The present invention relates to thiazolidinedione analogues that are useful for treating hypertension.

TECHNICAL FIELD OF THE INVENTION

The present invention provides a pharmaceutical composition that includes selective thiazolidinedione analogs for use in treating hypertension.

BACKGROUND OF THE INVENTION

Over the past several decades, scientists have postulated that PPARγ is the generally accepted site of action for insulin sensitizing thiazolidinedione compounds. Peroxisome Proliferator Activated Receptors (PPARs) are members of the nuclear hormone receptor super family, which are ligand-activated transcription factors regulating gene expression. PPARs have been implicated in autoimmune diseases and other diseases, i.e diabetes mellitus, cardiovascular and gastrointestinal disease, and Alzheimer's disease.

PPARγ is a key regulator of adipocyte differentiation and lipid metabolism. PPARγ is also found in other cell types including fibroblasts, myocytes, breast cells, human bone-marrow precursors, and macrophages/monocytes. In addition, PPARγ has been shown in macrophage foam cells in atherosclerotic plaques.

Thiazolidinediones, developed originally for the treatment of type-2 diabetes, generally exhibit high-affinity as PPARγ ligands. The finding that thiazolidinedones might mediate their therapeutic effects through direct interactions with PPARγ helped to establish the concept that PPARγ is a key regulator of glucose and lipid homeostasis. However, compounds that involve the activation of PPARγ also trigger sodium reabsorption and other unpleasant side effects.

SUMMARY OF THE INVENTION

In general, the invention relates to compounds that have reduced binding and activation of the nuclear transcription factor PPARγ. Compounds exhibiting PPARγ activity induce transcription of genes that favor sodium re-adsorption. The compounds of this invention have reduced binding or activation of the nuclear transcription factor PPARγ, do not augment sodium re-absorption, and are therefore more useful in treating hypertension. Advantageously, the compounds having lower PPARγ activity exhibit fewer side effects than compounds having higher levels of PPARγ activity. Most specifically, by lacking PPARγ binding and activation activity these compounds are particularly useful for treating hypertension both as single agents and in combination with other classes of antihypertensive agents

In one aspect, the present invention provides a pharmaceutical composition useful in treating hypertension comprising a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and ring A are described below.

Another aspect of the present invention provides methods of treating hypertension with a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier.

Another aspect of this invention provides pharmaceutical compositions comprising a compound of formula I and at least one diuretic, such as hydrocholothiazide. Other aspects provide pharmaceutical compositions useful for treating hypertension comprising a compound of formula I and one or more agents that limit the activity of the rennin-angiotensin system such as angiotensin concerting enzyme inhibitors, i.e. ACE inhibitors, e.g. ramipril, captopril, enalapril, or the like, and/or angiotensin II receptor blockers, i.e. ARBs, e.g. candesartan, losartan, olmesartan, or the like; and/or rennin inhibitors. Still other aspects provide a useful pharmaceutical composition for treating hypertension comprising of a compound of formula I and compounds that limit hypertension by alternate means including β-adrenergic receptor blockers and calcium channel blockers, e.g., amlodipine.

This invention also provides pharmaceutical combinations with lipid lowering agents. Compounds of formula I, because of their PPARγ-sparing properties and beneficial effects on lipids to lower triglycerides and elevate HDL cholesterol, are particularly useful in combination with one or more statin, i.e., HMG-CoA reductase inhibitor, e.g., atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, simvastatin, rosuvastatin, pravastatin, or any pharmaceutically acceptable combination thereof.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the following definitions shall apply unless otherwise indicated.

As described herein, compounds of the invention may optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention.

As used herein the term “aliphatic” encompasses the terms alkyl, alkenyl, alkynyl, each of which being optionally substituted as set forth below.

As used herein, an “amido” encompasses both “aminocarbonyl” and “carbonylamino”. These terms when used alone or in connection with another group refer to an amido group such as —N(RX)—C(O)—RYor —C(O)—N(RX)2, when used terminally, and —C(O)—N(RX)— or —N(RX)—C(O)— when used internally, wherein RXand RYare defined below. Examples of amido groups include alkylamido (such as alkylcarbonylamino or alkylaminocarbonyl), (heterocycloaliphatic)amido, (heteroaralkyl)amido, (heteroaryl)amido, (heterocycloalkyl)alkylamido, arylamido, aralkylamido, (cycloalkyl)alkylamido, or cycloalkylamido.

As used herein, an “amino” group refers to —NRXRYwherein each of RXand RYis independently hydrogen, aliphatic, cycloaliphatic, (cycloaliphatic)aliphatic, aryl, araliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, heteroaryl, carboxy, sulfanyl, sulfinyl, sulfonyl, (aliphatic)carbonyl, (cycloaliphatic)carbonyl, ((cycloaliphatic)aliphatic)carbonyl, arylcarbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, (heteroaryl)carbonyl, or (heteroaraliphatic)carbonyl, each of which being defined herein and being optionally substituted. Examples of amino groups include alkylamino, dialkylamino, or arylamino. When the term “amino” is not the terminal group (e.g., alkylcarbonylamino), it is represented by —NRX—. RXhas the same meaning as defined above.

As used herein, an “araliphatic” such as an “aralkyl” group refers to an aliphatic group (e.g., a C1-4alkyl group) that is substituted with an aryl group. “Aliphatic,” “alkyl,” and “aryl” are defined herein. An example of an araliphatic such as an aralkyl group is benzyl.

As used herein, a “bicyclic ring system” includes 8-12 (e.g., 9, 10, or 11) membered structures that form two rings, wherein the two rings have at least one atom in common (e.g., 2 atoms in common). Bicyclic ring systems include bicycloaliphatics (e.g., bicycloalkyl or bicycloalkenyl), bicycloheteroaliphatics, bicyclic aryls, and bicyclic heteroaryls.

As used herein, a “cycloaliphatic” group encompasses a “cycloalkyl” group and a “cycloalkenyl” group, each of which being optionally substituted as set forth below.

A “cycloalkenyl” group, as used herein, refers to a non-aromatic carbocyclic ring of 3-10 (e.g., 4-8) carbon atoms having one or more double bonds. Examples of cycloalkenyl groups include cyclopentenyl, 1,4-cyclohexa-di-enyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl, cyclopentenyl, bicyclo[2.2.2]octenyl, or bicyclo[3.3.1]nonenyl.

As used herein, the term “heterocycloaliphatic” encompasses a heterocycloalkyl group and a heterocycloalkenyl group, each of which being optionally substituted as set forth below.

As used herein, a “heterocycloalkyl” group refers to a 3-10 membered mono- or bicyclic (fused or bridged) (e.g., 5- to 10-membered mono- or bicyclic) saturated ring structure, in which one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof). Examples of a heterocycloalkyl group include piperidyl, piperazyl, tetrahydropyranyl, tetrahydrofuryl, 1,4-dioxolanyl, 1,4-dithianyl, 1,3-dioxolanyl, oxazolidyl, isoxazolidyl, morpholinyl, thiomorpholyl, octahydrobenzofuryl, octahydrochromenyl, octahydrothiochromenyl, octahydroindolyl, octahydropyrindinyl, decahydroquinolinyl, octahydrobenzo[b]thiopheneyl, 2-oxa-bicyclo[2.2.2]octyl, 1-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.03,7]nonyl. A monocyclic heterocycloalkyl group can be fused with a phenyl moiety to form structures, such as tetrahydroisoquinoline, which would be categorized as heteroaryls.

A “heterocycloalkenyl” group, as used herein, refers to a mono- or bicylic (e.g., 5- to 10-membered mono- or bicyclic) non-aromatic ring structure having one or more double bonds, and wherein one or more of the ring atoms is a heteroatom (e.g., N, O, or S). Monocyclic and bicyclic heterocycloaliphatics are numbered according to standard chemical nomenclature.

A “heteroaryl” group, as used herein, refers to a monocyclic, bicyclic, or tricyclic ring system having 4 to 15 ring atoms wherein one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof) and in which the monocyclic ring system is aromatic or at least one of the rings in the bicyclic or tricyclic ring systems is aromatic. A heteroaryl group includes a benzofused ring system having 2 to 3 rings. For example, a benzofused group includes benzo fused with one or two 4 to 8 membered heterocycloaliphatic moieties (e.g., indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl, benzo[b]thiophenyl, quinolinyl, or isoquinolinyl). Some examples of heteroaryl are azetidinyl, pyridyl, 1H-indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzthiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole, benzo[1,3]dioxole, benzo[b]furyl, benzo[b]thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, puryl, cinnolyl, quinolyl, quinazolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolyl, 4H-quinolizyl, benzo-1,2,5-thiadiazolyl, or 1,8-naphthyridyl.

A “heteroaraliphatic (such as a heteroaralkyl group) as used herein, refers to an aliphatic group (e.g., a C1-4alkyl group) that is substituted with a heteroaryl group. “Aliphatic,” “alkyl,” and “heteroaryl” have been defined above.

As used herein, “cyclic moiety” and “cyclic group” refer to mono-, bi-, and tri-cyclic ring systems including cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl, each of which has been previously defined.

As used herein, an “acyl” group refers to a formyl group or RX—C(O)— (such as alkyl-C(O)—, also referred to as “alkylcarbonyl”) where RXand “alkyl” have been defined previously. Acetyl and pivaloyl are examples of acyl groups.

As used herein, an “aroyl” or “heteroaroyl” refers to an aryl-C(O)— or a heteroaryl-C(O)—. The aryl and heteroaryl portion of the aroyl or heteroaroyl is optionally substituted as previously defined.

As used herein, an “alkoxy” group refers to an alkyl-O— group where “alkyl” has been defined previously.

As used herein, a “carbamoyl” group refers to a group having the structure —O—CO—NRXRYor —NRX—CO—O—RZ, wherein RXand RYhave been defined above and RZcan be aliphatic, aryl, araliphatic, heterocycloaliphatic, heteroaryl, or heteroaraliphatic.

As used herein, a “carboxy” group refers to —COOH, —COORX, —OC(O)H, —OC(O)RX, when used as a terminal group; or —OC(O)— or —C(O)O— when used as an internal group.

As used herein, a “haloaliphatic” group refers to an aliphatic group substituted with 1-3 halogen. For instance, the term haloalkyl includes the group —CF3.

As used herein, a “mercapto” group refers to —SH.

As used herein, a “sulfo” group refers to —SO3H or —SO3RXwhen used terminally or —S(O)3— when used internally.

As used herein, a “sulfamide” group refers to the structure —NRX—S(O)2—NRYRZwhen used terminally and —NRX—S(O)2—NRY— when used internally, wherein RX, RY, and RZhave been defined above.

As used herein, a “sulfonamide” group refers to the structure —S(O)2—NRXRYor —NRX—S(O)2—RZwhen used terminally; or —S(O)2—NRX— or —NRX—S(O)2— when used internally, wherein RX, RY, and RZare defined above.

As used herein a “sulfanyl” group refers to —S—RXwhen used terminally and —S— when used internally, wherein RXhas been defined above. Examples of sulfanyls include aliphatic-S—, cycloaliphatic-S—, aryl-S—, or the like.

As used herein a “sulfinyl” group refers to —S(O)—RXwhen used terminally and —S(O)—when used internally, wherein RXhas been defined above. Exemplary sulfinyl groups include aliphatic-S(O)—, aryl-S(O)—, (cycloaliphatic(aliphatic))-S(O)—, cycloalkyl-S(O)—, heterocycloaliphatic-S(O)—, heteroaryl-S(O)—, or the like.

As used herein, a “sulfonyl” group refers to —S(O)2—RXwhen used terminally and —S(O)2— when used internally, wherein RXhas been defined above. Exemplary sulfonyl groups include aliphatic-S(O)2—, aryl-S(O)2—, (cycloaliphatic(aliphatic))-S(O)2—, cycloaliphatic-S(O)2—, heterocycloaliphatic-S(O)2—, heteroaryl-S(O)2—, (cycloaliphatic(amido(aliphatic)))-S(O)2— or the like.

As used herein, a “sulfoxy” group refers to —O—SO—RXor —SO—O—RX, when used terminally and —O—S(O)— or —S(O)—O— when used internally, where RXhas been defined above.

As used herein, a “halogen” or “halo” group refers to fluorine, chlorine, bromine or iodine.

As used herein, an “alkoxycarbonyl,” which is encompassed by the term carboxy, used alone or in connection with another group refers to a group such as alkyl-O—C(O)—.

As used herein, an “alkoxyalkyl” refers to an alkyl group such as alkyl-O-alkyl-, wherein alkyl has been defined above.

As used herein, a “carbonyl” refer to —C(O)—.

As used herein, an “oxo” refers to ═O.

As used herein, an “aminoalkyl” refers to the structure (RX)2N-alkyl-.

As used herein, a “cyanoalkyl” refers to the structure (NC)-alkyl-.

As used herein, a “urea” group refers to the structure —NRX—CO—NRYRZand a “thiourea” group refers to the structure —NRX—CS—NRYRZwhen used terminally and —NRX—CO—NRY— or —NRX—CS—NRY— when used internally, wherein RX, RY, and RZhave been defined above.

As used herein, a “guanidine” group refers to the structure —N═C(N(RXRY))N(RXRY) or —NRX—C(═NRX)NRXRYwherein RXand RYhave been defined above.

As used herein, the term “amidino” group refers to the structure —C═(NRX)N(RXRY) wherein RXand RYhave been defined above.

In general, the term “vicinal” refers to the placement of substituents on a group that includes two or more carbon atoms, wherein the substituents are attached to adjacent carbon atoms.

In general, the term “geminal” refers to the placement of substituents on a group that includes two or more carbon atoms, wherein the substituents are attached to the same carbon atom.

The terms “terminally” and “internally” refer to the location of a group within a substituent. A group is terminal when the group is present at the end of the substituent not further bonded to the rest of the chemical structure. Carboxyalkyl, i.e., RXO(O)C-alkyl is an example of a carboxy group used terminally. A group is internal when the group is present in the middle of a substituent of the chemical structure. Alkylcarboxy (e.g., alkyl-C(O)O— or alkyl-OC(O)—) and alkylcarboxyaryl (e.g., alkyl-C(O)O-aryl- or alkyl-O(CO)-aryl-) are examples of carboxy groups used internally.

As used herein, an “aliphatic chain” refers to a branched or straight aliphatic group (e.g., alkyl groups, alkenyl groups, or alkynyl groups). A straight aliphatic chain has the structure —[CH2]v—, where v is 1-12. A branched aliphatic chain is a straight aliphatic chain that is substituted with one or more aliphatic groups. A branched aliphatic chain has the structure —[CQQ]v- where Q is independently a hydrogen or an aliphatic group; however, Q shall be an aliphatic group in at least one instance. The term aliphatic chain includes alkyl chains, alkenyl chains, and alkynyl chains, where alkyl, alkenyl, and alkynyl are defined above.

The phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted.” As described herein, compounds of the invention can optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention. As described herein, the variables R1, R2, and R3, and other variables contained in formulae described herein encompass specific groups, such as alkyl and aryl. Unless otherwise noted, each of the specific groups for the variables R1, R2, and R3, and other variables contained therein can be optionally substituted with one or more substituents described herein. Each substituent of a specific group is further optionally substituted with one to three of halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, cycloaliphatic, heterocycloaliphatic, heteroaryl, haloalkyl, and alkyl. For instance, an alkyl group can be substituted with alkylsulfanyl and the alkylsulfanyl can be optionally substituted with one to three of halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl. As an additional example, the cycloalkyl portion of a (cycloalkyl)carbonylamino can be optionally substituted with one to three of halo, cyano, alkoxy, hydroxy, nitro, haloalkyl, and alkyl. When two alkoxy groups are bound to the same atom or adjacent atoms, the two alkoxy groups can form a ring together with the atom(s) to which they are bound.

In general, the term “substituted,” whether preceded by the term “optionally” or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Specific substituents are described above in the definitions and below in the description of compounds and examples thereof. Unless otherwise indicated, an optionally substituted group can have a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position. A ring substituent, such as a heterocycloalkyl, can be bound to another ring, such as a cycloalkyl, to form a spiro-bicyclic ring system, e.g., both rings share one common atom. As one of ordinary skill in the art will recognize, combinations of substituents envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds.

The phrase “stable or chemically feasible,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40° C. or less, in the absence of moisture or other chemically reactive conditions, for at least a week.

As used herein, an “effective amount” is defined as the amount required to confer a therapeutic effect on the treated patient, and is typically determined based on age, surface area, weight, and condition of the patient. The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described by Freireich et al., Cancer Chemother. Rep., 50: 219 (1966). Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 537 (1970). As used herein, “patient” refers to a mammal, including a human.

It is commonly believed that efficacious insulin sensitizing compounds must have high PPARγ activity, and conversely, that compounds having reduced PPARγ activity would yield reduced insulin sensitizing activity. Contrary to this belief, thiazolidinedione compounds of the present invention are uniquely effective in treating hypertension and possess a reduced interaction with PPARγ.

Without wishing to be bound by theory, it is believed that metabolic inflammation is a central cause of the numerous key diseases including hypertension. It is further believed that thiazolidinediones of the present invention function to prevent hypertension via a mitochondrial mechanism. Furthermore since the dose limiting side effects due to PPARγ interaction are reduced in compounds of the present invention; especially steroselective isomers, these compounds are highly useful for treating hypertension.

The present invention provides pharmaceutical compositions that are useful for treating hypertension comprising a compound of formula I:

or a pharmaceutically acceptable salt thereof.

R1is hydrogen or an optionally substituted aliphatic.

Ring A is a phenyl or a monocyclic heteroaryl having 1-3 heteroatoms selected from N, O, or S, either of which is substituted with —CH2—R1at any chemically feasible position on ring A.

In several embodiments, R1is an optionally substituted C1-6aliphatic. For example, R1is an optionally substituted straight or branched C1-6alkyl, an optionally substituted straight or branched C2-6alkenyl, or an optionally substituted straight or branched C2-6alkynyl. In several other examples, R1is a methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, or hexyl, each of which is unsubstituted. In several embodiments, R1is hydrogen.

In several embodiments, R2is hydrogen, halo, hydroxy, oxo, or an optionally substituted C1-6aliphatic. For example, R2is an optionally substituted straight or branched C1-6alkyl, an optionally substituted straight or branched C2-6alkenyl, or an optionally substituted straight or branched C2-6alkynyl. In other examples, R2is a C1-6aliphatic optionally substituted with 1-2 hydroxy or halo. In other examples, R2is a C1-6alkyl optionally substituted with hydroxy. In several other examples, R2is a methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, or hexyl, each of which is optionally substituted with hydroxy. In several additional examples, R2is methyl or ethyl, each of which is substituted with hydroxy.

In several embodiments, R3is hydrogen, halo, or an optionally substituted C1-6aliphatic. For example, R3is an optionally substituted straight or branched C1-6alkyl, an optionally substituted straight or branched C2-6alkenyl, or an optionally substituted straight or branched C2-6alkynyl. In several other examples, R3is a methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, or hexyl, each of which is unsubstituted.

In several embodiments, ring A is a phenyl or a monocyclic heteroaryl having 1-3 heteroatoms selected from N, O, and S. For example, ring A is phenyl that is substituted with —CH2—R1, at any chemically feasible position on ring A. In other examples, ring A is a monocyclic 5-6 membered heteroaryl having 1-3 heteroatoms selected from N, O, or S that is substituted with —CH2—R1, at any chemically feasible position on ring A. In other examples, ring A is a furan-yl, thiophene-yl, pyrrole-yl, pyridine-yl, pyrazole-yl, 1,3,4-thiadiazole-yl, 1,3,5-triazine-yl, pyrazine-yl, pyrimidine-yl, pyridazine-yl, isoxazole-yl, or isothiazole-yl, each of which is substituted with —CH2—R1, at any chemically feasible position. In several examples, ring A is a pyridine-yl that is substituted with —CH2—R1, at any chemically feasible position.

In several other examples, ring A is bound to the carbon atom adjacent to R2at any chemically feasible position. For example, ring A is a pyridine-2-yl, pyridine-3-yl, or pyridine-4-yl, each of which is substituted with —CH2—R1at any chemically feasible position.

In several embodiments, the composition further comprises a pharmaceutically acceptable carrier.

The present invention provides pharmaceutical compositions that are useful for treating hypertension comprising a compound of formula Ia:

or a pharmaceutically acceptable salt thereof.

R1is hydrogen or an optionally substituted aliphatic.

Ring A is a monocyclic heteroaryl having 1-3 heteroatoms selected from N, O, or S, that is substituted with —CH2—R1at any chemically feasible position on ring A.

In several embodiments, R1is an optionally substituted C1-6aliphatic. For example, R1is an optionally substituted straight or branched C1-6alkyl, an optionally substituted straight or branched C2-6alkenyl, or an optionally substituted straight or branched C2-6alkynyl. In several other examples, R1is a methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, or hexyl, each of which is unsubstituted. In several embodiments, R1is hydrogen.

In several embodiments, R2is hydrogen, halo, hydroxy, oxo, or an optionally substituted C1-6aliphatic. For example, R2is an optionally substituted straight or branched C1-6alkyl, an optionally substituted straight or branched C2-6alkenyl, or an optionally substituted straight or branched C2-6alkynyl. In other examples, R2is a C1-6aliphatic optionally substituted with 1-2 hydroxy or halo. In other examples, R2is a C1-6alkyl optionally substituted with hydroxy. In several other examples, R2is a methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, or hexyl, each of which is optionally substituted with hydroxy. In several additional examples, R2is methyl or ethyl, each of which is substituted with hydroxy.

In several embodiments, R3is hydrogen, halo, or an optionally substituted C1-6aliphatic. For example, R3is an optionally substituted straight or branched C1-6alkyl, an optionally substituted straight or branched C2-6alkenyl, or an optionally substituted straight or branched C2-6alkynyl. In several other examples, R3is a methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, or hexyl, each of which is unsubstituted.

In several embodiments, ring A is a monocyclic heteroaryl having 1-3 heteroatoms selected from N, O, and S. For example, ring A is a monocyclic 5-6 membered heteroaryl having 1-3 heteroatoms selected from N, O, or S that is substituted with —CH2—R1at any chemically feasible position on ring A. In other examples, ring A is a furan-yl, thiophene-yl, pyrrole-yl, pyridine-yl, pyrazole-yl, 1,3,4-thiadiaziole-yl, 1,3,5-triazine-yl, pyrazine-yl, pyrimidine-yl, pyridazine-yl, isoxazole-yl, or isothiazole-yl, each of which is substituted with —CH2—R1at any chemically feasible position. In several examples, ring A is a pyridine-yl that is substituted with —CH2—R1at any chemically feasible position.

In several other examples, ring A is bound to the carbon atom adjacent to R2at any chemically feasible position. For example, ring A is a pyridine-2-yl, pyridine-3-yl, or pyridine-4-yl, each of which is substituted with —CH2—R1at any chemically feasible position.

In several embodiments, the composition further comprises a pharmaceutically acceptable carrier.

Another aspect of the present invention provides a pharmaceutical composition that is useful for treating hypertension comprising a compound of formula II:

or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and ring A are define above in formula Ia.

Another aspect of the present invention provides a pharmaceutical composition that is useful for treating hypertension comprising a compound of formula III:

or a pharmaceutically acceptable salt thereof, wherein R1, R3, and ring A are define above in formula Ia.

Another aspect of the present invention provides a pharmaceutical composition that is useful for treating hypertension comprising a compound of formula IV:

or a pharmaceutically acceptable salt thereof, wherein R1, R2, and R3are define above in formula III.

Another aspect of the present invention provides a pharmaceutical composition that is useful for treating hypertension comprising a compound of formula V:

or a pharmaceutically acceptable salt thereof, wherein R1, R2, and R3are defined above in formula III.

Another aspect of the present invention provides a pharmaceutical composition that is useful for treating hypertension comprising a compound of formula VI:

or a pharmaceutically acceptable salt thereof, wherein R1, R2, and R3are defined above in formula III.

In other aspects, the phenyl shown in the generic formulae I, Ia, II, III, IV, V, or VI can be replaced with any monocyclic heteroaryl such as pyridine, thiophene, furan, pyrazine, or the like.

Exemplary compositions according to the present invention includes a single unit dosage form having about 1 mg to about 200 mg of a compound of formulae I, Ia, II, III, IV, V, or VI, e.g., between about 10 mg to about 120 mg, between about 10 mg to about 100 mg, or about 15 mg to about 60 mg.

Several exemplary compounds of formulae I, Ia, II, III, IV, V, or VI are displayed in Table A, below.

Another aspect of the present invention provides a pharmaceutical composition comprising a compound of formulae I, Ia, II, III, IV, V, or VI, wherein the compound has a PPARγ activity of 50% or less relative to the activity of rosiglitazone when dosed to produce circulating levels greater than 3 μM or having a PPARγ activity of 10 times less than pioglitazone at the same dosage.

Another aspect of the present invention provides a method of treating hypertension comprising administering a pharmaceutical composition comprising a compound of formulae I, Ia, II, III, IV, V, or VI. The compositions of several alternative methods further comprise a pharmaceutically acceptable carrier.

Another aspect of the present invention provides a method of treating hypertension comprising administering a pharmaceutical composition comprising a compound of formulae III, IV, V, or VI wherein said compound has a purity of about 70 e.e. % or more. For example, the method treating hypertension comprising administering a pharmaceutical composition comprising a compound of formulae III, IV, V, or VI wherein the compound has a purity of about 80% e.e. or more (e.g., 90% e.e. or more, 95% e.e. or more, 97% e.e. or more, or 99% e.e. or more).

Pharmaceutical compositions of the present invention can also comprise one or more additional antihypertensive agents or other drugs. One aspect of the present invention provides pharmaceutical composition comprising a compound of formulae I, Ia, II, III, IV, V, or VI and at least one diuretic, such as hydrochlorothiazide, chlorothaladone, chlorothiazide, or combinations thereof. Other aspects provide pharmaceutical compositions useful for treating hypertension comprising a compound of formulae I, Ia, II, III, IV, V, or VI and one or more agents that limit the activity of the rennin-angiotensin system such as angiotensin concerting enzyme inhibitors, i.e. ACE inhibitors, e.g. ramipril, captopril, enalapril, or the like, and/or angiotensin II receptor blockers, i.e. ARBs, e.g. candesartan, losartan, olmesartan, or the like; and/or rennin inhibitors. Still other aspects provide a useful pharmaceutical composition for treating hypertension comprising of a compound of formulae I, Ia, II, III, IV, V, or VI and compounds that limit hypertension by alternate means including β-adrenergic receptor blockers, and calcium channel blockers, e.g., amlodipine.

This invention also provides pharmaceutical compositions that are useful for lowering lipids comprising compounds of formulae I, Ia, II, III, IV, V, or VI and one or more statin, i.e., HMG-CoA reductase inhibitor, e.g., atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, simvastatin, rosuvastatin, pravastatin, or any pharmaceutically acceptable combination thereof.

III. GENERAL SYNTHETIC SCHEMES

The compounds of formulae I, Ia, II, III, IV, V, or VI may be readily synthesized from commercially available or known starting materials by known methods. Exemplary synthetic routes to produce compounds of formulae I, Ia, II, III, IV, V, or VI are provided below in Scheme 1 below.

Referring to Scheme 1, the starting material 1a is reduced to form the aniline 1b. The aniline 1b is diazotized in the presence of hydrobromic acid, acrylic acid ester, and a catalyst such as cuprous oxide to produce the alpha-bromo acid ester 1c. The alpha-bromo acid ester 1c is cyclized with thiourea to produce racemic thiazolidinedione 1d. Compounds of formula I can be separated from the racemic mixture using any suitable process such as HPLC.

In Scheme 2 below, R2is an oxo group and R3is hydrogen.

Referring to Scheme 2, the starting material 2a is reacted with 4-hydroxybenzalde under basic conditions (e.g., aq. NaOH) to give a mixture of regioisomeric alcohols 2b that were separated by chromatography. The regioisomeric alcohols 2b is reacted with 2,4-thiazolidine dione using pyrrolidine as base to give compound 2c. Cobalt catalyzed reduction with sodium borohydride affords compound 2d, which is oxidized, for example, with phosphorus pentoxide, to give the ketone 2e.

As discussed above, the present invention provides compounds that are useful as treatments for hypertension.

Accordingly, in another aspect of the present invention, pharmaceutically acceptable compositions are provided, wherein these compositions comprise any of the compounds as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents.

It will also be appreciated that certain of the compounds of present invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative or a prodrug thereof. According to the present invention, a pharmaceutically acceptable derivative or a prodrug includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.

As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A “pharmaceutically acceptable salt” means any non-toxic salt or salt of an ester of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof.

In yet another aspect, the present invention provides a method of treating hypertension comprising administering a pharmaceutical composition comprising a compound of formulae I, Ia, II, III, IV, V, or VI, preferably a mammal, in need thereof.

According to the invention an “effective amount” of the compound or pharmaceutically acceptable composition is that amount effective for treating or lessening the severity of hypertension.

The pharmaceutical compositions, according to the method of the present invention, may be administered using any amount and any route of administration effective for treating or lessening the severity of hypertension.

As described generally above, the compounds of the invention are useful as treatments for hypertension.

The activity, or more importantly, reduced PPARγ activity of a compound utilized in this invention as a treatment of hypertension may be assayed according to methods described generally in the art and in the examples herein.

It will also be appreciated that the compounds and pharmaceutically acceptable compositions of the present invention can be employed in combination therapies, that is, the compounds and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated”.

The compounds of this invention or pharmaceutically acceptable compositions thereof may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Accordingly, the present invention, in another aspect, includes a composition for coating an implantable device comprising a compound of the present invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. In still another aspect, the present invention includes an implantable device coated with a composition comprising a compound of the present invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. Suitable coatings and the general preparation of coated implantable devices are described in U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121, each of which is incorporated by reference. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccarides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.

According to yet another embodiment, the present invention provides a method of treating or reducing the severity of hypertension.

Another aspect of the invention relates to treating hypertension in a biological sample or a patient (e.g., in vitro or in vivo), which method comprises administering to the patient, or contacting said biological sample with a pharmaceutical composition comprising a compound of formulae I, Ia, II, III, IV, V, or VI. The term “biological sample”, as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof, and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

Formulation of Pharmaceutical Compositions

A pharmaceutical composition including a compound of formulae I, Ia, II, III, IV, V, or VI can be produced, for example, by tabletinga. between about 1 mg to about 200 mg of a compound of formulae I, Ia, II, III, IV, V, or VI, e.g., between about 10 mg to about 100 mg, or between about 15 mg to about 60 mg;b. carboxymethylcellulose or carmellose;c. magnesium sterate,d. hydroxypropyl cellulose; ande. lactose monohydrate.

Assays for Measuring Reduced PPARγ Receptor Activation

Whereas activation of the PPARγ receptor is generally believed to be a selection criteria to select for molecules that may have anti-diabetic and insulin sensitizing pharmacology, this invention finds that activation of this receptor should be a negative selection criterion. Molecules will be chosen from this chemical space because they have reduced, not just selective, activation of PPARγ. The optimal compounds will have at least a 10-fold reduced potency as compared to pioglitazone and less than 50% of the full activation produced by rosiglitazone in assays conducted in vitro for transactivation of the PPARγ receptor. These assays will be conducted by first evaluation of the direct interactions of the molecules with the ligand binding domain of PPARγ. This will be performed with a commercial interaction kit that measures the direct interaction by florescence using rosiglitazone as a positive control. Further assays will be conducted in a manner similar to that described by Lehmann et al. [Lehmann J M, Moore L B, Smith-Oliver T A: An Antidiabetic Thiazolidinedione is a High Affinity Ligand for Peroxisome Proliferator-activated Receptor (PPAR) J. Biol. Chem. (1995) 270: 12953] but will use luciferase as a reporter as in Vosper et al. [Vosper, H., Khoudoli, G A, Palmer, C N (2003) The peroxisome proliferators activated receptor d is required for the differentiation of THP-1 moncytic cells by phorbol ester. Nuclear Receptor 1:9]. Compound stocks will be dissolved in DMSO and added to the cell cultures at final concentrations of 0.1 to 100 μM and the relative activation will be calculated as induction of the reporter gene (luciferase) as corrected for by the expression of the control plasmid (coding for galactosidase). Pioglitazone and rosiglitazone will be used as reference compounds as described above.

In addition to showing the reduced activation of the PPARγ receptor in vitro, the compounds will not produce significant activation of the receptor in animals. Compounds dosed to full effect for insulin sensitizing actions in vivo (see below) will be not increase activation of PPARγ in the liver as measured by the expression of a P2, a biomarker for ectopic adipogenesis in the liver [Matsusue K, Haluzik M, Lambert G, Yim S—H, Oksana Gavrilova O, Ward J M, Brewer B, Reitman M L, Gonzalez F J. (2003) Liver-specific disruption of PPAR in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes. J. Clin. Invest.; 111: 737] in contrast to pioglitazone and rosiglitazone, which do increase a P2 expression under these conditions.

The insulin sensitizing and antidiabetic pharmacology are measured in the KKAYmice as previously reported [Hofmann, C., Lornez, K., and Colca, J. R. (1991). Glucose transport deficiency corrected by treatment with the oral anti-hyperglycemic agent Pioglitazone. Endocrinology, 129:1915-1925.] Compounds are formulated in 1% sodium carboxy methylcellulose, and 0.01% tween 20 and dosed daily by oral gavage. After 4 days of once daily treatment, treatment blood samples are taken from the retro-orbital sinus and analyzed for glucose, triglycerides, and insulin as described in Hofmann et al. Doses of compounds that produce at least 80% of the maximum lowering of glucose, triglycerides, and insulin will not significantly increase the expression of a P2 in the liver of these mice.

Measuring PPARγ Receptor Activation

The ability of several exemplary compounds of the present invention, shown in Table A, to bind to PPARγ was measured using a commercial binding assay (Invitrogen Corporation, Carlsbad, Calif.) that measures the test compounds ability to bind with PPAR-LBD/Fluormone PPAR Green complex. These assays were performed on three occasions with each assay using four separate wells (quadruplicate) at each concentration of tested compound. The data are mean and SEM of the values obtained from the three experiments. Rosiglitazone was used as the positive control in each experiment. Compounds were added at the concentrations shown, which range from 0.1-100 micromolar. In Table B, “-” indicates that no data is available.

Referring toFIG. 1and Table B, compounds 1 and 2 were particularly poor binders to PPARγ. Stereochemical specificity for PPARγ activation was also observed in the disparity between PPARγ binding of stereoisomers, compound 2 and compound 3, as shown in Table B, above. Furthermore, the PPARγ-sparing compound 1 possesses unexpected antihypertensive action.

Measuring Antihypertensive Action

Antihypertensive Action of Compound 1)

Male Dahl salt-sensitive rats were made hypertensive by feeding of a high salt diet (4% salt) for 3 weeks and then treated daily with the indicated dose of hydrochlorothiazide (HCTZ), compound 1, or the combination of HCTZ and compound 1, as compared to the vehicle alone (1% carboxymethylcellulose/0.01% Tween 20) by oral gavage for 8 days. Mean blood pressure was measured by direct femoral arterial cannulation under fed conditions on day 7 and after a 6 hour fast on day 8. The hypertensive effects of compound 1, HCTZ, and the combination of compound 1 and HCTZ are displayed in Table C.

Referring toFIG. 2and Table C above, the antihypertensive action of compound 1 is additive with hydrocholothiazide (HCTZ). Data are mean and (SEM) mean blood pressure taken by direct cannulation. N=5; * p<0.05 less than blood pressure in HCTZ-treated rats.

These data clearly show that the poor PPARγ-binding compound 1 was able to significantly lower blood pressure in this model of hypertension. Moreover, the ability of this compound to lower blood pressure was more effective with the combination of the diuretic HCTZ.

Measuring Antihypertensive Action

Prevention of Medrol-Induced Hypertension

Hypertension was induced in normal male Sprague-Dawley rats by daily dosing with the glucocorticoid methylprednisolone (Medrol) for 8 days. Separate groups of rats received the vehicle (1% carboxymethylcellulose/0.01% Tween 20) by oral gavage and some of both the vehicle-treated and Medrol-treated rats also received daily doses of compound 1 as shown in Table D below. Mean blood pressure was measured by direct femoral arterial cannulation under fed conditions on day 7 and after a 6 hour fast on day 8. The data are mean and (SEM) mean blood pressure obtained by direct cannulation. N=9; * p<0.05 less than blood pressure in Medrol-treated rats.

Referring toFIG. 3and Table D above, these data clearly show that the poor PPARγ-binding compound 1 significantly lowered blood pressure in this model where hypertension was generated by treatment with a glucocorticoid.

Fasting Free Fatty Acids (FFA) and Adiponectin in Treated Dahl Rats

Male salt-sensitive Dahl rats were made hypertensive by feeding a high salt (4%) diet for 3 weeks and then treated with vehicle (1% carboxymethylcellulose/0.01% Tween 20), 20 mg/kg rosiglitazone, or 40 mg/kg compound 1 for an additional 3 weeks. Doses of these compounds were chosen to produce the same metabolic effects in terms of reduction of triglycerides and elevation of adiponectin (Table E). Direct blood pressure (systolic and diastolic) and heart rate was also measured by telemetry (Tables F—H andFIG. 4).

TABLE EEffects of compound 1 and rosiglitazoneon triglycerides and adiponectin.TreatmentVehicleCompound 1RosiglitazoneFFA1.30.70*0.77*(2)(0.1)(0.1)Adiponectin1436*36*(5)(2)(4)

Data in Tables F—H and depicted inFIGS. 4A-4Care 24 hour averages for the last 4 days before the start of the daily oral gavage of treatments (−4, −3, −2, −1) and for the days 1-17 during the treatments shown.

TABLE FSystolic blood pressure measured by telemetry in hypertensiverats treated with vehicle, compound 1, or rosiglitazone.VehicleRosiglitazoneCompound 1DayMeanSEMMeanSEMMeanSEM−4169417451714−3167417151704−2177517651754−117341735173411774169616742182417261675*3185517571714*4185517771704*5189617971735*6192617981735*7197718481765*8195418881806*9200519081825*10206619271855*11205619471845*12200719681876*13199919681896*14203719881926*15207720291936*16210820491976*17211820491956*Data are mean and (SEM); N = 9-10;* significantly different than vehicle.

TABLE GDiastolic blood pressure measured by telemetry in hypertensiverats treated with vehicle, compound 1, or rosiglitazone.VehicleRosiglitazoneCompound 1DayMeanSEMMeanSEMMeanSEM−4121312451243−3119312451234−2126412741274−112441244125411264119411932131412151173*3134412351203*4135412451194*5137412651224*6139512651214*7144613161254*8141313551285*9145413661294*10151513861324*11151613961325*12147614161325*13147814161355*14150614261355*15153514661375*16153614971385*17153614871415*

TABLE HHeart rate measured by telemetry in hypertensive ratstreated with vehicle, compound 1, or rosiglitazone.VehicleRosiglitazoneCompound 1DayMeanSEMMeanSEMMeanSEM−4395740354064−3393740054003−2388439453984−13864395539341392540744204239254026414433948405540644398739954053539573982400263926398539527396839353893*8400740153944*9398539863882*10404639873894*11406839963893*12406939963913*13396839563884*14399539363855*15403739873904*163981740173895*17396640283884*

In Tables F—H, data are mean and (SEM); N=9-10; and “*” indicates a response significantly different than the vehicle.

Referring toFIGS. 4A-4Cand Tables F—H, PPARγ-sparing compound 1 is more effective in reducing blood pressure than is the PPARγ-binding positive control rosiglitazone. Furthermore, compound 1 also achieves the reduction in blood pressure while reducing heart rate, which suggests that PPARγ-sparing compounds similar to compound 1 will be more effective antihypertensive treatments in clinical practice.

In Vivo Metabolism of Compound 1 and Pioglitazone

Referring toFIG. 5, dosing of compound 1 generates, in vivo, a primary metabolite that is compound 2 in Table A. Compound 1 and pioglitazone hydrochloride were given to normal Sprague Dawley rats and HPLC/mass spectroscopy was used to evaluate the alcohol metabolites. Where as pioglitazone was metabolized to both stereoisomers (compounds 2 and 3), compound 1 was metabolized selectively to compound 2 (seeFIG. 5), also a PPARγ-sparing compound (Table B). These data show that both compound 1 and compound 2 have unexpected efficacy to treat hypertension as shown in examples 2-4. This characteristic is part of the improved antihypertensive profile of compounds 1 and 2 illustrated inFIG. 5. Metabolites were measured by chiral HPLC/MS.

As the general consensus of the scientific community is that insulin sensitizing compounds are effective pharmacologically because they are activators of PPARγ, the antihypertensive activity of the PPARγ-sparing thiazolidinedione compounds of the present invention is unexpected.

Furthermore, the use of compound 1, and by inference, compound 2, which both possess reduced PPARγ interactions, in combination with HCTZ indicates that PPARγ-sparing thiazolidinediones within the scope of this invention are also suitable for use in combination therapies such as pharmaceutical compositions further comprising a diuretic (e.g., HCTZ or the like), an ACE inhibitor (e.g., ramipril, captopril, enalapril, or the like), an angiotensin II receptor blocker (e.g., losartan, olmesartan, telmisartan, or the like), a renin inhibitor, a β-adrenergic receptor blocker, an aldosterone receptor (e.g., eplerenone, or the like), or any combination thereof.

Other Embodiments