MXPA06008306A - Amine salt of carbostyril derivative - Google Patents

Abstract

The invention provides an amine salt of a carbostyril derivative formed from a carbostyril derivative represented by the formula (1) [wherein R is a halogen atom;the substituted position of the side chain is 3- or 4-position in the carbostyril skeleton;and the bonding between 3- and 4-positions of the carbostyril skeleton is a single bond or a double bond]and an amine;and the invention is useful as drugs for treating various diseases, especially as aqueous formulations due to the superior water solubility and the superior pharmacologic effects.

Description

AMINO SALT FROM CARBOHYDRATE DERIVATIVE TECHNICAL FIELD The present invention relates to pharmaceutically useful and novel amine salts of a carbostyril derivative, more specifically, amine salts of a carbostyril derivative formed from a carbostyril derivative represented by the formula (1): wherein: R is a halogen atom, the substituted position of the side chain is the 3 or 4 position in the basic structure of carbostyril, and the bond between positions 3 and 4 of the basic structure of carbostyril is an individual bond or a double bond, and an amine; A pharmaceutical formulation comprises the amine salt of the carbostyril derivative as the active ingredient.

BACKGROUND OF THE INVENTION It is known that the carbostyril derivatives represented by the general formula (1) are useful as an anti-ulcer agent (JP-B-63-35623). The representative example of the 2- (4-chlorobenzoyl-amino) -3- (2-quinolone-4-yl) -propionic acid derivative is a commercially available medicine, but the formulation thereof is limited to a solid formulation for oral administration or a liquid suspension-type formulation (an ophthalmic suspension, an enema, and a gargle) since the compound is very poorly soluble in water. The liquid suspension type formulation has several problems in the preparation, such as the difficulty in maintaining the uniformity of the content; the need to control particle distribution; the need to use a suspending agent, a dispersing agent, and the like; the impossibility of terminal sterilization through steam or sterilization through filtration; etc. In contrast, formulations in the form of a solution have some advantages such as rapid absorption compared to solid formulations and liquid suspension type formulations, and therefore are desirable to formulate the carbostyril derivatives in the form of a solution, such as injections, ophthalmic solutions, oral solutions, enemas, gargles, ear drippers, nose drops, and external preparations. The carbostyril derivatives represented by the above general formula (1) and the preparation thereof are described in JP-B-63-35623. It is also known that the carbostyril derivatives are formed in a bismuth salt thereof, in the carboxylate bismuth complex thereof, and a salt with a thiamine derivative or a piperazine derivative (WO 95/12579 and JP-). AB-2956 73). However, said salts also have low solubility in water.

DETAILED DESCRIPTION OF THE INVENTION The present invention is to provide a novel salt of a carbostyril derivative represented by the general formula (1) which can solve the above problems. The present inventors have studied extensively to find a salt of the carbostyril derivative of the formula (1) having a superior solubility to water, and have found that an amine salt of the carbostyril derivative of the aforementioned formula (1) exhibits A desired excellent water solubility. Based on the new findings, the present invention has been completed. The present invention includes a variety of embodiments as follows: 1. An amine salt of a carbostyril derivative formed of a carbostyril derivative represented by the formula (1): wherein R, the substituted position of the side chain and the bond between positions 3 and 4 of the basic carbostyril structure are as described above, and an amine. 2. The amine salt of the carbostyril derivative according to number 1 above, wherein said carbostyril derivative (1) is 2- (4-chlorobenzoylamino) -3- (2-quinolone-4-yl) -propionic acid co. 3. The amine salt of the carbostyril derivative according to number 2 above, wherein said amine is L-arginine. 4. The amine salt of the carbostyril derivative according to number 2 above, wherein said amine is L-lysine. 5. The amine salt of the carbostyril derivative according to number 2 above, wherein said amine is ethylenediamine. 6. The amine salt of the carbostyril derivative according to number 2 above, wherein said amine is tris (hydroxymethyl) -aminomethane. 7. The amine salt of the carbostyril derivative according to number 2 above, wherein said amine is monoethanolamine. 8. The amine salt of the carbostyril derivative according to number 2 above, wherein said amine is diethanolamine. 9. The amine salt of the carbostyril derivative according to number 2 above, wherein said amine is diisopropanolamine. 10. The amine salt of the carbostyril derivative according to number 2 above, wherein said amine is meglumine. 11. A pharmaceutical formulation comprising the amine salt of the carbostyril derivative according to any of numbers 1 to 10 above as the active ingredient. 12. A pharmaceutical formulation comprising a carbostyril derivative represented by the above formula (1) and an amine, which can be prepared in the form of an aqueous solution through the addition of an aqueous solvent when used. 13. The pharmaceutical formulation that can be prepared in a preparation when used according to number 12 above, wherein said carbostyril derivative (1) is 2- (4-chlorobenzoylamino) -3- (2-quinolone-4) acid -il) -propionic. 14. The pharmaceutical formulation to be prepared in a preparation when used according to number 13 above, wherein said amine is L-arginine. 15. The pharmaceutical formulation to be prepared in a preparation when used according to No. 13 above, wherein said amine is L-lysine. 16. The pharmaceutical formulation to be prepared in a preparation when used according to number 13 above, wherein said amine is ethylenediamine. 17. The pharmaceutical formulation to be prepared in a preparation when used according to No. 13 above, wherein said amine is tris (hydroxymethyl) aminomethane. 18. The pharmaceutical formulation to be prepared in a preparation when used according to No. 13 above, wherein said amine is monoethanolamine. 19. The pharmaceutical formulation to be prepared in a preparation when used according to No. 13 above, wherein said amine is diethanolamine. 20. The pharmaceutical formulation to be prepared in a preparation when used according to No. 13 above, wherein said amine is diisopropanolamine. 21. The pharmaceutical formulation to be prepared in a preparation when used according to No. 13 above, wherein said amine is meglumine. The halogen atom of the group R in the above formula (1) means a fluorine, chlorine, bromine or iodine atom. The amine includes an amino acid, an amine substituted with lower alkyl which may have a substituent selected from the group consisting of the hydroxy group and the amino group, an amino sugar, and the like. The amino acid includes a basic amino acid such as L-arginine, L-lysine, L-histidine, β-amino-allanine, α-amino-butyrine, ornithine, d-hydroxy-lysine, canavanine, lombricin, homoarginine, α-hydroxy- homoarginine,? -hydroxy-L-arginine,? -lanine,? -amino-butyric acid,? -amino-? -methylenebutyric acid, creatine, rhodoic acid, sarcosine,? -amino-a-methylenebutyric acid, cinurenin, agritin, L-tryptophan, ibotenic acid, latirin, trichotomic acid, quisqualic acid, linatin, ergothioneine, creatinine, and cycloserine. The lower alkyl substituted amine which may have a substituent selected from the group consisting of a hydroxy group and an amino group includes an amine substituted with from 1 to 3 straight or branched chain C?-6 alkyl groups which may also have 1 to 3 substituents selected from the group consisting of hydroxy group and amino group, such as tris- (hydroxymethyl) aminomethane, ethylenediamine, diethanolamine, diisopropanolamine, triethanolamine, triisopropanolamine, hydroxymethylamine, (2-hydroxyethyl) amine, -hydroxyethylamine, 3-hydroxypropylamine, 2,3-dihydroxy-ethylamine, 4-hydroxybutylamine, 3, 4-dihydroxybutylamine, 1, 1-dimethyl-2-hydroxyethylamine, 5-hydroxypentylamine, 6-hydroxyhexylamine, 2-methyl-3-hydroxypropylamine, 2,3,4-trihydroxybutylamine, aminomethylamine, 1-aminoethylamine, 3-aminopropylamine, 2,3-diaminoethylamine, 4-aminobutylamine, 3,4-diaminobutylamine, 1,1-dimethyl-2-aminoethylamine, 5-aminopentylamine, 6-aminohexylamine, 2-methyl-3-aminopropylamine, 2,3,4-triaminobutylamine, methylamine, ethylamine, propylamine, isopropylamine, butylamine, tert-butylamine, pentylamine, hexylamine, dimethylamine, diethylamine, dipropylamine, dibutylamine, dipentylamine, diethylamine, N-methyl-N-ethylamine, N-ethyl-N-propylamine, N-methyl- N-butylamine, N-methyl-N-hexylamine, N-methyl-N- (2-hydroxyethyl) amine, N-methyl-N- (2-aminoethyl) amine, N- (2-aminoethyl) -N- (2-hydroxyethyl) amine and the like. The amine sugar includes, for example, meglumine (ie, N-methyl-D-glucamine), D-glucosamine, D-galactosamine, D-mannosamine, mycosamine, canosamine, neosamine C, N-methyl-L-glucosamine, mycaminose, muramic acid, streptamine and the like. Preferably the amino acid is a basic amino acid such as L-arginine, L-lysine, and L-histidine; the amine substituted with lower alkyl which may have a substituent selected from the group consisting of the hydroxy group and amino group which is tris (hydroxymethyl) aminomethane, ethylenediamine, mono-ethanolamine, diethanolamine, diisopropanolamine, tri-ethanolamine, triisopropanolamine and the like; and the aminosugar is meglumine, D-glucosamine and the like. The amine salts of the carbostyril derivative can be prepared through the reaction of the derivative with an appropriate amine in a suitable solvent. The solvent used herein includes, for example, alcohols such as methanol, ethanol, and isopropanol. Ketones such as acetone, and methyl ethyl ketone, water; and the like; or the mixture of these. The reaction is generally completed from room temperature to 150 ° C, preferably from room temperature to about 120 ° C, for several minutes to 7 days. The amount of the amine used is at least 0.1 moles, preferably from 0.1 to 2 moles to 1 mole of the carbostyril derivative. Within the reaction system, an acid such as hydrochloric acid may optionally be added in order to prevent dissociation of the carbostyril derivative. In addition, the amine salt of the carbostyril derivative can be formed in the course of the aqueous preparation through the addition of an amine into an aqueous solution of the carbostyril derivative without the isolation as a salt. The compounds of the present invention exhibit anti-ulcer activities, activities to increase endogenous prostaglandin E2, the extinction or inhibition of active oxygen, the inhibition of IL-8 production, the inhibition of granulocyte activation, the inhibition of the expression of the granulocyte adhesion factor and the like, and are useful as an anti-ulcer drug, an agent for treating gastritis, a drug having an efficacy derived from prostaglandin E2, such as an agent to prevent and treat ulcer, an antioxidant , an agent for the prevention, protection, or treatment of acute or chronic inflammatory diseases. Additionally, they are useful for improving the biocompatibility of an artificial organ and an artificial blood vessel. In addition, the compounds of the invention are especially useful for preventing the recurrence of a peptic ulcer and inflammation. Inflammatory diseases include, but are not limited to, inflammatory dermatoses, such as inflammatory keratosis (psoriasis, etc.), atopic dermatitis, contact dermatitis and the like; autoimmune diseases which are chronic inflammatory diseases such as chronic rheumatoid, systemic lupus erythematosus (SLE), Behchet's disease and the like; inflammatory liver diseases such as hepatitis B, hepatitis C, alcoholic hepatitis; allergic hepatitis induced by drug and the like; inflammatory kidney diseases such as nephritis, glomerulonephritis, and the like; respiratory and inflammatory diseases, such as bronchitis and the like; stomatitis; laryngitis; inflammation of the vocal cords; disorders of the voice; inflammation due to the use of an artificial organ and an artificial blood vessel; mucosal disorder of the gastrointestinal tract and intestinal mucosal disorder due to a non-spheroidal anti-inflammatory drug, and the like. As the intestinal mucosal disorder, cryptogenic simple primary bowel ulcer, non-specific colonic ulcer, ulcerative colitis due to non-specific inflammation, Crohn's disease and the like are exemplified, and additional disorders due to infection, cardiovascular disease, collagen disease, radiation, drugs and the like; etc. Additionally, the compounds of the invention have effects of somatostatin release inhibition, antidiabetic effects, urease inhibition effects and the like and are useful as a somatostatin release inhibitor, an antidiabetic drug and a urease inhibitor. On the basis of the effects of urease inhibition, the compounds of the invention are useful for preventing and treating the disease which can be caused by the increase in urease activity through the increase of several bacteria and the production of ammonia, and in this way the compounds can be used for prevent and treat gastric mucosal disorders that can be caused by the production of ammonia through the increase of the pylorus H. Additionally, the compounds can be used to improve and treat hyperammonemia and diseases associated with hyperammonemia by decreasing the Ammonia production in the intestinal tract, for example, can be used to prevent and treat hepatic encephalopathies that are caused by liver diseases such as hepatitis, cirrhosis of the liver, and the like.; neuropsychiatric disorders; abnormality in the electroencephalogram; and trembling with undulations. The compounds of the invention also have an increased effect of cup cells in the eye, an increased effect of mucus in the eyes, facilitates the effect of proliferation of the corneal epithelial cell, and also an increased effect of the tear fluid, and in this way it can be useful as a drug to treat dry eye, that is, dry eye syndrome. Therefore, the compounds of the invention can increase the production of emucin through the increase of the cup cells in the eye and prevent the decrease of emucin as observed in the dry eye while controlling the aqueous layer by increasing the mucus in the eye. The compounds also exhibit the action of increasing tear fluid and thus are useful as a drug for treating dry eye. In addition, the compounds of the invention are not only useful for Sjoegren syndrome or Stevens-Johnson syndrome which may indicate dry eye syndrome, but are also useful as a drug to prevent and / or treat various ophthalmopathies which they are indicated through the secondary disease of dry eye or through the reduction of the cup cells and the amount of mucus. It is very easy to damage the eyeballs affected by the dry eye. Thus, the compounds of the invention are also useful as a drug for curing an eye wound, especially a wound of the cornea epithelium, or an infra-ocular perfusion, and the washing agents used in ophthalmological operations (cataracts, body vitreous, glaucoma), since the compounds have an effect of accelerating the proliferation of the epithelial cells of the cornea. The pharmaceutical composition of the compound of the present invention can be prepared in various forms of common pharmaceutical preparations through the formulation of amine salts of the carbostyril derivative as the active ingredient. The pharmaceutical formulations of the present invention are especially preferred for aqueous liquid formulations such as injections, ophthalmic solutions, oral solutions, enemas, gargles, ear drops, nasal drops, external liquid preparations and the like, and also include other conventional forms of formulations. pharmaceuticals, such as tablets, pills, powders, emulsions, granules, capsules, suppositories, aerosols, syrups and the like. The preparation of the aqueous solution of the present invention can be prepared through the addition of the amine salt of the carbostyril derivative in an aqueous solvent such as water, physiological saline and the like. Pharmaceutical formulations can be prepared in the form of a preparation when used, comprising the carbostyril derivative and the amine, can be prepared through the addition of an aqueous solvent when used, and therefore the amine salt of the carbostyril derivative is formed in the preparation. In the preparation of the pharmaceutical formulations of the present invention, conventional additives or excipients, such as fillers, an expander, a binder, a humectant, a disintegrator, a surface activating agent, a lubricant, an essence, can also be used. a perfume, a sweetener, a coloring agent. In addition, sustained release preparations can also be prepared through the incorporation of a suitable resin and the like. The formulations of the present invention for treating ophthalmopathies are especially preferred to form a pharmaceutical preparation applicable for ophthalmological purposes, such as an ophthalmic solution, an ophthalmic ointment and the like. Depending on the symptoms where it is going to be applied. In the case of the preparation of injections of this They can be prepared in the form of a solution, an emulsion, or a suspension, and are generally sterilized and preferably made sotonic for the blood. For the purposes of forming in a solution, emulsion, or suspension, any diluents that are widely used in this field may be applied, for example, solvents such as water, ethyl alcohol, propylene glycol, and the like; stearyl alcohols such as ethoxylated isostearyl alcohol, polyoxyethylated isostearyl alcohol, and the like; emulsifying agents such as polyoxyethylene sorbitan fatty acid esters and the like; suspending agents such as gum arabic, sodium carboxymethyl cellulose, hydroxypropyl ethyl cellulose and the like. In the case of the preparation of a blood injection solution for blood, a sufficient amount of sodium chloride, glucose, D-mannitol or the like may be contained therein. Additionally, auxiliaries for conventional dissolution such as polysorbate 80 and the like; pH regulating agents such as citric acid, sodium citrate, phosphoric acid, lactic acid and the like; softening agents such as glycerin and the like; etc., they can also be contained there. In addition, when necessary, colorants, preservatives, flavors, perfumes, sweeteners and the like, and other medicines can be contained therein. Applicable pharmaceutical preparations for ophthalmological purposes, such as ophthalmic solutions, ophthalmic ointments, and the like, are prepared according to a conventional method through the use of customary vehicles (diluting agents) acceptable for ophthalmological purposes. In this way, they are prepared by mixing the active ingredient with the appropriate base material (s), then the mixture is subjected to the sterilization treatment. For example, in the case of the preparation of ophthalmic ointments, the conventional emulsion-type ointment base, the water-soluble type ointment base, the suspension-type ointment base and the like can be used. As with the typical examples of these base materials, white petroleum, refined lanolin, liquid paraffin and the like can be exemplified. In the case of the production of ophthalmic solutions, sterilized distilled water can be used as the typical dilution agent. Further, if necessary, a solvent additive, a pH regulating agent, an antioxidant, an antiseptic agent, an isotonic agent, a pH controlling agent, and the like can be formulated with a pharmaceutical preparation applicable for ophthalmological purposes. As the dissolution additives, sodium carboxymethylcellulose can be exemplified; polyoxyethylene glycol ethers, such as polyoxyethylene lauryl ether, polyoxyethylene oleyl ether and the like; esters of polyethylene glycol higher fatty acids, such as polyethylene glycol monolaureate, polyethylene glycol monooleate, and the like; polyoxyethylene sorbitan monolaurate; polyoxyethylene fatty acid esters and the like. Examples of pH regulating agents are sodium phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, boric acid, sodium borate, citric acid, sodium citrate, tartaric acid, sodium tartrate, acetic acid, sodium, e-aminocaproic acid, sodium glutamate and the like. As the antioxidant can be exemplified, sodium sulfite, sodium pyrosulfite, sodium acid sulfite, sodium thiosulfite, ascorbic acid and the like. As the antiseptic agent can be exemplified, chlorobutanol, benzalkonium chloride, benzethonium chloride, phenylmercury salt, thimerosal, phenethyl alcohol, methylparaben, propylparaben and the like. As the isotonic agent can be exemplified, sodium chloride, glucose, D-mannitol, glycerin and the like. As the controlling agent of the pH can be exemplified, sodium hydroxide, hydrochloric acid and the like. For the purpose of preparing tablets, any known ingredient that can be widely used in this field can be applied, for example, excipients such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, cellulose crystalline, silicic acid, and the like; binders such as water, ethanol, and propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and the like; disintegrators such as dry starch, sodium alginate, agar powder, laminarán powder, sodium acid carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglycerides, starch, lactose, and the like; disintegration inhibitors such as white sugar, stearin, cocoa butter, hydrogenated oil and the like; absorption accelerators such as the quaternary ammonium base, sodium lauryl sulfate and the like; humectants such as glycerin, starch and the like; adsorbents such as starch, lactose, kaolin, bentonite, colloidal silicic acid and the like; lubricants such as refined talc, stearic acid salts, boric acid powder, polyethylene glycols and the like. Further, when necessary the tablets can be prepared in the form of common coated tablets, for example, sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets or in the form of tablets with double layers and tablets with multiple layers. For the purpose of preparing pills, any known ingredients that are widely used in this field can be applied, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oils, kaolin, talc and the like; binders such as gum arabic powder, gum tragacanth powder, gelatin, ethanol and the like; and disintegrators such as laminarán, agar, and the like can be exemplified. For the purpose of preparing suppositories, any known ingredients that are widely used in this field can be applied, for example polyethylene glycols, cocoa butter, higher alcohols, higher alcohol esters, gelatin, semi-synthesized glycerides and the like can be exemplified. The aerosols are usually prepared in the form of a liquid or suspension sterilized, and there you can add propellants. For the purposes of preparing the liquids and suspensions, any diluents which are widely used in this field can be applied for example, the aforementioned diluents for the injections can be exemplified. Any propellants that are widely used in this field can be applied, for example, chlorofluorocarbons such as flon 12 and the like can be exemplified; liquefied gas propellants such as flon 123 and the like; and compressed gas propellants such as nitrogen, carbon dioxide and the like. The aerosols may include conventional dissolving aids, pH regulating agents and the like, in addition when necessary preservative coloring agents, flavors, perfumes, sweeteners and the like. The amount of the amine salt of the carbostyril derivative of the present invention to be contained in the formulation is not specifically restricted and may be suitably selected from a wide range, and generally from 1 to 70%, preferably from 5 to 50. % by weight of the total composition. For preferred pharmaceutical preparations especially applicable for ophthalmological purposes, the amount is generally from 0.005 to 5%, preferably from 0.01 to 3% by weight of the total composition. The method for administration is not specifically restricted. In this way the pharmaceutical preparation can be administered through acceptable methods, depending on the form of each preparation, the age of the patient, the distinction of sex and other conditions, as well as the severity of the patient's diseases. For example, tablets, pills, a liquid preparation, a suspension preparation, an emulsion preparation, a granular preparation, a syrup preparation and capsules are orally administered. An injection preparation is intravenously administered alone or in combination with a conventional auxiliary solution such as glucose solution, an amino acid solution and the like. Additionally, when necessary the preparation of the injection is administered alone intramuscularly, intradermally, subcutaneously, or intraperitoneally. Suppositories are endorectally administered. The pharmaceutical preparations of the present invention applicable for ophthalmological purposes can be administered by a method similar to those of conventional preparations, for example, ophthalmic ointments are administered over the eyes. Ophthalmic solutions are administered through a method similar to those of conventional preparations, for example, 1 to 2 drops of an ophthalmic solution are dropped into the eyes from the container of eye drops, an ophthalmic solution can be Administer in the eyes through the use of a spray device. The dosage of the agent of the present invention may be suitably selected depending on the method for administration, the age of the patient, the sex distinction, and other conditions, as well as the severity of the patient's disease, and generally the agent of the invention. it may preferably contain from 0.6 to 50 mg / kg of body weight / day of the carbostyril derivative (1). In addition, 10 to 1000 mg of the active ingredient can be contained in the administrative unit form. Applicable pharmaceutical preparations for ophthalmological purposes, such as an ophthalmic solution or an ophthalmic ointment, are administered on a scale of 1 to 15 times, preferably 1 to 10 times per day. The amine salts of the carbostyril derivative of the present invention have superior solubility in water, and are useful for preparation in the form of a solution such as injections, ophthalmic solutions, oral solutions, enemas, gargles, eardrops, nasal drops, external liquid preparations and the like. Especially they have advantages such as that it is easy to maintain the uniformity of the content; they do not need control of the particle distribution; they do not need to add the suspending agent, dispersing agent and the like; It is easy to carry out the terminal sterilization through steam or sterilization by filtration, etc., and in this way the desired pharmaceutical products can be prepared industrially, simply and easily. Especially, the ophthalmic solutions of the invention have some advantages, for example, they do not need complicated re-dispersion as a suspension preparation, and they have a pleasant feel when used as well as attractive.

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be explained more specifically through the following examples, examples of the pharmaceutical preparation and pharmacological experiments.

EXAMPLE 1 L-arginine salt of 2- (4-chloro-benzoxylamino) -3- (2-quinolone-4-Qpropionic acid A suspension of 3.88 g of 2- (4-chlorobenzoylamino) -3- (2-quinolone-4-yl) -propionic acid (10.5 mmol) and 2.00 g of L-arginine (11.5 mmol) in 200 ml of ethanol was taken reflux for 30 minutes. 20 ml of water were added to the mixture, and the reflux continued, then the reaction product was temporarily completely dissolved. After this, precipitates appeared under reflux. After the heating was stopped, the reaction mixture was cooled to room temperature, and further cooled in ice water. The precipitates were collected through filtration through a Nutsche funnel, washed with ethanol in a Nutsche funnel, and dried with a blower at 50 ° C for 20 hours to give 5.38 g of 2- (4-chlorobenzoylamino) acid. -3- (2-quinolone-4-yl) -propionic • L-arginine salt (95% yield) as a white crystal. 1 H NMR (DMSO-d 6) d = 1.43-1.92 (4H, m), 2.95-3.85 (5H, m), 4. 41-4.58 (1 H, m), 6.42 (1 H, s), 7.20 (1 H, dd, J = 8.1, 7.6 Hz), 7.30 (1 H, d, J = 8.2 Hz), 7.47 (1 H, dd, J = 8.2, 7.6 Hz), 7.49 (2H, d, J = 8.4 Hz ), 7.81 (2H, d, J = 8.4 Hz), 7.96 (1 H, d, J = 8.1 Hz), 8.34 ppm (1 H, d, J = 8.2 Hz).

EXAMPLE 2 Salt of L-lysine of 2- (4-chlorobenzoylamino) -3- (2-quinolone-4-yl) -propionic acid - A suspension of 1.94 g of 2- (4-chlorobenzoylamino) -3- (2-quinolone-4-yl) -propionic acid (5.23 mmol) and 0.84 g of L-lysine (5.76 mmol) in 100 ml of ethanol was taken reflux for 30 minutes. 25 ml of water were added to the mixture, and the reflux continued, then the reaction product was completely dissolved. After this, precipitates appeared under reflux. After the heating was stopped, the reaction mixture was cooled to room temperature, and further cooled in ice water. The precipitates were collected by filtration through a Nutsche funnel, washed with ethanol in a Nutsche funnel, and dried with a blower at 60 ° C overnight to give 1.46 g of 2- (4-chlorobenzoylamino) acid. -3- (2-quinolone-4-yl) -propionic • L-lysine salt (54% yield) as a white crystal. 1H NMR (DMSO-d6) d = 1.18-1.80 (6H, m), 2.74 (2H, br.d, J = 6.7 Hz), 3.08 (1 H, br.dd, J = 13.6, 9.8 Hz), 3.29 (1 H, br.t, J = 5.8 Hz), 3. 43-3.59 (1 H, m), 4.48 (1 H, br.ddd, J = 9. 8, 8.0, 3.6 Hz), 6.44 (1 H, s), 7.18 (1 H, dd, J = 8.1, 7.5 Hz), 7.31 (1 H, d, J = 7.9 Hz), 7.45 (1 H, dd, J = 7.9, 7.5 Hz), 7.48 (2 H, d, J = 8.5 Hz), 7.81 (2 H, d, J = 8.5 Hz), 7.96 (1 H, d, J = 8.1 Hz), 8.40 ppm (1 H, d, J = 8.0 Hz).

EXAMPLE 3 1/2 2- (4-Chlorobenzoylamino) -3- (2-quinolone-4-yl) -propionic acid ethylenediamine salt • (A): A suspension of 2.00 g of 2- (4-chlorobenzoylamino) -3- (2-quinolone-4-yl) -propionic acid (5.39 mmol) and 0.18 ml of ethylenediamine (2.69 mmol) in 100 ml of ethanol refluxed for 30 minutes. Water was added thereto in portions of 5 ml each until the reaction product dissolved. The reaction product completely dissolved when a total of 35 ml of water was added. Then again the heating was stopped, the mixture was cooled to room temperature, and then the crystals were precipitated. After the reaction mixture was further cooled with ice-water, the precipitated crystals were collected through filtration through a Nutsche funnel, and dried with a blower at 60 ° C to give 1.92 g of 2- ( 4-chlorobenzoylamino) -3- (2-quinolone-4-yl) -propionic • 1/2 ethylene diamine salt (89% yield) as a white crystal. (B): A suspension of 2.00 g of 2- (4-chlorobenzoylamino) -3- (2-quinolone-4-yl) -propionic acid (5.39 mmol), 0.40 ml of ethylenediamine (5.98 mmol) in 100 ml of ethanol refluxed for 30 minutes. Water was added to this, in 5 ml portions of each until the reaction product dissolved. The reaction product was completely dissolved when a total of 25 ml of water was added. Then, heating was stopped and the mixture was cooled to room temperature, but no crystals were precipitated. So the solvent was removed under reduced pressure, 50 ml of ethanol was added to the residue, it was dispersed under reflux for purification and cooling to room temperature. The resulting crystals were collected by filtration through a Nutsche funnel, and dried with a blower at 60 ° C to give 1.96 g of 2- (4-chlorobenzoylamino) -3- (2-quinolone-4-yl) acid. ) -propionic • 1/2 ethylene diacona salt (91% yield) as a white crystal. H NMR (DMSO-d6) d = 2.87 (2H, s), 3.11 (1H, br.dd, J = 13.9, 9. 8 Hz), 3. 52 (1 H, br.dd, J = 13.9, 3.5 Hz), 4.50-4.57 (1 H, m), 6.41 (1 H, s), 7. 20 (1 H, dd, J = 8.0, 7.6 Hz), 7.30 (1 H, d, J = 7.5 Hz), 7.48 (1 H, dd, J = 8.0, 7.5 Hz), 7.52 (2H, d, J = 8.5 Hz), 7.80 (2H, d, J = 8.5 Hz), 7.93 (1 H, d, J = 7.6 Hz), 8.40 ppm (1 H, d, J = 8.0 Hz).

EXAMPLE 4 2- (4-Chlorobenzoylamino) -3- (2-quinolone-4-yl) -propionic acid (hydroxymethyl) aminomethane salt A suspension of 2.00 g of 2- (4-chlorobenzoylamino) -3- (2-quinolone-4-yl) -propionic acid (5.39 mmol) and 0.72 g of tris (hydroxymethyl) aminomethane (5.94 mmol) in 100 ml of ethanol refluxed for 30 minutes. Water was added thereto through portions of 5-10 ml each until the reaction product dissolved. The reaction product was completely dissolved when a total of 40 ml of water was added. After the heating was stopped and the mixture was cooled to room temperature, and further cooled on ice-water, but no crystals were precipitated. Then the solvent was removed under reduced pressure. Ethanol was added to the residue and the mixture was concentrated under reduced pressure. To the residue was added 50 ml of ethanol, and the mixture was stirred at room temperature. The resulting precipitates were separated through filtration through a Nutsche funnel, and dried with a blower at 60 ° C to give 2.58 g of 2- (4-chlorobenzoylamino) -3- (2-quinolone-4-yl) acid. ) -propionic • tris (hydroxymethyl) aminomethane salt (97% yield) as a white crystal. 1H NMR (DMSO-d6) d = 3.07 (1 H, br.dd, J = 13.8, 10.1 Hz), 3. 47 (6H, s), 3.54 (1H, br.dd, J = 13.9, 3.3 Hz) , 4.49-4. 56 (1H, m), 6.41 (1 H, s), 7. 21 (1 H, dd, J = 8.1, 7.7 Hz), 7.31 (1 H, d, J = 7.5 Hz), 7.45 (1 H, dd, J = 8.1, 7. 5 Hz), 7.51 (2H, d, J = 8.5 Hz), 7.81 (2H, d, J = 8.5 Hz), 7.94 (1 H, d, J = 7.7 Hz), 8.38 ppm (1 H, d, J = 8.3 Hz).

EXAMPLE 5 2- (4-Chlorobenzoylamino) -3- (2-quinolone-4-yl) -propionic acid diethanolamine salt A suspension of 2.00 g of 2- (4-chlorobenzoylamino) -3- (2-quinolone-4-yl) -propionic acid (5.39 mmol) and 0.62 g of diethanolamine (5.90 mmol) in 100 ml of ethanol was brought to reflux for 30 minutes. The reaction product was completely dissolved without the addition of water. Then, the heating was stopped and the mixture was cooled to room temperature and further cooled with ice-water. The resulting precipitates were separated through filtration through a Nutsche funnel, and dried with a blower at 60 ° C to give 1.95 g of 2- (4-chlorobenzoi-amino) -3- (2-quinolone-4-yl) acid. ) -propionic • diethanolamine salt (76% yield) as a white crystal. 1H NMR (DMS0-d6) d = 2.89 (4H, t, J = 5.4 Hz), 3.10 (1 H, br.dd, J = 13.9, 9.9 Hz), 3.52 (1 H, br.dd, J = 13.9, 3.6 Hz), 3.61 (4H, t, J = 5.4 Hz), 4. 50-4.56 (1 H, m), 6.41 (1 H, s), 7.21 (1 H, dd, J = 8.1, 7.6 Hz), 7.31 (1 H, d, J = 7. 5 Hz), 7.48 (1 H, dd, J = 8.1, 7.5 Hz), 7.52 (2 H, d, J = 8.5 Hz), 7.81 (2 H, d, J = 8.5 Hz), 7.94 (1 H, d, J = 7.6 Hz), 8.44 ppm (1 H, d, J = 8.2 Hz).

EXAMPLE 6 2- (4-Chlorobenzoylamino) -3- (2-quinolone-4-yl) -propionic acid diisopropanolamine salt A suspension of 2.00 g of 2- (4-chloro-benzoylamino) -3- (2-quinolone-4-yl) -propionic acid (5.39 mmol) 0.79 g of diisopropanolamine (5.93 mmol) in 100 ml of ethanol was brought to reflux for 30 minutes. The reaction product was completely dissolved without the addition of water. Then, heating was stopped and the mixture was cooled to room temperature and further cooled on ice-water. The resulting precipitates were separated through filtration through a Nutsche funnel, and dried with a blower at 60 ° C to give 1.66 g of 2- (4-chlorobenzoylamino) -3- (2-quinolone-4-yl) acid. ) -propionic • diisopropanolamine salt (61% yield) as a white crystal. 1H NMR (DMSO-d6) d = 1.07 (3H, d, J = 6.2 Hz), 1.13 (3H, d, J = 6.2 Hz), 2.54-2.68 (2H, m), 2.77 (2H, dd, J = 12.2, 3.5 Hz), 3.08-3.18 (1 H, m), 3.43-3.56 (1 H, m) "3.75-3.92 (2H, m), 4.47-4.60 (1 H, m), 6.41 (1 H, s), 7.21 (1 H, dd, J = 8.0, 7.7 Hz), 7.30 (1 H, d, J = 7.5 Hz), 7.49 (1H, t, J = 7.5 Hz), 7.52 (2H, d, J = 8.6 Hz), 7.81 (2H, d, J = 8.6 Hz), 7.93 (1 H, d, J = 7.7 Hz), 8.48 ppm (1H, d, J = 8.1 Hz).

EXAMPLE 7 Meglumine salt of 2- (4-chlorobenzoylamino) -3- (2-quinolone-4-iD-propionic acid) To 3.7 g of 2- (4-chlorobenzoylamino) -3- (2-quinolone-4-yl) -propionic acid (10 mmol) was added 1 mol / l of aqueous solution of meglumine (10 ml, 10 mmol), and it was heated to 50 ° C to dissolve. To the solution was added an aqueous solution of the equimolar mixture of meglumine and hydrochloric acid (0.05 mol / l, 20 ml), and the mixture was cooled. The resulting precipitates were separated through filtration, washed with water, and dried under reduced pressure at room temperature to give 0.9 g of 2- (4-chlorobenzoylamino) -3- (2-quinolone-4-yl) - propionic - meglumine salt (16% yield) with a white crystal. 11 H NMR (DMSO-d6) d = 2.82-3.14 (3H, m), 3.37-3.73 (6H, m), 3. 82-3.94 (1 H, m), 4.52 (1 H, ddd, J = 9.6, 8.2, 3.5 Hz), 6.41 (1 H, s), 7.20 (1 H, dd, J = 8.0, 7.2 Hz), 7.30 (1 H, d, J = 7.8 Hz), 7.48 (1 H, dd, J = 7.8, 7.2 Hz), 7. 51 (2H, d, J = 8.5 Hz), 7.80 (2H, d, J = 8.5 Hz), 7.94 (1 H, d, J = 8.0 Hz), 8.37 ppm (1 H, d, J = 8. 2 Hz).

EXAMPLE 8 Solubility test in aqua at 25 ° C Compound A: 2- (4-chlorobenzoylamino) -3- (2-quinolone-4-yl) -propionic acid.

Preparation of the test solution 0.5 g of the salt obtained in the above examples 1-7 was transferred into a 50 ml centrifuge tube and 5 ml of water was added thereto, and the mixture was stirred through a stirrer for 3 hours. hours (5 days for meglumine salt) on a thermostat (25 ° C). After stirring, the mixture was filtered through a 45 μm membrane filter (0.2 μm for meglumine salt). 1 ml of the filtrate was accurately measured with a pipette and 50% of DMF was added thereto for a total of 50 ml precisely. 2 ml of this solution were accurately measured with a pipette and at the same time 50% DMF was added to make a total of 20 ml precisely to give a sample solution.

Preparation of the standard solution 0.01 g of Compound A of 5 ml of dimethylformamide (DMF) was dissolved and 50% of DMF was added thereto to make a total of 100 ml precisely to give the standard solution (1). 5 ml of standard solution (1) were measured with a pipette precisely and 50% of DMF was added thereto to give the total of 10 ml precisely to give the standard solution (2). 1 ml of the standard solution (1) was precisely measured with a pipette and 50% DMF was added thereto to give a total of 10 ml precisely to give the standard solution (3). 1 ml of the standard solution (3) was precisely measured and at the same time 50% DMF was added to give a total of 10 ml precisely to give the standard solution (4).

Chromatography Using each 10 μl of the sample solutions and standard solutions, liquid chromatographic analyzes were carried out under the following conditions. A calibration curve was drawn based on the peak areas of Compound A and the concentrations of Compound A obtained from the standard solutions (1) - (4). Using this calibration curve, the concentration of Compound A in the sample solution was calculated from the peak area of Compound A of the sample solution and the data were corrected by means of a dilution ratio, and were therefore determined the solubilities (%) of the various salts.

EXAMPLE 9 Solubility test at 25 ° C of the salt in the prepared preparation when used without the isolation of the salt.

An equimolar amount of each amine compound was added to Compound A and then water was added in such an amount that the salt could not be completely dissolved, and stirred through a stirrer for 7 days in a thermostat (25 ° C) . And then as the sample to which arginine was added, the suspension was filtered through a 0.2 μm membrane filter. As with the samples to which lysine, diisopropanolamine, meglumine, monoethanolamine or diethanolamine was added, the mixture could not be filtered due to solidification, and therefore, additional water was added to the mixture until it was possible to filter. And then the mixture was filtered through a 0.2 μm membrane filter. According to the same method as Example 8, the solubilities (%) of each salt were measured by HPLC.

EXAMPLE OF PHARMACEUTICAL PREPARATION 1 The above ingredients were dissolved in distilled water and sterilized with a suitable filter to prepare the formulation of the present invention in the form of an ophthalmic solution.

EXAMPLE OF PHARMACEUTICAL PREPARATION 2 The compound of the invention, Avicel, corn starch and magnesium stearate were mixed and ground, and then compressed with bumps (10 nm R for the sugar layer). The resulting tablets were covered with film coating agent comprising hydroxypropylmethylcellulose, polyethylene glycol-6000, castor oil and methanol to prepare the film-coated tablets.

EXAMPLE OF PHARMACEUTICAL PREPARATION 3 The compound of the present invention, citric acid, lactose, dicalcium phosphate, Pluronic F-68 and sodium lauryl sulfate were mixed. The above mixture was filtered through a number 60 grid and wet granulated with an alcohol solution comprising polyvinylpyrrolidone, Carbowax 1500 and 6000. When necessary, some alcohol was added to convert the powder to a paste-like solid. . The corn starch was added thereto, the mixture was continued to form uniform particles. The granules were sieved through a No. 10 grid, placed on a tray and dried at 100 ° C for 12-14 hours in the oven. The dried granules were sieved through a No. 16 grid, dry sodium lauryl sulfate and dry magnesium stearate were added to the sifted granules, then all the ingredients were mixed and compressed into the desired shape through the use of a machine to form tablets. The central portions were treated with a varnish, the surfaces thereof were sprayed with talcum to prevent the surfaces from absorbing moisture. The surface of the central portions was also coated with a primary coating layer. The surface was also coated with a varnish to make a sufficient number of layers for the preparation of coated tablets for oral administration. In order to make the tablets coated in a complete spherical shape and to make the surfaces smooth, the coated tablets were further coated with primary coating layers and smoothed coating layers. The coated tablets were coated with color until the desired color of the surface was obtained. After drying, the coated tablets were polished to make them with a uniform gloss.

EXAMPLE OF PHARMACEUTICAL PREPARATION 4 The above-mentioned compound of the invention and the additives were dissolved in distilled water, transferred to glass containers and then sterilized by steam to prepare the injectable solution.

EXAMPLE OF PHARMACEUTICAL PREPARATION 5 The above-mentioned compound of the invention and the additives were formulated to prepare the oral solution.

INDUSTRIAL APPLICABILITY The amine salts of the carbostyril derivative of the present invention have a superior solubility to water and are especially useful for the preparation of formulations in the form of an aqueous solution, such as injections, ophthalmic solutions, oral solutions and the like; additionally they maintain the superior pharmacological effectiveness of carbostyril derivatives, such as anti-ulcer activity, activities to increase endogenous prostaglandin E2, extinction or inhibition of active oxygen, inhibition of IL-8 production, inhibition of granulocyte activation , inhibition of granulocyte adhesion factor expression, inhibitory activity for the release of somatostatin, antidiabetic activity, urease inhibitory activity, and in addition an increase of cup cells in the eye, an increase in mucus in the eye, an increased tear fluid; and they are useful as drugs for treating various diseases, especially as ophthalmic drops to treat various ophthalmopathies such as dry eye.

Claims (21)

NOVELTY OF THE INVENTION CLAIMS

1. - An amine salt of a carbostyril derivative formed from a carbostyril derivative represented by the formula (1): wherein: R is a halogen atom, the substituted position of the side chain is in the 3 or 4 position in the basic structure of carbostyril, and the bond between positions 3 and 4 of the basic structure of carbostyril is an individual bond or a double bond, and an amine.

2. The amine salt of the carbostyril derivative according to claim 1, further characterized in that said carbostyril derivative (1) is 2- (4-chlorobenzoylamino) -3- (2-quinolone-4-yl) - propionic

3. The amine salt of the carbostyril derivative according to claim 2, further characterized in that said amine is L-arginine.

4. The amine salt of the carbostyril derivative according to claim 2, further characterized in that said amine is L-lysine.

5. The amine salt of the carbostyril derivative according to claim 2, further characterized in that said amine is ethylenediamine.

6. The amine salt of the carbostyril derivative according to claim 2, further characterized in that said amine is tris (hydroxymethyl) -aminomethane.

7. The amine salt of the carbostyril derivative according to claim 2, further characterized in that said amine is monoethanolamine.

8. The amine salt of the carbostyril derivative according to claim 2, further characterized in that said amine is methanolamine.

9. The amine salt of the carbostyril derivative according to claim 2, further characterized in that said amine is diisopropanolamine.

10. The amine salt of the carbostyril derivative according to claim 2, further characterized in that said amine is meglumine.

11. A pharmaceutical formulation comprising the amine salt of the carbostyril derivative according to any of claims 1-10 as the active ingredient.

12. A pharmaceutical formulation that is prepared in the form of an aqueous solution through the addition of an aqueous solvent, when used, comprising a carbostyril derivative represented by the formula (1): wherein: R is a halogen atom, the substituted position of the 3 or 4 side chain in the carbostyril structure, and the bond between positions 3 and 4 of the basic carbostyril structure is an individual bond or a double bond, and an amine.

13. The pharmaceutical formulation to be prepared in a preparation when used according to claim 12, further characterized in that said carbostyril derivative (1) is 2- (4-chlorobenzoylamino) -3- (2-quinolone) -4-il) -propionic.

14. The pharmaceutical formulation to be prepared in a preparation when used according to claim 13, further characterized in that said amine is L-arginine.

15. The pharmaceutical formulation to be prepared in a preparation when used according to claim 13, further characterized in that said amine is L-lysine.

16. The pharmaceutical formulation to be prepared in the preparation when used according to claim 13, further characterized in that said amine is ethylenediamine.

17. The pharmaceutical formulation to be prepared in the preparation when used according to claim 13, further characterized in that said amine is tris (hydroxymethyl) amnomethane.

18. The pharmaceutical formulation to be prepared in the preparation when used according to claim 13, further characterized in that said amine is monoethanolamine.

19. The pharmaceutical formulation to be prepared in the preparation when used according to claim 13, further characterized in that said amine is diethanolamine.

20. The pharmaceutical formulation to be prepared in the preparation when used according to claim 13, further characterized in that said amine is diisopropanolamine.

21. The pharmaceutical formulation to be prepared in the preparation when used according to claim 13, further characterized in that said amine is meglumine.