SK51296A3 - Inhibiting photodecomposition of 3-substituted-2-oxindol-1- -carboxamides, a tablet and a capsule - Google Patents

Abstract

This invention relates to the protection of certain 3-substituted-2-oxindole-1-carboxamides of formula (I) and the pharmaceutically-acceptable base salts thereof wherein X is H, Cl or F; Y is H or Cl; and R is benzyl or thienyl, each optionally substituted with Cl or F from decomposition in the presence of light.

Description

Method for inhibiting light decomposition of 3-substituted

2-oxindole-1-carboxamides, tablet and capsule

Technical field

The invention relates to a method for inhibiting light decomposition

3-substituted 2-oxindole-1-carboxamides of formula

where

X represents a hydrogen, chlorine or fluorine atom;

Y represents a hydrogen or chlorine atom; and

R is benzyl or thienyl, each optionally substituted with chlorine or fluorine;

and pharmaceutically acceptable base salts thereof. The invention also relates to a light-stabilized tablet and a capsule containing the aforementioned active ingredient.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 4,569,642 discloses certain 2-oxindole-1-carboxamides of formula (i)

where

X is hydrogen, -fluoro, chloro or bromo, (C1-C4) alkyl, (C3-C7) cycloalkyl, (C1-C4) alkoxy, (C1-C4) alkylthio, trifluoromethyl, (C1-C4) alkylsulfinyl C 4 -C 4 alkylsulfonyl, C 1 -C 4 alkylsulfonyl, nitro, phenyl, C 2 -C 4 alkanoyl, benzoyl, tenoyl, C 1 -C 4 alkanido, benzamido or Ν, Ν-dialkylsulfamoyl each of the alkyl moieties;

Ϊ is hydrogen, fluoro, chloro or bromo, (C 1 -C 4) alkyl, (C 3 -C 7) cycloalkyl, (C 1 -C 4) alkoxy, (C 1 -C 4) alkylthio, and trifluoromethyl;

R ¹ is C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 4 -C 7 cycloalkenyl, phenyl, substituted phenyl, phenylalkyl of 1 to 3 carbon atoms in the alkyl moiety, (substituted phenyl) alkyl of 1 up to 3 carbon atoms in the alkyl moiety, (substituted phenoxy) alkyl having 1 to 3 carbon atoms in the alkyl moiety, (thiophenoxy) alkyl having 1 to 3 carbon atoms

- 3 in the alkyl moiety, naphthyl, bicyclo [2.2.1] heptan-2-yl, bicyclo [2.2.2] hept-5-en-2-yl or a group of the formula - (CH ₂ ) _n "QR> wherein n represents the number 0, 1 or 2;

Q represents a bivalent radical derived from furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole, 1,2,3-thiadiazole,

1,3,4-thiadiazole, 1,2,5-thiadiezole, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, tetrahydropyran, tetrahydrothiopyran, pyridine, pyrimidine, pyrazine, benzo [b] furan or benzo [b] thiophene; and is (C1 -C6) alkyl, (C3 -C7) cycloalkyl, benzyl, furyl, thienyl, pyridyl or ## STR6 ## wherein iP and R @ 1 are each hydrogen, fluorine or chlorine, C1 -C4 alkyl; C 1 -C 4 alkoxy or trifluoromethyl.

The patent also discloses that these 2-oxindole-1-carboxamides are cyclooxygenase and lipooxygenase inhibitors, have analgesic activity in mammals, and are useful in treating pain and ameliorating the symptoms of chronic diseases such as inflammation and pain associated with rheumatoid arthritis. arthritis and osteoarthritis.

- 4 In U.S. Pat. No. 4,556,672, certain 3-acyl-substituted 2-oxindole-1-carboxamides of the formula

wherein X, Y and are as defined above for the compounds of U.S. Pat. 4,569,942 ·

U.S. Pat. No. 4,361,794 discloses the use of compounds of the general formula

where

X represents a hydrogen, chlorine or fluorine atom;

Y represents a hydrogen or chlorine atom; and

R is benzyl or thienyl, and pharmaceutically acceptable salts thereof with bases for inhibiting interleukin-1 (IL-1) biosynthesis and for treating disorders and dysfunctions mediated by IL-1.

SUMMARY OF THE INVENTION

The present invention provides a method for inhibiting the light decomposition of 3-substituted 2-oxindole-1-carboxamides of formula I

where

X represents a hydrogen, chlorine or fluorine atom;

Y represents a hydrogen or chlorine atom; and

R is benzyl or thienyl, each optionally substituted with chlorine or fluorine;

and their enol forms, or pharmaceutically acceptable salts thereof, wherein the light decomposition occurs by the action of light emanating from a light source which comprises introducing a light absorbing agent between said compound and the light source.

In a preferred embodiment of the method) according to the invention, a dye selected from the group consisting of yellow no. 6, red no. 40, red no. 3, yellow lacquer no. 6, red lacquer no. 40 and red lacquer no. Third

In a further preferred embodiment of the method according to the invention, yellow absorbent no. 6 ·

The present invention also provides a tablet comprising a pharmaceutically active ingredient selected from the group consisting of 3-substituted 2-oxindole-1-carboxamides of Formula I

- 6 (I)

where

X represents a hydrogen, chlorine or fluorine atom;

Y represents a hydrogen atom or a chlorine atom; and

R is benzyl or thienyl, each optionally substituted with chlorine or fluorine;

and pharmaceutically acceptable base salts thereof, characterized in that the tablet is coated with a colorant-containing coating selected from the group consisting of yellow no. 6, red no. 40 »red no. 3, yellow lacquer no. 6, red lacquer no. 40 and Red lacquer no. 3 in an amount sufficient to inhibit the light decomposition of the pharmaceutically active ingredient.

In a preferred embodiment, the present invention relates to a coated tablet, characterized in that the coating comprises yellow no. 6 in an amount sufficient to inhibit the light decomposition of the pharmaceutically active ingredient.

The present invention also provides a capsule containing a pharmaceutically active ingredient selected from the group consisting of 3-substituted 2-oxindole-1-carboxamides of formula I

(I)

- 7 where

X represents a hydrogen, chlorine or fluorine atom;

Y represents a hydrogen or chlorine atom; and

R is benzyl or thienyl, each optionally substituted with chlorine or fluorine;

and pharmaceutically acceptable base salts thereof, characterized in that the capsule shell comprises a colorant selected from the group consisting of yellow no. 6, red no. 40, red no. 3, yellow lacquer no. 6, red lacquer no. 40 and Red lacquer no. 3 in an amount sufficient to inhibit the light decomposition of the pharmaceutically active ingredient.

A more detailed description of the invention follows.

3-Substituted 2-oxindole-1-carboxamides of formula I

and their enol forms of formula

- 8 where

X represents a hydrogen, chlorine or fluorine atom;

Y represents a hydrogen or chlorine atom; and

R. is benzyl or thienyl, each optionally substituted by chlorine or fluorine;

and their pharmaceutically acceptable base salts, as well as their preparation, are described in U.S. Pat. No. 4,556,672 and 5,290,802. These citations are intended to replace their entire content in the disclosure of this invention. These compounds were found to be; photosensitive and decompose under the influence of light. The present invention is directed to methods of preventing light decomposition of compounds of formula I and their enol forms by preventing light from coming into contact with these compounds.

The term light source in this description means sunlight or any artificial light source that emits light with a wavelength less than 600 nm. By light-absorbing agent is meant a material that captures all or most of the wavelengths of light, such as opaque glass or metal; or materials which absorb light with a wavelength less than 600 nm, such as ultraviolet stabilizers or dyes.

The light-absorbing agent can be used in packaging materials such as blisters, sachets or masses. Light absorbing chemicals, such as ultraviolet stabilizers, may be added to the packaging materials, for example, blisters, sachets or bottles, or may preferably be added to the capsule or tablet coating material. Chemical absorbents

The light can also be directly mixed with the active ingredient before processing into tablets or placing in a capsule shell.

Inhibition of light decomposition means a statistically significant reduction in the formation of decomposition products formed by light decomposition, as described below.

Among the methods of inhibiting light decomposition described below, preference is given to a method wherein the compound of formula I is a compound wherein X is chlorine, Y is hydrogen and R is thienyl; wherein X is fluorine, Y is chlorine and R is thienyl or 4-chlorothien-2-yl; wherein X is fluorine, Y is chlorine and R is 2-thienyl; and wherein X represents a hydrogen atom, Y represents a chlorine atom and R represents a benzyl group. Particularly preferred is a method comprising inhibiting the light decomposition of compounds of formula I wherein X is chlorine, Y is hydrogen and R is 2-thienyl. The compounds of formula I may exist in enol form, and all such enol forms and salts thereof are included within the scope of the present invention.

As described in US 4,556,672 and 5,290,802, the compounds protected by the process of the invention are acidic and form salts with bases. All such salts with bases are within the scope of this invention and can be obtained by the methods described in these patents. Suitable salts within the scope of this invention are both organic and inorganic salts. Such salts include, but are not limited to, salts formed by reaction with ammonia, organic amines, alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydrides, alkali metal alkoxides, alkaline earth metal hydroxides, alkaline earth metal carbonates, hydrides alkaline earth metal alkoxides. Representative bases which form such salts with bases 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, N-methylaniline, morpholine, pyrrolidine and piperidine; tertiary amines such as triethylamine, triethanolamine, Ν, Ν-dimethylaniline, N-ethylpiperidine and N-methylmorpholine; hydroxides such as sodium hydroxide; aloxides such as sodium ethoxide and potassium methoxide; hydrides such as potassium hydride and sodium hydride; and carbonates such as potassium carbonate and sodium carbonate. Preferred salts are sodium, potassium and ammonium salts and salts formed with ethanolamine, diethanolamine and three ethanolamine. Particular preference is given to sodium salts. Compounds to which the invention is applicable include solvates such as hemihydrates and monohydrates of the above-described compounds.

The light-induced degradation of the 3-substituted oxindole-1-carboxamides takes place mainly at light wavelengths less than 600 nm, and decomposition products predominantly produce benzoic acid or thiophenecarboxylic acid and indole-1-carboxamide. This degradation can be avoided by avoiding light contact with a wavelength less than 600 nm with the 3-substituted oxindole-1-carboxamide.

In the context of the invention, it has been found that red and yellow colors effectively prevent contact with light and the associated light-induced degradation of 3-substituted oxindole-1-carboxamides. Preferred dyes are FD-C red. 40, FDI (C Red No. 3 and FD&C Yellow No. 6. Particularly preferred is Yellow No. 6 * These dyes effectively prevent light-induced degradation of 3-substituted oxindole-1-carboxamides when mixed with oxindole, applied to the package on a preformed tablet, or introduced into a gelatin capsule containing oxindole.

Film coating of pharmaceutical tablets is well known in the art, as described, for example, in U.S. Pat. Nos. 4,828,841, 3,981,948, and 3,802,896. These citations are also incorporated herein by reference in their entirety in the disclosure. As packaging film-forming materials, white Opadry, Opadry II, Surelease, Aquacoat and Eudragit can be used. These materials are suitable for mixing with the selected dye and are commercially available from Colorcon, West Point, PA, USA; FMC Corp., Philadelphia, PA; and Rohm Pharma, Weiterstadt, Germany.

The dyes can also be mixed into gelatin capsules, which are then filled with oxindole. Capsule manufacturing technology is well known to those skilled in the art. Capsules containing the selected dyes are commercially available from Elanco Shinogi, Indianapolis, IN, USA and Capsugel, Greewood, SC, USA. The incorporation of opacifiers and colorants into gelatin capsule shells is described in U.S. Pat. 3,784,694.

The amount of dye in the coating or coating is not critical, but must be sufficient to absorb the entire amount of incident light. A quantity of yellow no. 6 to indicate an amount ranging from 1.2 to 2.8 mg / teblet. The light fastness of the active ingredient in the capsule is obtained using 0.28 to 0.9 mg of yellow no. 6 in a capsule shell.

A typical composition of the coated tablets according to the invention is given below.

Ingredient: mg / tablet

oxindole-1-carboxamide 21, 74 Klucel EF 6.00 lactose, anhydrous 122.26 Ac-Di-Sol 6.00 Avicel PH 102 40.00 magnesium stearate 3.60 sodium lauryl sulphate 0.40 total core weight 200.00 white Opadry / YS-5-7068 / ⁸ 10.00 distilled water yellow no. 6, lacquer / purity 39% / ^b 1.15

total weight of coated tablet 211,15 ^a For batches to be film coated ^b For batches that will contain dye

The invention is illustrated by the following examples. The above examples are illustrative only and do not limit the scope of the invention in any way.

Examples of embodiments of the invention

Example 1

Coated tablets

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

Orange Opadry containing yellow dye no. 6, obtained from Colorcon, West Point, PA, USA (144 g) was suspended in 816 ml of water. The tablet cores were introduced into a Hi Coater HCT30 Coating Machine where an orange Opadry suspension was applied at 42 ° C.

Two coated and one uncoated batch of 5-chloro-2,3-dihydro-3-hydroxy-2-thienylmethylene) -2-oxo-1H-indole-1-carboxamide tablets / compound of formula I wherein X is chlorine and Y is hydrogen atom / are heated to 30 ° C

Store at 50 ° C and 6 weeks in a light chamber. In all batches the tablet cores are identical. The coated tablets differ only in the amount of yellow no. 6 in the packaging film. The intensity in the light chamber is 400 PC / foot candles / center and 300 PC on the sides. The room temperature is maintained in the light chamber.

The appearance of samples stored at 30 and 50 ° C does not differ from the appearance of samples stored at 5 ° C. No scales are observed on the coating film on any tablet. The following observations shall be made on samples stored in the light chamber for 6 weeks:

- 14 Lot 1 (kernels / kernels are slightly darkened and contain brown spots / compared to a control stored at 5 ° C)

Batch 2 / coated tablets /

Batch 3 (coated tablets / slightly discolored) compared to a control stored at 5 ° C / slightly discolored / compared to a control stored at 5 ° C /

The results of the liquid chromatography testing of these batches are summarized in the following table. Each sample is analyzed in triplicate. Test values for uncoated tablets are close to the intended value of 100 mg / g. Thiophene-2-carboxylic acid content, 6-chloro-1H-quinazoline-2,4-dione,

T -carbanyl: 5-chloro-Ch 2 -xa.r 2, 3-dihydrocarbonyl-4-carboxylic acid thiophene-2-carboxylic acid, 6-chloro-2-hydroxyquinoline-4-carboxylic acid, and of unknown substance 2.3 in non-coated tablets in the light chamber increases significantly (compared to a control stored at 5 ° C). No significant degradation is observed with tablet cores stored at 5 ° C, ° C or 50 ° C.

No significant degradation was observed in coated tablets stored at 5 ° C, 30 ° C, 50 ° C or in a light chamber. After 6 weeks, the degradation level of the samples stored in the light chamber is approximately the same for both batches of coated tablets. The results of the above tests are shown in the following table.

15 mg of 5-chloro-2,3-dihydro-3 '(hydroxy-2-thienylmethylene) -2-oxo-1H-indole-1-carboxamide (compound of formula I, X = Cl, Y = H), 6 weeks*

Batch 1 / tablet cores / weeks 5 ° C 30 ° C 50 ° C LC

5-chloro-2,3-dihydro-3- (hydroxy-2-thienylmethylene) -2-oxo-1H-indole-1-carboxamide / compound of formula I, X-Cl, Y = H / (mg / tablet)

5-chloro-2,3-dihydro-3- (hydroxy-2-thienylmethylene) -2-oxo-1H-indole-1-carboxamide (compound of formula I, X = Cl, Y = H) (mg / g) thiophene-2 -carboxylic (%)

6-chloro-1H-quinazoline-2,4-dione (»)

Thiophene-2-carboxylic acid 1-carbamoyl-5-chloro-2-oxo-2,3-dihydro-1H-indol-3-yl ester (%)

39.4 39 ^ 7. 39 \ 8 38.7

99.0 99.8 100.8 97.8

0.01 0.02 0.04 0.28

ND ND <0.01 0.06

0.01 0.03 0.02 0.19

- 16 6-chloro-2-hydroxyquinazoline-4-carboxylic acid (%) 0,01 0,03 0,04 0,29 unknown substance δ. 3 (%) ** ND ND ND. 0.03

Batch 2 / coated teblets, 1.35 mg yellow no. 6 / wks 5 ° C 30 ° C LC

5-chloro-2,3-dihydro-3- (hydroxy-2-thienylmethylene) -2-oxo-1H-indole-1-carboxamide / compound of formula I, X = Cl,

Y = H / (mg / tablet) 39.4 39.4 38.7

5-chloro-2,3-dihydro-3- (hydroxy-2-thienylmethylene) -2-oxo-1H-indole-1-carboxamide / compound of formula I, X = Cl,

Y = H / (mg / g) 92.7 93.1 91.2 Thiophene-2-carboxylic acid

W

6-chloro-1H-quinazoline-2,4-dione («)

Thiophene-2-carboxylic acid 1-carbamoyl-5-chloro-2-oxo-2,3-dihydro-1H-indol-3-yl ester (%)

0.02 0.01 0.03

0.02 0.02 0.02

0.01 0.01 0.01

- 17 6-chloro-2-hydroxyquinoline-4-carboxylic acid (%) 0,03 0,02 0,04

Batch 2 / coated tablets, 0.9 mg yellow no. 6 / wks 5 ° C 30 ° C 50 ° C LC

5-chloro-2,3-dihydro-3- (hydroxy-2-thienylmethylene) -2-oxo-1H-indole-1-carboxamide / compound of 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-1-carboxamide / a compound of formula I wherein X = Cl, Y = H / (<Ng / 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 w 0.01 0.02 0.02 0.02

6-chloro-2-hydroxyquinazoline-4-carboxylic acid (%)

0.02 0.04 0.05 0.05

ND = not found * Stability comparison should be performed against a control sample stored at 5 ° C Area percentage

Example 2

capsules

The preparation based on the compound of the formula I, ⁱⁿ de X being a chlorine atom, Y being a hydrogen atom and E being a thienyl group, is prepared according to the following formula:

mg / unit sodium salt of compound of formula I 128,205 lactose, anhydrous 159,795 pregelatinized starch 112,500 croscarmellose sodium 9,000 magnesium stearate 9,000

The above ingredients are blended, part of the mixture is compacted on rollers, regrinded and blended with the remaining ingredients, a lubricant is added, and the mixture is filled with gelatin capsules from Capsugel (a division of Warner-Lambert Company). Sodium lauryl sulfate is used as a preferred lubricant. The capsules contain an FD ^ C Yellow dye in an amount

- 19 0.2651%, based on total dry weight / body; capsules / a in an amount of 0.1768% based on the total dry weight in the lid.

The capsules produced in this way provide a compound of formula I with a light fastness.

Claims (14)

A method of inhibiting light decomposition of 3-substituted 2-oxindole-1-carboxamides of the formula I: hydrogen or chlorine; and benzyl or thienyl, from anywhere X represents Y represents R is each optionally substituted with chlorine or fluorine; and their enol forms or pharmaceutically acceptable base salts, wherein the light decomposition occurs by the action of light emanating from a light source, characterized in that a light source is introduced between the compound. a light absorbing agent. 2. The process of claim 1 wherein X is chlorine, Y is hydrogen, and R is thienyl. 3. A process according to claim 2 wherein R is 2-thienyl. 4. A process according to claim 3 wherein the pharmaceutically acceptable base salt is the sodium salt. 5. The process of claim 1 wherein X is fluorine, Y is chlorine, and R is thienyl or 4-chlorothien-2-yl. » 6. The process of claim 5 wherein R is 4-chlorothien-2-yl. w 7. The method of claim 1 wherein X is hydrogen, Y is chlorine, and R is benzyl. A method according to claim 1, characterized in that a dye selected from the group consisting of yellow color no. 6, red no. 40, red no. 3, yellow lacquer no. 6, red lacquer Art. 40 and red lacquer δ. Third Method according to claim 8, characterized in that yellow light is used as the light absorbing agent. 6th A tablet comprising a pharmaceutically active ingredient selected from the group consisting of 3-substituted 2-oxindole-1-carboxamides of formula I wherein: X represents a hydrogen or fluorine atom; Y represents a hydrogen or chlorine atom; and R is benzyl or thienyl, each optionally substituted with chlorine or fluorine; and pharmaceutically acceptable base salts thereof, characterized in that the tablet is coated with a coating containing a colorant selected from the group consisting of yellow no. 6, red no. 40, red no. 3, yellow lacquer no. 6, red lacquer no. 40 and red lacquer no. 3 in an amount sufficient to inhibit the light decomposition of the pharmaceutically active ingredient. 11. A tablet according to claim 10, wherein the container comprises yellow dye no. 6th A capsule comprising a pharmaceutically active ingredient selected from the group consisting of 3-substituted 2-oxindole-1-carboxamides of formula I wherein: X represents a hydrogen, chlorine or fluorine atom; Y represents a hydrogen or chlorine atom; and R is benzyl or thienyl, each optionally substituted with chlorine or fluorine; and pharmaceutically acceptable base salts thereof, characterized in that the capsule shell comprises a colorant - 23 ~ selected from the group consisting of yellow no. 6, red no. 40, red no. 3, yellow lacquer no. 6, red lacquer Art. 40 and red lacquer no. 3 in an amount sufficient to inhibit the light decomposition of the pharmaceutically active ingredient. * Capsule according to claim 12, characterized in that the capsule shell comprises yellow dye no. 6th 14. The method of claim 1, wherein the light absorbing means is a light absorbent packaging material.