HRP960194A2 - Inhibiting photodecomposition of 3-substituted-2-oxindoles - Google Patents

Description

This invention relates to the prevention of degradation under the influence of light of certain 3-substituted-2-oxindole-1-carboxamides of the formula

[image]

and pharmaceutically acceptable 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.

In US Pat. 4,569,942 certain 2-osmdol-1-carboxamides of the formula are described

[image]

where X is H, fluorine, chlorine, bromine, (C1-C4)alkyl, (C3-C7)cycloalkyl, (C1-C4)alkoxy, (C1-C4)alkylthio, trifluoromethyl, (C1-C4)alkylsulfinyl, (C1 -C4)alkylsulfonyl, nitro, phenyl, (C2-C4)alkanoyl, benzoyl, thenoyl, (C1-C4)alkanamido, benzamido or N,N-dialkylsulfamoyl, having 1 to 3 carbon atoms in each of these alkyls; Y is H, fluoro, chloro, bromo, (C 1 -C 4 )alkyl, (C 2 -C 7 )cycloalkyl, (C 1 -C 4 )alkoxy. (C1-C4)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 having 1 to 3 carbon atoms in said alkyl, (substituted phenyl)alkyl having 1 to 3 carbon atoms in said alkyl, (thiophenoxy)alkyl having 1 to 3 carbon atoms in said alkyl, naphthyl, bicyclo[2.2.1 ]heptan-2-yl, bicyclo[2.2.1]hept-5-en-2-yl or -(CH2)n; nje zero, 1 or 2; Q is a divalent radical derived from furan, triophene, pyrrole, pyrazole, imidazole, 1,2,5-thiadiazole, 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;

R2 is (C1-C6)alkyl, (C3-C7)cycloalkyl, benzyl, furyl, thienyl, pyridyl or

[image]

wherein R 3 and R 4 are each H, fluoro, chloro, (C 1 -C 4 )alkyl), (C 1 -C 4 )alkoxy or trifluoromethyl. This patent also indicates that these 2-oxindole-1-carboxamides are cyclooxygenase and lipoxygenase inhibitors, have analgesic activity in mammals, and are useful in treating pain and relieving symptoms of chronic conditions such as inflammation and pain associated with rheumatoid arthritis and osteoarthritis.

US Patent 4,556,672 discloses certain 3-acyl substituted-2-oxindole-1-carboxamides of the formula

[image]

where X, Y and R 1 are as described above for the compounds of US Pat. 4,569,942. US patent no. 4,861,794 describes the use of a compound of formula

[image]

and their pharmaceutically acceptable base salts, wherein X is H, Cl or F, Y is H or Cl and R is benzyl or thienyl, for inhibiting the biosynthesis of interleukin-1 (IL-1) and for the treatment of IL-mediated disorders and dysfunctions -1.

This invention relates to a process for preventing degradation under the influence of light of a compound of formula I.

[image]

and its enol form or its pharmaceutically acceptable salts, 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, wherein said decomposition is produced by light radiating from a light source, and the process includes the introduction of a light-absorbing agent between said compound and said light source.

In one preferred method of the present invention, said light absorbing agent is one color selected from the group consisting of Yellow #6, Red #40, Red #3, Yellow Varnish #6, Red Varnish #40, and Red Varnish #3.

According to one of its other forms, this invention relates to a tablet containing a pharmaceutical active ingredient selected from the compound of the formula

[image]

or 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, wherein said tablet is coated with a coating containing a sufficient amount of yellow color #6, red color #40, red color #3, yellow lacquer color #6, red lacquer color #40 and red lacquer color #3, to prevent degradation under the influence of light of the mentioned pharmaceutical active ingredient.

According to one of its preferred forms, the present invention comprises a coated tablet, wherein said coating contains yellow dye #6 in an amount sufficient to prevent degradation under the influence of light of said pharmaceutically active ingredient.

According to another preferred form, this invention comprises a capsule containing a pharmaceutically active ingredient selected from compounds of the formula

[image]

or its pharmaceutically acceptable base salts, 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, wherein the capsule shell contains a sufficient amount of yellow color #6, red color #40, red color #3, yellow lacquer color #6, red lacquer color #40 and red lacquer color #3, in order to prevent degradation under the influence of light of the mentioned pharmaceutical active ingredient.

Compound formula

[image]

and their enol form:

[image]

and 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, or preparations thereof are described in U.S. Patent Nos. . 4,556.672 and 5,290.02, the subject matter of which is incorporated herein as known literature. These compounds have been found to be sensitive to light and to degrade under the action of light. This invention relates to methods for preventing degradation under the influence of light of the compound of formula I and its enol form by preventing light from coming into contact with said compounds.

As used in this document, "light source" means sunlight or any artificial light source that produces light of wavelength below 600 nm. The term "light absorbing agent" refers to materials that block all or most wavelengths of light, such as opaque glass or metals, or materials that absorb light at wavelengths below 600 nm, such as ultraviolet stabilizers or dyes.

The light absorbing agent can be used in packaging materials such as "boards" with special compartments for tablets, sachets or vials. Chemical light absorbing agents such as ultraviolet stabilizers may be incorporated into packages such as "boards" with separate compartments for tablets, pouches or vials, or preferably incorporated into capsule shells or tablet liners. Chemical light-absorbing agents can also be directly mixed with the active ingredient before tableting or encapsulation.

The term "inhibition of light-induced degradation" implies a statistically significant reduction in the formation of light-induced degradation products to be described later.

Of the procedures that will be described in the following text, those in which the compound of the above formula I is used, where X is Cl, Y is H and R is thienyl, those in which X is F, Y is Cl and R is thienyl are recommended or 4-chlorothien-2-yl, those in which X is F, Y is Cl and R is 2-thienyl, as well as those in which X is H, Y is Cl and R is benzyl. Processes where X is Cl, Y is H and R is 2-thienyl are particularly recommended.

Compounds of formula I can exist in enol form, so all these enol forms and their salts are covered by this invention.

As described in US Pat. Nos. 4,556,672 and 5,290,802, the compounds protected by this invention are acidic and form base salts. All of these base salts are within the scope of this invention and can be formed as described in those patents. Such suitable salts, within the scope of this invention, include both organic and inorganic species and include, but are not limited to, salts formed with ammonia, organic amines, alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydrides, alkali metal alkoxides metals, hydroxides of alkaline earth metals, carbonates of alkaline earth metals, hydrides of alkaline earth metals and alkoxides of alkaline earth metals.

Representative examples of bases forming these base salts include ammonia, primary amines such as n-propylamine, n-butylamine, 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, N,N-dimerylaniline, N-ethylpiperidine and N-methylmorpholine, hydroxides such as sodium hydroxide, alkoxides such as sodium ethoxide and potassium methoxide; hydrides such as calcium hydride and sodium hydride, and carbonates such as potassium carbonate and sodium carbonate. Sodium, potassium, ammonium, ethanolamine, diethanolamine and triethanolamine salts are recommended. Sodium salts are especially recommended. The compounds to which this invention is applicable include solvates such as hemihydrates and monohydrates of the compounds described above.

Degradation of 3-substituted-oxindole-1-carboxamide induced by light occurs primarily at wavelengths of light shorter than 600 nm, and gives as degradation products mainly benzoic and tenoic acid and oxindole-1-carboxamide. This degradation can be avoided by preventing light of wavelength less than 600 nm from contacting the 3-substituted oxindole-1-carboxamide.

Red and yellow colors were found to be effective in preventing light penetration and associated degradation of 3-substituted oxindole-1-carboxamide. Recommended colors are FD&C Red #40, FD&C Red #3, and FD&C Yellow #6. Yellow #6 is especially recommended. The dyes are effective in preventing light-induced degradation of 3-substituted-oxindole-1-carboxamide when mixed with oxindole, coated on a preformed tablet in a coating, or in a gelatin capsule containing oxindole. The recommended procedure is coating the tablets.

Thin film coating of pharmaceutical tablets is a known process and is described, for example, in US Patents 4,828,841; 3,981,948 and 3,802,896 which are incorporated herein by reference. Coating materials such as Opadry white, Opadry II, Surelease, Aquacoat, and Eudragit, suitable for selected color formulations, are commercially available from Colorcon, West Point, PA, USA, FMC Corp., Philadelphia, PA, USA, Rohm Pharma, Weiterstadt, Germany.

Colors can also be integrated into gelatin capsules which are then filled with oxindole. Average experts are familiar with the technology of preparing capsules. Capsules incorporating selected dyes are commercially available from Elanco Shinogi, Indianapolis, IN and Capsulegl, Greenwood, SC. US patent no. 3,784,684 describes the incorporation of opacifiers and colorants into the shell of gelatin capsules.

The amount of dye in the liner or capsule shell is not critical, except that sufficient dye must be incorporated to absorb all incident light. 1.2-2.8 mg/tablet of Yellow #6 was found to prevent degradation, while in capsule shells 0.60 to 0.5 mg/capsule provided light stability.

A typical coated tablet formulation of the present invention may be prepared as follows:

COMPONENT 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 sulfate 0.40

Total mass (core) 200.0

White Opadry (YS-5-7068) and 10.00

distilled water

yellow #6 lacquer (purity 39 %)b

Total mass (coated tablet) 211.15

and for meals that will be covered with a coating

b for meals containing color.

The following examples are provided by way of illustration and not to limit the invention as defined by the claims.

Example 1

Coated tablets

5-Moro-2,3-dihydro-3-(hydroxy-2-thienylmethylene)-2-oxo-1H-indole-1-carboxamide tablet cores (600 g) were prepared using the formulation described above.

Orange Opadry, containing Yellow #6, obtained from Colorcon, West Point PA (144 g) was suspended in 816 ml of water. The tablet cores were placed in a Hi Coater HCT30 coating machine and held at 42°C while the orange Opadry suspension was applied.

Two coated and one uncoated tablet portion of 5-chloro-2,3-dihydro-3-(hydroxy-2-thienylmethylene)-2-oxo-1H-indole-1-carboxamide (formula I, X = Cl, Y = H) they were heated to 30°C and 50°C and kept in a light chamber for 6 weeks. The tablet cores were identical for all three meals. The coated tablets differed only in the amount of yellow #6 dye in the coating layer. The light intensity in the light chamber was 4400 Ix in the center and 3224 Ix on the sides of the chamber which was maintained at room temperature.

The appearance of samples stored at 30°C and at 50°C did not differ from the appearance of samples stored at 5°C. Peeling of the coating layer was not observed on any tablet. The following visual observations were made on the samples stored in the light chamber for 6 weeks:

Meal 1 (kernel): Slightly darkened, dark spots (compared to control samples at 5°C)

Meal 2 (Coated): Faded slightly (compared to controls at 5°C)

Meal 3 (coated): Faded slightly (compared to controls at 5°C)

The test results for these meals are shown in the following table. All samples were analyzed in triplicate. Test values for uncoated tablets were close to the intended value of 100 mg/g. Levels of 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- il ester, 6-chloro-20-hydroxy-quinazoline-4-carboxylic acid and unknown #3 for uncoated tablets increased significantly in the light chamber (compared to control samples at 5°C). No significant degradation was observed in tablet cores stored at 5°C, 30°C or 50°C.

No significant degradation was observed for coated tablets stored at 5°C, 30°C or 50°C. After 6 weeks, degradation levels in the light cabinet samples were approximately the same for both rations of coated tablets.

The results of the described tests are shown in the following table.

[image]

Example 2

Capsules

The formulation of one compound of formula I, in which X is Cl, Y is H and R is thienyl, was prepared from the following components:

mg/unit

Compound of formula I. sodium 125,205

Lactose, anhydrous 159,795

Pregelatinized starch 112,500

Croscormellose Sodium 9,000

Magnesium stearate 9,000

The above ingredients were mixed and a portion was compacted with a roller, then ground and re-mixed with the remaining ingredients, lubricated and sealed in gelatin capsules obtained from Capsugel, a plant of the Warner-Lambert Company. The recommended lubricant is sodium lauryl sulfate. The capsules contained FD&C Yellow at 0.2651% of the total dry weight in the capsule body and 0.1768% in the cap.

It was found that the capsules prepared in this way ensure the light stability of the compound of formula I.

Claims (14)

1. A process for preventing degradation under the influence of light of a compound of formula I. [image] and its enol form or its pharmaceutically acceptable salts, characterized in that X is H, Cl or F, Y is H or Cl, and R is benzyl or thienyl, each of which is optionally substituted with Cl or F, at where the said decomposition is caused by light radiating from a light source, and the procedure includes the introduction of a light-absorbing agent between the said compound and the said light source. 2. Process according to claim 1, characterized in that X is Cl, Y is H and R is thienyl. 3. Process according to claim 2, characterized in that R is 2-thienyl. 4. The method according to claim 3, characterized in that the pharmaceutically acceptable base salt is the sodium salt. 5. The method according to claim 1, characterized in that X is F, Y is Cl and R is thienyl or 4-chlorothien-2-yl. 6. The method according to claim 5, characterized in that R is 4-chlorothien-2-yl. 7. The method according to claim 1, characterized in that X is H, Y is Cl, and R is benzyl. 8. The method according to claim 1, characterized in that the means for absorbing light is one color selected from the group consisting of yellow #6, red #40, red #3, yellow varnish #6, red varnish #40 and red lacquer color #3. 9. The method according to claim 8, characterized in that it is a yellow #6 light absorbing agent. 10. A table containing a pharmaceutical active ingredient selected from the compound of the formula [image] or 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, wherein said tablet is coated with a coating containing a sufficient amount of yellow color #6, red color #40, red color #3, yellow lacquer color #6, red lacquer color #40 and red lacquer color #3, to prevent degradation under the influence of light of the mentioned pharmaceutical active ingredient. 11. Tablet according to claim 10, characterized in that said coating contains yellow color #6. 12. A capsule containing a pharmaceutical active ingredient selected from the compound of the formula [image] or its pharmaceutically acceptable base salts, 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, wherein the capsule shell contains a sufficient amount of yellow color #6, red color #40, red color #3, yellow lacquer color #6, red lacquer color #40 and red lacquer color #3, in order to prevent degradation under the influence of light of the mentioned pharmaceutical active ingredient. 13. Capsule according to claim 12, characterized in that said capsule shell contains yellow color #6. 14. The method according to claim 1, characterized in that said light absorbing agent is a packaging material that acts to absorb light.