- (2,6- dichloro- 9H- purin-9- yl) tetrahydrofuran- Dibenzoate was reacted with 3-iodobenzylamine hydrochloride to give (2R, 3S, 4S, 5R) -2- (benzoyloxymethyl) -5- 9H-purin-9-yl) tetrahydrofuran-3,4-diyl dibenzoate;

(c) Synthesis of (2R, 3S, 4S, 5R) -2- (benzoyloxymethyl) -5- (2-chloro-6- Furan-3,4-diyl dibenzoate was dissolved in methanolic ammonia and then concentrated under reduced pressure to give a triol intermediate. ((3aR, 4R, 6R, 6aR) -6- (3-fluorobenzylamino) -9H-purin-9-yl) -2,2-dimethyltetrahydrofuro [3,4- d] [1,3] dioxol- 4-yl) methanol;

(d) By reacting the above ((3aR, 4R, 6R, 6aR) -6- (2-Chloro-6- (3-iodobenzylamino) -9H- purin-9- yl) -2,2-dimethyltetrahydro (2S, 5R) -5- (2-chloro-6- (3 < RTI ID = 0.0 & - iodobenzylamino) -9H-purin-9-yl) -3,4-dihydroxy-N-methyltetrahydrofuran-2-carboxamide; And

(e) Synthesis of (2S, 5R) -5- (2-chloro-6- (3-iodobenzylamino) -9H- purin-9- yl) -3,4-dihydroxy-N-methyltetrahydro (R) -1- (2-chloro-6- (3-iodobenzylamino) -9H-purine-9 -Yl) -2-hydroxyethoxy) -3-hydroxy-N-methylpropanamide.

On the other hand, the adenine derivative represented by the above formula (2) can also be prepared by the following process:

(a) Synthesis of (2R, 5R) -2- (6-chloro-9H-purin-9-yl) -5- (hydroxymethyl) tetrahydrofuran- ;

(b) blocking the CH ₂ OH group of the furan ring of the intermediate compound prepared in step (a) with a protecting group, followed by reacting R ₁ -NY-R ₂ ,

Wherein R ₁ and R ₂ are each independently a hydrogen atom, an alkyl group, an m-halo-benzyl group, an m-amino-benzyl group or an aromatic ring and Y is a halogen atom;

(c) deacetonatizing the intermediate compound produced in step (b), and blocking the diol group of the furan ring of the deacetonized intermediate compound with a protecting group, respectively;

(d) removing the protecting group of the CH ₂ OH group of the furan ring of the intermediate compound prepared in the step (c);

(e) reacting the intermediate compound prepared in step (d) with R ₅ -NH-R ₆ ,

Wherein R ₅ and R ₆ are each independently a hydrogen atom or an alkyl group; And

(f) removing the protecting group of the diol group of the furan ring of the intermediate compound prepared in the step (e) and performing a ring-opening reaction of the furan ring to prepare a compound of the formula (2).

In one embodiment of the present invention, there is provided a process for preparing (S) -3-hydroxy-2 - ((R) -2-hydroxy- 1- (6- (3- Amino) -9H-purin-9-yl) ethoxy) -N-methylpropanamide was prepared, the reaction scheme of which is as follows:

[Reaction Scheme 3]

(R) -2-hydroxy-1- (6- (3-iodobenzylamino) -9H-purin-9-yl) ethoxy) - N-methylpropanamide can be prepared by a process comprising the following steps:

(a) Synthesis of (2R, 5R) -2- (6-chloro-9H-purin-9-yl) -5- (hydroxymethyl) tetrahydrofuran- ((3aR, 4R, 6R, 6aR) -6- (6-Chloro-9H-purin-9- yl) -2,2- dimethyltetrahydrofuro [3,4d] [1,3] dioxane Sol-4-yl) methanol;

(b) A mixture of (3aR, 4R, 6R, 6aR) -6- (6-chloro-9H- purin-9- yl) -2,2-dimethyltetrahydrofuro [3,4d] Benzoyl chloride was added dropwise to a solution of (3aR, 4R, 6R, 6aR) -6- (6-chloro-9H-purin-9-yl) -2,2- Lt; / RTI > [3,4-d] [1,3] dioxol-4-yl) methyl benzoate;

(c) A mixture of (3aR, 4R, 6R, 6aR) -6- (6-Chloro-9H- purin-9- yl) -2,2- dimethyltetrahydrofuro [3,4- d] [1 (3R, 4R, 6R, 6aR) -6- (6- (3-iodobenzylamino) -9H -Purin-9-yl) -2,2-dimethyltetrahydrofuro [3,4-d] [1,3] dioxol-4-yl) methyl benzoate;

(d) A mixture of (3aR, 4R, 6R, 6aR) -6- (6- (3-iodobenzylamino) -9H- purin-9- yl) -2,2- dimethyltetrahydrofuro [ 4-d] [1,3] dioxol-4-yl) methyl benzoate was heated to reflux and concentrated under reduced pressure to give a diol intermediate, followed by addition of tetrabutyldimethylsilyl triflate ((2R, -9H-purin-9-yl) tetrahydrofuran-2-carboxamide < / RTI > Yl) methyl benzoate;

((2R, 3R, 4R, 5R) -3,4-bis (tert-butyldimethylsilyloxy) -5- (6- (3- iodobenzylamino) -9H- purin- Yl) methylbenzoate was dissolved in methanol and then sodium methoxide / methanol was added to the solution to obtain ((2R, 3R, 4R, 5R) -3,4-bis (tert- butyldimethylsilyloxy) (6- (3-iodobenzylamino) -9H-purin-9-yl) tetrahydrofuran-2-yl) methanol;

((2R, 3R, 4R, 5R) -3,4-bis (tert-butyldimethylsilyloxy) -5- (6- (3- iodobenzylamino) -9H- purin- Yl) methanol was subjected to ethyl esterification and then methylamine was added thereto to obtain (2S, 5R) -3,4-bis (tert-butyldimethylsilyloxy) -5- -9H-purin-9-yl) -N-methyltetrahydrofuran-2-carboxamide;

(g) Synthesis of (2S, 5R) -3,4-bis (tert-butyldimethylsilyloxy) -5- (6- (3- iodobenzylamino) -9H- purin- Methyl-tetrahydrofuran-2-carboxamide ethertylammonium fluoride was added dropwise to obtain 3,4-dihydroxy-5- (6- (3-iodobenzylamino) -9H-purin- To obtain N-methyltetrahydrofuran-2-carboxamide; And

(h) Preparation of the furan ring of the above 3,4-dihydroxy-5- (6- (3-iodobenzylamino) -9H-purin-9-yl) -N-methyltetrahydrofuran- (R) -2-hydroxy-1- (6- (3-iodobenzylamino) -9H-purin-9-yl) Methoxy) -N-methylpropanamide. ≪ / RTI >

In addition, the compound of Formula 1 may be an adenine derivative represented by Formula 3, and the adenine derivative represented by Formula 3 may be prepared as follows:

(3)

.

.

That is, the adenine derivative of formula (3) can be prepared by the following steps:

(a) The purine-based compound represented by the formula (4) is reacted with the starting compound, (2R, 3R, 4S, 5R) -2-acetoxy-5- (benzoyloxymethyl) tetrahydrofuran- , ≪ / RTI >

[Chemical Formula 4]

Wherein R ₃ is a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogen atom, and X is a halogen atom;

(b) reacting the intermediate compound prepared in step (a) with R ₁ -NY-R ₂ ,

Wherein R ₁ and R ₂ are each independently a hydrogen atom, an alkyl group, an m-halo-benzyl group, an m-amino-benzyl group or an aromatic ring and Y is a halogen atom;

(c) removing the benzyl group on the furan ring of the intermediate compound prepared in the step (b) and carrying out a ring-opening reaction of the furan ring to prepare a compound of the formula (3).

In one embodiment of the present invention, there is provided a process for preparing (R) -2- (1- (2-chloro-6- (3-iodobenzylamino) -9H-purin- ) -2-hydroxyethoxy) propane-1,3-diol, the reaction scheme of which is as follows:

[Reaction Scheme 2]

In another embodiment of the present invention, the novel adenine derivative according to the present invention significantly reduces brain damage compared to Cl-IB-MECA, which is known as the adenosine A3 receptor agonist as well as the non-administration group (control) Respectively. In particular, even when administered at a low concentration, it has a significant effect of preventing damage, and even when the drug is delayed for at least 10 hours, the brain damage is significantly reduced, and the inflammatory reaction after the primary injury is effectively prevented . Therefore, it has been confirmed that the adenine derivative according to the present invention can be effectively used as a preventive and therapeutic agent for stroke because it has an effect of inhibiting and preventing brain damage due to cerebral ischemia even when administered by intravenous injection. In addition, stroke is a disease in which cell damage occurs through a variety of intracellular signaling pathways, and brain damage is caused by the same cellular damage mechanism as many degenerative brain diseases. Thus, the prevention, control, and development of stroke for the mechanism of death of brain cells can be used for various brain diseases such as Parkinson's disease, head trauma, spinal cord injury, Alzheimer's disease, And the application range is very vast. Thus, it has been confirmed that the adenine derivative according to the present invention can be effectively used as an agent for treating or preventing various degenerative brain diseases in addition to stroke.

Accordingly, the present invention relates to a composition for treating or preventing degenerative brain diseases comprising, as an active ingredient, the above-mentioned adenine derivative or a pharmaceutically acceptable salt thereof.

In addition, the adenine derivative according to the present invention acts as an adenosine A3 receptor agonist, and the adenosine A3 receptor agonist has a protective effect against ischemic brain, lung and heart damage, anti-inflammatory / inflammatory action, and anti-cancer / Are reported. Cl-IB-MECA [2-Chloro-N6- ((2-Chloro-N, N-dibenzyl- 3-iodobenzyl) adenosine-5-Nmethylcarboxamide] Reduces Ischemia / Reperfusion Injury in Mice by Activating the A3 Adenosine Receptor. J Pharmacol Exp Ther 2006 Dec; 319 (3): 1200-10 .; Silvana Morello, Antonello Petrella, Michela Festa , Ada Popolo, Mario Monaco, Emilia Vuttariello, Gennaro Chiappetta, Luca Parente and Aldo Pinto. Cl-IB-MECA inhibits human thyroid cancer cell proliferation independently of A3 adenosine receptor activation. Activation of A1, A2A < RTI ID = 0.0 > A. < / RTI > , or A3 adenosine receptors attenuates lung ischemia-reperfusion injury. J Thorac Cardiovasc Surg. 2010 Aug; 140 (2): 440-6 .; Daniel P. Mulloy, MD, Ashish K. Sharma, MBBS, PhD, Lucas G. Fernandez , MD, Yunge Zhao, MD, PhD, Ch ristine L. Lau, MD, Irving L. Kron, MD, and Victor E. Laubach, PhD. Adenosine A3 Receptor Activation Attenuates Lung Ischemia-Reperfusion Injury. Ann Thorac Surg. May 201 (5): 1762-7. ; Bella Chanyshev, Asher Shainberg, Ahuva Isak, Alexandra Litinsky, Yelena Chepurko, Dilip K. Tosh, Khai Phan, Zhan-Guo Gao, Edith Hochhauser, Kenneth A. Jacobson. Anti-ischemic effects of multivalent dendrimeric A3 adenosine receptor agonists in cultured cardiomyocytes and in the isolated rat heart. Pharmacol Res. 2012 Mar; 65 (3): 338-46 .; Choi IJ, Lee JC, Ju C, Hwang S, Cho GS, Lee HW, Choi WJ, Jeong LS, Kim WK. A3 adenosine receptor agonist reduces brain ischemic injury and inhibits inflammatory cell migration in rats. Am J Pathol. 2011 Oct; 179 (4): 2042-52.). Accordingly, the adenine derivative according to the present invention can be used as a composition for preventing or treating pulmonary disease, heart disease, cancer or inflammation as an adenosine A3 receptor agonist.

Accordingly, the present invention, in another aspect, relates to a composition for preventing or treating pulmonary diseases, heart diseases, cancer or inflammation comprising an adenine derivative or a pharmaceutically acceptable salt thereof according to the present invention as an active ingredient.

The administration of the therapeutic or prophylactic composition of the present invention may be carried out by administering the adenine derivative or its pharmaceutically acceptable salt according to the present invention alone, but it may be administered orally or parenterally in the form of excipient, binder, lubricant, disintegrant, May be generally administered in the form of a pharmaceutical mixture formulated to be suitable for the particular use and desired purpose by mixing the active ingredient, solvent, stabilizer, absorption promoter and / or ointment base. The mixture may be used for oral, parenteral, rectal or topical administration. The term "pharmaceutically acceptable" as used herein refers to a composition that is physiologically acceptable and does not normally cause an allergic reaction such as a gastrointestinal disorder, dizziness, or the like when administered to a human.

In the case of the oral dosage form, it may be, for example, a tablet, a coated tablet, a dragees, a hard or soft gelatin capsule, a liquid, an emulsifier or a suspension. Administration can also be administered rectally, e.g., using suppositories; Topically or transdermally, for example, as ointments, creams, patches, gels or solutions; Or parenterally, e. G., Systemically or by injectable solutions for administration of spinal fluid.

For the preparation of tablets, coated tablets, dragees, hard or soft gelatine capsules, the adenine derivatives according to the invention, or pharmaceutically acceptable salts thereof, are formulated with pharmaceutically inert, inorganic or organic excipients, ≪ / RTI > Examples of suitable excipients for tablets, coated tablets, dragees, hard gelatine capsules include lactose, maize starches or derivatives thereof, talc or stearic acid or their salts. Suitable excipients for use in soft gelatine capsules include, for example, vegetable oils, waxes, fats, semi-solid or liquid polyols and the like. However, depending on the nature of the active ingredient, there may be cases where no excipient is needed in the soft gelatine capsules. For the preparation of solutions and syrups, excipients which may be used include, for example, water, polyols, saccharose, invert sugar and glucoses. For the preparation of injectable solutions, excipients which may be used include, for example, water alcohols, polyols, glycerin and vegetable oils. For suppositories and for the preparation of topical or transdermal applications, excipients which may be used include, for example, natural or hardened oils, waxes, fats and semi-solid or liquid polyols.

The compositions of the present invention may also contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, pigments, fragrances, salts for varying the osmotic pressure, buffers, coatings, tranquilizers, isotonic agents or antioxidants, As well as valuable medicines.

Consequently, pharmaceutical formulations for oral administration may be granules, tablets, sugar coated tablets, capsules, pills, suspensions or emulsions, and may be in the form of parenteral preparations, for example, intravenously, intramuscularly or subcutaneously Forms of sterile aqueous solutions may be used for the formulation, which may include other materials such as salts or glucoses to make an isotonic solution. It can also be administered in the form of suppositories or pessaries or externally applied in the form of patches, lotions, solutions, creams, ointments or dusting powders.

The appropriate dose of the composition of the present invention should be determined in view of various factors such as the formulation method, administration method, age, sex and weight, pathological condition, food, administration time, route of administration, excretion rate and responsiveness of the patient Should be understood, and therefore the dose is not limited in any way by the scope of the invention.

Example

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these examples are for illustrative purposes only and that the scope of the present invention is not construed as being limited by these examples.

Manufacturing example  1: To a solution of the compound of formula 5 ((S) -2 - ((R) -1- (2-Chloro-6- (3-iodobenzylamino) -9H- purin- Methoxy) -3-hydroxy-N-methylpropanamide)

[Reaction Scheme 1]

Step 1: A solution of (2R, 3S, 4S, 5R) -2- (benzoyloxymethyl) -5- (2,6- dichloro-9H- purin-9- yl) tetrahydrofuran- Preparation of benzoate (7)

Starting material A mixture of (2R, 3R, 4S, 5R) -2-acetoxy-5- (benzoyloxymethyl) tetrahydrofuran-3,4-diyldibenzoate (7.5 g, 14.9 mmol) (3.09 g, 16.4 mmol) was dissolved in acetonitrile (50 mL), and a solution of N, O-bis (trimethylsilyl) acetamid (8.9 mL, 36.4 mmol) was slowly added dropwise for 10-15 minutes Then, the mixture is stirred at 60 DEG C for 30 minutes. After cooling the reaction solution to -30 ° C, TiCl ₄ (60 mL, 1 M methylene chloride solution, 59.5 mmol) is added dropwise, and the mixture is stirred at 60-65 ° C for 20 minutes. After confirming the completion of the reaction, methylene chloride (500 mL) and saturated sodium hydrogencarbonate solution (500 mL) are added. The reaction solution was stirred at 0 ° C for 30 minutes, and the organic layer was extracted and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the obtained residue was separated by column chromatography to obtain the intermediate compound (2R, 3S, 4S, 5R) -2- (benzoyloxymethyl) -5- (2,6- dichloro- Yl) tetrahydrofuran-3,4-diyl dibenzoate (9.3 g, 98.8%).

The analytical data of the obtained compound are as follows.

^{1 H NMR (500 MHz; CDCl} 3) δ ppm 4.71-4.74 (dd, J = 12.22, 3.91 Hz, 1H), 4.85-4.93 (m, 2H), 6.12-6.14 (t, J = 4.89 Hz, 1H) (M, 1H), 6.16-6.19 (t, J = 5.38 Hz, 1H), 6.47-6.48 (d, J = 5.38 Hz, 1H), 7.35-7.38 4H), 7.54-7.61 (m, 3H), 7.92-7.93 (d, J = 7.33 Hz, 2H), 8.02-8.06 (m, 4H), 8.28 (s, 1H); ^{13 C NMR (125 MHz; CDCl} 3) δ 63.50, 71.59, 74.33, 81.56, 87.05, 128.14, 128.59 (3), 128.63 (2), 128.73 (2), 129.10, 129.63 (2), 129.88 (2), 129.92 (2), 131.38, 133.63, 133.87, 133.98, 143.81, 152.36, 152.64, 153.51, 165.13, 165.29, 166.03; mp = 76-80 [deg.] C.

Step 2: (2R, 3S, 4S, 5R) -2- (Benzoyloxymethyl) -5- (2-chloro-6- (3-iodobenzylamino) -9H- purin-9-yl) tetrahydrofuran -3,4-diyl dibenzoate (8)

The intermediate compound (204 mg, 0.32 mmol) and 3-iodobenzylamine hydrochloride (113 mg, 0.41 mmol) prepared in the above step 1 were dissolved in anhydrous ethanol (5 mL) under a nitrogen atmosphere, triethylamine (0.13 mL, 0.96 mmol) is stirred at room temperature for 24 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was separated by column chromatography to obtain the intermediate compound (2R, 3S, 4S, 5R) -2- (benzoyloxymethyl) (3-iodobenzylamino) -9H-purin-9-yl) tetrahydrofuran-3,4-diyldibenzoate (230 mg, 86.14%).

The analytical data of the obtained compound are as follows.

^{1 H NMR (500 MHz; CDCl} 3) δ ppm 4.71-4.90 (m, 5H), 6.13-6.17 (m, 2H), 6.33 (.. Br s, 1H), 6.43-6.44 (d, J = 4.89 Hz (M, 4H), 7.31-7.33 (m, 6H), 7.33-7.46 (m, 6H) 7.70-7.71 (t, J = 1.46 Hz, 1H), 7.88 (s, 1H), 7.94-7.96 (m, 2H), 7.99-8.01 (m, 2H), 8.07-8.09 (m, 2H); ^{13 C NMR (125 MHz; CDCl} 3) δ 43.91, 63.79, 71.56, 74.43, 80.97, 86.40, 94.49, 119.07, 127.14, 128.40, 128.52 (3), 128.62 (2), 128.71, 129.32, 129.68 (3), 129.86 (2), 129.93 (2), 130.39 (2), 133.41, 133.69, 133.78, 136.72, 136.80, 138.39, 140.20, 150.05, 155.00, 165.17, 165.31, 166.11; mp = 80-84 [deg.] C.

Step 3: ((3aR, 4R, 6R, 6aR) -6- (2-Chloro-6- (3-iodobenzylamino) -9H- purin-9- yl) -2,2- dimethyltetrahydrofur [3,4-d] [1,3] dioxol-4-yl) methanol (9)

The intermediate compound (20 g, 24.09 mmol) prepared in the above step 2 was dissolved in methanolic ammonia (1 L) and stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure to obtain a triol intermediate. The triol intermediate thus obtained (20 g, 38.63 mmol) was dissolved in anhydrous acetone (400 mL), and 2,2-dimethoxypropane (23.68 mL, 193.15 mmol) and p-toluenesulfonic acid monohydrate (7.34 g, 38.63 mmol) was added dropwise thereto, followed by stirring at room temperature for 12 hours. After confirming the completion of the reaction, saturated sodium hydrogencarbonate solution (400 mL) was added thereto. The reaction solution was concentrated under reduced pressure. The organic layer was extracted with chloroform (4 x 250 mL), washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The reaction mixture was concentrated under reduced pressure, and the obtained residue was then separated by column chromatography to obtain the intermediate compound ((3aR, 4R, 6R, 6aR) -6- (2-Chloro-6- (3-iodobenzylamino) Yl] -2,2-dimethyltetrahydrofuro [3,4-d] [1,3] dioxol-4-yl) methanol (12 g, 89.35%).

The analytical data of the obtained compound are as follows.

¹ H NMR (500 MHz; CDCl ₃ )? Ppm 1.36 (s, 3H), 1.62 (s, 3H), 3.77-3.80 (dd, J = 12.71, 1.95 Hz, 1H), 3.95-3.98 12.71, 1.95 Hz, 1H), 4.48-4.49 (d, J = 1.46 Hz, 1H), 4.68 (br. s., 1H, exchangeable with D 2 O, OH), 4.74 (br. s., 2H), (D, J = 5.86, 1.46 Hz, 1H), 5.15-5.17 (t, J = 5.38 Hz, 1H), 5.77-5.78 (d, J = 4.40 Hz, 1H), 6.81 (br s. _{, 1H, exchangeable with d 2 O} , NH), 7.03-7.06 (t, J = 7.82 Hz, 1H), 7.30-7.31 (d, J = 7.33 Hz, 1H), 7.59-7.61 (d, J = 7.82 Hz , ≪ / RTI > 1H), 7.67 (s, 1H), 7.70 (s, 1H); ^{13 C NMR (125 MHz; CDCl} 3) δ 25.26, 27.63, 43.93, 63.37, 81.52, 82.98, 86.12, 93.89, 94.55, 114.18, 120.09, 127.19, 130.44, 136.86 (2), 139.93, 140.01, 148.80, 154.50, 155.14; mp = 82-86 ° C

Step 4: (2S, 5R) -5- (2-Chloro-6- (3-iodobenzylamino) -9H- purin-9- yl) -3,4- dihydroxy- -2-carboxamide < / RTI > (10)

The intermediate compound (15 g, 26.89 mmol) prepared in step 3 was dissolved in a solution of acetonitrile-water (130 mL, 1: 1) and then (diacetoxy iodo) -benzene (19 g, 59.16 mmol) 2,2,6,6-Tetramethyl 1-piperidinyloxyl (840 mg, 5.37 mmol) was added dropwise, followed by stirring at room temperature for 4 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain an acid intermediate without purification. The obtained intermediate (15 g, 26.23 mmol) was dissolved in anhydrous ethanol (500 mL) under a nitrogen stream, cooled to 0 ° C, thionyl chloride (9.52 mL, 131.17 mmol) was slowly added dropwise and the mixture was stirred at room temperature for 12 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain an ethyl ester intermediate without purification. Methylamine (750 mL, 2 N THF solution) was added dropwise to the resulting ethyl ester intermediate (15.5 g, 25.84 mmol) and the mixture was stirred at room temperature for 12 hours. After confirming the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the intermediate compound (2S, 5R) -5- (2-Chloro-6- (3- -9-yl) -3,4-dihydroxy-N-methyltetrahydrofuran-2-carboxamide (5 g, 31.80%).

The analytical data of the obtained compound are as follows.

¹ H NMR (500 MHz; DMSO-d ₆ )? Ppm 2.72-2.73 (d, J = 3.91 Hz, 3H), 4.17 (brs, 1H), 4.33 (s, 1H), 4.55-4.56 (D, J = 6.35 Hz, 1H, exchangeable with D ₂ O, 2'-OH), 5.71-5.72 d, J = 3.91 Hz, 1H , exchangeable with d 2 O, 3'-OH), 5.92-5.93 (d, J = 7.33 Hz, 1H), 7.11-7.14 (t, J = 7.82 Hz, 1H), 7.35 (D, J = 6.84 Hz, 1H), 7.59-7.61 (d, J = 7.82 Hz, 1H), 7.75 (s, 1H), 8.27-8.28 exchangeable with D ₂ O, NH), 8.48 (s, 1 H), 8.98-8.99 (br. t, J = 5.86 Hz, 1H, exchangeable with D ₂ O, N ⁶ H); ¹³ C NMR (125 MHz; DMSO-d ₆ )? 26.07, 43.02, 72.79, 73.42, 84.95, 88.10, 95.12, 119.46, 127.31, 130.99, 136.06, 136.51, 141.57, 142.23, 150.00, 153.44, 155.31, 170.14; mp = 207-209 [deg.] C

Step 5: (S) -2 - ((R) -1- (2-Chloro-6- (3-iodobenzylamino) -9H- purin-9- yl) -2-hydroxyethoxy) -3 - < / RTI > hydroxy-N-methylpropanamide (5)

The intermediate compound (2.0 g, 3.67 mmol) prepared in step 4 was dissolved in water / methanol (210 mL, 1: 2), cooled to 0 ° C and then sodium per iodate (1.57 g, 7.34 mmol) And then stirred at the same temperature for 2 hours. After completion of the reaction was confirmed, sodium borohydride (694 mg, 18.35 mmol) was added and stirred for 1 hour. After confirming the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was concentrated under reduced pressure using toluene (3 x 50 mL). The residue was separated by column chromatography to obtain the title compound (1.58 g, 79%).

The analytical data of the obtained compound are as follows.

^{1 H NMR (500 MHz; DMSO} -d 6) δ ppm 2.40 (.. Br s, 3H), 3.53-3.60 (m, 1H), 3.71-3.73 (d, J = 10.27 Hz, 1H), 3.85 (br . s., 1H), 3.95 (br. s., 2H), 4.60 (br. s., 2H), 4.98-5.00 (t, J = 5.38 Hz, 1H, exchangeable with D 2 O, OH), 5.19 -5.20 (t, J = 5.86 Hz , 1H, exchangeable with D 2 O, OH), 5.78-5.80 (t, J = 5.38 Hz, 1H), 7.10-7.13 (t, J = 7.82Hz, 1H), 7.35 -7.36 (d, J = 6.84Hz, 1H), 7.59-7.60 (d, J = 5.86 Hz, 2H, exchangeable with d 2 O, NH), 7.73 (br. s., 1H), 8.30 (s, 1H ), 8.85 (br s, 1H, exchangeable with D ₂ O, NH); ¹³ C NMR (125 MHz; DMSO-d ₆ )? 25.59, 42.98, 62.02, 62.25, 80.43, 84.90, 95.11, 118.57, 127.27, 130.96, 136.03, 136.45, 140.78, 142.34, 150.69, 153.53, 155.17, 169.31; HRMS (FAB) m / z calcd for C 18 H 20 ClIN 6 O 4 [M + Na] + 546.0279, found 569.0162; mp = 226-229 [deg.] C

Preparation Example 2: Synthesis of Compound (11) ((R) -2- (1- (2-Chloro-6- (3-iodobenzylamino) -9H- purin-9-yl) -2- hydroxyethoxy) Propane-1,3-diol)

[Reaction Scheme 2]

The intermediate compound (230 mg, 0.27 mmol) prepared in Step 2 of Example 1 was dissolved in methanolic ammonia (25 mL) and stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure to obtain a triol intermediate. The obtained triol intermediate (248 mg, 0.47 mmol) was treated in the same manner as in Step 5 of Example 1 to obtain the desired compound (109 mg, 75.69%).

The analytical data of the obtained compound are as follows.

¹ H NMR (500 MHz; DMSO-d ₆ )? Ppm 3.13-3.17 (m, 1H), 3.22-3.26 (m, 1H), 3.43-3.47 (m, 2H), 3.54-3.56 (Br s, 2H), 4.41-4.42 (br t, J = 5.38 Hz, 1H, exchangeable with D ₂ O, OH), 4.60 , J = 5.38 Hz, 1H, exchangeable with D 2 O, OH), 5.13 (br. s., 1H, exchangeable with D 2 O, OH), 5.80-5.82 (t, J = 4.89 Hz, 1H), 7.11 (D, J = 7.33 Hz, 1H), 7.36-7.37 (d, J = 7.33 Hz, 1H), 7.59-7.60 s, 1 H), 8.82 (br s, 1H, exchangeable with D ₂ O, NH); ¹³ C NMR (125 MHz; DMSO-d ₆ )? 43.01, 61.12, 61.23, 62.64, 80.90, 84.53, 95.12, 118.56, 127.36, 130.99, 136.04, 136.58, 140.68, 142.44, 150.73, 153.40, 155.12; HRMS (FAB) m / z calcd for C 17 H 19 ClIN 5 O 4 [M + Na] + 519.0170, found 542.0054; mp = 170-172 ° C

Preparation Example 3: Synthesis of Compound (12) ((S) -3-Hydroxy-2 - ((R) -2-hydroxy- 1- (6- (3-iodobenzylamino) -9H- Yl) ethoxy) -N-methylpropanamide < / RTI >

[Reaction Scheme 3]

Step 1: ((3aR, 4R, 6R, 6aR) -6- (6-Chloro-9H- purin-9- yl) -2,2- dimethyltetrahydrofuro [3,4 d] [1,3 ] Dioxol-4-yl) methanol (14)

(Hydroxymethyl) tetrahydrofuran-3,4-diol (4.8 g, 16.74 mmol) and 2,2 < RTI ID = 0.0 & -Dimethoxypropane (10.26 mL, 83.71 mmol) was dissolved in anhydrous acetone (120 mL) under a nitrogen stream, p-toluenesulfonic acid monohydrate (3.18 g, 16.74 mmol) was added dropwise and the mixture was stirred at room temperature for 4 hours . After confirming the completion of the reaction, the reaction is terminated with a saturated sodium hydrogencarbonate solution. The reaction solution was concentrated under reduced pressure, the organic layer was extracted with chloroform (4 X 20 mL), washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the obtained residue was separated by column chromatography to obtain the intermediate compound ((3aR, 4R, 6R, 6aR) -6- (6-Chloro-9H-purin-9- 3,4-d] [1,3] dioxol-4-yl) methanol (4.87 g, 89.03%).

The analytical data of the obtained compound are as follows.

¹ H NMR (500 MHz; CDCl ₃ )? Ppm 1.38 (s, 3H), 1.65 (s, 3H), 3.80-3.83 (dd, J = 12.22, 1.46 Hz, 1H), 3.95-3.98 (Dd, J = 5.86, 1.46 Hz, 1H), 5.19 (d, J = 8.6 Hz, 1H), 4.53-4.55 5.21 (dd, J = 5.86, 4.40 Hz, 1H), 5.99-6.00 (d, J = 4.89 Hz, 1H), 8.25 (s, 1H), 8.75 (s, 1H); ¹³ C NMR (125 MHz; CDCl ₃ )? 25.22, 27.55, 63.22, 81.51, 83.35, 86.43, 94.02, 114.51, 133.25, 144.73, 150.50, 151.71, 152.31; mp = 146-150 [deg.] C

Step 2: ((3aR, 4R, 6R, 6aR) -6- (6-Chloro-9H-purin-9- yl) -2,2- dimethyltetrahydrofuro [3,4- d] 3] dioxol-4-yl) methyl benzoate (15)

The intermediate compound (2.8 g, 8.56 mmol) prepared in Step 1 was dissolved in anhydrous methylene chloride (100 mL), and then cooled to 0 ° C. Triethylamine (3.6 mL, 25.70 mmol) and dimethylaminopyridine (21 mg, 0.17 mmol). Benzoyl chloride (1.5 mL, 12.85 mmol) is slowly added dropwise at the same temperature and then stirred at room temperature for 2 hours. After confirming the completion of the reaction, the reaction is terminated with a saturated sodium hydrogencarbonate solution. The reaction solution was concentrated under reduced pressure, the organic layer was extracted with methylene chloride, washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the obtained residue was separated by column chromatography to obtain the intermediate compound ((3aR, 4R, 6R, 6aR) -6- (6-Chloro-9H-purin-9- 3,4-d] [1,3] dioxol-4-yl) methyl benzoate (3.68 g, 99.72%).

The analytical data of the obtained compound are as follows.

^{1 H NMR (500 MHz; CDCl} 3) δ ppm 1.40 (s, 3H), 1.62 (s, 3H), 4.42-4.46 (dd, J = 11.73, 3.9 Hz, 1H), 4.61-4.64 (m, 2H) (D, J = 7.33 Hz, 2H), 5.51-5.13 (d, J = 2.93 Hz, 1H), 5.53-5.54 7.47-7.50 (t, J = 7.33 Hz, 1 H), 7.79-7.81 (d, J = 7.82 Hz, 2H), 8.21 (s, 1H), 8.64 (s, 1H); ^{13 C NMR (125 MHz; CDCl} 3) δ 25.36, 27.15, 63.99, 81.42, 84.07, 85.04, 91.87, 114.92, 128.31 (2), 129.07, 129.39 (2), 132.42, 133.33, 144.10, 150.79, 151.40, 152.02 , 165.80; mp = 50-54 [deg.] C.

Step 3 : ((3aR, 4R, 6R, 6aR) -6- (6- (3-Iodobenzylamino) -9H- purin- 9-yl) -2,2 dimethyltetrahydrofuro [3,4 -d] [1,3] dioxol-4-yl) methyl benzoate (16)

The intermediate compound (1.24 g, 2.87 mmol) prepared in the above step 2 was prepared in the same manner as in step 2 of Example 1 to give the intermediate compound ((3aR, 4R, 6R, 6aR) -6- (6- Yl) -2,2-dimethyltetrahydrofuro [3,4-d] [1,3] dioxol-4-yl) methyl benzoate (1.73 g, 96.11 %).

The analytical data of the obtained compound are as follows.

¹ H NMR (500 MHz; CDCl ₃ )? Ppm 1.42 (s, 3H), 1.63 (s, 3H), 4.45-4.59 (m, 1H), 4.59-4.61 (m, 2H), 4.80 (br s. J = 5.38 Hz, 1H), 5.17 (d, J = 3.43 Hz, 1H), 5.58-5.59 , 7.32-7.05 (t, J = 7.33 Hz, 2H), 7.49-7.52 (t, J = = 7.33 Hz, 1 H), 7.58-7.60 (d, J = 7.33 Hz, 1 H), 7.71 (s, (br. s., 1 H); ^{13 C NMR (125 MHz; CDCl} 3) δ25.47, 27.21, 43.81, 64.35, 81.71, 84.21, 85.03, 91.38, 94.55, 114.61, 120.52, 126.85, 128.32 (3), 129.43, 129.62 (2), 130.34, 133.18, 136.53, 139.16, 140.99, 148.68, 153.34, 154.60, 166.02; mp = 68-72 [deg.] C.

Step 4: ((2R, 3R, 4R, 5R) -3,4-Bis (tert- butyldimethylsilyloxy) -5- (6- (3- iodobenzylamino) -9H-purin- ) Tetrahydrofuran-2-yl) methyl benzoate (17)

The intermediate compound (4.93 g, 7.85 mmol) prepared in the above step 3 was dissolved in 80% acetic acid (250 mL), and the mixture was refluxed at 100 ° C for 12 hours. After completion of the reaction was confirmed, the reaction solution was concentrated under reduced pressure, toluene (4 x 50 mL) was added, and the filtrate was concentrated under reduced pressure to obtain a diol intermediate without purification. The obtained diol intermediate (8.5 g, 14.47 mmol) was dissolved in anhydrous pyridine (250 mL), followed by addition of tetrabutyldimethylsilyl triflate (TBDMSOTf) (13.3 mL, 57.88 mmol) followed by stirring at 50 ° C for 5 hours. After confirming the completion of the reaction, the reaction solution was partitioned into methylene chloride / water. The organic layer was washed with water, saturated sodium hydrogencarbonate solution and saturated saturated sodium bicarbonate solution, and then dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the obtained residue was separated by column chromatography to obtain the intermediate compound ((2R, 3R, 4R, 5R) -3,4-bis (tert-butyldimethylsilyloxy) -9H-purin-9-yl) tetrahydrofuran-2-yl) methylbenzoate (4.47 g, 69.73%).

The analytical data of the obtained compound are as follows.

^{1 H NMR (500 MHz; CDCl} 3) δ ppm -0.17 (s, 3H), 0.01 (s, 3H), 0.1 (s, 3H), 0.12 (s, 3H), 0.83 (s, 9H), 0.93 ( (t, J = 4.40 Hz, 1H), 4.74-4.78 (dd, J = J = 4.40 Hz, 1H), 4.82 (br s, 2H), 5.07-5.09 (t, J = 4.40 Hz, 1H), 5.88-5.89 (d, J = 7.82 Hz, 1H), 7.31-7.33 (d, J = 7.82 Hz, 1H), 7.38-7.41 (t, J = 7.82 Hz, 1H) , 7.52-7.55 (t, J = 7.82 Hz, 1H), 7.59-7.60 (d, J = 7.82 Hz, 1H), 7.72 (s, 1H), 7.84 dd, J = 8.31, 0.97 Hz, 2H), 8.32 (s, 1H); ¹³ C NMR (125 MHz; CDCl ₃ )? -0.00, 0.11, 0.26, 0.54, 30.63 (3), 30.74 (3), 34.61 (2), 49.19,68.45,77.09,79.28,87.24,94.71,99.46,125.63 , 131.74, 133.32 (3), 134.52, 134.59, 135.23, 138.10, 141.41, 141.46, 144.66, 145.99, 153.87, 157.99, 159.53, 171.15; mp = 68-70 [deg.] C.

Step 5: ((2R, 3R, 4R, 5R) -3,4-Bis (tert-butyldimethylsilyloxy) -5- (6- (3- iodobenzylamino) -9H-purin- ) Tetrahydrofuran-2-yl) methanol (18)

The intermediate compound (1.28 g, 1.56 mmol) prepared in step 4 was dissolved in anhydrous methanol (100 mL), 25% sodium methoxide / methanol (15 mL) was added, and the mixture was stirred at room temperature for 12 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was separated by column chromatography to obtain the intermediate compound ((2R, 3R, 4R, 5R) -3,4- bis (tert- butyldimethylsilyloxy) Yl) tetrahydrofuran-2-yl) methanol (960 mg, 86.48%) was obtained as a pale-yellow amorphous solid.

The analytical data of the obtained compound are as follows.

^{1 H NMR (500 MHz; CDCl} 3) δ ppm -0.58 (s, 3H), -0.13 (s, 3H), 0.11-0.13 (d, J = 7.33 Hz, 6H), 0.74 (s, 9H), 0.95 (s, 9H), 3.68-3.71 (d, J = 12.71 Hz, 1H), 3.92-3.95 (d, J = 12.71 Hz, (D, J = 7.33, 4.40 Hz, 1H), 5.75-5.77 (d, J = 7.82 Hz, 1H), 6.39 (br s). J = 7.82 Hz, 1H), 7.30-7.32 (d, J = 7.82 Hz, 1H), 7.59-7.61 (d, J = 7.82 Hz, 1H), 7.70 (s, 1H), 7.76 (br s, 1H), 8.35 (br s, 1H); ^{13 C NMR (125 MHz; CDCl} 3) δ 0.00, 1.30, 1.35, 1.38, 31.62 (3), 31.75 (3), 35.61 (2), 49.54, 68.95, 79.91, 79.96, 95.50, 96.96, 100.51, 127.37, 132.70, 136.30, 142.42, 142.57, 146.54, 146.61, 153.78, 158.46, 160.79; mp = 82-86 [deg.] C.

Step 6: (2S, 5R) -3,4-Bis (tert-butyldimethylsilyloxy) -5- (6- (3- iodobenzylamino) -9H- purin- Preparation of tetrahydrofuran-2-carboxamide (19)

The intermediate compound (450 mg, 0.63 mmol) prepared in Step 5 and pyridinium dichromate (5.47 g, 14.54 mmol) were dissolved in DMF (50 mL) under a nitrogen stream, followed by stirring at room temperature for 12 hours. After confirming completion of the reaction, the resulting solid was washed with water to obtain an acid intermediate. The resulting intermediate (450 mg, 0.62 mmol) was dissolved in anhydrous ethanol (10 mL) under a nitrogen stream, cooled to 0 ° C, thionyl chloride (0.25 mL, 3.10 mmol) was slowly added dropwise and the mixture was stirred at room temperature for 5 hours Lt; / RTI > After completion of the reaction was confirmed, the reaction solution was concentrated under reduced pressure, and the residue was partitioned into ethyl acetate / water. The organic layer was washed with water and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, an intermediate ethyl ester was obtained. The ethyl ester thus obtained is added with a methylamine / 2N-THF solution under a nitrogen stream, followed by stirring at room temperature for 12 hours. After confirming the completion of the reaction, the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography to obtain the intermediate compound (2S, 5R) -3,4-bis (tert-butyldimethylsilyloxy) -5- -9H-purin-9-yl) -N-methyltetrahydrofuran-2-carboxamide (400 mg, 85.65%).

The analytical data of the obtained compound are as follows.

^{1 H NMR (500 MHz; CDCl} 3) δ ppm -0.61 (s, 3H), -0.16 (s, 3H), 0.15 (s, 3H), 0.25 (s, 3H), 0.71 (s, 9H), 0.97 (s, 9H), 2.93-2.94 (d, J = 4.40 Hz, 3H), 4.33-4.34 (d, J = 3.42 Hz, (D, J = 7.33 Hz, 1H), 6.42 (br s, 1H), 7.03-7.06 (t, J = 7.82 Hz, 1H), 7.30-7.32 ), 7.59-7.61 (d, J = 7.82 Hz, 1H), 7.70 (s, 1H), 7.75 (s, 1H), 8.36 , 1H); ¹³ C NMR (125 MHz; CDCl ₃ ) δ 0.00, 1.19, 1.21, 1.40, 23.71, 24.00, 31.53 (3), 31.58, 31.78 (2), 35.64, 49.60, 78.09, 81.25, 92.53, 95.48, 100.56, 127.30 , 132.72, 136.34, 142.44, 142.61, 146.64, 146.79, 154.27, 158.70, 160.96, 175.92; mp = 80-84 [deg.] C.

Step 7: (2S, 5R) -3,4-Dihydroxy-5- (6- (3-iodobenzylamino) -9H- purin-9- yl) -N- methyltetrahydrofuran- Manufacture of Radiate (20)

The intermediate compound (65 mg, 0.08 mmol) prepared in Step 6 was dissolved in anhydrous THF under a nitrogen stream, and then tetrabutylammonium fluoride (TBAF) (0.44 mL, 0.43 mmol, (1 M solution THF) Stir at room temperature for 1 hour. After confirming the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography to obtain the intermediate compound (2S, 5R) -3,4-dihydroxy-5- (6- (3-iodobenzylamino) -9H-purin-9-yl) -N-methyltetrahydrofuran-2-carboxamide (52 mg, 95.45%).

The analytical data of the obtained compound are as follows.

^{1 H NMR (500 MHz; DMSO} -d 6) δ ppm 2.70-2.71 (d, J = 4.40 Hz, 3H), 4.14-4.16 (t, J = 3.91 Hz, 1H), 4.31 (s, 1H), 4.57 (D, J = 4.40 Hz, 1H), 4.67 (d, 1H), 5.96-5.97 (d, J = 7.33 Hz, 1H), 7.09-7.12 (t, J = 7.82 Hz, 1H), 7.35-7.36 (d, J = 7.82 Hz, 1H), 7.56-7.58 1H, J = 7.82 Hz, 1H), 7.72 (s, 1H), 8.29 (s, 1H), 8.42 (s, 1H), 8.53 (br s., 1H), 8.85-8.86 (m, 1H); ¹³ C NMR (125 MHz; DMSO-d ₆ )? 25.81, 42.74, 72.56, 73.49, 85.09, 88.26, 95.06, 120.42, 127.11, 130.95, 135.86, 136.13, 141.17, 143.10, 148.70, 152.94, 154.86, 170.34; mp = 178-182 [deg.] C.

Step 8: (S) -3-Hydroxy-2 - ((R) -2-hydroxy-1- (6- (3-iodobenzylamino) -9H- purin- Preparation of N-methylpropanamide (12)

The intermediate compound (52 mg, 0.10 mmol) prepared in the above Step 7 was treated in the same manner as in Step 5 of Example 1 to obtain the title compound (35 mg, 83.33%).

The analytical data of the obtained compound are as follows.

^{1 H NMR. (500 MHz;} DMSO-d 6) δ ppm 2.35 (s, 3H), 3.5-3.6 (m, 1H), 3.72-3.74 (d, J = 9.29 Hz, 1H), 3.86 (br s. , 1H), 4.00 (d, J = 4.40 Hz, 2H), 4.66 (br. s., 2H), 4.99 (br. s., 1H, exchangeable with d 2 O, OH), 5.21 (br. s. _{, 1H, exchangeable with D 2 O} , OH), 5.87 (br. s., 1H), 7.08-7.11 (t, J = 7.82 Hz, 1H), 7.35-7.36 (d, J = 6.84 Hz, 1H), 7.56-7.57 (d, J = 6.35 Hz , 2H, exchangeable with D 2 O, NH), 7.71 (s, 1H), 8.22 (s, 1H), 8.30 (s, 1H), 8.37 (br. s., 1H, exchangeable with D ₂ O, NH); ^{13 C NMR (125 MHz; DMSO} -d 6) δ 25.53, 42.81, 61.98, 62.26, 80.30, 84.62, 95.09, 119.43, 127.11, 130.91, 135.81, 136.16, 140.19, 143.31, 149.79, 152.98, 154.66, 169.42; HRMS (FAB) m / z calcd for C 18 H 21 IN 6 O 4 [M + Na] + 512.0669, found 535.0578; mp = 176-182 [deg.] C.

Production Example 4: Synthesis of Compound (21) ((R) -2- (2-hydroxy-1- (6- (3-iodobenzylamino) -9H- purin- 3-diol)

[Reaction Scheme 4]

Step 1: ((3aR, 4R, 6R, 6aR) -6- (6- (3-Iodobenzylamino) -9H-purin-9- yl) -2,2-dimethyltetrahydrofuro [ 4-d] [1,3] dioxol-4-yl) methanol (22)

The intermediate compound (1.73 g, 2.75 mmol) prepared in the step 2 of Example 1 was treated in the same manner as in the step 5 of Example 3 with (3aR, 4R, 6R, 6aR) -6- L, 3-dioxol-4-yl) methanol (1.04 g, 93.69 < RTI ID = 0.0 > %).

The analytical data of the obtained compound are as follows.

^{1 H NMR (500 MHz; CDCl} 3) δ ppm 1.36 (s, 3H), 1.63 (s, 3H), 3.75-3.80 (t, J = 11.24 Hz, 1H), 3.95-3.97 (d, J = 12.71 Hz , 5.19 (br, s, 2H), 5.10-5.11 (d, J = 4.89 Hz, 1H), 5.19 = 3.91 Hz, 1H), 6.58 (br s, 2H), 7.01-7.04 (t, J = 7.82 Hz, 1H), 7.29-7.30 (d, J = 6.84 Hz, 1H), 7.58-7.59 , J = 7.33 Hz, 1H), 7.69 (br s, 2H), 8.33 (br s, 1H); ¹³ C NMR (125 MHz; CDCl ₃ ) δ 25.24, 27.66, 29.65, 63.36, 81.68, 83.03, 86.12, 94.26, 94.54, 113.93, 121.24, 126.80, 130.32, 136.52, 136.58, 139.71, 140.72, 147.66, 152.73, 154.94 ; mp = 72-76 [deg.] C.

Step 2: (2R, 3S, 4R, 5R) -2- (hydroxymethyl) -5- (6- (3-iodobenzylamino) -9H- purin-9- yl) tetrahydrofuran- - Preparation of diol (23)

The intermediate compound (250 mg, 0.47 mmol) prepared in the above step 1 was dissolved in 80% acetic acid (250 mL), and the mixture was heated under reflux at 100 ° C for 12 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, toluene (4 x 50 mL) was added, and the mixture was concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the intermediate (2R, 3S, 4R, Methyl) -5- (6- (3-iodobenzylamino) -9H-purin-9-yl) tetrahydrofuran-3,4-diol (177 mg, 76.95%).

The analytical data of the obtained compound are as follows.

¹ H NMR (500 MHz; DMSO-d ₆ )? Ppm 3.56 (br s, 1H), 3.67-3.69 (d, J = 10.27 Hz, 1H), 3.97 ), 4.61-4.67 (m, 3H) , 5.17 (d, J = 2.93 Hz, 1H, exchangeable with D 2 O, OH), 5.35-5.36 (t, J = 5.38 Hz, 1H, exchangeable with D 2 O, OH), 5.43-5.44 (d, J = 5.38 Hz, 1H, exchangeable with d 2 O, OH), 5.89-5.90 (d, J = 4.89 Hz, 1H), 7.09-7.11 (t, J = 7.33 Hz, 1H), 7.35-7.36 (d, J = 6.84 Hz, 1H), 7.56-7.58 (d, J = 7.33 Hz, 1H), 7.72 ), 8.45 (br s, 1H, exchangeable with D ₂ O, NH); ¹³ C NMR (125 MHz; DMSO-d ₆ )? 42.69, 62.08, 71.06, 73.97, 86.32, 88.42, 95.09, 120.24, 127.08, 130.91, 135.81, 136.16, 140.47, 143.22, 149.00, 152.76, 154.79; mp = 174-178 [deg.] C.

Step 3: (R) -2- (2-Hydroxy-1- (6- (3-iodobenzylamino) -9H-purin-9-yl) ethoxy) propane- )

The intermediate compound (77 mg, 0.15 mmol) prepared in the above Step 2 was treated in the same manner as in Step 5 of Example 1 to obtain the desired compound (62 mg, 80.51%).

The analytical data of the obtained compound are as follows.

¹ H NMR (500 MHz; CD ₃ OD)? Ppm 3.42 - 3.44 (d, J = 5.38 Hz, 2H), 3.54-3.58 (m, 1H), 3.65-3.68 ), 3.75-3.78 (dd, J = 11.73,4.44 Hz, 1H), 4.01-4.02 (d, J = 5.38 Hz, 2H), 4.53 (s, 2H), 6.04-6.06 J = 7.82 Hz, 1H), 7.76 (s, 1H), 7.07-7.10 (t, J = 7.82 Hz, 1H), 7.38-7.40 (d, J = 7.82 Hz, 1H), 7.59-7.60 ), 8.27 (s, 1 H), 8.29 (s, 1 H); ¹³ C NMR (125 MHz; CD ₃ OD)? 42.88, 60.80, 61.25, 62.76, 80.26, 84.02, 93.52, 119.00, 126.44, 129.93, 135.90, 136.10, 139.65, 141.72, 148.97, 152.52, 154.53; HRMS (FAB) m / z calcd for C 17 H 20 IN 5 O 4 [M + H] + 485.0560, found 486.0625; mp = 72-76 [deg.] C.

Identification of efficacy of novel adenine derivatives for local cerebral ischemia

5-1: Experimental animals

In this experiment, male Sprague-Dawley rats weighing 260g to 300g were supplied from Charles River Laboratories Inc. (Seoul, Korea) and maintained at room temperature and humidity of 20 ° C. They were kept indoors. In addition, feeding was stopped from the night before surgery until the day of surgery, and water was supplied continuously. This was done under the approval of the NIH Guidelines for the Care and Use of Laboratory Animals and the Korea University Institutional Animal Care & Use Committee.

5-2: Statistical processing

Data were expressed as means ± SD, and statistical significance was tested using Kruscal-Wallis test and Mann-Whitney U test. (*** P <0.001, ** P <0.01, * P <0.05; significant difference from the control group). N = 5 to 11

5-3: Production of local cerebral ischemia model and infarct volume measurement / neurobehavioral test method

Experiments were carried out as follows (Belayev L, Alonso OF, Busto L, Zhao W, et al.) To confirm the effect of topical samples of the samples prepared in Examples 1 to 4 in the local cerebral ischemia experiment Ginsberg MD, Middle cerebral artery occlusion in the rat by intraluminal suture, Stroke 1996 Sep 27 (9): 1616-1622, discussion 1623).

First, the local cerebral ischemia model was constructed as follows.

The animals were fasted for 24 hours, and then the animals were anesthetized with 3% isoflurane in a mixture of N ₂ O and O ₂ mixed at a volume ratio of 7: 3, and maintained in anesthesia. During the operation with the hiding pad, the body temperature was maintained at 37.0 to 37.9 degrees Celsius. The common carotid artery and the external carotid artery were ligated and a 19 mm probe (4-0 from the branch point of the internal carotid artery was rounded to fire one end of the nylon thread) ) Was inserted to induce local cerebral ischemia due to right sheath endovascular middle cerebral artery occlusion.

The ischemic state was maintained by blocking the flow of the middle cerebral artery for 90 minutes, and the probe was removed by reexposing the surgical site. The incised skin of the reperfused experimental animals was completely sealed with a surgical suture and maintained using a hiding pad used throughout the experiment so that the rectum temperature of the experimental animal did not drop below 37 degrees.

On the other hand, the prepared local cerebral ischemia model performed infarct volume measurement and neurobehavioral test as follows.

* Measurement of infarct volume

Experimental animals were anesthetized with 3% isoflurane in a mixture of N ₂ O and O ₂ mixed at a volume ratio of 7: 3 and cervical dislocated. (2% triphenyltetrazolium hydrochloride, Sigma-Aldrich, St. Louis, Mo.) was used as a reagent (2 mm) cut with a rat matrix matrix (Ted Pella, Redding, CA) And stained for 37 minutes at 37 ^° C. The cells were fixed with 4% paraformaldehyde (pH 7.4) and cryoprotected in 30% sucrose at 30% sucrose at 4 ^° C for two consecutive days. Infarct sections between +4 mm (anterior) and -6 mm (posterior) of the Bregma were measured by the analysis program (OPTIMAS5.1image analysis program, BioScan Inc. Edmonds, WA).

Edema rate (%) = (A-B) / B 100

A. Volume of ischemic cerebral hemispheres in each coronal slice (mm ³ )

B. Volume of normal cerebral hemispheres in each coronal slice (mm ³ )

Neurobehavioral tests

The neurobehavioral test was performed 24 hours after ischemia and the degree of damage was evaluated on a 3-point scale according to the following criteria.

Normal grade 0: no observable deficit

Moderate grade 1: forelimb flexion

Severe grade 2: decreased resistance to lateral push

                        (and forelimb flexion) without circling

grade 3: same behavior as grade 2, with circling

Score 0: When the mouse is touched by the tail on the table 1m, the two paws are extended towards the table (normal rat).

1 point: When the mouse is caught on the table 1 m, the mouse bends one paw.

2 points: When gripping the tail of a mouse by hand and gently sideways to the back of the shoulder, it is resistant to being pushed by the same force both when it is normal or when the damage is weak. In the case of severe symptoms, the resistance to paralysis is reduced.

3 points: When the rat is allowed to move freely and observe the circling behavior, bending of the forefoot is always observed while continuing to circulate.

5-4: Prevention and treatment efficacy of new adenine derivatives in brain damage (1)

After inducing cerebral ischemia in a white rat that induced local cerebral ischemia of Example 5-3, the novel adenine derivative (compound of Formula 5) according to the present invention or Cl-IB-MECA of the following formula was administered at 3 hours and 8 hours After oral administration at a dose of 2 mg / kg twice, the infarct volume was measured or the neurobehavioral test was performed according to the method of Example 5-3. The negative control (Control) is the non-administration group.

As a result, as shown in Fig. 1, when the drug was orally administered twice at a dose of 2 mg / kg, the novel adenine derivative according to the present invention was found to be effective in the control (Cl) -IB-MECA significantly reduced brain damage. FIG. 1A is a photograph of the coronary brain slices of each group. When the novel adenine derivative according to the present invention is administered, the volume of cerebral hemispheres induced by ischemia is apparently low. FIG. 1B is a graph showing the infarct volume of each group. The infarct volume of the new adenine derivative-treated group according to the present invention was significantly lower than that of the control or Cl-IB-MECA treated group, As shown in FIG. 1C, although the administration of Cl-IB-MECA had the effect of lowering the edema rate as compared with that of the non-administration group, the adenine derivative-administered group according to the present invention showed markedly lower edema , Respectively. In addition, as shown in FIG. 1d, neurobehavioral tests showed that the degree of damage to nerve action due to ischemia was higher in the non-administration group (Control) or the Cl-IB-MECA administration group, , The average score of the new adenine derivative-treated group was less than 1.5, indicating that the damaged nerve activity pattern due to ischemia was not observed or the damage was very slight.

In addition, in order to confirm whether there is a difference in the effect according to the route of administration, experiments were performed by intravenous injection of the drug at a dose of 4 mg / kg (2 mg / kg twice), and as a result, It was confirmed that the novel adenine derivative according to the present invention significantly reduced the brain damage as compared with the Cl-IB-MECA which is known as the adenosine A3 receptor agonist as well as the non-administration group (Control). FIG. 2A is a photograph of coronary brain slices of each group. When the novel adenine derivative according to the present invention is administered, the volume of cerebral hemispheres induced by ischemia is apparently low. FIG. 2B is a graph showing the infarct volume of each group. The infarct volume of the new adenine derivative-treated group according to the present invention was significantly lower than that of the control group or the Cl-IB-MECA treated group, As shown in FIG. 2C, although the Cl-IB-MECA administration group has lower edema rate than the non-administration group, the adenine derivative administration group according to the present invention is significantly lower than the Cl-IB-MECA administration group And swelling rate. In addition, as shown in FIG. 2d, neurobehavioral tests showed that the degree of damage to nerve action due to ischemia was higher in the non-administration group (Control) or the Cl-IB-MECA administration group, , The average score of the new adenine derivative-administered group was less than 2, indicating that the damage due to ischemia was relatively low. In the case of the Cl-IB-MECA-treated group, the infarct volume or edema rate was almost the same regardless of the route of administration (oral or intravenous injection), and the degree of damage was similar to that of the non-administered group. In contrast, the adenine derivative according to the present invention showed a high brain injury inhibitory effect even at a low dose of 4 mg / kg (2 mg / kg twice) irrespective of the administration route.

Accordingly, it has been confirmed that the adenine derivative according to the present invention has an effect of inhibiting and preventing brain damage due to cerebral ischemia, and thus can be used as a medicine for treating and preventing degenerative brain diseases such as stroke.

5-5: Confirmation of the efficacy of new adenine derivatives for brain damage prevention and treatment (2)

In order to confirm the effect of the adenine derivative according to the present invention on the dose, a white rat causing local cerebral ischemia of Example 5-3 caused brain ischemia, and then the novel adenine derivative (compound of Chemical Formula 5) Hour and 8 hours after the intravenous administration at a dose of 10 mg / kg, the infarct volume was measured or the neurobehavioral test was performed according to the method of Example 5-3. The negative control (Control) is the non-administration group.

As a result, as shown in Fig. 3, the adenine derivative according to the present invention significantly reduced brain damage compared with the control group even when administered intravenously. FIG. 3A is a photograph of a coronary brain slice of an experimental group and a control group (untreated group), and when the adenine derivative according to the present invention is administered, the volume of cerebral hemispheres induced by ischemia is apparently low. The adenine derivatives according to the present invention also showed a significantly lower degree of injury than the untreated group in infarct volume (FIG. 3B), edema rate (FIG. 3C) and neurobehavioral test (FIG. 3D).

Accordingly, the adenine derivative according to the present invention has an effect of inhibiting and preventing cerebral damage due to cerebral ischemia even when administered by intravenous injection at an increased dose, and thus is useful as a medicine for treating and preventing degenerative brain diseases such as stroke .

5-6: Identification of New Adenine Derivatives for Brain Injury Prevention and Therapeutic Effectiveness (3)

In order to confirm the effect of preventing and treating cerebral damage when the adenine derivative according to the present invention was administered at different times after ischemia, the cerebral ischemia caused by the cerebral ischemia of Example 5-3 was induced, The new adenine derivative (compound of formula 5) was intravenously administered at a dose of 2 mg / kg twice (Fig. 4) or twice over 10 hours and 18 hours (Fig. 5) , Infarct volume was measured according to the method of Example 5-3, or neurobehavioral test was performed. The negative control (Control) is the non-administration group.

As a result, as shown in FIG. 4 and FIG. 5, adenine derivatives according to the present invention were administered at 6 hours and 12 hours, 10 hours and 18 hours after the induction of local cerebral ischemia, Control) significantly reduced brain damage. FIGS. 4A and 5A are photographs of coronary brain slices of the experimental group and the control group (non-administered group), FIGS. 4B and 5B show the infarct volume, FIGS. 4C and 5C show the edema rate, The results of the test are shown.

Long-term survival rate by adenine derivative administration according to the present invention in a local cerebral ischemia model

The following experiments were conducted to investigate the effect of adenine derivatives according to the present invention on the long-term survival rate in inducing cerebral ischemia.

In other words, after a cerebral ischemia was induced in white rats that induced local cerebral ischemia of Example 5-3, new adenine derivatives (compound of Formula 5) according to the present invention were intravenously administered at 3 hours and 8 hours, Four times (four times) the drug was administered orally (no drug thereafter) and the survival rate was checked over 32 days. At this time, the intravenous and oral dose of the drug is 2 mg / kg each, and the negative control (control) is the non-administration group.

As a result, as shown in FIG. 6A, it was confirmed that the degree of tissue damage was smaller than that of the control group. 7A is a photograph taken by slicing on the 32nd day.

In addition, as shown in FIG. 6B, it was confirmed that the mortality of the mice administered with the adenine derivative according to the present invention was significantly reduced.

These experimental results show that the compounds according to the present invention and their pharmaceutically acceptable salts have an effect of treating brain damage, and thus they are effective as a composition for preventing and treating degenerative brain diseases.

Hereinafter, formulation examples of the composition containing the compound of the present invention will be described, but the present invention is not intended to be limited thereto but is specifically described.

Preparation Example 1. Preparation of powder

Compound 5 200 mg

Lactose 100 mg

Talc 10 mg

The above components are mixed and filled in airtight bags to prepare powders.

Formulation Example 2. Preparation of tablets

Compound 11 200 mg

Corn starch 100 mg

Lactose 100 mg

Magnesium stearate 2 mg

After mixing the above components, tablets are prepared by tableting according to the usual preparation method of tablets.

Formulation Example 3. Preparation of capsules

Compound 12 200 mg

Crystalline cellulose 3 mg

Lactose 14.8 mg

Magnesium stearate 0.2 mg

The above components are mixed in accordance with a conventional method for producing a capsule, and filled in a gelatin capsule to prepare a capsule.

Formulation Example 4. Preparation of injection

Compound 5 200 mg

180 mg mannitol

Sterile sterilized water for injection 2974 mg

Na ₂ HPO _4, 12H ₂ O 26 mg

(2 ml) per 1 ampoule according to the usual injection preparation method.

Formulation Example 5. Preparation of a liquid preparation

Compound 21 200 mg

10 g per isomer

5 g mannitol

Purified water quantity

Each component was added and dissolved in purified water according to the usual liquid preparation method, and the lemon flavor was added in an appropriate amount. Then, the above components were mixed, and purified water was added thereto. The whole was added with purified water to adjust the total volume to 100 ml, And sterilized to prepare a liquid preparation.

Formulation Example 6. Preparation of Healthy Foods

Compound 5 1000 mg

Vitamin mixture quantity

70 비 of vitamin A acetate

Vitamin E 1.0 mg

0.13 mg vitamin B1

0.15 mg of vitamin B2

0.5 mg vitamin B6

0.2 [mu] g vitamin B12

10 mg vitamin C

Biotin 10 μg

Nicotinic acid amide 1.7 mg

50 ㎍ of folic acid

Calcium pantothenate 0.5 mg

Mineral mixture quantity

1.75 mg of ferrous sulfate

0.82 mg of zinc oxide

Magnesium carbonate 25.3 mg

15 mg of potassium phosphate monobasic

Secondary calcium phosphate 55 mg

Potassium citrate 90 mg

100 mg of calcium carbonate

24.8 mg of magnesium chloride

Although the composition ratio of the above-mentioned vitamin and mineral mixture is comparatively mixed with a composition suitable for health food as a preferred embodiment, the compounding ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional method for producing healthy foods , Granules can be prepared and used in the manufacture of health food compositions according to conventional methods.

Formulation Example 7. Preparation of health drink

Compound 12 1000 mg

Citric acid 1000 mg

100 g of oligosaccharide

Plum concentrate 2 g

Taurine 1 g

Purified water was added to a total of 900 ml

The above components were mixed according to a conventional health drink manufacturing method, and the mixture was heated for about 1 hour at 85 DEG C with stirring, and the solution thus prepared was filtered to obtain a sterilized 2-liter container, which was sealed and sterilized, &Lt; / RTI &gt;

Although the composition ratio is a mixture of the components suitable for the preferred beverage as a preferred embodiment, the blending ratio may be arbitrarily varied according to the regional and national preferences such as the demand level, the demanding country, and the intended use.

While the present invention has been particularly shown and described with reference to specific embodiments thereof, those skilled in the art will appreciate that such specific embodiments are merely preferred embodiments and that the scope of the invention is not limited thereby. It will be obvious. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Unsigned

Claims (21)

Claims 1. An adenine derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]

Wherein R ₁ and R ₂ are each independently a hydrogen atom, an alkyl group, an m-halo-benzyl group, an m-amino-benzyl group, or an aromatic ring;
R ₃ is a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogen atom;
R ₄ is

or

ego;
R ₅ and R ₆ are each independently a hydrogen atom or an alkyl group.
The adenine derivative according to claim 1, wherein R ₁ and R ₂ are each independently a hydrogen atom or m-iodobenzyl, or a pharmaceutically acceptable salt thereof.
The adenine derivative according to claim 1, wherein R ₃ is a hydrogen atom or a chlorine atom, or a pharmaceutically acceptable salt thereof.
The adenine derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ₅ and R ₆ are each independently a hydrogen atom or a methyl group.
The method according to claim 1,
(R) -1- (2-chloro-6- (3-iodobenzylamino) -9H-purin-9-yl) -2-hydroxyethoxy) -3- -N-methylpropanamide;
(R) -2- (1- (2-Chloro-6- (3-iodobenzylamino) -9H-purin-9-yl) -2-hydroxyethoxy) propane-1,3-diol;
(R) -2-hydroxy-1- (6- (3-iodobenzylamino) -9H-purin-9-yl) ethoxy) -N-methyl Propanamide; And
(R) -2- (2-hydroxy-1- (6- (3-iodobenzylamino) -9H-purin-9-yl) ethoxy) propane-1,3-diol;
&Lt; / RTI &gt; or an &lt; RTI ID = 0.0 &gt; pharmaceutically &lt; / RTI &gt; acceptable salt thereof.
A pharmaceutical composition for the treatment or prevention of degenerative brain diseases comprising an adenine derivative according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient.
7. The method according to claim 6, wherein the adenine derivative (s)
(R) -1- (2-chloro-6- (3-iodobenzylamino) -9H-purin-9-yl) -2-hydroxyethoxy) -3- -N-methylpropanamide;
(R) -2- (1- (2-Chloro-6- (3-iodobenzylamino) -9H-purin-9-yl) -2-hydroxyethoxy) propane-1,3-diol;
(R) -2-hydroxy-1- (6- (3-iodobenzylamino) -9H-purin-9-yl) ethoxy) -N-methyl Propanamide; And
(R) -2- (2-hydroxy-1- (6- (3-iodobenzylamino) -9H-purin-9-yl) ethoxy) propane-1,3-diol;
Wherein the compound is selected from the group consisting of:
[Claim 7] The pharmaceutical composition according to claim 6, wherein the degenerative brain disease is stroke, stroke, dementia, Alzheimer's disease, Parkinson's disease or Huntington's disease.
A health functional food for improving or preventing degenerative brain diseases comprising an adenine derivative according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient.
10. The method according to claim 9,
(R) -1- (2-chloro-6- (3-iodobenzylamino) -9H-purin-9-yl) -2-hydroxyethoxy) -3- -N-methylpropanamide;
(R) -2- (1- (2-Chloro-6- (3-iodobenzylamino) -9H-purin-9-yl) -2-hydroxyethoxy) propane-1,3-diol;
(R) -2-hydroxy-1- (6- (3-iodobenzylamino) -9H-purin-9-yl) ethoxy) -N-methyl Propanamide; And
(R) -2- (2-hydroxy-1- (6- (3-iodobenzylamino) -9H-purin-9-yl) ethoxy) propane-1,3-diol;
&Lt; / RTI &gt; or a pharmaceutically acceptable salt thereof.
10. The health functional food according to claim 9, wherein the degenerative brain disease is stroke, stroke, dementia, Alzheimer's disease, Parkinson's disease or Huntington's disease.
A pharmaceutical composition for treating or preventing pulmonary disease, heart disease, cancer or inflammation comprising the adenine derivative according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient.
A health functional food for improving or preventing pulmonary disease, heart disease, cancer or inflammation containing the adenine derivative of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient.
A process for producing an adenine derivative represented by the following formula (2), comprising the steps of:
(2)

(a) The purine-based compound represented by the formula (4) is reacted with the starting compound, (2R, 3R, 4S, 5R) -2-acetoxy-5- (benzoyloxymethyl) tetrahydrofuran- , &Lt; / RTI &gt;
[Chemical Formula 4]

Wherein R ₃ is a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogen atom, and X is a halogen atom;
(b) reacting the intermediate compound prepared in step (a) with R ₁ -NY-R ₂ ,
Wherein R ₁ and R ₂ are each independently a hydrogen atom, an alkyl group, an m-halo-benzyl group, an m-amino-benzyl group or an aromatic ring and Y is a halogen atom;
(c) acetonizing the intermediate compound prepared in step (b);
(d) reacting the intermediate compound prepared in step (c) with R ₅ -NH-R ₆ ,
Wherein R ₅ and R ₅ are each independently a hydrogen atom or an alkyl group; And
(e) carrying out ring-opening reaction of the furan ring of the intermediate compound prepared in step (d) to prepare a compound of formula (2).
15. The compound according to claim 14, wherein the adenine derivative is (S) -2 - ((R) -1- (2-chloro-6- (3-iodobenzylamino) -9H- purin- Hydroxyethoxy) -3-hydroxy-N-methylpropanamide. &Lt; / RTI &gt;
(R) -1- (2-chloro-6- (3-iodobenzylamino) -9H-purin-9-yl) -2-hydroxyethoxy ) -3-hydroxy-N-methylpropanamide: &lt; EMI ID =
(a) A solution of 2,6-dichloropurine in (2R, 3R, 4S, 5R) -2-acetoxy-5- (benzoyloxymethyl) tetrahydrofuran- (2R, 3S, 4S, 5R) -2- (benzoyloxymethyl) -5- (2,6- dichloro-9H- purin-9- yl) tetrahydrofuran- Acetate;
(b) Synthesis of (2R, 3S, 4S, 5R) -2- (benzoyloxymethyl) -5- (2,6- dichloro- 9H- purin-9- yl) tetrahydrofuran- Dibenzoate was reacted with 3-iodobenzylamine hydrochloride to give (2R, 3S, 4S, 5R) -2- (benzoyloxymethyl) -5- 9H-purin-9-yl) tetrahydrofuran-3,4-diyl dibenzoate;
(c) Synthesis of (2R, 3S, 4S, 5R) -2- (benzoyloxymethyl) -5- (2-chloro-6- Furan-3,4-diyl dibenzoate was dissolved in methanolic ammonia and then concentrated under reduced pressure to give a triol intermediate. ((3aR, 4R, 6R, 6aR) -6- (3-fluorobenzylamino) -9H-purin-9-yl) -2,2-dimethyltetrahydrofuro [3,4- d] [1,3] dioxol- 4-yl) methanol;
(d) By reacting the above ((3aR, 4R, 6R, 6aR) -6- (2-Chloro-6- (3-iodobenzylamino) -9H- purin-9- yl) -2,2-dimethyltetrahydro (2S, 5R) -5- (2-chloro-6- (3 &lt; RTI ID = 0.0 & - iodobenzylamino) -9H-purin-9-yl) -3,4-dihydroxy-N-methyltetrahydrofuran-2-carboxamide; And
(e) Synthesis of (2S, 5R) -5- (2-chloro-6- (3-iodobenzylamino) -9H- purin-9- yl) -3,4-dihydroxy-N-methyltetrahydro (R) -1- (2-chloro-6- (3-iodobenzylamino) -9H-purine-9 -Yl) -2-hydroxyethoxy) -3-hydroxy-N-methylpropanamide.
A process for producing an adenine derivative represented by the following formula (2), comprising the steps of:
(2)

(a) Synthesis of (2R, 5R) -2- (6-chloro-9H-purin-9-yl) -5- (hydroxymethyl) tetrahydrofuran- ;
(b) blocking the CH ₂ OH group of the furan ring of the intermediate compound prepared in step (a) with a protecting group, followed by reacting R ₁ -NY-R ₂ ,
Wherein R ₁ and R ₂ are each independently a hydrogen atom, an alkyl group, an m-halo-benzyl group, an m-amino-benzyl group or an aromatic ring and Y is a halogen atom;
(c) deacetonatizing the intermediate compound produced in step (b), and blocking the diol group of the furan ring of the deacetonized intermediate compound with a protecting group, respectively;
(d) removing the protecting group of the CH ₂ OH group of the furan ring of the intermediate compound prepared in the step (c);
(e) reacting the intermediate compound prepared in step (d) with R ₅ -NH-R ₆ ,
Wherein R ₅ and R ₆ are each independently a hydrogen atom or an alkyl group; And
(f) removing the protecting group of the diol group of the furan ring of the intermediate compound prepared in the step (e) and performing a ring-opening reaction of the furan ring to prepare a compound of the formula (2).
18. The pharmaceutical composition according to claim 17, wherein the adenine derivative is (S) -3-hydroxy-2 - ((R) -2-hydroxy- 1- (6- (3-iodobenzylamino) -Yl) ethoxy) -N-methylpropanamide. &Lt; / RTI &gt;
(R) -2-hydroxy-1- (6- (3-iodobenzylamino) -9H-purin-9-yl) Methoxy) -N-methylpropanamide &lt; / RTI &gt;
(a) Synthesis of (2R, 5R) -2- (6-chloro-9H-purin-9-yl) -5- (hydroxymethyl) tetrahydrofuran- ((3aR, 4R, 6R, 6aR) -6- (6-Chloro-9H-purin-9- yl) -2,2- dimethyltetrahydrofuro [3,4d] [1,3] dioxane Sol-4-yl) methanol;
(b) A mixture of (3aR, 4R, 6R, 6aR) -6- (6-chloro-9H- purin-9- yl) -2,2-dimethyltetrahydrofuro [3,4d] Benzoyl chloride was added dropwise to a solution of (3aR, 4R, 6R, 6aR) -6- (6-chloro-9H-purin-9-yl) -2,2- Lt; / RTI &gt; [3,4-d] [1,3] dioxol-4-yl) methyl benzoate;
(c) A mixture of (3aR, 4R, 6R, 6aR) -6- (6-Chloro-9H- purin-9- yl) -2,2- dimethyltetrahydrofuro [3,4- d] [1 (3R, 4R, 6R, 6aR) -6- (6- (3-iodobenzylamino) -9H -Purin-9-yl) -2,2-dimethyltetrahydrofuro [3,4-d] [1,3] dioxol-4-yl) methyl benzoate;
(d) A mixture of (3aR, 4R, 6R, 6aR) -6- (6- (3-iodobenzylamino) -9H- purin-9- yl) -2,2- dimethyltetrahydrofuro [ 4-d] [1,3] dioxol-4-yl) methyl benzoate was heated to reflux and concentrated under reduced pressure to give a diol intermediate, followed by addition of tetrabutyldimethylsilyl triflate ((2R, -9H-purin-9-yl) tetrahydrofuran-2-carboxamide &lt; / RTI &gt; Yl) methyl benzoate;
((2R, 3R, 4R, 5R) -3,4-bis (tert-butyldimethylsilyloxy) -5- (6- (3- iodobenzylamino) -9H- purin- Yl) methylbenzoate was dissolved in methanol and then sodium methoxide / methanol was added to the solution to obtain ((2R, 3R, 4R, 5R) -3,4-bis (tert- butyldimethylsilyloxy) (6- (3-iodobenzylamino) -9H-purin-9-yl) tetrahydrofuran-2-yl) methanol;
((2R, 3R, 4R, 5R) -3,4-bis (tert-butyldimethylsilyloxy) -5- (6- (3- iodobenzylamino) -9H- purin- Yl) methanol was subjected to ethyl esterification and then methylamine was added thereto to obtain (2S, 5R) -3,4-bis (tert-butyldimethylsilyloxy) -5- -9H-purin-9-yl) -N-methyltetrahydrofuran-2-carboxamide;
(g) Synthesis of (2S, 5R) -3,4-bis (tert-butyldimethylsilyloxy) -5- (6- (3- iodobenzylamino) -9H- purin- Methyl-tetrahydrofuran-2-carboxamide ethertylammonium fluoride was added dropwise to obtain 3,4-dihydroxy-5- (6- (3-iodobenzylamino) -9H-purin- To obtain N-methyltetrahydrofuran-2-carboxamide; And
(h) Preparation of the furan ring of the above 3,4-dihydroxy-5- (6- (3-iodobenzylamino) -9H-purin-9-yl) -N-methyltetrahydrofuran- (R) -2-hydroxy-1- (6- (3-iodobenzylamino) -9H-purin-9-yl) Methoxy) -N-methylpropanamide. &Lt; / RTI &gt;
A process for producing an adenine derivative represented by the following formula (3), comprising the steps of:
(3)

(a) The purine-based compound represented by the formula (4) is reacted with the starting compound, (2R, 3R, 4S, 5R) -2-acetoxy-5- (benzoyloxymethyl) tetrahydrofuran- , &Lt; / RTI &gt;
[Chemical Formula 4]

Wherein R ₃ is a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogen atom, and X is a halogen atom;
(b) reacting the intermediate compound prepared in step (a) with R ₁ -NY-R ₂ ,
Wherein R ₁ and R ₂ are each independently a hydrogen atom, an alkyl group, an m-halo-benzyl group, an m-amino-benzyl group or an aromatic ring and Y is a halogen atom;
(c) removing the benzyl group on the furan ring of the intermediate compound prepared in the step (b) and carrying out a ring-opening reaction of the furan ring to prepare a compound of the formula (3).
21. The compound of claim 20, wherein the adenine derivative is (R) -2- (1- (2-chloro-6- ) Propane-1,3-diol. &Lt; / RTI &gt;

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