New use of peptide derivative

Abstract: An antiinflammatory or gastrointestinal motility-modulating composition comprising a peptide derivative of the general formula : wherein R¹ is hydrogen or an acyl group; R² is hydroxy and R³ is carboxy or protected carboxy, or R² and R³ are linked together to represent a group of the formula : R⁴ is hydroxy or protected hydroxy; R⁵ is hydroxy or protected hydroxy; R⁶ is hydroxy, protected hydroxy or lower alkoxy; and is a single bond or a double bond, or a pharmaceutically acceptable salt thereof as an active ingredient, in association with a pharmaceutically acceptable, substantially non-toxic carrier or excipient.

Description: This invention relates to a new use of known peptide derivatives, in particular it relates to the use of peptide derivatives of general formula (I) following below or pharmaceutical acceptable salts thereof for the manufacture of a medicament for preventing and/or treating inflammation, especially arthritis. Peptide derivatives of general formula (I) following below are already known from EP-A-0 336 230. It is also known from this reference that peptide derivatives of formula (I) possess pharmacological activities such as substance P antagonism and neurokinin A antagonism and are useful in the preparation of medicaments for use in the treatment and prevention of asthma. From EP-A-0 394 989 peptide compounds having a quite different basic structure are known which are useful in the preparation of medicaments for use in the treatment of inflammatory diseases such as rheumatoid arthritis. Furthermore, these peptide compounds are said to be antagonists of substance P and neurokinins A and B and therefore useful in the treatment or prevention of tachykinin mediated diseases, such as inflammation. It is the object of the present invention to find compounds which are more useful for treating or preventing inflammatory diseases as those disclosed in EP-A-0 394 989. Surprisingly, the applicant has found that the peptide derivatives of general formula (I) as disclosed in EP-A-0 336 230 have a strong antiinflammatory acitivity and therefore can be used for the manufacture of a medicament for preventing and/or treating inflammation, in particular arthritis. Subject-matter of the present invention is the use of a peptide derivative of the following general formula wherein R¹ is hydrogen, phenyl(C₁-C₆)alkoxycarbonyl, C₁-C₆-alkanoyl, C₁₅-C₂₀-alkanoyl, benzoyl, thienyl(C₁-C₆)alkanoyl, phenyl(C₃-C₆)alkenoyl substituted with a C₂-C₆-alkenyl group, or phenyl(C₁-C₆)alkanoyl substituted with a C₁-C₆-alkyl group; R² is hydroxy and R³ is carboxy or C₁-C₆-alkoxycarbonyl, or R² and R³ are linked together to represent a group of the formula: R⁴ is hydroxy, phenyl(C₁-C₆)alkoxy or C₁-C₆-alkanoyloxy; R⁵ is hydroxy, phenyl(C₁-C₆)alkoxy or C₁-C₆-alkanoyloxy; R⁶ is hydroxy, C₁-C₆-alkoxy, phenyl(C₁-C₆)alkoxy or C₁-C₆-alkanoyloxy; and is a single bond or a double bond, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing and/or treating inflammation. The peptide derivatives of the above general formula (I) used according to the present invention possess a strong antiinflammatory activity as can be seen from the test results summarized in the table at page 8 following below. According to preferred embodiments the present invention relates to the use of a peptide derivative of general formula (I), wherein: R¹ is 3-(2-pentylphenyl)propanoyl, R² and R³ are linked together to represent a group of the formula : R⁴ is hydroxy, R⁵ is hydroxy, R⁶ is hydroxy, and is a double bond, or a pharmaceutically acceptable salt thereof , especially the compound According to a further preferred embodiment the present invention relates to the use of a peptide derivative of general formula (I) as defined above or a pharmaceutical acceptable salt thereof for the manufacture of a medicament for preventing and/or treating arthritis. Suitable pharmaceutically acceptable salts of the compound (I) are conventional non-toxic salts and may include a salt with a base or an acid addition salt such as a salt with an inorganic base, for example an alkali metal salt (e.g. lithium salt, sodium salt, and potassium salt), an alkaline earth metal salt (e.g. calcium salt, and magnesium salt), an ammonium salt; a salt with an organic base, for example, an organic amine salt (e.g. triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, and N,N'-dibenzylethylenediamine salt); an inorganic acid addition salt (e.g. hydrochloride, hydrobromide, sulfate, and phosphate); an organic carboxylic or sulfonic acid addition salt (e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, and p-toluenesulfonate); a salt with a basic or acidic amino acid (e.g. arginine, aspartic acid, and glutamic acid). The compound (I) or a pharmaceutically acceptable salt thereof, used in accordance with the invention, has antiinflammatory activities and, as such, is of value as an active ingredient for use in antiinflammatory compositions. These antiinflammatory compositions are effective in preventing and treating inflammation such as various types of arthritis [e.g. articular rheumatism (e.g. rheumatoid arthritis), osteoarthrosis (e.g. osteoarthrosis of knee), periarthritis humeroscapularis, cervico-omo-brachial syndrome] or the like. The compound (I) or a pharmaceutically acceptable salt thereof, which is used as an active ingredient of said compositions, can be administered as it is but is generally administered in the form of a pharmaceutically acceptable preparation. The pharmaceutical preparation mentioned above may take a variety of forms such as oral preparation [e.g. solution, emulsion, suspension, capsule, granule, powder, tablet, and syrup], injection, suppository or the like. Such preparations can be manufactured by the established pharmaceutical procedures using appropriate excipients such as sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, and calcium carbonate; binders such as cellulose, methylcellulose, hydroxypropylcellulose, polypropylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, and starch; disintegrators such as starch, carboxymethylcellulose, hydroxypropyl starch, sodium bicarbonate, calcium phosphate, and calcium citrate; lubricants such as magnesium stearate, talc, and sodium laurylsulfate; corrigents such as citric acid, menthol, glycine, and orange powder; preservatives such as sodium benzoate, sodium bisulfite, benzyl alcohol, methylparaben, and propylparaben, stabilizers such as citric acid, sodium citrate, and acetic acid; suspending agents such as methylcellulose, polyvinylpyrrolidone, and aluminum stearate; dispersants such as hydroxypropylmethylcellulose, polysorbate 80, and carboxymethylcellulose; solvents such as water; isotonicity such as sodium chloride; base waxes such as cacao butter, polyethylene glycol, and white soft paraffine; and so on. The dosage for the pharmaceutical composition of this invention depends on the patient's age, body weight and clinical condition, the method of administration and other conditions. Generally speaking, however, the active compound (I) or a pharmaceutically acceptable salt thereof is administered in doses of 1 to 300 mg and preferably 10 to 100 mg, either orally or parenterally (for examples intraarticularly, intravenously). The following test example are intended to demonstrate the excellent antiinflammatory actions of the compound (I) or a pharmaceutically acceptable salt thereof used according to the present invention. Test compound The compound of the following structural formula : (hereinafter referred to briefly as tetrahydro-WS9326A) Effect on carrageenin-induced rat knee edema : Eight-week-old male Wistar rats were used. Each rat was anesthetized with 0.2 ml of pentobarbital sodium (50 mg/ml) in physiological saline i.p. and then intravenously dosed with 2 ml/kg of Evans blue (10 mg/ml) in physiological saline. Thereafter, 0.1 ml of 2% carrageenin in physiological saline was administered into the articular cavity of the right knee. After 4 hours, the animal was sacrificed, skinned to expose the articular region and observed for leakage of Evans blue. Then, physiological saline (0.15 ml) was injected into the articular cavity. After incision, 5 µl of synovial fluid was collected. The synovial fluid obtained was diluted with physiological saline (40 µl) and using a cell counter, the cells were counted under the microscope. The test compound (tetrahydro-WS9326A) was suspended in 0.1% methylcellulose in physiological saline and 0.1 ml of this suspension was administered into the knee joint 15 minutes before carrageenin administration. Test results Dose No. of animals No. of cells in synovial fluid (x 10⁴/ml) % Inhibition vehicle (0.1% methyl cellulose in physiologial saline) only 5 675.2 ± 105.7 - 1 µg 5 543.2 ± 135.1 19.5 10 µg 5 302.8 ± 77.1 55.2 100 µg 5 60.8 ± 11.8 91.0 Toxicity study An injectable suspension containing the test compound and other ingredients mentioned below was administered into the knee joint of rabbits (6 males and 6 females) and dogs (3 males and 3 females) twice a week for 4 weeks. The dose was 8 mg/kg for rabbits and 12 mg/kg for dogs. The administration of the test compound caused death in neither rabbits nor dogs. [Injectable suspension (ingredients per milliliter)] Tetrahydro-WS9326A 20 mg Polysorbate 80 2 mg Carboxymethylcellulose sodium 7.5 mg Benzyl alcohol 9 mg Sodium chloride 9 mg Distilled water for injection q.s. The following examples are illustrative of the invention. Example 1 A powder of the following composition is encapsulated to provide capsules. Formula Tetrahydro-WS9326A 100 mg Low-substituted hydroxypropylcellulose 10 mg Polyoxyl 40 stearate 1 mg Hydroxypropylcellulose 1 mg Example 2 The following ingredients are admixed and granulated in the routine manner to provide granules. Formula for granules Tetrahydro-WS9326A 30.0 (wt. %) Lactose 69.4 Polyoxyl 40 stearate 0.1 Hydroxypropylcellulose 0.5 Example 3 The following ingredients are admixed and powdered in the routine manner to provide a powder. Formula for powder Tetrahydro-WS9326A 30.0 (wt. %) Lactose 69.4 Polyoxyl 40 stearate 0.1 Hydroxypropylcellulose 0.5 Example 4 The following ingredients are admixed and compressed in the routine manner to provide tablets. Formula for tablets Tetrahydro-WS9326A 300 (mg) Lactose 100.8 Croscarmellose sodium, type A 9 Hydroxypropylcellulose 3 Polyoxyl 40 stearate 3 Magnesium stearate 4.2 420 mg/tablet Where necessary, the tablets thus obtained are film-coated or enteric-coated to provide film coated or enteric coated tablets. Example 5 To 100 ml of distilled water for injection is added 1 g of carboxymethylcellulose sodium and the mixture is stirred. To the resulting solution is added 40 mg of Polysorbate 80 and, after mixing, 1 g of tetrahydro-WS9326A is dispersed therein to provide an injectable suspension. Example 6 To 50 ml of macrogol 400 is added 1 g of tetrahydro-WS9326A and the mixture is stirred. The resulting solution is made up to 100 ml with distilled water for injection to provide an injectable solution. Example 7 After tetrahydro-WS9326A is dispersed in a solution of Polysorbate 80 in distilled water for injection, a solution of sodium chloride, benzyl alcohol and carboxymethylcellulose sodium in distilled water for injection is added thereto. 5 Ml of the resulting suspension is filled into an ampoule, which is then sealed by fusion to provide an injectable suspension containing the following ingredients. Ingredients (per milliliter) Tetrahydro-WS9326A 10 mg Polysorbate 80 2 mg Carboxymethylcellulose sodium 7.5 mg Benzyl alcohol 9 mg Sodium chloride 9 mg Distilled water for injection q.s. Reference Tetrahydro-WS9326A was obtained by subjecting the compound of the above structural formula to reduction with 10% Pd-C.

Claims: Use of a peptide derivative of the general formula : wherein R¹ is hydrogen, phenyl(C₁-C₆)alkoxycarbonyl, C₁-C₆-alkanoyl, C₁₅-C₂₀-alkanoyl, benzoyl, thienyl(C₁-C₆)alkanoyl, phenyl(C₃-C₆)alkenoyl substituted with a C₂-C₆-alkenyl group, or phenyl(C₁-C₆)alkanoyl substituted with a C₁-C₆-alkyl group; R² is hydroxy and R³ is carboxy or C₁-C₆-alkoxycarbonyl, or R² and R³ are linked together to represent a group of the formula: R⁴ is hydroxy, phenyl(C₁-C₆)alkoxy or C₁-C₆-alkanoyloxy; R⁵ is hydroxy, phenyl(C₁-C₆)alkoxy or C₁-C₆-alkanoyloxy; R⁶ is hydroxy, C₁-C₆-alkoxy, phenyl(C₁-C₆)alkoxy or C₁-C₆-alkanoyloxy; and is a single bond or a double bond, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing and/or treating inflammation. Use of claim 1, in which the peptide derivative is the compound (I) wherein R¹ is 3-(2-pentylphenyl)propanoyl, R² and R³ are linked together to represent a group of the formula : R⁴ is hydroxy, R⁵ is hydroxy, R⁶ is hydroxy, and is a double bond, or a pharmaceutically acceptable salt thereof. Use of claim 2, in which the peptide derivative is a compound of the formula: Use of a peptide derivative of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing and/or treating arthritis.

Inventors: FUJII TAKASHI, TOMOI MASAAKI, FUJII, TAKASHI, TOMOI, MASAAKI
Applicants: FUJISAWA PHARMACEUTICAL CO, FUJISAWA PHARMACEUTICAL CO., LTD.
Application year: 1991
Main classification: A61K38
IPC codes: A61K38, A61P1, A61P29, A61P43, C07C237, C07K7