MXPA98007564A - Preparation in combination containing 5-methyl-4'-trifluometil-4'-isoxazolcarboxanilide and n- (4-trifluorometilfenil) -2-cyano-3-hydroxicrotonam - Google Patents

Abstract

The present invention relates to a solid preparation containing 5-methyl-4'-trifluoromethyl-4-isoxazolecarboxanilide and N- (4-trifluoromethylphenyl) -2-cyano-3-hydroxycinone monide suitable for treating immunological diseases.

Description

PREPARATION IN COMBINATION CONTAINING 5-METHYL-4 '- TRIFLUOROMETHYL-4'-ISOXAZOLCARBOXANILIDE AND N- (4- TRIFLUOROMETHYLPHENID-2-CYANO-3-HYDROXYCROTONAMIDE The application of the European Patent with publication number 0 013 376 discloses that 5-methyl-4'-trifluororaethyl-4'-isoxazolecarboxanilide (compound 1) has anti-rheumatic, anti-inflammatory, antipyretic and analgesic activity and can be used against multiple sclerosis. Pharmaceutical preparations containing the active compound 5-methyl-4'-trifluoromethyl-4'-isoxazolecarboxanilide are administered orally in doses of 25 mg to 150 mg. The European patent application with publication number 0 217 206 reports that N- (4-trifluoromethylphenyl) -2-cyano-3-idroxy-thromonamide (compound 2) has immunomodulatory properties and is suitable for treating chronic diseases of graft versus host and autoimmune diseases. , in particular systemic lupus erythematosus. Pharmaceutical preparations containing a compound 1 or compound 2 can be administered in a dose from 100 to 200 mg, preferably, however, from 50 to 100 mg, in the case of a solution for injection in the form of an ampoule (intravenous) , in particular based on compound 2 or a salt thereof, from 1 to 30 mg, preferably from 5 to 10 mg, and in the case of rectal administration, from 50 to 300 mg, preferably from 100 to 200 mg . However, oral administration of 5 mg or 10 mg of compound 1 or compound 2, in each case, per kg has no significant effect. It has been found that a combination preparation, containing compounds 1 and 2, has surprisingly advantageous immunosuppressive effects. The addition of small amounts of compound 2 to the main active component compound 1 results in a marked increase in the activity of the preparation in combination. Due to the magnitude of this effect, the use of this combination can be extended to areas that until now have remained closed to immunosuppressive therapy using the individual components. In addition, the reduction in the dose, without decreasing the activity, gives rise to a greater safety in use. At the same time, it can be assumed that a reduction in dose associated with activity without change will allow the costs of therapy to be substantially reduced. The invention therefore relates to a solid preparation containing component 1) 5-methyl-4'-trifluoromethyl-4'-isoxazolecarboxanilide, component 2) N- (4-trifluoromethylphenyl) -2-cyano-3- hydroxy-chrononamide and / or a physiologically tolerated salt of. N- (4-trifluoromethylphenyl) -2-cyano-3-hydroxy-thromonamide and / or a stereoisomeric form of N- (4-trifluoromethylphenyl) -2-cyano-3-hydroxy-thromonamide and 3) a pharmaceutical excipient, wherein the content of the component 1 is from 2 to 20 mg and the content of component 2) is from 0.3% to 50% of component 1). The compounds 5-Rethyl-4'-trifluoromethyl-4'-isoxazolecarboxanilide and N- (4-trifluoromethylphenyl) -2-cyano-3-hydroxy-thromamide can be produced using the known methods (EP 0 529 500). The compound N- (4-trifluoromethylphenyl) -2-cyano-3-hydroxy-thromonamide has the following structural formula: OR it is used as such and / or as a physiologically tolerated salt of N- (4-trifluoromethylphenyl) -2-cyano-3-hydroxy-chrononamide and / or a stereoisomeric form of N- (4-trifluoromethylphenyl) -2-cyano-3-hydroxy-thromonamide in the preparation according to the invention. Examples of the suitable physiologically tolerated salts of N- (4-trifluoromethylphenyl) -2-cyano-3-hydroxy-romonitronamide are alkali metal, alkaline earth metal or ammonium salts, including physiologically tolerated organic ammonium bases. Solid novelty is suitable, for example, to treat: - acute immunological cases such as sepsis, allergy and graft-versus-host reactions and host-versus-graft reactions - autoimmune diseases, in particular * rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis. - psoriasis, atopic dermatitis, asthma, urticaria, rhinitis and uveitis - type II diabetes - hepatic fibrosis, cystic fibrosis and colitis - cancerous diseases such as lung cancer, leukemia, ovarian cancer, sarcoma, Kaposi's sarcoma, meningioma, bowel cancer , cancer of the lymphatic node, brain cancers, pancreatic cancer, prostate cancer or skin cancer. The novel solid preparation may also contain packages or compositions in combination, in which the components are juxtaposed and may also be administered simultaneously, separately or at graduated time intervals to one and the same human or animal body. According to the invention, components 1 and 2 can also be present in juxtaposed, separate medicinal forms, in particular when the spatial dimensions of the medicinal forms make administration more difficult. This applies, in particular, to oral forms, since elderly patients tend to dislike large tablets or capsules. It is imperative that the separate, juxtaposed medicinal forms be arranged so that they can be ingested at the same time. In this context, different forms, for example, a tablet and a capsule, may also be present next to each other. The invention further relates to the use of a combination of compound 1 and 2 to formulate a pharmaceutical preparation that exhibits a hyperactive increase in the immunosuppressive effect. The invention further relates to a process for producing the novel preparation, wherein compounds 1 and 2 and the pharmaceutical excipient are processed in a pharmaceutical administration form. The novel solid preparation may be present as a dosage unit in the form of the medicinal forms such as capsules (including microcapsules), tablets (including tablets, and coated pills) or suppositories, whereby, when using the capsules, the material of the capsule exerts the function of the excipient and the content may be present, for example, as a powder, gel, emulsion, dispersion or solution. However, it is particularly advantageous and simple to prepare oral (peroral) formulations with the two compounds 1 and 2, which formulations contain the calculated amounts of the active compounds together with each desired pharmaceutical excipient. A corresponding formulation (suppository) for rectal therapy is also possible. The transdermal administration in the form of ointments, creams or oral administration of solutions containing the novel preparation, in the same way is possible. In addition to the active compounds, the ointments, pastes, creams and powders may also contain the customary excipients, for example, fats of animal and vegetable origin, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, talc, zinc oxide, lactose, silicic acid, aluminum hydroxide, calcium silicate and polyamide powders or mixtures of these compounds. Tablets, pills or granulated bodies can be prepared by customary processes, such as by compression, dip or fluidized bed processes or coating, and contain excipients and other customary adjuvants such as gelatin, agarose, starch (eg, starch) of potato, corn or wheat), cellulose such as ethylcellulose, silicon dioxide, various sugars, such as lactose, magnesium carbonate and / or calcium phosphates. The coating solution is usually composed of sugar and / or corn syrup and usually also contains gelatin, gum arabic, plivinylpyrrolidone, synthetic cellulose esters, active surface substances, plasticizers, pigments and similar additives that correspond to the state of the technique. To produce the preparations it is possible to use any of the agents to improve the fluidity, lubricants or glidants, such as magnesium stearate and mold lubricants. Preferably, the preparations are in the form of a coated tablet / core or multi-layered tablets, with the compound 2 located in the shell or in the core or in a layer, while the compound 1 is located in the core or in the shell. cover or in another layer. Compounds 1 and 2 may also be present in delayed release forms, or they may be adsorbed to the release retarding material or they may be contained by the release retardant material (eg, the material of this class is based on a resin of cellulose or polystyrene, for example, hydroxyethyl cellulose). The delayed release of the active compounds can also be achieved by providing the layer in question, or the compartment with the customary coatings that are insoluble in gastric juice. The dose that can be used naturally will depend on different factors, such as the living (ie human or animal) being treated, the age, weight, general health status, the severity of the symptoms, the disease that is being treated, will treat, any accompanying disease, (if present) the nature of the concomitant treatment with other pharmaceutical preparations or the frequency of treatment. In general, the doses are administered several times a day and preferably from once to three times a day. In this context, the amounts of the individual active compound that are used are based on the recommended daily dose of the specific individual active compound and should be, in combination preparation, in general from 10% to 100% of the recommended daily dose, of preference from 20% to 80%, in particular 50%. The appropriate therapy with novel combinations accordingly consists of, for example, the administration of 1, 2 or 3 individual doses of the preparation composed of: 1) 5-methyl-4'-trifluoromethyl-4'-isoxazolecarboxanilide in an amount from 2 to 20 mg, 2 to 19.9 mg, 4.5 to 19.5 mg, 4.85 to 19 mg, 5 to 18 mg, 5 to 15 mg, 5 to 10 mg, 5 to 9.9 mg, 5 to 9.7 or 5 to 9.0 mg, and 2) N- (4-trifluoromethylphenyl) -2-cyano-3-hydroxycoranadale in an amount from 0.3% to 50%, preferably from 0.5% to 20%, in particular from 0.8% to 15%, particularly from preference from 1% to 10%, very particularly preferably from 1% to 5%; in each case based on the content of 5-methyl-4'-trifluoromethyl-4'-isoxazolecarboxanilide, and 3) a pharmaceutically tolerated excipient. The values in percent (%) of compounds 1 and 2 refer in each case to weight percent. The amounts of the active components will naturally depend on the number of individual doses and also on the disease in question. The individual dose may also be composed of several dosage units that are administered simultaneously.

Example 1 Pharmacological tests Arthritis induced by the adjuvant, modification according to Perper (Proc. Soc. Exp. Biol. Med. 137, 506 (1971)) Male rats, Lewis strain (Moellegard, Denmark), with a body weight from 160 to 210 g are used as the experimental animals. On the first day, the animals are injected subcutaneously, at the root of the tail, with complete Ereund adjuvant containing a suspension of Mycobacterium butyricu in dense paraffin oil (Difco, 6 mg / kg in paraffin oil). Merck). Compounds 1 and 2 are suspended in carboxymethyl cellulose (1% in water) and this suspension is administered orally. The compounds are administered once a day from the first day to the twelfth day of the experiment. Paw volume and arthritis index are determined on day 18. The severity of the disorder is determined by measuring the volumes of both hind paws. The measurement is carried out by the water displacement method, using a 2060 plethysmometer (Rhema-Labortechnik, Hofheira, Germany). In addition, the rate of arthritis is determined on day 18 after the injection.

Determination of the arthritis index: 1. Ears 0.5 points for each ear on which appears redness and nodules are formed 2. Nose 1 point due to inflammation of the connective tissue 3. Tail 1 point due to the appearance of nodules 4. Frontal legs 0.5 points for each leg in which at least one inflammation appears in a joint 5. Rear legs 1 point due to slight inflammation (swelling) 2 points for inflammation of average intensity 3 points for a massive inflammatory reaction The animals that form a control group only receive the solvent (1% carboxymethylcellulose in water). Six animals were used for each dose and in the control group. A reduction in the increase in paw volume and a decrease in the rate of arthritis, compared to the untreated control group, are used as the criteria for an effect that has been achieved. Table 1 shows the results. The total amount of compounds 1 and 2 is constant in each of the different experiments.

Table 1 At 5 mg / kg and at 10 mg / kg of the live weight of the rat, the effect of the novel preparation is markedly enhanced by increasing the amounts of the compound 2. Therefore, small additional amounts of the compound 2 give rise to a marked intensification of the effect of the novel preparation.

Claims (11)

1. CLAIMS A solid preparation containing: component 1) 5-methyl-4'-trifluoromethyl-4'-isoxazolecarboxanilide component 2) the compound of the formula I 3 and / or a stereoisomeric form of the compound of the formula I and / or a physiologically tolerated salt of the compound of the formula I, and 3) a pharmaceutically tolerated excipient, wherein the content of the compound 1 is from 2 to 20 mg and the content of compound 2) is from 0.3% to 50% of component 1).
2. The preparation, as claimed in claim 1, wherein the content of component 2) is from 0.5% to 20% of component 1).
3. The preparation as claimed in claims 1 0 2, where the content of component 2) is from 0.8 to 15% of component 1).
4. The preparation as claimed in one or more of claims 1 to 3, wherein the content of component 2) is from 1% to 10% of component 1.
5. The preparation as claimed in one or more of claims 1 to 4 , wherein the content of component 2) is from 1% to 5% of component 1.
6. The preparation as claimed in one or more of claims 1 to 5, which contains the components 1 and 2 in a form of administration for rectal or oral administration.
7. The preparation as claimed in one or more of claims 1 to 6, wherein components 1 and 2 are present in similar administration forms, separated to be administered at the same time.
8. The preparation as claimed in one or more of claims 1 to 7, wherein components 1 and 2 are present in separate, different administration forms to be administered at the same time.
9. The use of the preparation as claimed in one or more of claims 1 to 8. to treat immunological diseases.
10. 10. The use of the preparation, as claimed in one or more of claims 1 to 8 to treat acute immunological cases, such as sepsis, allergies and graft-versus-host reactions or host-versus-graft reactions, or autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus or multiple sclerosis or psoriasis, atopic dermatitis, asthma, urticaria, rhinitis, uveitis, type II diabetes, cystic fibrosis, hepatic fibrosis or colitis, or cancerous diseases, such as lung cancer, leukemia, ovarian cancer, sarcoma, Kaposi's sarcoma, meningioma, bowel cancer, cancer of the lymphoid node, brain tumors, breast cancer, pancreatic cancer, prostate cancer or skin cancer.
11. 11. A process for producing the preparation, as claimed in one or more of claims 1 to 8, which consists of processing 5-methyl-4'-trifluoromethyl-4"-isoxazolecarboxanilide, the compound of the formula I and / or a physiologically tolerated salt of the compound of the formula and / or a stereoisomeric form of the compound of the formula I and a pharmaceutical excipient, in a pharmaceutical administration form.