WO1998057644A1

WO1998057644A1 - Preventive and remedy for drug-induced nephropathy

Info

Publication number: WO1998057644A1
Application number: PCT/JP1998/002633
Authority: WO
Inventors: Junichi Shimada; Fumio Suzuki; Ken Nagashima; Hiroko Okano; Akira Karasawa
Original assignee: Kyowa Hakko Kogyo Co., Ltd.
Priority date: 1997-06-16
Filing date: 1998-06-16
Publication date: 1998-12-23
Also published as: AU7675498A

Abstract

Preventive and remedy for drug-induced nephropathy, containing a xanthine derivative of general formula (I) or a pharmacologically acceptable salt thereof as the active ingredient.

Description

Specification

Drug-induced renal disorder prevention and treatment

Technical field

The present invention relates to a drug for preventing and treating drug-induced renal disorder.

Background technology

Drugs that cause drug-induced nephropathy can be broadly classified into three types based on the pathogenesis of the renal disorder. The first is a drug that causes renal damage (mainly degeneration of the proximal tubular epithelial cells' necrosis) in a direct and dose-dependent manner by the drug or its metabolites. Aminoglycoside antibiotics such as kanamycin and genoamycin are typical examples, and cisplatin, which is frequently used as an anticancer agent, some nonsteroidal anti-inflammatory drugs, and contrast agents are also exemplified. The second group is drugs that cause drug-sensitive renal damage (primarily tubulointerstitial nephritis) by immunological mechanisms. Examples include i3-lactam antibiotics such as penicillins and cefms. The third group is drugs characterized by the site of the onset of the disorder, for example, methotrexate, a sulfa drug, etc., which cause obstructive disorders. The emergence of drugs that have a sufficient effect on the prevention and treatment of these drug-induced renal disorders is expected.

On the other hand, many of the xanthine derivatives related to the compound represented by the following formula (I) used in the present invention are known, and exhibit a selective antagonism to adenosine A1 receptor, a diuretic effect, It is known to exhibit a protective effect, a tracheal dilation effect, a cerebral function improving effect, an anti-dementia effect or an anti-ulcer effect [Japanese Patent Application Laid-Open No. Hei 3-173883 (EP Publication 038686). No. 75), Japanese Unexamined Patent Application Publication No. Hei 37-17389 (EP Publication No. 0 154 566), Japanese Unexamined Patent Application Publication No. 8913 publication (EP publication 497258), JP-A-5-59056 (EP publication 509379), JP-A 6-1 No. 6 668 (EP publication 0 560 354), Japanese Unexamined Patent Publication No. Hei 7-22853 (EP publication 0 193 166)] _c The fact that the compound represented by (I) is useful for the prevention and treatment of drug-induced nephropathy. It is not known. Disclosure of the invention

The present invention provides a compound of the formula (I)

[Wherein, R ¹ and R ² are the same or different and are hydrogen, aryl, propargyl, R ³ — (CH ₂ ) _m- (wherein, R ³ represents a substituted or unsubstituted alicyclic alkyl, and m is 0, 1 or 2) or hydroxy-substituted, oxo-substituted or unsubstituted lower alkyl, and Y represents a bond or alkylene.

Wherein R ⁴ and R ⁵ are the same or different and represent hydrogen or hydroxy, or together represent oxo, and n represents 0 or 1.

R ⁶

(Wherein, R ⁶ and R ⁷ represent the same or different substituted or unsubstituted alicyclic alkyl) R ⁷ effective to salts xanthine derivative or a pharmacologically allowable represented by representing the Ingredient Drug prevention and treatment for renal disorders.

The present invention also relates to a method for preventing and treating drug-induced renal disorder, comprising administering an effective amount of a xanthine derivative represented by the formula (I) or a pharmacologically acceptable salt thereof.

The present invention also relates to the use of a xanthine derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof for the production of a pharmacological composition useful for the prevention and treatment of drug-induced renal disorder. .

Hereinafter, the compound represented by the formula (I) is referred to as compound (I).

In the definition of compound (I), lower alkyl is straight-chain or branched having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl. Includes tyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc. Alkylene includes linear or branched C 1-4 alkylene, for example, methylene, ethylene, trimethylene, tetramethylene, methylmethylene, propylene, ethylethylene and the like. The number of hydroxy or oxo substitutions in R ¹ and R ² is 1-2, and the substitution position may be arbitrary. Alicyclic alkyls include those having 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Examples of the substituent of the alicyclic alkyl include the same or different substituents having 1 to 3 substituents, for example, lower alkyl, hydroxy, lower alkoxy, halogen, nitro, amino, carboxy, etc., and lower alkyl and lower alkoxy. The alkyl moiety has the same meaning as described above. Halogen includes atoms of fluorine, chlorine, bromine and iodine. As R ¹ and R ² , hydroxy-, oxo- or unsubstituted propyl at the 2- or 3-position can be exemplified. In the definition of Q, the bonding position with Y and the position of hydroxy or oxo substitution may be arbitrary. The preferred Q, 9-position or 6-position hydrate proxy substituted, Okiso substituted or unsubstituted 3 - tricyclo [3.3丄0 ³ ^'7] nonyl, Oh Rui 1 3-position hydroxy-substituted or unsubstituted Torishikuro [3.3 .1.1 ³ ' ⁷ ] decyl and the like.

Pharmaceutically acceptable salts of compound (I) include pharmacologically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like.

Pharmaceutically acceptable acid addition salts of compound (I) include, for example, inorganic salts such as hydrochloride, sulfate, phosphate, etc., acetate, maleate, fumarate, tartrate, quer Organic salts such as carboxylate and methanesulfonate are exemplified. Examples of pharmacologically acceptable metal salts include alkali metal salts such as sodium salt and potassium salt, alkali salts such as magnesium salt and calcium salt. Earth metal salts, aluminum salts, zinc salts, etc .; pharmacologically acceptable ammonium salts include, for example, salts of ammonium, tetramethylammonium, etc .; pharmacologically acceptable organic Amine Examples of the addition salts include addition salts such as morpholine and piperidine, and examples of the pharmacologically acceptable addition salts of amino acids include addition salts such as lysine, glycine, and phenylalanine.

Compound (I) can be produced by the method disclosed in the above publication or according to it. The target compound in the production method can be isolated and purified by a purification method commonly used in organic synthetic chemistry, for example, filtration, extraction, washing, drying, concentration, recrystallization, various types of chromatography and the like.

When it is desired to obtain a salt of compound (I), if compound (I) is obtained in the form of a salt, it can be purified as it is, and if it can be obtained in the form of a free base, dissolve in an appropriate solvent Alternatively, they may be suspended and an acid or a base may be added to form a salt.

Compound (I) and its pharmacologically acceptable salts may be present in the form of adducts with water or various solvents. These adducts may also be used as the therapeutic agent of the present invention. Can be.

Although some of the compounds (I) may have optical isomers, all possible stereoisomers and mixtures thereof can be used as the prophylactic / therapeutic agent of the present invention.

Drugs that cause drug-induced nephropathy to be prevented and treated in this case include, for example, aminoglycoside antibiotics such as kanamycin and genyumycin, cisplatin, which is widely used as an anticancer drug, and some non- Drugs that cause renal damage (mainly degeneration and necrosis of proximal tubular epithelial cells) directly and dose-dependently by drugs such as steroidal anti-inflammatory drugs or their metabolites, such as penicillins and cefms) 3- Drugs that cause drug-sensitive renal damage (mainly tubular interstitial nephritis) by immunological mechanisms such as lactam antibiotics and methotrexate and sulfa drugs that cause obstructive disorders Characteristic drugs are listed.

Specific examples of the compound (I) are shown below.

Compound 1: 8— (3-noradamantyl) —1,3-dipropylxanthine (Japanese Unexamined Patent Application Publication No. Hei 3-173889)

Melting point: 190.0 ~: 191.0 ° C (heptane)

Elemental _{_{_{analysis: C 20 H 28 N 4 O}}} 2

Calculated value (%): C67.39, H7.92, N15.72

Observed value (%): C67.41, H7.62, N15.78

IR (KBr) V maxicm " ¹ ): 1699, 1651, 1499

^ -NMRCDMSO-de) δ (ppm): 12.97 (s, 1H), 3.95 (t, 2H), 3.85 (t, 2H), 2.70-2.60 (m, 1H), 2.35-2.26 (m, 2H), 2.20-2.10 (m, 2H), 1.95-1.82 (m, 4H), 1.80-1.50 (m, 8H), 0.95-0.80 (m, 6H) ¹³ C-NMR (DMSO-d ₆ ) δ (ppm): 159.9, 153.9, 150.7, 147.6, 106.6, 48.8, 48.2, 45.1, 44.2, 43.2, 41.9, 36.9, 34.1, 20.8, 11.1, 10.9

Next, the pharmacological action of the compound (I) will be described by test examples.

Test Example 1: Effect of frequent administration of cisplatin on drug-induced nephropathy

Cisplatin was administered intravenously (2.5 mg / kg, once a week, for 6 weeks) to male Wistar rats (body weight 220-270 g) to induce chronic renal failure. As an untreated group, a group (6 cases per group) to which physiological saline was administered (5 ml / kg, once a week, for 6 weeks) was provided. Compound 1 (0.1 mg / kg) was suspended in 5% gum arabic (5 ml / kg), and the suspension was orally administered 1 hour before weekly administration of cisplatin. The control group and the normal group were orally administered 5% gum arabic (5 ml / kg) one hour before weekly administration of cisplatin. The control group and the compound 1 administration group were examined in 8 cases.

On the 5th day of cisplatin administration in the last week, body weight was measured, and blood was collected from the abdominal aorta under ether anesthesia. Blood was centrifuged to obtain serum, and serum creatinine and urea nitrogen were measured by an automatic analyzer (Olympus, AU510).

Table 1 shows the body weight, serum creatinine, and urea nitrogen of each group on the 5th day of cisplatin administration in the last week. Table 1

Drug Body weight Serum creatinine Serum urea nitrogen

(g) (mg / dl) (mg / dl) Normal group 371.3 ± 6.5 ** 0.48 ± 0.02 18.8 ± 1.1 ** Control group 201.4 ± 6.8 4.51 ± 0.23 311.3 ± 33.4 Compound 1 (0.lmg / kg) 282.0 ± 7.1 n 1.27 ± 0.07 72.1 5.9 ** Each value is shown by the average soil standard error. The significant difference test between the control group and the normal group or the compound 1 administration group was performed using Student's t-test. Regarding the obtained results, when the risk ratio was less than 1%, it was judged that there was a significant difference. From the above test results, it was clarified that Compound 1 has preventive and therapeutic effects on the development of chronic renal failure associated with frequent administration of cisplatin.

Test example 2: Acute toxicity test

The test compound was orally or intraperitoneally administered to three dd male mice (body weight: 20 ± lg) per group. The death status on the 7th day after administration was observed, and the minimum lethal dose (MLD) value was determined. As a result, the MLD of compound 1 was> 1000 mg / kg by oral administration.

From the above, it is clear that compound (I) or a pharmacologically acceptable salt thereof is useful as a drug for preventing or treating drug-induced renal disorder.

Compound (I) or a pharmaceutically acceptable salt thereof can be used as it is or in various pharmaceutical forms. The pharmaceutical composition used in the present invention can be produced by uniformly mixing an effective amount of the compound (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier as an active ingredient. These pharmaceutical compositions are desirably in a unit dosage form suitable for administration, for example, rectally, orally or parenterally (including subcutaneously, intravenously and intramuscularly).

In preparing the compositions in oral dosage form, any useful pharmaceutically acceptable carrier can be used. Oral liquid preparations such as suspensions and syrups include water, sugars such as sucrose, sorbie, Use glycols such as glycol and propylene glycol; oils such as sesame oil, olive oil and soybean oil; preservatives such as P-hydroxybenzoic acid esters; flavors such as stove belly flavor and peppermint. Can be manufactured. For powders, pills, capsules and tablets, excipients such as lactose, glucose, sucrose, mannitol, disintegrants such as starch and sodium alginate, and lubricants such as magnesium stearate and talc , A binder such as polyvinyl alcohol, hydroxypropyl cellulose and gelatin, a surfactant such as a fatty acid ester, and a plasticizer such as glycerin. Tablets and capsules are the most useful unit oral dosage forms because of their ease of administration. When manufacturing tablets and capsules, a solid pharmaceutical carrier is used.

The injection can be prepared using a carrier comprising distilled water, a salt solution, a glucose solution, or a mixture of a salt solution and a glucose solution. At this time, it is prepared as a solution, suspension or dispersion using an appropriate auxiliary according to a conventional method.

Compound (I) or a pharmacologically acceptable salt thereof can be administered orally or parenterally as an injection in the above-mentioned pharmaceutical form. Although it varies depending on the age, weight, symptoms, etc., 1 to 900 mgZ60 kgZ days, preferably 1 to 200 mgZ60 kgZ days is appropriate.

Hereinafter, embodiments of the present invention will be described with reference to examples.

BEST MODE FOR CARRYING OUT THE INVENTION

Example 1: Tablet

A tablet having the following composition was prepared by a conventional method.

40 g of Compound 1, 286.8 g of lactose and 60 g of potato starch were mixed, and 120 g of a 10% aqueous solution of hydroxypropyl cellulose was added thereto. The mixture was kneaded by a conventional method, granulated, dried, and then sized to obtain granules for tableting. 1.2 g of magnesium stearate was added and mixed, and the mixture was tableted using a tableting machine (RT-15 type, manufactured by Kikusui) with an 8 mm diameter punch, and tablets (containing 20 mg of active ingredient per tablet) To). Formulation Compound 1 20 mg

Lactose 143.4 mg

Potato starch 30 mg

Hydroxypropyl cellulose 6 mg

Magnesium stearate 0.6 mg

200 mg

Example 2: Capsule

A capsule having the following composition was prepared by a conventional method.

200 g of Compound 1, 995 g of Avicel and 5 g of magnesium stearate were mixed by a conventional method. This mixture was filled into Hard Capsule No. 4 (120 mg capacity per capsule) by a capsule filling machine (Zanasi LZ-64 type), and a capsule (containing 20 mg of active ingredient per capsule) was prepared. Obtained.

Formulation Compound 1 20 mg

Avicel 99.5 mg

Magnesium stearate 0.5 mg

120 mg

Example 3 Injection

An injection having the following composition was prepared by a conventional method.

1 g of Compound 1 was dissolved in 100 g of purified soybean oil, and 12 g of purified egg yolk lecithin and 25 g of glycerin for injection were added. This mixture was kneaded and emulsified in a conventional manner to 1000 ml with distilled water for injection. The resulting dispersion is aseptically filtered using a 0.2-m disposable membrane filter, and aseptically filled into glass vials in a volume of 2 ml each to give an injection (containing 2 mg of active ingredient per vial). Obtained. Formulation compound 1 2 mg

Refined soybean oil 200 mg

Purified egg yolk lecithin 24 mg

Glycerin for injection 50 mg

1.72 ml of distilled water for injection

2.00 ml

Example 4: Rectal suppository

A formulation for rectal administration having the following composition was prepared by a conventional method.

Uitepuzo Ichiru ¹ ^"M H15 (manufactured by Dynamite Nobel) 678.8G and Uitepuzo was Lumpur ^TM E75 (manufactured by Dynamite Nobel) 290.9G melted at 40 to 50 ° C to. This compound 1 2.5 g, first 13.6 g of potassium phosphate and 14.2 g of dibasic sodium phosphate were uniformly mixed and dispersed, and the mixed and dispersed product was filled in a plastic suppository mold, and then gradually cooled to prepare a rectal suppository ( 2.5 mg of active ingredient per formulation) was obtained.

Formulation compound 1 2.5 mg

Diepzol H15 678.8 mg

Witepsol E75 290.9 mg

Potassium monophosphate 13.6 mg

Sodium diphosphate 14.2 mg

1,000 mg

Industrial applicability

An object of the present invention is to provide an excellent drug for preventing and treating drug-induced nephropathy.

Claims

The scope of the claims

[Wherein R ¹ and R ² are the same or different and are hydrogen, aryl, propargyl, R ³ — (CH ₂ ) _m- (wherein, R ³ represents a substituted or unsubstituted alicyclic alkyl, and m is 0, 1 or 2) or hydroxy-substituted, oxo-substituted or unsubstituted lower alkyl, and Y represents a bond or alkylene.

(Wherein, R ⁴ and R ⁵ are the same or different and represent hydrogen or hydroxy, or together represent oxo, and n represents 0 or 1).

R ⁶

(Wherein, R ⁶ and R ⁷ represent the same or different substituted or unsubstituted alicyclic alkyl) R ⁷ effective to salts xanthine derivative or a pharmacologically allowable represented by representing the Ingredient Drug-induced renal disorder prevention and treatment.

2. The preventive / therapeutic drug according to claim 1, wherein the drug-induced renal disorder is an anticancer drug-induced renal disorder.

3. The drug according to claim 1, wherein the drug-induced renal disorder is cisplatin-induced renal disorder.

4. The medicament for preventing or treating physical renal disorder according to claims 1 to 3, wherein the xanthine derivative is 8- (3-noradamantyl) -1,3-dipropylxanthine or a pharmacologically acceptable salt thereof.