MXPA97008155A - Inhibition of the photo-composition of 2-oxindoles 3-substitute - Google Patents

Abstract

This invention relates to the protection of certain 3-substituted 2-oxindole-1-carboxamides of the formula (I) and the acceptable pharmaceutical base salts thereof, wherein X is H, C1 or F: Y is H or C1, and R is benzyl or thienyl, each optionally in the presence of

Description

INHIBITION OF THE FQTODESCOHOLDING OF 2-QXINDOLES 3- SUBSTITUTE FIELD OF THE INVENTION Ls < to invention i ollero < • the inhibition of the • deadening of certain substances in the formula and leaves them from pharmaceutically acceptable bases thereof, where X, is I-I, Cl or F; And e H or CL; and R is benzyl or Qenyl, l each optionally in its + + with 01 or F " BACKGROUND OF THE INVENTION Document U.C ... 4,569,942 describes certain oxygen oxides of the formula goes. where X < -s II, f lúor, chloro, bromo, ilquilo.üi 04), ci cloal qui lo .C3 -C? ), to cox i (Oí - (., /,), alqui 1 t? o (C? -C¿), . { ri 11 uoroifK.ri Lo, aLqui Lsu fm lo .Ci 14), alquL Lsuf on i lo lüi C «), nitro, leniLo alkane i lo (C2-C., benzol Lo, tenoiLo, ai carurní do (C? -C), benzami oo N, N- <l? Al? Lulul rainoi what? 1 of 1 3 carbons on each of these alludes, and is H, I- 1 uo r, c Lo ro b G? IÍIO, to which 1 o (Ci C¿), c 1 c Loa L qu 11 o ((.3 - C7), to co 1 (Oí -O4), to ui 1 t? O (C? - C4) and * • ri f- i uoromet L Lo; Rl is al (| u? lo (C? -Ce), ci cloalqu o (03- C7 J. ci cloal queni lo (Ü4 0?), í-enilo, f -onyl-substituted Muido, f-erulalkqui io with the 3 carbons of said alkyl, (substituted fonyl! alkyl with 1 to 3 carbons on said alkyl, (phenoxy susi Muido) alkyl having from L to 3 carbons in said alkyl, (thiophenoxy) ) Alkyl with 3 carbons in said alkyl, naphthyl, b? c? cloll2.2. L Hheptan-2-lO 1, bi ciLiL 2.2..1 lhept-5 -in ~ 2- L Lo o (CH2 ) n ~ 0-R; n is zero, 1 > 2; is a divalent radical derived from furan, t-iofen, pirro !, piraz ol, irnidazole, thiazole, isothiazole, oxazole, isoxazole, L, 2, 3-thiadiazole, 1,, 4-thiadiazole, 1, 2, 5 - 1 Ladiazol, rotrahx ro furan, tet rahí dro thiophene, te + rahidropirano, twenty - . 20 -Iopyran tetrahydroxy, pipdine, pyrirnidine, p-razine, benzoCb J f-urane and benzobothiophene; and R2 you rent it (0? -Ce), c? cloalkyl (C3-O7), benzyl, f-uplo, tierulo, pyridyl or • jr. where R3 and R * are each a H, f l, chloro, alkyl (C? 0") or i" i ("1 uoroinet i Lo. Pi patent also describes that said 2-ox i ndol 1 -carboxarnides are mh i bi doers of the oocyte, qenase and Lipox i genase, which have analgesic activity in mammals and which are + in the treatment of odor and in the relief of the symptoms of chronic diseases. such as inflammation and pain associated with La artrit is icuinatoide and \ osteoartriis I. a | > a + en < o < le I. s + ados Uní dos 4 56. b 72 < lesc i * be LU Certain substituted 3-acyl 2-ox? Nd? L 1 carboxainides of the foal wherein X, Y and R1 are as described above for the compounds of US Pat. No. 4,569,942. United States Patent No. 4,861,794 describes the use of compounds from i to formula ? p; and the pharmaceutically acceptable base salts thereof, wherein X is H, 01 or F; and it is H or 01 and R is boncilo or thienium, to inhibit the biosmtosis of the interleukin 1 (LL 1) and to treat disorders and digestion mediated by IL-1.

BRIEF DESCRIPTION OF THE INVENTION This invention relates to a method for inhibiting the 1 -destrodesociety of a compound of formula I . and the enolic form thereof or pharmaceutically acceptable salts thereof; where X is H, 01 or F; And it is H or 01; and R is benzyl or thienyl, each optionally in + and substituted with Ll or F; Resolving this photo-deactivation of a Light that comes from a luminous source, which comprises introducing a fo + oabsorbent medium between said compound and said Luminous source. In a preferred process of this invention, said photoabsorbent medium is a colora + e selected from the group consisting of yellow NQ 6, red NO 40, ro or NQ 3, Yellow lacquer NQ 6, Lacquer ro NQ 40 and lacquer ro a NQ 3. In another preferred method e is + a invention < Medium (otoabsorbent or o., Amalant H9 h.) In another aspect, it is + a invention refers to a tablet comprising a pharmaceutically active ingredient selected in + a compound of 1 < \ formula i 0 ^ ^ NH2 or a base salt lai maceuticament or acceptable thereof, where X os H, 01 or F; And H o (.1; and R e bencí lo or tierulo, each optionally substituted with 01 or F; said tablet being coated with a coating in which it contains a sufficient quantity of yellow dye NQ 6, red colorant or NQ 40, red dye NQ 3, yellow lacquer NQ 6, red lacquer NQ 40 and red cape NQ 3 to inhibit the photodeposition of said active ingredient farrnaceut · ee. In a preferred aspect, this invention comprises a tablet coated in which said coating contains yellow dye No. 6 in an amount sufficient to inhibit the photodeposition of said pharmaceutically active ingredient In preferred or preferred form, this invention comprises a capsule comprising a selected active ingredient Lance between a compound of the formula or a pharmaceutically acceptable base salt (ε), wherein es H H o o o o Y Y Y Y Y Y y y y y y y y y y y y y y entre entre entre entre entre entre entre entre entre entre entre entre entre entre entre entre entre entre entre entre entre entre entre. with Cl f; the cover of said capsule containing a < -antity, amount of Unto ll) yellow NQ h, red dye H 40, red dye NQ 3, yellow lacquer NQ b, red 1 NO 40 and red lacquer NQ 3 as to inhibit LA fo + odescornposition of said pharmaceutically active ingredient.

L 5 DESCRIPTION DETflLLflDfl OF THE INVENTION In U.S. Patent Nos. 4"556" b72 and 5,290,002, the teachings of which are incorporated herein by reference, compounds of the formula are described . and I d f o rina enol L ea and The salts of bases i arrnace? t i camon + e ..coptabl .. < s of Je. themselves, < Ionde X os H, i; L or h; i is II or OL; and R is benzyl or thienyl optionally in its + + by O, or F, and the preparation of the same,. It has been observed that these compounds are + ofosensible and are decomposed by light. This invention is related to procedures to prevent the 1 5 fo + odescornposicion of the compounds of Formula [and its enol ica form inhibiting the contact of the Light with said compounds. As den + is used in this document, "light source" refers to solar light or any artificial light source that produces light of wavelengths less than 0 6U0 nrn. "Photo-absorbent bristles" refers to materials that block all or most of the wavelengths of Light, such as opaque glass or metals; or to materials that absorb light with wavelengths less than 600 nm, such as ultraviolet stabilizers or dyes. •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• They can be incorporated or absorbed by means of a UV stabilizer in the container, including ampoules, blisters or flasks, or they are preferably incorporated in the capsule covers or in the lining of 5 tablets. The photoabsorbents can also be mixed with the active ingredient before forming the tablets or placing it in a capsule. "Inhibition of photodeposition" means a statistically significant reduction in the formulation of LO products degradation induced by the z described in this document later. Of the methods for inhibiting the photodisposition described below, those in which the compounds employed have the above Formula I are preferred. where X is 01, Y and H and R is time; those in the X is I ", Y is Cl and R is tienilü or -chlorot in -2- lio, those in which X is F, Y e 01 and R is 2-t? in? lo, and those in the that X and H, Y is 01 and R is benzyl, are the most preferred in the cases in which X and Cl, Y and H and R is 2-t? in? lo. compounds of Formula I can exist in an onollic form; All said enolic forms and their salts are contemplated in this invention. As described in U.S. 4,556,672 and b.290.002, the compounds protected by this invention are These acids and salts form bases, all of said base salts are within the scope of this invention and can be formed in the form of salts of bases. D ia liassa L that are within the scope of this invention, include both organic and inorganic types, and include, but are not limited to, salts formed with ammonia, organic amines, alkali metal droids, carbonates of alkali metals, bicarbonates of alkaline metals, alkali metal hydrides, alkali metal alkoxides, metal hydroxides, alkaline motrosols, alkaline earth metal carbonates, hydrides of alkali metals, alkali metals and alkoxes of alkaline metals + erreos. Representative examples of bases forming said base salts include ammonia, primary amines t a 1 e s co o n-p ro p 11 ain i na, n-b ut 11 arn ina, a n i L i na. , cyclooxylamino, benzylamine,? -tolu? d? na, ethanolarnine and glucarnine; secondary amines, such as diethyltin, die anoanillin, N-methyl Lglucarnin, N-? ne + ileum ina, or olma, pyrrolema and pipen di na; tertiary amines such as triet i lamina, t riet anolamma, N, N-d? rnet ilam 11 na, N-et lpipep dina and N-rnet? irnorfol? na; hydroxides, such as sodium hydroxide; alkoxides such as sodium ethoxide and? ne + potassium oxide; such hydrides as calcium hydride and sodium hydride; and carbonates such as potassium carbonate and sodium carbonate. The preferred salts are those of sodium, potassium, ammonium, ethanolamma, diet anolarnin and non-lamellar net t. Sodium salts are particularly preferred. The compounds to which this invention is applicable include solvates such as the hernihydrotes and rnonohydrams of the compounds described herein. The degradation induced by the light of oxidol-1 -earboxami J substituted mainly occurs rl wavelengths of light less than 600 nm, producing co or decomposition products mainly benzoic or tenoic acid and ox ndol - 1 - carboxarm da. The degradation can be avoided by preventing the contact of Longi + wave parts less than 100% with the oxidol-1-carboxamide 3 -substituted. It has been observed that the JOS and yellows are effective in preventing Light contact and the associated light-induced degradation of oxindole-1 -carboxarnides -substituted. The preferred dyes are FR »C red HQ 40, FD &C ro or NQ 3 and FD8C yellow NQ 6. lys especially preferred the yellow NQ 6. The dyes are effective to come from the degradation induced by the oxmdol-1-carboxarnda light 3-sustMuidas when mixed with the oxmdol, api Lean to a tablet previously formed in a coating or a capsule of gelatin containing oxmdol The preferred procedure in tablet coating Film coating of pharmaceutical tablets is well known in the art and is described, for example, in United States Patent 4 (328,841, 3,901. and 3.002. 09b, which are incorporated herein by reference. They are suitable for formulating with the selected dye filrnogenos coating materials taleß corno ihite Opadry, Opadry 11, SureLease, fiquacoat and hludragit which are suitable for formulating with the selected dye and are available in a morocate or- Oolorcon, Uest P? Int, | 'U; i no Corp., Phi ladelphia, r'fl; ° ohm Phapna, WeM crst ad < , Germany, respectively. The dyes that after the firing are used with the oxygen, the technology for preparing capsules is well known by the specialists usual in this technique. In the market there are available capsules that incorporate selected dyes, by Flanco Slunogí, Lndianapo L i s, IN and Capsugel, Greenwood, s ?. U.S. Patent No. J.'84. ? > 84 describes the co nta ra tio n of pa tificants and co n o n a n t e n n u u ge of gelatin capsules. The amount of colorant in the coating or capsule shell is not critical, except that enough color-before has to be incorporated to absorb any incident light. It has been observed that from 1.2 to 2.0 rng / cornprirn of yellow NQ b prevented the decomposition while (in capsules of 0.28 to 0.5 rng / capsule produced stability against L. z. typical formulation of the coated tablets of this invention as indicated below: COMPONENT rng / COrlPRIMÍ DO Ox? Ndol-1-carboxarn gives 21, 74 KLucel EF 6.00 Lactose, Anhydrous 122.26 Ac Di Sol HviceL PI-IL 2 40,, 00 \ '-, t o a r a < o d e rn a g n e s i o 3., bl) I .a l l a l l a l s a l,, 40 Weight fot al (Nucleus) 200,, 00 lh 11 e Opa < I ry (YS - 5 - 7068) * 10,, 00 Agua Do tliada Laca Amarilla NQ6 (39% purity) * »1,15 Weight I (.t l compressed rooubior + or film) > 11, 15"For Lots that will be covered with polu.ula., •• For lots that will contain dye, The following examples are presented to illustrate, but not to limit the invention that is defined by the laws. ions.

EXAMPLE 1 COATED TABLETS Nucleos of 5-chloro-, 3-d? H ro-3- (hi drox? -2- tien lrnet lien) - 2-oxo-lH-mdol-1 -carboxarnide (600 g) were prepared using the formulation described previously. Orante Opadry, containing yellow dye NQ 6 obtained from Colorcon, West Point, PA (144 g) in 816 rnl of water was suspended. The tablet cores were changed to a Hi Ooa HCT30 coating machine and were maintained at 42"0" and the Orange Opadry suspension was applied. Two coated batches were warmed and one not covered with bc parrot. - - (111 drox? -2 - 1 len linet i len) - 7 -oxo LH mdol 1 -carboxam na (Formula I, X-01, Y = H) at 30"C and b0" 0 and remained in a LC luminous display case for b weeks The nuclei of dental tablets for the bottles The r ecubated products differ only in the amount of yellow NQ 6 in the film coating, the intensity (ie the display case) luminous was 4305, bb lux I 'IOO foot candles) (F0) in the center and 3229.17 Lux (300 FO) on the sides of the showcase that was kept at room temperature. stored at 30 and 50"O was not different from the aspect e Samples stored at 5f > 0. No peeling of the film coating was observed for any tablet. The following were made + visual observations on samples stored in La lumrina Luminosa during The b weeks: Lot 1 (core): slightly dark, brown spots (compared to the control at 5 ° C) Lot 2 (coated): slightly discolored (compared to the control at 5 ° 0) Lot 3 (coated): slightly discolored (compared to the control at 5 ° O) The results of the LC test for these Lots are summarized in the table below. They were analyzed in triplicate.The values of analysis for the non-coated tablets were close to the 101) mg / g intended, the levels of aidophenone 2 -carboxyl 1, 6-cLoro IH-qui Nazolin 2,4-dLone, 1 -carbonLl 5 -.chloro -oxo 2,3 dihi ro 1H- i ndol- 3-? 1 stea of the acid t-ofeno-2- b carbox 11 i co, aci do b -c Lo ro -2 - h id rox i -qumazol iría- 4 -oarbo i L i co and unknown NQ 3 for Composites no Coaters increased their sign in the Luminous display case (compared in control to L.0C), no significant degradation was observed for the stored nuclei at 5 ° c,? IV'O or b0 ° 0. 1 No significant degradation was observed for coated tablets stored at 5 ° 0, 30 ° 0 or 50 ° W or in the Luminous display case. After 6 weeks, the levels of the degradation in the samples of the luminous showcase were approximately equal for the two batches of tablets coated. The results of the previous tests are shown in the table presented below twenty ? * I !.

EXAMPLE 2 CAPSULES A formulation of a formula of rindula in which X is 01, Y and H and K 'is prepared is prepared from the following compounds: g / unit Sodium Compound of Formula T 120,205 Lactose, anhydrous 159, 795 Pregelatinized Starch 112,500 Fatty Grade Sodium q, 000 Magnesium Stearate 9,000 The above ingredients were mixed and a part was compacted with rollers, then triturated and turned 1 to relate to the rest of the ingredients, be lubricated and oncapsul? in gelatin capsules obtained in a? his < jol, a division of Ularner- Lam rt Oornpanv ,, A preferred lubricant is the lupls? lf to sico, The capsules contained a 0, b 1% yellow dye I-DRO with respect to the dry weight tot di on the body of the capsule and an i), L.7faüon on the cover., (I observed that the capsules prepared in this way produced stability to the light to the compound of Formula I. "

Claims (2)

10 NOVELTY OF THE INVENTION CLAIMS 1"- A procedure to inhibit the fo + odeseompo i n of a compound of the formula and the l ica form thereof or a pharmaceutically acceptable base salt thereof, wherein X is H, 01 or F; And I H o 01; and R is benzyl or thienyl, each optionally substituted with 01 or F; resulting said photodescornposition of a light that comes from a light source, which comprises in + roducing a medium photoabsorben + e between said compound and said uen + e luminous- 2.- A procedure according to the claim

1, where X is 01; And it is H; and R is tjenilo. 3. A procedure according to the claim 2, where R is 2-t? In? Lo. 4"- A method according to claim 1, wherein the pharmaceutically acceptable base is" b "-One agreement procedure. on the rei indication 1, in which X and I-; And it's CL; and R is phonon or k -chlorot? in - - Lo. b.- A procedure according to claim 5, wherein R is /. -chlorot len- 2 - 1 lo. ? . - A method according to claim 1, wherein X is II, Y is 01; and R is benz i lo. 8.- Application according to claim 1, wherein said photoabsorbents medium is a color-selected from the group consisting of- aman Lio NQ 6, ro or NQ 40, ro or NP ü, yellow lacquer NP 6, red lacquer NP 40 and red lacquer NP:. "9.- A procedure according to the claim 15 8, wherein said medium [otoabsorbent is yellow NQ 6 LO. A tablet comprising a pharmaceutically active ingredient selected from a compound of the formula

2 - . or a pharmaceutically acceptable base salt thereof, wherein X is H, 01 or I; And I H o 01; and R is bencí lo or Moni Lo, each one opeíonalmente and substituted with OL or l:; said tablet being covered with a coating which contains a sufficient quantity of yellow co-agent NP 6, red dye NP 40, red-blue color NP 3, Yellow lacquer NP (3, Red lacquer NP <0. and red lacquer NP The photodeposition of said active pharmaceutical ingredient is indicated 11.- A tablet of claim 10, in which said substance contains yellow dye NO (. "10 12. A capsule comprising a tablet. pharmaceutically active compound selected from a compound of the formula or a pharmaceutically acceptable base salt thereof, wherein 0 is H, Cl or F; And it is H or Cl; and R is benzyl or thienyl, each optionally substituted with 01 or F; the cover of said capsule containing a sufficient amount of yellow dye NQ 6, dye ro or NQ 40, red dye NQ 3, yellow lacquer NQ 6, lac ro to NQ 40 and red lacquer NQ 3 to inhibit the! "photodescornposi tion of said pharmaceutically active ingredient. 13. A capsule of the ion cadi ion 12, wherein said cover (capsule contains an uncollo dye NP b 14.) A solution of the claim 1, in the said medium [otoabsorbent is an enveloping material that is efi caz i a g ra f otoabso re: i olí "