KR100863138B1 - Pharmaceutical composition comprising ?-aminoalcohol derivatives for preventing or treating tnf-? mediated?diseases - Google Patents

Abstract

The present invention provides a composition for inhibiting tumor necrosis factor-α (TNF-α) and TNF comprising β-aminoalcohol derivative of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. It relates to a pharmaceutical composition for the prevention and treatment of -α mediated diseases. Since the β-aminoalcohol derivatives of the general formula (1) used in the present invention effectively inhibit TNF-α secretion, it may be usefully used for the prevention and treatment of TNF-α mediated diseases:

[Formula 1]

Where

R ¹ is phenyl unsubstituted or substituted with halogen,

R ² is pyridinyl unsubstituted or substituted with cyano or halogen; Pyrimidinyl; Indolyl; Or quinolyl,

R ³ is hydrogen or C _1-4 alkyl.

Description

Pharmaceutical composition for the prevention or treatment of TNP-α mediated diseases, including β-amino alcohol derivatives {PHARMACEUTICAL COMPOSITION COMPRISING β-AMINOALCOHOL DERIVATIVES FOR PREVENTING OR TREATING TNF-α MEDIATED® DISEASES}

The present invention provides a tumor necrosis factor-alpha (TNF-α) inhibitor comprising β-aminoalcohol derivatives as an active ingredient and a pharmaceutical composition for preventing or treating TNF-α-mediated diseases including the same. It is about.

TNF-α is a cytokine that macrophages in animals, including humans, produce in response to various immune stimulants, including endotoxins, which are bacterial toxins, and play an important role in the immune system. to be.

Administration of TNF-α to animals or humans results in inflammation, fever, cardiovascular activity, bleeding, aggregation and acute phase similar to those in acute infections and shock conditions. Too much or not controlled is known to cause a number of diseases.

Representative diseases include endotoxin and / or toxic shock syndrome, sepsis and sepsis syndrome (Tracey et al ., Nature , 330, 662-664, 1987; And Hinshaw et al., Circ Shock , 30, 279-292, 1990); Adult Respiratory Distress Syndrom (ARDS) (Millar et al., Lancet , 2, 8665, 712-714, 1989), pulmonary fibrosis (BJ Sugarman et al., Science , 230, 943-945, 1985), arthritis and autoimmune diseases, inflammatory bone destruction diseases (JR Gamble et al . , Proc. Natl. Acad. Sci. USA. , 82, 8667-8673, 1985; J. Saklatvala, Nature , 322, 547-552, 1986; and Firestein et al . Nature 423: 356-361, 2003), inflammatory bowel disease (Ardizzone S et al., Drugs 65 : 2253-86, 2005), various infectious diseases including malaria (Langhorne J, Immunol Rev. , 201: 35-47, 2004), type 2 nares reaction (Tadesse A et al. , Clin Diagn Lab Immunol. , 12, 130 -134, 2005).

Specifically, septic shock is associated with massive bacterial invasion, the primary cause of which is known to be the release of bacterial endotoxins (lipopolysaccharides) by Gram-negative bacteria, but the cause of the specific disease has not been identified and includes TNF-α. Various cytokines are known to mediate septic shock (Carswell et al . , Proc. Natl. Acad. Sci. USA. , 72, 3666-3670, 1975).

Adult respiratory distress syndrome (ARDS) is a disease that causes dyspnea, shortness of breath, zyanose, severe hypoxemia, decreased pulmonary elasticity, and increased pulmonary vascular permeability. Animal studies have reported that is the most important medium (E. Ferrari-Baliviera et al., Arch. Surg , 124, 1400-1405, 1989).

Pulmonary fibrosis occurs at the last stage of various lung diseases, and is caused by the growth of fibroblasts and the accumulation of collagen in the alveolar walls. TNF-α plays a central role in the progression of pulmonary fibrosis (BJ Sugarman et al., Science , 230, 943-945, 1985).

In addition, TNF-α stimulates bone resorption, inhibits osteoblast function in and out of raw vegetables, stimulates and activates osteoclast formation, thereby inhibiting bone formation, and is known to be involved in inflammatory bone resorption diseases. On the other hand, arthritis is a disease in which chronic inflammation occurs in the joints, including rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, lupus erythematosus, gout, and the like. TNF-α plays an important role in the development and progression of arthritis. (Hofbause et al., Arthritis and Rheumatism , 44: 253-259, 2001; Firestein et al ., Nature , 423: 356-361, 2003; and Heike A et al., Nat Rev drug discov , 4, 332-344, 2005).

TNF-α is highly associated with hypercalcemia associated with tumors and malignancies (Calci, Tissue Int. (US) 46 (Suppl.) S3-10, 1990) and is a major cause of tissue transplantation. It is also associated with complications (Holler et al., Blood , 75 (4), 1011-1016, 1990).

In addition, Inflammatory Bowel Disease (IBD), which includes two syndromes of ulcerative colitis and Crohn's disease, results in the synthesis of large amounts of TNF-α in the intestine resulting in inflammatory cell infiltration. (Ardizzone S et al., Drugs , 65: 2253-86, 2005), cerebral malaria is a fatal hypersensitivity neurological syndrome associated with hypertension levels of TNF-α, the most severe complication in malaria patients ( Grau et al., N. Engl. J. Med. , 320 (24), 1586- 1591, 1989).

Therefore, preventing or inhibiting the production, secretion or action of TNF-α is considered to be an effective treatment for the above diseases, and thus, various studies continue. TNF-α inhibitors developed to date include steroidal drugs such as dexamethasone and trednisolone, mono- and polyclonal antibodies, and the like (Beutler et al., Science , 234, 470-474, 1985; and WO 92/11383). Reference).

Accordingly, the present inventors have completed the present invention while studying the efficacy of β-aminoalcohol derivatives and found that they can be effectively used for the prevention and treatment of TNF-α mediated diseases by effectively inhibiting the secretion of TNF-α. Was done.

Accordingly, it is an object of the present invention to provide a TNF-α inhibitor.

In addition, another object of the present invention to provide a pharmaceutical composition for the prevention and treatment of TNF-α mediated diseases.

In order to achieve the above object, the present invention provides an inhibitor of tumor necrosis factor-alpha (TNF-α) comprising a β-aminoalcohol derivative of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:

Where

R ¹ is phenyl unsubstituted or substituted with halogen,

R ² is pyridinyl unsubstituted or substituted with cyano or halogen; Pyrimidinyl; Indolyl; Or quinolyl,

R ³ is hydrogen or C _1-4 alkyl.

In addition, to achieve the above object, the present invention provides a pharmaceutical composition for the prevention and treatment of TNF-α-mediated disease, comprising the β-aminoalcohol derivative of Formula 1 or a pharmaceutically acceptable salt thereof. .

Hereinafter, the present invention will be described in more detail.

As used herein, the compound of Formula 1 is an asymmetric carbon atom to which R ¹ is bonded, and thus may be in the form of an R, S or racemic mixture thereof. The optical isomer can be separated from the racemic mixture by conventional optical splitting and can be purified by conventional techniques such as chromatography.

Preferred compounds as β-aminoalcohol derivatives of the general formula (1),

5- [3- ( rac -2-hydroxy-2-phenylethylamino) butyl] pyridine-2-carbonitrile;

5- [3-(( R ) -2-hydroxy-2-phenylethylamino) butyl] pyridine-2-carbonitrile;

5- [3-(( S ) -2-hydroxy-2-phenylethylamino) butyl] pyridine-2-carbonitrile;

rac -2- (4- (2-chloropyridin-3-yl) butan-2-ylamino) -1-phenylethanol;

( R ) -2- (4- (2-chloropyridin-3-yl) butan-2-ylamino) -1-phenylethanol;

( S ) -2- (4- (2-chloropyridin-3-yl) butan-2-ylamino) -1-phenylethanol;

rac -2- (4- (pyridin-3-yl) butan-2-ylamino) -1-phenylethanol;

( R ) -2- (4- (pyridin-3-yl) butan-2-ylamino) -1-phenylethanol;

( S ) -2- (4- (pyridin-3-yl) butan-2-ylamino) -1-phenylethanol;

rac -2- (4- (6-chloropyridin-3-yl) butan-2-ylamino) -1-phenylethanol;

( R ) -2- (4- (6-chloropyridin-3-yl) butan-2-ylamino) -1-phenylethanol;

( S ) -2- (4- (6-chloropyridin-3-yl) butan-2-ylamino) -1-phenylethanol;

rac -2- (4- (6-fluoropyridin-3-yl) butan-2-ylamino) -1-phenylethanol;

( R ) -2- (4- (6-fluoropyridin-3-yl) butan-2-ylamino) -1-phenylethanol;

( S ) -2- (4- (6-fluoropyridin-3-yl) butan-2-ylamino) -1-phenylethanol;

rac -2- (4- (pyrimidin-5-yl) butan-2-ylamino) -1-phenylethanol;

( R ) -2- (4- (pyrimidin-5-yl) butan-2-ylamino) -1-phenylethanol;

( S ) -2- (4- (pyrimidin-5-yl) butan-2-ylamino) -1-phenylethanol;

2- (4- ( 1H -indol-2-yl) butan-2-ylamino) -1-phenylethanol;

rac -2- (4- (quinolin-3-yl) butan-2-ylamino) -1-phenylethanol;

( R ) -2- (4- (quinolin-3-yl) butan-2-ylamino) -1-phenylethanol;

rac -2- (1- (pyridin-3-yl) pentan-3-ylamino) -1-phenylethanol;

( R ) -2- (1- (pyridin-3-yl) pentan-3-ylamino) -1-phenylethanol;

( S ) -2- (1- (pyridin-3-yl) pentan-3-ylamino) -1-phenylethanol;

2- (4- (pyridin-2-yl) butan-2-ylamino) -1- (2,4-difluorophenyl) ethanol;

2- (4- (pyridin-3-yl) butan-2-ylamino) -1- (2,4-difluorophenyl) ethanol;

2- (4- (pyridin-4-yl) butan-2-ylamino) -1- (2,4-difluorophenyl) ethanol;

2- (4- (6-chloropyridin-3-yl) butan-2-ylamino) -1- (2,4-difluorophenyl) ethanol;

2- (4- (6-fluoropyridin-3-yl) butan-2-ylamino) -1- (2,4-difluorophenyl) ethanol;

2- (4- (pyrimidin-5-yl) butan-2-ylamino) -1- (2,4-difluorophenyl) ethanol; And

2- (3- (pyridin-3-yl) propylamino) -1- (2,4-difluorophenyl) ethanol.

[Beta] -aminoalcohol derivatives of the formula (1) used in the present invention are disclosed in Korean Patent Application Publication No. 2002-20288 or AF Abdel-Magid et al . , J. Org . Chem . , 61, 3849, 1996] can be prepared using the reductive condensation reaction.

The synthesis method of the β-aminoalcohol derivative of the present invention may be represented by, for example, Scheme 1 below.

Wherein R ¹ , R ² , and R ³ are as defined in Formula 1 above.

First, the starting material aldehyde compound (2) is dissolved in an ether / water mixed solvent, and the temperature of the solution is brought to 0 ° C. using an ice bath. After adding sodium cyanide (NaCN) to this, concentrated hydrochloric acid is slowly dropped (about 1 ml / min). After the addition of hydrochloric acid, the ice bath was removed and reacted for 2 hours to obtain compound (3).

Lithium aluminum hydride (LiAlH ₄ ) is added to an ether solvent, and the compound (3) obtained above is also dissolved in ether and slowly added at 0 ° C. for 6 to 24 hours at room temperature. At the end of the reaction, the reaction was terminated with 3 N potassium hydroxide (KOH) solution and separated by column chromatography to obtain compound (4).

Meanwhile, bromine compound (5) is dissolved in dimethylformamide (DMF), and palladium acetate, lithium chloride, potassium acetate, and compound (6) are added thereto, followed by reaction at 100 ° C. for 4 hours (Heck reaction). After column chromatography, compound (7) can be synthesized.

However, when R <^2> is indolyl, compound (7) can be manufactured by the method similar to following Reaction Formula 2.

Indole (8) and indium chloride (InCl ₃ ) are dissolved in methylene chloride and stirred for about 1 hour, then compound (9) is added and stirred at room temperature again for about 18 hours. After the reaction, the compound (7-a) can be obtained by column chromatography.

The compounds used as starting materials in the preparation process can be easily prepared by conventional methods, and commercially available ones can be purchased and used if necessary.

Thereafter, Compound (4) and Compound (7) were dissolved in dimethylformamide, sodium triacetoxyborohydride and acetic acid were added thereto, stirred at room temperature, and reacted for 10 to 15 hours, followed by column chromatography. Finally, the compound of Formula 1 may be obtained.

If necessary, the isomeric compound obtained above may be further separated and purified by conventional separation methods including chromatography.

The compound of Formula 1 may be reacted with a pharmaceutically acceptable inorganic acid, organic acid or base to form an addition salt, and preferred salts are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid. , Malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methane Salts, such as a sulfonic acid, benzene sulfonic acid, and toluene sulfonic acid, are mentioned.

Salts β- amino alcohol derivatives and a pharmaceutically acceptable thereof, for use in the present invention because it effectively inhibit the secretion of TNF-α, can be used as inhibitors of TNF-α, also It can be usefully used for the prevention and treatment of TNF-α mediated diseases.

TNF-α mediated diseases to which the pharmaceutical composition of the present invention is applicable include sepsis, endotoxin shock, hemodynamic shock, sepsis syndrome, ischemic reperfusion injury, malaria infection, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrosis Disease, Kachexie, transplant rejection, cancer, autoimmune disease, AIDS opportunistic infection, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gout, ankylosing goutitis, Crohn disease, ulcerative cystitis, Multiple sclerosis, erythema nodosum leprosum (ENL) with systemic lupus erythematosus, erythema nodosum leprosum (ENL), radiation damage, oxygen pulmonary alveolar injury, and the like, but are not limited thereto.

The compositions of the present invention can be prepared in pharmaceutical formulations according to conventional methods. In the preparation of the formulation, it is preferred that the active ingredient is mixed or diluted with the carrier or enclosed in a carrier in the form of a container. When the carrier is used as a diluent, it may be a solid, semisolid or liquid substance which acts as a carrier, excipient or medium for the active ingredient. Thus, the formulations may be in the form of tablets, pills, powders, assays, elixirs, suspensions, emulsions, solutions, syrups, aerosols, soft or hard gelatin capsules, sterile injectables, sterile powders and the like.

Examples of suitable carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, Propylhydroxybenzoate, talc, magnesium stearate and mineral oil. The formulation may further comprise fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives and the like. Compositions of the present invention may be formulated using methods well known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal. Dosages of active ingredients such as β-aminoalcohol derivatives or pharmaceutically acceptable salts thereof used in the present invention depend on the subject being treated, the severity of the disease or condition, the rate of administration and the judgment of the prescribing physician. As an active ingredient, the compound of formula (I) may be used once daily at a weight of 0.1 to 10 mg / kg for parenteral administration and 1 to 100 mg / kg for oral administration on a daily basis for mammals including humans or Can be administered in divided oral or parenteral routes. In some cases, smaller dosages may be more suitable than the above-mentioned ranges, and larger amounts may be used without causing harmful side effects, and higher dosages may be dispensed in several smaller portions throughout the day. do.

Hereinafter, the present invention will be described in more detail with reference to Examples, which are only intended to assist in understanding the configuration and operation of the present invention, and the scope of the present invention is not limited to these Examples.

Example 1: 5- [3- ( rac Synthesis of -2-hydroxy-2-phenylethylamino) butyl] pyridine-2-carbonitrile

79 mg (0.574 mmol) of 2-amino-1-phenylethanol and 100 mg (0.574 mmol) of 5- (3-oxobutyl) pyridine-2-carbonitrile were dissolved by adding 10 ml of dry DMF, followed by sodium triacetoxy 0.365 g (1.722 mmol) of boron hydride (sodium triacetoxyborohydride) and 0.1 ml (1.722 mmol) of acetic acid were added thereto, and the mixture was reacted at room temperature overnight. After the reaction was completed, the reaction was terminated with 1 N sodium hydroxide solution, extracted with saturated aqueous sodium hydrogen carbonate solution, extracted with methylene chloride, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated. Column chromatography (CHCl ₃ : MeOH = 9: 1) afforded 0.154 g (0.521 mmol) of the title compound (yield 90.7%).

¹ H NMR (CDCl ₃ , 300 MHz, δ): 8.55 (s, 1H), 7.61 (m, 2H), 7.37-7.28 (m, 5H), 4.69 (m, 1H), 2.60-3.04 (m, 5H) , 2.20 (br s, 2H), 1.76 (m, 2H), 1.14 (d, J = 6.3 Hz, 3H); MS, m / z (relative strength) 296 (M ⁺ +1, 2), 188 (100), 172 (2), 159 (30), 13 (8), 117 (55), 107 (4), 90 (11), 77 (13); mp 86-88 ° C.

Examples 2 to 33

Using the same process as in Example 1 to prepare a variety of compounds as shown in Table 1 below. The S- and R- isomers in the following examples were obtained from Aldrich (USA) corresponding to the compounds of S- and R-optical activity (4) and prepared in the same manner as in Example 1.

Test Example: Measurement of TNF-α Inhibitory Effect

In order to investigate the effect of the β-aminoalcohol derivative of the above example on the secretion of TNF-α, lipopolysaccharide (LPS), which is an inducer of TNF-α, was treated with the β-aminoalcohol derivative as follows. Afterwards, the secretion amount of TNF-α was measured by enzyme immunoassay (ELISA).

Human monocytic cell line THP-1 cells (ATCC No .: TIB-202) were cultured in medium containing 10% FBS (fetal bovine serum) in RPMI 1640 (Gibco, BRL, USA).

The cultures were aliquoted to 5 × 10 ⁵ cells / ml / well in 96-well plates and 1 ug / ml of lipopolysaccharide (LPS) was added to activate the cells to release TNF-α.

The control group was treated only with LPS, and the experimental group was treated with 0.1 uM or 1 uM of the compounds of Examples 1 to 33 simultaneously with LPS treatment, and the comparative group was treated with 1 uM of dexamethasone (Sigma, USA) instead of the compound of Example. The plate was left for 24 hours, after which the amount of TNF-α in the cell culture was measured using an ELISA kit (Oscotec. Inc., Korea). Absorbance was measured at 450 mm using Dynatech MR-7000 (Dynatech Laboratorie), and the inhibition rate of TNF-α was calculated as a percentage of the control group and the results are shown in Table 2 below.

As can be seen in Table 2, the compounds of formula 1 exhibit TNF-α inhibitory activity equivalent to or better than the existing TNF-α inhibitor dexamethasone.

As described above, since the β-aminoalcohol derivative of Formula 1 shows excellent TNF-α inhibitory activity, the pharmaceutical composition containing it as an active ingredient may be usefully used as a prophylactic or therapeutic agent for TNF-α mediated diseases.

Claims (4)

Sepsis, endotoxin shock, hemodynamic shock, sepsis syndrome, ischemic reperfusion injury, malaria infection, mycobacterial infection, meningitis, comprising a β-aminoalcohol derivative of formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient Psoriasis, congestive heart failure, fibrosis disease, Kachexie, transplant rejection, cancer, autoimmune disease, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gout, ankylosing gout, Crohn disease, ulcerative bladder Tumor necrosis factor selected from the group consisting of triangitis, multiple sclerosis, systemic lupus erythematosus leprosy type erythema nodosum leprosum (ENL), and oxygen pulmonary alveolar injury composition for preventing or treating TNF-α) mediated diseases: Formula 1

Where R ¹ is phenyl unsubstituted or substituted with halogen, R ² is pyridinyl unsubstituted or substituted with cyano or halogen; Pyrimidinyl; Indolyl; Or quinolyl, R ³ is hydrogen or C _1-4 alkyl. delete The method of claim 1, A composition wherein the β-aminoalcohol derivative of Formula 1 is selected from the group consisting of: 5- [3- ( rac -2-hydroxy-2-phenylethylamino) butyl] pyridine-2-carbonitrile; 5- [3-(( R ) -2-hydroxy-2-phenylethylamino) butyl] pyridine-2-carbonitrile; 5- [3-(( S ) -2-hydroxy-2-phenylethylamino) butyl] pyridine-2-carbonitrile; rac -2- (4- (2-chloropyridin-3-yl) butan-2-ylamino) -1-phenylethanol; ( R ) -2- (4- (2-chloropyridin-3-yl) butan-2-ylamino) -1-phenylethanol; ( S ) -2- (4- (2-chloropyridin-3-yl) butan-2-ylamino) -1-phenylethanol; rac -2- (4- (pyridin-3-yl) butan-2-ylamino) -1-phenylethanol; ( R ) -2- (4- (pyridin-3-yl) butan-2-ylamino) -1-phenylethanol; ( S ) -2- (4- (pyridin-3-yl) butan-2-ylamino) -1-phenylethanol; rac -2- (4- (6-chloropyridin-3-yl) butan-2-ylamino) -1-phenylethanol; ( R ) -2- (4- (6-chloropyridin-3-yl) butan-2-ylamino) -1-phenylethanol; ( S ) -2- (4- (6-chloropyridin-3-yl) butan-2-ylamino) -1-phenylethanol; rac -2- (4- (6-fluoropyridin-3-yl) butan-2-ylamino) -1-phenylethanol; ( R ) -2- (4- (6-fluoropyridin-3-yl) butan-2-ylamino) -1-phenylethanol; ( S ) -2- (4- (6-fluoropyridin-3-yl) butan-2-ylamino) -1-phenylethanol; rac -2- (4- (pyrimidin-5-yl) butan-2-ylamino) -1-phenylethanol; ( R ) -2- (4- (pyrimidin-5-yl) butan-2-ylamino) -1-phenylethanol; ( S ) -2- (4- (pyrimidin-5-yl) butan-2-ylamino) -1-phenylethanol; 2- (4- ( 1H -indol-2-yl) butan-2-ylamino) -1-phenylethanol; rac -2- (4- (quinolin-3-yl) butan-2-ylamino) -1-phenylethanol; ( R ) -2- (4- (quinolin-3-yl) butan-2-ylamino) -1-phenylethanol; rac -2- (1- (pyridin-3-yl) pentan-3-ylamino) -1-phenylethanol; ( R ) -2- (1- (pyridin-3-yl) pentan-3-ylamino) -1-phenylethanol; ( S ) -2- (1- (pyridin-3-yl) pentan-3-ylamino) -1-phenylethanol; 2- (4- (pyridin-2-yl) butan-2-ylamino) -1- (2,4-difluorophenyl) ethanol; 2- (4- (pyridin-3-yl) butan-2-ylamino) -1- (2,4-difluorophenyl) ethanol; 2- (4- (pyridin-4-yl) butan-2-ylamino) -1- (2,4-difluorophenyl) ethanol; 2- (4- (6-chloropyridin-3-yl) butan-2-ylamino) -1- (2,4-difluorophenyl) ethanol; 2- (4- (6-fluoropyridin-3-yl) butan-2-ylamino) -1- (2,4-difluorophenyl) ethanol; 2- (4- (pyrimidin-5-yl) butan-2-ylamino) -1- (2,4-difluorophenyl) ethanol; And 2- (3- (pyridin-3-yl) propylamino) -1- (2,4-difluorophenyl) ethanol. delete