JPH11322600A - Chemokine production inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a chemokine production inhibitor useful for treatment and prevention of inflammatory pulmonary diseases or the like. SOLUTION: This chemokine production inhibitor contains (+)-(3R)-3-(4- fluorophenylsulfonamide)-1,2,3,4-tetrahydro-9-carbazole-propionic acid or its pharmaceutically permissible salt as an active ingredient. It is preferable that the chemokine is IL-8, MCP-1 or RANTES and the inhibitor is used for prevention or treatment of inflammatory pulmonary diseases, renal diseases, arteriosclerosis, inflammation of gastric mucosa, arthritis or eye diseases.

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the formula

[0002]

Embedded image

(+)-(3R) -3- (4-
Fluorophenylsulfonamido) -1,2,3,4-
The present invention relates to a chemokine production inhibitor comprising tetrahydro-9-carbazolepropionic acid or a pharmaceutically acceptable salt thereof as an active ingredient.

The compound of the above formula (I) (BAY u 3405, generic name: ramatroban) has a platelet aggregation inhibitory action and a thromboxane A ₂ receptor antagonistic action, and is useful for thrombosis, thromboembolism and ischemia. It is known that it is useful for treatment and as an anti-asthmatic agent, an anti-allergic agent, and a therapeutic agent for allergic dermatitis (for example, see Japanese Patent Publication No. 4-50301 and Japanese Patent Application Laid-Open No. 8-175991). It has not been known to have a chemokine production inhibitory effect.

A chemokine has four cysteine residues (Cys), and is a generic term for a basic heparin-binding protein having a molecular weight of 8 to 12 KD and forming an SS (disulfide) bond through each Cys. 8 (Interleukin-8), M
About 30 molecules such as CP-1 (Monocyte Chemotactic Protein-1) and Lantes have been identified. Recent studies have shown that chemokines play an important role in the inflammatory response of living organisms. That is, chemokines are not detected in normal tissues but detected in inflamed sites, promote leukocyte infiltration into tissue inflamed sites, and participate in inflammation.

For example, IL-8 mainly activates neutrophils, enhances the expression of cell adhesion molecules, and enhances the adhesion of neutrophils to vascular endothelial cells. IL-8 also has neutrophil chemotaxis, and IL-8 produced in damaged tissues promotes the migration of neutrophils attached to vascular endothelial cells into tissues, and inflammation associated with neutrophil infiltration Be evoked.

[0007] MCP-1 or Lantes also causes inflammation by the same mechanism as IL-8. That is, MCP-1 is mainly composed of monocytes and T
Activates lymphocytes and is involved in the infiltration of these blood cells into inflammatory sites. Lantes mainly activates eosinophils, T lymphocytes and monocytes, and plays an important role in tissue infiltration of these blood cells.

For example, inflammatory lung diseases such as acute respiratory distress syndrome, chronic lower respiratory tract infection, interstitial pneumonia, pulmonary fibrosis, renal diseases such as acute glomerulonephritis and chronic progressive nephritis, For patients with arteriosclerosis, gastric mucosal inflammation caused by Helicobacter pylori infection, ocular diseases such as acute and chronic rheumatoid arthritis, uveitis and corneal infection, all of IL-8, MCP-1 and Lantes It is well known that production of one or any one or two chemokines is enhanced. Therefore, IL-8, M
Compounds that inhibit chemokine production, such as CP-1 or Lanthes, are useful for treating various diseases based on tissue infiltration, such as neutrophils, monocytes, T lymphocytes, eosinophils, basophils, and NK cells. It is considered to be used as an anti-inflammatory lung disease agent, an anti-nephritis agent, an anti-atherosclerotic agent, an anti-gastric mucositis agent, an anti-arthritis agent, an anti-ocular disease agent for the purpose of prevention and prevention.

[0009] The present inventors have found that compounds of formula (I) is prostaglandin H ₂ IL-8 in human blood or human vascular endothelial cells induced by U-46619 or human TNFα is analogue, MCP-1 or Lantes
The inventors have found that mRNA expression or protein production is suppressed, and have completed the present invention.

The compound of the formula (I) is a compound known per se, and can be produced, for example, by the method described in Japanese Patent Publication No. 50301/1992. Pharmaceutically acceptable salts of the compound of the formula (I) include, for example, alkali metal salts or alkaline earth metal salts such as sodium salt, potassium salt, magnesium salt and calcium salt; ammonium salt; ethylamine; Di- or triethylamine, di- or tri-ethanolamine,
Dicyclohexylamine, dimethylaminoethanol,
Examples thereof include salts with organic amines such as arginine and ethylenediamine. The compound of the formula (I) or a salt thereof is used for the treatment or prevention of various diseases considered to be caused by enhanced chemokine production. More specifically, for example, acute respiratory distress syndrome, chronic lower respiratory tract infection, Inflammatory pulmonary diseases such as pulmonary pneumonia, pulmonary fibrosis, etc., renal diseases such as acute glomerulonephritis and chronic progressive nephritis, arteriosclerosis, cystitis, Kawasaki disease, endotoxemia, sepsis, helicobacter・
As a drug for the treatment or prevention of gastric mucosal inflammation caused by pylori infection, ulcerative colitis, joint diseases such as acute and chronic rheumatoid arthritis and gout, eye diseases such as uveitis and corneal infections, It can be administered to humans or non-human warm-blooded animals.

The administration can be carried out orally, parenterally or topically, and the dose is not particularly limited, and the severity of symptoms, age, weight, administration route, sex, judgment of a doctor, etc. Can vary over a wide range, but for adults, typically 0.5-10 mg / kg / day,
It is convenient to administer preferably 1 to 5 mg / kg / day once or several times a day.

The compound of formula (I) or a salt thereof is administered depending on the administration route, for example, an oral preparation such as fine granules, granules, capsules, tablets, liquids and syrups; Parenteral preparations such as infusions, drops and suppositories; and topical (transdermal or transmucosal) preparations such as ointments, creams, cataplasms and sprays.

Formulation of the compound of formula (I) or a salt thereof
It can be carried out by formulating the compound of the formula (I) or a salt thereof with an additive according to a conventional method.

Examples of additives that can be used in the preparation of oral administration preparations include starches such as corn starch and potato starch, sugars such as lactose, sucrose, glucose, mannitol, and inorganic salts such as calcium carbonate and synthetic aluminum silicate. Salts, paraffin, wax, fats and oils such as higher fatty acids, excipients such as cellulose; starches such as corn starch, potato starch, lactose, sucrose, glucose, saccharides such as mannitol, dextrin,
Natural substances such as gum arabic, tragacanth, carrageenin, sodium alginate and gelatin, cellulose derivatives such as methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and sodium carboxymethylcellulose, and synthetic polymers such as polyethylene glycol, polyvinylpyrrolidone, and polyvinyl alcohol Disintegrators such as starches, low-substituted hydroxypropylcellulose and crystalline cellulose; lubricants such as magnesium stearate, talc and synthetic aluminum silicate; coloring agents such as various food colorings; Artificial sweeteners, acidulants such as organic acids,
Flavoring and flavoring agents such as mint oil; solubilizing agents such as various surfactants; stabilizers such as benzoic acid esters (in the case of liquids)
And the like.

As a solvent in the case of a liquid or injection, water is preferably used, and if necessary, a buffer adjusted to an appropriate pH can be used. In addition, various kinds of amino acids, saccharides, salts and the like can be used. Isotonic agents, solubilizers such as alcohols, polyethylene glycol, sodium lauryl sulfate, and polysorbate can be added.

In transdermal preparations such as ointments and creams, the base may be an emulsion or water-soluble base such as hydrophilic ointment, water-absorbing ointment, lanolin hydrolyzate, hydrophilic vaseline, lanolin, polyethylene glycol, etc .; paraffin,
Oily bases such as simple ointment and white ointment can be used, and besides preservatives such as paraoxybenzoates, humectants such as glycerin, propylene glycol, butylene glycol, and surfactants Can be.

Further, cataplasms obtained by supporting a compound of the formula (I) or a salt thereof on a film made of various materials can also be suitably used.

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

[0019]

[Examples] Test example 1: IL-8 production inhibitory effect [Method] BAY was added to human blood collected by citrated blood collection.
The u3405 solution was added, gently stirred, and incubated at 37 ° C for 5 minutes. Subsequently, U-46619 (1 × 10 ⁻⁶ M) was added, and the mixture was incubated at 37 ° C. for 2 hours with shaking. After centrifugation at 5000 rpm for 30 seconds, the plasma was separated and the concentration of IL-8 was measured with an ELISA kit (Endogen Inc.).

[Results] The test results are shown in Table 1 in terms of the rate of inhibition of IL-8 production.

[0021]

[Table 1]

Test Example 2: Inhibitory effect on IL-8 mRNA expression [Method] BAY u3405 solution was added to human normal vascular endothelial cells (HUVEC) and incubated for 15 minutes. Then U-4661
9 (1 x 10 ^-6 M) or human TNFα (100 units / ml) and incubated for 6 hours, then IL-8 mRNA of HUVEC
Was examined by RT-PCR.

[Results] The test results are shown in Table 2 below.
It is shown by the suppression rate against expression.

[0024]

[Table 2]

Test Example 3 MCP-1 mRNA Expression Inhibitory Effect [Method] BAY u 3405 solution was added to HUVEC and incubated for 15 minutes. Subsequently, after adding U-46619 (1 × 10 ⁻⁶ M) or human TNFα (100 units / ml) and incubating for 6 hours, the expression of MCP-1 mRNA of HUVEC was examined by RT-PCR.

[Results] The test results are shown in Table 3 below.
It is shown by the suppression rate against expression.

[0027]

[Table 3]

Test Example 4: Inhibitory effect of lantes production [Method] BAY was added to human blood collected by citrated blood collection.
The u3405 solution was added, gently stirred, and incubated at 37 ° C for 5 minutes. Subsequently, U-46619 (1 × 10 ⁻⁶ M) was added, and the mixture was gently stirred, followed by further incubation at 37 ° C. for 5 minutes. Then, after centrifugation at 2000 xg for 10 minutes, the supernatant was separated and the Lantes concentration was measured with an ELISA system (Amersham).

[Results] The test results are shown in Table 4 below in terms of the rate of inhibition of Lantes production.

[0030]

[Table 4]

Formulation Example 1: Capsules 100 g of a finely pulverized compound of the formula (I) are mixed with 250 g of corn starch, 260 g of lactose and 216 of microcrystalline cellulose.
g of polyvinylpyrrolidone 25,
Granulated with an aqueous solution containing 20 g and then dried. The granulate was sieved and mixed with 4 g of magnesium stearate. The mixture was filled into capsules so as to contain 425 mg, and a capsule containing 50 mg of the drug in one capsule was produced.

Formulation Example 2: Tablets The granules produced as in Formulation Example 1 were sieved and mixed with 4 g of magnesium stearate. This mixture was compressed into 425 mg tablets weighing 11 mm.

Formulation Example 3: Fine granules 50 g of a finely pulverized compound of the formula (I) is mixed with 450 g of D-mannitol, 363 g of lactose and 100 g of microcrystalline cellulose.
And the mixture was granulated with an aqueous solution containing 35 g of hydroxypropylcellulose and then dried. The granules were sieved and the coarse granules were crushed and mixed again. Further, it was mixed with 2 g of light anhydrous silicic acid to produce fine granules.

Formulation Example 4: Dry syrup preparation Saccharose 94 obtained by pulverizing 50 g of the finely pulverized compound of formula (I)
0 g, 3 g of powder of tragacanth, 2 g of anhydrous citric acid and 3 g of sodium citrate, the mixture was granulated with an aqueous solution containing 3 g of hydroxypropylcellulose, and then dried. The granules were sieved and the coarse granules were ground and mixed again to produce a dry syrup.

Formulation Example 5: Injection 24 g of 0.1N sodium hydroxide, 1 g of sodium citrate and 9 g of sodium chloride were added to an appropriate amount of water for injection and dissolved, and 1 g of the compound of the formula (I) was further dissolved. The pH is then adjusted to 7.5 by adding about 1.3 g of 1N hydrochloric acid and made up to 1 liter with water for injection. This aqueous solution was sterilized and filtered through a membrane filter, and filled in an ampoule to produce an injection.

Formulation Example 6 Emulsion Ointment (Cream) A small amount of the Japanese Pharmacopoeia hydrophilic ointment is added to 1 g of the finely pulverized compound of the formula (I), and the mixture is thoroughly ground. Then, the emulsion ointment was manufactured by thoroughly kneading the mixture to obtain a uniform quality.

Formulation Example 7: Ointment A small amount of JP Vaseline was added to 1 g of the finely pulverized compound of the formula (I), and the mixture was thoroughly ground. Further, JP Vaseline was gradually added to make a total amount of 100 g. An ointment was produced as a quality equalizer.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/40 ACV A61K 31/40 ACV // C07D 209/88 C07D 209/88

Claims (3)

[Claims] (1) Formula (1) (+)-(3R) -3- (4-fluorophenylsulfonamido) -1,2,3,4-tetrahydro-9-carbazolepropionic acid or a pharmaceutically acceptable salt thereof as an active ingredient A chemokine production inhibitor comprising: 2. The chemokine production inhibitor according to claim 1, wherein the chemokine is IL-8, MCP-1 or Lanthes. 3. The chemokine production inhibitor according to claim 1, which is used for preventing or treating inflammatory pulmonary disease, renal disease, arteriosclerosis, gastric mucosal inflammation, arthritis or eye disease.