# Patent

## Title
Dihydropyridone amides as P2X7 modulators

## Abstract

Compounds of the formula I:




or pharmaceutically acceptable salts thereof, wherein m, n, R1, R2, R3, R4 and R5 are as defined herein. Also disclosed are methods of making the compounds and using the compounds for treatment of diseases associated with the P2X7 purinergic receptor.

## Background
CROSS REFERENCE TO RELATED APPLICATIONS
This application is entitled to the benefit of U.S. Provisional Application Ser. No. 61/203,470, filed Dec. 23, 2008, the disclosure of which is incorporated herein by reference.


FIELD OF THE INVENTION
This invention pertains to compounds useful for treatment of diseases associated with P2X purinergic receptors, and more particularly to P2X7 modulators usable for treatment of autoimmune and inflammatory diseases.
BACKGROUND OF THE INVENTION
P2X purinergic receptors are ATP-activated ionotropic receptors having seven subtypes. The P2X7 receptor subtype (also known as the P2Z receptor) is a ligand-gated ion channel found on mast cells, peripheral macrophages, lymphocytes, erythrocytes, fibroblasts and epidermal langerhans cells. Activation of P2X7 receptor on such immune system cells results in release of interleukin-1beta. (Solle et al., J. Biol. Chemistry 276, 125-132, (2001)). The P2X7 receptor is also found on microglia, Schwann cells and astrocytes within the central nervous system (Donnelly-Roberts et al., Br. J. Pharmacol. 151, 571-579 (2007)).
Antagonists of P2X7 have been showned to block P2X7-mediated IL-1beta release and P2X7-mediated cation flux (Stokes et al., Br. J. Pharmacol. 149, 880-887 (2006)). Mice lacking the P2X7 receptor show a lack of inflammatory and neuropathic hypersensitivity to mechanical and thermal stimuli (Chessell et al., Pain 114, 386-396 (2005)). P2X7 is thus believed to have a role in inflammatory responses (Ferrari et al., J. Immunol. 176, 3877-3883 (2006)) and in the onset and persistence of chronic pain (Honore et al., J. Pharmacol. Ex. Ther. 319, 1376-1385 (2006b)).
Modulators of the P2X7 receptor thus may have utility in the treatment of disease states such as rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, chronic obstructive pulmonary disease, airways hyper-responsiveness, septic shock, glomerulonephritis, irritable bowel disease, diabetes and Crohn's disease. P2X7 modulators may also be useful for treatment of pain, including chronic pain, neuropathic pain, and pain associated inflammatory processes and degenerative conditions.
There is accordingly a need for compounds that act as modulators of P2X receptors, including antagonists of P2X7 receptor, as well as a need for methods of treating diseases, conditions and disorders mediated by P2X7 The present invention satisfies these needs as well as others.
SUMMARY OF THE INVENTION
The invention provides compounds of the formula I:




or pharmaceutically acceptable salts thereof,

wherein:

m is 0 or 1;
n is 0 or 1;
R1 is:

    
    
        optionally substituted aryl;
        optionally substituted heteroaryl; or
        adamantyl;
    
    


R2 is:

    
    
        optionally substituted aryl;
        optionally substituted heteroaryl;
        C3-6cycloalkyl; or
        C3-6 branched alkyl; and
    
    


R3, R4 and R5 each independently is:

    
    
        hydrogen; or
        C1-6alkyl.
    
    


The invention also provides and pharmaceutical compositions comprising the compounds, methods of using the compounds, and methods of preparing the compounds.


DETAILED DESCRIPTION OF THE INVENTION
Definitions
Unless otherwise stated, the following terms used in this Application, including the specification and claims, have the definitions given below. It must be noted that, as used in the specification and the appended claims, the singular forms “a”, “an,” and “the” include plural referents unless the context clearly dictates otherwise.
“Agonist” refers to a compound that enhances the activity of another compound or receptor site.
“Alkyl” means the monovalent linear or branched saturated hydrocarbon moiety, consisting solely of carbon and hydrogen atoms, having from one to twelve carbon atoms. “Lower alkyl” refers to an alkyl group of one to six carbon atoms, i.e. C1-C6alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.
“Alkenyl” means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g., ethenyl, propenyl, and the like.
“Alkynyl” means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one triple bond, e.g., ethynyl, propynyl, and the like.
“Alkylene” means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, e.g., methylene, ethylene, 2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene, and the like.
“Alkoxy” and “alkyloxy”, which may be used interchangeably, mean a moiety of the formula —OR, wherein R is an alkyl moiety as defined herein. Examples of alkoxy moieties include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.
“Alkoxyalkyl” means a moiety of the formula Ra—O—Rb—, where Ra is alkyl and Rb is alkylene as defined herein. Exemplary alkoxyalkyl groups include, by way of example, 2-methoxyethyl, 3-methoxypropyl, 1-methyl-2-methoxyethyl, 1-(2-methoxyethyl)-3-methoxypropyl, and 1-(2-methoxyethyl)-3-methoxypropyl.
“Alkylcarbonyl” means a moiety of the formula —R′—R′′, where R′ is oxo and R′′ is alkyl as defined herein.
“Alkylsulfonyl” means a moiety of the formula —R′—R′′, where R′ is —SO2— and R′′ is alkyl as defined herein.
“Alkylsulfonylalkyl means a moiety of the formula —R′—R′′—R′′′ where where R′ is alkylene, R′′ is —SO2— and R′′′ is alkyl as defined herein.
“Amino means a moiety of the formula —NRR′ wherein R and R′ each independently is hydrogen or alkyl as defined herein. “Amino thus includes “alkylamino (where one of R and R′ is alkyl and the other is hydrogen) and “dialkylamino (where R and R′ are both alkyl.
“Alkoxyamino” means a moiety of the formula —NR—OR′ wherein R is hydrogen or alkyl and R′ is alkyl as defined herein.
“Alkylsulfanyl” means a moiety of the formula —SR wherein R is alkyl as defined herein.
“Aminoalkyl” means a group —R—R′ wherein R′ is amino and R is alkylene as defined herein. “Aminoalkyl” includes aminomethyl, aminoethyl, 1-aminopropyl, 2-aminopropyl, and the like. The amino moiety of “aminoalkyl” may be substituted once or twice with alkyl to provide “alkylaminoalkyl” and “dialkylaminoalkyl” respectively.  “Alkylaminoalkyl” includes methylaminomethyl, methylaminoethyl, methylaminopropyl, ethylaminoethyl and the like. “Dialkylaminoalkyl” includes dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, N-methyl-N-ethylaminoethyl, and the like.
“Aminoalkoxy” means a group —OR—R′ wherein R′ is amino and R is alkylene as defined herein.
“Alkylsulfonylamido” means a moiety of the formula —NR′SO2—R wherein R is alkyl and R′ is hydrogen or alkyl.
“Aminocarbonyloxyalkyl” or “carbamylalkyl” means a group of the formula —R—O—C(O)—NR′R′′ wherein R is alkylene and R′, R′′ each independently is hydrogen or alkyl as defined herein.
“Alkynylalkoxy” means a group of the formula —O—R—R′ wherein R is alkylene and R′ is alkynyl as defined herein.
“Antagonist” refers to a compound that diminishes or prevents the action of another compound or receptor site.
“Aryl” means a monovalent cyclic aromatic hydrocarbon moiety consisting of a mono-, bi- or tricyclic aromatic ring. The aryl group can be optionally substituted as defined herein. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl, diphenylsulfidyl, diphenylsulfonyl, diphenylisopropylidenyl, benzodioxanyl, benzofuranyl, benzodioxylyl, benzopyranyl, benzoxazinyl, benzoxazinonyl, benzopiperadinyl, benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl, methylenedioxyphenyl, ethylenedioxyphenyl, and the like, including partially hydrogenated derivatives thereof, each being optionally substituted.
“Arylalkyl” and “Aralkyl”, which may be used interchangeably, mean a radical-RaRb where Ra is an alkylene group and Rb is an aryl group as defined herein; e.g., phenylalkyls such as benzyl, phenylethyl, 3-(3-chlorophenyl)-2-methylpentyl, and the like are examples of arylalkyl.
“Arylsulfonyl means a group of the formula —SO2—R wherein R is aryl as defined herein.
“Aryloxy” means a group of the formula —O—R wherein R is aryl as defined herein.
“Aralkyloxy” means a group of the formula —O—R—R′′ wherein R is alkylene and R′ is aryl as defined herein.
“Cyanoalkyl” means a moiety of the formula —R′—R′′, where R′ is alkylene as defined herein and R′′ is cyano or nitrile.
“Cycloalkyl” means a monovalent saturated carbocyclic moiety consisting of mono- or bicyclic rings. Cycloalkyl can optionally be substituted with one or more substituents, wherein each substituent is independently hydroxy, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, or dialkylamino, unless otherwise specifically indicated. Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, including partially unsaturated derivatives thereof.
“Cycloalkylalkyl” means a moiety of the formula —R′—R′′, where R′ is alkylene and R′′ is cycloalkyl as defined herein.
“Heteroalkyl” means an alkyl radical as defined herein wherein one, two or three hydrogen atoms have been replaced with a substituent independently selected from the group consisting of —ORa, —NRbRc, and —S(O)nRd (where n is an integer from 0 to 2), with the understanding that the point of attachment of the heteroalkyl radical is through a carbon atom, wherein Ra is hydrogen, acyl, alkyl, cycloalkyl, or cycloalkylalkyl; Rb and Rc are independently of each other hydrogen, acyl, alkyl, cycloalkyl, or cycloalkylalkyl; and when n is 0, Rd is hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl, and when n is 1 or 2, Rd is alkyl, cycloalkyl, cycloalkylalkyl, amino, acylamino, monoalkylamino, or dialkylamino. Representative examples include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxypropyl, 1-hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl, 2-hydroxy-1-methylpropyl, 2-aminoethyl, 3-aminopropyl, 2-methylsulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl, amino sulfonylpropyl, methylaminosulfonylmethyl, methylaminosulfonylethyl, methylaminosulfonylpropyl, and the like.
“Heteroaryl” means a monocyclic or bicyclic radical of 5 to 12 ring atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from N, O, or S, the remaining ring atoms being C, with the understanding that the attachment point of the heteroaryl radical will be on an aromatic ring. The heteroaryl ring may be optionally substituted as defined herein. Examples of heteroaryl moieties include, but are not limited to, optionally substituted imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, benzothienyl, thiophenyl, furanyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidyl, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl and the like, including partially hydrogenated derivatives thereof, each optionally substituted.
Heteroarylalkyl” or “heteroaralkyl” means a group of the formula —R—R′ wherein R is alkylene and R′ is heteroaryl as defined herein.
“Heteroarylsulfonyl means a group of the formula —SO2—R wherein R is heteroaryl as defined herein.
“Heteroaryloxy” means a group of the formula —O—R wherein R is heteroaryl as defined herein.
“Heteroaralkyloxy” means a group of the formula —O—R—R′′ wherein R is alkylene and R′ is heteroaryl as defined herein.
The terms “halo”, “halogen” and “halide”, which may be used interchangeably, refer to a substituent fluoro, chloro, bromo, or iodo.
“Haloalkyl” means alkyl as defined herein in which one or more hydrogen has been replaced with same or different halogen. Exemplary haloalkyls include —CH2Cl, —CH2CF3, —CH2CCl3, perfluoroalkyl (e.g., —CF3), and the like.
“Haloalkoxy” means a moiety of the formula —OR, wherein R is a haloalkyl moiety as defined herein. An exemplary haloalkoxy is difluoromethoxy.
“Heterocycloamino” means a saturated ring wherein at least one ring atom is N, NH or N-alkyl and the remaining ring atoms form an alkylene group.
“Heterocyclyl” means a monovalent saturated moiety, consisting of one to three rings, incorporating one, two, or three or four heteroatoms (chosen from nitrogen, oxygen or sulfur). The heterocyclyl ring may be optionally substituted as defined herein. Examples of heterocyclyl moieties include, but are not limited to, optionally substituted piperidinyl, piperazinyl, homopiperazinyl, azepinyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, pyridinyl, pyridazinyl, pyrimidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinuclidinyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazolylidinyl, benzothiazolidinyl, benzoazolylidinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinylsulfone, dihydroquinolinyl, dihydrisoquinolinyl, tetrahydroquinolinyl, tetrahydrisoquinolinyl, and the like.
“Heterocyclylalkyl” means a moiety of the formula —R—R′ wherein R is alkylene and R′ is heterocyclyl as defined herein.
“Heterocyclyloxy” means a moiety of the formula —OR wherein R is heterocyclyl as defined herein.
“Heterocyclylalkoxy” means a moiety of the formula —OR—R′ wherein R is alkylene and R′ is heterocyclyl as defined herein.
“Hydroxyalkoxy” means a moiety of the formula —OR wherein R is hydroxyalkyl as defined herein.
“Hydroxyalkylamino” means a moiety of the formula —NR—R′ wherein R is hydrogen or alkyl and R′ is hydroxyalkyl as defined herein.
“Hydroxyalkylaminoalkyl” means a moiety of the formula —R—NR′—R′′ wherein R is alkylene, R′ is hydrogen or alkyl, and R′′ is hydroxyalkyl as defined herein.
“Hydroxycarbonylalkyl” or “carboxyalkyl” means a group of the formula —R—(CO)—OH where R is alkylene as defined herein.
“Hydroxyalkyloxycarbonylalkyl” or “hydroxyalkoxycarbonylalkyl” means a group of the formula —R—C(O)—O—R—OH wherein each R is alkylene and may be the same or different.
“Hydroxyalkyl” means an alkyl moiety as defined herein, substituted with one or more, preferably one, two or three hydroxy groups, provided that the same carbon atom does not carry more than one hydroxy group. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl
“Hydroxycycloalkyl” means a cycloalkyl moiety as defined herein wherein one, two or three hydrogen atoms in the cycloalkyl radical have been replaced with a hydroxy substituent. Representative examples include, but are not limited to, 2-, 3-, or 4-hydroxycyclohexyl, and the like.
“Urea” or “ureido” means a group of the formula —NR′—C(O)—NR′′R′′′ wherein R′, R′′ and R′′′ each independently is hydrogen or alkyl.
“Carbamate” means a group of the formula —O—C(O)—NR′R′′ wherein R′ and R′′ each independently is hydrogen or alkyl.
“Carboxy” means a group of the formula —O—C(O)—OH.
“Sulfonamido” means a group of the formula —SO2—NR′R′′ wherein R′, R′′ and R′′′ each independently is hydrogen or alkyl.
“Optionally substituted”, when used in association with “aryl”, phenyl”, “heteroaryl” “cycloalkyl” or “heterocyclyl”, means an aryl, phenyl, heteroaryl, cycloalkyl or heterocyclyl which is optionally substituted independently with one to four substituents, preferably one or two substituents selected from alkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, hydroxyalkyl, halo, nitro, cyano, hydroxy, alkoxy, amino, acylamino, mono-alkylamino, di-alkylamino, halo alkyl, haloalkoxy, heteroalkyl, —COR, —SO2R (where R is hydrogen, alkyl, phenyl or phenylalkyl), —(CR′R′′)n—COOR (where n is an integer from 0 to 5, R′ and R′′ are independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl), or —(CR′R′′)n—CONRaRb (where n is an integer from 0 to 5, R′ and R′′ are independently hydrogen or alkyl, and Ra and Rb are, independently of each other, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl). Certain preferred optional substituents for “aryl”, phenyl”, “heteroaryl” “cycloalkyl” or “heterocyclyl” include alkyl, halo, haloalkyl, alkoxy, cyano, amino and alkylsulfonyl. More preferred substituents are methyl, fluoro, chloro, trifluoromethyl, methoxy, amino and methanesulfonyl.
“Leaving group” means the group with the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or group displaceable under substitution reaction conditions. Examples of leaving groups include, but are not limited to, halogen, alkane- or arylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy, thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy, dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy, acyloxy, and the like.
“Modulator” means a molecule that interacts with a target. The interactions include, but are not limited to, agonist, antagonist, and the like, as defined herein.
“Optional” or “optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
“Disease” and “Disease state” means any disease, condition, symptom, disorder or indication.
“Inert organic solvent” or “inert solvent” means the solvent is inert under the conditions of the reaction being described in conjunction therewith, including for example, benzene, toluene, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, chloroform, methylene chloride or dichloromethane, dichloroethane, diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tert-butanol, dioxane, pyridine, and the like. Unless specified to the contrary, the solvents used in the reactions of the present invention are inert solvents.
“Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.
“Pharmaceutically acceptable salts” of a compound means salts that are pharmaceutically acceptable, as defined herein, and that possess the desired pharmacological activity of the parent compound. Such salts include:
acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphtoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, and the like; or
salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.
The preferred pharmaceutically acceptable salts are the salts formed from acetic acid, hydrochloric acid, sulphuric acid, methanesulfonic acid, maleic acid, phosphoric acid, tartaric acid, citric acid, sodium, potassium, calcium, zinc, and magnesium.
It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same acid addition salt.
“Protective group” or “protecting group” means the group which selectively blocks one reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry. Certain processes of this invention rely upon the protective groups to block reactive nitrogen and/or oxygen atoms present in the reactants. For example, the terms “amino-protecting group” and “nitrogen protecting group” are used interchangeably herein and refer to those organic groups intended to protect the nitrogen atom against undesirable reactions during synthetic procedures. Exemplary nitrogen protecting groups include, but are not limited to, trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl (carbobenzyloxy, CBZ), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), and the like. The artisan in the art will know how to chose a group for the ease of removal and for the ability to withstand the following reactions.
“Solvates” means solvent additions forms that contain either stoichiometric or non stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as H2O, such combination being able to form one or more hydrate.
“Subject” means mammals and non-mammals. Mammals means any member of the mammalia class including, but not limited to, humans; non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds, and the like. The term “subject” does not denote a particular age or sex.
“Disorders of the urinary tract” or “uropathy” used interchangeably with “symptoms of the urinary tract” means the pathologic changes in the urinary tract. Examples of urinary tract disorders include, but are not limited to, incontinence, benign prostatic hypertrophy (BPH), prostatitis, detrusor hyperreflexia, outlet obstruction, urinary frequency, nocturia, urinary urgency, overactive bladder, pelvic hypersensitivity, urge incontinence, urethritis, prostatodynia, cystitis, idiophatic bladder hypersensitivity, and the like.
“Disease states associated with the urinary tract” or “urinary tract disease states” or “uropathy” used interchangeably with “symptoms of the urinary tract” mean the pathologic changes in the urinary tract, or dysfunction of urinary bladder smooth muscle or its innervation causing disordered urinary storage or voiding. Symptoms of the urinary tract include, but are not limited to, overactive bladder (also known as detrusor hyperactivity), outlet obstruction, outlet insufficiency, and pelvic hypersensitivity.
“Overactive bladder” or “detrusor hyperactivity” includes, but is not limited to, the changes symptomatically manifested as urgency, frequency, altered bladder capacity, incontinence, micturition threshold, unstable bladder contractions, sphincteric spasticity, detrusor hyperreflexia (neurogenic bladder), detrusor instability, and the like.
“Outlet obstruction” includes, but is not limited to, benign prostatic hypertrophy (BPH), urethral stricture disease, tumors, low flow rates, difficulty in initiating urination, urgency, suprapubic pain, and the like.
“Outlet insufficiency” includes, but is not limited to, urethral hypermobility, intrinsic sphincteric deficiency, mixed incontinence, stress incontinence, and the like.
“Pelvic Hypersensitivity” includes, but is not limited to, pelvic pain, interstitial (cell) cystitis, prostatodynia, prostatitis, vulvadynia, urethritis, orchidalgia, overactive bladder, and the like.
“Respiratory disorder” refers to, without limitation, chronic obstructive pulmonary disease (COPD), asthma, bronchospasm, and the like.
“Gastrointestinal disorder” (“GI disorder”) refers to, without limitation, Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD), biliary colic and other biliary disorders, renal colic, diarrhea-dominant IBS, pain associated with GI distension, and the like.
“Pain” includes, without limitation, inflammatory pain; surgical pain; visceral pain; dental pain; premenstrual pain; central pain; pain due to burns; migraine or cluster headaches; nerve injury; neuritis; neuralgias; poisoning; ischemic injury; interstitial cystitis; cancer pain; viral, parasitic or bacterial infection; post-traumatic injury; or pain associated with irritable bowel syndrome.
“Therapeutically effective amount” means an amount of a compound that, when administered to a subject for treating a disease state, is sufficient to effect such treatment for the disease state. The “therapeutically effective amount” will vary depending on the compound, disease state being treated, the severity or the disease treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary practitioner, and other factors.
The terms “those defined above” and “those defined herein” when referring to a variable incorporates by reference the broad definition of the variable as well as preferred, more preferred and most preferred definitions, if any.
“Treating” or “treatment” of a disease state includes:

    
    
        (i) preventing the disease state, i.e. causing the clinical symptoms of the disease state not to develop in a subject that may be exposed to or predisposed to the disease state, but does not yet experience or display symptoms of the disease state.
        (ii) inhibiting the disease state, i.e., arresting the development of the disease state or its clinical symptoms, or
        (iii) relieving the disease state, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms.
    
    


The terms “treating”, “contacting” and “reacting” when referring to a chemical reaction means adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or the desired product. It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or the desired product.
Nomenclature and Structures
In general, the nomenclature used in this Application is based on AUTONOMTM v.4.0, a Beilstein Institute computerized system for the generation of IUPAC systematic nomenclature. Chemical structures shown herein were prepared using ISIS® version 2.2. Any open valency appearing on a carbon, oxygen sulfur or nitrogen atom in the structures herein indicates the presence of a hydrogen atom unless indicated otherwise. Where a nitrogen-containing heteroaryl ring is shown with an open valency on a nitrogen atom, and variables such as Ra, Rb or Rc are shown on the heteroaryl ring, such variables may be bound or joined to the open valency nitrogen. Where a chiral center exists in a structure but no specific stereochemistry is shown for the chiral center, both enantiomers associated with the chiral center are encompassed by the structure. Where a structure shown herein may exist in multiple tautomeric forms, all such tautomers are encompassed by the structure. The atoms represented in the structures herein are intended to encompass all naturally occurring isotopes of such atoms. Thus, for example, the hydrogen atoms represented herein are meant to include deuterium and tritium, and the carbon atoms are meant to include C13 and C14 isotopes.
All patents and publications identified herein are incorporated herein by reference in their entirety.
Compounds of the Invention
The invention provides compounds of the formula I:




or pharmaceutically acceptable salts thereof,

wherein:

m is 0 or 1;
n is 0 or 1;
R1 is:

    
    
        optionally substituted aryl;
        optionally substituted heteroaryl; or
        adamantyl;
    
    


R2 is:

    
    
        optionally substituted aryl;
        optionally substituted heteroaryl;
        C3-6cycloalkyl; or
        C3-6 branched alkyl; and
    
    


R3, R4 and R5 each independently is:

    
    
        hydrogen; or
        C1-6alkyl.
    
    


In certain embodiments of formula I, R3, R4 and R5 are hydrogen.
In certain embodiments of formula I, m is 0.
In certain embodiments of formula I, n is 0.
In certain embodiments of formula I, R3 is hydrogen.
In certain embodiments of formula I, R4 is hydrogen.
In certain embodiments of formula I, R5 is hydrogen.
In certain embodiments of formula I, R1 is optionally substituted aryl.
In certain embodiments of formula I, R1 is optionally substituted phenyl.
In certain embodiments of formula I, R1 is phenyl optionally substituted one, two, three or four times with a substituent or substituents each independently selected from: halo; C1-6alkyl; C1-6alkoxy; halo-C1-6alkyl; halo-C1-6alkoxy; C1-6alkylsulfonyl; C1-6alkylsulfanyl; C1-6alkylsulfinyl; phenylsulfonyl wherein the phenyl portion is optionally substituted with C1-6alkyl; nitrile; hydroxy; alkylcarbonyl; aminocarbonyl; alkoxycarbonyl; alkoxycarbonylalkoxy; hydroxycarbonyl; hydroxycarbonylalkoxy; alkylaminocarbonylalkoxy; alkoxyalkoxy; hydroxyalkoxy; alkylaminoalkoxy; alkylsulfonylalkoxy; hydroxyalkyl; C3-6cycloalkyl-C1-6alkoxy; amino; aminoalkyl; C1-6alkenyl; C1-6alkynyl; or nitro; or two adjacent substituents may form a C1-2alkylenedioxy or halo-C1-2alkylenedioxy.
In certain embodiments of formula I, R1 is phenyl substituted one, two, three or four times with a substituent or substituents each independently selected from: fluoro; chloro; bromo; iodo; methyl; ethyl; methoxy; ethoxy; trifluoromethyl; difluoromethoxy; methanesulfonyl; methanesulfanyl; methanesulfinyl; toluenesulfonyl; nitrile; acetyl; aminocarbonyl; methoxycarbonyl; methoxycarbonylmethoxy; carboxy; hydroxycarbonylmethoxy; methylaminocarbonylmethoxy; methoxyethoxy; hydroxyethoxy; methylaminoethoxy; methanesulfonylpropyloxy; hydroxymethyl; hydroxyethyl; cyclopropylmethoxy; amino; or nitro; or two adjacent substituents may form methylenedioxy, ethylenedioxy or difluoromethylenedioxy.
In certain embodiments of formula I, R1 is phenyl substituted one, two, three or four times with a substituent or substituents each independently selected from: halo; C1-6alkyl; C1-6alkoxy; halo-C1-6alkyl; halo-C1-6alkoxy; C1-6alkylsulfonyl; nitrile; alkoxyalkoxy; hydroxyalkoxy; alkylsulfonylalkoxy; hydroxyalkyl; or C3-6cycloalkyl-C1-6alkoxy.
In certain embodiments of formula I, R1 is phenyl substituted one, two, three or four times with a substituent or substituents each independently selected from: fluoro; chloro; bromo; iodo; methyl; ethyl; methoxy; ethoxy; trifluoromethyl; difluoromethoxy; methanesulfonyl; nitrile; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; or cyclopropylmethoxy.
In certain embodiments of formula I, R1 is phenyl optionally substituted one, two or three times with a substituent or substituents each independently selected from: fluoro; chloro; bromo; methyl; ethyl; methoxy; ethoxy; trifluoromethyl; difluoromethoxy; nitrile; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; or cyclopropylmethoxy.
In certain embodiments of formula I, R1 is: 2-bromo-4,5-dimethoxy-phenyl; 2-bromo-4-chloro-5-methoxy-phenyl; 2-bromo-4-fluoro-5-methoxy-phenyl; 2,4-dichloro-5-methoxy-phenyl; 2-bromo-5-methoxy-4-trifluoromethyl-phenyl; 2-bromo-4,5-dichloro-phenyl; 2-bromo-4-chloro-5-iodo-phenyl; 2-bromo-4-chloro-5-trifluoromethyl-phenyl; 2-bromo-5-methoxy-4-methyl-phenyl; 2-isopropyl-4,5-dimethoxy-phenyl; 2-bromo-4-chloro-5-methanesulfanyl-phenyl; 2-bromo-4-chloro-5-methanesulfonyl-phenyl; 2-bromo-4-chloro-5-methanesulfinyl-phenyl; 2-bromo-4-chloro-5-fluoro-phenyl; 2-bromo-5-methoxy-phenyl; 2-bromo-5-methoxy-4-methoxycarbonyl-phenyl; 2-bromo-4-chloro-5-hydroxy-phenyl; 2-bromo-4-chloro-5-(methylamino-carbonyl-methyoxy)-phenyl; 2-methyl-4,5-dimethoxy-phenyl; 2-bromo-4-chloro-5-methoxycarbonyl-phenyl; 2-bromo-4-methanesulfonyl-5-methoxy-phenyl; 2-bromo-4-methyl-5-methoxy-phenyl; 2-bromo-4-chloro-5-(methoxycarbonyl-methoxy)-phenyl; 2-bromo-4-chloro-5-(hydroxycarbonyl-methoxy)-phenyl; 2-bromo-4-chloro-5-(2-methoxyethoxy)-phenyl; 4,5-dimethoxy-phenyl; 2-fluoro-4-chloro-5-methoxy-phenyl; 2-bromo-4-methoxycarbonyl-5-methoxy-phenyl; 6-bromo-benzo[1,3]dioxol-5-yl; 2-bromo-4-chloro-5-(2-hydroxyethoxy)-phenyl; 2-bromo-4-difluoromethoxy-5-methoxy-phenyl; 5-methoxy-4-methyl-phenyl; 2-bromo-4-chloro-5-(2-methylamino-ethoxy)-phenyl; 2-bromo-4-cyano-5-methyl-phenyl; 2-fluoro-4-methyl-5-methoxy-phenyl; 2-bromo-4-chloro-5-acetyl-phenyl; 5-methoxy-2-methyl-phenyl; 2-bromo-4-chloro-5-(3-methanesulfonyl-propoxy)-phenyl; 2-bromo-5-methoxy-4-(tert-butoxycarbonyl)-phenyl; 5-methanesulfonyl-2-methoxy-phenyl; 2-bromo-4-chloro-5-(1-hydroxyethyl)-phenyl; 2-fluoro-5-(2-hydroxyethoxy)-4-methyl-phenyl; 2-bromo-5-methoxy-4-amino carbonyl-phenyl; 6-bromo-2,2-difluoro-benzo[1,3]dioxol-5-yl; 2,6-difluoro-phenyl; 2-bromo-4-cyano-5-methoxy-phenyl; 2,5-dimethoxy-phenyl; 3-methoxycarbonyl-2-methyl-phenyl; 3-methoxy-phenyl; 4-methoxy-phenyl; 2,4-dimethoxy-phenyl; 4-chloro-5-methoxy-phenyl; 4-fluoro-5-methoxy-phenyl; 2-bromo-4-methyl-5-(tert-butoxycarbonyl)-phenyl; 3,4,5-trimethoxy-phenyl; 2-bromo-4,6-difluoro-phenyl; 2-ethyl-4,5-dimethoxy-phenyl; 2-bromo-4-methoxy-phenyl; 4-chloro-5-(2-hydroxyethoxy)-2-methyl-phenyl; 3-methoxycarbonyl-2-methyl-phenyl; 2,5-dimethyl-phenyl; 2-bromo-5-methoxy-phenyl; 2,3-dimethyl-phenyl; 2-bromo-4-chloro-5-hydroxymethyl-phenyl; 2-bromo-3,5-dimethyl-phenyl; 4-methoxy-2-methyl-phenyl; 2,4-dimethyl-phenyl; 2-iodo-4,5-dimethoxy-phenyl; 2-chloro-4,5-dimethoxy-phenyl; 7-bromo-2,3-dihydrobenzo[1,4]dioxin-6-yl; 4,5-dimethoxy-2-trifluoromethyl-phenyl; 2-bromo-5-ethoxy-4-methoxy-phenyl; 2-bromo-4-ethoxy-5-methoxy-phenyl; 2-bromo-5-cyclopropylmethoxy-4-methoxy-phenyl; 2-bromo-4-cyclopropylmethoxy-5-methoxy-phenyl; 2-cyano-4,5-dimethoxyphenyl; 2-bromo-5-difluoromethoxy-4-methoxy-phenyl; 2-bromo-4,5-bis-difluoromethoxy-phenyl; 2-bromo-4-fluoro-5-(2-methoxyethoxy)-phenyl; 2-bromo-4-fluoro-5-(2-hydroxyethoxy)-phenyl; or 4-fluoro-4,5-dimethoxy-phenyl.
In certain embodiments of formula I, R1 is: 2-bromo-4,5-dimethoxy-phenyl; 2-bromo-4-chloro-5-methoxy-phenyl; 2-bromo-4-fluoro-5-methoxy-phenyl; 2,4-dichloro-5-methoxy-phenyl; 2-bromo-5-methoxy-4-trifluoromethyl-phenyl; 2-bromo-4,5-dichloro-phenyl; 2-bromo-4-chloro-5-iodo-phenyl; 2-bromo-4-chloro-5-trifluoromethyl-phenyl; 2-bromo-5-methoxy-4-methyl-phenyl; 2-isopropyl-4,5-dimethoxy-phenyl; 2-bromo-4-chloro-5-methanesulfanyl-phenyl; 2-bromo-4-chloro-5-methanesulfonyl-phenyl; 2-bromo-4-chloro-5-methanesulfinyl-phenyl; 2-bromo-4-chloro-5-fluoro-phenyl; 2-bromo-5-methoxy-phenyl; 2-bromo-5-methoxy-4-methoxycarbonyl-phenyl; 2-bromo-4-chloro-5-hydroxy-phenyl; 2-bromo-4-chloro-5-(methylamino-carbonyl-methyoxy)-phenyl; 2-methyl-4,5-dimethoxy-phenyl; 2-bromo-4-chloro-5-methoxycarbonyl-phenyl; 2-bromo-4-methanesulfonyl-5-methoxy-phenyl; 2-bromo-4-methyl-5-methoxy-phenyl; 2-bromo-4-chloro-5-(methoxycarbonyl-methoxy)-phenyl; 2-bromo-4-chloro-5-(hydroxycarbonyl-methoxy)-phenyl; 2-bromo-4-chloro-5-(2-methoxyethoxy)-phenyl; 4,5-dimethoxy-phenyl; 2-fluoro-4-chloro-5-methoxy-phenyl; 2-bromo-4-methoxycarbonyl-5-methoxy-phenyl; 6-bromo-benzo[1,3]dioxol-5-yl; 2-bromo-4-chloro-5-(2-hydroxyethoxy)-phenyl; 2-bromo-4-difluoromethoxy-5-methoxy-phenyl; 5-methoxy-4-methyl-phenyl; 2-bromo-4-chloro-5-(2-methylamino-ethoxy)-phenyl; 2-bromo-4-cyano-5-methyl-phenyl; 2-fluoro-4-methyl-5-methoxy-phenyl; 2-bromo-4-chloro-5-acetyl-phenyl; 5-methoxy-2-methyl-phenyl; 2-bromo-4-chloro-5-(3-methanesulfonyl-propoxy)-phenyl; 2-bromo-5-methoxy-4-(tert-butoxycarbonyl)-phenyl; 5-methanesulfonyl-2-methoxy-phenyl; 2-bromo-4-chloro-5-(1-hydroxyethyl)-phenyl; 2-fluoro-5-(2-hydroxyethoxy)-4-methyl-phenyl; 2-bromo-5-methoxy-4-aminocarbonyl-phenyl; 6-bromo-2,2-difluoro-benzo[1,3]dioxol-5-yl; 2,6-difluoro-phenyl; 2-bromo-4-cyano-5-methoxy-phenyl; 2,5-dimethoxy-phenyl; 3-methoxycarbonyl-2-methyl-phenyl; 3-methoxy-phenyl; 4-methoxy-phenyl; 2,4-dimethoxy-phenyl; 4-chloro-5-methoxy-phenyl; 4-fluoro-5-methoxy-phenyl; 2-bromo-4-methyl-5-(tert-butoxycarbonyl)-phenyl; 3,4,5-trimethoxy-phenyl; 2-bromo-4,6-difluoro-phenyl; 2-ethyl-4,5-dimethoxy-phenyl; 2-bromo-4-methoxy-phenyl; 4-chloro-5-(2-hydroxyethoxy)-2-methyl-phenyl; 3-methoxycarbonyl-2-methyl-phenyl; 2,5-dimethyl-phenyl; 2-bromo-5-methoxy-phenyl; 2,3-dimethyl-phenyl; 2-bromo-4-chloro-5-hydroxymethyl-phenyl; 2-bromo-3,5-dimethyl-phenyl; 4-methoxy-2-methyl-phenyl; or 2,4-dimethyl-phenyl.
In certain embodiments of formula I, R1 is: 2-bromo-4,5-dimethoxy-phenyl; 2-bromo-4-chloro-5-methoxy-phenyl; 2-bromo-4-fluoro-5-methoxy-phenyl; 2-bromo-5-methoxy-4-methyl-phenyl; 2-methyl-4,5-dimethoxy-phenyl; 2-bromo-4-chloro-5-(2-methoxy-ethyl-phenyl; 2-bromo-4-chloro-5-(2-hydroxy-ethyl-phenyl; 2-bromo-4-difluoromethoxy-5-methoxy-phenyl; 2,5-dimethoxy-phenyl; 2-ethyl-4,5-dimethoxy-phenyl; 2-methyl-5-(2-hydroxy-ethoxy)-4-chloro-phenyl; 2,5-dimethyl-phenyl; 2-bromo-5-methoxy-phenyl; or 2-bromo-4,5-dimethyl-phenyl.
In certain embodiments of formula I, R1 is: 2-iodo-4,5-dimethoxy-phenyl; 2-chloro-4,5-dimethoxy-phenyl; 7-bromo-2,3-dihydrobenzo[1,4]dioxin-6-yl; 4,5-dimethoxy-2-trifluoromethyl-phenyl; 2-bromo-5-ethoxy-4-methoxy-phenyl; 2-bromo-4-ethoxy-5-methoxy-phenyl; 2-bromo-5-cyclopropylmethoxy-4-methoxy-phenyl; 2-bromo-4-cyclopropylmethoxy-5-methoxy-phenyl; 2-cyano-4,5-dimethoxyphenyl; 2-bromo-5-difluoromethoxy-4-methoxy-phenyl; 2-bromo-4,5-bis-difluoromethoxy-phenyl; 2-bromo-4-fluoro-5-(2-methoxyethoxy)-phenyl; 2-bromo-4-fluoro-5-(2-hydroxyethoxy)-phenyl; or 4-fluoro-4,5-dimethoxy-phenyl.
In certain embodiments of formula I, R1 is 2-bromo-4,5-dimethoxy-phenyl.
In certain embodiments of formula I, R1 is 2-bromo-4-chloro-5-methoxy-phenyl.
In certain embodiments of formula I, R1 is 2-bromo-4-fluoro-5-methoxy-phenyl.
In certain embodiments of formula I, R1 is 2-bromo-5-methoxy-4-methyl-phenyl.
In certain embodiments of formula I, R1 is 2-methyl-4,5-dimethoxy-phenyl.
In certain embodiments of formula I, R1 is 2-bromo-4-chloro-5-(2-methoxy-ethyl-phenyl.
In certain embodiments of formula I, R1 is 2-bromo-4-chloro-5-(2-hydroxy-ethyl-phenyl.
In certain embodiments of formula I, R1 is 2-bromo-4-difluoromethoxy-5-methoxy-phenyl.
In certain embodiments of formula I, R1 is 2,5-dimethoxy-phenyl.
In certain embodiments of formula I, R1 is 2-ethyl-4,5-dimethoxy-phenyl.
In certain embodiments of formula I, R1 is 2-methyl-5-(2-hydroxy-ethoxy)-4-chloro-phenyl.
In certain embodiments of formula I, R1 is 2,5-dimethyl-phenyl.
In certain embodiments of formula I, R1 is 2-bromo-5-methoxy-phenyl.
In certain embodiments of formula I, R1 is 2-bromo-4,5-dimethyl-phenyl.
In certain embodiments of formula I, R1 is optionally substituted heteroaryl. In certain embodiments such heteroaryl may comprise: pyridinyl; indazolyl; indolyl; quinolinyl; thiophenyl; benzimidazolyl; benzofuranyl; dihydroindolyl; tetrahydroquinolinyl; each of which may be optionally substituted one, two or three times with a substituent or substituents independently selected from: fluoro; chloro; bromo; methyl; methoxy; ethoxy; trifluoromethyl; difluoromethoxy; nitrile; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; or cyclopropylmethoxy.
In certain embodiments of formula I, R1 is optionally substituted heteroaryl. In certain embodiments such heteroaryl may comprise: pyridinyl; indazolyl; indolyl; quinolinyl; or benzofuranyl; each of which may be optionally substituted one, two or three times with a substituent or substituents independently selected from: fluoro; chloro; bromo; methyl; methoxy; ethoxy; trifluoromethyl; difluoromethoxy; nitrile; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; or cyclopropylmethoxy.
In certain embodiments of formula I, R1 is adamantyl.
In certain embodiments of formula I, R2 is optionally substituted aryl.
In certain embodiments of formula I, R2 is optionally substituted phenyl.
In certain embodiments of formula I, R2 is phenyl optionally substituted one, two, three or four times with a substituent or substituents each independently selected from: halo; C1-6alkyl; C1-6alkoxy; halo-C1-6alkyl; halo-C1-6alkoxy; C1-6alkylsulfonyl; C1-6alkylsulfanyl; C1-6alkylsulfinyl; phenylsulfonyl wherein the phenyl portion is optionally substituted with C1-6alkyl; nitrile; alkylcarbonyl; aminocarbonyl; alkoxycarbonyl; alkoxycarbonylalkoxy; hydroxycarbonyl; hydroxycarbonylalkoxy; alkylaminocarbonylalkoxy; alkoxyalkoxy; hydroxyalkoxy; alkylaminoalkoxy; alkylsulfonylalkoxy; hydroxyalkyl; C3-6cycloalkyl-C1-6alkoxy; amino; aminoalkyl; or nitro; or two adjacent substituents may form a C1-2alkylenedioxy or halo-C1-2alkylenedioxy.
In certain embodiments of formula I, R2 is phenyl optionally substituted one, two, three or four times with a substituent or substituents each independently selected from: fluoro; chloro; bromo; iodo; methyl; ethyl; methoxy; ethoxy; trifluoromethyl; difluoromethoxy; methanesulfonyl; methanesulfanyl; methanesulfinyl; toluenesulfonyl; nitrile; acetyl; aminocarbonyl; methoxycarbonyl; methoxycarbonylmethoxy; carboxy; hydroxycarbonylmethoxy; methylaminocarbonylmethoxy; methoxyethoxy; hydroxyethoxy; methylaminoethoxy; methanesulfonylpropyloxy; hydroxymethyl; hydroxyethyl; cyclopropylmethoxy; amino; or nitro; or two adjacent substituents may form methylenedioxy, ethylenedioxy or difluoromethylenedioxy.
In certain embodiments of formula I, R2 is phenyl optionally substituted one, two, three or four times with a substituent or substituents each independently selected from: halo; C1-6alkyl; C1-6alkoxy; halo-C1-6alkyl; halo-C1-6alkoxy; C1-6alkylsulfonyl; nitrile; alkoxyalkoxy; hydroxyalkoxy; alkylsulfonylalkoxy; hydroxyalkyl; or C3-6cycloalkyl-C1-6alkoxy.
In certain embodiments of formula I, R2 is phenyl optionally substituted one, two, three or four times with a substituent or substituents each independently selected from: fluoro; chloro; bromo; iodo; methyl; ethyl; methoxy; ethoxy; trifluoromethyl; difluoromethoxy; methanesulfonyl; nitrile; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; or cyclopropylmethoxy.
In certain embodiments of formula I, R2 is phenyl optionally substituted one, two or three times with a substituent or substituents each independently selected from: fluoro; chloro; bromo; methyl; ethyl; methoxy; ethoxy; trifluoromethyl; difluoromethoxy; nitrile; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; or cyclopropylmethoxy.
In certain embodiments of formula I, R2 is phenyl substituted once or twice with a substituent or substituents each independently selected from: halo; methyl; methoxy; trifluoromethyl; difluoromethoxy; nitrile; or methanesulfonyl.
In certain embodiments of formula I, R2 is phenyl substituted once or twice with a substituent or substituents each independently selected from: fluoro; chloro; methyl; methoxy; or nitrile.
In certain embodiments of formula I, R2 is phenyl substituted once or twice with fluoro.
In certain embodiments of formula I, R2 is: phenyl; 4-fluoro-phenyl; 3-fluoro-phenyl; 2-fluoro-phenyl; 2-chloro-phenyl; 3,4-difluoro-phenyl; 3,5-difluoro-phenyl; 3-methyl-phenyl; 4-methyl-phenyl; or 3-cyano-phenyl.
In certain embodiments of formula I, R2 is: phenyl; 4-fluoro-phenyl; 3-fluoro-phenyl; 2-fluoro-phenyl; 2-chloro-phenyl; 3,4-difluoro-phenyl; or 3,5-difluoro-phenyl.
In certain embodiments of formula I, R2 is 4-fluoro-phenyl.
In certain embodiments of formula I, R2 is 3-fluoro-phenyl.
In certain embodiments, the compounds of formula I may be more specifically of formula II:




wherein:

p is from 0 to 3;
R6, R7, R8, R9 and R10 each independently is: hydrogen; halo; C1-6alkyl; C1-6alkoxy; halo-C1-6alkyl; halo-C1-6alkoxy; C1-6alkylsulfonyl; C1-6alkylsulfanyl; C1-6alkylsulfinyl; phenylsulfonyl wherein the phenyl portion is optionally substituted with C1-6alkyl; nitrile; hydroxy; alkylcarbonyl; aminocarbonyl; alkoxycarbonyl; alkoxycarbonylalkoxy; hydroxycarbonyl; hydroxycarbonylalkoxy; alkylaminocarbonylalkoxy; alkoxyalkoxy; hydroxyalkoxy; alkylaminoalkoxy; alkylsulfonylalkoxy; hydroxyalkyl; C3-6cycloalkyl-C1-6alkoxy; amino; aminoalkyl; or nitro; or two adjacent substituents may form a C1-2alkylenedioxy or halo-C1-2alkylenedioxy; and
each R11 independently is: halo; C1-6alkyl; C1-6alkoxy; halo-C1-6alkyl; halo-C1-6alkoxy; C1-6alkylsulfonyl; or nitrile.
In certain embodiments of formula II, the subject compounds may be more specifically of formula IIa or formula IIb;




wherein p, R6, R7, R8, R9, R10 and R11 are as defined herein.

In certain embodiments of the invention, the subject compounds are of formula IIa.
In certain embodiments of the invention, the subject compounds are of formula IIb.
In certain embodiments of any of formulas II, IIa and IIb, at least two of R6, R7, R8, R9 and R10 are not hydrogen.
In certain embodiments of any of formulas II, IIa and IIb, at least three of R6, R7, R8, R9 and R10 are not hydrogen.
In certain embodiments of any of formulas II, IIa and IIb, R6, R7, R8, R9 and R10 each independently is: hydrogen; fluoro; chloro; bromo; iodo; methyl; ethyl; methoxy; ethoxy; trifluoromethyl; difluoromethoxy; methanesulfonyl; methanesulfanyl; methanesulfinyl; toluenesulfonyl; nitrile; acetyl; aminocarbonyl; methoxycarbonyl; methoxycarbonylmethoxy; carboxy; hydroxycarbonylmethoxy; methylaminocarbonylmethoxy; methoxyethoxy; hydroxyethoxy; methylaminoethoxy; methanesulfonylpropyloxy; hydroxymethyl; hydroxyethyl; cyclopropylmethoxy; amino; or nitro; or two adjacent substituents may form methylenedioxy, ethylenedioxy or difluoromethylenedioxy.
In certain embodiments of any of formulas II, IIa and IIb, R6, R7, R8, R9 and R10 each independently is: hydrogen; halo; C1-6alkyl; C1-6alkoxy; halo-C1-6alkyl; halo-C1-6alkoxy; C1-6alkylsulfonyl; nitrile; alkoxyalkoxy; hydroxyalkoxy; alkylsulfonylalkoxy; hydroxyalkyl; or C3-6cycloalkyl-C1-6alkoxy.
In certain embodiments of any of formulas II, IIa and IIb, R6, R7, R8, R9 and R10 each independently is: hydrogen; fluoro; chloro; bromo; iodo; methyl; ethyl; methoxy; ethoxy; trifluoromethyl; difluoromethoxy; methanesulfonyl; nitrile; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; or cyclopropylmethoxy.
In certain embodiments of any of formulas II, IIa and IIb, R6, R7, R8, R9 and R10 each independently is: hydrogen; fluoro; chloro; bromo; methyl; ethyl; methoxy; ethoxy; trifluoromethyl; difluoromethoxy; nitrile; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; or cyclopropylmethoxy.
In certain embodiments of any of formulas II, IIa and IIb, R7 and R10 are hydrogen.
In certain embodiments of any of formulas II, IIa and IIb, R6 is: hydrogen; halo; or methyl.
In certain embodiments of any of formulas II, IIa and IIb, R8 is: hydrogen; methoxy; halo; methyl; or difluoromethoxy.
In certain embodiments of any of formulas II, IIa and IIb, R9 is: methoxy; hydrogen; 2-hydroxy-ethoxy; 2-methoxy-ethoxy; 1-hydroxy-ethyl; or cyclopropylmethyl.
In certain embodiments of any of formulas II, IIa and IIb, p is 0, 1 or 2.
In certain embodiments of any of formulas II, IIa and IIb, R11 is halo.
In certain embodiments of any of formulas II, IIa and IIb, R11 is fluoro.
In certain embodiments of any of formulas II, IIa and IIb:
R6 is: hydrogen; halo; methyl; or ethyl;
R7 is hydrogen; methyl; methoxy; or methoxycarbonyl;
R8 is: hydrogen; methoxy; halo; methyl; or difluoromethoxy;
R9 is: hydrogen; methoxy; hydrogen; 2-hydroxy-ethoxy; 2-methoxy-ethoxy; or 1-hydroxy-ethyl; and
R10 is hydrogen; or halo.
In certain embodiments of any of formulas II, IIa and IIb:
R6 is: halo; or methyl;
R7 is hydrogen;
R8 is: methoxy; halo; methyl; or difluoromethoxy;
R9 is: methoxy; 2-hydroxy-ethoxy; 2-methoxy-ethoxy; or 1-hydroxy-ethyl; and
R10 is hydrogen; or halo.
In certain embodiments of any of formulas II, IIa and IIb:
R6 is: bromo; or methyl;
R7 is hydrogen;
R8 is: methoxy; chloro; fluoro; methyl; or difluoromethoxy;
R9 is: methoxy; 2-hydroxy-ethoxy; 2-methoxy-ethoxy; or 1-hydroxy-ethyl; and
R10 is hydrogen.
In certain embodiments of any of formulas II, IIa and IIb, p is 1 or 2 and R11 is halo.
In certain embodiments of any of formulas II, IIa and IIb, p is 1 or 2 and R11 is fluoro.
In certain embodiments of any of formulas II, IIa and IIb, p is 1 and R11 is fluoro.
In certain embodiments of any of formulas II, IIa and IIb, p is 1 and R11 is fluoro at the 4-position.
In certain embodiments, the compounds of formula I may be more specifically of formula III:




wherein R6, R8, R9 and R11 are as defined herein.

In certain embodiments of formula III, the subject compounds may be more specifically of formula IIIa or formula IIIb;




wherein R6, R8, R9 and R11 are as defined herein.

In certain embodiments of any of formulas III, IIIa and IIIb, R6 is: halo; methyl; or ethyl.
In certain embodiments of any of formulas III, IIIa and IIIb, R8 is: methoxy; halo; methyl; or difluoromethoxy.
In certain embodiments of any of formulas III, IIIa and IIIb, R9 is: methoxy; 2-hydroxy-ethoxy; 2-methoxy-ethoxy; or 1-hydroxy-ethyl.
In certain embodiments of any of formulas III, IIIa and IIIb, R6 is: bromo; or methyl;
In certain embodiments of any of formulas III, IIIa and IIIb, R8 is: methoxy; chloro; fluoro; methyl; or difluoromethoxy.
In certain embodiments of any of formulas III, IIIa and IIIb, R9 is: methoxy; 2-hydroxy-ethoxy; 2-methoxy-ethoxy; or 1-hydroxy-ethyl.
In certain embodiments of any of formulas III, IIIa and IIIb, R11 is halo.
In certain embodiments of any of formulas III, IIIa and IIIb, R11 is fluoro.
Where any of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 or R11 is alkyl or contains an alkyl moiety, such alkyl is preferably lower alkyl, i.e. C1-C6alkyl, and more preferably C1-C4alkyl.
The invention also provides methods for treating a disease or condition mediated by or otherwise associated with a P2X7 receptor, the method comprising administering to a subject in need thereof an effective amount of a compound of the invention.
The invention also provides methods for treating an inflammatory, respiratory or diabetes condition, the method comprising administering to a subject in need thereof an effective amount of a compound of the invention together with an effective amount of a P2X3 inhibitor.
The disease may be an inflammatory disease such as arthritis, and more particularly rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, chronic obstructive pulmonary disease, airways hyper-responsiveness, septic shock, glomerulonephritis, irritable bowel disease, and Crohn's disease.
The disease may be a pain condition, such as inflammatory pain; surgical pain; visceral pain; dental pain; premenstrual pain; central pain; pain due to burns; migraine or cluster headaches; nerve injury; neuritis; neuralgias; poisoning; ischemic injury; interstitial cystitis; cancer pain; viral, parasitic or bacterial infection; post-traumatic injury; or pain associated with irritable bowel syndrome.
The disease may be a respiratory disorder, such as chronic obstructive pulmonary disorder (COPD), asthma, or bronchospasm, or a gastrointestinal (GI) disorder such as Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD), biliary colic and other biliary disorders, renal colic, diarrhea-dominant IBS, pain associated with GI distension.
The disease may be diabetes.
Representative compounds in accordance with the methods of the invention are shown in Table 1, together with pIC50 values for P2X7.










TABLE 1





#
Structure
Name
pIC50 P2X7


















1




1-[2-(2-Iodo-4,5-dimethoxy- phenyl)-acetyl]-2-phenyl-2,3- dihydro-1H-pyridin-4-one
6.984


 


2




1-[2-(2-Iodo-4,5-dimethoxy- phenyl)-acetyl]-2-o-tolyl-2,3- dihydro-1H-pyridin-4-one
5.963


 


3




1-[2-(2-Bromo-4,5-dimethoxy- phenyl)-acetyl]-2-phenyl-2,3- dihydro-1H-pyridin-4-one
7.03


 


4




(S)-1-[2-(2-Iodo-4,5-dimethoxy- phenyl)-acetyl]-2-phenyl-2,3- dihydro-1H-pyridin-4-one
7.418


 


5




(R)-1-[2-(2-Iodo-4,5-dimethoxy- phenyl)-acetyl]-2-phenyl-2,3- dihydro-1H-pyridin-4-one
5.425


 


6




2-(4-Fluoro-phenyl)-1-[2-(2-iodo- 4,5-dimethoxy-phenyl)-acetyl]-2,3- dihydro-1H-pyridin-4-one
6.97


 


7




1-[2-(2-Bromo-5-methoxy-phenyl)- acetyl]-2-phenyl-2,3-dihydro-1H- pyridin-4-one
6.765


 


8




1-[2-(2-Bromo-4-methoxy-phenyl)- acetyl]-2-phenyl-2,3-dihydro-1H- pyridin-4-one
5.685


 


9




1-[2-(2-Bromo-4,5-dimethoxy- phenyl)-acetyl]-2-isopropyl-2,3- dihydro-1H-pyridin-4-one
5.45


 


10




1-[2-(2-Bromo-4,5-dimethoxy- phenyl)-acetyl]-2-cyclohexyl-2,3- dihydro-1H-pyridin-4-one
7.193


 


11




1-[2-(2-Chloro-4,5-dimethoxy- phenyl)-acetyl]-2-phenyl-2,3- dihydro-1H-pyridin-4-one
6.806


 


12




1-[2-(7-Bromo-2,3-dihydro- benzo[1,4]dioxin-6-yl)-acetyl]-2- phenyl-2,3-dihydro-1H-pyridin-4- one
5.305


 


13




(S)-1-[2-(2-Bromo-4,5-dimethoxy- phenyl)-acetyl]-2-phenyl-2,3- dihydro-1H-pyridin-4-one
7.22


 


14




(S)-1-[2-(2-Chloro-4,5-dimethoxy- phenyl)-acetyl]-2-phenyl-2,3- dihydro-1H-pyridin-4-one
6.705


 


15




1-[2-(4,5-Dimethoxy-2- trifluoromethyl-phenyl)-acetyl]-2- phenyl-2,3-dihydro-1H-pyridin-4- one
5.395


 


16




(S)-1-[2-(2-Bromo-5-ethoxy-4- methoxy-phenyl)-acetyl]-2-(4- fluoro-phenyl)-2,3-dihydro-1H- pyridin-4-one
7.17


 


17




(S)-1-[2-(2-Bromo-4-ethoxy-5- methoxy-phenyl)-acetyl]-2-(4- fluoro-phenyl)-2,3-dihydro-1H- pyridin-4-one
6.535


 


18




(S)-1-[2-(2-Bromo-5- cyclopropylmethoxy-4-methoxy- phenyl)-acetyl]-2-(4-fluoro-phenyl)- 2,3-dihydro-1H-pyridin-4-one
6.93


 


19




(S)-1-[2-(2-Bromo-4,5-dimethoxy- phenyl)-acetyl]-2-(4-fluoro-phenyl)- 2,3-dihydro-1H-pyridin-4-one
7.6125


 


20




(S)-1-[2-(2-Bromo-4- cyclopropylmethoxy-5-methoxy- phenyl)-acetyl]-2-(4-fluoro-phenyl)- 2,3-dihydro-1H-pyridin-4-one
6.08


 


21




4,5-Dimethoxy-2-[2-oxo-2-(4-oxo- 2-phenyl-3,4-dihydro-2H-pyridin-1- yl)-ethyl]-benzamide
5.205


 


22




1-[2-(2-Bromo-4,5-dimethoxy- phenyl)-acetyl]-2-(4-fluoro-phenyl)- 2,3-dihydro-1H-pyridin-4-one
7.165


 


3




(S)-1-{2-[2-Bromo-4-methoxy-5- (2-methoxy-ethoxy)-phenyl]- acetyl}-2-(4-fluoro-phenyl)-2,3- dihydro-1H-pyridin-4-one
7.355


 


24




(S)-1-[2-(2-Bromo-5- difluoromethoxy-4-methoxy- phenyl)-acetyl]-2-(4-fluoro-phenyl)- 2,3-dihydro-1H-pyridin-4-one
6.305


 


25




1-[2-(2-Bromo-4,5-dimethoxy- phenyl)-acetyl]-2-(3-chloro-phenyl)- 2,3-dihydro-1H-pyridin-4-one
6.28


 


26




(S)-1-[2-(2-Bromo-4,5-bis- difluoromethoxy-phenyl)-acetyl]-2- (4-fluoro-phenyl)-2,3-dihydro-1H- pyridin-4-one
5.895


 


27




1-[2-(2-Bromo-4,5-dimethoxy- phenyl)-acetyl]-2-cyclopentyl-2,3- dihydro-1H-pyridin-4-one
6.35


 


28




1-[2-(2-Bromo-4,5-dimethoxy- phenyl)-acetyl]-2-(3-methoxy- phenyl)-2,3-dihydro-1H-pyridin-4- one
5.415


 


29




(S)-1-[2-(2-Bromo-5-methoxy-4- methyl-phenyl)-acetyl]-2-(4-fluoro- phenyl)-2,3-dihydro-1H-pyridin-4- one
6.625


 


30




(S)-1-[2-(2-Bromo-4-chloro-5- methoxy-phenyl)-acetyl]-2-(4- fluoro-phenyl)-2,3-dihydro-1H- pyridin-4-one
6.4


 


31




1-[2-(2-Bromo-5-methoxy-4- methyl-phenyl)-acetyl]-2-(4-fluoro- phenyl)-2,3-dihydro-1H-pyridin-4- one
6.59


 


32




1-[2-(2-Bromo-4-chloro-5-methoxy- phenyl)-acetyl]-2-(4-fluoro-phenyl)- 2,3-dihydro-1H-pyridin-4-one
6.17


 


33




1-[2-(2-Bromo-5-hydroxy-4-methyl- phenyl)-acetyl]-2-(4-fluoro-phenyl)- 2,3-dihydro-1H-pyridin-4-one
6.18


 


34




1-[2-(2-Bromo-4,5-dimethoxy- phenyl)-acetyl]-2-cyclohexylmethyl- 2,3-dihydro-1H-pyridin-4-one
5.94


 


35




1-[2-(2-Bromo-4,5-dimethoxy- phenyl)-acetyl]-2-(3-fluoro-phenyl)- 2,3-dihydro-1H-pyridin-4-one
6.815


 


36




(S)-1-[2-(2-Bromo-4-fluoro-5- methoxy-phenyl)-acetyl]-2-(4- fluoro-phenyl)-2,3-dihydro-1H- pyridin-4-one
7.55


 


37




1-[2-(2-Bromo-4,5-dimethoxy- phenyl)-acetyl]-2-m-tolyl-2,3- dihydro-1H-pyridin-4-one
6.425


 


38




1-[2-(2-Bromo-4,5-dimethoxy- phenyl)-acetyl]-2-p-tolyl-2,3- dihydro-1H-pyridin-4-one
5.325


 


39




3-{1-[2-(2-Bromo-4,5-dimethoxy- phenyl)-acetyl]-4-oxo-1,2,3,4- tetrahydro-pyridin-2-yl}- benzonitrile
5.45


 


40




1-[2-(2,4-Dimethoxy-phenyl)- acetyl]-2-(4-fluoro-phenyl)-2,3- dihydro-1H-pyridin-4-one
5.843


 


41




(S)-1-[2-(2-Bromo-4,5-dimethoxy- phenyl)-acetyl]-2-(3-fluoro-phenyl)- 2,3-dihydro-1H-pyridin-4-one
7.94


 


42




1-[2-(2,5-Dimethoxy-phenyl)- acetyl]-2-(4-fluoro-phenyl)-2,3- dihydro-1H-pyridin-4-one
5.995


 


43




(S)-1-{2-[2-Bromo-4-fluoro-5-(2- methoxy-ethoxy)-phenyl]-acetyl}-2- (4-fluoro-phenyl)-2,3-dihydro-1H- pyridin-4-one
7.89


 


44




(S)-1-[2-(3,4-Dimethoxy-phenyl)- acetyl]-2-(4-fluoro-phenyl)-2,3- dihydro-1H-pyridin-4-one
6.003


 


45




(S)-1-[2-(3,4-Dimethoxy-phenyl)- acetyl]-2-(3-fluoro-phenyl)-2,3- dihydro-1H-pyridin-4-one
6.006


 


46




(S)-1-{2-[2-Bromo-4-fluoro-5-(2- hydroxy-ethoxy)-phenyl]-acetyl}-2- (4-fluoro-phenyl)-2,3-dihydro-1H- pyridin-4-one
7.31


 


47




(S)-1-[2-(2-Fluoro-4,5-dimethoxy- phenyl)-acetyl]-2-(4-fluoro-phenyl)- 2,3-dihydro-1H-pyridin-4-one
6.4


 


48




(S)-1-[2-(2-Fluoro-4,5-dimethoxy- phenyl)-acetyl]-2-(3-fluoro-phenyl)- 2,3-dihydro-1H-pyridin-4-one
6.55


 


49




(S)-1-{2-[4-Fluoro-5-(2-hydroxy- ethoxy)-2-methyl-phenyl]-acetyl}-2- (4-fluoro-phenyl)-2,3-dihydro-1H- pyridin-4-one
7.12


 


50




(S)-1-{2-[2-Bromo-4-fluoro-5-(2- hydroxy-ethoxy)-phenyl]-acetyl}-2- (3-fluoro-phenyl)-2,3-dihydro-1H- pyridin-4-one
7.65


 


51




(S)-1-[2-(2-Chloro-4,5-dimethoxy- phenyl)-acetyl]-2-(4-fluoro-phenyl)- 2,3-dihydro-1H-pyridin-4-one
7.77









Synthesis

Compounds of the present invention can be made by a variety of methods depicted in the illustrative synthetic reaction schemes shown and described below.
The starting materials and reagents used in preparing these compounds generally are either available from commercial suppliers, such as Aldrich Chemical Co., or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, 1991, Volumes 1-15; Rodd's Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, Volumes 1-5 and Supplementals; and Organic Reactions, Wiley & Sons: New York, 1991, Volumes 1-40. The following synthetic reaction schemes are merely illustrative of some methods by which the compounds of the present invention can be synthesized, and various modifications to these synthetic reaction schemes can be made and will be suggested to one skilled in the art having referred to the disclosure contained in this Application.
The starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.
Unless specified to the contrary, the reactions described herein preferably are conducted under an inert atmosphere at atmospheric pressure at a reaction temperature range of from about −78° C. to about 150° C., more preferably from about 0° C. to about 125° C., and most preferably and conveniently at about room (or ambient) temperature, e.g., about 20° C.
Scheme A below illustrates one synthetic procedure usable to prepare specific compounds of formula I, wherein X is a leaving group and R6, R7, R8, R9, R10 and R11 are as defined herein.




In Scheme A, aryl acetic acid compound a is reacted with aryl dihyropyridone compound b in an amide coupling reaction to afford dihydropyridone amide compound II, which is a compound of formula I as noted above. Leaving group X, in many embodiments, may be —OH, and the amide coupling reaction of step 1 may be carried out using EDCI, HU, BOP, PyBOP or the like. In many embodiments compound a is an acid halide which may be prepared by treatment of the corresponding aryl acetic acid with thionyl chloride, phosphorous oxychloride, oxalyl chloride or the like. corresponding aryl nitro compounds, as illustrated in the experimental examples below.
Aryl dihydropyridone b may be prepared by reaction of the corresponding aryl Grignard reagent with 4-methoxy-pyridine, which may be protected to prevent reaction at the 2-position.
In the embodiment of Scheme A, aryl acetic acid compound a is shown as a phenyl compound, and aryl dihyropyridone b is shown as a phenyl compound. The phenyl moieties of these compounds in many embodiments may be replaced by various heteroaryl, such as indolyl, indazolyl, pyridinyl, and the like, as demonstrated in the experimental examples below.
Many variations of Scheme A are possible and will suggest themselves to those skilled in the art. Specific details for producing compounds of the invention are described in the Examples section below.
Utility
The compounds of the invention are usable for the treatment of a wide range of inflammatory diseases and conditions such as arthritis, including but not limited to, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis, gouty arthritis and other arthritic conditions. The subject compounds would be useful for the treatment of pulmonary disorders or lung inflammation, including adult respiratory distress syndrome, pulmonary sarcoidosis, asthma, silicosis, and chronic pulmonary inflammatory disease.
The compounds of the invention are also expected to find utility as analgesics in the treatment of diseases and conditions associated with pain from a wide variety of causes, including, but not limited to, inflammatory pain such as pain associated with arthritis (including rheumatoid arthritis and osteoarthritis), surgical pain, visceral pain, dental pain, premenstrual pain, central pain, pain due to burns, migraine or cluster headaches, nerve injury, neuritis, neuralgias, poisoning, ischemic injury, interstitial cystitis, cancer pain, viral, parasitic or bacterial infection, post-traumatic injuries (including fractures and sports injuries), and pain associated with functional bowel disorders such as irritable bowel syndrome.
Further, compounds of the invention are useful for treating respiratory disorders, including chronic obstructive pulmonary disorder (COPD), asthma, bronchospasm, and the like.
Additionally, compounds of the invention are useful for treating gastrointestinal disorders, including Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD), biliary colic and other biliary disorders, renal colic, diarrhea-dominant IBS, pain associated with GI distension, and the like.
The compounds of the invention are also useful for the treatment of muscular sclerosis.
Administration and Pharmaceutical Composition
The invention includes pharmaceutical compositions comprising at least one compound of the present invention, or an individual isomer, racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate thereof, together with at least one pharmaceutically acceptable carrier, and optionally other therapeutic and/or prophylactic ingredients.
In general, the compounds of the invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Suitable dosage ranges are typically 1-500 mg daily, preferably 1-100 mg daily, and most preferably 1-30 mg daily, depending upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication towards which the administration is directed, and the preferences and experience of the medical practitioner involved. One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this Application, to ascertain a therapeutically effective amount of the compounds of the present invention for a given disease.
Compounds of the invention may be administered as pharmaceutical formulations including those suitable for oral (including buccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. The preferred manner of administration is generally oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction.
A compound or compounds of the invention, together with one or more conventional adjuvants, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages. The pharmaceutical compositions and unit dosage forms may be comprised of conventional ingredients in conventional proportions, with or without additional active compounds or principles, and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. The pharmaceutical compositions may be employed as solids, such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use. Formulations containing about one (1) milligram of active ingredient or, more broadly, about 0.01 to about one hundred (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms.
The compounds of the invention may be formulated in a wide variety of oral administration dosage forms. The pharmaceutical compositions and dosage forms may comprise a compound or compounds of the present invention or pharmaceutically acceptable salts thereof as the active component. The pharmaceutically acceptable carriers may be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component. In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from about one (1) to about seventy (70) percent of the active compound. Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatine, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term “preparation” is intended to include the formulation of the active compound with encapsulating material as carrier, providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges may be as solid forms suitable for oral administration.
Other forms suitable for oral administration include liquid form preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended to be converted shortly before use to liquid form preparations. Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents, for example, such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents. Solid form preparations include solutions, suspensions, and emulsions, and may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
The compounds of the invention may be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Examples of oily or nonaqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.
The compounds of the invention may be formulated for topical administration to the epidermis as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also containing one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Formulations suitable for topical administration in the mouth include lozenges comprising active agents in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatine and glycerine or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
The compounds of the invention may be formulated for administration as suppositories. A low melting wax, such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, for example, by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and to solidify.
The compounds of the invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
The subject compounds may be formulated for nasal administration. The solutions or suspensions are applied directly to the nasal cavity by conventional means, for example, with a dropper, pipette or spray. The formulations may be provided in a single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump.
The compounds of the invention may be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration.  The compound will generally have a small particle size for example of the order of five (5) microns or less. Such a particle size may be obtained by means known in the art, for example by micronization. The active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC), for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by a metered valve. Alternatively the active ingredients may be provided in a form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP). The powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of e.g., gelatine or blister packs from which the powder may be administered by means of an inhaler.
When desired, formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient. For example, the compounds of the present invention can be formulated in transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is necessary and when patient compliance with a treatment regimen is crucial. Compounds in transdermal delivery systems are frequently attached to an skin-adhesive solid support. The compound of interest can also be combined with a penetration enhancer, e.g., Azone (1-dodecylazacycloheptan-2-one). Sustained release delivery systems are inserted subcutaneously into the subdermal layer by surgery or injection. The subdermal implants encapsulate the compound in a lipid soluble membrane, e.g., silicone rubber, or a biodegradable polymer, e.g., polylactic acid.
The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
Other suitable pharmaceutical carriers and their formulations are described in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton, Pa. Representative pharmaceutical formulations containing a compound of the present invention are described below.
EXAMPLES
The following preparations and examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof.
Unless otherwise stated, all temperatures including melting points (i.e., MP) are in degrees celsius (° C.). It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or the desired product. The following abbreviations may be used in the Preparations and Examples.
ABBREVIATIONS
BETBDMS 2-bromoethoxy tertbutyldimethylsilane
DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
DCM dichloromethane/methylene chloride
DIPEA diisopropyl ethylamine
DME 1,2-dimethoxyethane (glyme)
DMF N,N-dimethylformamide
DMFDMA N,N-dimethylformamide dimethyl acetal
DMSO dimethyl sulfoxide
DMAP 4-dimethylaminopyridine
ECDI 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide
EtOAc ethyl acetate
EtOH ethanol
gc gas chromatography
HMPA hexamethylphosphoramide
HOBt N-Hydroxybenzotriazole
hplc high performance liquid chromatography
IPA isopropanol
IPBAPE isopropenylboronic acid pinacol ester
mCPBA m-chloroperbenzoic acid
MeCN acetonitrile
NMM N-methyl morpholine
NMP N-methylpyrrolidinone
TBAF tetra-n-butyl ammonium fluoride
TEA triethylamine
THF tetrahydrofuran
LDA lithium diisopropylamine
TBDMS tert-butyl dimethylsilyl chloride
TLC thin layer chromatography
Preparation 1
(1R,2S,5R)-5-Methyl-2-(1-methyl-1-phenyl-ethyl)-cyclohexanol Chloroformate
The synthetic procedure used in this preparation is outlined in Scheme B.




To a solution of (−)-8-phenylmenthol (12.66 g, 54.4 mmol) and quinoline (15.88 mL, 134.1 mmol) in toluene (210 mL) at 0° C. was added 20% phosgene in toluene (45 mL, 87.9 mmol). The mixture was stirred at 0° C. for 30 minutes and at room temperature for 16 hours. Diethyl ether and 2N HCl were added and the mixture was stirred for 5 minutes. The layers were separated and the combined organics were washed with water, brine dried over MgSO4 and concentrated to dryness. The resulting crude 5-methyl-2-(1-methyl-1-phenyl-ethyl)-cyclohexyl chloroformate (14.43 g) was used without further purification.
Preparation 2
4-methoxy-3-triisopropylsilyl-pyridine
The synthetic procedure used in this preparation is outlined in Scheme C.




To a solution of 4-methoxypyridine (14.0 g, 128.3 mmol) in THF (150 mL) was added at −25° C., 2.0M LDA in heptane/THF/ethyl benzene (76.9 mL, 153.9 mmol). The mixture was stirred at −25° C. for 30 minutes. Triisopropylsilyl chloride (35.3 mL, 166.8 mmol) was added and the mixture was stirred at −25° C. for 15 minutes and then at room temperature for 16 hours. Water was added and the mixture was extracted with EtOAc. The extract was washed with water, brine dried over MgSO4 and concentrated to dryness. Purification of the residue by flash chromatography (hexane/ethylacetate 8:2-1:1) gave 4-methoxy-3-triisopropylsilanyl-pyridine (7.56 g, 22%) as an orange solid.
Preparation 3
(S)-2-(4-Fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one
The synthetic procedure used in this preparation is outlined in Scheme D.




Step 1 2-(4-Fluoro-phenyl)-4-oxo-5-triisopropylsilanyl-3,4-dihydro-2H-pyridine-1-carboxylic acid 5-methyl-2-(1-methyl-1-phenyl-ethyl)-cyclohexyl Ester
To a solution of 4-methoxy-3-triisopropylsilanyl-pyridine (6.06 g, 22.8 mmol) in toluene (160 mL) at −25° C. was added a solution of 5-methyl-2-(1-methyl-1-phenyl-ethyl)-cyclohexyl chloroformate (6.73 g, 26.2 mmol) in toluene (140 mL). After 15 minutes the mixture was cooled to −78° C. and 1.0M 4-fluorophenyl magnesium bromide in THF (26.1 mL, 26.2 mmol) was added slowly. The mixture was stirred at −78° C. for 1 hour. 2N HCl was added and the mixture was allowed to warm to room temperature and was stirred for additional 15 minutes. The mixture was extracted with ethyl acetate, washed with water and brine, dried over MgSO4, filtered and concentrated to dryness. Purification of the residue by flash chromatography (hexane/ethyl acetate 9:1) gave 2-(4-fluoro-phenyl)-4-oxo-5-triisopropylsilanyl-3,4-dihydro-2H-pyridine-1-carboxylic acid 5-methyl-2-(1-methyl-1-phenyl-ethyl)-cyclohexyl ester (1.06 g, 48%) as a white solid.
Step 2 (S)-2-(4-Fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one
To a solution of 2-(4-fluoro-phenyl)-4-oxo-5-triisopropylsilanyl-3,4-dihydro-2H-pyridine-1-carboxylic acid 5-methyl-2-(1-methyl-1-phenyl-ethyl)-cyclohexyl ester (7.78 g, 12.8 mmol) in methanol (95 mL) was added 25% sodium methoxide in methanol (29.4 mL, 128.4 mmol). The mixture was heated at reflux for 16 h. After cooling to rt, oxalic acid (46.3 g, 512 mmol) was added and the mixture was stirred for 2 h. The solvent was evaporated to dryness. The crude was partitioned between ethyl acetate and water. The organic layer was washed with water, brine dried over MgSO4, filtered and concentrated to dryness. Purification by flash chromatography (hex:EtOAc/2:8-0:1) gave (S)-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one (0.886 g, 36%, ee 99.3%) as a yellow solid.
Similarly prepared, using the appropriate substituted phenyl Grignard reagents, were:

    (S)-2-(3-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one; and
    (S)-2-(3,4-difluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one.


Preparation 4
(2-Bromo-4,5-dimethoxy-phenyl)-acetyl Chloride
The synthetic procedure used in this preparation is outlined in Scheme E.




To a solution of (2-bromo-4,5-dimethoxy-phenyl)-acetic acid (833 mg, 3.03 mmol) in dichloromethane (10 mL) were added oxalyl chloride (0.29 mL, 3.33 mmol) and dimethylformamide (1 drop) under argon atmosphere. The mixture was stirred for 3.5 hours at room temperature, then was concentrated to dryness under reduced pressure. Dichloroethane (15 mL) was added, and resulting solution was back evaporated to dryness to obtain crude (2-bromo-4,5-dimethoxy-phenyl)-acetyl chloride (917 mg).
Similarly prepared from the corresponding phenylacetic acids were:

    (2-Iodo-4,5-dimethoxy-phenyl)-acetyl chloride;
    (3,4-Dimethoxy-phenyl)-acetyl chloride;
    (2-Bromo-5-methoxy-phenyl)-acetyl chloride;
    (2-Bromo-4-methoxy-phenyl)-acetyl chloride;
    (2-Chloro-4,5-dimethoxy-phenyl)-acetyl chloride;
    (2,5-Dimethoxy-phenyl)-acetyl chloride;
    (2,4-Dimethoxy-phenyl)-acetyl chloride;
    (2-Bromo-4-chloro-5-methoxy-phenyl)-acetyl chloride;


Example 1
1-[2-(2-bromo-4,5-dimethoxy-phenyl)-acetyl]-2-phenyl-2,3-dihydro-1H-pyridin-4-one
The synthetic procedure used in this preparation is outlined in Scheme F.




To a stirring solution of 4-methoxypyridine (336 mg, 3.08 mmol) in THF (7 mL) at −25° C. was added phenylmagnesium bromide (3M in ether, 1.13 mL, 3.39 mmol) under Ar atmosphere. After 5 minutes a solution of (2-bromo-4,5-dimethoxy-phenyl)-acetyl chloride (904 mg, 3.08 mL) in THF (2 mL) was added slowly. The mixture was stirred at −25° C. for 90 minutes. 2N HCl was added at −25° C., and the mixture was allowed to warm to room temperature and was stirred for 10 minutes. The mixture was extracted with ethyl acetate, and the combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated to dryness under reduced pressure. Purification of the residue by flash chromatography (hexane/ethyl acetate gradient) gave 1-[2-(2-bromo-4,5-dimethoxy-phenyl)-acetyl]-2-phenyl-2,3-dihydro-1H-pyridin-4-one (742 mg, 57%). MS (M+H) 431.
In a similar fashion, using the appropriate phenylacetic acid chlorides and Grignard reagents, the following compounds were prepared:

    1-[2-(2-Iodo-4,5-dimethoxy-phenyl)-acetyl]-2-phenyl-2,3-dihydro-1H-pyridin-4-one;
    1-[2-(3,4-Dimethoxy-phenyl)-acetyl]-2-phenyl-2,3-dihydro-1H-pyridin-4-one;
    1-[2-(2-Iodo-4,5-dimethoxy-phenyl)-acetyl]-2-o-tolyl-2,3-dihydro-1H-pyridin-4-one;
    2-(4-Fluoro-phenyl)-1-[2-(2-iodo-4,5-dimethoxy-phenyl)-acetyl]-2,3-dihydro-1H-pyridin-4-one;
    1-[2-(2-Bromo-5-methoxy-phenyl)-acetyl]-2-phenyl-2,3-dihydro-1H-pyridin-4-one;
    1-[2-(2-Bromo-4-methoxy-phenyl)-acetyl]-2-phenyl-2,3-dihydro-1H-pyridin-4-one;
    1-[2-(2-Bromo-4,5-dimethoxy-phenyl)-acetyl]-2-isopropyl-2,3-dihydro-1H-pyridin-4-one;
    1-[2-(2-Bromo-4,5-dimethoxy-phenyl)-acetyl]-2-cyclohexyl-2,3-dihydro-1H-pyridin-4-one;
    1-[2-(2-Chloro-4,5-dimethoxy-phenyl)-acetyl]-2-phenyl-2,3-dihydro-1H-pyridin-4-one;
    1-[2-(2-Bromo-4,5-dimethoxy-phenyl)-acetyl]-2-p-tolyl-2,3-dihydro-1H-pyridin-4-one;
    1-[2-(2-Bromo-4,5-dimethoxy-phenyl)-acetyl]-2-m-tolyl-2,3-dihydro-1H-pyridin-4-one;
    1-[2-(2,5-Dimethoxy-phenyl)-acetyl]-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one;
    1-[2-(2,4-Dimethoxy-phenyl)-acetyl]-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one;
    1-[2-(2-Bromo-4,5-dimethoxy-phenyl)-acetyl]-2-(3-methoxy-phenyl)-2,3-dihydro-1H-pyridin-4-one;
    1-[2-(2-Bromo-4,5-dimethoxy-phenyl)-acetyl]-2-(3-chloro-phenyl)-2,3-dihydro-1H-pyridin-4-one; and
    1-[2-(2-Bromo-4-chloro-5-methoxy-phenyl)-acetyl]-2,3-dihydro-1H-[2,2′]bipyridinyl-4-one.


Example 2
3-{1-[2-(2-bromo-4,5-dimethoxy-phenyl)-acetyl]-4-oxo-1,2,3,4-tetrahydro-pyridin-2-yl}-benzonitrile
The synthetic procedure used in this preparation is outlined in Scheme G.




Step 1 1-benzoyl-2-(3-chlorophenyl)-2,3-dihydro-pyridin-4-one
To 510 mg 4-methoxy pyridine in 10 ml THF under argon at −30° C. was added 5.25 ml 1M 3-chloro-phenyl Grignard. The mixture was stirred at −30° C. for five minutes, and then 0.55 ml benzoyl chloride was added drop-wise. The mixture was stirred at −30° C. for three hours, then was quenched with 5 ml 10% aqueous HCl and allowed to warm to room temperature. After one hour the mixture was extracted with EtOAc, and the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed (gradient 0-40% EtOAc in hexanes) to yield 910 mg 1-benzoyl-2-(3-chlorophenyl)-2,3-dihydro-pyridin-4-one.
Step 2 3-(1-Benzoyl-4-oxo-1,2,3,4-tetrahydro-pyridin-2-yl)-benzonitrile
1-Benzoyl-2-(3-chlorophenyl)-2,3-dihydro-pyridin-4-one (910 mg) was placed in an argon filled flask together with 42 mg Pd(II) TFA2, 108 mg binaphthyl-di-tert-butyl phosphine, 39 mg zinc powder, 203.4 mg zinc cyanide and 45 ml dimethylacetamide. The solution was degassed with argon and heated at 90° C. for eight hours. After cooling to room temperature, the mixture was filtered through glass fiber filter paper. The supernatant was basified with ammonium hydroxide and the resulting mixture was extracted with diethyl ether. The combined ether extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography of the residue gave 350 mg 3-(1-benzoyl-4-oxo-1,2,3,4-tetrahydro-pyridin-2-yl)-benzonitrile.
Step 3 2-(3-Cyanophenyl)-2,3-dihydro-pyridin-4-one
3-(1-Benzoyl-4-oxo-1,2,3,4-tetrahydro-pyridin-2-yl)-benzonitrile (350 mg) was dissolved in 50 ml methanol at 0° C. and 1.5 ml of 0.5 M sodium methoxide in methanol was added. The solution was stirred at 0° C. for 3 hours, and then 25 ml of pH 7 phosphate buffer was added. The mixture was concentrated under reduced pressure and partitioned between buffer and ethyl acetate. The organic layer was dried over sodium sulfate and the drying agent filtered off. Racemic 2-(3-cyanophenyl)-2,3-dihydro-pyridin-4-one was crystallized by addition of hexane to give 131 mg.
Step 4 3-{1-[2-(2-bromo-4,5-dimethoxy-phenyl)-acetyl]-4-oxo-1,2,3,4-tetrahydro-pyridin-2-yl}-benzonitrile
To 75 mg of 2-(3-cyanophenyl)-2,3-dihydro-pyridin-4-one in 8 ml THF at −75° C. was added 0.2 ml 2.5M n-butyl lithium. The mixture is stirred under argon at −75° C. for 10 minutes and then 106 mg 2-(2-bromo-4,5-dimethoxy-phenyl)acetyl chloride in 2 ml THF was added slowly. The reaction mixture was then stirred at −75° C. for 30 minutes, then allowed to warm to room temperature and was stirred for an additional 30 minutes. To this mixture was added 10 ml saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Chromatography of the residue gave 45 mg 3-{1-[2-(2-bromo-4,5-dimethoxy-phenyl)-acetyl]-4-oxo-1,2,3,4-tetrahydro-pyridin-2-yl}-benzonitrile. MS (M+H) 457.
Example 3
(S)-1-[2-(2-Bromo-5-methoxy-4-methyl-phenyl)-acetyl]-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one
The synthetic procedure used in this preparation is outlined in Scheme H.




Step 1 (2-Bromo-5-methoxy-4-methyl-phenyl)-acetic Acid
To a solution of (3-methoxy-4-methyl-phenyl)-acetic acid (6.1 g, 33.9 mmol) in glacial acetic acid (30 mL) under argon was added bromine (1.96 mL, 37.2 mmol). The mixture was stirred at room temperature for three hours. Water (100 mL) was added, and solid was filtered off, washed with water and dried to obtain (2-bromo-5-methoxy-4-methyl-phenyl)-acetic acid (6.8 g, 77%).
Step 1 (2-Bromo-5-methoxy-4-methyl-phenyl)-acetic Acid Chloride
To a solution of (2-bromo-5-methoxy-4-methyl-phenyl)-acetic acid (149.4 mg) in dichloromethane (1.8 mL) was added oxalyl chloride (0.055 mL) followed by DMF (1 drop) uder argon. Mixture was stirred at rt for 3 h. Mixture was concentrated to dryness. Dichloroethane (ca. 10 mL) was added, and the mixture was back concentrated to dryness to obtain crude (2-bromo-5-methoxy-4-methyl-phenyl)-acetic acid chloride (151 mg).
Step 3 (S)-1-[2-(2-bromo-5-methoxy-4-methyl-phenyl)-acetyl]-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one
To a solution of (S)-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one (80 mg) in THF (1.5 mL) at −78° C. under argon was added n-butyllithium (0.184 mL, 2.5M in hexanes). After ten minutes a solution of (2-bromo-5-methoxy-4-methyl-phenyl)-acetic acid chloride (116 mg) in THF (1 mL) was added. The mixture was stirred at −78° C. for 30 minutes, then at room temperature for 30 minutes. Saturated aqueous ammonium chloride was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated to dryness under reduced pressure. Purification of the residue by flash chromatography (hexanes/ethyl acetate gradient) gave (S)-1-[2-(2-bromo-5-methoxy-4-methyl-phenyl)-acetyl]-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one as a foam. MS (M+H) 433.
In a similar fashion the following compounds were prepared:

    (S)-1-[2-(2-Bromo-4,5-dimethoxy-phenyl)-acetyl]-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one;
    (S)-1-[2-(2-Bromo-4,5-dimethoxy-phenyl)-acetyl]-2-(3-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one;
    (S)-1-[2-(2-Bromo-4,5-dimethoxy-phenyl)-acetyl]-2-phenyl-2,3-dihydro-1H-pyridin-4-one;
    (S)-1-[2-(2-Chloro-4,5-dimethoxy-phenyl)-acetyl]-2-phenyl-2,3-dihydro-1H-pyridin-4-one;
    (S)-1-[2-(2-Bromo-4-chloro-5-methoxy-phenyl)-acetyl]-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one;
    Racemic 1-[2-(2-Bromo-5-hydroxy-4-methyl-phenyl)-acetyl]-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one (the phenol was liberated (BBr3, dichloromethane) in the last step);
    (S)-1-[2-(2-Bromo-5-methoxy-4-methyl-phenyl)-acetyl]-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one;
    (S)-1-[2-(3,4-Dimethoxy-phenyl)-acetyl]-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one;
    (S)-1-[2-(3,4-Dimethoxy-phenyl)-acetyl]-2-(3-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one; and
    (S)-1-[2-(2-Bromo-4-fluoro-5-methoxy-phenyl)-acetyl]-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one.


Example 4
(S)-1-[2-(2-bromo-5-difluoromethoxy-4-methoxy-phenyl)-acetyl]-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one
The synthetic procedure used in this preparation is outlined in Scheme I.




Step 1 (2-Bromo-5-hydroxy-4-methoxy-phenyl)-acetic Acid
To 3-hydroxy-4-methoxy-phenyl acetic acid (8 g) in 150 ml acetic acid was added drop wise 2.48 ml bromine. The mixture was stirred 18 hours at room temperature under nitrogen. The solvent was then removed in vacuo and the residue was triturated with toluene, filtered, washed with toluene then hexane to yield 11.1 g (2-bromo-5-hydroxy-4-methoxy-phenyl)-acetic acid a solid.
Step 2 (2-Bromo-5-hydroxy-4-methoxy-phenyl)-acetic Acid Methyl Ester
(2-Bromo-5-hydroxy-4-methoxy-phenyl)-acetic acid (11 g) was dissolved in 150 ml methanol and 0.8 ml conc. H2SO4. The solution was stirred at room temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was added until the mixture was basic and the mixture was concentrated under reduced pressure. The residue was partitioned between bicarbonate solution and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was taken up in ethyl acetate and crystallized by the addition of hexanes. Filtration gave 8.8 g (2-bromo-5-hydroxy-4-methoxy-phenyl)-acetic acid methyl ester.
Step 3 (2-Bromo-5-difluoromethoxy-4-methoxy-phenyl)-acetic Acid Methyl Ester
A mixture of 1.1 g (2-bromo-5-hydroxy-4-methoxy-phenyl)-acetic acid methyl ester (4.2 mmol), 10 ml DMF (wet), 1.75 g potassium carbonate (12.6 mmol) and 1.6 ml ethyl chlorodifluoro acetate was heated at 90° C. for 18 hours. The mixture was cooled to room temperature and poured into cold water. The mixture was extracted with ethyl acetate and the combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed using 50% dichloromethane in hexanes to 100% dichloromethane to yield 400 mg (2-bromo-5-difluoromethoxy-4-methoxy-phenyl)-acetic acid methyl ester.
Step 4 (2-Bromo-5-difluoromethoxy-4-methoxy-phenyl)-acetic Acid
(2-Bromo-5-difluoromethoxy-4-methoxy-phenyl)-acetic acid methyl ester (400 mg) was dissolved in 5 ml methanol and treated with 150 mg lithium hydroxide in 1 ml of water. The mixture was stirred at room temperature for 18 hours, acidified with 10% aqueous hydrochloric acid, filtered and dried to yield 350 mg of (2-bromo-5-difluoromethoxy-4-methoxy-phenyl)-acetic acid.
Step 5 (2-Bromo-5-difluoromethoxy-4-methoxy-phenyl)-acetic Acid Chloride
(2-Bromo-5-difluoromethoxy-4-methoxy-phenyl)-acetic acid (350 mg, 1.12 mmol) was dissolved in 6 ml dichloromethane and 0.1 ml oxalyl chloride and 0.01 ml DMF was added. The solution was stirred at room temperature until gas evolution stopped, then concentrated under reduced pressure. Dichloromethane (6 ml) was added to the residue and the solvent removed again to assure that all the oxalyl chloride was removed giving 118 mg of crude (2-bromo-5-difluoromethoxy-4-methoxy-phenyl)-acetic acid chloride.
Step 6 (S)-1-[2-(2-bromo-5-difluoromethoxy-4-methoxy-phenyl)-acetyl]-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one
To 108 mg of (S)-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one in 8 ml THF (anhydrous, inhibitor free) at −78° C. under argon was added 0.18 ml of 2.5 M n-butyl lithium in hexanes. The mixture was stirred at −78° C. for 10 minutes and then 118 mg of (2-bromo-5-difluoromethoxy-4-methoxy-phenyl)-acetic acid chloride dissolved in 2 ml THF was added. The solution was stirred at −78° C. for 30 minutes, then allowed to warm to room temperature for 30 minutes with stirring. To this mixture was then added 10 ml saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate, the organic layer was dried over sodium sulfate, filtered and the solvent was removed in vacuo. Chromatography (20% Ethyl acetate in hexanes) gave 30 mg (S)-1-[2-(2-bromo-5-difluoromethoxy-4-methoxy-phenyl)-acetyl]-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one. MS (M+1) 485.
In a similar fashion, the following compounds were prepared:

    (S)-1-[2-(2-Bromo-4,5-bis-difluoromethoxy-phenyl)-acetyl]-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one, MS (M+1) 521;
    (S)-1-[2-(2-Bromo-5-cyclo-propylmethoxy-4-methoxy-phenyl)-acetyl]-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one, MS (M+1) 489;
    (S)-1-[2-(2-Bromo-5-(2-methoxy-ethoxy)-4-methoxy-phenyl)-acetyl]-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one;
    (S)-1-[2-(2-Bromo-5-ethoxy-4-methoxy-phenyl)-acetyl]-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one; MS (M+1) 462;
    (S)-1-[2-(2-Bromo-5-methoxy-4-ethoxy-phenyl)-acetyl]-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one; MS (M+1) 462; and
    (S)-1-[2-(2-Bromo-4-cyclopropylmethoxy-5-methoxy-phenyl)-acetyl]-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one.


Example 5
(S)-1-{2-[2-Bromo-4-fluoro-5-(2-hydroxy-ethoxy)-phenyl]-acetyl}-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one
The synthetic procedure used in this preparation is outlined in Scheme J.







Step 1 (2-Bromo-4-fluoro-5-methoxy-phenyl)-acetic Acid
To a solution of 4-fluoro-3-methoxyphenylacetic acid (5.0 g, 27.1 mmol) in AcOH (20 ml) was added bromine (1.5 ml, 29.8 mmol). The mixture was stirred at room temperature for three hours. Water was added and the precipitate was isolated by filtration. The white solid was washed with water and dried to give (2-bromo-4-fluoro-5-methoxy-phenyl)-acetic acid (6.21 g, 87%).
Step 2 (2-Bromo-4-fluoro-5-hydroxy-phenyl)-acetic Acid
To a solution of (2-bromo-4-fluoro-5-methoxy-phenyl)-acetic acid (6.2 g, 23.5 mmol) in dichloromethane (100 ml) was added 1.0 M borontribromide in dichloromathane (94 ml, 94 mml). The mixture was stirred at room temperature for one hour. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromathane. The combined organic extract was washed with water and brine, dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Purification by flash chromatography gave (2-bromo-4-fluoro-5-hydroxy-phenyl)-acetic acid (5.2 g, 89%) as a white solid.
Step 3 (2-Bromo-4-fluoro-5-hydroxy-phenyl)-acetic Acid Ethyl Ester
To a solution of (2-bromo-4-fluoro-5-hydroxy-phenyl)-acetic acid (5.06 g) in EtOH (100 ml) was added sulfuric acid (0.2 ml) and the mixture was stirred at room temperature for 24 hours. The mixture was heated at 70° C. with stirring for an additional 24 h. The mixture was evaporated to dryness under reduced pressure. Purification of the residue by flash chromatography (hexanes:EtOAc/9:1) gave (2-bromo-4-fluoro-5-hydroxy-phenyl)-acetic acid ethyl ester (4.66 g) as a solid.
Step 4 {2-bromo-5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-fluoro-phenyl}-acetic Acid Ethyl Ester
To a solution of (2-bromo-4-fluoro-5-hydroxy-phenyl)-acetic acid ethyl ester (0.42 1 g, 1.52 mmol) in NMP (5 ml) was added cesium carbonate (0.644 g, 1.97 mmol), sodium iodide (0.228 g, 1.52 mmol) and 2-bromoethoxy tert-butyldimethylsilane (0.424 g, 1.97 mmol). The mixture was heated at 100° C. for two hours. After cooling to room temperature, water was added and the product was extracted with EtOAc. The combined extracts were washed with water and brine, dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Purification of the residue by flash chromatography (hexanes:EtOAc/8:2) gave {2-bromo-5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-fluoro-phenyl}-acetic acid ethyl ester (0.508 g, 77%) as a white solid.
Step 5 {2-bromo-5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-fluoro-phenyl}-acetic Acid
To a solution of {2-bromo-5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-fluoro-phenyl}-acetic acid ethyl ester (0.508 g, 1.16 mmol) in MeOH was added LiOH.H2O (0.036 g, 1.51 mmol). The mixture was stirred at room temperature for two hours, and then solvent was removed under reduced pressure. 2N NaOH was added to the residue, and the mixture was washed with diethyl ether. The aqueous phase was taken to pH 1 with 2N HCl and was extracted with EtOAc. The combined EtOAc extracts were washed with water, brine dried over MgSO4, filtered and concentrated to dryness under reduced pressure to yield {2-bromo-5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-fluoro-phenyl}-acetic acid (0.352 g, 74%) as a white solid.
Step 6 {2-Bromo-5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-fluoro-phenyl}-acetyl-2,2-dimethyl-proprionic Anhydride
To a solution of {2-bromo-5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-fluoro-phenyl}-acetic acid (0.158 g, 0.387 mmol) in toluene (3 ml) was added at 0 C triethylamine (0.062 ml, 0.442 mmol) and pivaloyl chloride (0.048 ml, 0.387 mmol). The mixture was stirred at 0 C for 1 hour. The mixture was filtered and the filtrate was concentrated to dryness to give crude {2-bromo-5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-fluoro-phenyl}-acetyl-2,2-dimethyl-proprionic anhydride (0.192 g) as a clear oil.
Step 7 (S)-1-(2-{2-bromo-5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-fluoro-phenyl}-acetyl)-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one
To a solution of (S)-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one (0.07 g, 0.387 mmol) in THF (3 ml) at −78° C. was added 2.5M n-BuLi in hexane (0.155 ml, 0.387 mmol). The mixture was stirred at −78° C. for 10 minutes. A solution of the anhydride of step 6 (0.192 g, 0.387 mmol) in THF (2 ml) was added and the mixture was stirred at −78° C. for 30 minutes and at room temperature for 30 minutes. Saturated aqueous ammonium chloride was added and the product was extracted with EtOAc. The extract was washed with water and brine, dried over MgSO4, flittered and concentrated to dryness. Purification by flash chromatography (hex:EtOAc/6:4) gave 1-(2-{2-bromo-5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-fluoro-phenyl}-acetyl)-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one (0.112 g, 50%) as a white foam.
Step 8 (S)-1-{2-[2-Bromo-4-fluoro-5-(2-hydroxy-ethoxy)-phenyl]-acetyl}-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one
A mixture of acetic acid (4.5 ml), water (1.5 ml) and THF (1.5 ml) was added to a flask containing 1-(2-{2-bromo-5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-fluoro-phenyl}-acetyl)-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one (0.048 g, 0.082 mmol). The mixture was stirred at room temperature for 16 hours. Water was added and the product was extracted with EtOAc. The extract was washed with water and brine, dried over MgSO4, filtered and concentrated to dryness. Purification by flash chromatography (EtOAc) gave (S)-1-{2-[2-bromo-4-fluoro-5-(2-hydroxy-ethoxy)-phenyl]-acetyl}-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one (0.032 g) as a white foam.
In a similar fashion, the following compounds were prepared:
(S)-1-{2-[2-Bromo-4-fluoro-5-(2-methoxy-ethoxy)-phenyl]-acetyl}-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one, except that 1-bromo-2-methoxy-ethane was used as the alkylating agent in step 4.
Example 6
4,5-Dimethoxy-2-[2-oxo-2-(4-oxo-2-phenyl-3,4-dihydro-2H-pyridin-1-yl)-ethyl]-benzonitrile
The synthetic procedure used in this preparation is outlined in Scheme K.




Step 1 (2-iodo-4,5-dimethoxy-phenyl)-acetic Acid
3,4-Dimethoxyphenylacetic acid (4.0 g, 20.4 mmol) was dissolved in 100 ml of glacial acetic acid. Iodine monochloride (1.35 eq, 1.38 ml) was added slowly and the mixture was allowed to stir at room temperature overnight. To the mixture was added 300 ml of a 10% aqueous solution of sodium bisulfite. The mixture was concentrated in vacuo to remove most of the acetic acid. The aqueous residue was extracted with EtOAc. The organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with diethyl ether and the solid was then filtered and dried to give (2-iodo-4,5-dimethoxy-phenyl)-acetic acid (2.94 g, 44.8%) as an off-white solid.
Step 2 1-[2-(2-Iodo-4,5-dimethoxy-phenyl)-acetyl]-2-phenyl-2,3-dihydro-1H-pyridin-4-one
1-[2-(2-Iodo-4,5-dimethoxy-phenyl)-acetyl]-2-phenyl-2,3-dihydro-1H-pyridin-4-one was prepared by reacting (2-iodo-4,5-dimethoxy-phenyl)-acetic acid with 2-Phenyl-2,3-dihydro-1H-pyridin-4-one following the procedure of step 3 of Example 1.
Step 3
1-[2-(2-Iodo-4,5-dimethoxy-phenyl)-acetyl]-2-phenyl-2,3-dihydro-1H-pyridin-4-one (269 mg, 0.56 mmol), zinc cyanide (1.5 eq, 99 mg) and tetrakis(triphenylphosphine)palladium(0) (0.15 eq, 98 mg) were dissolved in DMF. The mixture was heated to 80° C. overnight. Upon cooling, the mixture was poured into water and extracted with EtOAc. The organic extracts were dried over anhydrous sodium sulfate and concentrated en vacuo. The residue was purified by flash chromatography (7:3 Hexanes/Ethyl Acetate) to give 4,5-dimethoxy-2-[2-oxo-2-(4-oxo-2-phenyl-3,4-dihydro-2H-pyridin-1-yl)-ethyl]-benzonitrile (43 mg, 20.3%) viscous oil.
Example 7
Formulations
Pharmaceutical preparations for delivery by various routes are formulated as shown in the following Tables. “Active ingredient” or “Active compound” as used in the Tables means one or more of the Compounds of Formula I.










Composition for Oral Administration










Ingredient
% wt./wt.














Active ingredient
20.0%



Lactose
79.5%



Magnesium stearate
0.5%










The ingredients are mixed and dispensed into capsules containing about 100 mg each; one capsule would approximate a total daily dosage.










Composition for Oral Administration










Ingredient
% wt./wt.














Active ingredient
20.0%



Magnesium stearate
0.5%



Crosscarmellose sodium
2.0%



Lactose
76.5%



PVP (polyvinylpyrrolidine)
1.0%










The ingredients are combined and granulated using a solvent such as methanol. The formulation is then dried and formed into tablets (containing about 20 mg of active compound) with an appropriate tablet machine.










Composition for Oral Administration










Ingredient
Amount















Active compound
1.0
g



Fumaric acid
0.5
g



Sodium chloride
2.0
g



Methyl paraben
0.15
g



Propyl paraben
0.05
g



Granulated sugar
25.5
g



Sorbitol (70% solution)
12.85
g



Veegum K (Vanderbilt Co.)
1.0
g



Flavoring
0.035
ml



Colorings
0.5
mg



Distilled water
q.s. to 100
ml










The ingredients are mixed to form a suspension for oral administration.










Parenteral Formulation










Ingredient
% wt./wt.







Active ingredient
0.25 g



Sodium Chloride
qs to make isotonic



Water for injection
 100 ml










The active ingredient is dissolved in a portion of the water for injection. A sufficient quantity of sodium chloride is then added with stirring to make the solution isotonic. The solution is made up to weight with the remainder of the water for injection, filtered through a 0.2 micron membrane filter and packaged under sterile conditions.










Suppository Formulation










Ingredient
% wt./wt.














Active ingredient
1.0%



Polyethylene glycol 1000
74.5%



Polyethylene glycol 4000
24.5%










The ingredients are melted together and mixed on a steam bath, and poured into molds containing 2.5 g total weight.










Topical Formulation










Ingredients
Grams







Active compound
0.2-2



Span 60
2



Tween 60
2



Mineral oil
5



Petrolatum
10



Methyl paraben
0.15



Propyl paraben
0.05



BHA (butylated hydroxy anisole)
0.01



Water
q.s. 100










All of the ingredients, except water, are combined and heated to about 60° C. with stirring. A sufficient quantity of water at about 60° C. is then added with vigorous stirring to emulsify the ingredients, and water then added q.s. about 100 g.
Nasal Spray Formulations
Several aqueous suspensions containing from about 0.025-0.5 percent active compound are prepared as nasal spray formulations. The formulations optionally contain inactive ingredients such as, for example, microcrystalline cellulose, sodium carboxymethylcellulose, dextrose, and the like. Hydrochloric acid may be added to adjust pH. The nasal spray formulations may be delivered via a nasal spray metered pump typically delivering about 50-100 microliters of formulation per actuation. A typical dosing schedule is 2-4 sprays every 4-12 hours.
Example 8
Intracellular Calcium Flux (FLIPR) Assay
Compound and Reagent Preparation
Stock solutions of compounds were prepared from powders as a 10 mM DMSO stock solution. These solutions were stored at RT during the two week period of these experiments to prevent freeze-thaw of the DMSO stocks. The DMSO stocks were added to the appropriate assay buffer at a concentration of 10 μM, and then diluted serially to the final concentrations that were tested. No observable precipitate was formed at any time during this process. The aqueous solutions of compounds as well as ATP (Sigma A7699) and BzATP (Sigma B6396) were prepared fresh for each day of experiment.
Cell culture: 1321N1-hP2X7 and HEK293-rP2X7 
1321N1 cells stably expressing the full length human P2X7 gene (1321N1-hP2X7) and HEK293 cells stably expressing the full length rat P2X7 gene (HEK293-rP2X7) were obtained from the Roche Cell Culture Facility. 1321N1-hP2X7 cells were grown in Dulbecco's Modified Eagle's Medium (DMEM) high glucose supplemented with 10% FBS and 250 μg/mL G418. HEK293-rP2X7 cells were grown in DMEM/F-12 supplemented with 10% FBS, 1 mM CaCl2, 2 mM MgCl2, 2 mM L-Glutamine and 500 μg/ml G418. Cells were split such that they never became >70% confluent.
Intracellular Calcium Flux (FLIPR)
On the day prior to the experiment, 1321N1-hP2X7 or HEK293-rP2X7 cells were released into suspension with calcium-free PBS+Versene and washed by centrifugation with calcium-free PBS to remove the Versene. Cells were resuspended in growth medium at a density of 2.5×105 cells/mL and seeded into black walled, clear bottom 96 well plates (50,000 cells/well) approximately 18 hr prior to intracellular calcium flux experiments.
On the day of the experiment, plates were washed with FLIPR buffer (calcium- and magnesium-free Hank's Balanced Salt Solution (HBSS) supplemented with 10 mM Hepes, 2.5 mM probenecid and 2 mM calcium chloride) using a BIO-TEK 96 channel plate washer and incubated with 2 mM fluo-3 dye at 37° C. for one hr. The dye was then removed by plate washing and the cells were allowed to equilibrate for 20 min at room temperature with antagonist or vehicle (FLIPR buffer). Agonist (100 μM BzATP final concentration for hP2X7; 5 μM BzATP final concentration or rP2X7) was added online with the FLIPR and fluorescence measurements made at 1 sec intervals for 60 sec followed by 3 sec intervals for a further 4 min (5 min total). A final addition of 5 μM ionomycin was made and the maximal BzATP-evoked fluorescence normalized to the maximal ionomycin-evoked fluorescence.
Example 9
Human Whole Blood IL-1β Release Assay
Compound & Reagent Preparation
10 mM stock solutions of compounds in DMSO (Sigma D2650) were prepared and used either fresh or after storage at −20° C. Appropriate (200×) serial dilutions of the compounds were made in DMSO, then freshly diluted 1 to 20 (10×) with Dulbecco's phosphate buffered saline (DPBS; Mediatech Inc., 21-030), such that final DMSO concentration in the blood always equaled 0.5%.
30 mM ATP (Sigma A7699) was prepared immediately before use in 50 mM HEPES (Gibco 15630) and the pH adjusted to 7.2 with 1M sodium hydroxide.
Blood Donors
Human blood donors were medication free and restricted from utilizing alcohol or caffeine for at least the 24 hr preceding collection. The blood was collected into sodium heparin vacutainer tubes and used the same day.
Assay Method
The OptEIA Human IL-1β ELISA Set, OptEIA Coating Buffer, Assay Diluent and TMB Substrate Reagent Set used in the assay were commercially obtained from BD Pharmingen. Blood was diluted 1:1 with Dulbecco's PBS, LPS (Escherichia Coli 0127:B8, Sigma L3129) added to a final concentration of 25 ng/mL and incubated for 2 hr at 37° C. 48 μL of this LPS primed blood was added to 6 μL of the 10× compound in 5% DMSO/PBS in the appropriate well of a 96-well polypropylene plate. The blood and compound were mixed and allowed to incubate for 30 min at 37° C. 6 μl of 30 mM ATP was added to the LPS-primed blood+compound, mixed thoroughly and incubated for a further 30 min at 37° C. 96 μL of ELISA assay buffer was added to each well and the plate centrifuged at 4° C. 1,200 rpm for 10 min. Supernatant was removed and assayed for IL-1β using the OptiEIA kit according to the manufacturer's protocol (Serum may be frozen at −20° C. prior to assay). IC50s were calculated using XLfit.
Example 10
In Vivo Assay for Asthma and Lung Function
BALb/cJ mice are immunized with a standard immunization protocol. Briefly, mice (N=8/group) are immunized i.p. with ovalbumin (OVA; 10 μg) in alum on days 0 and 14. Mice are then challenged with aerosolized OVA (5%) on day 21 and 22. Animals receive vehicle (p.o.) or a compound of the invention (100 mg/kg p.o.) all starting on day 20.
Lung function is evaluated on day 23 using the Buxco system to measure PenH in response to an aerosol methacholine challenge. Mice are then euthanized and plasma samples collected at the end of the study.
While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto.

## Claims

1. A compound of formula I:



or pharmaceutically acceptable salts thereof,
wherein:
m is 0 or 1;
n is 0 or 1;
R1 is:
optionally substituted aryl;
optionally substituted heteroaryl; or
adamantyl;

R2 is:
optionally substituted aryl;
optionally substituted heteroaryl;
C3-6cycloalkyl; or
C3-6 branched alkyl; and

R3, R4 and R5 each independently is:
hydrogen; or
C1-6alkyl.

2. The compound of claim 1, wherein m is 0.

3. The compound of claim 2, wherein n is 0.

4. The compound of claim 3, wherein R3, R4 and R5 are hydrogen.

5. The compound of claim 4, wherein R1 is optionally substituted phenyl.

6. The compound of claim 5, wherein R1 is phenyl substituted one, two, three or four times with a substituent or substituents each independently selected from: halo; C1-6alkyl; C1-6alkoxy; halo-C1-6alkyl; halo-C1-6alkoxy; C1-6alkylsulfonyl; C1-6alkylsulfanyl; C1-6alkylsulfinyl; phenylsulfonyl wherein the phenyl portion is optionally substituted with C1-6alkyl; nitrile; hydroxy; alkylcarbonyl; aminocarbonyl; alkoxycarbonyl; alkoxycarbonylalkoxy; hydroxycarbonyl; hydroxycarbonylalkoxy; alkylaminocarbonylalkoxy; alkoxyalkoxy; hydroxyalkoxy; alkylaminoalkoxy; alkylsulfonylalkoxy; hydroxyalkyl; C3-6cycloalkyl-C1-6alkoxy; amino; aminoalkyl; C1-6alkenyl; C1-6alkynyl; or nitro; or two adjacent substituents may form a C1-2alkylenedioxy or halo-C1-2alkylenedioxy.

7. The compound of claim 5, wherein R1 is phenyl substituted one, two, three or four times with a substituent or substituents each independently selected from: fluoro; chloro; bromo; iodo; methyl; ethyl; methoxy; ethoxy; trifluoromethyl; difluoromethoxy; methanesulfonyl; methanesulfanyl; methanesulfinyl; toluenesulfonyl; nitrile; acetyl; aminocarbonyl; methoxycarbonyl; methoxycarbonylmethoxy; carboxy; hydroxycarbonylmethoxy; methylaminocarbonylmethoxy; methoxyethoxy; hydroxyethoxy; methylaminoethoxy; methanesulfonylpropyloxy; hydroxymethyl; hydroxyethyl; cyclopropylmethoxy; amino; or nitro; or two adjacent substituents may form methylenedioxy, ethylenedioxy or difluoromethylenedioxy.

8. The compound of claim 5, wherein R1 is phenyl substituted one, two, three or four times with a substituent or substituents each independently selected from: halo; C1-6alkyl; C1-6alkoxy; halo-C1-6alkyl; halo-C1-6alkoxy; C1-6alkylsulfonyl; nitrile; alkoxyalkoxy; hydroxyalkoxy; alkylsulfonylalkoxy; hydroxyalkyl; or C3-6cycloalkyl-C1-6alkoxy.

9. The compound of claim 5, wherein R1 is phenyl substituted one, two, three or four times with a substituent or substituents each independently selected from: fluoro; chloro; bromo; iodo; methyl; ethyl; methoxy; ethoxy; trifluoromethyl; difluoromethoxy; methanesulfonyl; nitrile; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; or cyclopropylmethoxy.

10. The compound of claim 5, wherein R1 is phenyl optionally substituted one, two or three times with a substituent or substituents each independently selected from: fluoro; chloro; bromo; methyl; ethyl; methoxy; ethoxy; trifluoromethyl; difluoromethoxy; nitrile; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; or cyclopropylmethoxy.

11. The compound of claim 5, wherein R2 is optionally substituted phenyl.

12. The compound of claim 5, wherein R2 is phenyl optionally substituted one, two or three times with a substituent or substituents each independently selected from: fluoro; chloro; bromo; methyl; ethyl; methoxy; ethoxy; trifluoromethyl; difluoromethoxy; nitrile; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; or cyclopropylmethoxy.

13. The compound of claim 5, wherein R2 is phenyl substituted once or twice with a substituent or substituents each independently selected from: fluoro; chloro; methyl; methoxy; or nitrile.

14. The compound of claim 5, wherein R2 is phenyl substituted once or twice with fluoro.

15. The compound of claim 1, wherein said compound is of formula II:



wherein:
p is from 0 to 3;
R6, R7, R8, R9 and R10 each independently is: hydrogen; halo; C1-6alkyl; C1-6alkoxy; halo-C1-6alkyl; halo-C1-6alkoxy; C1-6alkylsulfonyl; C1-6alkylsulfanyl; C1-6alkylsulfinyl; phenylsulfonyl wherein the phenyl portion is optionally substituted with C1-6alkyl; nitrile; hydroxy; alkylcarbonyl; aminocarbonyl; alkoxycarbonyl; alkoxycarbonylalkoxy; hydroxycarbonyl; hydroxycarbonylalkoxy; alkylaminocarbonylalkoxy; alkoxyalkoxy; hydroxyalkoxy; alkylaminoalkoxy; alkylsulfonylalkoxy; hydroxyalkyl; C3-6cycloalkyl-C1-6alkoxy; amino; aminoalkyl; or nitro; or two adjacent substituents may form a C1-2alkylenedioxy or halo-C1-2alkylenedioxy; and

each R11 independently is: halo; C1-6alkyl; C1-6alkoxy; halo-C1-6alkyl; halo-C1-6alkoxy; C1-6alkylsulfonyl; or nitrile.

16. The compound of claim 15, wherein at least two of R6, R7, R8, R9 and R10 are not hydrogen.

17. The compound of claim 15, wherein R6, R7, R8, R9 and R10 each independently is: hydrogen; fluoro; chloro; bromo; iodo; methyl; ethyl; methoxy; ethoxy; trifluoromethyl; difluoromethoxy; methanesulfonyl; methanesulfanyl; methanesulfinyl; toluenesulfonyl; nitrile; acetyl; aminocarbonyl; methoxycarbonyl; methoxycarbonylmethoxy; carboxy; hydroxycarbonylmethoxy; methylaminocarbonylmethoxy; methoxyethoxy; hydroxyethoxy; methylaminoethoxy; methanesulfonylpropyloxy; hydroxymethyl; hydroxyethyl; cyclopropylmethoxy; amino; or nitro; or two adjacent substituents may form methylenedioxy, ethylenedioxy or difluoromethylenedioxy.

18. The compound of claim 15, wherein R6, R7, R8, R9 and R10 each independently is: hydrogen; halo; C1-6alkyl; C1-6alkoxy; halo-C1-6alkyl; halo-C1-6alkoxy; C1-6alkylsulfonyl; nitrile; alkoxyalkoxy; hydroxyalkoxy; alkylsulfonylalkoxy; hydroxyalkyl; or C3-6cycloalkyl-C1-6alkoxy.

19. The compound of claim 15, wherein R6, R7, R8, R9 and R10 each independently is: hydrogen; fluoro; chloro; bromo; iodo; methyl; ethyl; methoxy; ethoxy; trifluoromethyl; difluoromethoxy; methanesulfonyl; nitrile; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; or cyclopropylmethoxy.

20. The compound of claim 15, wherein R6, R7, R8, R9 and R10 each independently is: hydrogen; fluoro; chloro; bromo; methyl; ethyl; methoxy; ethoxy; trifluoromethyl; difluoromethoxy; nitrile; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; or cyclopropylmethoxy.

21. The compound of claim 15, wherein R7 and R10 are hydrogen.

22. The compound of claim 21, wherein R6 is: hydrogen; halo; or methyl.

23. The compound of claim 22, wherein R8 is: hydrogen; methoxy; halo; methyl; or difluoromethoxy.

24. The compound of claim 15, wherein R9 is: methoxy; hydrogen; 2-hydroxy-ethoxy; 2-methoxy-ethoxy; 1-hydroxy-ethyl; or cyclopropylmethyl.

25. The compound of claim 15, wherein p is 0, 1 or 2.

26. The compound of claim 25, wherein R11 is halo.

27. The compound of claim 25, wherein R11 is fluoro.

28. The compound of claim 15, wherein said compound is of formula III



wherein R6, R8, R9 and R11 are as recited in claim 15.

29. A pharmaceutical composition comprising:
(a) a pharmaceutically acceptable carrier; and
(b) a compound of claim 1.

30. A method for treating arthritis, said method comprising administering to a subject in need thereof an effective amount of a compound of claim 1.