MXPA99011212A - Use of anti-inflammatory steroids for the treatment of chronic inflammatory intestinal diseases - Google Patents

Abstract

The invention relates to the use of inflammatory compounds having general formula (I) wherein X is a member of the group consisting of H and halogen;Y is a member of the group consisting of H2, H(OH), H(O(C1-6)Acyl) and O;R1 is a member of the group consisting of H, CH3 and halogen;R2 is (C1-4)Alkyl;R3 is a member of the group consisting of H, O((C1-6)Acyl), O((C1-6)Alkyl) and CH3;R4 is a member of the group consisting of H and (C1-4)Alkyl, and C1-C2 and C6-C7 are saturated or unsaturated bonds, for the manufacture of a medicament for chronic inflammatory colon diseases.

Description

USE OF ANTMNFLAMATORY STEROIDS FOR THE TREATMENT OF CHRONIC INFLAMMATORY DISEASES INTESTINALS DESCRIPTION OF THE INVENTION The present invention relates to the use of therapeutic agents for the manufacture of a medicament for the treatment of inflammatory bowel diseases. Ulcerative colitis (UC) and Crohn's disease are chronic intestinal diseases also called Inflammatory Bowel Disease (IBD), characterized by inflammation of unknown etiology. It is believed that environmental, genetic and immunological factors are involved in the etiology of these diseases. Crohn's disease has also been called regional enteritis, due to the frequent involvement of the terminal ileum. Ulcerative colitis usually affects the descending and sigmoid segments of the colon. The diseases are characterized by exacerbations and remissions. Inflammation in Crohn's disease is discontinuous with non-involved areas of the normal bowel between the diseased areas, and transmural, involving all the layers of the intestinal tissue from the mucosa to the serosa. Since the inflammatory process is transmural, the non-adjacent loops of the intestine can adhere to each other and develop masses, fistulas or obstructions. He Inflammatory infiltrate in the enlarged wall of the intestine contains lymphocytes, macrophages, neutrophils and in about half of the cases, granulomas. The epithelium in ulcerative colitis is typically infiltrated with neutrophils and exhibits diffuse inflammation. There is an increased risk of colon cancer in patients who have ulcerative colitis. The primary manifestations are rectal bleeding, diarrhea, urgency, fever, weight loss, and sometimes abdominal pain. Current therapies involve the use of steroids, immunosuppressants and aminosalicylates that can produce a wide variety of side effects. So far, steroids have the best overall effect to reduce active inflammation, but they also have the most significant side effects. The beneficial effects of glucocorticoids can be attributed mainly to their anti-inflammatory activity, which manifests itself as a reduction in the production and activity of pro-inflammatory cytokines and in the reduced production of the enzymes, phospholipase A2, 5-lipoxygenase and cyclo-oxygenase, thus inhibiting the arachidonic acid cascade and avoiding the generation of prostaglandins and leukotrienes. In addition, glucocorticoids have some non-specific anti-inflammatory actions. The use of anti-inflammatory steroids, however, is not without risk. The chronic use of these compounds usually induces side effects of a systemic nature. One of the main ones is the suppression of the hypothalamic pituitary-adrenal axis, which can give As a result, the inability to respond to stress. Therefore, it is preferred to treat the damaged part of the colon locally. Thus, there is a need to develop pharmaceutical compositions, which lack systemic side effects.

It is a principal object of the present invention to provide pharmaceutical compositions that will be used in a local treatment of IBD without the risk of side effects. The present invention, therefore, relates to compounds of the general formula I: wherein: X is a member of the group consisting of H and halogen; And it is a member of the group consisting of H (OH), 1-1 (0 (0 ^ 6) acyl) and O; Ri is a member of the group consisting of H, CH 3 and halogen; R2 is (C1-4) alkyl; R3 is a member of the group consisting of H, 0 ((C1-6) acyl), 0 ((C1-6) alkyl) and CH3; R4 is a member of the group consisting of H and (C1-4) alkyl and C1-C2 and C6-C7 are saturated or unsaturated bonds, for the manufacture of a medicament for chronic intestinal inflammatory diseases. The term "acyl" means an acyl group derived from an organic carboxylic acid having 1-6 carbon atoms as also indicated by the suffix (C 1-6). The number of carbon atoms in the alkyl group is indicated by the suffix (C1-) or (C -? - 6). The compounds are described in the patent of E.U.A. Do not. 3,947,478 for alkylated steroids of 3,20-diceto-delta-4. This patent, which is incorporated herein by reference, describes the method for the preparation of these compounds. The compounds are described as having anti-inflammatory dermatological utility. In addition, the patent of E.U.A. No. 4,686,214 describes an ophthalmic utility for the same compounds. Especially preferred is a compound according to formula I, wherein X is H, Y is H (OH), R ^ is H, R2, R3 and R4 are CH3, C -? - C2 is a double bond and C6- C7 is an individual link. This compound is called rimexolone. Rimexolone is a non-halogenated glucocorticoid, which has been shown to suppress joint swelling in mono-arthritic arthritis induced by fibrin in rabbits, and has few systemic side effects after topical administration (J. Clin. Pharm. (1990) 30, 476-679). Once present in the current blood, it is rapidly metabolized and excreted. The compound has an extremely poor solubility in an aqueous medium. Oral toxicological experiments have indicated that the compounds are poorly absorbed after oral administration and that a large amount of unchanged steroid was excreted with the faeces. However, the compound has an effect on the diseased areas of the intestine comparable to that of dexamethasone. Depending on the route of administration and the formulation used, the compounds have a medium long residence time. They have a very pronounced anti-inflammatory effect and a long duration of beneficial effect. The compounds of the invention can be used in mammals as a medicament to mitigate inflammation of inflammatory bowel diseases. Preferably, the compounds according to the invention are used in the treatment of ulcerative colitis. The mammal, preferably, is a human being. The compounds according to the formula I, and the pharmaceutical preparations based thereon, have a beneficial effect on the accumulation of mediators of mucosal inflammation such as PGE2, LTB4 and TXB2. The compounds according to the invention, therefore, are suitable for therapeutic use in the treatment of colitis. The present invention, therefore, provides a method to reduce the process of inflammation chronic of the intestine, which comprises administering to a mammal, preferably a human, an effective amount of the compounds according to the general formula I, preferably rimexolone. A daily dose may be administered in one or more dose units through, for example, the oral route, rectal route or through injection. Preferably, one unit of individual dose per day is administered through the rectal route. Alternatively, a controlled release preparation can be used, releasing the total daily dose required. The pharmaceutical preparations for use in accordance with the invention can be prepared according to standard techniques such as, for example, described in the standard reference. Gennaro et al. (Ed.), Remmington's Pharmaceutical Sciences, (18th ed. Mack Publishing Company, 1990, for example, part 8: Pharmaceutical Preparations And Their Manufature). For the purpose of making the pharmaceutical preparations according to the invention, the compounds according to formula I, rimexolone, or their pharmaceutically acceptable salts, are mixed with or are dissolved in a pharmaceutically acceptable carrier. Examples of such preparations are tablets, pills, suppositories, (micro-) capsules, powders, emulsions, creams, ointments, suspensions, solutions. Examples of pharmaceutically acceptable carriers are: starch (eg, potato or corn starch), sugars (eg, example, lactose), lubricants (eg, magnesium stearate), binders (eg, amylopectin or polyvinylpyrrolidone), water, alcohol, glycerol and their derivatives, vegetable and animal oils and fats, fatty alcohols, polyalkylene glycols, cellulose derivatives, silica, dispersants, emulsifiers, surfactants, anti-oxidants, dyes and preservatives. In reality, any conventional pharmaceutical vehicle that does not interfere with the functioning of the active ingredient can be used in the preparations according to the present invention. A formulation for an enema typically contains about 100 ml of water, a pH regulator (such as a phosphate pH regulator) and salts (such as sodium chloride) to obtain a neutral iso-osmotic solution. In case the solubility of the active compound is too low to achieve complete dissolution, a thickener (such as a cellulose such as methylcellulose or such as polyvidon) is added to the suspension to limit the degree of sedimentation and cake formation. A detergent (such as polysorbate 20) can be used to increase the availability of the active material to the tissues. Finally, a preservative (such as methyl and propyl oxybenzoate) is added. The anti-inflammatory properties of rimexolone have been described in other occasions. The anti-inflammatory properties relative to the invention are disclosed in a rabbit model. The invention is illustrated through the following examples: Legends of the Figures Figure 1: rimexolone in a rabbit colitis model. Low and high refer to low and high concentrations of rimexolone (as indicated in Example 1). Dex refers to dexamethasone, PGE2 is prostaglandin E2 and TXB2 is thromboxane B2.

EXAMPLE 1 Induction of colitis Male white rabbits from New Zealand were anesthetized (SPF) with a weight of 2.5-3 kg, with Hypnorm 0.4 mg / kg i.m. (Jansen, Belgium), after which a 22G cannula was inserted into a marginal vein of the ear. 4 milliliters of diluted formalin (0.65% vol / vol) per rectum was instilled through a 10Fr feeding tube, with a length of 15 cm (time 0), followed by (two hours later) an intravenous infusion (vein of the ear) of 0.85 ml of heat-added rabbit immunoglobulin (10 mg / ml, at 63 ° C for 20 minutes) (Dako, Denmark). All animals were sacrificed 24 hours after the induction of colitis by intravenous injection of 150 mg / kg of sodium pentobarbital, followed by pre-medication with Hypnorm. Rectal dialysis was performed two hours before sacrifice. A Visking dialysis tube, with a diameter of 6.3 mm, a length of 6 cm (Medicell Int., London), filled with Rheomacrodex (NBPI, The Netherlands), was inserted at 18 cm and left in-situ for two hours.

After the removal, the volume of the dialysate was measured, and stored at -20 ° C for processing in 24 hours.

Treatment Regimen Four groups of 48 rabbits were randomly placed. The treatment consisted of a rectal application of rimexolone at a dose of 10 mg / kg (low dose group, N = 12) or 40 mg / kg (high dose group, N = 12), one hour before and four and eight hours after the induction of colitis. The control animals received 0.9% rectal saline instillation (n = 12) p 40 mg / kg dexamethasone (n = 12).

Sample Collection and Processing The distal colon was excised, opened and washed free of faeces in phosphate buffered saline, cooled with ice. The dialysis fluid was extracted for thromboxane B2 (TXB2) and prostaglandin E2 (PGE2) through solid phase columns Amprep C2 and C15 (Amersham, England), respectively. The eluents were dried under vacuum, resuspended and analyzed using Biotrak ELISA (Amersham). The lowest detection limits for these assays were TXB2 10 pg / ml and PGE2 20 pg / ml. The plates were read using a Thermomax plate reader (Molecular Devices, USA) and the results were analyzed with Softmax software (Molecular Devices).

Results The anti-inflammatory effect of rimexolone was studied over a period of 24 hours. The PGE2 dialysate and the TXB2 levels are shown in Figure 1. It can be concluded that the levels of PGE2 and TXB2 were reduced in animals when the rimexolone treatment was compared to the control group. In addition, the effect is dose-dependent. The effect of high dose is almost similar to the effect obtained with dexamethasone.

EXAMPLE 2 Enema composition: Rimexolone 10-100 mg phosphate P H regulator at a pH of 7 NaCl at isotonicity Methylcellulose 1-2% * Polysorbate 20 1% MOB 0.15% Water 100 ml ') depending on the degree of viscosity

Claims (9)

CLAIMS the use of compounds of the general formula I: wherein: X is a member of the group consisting of H and halogen; And it is a member of the group consisting of H (OH), HÍOIC ^ 6) aci I o) and O; R-i is a member of the group consisting of H, CH 3 and halogen;
1. R2 is (C1-4) alkyl; R3 is a member of the group consisting of H, 0 ((C1-6) acyl), 0 ((C1-6) alkyl) and CH3; R is a member of the group consisting of H and (C1-4) alkyl and d-C2 and C6-C7 are saturated or unsaturated bonds, for the manufacture of a medicament for chronic intestinal inflammatory diseases.
2. 2. - The use of compounds of the general formula I for the manufacture of a medicament for Crohn's disease.
3. 3. The use of compounds of the general formula I for the manufacture of a medicament for ulcerative colitis.
4. 4.- The use of rimexolone for the manufacture of a medicament for chronic inflammatory bowel diseases.
5. 5. - The use of rimexolone for the manufacture of a drug for Crohn's disease.
6. 6.- The use of rimexolone for the manufacture of a medicine for ulcerative colitis.
7. 7. A method for mitigating colitis comprising administering to a mammal an effective amount of a compound having the general formula I.
8. 8. A method for mitigating colitis comprising administering to a mammal an effective amount of a rimexolone.
9. 9. - The method according to claims 7-8, wherein the mammal is a human being.