MXPA99003793A - Immune response modifier compounds for treatment of th2 mediated and related diseases - Google Patents

Abstract

Immune response modifier compounds - imidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, and 1,2-bridged imidazoquinoline amines - are useful for the treatment of TH2 mediated diseases by administering a therapeutically effective amount of such compounds in order to inhibit TH2 immune response, suppress IL-4/IL-5 cytokine induction and eosinophilia, as well as enhance TH1 immune response.

Description

MODIFIED COMPOUNDS OF THE IMMUNE RESPONSE FOR THE TREATMENT OF MEDIATED DISEASES BY T CELL AUXILIARY TYPE TWO AND RELATED DISEASES BACKGROUND OF THE INVENTION The present invention is concerned with the use of immunomodification imidazoquinoline amines, imidazopyridine amines, fused cycloalkylimidazopyridine 6-7 amines and imidazoquinoline amines 1, --- bounded to inhibit the immune response of the auxiliary T cell type 2 (TH2) and by this to treat diseases mediated by TH2. It is also concerned with the ability of these compounds to inhibit the induction of interleukin (IL) -4 and IL-5 and to suppress eosinophilia. Many imidazoquinoline amine compounds, cycloalkylimidazopyridine 6,7 fused amine imidazopyridine amine and 1,2-ponteated imidazoquinoline amine have shown potent immunostimulant, antiviral and antitumor activity (in which anticancer is included) and have also proved useful as vaccine adjuvants to improve the response of the immune protective system to vaccines. These compounds are collectively referred to hereinbelow as "IRM" compounds (immune response modifiers) of the invention. Such compounds are described in for example, U.S. Patents 4,689,338, 5,389,640, 5,268,376, 4,929,624, 5,266,575, 5,352,784, 5,494,916, ,,,,,,,,,, 23, 944 and 5,525,612, WO 93/20847 and the European patent application 90.301776.3, where their iniaunoestimulantes, antiviral and antitumor activities, are discussed in detail and certain specific diseases are identified because they are susceptible to treatment with them, which include basal cell carcinoma, eczema, essential thrombocythemia, hepatitis B, multiple sclerosis, neoplastic diseases, psoriasis, rheumatoid arthritis, herpes simplex type I, herpes simplex type II and warts . One of these IRM compounds, known as i-miquimod, has been commercialized in a topical formulation, Aldara ™, for the treatment of anogenital warts, associated with the human papillomavirus. It is believed that the mechanism for the antiviral and antitumor activity of these IBM compounds is due in substantial part to the improvement of the immune response due to the induction of several important cytokines (e.g., interferon, interleukins, necrosis factor tumor, etc.). It has been shown that such compounds stimulate a rapid release of certain cytokines derived from monocyte / macrophage and are also capable of stimulating B cells to secrete antibodies that play an important role in the antiviral and antitumor activities of these MRI compounds. One of the predominant immunostimulatory responses to these compounds is the induction of production e nter er n. -aa, which is believed to be very important in antiviral and antitumor activities seen acute, - in addition, in the regulation of other cytokines such co or for example, tumor necrosis factor (TNF), IL-1 and IL -6 also have potentially beneficial activities and are thought to contribute to the antiviral and antitumor properties of these compounds. However, there are many diseases where the immune system itself really seems to play a significant role in mediating the disease (that is, the action of the immune system is actually part of causing the disease or an inappropriate type of immune response). prevent the correct response to eradicate the disease). It is thought that many diseases involve a pathological or inappropriate immune response by the humoral branch of the immune system, which is associated with the activity of the TH2 cell (as opposed to cell-mediated immunity of TH1). The humoral / TH2 branch of the immune system is generally directed to protection against extracellular immunogens such as bacteria and parasites through the production of antibodies by B cells; whereas the cell branch / TH1 is generally directed to the cell-like immunogens such as viruses and cancers by means of the activity of natural killer cells, cytotoxic T lymphocytes and activated macrophages. It is believed that TH2 cells produce the cytokines IL-3, IL-4, IL-5 and IL-10, which are believed to stimulate the production of IgE antibodies, as they are involved with recrudescence, proliferation, differentiation, maintenance and survival of eosinophils (this is leukocytes that accept a brand of eosin), which can result in eosinophilia. Eosinophilia is a hallmark of many diseases mediated by TH2, such as asthma, allergy and atopic dermatitis. The interrelationship and importance of various aspects of the immune system response, in which the interaction between the cytokines of TH1 and TH2 cells are discussed in WO 97/2688. Although WO 97/2688 is specifically concerned with the effects of a particular antiviral compound, known as Ribavirin®, which is different from the IRM compounds of the present invention, they nonetheless illustrate some of the complex and unpredictable effects of the drug compounds on the immune system.

BRIEF DESCRIPTION OF THE INVENTION It has now been found that in addition to its immunostimulatory, antiviral / antitumor effect on the immune system, the IR compounds of the present invention - imidazoquinoline amines, aminidopyridine amines, amines c as well as azop r na, - 1 and 2-ponteated imidazoquinoline and amidanes are also extremely useful in regulating certain key aspects of the immune response. Specifically, it has been found that the IRM compounds of the present invention inhibit the TH2 immune response (in addition to improving the immune response of TH1). This is extremely important for the treatment of TH2-mediated diseases, where an inappropriate TH2 response causes the disease or avoids the radiation of the disease by the TH1 response. Thus, when administered in a therapeutically effective amount, these MRI compounds can be used to treat TH2 mediated diseases. An obviously related effect of the IRM compounds present is to inhibit the induction of IL-4, IL-5 and perhaps other cytokines, which thereby allows the treatment of diseases associated with these cytokines. An important and surprising additional effect of these compounds is the suppression of eosinophils, which allows the treatment of eosinophilia and related diseases. It is believed that some diseases are caused / mediated in substantial part by the immune response of TH2, induction of cytokine IL-4 / IL-5 and / or eosinophilia (and thus sensitive to treatment by administration of a therapeutically effective amount of the compounds of MRI of the present invention), which include asthma, rhinitis to the rg ca, the subject is upus s st m co, s syndrome of Qmmen (hypereosinophilia syndrome), certain parasitic infections, for example, cutaneous and systemic leis-imaniasis, toxoplasma infection and infection of trypanosome and certain fungal infections, for example, candidiasis and histoplasmosis and certain intracellular bacterial infections, such as leprosy and tuberculosis. These are examples of non-viral and non-tumorous TH2 mediated diseases, for which effective treatment with the present IRM compounds clearly could not have been predicted. Additionally, it should also be noted that diseases having a viral or cancer-related basis, but "with a significant TH2-mediated pathology can also be treated beneficially with the IRM compounds of the present invention." MRI compounds of the present invention are for the treatment of diseases associated with eosinophilia, such as asthma and allergic rhinitis.The IBM compounds present can be administered via any appropriate means, for example, parenterally, transdermally or orally. Preferred administration is via a topical gel or cream formulation For the treatment of asthma and allergic rhinitis, it is preferred to administer the MRI compound orally and / or nasal inhalation of a metered dose inhaler.

Mention is preferably made of 4-amino-2-ethoxymethyl-alpha, alpha-dimethyl-lH-imidazo [4,5-c] quinoline-1-ethanol and 1- (2-methylpropyl) -lH-imidazo [4]. , 5-c] quinolin-4-amine (known as Imiquímod). Finally, it should be noted that the diseases identified as treatable in the published patents referred to above in the background (U.S. Patent Nos. 4,689,338, 5,389,640, 5,268,376, 4,929,624, 5,266,575, 5,352,784, 5,494,916, 5,482,936, 5,346,905, 5,395,937, 5,238,944 and 5,525,612, WO 93/20847 and European patent application 90.301776.3) are generally either viral / tumor based or else, it is believed that they are not TH2 mediated diseases. An exception is eczema (or eczema) which, although it is a disease mediated by TH2, is believed to have been identified due to its susceptibility to treatment with interferon (which was later understood to be the main cytokine response induced by the compounds present ). However, there was no recognition at that time that any TH2, IL-4/5 or eosinophilia suppressor capacity of the present IRM compounds could have been used for the treatment of eczema.

Detailed Description _ _ Preferred IRM Compounds As indicated above, many of the IBM imidazoquinoline amine compounds, imidazopyridine amine, 6,7-fused cycloalkylimidazopyridine amine, and 1,2-buffered imidazoquinoline amine of the present invention have demonstrated significant immunomodulatory activity. Preferred immune response modifying compounds include 1H-imidazo [4, 5-c] quinolin-4-amines defined by one of the formulas I-V below: wherein n is selected from the group consisting of alkyl of one to about ten carbon atoms, hydroxyalkyl of one to about six carbon atoms, acyloxyalkyl wherein the acyloxy portion is alkanoyloxy of two to about four carbon atoms, or benzoyloxy and the alkyl portion contains one to about six carbon atoms, benzyl, (phenyl) ethyl and phenyl, the benzyl (phenyl) ethyl or phenyl substituent are optionally substituted on the benzene ring by one or two portions independently selected from the group that consists of alkyl of one to about four carbon atoms, alkoxy of one to about four carbon atoms, and halogen, with the proviso that, if the benzene ring is substituted by two of the portions, then the portions together do not contain more than six carbon atoms; R21 is selected from the group consisting of hydrogen, alkyl of one to about eight carbon atoms, benzyl, (phenyl) ethyl and phenyl, the benzyl substituent, (phenyl) ethyl or phenyl are optionally substituted on the benzene ring by one or two portions independently selected from the group consisting of alkyl of one to about four carbon atoms, alkoxy of one to about four carbon atoms and halogen, with the proviso that when the benzene ring is replaced by two of the portions, then the portions together do not contain more than six carbon atoms; and each i is independently selected from the group consisting of alkoxy of one to about four carbon atoms, halogen and alkyl of one to about four. carbon atoms, and n is an integer from 0 to 2, with the proviso that if n is 2, then the R. groups together do not contain more than six carbon atoms; II wherein R-2 is selected from the group consisting of straight or branched chain alkenyl containing two to about ten carbon atoms and straight or branched chain alkenyl, substituted containing two to about ten carbon atoms, wherein the substituent is selected from the group consisting of straight or branched chain alkyl containing one to about four carbon atoms and cycloalkyl containing from three to about six carbon atoms; and cycloalkyl containing from three to about six carbon atoms substituted by straight or branched chain alkyl, containing from one to about four carbon atoms; and R22 is selected from the group consisting of hydrogen, straight or branched chain alkyl containing from one to about eight carbon atoms, a benzyl, (phenyl) ethyl and phenyl substituent, the benzyl, (phenyl) ethyl or phenyl substituent is optionally substituted on the benzene ring by one or two portions independently selected from the group consisting of chain alkyl straight or branched containing from one to about four carbon atoms, straight or branched chain alkoxy, containing one to about four carbon atoms and halogen, with the proviso that when the benzene ring is replaced by two such portions, then the portions as a whole do not contain more than six carbon atoms; and each B2 is independently selected from the group consisting of straight chain or branched chain alkoxy containing from one to about four carbon atoms, halogen and straight or branched chain alkyl containing from one to about four carbon atoms, and n is an integer from zero to 2, with the proviso that if n is 2, then groups B2 together do not contain more than six carbon atoms; III wherein R23 is selected from the group consisting of hydrogen, straight or branched chain alkyl of one to about eight carbon atoms, benzyl, (phenyl) ethyl and phenyl, the benzyl, (phenyl) ethyl or phenyl substituent is optionally substituted on the benzene ring by one or two portions independently selected from the group consisting of straight chain or branched chain alkyl of one to about four carbon atoms, straight chain or branched chain alkoxy of one to about four carbon atoms and halogen, with the proviso that, when the benzene ring is replaced by two such portions, then the portions as a whole do not contain more than six carbon atoms; and each R3 is independently selected from the group consisting of straight or branched chain alkoxy of one to about four carbon atoms, halogen and straight or branched chain alkyl of one to about four carbon atoms, and n is an integer number of zero - 2, with the proviso that if n is 2, then groups B together do not contain more than six carbon atoms; IV where RH is -CHRxRy, where Ry is hydrogen, or a carbon-carbon bond, with the proviso that when Ry is hydrogen, R? is alkoxy of one to four carbon atoms, hydroxyalkoxy of one to about four carbon atoms, 1-alkynyl of two to about ten carbon atoms, tetrahydropyranyl, alkoxyalkyl wherein the alkoxy portion contains one to about four carbon atoms and the alkyl portion contains from one to about four carbon atoms 2-, 3-, or 4-pyridyl and with the additional proviso that when Ry is a carbon-carbon bond, Ry and Rx together form a tetrahydrofuranyl group optionally substituted with one or more substituents independently selected from the group consisting of hydroxyl and hydroxyalkyl of one to about four carbon atoms; B2 < is selected from the group consisting of hydrogen, alkyl of one to about four carbon atoms, phenyl and substituted phenyl, wherein the substituent is selected from the group consisting of alkyl of one to about four carbon atoms, alkoxy of one to about four carbon and halogen atoms; and R 4 is selected from the group consisting of hydrogen, straight or branched chain alkoxy, containing from one to about four carbon atoms, halogen and straight or branched chain alkyl, containing from one to about four carbon atoms; wherein R-5 is selected from the group consisting of hydrogen; straight or branched chain alkyl, containing one to about ten carbon atoms and straight or branched chain alkyl, substituted, containing one to about ten carbon atoms, wherein the substituent is selected from the group consisting of cycloalkyl containing three to about six carbon atoms and cycloalkyl containing from three to about six carbon atoms, substituted by straight or branched chain alkyl containing from one to about four carbon atoms; straight or branched chain alkenyl containing from two to about ten carbon atoms and straight or branched chain alkenyl, substituted, containing from two to about ten carbon atoms, wherein the substituent is selected from the group consisting of cycloalkyl which contains from three to about six carbon atoms, and cycloalkyl containing from three to about six carbon atoms substituted by straight or branched chain alkyl containing from one to about four carbon atoms; hydroxyalkyl of one to about six carbon atoms; alkoxyalkyl wherein the alkoxy portion contains from one to about four carbon atoms and the alkyl portion contains from one to about six carbon atoms; acyloxyalkyl wherein the acyloxy portion is alkanoyloxy of two to about four carbon atoms or benzoyloxy, and the alkyl portion contains one to about six carbon atoms; benzyl; (phenyl) ethyl; and phenyl; the benzyl (phenyl) ethyl or phenyl substituent is optionally substituted on the benzene ring by one or two portions independently selected from the group consisting of alkyl of one to about four carbon atoms, alkoxy of one to about four carbon atoms , and halogen, with the proviso that when the benzene ring is substituted by two such portions, then the portions as a whole do not contain more than six carbon atoms; B_- is Rs Rt wherein Rs and Rt are independently selected from the group consisting of hydrogen, alkyl of one to about four carbon atoms, phenyl and substituted phenyl, wherein the substituent is selected from the group which consists of alkyl of one to about four carbon atoms, alkoxy of one to about four carbon atoms and halogen; X is selected from the group consisting of alkoxy containing from one to about four carbon atoms, alkoxyalkyl wherein the alkoxy portion contains from one to about four carbon atoms, and the alkyl portion contains from one to about four carbon atoms, hydroxyalkyl of one to about four carbon atoms, haloalkyl of one to about four carbon atoms, alkylamido wherein the alkyl group contains one to about four carbon atoms, amino, substituted amino, wherein the substituent is alkyl or hydroxyalkyl of one to about four carbon atoms, azido, chloro, hydroxy, 1-morpholino, 1-pyrrole dino, alkylthio of one to about four carbon atoms; Y R; is selected from the group consisting of hydrogen, straight or branched chain alkoxy containing from one to about four carbon atoms, halogen and straight or branched chain alkyl containing from one to about four carbon atoms; or a pharmaceutically acceptable salt of any of the foregoing.

Preferred 6, 7-fused cycloalkylimidazopyridine amine IRM compounds are defined by formula VI below: VI where m is 1, 2 or 3; R 6 is selected from the group consisting of hydrogen; cyclic alkyl of three, four or five carbon atoms; straight or branched chain alkyl containing from one to about ten carbon atoms and straight or branched chain alkyl substituted, containing from one to about ten carbon atoms, wherein the substituent is selected from the group consisting of cycloalkyl containing from three to about six carbon atoms and cycloalkyl containing from three to about six carbon atoms substituted by straight or branched chain alkyl containing from one to about four carbon atoms; fluoro- or chloroalkyl containing from one to about ten carbon atoms and one or more fluorine or chlorine atoms; straight or branched chain alkenyl containing from two to about ten carbon atoms and straight or branched chain alkenyl, substituted containing from two to about ten carbon atoms, wherein the substituent is selected from the group consisting of cycloalkyl containing from three to about six carbon atoms and cycloalkyl containing from three to about six carbon atoms substituted by chain alkyl straight or branched containing from one to about four carbon atoms; hydroxyalkyl of one to about six carbon atoms, alkoxyalkyl, wherein the alkoxy portion contains from one to about four carbon atoms and the alkyl portion contains from one to about six carbon atoms; acyloxyalkyl wherein the acyloxy portion is alkanoyloxy of two to about four carbon atoms or benzoyloxy and the alkyl portion contains from one to about six carbon atoms; with the proviso that any such alkyl, substituted alkyl, alkenyl, substituted alkenyl, hydroxyalkyl, alkoxyalkyl or acyloxyalkyl group does not have a carbon atom completely substituted with carbons attached directly to the nitrogen atom; benzyl; (phenyl) ethyl; and phenyl; the benzyl (phenyl) ethyl or phenyl substituent is optionally substituted on the benzene ring by one or two portions independently selected from the group consisting of alkyl of one to about four carbon atoms, alkoxy of one to about four carbon atoms and halogen , with the proviso that when the benzene ring is substituted by two of said portions, then the portions as a whole do not contain more than six carbon atoms; and -CHRxRy wherein: Ry is hydrogen or a carbon-carbon bond, with the proviso that when Ry is hydrogen, Rx is alkoxy of one to about four carbon atoms, hydroxyalkoxy of one to about four carbon atoms, 1- alkynyl of two to about ten carbon atoms, tetrahydropyranyl, alkoxyalkyl, wherein the alkoxy portion contains from one to about four carbon atoms, and the alkyl portion contains from one to about four carbon atoms, 2-, 3-, or 4-pyridyl, and with the additional proviso that when R is a carbon-carbon bond, Ry and Rx together form a tetrahydrofloranyl group optionally substituted with one or more substituents independently selected from the group consisting of hydroxyl and hydroxyalkyl of from one to about four carbon atoms, R2ß is selected from the group consisting of hydrogen, straight or branched chain alkyl, containing from one to about eight carbon atoms, hydroxyalkyl straight or branched chain, containing one to about six carbon atoms, morpholinomethyl, benzyl (phenyl) ethyl and phenyl, the benzyl substituent (phenyl) ethyl or phenyl, is optionally substituted on the benzene ring by a portion selected from the group consisting of methyl, methoxy and halogen; and -C (Rs) (Rt) (X) wherein R = and Rt are independently selected from the group consisting of hydrogen, alkyl of one to about four carbon atoms, phenyl and substituted phenyl, wherein the substituent is selected from the group consisting of a group consisting of alkyl of one to about four carbon atoms, alkoxy of one to about four carbon atoms and halogen; X is selected from the group consisting of alkoxy containing from one to about four carbon atoms, alkoxyalkyl wherein the alkoxy portion contains from one to about four carbon atoms and the alkyl portion contains from one to about four carbon atoms , haloalkyl of one to about four carbon atoms, alkylamido wherein the alkyl group contains one to about four carbon atoms, amino, substituted amino, wherein the substituent is alkyl or hydroxyalkyl of one to about four carbon atoms, azido , alkylthio from one to about four carbon atoms and morpholinoalkyl wherein the alkyl portion contains from one to about four carbon atoms, and Re is selected from the group consisting of hydrogen, fluoro, chloro, straight or branched chain alkyl, containing one to about four carbon atoms and straight or branched chain fluoro- or chloroalkyl containing from one to about four carbon atoms and at least one fluorine or chlorine atom; and pharmaceutically acceptable salts thereof.

The preferred imidazopyridine amine IRM compounds are defined by formula VII below: VI I where: Rn is selected from the group consisting of hydrogen; -CH-R? wherein Rw is selected from the group consisting of straight or branched chain, or cyclic alkyl containing from one to about ten carbon atoms, straight or branched chain alkenyl, containing from two to about ten carbon atoms, hydroxyalkyl straight or branched chain, containing from one to about six carbon atoms, alkoxyalkyl wherein the alkoxy portion contains from one to about four carbon atoms and the alkyl portion contains from one to about six carbon and phenylethyl atoms; and -CH = CRZR_. wherein each R- is independently straight or branched chain or cyclic alkyl of one to about six carbon atoms; R27 is selected from the group consisting of hydrogen, straight or branched chain alkyl, which contains from one to about eight carbon atoms, straight or branched chain hydroxyalkyl, containing from one to about six carbon atoms, alkoxyalkyl wherein the alkoxy portion contains from one to about four carbon atoms, and the alkyl moiety containing from one to about six carbon atoms, benzyl, (phenyl) ethyl and phenyl, the benzyl (phenyl) ethyl or phenyl substituent is optionally substituted on the benzene ring by a portion selected from the group consisting of methyl, methoxy and halogen; and morpholinoalkyl, wherein the alkyl portion contains from one to about four carbon atoms; R6 and R.7 are independently selected from the group consisting of hydrogen and alkyl of one to about five carbon atoms, with the proviso that R7 and 77 taken together contain no more than six carbon atoms and with the additional proviso that when R77 is hydrogen, then Re7 is different from hydrogen and R_- is different from hydrogen or morpholinoalkyl and with the condition further that when R67 is hydrogen then R71 and R27 are different from hydrogen; and pharmaceutically acceptable salts thereof.

The preferred IBM 1,4-dimidoquinoline amine compounds are defined by formula VIII below: VIII wherein: Z is selected from the group consisting of: - (CH2) P- where p is from 1 to 4; - (CHj), -C (BDRE) (CH2) b ~, where a and b are integers and a + b is from 0 to 3, RD is hydrogen or alkyl of one to four carbon atoms and BE is selected from the group that consists of alkyl of one to four carbon atoms, hydroxy, -ORF wherein RF is alkyl of one to four carbon atoms and -NRCR'G wherein R- and R'G are independently hydrogen or alkyl of one to four atoms of carbon; and - (CH2) "- (Y) - (CH2) b- where a and b are integers and a + b is from 0 to 3, and Y is 0, S, or -NR-- wherein R is hydrogen or alkyl from one to four carbon atoms; and wherein q is zero or 1 and Rβ is selected from the group consisting of alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms and halogen, and pharmaceutically acceptable salts thereof. The compounds mentioned above are described in the patents and applications indicated above in the background of the invention. The above Rn-Rp substituents are generally designated "substituents 1-" herein. The 1-preferred substituents are alkyl containing from one to six carbon atoms and hydroxyalkyl containing from one to six carbon atoms. More preferably, the substituent 1- is 2-methylpropyl or 2-hydroxy-methylpropyl. The above R-1-R-7 substituents are generally designated "substituents 2-" herein. Preferred 2 substituents are hydrogen, alkyl of one to six carbon atoms, alkoxyalkyl wherein the alkoxy portion contains one to four carbon atoms and the alkyl portion contains one to four carbon atoms and hydroxyalkyl of one to four carbon atoms. More preferably, the substituent 2- is hydrogen, methyl, butyl, hydroxymethyl, ethoxymethyl or methoxyethyl. In some instances where n may be zero, one or two, n is preferably zero or one.

The amounts of these MRI compounds that will be therapeutically effective in a specific situation "will of course depend on such factors as the activity of the particular compound, the mode of administration and the disease being treated." As such, it is not practical to identify administration amounts. specific herein, however, those skilled in the art will have the ability to determine the appropriate therapeutically effective amounts based on the guides provided herein, the information available in the art pertaining to these compounds, and routine tests.

Mechanisms of the immune system Recent evidence indicates that the immune system can be divided into two main branches, the humoral branch and the cell branch. The humoral branch is important to eliminate extracellular pathogens, such as bacteria and parasites by means of the production of antibodies by the cells B. On the other hand, the cell branch is important in the elimination of intracellular pathogens such as viruses by means of the activity of natural killer cells, cytotoxic T lymphocytes and activated macrophages. In recent years, it has become evident that these two branches are activated by different populations of T helper cells (TH) and their different profiles of atocin production.

It is believed that T helper type 1 (THL) cells improve the cellular branch of the immune response and produce predominantly the cytokines IL-2 and I-N-gamma; while it is believed that T-helper type 2 (TH2) cells improve the humoral branch of the immune response and produce cytokines, such as interleukin-3 (IL-3), interleukin-4 (IL-4), interleukin-5 ( IL-5) and granulocyte-acrophage colony stimulating factor (GM-CSF). In the case of TH2, it is believed that IL-3, IL-5 and GM-CSF stimulate eosinophilopoiesis. In addition, IL-5 facilitates cell differentiation and cell proliferation of eosinophils and promotes the survival, viability and migration of eosinophils, while IL-4 stimulates the production of antibodies of the IgE class. IgE is an important component in allergies and asthma. IL-5 can also prime eosinophils by the subsequent actions of other mediators. In contrast, TH1, IL-2 and I-TN-gamma cytokines are important in the activation of macrophages, NK cells and CTL (cytotoxic T lymphocytes). IFN-gamma also stimulates B cells to secrete specifically cytophilic antibodies for the elimination of virally infected cells Interestingly, IFN-alpha, a cytokine derived from macrophage, has been shown to antagonize TH2 responses. inhibit the proliferation and cytokine production of TM2 cells and improve IFN-gamma production by THL cells. In addition, IFN-alpha also appears to inhibit IgE production and antigen-induced increases in m-_RN levels of IL4.

Stimulation of TH1 against TH2 regulation It has been shown that the IRM compounds of the present invention, in a variety of models, increase the cell-mediated immunity, which is consistent with the stimulation of THL cells. Surprisingly, in models of eosinophilia (TH2 / humoral mediated immune process), these compounds actually inhibit eosinophilia. Further studies indicate that the manner in which these compounds obtain this is in part by their ability to inhibit the production of TH2 cells from the cytokine IL-5. The inhibition of IL-5 production by imidazoquinolines has been demonstrated in in vitro and in vivo models. For example, as shown in Table 1, an exemplary MRI compound, 4-amino-2-ethoxymethyl-alpha, alpha-dimethyl-lH-imidazo [4,5-c] quinolin-1-ethanol spectacularly inhibits the production of IL-5 in spleen cell cultures stimulated with antigen. Spleen cells from CFW mice sensitized by OVA (2 xlOViril) were cultured for 96 hours with OVA (100 micrograms / ml). Some cultures also received this MRI compound in a range of concentrations. The culture supernatants were collected and analyzed by ELISA (Endogenous) for IL-5. The results are presented as the mean of triplicate cultures +/- the standard deviation. The concentration of IL-5 is in picograms / ml.

Table 1 Inhibition of? L-5 production in the mouse spleen cell As can be seen from table 1, concentrations of the MRI compound, as low as 0.01 micrograms / ml, inhibit the production of IL-5 by more than 60%; while the higher concentrations inhibit the concentration of IL-5 by 100%. In vivo, the exemplary IBM compound 4-amino-2-ethoxymethyl-alpha, alpha-dimethyl-lH-imidazo [4,5-c] quinolin-1-ethanol is shown to inhibit IL-5 production induced by antigen in a dose-dependent manner, as shown in Table 2. Male CFW mice were sensitized with OVA as described above. Fourteen days after the last sensitization, the animals were validated with 100 micrograms of OVA s.c. Some animals received the free base of 4-amino-2-ethoxymethyl-alpha, alpha-dimethyl-1H-imidazo [4, 5 c] quinolin-1-ethanol, either at the time of validation of OVA or 24 hours before. The serum was collected 7 hours after the OVA and analyzed for the concentrations of IL-5 and IFN-gamma. The results are expressed as the average cytokine concentration +/- standard deviation.

Table 2 Effects of the IRM compounds on the production of II-5 e-FN-gap-ma It can thus be seen that 4-amino-2-ethoxymethyl-alpha, alpha-dimethyl-lH-imidazo- [4,5-c] quinolin-1-ethanol was active when administered either at the time of validation of the antigen or when it is provided one day before the antigen. Doses as low as Q.Ol mg / Kg inhibit the production of IL-5 by at least 65%. A common feature of many diseases mediated by TH2 is an accumulation of eosinophils, which is termed as eosinophilia. For example, chronic lung inflammation that involves the infiltration of eosinophils is a hallmark of bronchial asthma. Increased numbers of eosinophils in the blood, bronchoalveolar lavage fluid and pulmonary tissue have been observed in patients with asthma, but the mechanism (s) responsible for their recrudescence and regulation in the pulmonary tissues that suffer of allergic or pro-inflammatory reactions has not been fully understood. The mediators and cytokines of T lymphocytes and effector cells such as basophils, mast cells, macrophages and eosinophils, have been implicated in the improvement of cell maturation, chemotaxis and activation of eosinophils. Evidence suggests that there is an association between the immune system, especially CD4 * -T cells and eosinophils and recrudescence of eosinophils. Studies in patients with asthma and in animal models of allergic pulmonary responses support this theory with the evidence of close correlations between the relative numbers of T cells and eosinophils activated in the respiratory tract. The importance of T lymphocyte in the recrudescence of eosinophils is reinforced by studies with selective T-cell immunosuppressive agents such as cyclosporin A. FK506 and cyclophosphamide. It has been shown that these agents reduce eosinophilia. On the other hand, in general, immunostimulants have not been shown to clearly reduce eosinophilia. However, this may be a reflection of how these immunostimulants affect the immune system. The following three sets of studies clearly indicate that the IBM compounds of the present invention can be used to suppress eosinophilia. The first set of studies evaluates the IRM compound 4-amino-2-ethoxymethyl-alpha, alpha-dimethyl-lH-imidazo [4,5-c] quinolin-1-ethanol in terms of its ability to inhibit eosinophilia induced by antigens in the lung after aerosol validation with the antigen. The results in Table 3 show that 4-amino-2-ethoxymethyl-alpha, alpha-dimethyl-lH-imidazo [4, 5-c] quinolin-1-ethanol at 1 mg / Kg is capable of inhibiting induced eosinophilia by antigens in the lung of mice by 78% when provided 15 minutes before validation of the antigen. The concentrations of IL-4 were reduced in the BAL of these mice by 43% when compared to animals receiving the antigen alone.

Also, the IRM compound induces the inhibition of eosinophilia correlated with a significant inhibition in BAL concentrations of IL-5, which were reduced by 78%. CFW mice were sensitized on day 0 with 10 micrograms of ovalbumin (OVA) i.p., in 1% alum and then boosted 7 days later with the same regimen. Fourteen days after the reinforcement the animals are dosed by nebulization for 30 minutes, when using a 1% OVA solution. This is repeated on days 17 and 20. Twenty-four hours after the final nebulized dose the animals were sacrificed and a bronchoalveolar lavage (BAL) was performed using 1.0 ml of PBS containing 1% fetal bovine serum. The BAL was stored at -70 ° C before being analyzed. Then, the lungs were removed and placed in 0.5% cetrimide, 0.05 M KH2POs for homogenization of 4 x 30 seconds with cooling intervals of 30 seconds on ice. The centrifugation was then carried out at 1300 r.p.m. (400 X g) for 30 minutes at 4 ° C. The agglomerate was collected and resuspended in 4 ml of 0.5% cetrimide, buffer pH of KH_PO (0.05 M. The samples were then frozen until sonification and determination of EPO.) This was followed by sonification for 3 x 15 seconds. with intervals of 30 seconds on ice.

An analysis of EPO (eosinophil peroxidase, an "eosinophilic protein used as a marker of the presence of eosinophil), consisted in determining the levels of EPO in the lung tissue (or supernatant of BAl fluid) from each individual guinea pig sample. Fifty microliters of the "sample solution" consisting of 375 microliters of PBS (pH 7, RT) + 25 microliters of TRIs-HCL 0.05M containing 2% Triton (pH 8, RT) + 50 microliters of lung lobe Sonified was added to 860 microliters of TRIS-HCL 0.05M containing 0.1% Triton (pH 8, RT) in combination with 8.5 microliters of o-phenylenediamma dihydrochloride (OPD). To start the reaction, 1 microliter of 30% hydrogen peroxide was added to the cuvette. The optical density reading was measured spectrophotometrically during a time interval of 4 minutes at 490 nm in a Beckman Du-64 spectrophotometer. The BAL (bronchoalveolar lavage) was analyzed by ELISA (Endogenous) in terms of the concentrations of IL-5 and IL-4 with the data presented as the average of 11 animals +/- standard deviation. The results are presented as the mean of triplicate cultures +/- standard deviation. The concentration of IL-5 is in picograms / ml. Table 3 Inhibition of cosinophilia induced by antigen, IL-5 and H-4 Treatment Concentration of EPO Concentration of IL-5 Concentration of IL-4 in nulm n (ABS) in BAL- in physical BAL- pharm / ml) we were / ml) Control without 258 ± 28 0 8 ± G-3 30 ± 3 sensitize Sensitized by 600 * 87 (100) 59 ± 18 (100) 70 * 10 (100) Composite Antigen 1RM + 352 * 30 (78) * 13 ± 2 (78) * 53 ± 8 (42) Anti eno * = Significant difference of the ovalbumin control group at alpha = 0.05. The second set of studies evaluated the two IRM compounds 4-amino-alpha, alpha-2-trimethyl-1H-imidazo [4, 5-c] quinolin-1-ethanol (compound 1) and 4-amino-2-ethoxymethyl -alpha, alpha-dimethyl-lH-imidazo [4,5-c] uinolin-1-ethanol (compound 2) in terms of its ability to inhibit the eosinophilia induced by Sephadex in the validation of intravenous Sephadex of the lung. The results of Table 4 show that oral administration or intratracheal instillation of the MRI compound of Example 1 at a concentration greater than or equal to 0.7 mg / Kg and oral administration of the compound at a concentration greater than or equal to 0.01 / Kg are capable of inhibiting the eosinophilia induced by Sephadex in the lung of rats when given 60 minutes before validation. A maximum inhibition of 95% occurs with compound 1 and 87% "occurs with compound 2. Male Sprague Dawley rats, were injected on day 0 with Sephadex G-200 particles in a lateral vein of the tail (0.5 g On days 14-16, the rats were lightly anesthetized with halothane and subsequently dosed -either with medication or vehicle- (1.0 mg / kg orally) 24 hours and 1 hour before a second validation of Sepadhex in the day 14. A Sephadex-G-200 particle booster was administered intravenously into a lateral vein of the cola (0.5 mg / rat) to 1 hour post-edicamento (that is, immediately either of the medication or the vehicle) on day 14 only. The animals were sacrificed on day 17 to 72 hours post-dosing of Sephadex by a lethal injection of sodium pentobarbital (100-125 mg / kg, i.p.). The lungs were bled, washed and removed. Then, they were placed in 0.5% cetrimide, 0.05 M KH2P04 for homogenization of 4 x 30 seconds with cooling intervals of 30 seconds on ice. The centrifugation was then carried out at 1300 r.p.m. (400 X g) for 30 minutes at 4 ° C. The agglomerate was collected and resuspended in 4 ml of 0.5% cetrimide, buffer pH of KH_PO "0.05 M. Then the samples were frozen until sonification and determination of EPO. This was followed by sonification for 3 x 15 seconds with intervals of 30 seconds on ice. The study of EPO (eosinophil peroxidase, an eosinophilic protein used as a marker and the presence of eosinophil), consisted of determining the EPO levels in the lung tissue (or BAL fluid supernatant) of each individual rat sample. Fifty microliters of the "sample solution" consisting of 375 microliters of PBS (pH 7, RT) + 25 microliters of 0.05 M TRIS-HCL containing 2% "Triton (pH 8, RT) + 50 microliters of lobe Sonified lungs were added to 860 milliliters of TRIS-HCL 0.05 M containing 0.1% Triton (pH 8, RT), in combination with 8. 5 microliters of o-phenylenediamine dihydrochloride (OPD). To start the reaction, 1 microliter of 30% hydrogen peroxide was added to the cuvette. The optical density reading was measured spectrophotometrically during a time interval of 4 minutes at 490 nm in a Beckman Du-64 spectrophotometer.

Table 4 Inhibition of lung cosinophilia induced by Sephadex in rats * = Significant difference of the ovalbumin control group of alpha = 0.05.

The third set of studies evaluated 4-amino-alpha, alpha-2-trimethyl-1H-imidazo [4, 5-c] quinolin-1-ethanol (compound 1) and 4-amino-2-ethoxymethyl-alpha, alpha -dimethyl-1H-imidazo [4, 5-c] quinolin-1-ethanol (compound 2) in terms of its ability to inhibit ovalbumin-induced eosinophilia in the validation of antigen by aerosol of the lung. The results in table 5 show that the intraperitoneal administration or inhalation of aerosol of compound 1 at 0.05 mg / kg and the oral administration of compound 2 at 0.01 mg / kg are able to inhibit ovalbumin-induced eosinophilia in the guinea pig's lung. Indies when administered either 15 or 60 minutes before validation respectively. A maximum inhibition of 92% occurs with the IBM compound 1 and 96% occurs with the compound 2 of MRI. In the guinea pigs, these two imidazoquinoline compounds produce approximately equivalent effects on ovalbumin-induced eosinophilia of the lung. Male Hartley guinea pigs (approximately 250-500 g), sensitized to ovalbumin (50-mg / Kg, ip, greater than or equal to 14 days) were dosed with chlorpheniramine (5 mg / kg, ip) and the drug or vehicle intratracheally (or by another route) 15 minutes before validation. The animals were placed inside an inverted dryer container that was placed on a plexiglass platform. An aerosol is applied to the platform of H20 or ovalbumin (50 mg / ml) for 5 minutes via a DeVilbiss No. 40 nebulizer and to provide a constant flow of air to the chamber of a continuous source of air. The animals were sacrificed at 24 hours after validation by the lethal injection of sodium pentobarbital (100-125 mg / kg, i.p.). The lungs were bled, washed and removed. Then, they were placed in 0.5% cetpmida, 0.05 M KH2PO4 for homogenization of 4 x 30 seconds with cooling intervals of 30 seconds on ice. The centrifugation was performed at 1300 r.p.m. (400 X g) for 30 minutes at 4CC. The agglomerate was collected and resuspended in 4 ml of 0.5% citrate, buffer solution of pH of KH, PO "0.05 M. The samples were frozen until they were submitted to the study. This was followed by sonication for 3 ~ x 15 seconds with intervals of 30 seconds on ice. The study of EPO (eosinophil peroxidase, an eosinophilic protein, used as a marker for the presence of eosinophil) consisted in determining the EPO levels in the lung tissue (or BAL fluid supernatant) of each individual guinea pig sample. . Fifty microliters of the "sample solution" consisting of 375 microliters of PBS (pH 7, RT) + 25 microliters of 0.05 M TRIS-HCL containing 2% Triton (pH 8, RT) + 50 microliters of lung lobe sonicate were added to 860 microliters of 0.05 M TRIS-HCL containing 0.1% Triton (pH 8, RT) in combination with 8.5 microliters of o-phenylenediamine dihydrochloride (OPD). To start the reaction, 1 microliter of 30% hydrogen peroxide was added to the "cuvette." The optical density reading was measured spectrophotometrically during a time interval of 4 minutes at 490 nanometers in a Beckman Du-64 spectrophotometer.

Table 5 Inhibition of ovalbumin-induced lung eosinophilia in guinea pig * = Significant difference in the oval m na to alpha group = 0.05 The above studies indicate that the IBM compounds of the present invention can be used for the treatment of TH2-mediated diseases by inhibiting TH2 immune responses and suppressing the induction of IL-4 and IL-5 and eosinophilia. Examples of such diseases include asthma, allergy, atopic dermatitis, premature HIV disease, infectious mononucleosis and erythematosis of systemic lupus. There is also an association with an increased TH2 response in the Hodgkin's lymphoma and without Hodgkin's lymphoma, also as embryonal carcinoma. In addition, the capacity of the compounds of IBM of the present invention to inhibit the TH2 response and increase the TH1 response indicate that these compounds will be useful in the treatment of parasitic infections, for example, cutaneous and systemic leishmaniasis, toxoplasma infection and trypanosome infection, certain fungal infections, for example, candidiasis and histoplasmosis and intracellular bacterial infections, such as leprosy and tuberculosis. Studies in mice infected with major leishmania have shown that a TH1 response correlates with resistance, whereas a TH2 response correlates with susceptibility. Also, studies in mice have shown that parasites that live in macrophages, for example, greater leishmania, are killed when the host cells are activated by interferon-alpha, which is known as a product of the TH1 cell. In mice infected with candida and histoplasma, it is known that a THl response correlates with resistance, while a TH2 response correlates with susceptibility. Thus, from all of the foregoing, it is evident that the amines of limidazoquinoline, amines of midazopipdin, amines of cycloalkimidazopyridine 6, 7-fused and amines and imidazoquinolma 1,2-ponteadas of the present invention sor. useful for the treatment of diseases mediated by TH2 and other related diseases. Although the invention has been presented in terms of preferred embodiments and specific examples, there is no intent to limit the invention to such embodiments and examples. Additionally, it is proposed that the descriptions of all documents referenced in the foregoing description be expressly incorporated herein by reference.

Claims (20)

1. Claims 1. A method for the treatment of a disease mediated by non-viral and non-tumorous type 2 (TH2) helper cell, characterized in that it comprises the administration of an immune response modifying compound selected from the group consisting of imidazoquinoline amines , imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines and 1, 2-ponteated imidazoquinoline amines in an amount effective to inhibit the immune response mediated by the auxiliary T cell type 2 (TH2), with the proviso that the disease be different from eczema.
2. 2. The method of claim 1, characterized in that the disease is a parasitic infection.
3. 3. The method of claim 1, characterized in that the disease is a bacterial infection.
4. 4. The method of claim 1, characterized in that the disease is a fungal infection.
5. The method of claim 1, characterized in that the disease is selected from the group consisting of asthma, allergy, leprosy, systemic lupus erythematosis, Ommen syndrome, leishmaniasis, toxoplasma infection, trypanosome infection, candidiasis and histoplasmosis.
6. 6. The method of claim 1, characterized in that the disease is selected from the group consisting of asthma and allergic rhinitis.
7. 7. The method of claim 1, characterized in that the compound is administered via oral or nasal inhalation.
8. 8. The method of claim 1, characterized in that the compound is administered via a topical cream or gel.
9. 9. The method of claim 1, characterized in that the compound is selected from the group consisting of 4-amino-2-ethoxymethyl-alpha, alpha-dimethyl-1H-imidazo [4, 5-c] quinolin-1-ethanol and 1- (2-methylpropyl) -lH-imidazo [4, 5-c] quinolin-4-amine. The method of claim 1, characterized in that the immune response modifying compound is a compound of formula IX.
10. IX or a pharmaceutically acceptable salt thereof, wherein: R 9 is selected from the group consisting of alkyl containing from one to six carbon atoms and hydroxyalkyl containing from one to six carbon atoms; and R29 is selected from the group consisting of hydrogen, alkyl containing from one to six carbon atoms.
11. carbon, alkoxyalkyl, wherein the alkoxy portion contains from one to four carbon atoms and the alkyl portion contains from one to four carbon atoms and hydroxyalkyl containing from one to four carbon atoms. The method of claim 10, characterized in that R-, is 2-methylpropyl or 2-hydroxy-2-methylpropyl.
12. 12. A method according to claim 10, characterized in that R29 is selected from the group consisting of hydrogen, methyl, butyl, hydroxymethyl, ethoxymethyl and methoxymethyl.
13. 13. A method for inhibiting the induction of IL-4 and / or IL-5 cytokines, to treat a non-viral and non-tumorous disease, comprising the administration of an immune response modifying compound selected from the group consisting of amines of imidazoquinoline, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines and 1,2-imidazoquinoline amines in an effective amount to inhibit the IL-4 and / or IL-5 cytokines, with "the condition that the disease is different from eczema
14. 14. A method of treating eosinophilia, characterized in that it comprises the administration of an immune response modifying compound selected from the group consisting of imidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines and 1, 2-ponteated imidazoquinoline amines, in one

    effective amount to inhibit eosinophilia, with the condition that the disease is different from eczema.
15. 15. The method of claim 14, characterized in that the compound is administered orally or nasally inhaled.
16. 16. The method of claim 14, characterized in that the compound is administered via a topical cream or gel.
17. 17. The method of claim 14, characterized in that the compound is selected from the group consisting of 4-amino-2-ethoxymethyl-alpha, alpha-dimethyl-1H-imidazo [4,5-c] quinolin-1-ethanol and 1- (2-methylpropyl) -lH-imidazo [4, 5-c] quinolin-4-amine.
18. 18. The method of claim 14, characterized in that the immune response modifying compound is a compound of formula IX

    IX or a pharmaceutically acceptable salt thereof, wherein:

    Ri- is selected from the group consisting of alkyl containing from one to six carbon atoms and hydroxyalkyl containing from one to six carbon atoms; and R29 is selected from the group consisting of hydrogen, alkyl containing from one to six carbon atoms, alkoxyalkyl, wherein the alkoxy portion contains from one to four carbon atoms and the alkyl portion contains from one to four carbon atoms and hydroxyalkyl containing from one to four carbon atoms. The method of claim 18, characterized in that R19 is -methylpropyl or 2-hydroxy-2-methylpropyl. 20. A method according to claim 18, characterized in that R_3 is selected from the group consisting of hydrogen, methyl, butyl, hydroxy ethyl, ethoxymethyl and methoxymethyl.