HK1073778B - Pharmaceutical formulations comprising an immune response modifier - Google Patents

Description

Pharmaceutical formulations comprising an immune response modifier

Technical Field

The present invention relates to a pharmaceutical formulation comprising at least one immune response modifier selected from the group consisting of imidazoquinoline amine, imidazopyridine amine, 6, 7-fused cycloalkylimidazopyridine amine, 1, 2-bridged imidazoquinoline amine, thiazoloquinoline amine, oxazoloquinoline amine, thiazolopyridine amine, oxazolopyridine amine, imidazo 1, 5-naphthyridine amine, imidazotetrahydro 1, 5-naphthyridine amine, and thiazolo 1, 5-naphthyridine amine. Embodiments of the present invention relate to topical formulations for application to mammalian skin. Other embodiments of the present invention relate to methods for treating skin disorders.

Background

Many imidazoquinoline amines, imidazopyridine amines, 6, 7-fused cycloalkylimidazopyridine amines, 1, 2-bridged imidazoquinoline amines, thiazoloquinoline amines, oxazoloquinoline amines, thiazolopyridine amines, oxazolopyridine amines, imidazo 1, 5-naphthyridine amines, imidazotetrahydro 1, 5-naphthyridine amines and thiazolo 1, 5-naphthyridine amines have demonstrated potent immunostimulatory, antiviral and antitumor (including anticancer) activity and have also been shown to be useful as vaccine adjuvants. These compounds are hereinafter collectively referred to as "IRM" (immune response modifier) compounds. One such IRM compound, commonly known as imiquimod, has been in the form of a topical formulation Aldara^TMIs commercially available in the form of (a) for the treatment of anal and genital warts associated with human papillomavirus.

It is believed that the mechanism of the antiviral and antitumor activity of these IRM compounds is based in large part on the enhancement of the immune response by the induction of various important cytokines (e.g., interferons, interleukins, tumor necrosis factor, etc.). Such compounds have been shown to stimulate the rapid release of certain monocyte/macrophage derived cytokines and as such, to stimulate B cells to secrete antibodies that play an important role in the antiviral and antitumor activity of these IRM compounds. A significant immunostimulatory response to these compounds is the induction of Interferon (IFN) - α production, which is believed to be important in understanding acute antiviral and antitumor activity. Moreover, upregulation of other cytokines such as Tumor Necrosis Factor (TNF), interleukin-1 (IL-1) and IL-6 also have potentially beneficial activity and are believed to contribute to the antiviral and antitumor properties of these compounds.

While some of the beneficial effects of IRMs are known, the ability to provide therapeutic benefit by topically administering IRM compounds for treatment of a particular condition at a specific site may be limited by a number of factors. These factors include irritation of the skin to which the formulation is applied, rinsing of the formulation, insolubility and/or degradation of the IRM compound in the formulation, physical instability of the formulation (e.g., separation of components, thickening, precipitation/aggregation of active ingredients, etc.), poor penetration, and undesirable systemic delivery of the topically applied IRM compound. Thus, there is a continuing need for new methods and formulations to provide the greatest therapeutic benefit from such compounds.

Summary of The Invention

Throughout the several places of the specification, guidance is provided through lists of examples. In each case, the examples cited are merely exemplary in type; the described examples are not meant to be exclusive.

In one aspect, the present invention relates to a pharmaceutical formulation comprising an immunoreaction modifier selected from the group consisting of imidazoquinoline amine, imidazotetrahydroquinoline amine, imidazopyridine amine, 6, 7-fused cycloalkylimidazopyridine amine, 1, 2-bridged imidazoquinoline amine, thiazoloquinoline amine, oxazoloquinoline amine, thiazolopyridine amine, oxazolopyridine amine, imidazo 1, 5-naphthyridine amine, imidazotetrahydro 1, 5-naphthyridine amine, and thiazolo 1, 5-naphthyridine amine; a fatty acid; a hydrophobic aprotic component miscible with the fatty acid and comprising a hydrocarbon group of 7 or more carbon atoms; and a hydrophilic viscosity enhancing agent selected from the group consisting of cellulose ethers and carbomers.

In one embodiment, the pharmaceutical formulation comprises an immune response modifier selected from the group consisting of imidazo 1, 5-naphthyridine amine, imidazo tetrahydro 1, 5-naphthyridine amine, and thiazolo 1, 5-naphthyridine amine; a fatty acid; and a hydrophobic aprotic component miscible with the fatty acid and comprising a hydrocarbon group of 7 or more carbon atoms.

The formulation may further comprise one or more of a preservative system, an emulsifier and water.

In another aspect, the invention relates to a method of treating a condition associated with skin comprising administering to the skin a topical formulation comprising an immune response modifier selected from the group consisting of imidazoquinoline amine, imidazotetrahydroquinoline amine, imidazopyridine amine, 6, 7-fused cycloalkylimidazopyridine amine, 1, 2-bridged imidazoquinoline amine, thiazoloquinoline amine, oxazoloquinoline amine, thiazolopyridine amine, oxazolopyridine amine, imidazo 1, 5-naphthyridine amine, imidazotetrahydro 1, 5-naphthyridine amine, and thiazolo 1, 5-naphthyridine amine; a fatty acid; a hydrophobic aprotic component miscible with the fatty acid and comprising a hydrocarbon group of 7 or more carbon atoms; and a hydrophilic viscosity enhancing agent selected from the group consisting of a cellulose ether and a carbomer.

In one embodiment, the method of treating a skin-related condition comprises administering to the skin a formulation comprising an immune response modifier selected from the group consisting of imidazo 1, 5-naphthyridine amine, imidazo tetrahydro 1, 5-naphthyridine amine, and thiazolo 1, 5-naphthyridine amine; a fatty acid; and a hydrophobic aprotic component miscible with the fatty acid and comprising a hydrocarbon group of 7 or more carbon atoms.

In other embodiments, the method of treating a skin-related condition comprises administering to the skin a formulation comprising an immune response modifier selected from the group consisting of imidazo 1, 5-naphthyridine amine, imidazo tetrahydro 1, 5-naphthyridine amine, and thiazolo 1, 5-naphthyridine amine; a fatty acid; and a hydrophobic aprotic component miscible with the fatty acid and comprising a hydrocarbon group of 7 or more carbon atoms; and further comprising one or more preservative systems, an emulsifier and water.

In one embodiment, the skin-related disorder is selected from actinic keratosis, post-operative scars, basal cell carcinoma of the skin, atopic dermatitis, and warts.

In another aspect, the present invention relates to a method of delivering an immune response modifier to a skin surface, the method comprising the steps of: selecting a formulation comprising a compound selected from the group consisting of imidazoquinoline amine, imidazotetrahydroquinoline amine, imidazopyridine amine, 6, 7-fused cycloalkylimidazopyridine amine, 1, 2-bridged imidazoquinoline amine, thiazoloquinoline amine, oxazoloquinoline amine, thiazolopyridine amine, oxazolopyridine amine, imidazo 1, 5-naphthyridine amine, imidazotetrahydro 1, 5-naphthyridine amine, and thiazolo 1, 5-naphthyridine amine; a fatty acid; a hydrophobic aprotic component miscible with the fatty acid and comprising a hydrocarbon group of 7 or more carbon atoms; and a hydrophilic viscosity enhancing agent selected from a cellulose ether and a carbomer; and applying the selected formulation to the skin surface for a time sufficient for the formulation to deliver the IRM to the skin surface.

In one embodiment, the selected formulation includes an immune response modifier selected from the group consisting of imidazo 1, 5-naphthyridine amine, imidazo tetrahydro 1, 5-naphthyridine amine, and thiazolo 1, 5-naphthyridine amine; a fatty acid; and a hydrophobic aprotic component miscible with the fatty acid and comprising a hydrocarbon group of 7 or more carbon atoms.

Unless otherwise indicated, all numbers expressing quantities, ratios, and numerical characteristics of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about".

As used herein, "a" or "an" are used interchangeably herein, and "at least one" refers to "one or more" of the modified elements.

Detailed Description

In one aspect, the present invention relates to a pharmaceutical formulation comprising an immunoreactive modifier compound selected from the group consisting of imidazoquinoline amine, imidazotetrahydroquinoline amine, imidazopyridine amine, 6, 7-fused cycloalkylimidazopyridine amine, 1, 2-bridged imidazoquinoline amine, thiazoloquinoline amine, oxazoloquinoline amine, thiazolopyridine amine, oxazolopyridine amine, imidazo 1, 5-naphthyridine amine, imidazotetrahydro 1, 5-naphthyridine amine, and thiazolo 1, 5-naphthyridine amine; a fatty acid; a hydrophobic aprotic component miscible with fatty acid and comprising a hydrocarbon group of 7 or more carbon atoms and a hydrophilic viscosity enhancing agent selected from a cellulose ether and a carbomer.

These immune response modifier compounds, methods of making, methods of using, and compositions containing the same are disclosed in U.S. Pat. nos. 4,689,338; 4,929,624; 4,988,815; 5,037,986, respectively; 5,175,296, respectively; 5,238,944, respectively; 5,266,575, respectively; 5,268,376, respectively; 5,346,905, respectively; 5,352,784, respectively; 5,367,076, respectively; 5,389,640, respectively; 5,395,937, respectively; 5,446,153, respectively; 5,482,936, respectively; 5,693,811; 5,741,908, respectively; 5,756,747, respectively; 5,939,090, respectively; 6,039,969, respectively; 6,083,505, respectively; 6,110,929, respectively; 6,194,425; 6,245,776; 6,331,539, respectively; 6,376,669, respectively; and 6,451,810; european patent 0394026; U.S. publication 2002/0055517; and PCT publication WO 00/47719; WO 00/76518; WO 01/74343; WO 02/46188; WO 02/46189; WO 02/46190; WO 02/46191; WO 02/46192; WO 02/46193; WO 02/46194; and WO 02/46749, the contents of which are incorporated herein by reference.

As mentioned above, many IRM compounds useful in the present invention have shown important immunomodulatory activity. In certain embodiments of the invention, the IRM compound may be selected from imidazoquinoline amines, such as 1H-imidazo [4, 5-c ] quinolin-4-amine defined by one of formulas I-V:

wherein

R₁₁Selected from the group consisting of alkyl of 1 to 10 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, acyloxyalkyl, wherein the acyloxy moiety is alkanoyloxy or benzoyloxy of 2 to 4 carbon atoms and the alkyl moiety includes 1 to 6 carbon atoms, benzyl (phenyl) ethyl and phenyl, said benzyl, (phenyl) ethyl or phenyl substituents being optionally substituted on the phenyl ring by one or two moieties independently selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms and halogen, with the proviso that if said phenyl ring is substituted by two of said moieties, then said moieties contain no more than 6 carbon atoms in total.

R₂₁Selected from the group consisting of hydrogen, alkyl of 1 to 8 carbon atoms, benzyl, (phenyl) ethyl and phenyl, said benzyl, (phenyl) ethyl or phenyl substituents being optionally substituted on the phenyl ring by one or two moieties independently selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms and halogen, with the proviso that if said phenyl ring is substituted by two of said moieties, then said moieties contain no more than 6 carbon atoms in total; and is

Each R₁Independently selected from the group consisting of alkoxy of 1 to 4 carbon atoms, halogen and alkyl of 1 to 4 carbon atoms, and n is an integer from 0 to 2, with the proviso that if n is 2, then R is₁The group contains no more than 6 carbon atoms in total.

Wherein

R₁₂Selected from the group consisting of linear or branched alkenyl groups comprising 2 to 10 carbon atoms and substituted linear or branched alkenyl groups comprising 2 to 10 carbon atoms, wherein the substituents are selected from the group consisting of linear or branched alkyl groups comprising 1 to 4 carbon atoms and cycloalkyl groups comprising 3 to 6 carbon atoms; and cycloalkyl groups comprising 3 to 6 carbon atoms are substituted with straight or branched alkyl groups comprising 1 to 4 carbon atoms; and is

R₂₂Selected from the group consisting of hydrogen, straight or branched chain alkyl groups comprising from 1 to 8 carbon atoms, benzyl, (phenyl) ethyl and phenyl, said benzyl, (phenyl) ethyl or phenyl substituents being optionally substituted on the phenyl ring by one or two moieties independently selected from the group consisting of straight or branched chain alkyl groups comprising from 1 to 4 carbon atoms, straight or branched chain alkoxy groups comprising from 1 to 4 carbon atoms and halogen, with the proviso that if said phenyl ring is substituted by two of said moieties, then said moieties contain no more than 6 carbon atoms in total; and is

Each R₂Independently selected from the group consisting of linear or branched alkoxy comprising from 1 to 4 carbon atoms, halogen and linear or branched alkyl comprising from 1 to 4 carbon atoms, and n is an integer from 0 to 2, with the proviso that if n is 2, then said R is₂The group contains no more than 6 carbon atoms in total.

Wherein

R₂₃Selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 8 carbon atoms, benzyl, (phenyl) ethyl and phenyl, said benzyl, (phenyl) ethyl or phenyl substituents being optionally substituted on the phenyl ring by one or two moieties independently selected from the group consisting of straight or branched chain alkyl of 1 to 4 carbon atoms, straight or branched chain alkoxy of 1 to 4 carbon atoms and halogen, with the proviso thatIf the phenyl ring is substituted with two such moieties, then the moieties contain no more than 6 carbon atoms in total; and is

Each R₃Independently selected from the group consisting of linear or branched alkoxy of 1 to 4 carbon atoms, halogen and linear or branched alkyl of 1 to 4 carbon atoms, and n is an integer from 0 to 2, with the proviso that if n is 2, then said R is₃The group contains no more than 6 carbon atoms in total.

Wherein

R₁₄is-CHR_xR_yWherein Ry is a hydrogen or carbon-carbon bond, with the proviso that when R is_yWhen is hydrogen, R_xIs alkoxy of 1 to 4 carbon atoms, hydroxyalkoxy of 1 to 4 carbon atoms, 1-alkynyl of 2 to 10 carbon atoms, tetrahydropyranyl, alkoxyalkyl wherein the alkoxy moiety comprises 1 to 4 carbon atoms and the alkyl moiety comprises 1 to 4 carbon atoms or 2-, 3-, or 4-pyridyl, and further with the proviso that when R is_yWhen it is a carbon-carbon bond, R_yAnd R_xTaken together to form tetrahydrofuranyl optionally substituted with one or more substituents independently selected from hydroxy, and hydroxyalkyl of 1 to 4 carbon atoms;

R₂₄selected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms, phenyl, and substituted phenyl, wherein the substituents are selected from the group consisting of alkyl groups including 1 to 4 carbon atoms, alkoxy groups of 1 to 4 carbon atoms, and halogen; and is

R₄Selected from the group consisting of hydrogen, straight or branched chain alkoxy groups comprising 1 to 4 carbon atoms, halogen, and straight or branched chain alkyl groups comprising 1 to 4 carbon atoms;

wherein

R₁₅Selected from: hydrogen; a linear or branched alkyl group including 1 to 10 carbon atoms and a substituted linear or branched alkyl group including 1 to 10 carbon atoms, wherein the substituent is selected from the group consisting of a cycloalkyl group including 3 to 6 carbon atoms and a cycloalkyl group including 3 to 6 carbon atoms, substituted with a linear or branched alkyl group including 1 to 4 carbon atoms; a straight or branched chain alkenyl group including 2 to 10 carbon atoms and a substituted straight or branched chain alkenyl group including 2 to 10 carbon atoms, wherein the substituent is selected from the group consisting of a cycloalkyl group including 3 to 6 carbon atoms and a cycloalkyl group including 3 to 6 carbon atoms, substituted with a straight or branched chain alkyl group including 1 to 4 carbon atoms; hydroxyalkyl of 1 to 6 carbon atoms; alkoxyalkyl wherein the alkoxy moiety comprises 1 to 4 carbon atoms and the alkyl moiety comprises 1 to 6 carbon atoms; acyloxyalkyl wherein the acyloxy moiety is an alkanoyloxy or benzoyloxy of 2 to 4 carbon atoms and the alkyl moiety includes 1 to 6 carbon atoms; a benzyl group; (phenyl) ethyl; and a phenyl group; said benzyl, (phenyl) ethyl or phenyl substituent is optionally substituted on the phenyl ring with one or more moieties independently selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, and halogen, with the proviso that when said phenyl ring is substituted with two of said moieties, said moieties together comprise no more than 6 carbon atoms;

R₂₅is that

Wherein

R_SAnd R_TIndependently selected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms, phenyl, substituted phenyl wherein the substituents are selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms and halogen;

x is selected from the group consisting of alkoxy groups comprising 1 to 4 carbon atoms, alkoxyalkyl groups wherein the alkoxy moiety comprises 1 to 4 carbon atoms and the alkyl moiety comprises 1 to 4 carbon atoms, hydroxyalkyl groups of 1 to 4 carbon atoms, haloalkyl groups of 1 to 4 carbon atoms, alkylamido groups wherein the alkyl group comprises 1 to 4 carbon atoms, amino groups, substituted amino groups wherein the substituent is an alkyl or hydroxyalkyl group of 1 to 4 carbon atoms, azido, chloro, hydroxy, 1-morpholino, 1-pyrrolidino, alkylthio groups of 1 to 4 carbon atoms; and

R₅selected from hydrogen, straight or branched chain alkoxy comprising 1 to 4 carbon atoms, halogen, straight or branched chain alkyl comprising 1 to 4 carbon atoms;

and pharmaceutically acceptable salts of any of the foregoing.

The IRM compound may also be selected from 6, 7-fused cycloalkylimidazopyridinamines defined by the following formula VI:

wherein m is 1, 2, or 3;

R₁₆selected from: hydrogen; cycloalkyl groups comprising 3, 4 or 5 carbon atoms; a linear or branched alkyl group including 1 to 10 carbon atoms and a substituted linear or branched alkyl group including 1 to 10 carbon atoms, wherein the substituent is selected from the group consisting of a cycloalkyl group including 3 to 6 carbon atoms and a cycloalkyl group including 3 to 6 carbon atoms, substituted with a linear or branched alkyl group including 1 to 4 carbon atoms; a fluoro-or chloroalkyl group comprising 1 to 10 carbon atoms and one or more fluorine or chlorine atoms; and a straight or branched chain alkenyl group including 2 to 10 carbon atoms, and a substituted straight or branched chain alkenyl group including 2 to 10 carbon atoms, wherein the substituent is selected from the group consisting of a cycloalkyl group including 3 to 6 carbon atoms and a cycloalkyl group including 3 to 6 carbon atoms, substituted with a straight or branched chain alkyl group including 1 to 4 carbon atoms; hydroxyalkyl of 1 to 6 carbon atoms; alkoxyalkyl wherein the alkoxy moiety comprises 1 to 4 carbon atoms and the alkyl moiety comprises 1 to 6 carbon atoms; acyl radicalAn alkoxyalkyl group in which the acyloxy moiety is an alkanoyloxy or benzoyloxy group of 2 to 4 carbon atoms and the alkyl moiety includes 1 to 6 carbon atoms, with the proviso that any alkyl, substituted alkyl, alkenyl, substituted alkenyl, hydroxyalkyl, alkoxyalkyl, or acyloxyalkyl group is not fully carbon-substituted, a carbon atom directly bonded to a nitrogen atom; a benzyl group; (phenyl) ethyl; and a phenyl group; said benzyl, (phenyl) ethyl or phenyl substituent is optionally substituted on the phenyl ring with one or two moieties independently selected from alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, and halogen, with the proviso that when said phenyl ring is substituted with two said moieties, said moieties together comprise no more than 6 carbon atoms;

and-CHR_xR_y

Wherein

R_yIs a hydrogen or carbon-carbon bond with the proviso that when R is_yWhen is hydrogen, R_xIs alkoxy of 1 to 4 carbon atoms, hydroxyalkoxy of 1 to 4 carbon atoms, 1-alkynyl of 2 to 10 carbon atoms, tetrahydropyranyl, alkoxyalkyl wherein the alkoxy moiety comprises 1 to 4 carbon atoms and the alkyl moiety comprises 1 to 4 carbon atoms or 2-, 3-, or 4-pyridyl, and further with the proviso that when R is_yIn the case of a carbon-carbon bond, Ry and Rx are taken together to form a tetrahydrofuranyl group optionally substituted by one or more substituents independently selected from hydroxy and hydroxyalkyl having from 1 to 4 carbon atoms,

R₂₆selected from the group consisting of hydrogen, straight or branched chain alkyl groups comprising 1 to 8 carbon atoms, straight or branched chain hydroxyalkyl groups comprising 1 to 6 carbon atoms, morpholinoalkyl, benzyl, (phenyl) ethyl and phenyl, said benzyl, (phenyl) ethyl or phenyl substituents being optionally substituted on the phenyl ring by a moiety selected from the group consisting of methyl, methoxy, and halogen; and

-C(R_S)(R_T) (X) wherein R_SAnd R_TIndependently selected from hydrogen, alkyl of 1 to 4 carbon atoms, phenyl, andsubstituted phenyl, wherein the substituents are selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, and halogen;

x is selected from the group consisting of alkoxy groups comprising 1 to 4 carbon atoms, alkoxyalkyl groups wherein the alkoxy moiety comprises 1 to 4 carbon atoms and the alkyl moiety comprises 1 to 4 carbon atoms, haloalkyl groups of 1 to 4 carbon atoms, alkylamido groups wherein the alkyl group comprises 1 to 4 carbon atoms, amino groups, substituted amino groups wherein the substituent is an alkyl or hydroxyalkyl group of 1 to 4 carbon atoms, azido groups, alkylthio groups of 1 to 4 carbon atoms, and morpholinoalkyl groups wherein the alkyl moiety comprises 1 to 4 carbon atoms, and

r6 is selected from hydrogen, straight or branched chain fluoro, chloro alkyl groups comprising 1 to 4 carbon atoms, straight or branched chain fluoro or chloro alkyl groups comprising 1 to 4 carbon atoms and at least one fluorine or chlorine atom; and pharmaceutically acceptable salts thereof.

In other embodiments of the invention, the IRM compound may be selected from imidazopyridine amines defined by the following formula VII:

wherein

R₁₇Selected from hydrogen; -CH₂R_WWherein R is_WSelected from the group consisting of linear, branched, or cyclic alkyl groups comprising 1 to 10 carbon atoms, linear or branched alkenyl groups comprising 2 to 10 carbon atoms, linear or branched hydroxyalkyl groups comprising 1 to 6 carbon atoms, alkoxyalkyl groups wherein the alkoxy portion comprises 1 to 4 carbon atoms and the alkyl portion comprises 1 to 6 carbon atoms, and phenylethyl groups; and-CH ═ CR_ZR_ZWherein each R is_ZIndependently a straight, branched or cyclic alkyl group of 1 to 6 carbon atoms;

R₂₇selected from hydrogen; a linear or branched alkyl group comprising 1 to 8 carbon atoms; straight chain containing 1 to 6 carbon atoms orOr a branched hydroxyalkyl group; alkoxyalkyl wherein the alkoxy moiety comprises 1 to 4 carbon atoms and the alkyl moiety comprises 1 to 6 carbon atoms; benzyl, (phenyl) ethyl and phenyl, said benzyl, (phenyl) ethyl and phenyl being optionally substituted on the phenyl ring by a moiety selected from methyl, methoxy and halogen; and morpholinoalkyl wherein the alkyl portion comprises 1 to 4 carbon atoms;

R₆₇and R₇₇Independently selected from hydrogen and alkyl of 1 to 5 carbon atoms, with the proviso that R is₆₇And R₇₇Containing not more than 6 carbon atoms in total, with the further proviso that when R₇₇When is hydrogen, R₆₇Is not hydrogen, and R₂₇Is not hydrogen or morpholinoalkyl, and with the proviso that when R is₆₇When is hydrogen, R₇₇And R₂₇Is not hydrogen;

and pharmaceutically acceptable salts thereof.

In yet another embodiment of the invention, the IRM compound may be selected from 1, 2-bridged imidazoquinolinamines defined by the following formula VIII:

wherein

Z is selected from:

-(CH₂) p-wherein p is 1 to 4;

-(CH₂)_a-C(R_DR_E)(CH₂)_b-, where a and b are integers and a + b is 0 to 3, R_DIs hydrogen or alkyl of 1 to 4 carbon atoms, and R_ESelected from alkyl of 1 to 4 carbon atoms, hydroxy, -OR_FWherein R is_FIs alkyl of 1 to 4 carbon atoms, and-NR_GR′_GWherein R is_GAnd R'_GIndependently hydrogen or alkyl of 1 to 4 carbon atoms; and

-(CH₂)_a-(Y)-(CH₂)_b-, where a and b are integers, and a + b is 0 to 3, and Y is O, S or-NR_J-, wherein R_JIs hydrogen or alkyl of 1 to 4 carbon atoms;

and wherein q is 0 or 1 and R₈Selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, and halogen,

and pharmaceutically acceptable salts thereof.

In other embodiments, the IRM compound may be selected from thiazoloquinoline amines, oxazoloquinoline amines, thiazolo 1, 5-naphthyridine amines, thiazolopyridine amines, and oxazolopyridine amines represented by formula IX:

wherein:

R₁₉selected from oxygen, sulfur and selenium;

R₂₉is selected from

-hydrogen;

-an alkyl group;

-alkyl-OH;

-a haloalkyl group;

-an alkenyl group;

-alkyl-X-alkyl;

-alkyl-X-alkenyl;

-alkenyl-X-alkyl;

-alkenyl-X-alkenyl;

-alkyl-N (R)₅₉)₂；

-alkyl-N₃；

-alkyl-O-C (O) -N (R)₅₉)2；

-a heterocyclic group;

-alkyl-X-heterocyclyl;

-alkenyl-X-heterocyclyl;

-an aryl group;

-alkyl-X-aryl;

-alkenyl-X-aryl;

-a heteroaryl group;

-alkyl-X-heteroaryl; and

-alkenyl-X-heteroaryl;

R₃₉and R₄₉Each independently is:

-hydrogen;

-X-alkyl;

-a halogen;

-a haloalkyl group;

-N(R₅₉)₂；

or taken together, R₃₉And R₄₉Form a fused aromatic, heteroaromatic, cycloalkyl or heterocyclic ring;

x is selected from-O-, -S-, -NR-₅₉-, -C (O) -, -C (O) O-, -OC (O) -, and a bond; and is

Each R₅₉Independently is H or C_1-8An alkyl group;

and pharmaceutically acceptable salts thereof.

In another embodiment of the invention, the IRM compound may be selected from the group consisting of imidazo 1, 5-naphthyridine amines and imidazo tetrahydro 1, 5-naphthyridine amines represented by formulas X and XI:

wherein

A is N-CR; CR-N-CR; CR-N-CR; or CR-N;

R₁₁₀selected from:

-hydrogen;

-C unsubstituted or substituted by one or more substituents selected from_1-20Alkyl or C_2-20Alkenyl:

-an aryl group;

-a heteroaryl group;

-a heterocyclic group;

-O-C_1-20an alkyl group, a carboxyl group,

-O-(C_1-20alkyl radical)_0-1-an aryl group;

-O-(C_1-20alkyl radical)_0-1-a heteroaryl group;

-O-(C_1-20alkyl radical)_0-1-a heterocyclic group;

-CO-O-C_1-20an alkyl group;

-S(O)_0-2-C_1-20an alkyl group;

-S(O)_0-2-(C_1-20alkyl radical)_0-1-an aryl group;

-S(O)_0-2-(C_1-20alkyl radical)_0-1-a heteroaryl group;

-S(O)_0-2-(C_1-20alkyl radical)_0-1-a heterocyclic group;

-N(R₃₁₀)₂；

-N₃；

oxo;

-a halogen;

-NO₂；

-OH; and

-SH; and

-C_1-20alkyl-NR₃₁₀-Q-X-R₄₁₀or-C_2-20alkenyl-NR₃₁₀-Q-X-R₄₁₀Wherein Q is-CO-or-SO₂-; x is a bond, -O-or-NR₃₁₀-and R₄₁₀Is an aryl group; a heteroaryl group; a heterocyclic group; or-C unsubstituted or substituted by one or more substituents selected from_1-20Alkyl or C_2-20Alkenyl:

-an aryl group;

-a heteroaryl group;

-a heterocyclic group;

-O-C_1-20an alkyl group, a carboxyl group,

-O-(C_1-20alkyl radical)_0-1-an aryl group;

-O-(C_1-20alkyl radical)_0-1-a heteroaryl group;

-O-(C_1-20alkyl radical)_0-1-a heterocyclic group;

-CO-O-C_1-20an alkyl group;

-S(O)_0-2-C_1-20an alkyl group;

-S(O)_0-2-(C_1-20alkyl radical)_0-1-an aryl group;

-S(O)_0-2-(C_1-20alkyl radical)_0-1-a heteroaryl group;

-S(O)_0-2-(C_1-20alkyl radical)_0-1-a heterocyclic group;

-N(R₃₁₀)₂；

-NR₃₁₀-CO-O-C_1-20an alkyl group;

-N₃；

oxo;

-a halogen;

-NO₂；

-OH; and

-SH; or R₄₁₀Is that

Wherein Y is-N-or-CR-;

R₂₁₀selected from:

-hydrogen;

-C_1-10an alkyl group;

-C_2-10an alkenyl group;

-an aryl group;

-C_1-10alkyl-O-C_1-10An alkyl group;

-C_1-10alkyl-O-C_2-10An alkenyl group; and

-C substituted by one or more substituents selected from the group consisting of_1-10Alkyl or C_2-10Alkenyl:

OH；

-a halogen;

-N(R₃₁₀)2；

-CO-N(R₃₁₀)2；

-CO-C_1-10an alkyl group;

-N₃；

-an aryl group;

-a heteroaryl group;

-a heterocyclic group;

-CO-aryl; and

-CO-heteroaryl;

each R₃₁₀Independently selected from hydrogen and C_1-10An alkyl group; and is

Each R is independently selected from hydrogen, C_1-10Alkyl radical, C_1-10Alkoxy, halogen and trifluoromethyl,

and pharmaceutically acceptable salts thereof;

wherein

B is-NR-C (R)₂-C(R)₂-C(R)₂-；-C(R)₂-NR-C(R)₂-C(R)₂-；-C(R)₂-C(R)₂-NR-C(R)₂-or-C (R)₂-C(R)₂-C(R)₂-NR-；

R₁₁₁Selected from:

-hydrogen;

-C unsubstituted or substituted by one or more substituents selected from_1-20Alkyl or-C_2-20Alkenyl:

-an aryl group;

-a heteroaryl group;

-a heterocyclic group;

-O-C_1-20an alkyl group;

-O-(C_1-20alkyl radical)_0-1-an aryl group;

-O-(C_1-20alkyl radical)_0-1-a heteroaryl group;

-O-(C_1-20alkyl radical)_0-1-a heterocyclic group;

-CO-O-C_1-20an alkyl group;

-S(O)_0-2-C_1-20an alkyl group;

-S(O)_0-2-(C_1-20alkyl radical)_0-1-an aryl group;

-S(O)_0-2-(C_1-20alkyl radical)_0-1-a heteroaryl group;

-S(O)_0-2-(C_1-20alkyl radical)_0-1-a heterocyclic group;

-N(R₃₁₁)₂；

-N₃；

oxo;

-a halogen;

-NO₂；

-OH; and

-SH; and

-C-_1-20alkyl-NR₃₁₁-Q-X-R₄₁₁or-C_2-20alkenyl-NR₃₁₁-Q-X-R₄₁₁Wherein Q is CO-or-SO₂-; x is a bond, -O-or-NR₃₁₁-, and R₄₁₁Is an aryl group; a heteroaryl group; a heterocyclic group; or-C unsubstituted or substituted by one or more substituents selected from_1-20Alkyl or-C_2-20Alkenyl:

-an aryl group;

-a heteroaryl group;

-a heterocyclic group;

-O-C_1-20an alkyl group, a carboxyl group,

-O-(C_1-20alkyl radical)_0-1-an aryl group;

-O-(C_1-20alkyl radical)_0-1-a heterocyclic group;

-CO-O-C_1-20an alkyl group;

-S(O)_0-2-C_1-20an alkyl group;

-S(O)_0-2-(C_1-20alkyl radical)_0-1-an aryl group;

-S(O)_0-2-(C_1-20alkyl radical)_0-1-a heteroaryl group;

-S(O)_0-2-(C_1-20alkyl radical)_0-1-a heterocyclic group;

-N(R₃₁₁)2；

-NR₃₁₁-CO-O-C_1-20an alkyl group;

-N₃；

oxo;

-a halogen;

-NO₂；

-OH; and

-SH; or R411 is

Wherein Y is-N-or-CR-;

R₂₁₁selected from:

-hydrogen;

-C_1-10an alkyl group;

-C_2-10an alkenyl group;

-aryl radical

-C_1-10alkyl-O-C_1-10An alkyl group;

-C_1-10alkyl-O-C_2-10An alkenyl group; and

-C substituted by one or more substituents selected from the group consisting of_1-10Alkyl or C_2-10Alkenyl:

-OH；

-a halogen;

-N(R₃₁₁)₂；

-CO-N(R₃₁₁)₂；

-CO-C_1-10an alkyl group;

-N₃；

-an aryl group;

-a heteroaryl group;

-a heterocyclic group;

-CO-aryl; and

-CO-heteroaryl;

each R₃₁₁Independently selected from hydrogen and C_1-10An alkyl group; and

each R is independently selected from hydrogen, C_1-10Alkyl radical, C_1-10Alkoxy, halogen and trifluoromethyl,

and pharmaceutically acceptable salts thereof.

In a further embodiment, the IRM compound may be selected from imidazoquinoline amines, imidazotetrahydroquinoline amines, e.g., 1H-imidazo [4, 5-c ] quinolin-4-amine and tetrahydro-1H-imidazo [4, 5-c ] quinolin-4-amine as defined by the following formulas XII, XIII and XIV:

wherein

R₁₁₂is-alkyl-NR₃₁₂-CO-R₄₁₂or-alkenyl-NR₃₁₂-CO-R₄₁₂Wherein R is₄₁₂Is aryl, heteroaryl, alkyl or alkenyl, each of which may be unsubstituted or substituted with one or more substituents selected from:

-an alkyl group;

-an alkenyl group;

-an alkynyl group;

- (alkyl-)_0-1-an aryl group;

- (alkyl)_0-1- (substituted aryl);

- (alkyl)_0-1-a heteroaryl group;

- (alkyl)_0-1- (substituted heteroaryl);

-O-alkyl;

-O- (alkyl)_0-1-an aryl group;

-O- (alkyl)_0-1- (substituted aryl);

-O- (alkyl)_0-1-a heteroaryl group;

-O- (alkyl)_0-1- (substituted heteroaryl);

-CO-aryl;

-CO- (substituted aryl);

-CO-heteroaryl;

-CO- (substituted heteroaryl);

-COOH；

-CO-O-alkyl;

-CO-alkyl;

-S(O)_0-2-an alkyl group;

-S(O)_0-2- (alkyl)_0-1-an aryl group;

-S(O)_0-2- (alkyl)_0-1- (substituted aryl);

-S(O)_0-2- (alkyl)_0-1-a heteroaryl group;

-S(O)_0-2- (alkyl)_0-1- (substituted heteroaryl);

-P(O)(OR₃₁₂)₂；

-NR₃₁₂-CO-O-alkyl;

-N₃；

-a halogen;

-NO₂；

-CN；

-a haloalkyl group;

-O-haloalkyl;

-CO-haloalkyl;

-OH；

-SH; and oxo in the case of alkyl, alkenyl, or heterocyclyl;

or R₄₁₂Is that

(C_1-10Alkyl) -NR₃₁₂-(C_1-10Alkyl) -R₅₁₂

Wherein R is₅₁₂Is aryl, (substituted aryl), heteroaryl, (substituted heteroaryl), heterocyclyl or (substituted heterocyclyl) group;

R₂₁₂selected from:

-hydrogen;

-an alkyl group;

-an alkenyl group;

-an aryl group;

- (substituted aryl);

-a heteroaryl group;

- (substituted heteroaryl);

-a heterocyclic group;

- (substituted heterocyclyl);

-alkyl-O-alkyl;

-alkyl-O-alkenyl; and

-alkyl or alkenyl substituted with one or more substituents selected from:

-OH；

-a halogen;

-N(R₃₁₂)₂；

-CO-N(R₃₁₂)₂；

-CO-C_1-10an alkyl group;

-CO-O-C_1-10an alkyl group;

-N₃；

-an aryl group;

- (substituted aryl);

-a heteroaryl group;

- (substituted heteroaryl);

-a heterocyclic group;

- (substituted heterocyclyl);

-CO-aryl; and

-CO-heteroaryl;

each R₃₁₂Independently selected from hydrogen; c_1-10Alkyl-heteroaryl; c_1-10Alkyl- (substituted heteroaryl); c_1-10Alkyl-aryl; c_1-10Alkyl- (substituted aryl) and C_1-10An alkyl group;

v is 0 to 4;

and each occurrence of R₁₂Independently selected from C_1-10Alkyl radical, C_1-10Alkoxy, halogen and trifluoromethyl;

wherein

R₁₁₃is-alkyl-NR₃₁₃-SO₂-X-R₄₁₃or-alkenyl-NR₃₁₃-SO₂-X-R₄₁₃；

X is a bond or-NR₅₁₃-；

R₄₁₃Is aryl, heteroaryl, heterocyclyl, alkyl or alkenyl, each of which may be unsubstituted or substituted with one or more substituents selected from:

-an alkyl group;

-an alkenyl group;

-an aryl group;

-a heteroaryl group;

-a heterocyclic group;

-a substituted cycloalkyl group;

-a substituted aryl group;

-substituted heteroaryl;

-a substituted heterocyclic group;

-O-alkyl;

-O- (alkyl)_0-1-an aryl group;

-O- (alkyl)_0-1-a substituted aryl group;

-O- (alkyl)_0-1-a heteroaryl group;

-O- (alkyl)_0-1-substituted heteroaryl;

-O- (alkyl)_0-1-a heterocyclic group;

-O- (alkyl)_0-1-a substituted heterocyclic group;

-COOH；

-CO-O-alkyl;

-CO-alkyl;

-S(O)_0-2-an alkyl group;

-S(O)_0-2- (alkyl)_0-1-an aryl group;

-S(O)_0-2- (alkyl)_0-1- (substituted aryl);

-S(O)_0-2- (alkyl)_0-1-a heteroaryl group;

-S(O)_0-2- (alkyl)_0-1- (substituted heteroaryl);

-S(O)_0-2- (alkyl)_0-1-a heterocyclic group;

-S(O)_0-2- (alkyl)_0-1-a substituted heterocyclic group;

- (alkyl)_0-1-NR₃₁₃R₃₁₃；

- (alkyl)_0-1-NR₃₁₃-CO-O-alkyl;

- (alkyl)_0-1-NR₃₁₃-CO-alkyl;

- (alkyl)_0-1-NR₃₁₃-CO-aryl;

- (alkyl)_0-1-NR₃₁₃-CO-substituted aryl;

- (alkyl) 0-1-NR₃₁₃-CO-heteroaryl;

- (alkyl) 0-1-NR₃₁₃-CO-substituted heteroaryl;

-N3；

-a halogen;

-a haloalkyl group;

-a haloalkoxy group;

-CO-haloalkyl;

-CO-haloalkoxy;

-NO₂；

-CN；

-OH；

-SH; and at R₄₁₃Is alkyl, alkenyl, or, in the case of heterocyclyl, oxo;

R₂₁₃selected from:

-hydrogen;

-an alkyl group;

-an alkenyl group;

-an aryl group;

-a substituted aryl group;

-a heteroaryl group;

-substituted heteroaryl;

-alkyl-O-alkyl;

-alkyl O-alkenyl; and

-alkyl or alkenyl substituted with one or more substituents selected from:

-OH；

-a halogen;

-(N(R₃₁₃)₂；

-CO-N(R₃₁₃)₂；

-CO-C_1-10an alkyl group;

-CO-O-C_1-10an alkyl group;

-N₃；

-an aryl group;

-a substituted aryl group;

-a heteroaryl group;

-substituted heteroaryl;

-a heterocyclic group;

-a substituted heterocyclic group;

-CO-aryl;

-CO- (substituted aryl);

-CO-heteroaryl; and

-CO- (substituted heteroaryl);

each R₃₁₃Independently selected from hydrogen, C_1-10Alkyl, and when X is a bond, R₃₁₃And R₄₁₃May be combined into a 3 to 7 membered heterocyclic ring or a substituted heterocyclic ring;

R₅₁₃selected from hydrogen, C_1-10Alkyl radical, and R₄₁₃And R₅₁₃May be combined into a 3 to 7 membered heterocyclic ring or a substituted heterocyclic ring;

v is 0 to 4 and each R present₁₃Independently selected from: c_1-10Alkyl radical, C_1-10Alkoxy, halogen and trifluoromethyl;

wherein

R₁₁₄is-alkyl-NR₃₁₄-CY-NR₅₁₄-X-R₄₁₄or-alkenyl-NR₃₁₄-CY-NR₅₁₄-X-R₄₁₄，

Wherein

Y is ═ O or ═ S;

x is a bond, -CO-or-SO₂-；

R₄₁₄Is aryl, heteroaryl, heterocyclyl, alkyl or alkenyl, each of which may be unsubstituted or substituted with one or more substituents selected from:

-an alkyl group;

-an alkenyl group;

-an aryl group;

-a heteroaryl group;

-a heterocyclic group;

-a substituted aryl group;

-substituted heteroaryl;

-a substituted heterocyclic group;

-O-alkyl;

-O- (alkyl)_0-1-an aryl group;

-O- (alkyl)_0-1-a substituted aryl group;

-O- (alkyl)_0-1-a heteroaryl group;

-O- (alkyl)_0-1-substituted heteroaryl;

-O- (alkyl)_0-1-a heterocyclic group;

-O- (alkyl)_0-1-a substituted heterocyclic group;

-COOH；

-CO-O-alkyl;

-CO-alkyl;

-S(O)_0-2- (alkyl);

-S(O)_0-2- (alkyl)_0-1-an aryl group;

-S(O)_0-2- (alkyl)_0-1-a substituted aryl group;

-S(O)_0-2- (alkyl)_0-1-a heteroaryl group;

-S(O)_0-2- (alkyl)_0-1-substituted heteroaryl;

-S(O)_0-2- (alkyl)_0-1-a heterocyclic group;

-S(O)_0-2- (alkyl)_0-1-a substituted heterocyclic group;

- (alkyl)_0-1-NR₃₁₄R₃₁₄；

- (alkyl)_0-1-NR₃₁₄-CO-O-alkyl;

- (alkyl)_0-1-NR₃₁₄-CO-alkyl;

- (alkyl)_0-1-NR₃₁₄-CO-aryl;

- (alkyl)_0-1-NR₃₁₄-CO-substituted aryl;

- (alkyl)_0-1-NR₃₁₄-CO-heteroaryl;

- (alkyl)_0-1-NR₃₁₄-CO-substituted heteroaryl;

-N₃；

-a halogen;

-a haloalkyl group;

-a haloalkoxy group;

-CO-haloalkoxy;

-NO₂；

-CN；

-OH；

-SH; and at R₄₁₄In the case of alkyl, alkenyl, or heterocyclyl, oxo; with the proviso that when X is a bond, R₄₁₄May additionally be hydrogen; r₂₁₄Selected from:

-hydrogen;

-an alkyl group;

-an alkenyl group;

-an aryl group;

-a substituted aryl group;

-a heteroaryl group;

-substituted heteroaryl;

-alkyl-O-alkyl;

-alkyl-O-alkenyl; and

-alkyl or alkenyl substituted with one or more substituents selected from:

-OH；

-a halogen;

-N(R₃₁₄)₂；

-CO-N(R₃₁₄)₂；

-CO-C_1-10an alkyl group;

-CO-O-C_1-10an alkyl group;

-N₃；

-an aryl group;

-a substituted aryl group;

-a heteroaryl group;

-substituted heteroaryl;

-a heterocyclic group;

-a substituted heterocyclic group;

-CO-aryl;

-CO- (substituted aryl);

-CO-heteroaryl; and

-CO- (substituted heteroaryl);

each R₃₁₄Independently selected from hydrogen and C_1-10An alkyl group;

R₅₁₄selected from hydrogen, C_1-10Alkyl radical, and R₄₁₄And R₅₁₄May be combined into a 3 to 7 membered heterocyclic ring or a substituted heterocyclic ring;

v is 0 to 4, and each occurrence of R₁₄Independently selected from: c_1-10Alkyl radical, C_1-10Alkoxy, halogen and trifluoromethyl

And pharmaceutically acceptable salts thereof.

In another embodiment, the IRM compound may be selected from imidazoquinolinamines, imidazotetrahydroquinolinamines, for example, 1H-imidazo [4, 5-c ] quinolin-4-amines and tetrahydro-1H-imidazo [4, 5-c ] quinolin-4-amines as defined by the following formulas XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, and XXVI:

wherein: x is-CHR₅₁₅-，-CHR₅₁₅-alkyl-, or-CHR₅₁₅-alkenyl-;

r115 is selected from:

-R₄₁₅-CR₃₁₅-Z-R₆₁₅-an alkyl group;

-R₄₁₅-CR₃₁₅-Z-R₆₁₅-an alkenyl group;

-R₄₁₅-CR₃₁₅--R₆₁₅-an aryl group;

-R₄₁₅-CR₃₁₅-Z-R₆₁₅-a heteroaryl group;

-R₄₁₅-CR₃₁₅-Z-R₆₁₅-a heterocyclic group;

-R₄₁₅-CR₃₁₅-Z-H；

-R₄₁₅-NR₇₁₅-CR₃₁₅-R₆₁₅-an alkyl group;

-R₄₁₅-NR₇₁₅-CR₃₁₅-R₆₁₅-an alkenyl group;

-R₄₁₅-NR₇₁₅-CR₃₁₅-R₆₁₅-an aryl group;

-R₄₁₅-NR₇₁₅-CR₃₁₅-R₆₁₅-a heteroaryl group;

-R₄₁₅-NR₇₁₅-CR₃₁₅-R₆₁₅-a heterocyclic group; and

-R₄₁₅-NR₇₁₅-CR₃₁₅-R₈₁₅；

z is-NR₅₁₅-, -O-, or-S-;

R₂₁₅selected from:

-hydrogen;

-an alkyl group;

-an alkenyl group;

-an aryl group;

-a heteroaryl group;

-a heterocyclic group;

-alkyl-Y-alkyl;

-alkyl-Y-alkenyl;

-alkyl-Y-aryl; and

-alkyl or alkenyl substituted with one or more substituents selected from:

-OH；

-a halogen;

-N(R₅₁₅)₂；

-CO-N(R₅₁₅)2；

-CO-C_1-10an alkyl group;

-CO-O-C_1-10an alkyl group;

-N₃；

-an aryl group;

-a heteroaryl group;

-a heterocyclic group;

-CO-aryl; and

-CO-heteroaryl;

R₃₁₅is ═ O or ═ S;

R₄₁₅is alkyl or alkenyl, which may be interrupted by one or more-O-groups;

each R₅₁₅Independently is H or C_1-10An alkyl group;

R₆₁₅is a bond, alkyl, or alkenyl, which may be interrupted by one or more-O-groups;

R₇₁₅is H, C_1-10Alkyl, arylalkyl, or R₄₁₅And R₇₁₅May be linked together to form a 5-to 7-membered heterocyclic ring;

R₈₁₅is H, C_1-10Alkyl, or R₇₁₅And R₈₁₅May be linked together to form a 5-to 7-membered heterocyclic ring;

y is-O-or-S (O)_0-2-；

v is 0 to 4; and is

Each occurrence of R₁₅Independently selectFrom C_1-10Alkyl radical, C_1-10Alkoxy, hydroxy, halogen and trifluoromethyl;

wherein: x is-CHR₅₁₆-，-CHR₅₁₆-alkyl, or-CHR₅₁₆-an alkenyl group;

r116 is selected from:

-R₄₁₆-CR₃₁₆-Z-R₆₁₆-an alkyl group;

-R₄₁₆-CR₃₁₆-Z-R₆₁₆-an alkenyl group;

-R₄₁₆-CR₃₁₆-Z-R₆₁₆-an aryl group;

-R₄₁₆-CR₃₁₆-Z-R₆₁₆-a heteroaryl group;

-R₄₁₆-CR₃₁₆-Z-R₆₁₆-a heterocyclic group;

-R₄₁₆-CR₃₁₆-Z-H；

-R₄₁₆-NR₇₁₆-CR₃₁₆-R₆₁₆-an alkyl group;

-R₄₁₆-NR₇₁₆-CR₃₁₆-R₆₁₆-an alkenyl group;

-R₄₁₆-NR₇₁₆-CR₃₁₆-R₆₁₆-an aryl group;

-R₄₁₆-NR₇₁₆-CR₃₁₆-R₆₁₆-a heteroaryl group;

-R₄₁₆-NR₇₁₆-CR₃₁₆-R₆₁₆-a heterocyclic group; and

-R₄₁₆-NR₇₁₆-CR₃₁₆-R₈₁₆；

z is-NR₅₁₆-, -O-, or-S-;

R₂₁₆selected from:

-hydrogen;

-an alkyl group;

-an alkenyl group;

-an aryl group;

-a heteroaryl group;

-a heterocyclic group;

-alkyl-Y-alkyl;

-alkyl-Y-alkenyl;

-alkyl-Y-aryl; and

-alkyl or alkenyl substituted with one or more substituents selected from:

-OH；

-a halogen;

-N(R₅₁₆)₂；

-CO-N(R₅₁₆)2；

-CO-C_1-10an alkyl group;

-CO-O-C_1-10an alkyl group;

-N₃；

-an aryl group;

-a heteroaryl group;

-a heterocyclic group;

-CO-aryl; and

-CO-heteroaryl;

R₃₁₆is ═ O or ═ S;

R₄₁₆is an alkyl or alkenyl group which may be interrupted by one or more-O-groups；

Each R₅₁₆Independently is H or C_1-10An alkyl group;

R₆₁₆is a bond, alkyl, or alkenyl, which may be interrupted by one or more-O-groups;

R₇₁₆is H, C_1-10Alkyl, arylalkyl, or R₄₁₆And R₇₁₆May be linked together to form a 5-to 7-membered heterocyclic ring;

R₈₁₆is H, C_1-10Alkyl, or R₇₁₆And R₈₁₆May be linked together to form a 5-to 7-membered heterocyclic ring;

y is-O-or-S (O)_0-2-；

v is 0 to 4; and is

Each occurrence of R₁₆Independently selected from C_1-10Alkyl radical, C_1-10Alkoxy, hydroxy, halogen and trifluoromethyl;

wherein: x is-CHR₃₁₇-，-CHR₃₁₇-alkyl-, or-CHR₃₁₇-alkenyl-;

R₁₁₇selected from:

-an alkenyl group;

-an aryl group; and

-R₄₁₇-an aryl group;

R₂₁₇selected from:

-alkyl or alkenyl substituted with one or more substituents selected from:

-OH；

-a halogen;

-N(R₃₁₇)₂；

-CO-N(R₃₁₇)₂；

-CO-C_1-10an alkyl group;

-CO-O-C_1-10an alkyl group;

-N₃；

-an aryl group;

-a heteroaryl group;

-a heterocyclic group;

-CO-aryl; and

-CO-heteroaryl;

R₄₁₇independently is H or C_1-10Alkyl, which may be interrupted by one or more-O-groups;

each R₃₁₇Independently is H or C_1-10An alkyl group;

each Y is independently-O-or-S (O)_0-2-；

v is 0 to 4; and

each occurrence of R₁₇Independently selected from C_1-10Alkyl radical, C_1-10Alkoxy, hydroxy, halogen and trifluoromethyl;

wherein: x is-CHR₃₁₈-，-CHR₃₁₈-alkyl-, or-CHR₃₁₈-alkenyl-;

r118 is selected from:

-an aryl group;

-an alkenyl group; and

-R₄₁₈-aryl-;

-R₂₁₈selected from:

-alkyl or alkenyl substituted with one or more substituents selected from:

-OH；

-a halogen;

-N(R₃₁₈)₂；

-CO-N(R₃₁₈)₂；

-CO-C_1-10an alkyl group;

-CO-O-C_1-10an alkyl group;

-N₃；

-an aryl group;

-a heteroaryl group;

-a heterocyclic group;

-CO-aryl; and

-CO-heteroaryl;

R₄₁₈is alkyl or alkenyl, which may be interrupted by one or more-O-groups;

each R₃₁₈Independently is H or C_1-10An alkyl group;

each Y is independently-O-or-S (O)_0-2-；

v is 0 to 4; and

each occurrence of R18 is independently selected from C_1-10Alkyl radical, C_1-10Alkoxy, hydroxy, halogen and trifluoromethyl;

wherein: x is-CHR₃₁₉-，-CHR₃₁₉-alkyl-, or-CHR₃₁₉-alkenyl-;

R₁₁₉selected from:

-a heteroaryl group;

-a heterocyclic group;

-R₄₁₉-a heteroaryl group; and

-R₄₁₉-a heterocyclic group;

R₂₁₉selected from:

-alkyl or alkenyl substituted with one or more substituents selected from:

-OH；

-a halogen;

-N(R₃₁₉)₂；

-CO-N(R3₁₉)₂；

-CO-C_1-10an alkyl group;

-CO-O-C_1-10an alkyl group;

-N₃；

-an aryl group;

-a heteroaryl group;

-a heterocyclic group;

-CO-aryl; and

-CO-heteroaryl;

R₄₁₉is alkyl or alkenyl, which may be interrupted by one or more-O-groups;

each R₃₁₉Independently is H or C_1-10An alkyl group;

each Y is independently-O-or-S (O)_0-2-；

v is 0 to 4; and also

Each occurrence of R₁₉Independently selected from C_1-10Alkyl radical, C_1-10Alkoxy, hydroxy, halogen and trifluoromethyl;

wherein: x is-CHR₃₂₀-，-CHR₃₂₀-alkyl-or-CHR₃₂₀-alkenyl-;

R₁₂₀selected from:

-a heteroaryl group;

-a heterocyclic group;

-R₄₂₀-a heteroaryl group; and

-R₄₂₀-a heterocyclic group;

-R₂₂₀selected from:

-alkyl or alkenyl substituted with one or more substituents selected from:

-OH；

-a halogen;

-N(R₃₂₀)₂；

-CO-N(R₃₂₀)₂；

-CO-C_1-10an alkyl group;

-CO-O-C_1-10an alkyl group;

-N₃；

-an aryl group;

-a heteroaryl group;

-a heterocyclic group;

-CO-aryl; and

-CO-heteroaryl;

R₄₂₀is alkyl or alkenyl, which may be interrupted by one or more-O-groups;

each R₃₂₀Independently is H or C_1-10An alkyl group;

each Y is independently-O-or-S (O)_0-2-；

v is 0 to 4; and also

Each occurrence of R₂₀Independently selected from C_1-10Alkyl radical, C_1-10Alkoxy, hydroxy, halogen and trifluoromethyl;

wherein: x is-CHR₅₂₁-，-CHR₅₂₁-alkyl-, or-CHR₅₂₁-alkenyl-;

R₁₂₁selected from:

-R₄₂₁-NR₃₂₁-SO₂-R₆₂₁-an alkyl group;

-R₄₂₁-NR₃₂₁-SO₂-R₆₂₁-an alkenyl group;

-R₄₂₁-NR₃₂₁-SO₂-R₆₂₁-an aryl group;

-R₄₂₁-NR₃₂₁-SO₂-R₆₂₁-a heteroaryl group;

-R₄₂₁-NR₃₂₁-SO₂-R₆₂₁-a heterocyclic group;

-R₄₂₁-NR₃₂1-SO₂-R₇₂₁；

-R₄₂₁-NR₃₂₁-SO₂-NR₅₂₁-R₆₂₁-an alkyl group;

-R₄₂₁-NR₃₂₁-SO₂-NR₅₂₁-R₆₂₁-an alkenyl group;

-R₄₂₁-NR₃₂₁-SO₂-NR₅₂₁-R₆₂₁-an aryl group;

-R₄₂₁-NR₃₂₁-SO₂-NR₅₂₁-R₆₂₁-a heteroaryl group;

-R₄₂₁-NR₃₂₁-SO₂-NR₅₂₁-R₆₂₁-a heterocyclic group; and

-R₄₂₁-NR₃₂₁-SO₂-NH₂；

r221 is selected from:

-alkyl or alkenyl substituted with one or more substituents selected from:

-OH；

-a halogen;

-N(R₅₂₁)₂；

-CO-N(R₅₂₁)₂；

-CO-C_1-10an alkyl group;

-CO-O-C_1-10an alkyl group;

-N₃；

-an aryl group;

-a heteroaryl group;

-a heterocyclic group;

-CO-aryl; and

-CO-heteroaryl;

y is-O-or-S (O)_0-2-；

R₃₂₁Is H, C_1-10Alkyl, or arylalkyl；

Each R₄₂₁Independently an alkyl or alkenyl group which may be interrupted by one or more-O-groups, or R₃₂₁And R₄₂₁May be linked together to form a 5-to 7-membered heterocyclic ring;

each R₅₂₁Independently of each other is H, C_1-10Alkyl, or C_1-10An alkenyl group;

R₆₂₁is a bond, alkyl, or alkenyl, which may be interrupted by one or more-O-groups;

R₇₂₁is C_1-10Alkyl, or R₃₂₁And R₇₂₁May be linked together to form a 5-to 7-membered heterocyclic ring;

v is 0 to 4; and

each occurrence of R₂₁Independently selected from C_1-10Alkyl radical, C_1-10Alkoxy, hydroxy, halogen and trifluoromethyl;

wherein: x is-CHR₅₂₂-，-CHR₅₂₂-alkyl-, or-CHR₅₂₂-alkenyl-;

R₁₂₂selected from:

-R₄₂₂-NR₃₂₂-SO₂-R₆₂₂-an alkyl group; -

-R₄₂₂-NR₃₂₂-SO₂-R₆₂₂-an alkenyl group;

-R₄₂₂-NR₃₂₂-SO₂-R₆₂₂-an aryl group;

-R₄₂₂-NR₃₂₂-SO₂-R₆₂₂-a heteroaryl group;

-R₄₂₂-NR₃₂₂-SO₂-R₆₂₂-a heterocyclic group;

-R₄₂₂-NR₃₂₂-SO₂-R₇₂₂；

-R₄₂₂-NR₃₂₂-SO₂-NR₅₂₂-R₆₂₂-an alkyl group;

-R₄₂₂-NR₃₂₂-SO₂-NR₅₂₂-R₆₂₂-an alkenyl group;

-R₄₂₂-NR₃₂₂-SO₂-NR₅₂₂-R₆₂₂-an aryl group;

-R₄₂₂-NR₃₂₂-SO₂-NR₅₂₂-R₆₂₂-a heteroaryl group;

-R₄₂₂-NR₃₂₂-SO₂-NR₅₂₂-R₆₂₂-a heterocyclic group; and

-R₄₂₂-NR₃₂₂-SO₂-NH₂；

R₂₂₂selected from:

-alkyl or alkenyl substituted with one or more substituents selected from:

-OH；

-a halogen;

-N(R₅₂₂)₂；

-CO-N(R₅₂₂)₂；

-CO-C_1-10an alkyl group;

-CO-O-C_1-10an alkyl group;

-N₃；

-an aryl group;

-a heteroaryl group;

-a heterocyclic group;

-CO-aryl; and

-CO-heteroaryl;

y is-O-or-S (O)_0-2-；

R₃₂₂Is H, C_1-10Alkyl, or arylalkyl;

each R₄₂₂Independently an alkyl or alkenyl group which may be interrupted by one or more-O-groups, or R₃₂₂And R₄₂₂May be linked together to form a 5-to 7-membered heterocyclic ring;

each R₅₂₂Independently of each other is H, C_1-10Alkyl, or C_1-10An alkenyl group;

R₆₂₂is a bond, alkyl, or alkenyl, which may be interrupted by one or more-O-groups;

R₇₂₂is C_1-10Alkyl, or R₃₂₂And R₇₂₂May be linked together to form a 5-to 7-membered heterocyclic ring;

v is 0 to 4; and

each occurrence of R₂₂Independently selected from C_1-10Alkyl radical, C_1-10Alkoxy, hydroxy, halogen and trifluoromethyl;

wherein: x is-CHR₃₂₃-，-CHR₃₂₃-alkyl-, or-CHR₃₂₃-alkenyl-;

z is-S-, -SO-, or-SO₂-

R₁₂₃Selected from:

-an alkyl group;

-an aryl group;

-a heteroaryl group;

-a heterocyclic group;

-an alkenyl group;

-R₄₂₃-an aryl group;

-R₄₂₃-a heteroaryl group;

-R₄₂₃-a heterocyclic group;

R₂₂₃selected from:

-alkyl or alkenyl substituted with one or more substituents selected from the group consisting of;

-OH；

-a halogen;

-N(R₃₂₃)₂；

-CO-N(R₃₂₃)₂；

-CO-C_1-10an alkyl group;

-CO-O-C_1-10an alkyl group;

-N₃；

-an aryl group;

-a heteroaryl group;

a heterocyclic group;

-CO-aryl; and

-CO-heteroaryl;

each R₃₂₃Independently is H or C_1-10An alkyl group;

each R₄₂₃Independently is alkyl or alkenyl;

each Y is independently-O-or-S (O)_0-2-；

v is 0 to 4; and

each occurrence of R₂₃Independent of each otherIs selected from C_1-10Alkyl radical, C_1-10Alkoxy, hydroxy, halogen and trifluoromethyl;

wherein: x is-CHR₃₂₄-，-CHR₃₂₄-alkyl-, or-CHR₃₂₄-alkenyl-;

z is-S-, -SO-, or-SO₂-；

R₁₂₄Selected from:

-an alkyl group;

-an aryl group;

-a heteroaryl group;

-a heterocyclic group;

-an alkenyl group;

-R₄₂₄-an aryl group;

-R₄₂₄-a heteroaryl group; and

-R₄₂₄-a heterocyclic group;

R₂₂₄selected from:

-alkyl or alkenyl substituted with one or more substituents selected from:

-OH；

-a halogen;

-N(R₃₂₄)₂；

-CO-N(R₃₂₄)₂；

-CO-C_1-10an alkyl group;

-CO-O-C_1-10an alkyl group;

-N₃；

-an aryl group;

-a heteroaryl group;

a heterocyclic group;

-CO-aryl; and

-CO-heteroaryl;

each R₃₂₄Independently is H or C_1-10An alkyl group;

each R₄₂₄Independently is alkyl or alkenyl;

each Y is independently-O-or-S (O)_0-2-；

v is 0 to 4; and

each occurrence of R₂₄Independently selected from C_1-10Alkyl radical, C_1-10Alkoxy, hydroxy, halogen and trifluoromethyl;

wherein: x is-CHR₅₂₅-，-CHR₅₂₅-alkyl-, or-CHR₅₂₅-alkenyl-;

R₁₂₅selected from:

-R₄₂₅-NR₈₂₅-CR₃₂₅-NR₅₂₅-Z-R₆₂₅-an alkyl group;

-R₄₂₅-NR₈₂₅-CR₃₂₅-NR₅₂₅-Z-R₆₂₅-an alkenyl group;

-R₄₂₅-NR₈₂₅-CR₃₂₅-NR₅₂₅-Z-R₆₂₅-aryl radical

-R₄₂₅-NR₈₂₅-CR₃₂₅-NR₅₂₅-Z-R₆₂₅-a heteroaryl group;

-R₄₂₅-NR₈₂₅-CR₃₂₅-NR₅₂₅-Z-R₆₂₅-a heterocyclic group;

-R₄₂₅-NR₈₂₅-CR₃₂₅-NR₅₂₅R₇₂₅；

-R₄₂₅-NR₈₂₅-CR₃₂₅-NR₉₂₅-Z-R₆₂₅-an alkyl group;

-R₄₂₅-NR₈₂₅-CR₃₂₅-NR₉₂₅-Z-R₆₂₅-an alkenyl group;

-R₄₂₅-NR₈₂₅-CR₃₂₅-NR₉₂₅-Z-R₆₂₅-an aryl group;

-R₄₂₅-NR₈₂₅-CR₃₂₅-NR₉₂₅-Z-R₆₂₅-a heteroaryl group; and

-R₄₂₅-NR₈₂₅-CR₃₂₅-NR₉₂₅-Z-R₆₂₅-a heterocyclic group;

R₂₂₅selected from:

-alkyl or alkenyl substituted with one or more substituents selected from:

-OH；

-a halogen;

-N(R₅₂₅)₂；

-CO-N(R₅₂₅)₂；

-CO-C_1-10an alkyl group;

-CO-O-C_1-10an alkyl group;

-N₃；

-an aryl group;

-a heteroaryl group;

-a heterocyclic group;

-CO-aryl; and

-CO-heteroaryl;

each R₃₂₅Is ═ O or ═ S;

each R₄₂₅Independently an alkyl or alkenyl group, which may be interrupted by one or more-O-groups,

each R₅₂₅Independently is H or C_1-10An alkyl group;

R₆₂₅is a bond, alkyl, or alkenyl, which may be interrupted by one or more-O-groups;

R₇₂₅is H, C_1-10Alkyl, which may be interrupted by a heteroatom, or R₇₂₅Can be reacted with R₅₂₅Linked to form a 5 to 7 membered heterocyclic ring;

R₈₂₅is H, C_1-10Alkyl, arylalkyl, or R₄₂₅And R₈₂₅Taken together to form a 5 to 7 membered heterocyclic ring;

R₉₂₅is C_1-10Alkyl which may be substituted with R₈₂₅Taken together to form a 5 to 7 membered heterocyclic ring;

each Y is independently-O-or-S (O)_0-2-；

Z is a bond, -CO-, or SO₂-；

V is 0 to 4; and

each occurrence of R₂₅Independently selected from C_1-10Alkyl radical, C_1-10Alkoxy, hydroxy, halogen and trifluoromethyl;

wherein: x is-CHR₅₂₆-，-CHR₅₂₆-alkyl-, or-CHR₅₂₆-alkenyl-;

R₁₂₆selected from:

-R₄₂₆-NR₈₂₆-CR₃₂₆-NR₅₂₆-Z-R₆₂₆-an alkyl group;

-R₄₂₆-NR₈₂₆-CR₃₂₆-NR₅₂₆-Z-R₆₂₆-an alkenyl group;

-R₄₂₆-NR₈₂₆-CR₃₂₆-NR₅₂₆-Z-R₆₂₆-aryl radical

-R₄₂₆-NR₈₂₆-CR₃₂₆-NR₅₂₆-Z-R₆₂₆-a heteroaryl group;

-R₄₂₆-NR₈₂₆-CR₃₂₆-NR₅₂₆-Z-R₆₂₆-a heterocyclic group;

-R₄₂₆-NR₈₂₆-CR₃₂₆-NR₅₂₆R₇₂₆；

-R₄₂₆-NR₈₂₆-CR₃₂₆-NR₉₂₆-Z-R₆₂₆-an alkyl group;

-R₄₂₆-NR₈₂₆-CR₃₂₆-NR₉₂₆-Z-R₆₂₆-an alkenyl group;

-R₄₂₆-NR₈₂₆-CR₃₂₆-NR₉₂₆-Z-R₆₂₆-an aryl group;

-R₄₂₆-NR₈₂₆-CR₃₂₆-NR₉₂₆-Z-R₆₂₆-a heteroaryl group; and

-R₄₂₆-NR₈₂₆-CR₃₂₆-NR₉₂₆-Z-R₆₂₆-a heterocyclic group;

r226 is selected from:

-alkyl or alkenyl substituted with one or more substituents selected from:

-OH；

-a halogen;

-N(R₅₂₆)₂；

-CO-N(R₅₂₆)₂；

-CO-C_1-10an alkyl group;

-CO-O-C_1-10an alkyl group;

-N₃；

-an aryl group;

-a heteroaryl group;

a heterocyclic group;

-CO-aryl; and

-CO-heteroaryl;

each R₃₂₆Is ═ O or ═ S;

each R₄₂₆Independently an alkyl or alkenyl group, which may be interrupted by one or more-O-groups,

each R₅₂₆Independently is H or C_1-10An alkyl group;

R₆₂₆is a bond, alkyl, or alkenyl, which may be interrupted by one or more-O-groups;

R₇₂₆is H, C_1-10Alkyl, which may be interrupted by a heteroatom, or R₇₂₆Can be reacted with R₅₂₆Linked to form a 5 to 7 membered heterocyclic ring;

R₈₂₆is H, C_1-10Alkyl, arylalkyl, or R₄₂₆And R₈₂₆Combined together to form a 5 to 7 membered heterocyclic ring;

R₉₂₆is C_1-10Alkyl, with R₈₂₆Taken together to form a 5 to 7 membered heterocyclic ring;

each Y is independently-O-or-S (O)_0-2-；

Z is a bond-CO-, or SO₂-；

V is 0 to 4; and

each occurrence of R₂₆Independently selected from C_1-10Alkyl radical, C_1-10Alkoxy, hydroxy, halogen and trifluoromethyl;

and pharmaceutically acceptable salts of any of the foregoing.

In another embodiment, the IRM compound may be selected from 1H-imidazo [4, 5-c ] pyridin-4-amine compounds as defined by formula XXVII.

Wherein X is alkylene or alkenylene;

y is-CO-, -CS-, or-SO₂-；

Z is a bond, -O-, -S-, or-NR₅₂₇-；

R₁₂₇Is aryl, heteroaryl, heterocyclyl, C_1-20Alkyl or C_2-20Alkenyl, each of which may be unsubstituted or substituted with one or more substituents independently selected from:

-an alkyl group;

-an alkenyl group;

-an aryl group;

-a heteroaryl group;

-a heterocyclic group;

-a substituted cycloalkyl group;

-O-alkyl;

-O- (alkyl)_0-1-an aryl group;

-O- (alkyl)_0-1-a heteroaryl group;

-O- (alkyl)_0-1-a heterocyclic group;

-COOH；

-CO-O-alkyl;

-CO-alkyl;

-S(O)_0-2-an alkyl group;

-S(O)_0-2- (alkyl)_0-1-an aryl group;

-S(O)_0-2- (alkyl)_0-1-a heteroaryl group;

-S(O)_0-2- (alkyl)_0-1-a heterocyclic group;

- (alkyl)_0-1-N(R₅₂₇)₂；

- (alkyl)_0-1-NR₅₂₇-CO-O-alkyl;

- (alkyl)_0-1-NR₅₂₇-CO-alkyl;

- (alkyl)_0-1-NR₅₂₇-CO-aryl;

- (alkyl)_0-1-NR₅₂₇-CO-heteroaryl;

-N₃；

-a halogen;

-a haloalkyl group;

-a haloalkoxy group;

-CO-haloalkyl;

-CO-haloalkoxy;

-NO₂；

-CN；

-OH；

-SH; and oxo in the case of alkyl, alkenyl, and cycloalkyl;

R₂₂₇selected from:

-hydrogen;

-an alkyl group;

-an alkenyl group;

-alkyl-O-alkyl;

-alkyl-S-alkyl;

-alkyl-O-aryl;

-alkyl-S-aryl;

-alkyl-O-alkenyl;

-alkyl-S-alkenyl; and

-alkyl or alkenyl substituted with one or more substituents selected from:

-OH；

-a halogen;

-N(R₅₂₇)₂；

-CO-N(R₅₂₇)₂；

-CS-N(R₅₂₇)₂；

-SO₂-N(R₅₂₇)₂；

-NR₅₂₇-CO-C_1-10an alkyl group;

-NR₅₂₇-CS-C_1-10an alkyl group;

-NR₅₂₇-SO₂-C_1-10an alkyl group;

-CO-C_1-10an alkyl group;

-CO-O-C_1-10an alkyl group;

-N₃；

-an aryl group;

-a heteroaryl group;

-a heterocyclic group;

-CO-aryl; and

-CO-heteroaryl;

R₃₂₇and R₄₂₇Independently selected from: hydrogen, alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino and alkylthio;

each R₅₂₇Independently is H or C_1-10An alkyl group;

and pharmaceutically acceptable salts thereof.

The terms "alkyl", "alkenyl" and the prefix "alk/en (alk-)" as used herein include not only straight and branched chain groups but also cyclic groups, i.e., cycloalkyl and cycloalkenyl. Unless otherwise specified, these groups include from 1 to 20 carbon atoms and the alkenyl groups include from 2 to 20 carbon atoms. Preferred groups have up to 10 carbon atoms in total. The cyclic group may be monocyclic or polycyclic, and preferably has 3 to 10 ring carbon atoms. Exemplary cyclic groups include cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, and adamantyl.

The term "haloalkyl" includes groups substituted with one or more halogen atoms, including perfluorinated groups. These apply equally to groups comprising the prefix "halo-". Examples of suitable haloalkyl groups are chloromethyl, trifluoromethyl and the like.

The term "aryl" as used herein includes carbocyclic aromatic rings or ring systems. Examples of aryl groups include phenyl, naphthyl, biphenyl, fluorenyl, and indenyl. The term "heteroaryl" includes those aromatic rings or ring systems containing at least one ring heteroatom (e.g., O, S, N). Suitable heteroaryl groups include furyl, thienyl, pyridyl, quinolyl, isoquinolyl, indolyl, isoindolyl, triazolyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl, benzimidazolyl, quinoxalinyl, benzothiazolyl, 1, 5-diazanaphthyl, isoxazolyl, isothiazolyl, purinyl, quinazolinyl, and the like.

"Heterocyclyl" includes those non-aromatic rings or ring systems containing at least one ring heteroatom (e.g., O, S, N), and includes fully saturated as well as partially unsaturated derivatives of all of the above-mentioned heteroaryls. Exemplary heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, imidazolidinyl, isothiazolidinyl, and the like.

In some embodiments, the topical formulations of the present invention are prepared using the IRM compound in free base form.

The amount of an IRM compound that is therapeutically effective for a particular condition will be determined based on factors such as the activity of the particular compound, the manner of dosing, the site of administration, the particular formulation, and the condition to be treated. Also, it is generally not feasible to determine a specific amount administered herein; however, one skilled in the art will be able to determine an appropriate therapeutically effective amount based on the guidance provided herein, information in the art relating to such compounds, and routine testing. The term "therapeutically effective amount" refers to an amount of a compound sufficient to induce a therapeutic effect, such as cytokine induction, inhibition of TH2 immune response, antiviral or antitumor activity, reduction or elimination of post-operative scarring, or reduction or elimination of actinic keratosis or pre-actinic keratosis lesions.

Generally, the amount of IRM compound present in the topical formulations of the present invention is an amount effective to treat the condition of interest, prevent recurrence of the condition, or promote immunity against the condition. The amount or concentration of the IRM compound may range from 0.001 wt% to 10 wt%, such as, for example, from 0.03 wt% to 5.0 wt%, or from 0.1 to 1.0 wt%, based on the total formulation weight. In particular embodiments, the amount of IRM compound is at least 0.003 wt%, such as, for example, at least 0.005%, at least 0.01%, at least 0.03%, at least 0.10%, at least 0.30%, and at least 1.0%. In other embodiments, the amount of IRM compound is up to 5.0 wt%, such as, for example, up to 3.0%, and up to 1.0%.

The topical formulations of the present invention additionally comprise fatty acids. The term "fatty acid" as used herein refers to a saturated or unsaturated carboxylic acid comprising 6 to 28 carbon atoms, such as, for example, from 10 to 22 carbon atoms. Non-limiting examples of such fatty acids include isostearic acid of 6 to 18 carbon atoms, oleic acid and linear or branched carboxylic acids. The amount of fatty acid present in the formulation of the present invention should be sufficient to solubilize the IRM compound. In one embodiment, the amount of fatty acid may range from 0.05 wt% to 40 wt% based on the weight of the formulation, such as, for example, from 1% to 30%, from 3% to 15% and from 5% to 10%. In certain embodiments, the amount of fatty acid is at least 3.0 wt%, such as, for example, at least 5.0%, at least 10.0%, and at least 25%. The fatty acid component of the formulation may comprise one or more fatty acids.

The topical formulations of the present invention additionally comprise at least one hydrophobic aprotic component which is miscible with the fatty acid, and a hydrocarbon group comprising 7 or more carbon atoms. The term "hydrophobic" means that the component is substantially water-insoluble, i.e. immiscible with water and incapable of forming microcapsules in water, and does not contain polyethylene oxide or acid salt groups. Preferably, the hydrophobic aprotic component has a Hydrophilic Lipophilic Balance (HLB) of less than 2. The HLB of one component can be determined as described, for example, in Attwood, d., Florence, a.t. surfactant systems: its chemistry, pharmacy, and biology, new york: chapman & Hall, 471-. The term "aprotic" means that the component is incapable of donating a proton to the IRM and does not contain groups such as carboxyl, hydroxyl, primary and secondary amino, primary and secondary amide, or quaternary amine groups. Preferably, such components have a pKa of at least 14.2 and are substantially insoluble or form complexes such as acid-base pairs or complexes or hydrogen bond complexes with IRM compounds. The term "substantially free" means that the ratio of the solubility of the IRM compound in the hydrophilic aprotic component to the solubility of the IRM compound in isostearic acid is less than 1: 40.

Formulations intended for dermal or topical use desirably have a certain minimum amount of oil phase to provide properties such as spreadability, skin feel, texture, and the like. However, if all of the oil phase components dissolve the IRM, the saturation of the IRM in the formulation will decrease, making it more difficult to deliver the IRM from the formulation to the skin. The addition of the hydrophobic aprotic component can increase the oil phase volume of the topical formulation in order to provide desirable characteristics such as spreadability and feel, while not significantly altering the IRM's saturation or thermodynamic activity. For example, the amount of fatty acids that solubilize the IRM can be reduced to increase IRM saturation while maintaining sufficient oil phase volume by virtue of the addition of hydrophobic aprotic components that do not compensate for the increased IRM saturation. Thus, the topical formulations of the present invention may contribute to the physical properties and needs of administration. The IRM saturation and thermodynamic activity in these formulations corresponds to the concentration of IRM in the oil phase divided by the saturation concentration of IRM in the oil phase. When the topical formulation of the present invention contains a saturated IRM, the thermodynamic activity or saturation is consistent, and when partially saturated, the thermodynamic activity or saturation is inconsistent.

The amount of hydrophobic aprotic component in the formulations of the invention may be from 1 wt% to 30 wt%, for example from 3 wt% to 15 wt%, and from 5 wt% to 10 wt%, based on the total weight of the formulation. In certain embodiments, the amount of hydrophobic aprotic component is at least 3.0 wt%, such as, for example, at least 5.0%, at least 10.0%. The weight ratio of hydrophobic aprotic component to fatty acid can be from 0.025:1 to 600:1, e.g., from 0.5:1 to 50:1, and from 2:1 to 30: 1. The combined amount of hydrophobic aprotic component and fatty acid (total topical formulation weight/weight percent) can be from 2 wt% to 50 wt%, e.g., from 2% to 30%, from 5% to 30%, 5% to 20%, and 10% to 20%.

Examples of useful hydrophobic aprotic components include, but are not limited to, fatty acid esters, e.g., isopropyl myristate (isopropyl mysristerate), isopropyl palmitate, diisopropyl dimer dilinoleate; triglycerides, such as caprylic/capric triglyceride; cetyl esters wax; hydrocarbons of 8 or more carbon atoms, such as light mineral oil, white petrolatum; and waxes, for example, beeswax. In some embodiments, the hydrophobic aprotic component is selected from one or more of isopropyl myristate, isopropyl palmitate, caprylic/capric triglyceride, and diisopropyl dimer dilinoleate.

The formulation of the present invention may also contain a hydrophilic viscosity enhancer. Examples of suitable hydrophilic viscosity enhancing agents include cellulose ethers such as hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and carboxymethyl cellulose; polysaccharide gums such as xanthan gum; and homopolymers of acrylic acid and copolymers of acrylic acid crosslinked with allyl sucrose or allyl pentaerythritol, such as those polymers designated as carbomers in the U.S. pharmacopoeia. Suitable carbomers include, for example, the available carbopols^TM934P, Carbopol 971P, Carbopol940, Carbopol 974P, Carbopol 980, and Pemulen^TMTR-1 (United states Pharmacopeia/NF monograph; carbomer 1342), all of which are available from Noveon, Cleveland, Ohio. In one embodiment of the invention, the tack enhancer is selected from Carbopol 974P and 980. When included, the viscosity enhancing agent is typically present in an amount of from 0.1 wt% to 10 wt%, such as, for example, from 0.5 wt% to 5 wt%, from 0.5 wt% to 1.5 wt%, and from 0.7 wt% to 3 wt%, based on the total formulation weight. In certain embodiments, the amount of the tack enhancer is at least 0.5 wt%, for example, at least 0.6 wt%, at least 0.7 wt%, at least 0.9 wt%, and at least 1.0 wt%.

The formulation of the present invention additionally comprises an emulsifier. Suitable emulsifiers include nonionic surfactants such as, for example, polysorbate 60, sorbitan monostearate, polyglycerol-4 oleate, polyoxyethylene (4) lauryl ether and the like. In a particular embodiment, the emulsifier is selected from poloxamers (e.g., obtained from BASF, Lu)Pluronic in dwigshafen, Germany^TMF68, also known as poloxamer 188, poly (ethylene glycol) -block-poly (propylene glycol) -block-poly (ethylene glycol)), and sorbitan trioleate (e.g., Span85 available from Uniqema, New Castle, DE). If included, the emulsifier is typically present in an amount of from 0.1 wt% to 10 wt%, such as from 0.5 wt% to 5 wt%, and from 0.75 wt% to 3.5 wt%, based on the total formulation weight. In particular embodiments, the amount of emulsifier is at least 1.0 wt%, e.g., at least 2.5%, at least 3.5%, and at least 5.0%.

In a particular embodiment of the invention, the formulation may further comprise at least one chelating agent. The chelating agent serves to chelate metal ions that may be present in the formulation. Suitable chelating agents include salts of ethylenediaminetetraacetic acid (EDTA), such as the disodium salt. If included, the chelating agent is typically present in an amount of from 0.001 wt% to 0.1 wt%, preferably from 0.01 wt% to 0.05 wt%. In particular embodiments, the amount of chelating agent is at least 0.005 wt%, such as, for example, at least 0.01%, and at least 0.05%.

The formulation may also be a preservative system. The preservative system typically comprises at least one preservative compound selected from methyl paraben, ethyl paraben, propyl paraben, phenoxyethanol, iodopropynyl butylcarbamate (iodopropyl butyrylcarbamate), sorbic acid, fatty acid monoesters of glycerol such as glycerol monolaurate, and propylene glycol, such as propylene glycol monocaprylate. The preservative system may also include a preservative solubilizer to enhance the solubility of the preservative in the aqueous phase, examples of which include diethylene glycol monoethyl ether and propylene glycol. In one embodiment, the preservative system consists of methylparaben, propylparaben, and propylene glycol. In another embodiment, the preservative system consists of methylparaben, ethylparaben, and diethylene glycol monoethyl ether. In one embodiment, the preservative system consists of phenoxyethanol, methyl and ethyl parabens, and diethylene glycol monoethyl ether. In another embodiment, the preservative system may consist of iodopropynyl butyl carbamate. In another embodiment, the preservative system may consist of iodopropynyl butyl carbamate, diethylene glycol monoethyl ether, and poly (ethylene glycol) (4) monolaurate. In another embodiment, the preservative system may consist of iodopropynyl butyl carbamate, one or more of methyl paraben, ethyl paraben, propyl paraben, or phenoxyethanol, and diethylene glycol monoethyl ether. In the above embodiments, methyl paraben, ethyl paraben, and propyl paraben may be present in the formulation in an amount of from 0.01 to 0.5, e.g., from 0.05 to 0.25, and from 0.1 to 0.2, weight percent, respectively, based on the weight of the formulation. The amount of iodopropynyl butyl carbamate present in the formulation is from 0.01% to 0.1%. The amount of phenoxyethanol present in the formulation is from 0.1% to 1%. Propylene glycol and diethylene glycol monoethyl ether may be present in the formulation in an amount of from 1 wt% to 30 wt%, such as, for example, from 5 wt% to 25 wt%, and from 10 wt% to 15 wt%, respectively, based on the weight of the formulation. The preservative system can be present in the formulation in an amount of from 0.01 wt% to 30 wt%, for example, from 0.05 wt% to 30 wt%, from 0.1 wt% to 25 wt%, and from 0.2 wt% to 15 wt%, based on the weight of the formulation. In further embodiments, methyl paraben, ethyl paraben, propyl paraben, iodopropynyl butyl carbamate, and phenoxyethanol may be dissolved in propylene glycol, poly (ethylene glycol) (4) monolaurate, or diethylene glycol-monoethyl ether prior to addition to the formulation. The selection of the preservative system should meet the requirements of the standard for bactericidal effect in the united states pharmacopeia <51 >.

The formulations of the present invention may additionally comprise at least one pH adjusting agent. Suitable pH adjusting agents include organic bases as well as inorganic bases such as, for example, KOH, NaOH. The pH of the topical formulations of the present invention typically ranges from 3.5 to 7.0. In one embodiment, the pH of the topical formulation of the present invention may be in the range of 4.0 to 6.0, preferably 5.0. In another embodiment, the pH of the topical formulation of the present invention may be in the range of 5.5 to 6.5, preferably 6.0.

Any of the above formulations may be in the form of an oil-in-water emulsion, such as a cream or lotion. Such an emulsion may comprise an oil phase containing the IRM compound in an amount sufficient to solubilize the fatty acids of the IRM compound, a hydrophobic aprotic component; and an aqueous phase comprising a hydrophilic viscosity enhancing agent, e.g., a carbomer. In particular embodiments, the amount or concentration of IRM in the oil phase may be at least 0.01%, e.g., at least 0.02%, at least 0.1%, and at least 1% relative to the weight of the oil phase. In other embodiments, the amount or concentration of IRM in the oil phase may be up to 20%, e.g., up to 10%, and up to 5% by weight of the oil phase. The emulsions may be preserved to meet regulatory requirements for topical creams packaged in multiple use containers when challenged with antimicrobial efficacy tests.

Any of the above formulations according to the present invention may be applied to the skin surface of a mammal. Depending on the concentration of the IRM compound, the formulation composition, and the skin surface, the therapeutic effect of the IRM compound may only extend to the superficial layer of the skin surface or to the tissue below the skin surface. Accordingly, another aspect of the invention relates to a method of treating a skin-related condition comprising applying to the skin one of the formulations described above. As used herein, a "skin-related condition" refers to an inflammatory, infectious, neoplastic or other condition involving the surface of the skin, or a condition sufficiently close to the surface of the skin to be affected by a therapeutic agent topically applied to the skin surface. Examples of skin-related conditions include warts, atopic dermatitis, basal cell carcinoma of the skin, post-operative scars, and actinic keratosis.

In one embodiment, the formulation may be applied to the surface of the skin for the treatment of Actinic Keratosis (AK). Actinic keratosis is a premalignant lesion that is biologically recognized as either an carcinoma in situ or a squamous intraepidermal tumor. AK is the most common epidermal tumor and is induced by ultraviolet radiation (UV), usually from sunlight. Because of its precancerous nature, AK can be considered to be the most important manifestation of sun-induced skin damage.

In some embodiments, the formulations described above are particularly advantageous for application to the skin for a period of time sufficient to achieve the desired therapeutic effect without undesirable systemic absorption of the IRM.

Examples

The following examples are presented to further illustrate the various IRM formulations and methods of manufacture of the present invention. However, the examples should not limit the formulations and methods within the spirit and scope of the invention.

Examples 1-7 and comparative example Cl

Table 1 summarizes the topical formulations made according to the present invention, expressed as weight/weight percent.

The formulations listed in table 1 were prepared in the following manner:

oil phase preparation: 2-methyl-1- (2-methylpropyl) -1H-imidazo [4, 5-c ] [1, 5] naphthyridin-4-amine (IRM Compound 1) is dissolved in isostearic acid and isopropyl myristate, and heated if necessary. The carbomer 974P is then dispersed in the oil phase.

Aqueous phase preparation: disodium ethylenediaminetetraacetate was dissolved in water. Methyl and propyl parabens are dissolved in propylene glycol and the solution is then added to the aqueous phase. Poloxamer (Poloxamer)188 is then added to the aqueous phase and mixed until dissolved.

Mixing the materials: the oil phase was added to the aqueous phase at ambient conditions. The emulsion was then homogenized. After homogenisation, sodium hydroxide solution (20% w/w) was added and the resulting cream was mixed until smooth and homogeneous. The pH of the cream was measured and adjusted, if necessary, with additional sodium hydroxide solution to meet the production target pH of 5.

Formulations containing 2-methyl-1- (2-methylpropyl) -1H-imidazo [4, 5-c ] [1, 5] naphthyridin-4-amine (IRM compound 1) were tested for their ability to induce an increase in rat cytokine concentrations after topical administration. These studies were conducted to evaluate cytokine induction following single dose IRM compound 1 administration at various concentrations and at various time points, or multiple dose administration versus single dose IRM compound 1 administration. The formulations described above were tested by determining tissue and serum concentrations of TNF- α, MCP-1 (monocyte chemotactic protein-1) and IFN- α cytokines after drug treatment.

Female CD hairless rats weighing 200-250 grams (Charles river laboratories, Wilmington, Mass.) were used in all studies. Animals were randomized into experimental groups and administered 5 times per experimental group.

Rats were acclimatized to the neck collar two consecutive days prior to actual dosing. Rats were ringed prior to dosing to prevent ingestion of the drug and then dosed topically on the right flank with 50 μ l of active cream or appropriate placebo, followed by separate containment after dosing. At different time points after dosing, rats were anesthetized and blood was collected by cardiac puncture. Blood was coagulated at room temperature, serum was separated from the clot by centrifugation and stored at-20 ℃ until used for analysis of cytokine concentrations.

After blood collection, rats were euthanized and their skin removed. Tissues were obtained from the treatment site (in place) and the contralateral site (out of place) using an 8mm punch biopsy, weighed, placed in a sealed 1.8ml cryovial and flash frozen in liquid nitrogen. The frozen tissue samples were then suspended in 1.0mL of RPMI medium (Celox, Hopkins, MN) containing 10% fetal bovine serum (Sigma, St. Louis, MO), 2mM L-glutamine, penicillin/streptomycin, and 2-mercaptoethanol (RPMI complete) in combination with a cocktail of protease inhibitors of set III (Calbiochem, San Diego, Calif.). Using Tissue Tearor^TM(Biospec Products, Bartlesville, OK.) the tissue was homogenized for approximately 1 minute. The tissue suspension was then cryocentrifuged at 2000rpm for 10 minutes to obtain pellet debris and the supernatant was collected and stored at-20 ℃ until analysis for cytokine concentration.

Enzyme-linked immunosorbent assay reagents for rat MCP-1 were purchased from BioSource Intl. (Camarillo, Calif.) and rat TNF- α was purchased from BD Pharmingen (San Diego, Calif.) and were run according to the manufacturer's instructions. The products of TNF- α and MCP-1 are expressed as pg/200mg tissue or pg/ml serum. The sensitivity of TNF-alpha enzyme-linked immunosorbent assay is 31.2pg/ml, and the sensitivity of MCP-1 enzyme-linked immunosorbent assay is 11.7 pg/ml. The determination of the IFN-. alpha.concentration in serum and dermal tissues was performed using the previously described (Reiter, M.J., Testerman, T.L., Miller, R.L., Weeks, C.E., and Tomai, M.A. (1994) "Induction of mouse cytokines by the immunomodulator Imiquimod" J.Leucocyte biol.55, 234-240) bioassay to determine the inhibition of the cytopathic effect of mouse LMS-C2 fibroblasts by vesicular stomatitis virus. The IIT institute, Chicago IL, performed these analyses. The resulting IFN- α concentrations were normalized to standard reference rat IFN- α, and the formulation results were reported as U/mL and normalized per mg of tissue.

The data shown in tables 2-4 below are from three separate experiments and analyzed for 1) pharmacokinetics over the entire time period, 2) dose response, and 3) multiple dose versus single dose administration.

To determine the kinetics of local and systemic cytokine production following topical administration of IRM compound 1, a full time period study was conducted by topical administration of rats with the topical cream formulation of example 7 (study 1 was conducted with the results of table 2). Serum and tissue samples were collected at 1, 2, 4, 8, 16, 24 and 48 hours post-dose. A variety of cytokines (MCP-1, TNF-alpha and IFN-alpha) were analyzed separately.

The differences between treated and control tissues of the same animal were analyzed by paired t-test (to eliminate subject variability) from the hourly measured tissue data. A p-value less than 0.05 showed a statistically significant difference between the treated and control tissues at that hour. The data are listed in table 2.

TABLE 2 cytokine concentrations in rat serum and dermal tissue all time after administration of the topical formulation of example 7^a

^aFemale hairless CD rats were administered topically with compound 1 in a cream formulation.

^bTNF-alpha and MCP-1 were assayed by ELISA. Determination of IFN-alpha by bioanalysis_。Results in serum samples are expressed as pg/ml, while results for tissue samples are expressed as pg/200mg tissue and are expressed as mean ± SEM of 5 animals.

^CShows the difference, p, between treated and control tissues when compared to placebo-treated serum samples or of the same animals<0.05。

A multiple dose study was used to monitor the effect of the multiple dose regimen (study 2 conducted with the results shown in table 3). Rats were dosed twice a week for a total of 6 hours for three weeks with the topical cream formulation of example 5. Rats were administered placebo (comparative example C1) and a single dose for comparison and concurrently with the last dose of the multiple dose group. Serum and tissue samples were taken at 8 and 24 hours post-dose and analyzed for MCP-1.

Study 2 was subjected to the same analysis as study 1. These data sets were resolved by treatment (multiple dose or single dose application) and at different time points prior to analysis. Again, only data from placebo treatment of single dose applications at the 8 hour time point were recorded, but used to compare placebo to each treatment and time, respectively. The results are listed in table 3 below.

TABLE 3 comparison of cytokine concentrations in rat serum and dermal tissue treated with multiple doses after topical application of the topical cream formulation of example 5^a

^aFemale hairless CD rats were administered topically with compound 1 in a cream formulation.

^bMCP-1 was determined by ELISA. Results in serum samples are expressed as pg/ml, results in tissue samples are expressed as pg/200mg tissue, and are expressed as mean ± SEM of 5 animals.

^CShows the difference, p, between treated and control tissues when compared to placebo-treated serum samples or of the same animals<0.05。

A dose response study was performed by administering the topical cream formulations of examples 3-5 and 7 containing different concentrations of IRM compound 1 (study 3 was performed with the results shown in table 4). Serum and tissue samples were taken at 8 and 24 hours post-dose and analyzed for MCP-1. A topical delivery study was performed on creams containing IRM compound 1, which was tested for its ability to affect local MCP-1 induction at 4 concentrations.

Serum data were compared separately for the active treatment group and the placebo (comparative example C1) group at each given time point. Note that the placebo group was measured only 24 hours after dosing, and these observations were compared with each time point of the active group.

TABLE 4 cytokine concentrations in rat serum and dermal tissue following topical administration of the formulations of examples 3-5 and 7^a

^aFemale hairless CD rats were administered topically with compound 1 in a cream formulation.

^bMCP-1 was determined by ELISA. Results in serum samples are expressed in pg/ml, results in tissue samples are expressed in pg/200mg tissue and are expressed as mean ± SEM of 5 animals.

^CShows the difference, p, between treated and control tissues when compared to placebo-treated serum samples or of the same animals<0.05。

Examples 8 to 13

Table 5 summarizes the topical formulations made according to the present invention, expressed as weight/weight percent.

TABLE 5

The formulations listed in table 5 were prepared in the following manner:

oil phase preparation: n- [4- (4-amino-2-butyl-1H-imidazo [4, 5-c ] [1, 5] naphthyridin-1-yl) butyl ] -N' -cyclohexylurea (IRM Compound 2) is dissolved in isostearic acid and isopropyl myristate, if necessary, with heating. The carbomer 974P is then dispersed in the oil phase.

Aqueous phase preparation: disodium ethylenediaminetetraacetate was dissolved in water. Methyl and propyl parabens are dissolved in propylene glycol and the solution is then added to the aqueous phase. Poloxamer 188 was then added to the aqueous phase and mixed until dissolved.

Mixing the materials: the oil phase was added to the aqueous phase at ambient conditions. The emulsion was then homogenized. After homogenisation, sodium hydroxide solution (20% w/w) was added and the resulting cream was mixed until smooth and homogeneous. The pH of the cream was measured and adjusted, if necessary, with additional sodium hydroxide solution to meet the target pH value of 5 in production.

Formulations containing N- [4- (4-amino-2-butyl-1H-imidazo [4, 5-c ] [1, 5] naphthyridin-1-yl) butyl ] -N' -cyclohexylurea (IRM Compound 2) were tested for their ability to induce an increase in rat cytokine concentrations following topical administration. These studies were conducted to evaluate cytokine induction following single dose administration or multiple dose administration with single dose administration of IRM compound 2 at different concentrations and at different time points. The formulations described above were tested by examining tissue and serum concentrations of TNF- α, MCP-1 and IFN- α following drug treatment as described in examples 1-7.

The data shown in tables 6-8 below are from three separate experiments and analyzed for 1) determination of pharmacokinetics over the full time period, 2) determination of dose response and 3) determination of multiple doses versus single dose data.

To determine the kinetics of local and systemic cytokine production following topical administration of IRM compound 1, a full time period study was conducted by topical administration to rats as described in examples 1-7 using the topical cream formulation of example 11 (study 1 was conducted with the results shown in table 6). The data are shown in table 6.

TABLE 6 cytokine concentrations in rat serum and dermal tissue all time after administration of the topical formulation of example 11^a

^aFemale hairless CD rats were administered topically with compound 2 in cream formulation.

^bTNF-alpha and MCP-1 were measured by ELISA. Results in serum samples are expressed in pg/ml, results in tissue samples are expressed in pg/200mg tissue and are expressed as mean ± SEM of 5 animals.

^CShows the difference, p, between treated and control tissues when compared to placebo-treated serum samples or of the same animals<0.05。

A multiple dose study was used to monitor the effect of the multiple dose regimen (study 2 conducted with the results shown in table 7). Rats were dosed twice a week for a total of 6 hours for three weeks with the topical cream formulation of example 10. Rats were given placebo (comparative example C1) and a single dose for comparison, and concurrently with the last dose of the multiple dose group. Serum and tissue samples were taken at 16 and 24 hours post-dose and analyzed for MCP-1.

Study 1 was subjected to the same analysis as study 1. These data sets were resolved by treatment (multiple or single use) and at different time points prior to analysis. Again, only 16 hour time points were recorded for single use placebo data, but were used to compare placebo to each treatment and time point combination, respectively. The results are listed in table 7 below.

TABLE 7 comparison of cytokine concentrations in rat serum and dermal tissue after topical application of the topical cream formulation of example 10, multiple dose and single dose administration^a

^aFemale hairless CD rats were administered topically with compound 2 in cream formulation.

^bMCP-1 was determined by ELISA. Results in serum samples are expressed in pg/ml, results in tissue samples are expressed in pg/200mg tissue and are expressed as mean ± SEM of 5 animals.

^CShows the difference, p, between treated and control tissues when compared to placebo-treated serum samples or of the same animals<0.05。

A dose response study was performed by administering the topical cream formulations of examples 8-11 containing different concentrations of IRM compound 2 (study 3 was performed with the results shown in table 8). Serum and tissue samples were taken at 16 and 24 hours post-dose and analyzed for MCP-1. Topical delivery of creams containing IRM compound 2 was studied and tested for its ability to affect local MCP-1 induction at 4 concentrations.

Serum data for active treatment were compared to placebo (comparative example C1) separately at each given time point. Note that the placebo group was measured only 16 hours after dosing and these observations were compared to each time point in the active group.

TABLE 8 cytokine concentrations in rat serum and dermal tissue following topical administration of the formulations of examples 8-11^a

^aFemale hairless CD rats were administered topically with compound 2 in cream formulation.

^bMCP-1 was determined by ELISA. Results in serum samples are expressed in pg/ml, results in tissue samples are expressed in pg/200mg tissue and are expressed as mean ± SEM of 5 animals.

^CShows the difference, p, between treated and control tissues when compared to placebo-treated serum samples or of the same animals<0.05。

Examples 14 to 18

Table 9 summarizes the topical formulations made according to the present invention, expressed as weight/weight percent.

TABLE 9

^*Available from Uniquema, NewCastle, DE under the trade name PRIPURE3786

^**Available under the trade name Crodamol GTCC-PN from Croda, Parsippany, NJ.

Examples 19 to 24

Table 10 summarizes the topical formulations made according to the present invention, expressed as weight/weight percent.

Watch 10

The formulations described in tables 9 and 10 were prepared using the following general procedure:

oil phase preparation:

the IRM compound is dissolved in isostearic acid and diisopropyl dimer dilinoleate (or caprylic/capric triglyceride) and heated if necessary.

Aqueous phase preparation:

dissolving disodium ethylenediamine tetraacetate in water. Poloxamer 188 was then added to the aqueous phase and mixed until dissolved. The carbomer 980 is added to the aqueous phase and mixed until the carbomer is completely dispersed and hydrated. Methyl and propyl parabens were dissolved in diethylene glycol monoethyl ether and the solution was subsequently added to the aqueous phase.

Mixing the materials: the oil phase was added to the aqueous phase at ambient conditions. The emulsion was then homogenized. After homogenisation, sodium hydroxide solution (20% w/w) was added and the resulting cream was mixed until smooth and homogeneous. The pH of the cream was measured and adjusted, if necessary, with additional sodium hydroxide solution to meet the target pH value of 5 in production.

Examples 25 to 28

Table 11 summarizes the topical formulations made according to the present invention, expressed as weight/weight percent.

TABLE 11

Examples 29 to 135

Topical creams containing the IRM compounds listed in Table 12 were prepared using the general method described in examples 1-24. Each IRM was formulated into one or more of the model formulations shown in tables 13 and 14. Table 15 summarizes the topical creams prepared.

TABLE 12

IRM compounds	Chemical name
		3	1- (2-methylpropyl) -1H-imidazo [4, 5-c]Quinoline-4-amines
4	1- (2-methylpropyl) -1H-imidazo [4, 5-c][1，8]Naphthyridin-4-amines
		5	2-butyl-1- (2-methylpropyl) -1H-imidazo [4, 5-c][1，8]Naphthyridin-4-amines
6	1- (2-methylpropyl) -1H-imidazo [4, 5-c][1，5]Naphthyridin-4-amines
		7	2-methylthiazolo [4, 5-c ]]Quinoline-4-amines
8	2-ethoxymethyl-1-benzyl-1H-imidazo [4, 5-c][1，5]Naphthyridin-4-amines
		9	2-ethylthiazolo [4, 5-c ]]Quinoline-4-amines
10	4-amino-2-butyl-alpha, alpha-dimethyl-1H-imidazolesAzolo [4, 5-c][1，5]Naphthyridine-1-ethanol
		11	N- [2- (4-amino-1H-imidazo [4, 5-c ]]Quinolin-1-yl) ethyl]Benzamide derivatives
12	1- {2- [3- (3-pyridinyl) propoxy group]Ethyl } -1H-imidazo [4, 5-c)]Quinoline-4-amines
		13	1- (2-phenoxyethyl) -1H-imidazo [4, 5-c]Quinoline-4-amines
14	1- [ (R) -1-phenylethyl group]-1H-imidazo [4, 5-c][1，5]Naphthyridin-4-amines
		15	N- [4- (4-amino-1H-imidazo [4, 5-c ]]Quinolin-1-yl) butyl]-4-morpholinamides
16	N- [4- (4-amino-1H-imidazo [4, 5-c ]]Quinolin-1-yl) butyl]Nicotinamide
		17	1-2- [3- (1, 3-thiazol-2-yl) propoxy group]Ethyl } -1H-imidazo [4, 5-c)]Quinoline-4-amines
18	1- [2- (pyridin-4-ylmethoxy) ethyl]-1H-imidazo [4, 5-c]Quinoline-4-amines
		19	2-methyl-1- [5- (methylsulfonyl) pentyl]-1H-imidazo [4, 5-c]Quinoline-4-amines
20	N- [3- (4-amino-2-methyl-1H-imidazo [4, 5-c)]Quinolin-1-yl) propyl]Cyclohexanamides
		21	N- [3- (4-amino-2-methyl-1H-imidazo [4, 5-c)]Quinolin-1-yl) propyl]-2-methylpropionamide
22	N- [3- (4-amino-2-methyl-1H-imidazo [4, 5-c)]Quinolin-1-yl) propyl]Butylamide
		23	2-butyl-1- {2- [ (1-methylethyl) sulfonyl]Ethyl } -1H-imidazo [4, 5-c)]Quinoline-4-amines
24	N- {2- [ 4-amino-2- (ethoxymethyl)Radical) -1H-imidazo [4, 5-c]Quinolin-1-yl]Ethyl ethane sulfonic acid amide
		25	N- {2- [ 4-amino-2- (ethoxymethyl) -1H-imidazo [4, 5-c]Quinolin-1-yl]Ethyl propane amide
26	1- [2- (methylsulfonyl) ethyl]-2-propyl-1H-imidazo [4, 5-c]Quinoline-4-amines
		27	N-2- [ 4-amino-2- (ethoxymethyl) -1H-imidazo [4, 5-c]Quinolin-1-yl]Ethyl } -N' -ethylthiourea
28	2-Ethyl-1- {4- [ (1-methylethyl) sulfonyl]Butyl } -1H-imidazo [4, 5-c)]Quinoline-4-amines
		29	2-Ethyl-1- [4- (ethylsulfonyl) butyl]-1H-imidazo [4, 5-c]Quinoline-4-amines
30	N- {3- [ 4-amino-2- (ethoxymethyl) -1H-imidazo [4, 5-c]Quinolin-1-yl]Propyl cyclopentaneamide
		31	N- {3- [ 4-amino-2- (ethoxymethyl) -6, 7-dimethyl-1H-imidazo [4, 5-c [ ]]Pyridin-1-yl]Propyl morpholine-4-amide
32	1- (2-methylpropyl) -6, 7, 8, 9-tetrahydro-1H-imidazo [4, 5-c]Quinoline-4-amines
		33	8,9, 10, 11-tetrahydropyrido [1 ', 2': 1,2]Imidazo [4, 5-c)]Quinoline-6-amines
34	4-amino-alpha, 2-trimethyl-6, 7, 8, 9-tetrahydro-1H-imidazo [4, 5-c]Quinoline-1-ethanol
		35	2-hydroxymethyl group-1- (2-methylpropyl) -6, 7, 8, 9-tetrahydro-1H-imidazo [4, 5-c]Quinoline-4-amines
36	2-butyl-1- (2-phenoxyethyl) -1H-imidazo [4, 5-c][1，5]Naphthyridin-4-amines
		37	N- [3- (4-amino-2-methyl-1H-imidazo [4, 5-c)]Quinolin-1-yl) propyl]Methane sulfonamides

Watch 13

^*Qs (amount complement) to 100

TABLE 14

Watch 15

Examples	Compound (I)	Model formulations
			29	3	A
30	3	B
			31	3	C
32	4	A
			33	4	B
34	4	C
			35	5	A

Examples	IRM compounds	Model formulations
			36	5	B
37	5	D
			38	6	A
39	6	B
			40	6	C
41	7	A
			42	7	B
43	7	C
			44	8	A
45	8	B
			46	8	C
47	9	A
			48	9	B
49	9	C
			50	10	A
51	10	B
			52	10	C
53	11	A
			54	11	B
55	11	E
			56	12	A
57	12	B
			58	12	C
59	13	A
			60	13	B
61	13	F
			62	14	A
63	14	B

Examples	IRM compounds	Model formulations
			64	14	G
65	15	H
			66	15	I
67	15	K
			68	16	H
69	16	I
			70	16	K
71	17	A
			72	17	B
73	17	C
			74	18	H
75	18	I
			76	18	K
77	19	H
			78	19	I
79	19	K
			80	20	H
81	20	I
			82	20	K
83	20	L
			84	20	M
85	21	H
			86	21	I
87	21	K
			88	22	H
89	22	I
			90	22	J
91	23	H

Examples	IRM compounds	Model formulations
			92	23	I
93	23	J
			94	24	H
95	24	I
			96	24	K
97	25	H
			98	25	I
99	25	K
			100	26	H
101	26	I
			102	26	K
I03	27	H
			104	27	I
105	27	K
			106	28	H
107	28	I
			108	28	K
109	29	H
			110	29	I
111	29	K
			112	30	H
113	30	I
			114	30	K
115	31	H
			116	31	I
117	31	K
			118	32	A
119	32	B

Examples	IRM compounds	Model formulations
			120	32	C
121	33	A
			122	33	B
123	33	C
			124	34	A
125	34	B
			126	34	C
127	35	A
			128	35	B
129	35	C
			130	36	A
131	36	B
			132	36	C
133	37	H
			134	37	I
135	37	K

The topical creams of examples 29-135 were tested using the test method described below. The results are shown in table 16 below, where each value is the average of 3 rats in the treatment group.

Single dose MCP-1 induction test method

Female CD hairless rats weighing 200-250 grams (Charles River laboratories, Wilmington, Mass.) were used. Animals were randomized into treatment groups and three administrations per group were given.

Rats were acclimatized to the neck collar two consecutive days prior to actual dosing. A 50 μ L dose of active cream or suitable placebo was applied to the right wing and gently rubbed into the skin of the rat. Rats were then ringed and housed individually to prevent ingestion of the drug. At selected post-treatment time points, rats were anesthetized and blood (3ml) was collected by cardiac puncture. Blood was coagulated at room temperature. Serum was separated from the clot by centrifugation and stored at-20 ℃ until used for analysis of MCP-1 concentration.

After blood collection, rats were euthanized and their skin was removed. Tissue samples (4 per site) were obtained from the treatment site and contralateral site (untreated) using an 8mm punch biopsy procedure, weighed, placed in a sealed 1.8ml cryovial, and flash frozen in liquid nitrogen. Frozen tissue samples were suspended in 1.0mL of RPMI medium (Celox, Hopkins, MN) containing 10% fetal bovine serum (Sigma, St. Louis, Mo), 2mM L-glutamine, penicillin/streptomycin, and 2-mercaptoethanol (RPMI complete) in combination with a cocktail of the group III protease inhibitors (Calbiochem, San Diego, Calif.). Using Tissue Tearor^TM(Biospec Products, Bartlesville, OK.) the tissue was homogenized for approximately 1 minute. The tissue suspension was then freeze centrifuged at 2000rpm for 10 minutes to pellet debris, and the supernatant was collected and stored at-20 ℃ until analysis for MCP-1 concentration.

Enzyme-linked immunosorbent assay reagents for rat MCP-1 were purchased from BioSource Intl. (Camarillo, Calif.) and were run according to the manufacturer's instructions. Results are expressed in pg/ml and values for tissue samples are normalized to every 200mg of tissue. The sensitivity of MCP-1 enzyme-linked immunosorbent assay is 12 pg/ml.

^*MCP-1 concentration was not determined

^**MCP-1 concentration is the concentration at the treatment site.

^***The cream of example 82 was used in 2 separate experiments

Table 17 summarizes the topical formulations made according to the present invention, expressed as weight/weight percent.

TABLE 17

The topical cream of example 136-140 was tested using the test method described below. The results are shown in table 18 below, where each value is the average of 3 rats in the treatment group. The "control animals" did not receive any treatment.

Single dose cytokine induction assay

Female CD hairless rats (Charles Riverlaboratories, Wilmington, Mass.) weighing 200-250 grams were used. Animals were randomized into groups and three doses were administered per treatment group.

Rats were acclimatized to the neck collar two consecutive days prior to actual dosing. A 50 μ L dose of active cream or suitable placebo was applied to the right wing and gently rubbed into the skin of the rat. Rats were then ringed and housed individually to prevent ingestion of the drug. At 6 hours post-treatment, rats were anesthetized and blood (3ml) was collected by cardiac puncture. Blood was coagulated at room temperature. Serum was separated from the clot by centrifugation and stored at-20 ℃ until used for analysis of cytokine concentrations.

After blood collection, rats were euthanized and their skin was removed. Tissue samples (4 per site) were obtained from the treatment site and contralateral site (untreated) using an 8mm punch biopsy procedure, weighed, placed in a sealed 1.8ml cryovial, and flash frozen in liquid nitrogen. Frozen tissue samples were suspended in 1.0mL RPMI medium (Celox, Hopkins, MN) containing 10% fetal bovine serum (Sigma, St. Louis, Mo.), 2mM L-glutamine, penicillin/streptomycin, and cocktail with the III family protease inhibitorWine (Calbiochem, San Diego, Calif.) conjugated 2-mercaptoethanol (RPMI complete). Using Tissue Tearor^TM(Biospec Products, Bartlesville, OK.) the tissue was homogenized for approximately 1 minute. The tissue suspension was then freeze centrifuged at 2000rpm for 10 minutes to pellet debris. The supernatant was collected and stored at-20 ℃ until used for analysis of cytokine concentration.

Enzyme-linked immunosorbent assay reagents for rat MCP-1 were purchased from BioSource Intl, (Camarillo, Calif.) and rat TNF- α was purchased from BD Pharmingen (San Diego, Calif.) and were run according to the manufacturer's instructions. The results are expressed in pg/ml, values for tissue samples are normalized to 200mg of tissue per sample. The sensitivity of MCP-1 enzyme-linked immunosorbent assay is 12pg/ml, and the sensitivity of TNF-alpha enzyme-linked immunosorbent assay is 31 pg/ml.

Claims (15)

1. A pharmaceutical formulation comprising:

an Immune Response Modifier (IRM) compound 2-methyl-1- (2-methylpropyl) -1H-imidazo [4, 5-c ] [1, 5] naphthyridin-4-amine, or a pharmaceutically acceptable salt thereof;

a fatty acid; and

a hydrophobic aprotic component miscible with a fatty acid and comprising a hydrocarbon group of 7 or more carbon atoms, wherein the hydrophobic aprotic component is caprylic/capric triglyceride.

2. The pharmaceutical formulation according to claim 1, further comprising: a hydrophilic viscosity enhancing agent selected from the group consisting of cellulose ethers and carbomers.

3. The formulation according to claim 1, wherein the formulation further comprises a preservative system.

4. The formulation according to claim 2, wherein the formulation further comprises a preservative system and an emulsifier.

5. The formulation according to claim 2 wherein the hydrophilic viscosity enhancing agent comprises a carbomer.

6. The formulation according to claim 4, comprising:

(a) 0.001-5% w/w of

2-methyl-1- (2-methylpropyl) -1H-imidazo [4, 5-c ] [1, 5] naphthyridin-4-amine or a pharmaceutically acceptable salt thereof;

(b) 0.05-40% w/w isostearic acid;

(c) 1-30% w/w of a hydrophobic aprotic component, wherein the hydrophobic aprotic component is caprylic/capric triglyceride;

(d) 0.5-10% w/w emulsifier;

(e) 0.01-30% w/w of a preservative system; and

(f) 0.1-10% w/w carbomer.

7. The formulation of claim 6, comprising:

(a) 0.03-3% w/w 2-methyl-1- (2-methylpropyl) -1H-imidazo [4, 5-c ] [1, 5] naphthyridin-4-amine or a pharmaceutically acceptable salt thereof;

(b) 3-25% w/w isostearic acid;

(c) 3-15% w/w of a hydrophobic aprotic component, wherein the hydrophobic aprotic component is caprylic/capric triglyceride;

(d) 0.75-3.5% w/w emulsifier;

(e) 0.1-25% w/w preservative system; and

(f) 0.5-5% w/w carbomer.

8. A formulation according to claim 1 or 2, wherein the weight ratio of hydrophobic aprotic component to fatty acid is from 0.025:1 to 600: 1.

9. A formulation according to claim 1 or 2, wherein the combined amount of hydrophobic aprotic component and fatty acid is from 2 wt% to 50 wt%.

10. A formulation according to claim 1 or 2, wherein the fatty acid is isostearic acid.

11. A formulation according to claim 3 or 4 wherein the preservative system comprises a preservative solubilising agent.

12. The formulation according to claim 11, wherein the preservative solubilizer comprises diethylene glycol monoethyl ether, propylene glycol or a combination thereof.

13. The formulation of claim 3, comprising:

(a) 0.001-5% w/w 2-methyl-1- (2-methylpropyl) -1H-imidazo [4, 5-c ] [1, 5] naphthyridin-4-amine, or a pharmaceutically acceptable salt thereof;

(b) 0.05-40% w/w isostearic acid;

(c) 1-30% w/w of a hydrophobic aprotic component, wherein the hydrophobic aprotic component is caprylic/capric triglyceride; and

(d) 0.01-30% w/w preservative system.

14. The formulation of claim 3 or 13, further comprising an emulsifier and a hydrophilic viscosity enhancer.

15. The formulation according to claim 14 wherein the hydrophilic viscosity enhancing agent comprises a carbomer.