HU216544B - Process for inhibiting photodecomposition of 3-substituted 2-oxindoles and pharmaceutical tablet, capsule and composition - Google Patents

Abstract

SUMMARY OF THE INVENTION The present invention relates to the protection of 3-substituted 2-oxindole-1-carboxamides of the general formula (I) and their pharmaceutically acceptable base salts from luminosity, wherein X is hydrogen, chlorine or fluorine, R is hydrogen, chlorine or sulfur substituted benzyl or thienyl. ŕ

Description

The present invention relates to the inhibition of the degradation of certain 3-substituted 2-oxindole-1-carboxamides of formula I and their pharmaceutically acceptable basic salts by the action of light, wherein

X is hydrogen, chlorine or fluorine,

Y is hydrogen or chlorine;

R is benzyl or thienyl, each of which may be optionally substituted with chlorine or fluorine.

The invention also relates to pharmaceutical compositions containing the compounds of formula I.

U.S. Patent 4,569,942 discloses certain 2-oxindole-1-carboxamides of Formula A wherein X is hydrogen, fluorine, chlorine or bromine;

C 1-4 alkyl, C 3-7 cycloalkyl,

C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, trifluoromethyl, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, nitro, phenyl, C 2 -C 4 alkanoyl, benzoyl, tenoyl, C 1 -C 4 alkanamido, benzamido or C 1 -C 3 N, N-dialkylsulfamoyl groups,

Y is hydrogen, fluorine, chlorine or bromine,

C 1-4 alkyl, C 3-7 cycloalkyl,

C1-C4 alkoxy, C1-C4 alkylthio or trifluoromethyl,

R ¹ is C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 4 -C 7 cycloalkenyl, phenyl, substituted phenyl, or C 1 -C 3 phenylalkyl in the alkyl group, or C 1 -C 3 alkyl in the alkyl group. (substituted phenyl) alkyl, alkyl having 1 to 3 carbon atoms (substituted phenoxy), alkyl having 1 to 3 carbon atoms (thiophenoxy) alkyl, naphthyl, bicyclo [2.2.1] -heptan-2-yl, bicyclo [2,2,1] hept-5-en-2-yl or - (CD ₂ ) _n -Q-R, η 0, 1 or 2,

Q is a divalent radical selected from furan, thiophene, red, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole, 1,2,3-thiadiazole, 1,3,4-thiadiazole, 1,2,5-thiadiazole, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, tetrahydrothiopyran, pyridine, pyrimidine, pyrazine, benzo [b] furan and benzo [b] thiophene derivative

R ² is C 1-6 alkyl, C 3-7 cycloalkyl, benzyl, furyl, thienyl, pyridyl or a) wherein

R ³ , R ⁴ are hydrogen, fluoro, or chloro, C 1-4 alkyl, C 1-4 alkoxy, or trifluoromethyl.

It is also disclosed in this patent that 2-oxindole carboxamides are also cyclooxygenase and lipoxygenase inhibitors in mammals, which are analgesic and useful in the alleviation and treatment of chronic diseases such as inflammation and pain associated with rheumatoid arthritis and osteoarthritis.

U.S. Patent 4,556,672 discloses 3-acyl-substituted 2-oxindole-1-carboxamides of formula B wherein X, Y and

R ¹ has the same meaning as in the compounds of U.S. Patent 4,569,942.

U.S. Patent No. 4,861,794 discloses compounds of formula I and pharmaceutically acceptable basic salts thereof, wherein X is hydrogen, chlorine or fluorine;

Y is hydrogen or chlorine;

R denotes the effect of a benzyl or thienyl group to inhibit the biosynthesis of interleukin1 (IL-1) and to treat IL-1 mediated disorders and dysfunctions.

The present invention relates to a process for inhibiting the degradation of a compound of formula I or an enol form or a pharmaceutically acceptable salt thereof by exposure to light, wherein

X is hydrogen, chlorine or fluorine,

Y is hydrogen or chlorine,

R is benzyl or thienyl, which may be optionally substituted with chlorine or fluorine, and the light degradation results from light from a light source in which the absorbent is brought into intimate contact with the compound by coating the compound with it. or in a dosage form such that light from the light source does not affect the compound.

In a preferred embodiment of the invention, the light-absorbing device is a dye selected from the group consisting of yellow # 6 paint, red paint # 40, red paint # 3, yellow paint # 6, red paint # 40 and red paint # 3.

In another preferred embodiment of the invention, the light-absorbing device is a yellow # 6 paint.

The present invention further provides a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable basic salt thereof as an active ingredient, wherein

X is hydrogen, chlorine or fluorine,

Y is hydrogen or chlorine and

R is benzyl or thienyl, each optionally substituted with chlorine or fluorine, and the tablet is coated with a sufficient amount of yellow # 6, red # 40, red # 3 dye, and yellow # 6, red # 40 and contains red # 3 lacquer to prevent light-based degradation of the drug.

According to a preferred embodiment of the invention there is provided a coated tablet wherein the coating contains a yellow dye # 6 in an amount sufficient to prevent light-based degradation of the therapeutic agent.

In another preferred embodiment, there is provided a capsule containing a therapeutically active agent or a pharmaceutically acceptable salt thereof, wherein

X is hydrogen, chlorine or fluorine,

Y is hydrogen or chlorine,

R is benzyl or thienyl, each of which may be substituted with chlorine or fluorine, and the capsule coating will contain a sufficient amount of yellow # 6, red # 40, red # 3 dye, yellow # 6, red # 40 and red

Contains lacquer # 3 which inhibits the photolysis of the drug.

The compounds of formula I and their enol form, pharmaceutically acceptable basic salts thereof, wherein X is hydrogen, chlorine or fluorine;

Y is hydrogen or chlorine,

R is benzyl or thienyl, which may be optionally substituted with chlorine or fluorine and is prepared by U.S. Patents 4,556,672 and 5,290,802. These compounds were found to be photosensitive and to be degraded by light. SUMMARY OF THE INVENTION The present invention is directed to preventing the degradation of the compounds of Formula I by the action of light by the compounds of Formula I and their enol form by inhibiting light by contacting the compounds.

The light source may be sunlight or any artificial light source producing wavelengths below 600 nm. The opacifier refers to materials that block light at all or most wavelengths, such as opaque glass or metals, or materials that absorb light at less than 600 nm, such as ultraviolet stabilizers or dyes.

The light-absorbing devices may be used in packaging materials, such as foil wrappers, bags or bottles. Chemical light-absorbing devices may, for example, be incorporated into packaging materials, including foil wrapping, sachets or bottles, or may preferably be enclosed in capsules or tablet coatings. The chemical light absorber may also be directly mixed with the active ingredient, either prior to tableting or prior to encapsulation.

Inhibition of photolysis involves a statistically significant reduction in the amount of light produced by the degradation products described below.

Preferred methods of inhibiting the photolysis described below are those wherein the compound of formula I is a compound wherein X is chloro, Y is hydrogen and R is thienyl, and wherein X is fluoro, Y is chloro and R is thienyl or 4-chloro. thien-2-yl and those wherein X is fluoro, Y is chloro and R2 is thienyl, and wherein X is hydrogen, Y is chloro and R is benzyl. Particularly preferred methods are those wherein X is chlorine, Y is hydrogen and R2 is thienyl. The compounds of formula I may also exist in enol form and are encompassed by the invention as enol forms as their salts.

In U.S. Patent Nos. 4,556,672 and 5,290,802, the compounds of the invention are acidic and form basic salts. All basic salts are within the scope of the present invention and can be prepared according to the patents. Such suitable salts according to the invention may be of the organic or inorganic type and include ammonia, organic amines, alkali metal hydroxides, alkali metal bicarbonates, alkali metal hydrides, alkali metal alkoxides, alkaline earth metal hydroxides, alkali metal hydroxides, salts with alkaline earth metal alkoxides. Bases which form the basic salts include ammonia, primary amines such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine, p-toluidine, ethanolamine and glucamine; secondary amines such as diethylamine, diethanolamine, N-methylglucamine, Nmethylaniline, morpholine, pyrrolidine and piperidine; tertiary amines such as triethylamine, triethanolamine, N, N-dimethylaniline, N-ethylpiperidine and N-methylmorpholine, and hydroxides such as sodium hydroxide, alkoxides such as sodium ethoxide and potassium methoxide, hydrides such as calcium hydride and carbonates such as potassium carbonate and sodium carbonate. Preferred salts are those of sodium, potassium, ammonium, ethanolamine, diethanolamine and triethanolamine. Sodium salts are particularly preferred. The compounds of the invention also include solvates such as hemihydrates and monohydrates.

The light-induced degradation of the 3-substituted oxindole-1-carboxamides occurs primarily at a wavelength of less than 600 nm and is mainly produced as benzoic or tenenoic acid or oxindole-1-carboxamide. This degradation can be avoided by preventing the wavelength below 600 nm from contacting the 3-substituted oxindole-1-carboxamide.

Red and yellow dyes effectively prevent contact between light and light-induced degradation of 3-substituted oxindole-1-carboxamides. Preferred inks are FD&C (Food Drug & Cosmetic Law) red # 40, FD&C red # 3 and FD&C yellow # 6. Yellow # 6 is particularly preferred. The dyes effectively prevent light-induced degradation of the 3-substituted oxindole-1-carboxamides when mixed with oxindole and applied to a pre-formulated tablet in a coated or oxindole-containing gelatin capsule. Coating tablets is preferred.

Film coatings for pharmaceutical tablets are well known in the literature and are described, for example, in U.S. Patent No. 4,828,841; U.S. Patent Nos. 3,981,948 and 3,802,896. Film coatings such as white Opadry, Opadry,, Sureleas, Aquacoat and Eudragit, which are advantageously used to form together with the selected paint, are commercially available from Colorcon, West Point, PA; EMC Corporationtöl, Philadelphia, PA; From Rohm Pharma, Weiterstadt, Germany. The dyes may also be incorporated into gelatin capsules, which are then filled with oxindole. Capsule production technology is well known to those skilled in the art. Capsules containing selected dyes are commercially available from Elanco Shinogi (Indianapolis, IN and Capsugel, Greenwood, SC). U.S. Patent No. 3,784,684 describes the use of opacifying compounds and dyes in gelatin capsules.

The amount of paint in the coating or capsule is not critical, the important thing is to install an appropriate amount of paint to absorb any light that may occur. We found that 1.2-2.8 mg / tablet yellow # 6 succeeded in stopping the degradation while the capsule

In the outer casing, 0.28 to 0.5 mg / capsule volume resulted in slight stability.

A typical formulation of the coated tablets according to the invention is described below:

component mg / tablet oxindole-1-carboxamide 21.74 Clucel EF (hydroxypropyl cellulose, Hercules) 6.00 lactose, anhydrous Ac-Di-Sol (pharmaceutically acceptable 122.26 excipient) Avicel PH102 (microcrystalline cellulose, 6.00 FMC) 40.00 magnesium stearate 3.60 sodium laureth sulfate 0.40 Gross Weight (Shell) White Opadry (YS-5-7068 ^a ) (Colorcon, 200.00 Westpoint) distilled water 10.00 yellow # 6 lacquer (39% purity) ^b 1.15 Total weight (film-coated tablet) ^{a is} the film-coated material, ^{b is} the future paint containing material. 211.15

The invention is further illustrated by the following examples, which are not intended to limit the invention.

Example 1

Coated tablets

600 g of 5-chloro-2,3-dihydro-3- (hydroxy-2-thienylmethylene) -2-oxo-1H-indole-1-carboxamide were prepared using the composition described above.

Orange Opadry (Colorcon, Westpoint, PA; 144 g) containing yellow # 6 lacquer was suspended in 816 ml of water. The tablet cores were converted on an Hl Coater HCT30 coating machine and maintained at 42 ° C while using the orange Opadry suspension.

Two coated and one uncoated 5-chloro-2,3-dihydro-3- (hydroxy-2-thienylmethylene) -2-oxo-1H-indole-1-carboxamide 30 Formula I: X = Cl, Y = H ) tablet is heated to 30 ° C and 50 ° C and kept for 6 weeks in a light cabinet. The tablet cores differed only in the amount of yellow # 6 lacquer in the film coating. The lighting cabinet has an intensity of 4305.6 lux at the center and 322.92 lux at the cabinet edges and is kept at room temperature.

Samples stored at 30 and 50 ° C did not have the same appearance as samples stored at 5 ° C. The film coating was not cracked on any of the tablets. The following visual observations were made for samples stored in the illuminated cabinet for 6 weeks:

Material 1 (core): slightly dark brown spots (compared to 5 degrees control)

Substance 2 (Coated): Slightly faded (compared to ° C control)

Substance 3 (Coated): Slightly faded (compared to ° C control).

The LC experiments for these materials are listed in the table below. Each sample was analyzed three times with experimental values close to the desired 100 mg / g for uncoated tablets. Thiophene-2-carboxylic acid, 6-chloro-1H-quinazoline-2,4-dione, thiophene-2-carboxylic acid, 1-carbamoyl-5-chloro-2-oxo-2,3-dihydro-1H-indole -3-yl ester, 6-chloro-2-hydroquinazoline-4-carboxylic acid and unknown material # 3 showed significantly increased levels in uncoated tablets in the light cabinet compared to the 5 ° C control. No significant degradation was observed for coated tablet cores stored at 5 ° C, 30 ° C, 50 ° C.

There was no significant degradation for coated tablets stored at 5 ° C, 30 ° C, 50 ° C, or in the light cabinet. After 6 weeks, the degradation of the samples stored in the light cabinet was approximately the same for both coated tablets. The experimental results of the above tests are shown in the table below.

40 mg of 5-chloro-2,3-dihydro-3- (hydro-2-thienylmethylene) -2-oxo-1H-indole-1-carboxamide (Formula I, X = Cl, Y = H), Stability, 6 weeks * Substance 1 (tablet core) 6 weeks 5 ° C 30 ° C 50 ° C Lighting cabinet 5-Chloro-2,3-dihydro-3- (hydroxy-2-thienylmethylene) -2-oxo-1H-indole-1-carboxamide (Formula I, X = Cl, Y = H), (mg / tablet) 39.4 39.7 39.8 38.7 5-Chloro-2,3-dihydro-3- (hydroxy-2-thienylmethylene) -2-oxo-1H-indole-1-carboxamide (Formula I, X = Cl, Y = H), (mg / g) 99.0 99.8 100.8 97.8 % thiophene-2-carboxylic acid 0.01 0.02 0.04 0.28 % 6-chloro-1H-quinazoline-2,4-dione ND ND <0.01 0.06 % Thiophene-2-carboxylic acid 1-carbamoyl-5-chloro-2-oxo-2,3-dihydrol-H-indol-3-yl ester 0.01 0.03 0.02 0.19 % 6-chloro-2-hydroxyquinazoline-4-carboxylic acid 0.01 0.03 0.04 0.29 % unknown # 3 ** not defined 0.03

* stability comparison with 5% control ** surface%

HU 216 544 A

Substance 2 (coated tablets, 1.35 mg yellow # 6 dye) 6 weeks 5 ° C 30 ° C 50 ° C Lighting cabinet 5-Chloro-2,3-dihydro-3- (hydroxy-2-thienylmethylene) -2-oxo-1H-indole-carboxamide (Formula I, X = Cl, Y = H), (mg / tablet) 39.5 39.4 38.7 5-Chloro-2,3-dihydro-3- (hydroxy-2-thienylmethylene) -2-oxo-1H-indole-carboxamide (Formula I, X = Cl, Y = H), (mg / g) 92.7 93.1 91.2 % thiophene-2-carboxylic acid 0.02 0.01 0.03 % 6-chloro-1H-quinazoline-2,4-dione 0.02 0.02 0.02 % Thiophene-2-carboxylic acid 1-carbamoyl-5-chloro-2-oxo-2,3-dihydro-1H-indol-3-yl ester 0.01 0.01 0.01 % 6-chloro-2-hydroxyquinazoline-4-carboxylic acid 0.03 0.02 0.04

Substance 3 (coated tablets, 0.9 mg yellow # 6 dye) 6 weeks 5 ° C 30 ° C 50 ° C Lighting cabinet 5-Chloro-2,3-dihydro-3- (hydroxy-2-thienylmethylene) -2-oxo-1H-indole-carboxamide (Formula I, X = Cl, Y = H), (mg / tablet) 39.5 39.6 39.0 39.0 5-Chloro-2,3-dihydro-3- (hydroxy-2-thienylmethylene) -2-oxo-1H-indole-carboxamide (Formula I, X = Cl, Y = H), (mg / g) 94.9 94.8 94.3 93.3 % thiophene-2-carboxylic acid 0.01 0.03 0.04 0.04 % 6-chloro-1H-quinazoline-2,4-dione 0.01 0.01 0.01 0.01 % Thiophene-2-carboxylic acid 1-carbamoyl-5-chloro-2-oxo-2,3-dihydro-1H-indol-3-yl ester 0.01 0.02 0.02 0.02 % 6-chloro-2-hydroxyquinazoline-4-carboxylic acid 0.02 0.04 0.05 0.05

Example 2 Capsules

A composition comprising a compound of formula I is prepared from the following components (X = Cl, Y = H and R = thienyl):

Sodium salt of compound of formula I mg / unit 128.205 lactose, anhydrous 159.795 sharpened starch 112,500 Croscormellose sodium 9,000 magnesium stearate 9,000

The above components were mixed and rolled, then milled and the remaining components re-mixed, lubricated and gelatin capsules made from Capsugel (Warner-Lambert Company). A preferred lubricant is sodium lauryl sulfate. The capsules contain FD&C yellow ink in an amount of 0.2651% of the total dry weight in the capsule body and 0.1768% in the capsule lid.

The capsules thus prepared provided the light stability of the compound of formula I.

Claims (14)

PATENT CLAIMS A process for preventing the degradation by light of a compound of formula I, its enol form or a pharmaceutically acceptable basic salt thereof, wherein: X is hydrogen, chlorine or fluorine, Y is hydrogen or chlorine; R is benzyl or thienyl, each of which may be optionally substituted with chlorine or fluorine, and the photodegradation results from light emitted from the light source, characterized in that the opacifier is in close contact with the compound, mixed with the compound, or in a dosage form. wherein the light source does not affect the compound, wherein the light-absorbing material comprises one or more lacquers of yellow # 6, red # 40, red # 3, yellow # 6, red # 40 and red # 3. A process according to claim 1, characterized in that X is chlorine, Y is hydrogen and R is thienyl. The method of claim 2, wherein R is 2-thienyl. The process of claim 3, wherein the pharmaceutically acceptable basic salt is sodium. The method of claim 1, wherein X is fluoro, Y is chlorine, R is thienyl or 4-chlorothien-2-yl. The method of claim 5, wherein R is 4-chloro-thien-2-yl. The method of claim 1, wherein X is hydrogen, HU 216 544 A Y is chlorine, R is benzyl. The method of claim 1, wherein the light-absorbing agent is yellow # 6, red # 40, red # 3 paint, yellow # 6, red # 40 and red # 3 lacquer. The method of claim 8, wherein the light-absorbing agent is a yellow dye # 6. A tablet comprising an active ingredient and a pharmaceutically acceptable carrier comprising a compound of formula (I) or a pharmaceutically acceptable base salt thereof, wherein, in formula (I), X is hydrogen, chlorine or fluorine; Y is hydrogen or chlorine, and R is benzyl or thienyl, each of which may be chloro or fluoro-substituted, and the tablet is provided with a coating of opacifying material which is sufficient to contain one or more yellow # 6, red # 40, red # 3 dye, yellow # 6, red # 40, and red # 3 lacquer to prevent degradation of the pharmaceutical agent by light from a light source acting on the compound. The tablet of claim 10, wherein the coating material comprises yellow # 6 paint. A capsule comprising a compound of formula (I) or an enol form, or a pharmaceutically acceptable base salt thereof, as a pharmaceutically active agent, in a pharmaceutically acceptable carrier, wherein X is hydrogen, chlorine or fluorine; Y is hydrogen or chlorine and R is optionally chloro or fluoro-substituted benzyl or thienyl - and each capsule shell contains a light-absorbing material comprising one or more yellow # 6, red # 40, red # 3 dye, yellow # 6, red # It contains 40 and red # 3 varnishes to inhibit degradation of the pharmaceutical agent by light from a light source acting on the compound. The capsule of claim 12, wherein the capsule shell contains yellow # 6 paint. 14. A pharmaceutical composition comprising a compound of formula I, an enol form, or a pharmaceutically acceptable base salt thereof, wherein X is hydrogen, chlorine or fluorine, Y is hydrogen or chlorine and R is benzyl or thienyl, each of which may be optionally substituted with chlorine or fluorine, and in close contact with the compound also comprises an opacifier comprising one or more yellow # 6, red # 40 consisting of red # 3 paint, yellow # 6, red # 40 and red # 3 lacquer in sufficient amounts to prevent the degradation of the pharmaceutical agent by light from the light source acting on the compound.