KR20100088695A - Enantiomerically enriched imidazoazepinone compounds - Google Patents

Abstract

The present invention provides an enantiomerically pure compound of formula (I) together with a pharmaceutical formulation comprising the same and a method of using the same.

Description

Enantiomerically enriched imidazoazepinone compounds

Upon contact with the antigen, Type 1 T helper (Th1) and Type 2 helper T cells in which naïve CD4 + T helper precursor (Thp) are two different subsets Differentiate into (Th2). Such differentiated Th cells are defined by their different functions and unique cytokine profiles. In particular, Th1 cells produce interferon-gamma, interleukin (IL) -2, and tumor necrosis factor (TNF) -beta, which activate macrophages and give rise to cell-mediated immune and phagocytic-dependent protective responses. In contrast, Th2 cells induce strong antibody production, eosinophil activation, and inhibition of several macrophage functions, providing a phagocytic-independent protective response, IL-4, IL-5, IL-6, IL It is known to produce -9, IL-IO and IL-13. Thus, Th1 and Th2 cells are associated with different immunopathological responses.

In addition, the development of each Th cell type is mediated by different cytokine pathways. In particular, IL-4 has been shown to promote Th2 differentiation and at the same time disrupt Th1 development. In contrast, IL-12, IL-18 and IFN-gamma are important cytokines for the development of Th1 cells. Thus, cytokines themselves form positive and negative feedback systems that induce Th cell polarization and maintain a balance between Th1 and Th2.

Th1 cells are involved in the development of various organ-specific autoimmune diseases, Crohn's disease, Helicobacter pylori-induced peptic ulcer, acute renal allograft rejection, and unknown recurrent miscarriage. In contrast, allergen-specific Th2 responses are the cause of atopic disease in genetically susceptible individuals. In addition, Th2 responses to unknown antigens dominate in Omenn's syndrome, idiopathic pulmonary fibrosis, and progressive systemic sclerosis.

There is still a high unmet medical need to develop new therapeutic methods useful for treating the various conditions associated with unbalanced Th1 / Th2 cell differentiation. Currently available treatment options for many such conditions are insufficient. Thus, the Th1 / Th2 paradigm provides a fundamental rational for the development of strategies for the treatment of allergies and autoimmune diseases.

A first aspect of the present invention provides the following formula I:

Or in particular, as an enantiomerically pure compound of formula Ia or formula Ib, sometimes referred to herein as " active compound "

In the above formula,

R ¹ is C _{1 -3} alkyl;

X is methylene, ethylene, propylene, ethenylene, propenylene, or butenylene;

R ⁵ is C _{1 -4} alkyl, C _{1 -3} alkoxy, hydroxyl, C _{1 -3} alkylthio, cyclopropyl, cyclopropylmethyl, trifluoromethoxy, 5-methyl-thiazolyl a rapid-fire (5-methylisoxazolyl), pyrazolyl pyridazinyl, benzyloxycarbonyl, acetyl, (cyano carbonyl) C _{1 -3} alkyl, (phenyl) C _{2 -3} alkenyl; And phenyl, pyrrolyl, benzimidazolyl, oxazolyl, isoxazolyl, imidazothiazolyl, quinolinyl, isoquinolinyl, indazolyl, pyri substituted with 0-5 substituents independently selected from halo. Denyl, imidazopyridinyl, indolyl, benzotriazolyl, imidazolyl, benzofuranyl, benzothiadiazolyl, pyridimidinyl, benzopyranonyl, thiazolyl, thiadiazolyl, furyl, Thienyl, pyrazolyl, quinoxalinyl, or naphthyl;

R ⁸ is H, methyl, ethyl, propyl, (C _{1 -3} alkoxy) C _{1 -3} alkyl, (C _{1 -3} alkylthio) C _{1 -3} alkyl, C _{1 -3-hydroxy-alkyl,} phenyl, benzyl, Furyl, pyrrolyl, imidazolyl, pyrazolyl, pyrrolyl, isothiazolyl, isoxoxazolyl, pyridyl, and thienyl;

Wherein R ⁸ is methyl, ethyl, halo, hydroxyl, C _{1 -3} alkoxy, C _{1 -3} alkylthio, (C _{1 -3} alkoxy) C _{1 -3} alkyl, (C _{1 -3} alkylthio) C _{1 - 3} alkyl, C _{1 -3} alkyl, hydroxy, (C _{1 -3-mercapto} alkyl) phenyl, benzyl, furyl, imidazolyl, pyrazolyl, pyrrolyl, isothiazolyl, iso-oxazolyl, pyridyl, and thienyl Substituted with 0 to 3 substituents independently selected from; And

R ^a , R ^b , and R ^c are each independently selected from hydrogen, hydroxyl, methoxy, benzyloxy, fluoro, chloro, amino, methylamino, dimethylamino, and phenoxy;

Or ^a compound selected from R ^a and R ^b , and R ^b and R ^c , taken together, is -O- (CH ₂ ) -O- or -0-CH ₂ -CH ₂ -O-, or a pharmaceutical thereof acceptable salt thereof, and its C _{1 -6} alkyl ester or amide, or a C _{2 -6} alkenyl ester or amide.

A second aspect of the invention is a composition comprising the active compound described herein in a pharmaceutically acceptable carrier.

A third aspect of the invention provides a subject with the use of an active compound described herein for the manufacture of a medicament for the treatment of rheumatoid arthritis in a subject in need thereof, and a therapeutically effective amount of the active compound described herein to the subject. A method of treating rheumatoid arthritis in a subject in need thereof, comprising the step of administering.

A fourth aspect of the invention provides an individual with the use of an active compound described herein for the manufacture of a medicament for the treatment of multiple sclerosis in a subject in need thereof, and a therapeutically effective amount of the active compound described herein. A method of treating multiple sclerosis in a subject in need thereof, comprising the step of administering.

A fifth aspect of the invention relates to the use of the active compounds described herein for the manufacture of a medicament for the treatment of autoimmune diseases in a subject in need thereof, and to a therapeutically effective amount of the active compounds described herein. A method for treating an autoimmune disease in a subject in need thereof, comprising administering to a patient, wherein the autoimmune disease is selected from the group consisting of systemic lupus erythematosus, type 1 diabetes, psoriasis, and atherosclerosis.

Other aspects of the invention are disclosed herein and discussed in more detail below.

A. Definition

As used herein, “enantiomerically pure” refers to a stereoisomerically pure compound or composition of compounds, which compound has one chiral center.

As used herein, “sterereomerically pure” means a compound or composition thereof comprising one stereoisomer of a compound and substantially free of the other stereoisomers of that compound. For example, a stereoisomerically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomers of that compound. Stereoisomericly pure compositions of a compound having two chiral centers will be substantially free of other diastereomers of that compound. Conventional stereoisomerically pure compounds comprise more than about 80% by weight of one stereoisomer of the compound and less than 20% by weight of other stereoisomers of the compound, more preferably greater than about 90% by weight One stereoisomer of the compound and another stereoisomer of less than about 10% by weight of the compound, and even more preferably greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the compound Other stereoisomers, and most preferably one stereoisomer of a compound of greater than about 97% by weight and another stereoisomer of less than about 3% by weight of the compound. See, eg, US Pat. No. 7,189,715.

As used herein, “stable” means a compound that is substantially unchanged when placed in a state for its production, detection, and preferably for its recovery, purification, and use for one or more purposes disclosed herein. In some embodiments, a stable compound or chemically teasible compound is a compound that does not substantially change when left for more than one week at 40 ° C. or lower, in the absence of moisture or other chemically reactive conditions.

As used herein, "alkyl" or "alkyl group" means a fully saturated straight (ie, unbranched), branched, or cyclic hydrocarbon chain. In certain embodiments, the alkyl group contains 1-3 carbon atoms. In another embodiment, the alkyl group contains 2-3 carbon atoms, and in another embodiment the alkyl group contains 1-2 carbon atoms. In certain embodiments, the term "alkyl" or "alkyl group" refers to a cycloalkyl group, also known as a carbocycle. The exemplary C _{1 -3} alkyl groups include methyl, ethyl, propyl, isopropyl, and cyclopropyl.

As used herein, "alkenyl" or "alkenyl group" refers to a straight (ie unbranched), branched, or cyclic hydrocarbon chain having one or more double bonds. In certain embodiments, alkenyl groups contain 2-4 carbon atoms. In another embodiment, the alkenyl group contains 3-4 carbon atoms, and in yet another embodiment, the alkenyl group contains 2-3 carbon atoms. In another embodiment, the term alkenyl refers to a straight chain hydrocarbon having two double bonds, also referred to as "diene". In other embodiments the term "alkenyl" or "alkenyl group" refers to a cycloalkenyl group. Typical C _{2 -4} alkenyl groups -CH = CH _2, (also referred to as _{allyl) -CH 2 CH = CH 2,} -CH = CHCH 3, -CH 2 CH 2 CH = CH 2, -CH 2 CH = CHCH ₃ , -CH = CH ₂ CH ₂ CH ₃ , -CH = CH ₂ CH = CH ₂ , and cyclobutenyl.

As used herein, "alkoxy" or "alkylthio" refers to an alkyl group as previously defined, connected to the main carbon chain via oxygen ("alkoxy") or sulfur atoms ("alkylthio"). do.

As used herein, "methylene", "ethylene", and "propylene" are -CH _2- , -CH ₂ CH _2- , and -CH, each of which is a divalent moiety. ₂ CH ₂ CH _2- .

As used herein, "ethenylene", "propenylene", and "butenylene" are divalent moieties -CH = CH-, -CH = CHCH _2- , -CH _{2 CH = CH-, -CH = CHCH} 2 CH 2 -, -CH 2 CH = CH 2 CH 2 - refers to, and -CH ₂ CH ₂ CH = CH-, ethenylene, and propenylene, and butenylene The groups can be cis or trans configurations, respectively. In certain embodiments, the ethenylene, propenylene, or butenylene group may be in a trans configuration.

"Alkylidene" refers to a divalent hydrocarbon group formed by monoalkyl or dialkyl substitution of methylene. In certain embodiments, alkylidene groups have 1-6 carbon atoms. In other embodiments, the alkylidene group has 2-6, 1-5, 2-4, or 1-3 carbon atoms. Such groups include propylidene (CH ₃ CH ₂ CH =), ethylidene (CH ₃ CH =), isopropylidene (CH ₃ (CH ₃ ) CH =) and the like.

"Alkenylidene" refers to a divalent hydrocarbon group having one or more double bonds formed by monoalkenyl or dialkyl substitution of methylene. In certain embodiments, alkenylidene groups have 2-6 carbon atoms. In another embodiment the alkenylidene group has 2-6, 2-5, 2-4, or 2-3 carbon atoms. In one embodiment, the alkenylidene has two double bonds. Representative alkenylidene groups include CH ₃ CH═C═, CH ₂ = CHCH =, CH ₂ = CHCH ₂ CH =, and CH ₂ = CHCH ₂ CH = CHCH =.

"C _{1 -6} alkyl ester or amide _{(C 1 -6 alkyl ester or amide} )" are each a C _{1 -6} alkyl group is as defined above, C _{1 -6} alkyl ester or a C _{1 -6} alkyl amide Refer. C _{1 -6} alkyl ester group, such as those expression (C _{1 -6} alkyl) OC (= O) -, or (C _{1 -6} alkyl) has a C (= O) O-. Have or (C _1-6 alkyl) C (= O) NH- - C 1 -6 alkyl amide groups such as the formula (C _{1 -6} alkyl) NHC (= O).

"C _{2 -6} alkenyl ester or amide _{(C 2 -6 alkenyl ester or amide} )" are each C _{2 -6} alkenyl group of those defined above, C _{2 -6} alkenyl esters or C _{2 -6} Refer to alkenyl amides. C _{2 -6} alkenyl ester groups are obtained as with the (C _{2 -6} alkenyl) OC (= O) - or has a (C _2-6 alkenyl) C (= O) O-. C _{2 -6} alkenyl amide groups such as the formula (C _{2 -6} alkenyl) NHC (= O) -, or (C _{2 -6} alkenyl) C (= O) has a NH-.

"Treatment," "treat," and "treating" refers to reversing, alleviating, or delaying the onset of a disease or condition described herein, Refers to inhibiting or preventing progression. In some embodiments, the treatment may be performed after one or more symptoms have developed. In other embodiments, the treatment can be performed in the absence of symptoms. For example, treatment may be performed on a subject who is susceptible prior to the onset of symptoms (eg, taking into account the history of the symptoms and / or taking into account genetic or other susceptibility factors). For example, it may continue after the symptoms have been cured for the prevention or delay of its recurrence.

As used herein, “Patient” or “subject” refers to an animal subject, preferably a mammalian subject (eg, a dog, cat, horse, cow, sheep, goat, monkey, etc.), and in particular By human subjects (including both male and female subjects, including newborn, infant, adolescent, adolescent, adult and elderly subjects).

As used herein, "pharmaceutically acceptable carrier" refers to a nontoxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound formulated as such. Pharmaceutically acceptable carriers, adjuvants or carriers that can be used in the compositions of the invention include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, Potassium sorbate, a partial glyceride mixture of saturated vegetable fatty acids, an electrolyte such as water, salt, or protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium Trisilicate, polyvinyl pyrrolidone, cellulose-based materials, polyethylene glycols, cyclodextrins, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycols and lanolin (wool fats) Including but not limited to .

Unless stated otherwise, the naming used to describe chemical groups or moieties used herein follows the convention that the name is read from left to right and the point connecting to the rest of the molecule is placed to the right of the name. For example, the group "(C _{1 -3} alkoxy) C _{1 -3} alkyl" is connected to the rest of the molecule at the alkyl end. Other examples include methoxy ethyl, where the linking point is at the ethyl end, and methyl amino, where the linking point is at the amine end.

Unless stated otherwise, it will be understood that the attachment is read from left to right when the bivalent group is described by its formula comprising two terminal bond moieties denoted by "-".

Unless stated otherwise, the structures shown herein are intended to include all enantiomers, diastereomers, and geometric (or conformational) forms of the structure; For example, the R and S configurations of each asymmetric center, the (Z) and (E) double bond isomers, and the (Z) and (E) conformational isomers. Therefore, enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds as well as single stereochemical isomers are within the scope of the present invention. Unless stated otherwise, all tautomeric forms of the compounds of the invention are within the scope of the invention. Also, unless stated otherwise, the structures shown herein are intended to include compounds that differ only in the proportion of one or more isotopically enriched atoms. For example, compounds having the structure of the present invention, except for replacing hydrogen with deuterium or tritium, or replacing carbon with ¹³ C or ¹⁴ C-reinforced carbon, are within the scope of the present invention. Such compounds are useful, for example, as analytical tools or probes in biological assays.

B. Active Compounds

The active compounds of the invention described herein may be optionally substituted with one or more substituents, as generally exemplified above, or as exemplified by the particular class, subclass, and species of the invention. In general, the term “substituted” refers to the replacement of hydrogen radicals of a given structure with radicals of specifically specified substituents. Unless stated otherwise, a substituted group may have a substituent at each substitutable position of the group, and when substituted with two or more substituents selected from groups specifically specified at two or more positions of a given structure, the substituents are the same at each position or can be different.

As mentioned above, the present invention provides

Or more specifically as an enantiomerically pure compound or active compound of Formula Ia or Formula Ib,

In the above formula,

R ¹ is C _{1 -3} alkyl;

X is methylene, ethylene, propylene, ethenylene, propenylene, or butenylene;

R ⁵ is C _{1 -4} alkyl, C _{1 -3} alkoxy, hydroxyl, C _{1 -3} alkylthio, cyclopropyl, cyclopropylmethyl, trifluoromethoxy, 5-methyl-a rapid-fire thiazolyl, pyrazolyl, benzyloxy, acetyl, (cyano carbonyl) C _{1 -3} alkyl, (phenyl) C _{2 -3} alkenyl; And phenyl, pyrrolyl, benzimidazolyl, oxazolyl, isoxazolyl, imidazothiazolyl, quinolinyl, isoquinolinyl, indazolyl, pyri substituted with 0-5 substituents independently selected from halo. Denyl, imidazopyridinyl, indolyl, benzotriazolyl, imidazolyl, benzofuranyl, benzothiadiazolyl, pyridimidinyl, benzopyranononyl, thiazolyl, thiadiazolyl, furyl, thienyl, Pyrazolyl, quinoxalinyl, or naphthyl;

R ⁸ is H, methyl, ethyl, propyl, (C _{1 -3} alkoxy) C _{1 -3} alkyl, (C _{1 -3} alkylthio) C _{1 -3} alkyl, C _{1 -3-hydroxy-alkyl,} phenyl, benzyl, Furyl, pyrrolyl, imidazolyl, pyrazolyl, pyrrolyl, isothiazolyl, isoxazolyl, pyridyl, and thienyl;

Wherein R ⁸ is methyl, ethyl, halo, hydroxyl, C _{1 -3} alkoxy, C _{1 -3} alkylthio, (C _{1 -3} alkoxy) C _{1 -3} alkyl, (C _{1 -3} alkylthio) C _{1 - 3} alkyl, C _{1 -3} alkyl, hydroxy, (C _{1 -3-mercapto} alkyl) phenyl, benzyl, furyl, imidazolyl, pyrazolyl, pyrrolyl, isothiazolyl, iso-oxazolyl, pyridyl, and thienyl Substituted with 0 to 3 substituents independently selected from; And

R ^a , R ^b , and R ^c are each independently selected from hydrogen, hydroxyl, methoxy, benzyloxy, fluoro, chloro, amino, methylamino, dimethylamino, and phenoxy;

Or ^a compound selected from R ^a and R ^b and R ^b and R ^c taken together is —O— (CH ₂ ) —O— or —0-CH ₂ —CH ₂ —O— or a pharmaceutical thereof acceptable salt thereof, and provides its C _1-6 alkyl ester or amide, or a C _{2 -6} alkenyl ester or amide.

In some embodiments mentioned above,

R ¹ is C _{1 -2} alkyl;

R ⁵ is C _{1 -4} alkyl, C _{1 -3} alkoxy, hydroxyl, C _{1 -3} alkylthio, cyclopropyl, cyclopropylmethyl, trifluoromethoxy, 5-methyl-a rapid-fire thiazolyl, pyrazolyl, benzyloxy, acetyl, (cyano carbonyl) C _{1 -3} alkyl, (phenyl) C _{2 -3} alkenyl; And phenyl, pyrrolyl, benzimidazolyl, oxazolyl, isoxazolyl, imidazothiazolyl, quinolinyl, isoquinolinyl, indazolyl, pyri substituted with 0-5 substituents independently selected from halo. Denyl, imidazopyridinyl, indolyl, benzotriazolyl, imidazolyl, benzofuranyl, benzothiadiazolyl, pyridimidinyl, benzopyranononyl, thiazolyl, thiadiazolyl, furyl, thienyl, Pyrazolyl, quinoxalinyl, or naphthyl;

R ⁸ is methyl, ethyl, or propyl, wherein R ⁸ is substituted with 0 to 3 hydroxyl substituents;

X is methylene or ethylene; And

R ^a, R ^b, and R ^c is H and methoxy or a pharmaceutically acceptable phosphorus compound being independently selected from the group consisting of salts, their C _{1 -6} alkyl ester or amide, respectively, or a C _{2 - 6} alkenyl ester or amide.

In some embodiments mentioned above,

R ¹ is methyl;

R ⁵ is phenyl, pyrrolyl or pyrazolyl, each substituted 0, 1 or 2 times with methyl;

R ⁸ is ethyl;

X is methylene;

R ^a and R ^c are each methoxy; And

R ^b is H or a pharmaceutically acceptable salt thereof.

In certain embodiments mentioned above, the compounds of the invention

Or a pharmaceutically acceptable salt thereof.

The active compounds of the present invention include pharmaceutically acceptable salts of the aforementioned compounds. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic and organic acids and inorganic bases and organic bases. Examples of suitable acid salts are acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorrate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsul Fate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulphate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydrate Roxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylprop Cypionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, And a sulfate, tartrate, thiocyanate, tosylate and undecanoate. Other acids, such as oxalic acid, which are not themselves pharmaceutically acceptable, can be used in the preparation of salts, as intermediates useful in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.

Alkali salts derived from an appropriate base in a metal (e.g., sodium and potassium), alkaline earth metal (e.g., magnesium), an ammonium and N + (C _{1 -4} alkyl) ₄ salts. The invention also contemplates quaternization of basic nitrogen-containing groups of the compounds disclosed herein. In this quaternization, a water soluble or fat soluble or dispersible product can be obtained.

C. Pharmaceutical Formulations.

The active compounds of the present invention can be combined with pharmaceutically acceptable carriers to provide pharmaceutical preparations thereof. The specific choice of carrier and formulation will depend upon the particular route of administration for which the composition is intended.

The compositions of the present invention may be suitable for oral, parenteral, inhalation spray, topical, rectal, nasal, buccal, vaginal or implanted reservoir administration and the like. Preferably, the composition is administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of the invention may be aqueous or oily suspensions. Such suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may be sterile injectable solutions or suspensions in a nontoxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Among the acceptable carriers and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

For this purpose, non-irritating fixed oils comprising synthetic mono- or di-glycerides can be used. Fatty acids such as oleic acid and glyceride derivatives thereof are particularly useful in the preparation of injectables, such as natural pharmaceutically acceptable oils such as olive or castor oil, in their polyoxyethylated versions. Such oil solutions or suspensions may also include long chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants such as Tweens, Spans and other emulsifiers or bioavailability promoters commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms also serve the purpose of formulation. Can be used for

Pharmaceutically acceptable compositions of this invention may be administered orally in orally acceptable dosage forms, including but not limited to capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricants such as magnesium stearate are typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. If an aqueous suspension is required for oral use, the active ingredient is combined with emulsifiers and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

Alternatively, the pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration. It can be prepared by mixing the agent with an appropriate non-irritating excipient that is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

Pharmaceutically acceptable compositions of this invention include diseases of the eye, skin, or lower intestinal tract, especially when the target of treatment comprises a part or organ readily accessible by topical application. May be administered. Suitable topical formulations are readily prepared for each such area or organ.

 Topical application for the lower intestine can be achieved with rectal suppository formulations (see above) or appropriate enema formulations. Topical transdermal patches may also be used.

For topical application, pharmaceutically acceptable compositions may be formulated in a suitable ointment comprising the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxy propylene compound, emulsifying wax and water. Alternatively, the pharmaceutically acceptable composition may be formulated in a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, dioctyldodecanol, benzyl alcohol and water It doesn't work.

For use in the eye, a pharmaceutically acceptable composition is an isotonic, pH-micronized suspension in sterile saline, or preferably isotonic, pH-adjusted, with or without a preservative such as benzylalkonium chloride. In solution in sterile saline. Alternatively, for use in the eye, the pharmaceutically acceptable composition may be formulated in an ointment such as petrolatum.

Pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulations, and include benzyl alcohol or other suitable preservatives, absorption accelerators that enhance bioavailability, fluorocarbons, and / or other conventional dissolution aids or It can be prepared as a solution in saline solution using a dispersant.

Most preferably, pharmaceutically acceptable compositions of this invention are formulated for oral administration.

D. Target Objects and How to Use

The active compounds of the invention vary in a variety of different states, in particular

(a) rheumatoid arthritis;

(b) multiple sclerosis;

(c) systemic lupus erythematosus (eg, T-bet regulates IgG class switching and pathogenic auto Ab production, Proc. Natl. Acad. Sci. USA 99 (8): 5545-50 (2002); Imbalance of Th1 / Th2 transcription factors) in patients with lupus nephritis, Rheumatology (Oxford) 45 (8): 951-7 (2006));

(d) Type 1 diabetes (eg, Identification of a novel type 1 diabetes susceptibility gene, T-bet, Human Genetics 111 (3): 177-84 (2004); T-bet controls autoaggressive CD8 lymphocyte response in type I diabetes, J Exp. Med. 199 (8): 1153-62 (2004));

(e) psoriasis (see, eg, J. MoI. Med 81 (8): 471-80 (2003)); And

(f) atherosclerosis (see, eg, Proc. Natl. Acad. Sci. USA 102 (5): 1596-601 (2005))

It can be administered to a patient or individual to treat a patient or individual suffering from.

The active compound may be administered to the subject by any suitable route, including oral, parenteral, inhalation spray, topical, rectal, nasal, oral, vaginal or implanted depot. As used herein, the term “parenteral” refers to a subcutaneous, intravenous, intramuscular, intraarticular, intra-synovial, intraoral, intradural, intrahepatic, intralesional, intracranial injection or infusion technique. Include. Preferably, the composition is administered orally, intraperitoneally or intravenously.

The active compound is administered to the subject in a therapeutically effective amount or in a therapeutically effective amount. The amount of a compound of the invention that can be combined with a carrier material to produce a composition in a single dosage form will vary depending upon the subject being treated and the particular route of administration. Preferably, the composition should be formulated such that a dosage of 0.01 to 100 mg / kg body weight / day of inhibitor is administered to the patient receiving the composition. In certain embodiments, the compositions of the present invention provide a dosage of 0.01 mg to 50 mg. In another embodiment, a dosage of 0.1 to 25 mg or 5 mg to 40 mg is provided.

In addition, specific dosages and treatment regimens for specific patients may include the activity, age, weight, general health, sex, food intake, time of administration, rate of excretion, and drug use of the specific compound used. It is to be understood that the formulation will depend upon various factors, including the judgment of the treating physician and the severity of the particular disease being treated. The amount of the compound of the present invention in the composition will also depend on the particular compound in the composition.

In order that the invention described herein is more fully understood, the following examples are set forth. These examples are to be understood solely for the purpose of illustration and should not be construed as limiting the invention.

Example  1-41

Synthesis of Compound

 Reactions with microwaves were carried out using an Emrys Liberator device supplied by Biotage Corporation. Solvent removal was performed using a Buchi rotary evaporator or a Genevac centrifuge evaporator. Analysis and Preparation Chromatography was performed using a Waters autopurification instrument using normal or reversed phase HPLC columns under acidic, neutral, or basic conditions. The compound was estimated to be> 90% pure as measured by the area percent of the ELSD chromatogram. NMR spectra were recorded using a Varian 300 MHz spectrometer.

General methods and experiments for preparing the compounds of the present invention are described below. In certain cases, specific compounds are described by way of example. However, it should be understood that in each case the series of compounds of the present invention was prepared according to the reaction scheme and experiments described below.

ER-811160. As shown in Reaction Scheme 1 above, a solution of potassium cyanide (22.5 g, 0.335 mol) in water (50 mL) was added with 1-Boc-piperidone (32.48 g, 0.1598) in water (90 mL) and methanol (110 mL). mol) and ammonium carbonate (33.8 g, 0.351 mol) solution were added dropwise over 5 minutes. Shortly after the addition was completed, an off-white precipitate began to form. The reaction flask was sealed and the suspension stirred for 72 hours at room temperature. The resulting pale yellow precipitate was filtered and washed with a small amount of water to give ER-811160 (37.1 g, 86%) as a colorless solid.

ER-818039. As shown in Reaction Scheme 2, above, ER-811160 (30.0 g, 0.111 mol), 3,5-dimethoxybenzyl bromide (30.9 g, 0.134 mol) in acetone (555 mL), and potassium carbonate (18.5 g, 0.134 mol) The suspension was heated to reflux overnight. The reaction solution was cooled to room temperature, filtered and concentrated in vacuo. The crude orange residue was dissolved in a small amount of MTBE (250 mL). A small amount of hexane (50 mL) was added and the product precipitated as a colorless solid (over ˜2 hours) and separated by vacuum filtration. The filter cake was washed with a small amount of MTBE and dried in vacuo to give ER-818039 (39.6 g, 85%) as a colorless solid.

ER-823143-01. As shown in Reaction Scheme 3 above, 1,4-dioxane (3.8 mL, 1-neck round-bottom flask) containing ER-818039 (2.15 g, 0.00512 mol) 0.049 mol) in 4N HCl solution was added slowly. The starting material slowly dissolved over 20 minutes and after 30 minutes a colorless precipitate formed. MTBE (3 ml) was then added. After 2 hours, the reaction was filtered and washed with MTBE to give ER-823143-01 (1.81 g, 99%) as a colorless solid.

ER-817098: ER-823143-01 (41.5 mg, 0.000117 mol) and 4 ′ molecular sieve in 1,2-dimethoxyethane (0.5 mL, 0.004 mol) under nitrogen gas, as shown in reaction scheme 4 above To the suspension of sieve) 3,5-dimethoxybenzaldehyde (21.3 mg, 0.000128 mol) was added followed by triethylamine (16.2 μl, 0.000117 mol). The reaction was stirred for 1 hour. Sodium triacetoxyborohydride (34.6 mg, 0.000163 mol) was added and the reaction stirred overnight. Silica gel flash chromatography gave ER-817098 (45.3 mg, 83%) as a colorless solid.

ER-817116: ER-817098-00 (50.0 mg, 0.000106 mol) and 1-bromo-2-methoxy in N-methylpyrrolidinone (1.0 mL, 0.010 mol) as shown in reaction scheme 5 above To a solution of ethane (15.6 μl, 0.000160 mol) was added a 1.0 M lithium hexamethyl disilazide solution in tetrahydrofuran (0.16 mL). After raising the temperature of the reaction to 80 ° C., the reaction mixture was stirred overnight. The reaction mixture was cooled to room temperature, the reaction ended with water and extracted several times with MTBE. The MTBE extracts were combined and washed with water (2x) and brine (1x). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography gave ER-817116 (32.2 mg, 58%) as a colorless oil.

ER-817118: Add sodium hydride (364 mg, 0.00910 mol) to a solution of ER-817098 (2.85 g, 0.00607 mol) in N, N-dimethylformamide (15 mL) as shown in Reaction Scheme 6 above. Then iodineethane (758 μl, 0.00910 mol) was added. The reaction mixture was stirred overnight. Water was added very slowly and the reaction mixture was extracted several times with MTBE. The MTBE extracts were combined and washed with water (2x) and brine (1x). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography using ethyl acetate as eluent gave ER-817118 (2.89 g, 96%) as a colorless oil.

ER-823914: As shown in Reaction Scheme 7, above, a solution of ER-823143-01 (5.03 g, 0.0141 mol) in tetrahydrofuran (30.0 mL, 0.370 mol) at −78 ° C. was 1.0 in ether (71 mL). M allylmagnesium bromide was added slowly. The reaction mixture was allowed to warm up to room temperature and stirred overnight. The reaction mixture was cooled to −78 ° C., treated with dropwise addition of trifluoroacetic acid (21.8 mL, 0.283 mol), and then concentrated in vacuo until a small residual volume was obtained. Triethylamine was added to neutralize the remaining TFA and then the mixture was concentrated to dryness in vacuo. The residual red oil was dissolved in methanol (138 mL, 3.41 mol) and treated with di-tert-butyldicarbonate (3.34 g, 0.0148 mol) followed by triethylamine (2.38 mL, 0.0169 mol) and stirred at room temperature overnight I was. The reaction mixture was concentrated in vacuo and purified by flash chromatography (eluent: 50% hexanes in ethyl acetate) to give ER-823914 (3.25 g, 52%) as a colorless solid.

ER-823915: Sodium hydride (298 mg, 0.00744 mol) in a solution of ER-823914 (2.20 g, 0.00496 mol) in N, N-dimethylformamide (12.4 mL, 0.160 mol) as shown in Reaction Scheme 8 above. ) Was added followed by iodineethane (607 μl, 0.00744 mol). The reaction mixture was stirred overnight, after which the reaction was terminated with water and extracted several times with MTBE. The MTBE extracts were combined and washed with water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (eluent: 40% hexanes in ethyl acetate) gave ER-823915 (0.80 g, 34%) as a colorless foam.

ER-823917-01: As shown in Reaction Scheme 9 above, ER-823915 (799.2 mg, 0.001695 mol) was dissolved in 4 M hydrogen chloride solution in 1,4-dioxane (10 mL). The reaction mixture was stirred overnight and concentrated in vacuo to give ER-823917-01 (0.69 g, quantitative) as an orange solid.

ER-824184 & ER-824185: As shown in the reaction scheme 10 above, a solution of ER-823915 (200 mg) in acetonitrile (1 ml) was added to a CHIRALPAK® AS-H SFC column (30 mm x 250 mm, 5 microns). Particle size) and eluted with 95: 5 n-heptane: i-propanol at a flow rate of 40 ml / min. Eluted fractions were detected using a UV detector with a wavelength set to 290 nm. The first eluted fraction was separated and concentrated in vacuo by rotary evaporator to give ER-824184; The second eluted fraction was separated and concentrated by rotary evaporation in vacuo to give ER-824185.

ER-824188-01: As shown in Reaction Scheme 11 above, ER-824184 (25.33 g, 0.05371 mol) was dissolved in 4 M hydrogen chloride solution in 1,4-dioxane (135 mL). The reaction mixture was stirred overnight and concentrated in vacuo to give ER-824188-01 (21.9 g, quant.) As an orange solid. As a result of single crystal X-ray diffraction analysis of ER-824188-01, as shown in the reaction scheme 11, the absolute arrangement of the stereoscopic center was S.

ER-824280-01: As shown in Reaction Scheme 12 above, ER-824185 (457.2 mg, 0.0009695 mol) was dissolved in 4 M hydrogen chloride solution in 1,4-dioxane (2.5 mL). The reaction mixture was stirred overnight and concentrated in vacuo to give ER-824280-01 (383.2 mg, 97%) as an orange solid. Single crystal X-ray rotation analysis of the Mosher amide derivative of ER-824188-01 revealed an absolute configuration of the stereocenter as R, as shown in Reaction Scheme 11.

ER-819924: As shown in Reaction Scheme 13 above, ER-824188-01 (62.4 mg, 0.000153 mol) and N-methylpyrrole-2-carbaldehyde (0.000229 mol) were added to N, N-dimethylformamide (0.62 mL)). After stirring for 30 minutes, sodium triacetoxyborohydride (47.8 mg, 0.000214 mol) was added. The reaction mixture was stirred overnight and purified by reverse phase chromatography to give ER-819924 (71.1 mg, 83.4%) as an oil.

ER-819925: As shown in Reaction Scheme 14 above, ER-824280-01 (59.5 mg, 0.000146 mol and N-methylpyrrole-2-carbaldehyde (0.000219 mol) was added to N, N'-dimethylformamide (0.60). mL), after stirring for 30 minutes, sodium triacetoxyborohydride (45.6 mg, 0.000204 mol) was added The reaction mixture was stirred overnight, then purified by reverse phase chromatography to give an oil ER-819925 (51.9 mg, 76.6%) as obtained.

ER-819762: ER-824188-01 (5.7 g, 0.0140 mol), 1,8-diazabicyclo [5.4.0 in N, N-dimethylformamide (50 mL), as shown in reaction scheme 15 above. ] Undec-7-ene (1,8-diazabicyclo [5,4,0] undec-7-ene) (4.4 mL, 0.029 mol) and 3,5-dimethylbenzyl bromide (4.7 g, 0.024 mol) Heated at 97 ° C. overnight. Aqueous work-up and purification by flash chromatography gave ER-819762 (4.86 g, 71%) as a colorless solid.

ER-819762-01: As shown in Reaction Scheme 16 above, a solution of ER-819762 (4.77 g, 0.00974 mol), acetonitrile (10 mL) and 1M HCl in water (11 mL) for about 5 minutes at room temperature Stirred. The solution was concentrated to give ER-819762-01 (5.1 g, quant.) As a colorless crystalline solid after freeze drying. As a result of single crystal X-ray diffraction analysis of ER-819762-01, the absolute arrangement of the stereocenter is S as shown in Reaction Scheme 16.

ER-819763: ER-824280-01 (66.9 g, 0.1640 mol), 1,8-diazabicyclo [5.4.0] in N-methylpyrrolidinone (669 mL), as shown in reaction scheme 17 above. Undec-7-ene (54 mL, 0.361 mol) and 3,5-dimethylbenzyl chloride (42.4 g, 0.213 mol) solution were heated at 72 ° C. for 2 hours. After cooling, water was added to precipitate the desired product. Filtration and drying in vacuo afforded ER-819763 (74.4 g, 92%) as a colorless solid.

ER-824102: Alpha-bromomethylene (alpha) in a solution of ER-823143-01 (4.00 g, 0.0112 mol) in N, N-dimethylformamide (25 mL) at room temperature, as shown in reaction scheme 18 above. -bromomesitylene) (3.13 g, 0.0157 mol) was added followed by DBU (4.37 mL, 0.0292 mol). After stirring for 1 hour, the reaction was terminated with a semi-saturated aqueous NH ₄ Cl solution and diluted with ethyl acetate and stirred for 1 hour to give two clear layers. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2x). The combined extracts were dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo. Crystallization from MTBE gave ER-824102 (4.30 g, 87%) as a colorless solid.

ER-819929: 1.0 M allyl in ether (25.5 mL, 0.0255 mol) in a solution of ER-824102 (3.72 g, 0.0085 mol) in tetrahydrofuran (35 mL) at −65 ° C., as shown in reaction scheme 19 above. Magnesium bromide was added over 10 minutes while keeping the internal temperature below −50 ° C. The reaction mixture was warmed to 0 ° C. After 3 hours at 0 ° C., the reaction was terminated with saturated aqueous NH ₄ Cl solution and diluted with ethyl acetate and water and stirred for 10 minutes to give two cleanly separated layers. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined extracts were washed with water, brine, dried over Na 2 SO 4, filtered and concentrated in vacuo to yield the crude product ER-819929 (4.15 g, quantitative) as a colorless solid which was used in the next step without further purification. It was.

ER-819930: As shown in Reaction Scheme 20 above, a solution of ER-819929 (37 mg, 0.000077 mol) in trifluoroacetic acid (0.5 mL) was stirred at room temperature for 16 hours. The dark red brown reaction mixture was diluted with EtOAc (5 mL) and neutralized with saturated aqueous NaHCO ₃ solution (5 mL, attention: gas evolution). The two-layer mixture was stirred for 10 minutes and two cleanly separated, almost colorless layers were obtained. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo. Purification by flash chromatography eluting with 1: 1 heptane-EtOAc, 1: 3 heptane-EtOAc, 100% EtOAc gave ER-819930 (26 mg, 73%) as a colorless solid.

ER-820006 and ER-820007: Tetrahydrofuran in a solution of ER-819930 (110 mg, 0.000238 mol) and metaryl bromide (72 μL, 0.000715 mol) in DMF (1.5 mL), as shown in Reaction Scheme 21 above. A solution of 1.0 M lithium hexamethyldisilazide in (0.52 mL, 0.00052 mol) was added. After stirring for 18 hours at room temperature, the reaction mixture was diluted with MTBE and terminated with a semi-saturated aqueous NH ₄ Cl solution. The aqueous layer was separated and extracted with MTBE. The combined extracts were dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo. Purification by flash chromatography eluting with 3: 2 heptane-EtOAc, 1: 1 heptane-EtOAc gave the racemic product (68 mg, 55%) as colorless oil. The racemic product (55 mg) was applied on a Chiralpak AS column of chiral HPLC and eluted with heptane-isopropanol (9: 1) to elute the first eluted enantiomer ER-820006 (21 mg, 38%, [α]. _D = + 83.7 ° (c = 0.35, CHC13) and the second eluted enantiomer ER-820007 (23 mg, 42%, [α] _D = -74.2 ° (c = 0.38, CHC13). Absolute stereochemistry was temporarily assigned based on the inference of the optical rotation and chiral HPLC retention time of ER-819762 / ER-819763.

ER-819786 and ER-819787: As shown in the reaction scheme 22 above, a 5 mL microwave reactor vial equipped with a stir bar was loaded with ER-819930 (110 mg, 0.000238 mol), DMF (1.5). mL), 2- (2-bromoethoxy) tetrahydro-2H-pyran (108 μl, 0.000715 mol) and tetrahydrofuran (520 μl, 0.00052 mol) were charged with 1.00 M lithium hexamethyldisilazide. The reactor vial was irradiated with microwave at 200 ° C. for 15 minutes. 1.00 M lithium hexamethyldisilazide in 2- (2-bromoethoxy) tetrahydro-2H-pyran (108 μl, 0.000715 mol) and tetrahydrofuran (520 μl, 0.00052 mol) is further added and the reaction mixture is The microwaves were irradiated and further heated at 200 ° C. for 15 minutes. Purification by preparative reverse phase HPLC gave the racemic product (25 mg, 21%) as a colorless glassy oil. The first enantiomer ER-819786 (7.2 mg, 42%, [α] was subjected to chiral HPLC on a Chiralpac AS column eluting the racemic product (17 mg) with heptane-isopropanol (9: 1) [α ] _D = + 72.0 ° (c = 0.1, CHC13) and the second eluted enantiomer ER-819787 (7.5 mg, 44%, [α] _D = -73.0 ° (c = 0.1, CHC13). Stereochemistry was temporarily determined based on the inference of the optical rotation and chiral HPLC retention time of the enantiomer pair ER-819762 / ER-819763.

ER-819993 and ER-819994: As shown in Reaction Scheme 23 above, a 5 mL microwave reactor vial equipped with a stirring bar was loaded with ER-819930 (110 mg, 0.000238 mol), DMF (1.5 mL), ((4S) -2 1.00 M lithium hexamethyldisilazide in, 2-dimethyl-1,3-dioxolan-4-yl) methyl 4-methylbenzenesulfonate (205 mg, 0.000715 mol) and tetrahydrofuran (520 μl, 0.00052 mol) Filled with The reactor vial was heated at 200 ° C. for 15 minutes by microwave irradiation. 1.00 M in ((4S) -2,2-dimethyl-1,3-dioxolan-4-yl) methyl 4-methylbenzenesulfonate (157 mg, 0.000548 mol) and tetrahydrofuran (477 μl, 0.000477 mol) Lithium hexamethyldisilazide was further added and the reaction mixture was further heated at 200 ° C. for 15 minutes by microwave irradiation. Purification by preparative reverse phase HPLC gave acetonide ER-819993 (40 mg, 30%) and diol material (18 mg, 14%) in a 1: 1 mixture of diastereomers. Diastereomeric diols were separated by chiral HPLC on a Chiralpac AS column eluted with heptane-isopropanol (9: 1) to give the first eluted diastereomer ER-819788 (5.0 mg) and the second eluted diastereomer. Isomer ER-819789 (5.2 mg) was obtained. Absolute stereochemistry was temporarily determined based on an analogy of the chiral HPLC retention time of the enantiomer pair ER-819762 / ER-819763.

ER-81990: ER-824220-00 (51.8 mg, 0.000139 mol), triethylamine (97 μl, 0.00070 mol), 4-dimethylaminopyridine in methylene chloride (500 μl) as shown in reaction scheme 24 above (3.4 mg, 0.000028 mol) and (R)-(-)-α-methoxy-α-trifluoromethylphenylacetyl chloride (0.052 mL, 0.00028 mol) solution were stirred at room temperature for 5 hours. Purification by flash chromatography, followed by crystallization from ethyl acetate / heptane / pentane, gave ER-819990 (49.2 mg, 60%) as crystals.

Compounds, illustrated in the sections below and in Tables 1 and 2, but not explicitly shown above, can be synthesized using general methods consistent with Reaction Scheme 13 and / or Reaction Scheme 15. Compounds exemplified in the hydrochloride salt form can be prepared by applying the free base corresponding to the general conditions described in Reaction Scheme 16.

TABLE 1 Analytical data of representative compounds of Formula I.

Analytical Method:

Method A1

Solvent A: 0.2% Et ₃ N in water

Solvent B: 0.2% Et ₃ N in Acetonitrile

Flow rate: 2.0 ml / min

Linear Gradient:

Way C1

Mobile Phase: 0.1% Et ₂ NH in Ethanol

Flow rate: 1.0 ml / min

Isocratic

Example  42-126

In vitro biological activity

HEKT - bet - luc assay : This assay measures T-bet dependent reporter (luciferase) activity in HEK cells engineered to express human T-bet and T-box response elements inducing luciferase reporters. HEKT-bet cells were plated in 2 × 10 4 / well in 96-well plates and compounds were added to the cell culture and incubated for 24 hours. Luciferase activity was measured by adding 50 μl of Steady-Glo reagent (Promega) and samples were read on Victor V reader (PerkinElmer). The activity of the compounds was determined by comparing the compound treated samples with the compound untreated vehicle controls. IC ₅₀ values were calculated using the maximum corresponding to the amount of luciferase in the absence of the test compound and the minimum corresponding to the test compound value obtained under maximum inhibition.

Standardized HEKT - bet Determination of IC ₅₀ Values : Compounds were analyzed in microtiter plates. Each plate contained the reference compound, ER-819544. Relative potency values were obtained by dividing the un-normalized IC ₅₀ values of a particular compound by the IC ₅₀ value measured at the reference compound in the same microtiter plate. Relative potency values were then multiplied by the established potency of the reference compound to obtain normalized HEKT-bet IC ₅₀ values. In this assay, the established potency of ER-819544 was 0.035 μΜ. IC ₅₀ values provided herein were obtained using this standardization method.

Representative compounds of the invention were analyzed according to the methods presented in the HEKT-bet-luc assay described above. Table 2 below presents representative compounds of the invention with IC ₅₀ values below the indicated amounts (μM) determined by the standardized HEKT-bet-luc assay described above.

Table 2. Representative Compounds IC ₅₀  value

Example  126

In vivo Biological Activity: Active Immunity

Inhibition of the development of arthritis in the CIA . DBA1 / J mice were immunized with bCII / CFA on day 0 and then boosted with bCII / IFA on day 21. Arthritis development was monitored throughout the study phase. Arthritis scores are as follows: 0 = normal foot, score 1 = foot inflamed on 1-2 digits; Score 2 = 3 or 1-2 toes + inflamed wrist or ankle, score 3 = hand + 3 or more inflamed; And score 4 = plural toes (3-4) + significant wrist or ankle inflammation.

(A) Partial therapeutic evaluation of the compound. The active compound was administered once daily by oral administration at the indicated doses from the 20th day after induction of the antibody to collagen II but before the disease development. (B) Overall therapeutic evaluation of the compound. The active compound was administered after disease development (from day 7 after the second immunization). (C) X-ray analysis of rat paws from whole therapeutic CIA study. X-ray scores are a measure of the combination of osteopenia, bone erosion and new bone formation. (D) Representative X-ray radiographs.

The data is shown in Table 3 below. Usually, these data are advantageously compared to the activity of methotrexate in this model.

Example  127

In vivo Biological Activity: Passive Immunity

Inhibition of Arthritis Development in CAIA . BALB / c mice were injected intravenously (iv) with 1 mg of anti-type II collagen antibody on day 0, and after 3 days 25 μg of LPS was injected into the peritoneum (ip) with active compound and methotrexate (MTX) Once a day orally (PO) was administered from day 0 to day 7. Arthritis scores and body weight were monitored throughout the study phase.

The data is shown in Table 3 below. This data is advantageously compared to methotrexate, which is not particularly active in this model.

While many embodiments of the invention have been described, it is evident that the basic embodiments of the invention may be modified to provide other embodiments that utilize the compounds and methods of the invention. Therefore, it will be appreciated that the scope of the invention is defined by the appended claims rather than the specific embodiments presented by way of example.

Claims (29)

As the enantiomerically pure compound of formula Ia,

Wherein,
R ¹ is C _{1 -3} alkyl;
X is methylene, ethylene, propylene, ethenylene, propenylene, or butenylene;
R ⁵ is C _{1 -4} alkyl, C _{1 -3} alkoxy, hydroxyl, C _{1 -3} alkylthio, cyclopropyl, cyclopropylmethyl, trifluoromethoxy, 5-methyl-a rapid-fire thiazolyl, pyrazolyl, benzyloxy, acetyl, (cyano carbonyl) C _{1 -3} alkyl, (phenyl) C _{2 -3} alkenyl; And phenyl, pyrrolyl, benzimidazolyl, oxazolyl, isoxazolyl, imidazothiazolyl, quinolinyl, isoquinolinyl, substituted with 0 to 5 substituents independently selected from halo. Zolyl, pyridinyl, imidazopyridinyl, indolyl, benzotriazolyl, imidazolyl, benzofuranyl, benzothiadiazolyl, pyrimidinyl, benzopyranonyl, thiazolyl, thiadiazolyl, furyl, Thienyl, pyrazolyl, quinoxalinyl, or naphthyl;
R ⁸ is H, methyl, ethyl, propyl, (C _{1 -3} alkoxy) C _{1 -3} alkyl, (C _{1 -3} alkylthio) C _{1 -3} alkyl, C _{1 -3-hydroxy-alkyl,} phenyl, benzyl, Furyl, pyrrolyl, imidazolyl, pyrazolyl, pyrrolyl, isothiazolyl, isoxoxazolyl, pyridyl, and thienyl;
Wherein R ⁸ is methyl, ethyl, halo, hydroxyl, C _{1 -3} alkoxy, C _{1 -3} alkylthio, (C _{1 -3} alkoxy) C _{1 -3} alkyl, (C _{1 -3} alkylthio) C _{1 - 3} alkyl, C _{1 -3} alkyl, hydroxy, (C _{1 -3-mercapto} alkyl) phenyl, benzyl, furyl, imidazolyl, pyrazolyl, pyrrolyl, isothiazolyl, iso-oxazolyl, pyridyl, and thienyl Substituted with 0 to 3 substituents independently selected from; And
R ^a , R ^b , and R ^c are each independently selected from hydrogen, hydroxyl, methoxy, benzyloxy, fluoro, chloro, amino, methylamino, dimethylamino, and phenoxy;
Or a pair selected from R ^a and R ^b , and R ^b and R ^c taken together is —O— (CH ₂ ) —O— or —0-CH ₂ —CH ₂ —O—, or a pharmaceutically thereof acceptable salts, its C _1-6 alkyl ester or amide, or a C _{2 -6} alkenyl the compound to an ester or amide. The method of claim 1,
Wherein,
R ¹ is C _{1 -2} alkyl;
R ⁵ is C _{1 -4} alkyl, C _{1 -3} alkoxy, hydroxyl, C _{1 -3} alkylthio, cyclopropyl, cyclopropylmethyl, trifluoromethoxy, 5-methyl-a rapid-fire thiazolyl, pyrazolyl, benzyloxy, acetyl, (cyano carbonyl) C _{1 -3} alkyl, (phenyl) C _{2 -3} alkenyl; And phenyl, pyrrolyl, benzimidazolyl, oxazolyl, isoxazolyl, imidazothiazolyl, quinolinyl, isoquinolinyl, indazolyl, pyri substituted with 0-5 substituents independently selected from halo. Denyl, imidazopyridinyl, indolyl, benzotriazolyl, imidazolyl, benzofuranyl, benzothiadiazolyl, pyridimidinyl, benzopyranononyl, thiazolyl, thiadiazolyl, furyl, thienyl, Pyrazolyl, quinoxalinyl, or naphthyl;
R ⁸ is methyl, ethyl, or propyl, wherein R ⁸ is substituted with 0 to 3 hydroxyl substituents;
X is methylene or ethylene;
And R ^a , R ^b , and R ^c are each independently selected from the group consisting of H and methoxy, or a pharmaceutically acceptable salt thereof. The method of claim 1,
Wherein,
R ¹ is methyl;
R ⁵ is phenyl, pyrrolyl or pyrazolyl, each substituted zero, one or two times with methyl;
R ⁸ is ethyl;
X is methylene;
R ^a and R ^c are each methoxy;
R ^b is H or a pharmaceutically acceptable salt thereof. The method of claim 1,

And a pharmaceutically acceptable salt thereof. The method of claim 1,

And a pharmaceutically acceptable salt thereof. The method of claim 1,

And a pharmaceutically acceptable salt thereof. The method of claim 1,

And a pharmaceutically acceptable salt thereof. A composition comprising the compound of claim 1 in a pharmaceutically acceptable carrier. A method of treating rheumatoid arthritis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of claim 1. 10. The method of claim 9,
The compound of claim 1
R ¹ is C _{1 -2} alkyl;
R ⁵ is C _{1 -4} alkyl, C _{1 -3} alkoxy, hydroxyl, C _{1 -3} alkylthio, cyclopropyl, cyclopropylmethyl, trifluoromethoxy, 5-methyl-a rapid-fire thiazolyl, pyrazolyl, benzyloxy, acetyl, (cyano carbonyl) C _{1 -3} alkyl, (phenyl) C _{2 -3} alkenyl; And phenyl, pyrrolyl, benzimidazolyl, oxazolyl, isoxazolyl, imidazothiazolyl, quinolinyl, isoquinolinyl, indazolyl, pyri substituted with 0-5 substituents independently selected from halo. Denyl, imidazopyridinyl, indolyl, benzotriazolyl, imidazolyl, benzofuranyl, benzothiadiazolyl, pyridimidinyl, benzopyranononyl, thiazolyl, thiadiazolyl, furyl, thienyl, Pyrazolyl, quinoxalinyl, or naphthyl;
R ⁸ is methyl, ethyl, or propyl, wherein R ⁸ is substituted with 0 to 3 hydroxyl substituents;
X is methylene or ethylene;
R ^a , R ^b , and R ^c are each independently a compound selected from the group consisting of H and methoxy or a pharmaceutically acceptable salt thereof. The compound of claim 9, wherein the compound is

And pharmaceutically acceptable salts thereof. The compound of claim 9, wherein the compound is

And pharmaceutically acceptable salts thereof. The compound of claim 9, wherein the compound is

And pharmaceutically acceptable salts thereof. The compound of claim 9, wherein the compound is

And pharmaceutically acceptable salts thereof. A method of treating multiple sclerosis in a subject in need thereof, comprising administering a therapeutically effective amount of the compound of claim 1 to the subject. 16. The method of claim 15,
The compound of claim 1
R ¹ is C _{1 -2} alkyl;
R ⁵ is C _{1 -4} alkyl, C _{1 -3} alkoxy, hydroxyl, C _{1 -3} alkylthio, cyclopropyl, cyclopropylmethyl, trifluoromethoxy, 5-methyl-a rapid-fire thiazolyl, pyrazolyl, benzyloxy, acetyl, (cyano carbonyl) C _{1 -3} alkyl, (phenyl) C _{2 -3} alkenyl; And phenyl, pyrrolyl, benzimidazolyl, oxazolyl, isoxazolyl, imidazothiazolyl, quinolinyl, isoquinolinyl, indazolyl, pyri substituted with 0-5 substituents independently selected from halo. Denyl, imidazopyridinyl, indolyl, benzotriazolyl, imidazolyl, benzofuranyl, benzothiadiazolyl, pyridimidinyl, benzopyranononyl, thiazolyl, thiadiazolyl, furyl, thienyl, Pyrazolyl, quinoxalinyl, or naphthyl;
R ⁸ is methyl, ethyl, or propyl, wherein R ⁸ is substituted with 0 to 3 hydroxyl substituents;
X is methylene or ethylene;
R ^a , R ^b , and R ^c are each independently a compound selected from the group consisting of H and methoxy or a pharmaceutically acceptable salt thereof. The compound of claim 15, wherein the compound is

And pharmaceutically acceptable salts thereof. The compound of claim 15, wherein the compound is

And pharmaceutically acceptable salts thereof. The compound of claim 15, wherein the compound is

And pharmaceutically acceptable salts thereof. The compound of claim 15, wherein the compound is

And pharmaceutically acceptable salts thereof. A method of treating an autoimmune disease in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of claim 1; Said autoimmune disease is selected from the group consisting of systemic lupus erythematosus, type 1 diabetes, psoriasis, and atherosclerosis. The method of claim 21,
The compound of claim 1
R ¹ is C _{1 -2} alkyl;
R ⁵ is C _{1 -4} alkyl, C _{1 -3} alkoxy, hydroxyl, C _{1 -3} alkylthio, cyclopropyl, cyclopropylmethyl, trifluoromethoxy, 5-methyl-a rapid-fire thiazolyl, pyrazolyl, benzyloxy, acetyl, (cyano carbonyl) C _{1 -3} alkyl, (phenyl) C _{2 -3} alkenyl; And phenyl, pyrrolyl, benzimidazolyl, oxazolyl, isoxazolyl, imidazothiazolyl, quinolinyl, isoquinolinyl, indazolyl, pyri substituted with 0-5 substituents independently selected from halo. Denyl, imidazopyridinyl, indolyl, benzotriazolyl, imidazolyl, benzofuranyl, benzothiadiazolyl, pyridimidinyl, benzopyranononyl, thiazolyl, thiadiazolyl, furyl, thienyl, Pyrazolyl, quinoxalinyl, or naphthyl;
R ⁸ is methyl, ethyl, or propyl, wherein R ⁸ is substituted with 0 to 3 hydroxyl substituents;
X is methylene or ethylene;
R ^a , R ^b , and R ^c are each independently a compound selected from the group consisting of H and methoxy or a pharmaceutically acceptable salt thereof. The compound of claim 21, wherein the compound is

And pharmaceutically acceptable salts thereof. The compound of claim 21, wherein the compound is

And pharmaceutically acceptable salts thereof. The compound of claim 21, wherein the compound is

And pharmaceutically acceptable salts thereof. The compound of claim 21, wherein the compound is

And pharmaceutically acceptable salts thereof. Use of the compound of claims 1 to 8 for the manufacture of a medicament for treating rheumatoid arthritis in a subject in need thereof. Use of a compound of claims 1 to 8 for the manufacture of a medicament for treating multiple sclerosis in a subject in need thereof. Use of a compound of claims 1 to 8 for the manufacture of a medicament for treating an autoimmune disease in a subject in need thereof, wherein the autoimmune disease is systemic lupus erythematosus, type 1 diabetes, psoriasis, and atherosclerosis. Use selected from the group consisting of.