KR20170087813A - Novel heteroaromatic ring compound, preparation method thereof, and pharmaceutical composition for use in preventing or treating S1P receptor relating diseases containing the same as an active ingredient - Google Patents

Novel heteroaromatic ring compound, preparation method thereof, and pharmaceutical composition for use in preventing or treating S1P receptor relating diseases containing the same as an active ingredient Download PDF

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KR20170087813A
KR20170087813A KR1020160097847A KR20160097847A KR20170087813A KR 20170087813 A KR20170087813 A KR 20170087813A KR 1020160097847 A KR1020160097847 A KR 1020160097847A KR 20160097847 A KR20160097847 A KR 20160097847A KR 20170087813 A KR20170087813 A KR 20170087813A
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amino
compound represented
propane
diol
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KR101830244B1 (en
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김상희
최지웅
조현경
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서울대학교산학협력단
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The present invention relates to a novel heteroaromatic ring compound, a process for its production, and a pharmaceutical composition for the prevention or treatment of S1P receptor-related diseases containing the same as an active ingredient. The heteroaromatic ring compound, its optical isomer, The pharmaceutically acceptable salt thereof may be useful as an antagonist when it binds to the S1P receptor without phosphorylation and thus may be useful for the prevention or treatment of multiple sclerosis and cerebral ischemia.

Description

TECHNICAL FIELD [0001] The present invention relates to a novel heteroaromatic ring compound, a process for producing the heteroaromatic ring compound, and a pharmaceutical composition for preventing or treating S1P receptor-related diseases containing the same as an active ingredient. [0011]

The present invention relates to a novel heteroaromatic ring compound, a process for producing the same, and a pharmaceutical composition for preventing or treating S1P receptor-related diseases containing the same as an active ingredient.

Multiple sclerosis (MS) is the most common chronic inflammatory dehydration disease of the central nervous system (brain, spinal cord, optic nerve). It is pathologically characterized by multiple inflammation and dehydration of the central nervous system. Although the cause is not yet clear, it is thought to be an autoimmune disease caused by the environment in a genetically susceptible patient.

Treatment of multiple sclerosis can be classified into acute phase treatment, disease modifying therapy, and symptomatic therapy, which are represented by high-dose steroids. Above all, long-term disease relief that reduces recurrence and disorder is important .

In the past, interferon was used as a treatment for multiple sclerosis. However, it was repeatedly recurred and relieved. It was not fully remodeled and remained obstructed. There were various neurological symptoms according to the site of dehydrating cholestasis. The patients had very different symptoms and disease progression. Although there has been no definitive treatment to reduce recurrence over a period of more than 100 years, it has recently been shown that the action of sphingosine-1-phospohate (S1P) on T-type leukocytes effectively blocks the migration to the inflamed site, FTY720, Gilenya) was first marketed as a multi-oral therapeutic agent.

Specifically, FTY720 is an oral immunomodulatory drug that is taken once a day and is a synthetic analogue of sphingosine-1-phosphate (S1P). By reversibly capturing lymphocytes in lymph nodes, lymphocytes are isolated from secondary lymphatic organs to the central nervous system Is a therapeutic agent for multiple sclerosis having an action mechanism that suppresses entry or decreases the number of circulating lymphocytes in the bloodstream, thereby reducing the number of activated lymphocytes reaching the brain and reducing inflammatory destruction.

At this time, FTY720 is a compound that acts non-selectively in one or more S1P receptors S1P1, S1P2, S1P3, S1P4 and S1P5 as a Sphingosine 1-phosphate (S1P) receptor modulator in the form of FTY720-P after phosphorylation, , The intracellular heterotrimeric G-protein is dissociated into G [alpha] -GTP and G [beta] -GTP to regulate the downstream signal transduction pathway and kinase, and diseases mediated by lymphocyte interactions such as transplantation rejection, For example, autoimmune diseases such as systemic lupus erythematosus, Hashimoto's thyroiditis, peripheral neuropathy such as Guillain-Barré Syndrome (GBS), autoimmune diseases associated with autoimmune diseases, diseases, infectious diseases and cancer and mediated by lymphocyte interactions, (MMN), and paraproteinemic dehydrative peripheral neuropathy (PDN), and for the treatment or prevention of multiple sclerosis useful.

Thus, Fingolimod (FTY720), approved as an oral drug for multiple sclerosis, is attracting attention as an action mechanism to regulate immunity by simply regulating lymphocyte without depletion due to cell death of lymphocytes. However, a cardiopulmonary machine such as bradycardia and arrhythmia There is a problem due to serious side effects mainly, and there is a limitation that depends on the phosphorylation of FTY720 since it can be operated as a therapeutic agent after being phosphorylated by SphK (Sphingosine kinase) in vivo.

The most commonly reported side effects are nasopharyngitis, headache and fatigue, and the more frequent side effects are flu, diarrhea, back pain, elevated liver enzymes and colds, Decreased heart rate, AV conduction block, elevated blood pressure, macular edema, and elevated liver enzymes. Clinical studies in the following document demonstrate that treatment with FTY720 results in bradycardia in the first 24 hours of treatment (Non-Patent Document 1).

This is due to the fact that FTY720 acts non-selectively on subtypes of S1P receptors (S1P1, S1P2, S1P3, S1P4 and S1P5), resulting in side effects such as bradycardia, which is an animal test using S1P receptor subtype selective agonists, Patch clamp experiments using inhibitors, and knockout animal models. Therefore, it has become necessary to develop a compound having more selectivity for the S1P receptor.

In addition, since FTY720 is phosphorylated by Sph K (Sphingosine kinase) after administration and can be used as a therapeutic agent, pharmacological action is limited to the phosphorylated amount of FTY720 administered. Therefore, the therapeutic effect is limited It is necessary to develop a therapeutic agent free from the phosphorylation process.

Thus, while trying to find a compound that is effective for multiple sclerosis and is selective for the receptor of each S1P subtype and independent of the phosphorylation process of SphK, the compounds of the present invention are useful for the treatment of multiple sclerosis, The present invention has been accomplished by confirming that it is excellent in prevention and is relatively selective to S1P1 or S1P4 and can be used as a therapeutic agent without phosphorylation by SphK.

Kappos et al., N. Engl. J. Med., 335: 1124 (2006)

It is an object of the present invention to provide a compound useful as an active ingredient of a pharmaceutical composition for the prevention or treatment of S1P receptor-related diseases.

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

Still another object of the present invention is to provide a pharmaceutical composition for preventing or treating S1P receptor-related diseases containing the above-mentioned compound as an active ingredient.

Another object of the present invention is to provide a health functional food for improving S1P receptor-related diseases containing the above compound as an active ingredient.

In order to achieve the above object,

The present invention provides a compound represented by the following general formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

Figure pat00001

In Formula 1,

R 1 is hydrogen or

Figure pat00002
ego;

R 2 is hydrogen or an unsubstituted or substituted C 1-5 straight or branched chain alkylcarbonyl,

Wherein said substituted alkylcarbonyl is substituted with one or more substituents selected from the group consisting of hydroxy, halogen, cyano, nitro, and amino;

A is heteroarylene of pentavalent ring comprising at least one heteroatom selected from the group consisting of N, O and S;

B is C 1-11 linear or branched alkylene;

C is a single bond or C 6-10 arylene;

D is -H, or C 1-15 straight or branched chain alkyl; And

X is a single bond, C 1-5 alkylene, C 2-5 alkenylene or C 2-5 alkynylene.

The present invention also relates to a process for producing a compound represented by the formula (1)

Reacting a compound represented by the formula (2) with a compound represented by the formula (3) to prepare a compound represented by the formula (4) (step 1);

Reacting the compound represented by the formula (4) and the compound represented by the formula (5) prepared in the step 1 to prepare a compound represented by the formula (6) (step 2); And

And removing the protecting group of the compound represented by the formula (6) prepared in the step (2) to prepare a compound represented by the formula (1) (step 3).

[Reaction Scheme 1]

Figure pat00003

In the above Reaction Scheme 1,

R 1 , R 2 , X, A, B, C, and D are as defined in Formula 1;

m is an integer of 0 or 1;

R 3 is

Figure pat00004
Or -N 3, and;

-TIPS

Figure pat00005
ego; And

-Boc

Figure pat00006
to be.

Further, the present invention relates to a process for the preparation of

A step of hydrogenating the compound of formula (6a) to prepare a compound of formula (6b) (step 1); And

And removing the protecting group of the compound represented by the formula (6b) prepared in the step (1) to prepare a compound represented by the formula (1a) (step 2).

[Reaction Scheme 2]

Figure pat00007

In the above Reaction Scheme 2,

R 2 , A, B, C, D, and -Boc are as defined in Formula 1;

The compounds represented by formulas (6a) and (6b) are included in the compound represented by formula (6) of claim 5; And

The compound represented by the formula (Ia) is included in the compound represented by the formula (1).

The present invention also provides a pharmaceutical composition for preventing or treating diseases related to S1P receptor (sphingosine 1-phosphate receptors) containing the above compound, its optical isomer or a pharmaceutically acceptable salt thereof as an active ingredient.

Further, the present invention provides a health functional food for improving diseases related to S1P receptor (sphingosine 1-phosphate receptors) containing the above compound, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

The heteroaromatic ring compound according to the present invention, its optical isomer, or a pharmaceutically acceptable salt thereof, selectively binds to the S1P1 or S1P4 receptor without phosphorylation and functions as a functional antagonist to treat multiple sclerosis or cerebral ischemia There is a useful effect.

Figure 1 is a photograph of the cell surface photographed over time by activating S1P1 receptors with different ligands (S1P, FTY720-P and Example 1).
FIG. 2A shows the clinical scores obtained by administering the vehicle (10% Tween 80, po), the compound of Example 1 (3 mg / kg, po) or FTY720 (3 mg / kg, po) (▽ is the start time of administration, and ▼ is the time of stopping administration); FIG. 2B is a photograph showing dehydrated tissues colored with fluorine myelin; FIG. FIG. 2C is a photograph showing increased cell density with colored cresyl violet (arrows mark the increased cell density portion); 2D is a photograph showing an abnormal increase in astrocytosis; FIG. 2E is a photograph showing microglial cell activation (Iba1-immunoreactive cells).
FIG. 3 shows the results of the immediate administration of the compound of Example 1 (3 mg / kg, po) to the experimental rats after reperfusion, and FIGS. 3A and 3B show the volume of the infarcted part of the brain Fig. 3C is a numerical representation of neurological sequelae, and Fig. 3D shows the neuroprotective effect of Example 1 on cerebral ischemia as a change in activated microglial cells (Ibal-positive cell number).
FIG. 4 is a graph showing changes in the degree of neuronal necrosis observed after 22 hours from the administration of the compound of Example 1 (3 mg / kg, po) to the experimental rats after the reperfusion by cortex (Cx) staining through Fluoro-Jade B , and striatum (St). (The above three photographs are 200 ㎛ standard, and the middle and lower photographs are 50 ㎛ standard photograph.
Fig. 5 is a figure showing the shape where the different ligands of Example 1 (cyan), Example 7 (blue), S1P (green) and FTY720-P (orange) are located at the binding site of the receptor S1P1.
FIG. 6 is a diagram showing a binding drug molecule structure (Pharmacophore) in which Example 1 (cyan) or FTY720-P (orange) interacts with the S1P1 receptor upon binding.

Hereinafter, the present invention will be described in detail.

The present invention provides a compound represented by the following general formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

Figure pat00008

In Formula 1,

R 1 is hydrogen or

Figure pat00009
ego;

R 2 is hydrogen or an unsubstituted or substituted C 1-5 straight or branched chain alkylcarbonyl,

Wherein said substituted alkylcarbonyl is substituted with one or more substituents selected from the group consisting of hydroxy, halogen, cyano, nitro, and amino;

A is heteroarylene of pentavalent ring comprising at least one heteroatom selected from the group consisting of N, O and S;

B is C 1-11 linear or branched alkylene;

C is a single bond or C 6-10 arylene;

D is -H, or C 1-15 straight or branched chain alkyl; And

X is a single bond, C 1-5 alkylene, C 2-5 alkenylene or C 2-5 alkynylene.

Preferably,

R 1 is hydrogen or

Figure pat00010
ego;

R 2 is hydrogen or C 1-3 straight or branched chain alkylcarbonyl;

A is heteroarylene of pentavalent ring comprising at least one heteroatom selected from the group consisting of N, O and S;

B is C 1-9 linear or branched alkylene;

C is a single bond or C 6-10 arylene;

D is -H, or C 3-12 linear or branched alkyl; And

X is a single bond, C 1-3 alkylene, C 2-3 alkenylene or C 2-3 alkynylene.

More preferably,

R 1 is hydrogen or

Figure pat00011
ego;

R 2 is hydrogen or acetyl;

A is heteroarylene of pentavalent ring comprising at least one heteroatom selected from the group consisting of N, O and S;

B is C 2-8 alkylene;

C is a single bond or phenylene;

D is -H, or C 6-10 linear or branched alkyl; And

X is a single bond, -CH 2 CH 2 - is, -CH = CH- or -C≡C-.

Preferable examples of the compound represented by the formula (1) according to the present invention include the following compounds.

(1) 2-Amino-2- (2- (3-decylisoxazol-5-yl) ethyl) propane-1,3-diol;

(2) 2-Amino-2- (2- (1-decyl-1H-1,2,3-triazol-4-yl) ethyl) propane-1,3-diol;

(3) 2-Amino-2 - ((3-octylisoxazol-5-yl) ethynyl) propane-1,3-diol;

(4) 2-Amino-2- (2- (3-octylisoxazol-5-yl) ethyl) propane-1,3-diol;

(5) 2-Amino-2- (hydroxymethyl) -4- (3-octylisooxazol-5-yl) butyl dihydrogen phosphate;

(6) 2-Amino-2 - ((3-decylisoxazol-5-yl) ethynyl) propane-1,3-diol;

(7) 2-Amino-4- (3-decylisoxazol-5-yl) -2- (hydroxymethyl) butyl dihydrogen phosphate;

(8) 2-Amino-2- (2- (3- (4-hexylphenethyl) isooxazol-5-yl) ethyl) propane-1,3-diol;

(9) 2-Amino-2 - ((3-dodecylisoxazol-5-yl) ethynyl) propane-1,3-diol;

(10) 2-Amino-2- (2- (3-dodecylisoxazol-5-yl) ethyl) propane-1,3-diol;

(11) 2-Amino-4- (3-dodecylisoxazol-5-yl) -2- (hydroxymethyl) butyl dihydrogen phosphate;

(12) 2-Amino-2- (2- (1-octyl-1H-1,2,3-triazol-4-yl) ethynyl) propane-1,3-diol;

(13) 2-Amino-2- (2- (1-octyl-1H-1,2,3-triazol-4-yl) ethyl) propane-1,3-diol;

(14) 2-Amino-2 - ((1-decyl-1H-1,2,3-triazol-4-yl) ethynyl) propane-1,3-diol;

(15) 2-Amino-2- (2- (1- (4-hexylphenylethyl) -1H-1,2,3-triazol-4-yl) ethyl) propane-1,3-diol;

(16) 2-Amino-2- (1-butyl-1H-1,2,3-triazol-4-yl) propane-1,3-diol;

(17) 2-Amino-2- (3-dodecylisoxazol-5-yl) propane-1,3-diol;

(18) (E) -2-Amino-2- (2- (3-decylisoxazol-5-yl) vinyl) propane-1,3-diol;

(19) (E) -2-Amino-2- (1-butyl-1H-1,2,3-triazol-4-yl) propane-1,3-diol;

(20) 2-Amino-2- (2- (3- (8-phenyloctyl) -isooxazol-5-yl) ethyl) propane-1,3-diol;

(21) 2-Amino-2- (2- (1- (8-phenyloctyl) -1H-1,2,3-triazolobutyl-4-yl) propane-1,3-diol;

(22) N- (2- (1-Dodecyl-1H-1,2,3-triazol-4-yl) -1,3-dihydroxypropan-2-yl) acetamide;

(23) N- (2- (3-Dodecylisoxazol-5-yl) -1,3-dihydroxypropan-2-yl) acetamide;

(24) N- (4- (1-decyl-1H-1,2,3-triazol-4-yl) -1-hydroxy-2- (hydroxymethyl) butan-2-yl) acetamide;

(25) N- (4- (3-decylisoxazol-5-yl) -1-hydroxy-2- (hydroxymethyl) butan-2-yl) acetamide; And

(26) Synthesis of N- (4- (1- (4-hexylphenethyl) -1H-1,2,3-triazol-4-yl) -1-hydroxy- 2- (hydroxymethyl) Yl) acetamide.

The compound represented by the formula (1) of the present invention can be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid and the like, aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, Derived from organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid and the like. Examples of such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, But are not limited to, but are not limited to, but are not limited to, but are not limited to, but are not limited to, halides, halides, halides, halides, halides, halides, But are not limited to, lactose, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene Sulfonates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, and the like, as well as sulfonates such as benzyl sulfonate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, -Sulfonate, naphthalene-2-sulfonate, mandelate, and the like.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving a derivative of the formula (1) in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile and the like, Followed by filtration and drying, or by distillation of the solvent and excess acid under reduced pressure, followed by drying and crystallization in an organic solvent.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. In addition, the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable salt (such as silver nitrate).

Furthermore, the present invention encompasses the compounds represented by the formula (1) and pharmaceutically acceptable salts thereof as well as solvates, optical isomers and hydrates thereof which can be prepared therefrom.

The present invention also relates to a process for producing a compound represented by the formula (1)

Reacting a compound represented by the formula (2) with a compound represented by the formula (3) to prepare a compound represented by the formula (4) (step 1);

Reacting the compound represented by the formula (4) and the compound represented by the formula (5) prepared in the step 1 to prepare a compound represented by the formula (6) (step 2); And

And removing the protecting group of the compound represented by the formula (6) prepared in the step (2) to prepare a compound represented by the formula (1) (step 3).

[Reaction Scheme 1]

Figure pat00012

In the above Reaction Scheme 1,

R 1 , R 2 , X, A, B, C, and D are as defined in Formula 1;

m is an integer of 0 or 1;

R 3 is

Figure pat00013
Or -N 3, and;

-TIPS

Figure pat00014
ego; And

-Boc

Figure pat00015
to be.

Hereinafter, the process for preparing the compound represented by the formula (1) according to the present invention will be described in detail.

In the process for preparing the compound represented by the general formula (1) according to the present invention, step 1 of Scheme 1 is a step of reacting a compound represented by the general formula (2) with a compound represented by the general formula (3) to prepare a compound represented by the general formula to be.

At this time, methanol, ethanol, tetrahydrofuran (THF), dichloromethane (DCM), toluene, acetonitrile and the like can be used as the solvent in the above step, and methanol is preferably used.

In the above step, the reaction is preferably carried out at a temperature of 0 ° C between the boiling point of the solvent, and the reaction time is not particularly limited, but it is preferably 0.5-10 hours.

In the process for preparing a compound represented by the general formula (1) according to the present invention, in the step 2 of Scheme 1, the compound represented by the general formula (4) and the compound represented by the general formula (5) Is prepared.

The solvent used in this step may include dimethylformamide (DMF), methanol, ethanol, tetrahydrofuran (THF), dichloromethane (DCM), toluene, acetonitrile, Formamide (DMF) can be used.

In the above step, the reaction is preferably carried out at a temperature ranging from 0 ° C to the boiling point of the solvent. The reaction time is not particularly limited, but it is preferably 0.5-20 hours.

In the process for preparing a compound represented by the formula (1) according to the present invention, the step 3 of Scheme 1 is a step for preparing a compound represented by the formula (1) by removing the protecting group of the compound represented by the formula (6) to be.

The solvent used in the above step may be dichloromethane (DCM), dimethylformamide (DMF), methanol, ethanol, tetrahydrofuran (THF), toluene, acetonitrile, Chloromethane (DCM) can be used.

In the above step, the reaction is preferably carried out at a temperature ranging from 0 ° C to the boiling point of the solvent. The reaction time is not particularly limited, but it is preferably 0.5-20 hours.

In addition, Step 3 of Scheme 1 above may additionally comprise an alkylcarbonyl addition reaction. Specifically, it can be understood as a reaction of introducing an alkylcarbonyl at the R 2 position into the compound represented by the formula (1). For example, the compound represented by the formula (1) and acetic anhydride To introduce an acetyl group at the R 2 position.

At this time, as the usable solvent, dichloromethane (DCM), dimethylformamide (DMF), methanol, ethanol, tetrahydrofuran (THF), toluene, acetonitrile and the like can be used, have.

Further, the present invention relates to a process for the preparation of

A step of hydrogenating the compound of formula (6a) to prepare a compound of formula (6b) (step 1); And

And removing the protecting group of the compound represented by the formula (6b) prepared in the step (1) to prepare a compound represented by the formula (1a) (step 2).

[Reaction Scheme 2]

Figure pat00016

In the above Reaction Scheme 2,

R 2 , A, B, C, D, and -Boc are as defined in Formula 1;

The compounds represented by formulas (6a) and (6b) are included in the compound represented by formula (6); And

The compound represented by the formula (1a) is included in the compound represented by the above formula (1).

Hereinafter, the process for preparing the compound represented by the formula (1) according to the present invention will be described in detail.

In the process for preparing a compound represented by the general formula (1) according to the present invention, step 1 of Scheme 2 is a step of performing a hydrogenation reaction on a compound represented by the general formula (6a) to prepare a compound represented by the general formula (6b).

At this time, methanol, ethanol, tetrahydrofuran (THF), dichloromethane (DCM), toluene, acetonitrile and the like can be used as the solvent in the above step, and methanol is preferably used.

In the above step, the reaction is preferably carried out at a temperature of 0 ° C between the boiling point of the solvent, and the reaction time is not particularly limited, but it is preferably 0.5-10 hours.

In the process for preparing a compound represented by the general formula (1) according to the present invention, the step 2 of Scheme 2 is a step for preparing a compound represented by the general formula (1a) by removing the protecting group of the compound represented by the general formula to be.

The solvent used in the above step may be dichloromethane (DCM), dimethylformamide (DMF), methanol, ethanol, tetrahydrofuran (THF), toluene, acetonitrile, Chloromethane (DCM) can be used.

In the above step, the reaction is preferably carried out at a temperature ranging from 0 ° C to the boiling point of the solvent. The reaction time is not particularly limited, but it is preferably 0.5-20 hours.

In addition, Step 2 of Scheme 2 may additionally include an alkylcarbonyl addition reaction. Specifically, the reaction can be understood as a reaction of introducing an alkylcarbonyl at the R 2 position into the compound represented by the formula (1a). For example, the compound represented by the formula (1a) and acetic anhydride To introduce an acetyl group at the R 2 position.

At this time, as the usable solvent, dichloromethane (DCM), dimethylformamide (DMF), methanol, ethanol, tetrahydrofuran (THF), toluene, acetonitrile and the like can be used, have.

Further, the present invention provides a pharmaceutical composition for preventing or treating diseases related to S1P receptor (sphingosine 1-phosphate receptors) containing the compound represented by the formula (1), its optical isomer or a pharmaceutically acceptable salt thereof as an active ingredient to provide.

Herein, the S1P receptor-related diseases include multiple sclerosis, ischemic stroke, intracerebral hemorrhage, traumatic brain injury, spinal cord injury, systemic lupus erythematosus systemic lupus erythematosus, SLE), psoriasis, polymyositis, active dermatomyositis, hematological malignancies, Alzheimer's disease, Parkinson's disease, Lou Gehrig's disease, Huntington's disease, Creutzfeldt Jakob disease, (GBS), chronic inflammatory dehydrative polyneural neuropathy (CIDP), conduction-arrested multifocal motor neuropathy (MMN), paraproteinemia (MMN), hyperparathyroidism Dyslipidemic peripheral neuropathy (PDN), and the like, preferably multiple sclerosis or ischemic stroke.

The present invention also provides a health functional food for improving S1P receptor-related diseases, which comprises the compound represented by the above formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

Herein, the S1P receptor-related diseases include multiple sclerosis, ischemic stroke, intracerebral hemorrhage, traumatic brain injury, spinal cord injury, systemic lupus erythematosus systemic lupus erythematosus, SLE), psoriasis, polymyositis, active dermatomyositis, hematological malignancies, Alzheimer's disease, Parkinson's disease, Lou Gehrig's disease, Huntington's disease, Creutzfeldt Jakob disease, (GBS), chronic inflammatory dehydrative polyneural neuropathy (CIDP), conduction-arrested multifocal motor neuropathy (MMN), paraproteinemia (MMN), hyperparathyroidism Dyslipidemic peripheral neuropathy (PDN), and the like, preferably multiple sclerosis or ischemic stroke.

The compound of formula (I) according to the present invention may be administered orally or parenterally in a variety of formulations at the time of clinical administration. In the case of formulation, the compound of the present invention may be used as a filler, an extender, a binder, a wetting agent, a disintegrant, Diluents or excipients.

Solid formulations for oral administration include tablets, pills, powders, granules, capsules, troches, and the like, which may contain one or more excipients such as starch, calcium carbonate, Sucrose, lactose, gelatin or the like. In addition to simple excipients, lubricants such as magnesium stearate talc are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions or syrups. Various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like are included in addition to commonly used simple diluents such as water and liquid paraffin. .

Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like. Examples of the non-aqueous solvent and suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. As a base for suppositories, witepsol, macrogol, tween 61, cacao paper, laurin, glycerol, gelatin and the like can be used.

The effective dose of the compound of the present invention on the human body may vary depending on the age, weight, sex, dosage form, health condition and disease severity of the patient, and is generally about 0.001-100 mg / kg / 0.0 > mg / kg / day. ≪ / RTI > It is generally from 0.07 to 7000 mg / day, preferably from 0.7 to 2500 mg / day, based on adult patients weighing 70 kg, and may be administered once a day It may be divided into several doses.

The heteroaromatic ring compound, its optical isomer, or a pharmaceutically acceptable salt thereof according to the present invention binds to the S1P receptor without phosphorylation and acts as a functional antagonist and is useful for the treatment of multiple sclerosis or cerebral ischemia Were confirmed through experiments.

First, S1P receptor (S1P 1 - 5) the result of the experiment in order to evaluate the binding activity degree of the embodiment of the invention compounds relative to, the compounds of Examples 1 and 2 of the present invention are all binding activity of the S1P receptor In particular, the compound of Example 1 of the present invention showed a binding activity of 4 times or more as much as that of the S1P1 receptor (see Table 2 in Experimental Example 1) as compared with FTY720.

As a result of experiments conducted to confirm the difference in mechanism depending on the phosphorylation of the heterocyclic compound according to the present invention, Example 1 and FTY720-P showed that S1P1 receptor was still internalized even 30 minutes to 24 hours after receptor activation In contrast, when treated with S1P in Example 7, it was observed that the receptor was internalized for up to 30 minutes, and it was confirmed that S1P1 was not internalized due to recirculation after 2 hours (Example 2 1).

Furthermore, the compounds of Example 1 according to the present invention were tested to evaluate symptoms and efficacy of experimental autoimmune encephalomyelitis (EAE) experimental autoimmune encephalomyelitis in experimental rats (7-8 weeks old) , The clinical score began to decrease after 6 days of dosing, and the efficacy was maintained similar to that of FTY 720 (3 mg / kg, ip) (see FIG. 2 of Experimental Example 3).

In addition, the compounds of Example 1 according to the present invention were evaluated for the symptoms and efficacy of mice administered to middle-cerebral artery occlusion (MCAO) / rat cerebral artery stenosis / reperfusion (M / R) As a result, it has been found that the compounds according to the present invention can effectively treat cerebral ischemia by effectively reducing nerve damage resulting from cerebral ischemia at a level similar to that of FTY720 (see FIGS. 3 and 4 of Experimental Example 4).

Further, experiments were conducted to identify the functional antagonistic action of the heterocyclic compounds according to the present invention and the cause of the conversion to an agent such as S1P after phosphorylation.

As a result, it was found that the side chain portion of Trp269, which is a part of the binding portion, interacts with the alkyl chain portion of S1P when the S1P is located at the binding site of S1P1 by performing the induction-compatible binding with the natural agent S1P. 7 and S1P fully fill the S1P1 bond and in particular the alkyl chain occupies the hydrophobic bond and occupies the hydrophobic bond of S1P 1 , while FTY720-P and Example 1 occupy the hydrophobic bond of S1P 1 The binding is incomplete and the recirculation does not occur after the internalization, which leads to a functional antagonistic action (see FIGS. 5 and 6 of Experimental Example 5).

Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples.

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

< Example  1 > 2-Amino-2- (2- (3- Decylisoxazole Yl) ethyl) propane-1,3- die Preparation of all (I-10)

Figure pat00017

Step 1: tert - Butyl (2,2- Dimethyl -5 - (( Triisopropyl silyl ) Buta -1,3- Diein -1-yl) -1,3-dioxan-5-yl) carbamate

Figure pat00018

Under N 2 gas conditions to a solution of CuCl (10 mg, 0.10 mmol) , NH 2 OH · HCl (1.02 g, 14.67 mmol), n-BuNH 2 (3.87 mL, 39.15 mmol) of dissolved in methanol (50 mL), Ethyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate (1.25 g, 4.89 mmol) dissolved in methanol (30 mL) Bromo-1-triisopropylsilylacetylene (2.56 g, 9.78 mmol) dissolved in dichloromethane was added dropwise and the reaction mixture was stirred well at room temperature for 2 hours, then the reaction was quenched with water and concentrated . Diluting the concentrate with ethyl acetate and then washed with brine (Brine), the organic layer was concentrated after drying with MgSO 4 and filtered under vacuum. This was purified by flash column chromatography (hexane / EtOAc, 7: 1) to give the desired compound as a white solid (1.85 g, 4.25 mmol, 87%).

1 H NMR (400 MHz, CDCl 3 )? 1.04 (s, 21H), 1.38 (s, 3H), 1.43-1.45 (m, 12H), 3.95 (s, 4H), 5.11 13 C NMR (100 MHz, CDCl 3 )? 11.21 (3C), 18.47 (6C), 28.17 (2C), 28.32 (3C), 47.95,66.10 (2C), 70.47, 72.84, 80.40, 84.58, 88.88, 98.57, 154.25; IR (CHCl 3) υmax; HRMS (FAB) calcd for C 24 H 42 NO 4 Si ([M + H] + ) 436.2883, found 436.2884.

Step 2: tert - Butyl (5 - ((3- Decylisoxazole -5 days) Ethynyl ) -2,2- Dimethyl -1,3-dioxan-5-yl) carbamate

Figure pat00019

N-Hydroxyundecanimidoyl chloride (685 mg, 3.60 mmol) and CuI (114 mg, 0.60 mmol) were added to anhydrous DMF (12 mL) , DIPEA (N, N-Diisopropylethylamine) (0.63 mL, 3.6 mmol) and AgF (182 mg, 1.44 mmol). After the reaction mixture was stirred well at room temperature for 12 hours, the reaction was quenched with saturated NH 4 Cl, extracted twice with ethyl acetate, and the organic layer extract was washed with saturated NH 4 Cl and brine. This was dried over MgSO 4 and concentrated under reduced pressure. The concentrate was purified by flash column chromatography (hexane / EtOAc, 6: 1) to give the desired compound as a white solid (439 mg, 0.95 mmol, 79%).

1 H NMR (400 MHz, CDCl 3 )? 0.86 (t, J = 6.8 Hz, 3H), 1.22-1.24 (m, 14H) 1H), 6.27 (s, 3H), 1.57-1.64 (m, 2H), 2.62 (t, J = 7.6 Hz, 2H), 4.05 (dd, J = 1H); 13 C NMR (100 MHz, CDCl 3) δ 14.01, 18.72, 22.58, 25.76, 27.80, 28.08, 28.27 (3C), 28.97, 29.15, 29.20, 29.38, 29.45, 31.79, 47.96, 65.79, 71.95, 80.45, 95.07, 98.67, 108.09 (2C), 152.11, 154.21, 164.02; IR (CHCl 3) υmax; HRMS (FAB) calcd for C 26 H 43 N 2 O 5 ([M + H] + ) 463.3172, found 463.3169.

Step 3: tert - Butyl (5- (2- (3- Decylisoxazole Yl) ethyl) -2,2- Dimethyl -1,3-dioxan-5-yl) carbamate

Figure pat00020

10% Pd / C (45 mg, 30% wt of the compound prepared in Step 2) was added to a solution of the compound (149 mg, 0.32 mmol) prepared in Step 2 in methanol (30 mL). After creating the flask to vacuum, H 2 for the gas to fills one hour at room temperature and stir to give a Celite (Celite) to give were filtered off after the precipitate concentrate flash column chromatography (hexane / EtOAc mixture, 7: 1 or 2: 1) to give the target compound as a colorless oil (110 mg, 0.24 mmol, 74%).

1 H NMR (400 MHz, CDCl 3 )? 0.86 (t, J = 6.6 Hz, 3H), 1.24-1.29 (m, 14H), 1.40 (s, J = 7.6 Hz, 2H), 2.68 (t, J = 8.2 Hz, 2H), 3.75 (m, 2H) dd, J = 11.7, 69.6 Hz, 4H), 4.91 (br s, 1H), 5.82 (s, 1H); 13 C NMR (100 MHz, CDCl 3) δ 14.06, 19.96, 20.45, 22.63, 26.01, 27.03, 28.27, 28.35 (3C), 29.18, 29.26 (3C), 29.45, 29.36, 31.85, 51.32, 66.03 (2C), 79.60, 98.48, 100.48, 154.93, 164.17, 172.33; IR (CHCl 3) υmax; HRMS (FAB) calcd for C 26 H 47 N 2 O 5 ([M + H] + ) 467.3485, found 467.3484.

step 4: 2 -Amino-2- (2- (3- Decylisoxazole Yl) ethyl) propane-1,3- Diol  Produce

Figure pat00021

TFA (1.40 mL) was added to a solution of the compound prepared in Step 3 (65 mg, 0.14 mmol) in CH 2 Cl 2 (1.40 mL) at room temperature. After giving Stir the reaction for 12 hours, remove the solvent and the reagent under reduced pressure, and the concentrate flash column chromatography (CH 2 Cl 2 / MeOH / NH 4 OH, 100: 10: 1) to give the target compound as a white solid (36 mg, 0.11 mmol, 78%).

1 H NMR (400 MHz, CDCl 3 )? 0.86 (t, J = 6.7 Hz, 3H), 1.24-1.28 (m, 14H), 1.56-1.61 2H), 3.57 (dd, J = 11.0, 31.9 Hz, 4H), 5.83 (t, J = (s, 1 H); 13 C NMR (75 MHz, CDCl 3 )? 14.10, 20.81, 22.67, 26.01, 28.26, 29.32 (3C), 29.55, 29.60, 30.79, 31.89, 58.79, 63.88 (2C), 100.91, 164.40, 171.70; IR (CHCl 3) D max; HRMS (FAB) calcd for C 18 H 35 N 2 O 3 ([M + H] +) 327.2648, found 327.2657.

< Example  2> 2-Amino-2- (2- (1-decyl-1H-1,2,3- Triazole Yl) ethyl) propane-1,3-diol (T-10)

Figure pat00022

The title compound was prepared in the form of a white solid by following the procedure of Example 1 while using 1-azidecane (339 mg, 1.86 mmol) instead of using N-hydroxyundecanimidoyl chloride (38 mg, 0.12 mmol, 91%).

1 H NMR (400 MHz, CDCl 3 )? 0.86 (t, J = 6.8 Hz, 3H), 1.23-1.29 (m, 14H) 7.7 Hz, 2H), 2.47 (br s, 4H), 2.78 (t, J = 7.8 Hz, 2H), 3.57 (dd, J = 11.2,26.9 Hz, ), 7.31 (s, 1 H); 13 C NMR (75 MHz, CDCl 3 )? 14.03, 19.21, 22.57, 26.50 (2C), 28.95 (2C), 29.03 (2C), 30.19, 31.70, 50.42, 60.05, 63.09 (2C), 121.34, 146.82; IR (CHCl3) vmax; HRMS (FAB) calcd for C 17 H 35 N 4 O 2 ([M + H] +) 327.2760, found 327.2762.

< Example  3> 2-Amino-2 - ((3- Octylisoxazole -5 days) Ethynyl ) Propane-1,3- die Preparation of I-8-TR

Figure pat00023

Instead of using N-hydroxyundecanimidoyl chloride, N-hydroxynonanedimidoyl chloride is used; Except that step 3 of Example 1 was excluded.

1 H NMR (400 MHz, MeOD ) δ 0.86 (t, J = 6.7 Hz, 3H), 1.24-1.33 (m, 10H), 1.65 (t, J = 7.0 Hz, 2H), 2.63 (t, J = 7.3 Hz, 2H), 3.64 (q, J = 9.6 Hz, 4H), 6.45 (s, 1H).

< Example  4> 2-Amino-2- (2- (3- Octylisoxazole Yl) ethyl) propane-1,3- die Production of all (I-8)

Figure pat00024

The objective compound was prepared in the same manner as in Example 1, except that N-hydroxynonanedimidoyl chloride was used instead of N-hydroxyundecanimidoyl chloride.

1 H NMR (300 MHz, CDCl 3 )? 0.86 (t, J = 9.0 Hz, 3H), 1.24-1.28 (m, 10H), 1.40 (s, J = 11.0 Hz, 2H), 2.75 (t, J = 11.0 Hz, 2H), 2.57 dd, J = 15.7, 70.1 Hz, 4H), 4.91 (br s, 1H), 5.82 (s, 1H); 13 C NMR (75 MHz, CDCl 3) δ 14.0, 19.9, 20.4, 22.6, 26.0, 27.0, 28.25, 28.34, 29.10, 29.17, 29.2, 29.3, 31.8, 51.3, 66.0, 79.6, 98.5, 100.5, 154.9, 164.2 , 172.3; IR (CHCl 3) υ max 3351 , 3056, 2907, 2851, 1477 (cm -1).

< Example  5> 2-Amino-2- ( Hydroxymethyl ) -4- (3- Octylisoxazole -5-yl) butyl dihydrogenphosphate (I-8-P)

Figure pat00025

Step 1: Benzyl (4- (3-decylisoxazol-5-yl) -One- Hydroxy -2-( Hydroxymethyl ) Butan-2-yl) carbamate

To the saturated aqueous solution of NaHCO 3 (3 mL) and EtOAc (3 mL) was added the compound prepared in Example 4 above. Stirred well at room temperature for 20 minutes, additional benzyl chloroformate (0.072 mL, 0.48 mmol) was added and stirred for a further 40 minutes. After separating the organic layer, the aqueous layer was washed twice with ethyl acetate. The combined organic layers was dried with MgSO 4 and concentrated in vacuo. The concentrate was purified by flash column chromatography (CH 2 Cl 2 / MeOH, 20: 1) to give the target compound as a white solid.

Step 2: Benzyl (1 - ((bis (benzyloxy) phosphoryl) oxy ) -4- (3- Decylisoxazole -5-yl) -2- (hydroxymethyl) butan-2-yl) carbamate

DMAP (dimethylaminopyridine) (13 mg, 0.11 mmol) was added to a solution of the compound prepared in step 1 in CH 2 Cl 2 (0.50 mL). CH 2 Cl 2 (0.50 mL) in which dibenzylphosphorochlorideate (67 mg, 0.094 mmol) was dissolved was added dropwise to the solution, which was stirred at room temperature for 3 hours. The reaction was quenched with water and extracted twice with CH 2 Cl 2 . The organic layer was washed with brine, dried and concentrated in the back, a vacuum MgSO 4. The concentrate was purified by flash column chromatography (CH 2 Cl 2 / MeOH, 40: 1) to give the target compound as a white solid.

step 3: 4 - (3- Decylisoxazole -5-yl) -1- Hydroxy -2-(( Phosphonoxy ) methyl ) Butane-2-aminium TFA  Manufacture of salt

TFA (0.10 mL) was added to MeOH (1 mL) in which the objective compound of Step 2 (14 mg, 0.019 mmol) was dissolved at 0 ° C and then 10% Pd / C (4.20 mg, 30 % wt.) was added and the reaction flask was filled with hydrogen gas. Stirred well at room temperature for 1 hour and filtered through Celite. The filtrate was concentrated in vacuo to give the desired compound as a white solid (8 mg, 0.016 mmol, 83%).

1 H NMR (300 MHz, MeOD ) δ 0.85 (t, J = 8.9 Hz, 3H), 1.24-1.26 (m, 10H), 1.59-1.61 (m, 2H), 2.15-2.22 (m, 2H), 2.57 (t, J = 6.0 Hz, 2H), 2.80-2.92 (m, 2H), 3.34-3.35 (m, 2H), 3.54-3.63 (m, 2H), 6.09 (s,

< Example  6> 2-Amino-2 - ((3- Decylisoxazole -5 days) Ethynyl ) Propane-1,3- die Preparation of I-10-TR

Figure pat00026

In the preparation of Example 1 above, the same procedure was followed except for step 3 to produce the desired compound.

1 H NMR (400 MHz, MeOD)? 0.88 (t, J = 6.7 Hz, 3H), 1.24-1.33 (m, 14H), 1.64 Hz, 2H), 3.64 (q, J = 9.8 Hz, 4H), 6.47 (s, 1H).

< Example  7 > 2-Amino-4- (3- Decylisoxazole -5-yl) -2- ( Hydroxymethyl ) Butyl dihydrogen Phosphate (I-10-P)  Produce

Figure pat00027

The objective compound was prepared (8 mg, 0.016 mmol, 83%) in the same manner as in Example 5, except that the compound of Example 1 was used instead of the compound of Example 4.

1 H NMR (600 MHz, MeOD)? 0.89 (t, J = 7.1 Hz, 3H), 1.24-1.28 (m, 14H), 1.62-1.65 ), 3.93 (dd, J = 11.2,14.9 Hz, 2H), 4.13 (t, J = 10.1 Hz, 2H), 6.09 (s, 1H); 13 C NMR (150 MHz, MeOD)? 15.22, 22.05, 24.51, 27.58, 30.13, 30.99, 31.16, 31.22, 31.43, 31.48, 33.74, 33.84, 52.15, 75.71, 102.61, 102.66, 166.57, 175.15.

< Example  8> 2-Amino-2- (2- (3- (4- Hexylphenethyl ) Isoxazole Yl) ethyl) propane-1,3-diol (12)

Figure pat00028

The procedure of Example 1 was repeated except that 3- (4-hexylphenyl) -N-hydroxypropanimidoyl chloride was used instead of N-hydroxyundecanimidoyl chloride to obtain the desired compound .

< Example  9> 2-Amino-2 - ((3- Dodecylisoxazole -5 days) Ethynyl ) Propane-1,3- All Preparation of Iol (I-12-TR)

Figure pat00029

The objective compound was prepared in the same manner as in Example 6, except that N-hydroxyundecanimidoyl chloride was used instead of the N-hydroxyundecanimidoyl chloride of Example 6 above.

1 H NMR (400 MHz, MeOD)? 0.86 (t, J = 6.5 Hz, 3H), 1.24-1.34 (m, 18H), 1.64 Hz, 2H), 3.65 (q, J = 9.5 Hz, 4H), 6.43 (s, 1H).

< Example  10> 2-Amino-2- (2- (3- Dodecylisoxazole Yl) ethyl) propane-1,3- All Preparation of Iol (I-12)

Figure pat00030

The target compound was prepared in the same manner as in Example 1, except that N-hydroxytridecanimidoyl chloride was used instead of the N-hydroxydoundecanimidoyl chloride of Example 1 above.

1 H NMR (400 MHz, MeOD)? 0.89 (t, J = 6.8 Hz, 3H), 1.28-1.32 (m, 18H), 1.63 (t, J = 7.1 Hz, 2H), 1.76-1.79 ), 2.60 (t, J = 7.6 Hz, 2H), 2.79-2.83 (m, 2H), 3.45 (q, J = 9.4 Hz, 4H), 6.06 (s, 1H); 13 C NMR (100 MHz, MeOD)? 15.26, 22.49, 24.56, 27.59, 30.15, 31.01, 31.19, 31.30, 31.45, 31.55, 31.57, 31.58, 33.77, 33.89, 57.46, 66.97, 102.31, 166.48, 175.99.

< Example  11 > 2-Amino-4- (3- Dodecylisoxazole -5-yl) -2- ( Hydroxymethyl ) Preparation of butyl dihydrogen phosphate (I-12-P)

Figure pat00031

The target compound was prepared in the same manner as in Example 5, except that N-hydroxynaphthalimidoyl chloride was used instead of N-hydroxynonanedimidoyl chloride.

1 H NMR (500 MHz, MeOD ) δ 0.89 (t, J = 6.9 Hz, 3H), 1.32-1.38 (m, 18H), 1.61-1.65 (m, 2H), 2.10 (t, J = 8.8 Hz, 2H ), 2.61 (t, J = 7.6 Hz, 2H), 2.86-2.91 (m, 2H), 3.64-3.70 (m, 2H), 3.92-3.99 (m, 2H), 6.13 13 C NMR (125 MHz, MeOD)? 15.22, 22.28, 27.59, 30.14, 31.01, 31.16, 31.18, 31.26, 31.44, 31.54, 31.56, 33.86, 61.81, 61.87, 63.10, 66.37, 66.40, 102.86, 166.62, 174.07.

< Example  12> 2-Amino-2- (2- (1- Octyl -1H-1,2,3- Triazole Yl) Ethynyl ) Propane-1,3-diol (T-8-TR)

Figure pat00032

The aimed compound was prepared in the same manner as in the reaction procedure of Example 1 except for using 1-azaidoooctane instead of using N-hydroxyundecanimidoyl chloride and step 3 of Example 1 above.

1 H NMR (400 MHz, CDCl 3 )? 0.87 (t, J = 6.7 Hz, 3H), 1.27-1.32 (m, 10H), 1.87-1.90 t, J = 7.3 Hz, 2H), 7.33 (s, 1H).

< Example  13> 2-Amino-2- (2- (1- Octyl -1H-1,2,3- Triazole Yl) ethyl) propane-1,3-diol (T-8)

Figure pat00033

The procedure of Example 1 was repeated, except that 1-azaidoooctane was used instead of N-hydroxyundecanimidoyl chloride to prepare the target compound.

1 H NMR (400 MHz, CDCl 3) δ 0.86 (t, J = 6.8 Hz, 3H), 1.24-1.29 (m, 10H), 1.84-1.91 (m, 4H), 2.48 (br s, 4H), 2.77 (t, J = 7.4 Hz, 2H), 3.54 (q, J = 12.2 Hz, 4H), 4.28 (t, J = 7.2 Hz, 2H), 7.28 (s,

< Example  14> 2-Amino-2 - ((1-decyl-1H-1,2,3- Triazole Yl) Ethynyl ) Propane-1,3-diol (T-10-TR)

Figure pat00034

Instead of using N-hydroxyundecanimidoyl chloride, the objective compound was prepared in the same manner as in the reaction procedure of Example 1 except for using 1-azaidodecane and step 3 of the above-mentioned Example 1.

1 H NMR (400 MHz, CDCl 3 )? 0.88 (t, J = 6.7 Hz, 3H), 1.27-1.32 (m, 14H), 1.87-1.90 t, J = 7.3 Hz, 2H), 7.33 (s, 1H).

< Example  15> 2-Amino-2- (2- (1- (4- Hexylphenethyl ) -1H-1,2,3- Triazole Yl) ethyl) propane-1,3-diol (13)

Figure pat00035

The procedure of Example 1 was repeated except that 1- (2-azaidoethyl) -4-hexylbenzene was used instead of N-hydroxyundecanimidoyl chloride.

< Example  16> 2-Amino-2- (1-butyl-1H-1,2,3- Triazole Yl) propane-1,3- die Manufacturing

Figure pat00036

Substituting bromotriisopropylsilane for the 2-bromo-1-triisopropylsilylacetylene used in Step 1 of Example 1 above and using the N-hydroxyundecanimidoyl chloride of Step 2 The objective compound was prepared in the same manner as in Example 1 except that 1-azidododecane was used instead of 1-azidododecane.

1 H NMR (300 MHz, MeOD)? 0.89 (t, J = 6.7 Hz, 3H), 1.28-1.32 (m, 18H), 1.90-1.92 (m, 2H), 3.89-3.98 (t, J = 7.1 Hz, 2H), 8.07 (s, 1H).

< Example  17> 2-Amino-2- (3- Dodecylisoxazole -5-yl) propane-1,3- Diol  Produce

Figure pat00037

Substituting bromotriisopropylsilane for the 2-bromo-1-triisopropylsilylacetylene used in Step 1 of Example 1 above and using the N-hydroxyundecanimidoyl chloride of Step 2 The procedure of Example 1 was repeated except that N-hydroxytridecanedimidoyl chloride was used instead of N-hydroxytridecanedimidoyl chloride.

< Example  18> (E) -2-Amino-2- (2- (3- Decylisoxazole -5-yl) vinyl) propane-1,3-diol

Figure pat00038

THF (5 mL) solution containing the compound prepared in Step 2 of Example 1 was cooled to -78 ° C., and THF solution (0.3 mmol) in which lithium aluminum hydride (LAH) was dissolved was slowly added dropwise. The reaction was quenched with water after stirring at 0 ° C for three hours and extracted twice with CH 2 Cl 2 . The organic layer was washed with brine, dried and concentrated in the back, a vacuum MgSO 4. The concentrate was purified by flash column chromatography (CH 2 Cl 2 / MeOH, 20: 1) to give the target compound as a white solid. Then, the objective compound was prepared in the same manner as in the step 4 of Example 1. (24 mg, 0.074 mmol, 74%).

1 H NMR (300 MHz, CDCl 3 )? 0.85 (t, J = 6.7 Hz, 3H), 1.23-1.28 (m, 14H), 1.56-1.63 (t, J = 7.5 Hz, 2H), 3.61 (dd, J = 10.6,37.2 Hz, 4H), 5.99 (s, 1H), 6.52 (dd, J = 16.3, 32.4 Hz, 2H).

< Example  (E) -2-amino-2- (1-butyl-1H-1,2,3- Triazole -4-yl) propane-1,3-diol

Figure pat00039

The objective compound was prepared in the same manner as in Example 18, except that 1-azidecane was used instead of N-hydroxyundecanimidoyl chloride.

< Example  20> 2-Amino-2- (2- (3- (8- Phenyloctyl ) - Isoxazole 5-yl) ethyl) propane-1,3-diol

Figure pat00040

The procedure of Example 1 was repeated except that N-hydroxy-9-phenylnonanedimidoyl chloride was used instead of N-hydroxyundecanimidoyl chloride used in Step 2 of Example 1 To give the desired compound.

< Example  21> 2-Amino-2- (2- (1- (8- Phenyloctyl ) -1H-1,2,3- Triazole butyl -4-yl) propane-1,3-diol

Figure pat00041

The procedure of Example 1 was repeated, except that 8-azaido octylbenzene was used instead of N-hydroxyundecanimidoyl chloride used in Step 2 of Example 1 to prepare the desired compound .

< Example  22 > N- (2- (1- Dodecyl -1H-1,2,3- Triazole Yl) -1,3- Dihydroxyphosphate 2-yl) acetamide &lt; / RTI &gt;

Figure pat00042

Acetic anhydride (0.2 mL), MeOH (1 mL) and saturated aqueous NaHCO 3 solution (1 mL) were added to the compound prepared in Example 16 (50 mg, 1 eq, 0.15 mmol) , Concentrated and quenched with aqueous ammonium chloride solution, extracted twice with CH 2 Cl 2 , dried over MgSO 4 and concentrated to yield the desired compound in 98% yield (54 mg, 98% ).

1 H NMR (300 MHz, MeOD ) δ 0.89 (t, J = 6.7 Hz, 3H), 1.28-1.32 (m, 18H), 1.86-1.96 (m, 2H), 2.00 (s, 3H), 4.02 (q , J = 11.2 Hz, 4H), 4.35 (t, J = 7.2 Hz, 2H), 7.84 (s, 1H).

< Example  23 > N- (2- (3- Dodecylisoxazole -5-yl) -1,3- Dihydroxypropane Yl) acetamide &lt; / RTI &gt;

Figure pat00043

Acetic anhydride (0.2 mL), MeOH (1 mL) and saturated aqueous NaHCO 3 (1 mL) were added to the compound prepared in Example 17 (50 mg, 1 eq, 0.15 mmol) The reaction mixture was concentrated and the reaction was quenched with an aqueous solution of ammonium chloride. The reaction mixture was extracted twice with CH 2 Cl 2 , dried over MgSO 4 and concentrated to obtain the target compound in a yield of 94% (52 mg, 94%) without further purification. .

1 H NMR (300 MHz, MeOD ) δ 0.89 (t, J = 6.7 Hz, 3H), 1.22-1.33 (m, 18H), 1.59-1.78 (m, 2H), 1.99 (s, 3H), 2.61 (t J = 7.6 Hz, 2H), 4.01 (q, J = 11.4 Hz, 4H), 6.21 (s, 1H).

< Example  24> N- (4- (1-decyl-1H-1,2,3- Triazole -4-yl) -1-hydroxy-2- ( Hydroxy Methyl) butan-2-yl) acetamide

Figure pat00044

The target compound was prepared by conducting the acetylation reaction in the above Example 22 using the compound prepared in Example 2 as a starting material.

1 H NMR (300 MHz, MeOD)? 0.86 (t, J = 6.8 Hz, 3H), 1.23-1.32 (m, 14H), 1.86-1.92 (m, 2H), 2.47 (m, 2H), 3.62 (dd, J = 11.2,26.9 Hz, 4H), 4.31 (t, J = 7.3 Hz, 2H), 7.31 (s,

< Example  25 > N- (4- (3- Decyl isoxazole -5-yl) -1-hydroxy-2- ( Hydroxymethyl ) Butan-2-yl) acetamide &lt; / RTI &gt;

Figure pat00045

The target compound was prepared by conducting the acetylation reaction in the above Example 23 using the compound prepared in Example 1 as a starting material.

1 H NMR (300 MHz, MeOD)? 0.88 (t, J = 6.7 Hz, 3H), 1.25-1.29 (m, 14H), 1.56-1.61 J = 7.6 Hz, 2H), 2.68 (t, J = 8.3 Hz, 2H), 3.57 (dd, J = 11.0, 31.9 Hz, 4H), 5.83 , 1H).

< Example  26> N- (4- (1- (4- Hexylphenethyl ) -1H-1,2,3- Triazole Yl) -1-hydroxy-2- (hydroxymethyl) butan-2-yl) acetamide

Figure pat00046

The target compound was prepared by performing the acetylation reaction in the same manner as in Example 22 using the compound prepared in Example 15 as a starting material.

< Comparative Example  1> Of FTY720  Ready

Figure pat00047

The chemical structures of the compounds prepared in Examples 1-21 are shown in Table 1 below.

Example Chemical structure Example Chemical structure One

Figure pat00048
14
Figure pat00049
 2
Figure pat00050
 15
Figure pat00051
 3
Figure pat00052
 16
Figure pat00053
 4
Figure pat00054
 17
Figure pat00055
 5
Figure pat00056
 18
Figure pat00057
 6
Figure pat00058
 19
Figure pat00059
 7
Figure pat00060
 20
Figure pat00061
 8
Figure pat00062
 21
Figure pat00063
 9
Figure pat00064
 22
Figure pat00065
 10
Figure pat00066
 23
Figure pat00067
 11
Figure pat00068
 24
Figure pat00069
 12
Figure pat00070
 25
Figure pat00071
 13
Figure pat00072
 26
Figure pat00073

< Experimental Example  1> S1P  Evaluation of the binding activity to the receptor

S1P receptor with respect to (S1P 1 5), experiments were performed as described below in order to assess the degree of binding activity of example compounds of the present invention.

Carried on DiscoveRX (Fremont, USA) used in Example 1, Example 2, Example 4, Example 6 and Example 16, compounds of S1P each subtype receptor (S1P 1 - 5) beta- arrestin analysis the binding activity of the To be tested. At this time, the concentration of the compound of the example was set at 10 μM. The activity results provided by DiscoveRX were expressed as relative percentages (%) of binding activity to S1P subtype receptors (S1P 1-5 ) as shown in Table 2 below.

Analysis target Example 1 Example 2 Example 4 Example 6 Example 16 Comparative Example 1 EDG1 (S1P 1) 246.8% 53.9% 5.8% 19.3% 3% 60.6% EDG5 (S1P 2) 33.9% 5.5% 1.7% 4.7% 0.5% 43% EDG3 (S1P 3) 75.5% 11.3% 6.8% 12.6% 14% 1.0% EDG6 (S1P 4) 84.5% 89% 92.3% 29.2% 65.9% 103% EDG8 (S1P 5) 104.8% 9.1% 10.1% 21.6% 12.3% -

In Table 2,

- indicates that the experiment is not performed.

Table 2 shows that the compound of Example of the present invention has selective binding activity to the receptor of each S1P subtype, and in the case of the compound of Example 1, selective binding activity to S1P1 And in Example 2, Example 4 and Example 16, selective binding activity to S1P4 was confirmed. On the other hand, in the case of Comparative Example 1, it was confirmed that the binding activity for S1P1 and S1P4 was simultaneously exhibited and had non-selective binding activity.

Accordingly, the compounds of the present invention were found to exhibit selective binding activity against S1P1 or S1P4, which is expected to reduce side effects compared to non-selective compounds, and is also useful in diseases for each S1P subtype receptor Can be used.

< Experimental Example  2> S1P1  Receptor Internalization and Recirculation Assessment

The mechanism of action of S1P1 on the phosphorylated compound (FTY720-P) of FTY720 is functional antagonism. That is, in the early stage, S1P1 receptor internalization is induced in the same manner as S1P, which is a biosynthetic ligand. However, as time passes, S1P1 receptor is inhibited from recycling to S1P1 receptor, Lt; / RTI &gt; antagonist.

Therefore, in order to examine whether the non-phosphorylated heterocyclic compound according to the present invention has a functional antagonistic action like FTY720-P, experiments were conducted to evaluate the internalization and recirculation of the S1P1 receptor.

The same experiment was carried out to investigate the mechanism of action of the phosphorylated compound of the heterocyclic compound according to the present invention after binding to the S1P receptor.

Specifically, C6 glioma cells containing EGFP-S1P1 were activated using Example 1 (1 μM) according to the present invention and Example 7 (1 μM) showing the phosphorylated structure thereof, Min, 2 hours, 24 hours). At this time, S1P (1 [mu] M) and FTY720-P (1 [mu] M) were equally compared with each other and compared.

Fig. 1 is a photograph of cell surface photographed at different times by activation of S1P1 receptor with different ligands (S1P, FTY720-P, Example 1 and Example 7).

1, Example 1 and FTY720-P were still observed to have internalized S1P1 receptors 30 minutes to 24 hours after receptor activation, whereas when treated with S1P with Example 7, up to 30 minutes elapsed Receptors were observed to be internalized, and recirculation occurred after 2 hours, indicating that S1P1 was not internalized.

Thus, Example 1 according to the present invention can confirm that the S1P1 receptor is internalized and functions as a functional antagonist by blocking the recycling process as in FTY720-P, whereas Example 7 of the phosphorylated form shows that after S1P1 receptor internalization, , Which causes S1P1 to appear on the cell surface, thereby confirming that it functions as the same agonist as native S1P in vivo.

From this, it can be seen that the non-phosphorylated heterocyclic compound (Example 1) according to the present invention has a functional antagonistic action like FTY720-P, whereas the phosphorylated heterocyclic compound (Example 7) acts as an agent for S1P1 receptor Lt; / RTI &gt;

The present invention shows that the S1P1 receptor mechanism (agonists or functional antagonists) can be selected according to whether the compound according to the present invention is phosphorylated, and thus can be usefully used for diseases related to the S1P1 receptor.

< Experimental Example  3> Evaluation of drug efficacy against multiple sclerosis

The compounds of Example 1 according to the present invention were evaluated for symptoms and efficacy of experimental autoimmune encephalomyelitis (EAE) experimental autoimmune encephalomyelitis in experimental rats (7-8th births).

Specifically, the EAE experiment was performed by preparing a myelin spindle-cell glial cell glycoprotein (MOG) amino acid 35-55 (MEVGWYRSPFSRVVHLYRNGK; Peptron, Republic of Korea, 96% purity) in a laboratory mouse (C57BL / 200 μg (MOG / CFA) was subcutaneously injected as a pertussis toxin (PTX, 400 ng / mouse, ip) with Complete Freund's Adjuvant (CFA) Respectively. The compound of Example 1 (3 mg / kg in 10% Tween 80, po) was injected once a day for 14 days to mice with EAE symptoms after the symptom of the disease reached its peak (after 22 days of antigen challenge) and FTY720 (3 mg / kg, ip) as a positive control, 10% Tween 80 solution (10 mL / kg, pp) in which the compound of Example 1 was dissolved was equally injected into the mice as a negative control. Here, the FTY720 is phosphorylated in vivo and bound to the FTY720-P state before binding to the rat S1P1 receptor.

The mice were weighed daily and the symptoms of the disease were measured and the symptoms of the disease according to progression were shown using the following values (0, healthy state: 1, exhaustion state: 2, weakness of hind limb movement: 3 , Complete paralysis of the hind limb; 4, two leg paralysis; 5, death due to illness). The results are shown in Fig.

FIG. 2A shows the clinical scores obtained by administering the vehicle (10% Tween 80, po), the compound of Example 1 (3 mg / kg, po) or FTY720 (3 mg / kg, po) 2B is a photograph showing dehydrated tissues colored with fluorine myelin, and FIG. 2C is a photograph showing increased cell density colored cresyl violet (FIG. 2B) (Arrow indicates the increased cell density portion), FIG. 2D is a photograph showing an abnormal increase in astrocytosis, and FIG. 2E is a photograph showing microglial cell activation (Iba1-immunoreactive cells).

2A, the clinical score began to decrease from 6 days after administration, and the efficacy was maintained similarly to the administration of FTY 720 (3 mg / kg, ip), and the histopathic sequelae of FIGS. 2B to 2E The pathological phenomenon and the sequelae of the compound of Example 1 were remarkably reduced.

From this, it was confirmed that the compound according to the present invention can prevent or treat multiple sclerosis by effectively reducing nerve damage resulting from multiple sclerosis at a level similar to that of FTY720, and can be used as a drug without phosphorylation, May be useful as pharmaceutical compositions.

< Experimental Example  4> On cerebral ischemia  Evaluation of drug efficacy

The compounds of Example 1 according to the present invention were evaluated for symptoms and efficacy by administering to MCAO (middle cerebral artery occlusion) experimental rat (7-8th day) of middle cerebral artery stenosis / reperfusion (M / R).

MCAO cerebral artery stenosis / reperfusion (M / R) was induced by reperfusion (M / R) in male experimental rats (7th birthday, Orient Co., Ltd) after 90 minutes of MCAO 1.

Specifically, the occlusion was caused by paralysis of the right midbrain artery by inserting a silicone-coated staple fiber (9 mm long 5-0 nylon staple fiber) from the branch of the cerebral artery of the rat, (3 mg / kg, po) or FTY720 (3 mg / kg, po) in the vehicle (10% Tween 80, po) kg, po). After 22 hours of reperfusion, the degree of damage was expressed as a numerical value. Here, the FTY720 is phosphorylated in vivo and bound to the FTY720-P state before binding to the rat S1P1 receptor.

The neurological sequela was first quantified on the basis of the modified neurological severity score scale (mNSS) as follows: The total score for neurological sequelae was 18 points, (Total 6 points), sensory function (total 2 points), balance sensory function (total 6 points), and reflection function (total 4 points).

In addition, brains were removed from rats that had undergone neurological sequelae and stained with 2,3,5-triphenyltetrazolium (TTC), and the infarct volume was measured. Using ImageJ (NIH, Bethesda, MD, USA) Respectively.

The modified neurological severity score scale may be determined by the method described in Chen et al., 2001. Intravenous administration of human umbilical cord blood reduced behavioral deficits after stroke in rats. Stroke, a journal of cerebral circulation 32: 2682-2688. The reported analytical methods were used. The results are shown in Fig. 3 and Fig.

FIG. 3 shows the results of the immediate administration of the compound of Example 1 (3 mg / kg, po) to the experimental rats after reperfusion, and FIGS. 3A and 3B show the volume of the infarcted part of the brain Fig. 3C is a numerical representation of neurological sequelae, and Fig. 3D shows the neuroprotective effect of Example 1 on cerebral ischemia as a change in activated microglial cells (Ibal-positive cell number).

3A and 3B, it can be seen that the volume of cerebral infarction is significantly reduced (infarct volume M / R + veh = 30.91 ± 1.13%, M / R + FTY720 = 18.81 ± 0.96% and M / R + 16.18. + -. 1.11%). FIG. 3C shows that when the compound of Example 1 of the present invention was administered, neurological sequelae were decreased as compared with the untreated group. In FIG. 3D, microcystic activity (Ibal-positive cell number) The neuroprotective effect can be confirmed.

FIG. 4 is a graph showing changes in the degree of neuronal necrosis observed after 22 hours from the administration of the compound of Example 1 (3 mg / kg, po) to the experimental rats after the reperfusion by cortex (Cx) staining through Fluoro-Jade B , and striatum (St). (The above three photographs are 200 ㎛ standard, and the middle and lower photographs are 50 ㎛ standard photograph.

Referring to FIG. 4, it can be confirmed that administration of the compound of Example 1 reduced nerve cell necrosis.

Therefore, the compound of the present invention can effectively treat cerebral ischemia by effectively reducing nerve damage resulting from cerebral ischemia at a level similar to that of FTY720, and can be used as a drug without phosphorylation. Thus, a pharmaceutical composition containing the compound as an active ingredient Can be usefully used.

< Experimental Example  5> Molecular structure studies and ligands S1P  Correlation of receptors

In order to investigate the functional antagonistic action of the heterocyclic compound according to the present invention and the cause of the conversion to an agent such as S1P after phosphorylation, the following experiment was conducted.

Specifically, the antagonist and under ML056 (Protein Data Bank code 3V2Y) exists up the X-ray crystal structure of the S1P 1 to examine the binding portion of protein structure of S1P 1 the binding of agonist compound, an induced fit binding of natural agonists S1P Respectively. The results are shown in Figs. 5 and 6.

Fig. 5 is a figure showing the shape where the different ligands of Example 1 (cyan), Example 7 (blue), S1P (green) and FTY720-P (orange) are located at the binding site of the receptor S1P1.

FIG. 6 is a diagram showing a binding drug molecule structure (Pharmacophore) in which Example 1 (cyan) or FTY720-P (orange) interacts with the S1P1 receptor upon binding.

5, it can be seen that FTY720-P and FTY720-P are located upwards and do not completely occupy the binding portion of the S1P1 receptor. In particular, they maintain a certain distance from the hydrophobic binding portions (Phe125, Ile 203 and Leu276) While the bond is not complete, S1P and Example 7 completely occupy the bond portion of S1P1, indicating that the bond is complete.

6, the terminal phosphate group of FTY720-P was hydrogen bonded to Lys34, Arg120 and Tyr29, and the polarized amino group and hydroxyl group interacted with Glu121, Asn101 and Glu294 to form ionic bonds and hydrogen bonds. However, hydrophobicities of FTY720- Portion occupies a relatively small volume compared to S1P or I-10-P and maintains a certain distance from the hydrophobic binding portion composed of Phe125, Ile 203 and Leu276. In the case of Example 1, even though there is no phosphate group, it has a bonding structure and arrangement similar to FTY720-P. Specifically, since there is no phosphoric acid group, the binding is slightly upward and the amino alcohol group is located. The amino alcohol group acts as the phosphate group of FTY720-P, and the role of the isooxazole ring is the same as the amino group of FTY720-P. In addition, the hydrophobic occupying portion of Example 7 is maintained at a certain distance from the hydrophobic bonding portion similarly to FTY720-P, indicating that bonding is not complete.

Thus, depending on whether the phosphorylation of a compound according to the present invention varies the binding interactions between the ligand and the receptor, it can be seen that changing the shape of the S1P 1 and ultimately changing the internalization of S1P receptors, the recycle tendency.

Claims (10)

Claims 1. A compound represented by the following formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]
Figure pat00074

(In the formula 1,
R 1 is hydrogen or
Figure pat00075
ego;
R 2 is hydrogen or an unsubstituted or substituted C 1-5 straight or branched chain alkylcarbonyl,
Wherein said substituted alkylcarbonyl is substituted with one or more substituents selected from the group consisting of hydroxy, halogen, cyano, nitro, and amino;
A is heteroarylene of pentavalent ring comprising at least one heteroatom selected from the group consisting of N, O and S;
B is C 1-11 linear or branched alkylene;
C is a single bond or C 6-10 arylene;
D is -H, or C 1-15 straight or branched chain alkyl; And
X is a single bond, C 1-5 alkylene, C 2-5 alkenylene or C 2-5 alkynylene.
The method according to claim 1,
R 1 is hydrogen or
Figure pat00076
ego;
R 2 is hydrogen or C 1-3 straight or branched chain alkylcarbonyl;
A is heteroarylene of pentavalent ring comprising at least one heteroatom selected from the group consisting of N, O and S;
B is C 1-9 linear or branched alkylene;
C is a single bond or C 6-10 arylene;
D is -H, or C 3-12 linear or branched alkyl; And
X is a single bond, C 1-3 alkylene, C 2-3 alkenylene or C 2-3 alkynylene, an optical isomer thereof or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
R 1 is hydrogen or
Figure pat00077
ego;
R 2 is hydrogen or acetyl;
A is heteroarylene of pentavalent ring comprising at least one heteroatom selected from the group consisting of N, O and S;
B is C 2-8 alkylene;
C is a single bond or phenylene;
D is -H, or C 6-10 linear or branched alkyl; And
X is a single bond, -CH 2 CH 2 -, compound, its enantiomer or a pharmaceutically acceptable salt thereof, characterized in that -CH = CH- or -C≡C-.
The method according to claim 1,
The compound represented by the formula (1) is any one selected from the group consisting of the following compounds, an optical isomer thereof or a pharmaceutically acceptable salt thereof:
(1) 2-Amino-2- (2- (3-decylisoxazol-5-yl) ethyl) propane-1,3-diol;
(2) 2-Amino-2- (2- (1-decyl-1H-1,2,3-triazol-4-yl) ethyl) propane-1,3-diol;
(3) 2-Amino-2 - ((3-octylisoxazol-5-yl) ethynyl) propane-1,3-diol;
(4) 2-Amino-2- (2- (3-octylisoxazol-5-yl) ethyl) propane-1,3-diol;
(5) 2-Amino-2- (hydroxymethyl) -4- (3-octylisooxazol-5-yl) butyl dihydrogen phosphate;
(6) 2-Amino-2 - ((3-decylisoxazol-5-yl) ethynyl) propane-1,3-diol;
(7) 2-Amino-4- (3-decylisoxazol-5-yl) -2- (hydroxymethyl) butyl dihydrogen phosphate;
(8) 2-Amino-2- (2- (3- (4-hexylphenethyl) isooxazol-5-yl) ethyl) propane-1,3-diol;
(9) 2-Amino-2 - ((3-dodecylisoxazol-5-yl) ethynyl) propane-1,3-diol;
(10) 2-Amino-2- (2- (3-dodecylisoxazol-5-yl) ethyl) propane-1,3-diol;
(11) 2-Amino-4- (3-dodecylisoxazol-5-yl) -2- (hydroxymethyl) butyl dihydrogen phosphate;
(12) 2-Amino-2- (2- (1-octyl-1H-1,2,3-triazol-4-yl) ethynyl) propane-1,3-diol;
(13) 2-Amino-2- (2- (1-octyl-1H-1,2,3-triazol-4-yl) ethyl) propane-1,3-diol;
(14) 2-Amino-2 - ((1-decyl-1H-1,2,3-triazol-4-yl) ethynyl) propane-1,3-diol;
(15) 2-Amino-2- (2- (1- (4-hexylphenylethyl) -1H-1,2,3-triazol-4-yl) ethyl) propane-1,3-diol;
(16) 2-Amino-2- (1-butyl-1H-1,2,3-triazol-4-yl) propane-1,3-diol;
(17) 2-Amino-2- (3-dodecylisoxazol-5-yl) propane-1,3-diol;
(18) (E) -2-Amino-2- (2- (3-decylisoxazol-5-yl) vinyl) propane-1,3-diol;
(19) (E) -2-Amino-2- (1-butyl-1H-1,2,3-triazol-4-yl) propane-1,3-diol;
(20) 2-Amino-2- (2- (3- (8-phenyloctyl) -isooxazol-5-yl) ethyl) propane-1,3-diol;
(21) 2-Amino-2- (2- (1- (8-phenyloctyl) -1H-1,2,3-triazolobutyl-4-yl) propane-1,3-diol;
(22) N- (2- (1-Dodecyl-1H-1,2,3-triazol-4-yl) -1,3-dihydroxypropan-2-yl) acetamide;
(23) N- (2- (3-Dodecylisoxazol-5-yl) -1,3-dihydroxypropan-2-yl) acetamide;
(24) N- (4- (1-decyl-1H-1,2,3-triazol-4-yl) -1-hydroxy-2- (hydroxymethyl) butan-2-yl) acetamide;
(25) N- (4- (3-decylisoxazol-5-yl) -1-hydroxy-2- (hydroxymethyl) butan-2-yl) acetamide; And
(26) Synthesis of N- (4- (1- (4-hexylphenethyl) -1H-1,2,3-triazol-4-yl) -1-hydroxy- 2- (hydroxymethyl) Yl) acetamide.
As shown in Scheme 1 below,
Reacting a compound represented by the formula (2) with a compound represented by the formula (3) to prepare a compound represented by the formula (4) (step 1);
Reacting the compound represented by the formula (4) and the compound represented by the formula (5) prepared in the step 1 to prepare a compound represented by the formula (6) (step 2); And
A process for preparing a compound represented by the general formula (1) as set forth in claim 1, comprising the step of removing the protecting group of the compound represented by the formula (6) prepared in the step 2 to prepare a compound represented by the formula (1)
[Reaction Scheme 1]
Figure pat00078

(In the above Reaction Scheme 1,
R 1 , R 2 , X, A, B, C, and D are as defined in Formula 1 of Claim 1;
m is an integer of 0 or 1;
R 3 is
Figure pat00079
Or -N 3, and;
-TIPS
Figure pat00080
ego; And
-Boc
Figure pat00081
to be).
As shown in Reaction Scheme 2 below,
A step of hydrogenating the compound of formula (6a) to prepare a compound of formula (6b) (step 1); And
A process for preparing a compound represented by the general formula (1) as set forth in claim 1, comprising the step of removing the protecting group of the compound represented by the formula (6b) prepared in the step 1 to prepare a compound represented by the formula (1a)
[Reaction Scheme 2]
Figure pat00082

(In the above Reaction Scheme 2,
R 2 , A, B, C, D and -Boc are as defined in formula 1 of claim 1;
The compounds represented by formulas (6a) and (6b) are included in the compound represented by formula (6) of claim 5; And
The compound represented by the formula (Ia) is included in the compound represented by the formula (1) of the fifth aspect.
A pharmaceutical composition for preventing or treating diseases related to S1P receptor (sphingosine 1-phosphate receptors) containing the compound represented by the formula (1) of claim 1, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
8. The method of claim 7,
The S1P receptor-related diseases are selected from the group consisting of multiple sclerosis, ischemic stroke, intracerebral hemorrhage, traumatic brain injury, spinal cord injury, systemic lupus erythematosus, SLE), psoriasis, polymyositis, active dermatomyositis, hematological malignancies, Alzheimer's disease, Parkinson's disease, Lou Gehrig's disease, Huntington's disease, Creutzfeldt Jakob disease, (MMN) or paraproteinemic dehydration (MMN), which are associated with chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, Gilang-Barre syndrome (PDN). &Lt; / RTI &gt;
A health functional food for improving S1P receptor-related diseases containing the compound represented by the general formula (1) of claim 1, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
10. The method of claim 9,
The S1P receptor-related diseases are selected from the group consisting of multiple sclerosis, ischemic stroke, intracerebral hemorrhage, traumatic brain injury, spinal cord injury, systemic lupus erythematosus, SLE), psoriasis, polymyositis, active dermatomyositis, hematological malignancies, Alzheimer's disease, Parkinson's disease, Lou Gehrig's disease, Huntington's disease, Creutzfeldt Jakob disease, (MMN) or paraproteinemic dehydration (MMN), which are associated with chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, Gilang-Barre syndrome (PDN). &Lt; / RTI &gt;
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WO2019212196A1 (en) * 2018-04-30 2019-11-07 경북대학교 산학협력단 2-amino-2-(1,2,3-triazole-4-yl)propane-1,3-diol derivative of novel compound for directly inhibiting asm activity, and use thereof
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