Compounds for the modulation of ppar-gamma activity

Compounds for modulating the activity of PPAR and

5 SECTOR OF THE INVENTION

The present invention relates to compounds that modulate the PPARy receptor and that are useful in the diagnosis and treatment of type II diabetes (and the complications thereof), hypercholesterolemia (and diseases related to abnormally high or low levels of lipoprotein or of triglycerides in plasma) and inflammatory disorders.

BACKGROUND OF THE INVENTION

Peroxisome proliferator activated receptors (PPARs) are transducer proteins that belong to the

fifteen steroid / thyroid / retinoid receptor superfamily. PPARs were originally identified as orphan receptors, with no known ligands, but designated for their ability to mediate the plelotropic effects of peroxisome fatty acid proliferators. These receptors function as transcription factors regulated by ligands that control the expression of target genes by binding to their corresponding DNA sequence as heterodimers with RXR. The target genes encode enzymes involved in lipid metabolism and adipocyte differentiation. Accordingly, the discovery of transcription factors involved in the control of lipid metabolism has provided an understanding of the regulation of energy homeostasis in invertebrates, and has also provided objectives for the development of therapeutic agents for alterations such as Obesity, diabetes and dyslipidemia.

25 PPARy is a member of the nuclear receptor superfamily of ligand activated transcription factors, and has been shown to be expressed in the specific manner of adipose tissues. Its expression is induced early during the course of differentiation of several preadipocyte cell lines. Additional developments have currently demonstrated that PPARy plays a major role in the adipogenic signaling cascade. PPARy also regulates the ob / leptin gene that is involved in the regulation of energy homeostasis and adipocyte differentiation that has been shown to be a critical stage to focus for antiobesity and diabetic states.

In an effort to understand the role of PPARy in adipocyte differentiation, several investigations have focused on the identification of PPARy activators. A class of compounds, thiazolidinediones, which was known

35 that had adipogenic effects on preadipocytes and mesenchymal stem cells in vitro and antidiabetic effects in animal models of non-insulin dependent diabetes mellitus (NIDDM) were also shown to be selective PPARy ligands. More recently, compounds that selectively activate murine PPAR and have been shown to possess antidiabetic activity in vivo in mice.

Despite the advances made in the class of thiazolidinedione antidiabetic agents, unacceptable side effects have limited its clinical use. Accordingly, there is still a need for potent selective PPAR activators that will be useful for the treatment of NIDDM and other alterations related to lipid metabolism and energy homeostasis. Additionally, the compounds that block PPAR activity would be useful to interfere with the maturation of preadipocytes in adipocytes and, therefore,

Four. Five they would be useful in the treatment of obesity and related alterations associated with undesirable maturation of adipocytes. Surprisingly, the present invention discloses compounds that are useful as activators and also as antagonists of PPARy activity and compositions containing them, together with methods for their use.

DETAILED DESCRIPTION OF THE INVENTION

Abbreviations and definitions:

The following abbreviations are used in this description: PPARy: receptor and proliferator activated

55 peroxisome; NIDDM: non-insulin dependent diabetes mellitus; Et3N: triethylamine; MeGH: methanol and DMSO: dimethylsulfoxide.

The term "alkyl" means by itself, or as part of another substituent, if not otherwise indicated, a straight or branched chain or cyclic hydrocarbon radical, or a combination thereof, which can be completely saturated, mono or polyunsaturated and which may include di and multivalent radicals, the number of carbon atoms being designated (ie, C1-C10 means one to ten carbons). Examples of saturated hydrocarbon radicals include groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl) ethyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl and the like. An alkyl group is a group that has one or more double or triple bonds. Examples of unsaturated alkyl groups are vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl),

2,4-pentadienyl, 3- (1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher order homologs and isomers. The term "alkyl", if not indicated otherwise, is also intended to include the alkyl derivatives defined in more detail below as "heteroalkyl" "cycloalkyl" and "alkylene". The term "alkylene" by itself or as part of other substituents means a divalent radical derived from an alkane, for example, by

5 -CH2CH2CH2CH2-. Typically, an alkyl group will have 1 to 24 carbon atoms, with groups having 10 or less carbon atoms in the present invention being preferred. A "lower alkyl" or "lower alkylene" is a short chain alkyl or alkylene group, which generally has eight or fewer carbon atoms.

The term "heteroalkyl", by itself or in combination with another term, if not indicated otherwise, means a straight or branched chain or a cyclic hydrocarbon radical, or a combination thereof, consisting of the indicated number of atoms of carbon and one to three heteroatoms selected from the group consisting of O, N, Si and S, and in which the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heteroatom or heteroatoms O, N and S may be located in any interior position of the heterialkyl group. The heteroatom Si can be located in any position of the

fifteen heteroalkyl group, including the position in which the alkyl group is attached to the rest of the molecule. Examples include -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N (CH3) -CH3, -CH2-S-CH2-CH3, -CH2-CH2-S (O) -CH3, -CH2-CH2-S (O) 2-CH3, -CH = CH-O-CH3, -Si (CH3) 3, -CH2-CH = N-OCH3 and -CH = CH-N (CH3) -CH3. Up to two heteroatoms can be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si (CH3) 3. Also included in the term "heteroalkyl" are the radicals described in more detail below as "heteroalkylene" and "heterocycloalkyl." The term "heteroalkylene", by itself or as part of other substituents, means a divalent radical derived from heteroalkyl, for example, -CH2-CH2-S-CH2CH2- and -CH2-S-CH2-CH2-NH-CH2- . For heteroalkylene groups, heteroatoms can also occupy any or both terms of the chain. Additionally, for "alkylene" and "heteroalkylene" linkage groups, as well as other linkage groups provided for in the present invention, orientation of the linkage groups is not implied.

25 The terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination with other terms, if not stated otherwise, represent cyclic versions of "alkyl" and "heteroalkyl", respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position in which the heterocycle is attached to the rest of the molecule. Examples of cycloalkyl include cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl and the like. Examples of heterocycloalkyl include 1- (1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3 -yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl and the like.

The terms "halo" or "halogen," by itself or as part of other substituents, if not stated otherwise,

35 means a fluorine, chlorine, bromine or iodine atom. Additionally, terms such as "fluoroalkyl" are intended to include monofluoroalkyl and polyfluoroalkyl.

The term "aryl", used alone or in combination with other terms (for example, aryloxy, arylthioxy, arylalkyl), if not indicated otherwise, means an aromatic substituent which can be single ring or multi-ring (up to three ring ) that fuse together or bind covalently. Each of the rings may contain from zero to four heteroatoms selected from N, O and S, in which the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom or atoms are optionally quaternized. Aryl groups containing heteroatoms can be designated as "heteroaryl" and can be attached to the rest of the molecule through a heteroatom. Non-limiting examples of aryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl,

Four. Five 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidyl, 4-pyrimidyl, 2-benzothiazolyl, 5-benzothiazolyl, 2-benzoxazolyl, 5-benzoxazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolinyl, 5-isoquinolinyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolinyl and 6-quinolinyl. Substituents are selected for each of the aryl ring systems indicated above from the group of acceptable substituents described below. The term "arylalkyl" is intended to include radicals in which an aryl group is attached to an alkyl group (for example, benzyl, phenethyl, pyridylmethyl and the like) or a heteroalkyl group (for example, phenoxymethyl, 2-pyridyloxymethyl, 3 - (1-naphthyloxy) propyl and the like).

55 Each of the above terms (for example, "alkyl," "heteroalkyl" and "aryl") are intended to include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are indicated below.

Substituents for alkyl and heteroalkyl radicals (including the groups frequently referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl) may be a variety of groups selected from: -OR ', = O, = NR', = N-OR ', -NR'R ", -SR', halogen, -SiR'R" R "', -OC (O) R', -C (O ) R ', -CO2R', CONR'R ", -OC (O) NR'R", -NR "C (O) R ', -NR'-C (O) NR" R "', -NR" C (O) 2R ', -NH-C (NH2) = NH, -NR'C (NH2) = NH, -NH-C (NH2) = NR', -S (O) R ', -S (O ) 2R ', -S (O) 2NR'R ”, -CN and -NO2 in a number from zero to (2N + 1), in which N is the total number of carbon atoms in said radical. R ', R "and R"' each independently refer to hydrogen, (C1-C8) unsubstituted alkyl and heteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstituted alkyl,

alkoxy or thioalkoxy groups or aryl- (C1-C4) alkyl groups. When R 'and R "are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5, 6 or 7 member ring. For example, -NR'R "is intended to include 1-pyrrolidinyl and 4-morpholinyl. From the foregoing explanation of substituents, those skilled in the art will understand that the term "alkyl" is intended to include groups such as haloalkyl (for example,

5 -CF3 and -CH2CF3) and acyl (for example, -C (O) CH3, -C (O) CF3, -C (O) CH2OCH3 and the like). Preferably, the alkyl groups (and the related alkoxy, heteroalkyl, etc.) are unsubstituted or have 1 to 3 substituents selected from halogen, -OR ', = O, -NR'R ", -SR, -OC (O ) R ', -C (O) R', -CO2R ', -CONR'R ", -NR" C (O) R', -S (O) 2R ', -S (O) 2NR'R ", -CN and -NO2. More preferably, the alkyl and related groups have 0, 1 or 2 substituents selected from halogen, -OR ', = O, -NR'R ", -SR', -CO2R ', -CONR'R", -NR "C (O) R ', -CN and -NO2.

Similarly, the substituents for the aryl groups are varied and are selected from halogen, -OR ', -OC (O) R', -NR'R ", -SR ', -R', -CN, -NO2- CO2R ', -CONR'R ”, -C (O) R', -OC (O) NR'R", -NR "C (O) R ', -NR" C (O) 2R', -NR ' -C (O) NR "R" ', -NH-C (NH2) = NH, -NR'C (NH2) = NH, -NH-C (NH2) = NR', -S (O) R ', -S (O) 2R ', -S (O) 2NR'R ", -N3, -CH (Ph) 2, perfluoro (C1-C4) alkoxy and perfluoro (C1-C4) alkyl, in a number between zero and the total number

fifteen of free valences of the aromatic ring system, and in which R ', R "and R'" are independently selected from hydrogen, (C1-C8) alkyl and heteroalkyl, unsubstituted aryl, (unsubstituted aryl) - (C1- C4) alkyl and (unsubstituted aryl) oxy- (C1-C4) alkyl. Preferably, the aryl groups are unsubstituted or have 1 to 3 substituents selected from halogen, -OR ', -OC (O) R', -NR'R ", -SR ', -R', -CN, -NO2 -CO2R ', -CONR'R ”, -C (O) R', -NR" C (O) R ', -S (O) 2R', -S (O) 2NR'R ", perfluoro (C1- C4) alkoxy and perfluoro (C1-C4) alkyl. Even more preferably, the aryl groups have 0, 1 or 2 substituents selected from halogen, -OR ', -NR'R ", -SR', -R ', -CN, -NO2-CO2R', -CONR'R" , -NR "C (O) R ', -S (O) 2R', -S (O) 2NR'R", perfluoro (C1-C4) alkoxy and perfluoro (C1-C4) alkyl.

Two of the substituents on adjacent atoms of the aryl ring can be optionally substituted by a substituent of the formula in which T and U are independently -NH-, -O-, -CH2- or a single bond and q is an integer

25 from 0 to 2. Alternatively, two of the substituents on adjacent atoms of the aryl ring can be optionally substituted by the substituent of formula -A- (CH2) rB-, in which A and B are independently -CH2-, -O-, -NH-, -S-, -5 (O) -, -S (O) 2-, -S (O) 2NR'- or a single bond and r is an integer from 1 to 3. One of The unique bonds of the new ring formed in this way can be optionally substituted by a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl ring can be optionally substituted by a substituent of formula - (CH2), -X- (CH2) t-, in which syt are independently integers from 0 to 3 and X is -O-, -NR'-, -S-, -S (O) -, -S (O) 2- or -S (O) 2NR'-. The substituent R 'in -NR'- and -S (O) 2NR'- is selected from hydrogen or (C1-C6) unsubstituted alkyl.

As used in this description, the term "heteroatom" is intended to mean oxygen (O), nitrogen 35 (N), sulfur (S) and silicone (Si).

The terms "pharmaceutically acceptable salts" is intended to include salts of the active compounds that are prepared with relatively non-toxic acids or bases, depending on the specific substituents found in the compounds that have been described. When the compounds of the present invention contain relatively acidic functionalities, salts can be obtained by adding bases by contacting the neutral form of said compounds with a sufficient amount of the desired base as is or in a suitable inert solvent. Examples of pharmaceutically acceptable salts by addition of bases include sodium, potassium, calcium, ammonium, organic or magnesium amino salts, or a similar salt. When the compounds of the present invention contain relatively basic functionalities, salts may be obtained by the addition of acids by contacting the neutral form of said compounds with a sufficient amount of the desired acid, as is

or in the form of an appropriate inert solvent. Examples of pharmaceutically acceptable salts by addition of acid include those derived from inorganic acid, such as hydrochloric, hydrobromic, nitric, carbonic, carbonic monohydrogen, phosphoric, phosphoric monohydrogen, phosphoric dihydrogen, sulfuric, sulfuric monohydrogen, iodide or phosphorous and similar, as well as salts derived from relatively non-toxic organic acids, such as acetic, propionic, isobutyric, oxalic, maleic, malonic acids, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginates and the like and salts of organic acids such as glucuronic or galactunoric acids and the like (see, for example, Berge, SM, and others, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66 , 1-19). Certain specific compounds of the present invention contain

55 both basic and acidic functionalities, which allow the compounds to be converted into salts by the addition of acid or basic salts.

The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the main compound in a conventional manner. The main form of the compound differs from the different forms of salts in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the main form of the compound for the purposes of the present invention.

In addition to salt forms, the present invention discloses compounds that are in the form of averages. The pro-medications of the compounds described in this description are the compounds that readily undergo physical changes under physiological conditions to provide the compounds of the present invention. Additionally, pro-medications may be converted into the compounds herein.

invention by chemical or biochemical methods in an ex vivo environment. For example, pro-medications can be slowly converted to the compounds of the present invention when placed in a transdermal patch vessel, with an appropriate enzyme or chemical reagent.

5 Certain compounds of the present invention may exist in non-solvated forms and also as solvated forms, including hydrated forms. In general, solvated forms are equivalent to non-solvated forms and are intended to fall within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline forms or in amorphous forms. In general, all physical forms are equivalent for the uses provided for by the present invention and are intended to fall within the scope thereof.

Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; Racemates, diastereomers, geometric isomers and individual isomers are all intended to fall within the scope of the present invention.

fifteen The compounds of the present invention may also comprise unnatural proportions of atomic isotopes in one or more of the atoms constituting said compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as, for example, tritium (3H), iodine 125 (125I) or carbon 14 (14C). All isotopic variations of the compounds of the present invention, radioactive or not, are intended to be included within the scope of the present invention.

Generalities:

A new class of compounds that interact with PPARy has been discovered. Depending on the environment

25 Biological (for example, cell type, host disease status, etc.), these compounds can activate or block the actions of PPARy. By activating the PPAR receptor, the compounds may be used as therapeutic agents capable of modulating states mediated by the PPAR receptor. As noted above, an example of such states is NIDDM. Additionally, the compounds are useful for preventing and treating diabetes states (for example, neuropathy, retinopathy, glomerulosclerosis and cardiovascular disorders), and treating hyperlipidemia. Additionally, the compounds are useful for modulating inflammatory conditions that have been observed more recently that are controlled by PPARy (see, Ricote, et al., Nature, 391: 79-82 (1998) and Jiang, et al., Nature , 391: 82-86 (1998)). Examples of inflammatory conditions include rheumatoid arthritis and atherosclerosis.

35 Compounds that act by PPARy antagonism are useful for treating hypertension, hyperlipidemia, hypercholesterolemia, hyperlipoproteinemia and metabolic disorders.

Embodiments of the invention:

In one aspect, the present invention discloses compounds represented by the formula

Four. Five or a pharmaceutically acceptable salt thereof, in which

Ar1 is a substituted or unsubstituted 3-quinolinyl; X is -O-, -NH-, or -S-; Y is -NH-S (O) 2-; R1 is an element selected from the halogen group, (C1-C8) alkyl, (C1-C8) alkoxy, -C (O) R14, -CO2R14, and -C (O) NR15R16, in which R14 is an element selected from the group consisting of hydrogen, (C1-C8) alkyl, (C2-C8) heteroalkyl; wherein heteroalkyl means a straight or branched stable chain or a cyclic hydrocarbon radical or combinations thereof, consisting of the indicated number of carbon atoms and one to three

55 heteroatoms selected from the group consisting of O, N, Si and S, and in which the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom may be optionally quaternized, the heteroatoms O, N and S may be located at any inner position of the heteroalkyl group; aryl, and (C1-C4) aryl alkyl; R15 and R16 are elements independently selected from the group consisting of hydrogen, (C1-C8) alkyl, (C2-C8) heteroalkyl; wherein heteroalkyl means a straight or branched stable chain or a cyclic hydrocarbon radical or combinations thereof, consisting of the indicated number of carbon atoms and one to three heteroatoms selected from the group consisting of O, N, Si and S, and in which the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom may be optionally quaternized, the heteroatoms O, N and S may be located in any interior position of the heteroalkyl group; aryl, and (C1-C4) aryl alkyl; or considered together with the nitrogen to which each one is fixed form an element of

5 ring with 5, 6 or 7 members; R2 is a phenyl group having 0 to 3 substituents selected from the group consisting of halogen, -OCF3, -OH, -O (C1-C8) alkyl, -C (O) - (C1-C8) alkyl, -CN , -CF3, (C1-C8) alkyl, and -NH2; and R3 is an element selected from the group consisting of halogen, methoxy and trifluoromethoxy.

10 Preferably, represented by a formula selected from the group consisting of

More preferably, represented by the formula

Advantageously, in it R1 is an element selected from the group consisting of halogen, (C1-C8) alkyl and (C1-C8) alkoxy; R2 is a phenyl group having 0 to 3 substituents selected from the group consisting of halogen, -OCF3, -OH, -O (C1-C8) alkyl, -C (O) - (C1-C8) alkyl, -CN , -CF3, (C1-C8) alkyl and -NH2; and R3 is

25 selected from the group consisting of halogen, methoxy and trifluoromethoxy.

Preferably, in which R2 is a phenyl group having 0 to 3 substituents selected from the group consisting of halogen, -OCF3, and -CF3.

More preferably, wherein R1 and R3 are each independently a halogen and R2 is a phenyl group having 0 to 3 substituents selected from the group consisting of halogen, -OCF3 and -CF3.

Advantageously, in which the compound is of formula

Preferably, the quinolinyl is unsubstituted.

10 In another aspect of the present invention, a composition comprising a pharmaceutically acceptable excipient and a compound according to any of the above embodiments is disclosed.

In another aspect of the present invention, the use of a compound of any of the above 15 embodiments for the manufacture of a medicament for use in modulating a metabolic alteration or inflammatory state in a host is disclosed.

In another aspect of the present invention, a compound of any of the above embodiments is disclosed for use in modulating a metabolic alteration or inflammatory state in a host.

twenty Preferably, wherein said host is a mammal selected from the group comprising humans, dogs, monkeys, mice, rats, horses and cats.

Further preferably, wherein said compound is formulated for oral administration. Advantageously, wherein said compound is formulated for topical administration.

Preferably, in which said modulation prevents a state mediated by PPARy.

30 Further preferably, in which said alteration or condition is selected from the group consisting of NIDDM, obesity and hypercholesterolemia, and other lipid-mediated diseases, and inflammatory conditions.

Advantageously, wherein said compound is formulated for parenteral administration.

35 Preferably, in which said metabolic alteration is mediated by PPARy.

Furthermore preferably, wherein said metabolic alteration is NIDDM:

Advantageously, in which said inflammatory state is rheumatoid arthritis or atherosclerosis. Preferably, in which the host is human.

Preparation of the compounds

Four. Five The compounds of the present invention can be prepared using standard synthetic methods. For example, scheme 1 shows procedures for the preparation of compounds of structural formula (Ia). Those skilled in the art will understand that similar procedures can be used for the synthesis of compounds in the other structural classes.

fifty As shown in Scheme 1, compounds of the present invention can be prepared starting from commercially available 2-chloro-5-nitrobenzonitrile (i). Treatment of J with a phenol, thiophenol or optionally protected aniline in the presence of a base and heat provides adduct (ii). Reduction of the nitro group in ii, for example, with H2, in the presence of Raney nickel catalyst, provides an aniline derivative (iii). The sulfonylation of iii with an appropriate arylsulfonyl halide (Ar1 502C1) in the presence of a base (typically a tertiary amine) provides the target compound (iv). Compound iii can also be converted into a related compound of formula (vi) in which the orientation of the sulfonamide bond is reversed. Thus, the conversion of aniline iii to benzenesulfonyl chloride v can be achieved using procedures described in Hoffman, Organic Syntheses Collective Volume VII, p. 508-511. Subsequent treatment of v with an appropriate aniline provides the objective compound vi.

10 Other compounds of the present invention can be prepared starting, for example, from 3,4-difluoronitrobenzene, 3-chloro-4-fluoronitrobenzene, 2-chloro-5-nitroanisole, 3-bromo-4-fluoronitrobenzene and the like.

Compound Analysis

fifteen The compounds of the present invention can be evaluated by modulation of the PPAR receptor using assays such as those described by Jiang, et al., Nature 391: 82-86 (1998), Ricote, et al., Nature 391: 79-82 (1998) and Lehmann, et al., J. Biol. Chem. 270 (12): 12953-12956 (1995). Alternatively, the compounds can be evaluated for their ability to displace radiolabeled BRL 49653 from a PPARy-GST fusion protein as follows:

Materials:

PPARy-GST fusion protein (prepared according to standard procedures), [3H] - BRL 49653 having 50 Ci / mmol of specific activity, Polyfiltronics Unifilter 350 filtering plate and Sepharose® glutathione beads (from 5 pharmacy: washed two times with 10x binding buffer in which BSA and DTT can be excluded).

Process:

Binding buffer (10 mM Tris-HCl, pH 8.0, 50 mM KCI, 10 mM DTT, 0.02% BSA and 0.01% NP-40) is added in

10 amounts of 80 microliters to the wells of a filtration plate. The test compound is then added to 10 microliters of DMSO. The PPARy-GST fusion protein and the radiolabeled BRL compound are pre-mixed in binding buffer containing 10 mM DTT and added in amounts of 10 microliters in the wells of the plate to provide final concentrations of 1 µg / well of PPARy-GST fusion protein and 10 nM compound [3H] -BRL 49653. The plate is incubated for 15 minutes. Glutathione agarose beads are added

fifteen in 50 µl of binding buffer and the plate is shaken vigorously for one hour. The plate is washed four times with 200 µL / well of binding buffer (without BSA and DTT). The bottom of the plate is sealed and 200 µL / well of scintillation cocktail is added. The upper part of the plate is then sealed and the radioactivity is determined.

twenty Formulation and administration of the compounds (compositions)

The compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms. Thus, the compounds of the present invention can be administered by injection, that is, intravenous, intramuscular, intracutaneous, subcutaneous, intraduodenal or

25 intraperitoneal Likewise, the described compounds can be administered by inhalation, for example, intranasally. In addition, the compounds of the present invention can be administered transdermally. Accordingly, the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I).

30 To prepare pharmaceutical compositions from the compounds of the present invention, solid or liquid pharmaceutically acceptable carriers can be used. Solid preparations have forms comprising powdered materials, tablets, pills, capsules, tablets, suppositories and dispersible granules. A solid carrier can be one or more substances that can also act as diluents, flavoring agents,

35 binders, preservatives, tablet disintegrating agents or encapsulation material.

In powdered materials, the carrier is a finely divided solid that is in admixture with the finely divided active component. In tablets, the active component is mixed with the carrier that has the necessary binder characteristics in appropriate proportions and is compacted in the form and

40 desired dimensions.

The powdered materials and tablets contain preferably 5% or 10% to 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter

Four. Five and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulation material, such as a carrier, facilitating a capsule in which the active component, with or without other carriers, is surrounded by a carrier which, in this way , is associated with it. Similarly, tablets and pills are included. Tablets, powders, capsules, pills, tablets and tablets may be used as solid dosage forms suitable for oral administration.

fifty To prepare suppositories, a low melting wax is melted first, such as a mixture of fatty acid glycerides or cocoa butter, and the active component is homogeneously dispersed therein by stirring. The homogeneous molten mixture is then poured into molds of suitable sizes. It is allowed to cool and, therefore, solidify.

55 Liquid form preparations comprise solutions, suspensions and emulsions, for example, water or water / propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in aqueous polyethylene glycol solution.

60 Aqueous solutions prepared for oral use can be prepared by dissolving the active component in water and adding suitable coloring agents, flavorings, stabilizers and thickeners, as desired. Aqueous suspensions prepared for oral use can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other well known suspending agents.

65 Solid forms are also included in preparations intended for conversion, shortly before use, in liquid form preparations for oral administration. These liquid forms include solutions, suspension and emulsions. These preparations may contain, in addition to the active component, coloring agents, flavorings, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners,

5 solubilizers and the like.

The pharmaceutical preparation preferably takes place in unit dosage. In this form, the preparation is subdivided into unit doses containing appropriate amounts of the active component. The unit dosage form can be a packaged preparation containing the package determined amounts of preparation, such

10 as packaged tablets, capsules and powdered materials in vials or ampoules. Also, the unit dosage may be a capsule, tablet, tablet or tablet or it may be the appropriate number of any of these in packaged form.

The amount of active component in a unit dose preparation can be varied or adjusted from 0.1 mg to

fifteen 1,000 mg, preferably 1.0 mg to 100 mg according to the particular application and potency of the active component. If desired, the composition may also comprise other active therapeutic agents.

In therapeutic use for the treatment of obesity, NIDDM or inflammatory conditions, the compounds used in the pharmaceutical method of the invention are administered with an initial dose of about 20 0.001 mg / kg to about 100 mg / kg daily. A daily dose ranging from about 0.1 mg / kg to about 10 mg / kg is preferable. However, the dosages may vary depending on the requirements of the patient, the severity of the condition being treated and the compound used. The determination of the appropriate dose for a specific situation is within the knowledge of the practitioner. In general, treatment begins with smaller doses that are less than the optimal dose.

25 of the compound. Subsequently, the dose is increased with small increases until the optimum effect is reached in the circumstances of the moment. For convenience, the total daily dose may be divided and administered in portions during the day, if desired.

The following examples are explained by way of illustration, not intended to limit the scope of the invention. 30

EXAMPLES

The reagents and solvents used below can be obtained from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA). The 1H-NMR spectra were recorded on a Varian 35 Gemini 400 MHz NMR spectrometer. Significant peaks are tabulated in the following order: number of protons, multiplicity (s, singlet (“singlet”); d, doublet (“doublet”); t, triplet (“triplet”); q, quartet (“quartet”) ); m, multiplet (“multiplet”); br s, broad singlet (“broad singlet”)) and coupling constant (s) in Herzios. Electron ionization (EI) mass spectra were recorded on a Hewlett Packard 5989A mass spectrometer. The results of mass spectrometry are indicated as the proportion of mass with respect to the charge, followed by the relative abundance of each ion (in parentheses). The tables indicate a unique m / e value for M + H (or indicated in MH form) of the ion that contains the most common atomic isotopes. The isotope models correspond to the expected formula in all cases. Electrospray ionization (ESI) mass spectrometry analysis (ESI) was performed on a Hewlett-Packard 1100 MSD electrospray mass spectrometer using the HP1 100 HPLC for sample delivery.

Four. Five Normally, the analyte was dissolved in methanol at 0.1 mg / mL and 1 microliter was infused with the administration solvent in the mass spectrometer that scanned 100 to 1500 daltons. All compounds could be analyzed in the positive ESI mode using 1: 1 acetonitrile / water with 1% acetic acid as administration solvent. The compounds indicated below could also be analyzed in the ESI negative mode using 2 mM NH4OAc in acetonitrile / water as administration solvent.

fifty Abbreviations: N-hydroxybenzotriazole (HOBT), 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), N-methylmorpholine (NMM), 1-hydroxy-7-azabenzotriazole ( HOAT), O- (7-azabenzotriazol-1-yl) -N, N, N ', N'tetramethyluronium hexafluorophosphate (HATU), 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride (EDCI).

55 EXAMPLE 85

Shows the synthesis of compound 85.3

Compound 85.1 was prepared by a modification of the published procedure of Albert and Barlin (J. Chem. Soc. 2384-2396 (1959)). 3-Aminoquinoline (15.0 g, 105 mmol) was suspended in a mixture of 10N HCl (40 mL), ice (21 g) and water (100 mL) at 0-5 ° C, before sodium nitrite (7, slowly added) 6 g, 110 mmol). The mixture was then added portionwise to another solution of potassium ethyl xanthate (20.8 g, 125 mmol) in water (60 mL) at 45 ° C. The mixture was heated for 1 hour before cooling. The mixture was then extracted with ether. The ethereal solution was washed with a solution of 2N NaOH, water and saline before drying over magnesium sulfate. After filtration, solvent removal provided a brown oil (15 g), which was then dissolved in ethanol (150 mL) and refluxed with KOH (25 g) under a nitrogen atmosphere overnight. The ethanol solvent was then removed in vacuo, and the residue was separated between water and ether. The ethereal solution was discarded. The aqueous solution was acidified to pH = ~ 4, before extracting with ether. The ethereal solution was then washed with saline, dried over magnesium sulfate, filtered and concentrated in vacuo to provide crude product (7.5 g) as brown oil. Subsequent flash chromatography with eluent (0% -5% -10% ethyl acetate / dichloromethane) yielded 3-mercaptoquinoline (85.1) (5.35 g, 32% yield) as a solid. 1 H NMR (DMSO) 8 9.02 (1H, d, J = 2.3 Hz), 8.63 (1H, d, J = 2.2 Hz), 7.95-8.05 (2H, m) , 7.75-8.02 (1H, m), 7.60-7.67 (1H, m).

To a mixture of 3-mercaptoquinoline (85.1) (1.18 g, 7.33 mmol) and 1,2,3-chloro-5-nitrobenzene (1.66 g, 7.33 mmol) dissolved in ethanol (100 mL ), a THF solution of t-BuOK (7.5 mL, 1M) was added. The mixture was then heated at 80 ° C overnight before cooling. After removal of the ethanol solvent, the mixture was separated between ethyl acetate and water. The organic solution was washed with saline, dried over magnesium sulfate and filtered. The filtrate was then concentrated to provide a crude product, which was then subjected to flash chromatography with eluent (10% hexane / dichloromethane) to provide 85.2 (1.80 g, 70% yield) as yellow oil. 1H NMR (DMSO) 8 8.75 (1H, d, J = 2.3), 8.51 (1H, s), 8.22 (1H, s), 8.01 (1H, d, J = 8 , 4 Hz), 7.92 (1H, d, J = 7.6 Hz), 7.74-7.80 (1H, m), 7.60-7.66 (1H, m).

A solution of ethyl acetate (100 mL) of 85.2 (1.80 g, 5.1 mmol) and tin (II) chloride dihydrate (6.88 g, 30 mmol) was heated under reflux overnight before cooling. The solution was then poured into a solution of 1N NaOH (400 mL). After stirring for 30 min, the mixture was separated, and the organic solution was washed with water, saturated sodium bicarbonate and saline. After drying over magnesium sulfate, the solution was filtered and concentrated in vacuo. The residue was mixed with dichloromethane (10 mL) and subjected to sonication. Subsequent vacuum filtration facilitated aniline 85.3 (1.35 g, 82% yield) as an off-white solid. 1 H NMR (DMSO) 8 8.61 (1H, d, J = 2.4), 7.96 (1H, d, J = 8.4 Hz), 7.88 (1H, d, J = 8.2 Hz), 7.83 (1H, d, J = 2.2 Hz), 7.67-7.72 (1H, m), 7.54-7.60 (1 H, m). mp 213.2 ° C.

EXAMPLE 86

It shows the synthesis of compound 86 (see table 16).

Aniline 85.3 (250 mg, 0.78 mmol) and 2-chlorobenzenesufonyl chloride (339 mg, 1.60 mmol) were dissolved in a mixed solvent of THF (5 mL) and dichloromethane (5 mL). To the solution was added pyridine (0.185 mL, 2.34 mmol) and a catalytic amount of DMAP. The solution was heated at 50 ° C to remove dichloromethane by distillation, and then THF with the aid of vacuum. The residue was subjected to flash chromatography with eluent (2.5% ethyl acetate / dichloromethane) to provide sulfonamide 86 (302 mg, 78%) as an off-white solid. 1 H NMR (DMSO) 8 11.58 (1H, s), 8.61 (1H, d, J = 2.4 Hz), 8.19 (1H, d, J = 7.6 Hz), 7.83-8.00 (3H, m), 7.67-7 , 75 (3H, m), 7.56-7.65 (2H, m), 7.31 (2H, s). MS (M + H) 494.9. mp: 219.6 ° C. Anal. calcd: C 50.87, H 2.64, N 5.65; found C 50.86, H 2.62, N 5.52.

The compounds of Table 16 were prepared by the procedure of Example 86 from compound 84.3 and the corresponding arylsulfonyl chloride.

Table 16

k Ra Rb Rc Rd m / e (M + H) 86 0 ClH HH 495

87.1 0 ClH Cl H 529

87.2 0 HHHH 461

<dl><dt>87.3 </dt><dd>0 Cl H CF3 H 561 (MH) </dd></dl>

<dl><dt>88.1 </dt><dd>1 ClH HH 511 </dd></dl>

88.2 1 Cl H Cl H 543 (MH)

88.3 1 HHHH 477

EXAMPLE 87

Example 87.1

1 H NMR (DMSO) 8 11.66 (1H, broad), 8.63 (1H, d, J = 2.3 Hz), 8.18 (1H, d, J = 8.6 Hz), 7.85 -8.00 (4H, m), 7.70-7.75 (2H, m), 7.57-7.62 (1H, m), 7.32 (2H, s). MS (M + H) 529.0. mp 214.0 ° C. Elemental analysis: theory C 47.56, H 2.28, N 10 5.28; found C 47.30, H 2.36, N 5.37.

Example 87.2

1 H NMR (DMSO): 8 11.22 (1H, s), 8.61 (1H, d, J = 2.3 Hz), 7.82-7.98 (5H, m), 7.57-7 , 75 (5H, m), 7.34 (2H, s). MS 15 (M + H) 461.0. mp 246.8 ° C. Elemental analysis theory C 54.67, H 3.06, N 6.07; found C 54.71, H 3.05, N 5.94.

Example 87.3

1 H NMR (DMSO) 8 11.70-12.00 (1 H, broad), 8.60-8.67 (1 H, m), 8.35-8.43 (1 H, m), 8.20- 8.25 (1H, m), 7.56-8.06 (6H, m), 7.32-7.38 (2H, m). MS (MH) 560.9. mp: 225.1 ° C. Elementary analysis: theory C 46.86, H 2.15, N 4.97; found C 47.01, H 2.26, N 4.98.

EXAMPLE 88

25 General procedure for the oxidation of sulfur to sulfoxide:

A naphthylthioether of examples 86 or 87 (0.2 mmol) was dissolved in a mixed solvent of dichloromethane (10 mL) and methanol (5 mL). To the solution was added mCPBA (120 mg, 0.7 mmol, 77% pure) in six batches for 20 minute intervals. Then the solution was washed with 5% sodium thiosulfate solution, 1% bicarbonate solution

30 sodium and saline and then dried over magnesium sulfate. After filtering, the filtrate was concentrated to provide a crude product, which was subjected to flash chromatography with eluent (5% -30% ethyl acetate / dichloromethane) to provide the corresponding sulfoxide.

Example 88.1

35 1H NMR (DMSO): 8 11.75 (1H, s), 8.82 (1H, s), 8.68 (1H, s), 8.15-8.20 (2H, m), 8.09 (1H, d, J = 8.5 Hz), 7.85-7.91 (1H, m), 7.67-7.75 (3H, m), 7.57-7.64 (1H, m ), 7.17 (2H, s). MS (M + H) 511. mp 239.5 ° C with decomposition. Elementary analysis: theory C 49.28, H 2.56, N 5.47; found C 49.30, H 2.63, N 5.37.

40 Example 88.2

1H NMR (DMSO): 8 11.5-12.0 (broad), 8.83 (1H, s), 8.68 (1H, s), 8.15-8.20 (2H, m), 8 , 09 (1H, d, J = 8.5 Hz), 7.857.92 (2H, m), 7.55-7.75 (2H, m), 7.17 (2H, s). MS (MH) 542.9. mp: 234.4. Elemental analysis: theory C 46.17, H 2.21, N 5.13; found C 45.97, H 2.26, N 4.92.

Example 88.3

1H NMR (DMSO) 8 11.43 (1H, s), 8.81 (1H, s), 8.68 (1H, s), 8.18 (1H, d, J = 8.2 Hz), 8 , 09 (1H, d, J = 8.5 Hz), 7.827.90 (3H, m), 7.58-7.74 (4H, m), 7.21 (2H, s). MS (M + H) 476.9. mp 261.8 ° C with decomposition. Elemental analysis: theory C 52.83, H 2.96, N 5.87; found C 52.71, H 3.05, N 5.71.

EXAMPLE 174

10 3-Hydroxyquinoline (prepared according to the procedure of Naumann, et al., Synthesis, 1990, 4, 279-281) (3 g) and 1,2,3-trichloro-5-nitrobenzene (4.7 g) were dissolved in DMF (80 mL) and heated with cesium carbonate (7.4 g) for 2 hr at 60 ° C. The reaction was poured into ice / water (500 ml). The resulting off-white precipitate was collected by filtration and rinsed with hexane to provide compound 174 as a suitable solid (6.9 g).

fifteen for use in the next reaction. 1 H NMR in CDCl 3 8.863 (d, J = 2.2Hz, 1H), 8.360 (s, 2H), 8.106 (d, J = 8.6Hz, 1H), 7.646 (m, 2H), 7.529 (d, J = 8.6Hz, 1H), 7.160 (d, J = 2.2Hz, 1H).

EXAMPLE 175

twenty To a solution of compound 180 (6.9 g) in ethanol / THF / water (ratio 40:20:10) was added ammonium chloride (3.3 g) and iron powder (3.4 g). This mixture was heated at reflux for 5 hr. The heated mixture was then filtered through Celite and concentrated. The residue was dissolved in ethyl acetate and washed with saturated NaHCO3 solution followed by water and then saline. The solution was dried over magnesium sulfate and concentrated to

25 provide compound 175 as an off-white solid (5.6 g). 1 H NMR in (DMSO) 8 8.846 (d, J = 2.9 Hz, 1 H), 8.010 (m, 1 H), 7.915 (m, 1 H), 7.645 (m, 1 H), 7.560 (m, 1 H), 7.401 ( d, J = 2.9Hz, 1H), 6.778 (s, 2H), 5,762 (s, 2H).

Treatment of aniline 175 with various sulfonyl chloride, according to conventional procedures, 30 provided the sulfonamides in Table 24.

Table 24

Example XYV AB CD 176 HH ClCF3 H ClH 177 HH ClClH CF3 H 178 HH ClCl H Cl H 180 HHH ClH ClH 181 -CO2Me H Cl Cl H Cl H 182 H -CO2Me Cl Cl H Cl H 183 -CO2H H ClCl H Cl H 184 H -CO2H Cl Cl H Cl H 185 Me H ClCl H Cl Me 186 HHF Cl H Cl Me

EXAMPLE 176

5 1 H NMR (DMSO) 8 11.4-11.6 (1H, broad), 8.87 (1H, d, J = 2.9 Hz), 8.15-8.22 (2H, m), 8, 00-8.08 (2H, m), 7.87 (1H, d, J = 8.0 Hz), 7.55-7.68 (2H, m), 7.47 (1H, d, J = 2.9 Hz), 7.35 (2H, s). MS (MH) 545. mp 98.8 ° C.

EXAMPLE 177

10 1 H NMR (DMSO) 8 11.58 (1 H, s), 8.86 (1 H, d, J = 2.9 Hz), 8.38 (1 H, d, J = 8.4 Hz), 8.23 (1H, s), 8.01 (1H, d, J = 8.4 Hz), 7.86 (1H, d, J = 8.1 Hz), 7.53-7.68 (2H, m) , 7.46 (1H, d, J = 2.9 Hz), 7.34 (2H, s). MS (MH) 545.0

EXAMPLE 178

fifteen 1 H NMR (d6-acetone) 9.9 (1H, br s), 8.794 (1H, d, J = 2.9 Hz), 8.23 ​​(1H, d, J = 8.4 Hz), 8.035 (1H , br d, J = 8.4 Hz), 7.793 (1H, d, J = 1.5 Hz), 7.78 (1H, m), 7.62-7.70 (2H, m), 7, 57 (1 H, td, J = 6.8, 1.2 Hz), 7.476 (2H, s), 7.364 (1H, d, J = 2.6 Hz). MS (MH) 511.0.

twenty EXAMPLE 179

1H NMR (300MHz / CDCl3) 8 2.43 (3H, s), 7.10 (1H, d, J = 3Hz), 7.26 (2H, s), 7.48-7.64 (4H, m ), 7.96 (1H, s), 8.09 (1H, d, J = 8.7Hz), 8.78 (1H, d, J = 3Hz). MS (M + H) 527. mp 233-235

25 EXAMPLE 180

1H NMR (300MHz / CDCl3) 8 7.14 (1H, dd, J = 2.6Hz, J = 8.9Hz), 7.26 (1H, d, J = 8.9Hz), 7.33 (1H, d, J = 2.6Hz), 7.56-7.58 (2H, m), 7.66-7.69 (2H, m), 7.87 (1H, m), 7.93 (1H, d, J = 2.0Hz), 8.00 (1H, m), 8.09 (1H, d, J = 8.5Hz), 8.80 (1H, d, J = 2.9Hz), 11, 06 (1H, brs). MS (M + H)) 479. mp 12: ° C

EXAMPLE 181

3- [2,6-Dichloro-4- (2,4-dichloro-benzenesulfonylamino) -phenoxy] -quinolin-6-carboxylic acid methyl ester (181)

35 A solution of 3- (4-amino-2,6-dichloro-phenoxy) -quinolin-6-carboxylic acid methyl ester (312) (0.93 mmol) and 2,4-dichlorobenzenesulfonyl chloride (250 mg) was stirred. , 1.02 mmol) in pyridine (0.13 ml, 1.53 mmol) -CH2Cl2 (3.7 ml) at room temperature for 12 hr. Saturated NaHCO3 was added to the reaction mixture, which was then extracted twice with AcOEt. The organic layer was washed with saline, dried over anhydrous MgSO4 and concentrated. The crude residue was purified by column chromatography (Hexane / AcOEt = 2 / 1.80 g of silica gel) to

40 provide compound 181 (237 mg, 41%, in 3 steps).

1H NMR (300MHz, DMSO-d6) 8 3.90 (3H, s), 7.31 (2H, s), 7.72 (1H, dd, J = 1.8, 7.8Hz), 7.79 (1H, d, J = 3.0Hz), 7.96 (1H, d, J = 1.8Hz), 8.11 (2H, s), 8.18 (1H, d, J = 7.8Hz) , 8.64 (1H, s), 8.99 (1H, d, J = 3.0Hz), 11.42 (1H, br s). MS (M + H)

571.

5 EXAMPLE 182

3- [2,6-Dichloro-4- (2,4-dichloro-benzenesulfonylamino) -phenoxy] -quinolin-8-carboxylic acid methyl ester (182)

To a solution of 3- (4-amino-2,6-dichloro-phenoxy) -quinolin-8-carboxylic acid methyl ester (315) (1.26 mmol) in pyridine (0.15 ml, 1.80 mmol ) and CH2Cl2 (5 ml), 2,4-dichlorobenzenesulfonyl chloride (381 mg, 1.55 mmol) was added. The mixture was stirred at room temperature for 12 hr. Saturated NaHCO3 was added to the reaction mixture, which was then extracted twice with AcOEt. The organic layer was washed with saline, dried over MgSO4, and concentrated. The crude residue was purified by column chromatography (Hexane / AcOEt = 2 / 1.80 g of silica gel) to give compound 182 (506 mg, 70%) as a white solid.

fifteen 1H NMR (300MHz, DMSO-d6) 8 3.91 (3H, s), 7.31 (2H, s), 7.57-7.65 (2H, m), 7.72 (1H, dd, J = 2.1, 8.6Hz), 7.83 (1H, d, J = 8.6Hz), 7.96 (2H, d, J = 2.1Hz), 8.03 (1H, d, J = 8.6Hz), 8.18 (1H, d, J = 8.6Hz), 8.94 (1H, d, J = 2.1Hz), 11.4 (1H, br s). MS (M + H) 571

EXAMPLE 183

3- [2,6-Dichloro-4- (2,4-dichloro-benzenesulfonylamino) -phenoxy] -quinolin-6-carboxylic acid (183)

To a solution of 3- [2,6-dichloro-4- (2,4-dichloro-benzenesulfonylamino) -phenoxy] -quinolin-6-carboxylic acid methyl ester (181) (200 mg, 0.35 mmol) in THF / MeOH (2 ml / 2 ml) 4N NaOH (0.1 ml, 0.4 mmol) was added. This

25 mixture was refluxed for 2.5 hr. The reaction mixture was cooled to room temperature and neutralized with 2N HCl, and then concentrated. The residue was extracted twice with AcOEt. The organic layer was washed with saline, dried over anhydrous MgSO4, and concentrated to provide a solid. The crude product was recrystallized with Hexane / AcOEt to provide compound 183 (153 mg, 78%). 1H NMR (300MHz, DMSO-d6) 8 7.16 (2H, s), 7.62 (1H, dd, J = 2.0, 8.5H), 7.73 (1H, d, J = 2, 9Hz), 7.82 (1H, s), 8.088.11 (3H, m), 8.60 (1H, s), 8.95 (1H, d, J = 2.9Hz), 13.2 (1H , br s). MS (M + H) 557. mp 228-2

EXAMPLE 184

3- [2,6-Dichloro-4- (2,4-dichloro-benzenesulfonylamino) -phenoxy] -quinolin-8-carboxylic acid (184)

35 To a solution of 3- [2,6-dichloro-4- (2-chloro-4-trifluoromethyl-benzenesulfonylamino) -phenoxy] -quinolin8-carboxylic acid methyl ester (183) (402 mg, 0.7 mmol) in THF / MeOH = 0.1 ml / 0.3 ml 4N NaOH (0.2 ml, 0.77 mmol) was added. The mixture was refluxed for 12 hr. After cooling to room temperature, the reaction mixture was filtered to remove insoluble materials. The filtrate was concentrated and the residue was dissolved in aqueous NH4Cl, extracted twice with AcOEt. The organic layer was washed with saline, and dried over anhydrous MgSO4, and concentrated to provide compound 184 (197 mg, 50%) as a white solid. 1 H NMR (300 MHz, DMSO-d 6) 8 7.32 (2H , s), 7.70-7.81 (2H, m), 7.90 (1H, d, J = 2.2Hz), 7.96 (1H, d, J = 2.2Hz), 8,178.19 (1H, m), 8.22-8.24 (1H, m), 8.38-8.39 (1H, m), 9.11 (1H, d, J = 2.2Hz), 11.4 (1H, br s), 15.4 (1H, br s). MS (M + H)

557. mp 263-266 ° C. Four. Five

EXAMPLE 185

2,4-Dichloro-N- [3,5-dichloro-4- (6-methyl-quinolin-3-yloxy) -phenyl] -5-methyl-benzenesulfonamide (185)

To a solution of 3,5-dichloro-4- (6-methyl-quinlin-3-yloxy) -phenylamine (339) (400 mg, 1.25 mmol) in pyridine (0.12 ml, 1.48 mmol) -CH2Cl2 (4 ml) 2,4-dichloro-5-methylbenzenesulfonyl chloride (325 mg, 1.25 mmol) was added. The mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated and the residue was purified by column chromatography (Hexane / AcOEt = 2 / 1.80 g of silica gel) to provide compound (185) (453 mg, 66%) as a white solid.

55 1H NMR (300MHz, DMSO-d6) 8 2.41 (3H, s), 2.44 (3H, s), 7.31 (3H, s), 7.49 (1H, d, J = 8.7Hz ), 7.61 (1H, s), 7.88-7.91 (2H, m), 8.19 (1H, s), 8.74 (1H, d, J = 3.0Hz), 11, 3 (1H, br s). MS (M + H) 541 mp 228-230 ° C.

EXAMPLE 186

PART 1

Preparation of 3-chloro-5-fluoro-4- (quinolin-3-yloxy) nitrobenzene (186.1)

To a solution of 3,4-difluoronitrobenzene 1.00 g in concentrated H2SO4 (20 ml), Cl2O was added portionwise in 65 CCl4 (25 ml, prepared as described in Cady GH and others in Inorg. Synth. Vol 5, p156 (1957)). The mixture is

stirred at room temperature overnight. The mixture was poured into crushed ice and extracted with Et2O (30 ml x 3). The combined ether layers were washed with 10% Na2SO3 and saline, and dried over Na2SO4. The solvent was concentrated to approximately 10 ml (this solution contained 3-Chloro-4,5-difluoronitrobenzene). This solution was diluted with acetone (60 ml), and then 0.75 g 3-hydroxyquinoline and 2.2 g K2CO3 5 were added to this solution. The mixture was heated at reflux for 1.5 hr. After cooling the reaction mixture was filtered through a short bed of Celite. The filtrate was concentrated to provide an oil, which was then purified by column chromatography (silica gel, AcOEt: Hexane = 1: 5) to provide the intermediate of the compound.

186.1 (0.980 g) as yellow oil.

PART 2

Preparation of 3-chloro-5-fluoro-4- (quinolin-3-yloxy) phenylamine (186.2)

Powdered iron (1.92 g) was added to a solution of 3-chloro-5-fluoro-4- (quinolin-3-yloxy) nitrobenzene (186.1)

fifteen (0.980 g) and NH4Cl (1.64 g) in EtOH (50 ml) -H2O (5 ml). The mixture was heated at reflux for 1 hr. After cooling the reaction mixture was filtered by a short bed of Celite. The filtrate was concentrated, diluted with saturated NaHCO3 and extracted with AcOEt (30 ml x 3). The combined organic layers were washed with saline and dried over Na2SO4. The solvent concentration provided crude product, which was purified by column chromatography (silica gel, AcOEt: Hexane = 1: 3) to provide 186.2 aniline (0.420 g) as a colorless solid.

PART 3

Preparation of N- [3-Chloro-5-fluoro-4- (quinolin-3-yloxy) phenyl] -2,4-dichloro-5-methyl-benzenesulfonamide (186)

25 2,460-Dichloro-5-methylbenzenesulfonyl chloride 0.360 g was added to a solution of 3-chloro-5-fluoro-4- (quinolin-3-yloxy) phenylamine (186.2) (0.420 g) in pyridine (2.2 ml). The mixture was stirred at room temperature for 1 hr. The reaction mixture was purified directly by column chromatography (silica gel, AcOEt: Hexane = 1: 3). The product was triturated by hexane to provide the title compound (0.522 g). (73%) as a solid. 1H NMR (300MHz / CDCl3) 8 2.43 (3H, s), 7.05 (1H, d, J = 2.6Hz), 7.09-7.11 (1H, m), 7.21 (1H , d, J = 2.6Hz), 7.36 (1H, brs), 7.49-7.66 (4H, m), 7.96 (1H, s), 8.10 (1H, d, J = 8.2Hz), 8.80 (1H, brs). MS (M + H) 511, mp 187 ° C.

EXAMPLE 308

35 3-Hydroxy-6-methylquinoline (308)

A solution of 3-Amino-6-methylquinoline [(1.21 g, 7.65 mmol), prepared according to J.Chem.Soc. 2024-2027 (1948) Morley, JS; Simpson, JCE] in 6N H2SO4 (25 ml) was cooled in an ice bath. To the solution was added NaNO2 (560 mg, 8.10 mmol) in water (2 ml) and stirred for 30 min at 0 degrees. Separately refluxed 5% of H2SO4 and the previous Diazo reaction mixture was added to this solution under reflux. After 30 min the mixture The reaction was cooled to room temperature, and neutralized by 6N NaOH. The resulting insoluble material is collected by filtration. This solid was recrystallized by CHCl3 / AcOEt to provide compound (308) (348 mg, 29%). 1H NMR (300MHz, DMSO-d6) 8 7.34 (1H, dd, J = 1.9, 8.6Hz), 7.42 (1H, d, J = 2.8Hz), 7.55 (1H, s), 7.79 (1H, d,

Four. Five J = 8.6Hz), 8.50 (1H, d, J = 2.8Hz).

EXAMPLE 309

3- (2,6-Dichloro-4-nitro-phenoxy) -6-methyl-quinoline (309)

To a solution of 3-Hydroxy-6-methylquinoline (308) (348 mg, 2.19 mmol) in DMF (3.5 ml), NaH (60% oil suspension, 90 mg, 2.25 mmol) was added in one serving at room temperature. After 5 min 3,4,5-trichloronitrobenzene (509 mg, 2.25 mmol) in DMF (2 ml) was added and the reaction mixture was heated at 50 degrees with stirring for 2 hr. After cooling to room temperature. Ice / water was added to the mixture of

55 reaction, which was then acidified with 2N HCl and extracted twice with AcOEt. The organic layer was washed with saline, dried over anhydrous MgSO4, and concentrated. The crude residue was purified by column chromatography (Hexane / AcOEt = 4 / 1.80 g of silica gel) to give compound 309 (510 mg, 67%). 1H NMR (300MHz, DMSO-d6) 8 7.52-7.57 (2H, m), 7.61 (1H, s), 7.94 (1H, d, J = 8.6Hz), 8.63 (2H, s), 8.86 (1H, d, J = 2.9Hz).

EXAMPLE 310

3- (2,6-Dichloro-4-nitro-phenoxy) -quinolin-6-carboxylic acid (310).

65 To solution of 3- (2,6-dichloro-4-nitro-phenoxy) -6-methyl-quinoline (309) (510 mg, 1.46 mmol) and chromium oxide (VI) (292 mg, 2.92 mmol) in H2SO4 / H2O = 2.4 ml / 4.7 ml was heated to 100 degrees while three portions of

Chromium anhydride 292 mg in eight hour intervals. After heating for 32 hr it was stopped and left stand overnight The insoluble material was collected by filtration, and this solid was washed with two water times to provide compound (310) (443 mg, 80%). 1H NMR (300MHz, DMSO-d6) 8 7.94 (1H, d, J = 3.0Hz), 8.14 (2H, s), 8.56 (1H, s), 8.65 (2H, s ), 9.09 (1H, d, J = 3.0Hz).

EXAMPLE 311

3- (2,6-Dichloro-4-nitro-phenoxy) -quinolin-6-carboxylic acid methyl ester (311)

10 To a solution of 3- (2,6-dichloro-4-nitro-phenoxy) -quinolin-6-carboxylic acid (310) (443 mg, 0.93 mmol) in dry THF (20ml) was added CH2N2 in Et2O solution [Prepared from Nitrosomethylurea (1.65 g) and 50% KOH (5 ml)]. This mixture was stirred at room temperature for 1 hr. AcOH (1 ml) was added to the reaction mixture, which was then concentrated. Saturated NaHCO3 was added to the residue, which was extracted twice with AcOEt. The organic layer was washed with saline, dried over anhydrous MgSO4, and concentrated to provide the compound.

fifteen 311 (415mg). 1H NMR (300MHz, DMSO-d6) 8 3.89 (3H, s), 5.75 (2H, br s), 6.76 (2H, s), 7.73 (1H, d, J = 2, 9Hz), 8.09 (2H, s), 8.67 (1H, s), 8.94 (1 H, d, J = 2.9Hz).

EXAMPLE 312

twenty 3- (4-Amino-2,6-dichloro-phenoxy) -quinolin-6-carboxylic acid methyl ester (312)

Powdered iron (296 mg, 5.3 mmol) was added to a solution of 3- (2,6-dichloro-4-nitro-phenoxy) quinolin-6-carboxylic acid methyl ester (311) (0.93 mmol ) and NH4Cl (283 mg, 5.3 mmol) in EtOH / THF / water (8 ml / 16 ml / 1 ml). The

25 reaction mixture was refluxed for 4 hr. Insoluble materials were removed by Celite bed, which was washed by THF, acetone and then EtOH. The filtrate was concentrated, and saturated NaHCO3 was added, extracted twice with AcOEt. The organic layer was washed with saline, dried over anhydrous MgSO4, and concentrated to provide compound 312 (372 mg, by weight) .1 H NMR (300MHz, DMSO-d6) 8 3.89 (3H, s), 5.75 (2H, s), 6.76 (2H, s), 7.73 (1H, d, J = 2.9Hz), 8.09 (2H, s), 8.67 (1H,

30 s), 8.94 (1H, d, J = 2.9Hz).

EXAMPLE 313

3-Hydroxy-8-quinolinecarboxylic acid methyl ester (313)

35 To the mixture of 8-quinoline carboxylic acid (500 mg, 2.89 mmol) in THF (80 ml) was added CH2N2 in Et2O solution [Prepared from Nitrosomethylurea (1.65 g) and 50% KOH (5 ml )] at room temperature. The reaction mixture was stirred for 12 hr and then concentrated to provide the ester intermediate 1 H NMR (300MHz, DMSO-d6) 5.92 (3H, s), 7.60-7.70 (2H, m ), 7.93-7.96 (1H, m), 8.14-8.17 (1H, m), 8.44-8.48 (1H,

40 m), 8.97-8.99 (1H, m)

30% H2O2 (0.6 ml) was added to a solution of the 8-quinolinecarboxylic acid methyl ester intermediate (2.89 mmol) in AcOH (4 ml). The reaction mixture was heated at 85 degrees for 7.5 hr. The reaction mixture was treated with saturated NaHCO3, and extracted six times with CHCl3. The organic layer was dried over anhydrous MgSO4, and

Four. Five He concentrated. The crude residue was triturated with CHCl3 / Toluene to provide compound 313 (256 mg, 44%, in 2 steps) .1 H NMR (300MHz, DMSO-d6) 8 3.89 (3H, s), 7.52 ( 1H, d, J = 6.9Hz), 7.57 (1H, d, J = 1.5Hz), 7.66 (1H, dd, J = 1.5, 6.9Hz), 7.95 (1H , dd, J = 1.5, 8.1Hz), 8.63 (1H, d, J = 2.7Hz), 10.5 (1H, br s).

fifty EXAMPLE 314

3- (2,6-Dichloro-4-nitro-phenoxy) -quinolin-8-carboxylic acid methyl ester (314)

K2CO3 (870 mg, 6.30 mmol) was added to a solution of 3-hydroxy-8-quinolinecarboxylic acid methyl ester (313)

55 (256 mg, 1.26 mmol) and 3,4,5-trichloronitrobenzene (294 mg, 1.30 mmol) in acetone (40 ml). This mixture was refluxed for 3.5 hr. The reaction mixture was cooled to room temperature and insoluble materials were removed by Celite filtration. The filtrate was concentrated and the residue was purified by column chromatography. (Hexane / AcOEt = 4 / 1.80 g of silica gel) to provide compound 314. 1H NMR (300MHz, DMSO-d6) 8 3.92 (3H, s), 7.67 (1H, dd, J = 7.3Hz), 7.79 (1H, d, J = 2.9Hz), 7 , 88 (1H, dd, J = 1.5,

60 7.3Hz), 9.05 (1H, d, J = 2.9Hz).

EXAMPLE 315

3- (4-Amino-2,6-dichloro-phenoxy) -quinolin-8-carboxylic acid methyl ester (315).

5 Powdered iron (386 mg, 6.91 mmol) was added to a solution of 3- (2,6-dichloro-4-nitro-phenoxy) quinolin-8-carboxylic acid methyl ester (314) (1.26 mmol ) and NH4Cl (370 mg, 6.91 mmol) in EtOH / THF / H2O = 8 ml / 4 ml / 2 ml. The reaction mixture was refluxed for 3.5 hr. After cooling to room temperature, insoluble materials were filtered by Celite filtration. The filtrate was concentrated and saturated NaHCO3 was added to the residue, which was extracted twice with AcOEt. The organic layer was washed with saline, dried over MgSO4, and dried.

10 concentrated. The crude residue was purified by column chromatography (Hexane / AcOEt = 2 / 1.80 g of silica gel) to give compound 315 (543 mg). 1H NMR (300MHz, DMSO-d6) 8 3.91 (3H, s), 5.77 (2H, br s), 6.78 (2H, s), 7.50 (1H, d, J = 3, 0Hz), 7.61 (1H, dd, J = 8.1Hz), 7.81 (1H, dd, J = 1.4, 6.4Hz), 8.08 (1H, dd, J = 1.4Hz , 6.4Hz), 8.93 (1H, d, J = 3.0Hz).

fifteen EXAMPLE 339

3,5-dichloro-4- (6-methyl-quinolin-3-yloxy) -phenylamine (339)

Powdered iron (1.04 g, 18.55 mmol) was added to a solution of 3- (2,6-dichloro-4-nitro-phenoxy) -6-methyl-quinoline

twenty (309) (1.30 g, 3.71 mmol) and NH4Cl (992 mg, 18.55 mmol) in EtOH / THF / H2O = 12 ml / 12 ml / 3 ml. The mixture was refluxed for 4 hr. Insoluble materials were removed by Celite filtration. The filtrate was concentrated and saturated NaHCO3 was added to the residue, which was then extracted twice with AcOEt. The organic layer was washed with saline, dried over anhydrous MgSO4, and concentrated to provide compound 339 (1.18 g, 98%). 1H NMR (300MHz, DMSO-d6) 8 2.44 (3H, s), 5.75 (2H, br s), 6.77 (2H, s), 7.27 (1H, d, J = 2, 8Hz), 7.48 (1H, d,

25 J = 8.6Hz), 7.67 (1H, s), 7.89 (1H, d, J = 8.6Hz), 8.74 (1H, d, J = 2.8Hz).

EXAMPLE 373

Using procedures similar to Lehmann, and others, see above, the selected compounds showed the

30 following IC50 values ​​in a PPAR ligand binding assay using [3H] -BRL 49653 as the radioligand. IC50 values ​​are defined as the concentration of test compounds necessary to reduce the specific binding of [3H] -BRL 49653 by 50% and are represented by (+) &lt;30 µM; (++) &lt;10 µM; (+++) &lt;1! M.

35 TABLE 38 Compound IC50 (! M) 86 +++

87.3 +++ 178 +++ 179 +++

EXAMPLE 374

40 Selected compounds were administered to KK-Ay mice as a 0.018% diet mixture (30 mg / kg) in a powdered diet and evaluated for antidiabetic efficacy as described (T. Shibata, K. Matsui, K. Nagao,

H. Shinkai, F. Yonemori and K. Wakitani 1999; European Journal of Pharmacology 364: 211-219). The change in serum glucose levels compared to untreated control animals is shown as an example in Table 39.

Four. Five TABLE 39 Example # KKAy Glucose

87.3 ++ 178 ++ 179 ++

(-) &lt;10%; (+) 10% to 20%; (++) glucose decrease&gt; 20%.