MXPA97005940A - . methods and compositions to inhibit the effects of interleucin - Google Patents

Abstract

A method for inhibiting the effects of IL-6, consists of administration to a human in need thereof, in an effective amount of a compound having the formula (I), wherein R1 and R2 are independently hydrogen, -CH3, ( a) or (b), where Ar is an optionally substituted phenyl R is selected from the group consisting of pyrrolidone, hexamethyleneimino, and piperidine, or a pharmaceutically acceptable solvate salt thereof.

Description

METHODS AND COMPOSITIONS TO INHIBIT THE EFFECTS OF INTERLEUCINE 6 BACKGROUND OF THE INVENTION.

Interleukin 6 (IL-ß) is a multifunctional cytokine produced by several cells. The molecular cloning of B cell enumerated cDNA stimulation factor 2 (BSF-2), interferon-b2, and protein 26-Da shows that all these molecules are identical. In addition, the hybridoma / plasmacytoma growth factor HPGF) and the hepatocyte stimulation factor (HSF) is also found to be identical to the molecule and, therefore, this molecule is called IL-6. Subsequent studies show that IL-6 acts not only on B cells but also on hematopoietic stem cells and hepatocytes and induced hematopoiesis as well as in penetrating phase reactions. It has also been shown to act on T cells, nerve cells, keratmocytes, renal mesangial cells, egacapocytes, and myeloma / plasma cells. From the production of antibodies, hematopoiesis, and penetrating-phase reactions are the three main reactions against infection, inflammation, and tissue injury, IL-6 can play a central role in a multitude of defense mechanisms.

REF: 25195 On the other hand, the deregulation of the expression gene XL-6 shows to be involved in the pathogenesis of monoclonal and polyclonal B cell abnormalities, such as rheumatoid arthritis and myelomas multiple. Interleukin 6 was originally identified as a T cell derived from lymphokine that induces the final maturation of B cells in the antibody producing cells. Recombinant human IL-6 acts on B cells activated with Staphylococcus aureus covan I or introduced to mitogen (PWM) to induce the production of IgM, IgG, and IgA, but not on the remaining B cells. The anti-IL-6 antibody is found to inhibit the production of Ig induced by PWM, indicating that IL-6 is one of the essential factors in the production of Ig induced by PWM. In addition, IL-6 is shown to increase the production of primary and secondary anti-SRBC antibodies in mice in vivo. Also IL-6 can improve the synthesis of IgA in B cells in murine Peyer patches which are committed to the production of IgA. Murine IL- € also shows acting on murine B cells activated with dextran or anti-Ig sulfates; IL-6 and IL-1 synergistically stimulate growth and differentiation of these murine B cells.

Interleukin 6 can also induce the growth and differentiation of T cells and advance the growth of thymocytes stimulated by itogen and peripheral T cells. This is also shown by S inducing T cells in the presence of IL-2 in murine as well as human thymocytes and splenic cells T.

By shortening the period of operation of the stem cells IL-6 and IL-3 synergistically induces the formation of the colony of multisomponent hematopoietic progenitors. This synergistic effect of IL-3 and IL-6 is also observed under serum-free culture conditions; suggesting that IL-6 may increase the sensitivity of raultipotent stem cells to IL-3. 5 When bone marrow cells are transplanted into lethally irradiated containers, the 30-day survival ratio is only 20%. However, when these cells are precultured with IL-6 and IL-3 before transplantation, the survival ratio is high at 90%.

In addition, IL-6 induces the maturation of megakaryosites in vitro and in vivo. IL-6 promotes a marked increase in the size and activity of acetylcholinesterase, a marked enzyme of this lineage.

IL-6 also induces a significant change towards large classes of chromosomes. The penetrating phase response is a systemic reaction against inflammation, infection or wounds in the tissue, which are characterized by leukocytosis, fever, increased vascular permeability, alteration in the concentration of steroid and metal in the plasma, together with an increase in the levels of penetrating phase proteins. The production of penetrating phase proteins by hepatocytes is regulated by various soluble factors, such as IL-1, TNF, and HSF. Among these factors, only HSF can induce the filling of penetrating phase proteins. This demonstrates that recombinant IL-6 can function as HSF. This can induce several penetrating phase proteins, such as fibrinogens, a-1-antichymotrypsin, α-1-glycoprotein acid, and haptoglobin in a human hepatoma cell line. In addition, IL-6 induces amyloid serum A, reactive protein C, and a-1-antitrypsin in human primary hepatocytes. In the rat, IL-6 induces fibrinogen, inhibitor proteinase cysteine and a.2 macroglobulin. Albumin serum is down-regulated by IL-6. The interleukin 6 mRNA induced by gliobastone cells stimulated IL-1 or astrocytoma cells, suggests that IL-6 may have certain effects on nerve cells. The pheochromocytoma cell line, PC12, of the rat, is a model of characteristic nervous differentiation. The nerve growth factor (NGF) induces chemical, ultrastructural and morphological changes in the PC12 cell. Also IL-6 is found to induce the characteristic differentiation of this cell within nerve cells and has been found to be produced by astrocytes and microglial cells infected by viruses. This also induces the secretion of NGF by astrocytes. In the production of IL-6 CNS a mechanism of repair may be involved in the course of virial infection. The involvement of IL-6 in the disease first suggests a cardiac myxoma. Patients frequently present symptoms related to polyclonal plasmacytosis, such as hypergammaglobulinemia and the presence of several antibodies and an increase in penetrating phase proteins. These symptoms disappear on the resection of the tumor, suggesting that the factors derived from the myxoma can induce this phenomenon. It has been found that myxoma cells deliver a large amount of IL-6. Abnormal production of IL-6 is also observed in patients with Castle an's disease. In these patients, activated B cells in the germinal center of hyperplastic lymph nodes are found to produce IL-6. After resection of these lymph nodes, a decrease in serum IL-6 levels and clinical improvement is observed. This evidence suggests that the deregulated production of IL-6 can induce the increase and activation of polyclonal B cells in penetrating phase proteins. This possibility is also suggested in rheumatoid arthritis (RA) High levels of IL-6 are detected in synovial fluids of the joints of patients with active rheumatoid arthritis. Interleukin 6 is a potent growth factor for murine hybridomas / plasmacytes, which suggests the possible involvement of IL-6 in the generation of plasmacytomas / myelomas. In addition, a study with isolated human myeloma cells, from patients with multiple myelomas, demonstrates that IL-6 is an autocrine growth factor for human myeloma cells. All the evidence suggests that the expression deregulated IL-€ gene may be involved in the activation of polysilon B cell and generation of plasma cell neoplasia. Mesangial proliferative glomerulonephritis (PGN) is characterized histologically by the proliferation of mesangial (MC) cells, suggesting the involvement of growth factor for mesangial cells in the pathogenesis of this disease. This shows that IL-6 is an autocrine growth factor for mesangial cells. This can be detected in the urine tests of patients with PGN. In addition, a close relationship is observed between the level of IL-6 in the urine and the progression of PGN. These results suggest that the dysregulated production of IL-6 in mesangial cells is implicated in the pathogenesis of PGN.

DETAILED DESCRIPTION OF THE INVENTION.

This invention provides methods for inhibiting the effects of IL-6 which comprise administering, to a human in need thereof, an effective amount of a compound of formula I.

(I) wherein R1 and R3 are independently hydrogen, -CH3, -C-I ^ -Gs alkyl), or -C-Ar, where Ar is a phenyl O optionally substituted; R * - is selected from the group consisting of pyrrolidino, hexamethylsimino, and piperidino and pharmaceutically acceptable pharmaceutically acceptable salts and solvates thereof. The present invention relates to the discovery of a select group of 2-phenyl-3-aroylbenzothiophosphines (benzothiophenes), those of the formula I, which are useful for inhibiting the effects of IL-6. Also, the compounds are useful for inhibiting the effects of leukemia inhibitory factor (LIF). Finally, the compounds are useful for receptor inhibition systems using the transmembrane protein gpl30 for the transduction of ligated signals. Such receptor systems include IL-6, LIF, onconstatma M, ciliary neurotrophic factor and IL-11.

The methods of use provided by this invention are practiced by the administration, to humans in need of a dose of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, which is effective to inhibit the effects of IL-α. The term "inhibit" includes these generally accepted meanings in which prohibition, prevention, impediment and delay, detention or reversal are included. As such, the present method includes both prophylactic and / or medical therapeutic administration as appropriate. When it is not desired to be subject by theory, it is believed that the components of formula I may inhibit the secretion and / or utilization of IL- 6 and therefore be useful in disorders associated with an excess of IL-6. In addition, the compounds appear to inhibit the receptor systems using transmembrane gpl30 protein for the binding signal transduction. Raloxifene, a compound of this invention, wherein this is a hydrochloride salt of a compound of formula I, R1 and R3 are hydrogens and R2 is 1-piperidinyl, which is a nuclear regulatory molecule. Raloxifene is shown to be linked to the estrogen receptor and was originally thought to be a molecule whose function and pharmacology were those of an antiestrogen in which the ability of estrogen to activate uterine tissue is blocked, and breast cancer depends on estrogen. Of course, raloxifene blocks the action of estrogen in some cells; however in other cell types, raloxifene activates the same genes as estrogen does and exhibits the same pharmacology, for example, anti-osteoporosis, hyperlipidemia. As a result, raloxifene refers to an antiestrogen with mixed agonist-antagonist properties. The only profile in which raloxifene exhibits and differs from estrogen is now considered to be the one expected for the single activation and / or suppression of several functions of the gene by the raloxifene-estrogen receptor complex by opposing gene activation and / or deletion by the estrogen-estrogen receptor complex. Therefore, although raloxifene and estrogen use and compete for the same receptor, the pharmacological result of gene regulation of the two is not easily predicted and is unique to each. Generally, the compound is formulated with common excipients, diluents or carriers, and compressed into tablets, or formulated as elixirs or solutions for convenient oral administration, or administered by the intravenous or intramuscular route. The compounds may be administered transdermally, and may be formulated as prolonged relief dosage forms and the like. The compounds that are used in the methods of the invention can be made according to established procedures such as those detailed in the Patent of BU, Nos. 4, 133, 814, 4, 41T, 068, and 4, 380, 635 all they are incorporated in the attached reference. In general, the process begins with a benzo (b) thiophene which has a 6-hydroxyl group and a 2- (4-hydroxyphenyl) group. The starting compound is protected, acylated, and deprotected to form the compounds of formula I. Examples of the preparation of such compounds are provided in US Patents. mentioned above. Optionally substituted phenyl includes phenyl and phenyl substituted once or twice with Ci-C? alkyl, C 1 -C 4 alkoxy, hydroxy, nitro, chloro, fluoro, or tri (chloro or fluoro) methyl. The compounds which are used in the methods of this invention form pharmaceutically accepted basic and acid addition salts with a wide variety of inorganic and organic bases and acids and include the physiologically acceptable salts which are frequently used in pharmaceutical chemistry. Such salts are also part of this invention. The characteristic inorganic acids which are used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric and the like. Salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acid, hydroxyalkanedioic and hydroxyalkanoic acids, aromatic acids, aromatic and aliphatic sulphonic acids, may also be used.

Such pharmaceutically acceptable salts in this manner include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dynitrobenzoate, hydroxybenzoate, ethoxybenzoate, methylbenzoate, o-asetoxibenzoate, naphthalene-2-benzoate, bromides, isobutyrate, phenylbutyrate, β-hydroxybutyrate, butyne-1,4-dioate, hexane-l, 4-dioate, caprate, caprylate, chlorides, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, hippurate, lactate, malate, maleate, hydroxyalate, malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, teraphthalate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate, bisulfate, pyrosulfite, sulfite, bisulfite, sulfonate, benzene -sulfonate, p-bromophenylsulfunate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluensu lonato, xylenesulfonate, tartarate, and the like. A preferred salt is the hydrochloric salt. The pharmaceutically accepted acid addition salts are characteristically formed by the reaction of a compound of the formula I with an im molar amount or excess of acid. The reagents are generally combined in a mutual solvent such as diethyl ether or benzene. The salt usually precipitates out of the solution, in about one hour to ten days and it may be isolated by filtration or the solvent may be depleted by conventional means. Bases are commonly used for the formation of salts including ammonium hydroxide and alkaline earth metal hydroxides and alkalis, carbonates, as well as aliphatic and primary, secondary and tertiary amines and aliphatic diamines. Bases useful especially in the preparation of addition salts include ammonium hydroxide, potassium carbonate, methylamine, diethylamine, ethylenediamine and cishexyl amine. The pharmaceutically accepted salts generally have improved solubility characteristics compared to the compounds from which they are derived, and thus are often easier for formulation as liquids or emulsions. The pharmaceutical formulations can be prepared by methods known in the art. For example, the compounds can be formulated with common excipients, diluents, or vehicles and formed into tablets, capsules, suspensions, powders and the like. Examples of excipients, diluents, and vehicles that are suitable for such formulations include the following: fillers and extenders such as starches, sugars, mannitol, and silicic derivatives; binding agents such as carboxymethyl cellulose and other cellulose derivatives, gelatins, alginates, and polyvinyl pyrrolidone, wetting agents such as glycerol; disintegrating agents such as calcium carbonate and sodium bicarbonate; agents for delaying dissolution such as paraffins, resorption accelerators such as quaternary ammonium compounds, surface active agents such as cetyl alcohol, glycerol monostearate; adsorptive vehicles such as kaolin and bentonite; and lubricants such as talc, magnesium and calcium stearate, and solid polyethylic glycols. The compounds may also be formulated as elixirs or solutions for convenient oral administration or as appropriate solutions for parenteral administration, for example by intravenous, intramuscular or subcutaneous routes. Additionally, the compounds are quite suitable for formulation as prolonged relief dosage form and the like. The formulations may be constituted by relief active ingredients only or preferably in a particular part of the intestinal tract, possibly over a period of time. The layers, cover and protective matrices can be made, for example, of polymeric substances or waxes.

The dose and particular regimen of a compound of formula I, which is required to inhibit the effects of IL-6, LIF or receptor systems which use the transmembrane gpl30, according to this invention, will depend on the severity of the condition, the route of administration, and the related factors to be determined by the attending physician. Generally, the effective and accepted daily dose is from about 0.1 to about 1000 rog / day, and more characteristically about 50 to about 200 mg / day. Such doses are administered to a subject in need thereof, and one to three times each day, or more if needed, in a sufficient time to effectively inhibit the effects of IL-6.

This is usually preferred for administering a compound of formula I in the form of an acid addition salt, as is customary in the administration of pharmaceutical carriers of a basic group, such as the piperidine ring. It is also advantageous to administer such compound by the oral route. For such purpose, the following oral doses are available.

FORMULATIONS.

In the formulations that follow, the "active ingredient" refers to a compound of formula I.

Formulation 1: Gelatin capsules. Hard gelatine capsules are prepared using the following: Ingredient Quantity (mg / capsule) Active ingredient 0.1-1000 NF 0-650 starch Fluid starch 0-650 Liquid silicone 350 0-15 centistokes The ingredients are mixed, passed through a 45 mesh screen, and filled into hard gelatin capsules.

The formula-J specific formulations of raloxifene capsules are made including the following: Formulation 2: Raloxifene capsule.

Ingredient Quantity (mg / capsule) Raloxifene 1 NF in starch I 112 Fluid starch powder 225.3 Liquid silicone 350 I 1.7 centistokes Formulation 3: Raloxifene capsule.

Ingredient Quantity i (mg / capsule) Raloxifene j 5 NF in starch 1 108 Powdered starch powder j 225.3! Liquid silicone 350 1.7 centistokes Formulation 4: Raloxifene capsule.

Ingredient Quantity (mg / capsule) Raloxifene 10 Starch NF 103 Fluid starch powder 225.3 Liquid silicone 350 1.7 centistokes Formulation 5: Raloxifene capsule.

Ingredient Quantity (mg / capsule) Raloxifene 50 Starch NF 150 Powdered starch powder 397 Liquid silicone 350 3.0 centistokes The above specific formulations may be changed in compliance with the reasonable variations provided. A tablet formulation is prepared using the ingredients below: Formulation 6: Tablets Ingredient Quantity (mg / tablet) Active ingredient 0.1-1000 Microcrystalline cellulose 0-650 carbon dioxide 0-650 silicon Stearic acid 0-15 The compounds are mixed and compressed to form tablets. Alternatively each tablet contains 0.1-1000 mg of active ingredient as follows: Formulation 7: Tablets.

Ingredient Quantity (mg / tablet) Active ingredient 0.1-1000 Starch 45 Microcrystalline cellulose 35 Polyvinyl pyrrolidone 4 (as a 10% solution in water) Carboxymethyl cellulose 4.5 Sodium magnesium stearate 0.5 Talcum 1.0 The active ingredient, starch, and cellulose They pass through a No. 45 mesh screen and mix thoroughly. The polyvinylpyrrolidone solution is mixed with the resulting powders which are passed through a No. 14 mesh screen. The granules that are produced are dried at 50-60 ° C and passed through a No. 10 mesh screen. 18. Sodium carbolytic starch, magnesium stearate and talcum are previously passed through a No. 60 mesh screen, are added to the granules, which after mixing, are compressed on a tablet machine to produce tablets. All suspensions contain 0.1-1000 mg of medication for every 5 ml of dose, and are made as follows: Formulation 8: Suspensions.

Ingredient Quantity (mg / 5 ml) Active ingredient 0.1-1000 mg Carboxymethyl cellulose 50 mg sodium Syrup 1.25 mg Benzoic acid solution > 0.10 my Flavor q.v. Coloring q.v. Purified water for 5 ml The drug is passed through a No. 45 mesh screen, and mixed with syrup and sodium carboxymethyl cellulose to form a smooth paste. The solution of benzoic acid, flavoring and coloring is diluted with some water and added, with agitation. Sufficient water is added to produce the required volume.

Test 1 At six months of age, virgin SD rats are ovx or ovx / hypophysectomized (HYPOX), treated with vehicle (20% cyclodextrin, PO), raloxifene (0.1 to 10 g / Kg / day, PO) or EE2 estradiol ethinyl; 0.001 to 0.1 mg / Kg / day, PO. A vehicle treatment simulator control is also included. Serum, and / or large amounts of bone, are collected after a treatment period of 35 days or less. Serum cytokine determinations were performed by bioassays. The OVX results in a marked decrease in bone mass after 35 days of treatment is accompanied by a consistent and marked increase in levels of serum IL-6, (Tablal). Interestingly, both raloxifene and ΔE2 are significantly attenuated both in the OVX induced osteopenia, and in the increase in serum IL-6 levels. In treated animals for every 4 days post-OVX, there is a significant reduction in the treatment of raloxifene and EE2. In contrast, in OVX / HYOX rats the non-increase in serum IL-6 is observed, which also does not respond neither to EE2 nor to raloxifene in terms of bone density. No consistent changes in other serum cytokines are detected. TABLE 1.

Serum IL-6% BDM (ng / ml) (protection) Simulator 0.42 ± 0.13 100 ± 4.65 OVX 7.18 ± 2.0 0.00 ± 10.24 Ralox 10 g / kg 1.23 ± 0.45 82.09 ± 7.02 Ralox 1 mg / kg 1.55 ± 0.48 82.50 ± 17.17 Ralox 0.1 mg / kg 4.32 ± 1.65 63.88 ± 19.8 Ethyl lOOμg / kg 0.20 ± 0.10 76.00 ± 18.3 Estradiol lOμg / kg 1.84 ± 0.60 57.25 ± 16.07 Estradiol lμg / kg 3.42 ± 2.23 5.28 ± 11.83 17-ß-E2 100 μg / kg, 0.07 ± 0.10 106.4 ± 11.8 Test 2. At ten weeks of age, the BALB / c male mouse is treated with vehicle (20% cyclodextrin, PO) or raloxifene (1 mg / kg, PO) for 3 days. On day 4, the mouse is treated with vehicle (solution, IP), monoclonal antibody receptor LA-15.1 anti-IL-1 (mAb) (250 ug, IP) or human IL-lb recombinant (3 ug, SC) . After two hours, serum is collected by perforation in the orbital sinus and IL-6 levels are quantified by ELISA.

Injection of IL-1 in the mouse treated with siclodextrin induces a significant increase in serum IL-6 (193 ± 29 ng / ml) against saline injection in the mouse treated with cyclodextrin (<1 ng / ml) (Table 2) . Interestingly, raloxifene significantly attenuates the elevation in IL-6 serum levels induced by IL-1 (90 ± 21 ng / ml). The anti-IL-1 mAb LS-15.1 receptor completely attenuates the elevation in IL-1 serum levels induced by IL-1.

TABLE 2 IL-6 (ng / ml) CDX / Salt / Salt < 0.5 CDX / Salt / IL-1 193 ± 2.9 139478 / Salt / IL-1 90 ± 2.1 CDX / 15.6 mAb / lL-1 < 0.5 Test 3. The following mouse cell lines are used for cytosma bioprobes: cytolytic T cell CTLL.6-IL-2, IL-4; T helper cell 11.6-IL4; Plasmacytoma T1165.17-IL-1, IL-6; hibpdoma B9-IL-6, LIF (Leukemia inhibitory factor). Approximately, 5,000 cells are seeded in duplicate in 96-well flat microtiter dishes in standard tissue culture media (eg, Iscove modified Dubelco media or Dubelco modified eagle media supplemented with 25 Hepes mM, 2 mM L-glutamine, 50 μM 2-mercaptoethanol, 50 units / ml of penicillin, 50 μg of streptomycin sulfate, and fetal bovine serum) containing vehicle (DMS0), raloxifene (0.01 to 1 μM) or 17-b-estradiol (0.01 to 1 μM) ) in the absence or presence of the indicated recombinant cytokine. The microtiter plates are incubated at 37 * C in a 10% C0 incubator humidified for 24 to 72 hours. At the end of this time, the 1-μC? 3H-t? M? Dma or 100 μg of MTT 3- (4,5-d? Met? Lt? Azol-2-? L) -diphenyl tetrazolium bromide is added followed by an additional incubation of 4 to 6 hours. Crops are pulsed using MTT receiving 100 μl of SDS / 0.01H of 10% HCl for good follow-up of overnight incubation in the dark at room temperature. The optical density readings are taken at 570 nm with a reference wavelength of 690 nm to quantify cell proliferation.

The comparison of results from raloxifene to estrogen for cytokine inhibition depends on proliferation as shown in Table 3. The data are expressed as an IC value: for 50% inhibition of cytokine dependent cell proliferation.

Interestingly, raloxifene significantly attenuates IL-6 and cell proliferation stimulated by LIF (IL-6, IC-719nM, LIF IC5¿ = 603nM), but has no effect on proliferation stimulated by IL-2 and IL-4 (IC? (-. => 1 μM). In contrast 17-b-estradiol does not significantly inhibit cell proliferation for any examined sitocin (IC5oSB> 1 μ) These results suggest that cell proliferation inhibits raloxifene, stimulated by the cytokine bound to the surface receptor using the transmembrane protein gpl30 for the transduction of ligated signal Such receptor systems include IL-6, LIF, onconstantin M, ciliary neurotrophic factor, and IL-11.

TABLE 3 IC5 values. Cytochrome 17-B-E2 Raloxifene IL-6 > lμM (n = 2) 719 (n = 2) LIF > lμM (n = 6) 603 ± 212 nM (n = 6) IL-2 > lμM (n = l) > lμM (n = l) IL-4 > lμM (n = 3) > lμM (n = 3) Pruueebi a 4. The non-ovex female mouse is treated with raloxifene or analogs and after 3-4 days of dosing the mouse is stimulated with a dose of lipopolysaccharide between 20-200 ug per mouse. At 3 hours after the stimulus, the animals are bled and serum IL-6 determinations are made. At the time of the 3 hours of time based on the preliminary experiments, the peak detection in IL-6 is represented. In a separate series of experiments while estrogen analogues are able to reduce the levels of IL-6 in a mouse stimulated with LPS, the combination of estrogen plus the raloxifene analog results in a synergistic reduction in IL-6, larger than the one observed for each agent only.

Therefore, it is observed that the most effective way to reduce the levels of IL-6 in vivo will be the combination of a low dose of estrogen with raloxifene. The final test should involve ex vivo or m vitro experiments in which macrophages are exposed to raloxifene or analogs in the presence or absence of estrogen, and superfluous IL-6 levels will be measured following an LPS stimulus in vitro.

TABLE 4 Test O.D. ng / ml Bird (mg / kg) Vehicle 0.891 363.0 Vehicle 0.524 227.2 Vehicle 1.001 417.7 Vehicle 0.802 323.9 332.9 Ralox 0.5 0.892 363.2 Ralox 0.5 0.820 331.5 RaloxO .5 0.613 254.4 Ralox 0.5 0.613 254.5 300.9 Ralox 5.0 0.576 242.6 Ralox 5.0 0.648 266.2 Ralox 5.0 0.595 248.6 Ralox 5.0 0.414 181.6 234.7 Estrogen 0.5 i 0.341 130.3 Estrogen 0.5, 0.355 139.1? Strgenic 0.5 0 .364 144.5 Estrogen 0.5 0 .447 205.9 155 .0 E3trogen 5.0 0 .306 111.2 Estrogen 5.0 0 .469 211.8 Estrogen 5.0 0 .226 77.5 Estrogen 5.0 0 .291 104.1 126. 1 ? 3-estrogen + 0 .225 77.3 Tamox Estrogen + 0 .315 116.1 Tamox Estrogen + 0 .282 100.0 Tamox Estrogen + 0.333 125.6 104 .8 Tamox Estrogen + 0 .260 90.5 Ralox 0.5 Estrogen + 0 .206 70.8 Ralox 0.5 ? strógeno + 0.195 67.5 Ralox 0.5 Sstrogen + 0.298 107.3 84.0 Ralox ú.5 Estrogen + 0.156 51.1 Ralox 5.0? strgenic + 0.220 75.6 Ralox 5.0? 3 estrogen + 0.229 78.7 Ralox 5.0 Estrogen + 0.120 32.6 59.5 Ralox 5.0 It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as an antecedent, the content of the following is claimed as property:

Claims (4)

CLAIMS FOR MEXICO
1. The use of a compound of the formula (I) and*-. where R 'and R- are independently, hydrogen, -CH;. , -C- (C-;, alkyl), or -C-Ar. where Ar is an phenyl optionally substituted; R ~ is selected from the group consisting of pyrrolidone, nexamethyleneimam. and piperidma; or a pharmaceutically acceptable solvate salt thereof, for the preparation of a medicament for inhibiting the effects of Interleu-c? na-6.
2. 2. The use according to claim 1, wherein said compound is the salt! -. idroclcrada of the same.
3. 3. The use according to claim 1, wherein said compound is or its hydrochlorinated salt.
4. 4. The use of a compound having the formula I (II eri where R * and R- are independent hydrogens, -CH3, ^ -C alkyl), or -C-Ar where Ar is an optionally substituted phenyl; R is selected from the group consisting of pyrrolidone, hexamethyleneimine, and piperidm; or a solvate salt thereof pharmaceutically acceptable. for the preparation of a drug to inhibit the LIF effector. S. A use of a compound of the formula I (I) where R 'and R- are independent hydrogens, -CH: C- (C-.C;, alkyl), or -C-Ar, donote Ar is an optionally substituted phenyl O; R ~ is selected from the group consisting of pyrrolidone, hexamethyleneimine, and piperidm; or a pharmaceutically acceptable solvate salt of the solvate thereof, for said surface receptor system, for the preparation of a compound for inhibiting the surface receptor system, using the transmembrane receptor gpl30.