Immune response modifier compounds for treatment of th2 mediated and related diseases

ES 2 290 969 T3

DESCRIPTION

Immune response modifying compounds for the treatment of TH2-mediated and related diseases.

The present invention relates to the use of imidazoquinolinamines, imidazopyridinamines, 6,7-fused cycloalkylimidazopyridinamines, and immunomodifying 1,2-linked imidazoquinolinamines for the preparation of a pharmaceutical composition for the treatment of a non-viral and non-tumor disease mediated by T helper cells. type 2 (TH2). It also refers to the use of these compounds for the preparation of a pharmaceutical composition for the treatment of a non-viral and non-tumor disease, by which the induction of interleukin (IL) -4 and IL-5 is inhibited, and to the use of these compounds for the preparation of a pharmaceutical composition for the treatment of eosinophilia.

Many compounds of imidazoquinolinamine, imidazopyridinamine, 6,7-fused cycloalkylimidazopyridinamine, and 1,2-linked imidazoquinolinamine have demonstrated potent immunostimulatory, antiviral, and antitumor (including anticancer) activity, and have also been shown to be useful as vaccine adjuvants to enhance a response. protective of the immune system against vaccines. These compounds are referred to, sometimes hereinafter, collectively as "MRI" (immune response modifier) ​​compounds useful in the invention. These compounds are described, for example, in US Patents 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, document WO 93/20847, and European patent application 90301766.3, in which its immunostimulating, antiviral and antitumor activities are analyzed in detail, and certain specific diseases are identified as susceptible to a treatment with these, including 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 MRI compounds, known as imiquimod, has been marketed in a topical formulation, Aldara ™, for the treatment of anogenital warts associated with the human papillomavirus.

The mechanism for the antiviral and antitumor activity of these MRI compounds is believed to be due, in substantial part, to the immune response due to the induction of various important cytokines (eg, interferons, interleukins, tumor necrosis factor, etc. ). These compounds have been shown to stimulate a rapid release of certain monocyte / macrophage derived cytokines, and that they are capable of stimulating B cells to secrete antibodies that play an important role in these antiviral and antitumor activities of MRI compounds. One of the predominant immunostimulatory responses of these compounds is the induction of interferon (IFN) -a production, which is believed to be very important in the observed acute antiviral and antitumor activities. In addition, the upregulation of other cytokines, such as, for example, tumor necrosis factor (TNF), IL-1, and IL-6, also have potentially beneficial activities and are believed to contribute to the antiviral and antitumor properties of these compounds. .

However, there are many diseases in which the immune system itself appears to actually play a significant role in mediating the disease (i.e. the action of the immune system is actually involved in the onset of the disease, or an inappropriate type of immune response prevents the correct response to eradicate the disease). Many of these diseases are believed to involve a pathological or inappropriate immune response by the humoral branch of the immune system, which is associated with TH2 cell activity (as opposed to TH1 cell-mediated immunity).

The humoral / TH2 arm of the immune system is generally aimed at protection against extracellular immunogens, such as bacteria and parasites, through the production of antibodies against B cells; while the cell branch / TH1 targets, in general, intracellular immunogens, such as viruses and cancers through the activity of natural killer cells, cytotoxic T lymphocytes and activated macrophages. TH2 cells are believed to produce the cytokines IL-3, IL-4, IL-5, and IL-10, which are believed to stimulate the production of IgE antibodies, as well as being involved in recruitment, proliferation, differentiation, maintenance and survival of eosinophils (ie, leukocytes that accept an eosin dye), which can cause eosinophilia. Eosinophilia is a key feature of many TH2-mediated diseases, such as asthma, allergy, and atopic dermatitis.

The interaction and importance of various aspects of the immune system response, including the interaction between TH1 and TH2 cell cytokines, is discussed in WO 97/2688. Although WO 97/2688 specifically addresses the effects of a particular antiviral compound known as Ribavirin^®, which is distinct from the MRI compounds useful in the present invention, nevertheless illustrates some of the complex and unpredictable effects of drug compounds on the immune system.

EP-A-0 193 329 describes certain pyrazolopyridines, their preparation, and pharmaceutical compositions containing them.

It has now been discovered that, in addition to their immunostimulating, antiviral / antitumor effect on the immune system, the MRI compounds useful in the present invention (imidazoquinolinamines, imidazopyridinamines, 6,7-fused cycloalkylimidazopyridinamines, and 1,2-linked imidazoquinolinamines) are also extremely useful in downregulating certain key aspects of the immune response. Specifically, the MRI compounds useful in the present invention have been found to inhibit the TH2 immune response (in addition to

ES 2 290 969 T3 enhance the immune response of TH1). This is extremely important for treating TH2-mediated diseases, in which an inappropriate TH2 response causes the disease or prevents eradication 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. Accordingly, in a first embodiment, the present invention relates to the use of an immune response modifying compound selected from imidazoquinolinamines, imidazopyridinamines, 6,7-fused cycloalkylimidazopyridinamines, and 1,2-linked imidazoquinolinamines for the preparation of a pharmaceutical composition. for the treatment of a non-viral and non-tumor disease mediated by TH2 cells, provided that said disease is other than eczema.

An apparently related effect of the MRI compounds useful in the present invention is to inhibit the induction of IL-4, IL-5, and perhaps other cytokines, which allows the treatment of diseases associated with these cytokines. Accordingly, in a second embodiment, the present invention relates to the use of an immune response modifying compound selected from imidazoquinolinamines, imidazopyridinamines, 6,7-fused cycloalkylimidazopyridinamines, and 1,2-linked imidazoquinolinamines for the preparation of a pharmaceutical composition. for the treatment of a non-viral and non-tumor disease, by which the induction of the cytokines IL-4 and / or IL-5 is inhibited, provided that said disease is different from eczema. Another important and surprising effect of the compounds useful in the present invention is the suppression of eosinophils, which allows the treatment of eosinophilia and related diseases. Accordingly, in a third embodiment, the present invention relates to the use of an immune response modifying compound selected from imidazoquinolinamines, imidazopyridinamines, 6,7-fused cycloalkylimidazopyridinamines, and 1,2-linked imidazoquinolinamines for the preparation of a pharmaceutical composition. for the treatment of eosinophilia, provided that the disease is other than eczema.

Some diseases are believed to be caused / mediated in substantial part by TH2 immune response, induction of IL-4 / IL-5 cytokines, and / or eosinophilia (and therefore respond to treatment by administering of a therapeutically effective amount of the MRI compounds) include asthma, allergic rhinitis, systemic lupus erythematosus, Ommen syndrome (hypereosinophilia syndrome), certain parasitic infections, for example, cutaneous and systemic leishmaniasis, toxoplasma infection and trypanosome infection, and certain fungal infections, eg, candidiasis and histoplasmosis, and certain intracellular bacterial infections, such as leprosy and tuberculosis. These are examples of TH2-mediated non-viral and non-tumor diseases for which effective treatment with the MRI compounds useful in the present invention clearly could not be predicted. Furthermore, it should be noted that diseases that have a virus or cancer-related basis, but with significant TH2-mediated pathology, can also be beneficially treated with the MRI compounds useful in the present invention. In particularly preferred uses of the present invention, the pharmaceutical compositions are for the treatment of diseases associated with eosinophilia, such as asthma and allergic rhinitis.

The MRI compounds useful in the present invention can be administered by any suitable means, eg, parenterally, transdermally, and orally. A preferred route of administration is a topical cream or gel formulation. For the treatment of asthma and allergic rhinitis, it is preferred to administer the MRI compound by oral and / or nasal inhalation from a metered dose inhaler.

Particularly preferred MRI compounds include 4-amino-2-ethoxymethyl-α, α-dimethyl-1H-imidazo [4,5-c] quinolin-1-ethanol and 1- (2-methylpropyl) -1H-imidazo [4, 5-c] quinolin-4-amine (known as Imiquimod).

Finally, it should be noted that the diseases identified as treatable in the published patents indicated above (US patents 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 90301766.3), in general, have a viral / tumor basis or, if not, they are believed to be not TH2-mediated diseases. An exception is eczema, which although it is a TH2-mediated disease, is believed to have been identified due to a susceptibility to interferon treatment (which was then believed to be the main cytokine response induced by the compounds useful in the present invention. ). However, at that time it was not recognized that any of the TH2, IL-4/5, or eosinophilia suppressive abilities of these MRI compounds could be used to treat eczema.

Preferred MRI compounds

As noted above, many of the MRI compounds of imidazoquinolinamine, imidazopyridinamine, 6,7-fused cycloalkylimidazopyridinamine, and 1,2-linked imidazoquinolinamine useful in the present invention have demonstrated significant immunomodulatory activity. Preferred immune response modifying compounds include the 1H-imidazo [4,5-c] quinolin-4-amines defined by one of the formulas IV below:

ES 2 290 969 T3

<img file="ES2290969T3_D0001.tif" />

in which

R₁₁ 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 moiety is alkanoyloxy of two to about four carbon atoms or benzoyloxy, and the alkyl moiety contains from one to about six carbon atoms, benzyl, (phenyl) ethyl and phenyl, said substituent being benzyl, (phenyl) ethyl or phenyl optionally substituted on the benzene ring with one or two moieties 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, provided that that if said benzene ring is substituted with two of said moieties, then said moieties together contain no 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 substituent being benzyl, (phenyl) ethyl, or phenyl optionally substituted on the benzene ring with one or two moieties 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, provided that if said benzene ring is substituted with two of said moieties, then said moieties together contain not more than six carbon atoms; and each R₁ 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, provided that si n is 2 , then said Ri groups together contain no more than six carbon atoms;

<img file="ES2290969T3_D0002.tif" />

in which

R₁₂ is selected from the group consisting of straight chain or branched chain alkenyl containing from two to about ten carbon atoms and substituted straight chain or branched chain alkenyl containing from two to about ten carbon atoms, wherein the substituent is selected from the group consisting of straight chain or branched chain alkyl containing one to about four carbon atoms and cycloalkyl containing three to about six carbon atoms; and cycloalkyl containing from three to about six carbon atoms substituted with straight chain or branched chain alkyl containing from one to about four carbon atoms; Y

R₂₂ is selected from the group consisting of hydrogen, straight chain or branched chain alkyl containing one to about eight carbon atoms, benzyl, (phenyl) ethyl and phenyl, the substituent being benzyl, (phenyl) ethyl or phenyl optionally substituted on the benzene ring with one or two moieties independently selected from the group consisting of straight chain or branched chain alkyl containing one to about four carbon atoms, straight-chain or branched-chain alkoxy containing from one to about four carbon atoms, and halogen, provided that when the benzene ring is substituted with two such moieties, then the moieties together contain no more than six carbon atoms carbon; Y

ES 2 290 969 T3 each R₂ is independently selected from the group consisting of straight chain or branched chain alkoxy containing one to about four carbon atoms, halogen, and straight chain or branched chain alkyl containing one to about four carbon atoms, and n is an integer from zero to 2, provided that if n is 2, then said R2 groups together contain no more than six carbon atoms;

<img file="ES2290969T3_D0003.tif" />

in which

R₂₃ is selected from the group consisting of hydrogen, straight chain or branched chain alkyl of one to about eight carbon atoms, benzyl, (phenyl) ethyl and phenyl, the substituent being benzyl, (phenyl) ethyl or phenyl optionally substituted on the benzene ring with one or two moieties 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, provided that when the benzene ring is substituted with two such moieties, then the moieties together contain not more than six carbon atoms; and each R₃ is independently selected from the group consisting of straight chain or branched chain alkoxy of one to about four carbon atoms, halogen, and straight chain or branched chain alkyl of one to about four carbon atoms, and n is an integer from zero to 2, provided that if n is 2, then said R3 groups together contain no more than six carbon atoms;

<img file="ES2290969T3_D0004.tif" />

in which

R_í4 is -CHR_xR_Y, in which R_Y is hydrogen or a carbon-carbon bond, provided that when R_Y is hydrogen, R_x 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 moiety contains one to about four atoms carbon and the alkyl moiety contains from one to about four carbon atoms, 2-, 3- or 4-pyridyl, and with the further proviso that when R_Y is a carbon-carbon bond, R_Y and R_x together they form a tetrahydrofuranyl group, optionally substituted with one or more substituents independently selected from the group consisting of hydroxy and hydroxyalkyl of one to about four carbon atoms;

R₂₄ 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 at about four carbon atoms, and halogen; Y

R₄ is selected from the group consisting of hydrogen, straight chain or branched chain alkoxy containing one to about four carbon atoms, halogen, and straight chain or branched chain alkyl containing one to about four carbon atoms;

ES 2 290 969 T3

<img file="ES2290969T3_D0005.tif" />

in which

Ru is selected from the group consisting of: hydrogen; straight chain or branched chain alkyl containing one to about ten carbon atoms, and substituted straight chain or branched chain alkyl 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 three to about six carbon atoms substituted with straight chain or branched chain alkyl containing one to about four carbon atoms; straight chain or branched chain alkenyl containing from two to about ten carbon atoms, and substituted straight chain or branched chain alkenyl containing from two 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 three to about six carbon atoms substituted with straight chain or branched chain alkyl containing one to about four carbon atoms; hydroxyalkyl of one to about six carbon atoms; alkoxyalkyl, wherein the alkoxy moiety contains one to about four carbon atoms and the alkyl moiety contains one to about six carbon atoms; acyloxyalkyl, wherein the acyloxy moiety is alkanoyloxy of two to about four carbon atoms or benzoyloxy, and the alkyl moiety contains one to about six carbon atoms; benzyl; (phenyl) ethyl; and phenyl; said substituent being benzyl, (phenyl) ethyl or phenyl optionally substituted on the benzene ring with one or two moieties 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, provided that when said benzene ring is substituted with two such moieties, then the moieties together contain no more than six carbon atoms;

R25 is

<img file="ES2290969T3_D0006.tif" />

in which

R_S and R_T 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 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 one to about four carbon atoms, alkoxyalkyl, wherein the alkoxy moiety contains one to about four carbon atoms and the alkyl moiety contains 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-pyrrolidino , alkylthio of one to about four carbon atoms; Y

R₅ is selected from the group consisting of hydrogen, straight chain or branched chain alkoxy containing one to about four carbon atoms, halogen, and straight chain or branched chain alkyl containing one to about four carbon atoms;

or a pharmaceutically acceptable salt of any of the above compounds.

ES 2 290 969 T3

Preferred 6,7-fused cycloalkylimidazopyridinamine MRI compounds are defined by formula VI below:

<img file="ES2290969T3_D0007.tif" />

where m is 1, 2, or 3;

R₁₆ is selected from the group consisting of hydrogen; cycloalkyl of three, four or five carbon atoms; straight chain or branched chain alkyl containing one to about ten carbon atoms, and substituted straight chain or branched chain alkyl 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 three to about six carbon atoms substituted with straight chain or branched chain alkyl containing 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 chain or branched chain alkenyl containing from two to about ten carbon atoms, and substituted straight chain or branched chain alkenyl containing from two 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 three to about six carbon atoms substituted with straight chain or branched chain alkyl containing one to about four carbon atoms; hydroxyalkyl of one to about six carbon atoms; alkoxyalkyl, wherein the alkoxy moiety contains one to about four carbon atoms and the alkyl moiety contains one to about six carbon atoms; acyloxyalkyl, wherein the acyloxy moiety is alkanoyloxy of two to about four carbon atoms or benzoyloxy, and the alkyl moiety contains one to about six carbon atoms, provided that none of such alkyl, substituted alkyl, alkenyl groups , substituted alkenyl, hydroxyalkyl, alkoxyalkyl, or acyloxyalkyl has a fully substituted carbon atom directly attached to the nitrogen atom; benzyl; (phenyl) ethyl; and phenyl; said substituent being benzyl, (phenyl) ethyl or phenyl optionally substituted on the benzene ring with one or two moieties 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, provided that when said benzene ring is substituted with two such moieties, then the moieties together contain no more than six carbon atoms;

and -CHR_xR_Yin which

R_Y is hydrogen or a carbon-carbon bond, provided that when R_Y is hydrogen, R_x 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 moiety contains one to about four atoms carbon and the alkyl moiety contains from one to about four carbon atoms, 2-, 3- or 4-pyridyl, and with the further proviso that when Ry is a carbon-carbon bond, R_Y and R_x together they form a tetrahydrofuranyl group, optionally substituted with one or more substituents independently selected from the group consisting of hydroxy and hydroxyalkyl of one to about four carbon atoms;

R₂6 is selected from the group consisting of hydrogen, straight chain or branched chain alkyl containing one to about eight carbon atoms, straight chain or branched chain hydroxyalkyl containing one to about six carbon atoms, morpholinmethyl, benzyl , (phenyl) ethyl and phenyl, the substituent being benzyl, (phenyl) ethyl or phenyl optionally substituted on the benzene ring with a moiety selected from the group consisting of methyl, methoxy, and halogen; Y

-C (R_S) (R_T) (X), in which R_S and R_T 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 alkyl of one to about four carbon atoms, alkoxy of one to about four carbon atoms, and halogen;

ES 2 290 969 T3

X is selected from the group consisting of alkoxy containing one to about four carbon atoms, alkoxyalkyl, wherein the alkoxy moiety contains one to about four carbon atoms and the alkyl moiety contains 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 of one to about four carbon atoms, and morpholinoalkyl, wherein the alkyl moiety contains one to about four carbon atoms; Y

R₆ is selected from the group consisting of hydrogen, fluoro, chloro, straight-chain or branched-chain alkyl containing from one to about four carbon atoms, and straight-chain or branched-chain fluoro- or chloroalkyl containing from one to about four carbon atoms and at least one fluorine or chlorine atom;

and their pharmaceutically acceptable salts.

Preferred imidazopyridinamine MRI compounds are defined by formula VII below:

<img file="ES2290969T3_D0008.tif" />

in which

R₁₇ is selected from the group consisting of hydrogen; -CH₂R_W, in which R_W is selected from the group consisting of straight chain, branched chain or cyclic alkyl containing one to about ten carbon atoms, straight chain or branched chain alkenyl containing two to about ten carbon atoms, hydroxyalkyl chain straight or branched chain containing from one to about six carbon atoms, alkoxyalkyl, wherein the alkoxy moiety contains one to about four carbon atoms and the alkyl moiety contains one to about six carbon atoms, and phenylethyl; and -CH = CR_ZR_Z, in which each R_Z is independently straight chain, branched chain or cyclic alkyl of one to about six carbon atoms;

R₂₇ is selected from the group consisting of hydrogen, straight chain or branched chain alkyl containing one to about eight carbon atoms, straight chain or branched chain hydroxyalkyl containing one to about six carbon atoms, alkoxyalkyl, in where the alkoxy moiety contains one to about four carbon atoms and the alkyl moiety contains one to about six carbon atoms, benzyl, (phenyl) ethyl, and phenyl, the substituent being benzyl, (phenyl) ethyl or phenyl optionally substituted on the benzene ring with a moiety selected from the group consisting of methyl, methoxy, and halogen; and morpholinoalkyl, where the alkyl moiety contains from one to about four carbon atoms;

R₆₇ and R₇₇ are independently selected from the group consisting of hydrogen and alkyl of one to about five carbon atoms, provided that R₆₇ and R₇₇ taken together they contain no more than six carbon atoms, and with the additional condition that when R₇₇ is hydrogen, so R₆₇ is different from hydrogen and R₂₇ is other than hydrogen or morpholinoalkyl, and with the additional proviso that when R₆₇ is hydrogen, so R77 and R27 are other than hydrogen;

and their pharmaceutically acceptable salts.

Preferred 1,2-linked imidazopyridinamine MRI compounds are defined by formula VIII below:

ES 2 290 969 T3

<img file="ES2290969T3_D0009.tif" />

in which

Z is selected from the group consisting of:

- (CH₂)_p- where p is from 1 to 4;

- (CH₂)_to-C (R_DR_AND) (CH₂)_b-, where a and b are integers and a + b is from 0 to 3, R_D is hydrogen or alkyl of one to four carbon atoms, and R_AND is selected from the group consisting of alkyl of one to four carbon atoms, hydroxy, -OR_F in which R_F is alkyl of one to four carbon atoms, and -NR_GR '_G, in which R_G and R '_G they are independently hydrogen or alkyl of one to four carbon atoms; Y

- (CH₂)_to- (Y) - (CH₂)_b- where a and b are integers and a + b is 0 to 3, and Y is O, S, or -NRj-, where Rj is hydrogen or alkyl of one to four carbon atoms;

and where q is 0 or 1 and R₈ is selected from the group consisting of alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and halogen; and their pharmaceutically acceptable salts.

The compounds mentioned above are described in the patents and applications listed above.

The R substituents_G - R_n The foregoing are generally referred to herein as "1-substituents." Preferred 1-substituents include alkyl containing one to six carbon atoms and hydroxyalkyl containing one to six carbon atoms. More preferably, the 1-substituent is 2-methylpropyl or 2-hydroxy-2-methylpropyl.

The R substituents_2! - R₂₇ The foregoing are generally referred to herein as "2-substituents." Preferred 2-substituents include hydrogen, alkyl of one to six carbon atoms, alkoxyalkyl, where the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms, and hydroxyalkyl of one to four carbon atoms. More preferably, the 2-substituent is hydrogen, methyl, butyl, hydroxymethyl, ethoxymethyl, or methoxyethyl.

In cases where n can 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 considerations such as the activity of the particular compound, the route of administration, and the disease being treated. Therefore, it is not practical to identify specific administration amounts here; however, those skilled in the art will be able to determine appropriate therapeutically effective amounts based on the guidance provided herein, the information available in the art on these compounds, and routine assays.

Mechanisms of the immune system

Recent evidence indicates that the immune system can be divided into two main branches, the humoral branch and the cellular branch. The humoral branch is important for eliminating extracellular pathogens, such as bacteria and parasites, through the production of antibodies by B cells. On the other hand, the cell branch is important in the elimination of intracellular pathogens, such as viruses, through the activity of natural killer cells, cytotoxic T lymphocytes, and activated macrophages. In recent years it has become apparent that these two branches are activated through differentiated populations of T helper (TH) cells and their differentiated cytokine production profiles. T helper type 1 (TH1) cells are believed to enhance the cellular branch of the immune response and predominantly produce the cytokines IL-2 and IFN-γ; while T helper type 2 (TH2) cells are believed to enhance the humoral branch of the immune response and produce cytokines, such as interleukin-3 (IL3), interleukin-4 (IL-4), interleukin-5 (IL -5) and granulocyte-macrophage colony stimulating factor (GMCSF). In the case of TH2, IL-3, IL-5, and GM-CSF are believed to stimulate eosinophylopoiesis. In addition, IL-5 facilitates terminal differentiation and cell proliferation of eosinophils, and stimulates the survival, viability and migration of

ES 2 290 969 T3 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 for the subsequent actions of other mediators.

In contrast, the cytokines of TH1, IL-2 and IFN-γ are important for activating macrophages, NK cells (natural killers) and CTL (cytotoxic T lymphocytes). IFN-γ also stimulates B cells to secrete specifically cytophilic antibodies for the elimination of virus-infected cells. Interestingly, IFN-α, a macrophage-derived cytokine, has been shown to antagonize TH2-like responses. IFN-α also appears to inhibit TH2 cell proliferation and cytokine production, and enhances IFN-γ production by TH1 cells. Furthermore, IFN-α also appears to inhibit IgE production and the antigen-induced increase in IL-4 mRNA levels.

TH1 stimulation versus TH2 downregulation

The MRI compounds useful in the present invention have been shown, in a number of models, to enhance cell-mediated immunity, which is consistent with TH1 cell stimulation. Surprisingly, in models of eosinophilia (a process mediated by humoral immunity / TH2), these compounds actually inhibit eosinophilia. Other studies indicate that the way these compounds achieve this is, in part, due to their ability to inhibit the production by TH2 cells of the cytokine IL-5. The inventors have demonstrated, in in vitro and in vivo models, the inhibition of IL-5 production by imidazoquinolines. For example, as shown in Table 1, an example of an MRI compound, 4-amino-2-ethoxymethyl-a, α-dimethyl-1H-imidazo [4,5-c] quinoline-1-ethanol, markedly inhibits IL-5 production in antigen-stimulated spleen cell cultures. Spleen cells from OVA sensitized CFW mice (2 x 10⁶/ ml) were cultured for 96 hr with OVA (100 jug / ml). Some cultures also received this compound MRI in a range of concentrations. Culture supernatants were collected and analyzed by ELISA (Endogen) for IL-5. Results are presented as the mean of triplicate cultures ± SEM. The IL-5 concentration is reported in pg / ml.

TABLE 1

<td colspan="3">Inhibition of IL-5 production by mouse spleen cells</td>

<td>Treatment</td><td>Concentration of composite MRI</td><td>IL-5 concentration (pg / ml)</td>

<td>only OVA</td><td></td><td> 240±20</td>

<td>OVA + compound MRI</td><td>10 pg / ml</td><td> 12±2</td>

<td>OVA + compound MRI</td><td>1 pg / ml</td><td> 22±3</td>

<td>OVA + compound MRI</td><td>0.1 pg / ml</td><td> 25±8</td>

<td>OVA + compound MRI</td><td>0.01 pg / ml</td><td> 125±46</td>

<td>half</td><td></td><td> 57±27</td>

As can be seen in Table 1, MRI compound concentrations as low as 0.01ng / ml inhibit IL-5 production by more than 60%; while higher concentrations inhibit IL-5 production by 100%.

In vivo, the MRI compound example 4-amino-2-ethoxymethyl-α, α-dimethyl-1H-imidazo [4,5-c] quinolin-1-ethanol was shown to inhibit IL-5 production induced by antigen in a dose-dependent manner, as shown in Table 2. Male CFW mice were primed with OVA as described above. Fourteen days after the last challenge, the animals were challenged with 100 pg of OVA subcutaneously. Some animals received the free base of 4-amino-2-ethoxymethyl-a, a-dimethyl-1H-imidazo [4,5-c] quinolin-1-ethanol orally, at the same time as the challenge with OVA or 24 hr before. Serum was collected 7 hr after OVA and analyzed for IL-5 and IFN-γ concentrations. Results are expressed as mean cytokine concentration ± SEM.

ES 2 290 969 T3

TABLE 2

<td colspan="3">Effects of MRI compounds on IL-5 and IFN-γ production</td>

<td>MRI compound dose (mg / kg)</td><td>Concentration of ΕΕΓ</td><td>cytokines (pg / mL) ± l / l</td>

<td></td><td>-24 hr IL-5 (pg / mL)</td><td>0 hr IL-5 (pg / mL)</td>

<td> 0,01</td><td> 78</td><td> 96</td>

<td> 0,1</td><td> 49</td><td> 62</td>

<td> 1,0</td><td> 38</td><td> 40</td>

<td> 10,0</td><td> 8</td><td> 29</td>

<td>Sen control.</td><td> 213</td><td> 270</td>

<td>Normal control</td><td> 1</td><td> 1</td>

Thus, it can be noted that 4-amino-2-ethoxymethyl-α, α-dimethyl-1H-imidazo [4,5-c] quinolin-1-ethanol is active when administered at the same time as antigen challenge, or when it is administered one day before the antigen. Doses as low as 0.01 mg / kg inhibit IL-5 production by at least 65%.

Another common feature of many TH2-mediated diseases is an accumulation of eosinophils, called eosinophilia. For example, chronic lung inflammation involving eosinophil infiltration is a key feature of bronchial asthma. A higher number of eosinophils have been observed in the blood, bronchoalveolar lavage fluid and lung tissue in patients with asthma, but the mechanism (s) responsible for their recruitment into lung tissues, and their regulation in them, suffering from allergic or pro-inflammatory reactions is not fully understood. T lymphocyte and effector cell mediators and cytokines, such as basophils, mast cells, macrophages, and eosinophils, have been implicated in enhancing 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 eosinophil recruitment. Studies in asthmatics and animal models of allergic lung responses support this idea with evidence of close correlations between the relative numbers of activated T cells and eosinophils in the airways. The importance of T lymphocytes in eosinophil recruitment is reinforced by studies with T cell selective immunosuppressive agents such as cyclosporin A, FK506, and cyclophosphamide. These agents have been shown to reduce eosinophilia. On the other hand, immunostimulants have not, in general, been shown to clearly reduce eosinophilia. However, this may be a reflection of how these immunostimulants are affecting the immune system.

The following three sets of studies clearly indicate that the MRI compounds useful in the present invention can be used to suppress eosinophilia.

The first set of studies evaluates the MRI compound 4-amino-2-ethoxymethyl-a, a-dimethyl-1H-imidazo [4,5-c] quinolin-1-ethanol to determine its ability to inhibit antigen-induced eosinophilia in the lung after an aerosol exposure with the antigen. The results in Table 3 demonstrate that 4-amino-2-ethoxymethyl-a, adimethyl-1H-imidazo [4,5-c] quinolin-1-ethanol at 1 mg / kg is capable of inhibiting antigen-induced eosinophilia in the lung of mice in 78% when administered 15 minutes before antigen challenge. IL-4 concentrations in the BAL of these mice were reduced by 43% when compared to animals receiving only antigen. Furthermore, the MRI compound induces an inhibition of eosinophilia that correlates with a significant inhibition in IL-5 concentrations in BAL, which were reduced by 78%. CFW mice were primed on day 0 with 10 µg ovalbumin (OVA) intraperitoneally in 1% alum, and then booster immunization was performed 7 days later with the same regimen. Fourteen days after the boost, the animals were dosed by nebulization for 30 minutes using a 1% OVA solution. This was repeated on days 17 and 20. Twenty-four hours after the final nebulized dose, the animals were sacrificed and bronchoalveolar lavage (BAL) was performed using 1.0 ml of PBS containing 1% fetal calf serum. The LBA was stored at -70 ° C before being analyzed. The lungs were then removed and placed in 0.5% cetrimide, 0.05 M KH2PO4 for homogenization for 4 x 30 seconds with 30 second cooling intervals on ice. Centrifugation was then performed at 1300 rpm (400 xg) for 30 minutes at 4 ° C. The pellet was collected and resuspended in 4 ml of 0.5% cetrimide buffer, 0.05 M KH2PO4. Samples were then frozen until sonication and EPO evaluation. This was followed by sonication for 3x15 seconds with 30 second intervals on ice.

ES 2 290 969 T3

An EPO (eosinophil peroxidase, an eosinophil protein used as a marker for the presence of eosinophils) assay involves determining the levels of EPO in lung tissue (or the supernatant of the BAL fluid) from each individual guinea pig sample. 50 ul of the "sample solution" consisting of 375 ul of PBS (pH 7, RT) + 25 ul of 0.05 M TRIS-HCl containing 2% Triton (pH 8, RT) + 50 ul were added. lung lobe sonicated, at 860 ul of 0.05 M TRIS-HCl containing 0.1% Triton (pH 8, RT) in combination with 8.5 ul mM of 0-phenylenediamine dihydrochloride (OPD). To start the reaction, 1 ul of 30% hydrogen peroxide was added to the cuvette. The optical density reading was measured spectrophotometrically over a 4 minute time interval at 490 nm on a Beckman Du-64 spectrophotometer.

The BAL was analyzed by ELISA (Endogen) to determine the concentrations of IL-5 and IL-4, presenting the data as the mean of 11 animals ± SEM. Results are presented as the mean of triplicate cultures ± SEM. The IL-5 concentration is presented in pg / ml.

TABLE 3

<td colspan="4">Inhibition of antigen-induced pulmonary eosinophilia, IL-5 and IL-4</td>

<td>Treatment</td><td>Concentration of</td><td>Concentration of</td><td>Concentration of</td>

<td rowspan="2"></td><td>EPO in lung</td><td>IL-5 in BAL (pq / ml)</td><td>iL-4 in BAL (pq / ml)</td>

<td>(ABS)</td><td></td><td></td>

<td>Control no sensitized</td><td> 258±28</td><td> 0,8±0,3</td><td> 30±3</td>

<td>Sensitized with antigen</td><td> 600±87 (100)</td><td> 59±18 (100)</td><td> 70±10(100)</td>

<td>Composite MRI + antigen</td><td> 352±30 (78)*</td><td> 13±2 (78)*</td><td> 53+8 (42)</td>

<td colspan="4">* = significant difference compared to the control group with ovalbumin aa = 0.05</td>

The second set of studies evaluates the two MRI compounds 4-amino-a, a, -2-trimethyl-1H-imidazo [4,5-c] quinolin-1-ethanol (Comp.1) and 4-amino-2- ethoxymethyl-α, α-dimethyl-1H-imidazo [4,5-c] quinolin-1-ethanol (Compound 2) to determine its ability to inhibit Sephadex-induced eosinophilia on pulmonary intravenous challenge with Sephadex. The results in Table 4 demonstrate that oral administration or intratracheal instillation of MRI Comp. 1 of the example at&gt; 0.7 mg / kg and oral administration of Comp. 2 as&gt; 0.01 mg / kg is capable of inhibiting Sephadex-induced eosinophilia in rat lung when administered 60 minutes prior to challenge. A maximum of 95% inhibition occurred with Comp. 1, and 87% with Comp. 2.

Male Sprague Dawley rats were injected on day 0 with Sephadex G-200 particles in the lateral tail vein (0.5 mg / rat). On days 14-16, the rats were lightly anesthetized with halothane and subsequently dosed with the drug or a vehicle (1.0 mg / kg, orally) 24 hours and 1 hour before a second exposure to Sephadex in the day 14. A Sephadex G-200 particle booster immunization was administered intravenously into the lateral tail vein (0.5 mg / rat) 1 hour after drug (i.e., after drug or vehicle) only on day 14. Animals were sacrificed on day 17 at 72 hours after Sephadex dosing by lethal injection of pentobarbital sodium (100-125 mg / kg, intraperitoneally). The lungs were exsanguinated, washed, and removed. They were then placed in 0.5% cetrimide, 0.05 M KH2PO4 for homogenization for 4x30 seconds with 30 second cooling intervals on ice. Centrifugation was then performed at 1300 rpm (400 xg) for 30 minutes at 4 ° C. The pellet was collected and resuspended in 4 ml of 0.5% cetrimide buffer, 0.05 M KH2PO4. Samples were then frozen until sonication and EPO evaluation. This was followed by sonication for 3x15 seconds with 30 second intervals on ice.

An EPO assay (eosinophil peroxidase, an eosinophil protein used as a marker for the presence of eosinophils) consists of determining the levels of EPO in lung tissue (or the supernatant of BAL fluid) from each individual rat sample. 50 ul of the "sample solution" consisting of 375 ul of PBS (pH 7, RT) + 25 ul of 0.05 M TRIS-HCl containing 2% Triton (pH 8, RT) + 50 ul were added of sonicated lung lobe, at 860 ul of 0.05 M TRIS-HCl containing 0.1% Triton (pH 8, RT) in combination with 8.5 ul mM of

ES 2 290 969 T3 0-phenylenediamine dihydrochloride (OPD). To start the reaction, 1 ul of 30% hydrogen peroxide was added to the cuvette. The optical density reading was measured spectrophotometrically over a 4 minute time interval at 490 nm on a Beckman Du-64 spectrophotometer.

TABLE 4

Inhibition of Sephadex-induced pulmonary eosinophilia in rats

<td>Treatment</td><td>Drug</td><td>EPO concentration</td><td rowspan="2">% inhibition</td>

<td></td><td>mq / k</td><td>in the Dulmon^{b, c} (γ + ES)</td>

<td>Group 1:</td><td></td><td></td><td></td>

<td>Comp. 1 intratrachea instillation</td><td></td><td></td><td></td>

<td>Control without Sephadex</td><td> 0,0</td><td> 0,0923 ±0,017</td><td></td>

<td>Exposed to Sephadex</td><td> 0,0</td><td> 0,5456 ± 0,085</td><td></td>

<td>Drug + exposed to Sephadex</td><td> 0,03</td><td> 0,7107 ±0,129</td><td> 0%</td>

<td></td><td> 0,1</td><td> 0,5030 ± 0,089</td><td> 9%</td>

<td></td><td>0.3 i</td><td> 0,3440 ± 0,201</td><td> 44%</td>

<td></td><td> 0,7</td><td> 0,1967 + 0,080*</td><td> 77%</td>

<td>Group 2:</td><td></td><td></td><td></td>

<td>Comp. 1 oral administration</td><td></td><td></td><td></td>

<td>Control without Sephadex</td><td> 0,0</td><td> 0,0390 ± 0,008</td><td></td>

<td>Exposed to Sephadex</td><td> 0,0</td><td> 0,3453 ±0,100</td><td></td>

<td>Drug + exposed to Sephadex</td><td> 0,1</td><td> 0,4240 ±0,138</td><td> 0%</td>

<td></td><td> 0,7</td><td> 0,1497 ±0,030*</td><td> 64%</td>

<td></td><td> 1,0</td><td> 0,0780 ± 0,039*</td><td> 87%</td>

<td></td><td> 5,0</td><td> 0,0790 + 0,030*</td><td> 87%</td>

<td></td><td> 30,0</td><td> 0,0550 + 0,013*</td><td> 95%</td>

<td>Group 3:</td><td></td><td></td><td></td>

<td>i '' ' Comp. 2 oral administration</td><td></td><td></td><td></td>

<td>i ) Control without Sephadex</td><td> 0,0</td><td> 0,1072 ±0,020</td><td></td>

<td>I Exposed to Sephadex</td><td> 0,0</td><td> 0,6738 ±0,100</td><td></td>

<td>! Drug + exposed to Sephadex</td><td> 0,001</td><td> 0,6775 ±0,140</td><td> 0%</td>

<td></td><td> 0,01</td><td> 0,4908 ± 0,070*</td><td> 32%</td>

ES 2 290 969 T3

<td colspan="4">Inhibition of Sephadex-induced pulmonary eosinophilia in rats</td>

<td>Treatment</td><td>Drug</td><td>EPO concentration</td><td rowspan="2">% inhibition</td>

<td></td><td>mq / k</td><td>in the lung *⁵’⁰ (and ± ES)</td>

<td>Group 3:</td><td></td><td></td><td></td>

<td>Comp. 2 oral administration</td><td></td><td></td><td></td>

<td></td><td> 0,1 :</td><td> 0,2000 ± 0,060*</td><td> 84%</td>

<td></td><td> 1,0</td><td> 0, 1824 + 0,060*</td><td> 87%</td>

<td colspan="4">* = significant difference compared to the control group with ovalbumin aa = 0.05</td>

The third set of studies evaluates 4-amino-a, a, -2-trimethyl-1H-imidazo [4,5-c] quinolin-1-ethanol (Comp.1) and 4-amino-2-ethoxymethyl- a, α-dimethyl-1H-imidazo [4,5-c] quinolin-1-ethanol (Compound 2) to determine its ability to inhibit ovalbumin-induced eosinophilia on aerosolized lung antigen exposure. The results in Table 5 demonstrate that intraperitoneal administration or aerosol inhalation of Comp. 1 to 0.01 mg / kg and oral administration of Comp. 2 at 0.01 mg / kg is capable of inhibiting ovalbumin-induced eosinophilia in guinea pig lung when administered 15 or 60 minutes before challenge, respectively. A maximum of 92% inhibition occurred with the MRI Comp. 1, and 96% with the MRI Comp. 2. In guinea pigs, these two imidazoquinoline compounds produce approximately equivalent effects in ovalbumin-induced pulmonary eosinophilia.

Male Hartley guinea pigs (approximately 250-500 g), sensitized to ovalbumin (50 mg / kg, intraperitoneally, equal to or more than 14 days) were dosed with chlorpheniramine (5 mg / kg, intraperitoneally) and drug or vehicle intratracheally (or by other route) 15 minutes before exposure. The animals were placed inside an inverted blotter jar that was placed on a Plexiglas platform. The platform allows the aerosolization of H₂O or ovalbumin (50 mg / ml) for 5 minutes through a DeVilbiss # 40 nebulizer, and provides a constant flow of air into the chamber from a continuous air source. Animals were sacrificed 24 hours after challenge by lethal injection of pentobarbital sodium (100-125 mg / kg, intraperitoneally). The lungs were exsanguinated, washed, and removed. They were then placed in 0.5% cetrimide, 0.05 M KH2PO4 for homogenization for 4 x 30 seconds with 30 second cooling intervals on ice. Centrifugation was then performed at 1300 rpm (400 xg) for 30 minutes at 4 ° C. The pellet was collected and resuspended in 4 ml of 0.5% cetrimide buffer, 0.05 M KH2PO4. Samples were frozen until assayed. This was followed by sonication for 3x15 seconds with 30 second intervals on ice.

An EPO (eosinophil peroxidase, an eosinophil protein used as a marker for the presence of eosinophils) assay involves determining the levels of EPO in lung tissue (or the supernatant of the BAL fluid) from each individual guinea pig sample. 50 ul of the "sample solution" consisting of 375 ul of PBS (pH 7, RT) + 25 ul of 0.05 M TRIS-HCl containing 2% Triton (pH 8, RT) + 50 ul were added. lung lobe sonicated, at 860 ul of 0.05 M TRIS-HCl containing 0.1% Triton (pH 8, RT) in combination with 8.5 ul mM of 0-phenylenediamine dihydrochloride (OPD). To start the reaction, 1 ul of 30% hydrogen peroxide was added to the cuvette. The optical density reading was measured spectrophotometrically over a 4 minute time interval at 490 nm on a Beckman Du-64 spectrophotometer.

ES 2 290 969 T3

TABLE 5

<td rowspan="2"> 5</td><td colspan="4">Inhibition of ovalbumin-induced pulmonary eosinophilia in guinea pigs</td>

<td>Treatment</td><td>Drug</td><td>EPO concentration</td><td>% inhibition</td>

<td></td><td></td><td>mq / kq i</td><td>in the lung^{b, c} (v ± ES)</td><td></td>

<td> 10</td><td>Group 1:</td><td></td><td></td><td></td>

<td> 15</td><td>Comp. 1 inhalation per aerosol</td><td></td><td></td><td></td>

<td></td><td>Control without ovalbumin</td><td> 0,0</td><td> 0,0312 ±0,005</td><td></td>

<td></td><td>Exposed to ovalbumin</td><td> 0,0</td><td> 0,2959 ± 0,035</td><td></td>

<td> 20</td><td>Drug + exposed to ovalbumin</td><td> 0,003</td><td> 0,2620 ±0,116</td><td> 13%</td>

<td rowspan="2"> 25</td><td></td><td> 0,01</td><td> 0,1806 ± 0,035*</td><td> 44%</td>

<td>Group 2:</td><td></td><td></td><td></td>

<td> 30</td><td>Comp. 1 administration intraperitoneal</td><td></td><td></td><td></td>

<td></td><td>Control without ovalbumin</td><td> 0,0</td><td> 0,0338 ± 0,004</td><td></td>

<td></td><td>Exposed to ovalbumin</td><td> 0,0</td><td> 0,3268 ± 0,046</td><td></td>

<td> 35</td><td>Drug + exposed to ovalbumin</td><td> 0,003</td><td> 0,2435 ± 0,0515</td><td> 28%</td>

<td></td><td></td><td> 0,01</td><td> 0,1690 ± 0,053*</td><td> 54%</td>

<td> 40</td><td></td><td> 0,03</td><td> 0,1693 ±0,060*</td><td> 54%</td>

<td></td><td></td><td> 3,0</td><td> 0,0580 + 0,018*'</td><td> 92%</td>

<td> 45</td><td>Group 3:</td><td></td><td></td><td></td>

<td></td><td>Comp. 2 administration oral</td><td></td><td></td><td></td>

<td> 50</td><td>Control without ovalbumin</td><td> 0,0</td><td> 0,0203 ± 0,008</td><td></td>

<td></td><td>Exposed to ovalbumin</td><td> 0,0</td><td> 0,2307 ±0,010</td><td></td>

<td> 55</td><td>Drug + exposed to ovalbumin</td><td> 0,001</td><td> 0,1862 ±0,030</td><td> 19%</td>

<td></td><td></td><td> 0,01</td><td> 0,1181± 0,020*</td><td> 49%</td>

<td> 60</td><td></td><td> 0,1</td><td> 0,0118 ±0,005*</td><td> 95%</td>

<td></td><td></td><td> 1,0</td><td> 0,0084 ± 0,005*</td><td> 96%</td>

<td></td><td colspan="4">* = significant difference compared to the control group with ovalbumin aa = 0.05</td>

The above studies indicate that the MRI compounds useful in the present invention can be used for the treatment of tH2-mediated diseases, by inhibiting TH2 immune responses, and suppressing eosinophilia and inducing IL-4 and IL- 5. Examples of these diseases include asthma,

ES 2 290 969 T3 allergy, atopic dermatitis, early HIV disease, infectious mononucleosis, and systemic lupus erythematosus. There is also an association with an increased TH2 response in Hodgkian and non-Hodgkian lymphoma, as well as embryonal carcinoma. Furthermore, the ability of the MRI compounds useful in the present invention to inhibit the TH2 response and increase the TH1 response indicates 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 Leishmania major have shown that a TH1 response correlates with resistance, while a TH2 response correlates with susceptibility. Furthermore, studies in mice have shown that macrophage-living parasites, eg, Leishmania major, are killed when host cells are activated by interferon-γ, which is known to be a product of TH1 cells. In mice infected with Candida and Histoplasma, a TH1 response is known to correlate with resistance, while a TH2 response correlates with susceptibility.

Accordingly, as a consequence of all of the foregoing, it is apparent that the imidazoquinolinamines, imidazopyridinamines, 6,7-fused cycloalkylimidazopyridinamines, and 1,2-linked imidazoquinolinamines useful in the present invention are useful for treating TH2-mediated diseases and other related diseases. Although the invention has been presented in terms of preferred embodiments and specific examples, it is not intended to limit the invention to such embodiments and examples.