ZA200500914B - Indoles having anti-diabetic activity - Google Patents

Description

INDOLES HAVING ANTI-DIABETIC ACTIVITY . FIELD OF THE INVENTION

The instant invention is concerned with indoles having an aryloxyalkanoic acid substituent, and pharmaceutically acceptable salts and prodrugs thereof, which are useful as therapeutic compounds, particularly in the treatment of

Type 2 diabetes mellitus, and of conditions that are often associated with this disease, including obesity and lipid disorders.

BACKGROUND OF THE INVENTION

Diabetes is a disease derived from multiple causative factors and characterized by elevated levels of plasma glucose (hyperglycemia) in the fasting state or after administration of glucose during an oral glucose tolerance test. There are two generally recognized forms of diabetes. In type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), patients produce little or no insulin, the hormone which regulates glucose utilization. In type 2 diabetes, or noninsulin-dependent diabetes mellitus (NIDDM), insulin is still produced in the body. Patients having type 2 diabetes often have hyperinsulinemia (elevated plasma insulin levels); however, these patients are insulin resistant, which means that they have a resistance to the effect of insulin in stimulating glucose and lipid metabolism in the main insulin-sensitive tissues, which are muscle, liver and adipose tissues. Patients who are insulin resistant but not diabetic compensate for the insulin resistance by secreting more insulin, so _ that serum glucose levels are not elevated enough to meet the criteria of Type 2 diabetes. In patients with Type 2 diabetes, even elevated plasma insulin levels are insufficient to overcome the pronounced insulin resistance.

Persistent or uncontrolled hyperglycemia that occurs with diabetes is associated with increased and premature morbidity and mortality. Often abnormal glucose homeostasis is associated both directly and indirectly with obesity, hypertension, and alterations of the lipid, lipoprotein and apolipoprotein metabolism, ' as well as other metabolic and hemodynamic disease. Patients with type 2 diabetes mellitus have a significantly increased risk of macrovascular and microvascular ' complications, including atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Therefore, therapeutic control of glucose homeostasis, lipid metabolism, obesity, and hypertension are critically important in the clinical management and treatment of : diabetes mellitus.

Many patients who have insulin resistance or Type 2 diabetes often : have several symptoms that together are referred to as syndrome X, or the metabolic syndrome. A patient having this syndrome is characterized as having three or more symptoms selected from the following group of five symptoms: (1) abdominal obesity; (2) hypertriglyceridemia; (3) low high-density lipoprotein cholesterol (HDL); (4) high blood pressure; and (5) elevated fasting glucose, which may be in the range characteristic of Type 2 diabetes if the patient is also diabetic. Each of these symptoms is defined in the recently released Third Report of the National Cholesterol

Education Program Expert Panel on Detection, Evaluation and Treatment of High

Blood Cholesterol in Adults (Adult Treatment Panel II, or ATP III), National

Institutes of Health, 2001, NIH Publication No. 01-3670. Patients with metabolic syndrome, whether or not they have or develop overt diabetes mellitus, have an increased risk of developing the macrovascular and microvascular complications that are listed above that occur with type 2 diabetes, such as atherosclerosis and coronary heart disease.

Insulin resistance is not primarily caused by a diminished number of insulin receptors but by a post-insulin receptor binding defect that is not yet completely understood. This lack of responsiveness to insulin results in insufficient insulin-mediated activation of uptake, oxidation and storage of glucose in muscle and inadequate insulin-mediated repression of lipolysis in adipose tissue and of glucose production and secretion in the liver.

There are several available treatments for type 2 diabetes, each of which has its own limitations and potential risks. Physical exercise and a reduction in dietary intake of calories often dramatically improve the diabetic condition and are the best first line treatment of type 2 diabetes. Compliance with this treatment is very poor because of well-entrenched sedentary lifestyles and excess food consumption, especially of foods containing high amounts of fat. A widely used drug treatment involves the administration of meglitinide or a sulfonylurea (e.g. tolbutamide or glipizide), which are insulin secretagogues. These drugs increase the plasma level of insulin by stimulating the pancreatic cells to secrete more insulin. When ) administration of a sulfonylurea or meglitinide becomes ineffective, the amount of insulin in the body can be supplemented by the injection of insulin so that insulin concentrations are high enough to stimulate even the very insulin-resistant tissues.

However, dangerously low levels of plasma glucose can result from administration of : insulin and/or insulin secretagogues, and an increased level of insulin resistance due to the even higher plasma insulin levels can occur. : The biguanides are another class of drugs that are widely used to treat type 2 diabetes. The two best known biguanides, phenformin and metformin, cause some correction of hyperglycemia without risk of causing hypoglycemia. The biguanides can be used either with insulin or with an insulin secretagogue without increasing the risk of hypoglycemia. However, phenformin and metformin can induce lactic acidosis and nausea/diarrhea. Metformin has a lower risk of side effects than phenformin and is widely prescribed for the treatment of Type 2 diabetes.

The glitazones (i.e. 5-benzylthiazolidine-2,4-diones) are a newer class of compounds that can ameliorate hyperglycemia and other symptoms of type 2 diabetes. These agents substantially increase insulin sensitivity in muscle, liver and adipose tissue in several animal models of type 2 diabetes, resulting in partial or complete correction of elevated plasma glucose levels without the occurrence of hypoglycemia. The glitazones that are currently marketed (rosiglitazone and pioglitazone) are agonists of the peroxisome proliferator activated receptor (PPAR) gamma subtype. PPAR-gamma agonism is generally believed to be responsible for the improved insulin sensititization that is observed with the glitazones. New PPAR agonists are being developed for the treatment of Type 2 diabetes and/or dyslipidemia.

Many of the newer PPAR compounds are agonists of one or more of the PPAR alpha, gamma and delta subtypes. Compounds that are agonists of both the PPAR alpha and

PPAR gamma subtypes (PPAR alpha/gamma dual agonists) are promising because . they reduce hyperglycemia and also improve lipid metabolism.

PPAR agonists, and particularly glitazones, have had shortcomings which have so far detracted from their attractiveness. Some of the compounds, and especially troglitazone, have exhibited liver toxicity. Troglitazone was eventually withdrawn from the marketplace because of hepatotoxicity. Another weakness in the currently marketed PPAR agonists is that monotherapy for type 2 diabetes produces only modest efficacy — a reduction in average plasma glucose of = 20% and a decline from = 9.0% to ~8.0% in HemoglobinA1C. The current compounds also do not greatly improve lipid metabolism, and may actually have a negative effect on the lipid ) profile. These shortcomings have provided an incentive to develop better insulin sensitizers for Type 2 diabetes which function via similar mechanism(s) of action.

Recently, there have been reports of compounds that are PPAR gamma : antagonists or partial agonists. WO01/30343 describes a specific compound that is a

PPAR partial agonist/antagonist that is useful for the treatment of obesity and Type 2 : diabetes. WO02/08188 discloses a class of PPAR agonists and partial agonists that are indole derivatives and that are useful in the treatment of Type 2 diabetes, with reduced side effects relating to body and heart weight gain

SUMMARY OF THE INVENTION

The class of compounds described herein is a new class of PPAR agonists that do not contain a 1,3-thiazolidinedione moiety. The class of compounds includes many compounds that are PPARYy partial agonists, but also may include

PPARY full agonists and/or PPARy antagonists. Some compounds may also have

PPAR activity in addition to PPARY activity. Some compounds may be mixed full or partial PPARoUy agonists. These compounds are useful in the treatment and control of diabetes, hyperglycemia, and insulin resistance.

The compounds may also be useful in the treatment of one or more lipid disorders, including mixed or diabetic dyslipidemia, isolated hypercholesterolemia, which may be manifested by elevations in LDL-C and/or non-

HDL-C, hyperapoBliproteinemia, hypertriglyceridemia, an increase in triglyceride- rich-lipoproteins, and low HDL cholesterol concentrations. They may also be useful in the treatment or amelioration of atherosclerosis, obesity, vascular restenosis, inflammatory conditions, psoriasis, polycystic ovary syndrome, and other PPAR mediated diseases, disorders and conditions.

The present invention is directed to compounds of formula I:

RS

A ,

ZN

1

R

I

' and pharmaceutically acceptable salts and prodrugs thereof.

Inthe compounds of formula I,

R1 is selected from . (a) -X-Aryl-Y-Z, and (b) —X-Heteroaryl-Y-Z, : where Aryl and Heteroaryl are unsubstituted or substituted with 1-3 groups independently selected from A;

Aryl is phenyl or naphthyl;

Heteroaryl is a monocyclic or fused bicyclic aromatic ring structure containing 1-4 heteroatoms independently selected from N, O, and S(O)p; (Note that

S(O) and S(O)2 are included in the ring structure through the S atom, and that

Heteroaryl may be a benzene ring that is fused to an aromatic heterocycle, such as occurs in indole.);

X is a bond or a divalent group selected from CH, CH(CH3), C(CH3)2 , and C3-Cgcycloalkylidene;

Y is a divalent group selected from -CH=CH-, -CH(OH)CH(OH)-, -OCR’R8- , .SCR7RS-, and -CH2CR5R6-;

Z is selected from the group consisting of -CO2H and tetrazole;

A is selected from the group consisting of Cj_4 alkyl, C14 alkenyl, -OC1-4 alkyl, and halogen, wherein alkyl, alkenyl, and -Oalky! are each optionally substituted with 1-5 halogens;

R35, R6, R7, and R8 are each independently selected from the group consisting of H, halogen, C1-C5 alkyl, -OC1-Cj5 alkyl, C2-C5 alkenyl, -OC2-C5 alkenyl, C3.¢ cycloalkyl, phenyl, and -CO2H, wherein C1-C5 alkyl, -OC]-C5 alkyl,

C2-Cs alkenyl, -OC2-C5 alkenyl, C3.6 cycloalkyl, and phenyl are optionally : substituted with 1-5 halogens, and C3_6 cycloalkyl and phenyl are further optionally substituted with 1-3 groups independently selected from C3-C3 alkyl and -OC1-C3 . alkyl, said C1-C3 alkyl and -OC]-C3 alkyl being optionally substituted with 1-3 halogens;

Or alternatively R7 and R8 may be joined to form a C3-Cé cycloalkyl group, said C3-Cg cycloalkyl group being optionally substituted with 1-3 halogens;

Or alternatively, when R1 is -X-Phenyl-Y-Z, Y is -OCR7R8 , and R7 is selected from the group consisting of H, halogen, C1-C5 alkyl, -OC-Cs alkyl, C2_5 alkyl, -OC2.5 alkyl, C3.6 cycloalkyl, and phenyl, then R8 may optionally be a 1-2- carbon bridge connected to the phenyl ring at the position ortho to Y, thereby yielding a 5 or 6-membered heterocyclic ring fused to the phenyl ring;

R2 is C1-C4 alkyl, which is optionally substituted with 1-5 halogens;

R3 is selected from the following substituent groups: (a) benzisoxazolyl, (b) benzisothiazolyl, (c) benzpyrazolyl, (d) Aryl (e) -C(=0)Aryl, (f) -C(=O)Heteroaryl, (8) -OAryl, (h) -OHeteroaryl, (1) -S(O)pAryl, and (G) -S(O)pHeteroaryl, wherein R3 is optionally substituted with 1-3 substituent groups independently selected from halogen, C1-3alkyl, -OCj-3alkyl, and -SCj.- 3alkyl, wherein C1-3alkyl, -OC]-3alkyl, and -SC1-3alkyl are optionally substituted with 1-5 halogens; each R4 is optionally selected from H, halogen, C1-Cs alkyl and -0C1-Cs alkyl, wherein C1-C5 alkyl and -OC-C5 alkyl are optionally substituted with 1-5 halogens; . 30 n is an integer from 0-2; and p is an integer from 1 to 3.

In the above definitions and subsequent definitions, alkyl groups may : be either linear or branched, unless otherwise specified. ’ The present compounds are effective in lowering glucose, lipids, and insulin in diabetic patients and in non-diabetic patients that have impaired glucose tolerance and/or are in a pre-diabetic condition. The compounds are expected to be efficacious in the treatment of non-insulin dependent diabetes mellitus (NIDDM) in human and mammalian patients, particularly in the treatment of hyperglycemia and in the treatment of conditions associated with NIDDM, including hyperlipidemia, dyslipidemia, obesity, hypercholesterolemia, hypertriglyceridemia, atherosclerosis, vascular restenosis, inflammatory conditions, and other PPAR mediated diseases, disorders and conditions.

DETAILED DESCRIPTION OF THE INVENTION

The invention has numerous embodiments. It provides compounds of formula I, including pharmaceutically acceptable salts of these compounds, prodrugs of these compounds, and pharmaceutical compositions comprising these compounds and a pharmaceutically acceptable carrier.

In preferred embodiments, R3 is selected from the group consisting of 3-benzisoxazolyl, -O-Phenyl, and -C(=O)Phenyl, wherein R3 is optionally substituted with 1-3 substituents independently selected from halogen, -OC1-C3alkyl, and Ci- 3alkyl, wherein said -OC1-C3alkyl and C}-C3alkyl are optionally substituted with 1-5 halogens.

In preferred embodiments of the invention, R1 is -X-Phenyl-Y-Z, where Phenyl is unsubstituted or substituted with 1-3 groups independently selected from A.

A subset of compounds of Formula I includes compounds in which X is a bond.

A subset of compounds of Formula I includes compounds in which X is CHa,

In a desirable subset of compounds, Y is -OCR7R8-, R7 is selected ] from the group consisting of H and C1-C3 alkyl, and R8 is C1-C3 alkyl, where R7 and R8 are optionally substituted with 1-3 halogens.

In another desirable subset of compounds, Y is -OCR7R8-, R7 is selected from H and C-C3 alkyl, and R8 is C}-C3 alkyl.

In another useful set of compounds, Y is -CH2CHRO- where R6 is selected from C1-3alkyl and -OC]-3 alkyl, which are optionally substituted with 1-3 halogens.

In another set of compounds, Y is -CH2CHRS- where R6 is -OC]._3 alkyl, which is optionally substituted with 1-3 halogens.

In preferred embodiments, A is selected from the group consisting of

C1-C3alkyl, CF3, -OCH3, -OCF3, and halogen.

A preferred subset of compounds includes compounds in which R2 is

Cjp-3 alkyl or CFs.

In many preferred compounds, R3 is -C(=O)Phenyl, where R3 is optionally substituted with 1-3 substituents independently selected from -OCH3, -OCF3, and halogen.

In other useful compounds, R3 is 3-benzisoxazolyl or aryl, which is optionally substituted with 1-3 substituents independently selected from halogen,

OCH3, OCF3, CH3, and CF3.

In another subset of compounds, R3 is 3-benzisoxazolyl, aryl, ’ -OPhenyl, or -SPhenyl, where R? is optionally substituted with 1 substituent selected from halogen, OCH3, OCF3_ and CF3.

In another subset of compounds, R1 is -X-Pyridinyl-YZ.

. A subset of compounds includes compounds in which pis 1. . Preferred compounds generally have a group Z which is -CO,H.

In preferred sets of compound, Rl! is generally

Al x ) “N

Aq where X is selected from the group consisting of a bond, CH2,

CH(CH3) , C(CH3)2 , and C3-Cgcycloalkylidene;

Y is selected from the group consisting of -OCR7R8- and

CH2CRS5R6;

Z is selected from -CO2H and tetrazole;

A is selected from C1-C3 alkyl, CF3, -OCH3, -OCF3, and halogen,

R5, R6, and Rare each independently selected from the group consisting of H, halogen, C1-C3 alkyl, and -OC1-C3 alkyl, and R8 is selected from the group consisting of halogen, C1-C3 alkyl, and -OC1-C3 alkyl, wherein C1-C3 alkyl and -OC1-C3 alkyl of RS, R6, R7, and R8 are each optionally substituted with 1- 3 halogens; q is an integer from 0-3; pisl;

R2 is selected from CF3 and C1-C3 alkyl;

R3 is selected from the group consisting of . (a) 3-benzisoxazolyl, (b) 3-benzisothiazolyl, i 30 (c) 3-benzpyrazolyl, (d) Aryl (e) -C(=O)Phenyl,

(f) —C(=0)Heteroaryl, . (g) —OPhenyl, (h) -OHeteroaryl,

Rk (1) -S(O)pPhenyl, and (4) -S(O)pHeteroaryl, wherein Heteroaryl is selected from the group consisting of pyridyl and quinolyl, n is an integer from 0-2, and

R3 is optionally substituted with 1-3 groups independently selected from halogen, -OC1-C3alkyl, and C]-3alkyl, wherein said -OC)-C3alkyl and C1-C3alkyl are optionally substituted with 1-5 halogens.

A desirable subset of the compounds described immediately above have the following substituents:

X is a bond or CH?;

Y is _OCR7R8- or -CH2CRS5R6- ;

Zis -CO2H;

A is selected from CH3, CF3, -OCH3, -OCF3, and halogen;

RI is H;

RO is selected from the group consisting of H, C1-C3 alkyl, and -OC1-C3 alkyl, wherein C1-C3 alkyl and -OC1-C3 alkyl are optionally substituted with 1-3 halogens; : R7 is selected from the group consisting of H and C1-C3 alkyl; : R8 is C1-C3 alkyl;

R2 is CH3;

R3 is selected from the group consisting of (a) 3-benzisoxazolyl, (b) Aryl, (¢) -C(=0O)Phenyl, (d) -C(=0)Pyridyl, and (e)-C(=0)Quinolyl, wherein R3 is optionally substituted with 1-3 groups independently selected from halogen, -OC]-C3alkyl, and C1.3alkyl, wherein said -OC1-C3alkyl and Cj-Caalkyl are optionally substituted with 1-5 halogens; and q is an integer from 0-3.

In preferred groups of the above compounds, Y is .OCR/R®-, R7 is

H, and R8 is Cj_3alkyl, which is optionally substituted with 1-3 halogens.

In other preferred groups of the above compounds, Y is -CH2CRIR6-,

RS is H, and RO is Ci-3alkyl or —OC,.3 alkyl, where C,.3 alkyl and -0C, 3 alkyl are optionally substituted with 1-3 halogen atoms.

In preferred compounds, the X and -YZ substitutents on the phenyl groups above are meta or para to one another, and in more preferred compounds, X and -YZ are meta with respect to one another, as shown below as Formula IA.

Compounds having Formula IA as shown below, and pharmaceutically acceptable salts thereof, have especially useful properties in treating insulin resistance, type 2 diabetes, and dyslipidemia that is associated with type 2 diabetes and insulin resistance:

RS

NN

ZN

X a= =

YZ

IA

In the compounds of Formula IA, X is a bond or CH2;

Y is .OC*R7R8- or -CH2C*R5R6- ;

Zis -CO2H;

A is selected from CH3, CF3, -OCH3, -OCF3, and halogen; qisOorl;

R4 is C1-3alkyl, CF3, -OCH3, or -OCF3; pis Oor 1;

RS is selected from H and C1-C3 alkyl, wherein C1-C3 alkyl is optionally substituted with 1-3 halogens;

R6 is C1-C3 alkyl or -OC1-C3 alkyl, wherein C1-C3 alkyl, and -OC1-

C3 alkyl are optionally substituted with 1-3 halogens;

R7 is selected from the group consisting of H and C1-C3 alkyl, which - is optionally substituted with 1-3 halogens;

R8 is C1-C3 alkyl, which is optionally substituted with 1-3 halogens;

. R2 js CH3; and : R3 is selected from the group consisting of (a) 3-benzisoxazolyl, (b) -O-Phenyl, and (c) -C(=O)Phenyl, where R3 is optionally substituted with 1-3 groups independently selected from halogen, -OC}-C3alkyl, and C1-3alkyl, wherein said -OC1-C3alkyl and Cj1-C3alkyl are optionally substituted with 1-5 halogens.

In a subset of the compounds described immediately above, p is 1.

The carbon atom which is indicated with an asterisk (C*) in the structures above, when Y is -OC*H(R®)- or -CHC*HR®)- , is an asymmetric carbon. Generally, both the R and S stereochemical configurations at the carbon C* are active, though they have somewhat different activities in terms of the amount of

PPARa and PPARY activity.

Preferred sets of compounds of Formula IA in which X is a bond have the following substituents:

Y is -OC*R7RS8-;

R4 is CH3, CF3, -OCH3, or -OCF3 ; pisOor 1;

R7 is H; and

R8 is C1-C3 alkyl, which is optionally substituted with 1-3 halogens.

These compounds have an asymmetric center on the carbon of

Y. Compounds having the R and S stereochemical configuration at C* are active

PPAR agonists, though they have somewhat different activities in terms of the relative : amounts of PPARa and PPARY activity. : In another preferred subset of compounds of formula IA, X is CH2 ;

Yis -oC*R7R%-;

R4 is CH3, CF3, -OCH3, or -OCF3 ; pisOorl;

R7 is H; and

R8 is C1-C3 alkyl, which is optionally substituted with 1-3 halogens.

These compounds also have an asymmetric center on the carbon of Y.

Compounds having the R and S stereochemical configuration at C* are active PPAR agonists, though they have somewhat different activities in terms of the relative amounts of PPAR and PPARY activity.

In other preferred subsets of compounds of Formula IA, where Xis either CH, or a bond, R3 is -C(=0)Phenyl, which is optionally substituted with 1-2 groups independently selected from the group consisting of Cl, CH3, CF3, -OCH3, and -OCF3.

In a subset of the compounds above, p is 1.

Structures of specific compounds are disclosed in Tables 1-4. The names are provided for the compounds in separate Tables 1A-4A. Each compound is given the same number in the two sets of tables. The syntheses of some of these ’ compounds are also provided in the Examples.

The compounds of this invention can be used in pharmaceutical compositions comprising the compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The compounds of this invention can also be used in pharmaceutical compositions in which a compound of Formula I or a pharmaceutically acceptable salt thereof is the only active ingredient.

The compounds of the invention and a pharmaceutically acceptable salts thereof can be used in the manufacture of a medicament for the treatment of type 2 diabetes mellitus in a human or other mammalian patient.

The compounds especially have utility in a method for treating or ameliorating hyperglycemia in a human or other mammalian patient having Type 2 diabetes mellitus in need of such treatment by administering to the patient a therapeutically effective amount of the compound.

Specific embodiments of compounds of this invention are provided in the Examples and in the tables that are appended hereto.

Some of the compounds of this invention were disclosed in a provisional application which was filed after the filing dates of the two US Provisional :

Applications from which priority is claimed in this application, to illustrate the use of these compounds in the invention disclosed in the later application. The seven compounds are listed below according to where they are disclosed herein: 1. Tables 1 and 1A, Compound 1 2. Tables 1 and 1A, Compound 10 3. Tables 2 and 2A, Compound 8; also Example 31 4, Tables 2 and 2A, Compound 25 5. Tables 3 and 3A, Compound 29 6. Tables 3 and 3A, Compound 60; also Example 29 7. Tables 3 and 3A, Compound 78

It is to be understood that the invention herein includes the generic claims as : written, and furthermore includes each of the generic claims with a disclaimer of one or more of the seven compounds listed above. Such a disclaimer may be made during examination. The compounds above are also claimed herein.

The compounds as defined herein may be used to treat the following diseases, ) as well as other diseases not listed below by administering a therapeutically effective amount to a patient in need of treatment: (1) type 2 diabetes, and especially hyperglycemia; (2) metabolic syndrome; 3) obesity; and 4) hypercholesterolemia;

Definitions “Ac” is acetyl, which is CH3C(O)-. “Alkyl” means saturated carbon chains which may be linear or branched or combinations thereof, unless the carbon chain is defined otherwise.

Other groups having the prefix "alk", such as alkoxy and alkanoyl, also may be linear or branched or combinations thereof, unless the carbon chain is defined otherwise.

Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert- butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like. "Alkenyl" means carbon chains which contain at least one carbon- carbon double bond, and which may be linear or branched or combinations thereof.

Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1- propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like. ’ "Alkynyl" means carbon chains which contain at least one carbon- carbon triple bond, and which may be linear or branched or combinations thereof.

Examples of alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like. "Cycloalkyl” means mono- or bicyclic saturated carbocyclic rings, each having from 3 to 10 carbon atoms, uniess otherwise stated. The term also includes a monocyclic ring fused to an aryl group. Examples of cycloalkyl include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

A cycloalkylidene group is a divalent cycloalkane radical in which : 30 both attachments are at the same carbon. For example, the cyclopropyl group of 1,1- dimethylcyclopropane is a cyclopropylidene group. : "Aryl" (and “arylene”) when used to describe a substituent or group in a structure means a monocyclic, bicyclic or tricyclic compound in which all the rings are aromatic and which contains only carbon ring atoms. The term “aryl” can also refer to an aryl group that is fused to a cycloalkyl or heterocycle. "Heterocyclyl," : “heterocycle,” and “heterocyclic” means a fully or partially saturated monocyclic, bicyclic or tricyclic ring system containing at least one heteroatom selected from N, S : and O, each of said rings having from 3 to 10 atoms. Examples of aryl substitiuents include phenyl and naphthyl. Aryl rings fused to cycloalkyls are found in indanyl, indenyl, and tetrahydronaphthyl. Examples of aryl fused to heterocyclic groups are found in 2,3-dihydrobenzofuranyl, benzopyranyl, 1,4-benzodioxanyl, and the like.

Examples of heterocycles include tetrahydrofuran, piperazine, and morpholine.

Preferred aryl groups are phenyl or naphthyl. Phenyl is generally the most preferred. "Heteroaryl" (and heteroarylene) means a mono-, bi- or tricyclic aromatic ring containing at least one ring heteroatom selected from N, O and S (including SO and SO2), with each ring containing 5 to 6 atoms. Examples of heteroaryl include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl (including S-oxide and dioxide), furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl, dibenzofuran and the like. "Halogen" includes fluorine, chlorine, bromine and iodine. “Me” represents methyl.

The term "composition," as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients,

B 25 or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.

The substituent “tetrazole” means a 2H-tetrazol-5-yl substituent group or a tautomer thereof.

Optical Isomers - Diastereomers - Geometric Isomers - Tautomers

Compounds of Formula I may contain one or more asymmetric centers and can thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is meant to comprehend : all such isomeric forms of the compounds of Formula I.

Some of the compounds described herein may contain olefinic double : bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.

Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers. An example is a ketone and its enol form, known as keto-enol tautomers. The individual tautomers as well as mixtures thereof are encompassed with compounds of Formula I.

Compounds of the Formula I having one or more asymmetric centers may be separated into diastereoisomers, enantiomers, and the like by methods well known in the art.

Alternatively, enantiomers and other compounds with chiral centers may be synthesized by stereospecific synthesis using optically pure starting materials and/or reagents of known configuration.

Salts

The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, eyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N.N'- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N- ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, ) procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

When the compound of the present invention is basic, salts may be ‘ prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, ‘ citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.

It will be understood that, as used herein, references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.

Metabolites — Prodrugs

Therapeutically active metabolites of other compounds, where the metabolites themselves fall within the scope of the claimed invention, are also compounds of the current invention. Prodrugs, which are compounds that are converted to the claimed compounds as they are being administered to a patient or after they have been administered to a patient, are also compounds of this invention.

A non-limiting example of a prodrug of the carboxylic acids of this invention would be an ester of the carboxylic acid group, for example a C1 to Cg ester, which may be linear or branched, which metabolizes to a carboxylic acid of this invention. An ester which has functionality that makes it more easily hydrolyzed after administration to a patient may also be a prodrug.

Utilities

Compounds of the present invention are potent ligands having agonist, partial agonist or antagonist activity on one or more of the various peroxisome proliferator activated receptor subtypes, particularly PPARY. The compounds may also be ligands or agonists, partial agonists or antagonists of the PPARc. subtype as well as the PPARY subtype, resulting in mixed PPARoVY agonism or in agonism of mainly the PPARO. subtype. Some compounds (generally less preferred) may also be

PPARS ligands and have PPARS activity in addition to their other PPAR activity. The compounds of this invention are useful in treating or controlling diseases, disorders or } conditions which are mediated by one or more ligands of the individual PPAR subtypes (eg. Y or 0) or a combination of PPAR subtypes (e.g. o/y). One aspect of the present invention provides a method for the treatment and control of diseases that can be mediated by administration of a PPAR agonist or partial agoinist, such as type - 2 diabetes. : Administration and Dose Ranges

Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. Preferably compounds of Formula I are administered orally.

The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.

When treating or controlling diabetes mellitus and/or hyperglycemia or hypertriglyceridemia or other diseases for which compounds of Formula I are indicated, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 1.0 milligrams to about 1000 milligrams, preferably from about 1 milligrams to about 50 milligrams. In the case of a 70 kg adult human, the total daily dose will generally be from about 1 milligram to about 350 milligrams. For a particularly potent compound, the dosage for an adult human may be as low as 0.1 mg. The dosage regimen may be adjusted within this range or even outside of this range to provide the optimal therapeutic response.

Oral administration will usually be carried out using tablets. Examples of doses in tablets are 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, and 250 mg. Similar dosages may also be used in other oral formulations (e.g.capsules).

Pharmaceutical Compositions ’ Another aspect of the present invention provides pharmaceutical compositions which comprise a compound of Formula I and a pharmaceutically acceptable carrier. The pharmaceutical compositions of the present invention comprise a compound of Formula I or a pharmaceutically acceptable salt as an active : ingredient, as well as a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term "pharmaceutically acceptable salts” refers to salts . prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids.

The compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient.

They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.

In practical use, the compounds of Formula I can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.

Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active : compound in such therapeutically useful compositions is such that an effective dosage will be obtained. The active compounds can also be administered intranasally as, for example, liquid drops or spray.

Claims (21)

1. ) W() 2004 020408 PCT USZ005 02007" WHAT IS CLAIMED IS:

   I. A compound having Formula TA. or a pharmaceutically acceptable salt thereof: R* A +b SR 2 R 0 ; —R = N X ANN YZ 1A wherein X is selected from a bond and CH>; Y is -OCR'R": Zis -CO2H; Als selected from the group consisting of CH3, CF3, -OCH3. -OCF3, and halogen; qisOor I; 5) R+ is selected from the group consisting of C.zalkyl, CF3. -OCH3. and -OCF3 pisOorl; Ris selected from the group consisting of Hand CC; alkyl, which is optionally substituted with 1-3 halogens: AMENDED SHEET k WO end aang PCT US2003. 020077 RY x (1-0 al bowhich is optionedls sub ened ag 1-2 RINSE R2 1s CH: and R315 selected from the froup consisting of 1) 3-benzisoxazolyl, (1) ~-0O-Phenyl, and ™~ -C{=O)Phenyl, 19 wherein R3 is optionally substituted with 1-3 croups dependently selected from halogen, -OC1-C3alkyl, and C1-3alkyl, wherein said -OC|-C3alky! and C1-C3alkyl are optionally substituted with 1-5 halogens.
2. 2. The compound according to Claim 1, wherein X is a bond: 13 Y is .OC*R7RS-; R+# is sclected from the group consisting of CH3, CF3, -OCHj3. and -OCF3; R7 is H: and R8i5C1-C3 alkyl, which is optionally substituted with 1-3 halozens., 55
3. 3. The compound according to Claim 2, wherein the carbon atom Cel seid zroup Y has the R stereochemical configuration.
4. 4. Ihe compound according to Claim 2. wherein the carbon atom Col nd pronp Y has the S stereochemical contmratien, “0
5. 5. Fhe compound according to Claim 2. wherein Ris -CosGePheavlow Biles cptionally substituted wah 1-2 shai ents independently cectd ten tbe crnp consist of CLOTH CFL OC iu amd On 13.
6. i 0. Fhe compound according to Claim 1. wherein X is CH: AMENDED SHEET i WO C004 1020408 PCT LS2003 0200™" Y is OCR pS: Rts selected from the froup corsisting of CH3, CF3. -OCH2. h and -OCF3 ; R7 is H: and RS is C1-C3 alkyl, which is optionally substituted with 1-3 halogens.
7. 7. The compound according to Claim 6, wherein the carbon atom C* of said group Y has the R stereochemical configuration.
8. 8. The compound according to Claim 6, wherein R” is C* of said group Y has the S stereochemical configuration.
9. 9. The compound according to Claim 6, wherein Ris -C(=0)Phenyl, which is optionally substituted with 1-2 substituents independently sclected from the group consisting of Cl, CH3, CF3, -OCH3. and -OCF3. AMENDED SHEET
10. 10. A pharmaceutical composition comprising a compound of Claim |, er a pharmaceutically acceptable salt thereof. and a phanmaceutically acceptable carrier.
11. I. A compound of Claim I for use in treating Type 2 diabetes mellitus in a mammal.
12. 12. The compound of Claim 11, in combination with one or more additional antidiabetic compounds selected from the group consisting of metformin, a sulfonylurea, insulin, and a DP-IV inhibitor.
13. 13. The compound of Claim 11. in combination with a therapeutically etfective amount of a statin selected from the group consisting of simvastatin, lovastatin, rosuvastatin, atorvastatin, fluvastatin, itavastatin, rivastatin, and ZD-4522.
14. 14. The use of a compound of Claim | or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of Type 2 diabetes mellitus.
15. IS. A compound according to claim |, substantially as herein described and exemplified.
16. 6. A pharmaceutical composition according to claim 10), substantially as herein described and exemplified.
17. 17. A compound according to claim 11. substantially as herein described and exemplified.
18. IR. Use according to claim 14. substantially as herein described and cxemplitied. AMENDED SHEET
19. 19. A compound according to Claim 1 as shown below, ora pharmaceutically acceptable salt thereof: TS I Ex___ | Structure [Ex Structure - 9 } !

    Ex. 1 ¢ Neo ; i Ex. 2 : ¢ Oo, id : I FR = I A Sat FyCO No N i , FiO Nn N ) \ /=Q =o) : > ~ NZ | Wo i veg | ad

    Ex. 3 [0 |Ex.4 =o Nt on i Ps r” “OH : F;CO N | ; b

    ) y. , CFO “w—N ~ = Tr I NP 0 = o) \ MeO HCO AMENDED SHEET

    ! Ln Nj . —

    Ex.S J TA Ex. 6 TN 0 NE N= om : FICO \ i FCO Nn LL [ TT ET | | ~ JE I x20 i . a i | ~v 9 Co : I 1 § i Raa ! he 7 I 2'e0 a’ — fo] t Ex. 7 d Od Ex. 8 JNO ? =z EE / ! reo oH ! w= om FICO ~\ FaCO._ nN N ; | 19s NF ! CN J ~~ 0] ) 0] » | of a’ cl’

    Ex.9 red Ex ore { = i OH = 2 on FCO 10° freon A hp i Lp 0 0 y > NZ { Y a a”

    Ex. F Q To, | Ex. ba Neo, 2 1 = OH 12 BA FCO N i F1€O Fo I \ : 3 NN => / | [ = Vj 0 0 | = ° \ \ [ol cl

    Ex. Ao 0 'E g Tyo pox io 7 13 Va a OH 14 EET FICO_~, _N : ; FICO _~ .N ~ ; - a RE t | } NEP & : A 2 ! Lo ‘ 0 t oy no Ls A , ; 2 a 2 Ma] EE Sy a Phx yy IRENE Lx. 16 | FRCIN 2 ! ed EEE i EPR T #7 Co on ! ! Foo CON FLO ' / oH ES BEER ; 7 X i [7 i | : !

    [8] ! 0 I E . ‘ m— EE AMENDED SHEET

    EE i Ex. 17 “No © "Ex. 18 | = 0 ! rt | | Tee . ee oH | : ~~ _ , i (Sd IH : FICO... NN FCI. u.oN 4 md | 4 Ay i a VO 0 ! Lo { 7 med” ow

    Ex. 19 { Ex. 20 4 . { 0 X. 4 ) EN Noo N = / OH Cf A on ! i ! FCO N nN FEO oN NF Ne ~~ 0 Ye (o] \ 4 & Pp ct J

    Ex. 23 a Ex. 24 e Sas Sod ) HES i oH FiCO N F.CO N Vs ! PW lo} o) \_z ® MeO a’ o {

    Ex. 25 Ao, © Ex. 26 yo L 4 a y= OM #,60 N > ONS N \ 3 I af ® / dl 0 «=O C y 7 [ol a’ 5)

    Ex. 27 FNy-0 Ex 28 o. Na -y on SA J

    FCO. ~~ N \ x 0 Sr Co Aeon I CF0” NG °~( Te (™Y NA LS I a —— eel ee hx 29 GO. 0 eed eo | yoo a Ex 10 | LO EE EN EI BE n | 1 vo i ed ol ' bl { . 1 { + KE AMENDED SIEET

    ! I Sl | ' ! Ex i = | : PRON RS s | i I : EN I IES wc ! | NTT ! i OA em,
20. 20. The compound of Claim | shown below. or a pharmaceutically acceptable salt thereof: i (Bx. 3) 0 rcs

    FCO. N 0
21. 21. The compound of Claim 1 shown below, or a pharmaccutically acceptable salt thereof: 1

    (Ex. 29) 0 a \S 3 N 0 FiCO : I 8 6 AMENDED SHEET