KR100380520B1 - β-Aminoalcohol derivatives with pyridine substituents - Google Patents

Abstract

The present invention relates to a β-aminoalcohol derivative including pyridine, a pharmaceutically acceptable salt thereof, and a preparation method thereof, wherein the β-aminoalcohol derivative including pyridine, represented by the following Chemical Formula 1, has a high hypoglycemic effect and weight It can be used as a therapeutic agent for hyperglycemia-related diseases and obesity because it reduces.

Wherein A, R, Y and G are as described in the specification.

Description

Β-aminoalcohol derivatives with pyridine substituents

The present invention relates to β-aminoalcohol derivatives including pyridine and pharmaceutically acceptable salts thereof, and to the β-aminoalcohol derivatives including pyridine, represented by the following general formula (1) showing lipolysis and hypoglycemic effect, It relates to an acceptable salt thereof, a preparation method thereof, and a pharmaceutical composition comprising the compound of formula 1 as an active ingredient.

Formula 1

In the above formula,

A is phenyl substituted or unsubstituted with a halogen element or haloalkyl group; Thiophene; Phenyloxymethyl; Naphthyloxymethyl; Or a biphenyloxymethyl group,

R represents hydrogen or an alkyl group of C _1-4 ,

Y represents methylene or oxygen,

G is hydrogen; Halogen element; C _1-3 alkyl; Alkoxy; Amino; Cyano; Urea substituted with phenyl group; Carboxamide in which phenyl or C _1-3 alkyl group is substituted; Carboxyl esters; Alkoxycarbonylmethyloxy; Alkoxycarbonylalkyl group; One or more substituents selected from the group consisting of alkoxycarbonylacryl and tetrazole groups,

Compounds of formula (I) include all optical isomers.

Currently, the treatment of type 2 diabetes and obesity is known to be effective treatment with diet and exercise to reduce weight and improve insulin sensitivity. However, patients do not follow well, and drugs that can effectively treat type 2 diabetes or obesity are not known.

The protein sequence of the β ₃ -adrenergic receptor was discovered in the late 80s, and recently, it has been shown that the β ₃ -adrenergic receptor can be stimulated to control weight loss as well as hyperglycemia. β ₃ -adrenergic receptors are known to be distributed in white adipocytes and brown adipocytes and act to help break down fat or generate heat. Therefore, many research results related to the development of β ₃ -adrenergic receptor anti-inflammatory drugs have been published, and the anti-inflammatory drugs have a clear effect on blood glucose control in experimental animals showing lipolysis, heat generation and type 2 diabetes. However, there is still a need for an excellent antidepressant due to its poor efficacy and selectivity.

The biggest drawback of the beta ₃ -adrenergic agonist is that it exhibits side effects by stimulating other β-receptors, i.e., the β ₁ -adrenergic receptor involved in the heartbeat, and the β ₂ -adrenergic receptor involved in the relaxation of smooth muscle. Early development of β ₃ -adrenergic receptors is represented by USP 4,478,849 and phenylethanolamine derivatives published in USP 4,396,627. Published in 455006. On the other hand, as a result of efforts to develop a compound that selectively acts on the β ₃ -adrenergic receptor through modification of various heterocyclic compounds, JP 98007647, JP 98158233, WO 9832742, EP 822185, JP 98007647, etc. Was released.

WO 9803485 discloses that in Formula 1, A is o -alkylphenyloxymethyl; R is hydrogen; Y is 2-amino or 2-methylamino; A β-aminoalcohol compound wherein G is hydrogen or a 5-position electron attractant is known, and Japanese Patent Laid-Open No. 96-165276 discloses that A is phenyl substituted with a halogen or a trifluoromethyl group at the 3-position; There is no Y; Pyridyl ethylamine derivatives in which G has been substituted with hydrogen, halogen, lower alkyl, or lower alkoxy have been reported.

In the present invention, new β-aminoalcohol derivatives including pyridine represented by Chemical Formula 1 were synthesized, and these compounds were found to bind with the β ₃ -adrenergic receptor to reduce blood sugar and weight, thereby completing the present invention.

An object of the present invention is a β-aminoalcohol derivative including pyridine, a pharmaceutically acceptable salt thereof, a preparation method thereof, and a compound represented by the formula (1), represented by the formula (1), which exhibits lipolytic and hypoglycemic effect. To provide a composition.

Figure 1 shows the blood glucose level change of the experimental rat to which the compound according to the invention was administered,

Figure 2 shows the weight change of the experimental rat administered the compound according to the present invention.

In order to achieve the above object, the present invention provides a β-aminoalcohol derivative including a pyridine represented by the following formula (1) and a pharmaceutically acceptable salt thereof.

Formula 1

In the above formula,

A is phenyl substituted or unsubstituted with a halogen element or haloalkyl group; Thiophene; Phenyloxymethyl; Naphthyloxymethyl; Or a biphenyloxymethyl group,

R represents hydrogen or an alkyl group of C _1-4 ,

Y represents methylene or oxygen,

G is hydrogen; Halogen element; C _1-3 alkyl; Alkoxy; Amino; Cyano; Urea substituted with phenyl group; Carboxamide in which phenyl or C _1-3 alkyl group is substituted; Carboxyl esters; Alkoxycarbonylmethyloxy; Alkoxycarbonylalkyl group; One or more substituents selected from the group consisting of alkoxycarbonylacryl and tetrazole groups,

Compounds of formula (I) include all optical isomers.

Preferably, in the formula

A is phenyl optionally substituted with fluorine or chlorine; Or phenyloxymethyl,

R is hydrogen or a methyl group,

Y represents methylene,

G represents cyano, or carboxyl ester, and these compounds of formula (I) include all of the optical isomers.

Β-aminoalcohol derivatives including the pyridine of the present invention represented by the formula (1) may be used in the form of a pharmaceutically acceptable salt, and salts include acid addition salts formed by pharmaceutically acceptable free acid. useful. Inorganic acids and organic acids can be used as the free acid. Hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, etc. may be used as the inorganic acid, and citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, gluconic acid, methanesulfonic acid, glyconic acid, succinic acid, 4-toluene Sulfonic acid, gluturonic acid, embonic acid, glutamic acid, aspartic acid and the like can be used. The compound of formula 1 may also be a pharmaceutically acceptable metal salt, in particular an alkali metal salt, formed due to the base. Examples of these are sodium salts and potassium salts.

The present invention also provides a method for preparing β-aminoalcohol derivative including pyridine having various substituents introduced at various positions.

Specifically, the present invention provides a method for preparing β-aminoalcohol derivative (I) comprising pyridine of formula (1), represented by Scheme 1 below. ( Manufacturing Method Ⅰ )

Wherein A, R, Y and G are as defined above.

Compound (I) of the present invention is obtained by condensation of a compound of formula (II) with a compound of formula (III) and reduction reaction using an organometallic catalyst. In the present invention, the compound of formula 1 may also be prepared as each pure optical isomer by using amino alcohol derivatives which are each pure optical isomer as starting materials.

In addition, the present invention provides another method for preparing β-aminoalcohol derivative (I) containing pyridine, represented by the following Scheme 2. ( Manufacturing Method Ⅱ )

Wherein A and G are as previously mentioned, X is a halogen, Z is hydrogen, Y is oxygen, and R is hydrogen.

Compound (I) of the present invention can also be obtained by introducing an aminoethoxy group into 2-fluoropyridine and reacting with an epoxide followed by introducing a cyano group or a carboxyl ester group.

Hereinafter, the preparation method of Chemical Formula 1 according to the present invention will be described in more detail.

I. Preparation of Starting Material

(1) Preparation of Pyridine Compound (II)

The compound of formula (II) used as a starting material in Scheme 1 may be prepared as in Scheme 3 below.

In the above formula, G, R, Y and X are as mentioned above.

Ketones or aldehyde compounds of formula (II) are prepared by reacting a compound having a variety of double bonds with a pyridine halide derivative under a palladium catalyst.

Starting materials containing the pyridine are readily available commercially, trifluorosulfonyl (-OSO ₂ ) by reaction of a compound having a hydroxy group with CF ₃ SO ₂ Cl or (CF ₃ SO ₂ ) ₂ O Aromatic compounds having CF ₃ ) groups can be easily synthesized by known methods [ Bull. Chem. Soc. Jpn ., 1988 , 61 , 455-459.

Pyridine halide (I, Br, CF ₃ SO ₂ O) derivatives, various allyl alcohols, trimethylsilyl enol ethers, tin enolates or enol acetates When reacted under a palladium catalyst, compound (II) substituted with ketones or aldehydes at various positions of pyridine can be easily synthesized [(1) Palladium reagents and catalysts: innovations in organic synthesis, Tsuji, 1995 , John Wiley Sons Ltd ; (2) Palladium reagents in Organic Syntheses, RF Heck, 1987 , Academic Press, Inc .; (3) Chem. Lett , 1978 , 975-978]

(2) Preparation of β-amino Alcohol Derivative (III)

The compound of formula (III) used as a starting material in Scheme 1 may be prepared as in Scheme 4 below.

β-aminoalcohol compound (III) synthesizes 1,2-azido alcohol derivatives through the reaction of NaN ₃ with epoxide compounds substituted with various aromatic compounds, and organometals such as palladium, platinum, nickel or LiAlH ₄ , It can be easily synthesized using a known method of reduction reaction using NaBH ₄ , NaBH ₃ CN and the like [(1) Maurice Caron, KB Sharpless, J. Org. Chem, 1985 , 50 , 1557 .; (2) Compreheusive Organic Trans Formations by Richard C. Larock Second Edition].

Alternatively, compound (III), which is a desired β-amino alcohol derivative, can be easily prepared by reacting an aldehyde compound having an aromatic compound with (CH ₃ ) ₃ SiCN followed by a reduction reaction.

Optically active aminoalcohols can be obtained from optically active epoxides using known methods, and can also be prepared by purchasing pure optical isomers ( R )-(+)-3-chlorostyrene oxide and the like. [(1) Janice M. Klunder, Tetsuo Onami, and K. Barry Sharpless J. Org. Chem . 1989 , 54 , 1295-1304 .; (2) JACS 1979 , 101 , 3666.

II. Manufacturing Method Ⅰ

The compound of the present invention is condensation reaction of compound (II) substituted with ketone or aldehyde at various positions of pyridine and compound (III) which is β-amino alcohol derivative in a solvent such as benzene and toluene to synthesize imine, When the reaction is carried out under hydrogen of 1-4 atm using a solvent such as methanol or ethanol using a metal catalyst such as palladium, platinum or nickel, the compound of formula (I) can be easily prepared. In the condensation reaction, it is preferable to carry out by removing water using Dean-Stark or Molecular Sieve.

III. Synthesis and Separation of Pure Optical Isomers

Enantiomers and diastereomers of compound (I) of the present invention can be stereoselectively synthesized using known optically pure compounds. That is, it can synthesize | combine using the ketone or the aldehyde compound containing amino alcohol and pyridine synthesize | combined from the optically active epoxide.

The optical isomer can be separated by a general method, an acid having optical activity can be used as a separating agent, or a stereoselective compound can be separated by making a chloride using a common acid and crystallizing it. Topics in Stereochemistry, Vol. 6, Wiley Interscience, 1971, Allinger, N. L. and Eliel, W. L,. Eds.]

In addition, β-aminoalcohol derivatives including pyridine obtained from optically active aminoalcohols were treated with di- tert -butyl dicarbonate (Boc ₂ O) as shown in Scheme 5 below to synthesize Boc derivatives, followed by column chromatography. This can be obtained by separating the diastereomers of the aminoalcohol derivatives and removing the Boc protecting group.

Wherein A, R ₁ , Y and G are as previously mentioned and * denotes an optically pure asymmetric carbon.

The present invention provides a pharmaceutical composition for treating endocrine diseases, including diabetes, obesity, hyperinsulinemia using the compound of claim 1 as an active ingredient as an active ingredient.

Preferred compounds of the present invention selectively bind to β ₃ -adrenergic receptors up to 74 times stronger than known compounds BRL 35135, up to 59 times stronger than CL316243, and most compounds are about 0.6-1.2 times greater than BRL 35135 Lipolytic effect was shown. In addition, when the compound of the present invention was administered to experimental rats showing diabetes and obesity symptoms, blood glucose and weight were observed, and it was found that up to 85% of fat was broken down.

By using the compound represented by the formula (1), pharmaceutically acceptable salts, esters, or amides, solvents that can be used pharmaceutically and the like can be used as an effective hyperglycemic and obesity treatment particularly effective in humans or animals.

Pharmaceutical compositions of the compounds of the present invention may be administered in a variety of oral and parenteral formulations during clinical administration, but oral administration is most suitable. Possible compositions for oral administration are suitable for tablets, capsules and powders.

In addition, parenteral administration is possible by vascular administration, and non-aqueous solvents and suspensions may be added as preparations for parenteral administration, for example, vegetable oils such as propylene glycol, polyethylene glycol, olive oil, ethyl Injectable esters such as oleate and the like can be used.

Carriers for making conventional drugs include cellulose, starch, starch glycollate sodium salt, polyvinylpyrrolidone, polyvinylpyrrolidone, magnesium stearate, or Sodium lauryl sulphate and the like can be used.

Preferably, the effective daily dose of 70 Kg of adults is 0.1-1000 mg and more preferably 2-100 mg.

As a result of the toxicity test when the compound of the present invention is administered orally to the mouse, the 50% lethal dose (LD ₅₀ ) by the oral toxicity test was found to be at least 1000 mg / kg or more it can be seen that the compound of formula 1 is a safe compound.

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

However, the following examples are merely to illustrate the content of the present invention is not limited to the scope of the present invention.

Starting materials (II) and (III) were prepared through the following preparations.

I. Preparation of Starting Material

<Manufacture Examples 1 to 33> Preparation of Ketones or Aldehyde (II) Including Pyridine

Ketones or aldehydes (II) containing pyridine were synthesized by the following method and the results of compound identification analysis are shown in Table 1 .

Pyridine (10 mmol) substituted with halogen (I or Br), lithium chloride (10 mmol), 5 mol% palladium acetate, KOAc (20 mmol) and 1-buten-3-ol or allyl alcohol (20 mmol) Add to a pressure bottle and react for 5-6 hours at 100 ^o C in dimethylformaldehyde (DMF, 15 ml) solvent and use column chromatography to obtain approximately 60% of the three carbon-linked aldehyde or ketone derivatives from pyridine. Obtained in the yield.

Production Example R Y Substitution position of Y G ¹ H NMR (CDCl ₃ , 200 MHz) δ MS ( m / e ) One H CH ₂ 3 5-CO ₂ Me 9.60 (s, 1H), 9.05 (s, 1H), 8.60 (s, 1H), 8.10 (s, 1H), 3.90 (s, 3H), 3.10-2.80 (m, 4H); 77 (100), 103 (24), 120 (43), 132 (45), 161 (91), 193 (27). 193 (27), 161 (91), 132 (45), 120 (43), 103 (24), 77 (100), 51 (73) 2 Me CH ₂ 3 5-CO ₂ Me 9.05 (s, 1H), 8.60 (s, 1H), 8.10 (s, 1H), 3.95 (s, 3H), 3.00-2.75 (m, 4H), 2.15 (s, 3H). 43 (80), 63 (22), 92 (18), 160 (100), 162 (13), 193 (5) 3 Me CH ₂ 3 2-F 8.10 (d, 1H, J = 4.8 Hz), 7.65 (m, 1H), 7.17 (m, 1H), 2.90 (m, 4H), 2.25 (s, 3H) - 4 Me CH ₂ 3 2-OMe 8.02 (dd, 1H, J = 5.0, 1.9 Hz), 7.41 (dd, 1H, J = 7.0, 1.9 Hz), 6.80 (dd, 1H, J = 7.1, 5.0 Hz), 3.95 (S, 3H), 2.15 (s, 3H), 2.70-2.88 (m, 4H) - 5 H O 2 3-I δ 8.10 (m, 2H), 6.65 (m, 1H), 4.35 (t, J = 5.2 Hz), 3.15 (t, J = 5.2 Hz), 2.15 (brs, 2H) - 6 Me CH ₂ 3 2-OCH ₂ CO ₂ Me 7.96 (dd, 1H, J = 5.0, 1.8 Hz), 7.47 (dd, 1H, J = 7.0, 1.8 Hz), 6.85 (dd, 1H, J = 7.0, 5.0 Hz), 4.96 (s, 2H), 3.77 (s, 3H), 2.84-2.90 (m, 4H), 2.15 (s, 3H) 237 (M ⁺ , 8), 206 (7), 193 (23), 162 (17), 134 (37), 122 (38), 104 (33), 92 (19), 77 (18) 7 Me CH ₂ 3 5-CONH (3-F-Ph) 8.88-8.87 (m, 2H), 8.53 (1H), 8.01 (1H), 7.55 (m, 1H), 7.35-7.25 (m, 2H), 6.88-6.80 (m, 1H), 2.95-2.75 (m, 4H), 2.12 (s, 3H). - 8 Me CH ₂ 5 2-CO ₂ Me 8.59 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 8.1 Hz, 1H), 7.69 (d, J = 8.1 Hz, 1H), 4.00 (s, 3H), 2.96 (m, 2H), 2.84 (m, 2 H), 2.16 (s, 3 H). 208 (26.7, M ⁺ +1), 177 (19.7), 149 (100) 9 Me CH ₂ 3 5-CO ₂ Et 1.41 (t, 3H, J = 7.1 Hz), 2.17 (s, 3H), 2.82-2.98 (m, 4H), 4.41 (q, 2H, J = 7.1 Hz), 8.12 (d, 1H, J = 2.0 Hz ), 8.62 (d, 1H, J = 2.2 Hz), 9.06 (d, 1H, J = 2.0 Hz). -

Production Example R Y Substitution position of Y G 10 H CH ₂ 3 H 11 H CH ₂ 4 H 12 H CH ₂ 4 3-CN 13 H CH ₂ 4 2-CO ₂ Me 14 Me CH ₂ 3 H 15 Me CH ₂ 4 H 16 Me CH ₂ 3 2-Cl 17 Me CH ₂ 2 6-Me 18 Me CH ₂ 3 4-OMe 19 Me CH ₂ 5 2-OMe 20 Me CH ₂ 3 2-CN 21 Me CH ₂ 4 2-CN 22 Me CH ₂ 5 2-CN 23 Me CH ₂ 3 2-Cl-6-CN 24 Me CH ₂ 3 4-OMe-2-CN 25 Me CH ₂ 5 4-OMe-2-CN 26 Me CH ₂ 5 2-NHCOCH ₃ 27 Me CH ₂ 5 2-NHCONHPh 28 Me CH ₂ 5 2-OCH ₂ CO ₂ Me 29 Me CH ₂ 3 2- (2-Me-tetrazol-5-yl) 30 H O 2 3-CH = CHCO ₂ Me 31 H O 2 3-CH = CHCO ₂ Et 32 H O 2 3-CH ₂ CH ₂ CO ₂ Me

In addition, ketones, aldehydes or amines including pyridine used as starting materials can be synthesized by various methods as follows.

Preparation Example 33 Preparation of 2- (3-iodo-2-oxopyridin) ethylamine

Ethanolamine (2 g, 32 mmol) was dissolved in 40 mL of tetrahydrofuran and sodium (750 mg, 32 mmol) was added to reflux to dissolve sodium. At this time, 2-fluoro-3-iodopyridine (2.24 g, 10 mmol) was added to reflux for 12 hours, the reaction product was removed, and then separated by column chromatography to obtain 2- (3-iodo-2-oxypyridine) ethylamine. (1.3 g, 5 mmol, 50%) was obtained.

¹ H NMR (CDCl ₃ , 200 MHz) δ 8.10 (m, 2H, ArH), 6.65 (m, 1H, ArH), 4.35 (t, J = 5.2 Hz, OCH ₂ ), 3.15 (t, J = 5.2 Hz ), 2.15 (brs, 2H, NH ₂ ).

Preparation 34 Preparation of 3- (2-fluoro-3-pyridyl) propanal

Dissolve CuCl (100 mg) and PdCl ₂ (56 mg) in 2 mL of dimethylformaldehyde, add 0.2 mL of water, allow oxygen to pass through, and add 2-fluoro-3-allylpyridine (134 mg) at room temperature. The reaction was carried out in the presence of oxygen for 20 hours. The reaction mixture was diluted with HCl, extracted with ethyl acetate, and separated by column chromatography to give 1- (2-fluoro-3-pyridyl) acetone and 3- (2-fluoro-3-pyridyl) propanal. A ratio of ¹ was obtained ( ¹ H NMR).

¹ H NMR (CDCl ₃ ) δ 9.80 (s, 1H, CHO), 8.10 (d, J = 4.8 Hz, 1H, ArH), 7.65 (t, J = 8.2 Hz, 1H, ArH), 7.10 (t, J = 8.2 Hz, 1H, ArH), 2.90 (m, 4H, -CH ₂ ).

Preparation Example 35 Preparation of 4- (2-methoxy-3-pyridyl) -2-butanone

Dissolve 4- (2-fluoro-3-pyridyl) -2-butanone (0.5 g, 3 mmol) and 99% sodium methoxide (0.39 g, 7.2 mmol) in methanol (10 ml) and in a pressure tube ( pressure bottle) was heated to 160 ° C. for 4 hours. The reaction mixture was cooled to room temperature, extracted with ethyl acetate, and separated by column chromatography to obtain the desired compound (150 mg).

¹ H NMR (CDCl ₃ ) δ 8.02 (dd, J = 5.0, 1.9 Hz, 1H), 7.41 (dd, J = 7.0, 1.9 Hz, 1H), 6.80 (dd, J = 7.1, 5.0 Hz, 1H), 2.15 (s, 3 H), 2.70-2.88 (m, 4 H).

Preparation 36 Preparation of Methyl (3-iodopyridin-2-yloxy) Acetate

Sodium was added to (0.9 g) methyl glycolate (15 g) and refluxed for 30 minutes, to which 2-fluoro-3-iodopyridine was added (2.3 g) and refluxed at 150 ^° C. for 7 hours. After cooling the reaction mixture was extracted with methylene chloride and separated by column chromatography to give the target compound of the yellow oil (2.32 g, yield = 77%).

¹ H NMR (CDCl ₃ ) δ 8.02-8.05 (m, 2H), 7.67 (dd, J = 6.6, 5.7 Hz, 1H), 4.91 (s, 2H), 3.74 (s, 3H); MS ( m / e ) 293 (M ^&lt; ^{+ &gt;} , 30), 262 (15), 234 (100), 204 (29).

Preparation Example 37 Preparation of Methyl [3- (3-oxobutyl) pyridin-2-yloxy] acetate

Methyl (3-iodopyridin-2-yloxy) acetate (0.87 g, 2.9 mmol), 3-buten-2-ol (0.5 g, 7.3 mmol), lithium chloride (0.26 g, 3 mmol), potassium acetate (0.6 g, 6 mmol) was suspended in dimethylformaldehyde (15 ml) solvent and heated at 150 ° C. for 5 hours under a palladium acetate (30 mg) catalyst. The reaction mixture was cooled, extracted with ethyl acetate, and separated by column chromatography to obtain the title compound (0.46 g, yield = 65%) as a colorless oil.

¹ H NMR (CDCl ₃ ) δ 7.96 (dd, J = 5.0, 1.8 Hz, 1H), 7.47 (dd, J = 7.0, 1.8 Hz, 1H), 6.85 (dd, J = 7.0, 5.0 Hz, 1H), 4.96 (s, 2H), 3.77 (s, 3H), 2.84-2.90 (m, 4H), 2.15 (s, 3H); MS ( m / e ) 237 (M ⁺ , 8), 206 (6), 193 (22), 162 (17), 134 (36), 122 (38), 104 (33), 92 (18), 77 (18), 43 (100).

Preparation Example 38 Preparation of 4- (2-amino-5-pyridyl) -2-butanone

2-amino-5-iodopyridine (1.98 g, 9 mmol), 3-buten-2-ol (1.558 g, 21.6 mmol), lithium chloride (381.5 mg, 9 mmol), potassium acetate (1767 mg, 18 mmol ) And palladium acetate (101 mg, 5 mmol%) were added to dimethylformaldehyde (20 mL) and reacted at 120 ° C. for 4 hours. The reaction mixture is cooled, extracted with methylene chloride, the organic layer is dried over anhydrous magnesium sulfate, the solvent is removed under reduced pressure, and then the column chromatography (developed with CH ₂ Cl ₂ : ethyl acetate: MeOH = 6: 4: 1) The desired compound (yield; 660 mg, 45%) was isolated.

¹ H NMR (CDCl ₃ , 200 MHz) δ 7.89 (s, 1H), 7.75-7.30 (m, 1H), 6.42-6.47 (m, 1H), 3.20-4.80 (br, 2H), 2.66-2.79 (m , 4H), 2.14 (s, 3H); MS ( m / e ) 166 (M ⁺⁺ 2H, 2), 165 (M ⁺⁺ H, 19), 164 (M ⁺ , 53), 149 (M ⁺ −CH ₃ , 5), 121 (13), 107 (100)

Preparation Example 39 Preparation of 5- (2-oxopropyl) nicotinic acid methyl ester

5-bromonicotinic acid methyl ester (1.08 g, 4.90 mmol), isopropenyl acetate (0.90 mg, 9 mmol), tributyltin methoxide (2.25 g, 7.02 mmol) dichlorobisiso-o-tolyl palladium ( 560 mg, 15 mol%) was added to anhydrous toluene (60 mL), followed by stirring at room temperature for 1 hour, refluxing again for 24 hours, and then removing the solvent under reduced pressure, followed by column chromatography (ethyl acetate: hexane = 1: 10 to 10). 1: 5 to 1: 1), and then recrystallized with diethyl ether and hexane to separate the target compound (0.39 g, 40%).

^OneH NMR (CDCl₃, 200 MHz) δ 8.59-8.60 (m, 1H), 8.14-8.15 (m, 1H), 3.96 (s, 3H), 3.82 (s, 3H), 2.28 (s, 3H); MS (m / e) 195 (M⁺+ 2H, 1), 194 (M⁺+ H, 11), 193 (M⁺, 5), 162 (8), 151 (100)

II. Preparation of β-aminoalcohol (I) containing pyridine

Compounds of Formula 1 were synthesized by the following examples, and the synthesized compounds are shown in Table 2 .

Example A R Y Substitution position of Y G Remarks One Ph H CH ₂ 3 H 2 Ph-3-Cl H CH ₂ 3 H 3 CH ₂ OPh H CH ₂ 3 H 4 CH ₂ O-1-Naph H CH ₂ 3 H 5 Ph H CH ₂ 4 H 6 Ph H CH ₂ 4 3-CN 7 Ph H CH ₂ 4 2-CO ₂ Me 8 Ph-3-Cl H CH ₂ 4 2-CO ₂ Me 9 Ph H CH ₂ 3 5-CO ₂ Me 10 Ph-3-F H CH ₂ 3 5-CO ₂ Me 11 Ph-3-Cl H CH ₂ 3 5-CO ₂ Me 12 5-Cl-2-thienyl H CH ₂ 3 5-CO ₂ Me 13 Ph-3-Cl Me CH ₂ 3 H 14 CH ₂ OPh Me CH ₂ 3 H 15 Ph Me CH ₂ 4 H 16 Ph-3-Cl Me CH ₂ 4 H 17 CH ₂ OPh Me CH ₂ 4 H 18 CH ₂ O-1-Naph Me CH ₂ 4 H 19 CH ₂ OPh Me CH ₂ 3 2-F 20 CH ₂ OPh Me CH ₂ 3 2-F 21 Ph Me CH ₂ 3 2-Cl 22 Ph-3-Cl Me CH ₂ 3 2-Cl 23 CH ₂ OPh Me CH ₂ 3 2-Cl 24 CH ₂ OPh Me CH ₂ 2 6-Me 25 Ph-3-Cl Me CH ₂ 3 2-OMe 26 CH ₂ OPh Me CH ₂ 3 2-OMe 27 CH ₂ OPh Me CH ₂ 5 2-OMe 28 CH ₂ OPh Me CH ₂ 3 4-OMe 29 Ph Me CH ₂ 3 2-CN 30 Ph-3-Cl Me CH ₂ 3 2-CN

Example A R Y Substitution position of Y G Remarks 31 CH ₂ OPh Me CH ₂ 3 2-CN 32 Ph-3-Cl Me CH ₂ 4 2-CN 33 CH ₂ OPh Me CH ₂ 4 2-CN 34 CH ₂ O-1-Naph Me CH ₂ 4 2-CN 35 Ph Me CH ₂ 5 2-CN 36 Ph-3-Cl Me CH ₂ 5 2-CN 37 CH ₂ OPh Me CH ₂ 5 2-CN 38 Ph Me CH ₂ 3 2-Cl-6-CN 39 CH ₂ OPh Me CH ₂ 5 4-OMe-2-CN 40 CH ₂ OPh Me CH ₂ 3 4-OMe-2-CN 41 Ph-3-Cl Me CH ₂ 5 2-NHCOCH ₃ 42 CH ₂ OPh Me CH ₂ 5 2-NHCOCH ₃ 43 CH ₂ OPh Me CH ₂ 5 2-NHCONHPh 44 Ph Me CH ₂ 3 5-CO ₂ Me 45 Ph-3-F Me CH ₂ 3 5-CO ₂ Me 46 Ph-3-Cl Me CH ₂ 3 5-CO ₂ Me 47 Ph-3-CF ₃ Me CH ₂ 3 5-CO ₂ Me 48 CH ₂ OPh Me CH ₂ 3 5-CO ₂ Me 49 CH ₂ OPh-2-Ph Me CH ₂ 3 5-CO ₂ Me 50 CH ₂ O-1-Naph Me CH ₂ 3 5-CO ₂ Me 51 5-Cl-2-thienyl Me CH ₂ 3 5-CO ₂ Me 52 Ph-3-Cl Me CH ₂ 3 5-CO ₂ Et 53 CH ₂ OPh Me CH ₂ 3 5-CONHPh-3-F 54 Ph Me CH ₂ 3 2-OCH ₂ CO ₂ Me 55 Ph-3-Cl Me CH ₂ 3 2-OCH ₂ CO ₂ Me 56 Ph-3-Cl Me CH ₂ 5 2-OCH ₂ CO ₂ Me 57 CH ₂ OPh Me CH ₂ 5 2-OCH ₂ CO ₂ Me 58 CH ₂ OPh Me CH ₂ 3 2- (2-Me-tetrazol-5-yl) 59 Ph-3-Cl Me CH ₂ 3 5-CO ₂ Me ( R ) -OH 60 Ph H O 2 3-I

Example A R Y Substitution position of Y G Remarks 61 Ph H O 2 3-CH = CHCO ₂ Me 62 Ph H O 2 3-CH = CHCO ₂ Et 63 Ph H O 2 3-CH ₂ CH ₂ CO ₂ Me 64 Ph-3-Cl H O 2 3-CH = CHCO ₂ Me ( R ) -OH 65 Ph-3-Cl H O 2 3-CH ₂ CH ₂ CO ₂ Me ( R ) -OH 66 CH ₂ OPh Me CH ₂ 3 2-CN ( S ) -OH 67 CH ₂ OPh Me CH ₂ 3 2-CN ( S ) -OH, ( S ) -Me 68 CH ₂ OPh Me CH ₂ 3 2-CN ( S ) -OH, ( R ) -Me 69 CH ₂ OPh Me CH ₂ 3 2-OMe ( R ) -OH 70 CH ₂ OPh Me CH ₂ 3 5-CO ₂ Me ( S ) -OH 71 CH ₂ OPh Me CH ₂ 3 5-CO ₂ Me ( S ) -OH, ( R ) -Me 72 CH ₂ OPh Me CH ₂ 3 5-CO ₂ Me ( S ) -OH, ( S ) -Me 73 CH ₂ OPh Me CH ₂ 3 5-CO ₂ Me ( R ) -OH 74 CH ₂ OPh Me CH ₂ 3 5-CO ₂ Me ( R ) -OH, ( R ) -Me 75 CH ₂ OPh Me CH ₂ 3 5-CO ₂ Me ( R ) -OH, ( S ) -Me 76 CH ₂ O-1-Naph Me CH ₂ 2 6-Me - 77 Ph-3-Cl Me CH ₂ 3 6-CO ₂ Me (R) -OH

Example 1 Preparation of 1-phenyl-2- [3- (3-pyridyl) propylamine] -1-ethanol

2-amino-1-phenyl-1-ethanol (136 mg, 1 mmol), 3- (3-pyridyl) propanal (142 mg, 1.05 mmol) and molecular sieve (1.6 g) in benzene (12 mL) was added and refluxed for 19 h. The reaction solution was filtered, the solvent was removed under reduced pressure, PtO ₂ (23 mg, 10 mol%) was added under anhydrous methanol (20 mL) solvent, the reaction was carried out under hydrogen stream (70 psi) for 4 hours, and filtered. The solvent was removed under, and then 72.6 mg (29%) of the target compound were obtained by column chromatography.

¹ H NMR (CDCl ₃ , 200 MHz) δ 8.42-8.43 (d, J = 2.8 Hz, 2H), 7.49 (d, J = 7.7 Hz, 1H), 7.17-7.36 (m, 6H), 4.72-4.78 ( m, 1H), 2.62-2.94 (m, 8H), 1.76-1.90 (m, 2H); MS ( m / e ) 257 (M ⁺ +1, 2), 150 (20), 149 (100), 120 (7), 106 (35), 92 (41), 77 (25)

<Examples 2 to 59 and 76 to 77>

To prepare a compound of Formula 1 in the same manner as in Example 1, Table 3 shows the results of the identification analysis of each compound.

Example ¹ H NMR (CDCl ₃ , 200 MHz) δ MS ( m / e ) 2 8.41-8.44 (d, J = 2.7 Hz, 2H), 7.49 (d, J = 7.7 Hz, 1H), 7.37 (s, 1H), 7.18-7.27 (m, 4H), 4.65-4.71 (m, 1H) , 2.58-2.92 (m, 8H), 1.74-1.89 (m, 2H) 293 (M ⁺ +3, 0.48), 291 (M ⁺ +1, 0.48), 150 (17), 149 (100), 120 (4), 106 (23), 92 (23), 77 (17) 3 8.42-8.45 (d, 2H), 7.42-7.53 (m, 1H), 7.17-7.32 (m, 3H), 6.88-6.99 (m, 3H) 3.93-4.11 (m, 3H), 2.64-2.92 (m, 8H), 1.80-1.88 (m, 2H) 287 (M ⁺ +1, 3), 179 (3), 149 (100), 106 (22), 92 (21), 77 (14) 4 8.42-8.45 (m, 1H), 8.20-8.25 (m, 1H), 7.77-7.82 (m, 1H), 7.16-7.53 (m, 6H), 6.80-6.84 (m, 1H) 4.12-4.25 (m, 3H), 2.53-3.00 (m, 8H), 1.80-1.92 (m, 2H) 337 (M ⁺ +1, 3), 336 (M ^+, 2), 149 (100), 106 (15), 92 (10) 5 8.45 (d, 2H, J = 4.9 Hz), 7.76-7.35 (m, 5H), 7.09 (d, 2H, J = 5.3 Hz), 4.68-4.74 (m, 1H), 2.54-2.91 (m, 8H) , 1.74-1.88 (m, 2H) 258 (M ⁺ +2, 3), 257 (M ⁺ +1, 15), 239 (1), 150 (19), 149 (100), 106 (32), 92 (33) 6 8.54 (d, J = 5 Hz, 1H), 7.47-7.27 (m, 7H), 4.75 (m, 1H), 3.00-2.65 (m, 9H), 1.85 (m, 2H) - 7 1.87 (m, 2H), 2.37 (br, 2H), 2.67-2.95 (m, 6H), 4.00 (s, 3H), 4.73 (m, 1H), 7.26-7.36 (m, 6H), 7.98 (s, 1H), 8.62 (d, J = 4.8 Hz, 1H) 315 (M ⁺ +1, 1), 207 (100) 8 1.90 (m, 2H), 2.17 (br, 2H), 2.65-2.96 (m, 6H), 4.02 (s, 3H), 4.70 (m, 1H), 7.25-7.38 (m, 5H), 7.99 (s, 1H), 8.63 (d, J = 4.8 Hz, 1H) 349 (M ⁺ +1, 7), 207 (100) 9 9.01 (s, 1H), 8.59 (s, 1H), 8.10 (s, 1H), 7.21-7.36 (m, 5H), 4.90 (m, 1H), 4.10 (brs, 2H), 3.93 (s, 3H) , 2.70-2.99 (m, 6H), 1.93 (m, 2H) 315 (2), 283 (3), 221 (2), 207 (100), 175 (16), 164 (34), 150 (11), 91 (15), 77 (32) 10 1.85 (m, 2H), 2.70-2.95 (m, 6H), 3.94 (s, 3H), 4.73 (m, 1H), 6.90-7.30 (m, 4H), 8.10 (d, 1H, J = 1.9 Hz) , 8.55 (d, 1H, J = 2.1 Hz), 9.01 (d, 1H, J = 1.9 Hz). -

Example ¹ H NMR (CDCl ₃ , 200 MHz) δ MS ( m / e ) 11 9.03 (s, 1H), 8.6 (s, 1H), 8.12 (s, 1H), 7.37 (s, 1H), 7.24-7.27 (m, 3H), 4.75 (m, 1H), 3.95 (s, 3H) , 2.66-3.02 (m, 8H), 1.88 (m, 2H). - 12 1.97 (m, 2H), 2.71-3.03 (m, 6H), 3.94 (s, 3H), 5.03 (m, 1H), 6.70-6.74 (m, 2H), 8.10 (s, 1H), 8.60 (s, 1H). 8.99 (s, 1 H). - 13 7.13-7.50 (m, 6H), 4.65 (m, 1H), 3.10 (brs, 2H), 2.53-2.95 (m, 5H), 1.65 (m, 2H), 1.10 (d, 3H, J = 6.3 Hz) 307 (12), 305 (35), 180, 163, 134, 106, 92, 77, 58. 14 8.42-8.47 (m, 2H), 7.49-7.53 (m, 1H), 7.17-7.33 (m, 3H), 6.89-7.00 (m, 3H), 3.98-4.05 (m, 3H), 2.65-2.86 (m , 5H), 2.49 (br, 2H, O H , N H ), 1.71-1.78 (m, 2H) 1.16 (d, 3H, J = 6.3 Hz) 302 (M ⁺ +2, 0.2), 301 (M ⁺ + H, 1), 300 (M ⁺ , 0.4), 285 (1), 220 (4), 194 (38), 163 (100), 134 ( 33) 15 1.12 (d, J = 6.3 Hz, 3H), 1.71 (m, 2H), 2.41 (br, 2H), 2.53-3.03 (m, 5H), 4.66 (m, 1H), 7.08-7.37 (m, 7H) , 8.46 (dd, J = 1.6, 4.7 Hz, 2H) 271 (M ⁺ +1, 0.9), 175 (1.6), 163 (97.3), 134 (100) 16 1.09 (d, J = 4.9 Hz, 3H), 1.70 (m, 2H), 2.04-3.04 (m, 7H), 4.62 (m, 1H), 7.09-7.37 (m, 6H), 8.47 (dd, J = 1.4, 4.3 Hz, 2H) 305 (M ⁺ +1, 0.6), 163 (100) 17 1.14 (d, J = 6.3 Hz, 3H), 1.74 (m, 2H), 2.45 (br, 2H), 2.63-2.99 (m, 5H), 3.99-4.05 (m, 3H), 6.89-6.99 (m, 3H), 7.11 (d, J = 5.1 Hz, 2H), 7.24-7.32 (m, 2H), 8.47 (dd, J = 1.4, 4.5 Hz, 2H) 300 (M ⁺ , 3), 285 (3), 194 (37), 163 (100), 134 (41) 18 1.15 (d, J = 6.3 Hz, 3H), 1.71 (m, 2H), 2.58 (br, 2H), 2.62-3.04 (m, 5H), 4.06-4.22 (m, 3H), 6.82 (d, J = 7.1 Hz, 1H), 7.06-7.10 (m, 2H), 7.26-7.53 (m, 4H), 7.67 (m, 1H), 8.23 (m, 1H), 8.44-8.48 (m, 2H) 350 (M ⁺ , 6), 335 (2), 306 (2), 244 (20), 163 (100)

Example ¹ H NMR (CDCl ₃ , 200 MHz) δ MS ( m / e ) 19 8.05 (d, 1H, J = 4.7 Hz), 7.56-7.65 (m, 1H), 7.24-7.32 (m, 2H), 7.06-7.13 (m, 1H), 6.89-6.99 (m, 3H), 3.98- 4.10 (m, 3H), 2.63-2.86 (m, 7H), 1.70-1.79 (m, 2H) 1.18 (d, 3H, J = 6.3 Hz) 320 (M ⁺ +2, 3), 319 (M ⁺ + 1, 16), 299 (M ⁺ -F, 35), 181 (36), 161 (100), 133 (15), 110 (10) 20 8.03 (d, 1H, J = 1.8 Hz), 7.55-7.64 (m, 1H), 7.23-7.33 (m, 2H), 6.81-7.00 (m, 4H), 4.02 (s, 3H), 2.62-2.95 ( m, 5H), 2.23 (br, 2H), 1.61-1.78 (m, 2H) 1.14 (d, 3H, J = 6.3 Hz) 320 (M ⁺ + 2H, 3), 319 (M ⁺ + H, 12), 318 (M ⁺ , 5), 274 (3), 194 (40), 181 (100), 152 (23) 21 1.24 (d, J = 6.5 Hz, 3H), 1.74 (m, 2H), 2.25 (br, 2H), 2.57-3.08 (m, 5H), 4.69 (m, 1H), 7.13-7.56 (m, 7H) , 8.24 (m, 1H) 305 (M ⁺ +1, 0.7), 197 (100) 22 1.16 (d, J = 6.3 Hz, 3H), 1.71 (m, 2H), 2.41 (br, 2H), 2.52-3.07 (m, 5H), 4.65 (m, 1H), 7.13-7.32 (m, 4H) , 7.38 (s, 1H), 7.53 (d, J = 7.3 Hz, 1H), 8.24 (m, 1H), 9.05 (d, J = 2.0 Hz, 1H) 339 (M ⁺ , 11.5), 197 (100), 168 (49.3) 23 1.17 (d, J = 6.3 Hz, 3H), 1.75 (m, 2H), 2.21 (br, 2H), 2.72-2.98 (m, 5H), 3.94 (s, 3H), 4.01-4.05 (m, 3H) , 6.90-7.00 (m, 3H), 7.16 (dd, J = 5.1, 7.5 Hz, 1H), 7.17-7.33 (m, 2H), 7.55 (d, J = 7.5 Hz, 1H), 8.24 (dd, J = 1.6, 4.8 Hz, 1H) 358 (M ⁺ , 0.6), 343 (1.5), 251 (6.1), 221 (100), 194 (67) 24 8.34 (s, 1H), 7.25-7.41 (m, 3H), 6.89-7.08 (m, 4H), 3.98-4.05 (m, 3H), 2.52-2.85 (m, 10H), 1.65-1.76 (m, 2H ) 1.15 (d, 3H, J = 6.3 Hz) 316 (M ⁺ + 2H, 10), 315 (M ⁺ + H, 47), 358 (M ⁺ + H, 5), 299 (2), 194 (42), 177 (100), 120 (36) 25 8.01 (dd, 1H, J = 5.0, 1.7 Hz), 7.24-7.40 (m, 5H), 6.79 (dd, 1H, J = 7.0, 5.0 Hz), 4.94 (m, 1H), 4.50 (brs, 2H) , 3.93 (s, 3H), 2.60-3.15 (m, 5H), 1.80 (m, 2H), 1.27 (d, 3H, J = 6.4 Hz) 195 (12), 193 (35.5), 164 (23.1), 136 (20.5), 122 (60.6), 58 (100). 26 8.01 (m, 1H), 7.45-7.24 (m, 3H), 7.00-6.89 (m, 3H), 6.83-6.77 (m, 1H), 4.05-3.95 (m, 3H), 3.94 (s, 3H), 2.96-2.59 (m, 7H), 1.70 (m, 2H), 1.18 (d, J = 6.3 Hz, 3H) 330 (M ⁺ , 14), 315 (4), 194 (92), 193 (100).

Example ¹ H NMR (CDCl ₃ , 200 MHz) δ MS ( m / e ) 27 7.95 (s, 1H), 7.23-7.41 (m, 3H), 6.87-6.98 (m, 3H), 6.66 (d, 1H, J = 8.6 Hz), 3.97 (s, 3H), 3.89 (s, 3H) , 2.53-2.92 (m, 5 ₂ ), 2.22 (br, 2H, O H , N H ), 1.56-1.75 (m, 2H) 1.11 (d, 3H, J = 6.3 Hz) 332 (M ⁺ + 2H, 2), 331 (M ⁺ + 1H, 10), 330 (M ⁺ , 11), 194 (47), 136 (31), 122 (35), 58 (100) 28 8.34 (d, 1H, J = 5.7 Hz), 8.24 (s, 1H) 7.22-7.32 (m, 2H), 6.89-6.98 (m, 3H), 6.74 (d, 1H, J = 5.7 Hz), 3.85- 4.08 (m, 3H), 3.77 (s, 3H), 2.60-3.00 (m, 7H), 1.59-1.77 (m, 2H) 1.15 (d, 3H, J = 6.3 Hz) 332 (M ⁺ + 2H, 5), 331 (M ⁺ + H, 22), 315 (M ⁺ -CH ₃ , 3), 248 (3), 194 (55), 193 (100), 164 (14) 29 8.54-8.57 (m, 1H), 7.65-7.71 (m, 1H), 7.39-7.47 (m, 2H), 7.20-7.27 (m, 3H), 4.65-4.74 (m, 1H) 2.54-3.09 (m, 7H), 1.18 (d, 3H, J = 6.3 Hz) 333 (M ⁺ +3, 1.28), 332 (M ⁺ +2, 6.26), 331 (M ⁺ +1, 3.95), 330 (M ⁺ , 17.66), 312 (M ⁺ -H ₂ O, 2), 188 (100), 159 (49) 30 8.53-8.57 (m, 1H), 7.64-7.70 (m, 1H), 7.23-7.46 (m, 6H), 4.68-4.76 (m, 1H) 2.49-3.08 (m, 7H), 1.16 (d, 3H, J = 6.3 Hz) 298 (M⁺+2, 1), 297 (M⁺+1, 9), 296 (M⁺, 46), 278 (M⁺-H₂O, 9), 188 (100), 159 (54) 31 8.54-8.57 (m, 1H), 7.69 (d, 1H, J = 8.1 Hz), 7.39-7.46 (m, 1H), 7.25-7.33 (m, 2H), 6.90-7.00 (m, 3H), 3.99- 4.07 (m, 3H), 2.77-2.99 (m, 5H), 2.25 (br, 2H), 1.78-1.81 (m, 2H), 1.20 (d, 3H, J = 6.3 Hz) - 32 1.14 (d, J = 6.1 Hz, 3H), 1.72 (m, 2H), 2.48-3.11 (m, 7H), 4.61 (m, 1H), 7.26-7.37 (m, 5H), 7.53 (s, 1H) , 8.57 (d, J = 4.7 Hz, 1H) 330 (M + 1, 0.7), 188 (100) 33 8.57 (d, J = 5.0 Hz, 1H), 7.53 (s, 1H), 7.34-7.24 (m, 3H), 7.00-6.89 (m, 3H), 4.09-3.98 (m, 3H), 3.04-2.50 ( m, 7H), 1.74 (m, 2H), 1.17 (d, J = 6.5 Hz, 3H) 325 (M ⁺ , 4.9), 281 (5.2), 187 (100), 159 (29.4) .IR (KBr) 3337, 3058, 2926, 1597, 1494, 1244 1040, 756, 406 cm ^-1

Example ¹ H NMR (CDCl ₃ , 200 MHz) δ MS ( m / e ) 34 8.52-8.55 (m, 1H,), 8.20-8.24 (m, 1H), 7.79-7.83 (m, 1H), 7.26-7.51 (m, 6H), 6.84 (d, 1H, J = 7.3 Hz), 4.19 (s, 3H), 2.93-2.95 (m, 1H), 2.68-2.78 (m, 4H), 1.64-1.75 (m, 2H), 1.16 (d, 3H, J = 6.3 Hz) 376 (M ⁺ +1, 11), 375 (M ⁺ , 22), 360 (2), 244 (17), 232 (12), 188 (100), 159 (32), 144 (51), 127 ( 5) 35 8.54 (s, 1H), 7.60 (s, 2H), 7.23-7.36 (m, 5H), 4.64-4.71 (m, 1H), 2.36-2.85 (m, 7H), 1.66-1.77 (m, 2H), 1.13 (d, 3H, J = 6.3 Hz) 297 (M ⁺ +2, 1), 296 (M ⁺ +1, 4) 278 (1), 188 (100), 159 (26) 36 8.56 (s, 1H), 7.20-7.70 (m, 6H), 4.87 (m, 1H), 4.65 (brs, 2H), 3.15-2.65 (m, 5H), 2.90 (m, 2H), 1.25 (d, 3H, J = 7 Hz) 332 (0.4), 330 (1.8), 188 (100), 159 (77.3), 117 (85.7), 77 (64.7), 58 (84.5). 37 8.56 (s, 1H), 7.57-7.67 (m, 2H), 7.24-7.33 (m, 2H), 6.89-7.01 (m, 3H), 3.98-4.07 (m, 3H), 2.62-2.97 (m, 5H ), 2.16 (br, 2H), 1.65-1.80 (m, 2H) 1.16 (d, 3H, J = 6.3 Hz) 330 (M ⁺ + H, 51), 310 (2), 281 (4), 194 (30), 188 (100), 159 (24) 38 1.26 (m, 3H), 1.79 (m, 2H), 2.74-2.95 (m, 5H), 3.89 (s, 3H), 4.81 (m, 1H), 7.14-7.36 (m, 6H), 7.58 (d, J = 7.7 Hz, 1H) 294 (1.9), 186 (100) 39 8.33 (s, 1H), 7.24-7.32 (m, 2H), 7.13 (s, 1H), 6.88-7.00 (m, 3H), 3.96-4.08 (m, 3H), 3.91 (s, 3H), 2.61- 2.88 (m, 7H), 1.66-1.75 (m, 2H) 1.18 (d, 3H, J = 6.3 Hz) 356 (M ⁺ + H, 0.8), 355 (M ⁺ , 1), 340 (1), 311 (0.7), 218 (100), 194 (55), 147 (66) 40 8.41 (d, 1H, J = 4.7 Hz), 7.24-7.32 (m, 2H), 6.90-6.99 (m, 4H), 4.00 (s, 3H), 3.92 (s, 3H), 2.75-2.94 (m, 5H), 1.96 (br, 2H), 1.62-1.78 (m, 2H) 1.18 (d, 3H, J = 6.3 Hz) 356 (M ⁺ + H, 5), 355 (M ⁺ , 1), 340 (1), 248 (3), 218 (100), 194 (18), 189 (29) 41 8.42 (s, 1H), 8.08 (m, 2H), 7.51-7.55 (m, 1H), 7.49-7.50 (m, 1H,), 7.37 (s, 1H), 7.22-7.27 (m, 3H), 4.62 -4.68 (m, 1H), 2.49-2.98 (m, 7H), 1.59-1.77 (m, 2H), 1.13 (d, 3H, J = 6.3 Hz) 363 (M ⁺ +1, 2.5), 393 (15.3), 375 (1), 251 (90), 194 (61), 180 (85), 5 (100)

Example ¹ H NMR (CDCl ₃ , 200 MHz) δ MS ( m / e ) 42 8.51 (s, 1H), 8.11 (d, 2H, J = 8.7 Hz), 7.50-7.55 (m, 1H), 7.24-7.32 (m, 2H), 6.88-6.99 (m, 3H), 3.97-4.07 ( m, 3H), 2.59-2.86 (m, 7H), 2.18 (s, 3H), 1.65-1.77 (m, 2H) 1.16 (d, 3H, J = 6.3 Hz) 358 (M ⁺ + H, 5), 356 (M ⁺ -H, 0.3), 342 (0.6), 264 (0.8), 220 (81), 163 (40), 107 (100) 43 11.74 (s, 1H), 8.81 (s, 1H), 8.08 (s, 1H), 758-7.63 (m, 2H), 7.44-7.50 (m, 1H), 7.22-7.38 (m, 4H), 6.86- 7.12 (m, 5H), 3.98-4.14 (m, 3H), 2.60-2.97 (m, 5H), 2.38 (br, 2H, O H , N H ), 1.62-1.80 (m, 2H), 1.16 (d , 3H, J = 6.3 Hz) 435 (M ⁺ + H, 0.1), 434 (M ⁺ , 0.1), 419 (0.1), 341 (4), 315 (2), 121 (100) 44 9.02 (s, 1H), 8.60 (s, 1H), 8.11 (s, 1H), 7.26-7.38 (m, 5H), 4.83 (m, 1H), 3.94 (s, 3H), 2.69-3.04 (m, 5H), 1.80 (m, 2H), 1.20 (d, 3H, J = 6.3 Hz) M ⁺ , 221 (100), 192 (30.7), 150 (28.1), 91 (17.7), 77 (33.3), 58 (91.5). 45 1.13 (d, 3H, J = 6.3 HZ), 1.70 (m, 2H), 2.63-3.00 (m, 5H), 3.94 (s, 3H), 4.68 (m, 1H), 6.93-7.30 (m, 4H, ArH), 8.10 (d, 1H, 2.2 Hz), 8.56 (d, 1H, 2.2 Hz), 9.01 (d, 1H, 1.8 Hz) - 46 9.00 (s, 1H), 8.57 (s, 1H), 8.11 (s, 1H), 7.37 (s, 1H), 7.19-7.24 (m, 3H), 4.74 (m, 1H), 3.69 (brs, 2H) , 2.60-2.97 (m, 5H), 1.73 (m, 2H), 1.16 (d, 3H, J = 6.3 Hz) 363 (M ⁺⁺ 1, 7.9), 221 (100), 192 (33.4), 150 (28.3), 77 (38.2), 58.7 (7). 47 1.15 (d, 3H), 1.80 (m, 2H), 2.70-2.99 (m, 5H), 3.94 (s, 3H), 4.55-5.05 (m, 1H), 7.40-7.65 (m, 4H), 8.11 ( d, 1H, J = 1.8 Hz), 8.60 (d, 1H, 1.4 Hz), 9.03 (d, 1H, 2.0 Hz). - 48 9.03 (s, 1H), 8.60 (s, 1H), 8.12 (s, 1H), 7.23-7.31 (m, 2H), 6.88-6.98 (m, 3H), 3.99-4.09 (m, 3H), 3.94 ( s, 3H), 2.62-2.95 (m, 5H), 2.23 (br, 2H), 1.65-1.81 (m, 2H), 1.15 (d, 3H, J = 6.3 Hz) -

Example ¹ H NMR (CDCl ₃ , 200 MHz) δ MS ( m / e ) 49 10.4 (m, 3H), 1.61 (m, 2H), 2.46 (br, 2H), 2.46-2.85 (m, 5H), 3.95 (m, s, 3H), 3.98 (s, 3H), 6.97-7.09 ( m, 2H), 7.26-7.43 (m, 5H), 7.50 (d, J = 6.9 Hz, 2H), 8.10 (d, J = 1.6 Hz, 1H), 8.59 (d, J = 1.8 Hz, 1H), 9.05 (d, J = 1.8 Hz, 1H) 221 (M ⁺ , 100) 50 1.26 (m, 3H), 1.77-1.98 (m, 2H), 2.86-3.21 (m, 7H), 3.88 (s, 3H), 4.06-4.25 (m, 3H), 4.37 (br, 2H), 6.74 ( d, J = 7.3 Hz, 1H), 7.26-7.66 (m, 4H), 7.75 (m, 1H), 8.08 (d, J = 2.0 Hz, 1H), 8.17 (m, 1H), 8.59 (s, 1H) ), 8.98 (s, 1 H) 408 (M ⁺ , 3.8), 393 (0.9), 244 (21.0), 21 (100) 51 1.15 (d, 3H, J = 6.3 Hz), 1.75 (m, 2H), 2.68-3.00 (m, 5H), 3.94 (s, 3H), 4.85 (m, 1H), 6.70-6.75 (m, 2H, ArH), 8.11 (s, 1 H), 8.56 (s, 1 H), 9.00 (s, 1 H). - 52 1.13 (d, 3H, J = 6.3 Hz), 1.39 (t, 3H, J = 7.1 Hz), 1.70 (m, 2H), 2.70-3.05 (m, 5H), 4.40 (q, 2H, J = 7.1 Hz ), 4.63 (m, 1H), 7.20-7.36 (m, 4H), 8.10 (d, 1H, J = 2.2 Hz), 8.58 (d, 1H, J = 2.0 Hz), 9.03 (d, 1H, J = 1.8 Hz). - 53 8.99 (s, 1H), 8.90 (d, 1H, J = 2.2 Hz), 8.54 (s, 1H), 8.04 (s, 1H), 7,62-7.64 (m, 1H), 7.15-7.41 (m, 4H), 6.77-6.97 (m, 4H), 3.93-4.08 (m, 3H), 2.54-3.04 (m, 7H), 1.75-1.85 (m, 2H) 1.14 (d, 3H, J = 6.3 Hz) 438 (M ⁺ + H, 1), 437 (M ⁺ , 0.5), 422 0.9), 326 (9), 300 (100), 194 (33), 185 (54) 54 7.91 (m, 1H), 7.45-7.20 (m, 6H), 6.80 (m, 1H), 4.88 (s, 2H), 4.65 (m, 1H), 3.70 (s, 3H), 3.40 (brs, 2H) , 2.55-2.97 (m, 5H), 1.70 (m, 2H) - 55 7.91 (dd, 1H, J = 5.1, 1.8 Hz), 7.19-7.38 (m, 5H), 6.80 (dd, 1H, J = 7.2, 5.1 Hz), 4.88 (s, 2H), 4.65 (m, 1H) , 3.70 (s, 3H), 3.40 (brs, 2H), 2.55-2.97 (m, 5H), 1.70 (m, 2H) 395 (3.9), 393 (10.4), 251 (100), 222 (39.1), 194 (27.5), 190 (17.3), 122 (10.2), 58 (100). 56 7.90 (s, 1H), 7.38-7.47 (m, 2H), 7.22-7.27 (m, 3H), 6.78-6.82 (d, 1H), 4.88 (s, 2H), 4.65-4.95 (m, 1H), 3.76 (s, 3H), 2.56-3.17 (m, 7H), 1.28-1.90 (m, 2H), 1.17 (d, 3H, J = 6.3 Hz) 394 (M ⁺ +1, 4.22), 393 (M ⁺ , 15.3), 375 (1), 251 (90), 194 (61), 180 (85), 58 (100)

Example ¹ H NMR (CDCl ₃ , 200 MHz) δ MS ( m / e ) 57 7.91 (s, 1H), 7.24-7.32 (m, 3H), 6.78-7.00 (m, 4H), 4.48 (s, 2H), 3.98 (s, 3H), 3.76 (s, 3H), 2.55-2.83 ( m, 5H), 2.11 (br, 2H), 1.67-1.75 (m, 2H), 1.13 (d, 3H, J = 6.3 Hz) 389 (M ⁺ + H, 15), 357 (1), 251 (100), 194 (44) 58 8.06-8.02 (m, 2H), 7.33-7.24 (m, 4H), 6.99-6.89 (m, 3H), 4.38 (s, 3H), 4.03-3.96 (m, 3H), 2.87-2.70 (m, 5H ), 2.32 (m, 2H), 1.96-1.62 (m, 2H), 1.17 (d, J = 6.3 Hz, 3H). 381 (M ⁺ , 12), 244 (81), 194 (51), 58 (100). 59 1.15 (d, J = 6.3 Hz, 3H), 1.73 (m, 2H), 2.25 (br, 2H), 2.50-3.09 (m, 5H), 3.95 (s, 3H), 4.64 (m, 1H), 7.22 -7.26 (m, 3H), 7.38 (s, 1H), 8.13 (dd, J = 2.0, 4.0 Hz, 1H), 8.60 (dd, J = 2.0, 3.9 Hz, 1H), 9.05 (d, J = 2.0 Hz, 1H); 362 (M ⁺ , 4.9), 330 (1.6), 221 (100) 77 8.56 (s, 1H), 8.05 (d, J = 7.9 Hz, 1H), 7.65 (dd, J = 8.1, 2.0 Hz), 7.37 (s, 1H), 7.28-7.21 (m, 3H), 4.66 (m , 1H), 3.99 (s, 3H), 3.04-2.50 (m, 7H), 1.71 (m, 2H), 1.14 (d, J = 6.3 Hz) - 76 8.22-8.26 (m, 1H), 7.77-7.82 (m, 1H), 7.32-7.56 (m, 5H), 6.981-6.99 (m, 3H) 4.12-4.23 (m, 3H), 2.68-3.06 (m, 7H), 2.58 (d, 3H), 1.73-1.90 (m, 2H), 1.12 (d, 3H, J = 6.5 Hz) 366 (M ⁺ +2, 2), 365 (M ⁺ +1, 7) 258 (41), 244 (3), 107 (100)

Example 60 Preparation of 2- {2- {3-iod-2-pyridyloxy) ethylamino} -1-phenyl-1-ethanol

(3-iodopyridin-2-yloxo) ethylamine and (3.3 mmol) styrene oxide were dissolved in (3.3 mmol) benzene (20 mL) and refluxed for 48 h. The solvent was removed by distillation under reduced pressure, and then separated by column chromatography to obtain the desired product in 65% yield.

Compounds obtained in Example 60 can be introduced at the 3-position of pyridine via a Heck reaction under a palladium catalyst.

Example 61 Methyl ( E Preparation of) -3- [2- {2- (2-hydroxy-2-phenylethylamino) ethoxy} -3-pyridyl] propenoate

Compound of Example 60 (377 mg, 1 mmol), methyl acrylate (176 mg, 2 mmol), palladium acetate (11 mg, 0.05 mmol), n- Bu ₄ NCl (273 mg, 1 mmol) in tetrahydrofuran solvent Together in a pressure tube and reacted at 80 ° C. for 3 hours. The reaction solvent was removed, dissolved in ethyl acetate, dried over anhydrous magnesium sulfate, filtered and the residue was separated by column chromatography to obtain the target compound.

¹ H NMR (CDCl ₃ , 200 MHz) δ 8.90 (m, 1H, ArH), 8.51 (s, 1H, ArH) 8.11 (s, 1H, ArH), 7.75 (d, 1H, J = 16 Hz, vinylic) , 7.35-7.26 (m, 5H, ArH), 6.60 (d, 1H, J = 16 Hz, vinylic), 4.55 (m, 1H, CHOH), 4.40 (t, 2H, CH ₂ O), 4.10 (brs, 2H) 3.60 (s, 1H, CH ₃ O), 3.10-2.90 (m, 4H, CH ₂ )

Example 62 Ethyl ( E Preparation of) -3- [2- {2- (2-hydroxy-2-phenylethylamino) ethoxy} -3-pyridyl] propenoate

Ethyl acrylate was used instead of methyl acrylate in the same manner as in Example 61.

¹ H NMR (CDCl ₃ ) δ 9.00 (m, 1H, ArH), 8.50 (s, 1H, ArH) 8.11 (s, 1H, ArH), 7.85 (d, 1H, J = 16 Hz, vinylic), 7.35- 7.26 (m, 5H, ArH), 6.60 (d, 1H, J = 16.6 Hz, vinylic), 4.80 (m, 1H, CHOH), 4.50 (t, 2H, J = 6.6 Hz, CH ₂ O), 4.25 ( q, 2H, J = 6.8 Hz, CH ₂ O), 4.10 (brs, 2H), 3.2-2.85 (m, 4H, CH ₂ N), 1.45 (t, 3H, J = 6.8 Hz, CH ₃ )

Example 63 Preparation of Methyl 3- [2- {2- (2-hydroxy-2-phenylethylamino) ethoxy} -3-pyridyl] propionate

Example 62 was dissolved in methanol, PtO ₂ (5 mol%) was added and the reaction was carried out for 2 hours under hydrogen stream (60 Psi), followed by filtration to obtain the target product.

¹ H NMR (CDCl ₃ ) δ 8.90 (m, 1H, ArH), 8.53 (s, 1H, ArH) 8.11 (s, 1H, ArH), 7.35-7.26 (m, 5H, ArH), 4.55 (m, 1H , CHOH), 4.10 (brs, 2H), 3.60 (s, 1H, CH ₃ O), 3.2-3.00 (m, 4H, CH ₂ N), 2.95-2.55 (m, 4H, CH ₂ ).

Example 64 (R) -methyl ( E Preparation of) -3- [2- {2- (3-chlorophenyl) -2-hydroxyethylamino) ethoxy} -3-pyridyl] propenoate

¹ H NMR (CDCl ₃ ) δ 8.15 (m, 1H, ArH), 7.85 (d, 1H, J = 16.6 Hz), 7.75 (m, 1H, ArH), 7.30-6.90 (m, 5H, ArH), 6.60 (d, 1H, J = 16.6 Hz, vinylic), 4.80 (m, 1H, CHOH), 4.50 (t, 2H, J = 6.6 Hz, CH ₂ O), 3.60 (s, 1H, OCH ₃ ), 3.20- 2.85 (m, 4H, CH ₂ N).

Example 65 (R) -methyl ( E Preparation of) -3- [2- {2- (3-chlorophenyl) -2-hydroxyethylamino) ethoxy} -3-pyridyl] propionate

Example 64 The compound was dissolved in anhydrous methanol, added to PtO ₂ (5 mol%), reacted under a stream of hydrogen (H ₂ , 60 psi) for 2 hours, filtered, the solvent was removed under reduced pressure, and the target compound was purified using column chromatography. (Yield = 95%) was obtained.

¹ H NMR (CDCl ₃ ) δ 8.15 (m, 1H, ArH), 7.75 (m, 1H, ArH), 7.30-6.90 (m, 5H, ArH), 4.80 (m, 1H, CHOH), 4.50 (t, 2H, J = 6.6 Hz, CH ₂ O), 3.60 (s, 1H, OCH ₃ ), 3.2-2.90 (m, 4H, CH ₂ N), 2.75-2.55 (m, 4H, CH ₂ ).

Example 66 Preparation of (S) -3- [3- (2-hydroxy-3-phenoxypropylamino] butyl-2-pyridinecarbonitrile

The optically active material of Example 31 was prepared using the starting material.

¹ H nmr (CDCl ₃ , 200 MHz) δ 8.55 (m, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.42 (m, 1H), 7.32-7.25 (m, 2H), 6.99-6.90 (m , 3H), 4.09-3.99 (m, 3H), 2.97-2.70 (m, 5H), 2.32 (m, 2H), 1.74 (m, 2H), 1.20 (d, J = 6.3 Hz, 3H)

m / s 326 ((M ⁺ +1, 16), 188 (100), 159 (38)

<Examples 67 and 68> ( S, S ) -3- [3- (2-hydroxy-3-phenoxypropylamino] butyl-2-pyridinecarbonitrile and ( S, R ) -3- [3- (2-hydroxy-3-phenoxypropylamino] butyl-2-pyridinecarbonitrile

The diastereomeric mixture of Example 66 was dissolved in methylene chloride solvent, 2 equivalents of di tert -butyl dicarbonate was added and stirred at room temperature for 12 hours. The reaction mixture is concentrated and purified by primary column chromatography. At this time, no separation occurred in thin layer chromatography, and the first purified diasteremic mixture was analyzed by HPLC, and then separated by RP-18 (Merck Lobar) column.

The Boc compound of Example 67 (14.2 min) and Example 68 Boc compound (16.2 min) were dissolved in methylene chloride, and trifluoroacetic acid (10 equivalents) was added thereto to react at room temperature for 12 hours, followed by soda bicarbonate solution. The organic layer separated by neutralization was dried, concentrated, and the optically pure Examples 67 and 68 were obtained by column chromatography.

Example 69 Preparation of (R) -1- [3- (2-methoxy-3-pyridyl) -1-methylpropylamino] -3-phenoxy-2-propanol

The optically active material of Example 26 was prepared using the starting material.

¹ H nmr (200 MHz, CDCl ₃ ) δ 8.01 (m, 1H), 7.39-7.24 (m, 3H), 6.99-6.90 (m, 3H), 6.83-6.77 (m, 1H), 4.04-3.94 (m , 3H), 3.94 (s, 3H), 2.94-2.58 (m, 5H), 2.28 (m, 2H), 1.71 (m, 2H), 1.14 (d, J = 6.3 Hz, 3H).

m / s 330 (M ⁺ , 3), 315 (3), 194 (53), 193 (64), 58 (100)

<Example 70> ( S Preparation of) -methyl 5- [3- (hydroxy-3-phenoxypropylamine) butyl] nicotinate

The optically active material of Example 48 was prepared using the starting material.

¹ H nmr (200 MHz, CDCl ₃ ) δ 9.05 (s, 1H), 8.62 (s, 1H), 8.13 (s, 1H), 7.32-7.25 (m, 2H), 6.99-6.89 (m, 3H), 4.00 (m, 3H), 3.95 (s, 3H), 2.85-2.69 (m, 5H), 2.22 (m, 2H), 1.71 (m, 2H), 1.15 (d, J = 6.3 Hz, 3H)

Examples 71 and 72 (S, R) -Methyl 5- [3- (hydroxy-3-phenoxypropylamine) butyl] nicotinate and (S, S) -methyl 5- [3- (hydroxy Preparation of Roxy-3-phenoxypropylamine) butyl] nicotinate

Boc derivatives were synthesized in the same manner as in Examples 67 and 68, and then separated and purified.

BOC compound of Example 71 (S, R; 31 minutes)

¹ H nmr (200 MHz, CDCl ₃ ) δ 9.05 (d, J = 2.0 Hz, 1H), 8.60 (d, J = 2.2 Hz, 1H), 8.10 (t, 1H), 7.32-7.23 (m, 2H) , 6.99-6.86 (m, 3H), 4.11-3.91 (brm, 3H), 3.41 (s, 3H), 3.41 (br, 2H), 2.65 (t, J = 8.0 Hz, 2H), 1.91 (m, 1H ), 1.77 (m, 1 H), 1.47 (s, 9 H), 1.24 (d, J = 6.8 Hz, 3 H).

Boc compound of Example 72 (S, S; 27.4 min)

¹ H nmr (200 MHz, CDCl ₃ ) δ 9.06 (d, J = 1.8 Hz, 1H), 8.58 (d, J = 1.8 Hz, 1H), 8.10 (t, J = 1.8 Hz, 1H), 7.30-7.22 (m, 2H), 6.97-6.85 (m, 3H), 4.13-4.02 (m, 3H), 3.91 (s, 3H), 3.42 (br, 2H), 2.67 (t, J = 7.9 Hz, 2H), 1.94 (m, 1 H), 1.77 (m, 1 H), 1.47 (s, 9 H), 1.21 (d, J = 6.4 Hz, 3 H).

The separated BOC compound of Example 71 was dissolved in methylene chloride, reacted with trifluoro acetic acid (10 equivalents) for 12 hours at room temperature, neutralized with sodium bicarbonate solution, and the separated organic layer was purified by column chromatography ( Example 71, yield = 85%) was obtained.

Example 71: ¹ H nmr (200 MHz, CDCl ₃ ) δ 8.96 (d, J = 1.8 Hz, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.04 (t, 1H), 7.23-7.15 ( m, 2H), 6.90-6.80 (m, 3H), 4.01-3.89 (m, 3H), 3.86 (s, 3H), 2.85-2.62 (m, 7H), 1.67 (m, 2H), 1.08 (d, J = 6.3 Hz, 3H)

ms 358 (7.8, M ⁺ ), 221 (100), 194 (27.2)

Example 72: ¹ H nmr (200 MHz, CDCl ₃ ) δ 8.97 (d, J = 2.0 Hz, 1H), 8.54 (d, J = 2.0 Hz, 1H), 8.04 (t, J = 2.2 Hz, 1H) , 7.24-7.16 (m, 2H), 6.91-6.80 (m, 3H), 4.03-3.83 (m, 3H), 3.87 (s, 3H), 2.97-2.60 (m, 7H), 1.68 (m, 2H) , 1.11 (d, J = 6.3 Hz, 3H)

ms 358 (5.6, M ⁺ ), 221 (100), 194 (28.8)

<Example 73> ( R Preparation of) -methyl 5- [3- (hydroxy-3-phenoxypropylamine) butyl] nicotinate

In Example 70, starting materials with opposite optical activities were obtained.

<Examples 74 and 75> ( R, R ) -Methyl 5- [3- (hydroxy-3-phenoxypropylamine) butyl] nicotinate and ( R, S Preparation of) -methyl 5- [3- (hydroxy-3-phenoxypropylamine) butyl] nicotinate

The Boc compound of Example 74 (R, R; 27.4 min) and the Boc compound of Example 75 (R, S; 31 min) were synthesized in the same manner as in Examples 67 and 68 and separated after ¹ H nmr (200 MHz). , CDCl ₃ ) and all the peaks were identical to those of Example 72 within 0.5 Hz.

Pharmaceutical compositions comprising the compound of formula 1 as an active ingredient of the present invention can be administered parenterally and orally, and are prepared in parenteral formulations as injections, oral formulations as syrups and tablets.

Preparation Example 1 Preparation of Injection Solution

Injection solution containing 10 mg of the active ingredient was prepared by the following method.

1 g of the compound of Example 1, 0.6 g of sodium chloride and 0.1 g of ascorbic acid were dissolved in distilled water to make 100 ml. The solution was bottled and sterilized by heating at 20 ° C. for 30 minutes.

The components of the injection solution are as follows.

Compound of Example 1 ... 1 g

Sodium Chloride ・ ・ ・ ・ 0.6 g

0.1 g of ascorbic acid

Distilled water ··················

Preparation Example 2 Preparation of Syrup

Syrups containing an acid addition salt of a β-aminoalcohol derivative including pyridine of the present invention and a pharmaceutically acceptable salt thereof as an active ingredient of 2% (weight / volume) are prepared by the following method.

Acid addition salts, saccharin and sugars of β-aminoalcohol derivatives containing pyridine were dissolved in 80 g of warm water. After the solution was cooled, a solution consisting of glycerin, saccharin, spices, ethanol, sorbic acid and distilled water was prepared and mixed thereto. Water was added to this mixture to 100 ml.

The components of the syrup are as follows.

Acid addition salts of the compound of Example 1 2 g

Saccharin: 0.8 g ················

25.4 g of sugar

Glycerin ... 8.0 g

Spices ··················· 0.04 g

Ethanol 4.0 g

0.4 g of sorbic acid

Distilled water ·····················

Preparation Example 3 Manufacturing Method

A tablet containing 15 mg of active ingredient is prepared by the following method.

250 g of the compound of Example 1 were mixed with 175.9 g of lactose, 180 g of potato starch and 32 g of colloidal silicic acid. 10% gelatin solution was added to the mixture, which was then ground and passed through a 14 mesh sieve. It was dried and the mixture obtained by adding 160 g of potato starch, 50 g of talc and 5 g of magnesium stearate was made into a tablet.

The components of the tablet are as follows.

Compound of Example 1 ... 250 g

Lactose ········ 175.9 g

Potato starch ········· 180 g

Colloidal silicic acid 32 g

10% gelatin solution

Potato starch · 160 g

Talc · 50 g

Magnesium stearate ·········· 5

Experimental Example 1 β ₃ Selective binding to adrenergic receptors

In order to determine the binding capacity of the compounds of the present invention to the β ₃ -receptor, the following experiment was performed and the results are shown in Table 4 below.

First, the purchased RB-HBETA3 cell membrane (10 μg, Receptor biology, MD, USA) was subjected to [ ¹²⁵ I] iodocyanopindolol (iodocyanopindolol) in the presence of 50 mM HEPES (pH 7.5), 4 mM MgCl ₂ , 0.004% BSA. ) And the total volume was 0.1 ml and left at 37 ° C. for 90 minutes. Profranolol (1 mM) was used to measure nonspecific binding and 0.1 μM propranolol was used to saturate the remaining β ₁ adrenergic receptor. This mixture was filtered through a PF / A filter and washed with 50 mM Tris / Cl, pH 7.4, 4 mM MgCl ₂ . The binding rate was determined by measuring γ rays.

Sf9 baculovirus systems expressing β ₁ (CRM-009, 27 μg) and β ₂ (CRM-010, 30 μg) receptors (NEN, MA, USA) 75 mM Tris / Cl (pH 7.4) with [ ³ H] CGP, Adipocytes saturated with β ₁ adrenergic receptors were treated in 12.5 mM MgCl ₂ and 2 mM EDTA buffer at 27 ° C. for 60 minutes. Propranolol (1 mM) was used to measure nonspecific binding. This mixture was filtered through a PF / A filter and washed with 50 mM Tris / Cl, pH 7.4, 4 mM MgCl ₂ . The binding rate was expressed as IC ₅₀ (μM) by measuring β-rays. BRL35135 and CL316243 were used as controls.

As can be seen in Table 4 , the control group requires a compound at a concentration of at least 1 μM to bind 50% to the β ₃ -adrenergic receptor, whereas Examples 3, 14, 17, 19, 20, 23, 26 of the compounds of the present invention. , Compounds of 28, 31, 33, 39, 42, 48, 50, 52, 53, 59, 66, 68 and 70 are sufficient at concentrations of 0.50 μM or less. That is, it can be seen that the compound of the present invention binds to β ₃ -adrenergic receptor selectively compared to the compound of the control group.

Test substance Combined test IC ₅₀ Test substance Combined test IC ₅₀ BRL 35135 1.47 35 3.31 CL316243 1.17 37 0.08 One 23.53 39 0.13 2 7.17 40 0.65 3 0.40 41 11.58 4 0.85 42 0.17 5 - 43 2.03 7 52.64 44 0.99 8 21.34 45 1.29 9 36.59 46 0.62 10 6.96 47 1.56 11 5.35 48 0.12 13 0.64 49 1.18 14 0.020 50 0.18 15 13.09 51 1.08 16 3.80 52 0.64 17 0.20 53 0.19 18 0.62 56 37.28 19 0.09 57 1.20 20 0.15 58 1.17 21 3.76 59 0.37 22 1.37 66 0.12 23 0.12 67 2.21 24 0.84 68 0.12 26 0.10 69 6.71 27 87.35 70 0.03 28 0.11 71 1.28 29 63.04 72 1.15 30 32.86 73 2.95 31 0.10 74 4.57 33 0.22 75 1.10 34 0.72

Experimental Example 2 Lipid Degradation Effect

In order to determine the lipolysis effect of the compounds of the present invention, the following experiment was conducted, and the results are shown in Table 5 below.

Adipose tissue was isolated from the males of SD rats and treated with collagenase to obtain adipocytes and cultured by standard methods. Obtained using 3 × 10 ⁻⁶ M isoprenaline, which exhibits the maximum lipolysis effect. Supernatants were taken and free fatty acids were measured with a WAKO NEFA-C assay kit (Alpha Laboratories). Free fatty acids obtained by treatment with the same concentration of drug are shown in Table 5 as the ratio of the amount of free fatty acids obtained using isoprenal as a control.

Combining the results of Experimental Example 1 and Experimental Example 2, the compounds of Examples 9, 10, 11, 13, 44, 46, 47, 52 and 59 in the compounds of the present invention are similar to the control compound isoprenin or More excellent lipolysis effect was shown. In particular, the compounds of Examples 13, 37, 42, 46, 47, 52 and 59, that is, A is a phenyl group or phenyloxymethyl group substituted with a halogen compound, R is a methyl group, Y is a methylene group, G is hydrogen, It was found that the compound of Formula 1, which is a cyano group, a methyl carboxamide group, or a carboxyl ester group, selectively binds to the β ₃ -adrenergic receptor and has a similar or better effect than a compound having an existing lipolytic effect.

Test substance Relative fat breakdown Test substance Relative fat breakdown Isoprenaline 1.00 35 0.54 One - 37 0.99 2 - 39 0.65 3 - 40 0.56 4 - 41 0.91 5 0.25 42 0.92 7 0.15 43 - 8 0.56 44 1.26 9 1.21 45 0.94 10 1.08 46 1.19 11 1.13 47 1.15 13 1.05 48 - 14 0.68 49 - 15 0.68 50 - 16 0.77 51 0.82 17 - 52 1.11 18 - 53 0.60 19 0.83 56 0.56 20 0.79 57 - 21 - 58 - 22 - 59 1.11 23 - 66 0.91 24 0.71 67 - 26 0.63 68 - 27 0.79 69 - 28 0.68 70 0.96 29 0.62 71 - 30 0.71 72 - 31 - 73 - 33 0.58 74 - 34 - 75 -

Experimental Example 3 Blood Sugar Drop and Weight Loss Effect

Example 3, 14, 37, 42, 52, 53, 59, 68, and 71, which are compounds that bind strongly to the β ₃ -adrenergic receptor in Experimental Example 1, were administered to experimental rats showing diabetes and obesity. Results The changes in blood glucose and weight are shown in FIGS . 1 and 2 .

The drug was prepared by dissolving the compound of Examples 31, 48, or 59 in 0.25% w / v methyl cellulose, and preparing the drug by dissolving BRL35135 as a control, orally for 13 days at a dose of 5 mg / kg / day. Administered. Blood was collected from the fundus vein at 1, 3, 5, 7, and 10 days (10-15 μg). Drug administration was performed at 10 am and blood collection was performed at 2 pm. The collected blood was immediately diluted 1: 5 with physiological saline containing 2.5 mg / ml sodium fluoride and 2% sodium heparin on ice and centrifuged at room temperature (2 min, 10,000 xg). Using the supernatant, blood glucose was measured by Glucose Analyzer 2 (Glucose Analyzer, Beckman Instruments, Portville, Calif.) And insulin was measured by Rat Ultrasensitive Insulin ELISA Kit (ALPCO, Windham, NH). In this process, the weight change of rats was also observed for 5 days.

As shown in FIG. 1 , the blood glucose level gradually increased in the case of the solvent group, whereas the blood glucose level decreased rapidly when the drug containing the control compound BRL35135, a compound of Example 31, 48, or 59 was administered. Minimal blood glucose levels were shown on day 13. Since these compounds have an excellent hypoglycemic effect, it has been confirmed that they can be usefully used for the treatment of endocrine diseases including diabetes, obesity, hyperinsulinemia.

As shown in the weight change result of the rat of FIG. 2 , when the solvent group was administered, about 5 g was increased, and when the drug containing the active ingredient was added to the control compound, about 2 g was increased. Examples 3, 42, and 52 In the case of administration of the drug containing the compounds of the formulas, 53 and 71, the weight gain was less than 1 g, in particular, the compound of Example 42 resulted in a weight loss of about 1 g or more. This confirmed that the compound of the present invention can be usefully used as a therapeutic agent for obesity due to the weight loss effect superior to the conventionally known compound CL316243.

Experimental Example 4 Acute Toxicity in Rats

On the other hand, the following experiment was carried out to determine the acute toxicity of the compound of Formula 1.

Acute toxicity test was performed using 6-week-old SPF SD rats. Two animals per group were dosed orally at a dose of 1 g / kg / 15 mL with compounds obtained from Examples 3, 14, 37, 42, 52, 59, 68 and 71 suspended in 0.5% methylcellulose solution, respectively. After administration of the test substance, mortality, clinical symptoms, and changes in body weight were examined. Hematological and hematological examinations were performed. Necropsy was performed to visually observe abdominal and thoracic organ abnormalities. As a result, all animals treated with test substance showed no clinical symptoms and no dead animals, and no toxic changes were observed in weight change, blood test, blood biochemical test, autopsy findings. As a result, all of the tested compounds did not show toxicity change up to 1000 mg / kg in rats, and the minimum lethal dose (LD ₅₀ ) was determined to be a safe substance of 1000 mg / kg or more.

As described in detail above, the β-aminoacohol derivative including the pyridine of the present invention has an excellent effect on lowering blood sugar and has an effect of reducing weight, and thus can be used as a therapeutic agent for obesity, and high density lipoprotein cholesterol in blood You can also treat or prevent atherosclerosis by increasing your HDL cholesterol and increasing your triglyceride levels. It can also be used to treat hyperinsulinemia.

Claims (5)

Β-aminoalcohol derivatives including pyridine represented by the following formula (1) and pharmaceutically acceptable salts thereof. Formula 1 In the above formula, A is phenyl substituted or unsubstituted with a halogen element or haloalkyl group; Thiophene; Phenyloxymethyl; Naphthyloxymethyl; Or a biphenyloxymethyl group, R represents hydrogen or an alkyl group of C _1-4 , Y represents methylene or oxygen, G is hydrogen; Halogen element; C _1-3 alkyl; Alkoxy; Amino; Cyano; Urea substituted with phenyl group; Carboxamide in which phenyl or C _1-3 alkyl group is substituted; Carboxyl esters; Alkoxycarbonylmethyloxy; Alkoxycarbonylalkyl group; One or more substituents selected from the group consisting of alkoxycarbonylacryl and tetrazole groups, Compounds of formula (I) include all optical isomers. The method of claim 1, A is phenyl optionally substituted with fluorine or chlorine; Or phenyloxymethyl, R is hydrogen or a methyl group, Y represents methylene, G represents cyano, or carboxyester, wherein the compound of formula (1) is represented by the formula (1), characterized in that it contains all of the optical isomers, β-aminoalcohol derivatives including pyridine and pharmaceutically acceptable salts thereof. Β-aminoalcohol containing pyridine represented by the formula (1) of claim 1 to condense the compound of formula (II) and the compound of formula (III) and obtain compound (I) by hydrogenation using an organometallic catalyst. Process for the preparation of derivatives. Scheme 1 Wherein A, R, Y and G are as defined above and the compound of formula (III) and the compound of formula (I) include optical isomers. Β-aminoalcohol containing pyridine represented by the formula (1) of claim 1, wherein aminoethoxy group is introduced into 2-fluoropyridine and reacted with epoxide, followed by introducing cyano group or carboxyl ester group to obtain compound (I). Process for the preparation of derivatives. Scheme 2 Wherein A and G are as mentioned in Formula 1, X is a halogen element, Z is hydrogen, Y is oxygen, and R is hydrogen. A pharmaceutical composition for treating a disease selected from the group consisting of diabetes, obesity and hyperinsulinemia using the compound of claim 1 as an active ingredient.