WO2010141690A2 - Indane analogs and use as pharmaceutical agents and process of making - Google Patents

Abstract

This invention relates to novel indane analogues that are useful in the treatment of diseases and disorders such as treating and/or preventing diabetes and related disorders such as Syndrome X, impaired glucose tolerance, impaired fasting glucose, and hyperinsulinemia obesity, atherosclerotic disease, dyslipidemia, and related disorders such as hypertriglyceridemia, low HDL cholesterol, and hypercholesteremia, cardiovascular disease, cerebrovascular disease, psoriasis, or Alzheimer's disease. The invention also relates to intermediates useful in preparation of indane acetic derivatives and to methods of preparation.

Description

INDANE ANALOGS AND USE AS PHARMACEUTICAL AGENTS AND PROCESS OF

MAKING

Mary Katherine Delmedico, Kenneth James Ingold

FIELD OF THE INVENTION

This invention is generally related to indane analogs and their use in pharmaceutical compositions for the medical treatment.

BACKGROUND OF THE INVENTION

Type II diabetes is a common form of diabetes, with 90-95% of hyperglycemic patients experiencing this form of the disease. In Type II diabetes, there appears to be a reduction in the pancreatic β-cell mass, several distinct defects in insulin secretion, and a decrease in tissue sensitivity to insulin. The symptoms and consequences of this form of diabetes include fatigue, frequent urination, thirst, blurred vision, frequent infections and slow healing of sores, diabetic nerve damage, retinopathy, micro and macro blood vessel damage, and heart and renal disease.

Resistance to the metabolic actions of insulin is one of the key features of Type II diabetes. Insulin resistance is characterized by impaired uptake and utilization of glucose in insulin-sensitive target organs, for example, adipocytes and skeletal muscle, and by impaired inhibition of hepatic glucose output. Functional insulin deficiency, insulin resistance in the periphery, and the failure of insulin to suppress hepatic glucose output results in fasting hyperglycemia. Pancreatic β-cells compensate for the insulin resistance by secreting increased levels of insulin. However, the β-cells are unable to maintain this high output of insulin, and eventually, the glucose-induced insulin secretion falls, leading to the deterioration of glucose homeostasis and to the subsequent development of overt diabetes. Hyperinsulinemia is also linked to insulin resistance, hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol, and increased plasma concentration of low-density lipoproteins (LDL). The association of insulin resistance and hyperinsulinemia with these metabolic disorders has been termed "Syndrome X," and has been strongly linked to an increased risk of hypertension and coronary artery disease.

Obesity is an excessive accumulation of adipose tissue. Excess adipose tissue is associated with the development of serious medical conditions, for example, Type II diabetes, hypertension, coronary artery disease, hyperlipidemia, obesity, and certain malignancies. The adipocyte may also influence glucose homeostasis through the production of tumor necrosis factor α (TNFα) and other molecules.

Atherosclerotic disease is known to be caused by a number of factors, for example, hypertension, diabetes, low levels of HDL, and high levels of LDL. Atherosclerotic-related diseases include cardiovascular disease, coronary heart disease (CHD), cerebrovascular disease, and peripheral vessel disease. Coronary heart disease includes CHD death, myocardial infarction, and coronary revascularization. Cerebrovascular disease includes ischemic or hemorrhagic stroke, and transient ischemic attacks.

Psoriasis is a chronic, genetically-influenced, remitting skin disorder. It is estimated that psoriasis affects 1 to 3 percent of the world's population. The skin lesions of psoriasis are variably pruritic. There are several types of psoriasis, including plaque, pustular, guttate and arthritic variants. The disease may appear at two different age ranges. Premature disease presentation (type 1), with a peak between 15 and 35 years of age, is the most frequent and is normally associated with family history. Late disease presentation (type 2) is presented with a peak between 55 and 60 years of age.

Currently, the available treatments for plaque psoriasis incorporate the use of emollients, keratolytic agents, coal tar, anthralin, corticosteroids of medium to strong potency, and calpotriene. All of these treatments have variable efficacy. However, none of these treatments can prevent frequent relapses of the disease, and they all exhibit different degrees of side effects. In some cases, systemic treatment has been used in patients with physically, socially, or economically disabling psoriasis who have not responded to topical treatment. The choices to date have been limited to phototherapy or systemic drug therapy. Generally, systemic treatment has employed phototherapy with Ultraviolet B irradiation, photo chemotherapy which combines the photosensitizing drug methoxsalen with Ultraviolet A phototherapy (PUVA), methotrexate, etretinate, systemic corticosteroids, and cyclosporine. However, each of these systemic treatments has variable efficacy and undesired side effects.

Alzheimer's disease ("AD") is a major cause of dementia among the elderly throughout the world. Beginning at age 65, the incidence of the disease rises steadily until age 85. An estimated 26.6 million people worldwide suffered from Alzheimer's in 2006.

AD has been identified as a protein misfolding disease caused by accumulation of abnormally folded A-β and tau proteins in the brain. Plaques are made up of small peptides, 39-43 amino acids in length, called beta-amyloid (also written as A-beta or Aβ). β-amyloid is a fragment from a larger protein called amyloid precursor protein (APP), a transmembrane protein that penetrates through the neuron's membrane. APP is involved in to neuronal growth, survival and post-injury repair. In Alzheimer's disease, APP is divided into smaller fragments by enzymes through proteolysis. One of these fragments gives rise to fibrils of beta-amyloid, which form clumps that deposit outside neurons in dense formations known as senile plaques. The disease typically results in an inexorable decline in cognitive functions often coupled with gross behavioral changes, leading to the patient's inability to care for his or herself in the community resulting in the need for increased assistance for care givers and home care and nursing home providers. To date, there is no universally satisfactory treatment for

Alzheimer's disease. Accordingly, despite the presence of some pharmaceuticals that are used to treat these diseases, there remains a need for new pharmaceuticals that are both safe and effective agents for the treatment of diseases.

SUMMARY OF THE INVENTION

The present invention relates to compounds of Formula I,

Formula I wherein

R is H or Ci-C₆ alkyl;

R¹ is H, COOH, -C(=0)-0R, C₃-C₈ cycloalkyl, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C_rC₆ alkoxy, wherein R¹ is Ci -C₆ alkyl, and said alkyl, cycloalkyl, akenyl or alkoxy may be optionally substituted with one or more groups selected from the group consisting of fluoro, methylenedioxyphenyl and phenyl, wherein said methylenedioxyphenyl, or phenyl may be optionally and independently substituted with R⁶;

R² is H, halo, or Ci-C₆ alkyl wherein said alkyl may be optionally substituted with one or more groups selected from the group consisting Of Cj-C₆ alkoxy, oxo and fluoro, or

R² is C_5-14 aryl, C_3-I4 heterocycle or C₅.i₄ heteroaryl, wherein said aryl, heterocycle or heteroaryl may be optionally substituted with one or more R⁶;

R³ is H, C₁-C₆ alkyl, or phenyl, wherein said alkyl or phenyl may be optionally substituted with one or more R⁶;

X is O or S;

R⁴ is C_5-I4 aryl, C_3-14 heterocycle or C_5-J4 heteroaryl, wherein said aryl, heterocycle or heteroaryl is substituted with one or more R⁷,

R⁵ is H, halo or C₁-C₆ alkyl wherein said alkyl may be optionally substituted with oxo;

R⁶ is halo, CF₃, C₁-C₆ alkyl wherein said alkyl may be optionally substituted with oxo or hydroxy, or Cj-C₆ alkoxy optionally substituted with fluoro;

R⁷ is selected from the group consisting of

(a) hydroxyl,

(b) C_rC₆ alkoxyl, wherein one or more H of the alkoxyl is ²H (D), and (c) -O-protecting group;

(d) -O-C(=O)-R" wherein R" is Q -C₆ alkyl or C_5-M aryl wherein said alkyl or aryl may be optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, -SH, amide, carboxylic acid, CN, Cj-C₆ alkyl, Q-C₆ thioalkyl, C_{fi ]4} aryl and C_{5 14} heteroaryl and -NR_cR_<i_> and wherein R₀ and R_d are independently hydrogen, or CpC₆ alkyl;

(e) -O-C(=O)-R^m, wherein R¹" is -NR_eR_f and wherein R_e and R_f are independently hydrogen, or Ci-C₆ alkyl; or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer, diastereomer, enantiomer or racemate thereof.

In some embodiments, the compound of Formula I is a meglumine, potassium or sodium salt thereof.

In one embodiment, for the compound of Formula I, R is H, R¹ is H, R² is H, R³ is Cj-C₆ alkyl, X is O, and R⁴ is a phenyl substituted with one or more R⁷, wherein R⁷ is selected from the group consisting of (a) hydroxyl, (b) Ci-C₆ alkoxyl, and one or more H of the alkoxyl is ²H (D), and (c) -0-CH₂-Ph, wherein said phenyl may be optionally substituted with C]-C₆ alkoxyl; and R⁵ is H, or a pharmaceutically acceptable salt thereof. hi another embodiment, the compounds have the following structure:

Another aspect of the present invention provides processes of preparing a compound of Formula Ia comprising dealkylation of a compound of Formula B to give a compound of Formula Ia

Formula B

Formula Ia wherein for Formula B and Formula Ia

R is H or C₁-C₆ alkyl;

R¹ is H, COOH, -C(=O)-OR', C₃-C₈ cycloalkyl, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₁-C₆ alkoxy, wherein R is C_rC₆ alkyl, and said alkyl, cycloalkyl, akenyl or alkoxy may be optionally substituted with one or more groups selected from the group consisting of fluoro, methylenedioxyphenyl and phenyl, wherein said methylenedioxyphenyl, or phenyl may be optionally substituted with R⁶;

R² is H, halo, or Q-C₆ alkyl wherein said alkyl may be optionally substituted with one or more groups selected from the group consisting Of C₁-C₆ alkoxy, oxo and fluoro, or

R² is C₅-C₁₄ aryl, C₃-C₁₄ heterocycle or C₅-C₁₄ heteroaryl, wherein said aryl, heterocycle and heteroaryl may be optionally and independently substituted with one or more R⁶;

R³ is H, C₁-C₆ alkyl, or phenyl, wherein said alkyl or phenyl may be optionally and independently substituted with one ore more R⁶;

X is O or S;

R^a C₁-C₆ alkoxyl,

R⁵ is H, halo or C₁-C₆ alkyl wherein said alkyl optionally substituted with oxo; and

R⁶ is halo, CF₃, Ci-C₆ alkyl optionally substituted with oxo or hydroxy, or Cj-C₆ alkoxy optionally substituted with fluoro.

According to another aspect of the present invention, processes of making compound B are provided. The processes include dealkylation of compound A

A

to give compound B

B

wherein R° is hydrogen or Ci-Ce alkyl.

In another embodiment, in the process of making compound B, compound A has the structure of COOH

and compound B has the structure of COOH

Further, one aspect of the present invention provides processes of making compound D. The processes include cleaving the ether bond of 0-CH₂Ph of compound C

to provide compound D

D

wherein R^c is hydrogen or Ci.Cβ alkyl.

In some embodiments, for the process of making compound D, compound C has the structure of

and compound D has the structure of COOH

According to another aspect of the present invention, pharmaceutical compositions of compounds described herein are provided, hi some embodiments, the pharmaceutical compositions further include a pharmaceutically acceptable carrier. hi some embodiments, the pharmaceutical compositions described herein may further include one or more additional therapeutic agents.

A further aspect of the present invention relates to methods of treating and/or preventing diabetes and related disorders such as Syndrome X, impaired glucose tolerance, impaired fasting glucose, and hyperinsulinemia; obesity; atherosclerotic disease, dyslipidemia, and related disorders such as hypertriglyceridemia, low HDL cholesterol, and hypercholesteremia; cardiovascular disease; and cerebrovascular disease.

Another aspect of the present invention provides methods of treating and/or preventing psoriasis, and/or Alzheimer's disease.

Objects of the present invention will be appreciated by those of ordinary skill in the art from a reading of the Figures and the detailed description of the embodiments which follow, such description being merely illustrative of the present invention.

DETAILED DESCRIPTION

A. Definition:

The term "halo" means F, Cl, Br, or I.

The term "Cj-Cβ alkyl" means a straight or branched saturated hydrocarbon carbon chain of from 1 to about 6 carbon atoms, respectively. Examples of such groups include methyl, ethyl, isopropyl, sec-butyl, 2-methylpentyl, n-hexyl, and the like. The term "C₂-C6 alkenyl" means a straight or branched unsaturated hydrocarbon carbon chain of from 2 to about 6 carbon atoms. Examples of such groups include vinyl, allyl, isopropenyl, 2- butenyl, 3-ethyl-2-butenyl, 4-hexenyl, and the like.

The term "CpC₆ haloalkyl" means a C]-C₆ alkyl group substituted by 1 to 3 halogen atoms or fluorine up to the perfluoro level. Examples of such groups include trifluoromethyl, tetrafluoroethyl, 1, 2-dichloropropyl, 5-bromopentyl, 6-iodohexyl, and the like.

The terms "C₃-C₆ cycloalkyl" and "C₃-C₈ cycloalkyl" mean a saturated carbocyclic ring system of from 3 to about 6 carbon atoms or from 3 to about 8 carbon atoms, respectively. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term "C_rC₆ acyl" means a CpC₆ alkyl group attached at the carbonyl carbon atom. The radical is attached to the rest of the molecule at the carbonyl bearing carbon atom. Examples of such groups include acetyl, propionyl, n- butanoyl, 2-methylpentantoyl, and the like.

The term "CpC₆ alkoxy" means a linear or branched saturated carbon group having from 1 to about 6 C atoms, said carbon group being attached to an O atom. The O atom is the point of attachment of the alkoxy substituent to the rest of the molecule. Such groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and the like.

The term "C]-C₆ thioalkyl" means a linear or branched saturated carbon group having from 1 to about 6 C atoms, said carbon group being attached to an S atom. The S atom is the point of attachment of the thioalkyl substituent to the rest of the molecule. Such groups include, for example, methylthio, propylthio, hexylthio, and the like.

The term "C]-C₆ haloalkoxy" means a Ci-C₆ alkoxy group further substituted on C with 1 to 3 halogen atoms or fluorine up to the perfluoro level.

The term "C₃-C₈ cycloalkoxy" means a C₃-C₈ cycloalkyl group attached to an O atom. The O atom is the point of attachment of the cycloalkoxy group with the rest of the molecule.

The term "phenoxy" means a phenyl group attached to an O atom. The O atom is the point of attachment of the phenoxy group to the rest of the molecule.

The term "6-membered heteroaryl ring" means a 6-membered monocyclic heteroaromatic ring radical containing 1-5 carbon atoms and up to the indicated number of N atoms. Examples of 6- membered heteroaryl rings are pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, and the like.

The term "5- or 6-membered heterocyclic ring" means a 5 or 6-membered ring containing 1-5 C atoms and up to the indicated number of N, O, and S atoms, and may be aromatic, partially saturated, or fully saturated.

The term "optionally substituted" means that, unless indicated otherwise, the moiety so modified may have from one to up to the number of the substituents indicated, provided the resulting substitution is chemically feasible as recognized in the art. Each substituent may replace any H atom on the moiety so modified as long as the replacement is chemically possible and chemically stable. For example, a chemically unstable compound would be one where each of two substituents is bonded to a single C atom through each substituents heteroatom. Another example of a chemically unstable compound would be one where an alkoxy group is bonded to the unsaturated carbon of an alkene to form an enol ether. When there are two or more substituents on any moiety, each substituent is chosen independently of the other substituent so that, accordingly, the substituents can be the same or different.

When the 5-or 6-membered heterocyclic ring is attached to the rest of the molecule as a substituent, it becomes a radical. Examples of 5- or 6-membered heteroaryl ring radicals are furyl, pyrrolyl, thienyl, pyrazolyl, isoxazolyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, and the like. Examples of partially unsaturated 5- or 6-membered heterocyclic ring radicals include dihydropyrano, pyrrolinyl, pyrazolinyl, imidazolinyl, dihydrofuryl, and the like. Examples of saturated 5- or 6- membered heterocyclic ring radicals include pyrrolidinyl, tetrahydropyridyl, piperidinyl, morpholinyl, tetrahydrofuryl, tetrahydrothienyl, piperazinyl, and the like. The point of attachment of the radical may be from any available C or N atom of the ring to the rest of the molecule. When the 5-or 6- membered heterocyclic ring is fused to another ring contained in the rest of the molecule, it forms a bicyclic ring. Examples of such 5-and 6-heterocyclic fused rings include pyrrolo, furo, pyrido, piperido, thieno, and the like. The point of fusion is at any available face of the heterocyclic ring and parent molecule.

As used herein, "subject", as used herein, means a mammalian subject (e.g., dog, cat, horse, cow, sheep, goat, monkey, etc.), and particularly human subjects (including both male and female subjects, and including neonatal, infant, juvenile, adolescent, adult and geriatric subjects, and further including various races and ethnicities including, but not limited to, white, black, Asian, American Indian and Hispanic).

As used herein, "treatment", "treat", and "treating" refer to reversing, alleviating, mitigating or slowing the progression of or inhibiting the progress of a disorder or disease as described herein.

As used herein, "prevention", "prevent", and "preventing" refer to eliminating or reducing the incidence or onset of a disorder or disease as described herein, as compared to that which would occur in the absence of the measure taken.

As used herein "an effective amount" refers to an amount that causes relief of symptoms of a disorder or disease as noted through clinical testing and evaluation, patient observation, and/or the like. An "effective amount" can further designate a dose that causes a detectable change in biological or chemical activity. The detectable changes may be detected and/or further quantified by one skilled in the art for the relevant mechanism or process. Moreover, an "effective amount" can designate an amount that maintains a desired physiological state, i.e., reduces or prevents significant decline and/or promotes improvement in the condition of interest. An "effective amount" can further refer to a therapeutically effective amount.

B. Compounds

The present invention encompasses the compounds of Formula I,

Formula I wherein

R is H or C₁-C₆ alkyl;

R¹ is H, COOH, -C(=O)-OR', C₃-C₈ cycloalkyl, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₁-C₆ alkoxy, wherein R' is C₁-C₆ alkyl, and said alkyl, cycloalkyl, akenyl or alkoxy may be optionally substituted with one or more groups selected from the group consisting of fluoro, methylenedioxyphenyl and phenyl, wherein said methylenedioxyphenyl, or phenyl may be optionally and independently substituted with R⁶;

R² is H, halo, or C₁-C₆ alkyl wherein said alkyl may be optionally substituted with one or more groups selected from the group consisting Of C₁-C₆ alkoxy, oxo and fluoro, or

R² is C_5-14 aryl, C_3-14 heterocycle or C_5-14 heteroaryl, wherein said aryl, heterocycle or heteroaryl may be optionally substituted with one or more R⁶;

R³ is H, C₁-C₆ alkyl, or phenyl, wherein said alkyl or phenyl may be optionally substituted with one or more R⁶;

X is O or S;

R⁴ is C_5-14 aryl, C_3-14 heterocycle or C_5-14 heteroaryl, wherein said aryl, heterocycle or heteroaryl is substituted with one or more R⁷,

R⁵ is H, halo or C₁-C₆ alkyl wherein said alkyl may be optionally substituted with oxo;

R⁶ is halo, CF₃, C₁-C₆ alkyl wherein said alkyl may be optionally substituted with oxo or hydroxy, or C₁-C₆ alkoxy optionally substituted with fluoro;

R⁷ is selected from the group consisting of

(a) hydroxyl,

(b) C₁-C₆ alkoxyl, wherein one or more H of the alkoxyl is ²H (D), and

(c) -O-protecting group; (d) -O-C(=O)-R^U wherein R" is C]-C₆ alkyl or C₅.₁₄ aryl wherein said alkyl or aryl may be optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, -SH, amide, carboxylic acid, CN, C₁-C₆ alkyl, C₁-C₆ thioalkyl, C_{6 H} aryl and C_{5 u} heteroaryl and -NR₀Rj₁ and wherein R₀ and Rj are independently hydrogen, or C₁-C₆ alkyl;

(e) -O-C(=O)-R'", wherein R¹¹¹ is -NR₆R_f and wherein R₆ and R_f are independently hydrogen, or C₁-C₆ alkyl; or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer, diastereomer, enantiomer or racemate thereof.

In some embodiments, the compounds of Formula I is alkali metal salt, basic nitrogen containing group.

In some embodiments, the compounds of Formula I is a meglumine, caclsium, magnesium, ammonium salts, potassium or sodium salt thereof.

In another embodiment, the compound of Formula I has the structure of

As used herein in Formula I, the term "O-protecting group" refers to oxygen containing functional groups such as hydroxyl that are temporarily blocked so that a reaction can be carried out selectively at another reactive site in a multifunctional compound. Protecting groups may be introduced and removed at appropriate stages during the synthesis of a compound using methods that are known to those of ordinary skill in the art. The protecting groups are applied according to standard methods of organic synthesis as described in the literature (Theodora W. Green and Peter G.M. Wuts (2007) Protecting Groups in Organic Synthesis, 4^th edition, John Wiley and Sons, incorporated by reference with respect to protecting groups).

Exemplary oxygen protecting groups include, but are not limited to, methyl ethers, substituted methyl ethers (e.g., MOM (methoxymethyl ether), MTM (methylthiomethyl ether), BOM (benzyloxymethyl ether), PMBM (p-methoxybenzyloxymethyl ether), optionally substituted ethyl ethers, optionally substituted benzyl ethers, silyl ethers (e.g., TMS (trimethylsilyl ether), TES (triethylsilylether), TIPS (triisopropylsilyl ether), TBDMS (t-butyldimethylsilyl ether), tribenzyl silyl ether, TBDPS (?-butyldiphenyl silyl ether), esters (e.g. formate, acetate, benzoate (Bz), trifluoroacetate, dichloroacetate) carbonates, cyclic acetals and ketals. In some embodiments, the -O-protecting group is -0-CH₂-Ph, wherein said phenyl may be optionally substituted with Ci-Ce alkoxyl, (e.g. -4 methoxybenzyl).

In another embodiment, for the compound of Formula I, R₇ is an ester having the structure of -O-C(=O)-R", wherein R" is defined as in Formula I. The ester of "-O-C(=O)-Rⁿ" may be a product of compound of Formula I, wherein R₇ is -OH, reacting with an appropriate carboxylic acid. Any applicable carboxylic acid may be used. In some embodiments, the carboxylic acid may be an amino acid. In another embodiment, the carboxylic acid may be a natural α amino acid.

As used herein, the term "amino acid" refers to a compound comprising a primary amino (- NH₂) group and a carboxylic acid (-COOH) group. The amino acids used in the present invention include naturally occurring and synthetic α, β, γ or δ amino acids, and include, but are not limited to, amino acids found in proteins. Exemplary amino acids include, but are not limited to, glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine and histidine. In some embodiments, the amino acid may be a derivative of alanyl, valinyl, leucinyl, isoleucinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl, argininyl, histidinyl, β-alanyl, β-valinyl, β- leucinyl, β-isoleucinyl, β-prolinyl, β-phenylalaninyl, β-tryptophanyl, β-methioninyl, β-glycinyl, β- serinyl, β-threoninyl, β-cysteinyl, β-tyrosinyl, β-asparaginyl, β-glutaminyl, β-aspartoyl, β-glutaroyl, β- lysinyl, β-argininyl or β-histidinyl. Additionally, as used herein, "amino acids" also include derivatives of amino acids such as esters, and amides, and salts, as well as other derivatives, including derivatives having pharmaco-properties upon metabolism to an active form.

As used herein, the term "natural α amino acid" refers to a naturally occurring α-amino acid comprising a carbon atom bonded to a primary amino (-NH₂) group, a carboxylic acid (-C00H) group, a side chain, and a hydrogen atom. Exemplary natural α amino acids include, but are not limited to, glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophane, proline, serine, threonine, cysteine, tyrosine, asparaginate, glutaminate, aspartate, glutamate, lysine, arginine and histidine.

In one embodiment, for the compound of Formula I, R is H, R is H, R is H, R is CpC 6₁ alkyl, X is O, and R⁴ is a phenyl substituted with one or more R⁷, wherein R⁷ is selected from the group consisting of (a) hydroxyl, (b) Ci-Cβ alkoxyl, and one or more H of the alkoxyl is ²H (D), and (c) -0-CH₂-Ph, wherein said phenyl may be optionally substituted with Ci-C₆ alkoxyl; and R⁵ is H, or a pharmaceutically acceptable salt thereof.

In another embodiment, the compounds have the following structure:

or a pharmaceutically acceptable salt thereof .

In another embodiment, the compound has the following structure:

COOH

or

or a pharmaceutically acceptable salt thereof .

Further, in one embodiment, the compound of Formula I is a meglumine (N-Methyl-d- glucamine), potassium or sodium salt of the following structure

or a pharmaceutically acceptable salt thereof .

In one embodiment, for compounds of Formula I, R² is selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl and morpholinyl, each of which may be optionally substituted with one or more R⁶ as defined herein.

In one embodiment, for compounds of Formula I, R⁴ is selected from the group consisting of phenyl, naphthyl, furyl, thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, tetrahydrothienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, morpholinyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, indazolyl, benzoxazolyl, benxothiazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzodioxolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxazolinyl, dihydrobenzopyranyl, dihydrobenzotliiopyranyl, and 1,4-benzodioxanyl, each of which may be substituted with one or more R⁷ as defined herein.

In one embodiment, for compounds of Formula I, R⁷ is Cj-C₆ alkoxyl, wherein one or more H of the alkoxyl is ²H (D). The deuterated substituted compounds may be used as medical treatment as described below. In addition, the deuterated substituted compounds may also be used as a biomarker for pharmacological study of the compounds. For example, the deuterated compounds may be used to determine the bioavailability and quantification of the compounds by measuring the amount of compounds in serum using mass spectroscopy.

When an alkyl, cycloalkyl, alkenyl, or alkoxy group is described as being substituted with fluoro, it may be substituted with one or more fluorine atoms at any available carbon atom up to the perfluoro level.

When an alkyl substituent is described as being substituted by oxo, it means substitution by a doubly bonded oxygen atom, which forms together with the carbon to which it is attached, a carbonyl group -(C=O)-.

When any moiety is described as being substituted, it can have one or more of the indicated substituents that may be located at any available position on the moiety. When there are two or more substituents on any moiety, each substituent may be defined independently of any other substituent and may, accordingly, be the same or different.

The term "optionally substituted" means that the moiety so modified may be unsubstituted or substituted with the identified substituent(s).

R³ may be attached to the heterocyclic moiety of the compound of Formula I at either the 4 or 5 position (i.e., at either available carbon atom) and, accordingly, the remaining portion of the molecule will be attached at the remaining available carbon atom.

Examples of the compounds of Formula I, which are illustrative of the present invention, but not limiting in any way, include the following:

or a pharmaceutically acceptable salt thereof .

A salt of a compound of Formula I may be prepared in situ during the final isolation and purification of a compound or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Likewise, when the compound of Formula I contains a carboxylic acid moiety, (e.g., R = H), a salt of said compound of Formula I may be prepared by separately reacting it with a suitable inorganic or organic base and isolating the salt thus formed. The term "pharmaceutically acceptable salt" refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention (see, e.g., Berge et al., J. Pharm. Sci. 66:1-19, 1977).

Representative salts of the compounds of Formula I include the conventional non-toxic salts and the quaternary ammonium salts which are formed, for example, from inorganic or organic acids or bases by means well known in the art. For example, such acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Base salts include, for example, alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine. Additionally, basic nitrogen containing groups in the conjugate base may be quatemized with alkyl halides, e.g., C_1-9 alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, C₁₀^o alkyl halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides; or aralkyl halides like benzyl and phenethyl bromides. In some embodiments, the salts are alkali salt such as sodium or potassium salt or an adduct with an acceptable nitrogen base such as meglumine (N-Methyl-d-glucamine) salt.

The esters of Formula I in the present invention are non-toxic, pharmaceutically acceptable esters, for example, alkyl esters such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or pentyl esters. Additional esters such as, for example, methyl ester or phenyl-C_rC₅ alkyl may be used. The compound of Formula I may be esterifϊed by a variety of conventional procedures including reacting the appropriate anhydride, carboxylic acid, or acid chloride with the alcohol group of the Formula I compound. The appropriate anhydride may be reacted with the alcohol in the presence of a base to facilitate acylation such as 1, 8-bis[dimethylamino]naphthalene or N,N-dimethylaminopyridine. An appropriate carboxylic acid may be reacted with the alcohol in the presence of a dehydrating agent such as dicyclohexylcarbodiimide, l-[3-dimethylaminopropyl]-3-ethylcarbodiimide, or other water soluble dehydrating agents which are used to drive the reaction by the removal of water, and optionally, an acylation catalyst. Esterification may also be effected using the appropriate carboxylic acid in the presence of trifluoroacetic anhydride and optionally, pyridine, or in the presence of N, N- carbonyldiimidazole with pyridine. Reaction of an acid chloride with the alcohol may be carried out with an acylation catalyst such as 4-DMAP or pyridine.

One skilled in the art would readily know how to successfully carry out these as well as other methods of esterification of alcohols.

Additionally, sensitive or reactive groups on the compound of Formula I may need to be protected and deprotected during any of the above methods for forming esters. Protecting groups in general may be added and removed by conventional methods well known in the art (see, e.g., T. W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis; Wiley: New York, (1999)).

The compounds of Formula I may contain one or more asymmetric centers, depending upon the location and nature of the various substituents desired. Asymmetric carbon atoms may be present in the (R) or (S) configuration. Preferred isomers are those with the absolute configuration which produces the compound of Formula I with the more desirable biological activity, hi certain instances, asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two aromatic rings of the specified compounds. Substituents on a ring may also be present in either cis or trans form, and a substituent on a double bond may be present in either Z or E form.

It is intended that all isomers (including enantiomers and diastereomers), either by nature of asymmetric centers or by restricted rotation as described above, as separated, pure or partially purified isomers or racemic mixtures thereof, be included within the scope of the instant invention. The purification of said isomers and the separation of said isomeric mixtures may be accomplished by standard techniques known in the art.

C. Synthesis

The particular process to be utilized in the preparation of the compounds of this invention depends upon the specific compound desired. Such factors as the selection of the specific X moiety, and the specific substituents possible at various sites on the molecule, all play a role in the path to be followed in the preparation of the specific compounds of this invention. Those factors are readily recognized by one of ordinary skill in the art.

In general, the compounds of the present invention may be prepared by standard techniques known in the art and by known processes analogous thereto. Exemplary synthetic methods are shown in the General Reaction Scheme. The compounds of Formula A (Formula I, wherein R^4a is Cs_-H aryl, and said aryl is substituted with C^₆ alkoxyl or -O-protecting group) may be prepared according to methods described in the literature with modifications known to those skilled in the art. For example, the compound of Formula A may be prepared according to methods described in U.S. Patent No. 6,828,335 with modifications known to those skilled in the art.

The compounds of Formula A may first undergo dealkylation or deprotection to provide the compound of Formula B. Subsequently, the compound of Formula B may react with an appropriate acid to provide an ester of Formula C. The compound of Formula B may also react with an appropriate reagent to provide compounds of Formula D, wherein R^4d is an -O-protecting group. For example, Formula B may undergo an alkylation to provide a compound of Formula D, wherein R⁴ is Cj-C₆ alkoxyl optionally with one or more H of the alkoxyl is D. Alternatively, the compound of Formula B may be subjected to other appropriate reaction conditions to provide other analogues. For example, the compound of Formula B may react with a compound containing an isocyanate group to provide a carbamate analogue of a compound of Formula B, as shown in General Reaction Scheme.

Compounds of Formula I, wherein R⁴ is CpC₆ alkoxyl and one or more H of the alkoxyl is ²H (D) may be prepared according to methods known to those skilled in the art. For example, they may be prepared by using an appropriate deuterated starting material or deuterated intermediates according to methods described herein, e.g., Example 5. General Reaction Scheme

R⁴¹ is C₅ ^

aryl substituted with -OH

E

E g -0-C(=0)-R"' as defined in Claim 1

Another aspect of the present invention provides processes of preparing a compound of Formula Ia including dealkylation of a compound of Formula B to give a compound of Formula Ia

Foimula B

Formula Ia wherein for Formula B and Formula Ia

R is H or C₁-C₆ alkyl;

R¹ is H, COOH, -Q=O)-OR', C₃-C₈ cycloalkyl, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₁-C₆ alkoxy, wherein R' is C₁-C₆ alkyl, and said alkyl, cycloalkyl, akenyl or alkoxy may be optionally substituted with one or more groups selected from the group consisting of fluoro, methylenedioxyphenyl and phenyl, wherein said methylenedioxyphenyl, or phenyl may be optionally substituted with R⁶;

R is H, halo, or C₁-C₆ alkyl wherein said alkyl may be optionally substituted with one or more groups selected from the group consisting Of C₁-C₆ alkoxy, oxo and fluoro, or

R² is C_S-C_H aryl, C₃-C^ heterocycle or C₅-C_H heteroaryl, wherein said aryl, heterocycle and heteroaryl may be optionally and independently substituted with one or more R⁶;

R³ is H, C₁-C₆ alkyl, or phenyl, wherein said alkyl or phenyl may be optionally and independently substituted with one ore more R⁶;

X is O or S;

R^a C₁-C₆ alkoxyl,

R⁵ is H, halo or C₁-C₆ alkyl wherein said alkyl optionally substituted with oxo; and

R⁶ is halo, CF₃, C₁-C₆ alkyl optionally substituted with oxo or hydroxy, or C₁-C₆ alkoxy optionally substituted with fluoro.

According to another aspect of the present invention, processes of making compound B are provided. The processes include dealkylation of compound A

to give compound B COOR^C

B

wherein said R^c is hydrogen or C₁-C₆ alkyl.

In some embodiments, in the process of preparing compound B, the dealkylation is carried out by treating compound A with boron tribromide (BBr₃) in a solvent such as a halogenated solvent, for example, methylene chloride (CH₂Cl₂), carbon tetrachloride (CCI₄), chloroform (CHCl₃), 1,1,1- trichloroethane (methyl chloroform, CH3-CC1), tthylene dibromide (1,2-dibromoethane, BrCH₂- CH₂Br), methylene chlorobromide (bromochloromethane, CH₂BrCl), methyl bromine (bromomethane, CH₂Br), etc.

Alternatively, the dealkylation may be carried out by treating compound A with aluminum chloride in dodecyl thiol in a solvent.

In one embodiment, when compound A is an ester, R° is Ci-C₆ alkyl. The process further includes hydrolysis of compound B to give a compound of the following structure:

Li some embodiments, in the process of making compound B, compound A has the structure of COOH

and compound B has the structure of COOH

In another embodiment, in the process of making compound B, compound A has the structure of

and compound B has the structure of

Further, one aspect of the present invention provides processes of making compound D. The processes include cleaving the ether bond of 0-CH₂Ph of compound C.

to provide compound D.

D

wherein R^c is hydrogen or Ci.Cβ alkyl.

In some embodiments, the cleaving step is carried out by hydrogenolysis. The hydrogenolysis may be carried out by any known methods that may cleave the ether bond of 0-CHaPh to provide compound D. For example, hydrogenolysis may be carried out by treating compound C with a catalyst and hydrogen (H₂) gas. Exemplary catalysts include, but are not limited to, palladium (Pd) on carbon, platinum oxide, Raney nickel or a combination thereof,

In one embodiment, the cleaving step is carried out by treating compound C with boron tribromide or boron trichloride.

Further, in one embodiment, the cleaving step is carried out by treating compound C with trimethylsilyl iodide. In one embodiment, in the process of making compound D, for compound C, when R^c is Ci. C₆ alkyl, the processes further include hydrolysis of compound D to give a compound of the following structure

In some embodiments, for the process of making compound D, compound C has the structure of

and compound D has the structure of COOH

In another embodiment, for the process of making compounds D, compound C has the structure of

and compound D has the structure of

D. Evaluation of biological activity of compounds Demonstration of the activity of the compounds of the present invention may be accomplished through in vitro, ex vivo, and in vivo assays that are well known in the art.

1. Diabetes and related diseases and disorders

For example, to demonstrate the efficacy of a pharmaceutical agent for the treatment of diabetes and related disorders such as Syndrome X, impaired glucose tolerance, impaired fasting glucose, and hyperinsulinemia or atherosclerotic disease and related disorders such as hypertriglyceridemia and hypercholesteremia, the following assays may be used.

A. Insulin Receptor Binding in 3T3-L1 Cells Treated with Compounds

3T3-L1 cells are seeded at 9300 cells per well in Costar flat bottom TC and incubated for 1 week until they are 2 days post-confluent (e.g., cells have reached maximum density). The cells are then treated for 2 days with differentiation media (Dulbecco's Modified Eagle Medium (DMEM), 100 μg/ml Penicillin/Streptomycin, 2 mM L-Glutamine, 10% Fetal Bovine Serum) containing 0.5 μM human Insulin-like Growth Factor (IGF-I) and test compounds. After treatment, the media is replaced with differentiation media, and the cells are incubated for 4 days. The cells are then assayed for insulin receptor activity. After washing the cells with buffer, they are incubated with 0.1 iiM ¹²⁵I- insulin and (+/-) 100 nM unlabeled insulin, and incubated at rt for 1 hour. The cells are then washed 3x with buffer, dissolved with IN NaOH, and counted on a gamma counter. An EC50 value is determined if a plateau is attained and percent maximum stimulation is assessed.

B. In Vivo Assays

(1). Method for Measuring Blood Glucose Levels db/db mice (obtained from Jackson Laboratories, Bar Harbor, ME) are bled (by either eye or tail vein) and grouped according to equivalent mean blood glucose levels. They are dosed orally (by gavage in a pharmaceutically acceptable vehicle) with the test compound once daily for 14 days. At this point, the animals are bled again by eye or tail vein and blood glucose levels were determined. In each case, glucose levels are measured with a Glucometer Elite XL (Bayer Corporation, Elkhart, IN).

(2). Method for Measuring Triglyceride Levels hApoAl mice (obtained from Jackson Laboratories, Bar Harbor, ME) are bled (by either eye or tail vein) and grouped according to equivalent mean serum triglyceride levels. They are dosed orally (by gavage in a pharmaceutically acceptable vehicle) with the test compound once daily for 8 days. The animals are then bled again by eye or tail vein, and serum triglyceride levels are determined. In each case, triglyceride levels are measured using a Technicon Axon Autoanalyzer

(Bayer Corporation, Tarrytown, NY). (3). Method for Measuring HDL-Cholesterol Levels

To determine plasma HDL-cholesterol levels, hApoAl mice are bled and grouped with equivalent mean plasma HDL-cholesterol levels. The mice are orally dosed once daily with vehicle or test compound for 7 days, and then bled again on day 8. Plasma is analyzed for HDL-cholesterol using the Synchron Clinical System (CX4) (Beckman Coulter, Fullerton, CA).

(4). Method for Measuring Total Cholesterol, HDL-Cholesterol, Triglycerides, and Glucose Levels

In another in vivo assay, obese monkeys are bled, then orally dosed once daily with vehicle or test compound for 4 weeks, and then bled again. Serum is analyzed for total cholesterol, HDL- cholesterol, triglycerides, and glucose using the Synchron Clinical System (CX4) (Beckman Coulter, Fullerton, CA). Lipoprotein subclass analysis is performed by NMR spectroscopy as described by Oliver et al, (Proc. Natl. Acad. Sci. USA 98:5306-5311, 2001).

(5). Method for Measuring an Effect on Cardiovascular Parameters

Cardiovascular parameters (e.g., heart rate and blood pressure) are also evaluated. SHR rats are orally dosed once daily with vehicle or test compound for 2 weeks. Blood pressure and heart rate are determined using a tail-cuff method as described by Grinsell et al., (Am. J. Hypertens. 13:370- 375, 2000). In monkeys, blood pressure and heart rate are monitored as described by Shen et al., (J. Pharmacol. Exp. Therap. 278: 1435-1443, 1996).

2 Psoriasis, Alzheimer's disease

Some recent research indicates that agonists of the peroxisome proliferator-activated receptor (PPAR) may be used as a potential treatment for psoriasis (See Romanowska, PPARd Enhances Keratinocyte Proliferation in Psoriasis and Induces Heparin-Binding EGF-Like, Growth Factor, J Investigative Dermatology, 128, 110-124, (2008); Ellis, Troglitazone Improves Psoriasis and Normalizes Models of Proliferative Skin Disease, Arch Dermatology, 136, 609-616 (2000), and Bongartz, Rheumatology, V 44, 2004, p. 126). It is also indicated that PPAR agonists may be used to treat Alzheimer's disease. (See Escribano et al., Rosiglitazone reverses memory decline and hippocampal glucocorticoid receptor down-regulation in an Alzheimer's disease mouse model, Biochemical and Biophysical Research Communications, 379, 406-410(2009)).

PPAR receptor agonist activity may be determined by conventional screening methods known to those skilled in the art. For example, methods described in U.S. Patent Application Publication No. 2007/0054907, 2008/0262047 and U.S. Patent No. 7,314,879, which are incorporated by reference in their entireties. Exemplary screening tests are described below: A. Binding Assay

Compounds may be tested for their ability to bind to hPPAR gamma, hPPAR alpha or hPPAR delta using a Scintillation Proximity Assay (SPA). The PPAR ligand binding domain (LBD) may be expressed in E. coli as polyHis tagged fusion proteins and purified. The LBD may then be labelled with biotin and immobilized on streptavidin-modified scintillation proximity beads. The beads may then be incubated with a constant amount of the appropriate radioligand (5-{4-[2-(Methyl-pyridin-2- yl-amino)-ethoxy]-benzyl}-thiazolidine-2,4-dio-ne (J. Med. Chem. 1994, 37(23), 3977), for PPAR gamma), and labelled GW 2433 (see Brown, P. J et al. Chem. Biol. 1997 4: 909-918), for the structure and synthesis of this ligand) for PPAR alpha and PPAR delta) and variable concentrations of test compound, and after equilibration the radioactivity bound to the beads may be measured by a scintillation counter. The amount of nonspecific binding, as assessed by control wells containing 50 μM of the corresponding unlabeled ligand, is subtracted from each data point. For each compound tested, plots of ligand concentration vs. CPM of radioligand bound may be constructed and apparent Ki values are estimated from nonlinear least squares fit of the data assuming simple competitive binding. The details of this assay have been reported elsewhere (see, Blanchard, S. G. et. al. Anal. Biochem., 257 112-119 (1998)).

B. Functional Assays

(a) Functional cell based assays are developed to discriminate agonists and antagonists.

Agonist Assay: HEK 293 cells stably expressing a human melanocortin receptor (see e.g., Yang, et al., Mol-Endocrinol., 11(3): 274-80, 1997) are dissociated from tissue culture flasks using a trypsin/EDTA solution (0.25%; Life Technologies, Rockville, Md.). Cells are collected by centrifugation and resuspended in DMEM (Life Technologies, Rockville, Md.) supplemented with 1% L-glutamine and 0.5% fetal bovine serum. Cells are counted and diluted to 4.5 x l0⁵/ml.

A compound of present invention is diluted in dimethylsulfoxide (DMSO) (3xlO^"5 to 3 ^χ lθ^'10 M final concentrations) and 0.05 volume of compound solution is added to 0.95 volumes of cell suspension; the final DMSO concentration is 0.5%. After incubation at 37⁰C /5% CO₂ for 5 hours, cells are lysed by addition of luciferin solution (50 niM Tris, 1 inM MgCl₂, 0.2% Triton-XIOO, 5 niM DTT, 500 micromolar Coenzyme A, 150 micromolar ATP, and 440 micromolar luciferin) to quantify the activity of the reporter gene luciferase, an indirect measurement of intracellular cAMP production.

Luciferase activity is measured from the cell lysate using a Wallac Victor 2 luminometer. The amount of lumen production which results from a compound of present invention is compared to that amount of lumens produced in response to NDP-alpha-MSH, defined as a 100% agonist, to obtain the relative efficacy of a compound. The EC₅₀ is defined as the compound concentration that results in half maximal stimulation, when compared to its own maximal level of stimulation. (b) Melanocortin Receptor Whole Cell cAMP Accumulation Assay Compound preparation: In the agonist assay, compounds are prepared as 10 mM and NDP-aMSH (control) as 33.3 μM stock solutions in 100% DMSO. These are serially diluted in 100% DMSO. The compound plate is further diluted 1:200 in compound dilution buffer (HBSS-092, 1 mM Ascorbic Acid, 1 mM IBMX, 0.6% DMSO, 0.1% BSA). The final concentration range being 10 μM-100 pM for compound and 33.33 nM-0.3 pM for control in 0.5% DMSO. Transfer 20 μl from this plate into four PET 96-well plates (all assays are performed in duplicate for each receptor).

(c) Cell Culture and Cell Stimulation:

HEK 293 cells stably transfected with the MC3R and MC4R are grown in DMEM containing 10% FBS and 1% Antibiotic/Antimycotic Solution. On the day of the assay the cells are dislodged with enzyme free cell dissociation solution and resuspended in cell buffer (HBSS-092, 0.1% BSA, 10 mM HEPES) at I x e6 cells/ml. Add 40 μl of cells/well to the PET 96-well plates containing 20 ul diluted compound and control. Incubate @ 37 ⁰C in a water bath for 20 minutes. Stop the assay by adding 50 μl Quench Buffer (50 mM Na Acetate, 0.25% Triton X-100).

C. Radioligand Binding Assays

Radioligand binding assays are run in SPA buffer (50 mM Sodium Acetate, 0.1% BSA). The beads, antibody and radioligand are diluted in SPA buffer to provide sufficient volume for each 96- well plate. To each quenched assay well is added 100 ul cocktail containing 33.33 μl of beads, 33.33 μl antibody and 33.33 μl ¹²⁵ I-cAMP. This is based on a final concentration of 6.3 mg/ml beads, 0.65% anti-goat antibody and 61 pM of ¹²⁵ I-cAMP (containing 25000-30000 CPM) in a final assay volume of 210 μl. The plates are counted in a Wallac MicroBeta counter after a 12-hour incubation.

The data is converted to pmoles cAMP using a standard curve assayed under the same conditions. The data is analyzed using Activity Base software to generate agonist potencies (EC₅o) and percent relative efficacy data to NDP-aMSH.

D. Transfection Assay

Compounds may be screened for functional potency in transient transfection assays in CV-I cells for their ability to activate the PPAR subtypes (transactivation assay). A previously established chimeric receptor system may be utilized to allow comparison of the relative transcriptional activity of the receptor subtypes on the same target gene and to prevent endogenous receptor activation from complicating the interpretation of results. See, for example, Lehmann, J. M et al J. Biol. Chem., 1995 270: 12953-6. The ligand binding domains for murine and human PPAR alpha, PPAR gamma and PPAR delta are each fused to the yeast transcription factor GAL4 DNA binding domain. CV-I cells are transiently transfected with expression vectors for the respective PPAR chimera along with a reporter construct containing five copies of the GAL4 DNA binding site driving expression of secreted placental alkaline phosphatase (SPAP) and beta-galactosidase. After 16 h, the medium are exchanged to DME medium supplemented with 10% delipidated fetal calf serum and the test compound at the appropriate concentration. After an additional 24 h, cell extracts are prepared and assayed for alkaline phosphatase and beta-galactosidase activity. Alkaline phosphatase activity is corrected for transfection efficiency using the beta-galactosidase activity as an internal standard (see, for example, Kliewer, S. A., et. al. Cell 1995 83: 813-819). Rosiglitazone (BRL 49653) may be used as a positive control in the hPPAR gamma assay. The positive control in the hPPAR alpha assays may be 2-4-[2-(3-[4-fluorophenyl]-l-heptylureido)ethyl]-phenoxy-(2-methyl propionic acid (WO 97/36579). The positive control for PPAR delta assays may be 2-{2-methyl-4-[({4-methyl-2- {trifluoromethyl)phenyl]-l,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic acid (WO 01/00603). An EC50 may be determined as the concentration at which a compound achieves 50% activation relative to the appropriate positive control.

An "agonist" will typically have a pKi of at least 6.0 preferably at least 7.0 to the relevant PPAR in the Binding Assay described above, and achieves at least 50% activation of the relevant PPAR relative to the appropriate indicated positive control in the Transfection Assay described above at concentrations of 10^{"5 M} or less.

E. Animal Model

(1) Alzheimer's disease

The compounds described in the present invention may be tested in any animal model known to those skilled in the art. Exemplary animal models include, but are not limited to, transgenic mouse models of Alzheimer's disease; aged rats; rats with induced damage to the entorhinal cortex; aged rhesus monkeys, and monkeys with entorhinal cortex damage.

For each model, the test result is compared with a control group that is not treated with the compounds described in the present invention. The treated animals are expected to demonstrate significant improvement in the performance of a variety of learning and memory tests. For example, it is expected to observe that the brains of the treated animals also exhibit enhanced cell size, improved cell signaling, and/or activation of function in neurons that would otherwise have degenerated, compared to untreated animals. These benefits may extend to the degenerating hippocampus where short-term memory is processed, one of the first regions of the brain to suffer damage in Alzheimer's disease.

(2) Psoriasis

Any animal model known to those skilled in the art may be used in the present invention. Exemplary animal model include, but are not limited to, human psoriatic skin-severe combined immunodeficient (SCID) mouse transplant model and AGR₁₂₉ mice model. An exemplary SCID mouse model is described below.

Skin transplanted to SCID mice from normal human volunteers or from psoriatic lesional skin is allowed to heal for 3 to 5 weeks before application of compounds of the present invention. During this period, psoriatic skin, which is about 3- 4 fold thicker than the corresponding normal skin before transplantation, maintains its phenotype (ie, increased epidermal thickness, rete ridges with blunted ends, and intralesional presence of T lymphocytes). Transplanted normal human skin, however, undergoes a hyperplastic response during this period, resulting in about 2-3 fold increase in epidermal thickness. After the healing period, animals transplanted with normal or psoriatic skin are treated for 14 days by an appropriate application of compounds described in the present invention such as topical application or injection. At the end of the treatment period, the mice are sacrificed and the tissue is evaluated morphometrically for changes in epidermal thickness and immunohistologically for the presence of T lymphocytes for psoriatic lesional skin and normal skin.

E. Pharmaceutical compositions

According to another aspect of the present invention, pharmaceutical compositions of compounds described herein are provided. In some embodiments, the pharmaceutical compositions further include a pharmaceutically acceptable carrier.

In some embodiments, the pharmaceutical compositions described herein may further include one or more additional therapeutic agents. hi one embodiment, the additional therapeutic agents are used to treat or prevent Alzheimer's disease. Exemplary additional therapeutic agents include, but are not limited to cholinesterase inhibitors (for example tacrine, galantamine, rivastigamine or donepezil) and NMDA inhibitors (for example memantine). The compounds described herein may be administered in combination with one or more further medicaments of use for the treatment or prevention of other dementias. Other further medicaments include non-steroidal anti-inflammatory drugs (NSAIDs) such as such as naproxen, ibuprofen, diclofenac, indomethacin, nabumetone, piroxicam, celecoxib and aspirin. Other medicaments that may be combined with compounds described herein include HMG-CoA reductase inhibitors such as statins (eg simvastatin (Zocor), atovastatin (Lipitor), rosuvastatin (Crestor), fluvastatin (Lescol)).

In some embodiments, the additional therapeutic agents are used to treat or prevent other diseases. Exemplary additional therapeutical agents include, but are not limited to, an antioxidant, an anti- inflammatory, a gamma secretase inhibitor, a neurotrophic agent, an acetyl cholinesterase inhibitor, a statin, an A beta peptide, and an anti-A beta peptide. Yet, in a different embodiment, exemplary additional therapeutic agents includes, but are not limited to, corticoid; a vitamin D analog; methrotrexate; ciclosporin; a fumarate; adalimunag; alefecept; afalizumab; etanercept; infliximab; a steroid, a retinoid; an antimicrobial compound; an antioxidant; an anti-inflammatory compound; salicylic acid; an endothelin antagonist; an immunomodulating agent; an angiogenesis inhibitor; a inhibitor of FGF, VEGF, HGF or EGF; an inhibitor of an EGF, FGF, VEGF, or HGF receptor; a tyrosine kinase inhibitor; a protein kinase C inhibitor; and a combination thereof.

Based on the above tests, or other well known assays used to determine the efficacy for treatment of conditions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, the effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication. The amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.

The total amount of the active ingredient to be administered may generally range from about 0.001 mg/kg to about 200 mg/kg, and preferably from about 0.01 mg/kg to about 200 mg/kg body weight per day. A unit dosage may contain from about 0.05 mg to about 1500 mg of active ingredient, and may be administered one or more times per day. The daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous, and parenteral injections, and use of infusion techniques may be from about 0.01 to about 200 mg/kg. The daily rectal dosage regimen may be from 0.01 to 200 mg/kg of total body weight. The transdermal concentration may be that required to maintain a daily dose of from 0.01 to 200 mg/kg.

Of course, the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age of the patient, the diet of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt thereof may be ascertained by those skilled in the art using conventional treatment tests.

The compounds of this invention may be utilized to achieve the desired pharmacological effect by administration to a patient in need thereof in an appropriately formulated pharmaceutical composition. A patient, for the purpose of this invention, is a mammal, including a human, in need of treatment for a particular condition or disease. Therefore, the present invention includes pharmaceutical compositions which are comprised of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound identified by the methods described herein, or a pharmaceutically acceptable salt or ester thereof. A pharmaceutically acceptable carrier is any carrier which is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient. A pharmaceutically effective amount of a compound is that amount which produces a result or exerts an influence on the particular condition being treated. The compounds identified by the methods described herein may be administered with a pharmaceutically-acceptable carrier using any effective conventional dosage unit forms, including, for example, immediate and timed release preparations, orally, parenterally, topically, or the like.

For oral administration, the compounds may be formulated into solid or liquid preparations such as, for example, capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions. The solid unit dosage forms may be a capsule which can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch.

In another embodiment, the compounds of this invention may be tableted with conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders such as acacia, cornstarch, or gelatin; disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum; lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example, talc, stearic acid, or magnesium, calcium or zinc stearate; dyes; coloring agents; and flavoring agents intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient. Suitable excipients for use in oral liquid dosage forms include diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance tablets, pills or capsules may be coated with shellac, sugar or both.

Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, those sweetening, flavoring and coloring agents described above, may also be present.

The pharmaceutical compositions of this invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils. Suitable emulsifying agents may be (1) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as soy bean and lecithin, (3) esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monooleate, and (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents. Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as, for example, arachis oil, olive oil, sesame oil, or coconut oil; or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent such as, for example, beeswax, hard paraffin, or cetyl alcohol. The suspensions may also contain one or more preservatives, for example, ethyl or /7-propyl p-hydroxybenzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.

Syrups and elixirs may be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain a demulcent, and preservative, flavoring and coloring agents.

The compounds of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intramuscularly, or interperitoneally, as injectable dosages of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which may be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions; an alcohol such as ethanol, isopropanol, or hexadecyl alcohol; glycols such as propylene glycol or polyethylene glycol; glycerol ketals such as 2,2-dimethyl-l,l-dioxolane-4-methanol, ethers such as poly(ethyleneglycol) 400; an oil; a fatty acid; a fatty acid ester or glyceride; or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant such as a soap or a detergent, suspending agent such as pectin, carbomers, methycellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agent and other pharmaceutical adjuvants.

Illustrative of oils which can be used in the parenteral formulations of this invention are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum, and mineral oil. Suitable fatty acids include oleic acid, stearic acid, and isostearic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps include fatty alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example, dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates; nonionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylenepolypropylene copolymers; and amphoteric detergents, for example, alkyl-beta- aminopropionates, and 2-alkylimidazoline quarternary ammonium salts, as well as mixtures.

The parenteral compositions of this invention may typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be used advantageously. In order to minimize or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulation ranges from about 5% to about 15% by weight. The surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.

Illustrative of surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.

The pharmaceutical compositions may be in the form of sterile injectable aqueous suspensions. Such suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadecaethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived form a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, for example polyoxyethylene sorbitan monooleate.

The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Diluents and solvents that may be employed are, for example, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as solvents or suspending media. For this purpose, any bland, fixed oil may be employed including synthetic mono or diglycerides. Li addition, fatty acids such as oleic acid may be used in the preparation of injectables.

A composition of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions may be prepared by mixing the drug with a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are, for example, cocoa butter and polyethylene glycol.

Another formulation employed in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art {see, e.g., U.S. Patent No. 5,023,252, incorporated herein by reference). Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

It may be desirable or necessary to introduce the pharmaceutical composition to the patient via a mechanical delivery device. The construction and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art. For example, direct techniques for administering a drug directly to the brain usually involve placement of a drug delivery catheter into the patient's ventricular system to bypass the blood-brain barrier, One such implantable delivery system, used for the transport of agents to specific anatomical regions of the body, is described in U.S. Patent No. 5,011,472, incorporated herein by reference.

The compositions of the invention may also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired. Any of the compositions of this invention may be preserved by the addition of an antioxidant such as ascorbic acid or by other suitable preservatives. Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized.

Commonly used pharmaceutical ingredients which may be used as appropriate to formulate the composition for its intended route of administration include: acidifying agents, for example, but are not limited to, acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid; and alkalinizing agents such as, but are not limited to, ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine.

Other pharmaceutical ingredients include, for example, but are not limited to, adsorbents (e.g., powdered cellulose and activated charcoal); aerosol propellants (e.g., carbon dioxide, CCl₂F₂, F₂ClC- CClF₂ and CClF₃); air displacement agents (e.g., nitrogen and argon); antifungal preservatives (e.g., benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate); antimicrobial preservatives (e.g., benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal); antioxidants (e.g., ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite); binding materials (e.g., block polymers, natural and synthetic rubber, polyacrylates, polyurethanes, silicones and styrene-butadiene copolymers); buffering agents (e.g., potassium metaphosphate, potassium phosphate monobasic, sodium acetate, sodium citrate anhydrous and sodium citrate dihydrate); carrying agents (e.g., acacia syrup, aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, syrup, com oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection and bacteriostatic water for injection); chelating agents (e.g., edetate disodium and edetic acid); colorants (e.g., FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel and ferric oxide red); clarifying agents (e.g., bentonite); emulsifying agents (but are not limited to, acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyethylene 50 stearate); encapsulating agents (e.g., gelatin and cellulose acetate phthalate); flavorants (e.g., anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin); humectants (e.g., glycerin, propylene glycol and sorbitol); levigating agents (e.g., mineral oil and glycerin); oils (e.g., arachis oil, mineral oil, olive oil, peanut oil, sesame oil and vegetable oil); ointment bases (e.g., lanolin, hydrophilic ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment, and rose water ointment); penetration enhancers (transdermal delivery) (e.g., monohydroxy or polyhydroxy alcohols, saturated or unsaturated fatty alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl derivatives, cephalin, terpenes, amides, ethers, ketones and ureas); plasticizers (e.g., diethyl phthalate and glycerin); solvents (e.g., alcohol, corn oil, cottonseed oil, glycerin, isopropyl alcohol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection and sterile water for irrigation); stiffening agents (e.g., cetyl alcohol, cetyl esters wax, microcrystalline wax, paraffin, steaiyl alcohol, white wax and yellow wax); suppository bases (e.g., cocoa butter and polyethylene glycols (mixtures)); surfactants (e.g., benzalkonium chloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium lauryl sulfate and sorbitan monopalmitate); suspending agents (e.g., agar, bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, kaolin, methylcellulose, tragacanth and veegum); sweetening e.g., aspartame, dextrose, glycerin, mannitol, propylene glycol, saccharin sodium, sorbitol and sucrose); tablet anti-adherents (e.g., magnesium stearate and talc); tablet binders (e.g., acacia, alginic acid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, povidone and pregelatinized starch); tablet and capsule diluents (e.g., dibasic calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol and starch); tablet coating agents (e.g., liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, cellulose acetate phthalate and shellac); tablet direct compression excipients (e.g., dibasic calcium phosphate); tablet disintegrants (e.g., alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrillin potassium, sodium alginate, sodium starch glycollate and starch); tablet glidants (e.g., colloidal silica, corn starch and talc); tablet lubricants (e.g., calcium stearate, magnesium stearate, mineral oil, stearic acid and zinc stearate); tablet/capsule opaquants (e.g., titanium dioxide); tablet polishing agents (e.g., carnuba wax and white wax); thickening agents (e.g., beeswax, cetyl alcohol and paraffin); tonicity agents (e.g., dextrose and sodium chloride); viscosity increasing agents (e.g., alginic acid, bentonite, carbomers, carboxymethylcellulose sodium, methylcellulose, povidone, sodium alginate and tragacanth); and wetting agents (e.g., heptadecaethylene oxycetanol, lecithins, polyethylene sorbitol monooleate, polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).

The compounds identified by the methods described herein may be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects. For example, the compounds of this invention can be combined with known anti-obesity, or with known antidiabetic or other indication agents, and the like, as well as with admixtures and combinations thereof.

The compounds identified by the methods described herein may also be utilized, in free base form or in compositions, in research and diagnostics, or as analytical reference standards, and the like. Therefore, the present invention includes compositions which are comprised of an inert carrier and an effective amount of a compound identified by the methods described herein, or a salt or ester thereof. An inert carrier is any material which does not interact with the compound to be carried and which lends support, means of conveyance, bulk, traceable material, and the like to the compound to be carried. An effective amount of compound is that amount which produces a result or exerts an influence on the particular procedure being performed.

Formulations suitable for subcutaneous, intravenous, intramuscular, and the like; suitable pharmaceutical carriers; and techniques for formulation and administration may be prepared by any of the methods well known in the art {see, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 20^th edition, 2000)

The following examples are presented to illustrate the invention described herein, but should not be construed as limiting the scope of the invention in any way.

Capsule Formulation

A capsule formula is prepared from: Compound of this invention 40 mg

Starch 109 mg

Magnesium stearate 1 mg

The components are blended, passed through an appropriate mesh sieve, and filled into hard gelatin capsules.

Tablet Formulation

A tablet is prepared from:

Compound of this invention 25 mg

Cellulose, microcrystaline 200 mg

Colloidal silicon dioxide 10 mg

Stearic acid 5.0 mg The ingredients are mixed and compressed to form tablets. Appropriate aqueous and non-aqueous coatings may be applied to increase palatability, improve elegance and stability or delay absorption.

Sterile IV Solution

A 5 mg/ml solution of the desired compound of this invention is made using sterile, injectable water, and the pH is adjusted if necessary. The solution is diluted for administration to 1-2 mg/ml with sterile 5% dextrose and is administered as an IV infusion over 60 minutes.

Intramuscular suspension

The following intramuscular suspension is prepared:

Compound of this invention 50 mg/ml

Sodium carboxymethylcellulose 5 mg/ml

TWEEN 80 4 mg/ml

Sodium chloride 9 mg/ml

Benzyl alcohol 9 mg/ml

The suspension is administered intramuscularly.

Hard Shell Capsules

A large number of unit capsules are prepared by filling standard two-piece hard galantine capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed and dried. The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix.

Immediate Release Tablets/Capsules

These are solid oral dosage forms made by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the medication. The active ingredient is mixed in a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques. The drug compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water.

F. Methods of treatment

(1) Diabetes and related diseases and disorders

The compounds of Formula I are effective in the treatment of Type II diabetes mellitus (including associated diabetic dyslipidemia and other diabetic complications), as well as for a number of other pharmaceutical uses associated therewith, such as hyperglycemia, hyperinsulinemia, impaired glucose tolerance, impaired fasting glucose, dyslipidemia, hypertriglyceridemia, Syndrome X, and insulin resistance, hi addition, the compounds of the present invention are also effective in the regulation of appetite and food intake in such disorders as obesity, and in the treatment of atherosclerotic disease, hyperlipidemia, hypercholesteremia, low HDL levels, hypertension, cardiovascular disease (including atherosclerosis, coronary heart disease, coronary artery disease, and hypertension), cerebrovascular disease and peripheral vessel disease; and for the treatment of lupus, polycystic ovary syndrome, carcinogenesis, and hyperplasia. The compounds of Formula I are also useful for treating physiological disorders related to, for example, cell differentiation to produce lipid accumulating cells, regulation of insulin sensitivity and blood glucose levels, which are involved in, for example, abnormal pancreatic beta cell function, insulin secreting tumors and/or autoimmune hypoglycemia due to autoantibodies to insulin, autoantibodies to the insulin receptor, or autoantibodies that are stimulatory to pancreatic beta cells), macrophage differentiation which leads to the formation of atherosclerotic plaques, inflammatory response, carcinogenesis, hyperplasia, adipocyte gene expression, adipocyte differentiation, reduction in the pancreatic β-cell mass, insulin secretion, tissue sensitivity to insulin, liposarcoma cell growth, polycystic ovarian disease, chronic anovulation, hyperandrogenism, progesterone production, steroidogenesis, redox potential and oxidative stress in cells, nitric oxide synthase (NOS) production, increased gamma glutamyl transpeptidase, catalase, plasma triglycerides, HDL, and LDL cholesterol levels, and the like.

Particularly useful compounds described in the present invention are those with efficacy in lowering blood glucose concentration and serum triglyceride levels, and raising serum HDL cholesterol levels.

Therefore, the compounds described in the present invention are expected to be valuable as therapeutic agents. Accordingly, an embodiment of this invention includes a method of treating the various conditions identified above in a patient (including mammals) which includes administering to said patient a composition containing an amount of the compound of Formula I that is effective in treating the target condition.

As indicated above, a compound described in the present invention may be administered alone or in combination with one or more additional hypoglycemic agents. Combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound described in the present invention and one or more additional hypoglycemic agent, as well as administration of the compound described in the present invention and each additional hypoglycemic agents in its own separate pharmaceutical dosage formulation. For example, a compound described in the present invention and hypoglycemic agent may be administered to the patient together in a single oral dosage composition such as a tablet or capsule, or each agent may be administered in separate oral dosage formulations.

Where separate dosage formulations are used, the compound of present invention and one or more additional hypoglycemic agents may be administered at essentially the same time (e.g., concurrently) or at separately staggered times (e.g., sequentially).

For example, the compound of present invention may be administered in combination with one or more of the following additional hypoglycemic agents: insulin; biguanidines such as metformin or buformin; sulfonylureas such as acetohexamide, chloropropamide, tolazamide, tolbutamide, glyburide, glipizide, glyclazide; or any other insulin secretagogue such as, for example, repaglinide and nateglinide; α-glycosidase inhibitors such as acarbose, voglibose, or miglitol; or β₃- adrenoreceptor agonists such as CL-316,243.

The compounds described in the present invention may also be utilized, in free base form or in compositions, as well as in research and diagnostics or as analytical reference standards, and the like, which are well known in the art. Therefore, the present invention includes compositions which are comprised of an inert carrier and an effective amount of a compound described in the present invention or a salt, or ester thereof. An inert carrier is any material which does not interact with the compound to be carried and which lends support, means of conveyance, bulk, traceable material, and the like to the compound to be carried. An effective amount of the compound is that amount which produces a result or exerts an influence on the particular procedure being performed.

In another aspect, the present invention provides a method for treating a disease state in a patient, wherein the disease is associated with a physiological detrimental level of insulin, glucose, free fatty acids (FFA), cholesterol, or triglycerides in the blood, comprising administering to the patient a therapeutically effective amount of a compound of Formula I. hi a further embodiment, the present invention provides a method for treating a disease state in a patient, wherein the disease is associated with a physiological detrimental level of insulin, glucose, free fatty acids (FFA), or triglycerides in the blood, comprising administering to the patient a therapeutically effective amount of a compound of Formula I and also administering a therapeutically effective amount of an additional hypoglycemic agent such as, for example, insulin, a biguanidine compound, and the like.

Since sulfonylureas and other insulin secretagogues are known to be capable of stimulating insulin release, but are not capable of acting on insulin resistance, and compounds described in the present invention are able to act on insulin resistance, it is envisaged that a combination of these medicaments may be used as a remedy for conditions associated with both deficiency in insulin secretion and insulin resistance. Therefore, the invention also provides a method of treating Type II diabetes mellitus in a patient comprising administering a compound described in the present invention and one or more additional hypoglycemic agents such as, for example, sulfonylureas, biguanidines, β- adrenoreceptor agonists, α-glycosidase inhibitors, and insulin. Also, compounds of Formula I may be used in combination with HMG Co-A reductase inhibitors (statins), bile acid binding resin, or fibric acid derivatives to improve the lipid profile of subjects with dyslipidemia and insulin resistance. Compounds described in the present invention may also be used in combination with agents that regulate hypertension (e.g., inhibitors of angiotension converting enzyme (ACE), β-blockers, calcium channel blockers) and body weight of subjects with insulin resistance or type 2 diabetes.

(2) Psoriasis

Another aspect of the present invention provides methods of preventing or treating psoriasis in a subject. The methods include administering to a subject in need thereof an effective amount of a compound of the present invention. In some embodiments, the compound of the present invention is administered topically. In another embodiment, the compound of the present invention is administered intracutaneously, subcutaneously, orally, buccally, transdermally, rectally, or otically.

In some embodiments, the compounds of the present invention may be administered in combination with one or more therapeutic agents. In one embodiment, the therapeutic agent is selected from the group consisting of a corticoid; a vitamin D analog; methrotrexate; ciclosporin; a fumarate; adalimunag; alefecept; afalizumab; etanercept; infliximab; a steroid, a retinoid; an antimicrobial compound; an antioxidant; an anti-inflammatory compound; salicylic acid; an endothelin antagonist; an immunomodulating agent; an angiogenesis inhibitor; a inhibitor of FGF, VEGF, HGF or EGF; an inhibitor of an EGF, FGF, VEGF, or HGF receptor; a tyrosine kinase inhibitor; a protein kinase C inhibitor; and a combination thereof.

In another embodiment, the compounds of the present invention may be administered in combination with one or more coadjuvant therapy selected from phototherapy and/or photochemotherapy.

(3) Alzheimer's disease

According to one aspect of the present invention, methods of preventing or treating Alzheimer's disease are provided. The methods include administering to a subject in need of such treatment an effective amount of a compound of the present invention. In some embodiments, the compound is administered intravenously, orally, buccally, transdermally, rectally, nasally or otically.

In another embodiment, the compounds of the present invention may be administered in combination with at least one additional therapeutic agent. Exemplary additional therapeutic agents includes, but are not limited to, an antioxidant, an anti-inflammatory, a gamma secretase inhibitor, a neurotrophic agent, an acetyl cholinesterase inhibitor, a statin, an A beta peptide, and an anti-A beta peptide.

The compounds described herein may be administered in combination with one or more further medicaments of use for the treatment or prevention of Alzheimer's disease. Further medicaments for the treatment or prevention of Alzheimer's disease include cholinesterase inhibitors (for example tacrine, galantamine, rivastigamine or donepezil) and NMDA inhibitors (for example memantine). The compounds described herein may be administered in combination with one or more further medicaments of use for the treatment or prevention of other dementias. Other further medicaments include non-steroidal anti-inflammatory drugs (NSAIDs) such as such as naproxen, ibuprofen, diclofenac, indomethacin, nabumetone, piroxicam, celecoxib and aspirin. Other medicaments that may be combined with compounds described herein include HMG-CoA reductase inhibitors such as statins (eg simvastatin (Zocor), atovastatin (Lipitor), rosuvastatin (Crestor), fluvastatin (Lescol)).

Depending on the individual medicaments utilized in a combination therapy for simultaneous administration, they may be formulated in combination (where a stable formulation may be prepared and where desired dosage regimes are compatible) or the medicaments may be formulated separately (for concomitant or separate administration through the same or alternative routes).

In some embodiments, the subject of the present invention possesses one or more risk factors for developing Alzheimer's disease selected from a family history of the disease; a genetic predisposition to the disease; elevated serum cholesterol; adult-onset diabetes mellitus; elevated baseline hippocampal volume; elevated cerebrospinal fluid levels of total tau; elevated cerebrospinal fluid levels of phospho-tau; and lowered cerebrospinal fluid levels of A β(l-42).

EXAMPLES

HPLC-electrospray mass spectra (HPLC ES-MS) are obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector, a YMC Pro C18 2.0 mm x 23 mm column, and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Gradient elution from 90% A to 95% B over 4 minutes is used on the HPLC. Buffer A is 98% water, 2% Acetonitrile, and 0.02% TFA, and Buffer B was 98% Acetonitrile, 2% water, and 0.018% TFA. Spectra are scanned from 140-1200 amu using a variable ion time according to the number of ions in the source.

Proton (¹H) nuclear magnetic resonance (NMR) spectra are measured with a General Electric GN-Omega 300 (300 MHz) spectrometer with either Me₄Si (δ 0.00) or residual protonated solvent

(CHCl₃ δ 7.26; MeOH δ 3.30; DMSO δ 2.49) as standard. Carbon (¹³C) ΝMR spectra are measured with a General Electric GN-Omega 300 (75 MHz) spectrometer with solvent (CDCl₃ δ 77.0; d₃- MeOD; δ 49.0; d₆-DMSO δ 39.5) as standard.

Chiral separations are performed using a commercially available Chiracel® AD HPLC column, eluting with a gradient of isopropanol in hexane (from 1% to 15%) with addition of 0.1% trifluoroacetic acid.

For example 5, the following analytical instruments are used:

(1) HPLC: Instrument: Perkin-Elmer Series 200, Column: YMC Pro Cl 8, S-3um, 12mm (4.6 x 150 mm/AS 12503-1546 WT); Mobile A: 0.1% TFA in HPLC H₂O, Mobile B: 0.1% TFA in HPLC CH₃CN, Temperature = Ambient; Wavelength = 220 nm Gradient:

(2) NMR: Bruker 400 MHz

(3) Mass Spectrometer: Waters Micromass ZQ

ABBREVIATIONS AND ACRONYMS

When the following abbreviations are used herein, they have the following meaning:

Ac₂O acetic anhydride

ADDP l,r-(azodicarbonyl)dipiperidine anhy anhydrous

BOC fert-butoxycarbonyl

77-BuOH M-butanol f-BuOH tert-butanol

?-BuOK potassium tø^-butoxide

CDI carbonyl diimidazole

CD₃OD methanol-^

Celite^® diatomaceous earth filter agent, ^®Celite Corp. CH₂Cl₂ methylene chloride

CI-MS chemical ionization mass spectroscopy cone concentrated

DCC dicyclohexylcarbodiimide

DCM dichloromethane de diastereomeric excess

DEAD diethyl azodicarboxylate dec decomposition

DIA diisopropyl amine

DIBAL-H diisobutylaluminum hydroxide

DMAP 4-(N,N-dimethylamino)pyidine

DME dimethoxyethane

DMF N,N-dimethylformamide

DMSO dimethylsulfoxide

EDCl 1 -(3 -dimethylaminopropy l)-3 -ethylcarbodiimide hydrochloride ee enantiomeric excess

ELSD evaporative light scattering detector

ES-MS electrospray mass spectroscopy

EtOAc ethyl acetate

EtOH ethanol (100%)

EtSH ethanethiol

Et₂O diethyl ether

Et₃N triethylamine

GC-MS gas chromatography-mass spectroscopy

HPLC high performance liquid chromatography

IPA isopropylamine

LAH lithium aluminum hydride

LC-MS liquid chromatography-mass spectroscopy

LDA lithium diisopropylamide m/z mass-to-charge ratio

MeCN acetonitrile

NMM 4-methylmorpholine

Ph₃P triphenylphosphine

Pd(dppf)Cl₂ [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II)

Pd(PPh₃)₄ tetrakis(triphenylphosphine)palladium(0)

Pd(OAc)₂ palladium acetate P(O)Cl₃ phosphorous oxychloiϊde

Rf retention factor (TLC)

RT retention time (HPLC) rt room temperature

TEA triethyl amine

THF tetrahydrofuran

TFA trifluoroacetic acid

TLC thin layer chromatography

TMAD N,N,N',N'-tetramethylethylenediamine

TMSCl trimethylsilyl chloride

Example 1.

Preparation of compound 1 (5-{2-[5-Ethyl-2-(4-hydroxy-phenyl)-oxazol-4-yl]-ethoxy}-indan-l- yl)-acetic acid

compound 1

Reaction Scheme 1 begins with compound Ia reacting with compound Ib to provide compound Ic by using an organic or inorganic base in a suitable solvent under suitable reaction conditions (e.g., Cs₂CO₃ in acetonitrile (ACN) at an elevated temperature of about 70⁰C). Compound Ic is treated with an appropriate base under suitable reaction conditions (e.g. NaOH/EtOH at about 65 ⁰C) to hydrolyze the ester moiety, and then followed by acidification (e.g. HCl) to produce compound Id. Subsequently, compound Id is treated with boron tribromide (BBr₃) in dichloromethane (DCM) to give compound 1. Alternatively, compound Id may be treated with aluminum chloride/ dodecyl thiol in an appropriate solvent to give compound 1.

Compounds Ia and Ib may be prepared according to methods described in the literature with modifications known to those skilled in the art (e.g. U.S. Patent No. 6,828,335). Reaction Scheme 1

Ic

COOH

BBr₃ / CH₂Cl₂ alternatively: AlCl₃/dodecyl thiol COOH

Example 2

Synthesis of compound 2 (5-{2-[2-(4-Benzyloxy-phenyl)-5-ethyl-oxazol-4-yl]-ethoxy}-indan-l- yl)-acetic acid

Compound 2

Reaction Scheme 2 begins with compound Ia coupling with compound 2b under suitable reaction conditions (e.g., Cs₂CO₃ in acetonitrile (ACN) at an elevated temperature of 7O⁰C) to provide compound 2c. Then, compound 2c is treated with an appropriate base under suitable reaction conditions (e.g. NaOH/EtOH at about 65 ⁰C) to hydrolyze the ester moiety. Subsequent acidification (with, e.g., HCl) provides compound 2.

Compound 2b may be prepared according to methods described in the literature with modifications known to those skilled in the art (e.g., U.S. Patent No. 6,828,335).

Reaction Scheme 2

2c COOH

Example 3 Alternative synthesis of compound 1

According to Reaction Scheme 3, compound 1 may also be prepared by hydrogeno lysis of compound 2c to produce compound 3b. Then, compound 3b may be treated with an appropriate base under suitable reaction conditions (e.g. NaOH/EtOH at about 65 ⁰C) to hydrolyze the ester moiety. Subsequent acidification (with, e.g. HCl) produces compound 2. Alternatively, compound 1 may be prepared by hydrogenation of compound 2 to give compound 1. Reaction Scheme 3

1 Example 4 preparation of salts of compound 1-3

Exemplary procedures of preparing salts of compound 1-3 are shown in Reaction Scheme 4. Compounds 1-3 may be converted to salts by treatment with an appropriate base in a suitable solvent (e.g. NaOEt in ethanol) followed by precipitation using an appropriate anti-solvent (e.g. ethers) to produce salts of compounds 1 -3.

Reaction Scheme 4 COOH

Co Co Co ether)

Compund 1 : R⁴ is OH Compound 2: R⁴ is -OBn Compound 3: R⁴ is -OCD₃

Example 5. Preparation of compound 4 (5-{2-[5-Ethyl-2-(D3-4-methoxy-phenyl)-oxazol-4-yl]-ethoxy}-indan-l-yl)-acetic acid

acid Compound 4 may be similarly prepared as compounds Id and 2 by starting from appropriate deuterated starting materials or intermediates as shown in Reaction Scheme 5,

MS: m/z: 425.3 (M+H); ¹HNMR (CDCl₃) δ 7.906(d, 2H), 7.07(d, H), 6.93(d, 2H), 6.72(d,

IH), 6.70(dd, IH), 4.19(t, 2H), 3.51(q, IH), 2.86(t, 2H), 2.75(m, 5H), 2.48(m, 2H), 1.75(t, IH), 1.29(t,

3H). Reaction Scheme 5

OOH

It should be apparent to one of ordinary skill in the art that changes and modifications can be made to this invention without departing from the spirit or scope of the invention as it is set forth herein.

Claims

THAT WHICH IS CLAIMED IS:

1. A compound of Formula I,

Formula I

wherein

R is H or CpC₆ alkyl;

R¹ is H, COOH, -C(=O)-OR', C₃-C₈ cycloalkyl, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₁-C₆ alkoxy, wherein R¹ is C₁-C₆ alkyl, and said alkyl, cycloalkyl, akenyl or alkoxy may be optionally substituted with one or more groups selected from the group consisting of fluoro, methylenedioxyphenyl and phenyl, wherein said methylenedioxyphenyl, or phenyl may be optionally and independently substituted with R⁶;

R² is H, halo, or C₁-C₆ alkyl wherein said alkyl may be optionally substituted with one or more groups selected from the group consisting Of C₁-C₆ alkoxy, oxo and fluoro, or

R² is C₅₄₄ aryl, C_3-U heterocycle or C₅.₁₄ heteroaryl, wherein said aryl, heterocycle or heteroaryl may be optionally substituted with one or more R⁶;

R³ is H, C₁-C₆ alkyl, or phenyl, wherein said alkyl or phenyl may be optionally substituted with one or more R⁶;

X is O or S;

R⁴ is C_5-14 aryl, C_3-14 heterocycle or C_5-14 heteroaryl, wherein said aryl, heterocycle or heteroaryl is substituted with one or more R⁷,

R⁵ is H, halo or C₁-C₆ alkyl wherein said alkyl may be optionally substituted with oxo;

R⁶ is halo, CF₃, C₁-C₆ alkyl wherein said alkyl may be optionally substituted with oxo or hydroxy, or C₁-C₆ alkoxy optionally substituted with fluoro;

R⁷ is selected from the group consisting of

(a) hydroxyl,

(b) C₁-C₆ alkoxyl, wherein one or more H of the alkoxyl is ²H (D), and

(c) -0-CH₂-Ph, wherein said phenyl may be optionally substituted with C₁-C₆ alkoxyl; (d) -O-C(=O)-R" wherein R" is Ci-C₆ alkyl or C_5-H aryl wherein said alkyl or aryl may be optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, -SH, amide, carboxylic acid, CN, Cj-C₆ alkyl, Ci-C₆ thioalkyl, C_{6 ]4} aryl and C₅ heteroary and -NR₀R(_J, and wherein R₀ and Rj are independently hydrogen, or Ci-C₆ alkyl;

(e) -O-C(=O)-R^m, wherein R"¹ is -NR_eR_f and wherein R_e and R_f are independently hydrogen, or C₁-C₆ alkyl; or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer, diastereomer, enantiomer or racemate thereof.

2. The compound of Claim 1, wherein the compound of Formula I has the following structure:

3. The compound of Claim 1 or 2, wherein

R is H; R¹ is H; R² is H;

R³ is C₁-C₆ alkyl; X is O;

R⁴ is a phenyl substituted with one or more R⁷, wherein R⁷ is selected from the group consisting of

(a) hydroxyl,

(b) C₁-C₆ alkoxyl, and one or more H of the alkoxyl is ²H (D), and

(c) -0-CH₂-Ph, wherein said phenyl may be optionally substituted with C_rC₆ alkoxyl; and R⁵ is H; or a pharmaceutically acceptable salt thereof.

4. The compound of Claim 1, wherein the compound has the following structure:

or a pharmaceutically acceptable salt thereof .

5. The compound of Claim 1, wherein the compound has the following structure:

or a pharmaceutically acceptable salt thereof .

6. The compound of Claim 1, wherein the compound has the following structure:

or a pharmaceutically acceptable salt thereof .

7. The compound of any of Claims 1 to 6 is a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is selected from the group consisting of alkali metal salts, alkaline earth metal salts, ammonium salts with organic bases, and basic nitrogen containing groups in the conjugate base that is quaternized with agents selected from the group consisting of alkyl halides and aralkyl.

8. The compound of any of Claims 1 to 7, wherein the compound is a meglumine, potassium or sodium salt thereof.

9. The compound of Claim 1, wherein R² is selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl and morpholinyl, each of which may be optionally substituted with one or more R⁶.

10. The compound of Claim 1, wherein R⁴ is selected from the group consisting of phenyl, naphthyl, furyl, thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, tetrahydrothienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, morpholinyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, indazolyl, benzoxazolyl, benxothiazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzodioxolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxazolinyl, dihydrobenzopyranyl, dihydrobenzothiopyranyl, and 1,4-benzodioxanyl, each of which may be substituted with one or more R⁷.

11. A pharmaceutical composition comprising an effective amount of a compound according to any of Claims 1-10 and a pharmaceutically acceptable carrier.

12. The pharmaceutical composition of Claim 11 further comprising one or more hypoglycemic agents.

13. The pharmaceutical composition of Claim 12, wherein said hypoglycemic agent is selected from the group consisting of insulin, biguanidines, sulfonylureas, insulin secretagogues, α-glycosidase inhibitors, and β₃-adrenoreceptor agonists.

14. The pharmaceutical composition of any of Claims 11-13 further comprising one or more agents selected from the group consisting of a HMG CoA reductase inhibitor, a bile acid binding agent, a fibric acid derivative, an agent that regulates hypertension, and an agent that regulates body weight.

15. The pharmaceutical composition of any of Claims 11-14 further comprising one or more agents selected from the group consisting of a corticoid; a vitamin D analog; methotrexate; cyclosporin; a fumarate; adalimunag; alefecept; afalizumab; etanercept; infliximab; a steroid, a retinoid; an antimicrobial compound; an antioxidant; an anti-inflammatory compound; salicylic acid; an endothelin antagonist; an immunomodulating agent; an angiogenesis inhibitor; a inhibitor of FGF, VEGF, HGF or EGF; an inhibitor of an EGF, FGF, VEGF, or HGF receptor; a tyrosine kinase inhibitor; a protein kinase C inhibitor; and a combination thereof.

16. The pharmaceutical composition of any of Claims 11-15 further comprising one or more agents selected from the group consisting of an antioxidant, an anti-inflammatory, a gamma secretase inhibitor, a neurotrophic agent, an acetyl cholinesterase inhibitor, a statin, an A beta peptide, and an anti-A beta peptide.

17. A method of treating or preventing diabetes comprising administering to a subject in need thereof an effective amount of a compound according to any of Claims 1-10.

18. A method of treating or preventing Syndrome X comprising administering to a subject in need thereof an effective amount of a compound according to any of Claims 1-10.

19. A method of treating or preventing diabetes-related disorders comprising administering to a subject in need thereof an effective amount of a compound according to any of Claims 1-10.

20. The method of Claim 19, wherein said diabetes-related disorder is selected from the group consisting of hyperglycemia, hyperinsulinemia, impaired glucose tolerance, impaired fasting glucose, dyslipidemia, hypertriglyceridemia, and insulin resistance.

21. A method of treating or preventing obesity comprising administering to a subject in need thereof an effective amount of a compound according to any of Claims 1-10.

22. A method of treating or preventing cardiovascular disease comprising administering to a subject in need thereof an effective amount of a compound according to any of Claims 1-10.

23. The method of Claim 22, wherein said cardiovascular disease is selected from the group consisting of atherosclerotic disease, dyslipidemia, hypercholesterolemia, decreased HDL levels, hypertension, coronary heart disease, and coronary artery disease.

24. A method of treating or preventing cerebrovascular disease comprising administering to a subject in need thereof an effective amount of a compound according to any of Claims 1-10.

25. A method of treating or preventing peripheral vessel disease comprising administering to a su bj ect in need thereof an effective amount of a compound according to any of Claims 1-10.

26. A method of treating or preventing lupus comprising administering to a subject in need thereof an effective amount of a compound according to any of Claims 1-10.

27. A method of treating or preventing polycystic ovary disease comprising administering to a subject in need thereof an effective amount of a compound according to any of Claims 1-10.

28. A method of treating or preventing carcinogenesis and hyperplasia comprising administering to a subject in need thereof an effective amount of a compound according to any of Claims 1-10.

29. A method of treating or preventing diabetes, Syndrome X and/or diabetes-related disorders comprising administering to a subject in need thereof an effective amount of a compound according to any of Claims 1-10 in combination with one or more hypoglycemic agents.

30. The method of Claim 29, wherein said diabetes-related disorder is selected from the group consisting of hyperglycemia, hyperinsulinemia, impaired glucose tolerance, impaired fasting glucose, dyslipidemia, hypertriglyceridemia, and insulin resistance.

31. The method of Claim 29, wherein the compound and the one or more hypoglycemic agents are administered as a single pharmaceutical dosage formulation.

32. A method of treating diabetes, Syndrome X, and/or diabetes-related disorders comprising administering to a subject in need thereof an effective amount of a compound according to any of Claims 1-10 in combination with one or more agents selected from the group consisting of a HMG CoA reductase inhibitor, a bile acid binding agent, a fibric acid derivative, an agent that regulates hypertension, and an agent that regulates body weight.

33. The method of Claim 32, wherein said diabetes-related disorder is selected from the group consisting of hyperglycemia, hyperinsulinemia, impaired glucose tolerance, impaired fasting glucose, dyslipidemia, hypertriglyceridemia, and insulin resistance.

34. A method of treating or preventing psoriasis comprising administering to a subject in need thereof an effective amount of a compound according to any of Claims 1-10.

35. The method of Claim 34, wherein said compound is administered topically.

36. The method of Claim 34, wherein said compound is administered intracutaneously, subcutaneously, orally, buccally, transdermally, rectally or otically.

37. The method of Claim 34 in combination with one or more additional therapeutic agents.

38. The method of Claim 37, wherein the additional therapeutic agent is selected from the group consisting of a corticoid; a vitamin D analog; methotrexate; ciclosporin; a fumarate; adalimunag; alefecept; afalizumab; etanercept; infliximab; a steroid, a retinoid; an antimicrobial compound; an antioxidant; an anti-inflammatory compound; salicylic acid; an endothelin antagonist; an immunomodulating agent; an angiogenesis inhibitor; a inhibitor of FGF, VEGF, HGF or EGF; an inhibitor of an EGF, FGF, VEGF, or HGF receptor; a tyrosine kinase inhibitor; a protein kinase C inhibitor; and a combination thereof.

39. The method of any of Claims 34-38 further comprising one or more coadjuvant therapy chosen from phototherapy or photochemotherapy.

40. A method of treating or preventing Alzheimer's disease comprising administering to a subject in need thereof an effective amount of a compound according to any of Claims 1-10.

41. The method of Claim 40, wherein said compound is administered through intravenously, orally, buccally, transdermally, rectally, nasally or otically.

42. The method of Claim 41 further comprising administration of one or more additional therapeutic agent.

43. The method of Claim 42, wherein said one or more additional therapeutic agent is used to treat or prevent Alzheimer's disease.

44. The method of Claim 42, wherein said one or more additional therapeutic agent is a cholinesterase inhibitor or a NMDA inhibitor.

45. The method of any of Claims 42, wherein said additional therapeutic agent is selected from the group consisting of tacrine, galantamine, rivastigamine, donepezil and memantine.

46. The method of Claim 42, wherein one or more additional therapeutic agent is selected from the group consisting of an antioxidant, an anti-inflammatory, a gamma secretase inhibitor, a neurotrophic agent, an acetyl cholinesterase inhibitor, HMG-CoA reductase inhibitors (or statin), an A beta peptide, and an anti-A beta peptide.

47. The method of Claim 42, wherein one or more additional therapeutic agent is selected from the group consisting of naproxen, ibuprofen, diclofenac, indomethacin, nabumetone, piroxicam, celecoxib, aspirin, simvastatin (Zocor), atovastatin (Lipitor), rosuvastatin (Crestor), and fluvastatin (Lescol).

48. The method of any of Claims 40-47, wherein the subject possesses one or more risk factors for developing Alzheimer's disease selected from a family history of the disease; a genetic predisposition for the disease; elevated serum cholesterol; adult-onset diabetes mellitus; elevated baseline hippocampal volume; elevated cerebrospinal fluid levels of total tan; elevated cerebrospinal fluid levels of phospho-tau; and lowered cerebrospinal fluid levels of A β(l-42).

49. A process of preparing a compound of Formula Ia comprising dealkylation of a compound of Formula B to give a compound of Formula Ia

Formula B

Formula Ia wherein for Formula B and Formula Ia

R is H or Ci - C₆ alkyl;

R¹ is H, COOH, -C(=O)-OR', C₃-C₈ cycloalkyl, C₁-C₆ alkyl, C₂-C₆ alkenyl, or Ci-C₆ alkoxy, wherein R' is Ci-C₆ alkyl, and said alkyl, cycloalkyl, akenyl or alkoxy may be optionally substituted with one or more groups selected from the group consisting of fluoro, methylenedioxyphenyl and phenyl, wherein said methylenedioxyphenyl, or phenyl may be optionally substituted with R⁶;

R² is H, halo, or Ci-C₆ alkyl wherein said alkyl may be optionally substituted with one or more groups selected from the group consisting Of Ci-C₆ alkoxy, oxo and fluoro, or

R² is C_5-H aryl, C₃.₁₄ heterocycle or C_5-I4 heteroaryl, wherein said aryl, heterocycle and heteroaryl may be optionally and independently substituted with one or more R⁶;

R³ is H, CpC₆ alkyl, or phenyl, wherein said alkyl or phenyl may be optionally and independently substituted with one ore more R⁶;

X is O or S;

R^a C₁-C₆ alkoxyl;

R⁵ is H, halo or Cj-C₆ alkyl wherein said alkyl optionally substituted with oxo; and

R⁶ is halo, CF₃, Cj-C₆ alkyl optionally substituted with oxo or hydroxy, or Ci-C₆ alkoxy optionally substituted with fluoro.

50. A process of making compound B comprising dealkylation of compound A

to give compound B

B

wherein said R° is hydrogen or CpCe alkyl.

51. The process of Claim 50, wherein said deallocation is carried out by treating compound A with boron tribromide (BBi^) in a solvent.

52. The process of Claim 51, wherein said solvent is dichloromethane.

53. The process of Claim 50, wherein said dealkylation is carried out by treating compound A with aluminum chloride in dodecyl thiol in a solvent.

54. The process of Claim 50, wherein R° is Q-C₆ alkyl, further comprising hydrolysis of compound B to give a compound of the following structure:

55. The process of Claim 50, wherein compound A has the following structure: COOH

and compound B has the following structure: COOH

56. A process of making compound D comprising cleaving the ether bond Of O-CH₂Ph of compound C

C to provide compound D

D

wherein R° is hydrogen or Ci-C₆ alkyl.

57. The process of Claim 56, wherein said cleaving step is carried out by hydrogenolysis.

58. The process of Claim 57, wherein said hydrogenolysis is carried out by treating compound C with a catalyst and hydrogen (H₂) gas.

59. The process of Claim 58, wherein said catalyst is selected from the group consisting of palladium (Pd) on carbon, platinum oxide, and Raney nickel.

60. The process of Claim 56, wherein said cleaving step is carried out by treating compound C with boron tribromide or boron trichloride.

61. The process of Claim 56, wherein said cleaving step is carried out by treating compound C with trimethylsilyl iodide.

62. The process of Claim 56, wherein R⁰ is Ci-C₆ alkyl, further comprising hydrolysis of compound D to give a compound of the following structure:

63. The process of Claim 56, wherein compound C has the following structure:

and compound D has the following structure: COOH

64. A compound according to any of Claims 1-10 for carrying out a method of treatment of any of claims 1-48.

65. The use of a compound according to any of Claims 1-10 for the preparation of a medicament for carrying out a method of any one of claims 1-48.