WO2009151800A1 - Soluble epoxide hydrolase inhibitors, compositions containing such compounds and methods of treatment - Google Patents

Soluble epoxide hydrolase inhibitors, compositions containing such compounds and methods of treatment Download PDF

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WO2009151800A1
WO2009151800A1 PCT/US2009/041766 US2009041766W WO2009151800A1 WO 2009151800 A1 WO2009151800 A1 WO 2009151800A1 US 2009041766 W US2009041766 W US 2009041766W WO 2009151800 A1 WO2009151800 A1 WO 2009151800A1
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alkyl
phenyl
pharmaceutically acceptable
nhc
compound
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Cangming Yang
Zhicai Wu
Rui Liang
Steven L. Colletti
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Merck and Co Inc
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Merck and Co Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/20—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/20—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to amino substituted heteroaryl compounds possessing soluble epoxide hydrolase (sEH) inhibitory activity, compositions containing sEH inhibitory compounds, and methods of treatment relating to diseases and conditions in which soluble epoxide hydrolase is implicated.
  • Epoxide hydrolases are a group of enzymes ubiquitous in nature, detected in species ranging from plants to mammals. These enzymes are functionally related in that they catalyze the addition of water to an epoxide, resulting in the formation of a diol. Diols are frequently found as intermediates in metabolic pathways.
  • epoxide hydrolases include soluble epoxide hydrolase, also referred to as cytosolic epoxide hydrolase, cholesterol epoxide hydrolase, LT A4 hydrolase, hepoxilin hydrolase, and microsomal epoxide hydrolase (mEH), (Fretland, et al. Chem. Biological Interactions, 129: 41-59 (2000)) .
  • Epoxide hydrolases have been found in mammalian heart, kidney and liver tissue (Vogel et al. Eur. J. Biochem. 126: 425-431(1982) Schladt et al,, Biochem Pharmacol. 35: 3309-3316(1986).
  • Epoxide hydrolases have also been detected in human blood components including lymphocytes (e.g., T-lymphocytes), monocytes, erythrocytes, and platelets. In the blood, most of the sEH detected was present in lymphocytes (Seidegard, et al. Cancer Research 44: 3654-3660 (1984).
  • the epoxide hydrolases differ in their specificity towards epoxide substrates.
  • sEH is selective for aliphatic epoxides such as epoxide fatty acids while microsomal epoxide hydrolase (mEH) is more selective for cyclic and arene epoxides.
  • the primary known physiological substrates of sEH are the four regioisomeric epoxides of arachidonic acid, 5,6-, 8,9-, 11,12- and 14,15-epoxyeicosatrienoic acid, also known as epoxyeicosatrienoic acids or EETs. It has been reported that red blood cells can be reservoirs of EETs as well (Mini review: Jiang, H. Prostaglandins & other Lipid Mediators 2007, 82, 4).
  • substrates for sEH are epoxides of linoleic acid known as leukotoxin or isoleukotoxin.
  • EETs are known to be vasodilatory mediators. Their role in vessel relaxation of peripheral vessels and renal microvessels, stems from their activation of Ca(+2)-activated potassium BK(Ca) ion channels. Furthermore 11 ,12-EET has been identified as the endothelial derived hyperpolarization factor (EDHF). These properties of EETs render them an attractive target for elevation in vivo, with application to improving endothelial dysfunction. Endothelial dysfunction plays a significant role in a large number of pathological conditions including type 2 diabetes, insulin resistance, hypertension, atherosclerosis, coronary artery disease, angina, ischemia, ischemic stroke, Raynaud's disease and renal disease (Cersosimo, et.al.
  • one object of the present invention is to provide compounds that are useful for the treatment of type 2 diabetes and related conditions.
  • Other effects of EET's involve kidney function.
  • treatment with a selective sEH inhibitor attenuated the afferent arteriolar diameter in the kidney and lowered urinary albumin secretion, a marker of compromised renal function, suggesting antihypertensive and renal vascular protective effects of increased EET levels.
  • one object of the present invention is to provide end organ protection along with the treatment of hypertension.
  • EETs, and especially 11,12-EET also have been shown to exhibit anti- inflammatory properties (Node, et al. Science 285: 1276-1279(1999)); Campbell, TIPS 21 : 125- 127 (2000); Zeldin et al. TIPS 21 : 127-128 (2000)). Node et al.
  • EETs decreased expression of cytokine induced endothelial cell adhesion molecules, especially VCAM-I. Moreover, EETs prevented leukocyte adhesion to the vascular wall and the mechanism responsible involved inhibition of NFKB and 1KB kinase. vascular inflammation plays a role in endothelial dysfunction (Kessler, et al. Circulation, 99: 1878-1884 (1999)). Hence, the ability of EETs to inhibit the NFKB pathway should also help ameliorate this condition.
  • EETs and/or the administration of a selective sEH inhibitor was demonstrated to attenuate tobacco smoke induced inflammation, as assessed by total bronchoalveolar lavage cell numbers and concomitant reduction in neutrophils, alveolar macrophages and lymphocytes.
  • Hammock et al. have demonstrated usefulness in the treatment of inflammatory diseases, in particular, acute respiratory distress syndrome (ARDS) and other acute inflammatory conditions mediated by lipid metabolites, by the administration of inhibitors of epoxide hydrolase (WO98/06261, US Pat No. 5,955,496).
  • Hammock, et al. disclosed certain biologically stable inhibitors of sEH for the treatment of inflammatory diseases, for use in affinity separations of epoxide hydrolases and in agricultural applications (US Pat No. 6,150,415).
  • Hammock et al. generally described compounds that can be used to deliver a reactive functionality to the catalytic site, e.g., alkylating agents or Michael acceptors, and that these reactive functionalities can be used to deliver fluorescent or affinity labels to the enzymes active site for enzyme detection.
  • Certain urea and carbamate inhibitors of sEH have also been described in the literature (Morisseau, et al. Proc. Nat. Acad. Sci. 96: 8849-8854 (1999)).
  • chalcone oxide derivatives Miyamoto, et al. Arch. Biochem. Biophys. 254; 203-213 (1987)
  • various trans-3 -phenyl glyucidols Dietze, et al. Biochem. Pharm. 42: 1163- 1175 (1991)
  • sEH inhibition reduces COX-2 expression in mammals, and decreases PGE2 and PGD2 levels, similar to coxibs. Therefore, sEH inhibitors could be indicated for inflammatory pain (Schmelzer, et.al. PNAS 2006, 103, 13646). It has also been disclosed that 14,15-EET is 100-fold more potent than morphine dosed vPAG in rat brains, and EETs induce Met-enkephalin release in the spinal cord. This suggests that sEH inhibitors could also be used for CNS analgesia (Harder, D. presented at 9 th Annual WEC, March 2007).
  • EETs The anti-inflammatory functions of EETs also indicate that it is possible to use sEH inhibitors as ophthalmic agents to alleviate eye disorders, such as reducing intraocular pressure and reducing progression of age-related macular degeneration (WO 2007/009001 Al).
  • An object of the present invention is to provide compounds that are useful for the treatment of hyperlipidemias, dyslipidemias, atherosclerosis and related conditions.
  • Another object is to provide a pharmaceutical composition for oral use.
  • one of W and X represents a carbon or nitrogen atom, and the other represents a carbon atom;
  • Ring A represents an Aryl group or a 5-6 membered Heteroaryl group containing
  • Ring B represents a member selected from the group consisting of: a) a 3-7 membered monocyclic or bridged bicyclic aliphatic carbocycle; b) a 5-6 membered heterocycle, containing 1-2 heteroatoms, 0-1 of which is selected from oxygen and sulfur, and 0-2 of which are nitrogen atoms; c) a 6-10 membered aromatic group, and d) a 5-6 membered heteroaryl ring containing 1-2 nitrogen atoms, and 0-1 oxygen or sulfur atom;
  • R s is halo, Q -6 alkyl, haloQ-ealkyl or phenyl; each R 2 is H or is selected from the group consisting of halo; C 1-6 alkyl; haloCi. 6 alkyl; CO 2 R a ; C(O)NH 2 ; C(O)NHC ⁇ alkyl; S (O) 2 NHC I-8 alkyl; NHC(O)NHC l-g alkyl; OC 1- 6 alkyl-CO 2 R a ; C(O)-Hetcy optionally substituted with 1-3 halo atoms and one group selected from C 1-6 alkyl, haloCi ⁇ alkyl and CO 2 R a ; phenyl and HAR 5 said Phenyl and HAR being optionally substituted with 1-3 halogen atoms and 1-2 members selected from the group consisting of: Ci -6 alkyl, haloCi-galkyl, CO 2 R a , (CH
  • Alkyl as well as other groups having the prefix "alk”, such as alkoxy, alkanoyl and the like, means carbon chains which may be linear, branched, or cyclic, or combinations thereof, containing the indicated number of carbon atoms. If no number is specified, 1-6 carbon atoms are intended for linear and 3-7 carbon atoms for branched alkyl groups. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, cyclopropyl and the like.
  • Cycloalkyl and “carbocycle” are thus a subset of alkyl; if no number of atoms is specified, 3-7 carbon atoms are intended, forming 1-3 carbocyclic rings that are fused. "Cycloalkyl” can also be fused to an aryl or heteroaryl group. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl and the like.
  • Haloalkoxy, Ohaloalkyl and haloOalkyl are used interchangeably and refer to halo substituted alkyoxy groups linked through the oxygen atom.
  • Haloalkyl and haloalkoxy include mono- substituted as well as multiple substituted alkyl and alkoxy groups, up to perhalo substituted alkyl and alkoxy. For example, trifluoromethyl and trifluoromethoxy are included.
  • Aryl (Ar) and “aromatic group” mean mono- and bicyclic aromatic rings containing 6-10 carbon atoms. Examples of aryl include phenyl, naphthyl, indenyl and the like. ⁇ eteroaryl” (HAR) and “heteroaromatic group” unless otherwise specified, mean mono-, bicyclic and tricyclic aromatic ring systems containing at least one heteroatom selected from O, S 5 S(O), SO 2 and N, with each ring containing 5 to 6 atoms. HAR groups may contain from 5-14, preferably 5-13 atoms.
  • Examples include, but are not limited to, pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofurany ⁇ benzothiophenyl, benzopyrazolyl, benzotriazolyl, furo(2,3-b) ⁇ yridyl, benzoxazinyl, tetrahydrohydroquinolinyl, tetrahydroisoquinolinyl., quinolyl, isoquinolyl, indolyl, dihydroindolyl,
  • Heteroaryl also includes aromatic carbocyclic or heterocyclic groups fused to heterocycles that are non-aromatic or partially aromatic, and optionally containing a carbonyl.
  • additional heteroaryl groups include indolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, and aromatic heterocyclic groups fused to cycloalkyl rings.
  • Heteroaryl also includes such groups in charged form, e.g., pyridinium.
  • Heterocyclyl mean mono- and bicyclic saturated and partially saturated rings and ring systems containing at least one heteroatom selected from N, S and O, each of said ring having from 3 to 10 atoms in which the point of attachment may be carbon or nitrogen.
  • heterocyclyl examples include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, tetrahydrofuranyl, 1 ,4-dioxanyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl and the like.
  • Heterocycles can also exist in tautomeric forms, e.g., 2- and 4-pyridones. Heterocycles moreover includes such moieties in charged form, e.g., piperidinium, "Halogen" (Halo) includes fluorine, chlorine, bromine and iodine.
  • the invention relates to a compound in accordance with structural formula I:
  • one of W and X represents a carbon or nitrogen atom, and the other represents a carbon atom;
  • Ring A represents an Aryl group or a 5-6 membered Heteroaryl group containing 1-3 N atoms and 0-1 O or S atom
  • Ring B represents a member selected from the group consisting of: a) a 3-7 membered monocyclic or bridged bicyclic aliphatic carbocycle; b) a 5-6 membered heterocycle, containing 1-2 heteroatoms, 0-1 of which is selected from oxygen and sulfur, and 0-2 of which are nitrogen atoms; c) a 6- 10 membered aromatic group, and d) a 5-6 membered heteroaryl ring containing 1-2 nitrogen atoms, and 0-1 oxygen or sulfur atom;
  • R 1 is halo, Ci -6 alkyl, haloCi_ 6 alkyl or phenyl; each R 2 is H or is selected from the group consisting of halo; C ⁇ alkyl; haloQ. 6 alkyl; CO 2 R 3 ; C(O)NH 2 ; C(O)NHC 1-8 alkyl; S(O) 2 NHC 3-8 alkyl; OC ⁇ 6 alky ⁇ -C ⁇ 2 R a ; C(O)-Hetcy optionally substituted with 1-3 halo atoms and one group selected from Ci -6 alkyl, haloC ⁇ ealkyl and CO 2 R 8 ; phenyl and HAR, said Phenyl and HAR being optionally substituted with 1-3 halogen atoms and 1-2 members selected from the group consisting of: C ⁇ 6 alkyl, haioCi -6 alkyl, CO 2 R a , (CH 2 ) 1-6 CO 2 R a , OC
  • An aspect of the invention that is of interest relates to compounds of formula I, or a pharmaceutically acceptable salt or solvate thereof wherein W and X each represent a carbon atom.
  • Another aspect of the invention that is of interest relates to compounds of formula I or a pharmaceutically acceptable salt or solvate thereof, wherein ring A represents a phenyl or pyridyl ring.
  • Another aspect of the invention that is of interest relates to compounds of formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein ring A represents a phenyl ring.
  • Another aspect of the invention that is of interest relates to compounds of formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein ring B represents a 3-7 membered monocyclic or bridged bicyclic aliphatic carbocycle.
  • ring B represents a 5-6 membered heterocycle, containing 1-2 heteroatoms, 0-1 of which is selected from oxygen and sulfur, and 0-2 of which are nitrogen atoms.
  • Another aspect of the invention that is of interest relates to compounds of formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein ring B represents a 6-10 membered aromatic group.
  • Another aspect of the invention that is of interest relates to compounds of formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein ring B represents a 5-6 membered heteroaryl ring containing 1-2 nitrogen atoms, and 0-1 oxygen or sulfur atom.
  • Another aspect of the invention that is of more particular interest relates to compounds of formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein ring B represents a member selected from the group consisting of: cyclohexane, piperidine, piperazine, pyrrolidine, phenyl and pyridine.
  • ring B represents a member selected from the group consisting of: cyclohexane, piperidine, piperazine, phenyl and pyridine.
  • Another aspect of the invention that is of interest relates to compounds of formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein R represents halo or haloC ⁇ f salkyl. More particularly, another aspect of the invention that is of interest relates to compounds of formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 represents haloCj-galkyl.
  • each R is selected from the group consisting of H; HAR; C(O)-Hetcy optionally substituted with halo, C ⁇ aHcyl, CF 3 or CO 2 R*; 0-Ci -S aIlCyI-CO 2 R 3 wherein R a is H or C l-4 alkyl; phenyl optionally substituted with Ci- ealkyl or CO 2 R a ; C(O)NHC 1-8 alkyl and C(O)NH 2 .
  • each R 2 is selected from the group consisting of H; phenyl optionally substituted with Ci-ealkyl or CO 2 R 11 ; HAR which is selected from pyridyl and tetrazolyl; C(O)-Hetcy wherein the Hetcy represents a piperidinyl group, optionally substituted with CO 2 H; O-Ci- 3 alkyl- CO 2 H; C(O)NH 2 ; and C(O)NHC l -salkyl wherein the alkyl portion represents -CH 2 -cyclohexyL
  • each R represents H.
  • R 3 is selected from the group consisting of: H; halo selected from Cl and F; CO 2 R a wherein R a represents H or C 1 .
  • haloCi-ealkyl wherein the halo portion is F
  • OhaloQ-ealkyl wherein the halo portion is F
  • C(O)C i ⁇ alkyl C(O)haloCi -6 alkyl wherein the halo portion is F
  • C(O)-Phenyl NHC(O>Phenyl
  • S(O) 2 haIoCi_ 6 alkyl wherein the halo portion is F
  • SO 2 Phenyl SO 2 NHCi.
  • Another aspect of the invention that is of interest relates to compounds of formula I, or a pharmaceutically acceptable salt or solvate thereof wherein:
  • W and X each represent a carbon atom
  • Ring A represents a phenyl or pyridyl ring
  • Ring B represents a member selected from the group consisting of: a) a 3-7 rnembered monocyclic or bridged bicyclic aliphatic carbocycle; b) a 5-6 membered heterocycle, containing 1-2 heteroatoms, 0-1 of which is selected from oxygen and sulfur, and 0-2 of which are nitrogen atoms; c) a 6-10 membered aromatic group, and d) a 5-6 membered heteroaryl ring containing 1-2 nitrogen atoms, and 0-1 oxygen or sulfur atom;
  • R 1 represents halo or haloC ⁇ alkyl
  • each R 2 is selected from the group consisting of H; HAR; C(O)-Hetcy optionally substituted with halo, R a is H or C M alkyl; phenyl optionally substituted with d-salkyl or CO 2 R 8 ; C(O)NHCi. 8 alkyl and C(O)NH 2 .
  • each R 3 is selected from the group consisting of: H; halo selected from CI and F; CO 2 R 3 wherein R a represents H or Q ⁇ alkyl; C ⁇ alkyl; haloCj-ealkyl wherein the halo portion is F; OhaloCi ⁇ alkyl wherein the halo portion is F; C(O)C j.
  • Another aspect of the invention that is of particular interest relates to a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein:
  • W and X each represent a carbon atom;
  • ring A represents a phenyl or pyridyl ring;
  • Ring B represents a member selected from the group consisting of: a) a 3-7 membered monocyclic or bridged bicyclic aliphatic carbocycle; b) a 5-6 merabered heterocycle, containing 1-2 heteroatoms, 0-1 of which is selected from oxygen and sulfur, and 0-2 of which are nitrogen atoms; c) a 6-10 membered aromatic group, and d) a 5-6 membered heteroaryl ring containing 1-2 nitrogen atoms, and 0-1 oxygen or sulfur atom;
  • R 1 represents trifluoromethyl or chloro; each R 2 is selected from the group consisting of H; HAR; C(O)-Hetcy optionally substituted with halo, C ]-3 alkyl, CF 3 or C0 2 R a ; O-Ci -6 alkyl-CO 2 R a wherein R a is H or C 1-4 alkyl; phenyl optionally substituted with C h alky, or CO 2 R a ; C(O)NHC j_ s alkyl and C(O)NH 2 ; each R 3 is selected from the group consisting of: H; halo selected from Cl and F; CO 2 R a wherein R a represents H or C ⁇ alkyl; Ci ⁇ alkyl; haloCj-ealkyl wherein the halo portion is F; OhaloCi- 6 alkyl wherein the halo portion is F; C(O)C i-galkyl, C(O)haloCi.
  • halo portion is F; C(O)-Phenyl; NHC(O)-Phenyl; S (O) 2 haloCi -6 alkyl wherein the halo portion is F; SO 2 Phenyl; SO 2 NHCi -8 alkyl; NHC (O)NHC i_ 8 alkyl; NHC(O)C !-8 aIkyl; C(O)HAR and, the Phenyl and HAR portions of C(O)Phenyl, SO 2 Phenyl, NHC(O)Phenyl and C(O)HAR being optionally substituted with 1-3 halo groups selected from F and Cl, and 1-2 Ci-ealkyl or haloCi- ealkyl groups the halo portions of which arc F. Examples of compounds that are of interest are set forth in Table 1 below.
  • Yet another aspect of the invention that is of interest relates to a pharmaceutical composition comprised of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in combination with a pharmaceutically acceptable carrier.
  • Yet another aspect of the invention that is of interest relates to a method of treating diabetes in a mammalian patient in need of such treatment comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective for treating diabetes.
  • Yet another aspect of the invention that is of interest relates to a method of treating pain in a mammalian patient in need of such treatment comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective for treating pain.
  • Yet another aspect of the invention that is of interest relates to a method of treating atherosclerosis in a mammalian patient in need of such treatment comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective for treating atherosclerosis.
  • Yet another aspect of the invention that is of interest relates to a method of treating hypertension in a mammalian patient in need of such treatment comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective for treating hypertension. .
  • racemic mixtures of compounds may be separated so that individual enantiomers are isolated.
  • the separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds of Formula I to an enantiomerically pure compound to form a diastereomeric mixture, which is then separated into individual diastereomers by standard methods, such as fractional crystallization or chromatography.
  • the coupling reaction is often the formation of salts using an enantiomerically pure acid or base.
  • the diasteromeric derivatives may then be converted to substantially pure enantiomers by cleaving the added chiral residue from the diastereomeric compound.
  • racemic mixture of the compounds of Formula I can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.
  • enantiomers of compounds of the general Formula I may be obtained by stereoselective synthesis using optically pure starting materials or reagents.
  • tautomers which have different points of attachment for hydrogen accompanied by one or more double bond shifts.
  • a ketone and its enol form are keto-enol tautomers.
  • a 2- hydroxyquinoline can reside in the tautomeric 2-quinolone form.
  • the individual tautomers as well as mixtures thereof are included.
  • Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention.
  • oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
  • compounds of Formula I are administered orally.
  • the effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.
  • the compounds of the present invention are administered at a dosage of from about 0.05 milligrams to about 100 milligrams per kilogram of animal body weight, preferably given as a daily dose, or in sustained release form.
  • a dosage of from about 0.05 milligrams to about 100 milligrams per kilogram of animal body weight preferably given as a daily dose, or in sustained release form.
  • the total dosage administered is from about 0.1 milligrams to about 1000 milligrams, is likely to be from about 0.5 milligrams to about 350 milligrams, and is often from about 1 milligram to about 50 milligrams.
  • the dosage for an adult human may be as low as 0.1 mg.
  • Examples of dosages for a 70 kg adult human are 0.1 mg, 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 350 mg, and 500 mg per day.
  • the dosage regimen may be adjusted within the above ranges or even outside of these ranges to provide the optimal therapeutic response.
  • Oral administration will usually be carried out using tablets.
  • Examples of doses in tablets which may be administered include about 0.1 mg, 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 350 mg, and 500 mg.
  • Other oral forms e.g, capsules or suspensions
  • Dosing can be carried out on a daily basis, such as once, twice or three times daily, or less often, such as every other day, every third day, once weekly or even once monthly.
  • Compounds of Formula I may be used in combination with other drugs that may also be useful in the treatment or amelioration of one or more of the diseases or conditions for which compounds of Formula I are useful.
  • Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously (such as via co-administration) or sequentially with a compound of Formula I.
  • a pharmaceutical composition in unit dosage form containing such other drugs and the compound of Formula I is preferred.
  • the combination therapy also includes therapies in which the compound of Formula I and one or more other drugs are administered on different overlapping schedules.
  • compositions of the present invention include those that contain one or more other active ingredients , in addition to a compound of Formula I.
  • Examples of other active ingredients that may be administered in combination with a compound of Formula I, and either administered separately or in the same pharmaceutical composition include, but are not limited to:
  • PPAR gamma agonists and partial agonists such as the glitazones (e.g. troglitazone, pioglitazone, eng ⁇ tazone, MCC-555, rosiglitazone, balaglitazone, netoglitazone, and the like), and PPAR gamma agonists and partial agonists that do not have a glitazone structure (e.g. K-I l 1, INT-131, MBX-102 [metaglidisen], MBX-2044, FK614 including SPPAR ⁇ M GSK-376501 and the like);
  • glitazones e.g. troglitazone, pioglitazone, eng ⁇ tazone, MCC-555, rosiglitazone, balaglitazone, netoglitazone, and the like
  • PPAR gamma agonists and partial agonists that do not have a glitazone structure (
  • DPP-4 dipeptidyl peptidase IV (DPP-4) inhibitors, including sitagliptin, vildagliptin, saxagliptin, as well as those disclosed in the following published patents and applications: US
  • Specific DPP-4 inhibitor compounds include isoleucine thiazolidide (P32/98); NVP-DPP-728; vildagliptin (LAF 237); P93/01; and saxagliptin (BMS 477118). Additional specific DPP-IV inhibitors that are of interest herein include:
  • insulin or insulin mimetics including rapid acting insulin,, regular insulin, long acting insulin, complexed forms of insulin and the like, administered by any conventional route, such as subcutaneous, intradermal or intramuscular injection, oral, transdermal, intranasal, intrapulmonary, and the like;
  • insulin secretagogues such as sulfonylureas (e.g. tolbutamide, glimep ⁇ ride, glicazinde, and glipizide) and meglitinides (eg. repaglinide and nateglinide);
  • ⁇ -glucosidase inhibitors such as acarbose and miglitol
  • agents which improve a patient's lipid profile such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, rosuvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, ZD-4522 and other statins), (ii) bile acid sequestrants (cholestyramine, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran), (iii) nicotinyl alcohol, nicotinic acid (niacin) or a salt thereof, (iv) niacin receptor agonists, (v) PP ARa agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate), (vi) cholesterol absorption inhibitors, such as for example ezetimibe, (vii)
  • antiobesity compounds such as fenfluramine, dexfenfluramme, phentermine, sibutramine, orlistat, exentin-4, neuropeptide Y5 inhibitors, MC4R agonists, cannabinoid receptor 1 (CB-I) antagonists/inverse agonists, such as rimonabant and taranabant, and ⁇ 3 adrenergic receptor agonists;
  • agents intended for use in inflammatory conditions such as aspirin, nonsteroidal anti-inflammatory drugs as further described below, glucocorticoids, azulfidine, and cyclooxygenase 2 selective inhibitors;
  • GLP-I analogs such as exentin-4, including exenatide
  • GPR 119 agonists
  • PPAR ⁇ agonists such as those disclosed in WO 97/28149;
  • prandial glucose releasing agents such as repaglinide and nateglinide,
  • antihypertensives such as diuretics, e.g., hydrochlorothiazide, furosemide and the like; beta adrenergic blocking drugs, such as propranolol, metaprolol and the like; ACE inhibitors, such as enalapril, lisinopril, ramipril,, quinapril and the like, ARBs, such as losartan, valsartan, irbesartan, candesartan and the like, and calcium channel blocking drugs, such as amlodipine, diltiazem and verapamil; and
  • NSAIDS such as ibuprofen, naproxen, meloxicam, diclofenac, indomethacin, prioxicam, COX-2 inhibitors such as nabumetone, etodolac, rofecoxib, etoricoxib, celecoxib, and valdecoxib, and conventional non-opioid and opioid analgesics, such as aspirin, acetaminophen, codeine, meperidine, oxycodone, hydrocodone, pentazocine, morphine and the like.
  • the above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds.
  • Non-limiting examples include combinations of compounds having Formula ⁇ with two or more active compounds selected from biguanides, sulfonylureas, HMG-CoA reductase inhibitors, other PPAR agonists, PTP-IB inhibitors, DPP-4 inhibitors, and anti-obesity compounds.
  • glucagon receptor antagonist compounds that are useful as described herein include : N- [4-(( 1 S)- 1 - ⁇ 3 -(3 , 5 -Dichlorophenyl)-5- [6-(trifluoromethoxy)-2-na ⁇ hthyl] - 1 H- pyrazol- 1 -yl ⁇ ethyl)benzoyl]- ⁇ -alanine;
  • GPR- 119 agoni sts that are of interest as described herein include :
  • PPAR alpha, gamma or delta selective agonists include, but are not limited to the following: netoglitazone, pioglitazone, rosiglitazone, troglitazone, balaglitazone, CS204,
  • AZD6610 ZYHl, GFT505, LY-465608, DRF-2519, DRF-11605, DRF-2725, GW-626019, GW- 625019, CS038, ONO-5129, aleglitazar, muraglitazar, soldeglitazar, teseglitazar s naveglitazar, farglitazar, KRP-297, AVE0897, AVE 0847, LBM642, PPM263, PPM202, PPM201, PPM204, PLX-204, GW-677954, NN0606, AVE8134, NS-220, SAR 35034, KD3010, GW-501516, FK614, K-111, metaglidasen, MBX-2044, INT-131, KD3010, KR-62980, SVT002149,
  • SPPARMs that are of interest as described herein include:
  • IB-HSD 1 inhibiting compounds that are of interest as described herein include: 3-[ 1 -(4-cnlorophenyl)-fr ⁇ r ⁇ -3-fluorocyclobutyl]-4 J 5-dicyclopropyl-r-4if- 1 ,2,4- triazole; 3-[l -(4-chlorophenyl)-fr ⁇ ? ⁇ 5 r -3-fluorocyclobutyl]-4-cyclopropyl-5-(l - methylcyclopropyl)-r-4/i- 1 ,2 f 4 ⁇ triazole; (trifluoromethoxy)phenyl]"r-4J ⁇ -l 5 2,4-triazole; 3 - [ 1 -(4-chl orophenyl)cyclobutyl] -4-methyl- 5 - [2-(trifluoromethyl)phenyl] -4H-
  • glucokinase activating drugs examples include: 6-( 1 -acetylpyrrolidin-2-yl)-5-(6-metho ⁇ ymethylpyridin-3 -yl)oxy)-2-pyridin-2-yl-
  • Compounds of the present invention can be used to treat one or more diseases or conditions selected from hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia, and dyslipidemia by administering a therapeutically effective amount of a compound of Claim 1 in combination with an HMG-CoA reductase inhibitor to a patient in need of such treatment.
  • Statins are the preferred HMG-CoA reductase inhibitors for use in this combination therapy.
  • Preferred statins include lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, itavastatin, ZD-4522, rivastatin, and rosuvastatin.
  • This combination treatment may be particularly desirable for treating or reducing the risk of developing atherosclerosis.
  • Such a combination can optionally have a third pharmaceutically active ingredient, such as a CETP inhibitor (e.g. torcelrapib), niacin, or a cholesterol absorption inhibitor (e.g. ezetimibe).
  • Cholesterol absorption inhibitors can also be used in the present invention. Such compounds block the movement of cholesterol from the intestinal lumen into enterocytes of the small intestinal wall, thus reducing serum cholesterol levels.
  • Examples of cholesterol absorption inhibitors are described in U.S. Patent Nos. 5,846,966, 5,631,365, 5,767,1 15, 6,133,001, 5,886,171, 5,856,473, 5,756,470, 5,739,321, 5,919,672, and in PCT application Nos. WO 00/63703, WO 00/60107, WO 00/38725, WO 00/34240, WO 00/20623, WO 97/45406, WO 97/16424, WO 97/16455, and WO 95/08532.
  • ezetimibe also known as l-(4-fluoro ⁇ henyl)-3(R)-[3(S)-(4-fluorophenyl)-3-hydroxypropyl)]- 4(S)-(4-hydroxyphenyl)-2-azetidinone, described in U.S. Patent Nos. 5,767,115 and 5,846,966.
  • Therapeutically effective amounts of cholesterol absorption inhibitors include dosages of from about 0.01 mg/kg to about 30 mg/kg of body weight per day, preferably about 0.1 mg/kg to about 15 mg/kg.
  • the compounds used in the present invention can be administered with conventional diabetic medications as outlined above.
  • a diabetic patient receiving treatment as described herein may also be taking insulin or an oral antidiabetic medication.
  • an oral antidiabetic medication useful herein is metformin.
  • the compounds used in the present invention can be administered with conventional antihypertensive medications as outlined above.
  • a patient with high blood pressure receiving treatment as described herein may also be taking
  • ARBS or an ACE inhibitor.
  • An oral antihypertensive medication useful herein is losartin.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 1- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl- morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion exchange resins such
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
  • Preferred acids include citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, tartaric, toluenesulfonic (tosylate), methanesulfonic (mesylate) and benzenesulfonic (besylate) acid salts, most preferably the benzenesulfonic, toluenesulfonic and methanesulfonic acid salts.
  • the compounds of the invention may be present in zwitterionic forms.
  • Metabolites of the compounds described herein which themselves fall within the scope of the invention are also compounds of the current invention.
  • Prodrugs which are metabolically or physically labile compounds that are converted to the active pharmaceutical ingredient (API) as they are being administered to a patient or after they have been administered to a patient, also may be considered compounds of this invention.
  • compositions described herein are generally comprised of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, in combination with a pharmaceutically acceptable carrier.
  • the compounds used in the present invention can be administered via any conventional route of administration.
  • the preferred route of administration is oral.
  • suitable oral compositions include tablets, capsules, troches, lozenges, suspensions, dispersible powders or granules, emulsions, syrups and elixirs.
  • carrier ingredients include diluents, binders, disintegrants, lubricants, sweeteners, flavors, colorants, preservatives, and the like.
  • diluents include, for example, calcium carbonate, sodium carbonate, lactose, calcium phosphate and sodium phosphate.
  • granulating and disintegrants include corn starch and alginic acid.
  • binding agents include starch, gelatin and acacia.
  • lubricants examples include magnesium stearate, calcium stearate, stearic acid and talc.
  • the tablets may be uncoated or coated by known techniques. Such coatings may delay disintegration and thus, absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • One embodiment of the invention that is of interest is a tablet or capsule that is comprised of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in an amount ranging from about O.lmg to about lOOOmg, in combination with a pharmaceutically acceptable carrier.
  • a compound of formula I or a pharmaceutically acceptable salt or solvate thereof is combined with another therapeutic agent and the carrier to form a fixed combination product.
  • This fixed combination product may be a tablet or capsule for oral use.
  • a compound of formula I or a pharmaceutically acceptable salt or solvate thereof (about 0.1 to about 1000 mg) and the second therapeutic agent (about 0.1 to about 500 mg) are combined with the pharmaceutically acceptable carrier, providing a tablet or capsule for oral use.
  • Sustained release over a longer period of time may be particularly important in the formulation.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
  • the dosage form may also be coated by the techniques described in the U.S. Patent Nos. 4,256,108; 4,166,452 and 4,265,874 to form osmotic therapeutic tablets for controlled release.
  • Typical ingredients that are useful to slow the release of nicotinic acid in sustained release tablets include various cellulos ⁇ c compounds, such as methylcel ⁇ ulose, ethylcellulose, propylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, starch and the like.
  • Various natural and synthetic materials are also of use in sustained release formulations. Examples include alginic acid and various alginates, polyvinyl pyrrolidone, tragacanth, locust bean gum, guar gum, gelatin, various long chain alcohols, such as cetyl alcohol and beeswax.
  • a tablet as described above comprised of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, and further containing an HMG Co-A reductase inhibitor, such as simvastatin or atorvastatin.
  • an HMG Co-A reductase inhibitor such as simvastatin or atorvastatin.
  • Typical release time frames for sustained release tablets in accordance with the present invention range from about 1 to as long as about 48 hours, preferably about 4 to about 24 hours j and more preferably about 8 to about 16 hours.
  • Hard gelatin capsules constitute another solid dosage form for oral use. Such capsules similarly include the active ingredients mixed with carrier materials as described above.
  • Soft gelatin capsules include the active ingredients mixed with water-miscible solvents such as propylene glycol, PEG and ethanol, or an oil such as peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions are also contemplated as containing the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients include suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth and acacia; dispersing or wetting agents,e.g- > lecithin; preservatives, e.g., ethyl, or n ⁇ propyl parahydroxybenzoate, colorants, flavors, sweeteners and the like.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredients in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, ka
  • Syrups and elixirs are also included.
  • a pharmaceutical composition that is of interest is a sustained release tablet that is comprised of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in combination with a pharmaceutically acceptable carrier.
  • Another aspect of the invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament. This medicament has the uses described herein.
  • another aspect of the invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, and an HMG Co-A reductase inhibitor, such as simvastatin, in the manufacture of the medicament.
  • This medicament has the uses described herein.
  • the compounds defined above may be used in any of the following methods to treat or control diseases, as well as methods to treat other diseases not listed below, in a mammalian patient, especially a human, by administering to the patient a therapeutically effective amount for the specific disease (or diseases) of a compound of Formula I: (1 ) non-insulin dependent diabetes mellitus (type 2 diabetes);
  • one or more lipid disorders including mixed or diabetic dyslipidemia, hyperlipidemia, and hypercholesterolemia; (9) glaucoma, age related macular degeneration and the like;
  • kidney malfunction such as proteinuria, and in particular, albuminuria, and subsequent edema resulting therefrom, macrophage infiltration, and the like.
  • the compounds may also be used in a method for reducing the risks of adverse sequelae associated with metabolic syndrome in a human or other mammalian patient in need of such treatment which comprises administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the compounds may also be used in a method for treating atherosclerosis, for reducing the risk of developing atherosclerosis, for delaying the onset of atherosclerosis, and/or reducing the risk of sequelae of atherosclerosis in a human or other mammalian patient in need of such treatment or at risk of developing atherosclerosis or sequelae of atherosclerosis, which comprises administering to the patient a therapeutically effective amount of a compound of
  • Sequelae of atherosclerosis include for example angina, claudication, heart attack, stroke, etc.
  • the compounds are especially useful in the treatment of the following diseases, by administering a therapeutically effective amount (for the specific disease) of the compound, or a pharmaceutically acceptable salt thereof, to a patient in need of treatment:
  • Another aspect of the invention that is of interest relates to a method of treating atherosclerosis in a human patient in need of such treatment comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective for treating atherosclerosis.
  • Another aspect of the invention that is of interest relates to a method of treating diabetes, and in particular, type 2 diabetes, in a human patient in need of such treatment comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective for treating diabetes.
  • Another aspect of the invention that is of interest relates to a method of treating metabolic syndrome in a human patient in need of such treatment comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective for treating metabolic syndrome.
  • Another aspect of the invention that is of interest relates to a method of treating high blood pressure in a human patient in need of such treatment comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective for treating hypertension.
  • Another aspect of the invention that is of interest relates to a method of treating inflammatory pain or CN S -mediated pain in a human patient in need of such treatment comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective for treating pain.
  • Another aspect of the invention that is of interest relates to a method of treating disorders of the eye in a human patient in need of such treatment comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective for alleviating eye disorders.
  • Another aspect of the invention that is of interest relates to a method of treating cardiac hypertrophy and renal failure in a human patient in need of such treatment comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective for anti-inflammatory end organ protection.
  • Another aspect of the invention that is of particular interest relates to a method of treating or preventing atherosclerosis, diabetes, hypertension, metabolic syndrome or a related condition in a human patient in need of such treatment, comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof administered in an amount that is effective to treat or prevent atherosclerosis, diabetes, hypertension, metabolic syndrome or a related condition.
  • Compounds of the present invention are inhibitors of the enzyme, soluble epoxide hydrolase (sEH).
  • the compounds of this invention are useful in treating or controlling diseases, disorders or conditions which are mediated by sEH and EETs (Larsen, Campbell and Gutterman TRENDS in Pharmacol Sci. 2007, 28(1), 32).
  • One aspect of the present invention provides a method for the treatment and control of diseases that can be mediated by administration of an sEH inhibitor, such as type 2 diabetes or hypertension.
  • Compounds of the present invention may be useful in treating or controlling many sEH mediated diseases and conditions, including, but not limited to, (1) diabetes mellitus, and especially non-insulin dependent type 2 diabetes mellitus (NIDDM), (2) hyperglycemia, (3) low glucose tolerance, (4) pre-diabetes or insulin resistance, (5) obesity, (6) hypertension, (7) dyslipidemia, (8) hyperlipidemia, (9) hypercholesterolemia, (10) atherosclerosis and its sequelae, (11) kidney failure, (12) cardiac hypertrophy, (13) pancreatitis, (14) vascular restenosis, (15) inflammatory pain, (16) CNS- mediated pain, (17) glaucoma, (18) macular degeneration, (19) retinopathy, (20) thrombosis, (21) metabolic syndrome, and (22) Raynaud's syndrome.
  • NIDDM non-insulin dependent type 2 diabetes mellitus
  • Another aspect of the invention provides a method of treating inflammatory conditions, including acute respiratory distress syndrome (ARDS), ischem ⁇ a/reperfusion injury and related diseases.
  • ARDS acute respiratory distress syndrome
  • the present compounds can be used to lower glucose and insulin in non-diabetic patients who have impaired glucose tolerance and/or are in a pre-diabetic condition by the administration to a patient in need of treatment a therapeutically effective amount of a compound having Formula I, or pharmaceutically acceptable salt thereof.
  • the present compounds can be used to treat obesity in a patient in need of such treatment by administering to the patient a therapeutically effective amount of a compound of Formula I, or pharmaceutically acceptable salt thereof.
  • the present compounds can be used to treat or reduce the risk of developing atherosclerosis in a patient in need of such treatment by administering to the patient a therapeutically effective amount of a compound of Formula 1 classroom or a pharmaceutically acceptable salt thereof.
  • the present compounds can be used to treat or reduce hyperglycemia in a diabetic patient in need of such treatment by administering to the patient a therapeutically effective amount of a compound of Formula 1, or a pharmaceutically acceptable salt thereof.
  • the present compounds can be used to treat or reduce blood pressure and provide kidney end organ protection in a hypertensive patient in need of such treatment by administering to the patient a therapeutically effective amount of a compound of Formula 1 , or a pharmaceutically acceptable salt thereof.
  • One aspect of the invention provides a method for the treatment and control of mixed or diabetic dyslipidemia, and/or atherosclerosis, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound having formula I.
  • the compound may be used alone or advantageously may be administered with a cholesterol biosynthesis inhibitor, particularly an HMG-CoA reductase inhibitor such as lovastatin, simvastatin, rosuvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, or ZD-4522.
  • the compound may also be used advantageously in combination with other lipid lowering drugs such as cholesterol absorption inhibitors (for example stanol esters, sterol glycosides such as tiqueside, and azetidinones such as ezetimibe), ACAT inhibitors (such as avasimibe), CETP inhibitors (such as torcetrapib), niacin, niacin receptor agonists, bile acid sequestrants, microsomal triglyceride transport inhibitors, and bile acid reuptake inhibitors.
  • cholesterol absorption inhibitors for example stanol esters, sterol glycosides such as tiqueside, and azetidinones such as ezetimibe
  • ACAT inhibitors such as avasimibe
  • CETP inhibitors such as torcetrapib
  • niacin niacin receptor agonists
  • bile acid sequestrants bile acid sequestrants
  • These combination treatments may also be effective for the treatment or control of one or more related conditions selected from the group consisting of hypercholesterolemia, atherosclerosis, hyperlipidemia, hypertriglyceridemia, dyslipidemia, high LDL ⁇ c levels, and low HDL-c levels.
  • Another aspect of the invention that is of interest relates to a method of treating or controlling one or more of: mixed or diabetic dyslipidemia, hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, and/or hypertriglyceridemia., type 2 diabetes, hyperglycemia, insulin resistance and related conditions, hypertension, and/or kidney failure, and inflammatory pain which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound having formula I in combination with a compound selected from the group consisting of: a DPP -4 antagonist; a glucagon receptor antagonist; a glucokinase activator; a GPRl 19 agonist; a GPR 40 modulator; a GPR 120 agonist; an insulin sensitizer; a sulfonylurea or other insulin secretogogue; a SPPAR ⁇ M such as those disclosed in WO 2006/099077 Al; an ⁇ -glucosidase inhibitor; an SGLT
  • compositions which comprise a compound of Formula I and a pharmaceutically acceptable carrier.
  • the pharmaceutical compositions of the present invention comprise a compound of Formula I or a pharmaceutically acceptable salt as an active ingredient, as well as a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids.
  • a pharmaceutical composition may also comprise a prodrug, or a pharmaceutically acceptable salt thereof, if a prodrug is administered.
  • the compounds of Formula I can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalHne cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
  • oral liquid preparations such as, for example, suspensions, elixirs and solutions
  • carriers such as starches, sugars, microcrystalHne cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the
  • tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained.
  • the active compounds can also be administered intranasally as, for example, liquid drops or spray.
  • the tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
  • a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
  • tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
  • Compounds of formula I may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • Step A 2-fluoro-5-f2-fl ⁇ oro-6-( ' trifl ⁇ ororoetlw ⁇ phenvl]pvridme
  • Step B N-CcyclohexylmethyD-S-P-fluoro- ⁇ -ftrifiuoromethv ⁇ phenyljpyridin ⁇ -amine 2-Fluoro-5-[2-fluoro-6-(trifluorometliyl)phenyl]pyridme ⁇ 1700 mg, 6.56 mmol) and 1- cyclohexylmethanamine (2.56 niL, 19.68 mmol) were mixed in NMP, stirred at 200 0 C for 1 h, cooled to room temperature, diluted with water, extracted with EtOAc twice. The combined organic extracts were washed with brine, dried over Na 2 SO ⁇ filtered, concentrated.
  • Step A 4-(6-fluoropwidin-3-yl)-3-(trifluoromethyl)benzamide
  • Step B 4-(6- ⁇ [2-(2-chloro-6-fluorophenyl)ethyl] amino ⁇ pyridm-3-y l)-3 - (trifluoromethyl)benzamide
  • Step C ethyl H4-(6-f r2-(2-chloro-6-fluorophenyl)ethyll amino ⁇ pyridin-3-vD-3- (trifluoromethyl)benzoyl] ⁇ iperidine-4-carboxylate
  • Step D 1 -[4 ⁇ (6- ( r2-(2-chloro-6-fluorophenyl)ethyl1 amino ⁇ pyridin-3-yi)-3 - (trifIuoromethyl)benzovl]piperidme-4-carboxylic acid
  • Step B 1 -(6-fluoropyridin-3-yl)-3-pyridin-3-yl-5-ftrifiuoromethyl)-4,5-dihydro-l H-p ⁇ razol-5-ol
  • the DNA for expressing sEH was designed based on a rhesus monkey sEH cDNA, modified to optimize for expression both in E. coli and insect cells.
  • the designed DNA fragment encodes a protein sequence that is identical to full length human sEH, and the DNA was synthesized in vitro.
  • the DNA was then subcloned into the pETlOO vector that will generate a fusion protein with an N-terminal His-tag.
  • the recombinant protein was expressed in E. coli.
  • the sEH enzyme was affinity purified by a Ni +4" column. His-tag was removed by Enter Kinase (EK) digestion. The purified enzyme aliquots were frozen and held at -80 0 C for later use.
  • Fluorescence based enzyme in vitro assay For each assay (100 ul), an aliquot of enzymes (about 1 nM final concentration) was incubated with a fluorescence substrate, S7 (lOuM final concentration), in sEH assay buffer (25 mM HEPES, pH7.0, O.lmg/ml BSA) in a 96-well plate. The kinetic reaction reading (Ex330/Em465) was conducted using a plate reader, Spectra max (Molecular Devices) at 25 0 C.
  • HEK293 (human kidney) cells were seeded at 4.2X10 4 cells/well (10OuI) in 96- well plate in DMEM medium (high glucose) containing 10% FBS, 100 units/ml Penicillin and 100 ug/ml Streptomycin at 37 0 C in a humidified atmosphere of 10% CO 2 . After 24 h ⁇ the medium was changed to the same medium but without FBS for 1 h. The compound, diluted in DMSO, was added to each well for 1 h. Then, the substrate EET (3 uM final cone.) was added to each well for 2 h. At the end of the incubation period, 80 ul of medium was transferred to a new 96 well plate followed by LC-MS/MS analysis for the production of DHET.
  • Liver, skeletal muscle (Gastrocnemius), epididymal white adipose tissues and kidneys (cut longitudinally) from some animals are collected, wrapped into foils and frozen into liquid nitrogen immediately. Tissue target engagement, biomarkers and drug levels are measured.
  • Vehicle 1 0.5% methocel (with 10% vol. of cone. HCl and 20% vol. of 5N NaOH, pH ⁇ 7)
  • Inhibitor Compound dissolve the compound in 10% volume of cone HCl ( ⁇ 10N), add 70% volume of 0.5% methocel (at pH 3), mix well and then add 20% volume of 5N NaOH and mix. Adjust pH to neutral (pH 7).
  • Vehicle 2 0.5% methocel Rosiglitazone: in 0.5% methocel.

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Abstract

Compounds of the formula (I) or a pharmaceutically acceptable salt or solvate thereof is disclosed. The compounds are useful for treating diabetes, inflammation, atherosclerosis, hypertension, pain and the like. Pharmaceutical compositions and methods of use are also included.

Description

TITLE OF THE INVENTION
SOLUBLE EPOXIDE HYDROLASE INHIBITORS, COMPOSITIONS CONTAINING SUCH
COMPOUNDS AND METHODS OF TREATMENT
BACKGROUND OF THE INVENTION
The present invention relates to amino substituted heteroaryl compounds possessing soluble epoxide hydrolase (sEH) inhibitory activity, compositions containing sEH inhibitory compounds, and methods of treatment relating to diseases and conditions in which soluble epoxide hydrolase is implicated. Epoxide hydrolases are a group of enzymes ubiquitous in nature, detected in species ranging from plants to mammals. These enzymes are functionally related in that they catalyze the addition of water to an epoxide, resulting in the formation of a diol. Diols are frequently found as intermediates in metabolic pathways.
Several types of epoxide hydrolases have been characterized, including soluble epoxide hydrolase, also referred to as cytosolic epoxide hydrolase, cholesterol epoxide hydrolase, LT A4 hydrolase, hepoxilin hydrolase, and microsomal epoxide hydrolase (mEH), (Fretland, et al. Chem. Biological Interactions, 129: 41-59 (2000)) . Epoxide hydrolases have been found in mammalian heart, kidney and liver tissue (Vogel et al. Eur. J. Biochem. 126: 425-431(1982) Schladt et al,, Biochem Pharmacol. 35: 3309-3316(1986). Epoxide hydrolases have also been detected in human blood components including lymphocytes (e.g., T-lymphocytes), monocytes, erythrocytes, and platelets. In the blood, most of the sEH detected was present in lymphocytes (Seidegard, et al. Cancer Research 44: 3654-3660 (1984).
The epoxide hydrolases differ in their specificity towards epoxide substrates. For example, sEH is selective for aliphatic epoxides such as epoxide fatty acids while microsomal epoxide hydrolase (mEH) is more selective for cyclic and arene epoxides. The primary known physiological substrates of sEH are the four regioisomeric epoxides of arachidonic acid, 5,6-, 8,9-, 11,12- and 14,15-epoxyeicosatrienoic acid, also known as epoxyeicosatrienoic acids or EETs. It has been reported that red blood cells can be reservoirs of EETs as well (Mini review: Jiang, H. Prostaglandins & other Lipid Mediators 2007, 82, 4). Also known to be substrates for sEH are epoxides of linoleic acid known as leukotoxin or isoleukotoxin.
The EETs are known to be vasodilatory mediators. Their role in vessel relaxation of peripheral vessels and renal microvessels, stems from their activation of Ca(+2)-activated potassium BK(Ca) ion channels. Furthermore 11 ,12-EET has been identified as the endothelial derived hyperpolarization factor (EDHF). These properties of EETs render them an attractive target for elevation in vivo, with application to improving endothelial dysfunction. Endothelial dysfunction plays a significant role in a large number of pathological conditions including type 2 diabetes, insulin resistance, hypertension, atherosclerosis, coronary artery disease, angina, ischemia, ischemic stroke, Raynaud's disease and renal disease (Cersosimo, et.al. Diabetes/Metabolism Research and Reviews 2006, 22, 423). Endothelial mediated vessel relaxation can contribute 25-40% of insulin stimulated glucose uptake during a euglycemic clamp (Kim, et.al. Circulation 2006, 113, 1888). Hence, one object of the present invention is to provide compounds that are useful for the treatment of type 2 diabetes and related conditions. Other effects of EET's involve kidney function. In angiotensin II infused rats, treatment with a selective sEH inhibitor attenuated the afferent arteriolar diameter in the kidney and lowered urinary albumin secretion, a marker of compromised renal function, suggesting antihypertensive and renal vascular protective effects of increased EET levels. Administration of a (selective) sEH inhibitor to angiotensin II treated rats was demonstrated to lower systolic blood pressure (Imig, et al. Hypertension, 39: 690-694 (2002)). Hence, one object of the present invention is to provide end organ protection along with the treatment of hypertension. EETs, and especially 11,12-EET, also have been shown to exhibit anti- inflammatory properties (Node, et al. Science 285: 1276-1279(1999)); Campbell, TIPS 21 : 125- 127 (2000); Zeldin et al. TIPS 21 : 127-128 (2000)). Node et al. demonstrated that 11,12-EET decreased expression of cytokine induced endothelial cell adhesion molecules, especially VCAM-I. Moreover, EETs prevented leukocyte adhesion to the vascular wall and the mechanism responsible involved inhibition of NFKB and 1KB kinase. Vascular inflammation plays a role in endothelial dysfunction (Kessler, et al. Circulation, 99: 1878-1884 (1999)). Hence, the ability of EETs to inhibit the NFKB pathway should also help ameliorate this condition. In addition, the administration of EETs and/or the administration of a selective sEH inhibitor was demonstrated to attenuate tobacco smoke induced inflammation, as assessed by total bronchoalveolar lavage cell numbers and concomitant reduction in neutrophils, alveolar macrophages and lymphocytes. Hammock et al. have demonstrated usefulness in the treatment of inflammatory diseases, in particular, acute respiratory distress syndrome (ARDS) and other acute inflammatory conditions mediated by lipid metabolites, by the administration of inhibitors of epoxide hydrolase (WO98/06261, US Pat No. 5,955,496).
More recently, Hammock, et al. disclosed certain biologically stable inhibitors of sEH for the treatment of inflammatory diseases, for use in affinity separations of epoxide hydrolases and in agricultural applications (US Pat No. 6,150,415). Hammock et al. generally described compounds that can be used to deliver a reactive functionality to the catalytic site, e.g., alkylating agents or Michael acceptors, and that these reactive functionalities can be used to deliver fluorescent or affinity labels to the enzymes active site for enzyme detection. Certain urea and carbamate inhibitors of sEH have also been described in the literature (Morisseau, et al. Proc. Nat. Acad. Sci. 96: 8849-8854 (1999)). A number of other chemical classes of sEH inhibitors have been identified. Among these are chalcone oxide derivatives (Miyamoto, et al. Arch. Biochem. Biophys. 254; 203-213 (1987)) and various trans-3 -phenyl glyucidols (Dietze, et al Biochem. Pharm. 42: 1163- 1175 (1991)) and Dietze, et al. Comp. Biochem. Physiol. B. 104: 309-314(1993)).
It has recently been shown that sEH inhibition reduces COX-2 expression in mammals, and decreases PGE2 and PGD2 levels, similar to coxibs. Therefore, sEH inhibitors could be indicated for inflammatory pain (Schmelzer, et.al. PNAS 2006, 103, 13646). It has also been disclosed that 14,15-EET is 100-fold more potent than morphine dosed vPAG in rat brains, and EETs induce Met-enkephalin release in the spinal cord. This suggests that sEH inhibitors could also be used for CNS analgesia (Harder, D. presented at 9th Annual WEC, March 2007).
The anti-inflammatory functions of EETs also indicate that it is possible to use sEH inhibitors as ophthalmic agents to alleviate eye disorders, such as reducing intraocular pressure and reducing progression of age-related macular degeneration (WO 2007/009001 Al).
All four EET regioisomers inhibit arachidonic acid- induced aggregation of human platelets, induce t-PA expression and hyperpolarize platelets (Node, et al. J. Biol. Chem. 2001, 276(19), 15983). This supports the potential use of sEH inhibitors as anti-thrombotic agents.
An object of the present invention is to provide compounds that are useful for the treatment of hyperlipidemias, dyslipidemias, atherosclerosis and related conditions.
Another object is to provide a pharmaceutical composition for oral use.
These and other objects will be apparent from the description provided herein.
SUMMARY OF THE INVENTION
A compound in accordance with structural formula I:
Figure imgf000004_0001
or a pharmaceutically acceptable salt or solvate thereof is disclosed wherein: one of W and X represents a carbon or nitrogen atom, and the other represents a carbon atom;
Ring A represents an Aryl group or a 5-6 membered Heteroaryl group containing
1-3 N atoms and 0-1 O or S atom;
Ring B represents a member selected from the group consisting of: a) a 3-7 membered monocyclic or bridged bicyclic aliphatic carbocycle; b) a 5-6 membered heterocycle, containing 1-2 heteroatoms, 0-1 of which is selected from oxygen and sulfur, and 0-2 of which are nitrogen atoms; c) a 6-10 membered aromatic group, and d) a 5-6 membered heteroaryl ring containing 1-2 nitrogen atoms, and 0-1 oxygen or sulfur atom;
Rs is halo, Q-6 alkyl, haloQ-ealkyl or phenyl; each R2 is H or is selected from the group consisting of halo; C1-6alkyl; haloCi. 6alkyl; CO2Ra; C(O)NH2; C(O)NHC ^alkyl; S (O)2NHC I-8alkyl; NHC(O)NHCl-galkyl; OC1- 6alkyl-CO2Ra; C(O)-Hetcy optionally substituted with 1-3 halo atoms and one group selected from C1-6alkyl, haloCi^alkyl and CO2Ra; phenyl and HAR5 said Phenyl and HAR being optionally substituted with 1-3 halogen atoms and 1-2 members selected from the group consisting of: Ci-6 alkyl, haloCi-galkyl, CO2Ra, (CH2)I-6CO2R3, OCi-6alkyl and OhaloCi^alkyl; each Ra is selected from the group consisting of H and
Figure imgf000005_0001
each R3 is selected from the group consisting of: H, halo,
Figure imgf000005_0002
haloCi-6alkylf OhaloCi-6alkyl C(O)C i^alkyl, C(O)haloCμ6alkyl, C(O)Aryl, NHC(O)Aryl, S(O)2haloC1-6alkyl, S(O)2ATyI, S(O)2NHC i.8alkyl, NHC(O)NHC ^alkyl, NHC(O)C 1-8alkyl, C(O)HAR and CO2Ra, the Aryl and HAR portions of C(O)Aryl, S(O)2AIyI, NHC(O) Aiyl and C(O)HAR being optionally substituted with 1-3 halo groups and 1-2
Figure imgf000005_0003
or haloCi-6alkyl groups; j represents an integer of from 0-4; and R4 is selected from the group consisting of
H, halo, Cμgalkyl and phenyl, such that no more than two R4 groups represent phenyl.
DETAILED DESCRIPTION OF THE INVENTION
The invention is described herein in detail using the terms defined below unless otherwise specified.
"Alkyl", as well as other groups having the prefix "alk", such as alkoxy, alkanoyl and the like, means carbon chains which may be linear, branched, or cyclic, or combinations thereof, containing the indicated number of carbon atoms. If no number is specified, 1-6 carbon atoms are intended for linear and 3-7 carbon atoms for branched alkyl groups. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, cyclopropyl and the like. Cycloalkyl and "carbocycle" are thus a subset of alkyl; if no number of atoms is specified, 3-7 carbon atoms are intended, forming 1-3 carbocyclic rings that are fused. "Cycloalkyl" can also be fused to an aryl or heteroaryl group. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl and the like. Haloalkoxy, Ohaloalkyl and haloOalkyl are used interchangeably and refer to halo substituted alkyoxy groups linked through the oxygen atom. Haloalkyl and haloalkoxy include mono- substituted as well as multiple substituted alkyl and alkoxy groups, up to perhalo substituted alkyl and alkoxy. For example, trifluoromethyl and trifluoromethoxy are included.
"Aryl" (Ar) and "aromatic group" mean mono- and bicyclic aromatic rings containing 6-10 carbon atoms. Examples of aryl include phenyl, naphthyl, indenyl and the like. Ηeteroaryl" (HAR) and "heteroaromatic group" unless otherwise specified, mean mono-, bicyclic and tricyclic aromatic ring systems containing at least one heteroatom selected from O, S5 S(O), SO2 and N, with each ring containing 5 to 6 atoms. HAR groups may contain from 5-14, preferably 5-13 atoms. Examples include, but are not limited to, pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyζ benzothiophenyl, benzopyrazolyl, benzotriazolyl, furo(2,3-b)ρyridyl, benzoxazinyl, tetrahydrohydroquinolinyl, tetrahydroisoquinolinyl., quinolyl, isoquinolyl, indolyl, dihydroindolyl, quinoxalinyl, quinazolinyl, naphthyridinyl, pteridinyl, 2,3- dihydrofuro(2,3-b)pyridyl and the like. Heteroaryl also includes aromatic carbocyclic or heterocyclic groups fused to heterocycles that are non-aromatic or partially aromatic, and optionally containing a carbonyl. Examples of additional heteroaryl groups include indolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, and aromatic heterocyclic groups fused to cycloalkyl rings. Heteroaryl also includes such groups in charged form, e.g., pyridinium. "Heterocyclyl", "heterocycle" and "heterocyclic group" (Hetcy) unless otherwise specified, mean mono- and bicyclic saturated and partially saturated rings and ring systems containing at least one heteroatom selected from N, S and O, each of said ring having from 3 to 10 atoms in which the point of attachment may be carbon or nitrogen. Examples of "heterocyclyl" include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, tetrahydrofuranyl, 1 ,4-dioxanyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl and the like. Heterocycles can also exist in tautomeric forms, e.g., 2- and 4-pyridones. Heterocycles moreover includes such moieties in charged form, e.g., piperidinium, "Halogen" (Halo) includes fluorine, chlorine, bromine and iodine. In one aspect, the invention relates to a compound in accordance with structural formula I:
Figure imgf000006_0001
or a pharmaceutically acceptable salt or solvate thereof is disclosed wherein: one of W and X represents a carbon or nitrogen atom, and the other represents a carbon atom;
Ring A represents an Aryl group or a 5-6 membered Heteroaryl group containing 1-3 N atoms and 0-1 O or S atom; Ring B represents a member selected from the group consisting of: a) a 3-7 membered monocyclic or bridged bicyclic aliphatic carbocycle; b) a 5-6 membered heterocycle, containing 1-2 heteroatoms, 0-1 of which is selected from oxygen and sulfur, and 0-2 of which are nitrogen atoms; c) a 6- 10 membered aromatic group, and d) a 5-6 membered heteroaryl ring containing 1-2 nitrogen atoms, and 0-1 oxygen or sulfur atom;
R1 is halo, Ci-6 alkyl, haloCi_6alkyl or phenyl; each R2 is H or is selected from the group consisting of halo; C^alkyl; haloQ. 6alkyl; CO2R3; C(O)NH2; C(O)NHC 1-8alkyl; S(O)2NHC3-8alkyl;
Figure imgf000007_0001
OCμ 6alkyϊ-Cθ2Ra; C(O)-Hetcy optionally substituted with 1-3 halo atoms and one group selected from Ci-6alkyl, haloC^ealkyl and CO2R8; phenyl and HAR, said Phenyl and HAR being optionally substituted with 1-3 halogen atoms and 1-2 members selected from the group consisting of: Cμ6alkyl, haioCi-6alkyl, CO2Ra, (CH2) 1-6CO2Ra, OCl-6alkyl and OhaloCi-6alkyl; each Ra is selected from the group consisting of H and C1-6alkyl; each R3 is selected from the group consisting of: H, halo,
Figure imgf000007_0002
haloC1-6alkyls OhaloCϊ-6aϊkyl C(O)C 1-6alkyl, C(O)haloC1-6alkyl5 C(O)Aryl, NHC(O)Aryl, S(O)2haloC1-6alkyl, S(O)2Aryl, S(O)2NHC 1-8alkyl, NHC(O)NHC i-galkyl, NHC(O)C 1-8alky I5 C(O)HAR and CO2Ra, the Aryl and HAR portions of C(O)Aryl5 S(O)2AIyI, NHC(O)Aryl and C(O)HAR being optionally substituted with 1-3 halo groups and 1-2 Ct-($alkyl or haloCi-ealkyl groups;r j represents an integer of from 0-4; and R4 is selected from the group consisting of H, halo, Chalky, and phenyl, such that no more than two R4 groups represent phenyl.
An aspect of the invention that is of interest relates to compounds of formula I, or a pharmaceutically acceptable salt or solvate thereof wherein W and X each represent a carbon atom.
Another aspect of the invention that is of interest relates to compounds of formula I or a pharmaceutically acceptable salt or solvate thereof, wherein ring A represents a phenyl or pyridyl ring.
More particularly, another aspect of the invention that is of interest relates to compounds of formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein ring A represents a phenyl ring. Another aspect of the invention that is of interest relates to compounds of formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein ring B represents a 3-7 membered monocyclic or bridged bicyclic aliphatic carbocycle.
Another aspect of the invention that is of interest relates to compounds of formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein ring B represents a 5-6 membered heterocycle, containing 1-2 heteroatoms, 0-1 of which is selected from oxygen and sulfur, and 0-2 of which are nitrogen atoms.
Another aspect of the invention that is of interest relates to compounds of formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein ring B represents a 6-10 membered aromatic group.
Another aspect of the invention that is of interest relates to compounds of formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein ring B represents a 5-6 membered heteroaryl ring containing 1-2 nitrogen atoms, and 0-1 oxygen or sulfur atom. Another aspect of the invention that is of more particular interest relates to compounds of formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein ring B represents a member selected from the group consisting of: cyclohexane, piperidine, piperazine, pyrrolidine, phenyl and pyridine.
Another aspect of the invention that is of even more particular interest relates to compounds of formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein ring B represents a member selected from the group consisting of: cyclohexane, piperidine, piperazine, phenyl and pyridine.
Another aspect of the invention that is of interest relates to compounds of formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein R represents halo or haloCμ fsalkyl. More particularly, another aspect of the invention that is of interest relates to compounds of formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 represents haloCj-galkyl.
Even more particularly, another aspect of the invention that is of interest relates to compounds of formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 represents trifiuoromethyl.
Another aspect of the invention that is of interest relates to compounds of formula I5 or a pharmaceutically acceptable salt or solvate thereof, wherein each R is selected from the group consisting of H; HAR; C(O)-Hetcy optionally substituted with halo, C^aHcyl, CF3 or CO2R*; 0-Ci-SaIlCyI-CO2R3 wherein Ra is H or Cl-4alkyl; phenyl optionally substituted with Ci- ealkyl or CO2Ra; C(O)NHC 1-8alkyl and C(O)NH2.
More particularly, another aspect of the invention that is of interest relates to compounds of formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 is selected from the group consisting of H; phenyl optionally substituted with Ci-ealkyl or CO2R11; HAR which is selected from pyridyl and tetrazolyl; C(O)-Hetcy wherein the Hetcy represents a piperidinyl group, optionally substituted with CO2H; O-Ci-3alkyl- CO2H; C(O)NH2; and C(O)NHC l-salkyl wherein the alkyl portion represents -CH2-cyclohexyL Even more particularly, another aspect of the invention that is of interest relates to compounds of formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein each R represents H.
Another aspect of the invention that is of interest relates to compounds of formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is selected from the group consisting of: H; halo selected from Cl and F; CO2Ra wherein Ra represents H or C1. 4alkyl; haloCi-ealkyl wherein the halo portion is F; OhaloQ-ealkyl wherein the halo portion is F; C(O)C i^alkyl, C(O)haloCi-6alkyl wherein the halo portion is F; C(O)-Phenyl; NHC(O>Phenyl; S(O)2haIoCi_6alkyl wherein the halo portion is F; SO2 Phenyl; SO2NHCi. galkyl; NHC(O)NHC μ8alkyl; NHC(O)C 1-8alkyl; C(O)HAR and, the Phenyl and HAR portions of C(O)Phenyl, SO2Phenyl, NHC(O)Phenyl and C(O)HAR being optionally substituted with 1 -3 halo groups selected from F and Cl, and 1-2 Ci-ealkyl or haloCi-ealkyl groups the halo portions of which are F.
More particularly, another aspect of the invention that is of interest relates to compounds of formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 represents hydrogen.
Another aspect of the invention that is of interest relates to compounds of formula I, or a pharmaceutically acceptable salt or solvate thereof wherein:
W and X each represent a carbon atom;
Ring A represents a phenyl or pyridyl ring; Ring B represents a member selected from the group consisting of: a) a 3-7 rnembered monocyclic or bridged bicyclic aliphatic carbocycle; b) a 5-6 membered heterocycle, containing 1-2 heteroatoms, 0-1 of which is selected from oxygen and sulfur, and 0-2 of which are nitrogen atoms; c) a 6-10 membered aromatic group, and d) a 5-6 membered heteroaryl ring containing 1-2 nitrogen atoms, and 0-1 oxygen or sulfur atom;
R1 represents halo or haloC^alkyl; each R2 is selected from the group consisting of H; HAR; C(O)-Hetcy optionally substituted with halo,
Figure imgf000009_0001
Ra is H or CMalkyl; phenyl optionally substituted with d-salkyl or CO2R8; C(O)NHCi.8alkyl and C(O)NH2. each R3 is selected from the group consisting of: H; halo selected from CI and F; CO2R3 wherein Ra represents H or Q^alkyl; C^alkyl; haloCj-ealkyl wherein the halo portion is F; OhaloCi^alkyl wherein the halo portion is F; C(O)C j.6alkyl, C(O)haloCi-6alkyl wherein the halo portion is F; C(O)-Phenyl; NHC(O)-Phenyl;
Figure imgf000010_0001
wherein the halo portion is F; SO2 Phenyl; SO2NHC l-salkyl; NHC(O)NHC i-8alkyl; NHC(O)d.8alkyl; C(O)HAR and, the Phenyl and HAR portions of C(O)Phenyl, SO2Phenyl, NHC(O)Phenyl and C(O)HAR being optionally substituted with 1-3 halo groups selected from F and Cl, and 1-2 C^alkyl or haloC). ealkyl groups the halo portions of which are F.
Another aspect of the invention that is of particular interest relates to a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein:
W and X each represent a carbon atom; ring A represents a phenyl or pyridyl ring;
Ring B represents a member selected from the group consisting of: a) a 3-7 membered monocyclic or bridged bicyclic aliphatic carbocycle; b) a 5-6 merabered heterocycle, containing 1-2 heteroatoms, 0-1 of which is selected from oxygen and sulfur, and 0-2 of which are nitrogen atoms; c) a 6-10 membered aromatic group, and d) a 5-6 membered heteroaryl ring containing 1-2 nitrogen atoms, and 0-1 oxygen or sulfur atom;
R1 represents trifluoromethyl or chloro; each R2 is selected from the group consisting of H; HAR; C(O)-Hetcy optionally substituted with halo, C]-3alkyl, CF3 or C02Ra; O-Ci-6alkyl-CO2Ra wherein Ra is H or C1-4alkyl; phenyl optionally substituted with Chalky, or CO2Ra; C(O)NHC j_salkyl and C(O)NH2; each R3 is selected from the group consisting of: H; halo selected from Cl and F; CO2Ra wherein Ra represents H or C^alkyl; Ci^alkyl; haloCj-ealkyl wherein the halo portion is F; OhaloCi-6alkyl wherein the halo portion is F; C(O)C i-galkyl, C(O)haloCi.6alkyl wherein the halo portion is F; C(O)-Phenyl; NHC(O)-Phenyl; S (O)2haloCi-6alkyl wherein the halo portion is F; SO2 Phenyl; SO2NHCi-8alkyl; NHC (O)NHC i_8alkyl; NHC(O)C!-8aIkyl; C(O)HAR and, the Phenyl and HAR portions of C(O)Phenyl, SO2Phenyl, NHC(O)Phenyl and C(O)HAR being optionally substituted with 1-3 halo groups selected from F and Cl, and 1-2 Ci-ealkyl or haloCi- ealkyl groups the halo portions of which arc F. Examples of compounds that are of interest are set forth in Table 1 below.
Table 1
Cpd Structure Cpd Structure
Figure imgf000011_0001
Figure imgf000012_0001
Figure imgf000013_0001
as well as the pharmacetucially acceptable salts and solvates thereof.
Yet another aspect of the invention that is of interest relates to a pharmaceutical composition comprised of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in combination with a pharmaceutically acceptable carrier.
Yet another aspect of the invention that is of interest relates to a method of treating diabetes in a mammalian patient in need of such treatment comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective for treating diabetes.
Yet another aspect of the invention that is of interest relates to a method of treating pain in a mammalian patient in need of such treatment comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective for treating pain.
Yet another aspect of the invention that is of interest relates to a method of treating atherosclerosis in a mammalian patient in need of such treatment comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective for treating atherosclerosis.
Yet another aspect of the invention that is of interest relates to a method of treating hypertension in a mammalian patient in need of such treatment comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective for treating hypertension. .
Many of the compounds of formula I contain asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. All such isomeric forms are included. Moreover, chiral compounds possessing one stereocenter of general formula I, may be resolved into their enantiomers in the presence of a chiral environment using methods known to those skilled in the art. Chiral compounds possessing more than one stereocenter may be separated into their diastereomers in an achiral environment on the basis of their physical properties using methods known to those skilled in the art. Single diastereomers that are obtained in racemic form may be resolved into their enantiomers as described above.
If desired, racemic mixtures of compounds may be separated so that individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds of Formula I to an enantiomerically pure compound to form a diastereomeric mixture, which is then separated into individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diasteromeric derivatives may then be converted to substantially pure enantiomers by cleaving the added chiral residue from the diastereomeric compound.
The racemic mixture of the compounds of Formula I can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.
Alternatively, enantiomers of compounds of the general Formula I may be obtained by stereoselective synthesis using optically pure starting materials or reagents.
Some of the compounds described herein exist as tautomers, which have different points of attachment for hydrogen accompanied by one or more double bond shifts. For example, a ketone and its enol form are keto-enol tautomers. Or for example, a 2- hydroxyquinoline can reside in the tautomeric 2-quinolone form. The individual tautomers as well as mixtures thereof are included.
Administration and Dose Ranges
Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. Preferably compounds of Formula I are administered orally.
The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.
When treating or controlling diabetes mellitus and/or hyperglycemia or hypertriglyceridemia or other diseases for which compounds of Formula I are indicated, generally satisfactory results are obtained when the compounds of the present invention are administered at a dosage of from about 0.05 milligrams to about 100 milligrams per kilogram of animal body weight, preferably given as a daily dose, or in sustained release form. For most large mammals, including humans (e.g. a 70 kg adult), the total dosage administered is from about 0.1 milligrams to about 1000 milligrams, is likely to be from about 0.5 milligrams to about 350 milligrams, and is often from about 1 milligram to about 50 milligrams. For a particularly potent compound, the dosage for an adult human may be as low as 0.1 mg. Examples of dosages for a 70 kg adult human are 0.1 mg, 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 350 mg, and 500 mg per day. The dosage regimen may be adjusted within the above ranges or even outside of these ranges to provide the optimal therapeutic response. Oral administration will usually be carried out using tablets. Examples of doses in tablets which may be administered include about 0.1 mg, 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 350 mg, and 500 mg. Other oral forms (e.g, capsules or suspensions) can be administered in doses having similar sizes.
Dosing can be carried out on a daily basis, such as once, twice or three times daily, or less often, such as every other day, every third day, once weekly or even once monthly.
Combination Therapy
Compounds of Formula I may be used in combination with other drugs that may also be useful in the treatment or amelioration of one or more of the diseases or conditions for which compounds of Formula I are useful. Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously (such as via co-administration) or sequentially with a compound of Formula I. When a compound of Formula I is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of Formula I is preferred. However, the combination therapy also includes therapies in which the compound of Formula I and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compound of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients , in addition to a compound of Formula I.
Examples of other active ingredients that may be administered in combination with a compound of Formula I, and either administered separately or in the same pharmaceutical composition, include, but are not limited to:
(a) PPAR gamma agonists and partial agonists, such as the glitazones (e.g. troglitazone, pioglitazone, engϋtazone, MCC-555, rosiglitazone, balaglitazone, netoglitazone, and the like), and PPAR gamma agonists and partial agonists that do not have a glitazone structure (e.g. K-I l 1, INT-131, MBX-102 [metaglidisen], MBX-2044, FK614 including SPPARγM GSK-376501 and the like);
(b) biguanides such as metformin and phenformin;
(c) protein tyrosine phosphatase- IB (PTP-IB) inhibitors,
(d) dipeptidyl peptidase IV (DPP-4) inhibitors, including sitagliptin, vildagliptin, saxagliptin, as well as those disclosed in the following published patents and applications: US
Patent No. 6,699,871; U.S. Patent No. 7,101,871; WO 02/076450 (3 October 2002); WO 03/004498 (16 January 2003); WO 03/004496 (16 January 2003); EP 1 258 476 (20 November 2002); WO 02/083128 (24 October 2002); WO 02/062764 (15 August 2002); WO 03/000250 (3 January 2003); WO 03/002530 (9 January 2003); WO 03/002531 (9 January 2003); WO 03/002553 (9 January 2003); WO 03/002593 (9 January 2003); WO 03/000180 (3 January
2003); WO 03/082817 (9 October 2003); WO 03/000181 (3 January 2003); WO 04/007468 (22 January 2004); WO 04/032836 (24 April 2004); WO 04/037169 (6 May 2004); and WO 04/043940 (27 May 2004). Specific DPP-4 inhibitor compounds include isoleucine thiazolidide (P32/98); NVP-DPP-728; vildagliptin (LAF 237); P93/01; and saxagliptin (BMS 477118). Additional specific DPP-IV inhibitors that are of interest herein include:
(2i?,35,5iϊ)-5~(l-methyl-456~dihydropyrrolo[3J4-c]pyrazol-5(lH)-yl)-2-(2,4J5- trifluorophenyl)tetrahydro~2H-pyran-3-amine;
(2i?,35',5S)-5-(l-methyl-456-dihydropyrrolo[3,4-c]pyrazol-5(l/-/)-yl)-2-(2!4J5- trifiuorophenyl)tetrahydro-2/i-pyran-3-amine; (2i?,3,S',5i?)-2-(2,5-difluoroρhenyl)tetrahydro)-5-(4,6-dihydropyrrolo[334- c]pyrazol-5(l H)-yl) tetrahydro-2/i-pyran-3-amine;
(2^,3S'?51$)-2-(2,5-difluorophenyl)tetrahydro)-5-(4,6-dihydropyrrolo[3,4- c]pyrazol-5(lJy)-yl) tetrahydro-2/f-pyran-3-amine;
2i?,35,5i?)-2-(2,4J5-trifluorophenyl)tetrahydro)-5-(4,6-dihydropyrrolo[3,4- c]ρyrazol-5(lH)-yl) tetrahydro-2/f-ρyran-3 -amine; and
(2i?}3^55)-2-(254s5-trifluorophenyl)tetralαydro)-5-(4,6-dihydropyrrolo[3,4- cjpyrazol- 5 ( 1 H)-y 1) tetrahydro-2/f-pyran-3 -amine; (e) insulin or insulin mimetics, including rapid acting insulin,, regular insulin, long acting insulin, complexed forms of insulin and the like, administered by any conventional route, such as subcutaneous, intradermal or intramuscular injection, oral, transdermal, intranasal, intrapulmonary, and the like; (f) insulin secretagogues, such as sulfonylureas (e.g. tolbutamide, glimepϊride, glicazinde, and glipizide) and meglitinides (eg. repaglinide and nateglinide);
(g) α-glucosidase inhibitors (such as acarbose and miglitol);
(h) agents which improve a patient's lipid profile, such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, rosuvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, ZD-4522 and other statins), (ii) bile acid sequestrants (cholestyramine, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran), (iii) nicotinyl alcohol, nicotinic acid (niacin) or a salt thereof, (iv) niacin receptor agonists, (v) PP ARa agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate), (vi) cholesterol absorption inhibitors, such as for example ezetimibe, (vii) acyl CoA: cholesterol acyltransferase (ACAT) inhibitors, such as avasimibe, (viii) CETP inhibitors, such as torcetrapib, JTT-705, and compounds disclosed in WO2005/100298, WO2006/014357, and WO2006/014413, and (ix) phenolic anti-oxidants, such as probucol;
(i) antiobesity compounds such as fenfluramine, dexfenfluramme, phentermine, sibutramine, orlistat, exentin-4, neuropeptide Y5 inhibitors, MC4R agonists, cannabinoid receptor 1 (CB-I) antagonists/inverse agonists, such as rimonabant and taranabant, and β3 adrenergic receptor agonists;
(j) ileal bile acid transporter inhibitors;
(k) agents intended for use in inflammatory conditions such as aspirin, nonsteroidal anti-inflammatory drugs as further described below, glucocorticoids, azulfidine, and cyclooxygenase 2 selective inhibitors;
(1) glucagon receptor antagonists;
(m) GLP-I;
(n) GIP-I; and
(o) GLP-I analogs, such as exentin-4, including exenatide; (p) GPR 119 agonists;
(q) 11-B HSD 1 inhibitors;
(r) glucokinase activators;
(s) SGLT3 particularly SGLT2 inhibitors;
(t) PPARδ agonists such as those disclosed in WO 97/28149; (u) prandial glucose releasing agents such as repaglinide and nateglinide,
(v) antihypertensives, such as diuretics, e.g., hydrochlorothiazide, furosemide and the like; beta adrenergic blocking drugs, such as propranolol, metaprolol and the like; ACE inhibitors, such as enalapril, lisinopril, ramipril,, quinapril and the like, ARBs, such as losartan, valsartan, irbesartan, candesartan and the like, and calcium channel blocking drugs, such as amlodipine, diltiazem and verapamil; and
(w) NSAIDS such as ibuprofen, naproxen, meloxicam, diclofenac, indomethacin, prioxicam, COX-2 inhibitors such as nabumetone, etodolac, rofecoxib, etoricoxib, celecoxib, and valdecoxib, and conventional non-opioid and opioid analgesics, such as aspirin, acetaminophen, codeine, meperidine, oxycodone, hydrocodone, pentazocine, morphine and the like.
The above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds. Non-limiting examples include combinations of compounds having Formula ϊ with two or more active compounds selected from biguanides, sulfonylureas, HMG-CoA reductase inhibitors, other PPAR agonists, PTP-IB inhibitors, DPP-4 inhibitors, and anti-obesity compounds. Examples of glucagon receptor antagonist compounds that are useful as described herein include : N- [4-(( 1 S)- 1 - { 3 -(3 , 5 -Dichlorophenyl)-5- [6-(trifluoromethoxy)-2-naρhthyl] - 1 H- pyrazol- 1 -yl } ethyl)benzoyl]-β-alanine;
/V-[4-((l R)- 1 -{3-(3 J5-Dichlorophenyl)-5-[6-(trifluoromethoxy)-2-naphthyl]-l H- pyrazol- 1 -yl} ethyl)benzoyl]-β-alanine; N-(4-{l-[3-(2,5-dichlorophenyl)-5-(6-methoxy-2-naphthyi)-lH-pyrazol-l- yl]ethyl } benzoyl)-β-alanine;
W'<4-{(l^-l-[3<3,5-Dichloroρhenyl)-5<6-methoxy-2-naphthyl)-l/ir-pyrazol-l- yl]ethyl}benzoyl)-β-alanme;
3-({4-[(2S}-2-({5-chloro-l-[3-(trifluoromethyl)phenyl]-lH-indol-2- yl}carbonyl)heptyl] benzoyl }amino)propanoic acid and 3-({4-[(2i?)-2-({5-chloro-l-[3- (trifluoromethyl)phenyl]-li7-indol-2-yt}carbonyl)heptyl]benzoyl}amino)propanoic acid;
3-[(3-Bromo-4-{(25)-2-[(5-chloκ>-l-methyl-l/f-indol~2- yl)carbonyl]heptyl}benzoyl)amino]propanoic acid and 3-[(3-Bromo-4-{(2J?)-2-[(5-chloro-l- methyl- 1 i/-indol-2-yl)carbonyl]heptyl } benzoyl)amino]ρroρanoic acid; 3- { [4-((2Λ)-2-{ [1 -(4-terf-butylbenzyl)-5-chloro-li/-indol-2- yl]carbonyl}pentyl)benzoyl] amino} propanoic acid and 3-{[4-((2iS)-2-{[l-(4-ferϊ-butylbenzyl)-5- chloro- 1 /f-indol-2-yl] carbonyl } pentyl)benzoyl] amino } propanoic acid;
3- { [4-((2Λ)-2- { [5-Chloro-l -(3 ,5-dichlorophenyl)-l /T-indol-2- yl]carbonyl}pentyl)benzoyl]amino}propanoic acid and 3-{[4-((25)-2-{[5-Chloro~l~(3,5- dich!orophenyl)-liϊ-indol-2-yl]carbonyl}pentyl)benzoyl]amino}propanoic acid;
N-(4- { ( 1 S)- 1 - [3 - [2-Ethoxy-5-(trifluoromethyl)pheny 1] - 5 -(6-methoxy-2-naphthyl)- 1/i-pyrazol- 1 -yl]ethyl}benzoyl)-β~alanine; N-(4»{(15)-l-[3-[2-methoxy-5-Ctrifluoromethyl)phenyl]-5-(6-methoxy-2- naphthyl)- 1 /f-pyrazol- 1 -yl]etliyl } benzoyl)-β-alanine;
N-[HQS)-I - { 5-(6-methoxy-2-naphthyl)-3-[2-methoxy-5- (trifluoromethyl)ρhenyl]-l/f-pyrazol-l-yl}pentyl)benzoyl]-β-alanine; N- [4-(( 1 S)- 1 - { 5-(6-chloro-2-naphthyl)-3-[2-methoxy-5-(trifluoromethyl)phenyl]-
1 H-pyrazol- 1 -yl}pentyl)benzoyl]-β~alamne;
N-(4-{(lS)-l-[(R)-(4-chlorophenyl)(7-fluoro-5-methyl-lH-indol-3- yl)methyl]butyl}benzoyl)-β-alanine;
Λr-(4-{l-[(4-chlorophenyl)(5,7-dichloro-l//-indol-3-yl)methyl]butyl}benzoyl)-β- alanine;
N-(4- { 1 -[(3 -chloro-4-methoxyphenyl)(5 , 7-dichloro- 1 H-indol-3 - yl)methyl]pentyl}benzoyl)-β-alanine; and
N-(4-{l-[(5!7-dichloro-l/f-indol-3-yl)(3J5-dichloro-4- methoxyphenyl)methyl]pentyl}benzoyl)-β-alanine. Examples of GPR- 119 agoni sts that are of interest as described herein include :
4-Methyl-6-[r-(5-methylpyrazin-2-yl)-4>4'-biρiperidin-l-yl]ρyrimidine-2- carbonitrile; l-(5-chloropyrazin-2-yl)-r-[5-(methylsulfonyl)pyridin-2-yl]-4,4!-bipiperidine;
2-chloro-4-(r-pyrimidin-2-yl"4}4'~bipiperidin-l-yl)benzomtriIe and 1 -(5-chloro-2-methylpyrimidin-4-yl)- 1 '-(5-chloropyrimidin-2-yl)-4,4>-biρiperidine.
Also included is the use of additional PPAR alpha, gamma or delta selective agonists, PPAR alpha/gamma, gamrna/delta, alpha/delta dual agonists, or PPAR alpha/gamma/delta pan agonists. These agents are useful for the treatment of diabetes, dyslipidemia and weight loss. Examples of such agents include, but are not limited to the following: netoglitazone, pioglitazone, rosiglitazone, troglitazone, balaglitazone, CS204,
AZD6610, ZYHl, GFT505, LY-465608, DRF-2519, DRF-11605, DRF-2725, GW-626019, GW- 625019, CS038, ONO-5129, aleglitazar, muraglitazar, soldeglitazar, teseglitazars naveglitazar, farglitazar, KRP-297, AVE0897, AVE 0847, LBM642, PPM263, PPM202, PPM201, PPM204, PLX-204, GW-677954, NN0606, AVE8134, NS-220, SAR 35034, KD3010, GW-501516, FK614, K-111, metaglidasen, MBX-2044, INT-131, KD3010, KR-62980, SVT002149,
AVE8134, AVE5378, AVE0897, SAR35034, AVE5376, MBX2130, PAT-5A, GW-501516, GW-1262570, GW677954, GW590735, R-483, and BAY-54-9801.
Examples of SPPARMs that are of interest as described herein include:
(25)-2-( { 6~chloro-3 -[6-(4-chlorophenoxy)-2-ρropylpyridin~3 -yl] - 1 ,2- benzisoxazol-5-yl}oxy)propanoic acid;
(2S)-2-({6-chloro-3-[6-(4-fiuorophenoxy)-2-propylpyridin-3-yl]-l,2- benzisoxazol-5 -yl } oxy)propanoic acid; (25)-2-{[6-cbloro-3-(6-phenoxy-2-ρropyIpyridin-3-yl)-l,2-benzisoxazol-5- yl]oxy} propanoic acid;
(2R)-2-( { 6-chloro-3- [6-(4-chloroρhenoxy)-2-propylpyridin-3-yl] - 1 ,2- benzisoxazol- 5 -yl } oxy)propanoic acid; (2R)-2- { 3 -[3 -(4-methoxy)benzoyl-2-methyl-6-(trifluoromethoxy)- 1 H-indol- 1 - yl]phenoxy}butanoic acid;
(2S)-2- { 3 -f 3 -(4-methoxy)benzoyl-2-methyl-6-(lrifluoromethoxy)- 1 H -indol- 1 - yl]phenoxy}butanoic acid;
2- { 3 - [3-(4-melhoxy)benzoyl-2-methyl~6-(trifl uoromethoxy)- 1 H-indol- 1 ~ yl]phenoxy}-2-methylpropanoic acid; and
(2R)-2- { 3 - [3 -(4-chI oro)benzoyl-2-methyl-6-(trifluoromethoxy> 1 H-indol- 1 - yljphenoxy} propanoic acid.
Examples of 1 IB-HSD 1 inhibiting compounds that are of interest as described herein include: 3-[ 1 -(4-cnlorophenyl)-frαrø-3-fluorocyclobutyl]-4J5-dicyclopropyl-r-4if- 1 ,2,4- triazole; 3-[l -(4-chlorophenyl)-frα?ϊ5r-3-fluorocyclobutyl]-4-cyclopropyl-5-(l - methylcyclopropyl)-r-4/i- 1 ,2f4~triazole;
Figure imgf000020_0001
(trifluoromethoxy)phenyl]"r-4Jϊ-l52,4-triazole; 3 - [ 1 -(4-chl orophenyl)cyclobutyl] -4-methyl- 5 - [2-(trifluoromethyl)phenyl] -4H-
1,2,4-triazole;
3-{4-[3-(Ethylsulfonyl)propyl]bicyclo[2.2.2]oct-l-yl}-4-methyl-5-f2- (trifiuoroniethyl)phenyl]-4H -1 ,2,4-triazole;
4-Methyl-3- (4- [4-(methylsulfonyl)phenyl] bicyclo [2.2.2] oct- 1 -yl } -5 - [2- (trifluoromethyl)phenyl]-4H- 1 ,2,4-triazole;
3_(4-{4.Methyl-5-[2-(trifiuoromethyl)phenyl]-4H-l,254-triazol-3- yllbicyclo^^^Joct-l-yO-S^S^^-trifluoropropyO-l^^-oxadiazole;
3-(4-{4-Methyl-5-[2-(trifluoromethyl)phenyl]-4H-l,2?4-triazoI-3- yllbicyclop^^joct-l-yO-S-tS^^-trifluoroethyO-l^^-oxadiazole; 5-(353-Difluorocyclobutyl)-3-(4- {4-methyl-5-[2-(trifluoromelhyl)phenyl]-4Η-
1 ,2,4-triazol-3-yl}bicydo[2.2.2]ocl-l-yl)-l ,2,4-oxadiazole ;
5-(l -Fluoro- 1 -methylethyl)-3-(4- {4-methyl-5-[2-(trifiuoromethyl)phenyl]-4H- 1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-l-yl)-l ,2,4-oxadiazole;
2-(l , 1 -Difluoroethyl)-5-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-l ,2,4- triazol-3-yl}bicyclo[2.2.2]oct-l-yl)-ls3,4-oxadiazole;
2-(3,3-Difluorocyclobutyl)-5-C4-{4-melhyl-5-[2-(trifluoromethyl)plienyl]-4H- 1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct-l -yl)- 1 ,3,4-oxadiazole; and 5"(l,l-Difluoroethyl)-3-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-l,254- triazol-3-yl}bicyclo[2.2.2]oct-l -yl)-l ,2,4-oxadiazoIe.
Examples of glucokinase activating drugs that are of interest for use as described herein include: 6-( 1 -acetylpyrrolidin-2-yl)-5-(6-methoχymethylpyridin-3 -yl)oxy)-2-pyridin-2-yl-
1 H-benzimidazole
6-(l-acetylpyrrolidin-2-yl)-5-((6-methyIpyridm-3-yl)oxy)-2-pyridin-2-yl-lH- benzimidazole,
6-(l -acetylpyrrolidin-2-yl)-5-((6-pyrazin-2-ylpyridin-3-yl)oxy)-2-pyridin-2-yl- 1 H- benzimidazole,
6-(l~acetyl~3~fiuoropyrrolidin-2"yl)-5-((2'-fluorobiphenyl-4-yl)oxy)-2-pyridin-2- yl- 1 H-benzimidazole,
3-(6-ethanesuIfonyl-pyridin-3-yloxy)-5-(2-hydroxy- 1 -methyl-ethoxy)-N-(l - methyl- 1 H-pyrazol-3 -yl)benzamide ; 3 -(6-ethanesulfonyl-pyridin-3 -yloxy)-5-isopropoxy-N-( 1 -methyl- 1 H-pyrazol-3 - yl)benzamide;
5-(2-fluoro-l-fluoromethyl-ethoxy)~3-(6-methanesulfonyl-pyridin-3-yloxy)-N-(l- methyl- 1 H-pyrazol-3 -yl)benzamide;
3-(6-ethanesulfonyl-pyridin-3-yloxy)-5-(2-hydroxy-l-methyl-ethoxy)-N- (isoxazol-3-yl)benzamide;
1 -[(5- { [6-(5-methyl- 1 ,2,4-oxadiazol-3-yl)-3~pyridmyl]oxy}-2-(2-pyridinyl)- IH- benzim idazol-6-yl)methyl] -2-pyrrolidinone,
N-( { 5 - [4-(ethylsulfonyl)phenoxy] -2-(2»ρyridinyl)- 1 H-benzimidazol-6-yl } methyl)- N-methylacetamide, 3-{[5-[4-(5 -methyl- 1 ,2,4-oxadiazol -3 -yl)ρhenoxy] -2-(2-pyridinyl)- 1 H- benzimidazo!-6-yl]methyl} - 1 ,3-oxazolidine-2;>4-dione5
5-[4-(ethylsulfonyl)phenoxy]-6-((2-methyl-2H-tetrazol-5-yl)methyl)-2-(2~ pyridinyl)- 1 H-benzimidazole,
3-( {4- [2-(dimethylamino)ethoxy]ρhenyl } thio)-N-(3 -methyl- 1 ,2,4-thiadiazol-5-yl)- 6-[(4-methyl-4H-l52,4-triazol-3-yl)thio]pyridine-2-carboxamide;
3-({4-[(l -methylazetidin-3-yl)oxy]phenyl}thio)-N-(3-methyl- 1 ,2;4-thiadiazol~5- yl)~6- [(4-m.ethyl"4H- 1 ,2,4-triazol- 3 -yl)thio] pyridine-2-carboxamide ;
3-{ [4-(2-methoxyelho3cy)phenyl]thio}-N-(3-methyl- 1 s2f4-thiadiazol-5-yl)-6-[(4- methyl-4H-l ,2,4-triazol-3-yl)thio]pyridine-2-carboxamide; and 3-[(4-acetylphenyl)thio]-N-(3-methyl-l52,4-thiadiazol-5-yl)-6-i;(4-methyl-4H-
1 ,2 ,4-triazol-3 -yl)thio] pyridine-2»carboxamide . Compounds of the present invention (i.e. compounds having Formula I) can be used to treat one or more diseases or conditions selected from hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia, and dyslipidemia by administering a therapeutically effective amount of a compound of Claim 1 in combination with an HMG-CoA reductase inhibitor to a patient in need of such treatment. Statins are the preferred HMG-CoA reductase inhibitors for use in this combination therapy. Preferred statins include lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, itavastatin, ZD-4522, rivastatin, and rosuvastatin. This combination treatment may be particularly desirable for treating or reducing the risk of developing atherosclerosis. Such a combination can optionally have a third pharmaceutically active ingredient, such as a CETP inhibitor (e.g. torcelrapib), niacin, or a cholesterol absorption inhibitor (e.g. ezetimibe).
Cholesterol absorption inhibitors can also be used in the present invention. Such compounds block the movement of cholesterol from the intestinal lumen into enterocytes of the small intestinal wall, thus reducing serum cholesterol levels. Examples of cholesterol absorption inhibitors are described in U.S. Patent Nos. 5,846,966, 5,631,365, 5,767,1 15, 6,133,001, 5,886,171, 5,856,473, 5,756,470, 5,739,321, 5,919,672, and in PCT application Nos. WO 00/63703, WO 00/60107, WO 00/38725, WO 00/34240, WO 00/20623, WO 97/45406, WO 97/16424, WO 97/16455, and WO 95/08532. The most notable cholesterol absorption inhibitor is ezetimibe, also known as l-(4-fluoroρhenyl)-3(R)-[3(S)-(4-fluorophenyl)-3-hydroxypropyl)]- 4(S)-(4-hydroxyphenyl)-2-azetidinone, described in U.S. Patent Nos. 5,767,115 and 5,846,966.
Therapeutically effective amounts of cholesterol absorption inhibitors include dosages of from about 0.01 mg/kg to about 30 mg/kg of body weight per day, preferably about 0.1 mg/kg to about 15 mg/kg.
For diabetic patients, the compounds used in the present invention can be administered with conventional diabetic medications as outlined above. For example, a diabetic patient receiving treatment as described herein may also be taking insulin or an oral antidiabetic medication. One example of an oral antidiabetic medication useful herein is metformin.
For hypertensive patients, the compounds used in the present invention can be administered with conventional antihypertensive medications as outlined above. For example, a patient with high blood pressure receiving treatment as described herein may also be taking
ARBS or an ACE inhibitor. One example of an oral antihypertensive medication useful herein is losartin.
Salts The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 1- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl- morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
When the compound of the present invention is basic or has a basic group in the structure, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Preferred acids include citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, tartaric, toluenesulfonic (tosylate), methanesulfonic (mesylate) and benzenesulfonic (besylate) acid salts, most preferably the benzenesulfonic, toluenesulfonic and methanesulfonic acid salts. In some instances the compounds of the invention may be present in zwitterionic forms.
It will be understood that, as used herein, references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.
Metabolites - Prodrugs
Metabolites of the compounds described herein which themselves fall within the scope of the invention are also compounds of the current invention. Prodrugs, which are metabolically or physically labile compounds that are converted to the active pharmaceutical ingredient (API) as they are being administered to a patient or after they have been administered to a patient, also may be considered compounds of this invention.
Pharmaceutical Compositions
The pharmaceutical compositions described herein are generally comprised of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, in combination with a pharmaceutically acceptable carrier.
The compounds used in the present invention can be administered via any conventional route of administration. The preferred route of administration is oral. Examples of suitable oral compositions include tablets, capsules, troches, lozenges, suspensions, dispersible powders or granules, emulsions, syrups and elixirs. Examples of carrier ingredients include diluents, binders, disintegrants, lubricants, sweeteners, flavors, colorants, preservatives, and the like. Examples of diluents include, for example, calcium carbonate, sodium carbonate, lactose, calcium phosphate and sodium phosphate. Examples of granulating and disintegrants include corn starch and alginic acid. Examples of binding agents include starch, gelatin and acacia. Examples of lubricants include magnesium stearate, calcium stearate, stearic acid and talc. The tablets may be uncoated or coated by known techniques. Such coatings may delay disintegration and thus, absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
One embodiment of the invention that is of interest is a tablet or capsule that is comprised of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in an amount ranging from about O.lmg to about lOOOmg, in combination with a pharmaceutically acceptable carrier., In another embodiment of the invention, a compound of formula I or a pharmaceutically acceptable salt or solvate thereof is combined with another therapeutic agent and the carrier to form a fixed combination product. This fixed combination product may be a tablet or capsule for oral use.
More particularly, in another embodiment of the invention, a compound of formula I or a pharmaceutically acceptable salt or solvate thereof (about 0.1 to about 1000 mg) and the second therapeutic agent (about 0.1 to about 500 mg) are combined with the pharmaceutically acceptable carrier, providing a tablet or capsule for oral use.
Sustained release over a longer period of time may be particularly important in the formulation. A time delay material such as glyceryl monostearate or glyceryl distearate may be employed. The dosage form may also be coated by the techniques described in the U.S. Patent Nos. 4,256,108; 4,166,452 and 4,265,874 to form osmotic therapeutic tablets for controlled release.
Other controlled release technologies are also available and are included herein. Typical ingredients that are useful to slow the release of nicotinic acid in sustained release tablets include various cellulosϊc compounds, such as methylcelϊulose, ethylcellulose, propylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, starch and the like. Various natural and synthetic materials are also of use in sustained release formulations. Examples include alginic acid and various alginates, polyvinyl pyrrolidone, tragacanth, locust bean gum, guar gum, gelatin, various long chain alcohols, such as cetyl alcohol and beeswax. Optionally and of even more interest is a tablet as described above, comprised of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, and further containing an HMG Co-A reductase inhibitor, such as simvastatin or atorvastatin.
Typical release time frames for sustained release tablets in accordance with the present invention range from about 1 to as long as about 48 hours, preferably about 4 to about 24 hours j and more preferably about 8 to about 16 hours.
Hard gelatin capsules constitute another solid dosage form for oral use. Such capsules similarly include the active ingredients mixed with carrier materials as described above. Soft gelatin capsules include the active ingredients mixed with water-miscible solvents such as propylene glycol, PEG and ethanol, or an oil such as peanut oil, liquid paraffin or olive oil.
Aqueous suspensions are also contemplated as containing the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth and acacia; dispersing or wetting agents,e.g-> lecithin; preservatives, e.g., ethyl, or n~propyl parahydroxybenzoate, colorants, flavors, sweeteners and the like.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredients in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above.
Syrups and elixirs are also included.
More particularly, a pharmaceutical composition that is of interest is a sustained release tablet that is comprised of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in combination with a pharmaceutically acceptable carrier. Another aspect of the invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament. This medicament has the uses described herein.
More particularly, another aspect of the invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, and an HMG Co-A reductase inhibitor, such as simvastatin, in the manufacture of the medicament. This medicament has the uses described herein.
Utilities
The compounds defined above may be used in any of the following methods to treat or control diseases, as well as methods to treat other diseases not listed below, in a mammalian patient, especially a human, by administering to the patient a therapeutically effective amount for the specific disease (or diseases) of a compound of Formula I: (1 ) non-insulin dependent diabetes mellitus (type 2 diabetes);
(2) pre-diabetes (insulin resistance);
(3) hyperglycemia;
(4) metabolic syndrome; (5) obesity;
(6) atherosclerosis;
(7) hypertension;
(8) one or more lipid disorders, including mixed or diabetic dyslipidemia, hyperlipidemia, and hypercholesterolemia; (9) glaucoma, age related macular degeneration and the like;
(10) organ protection, such as protection from reperfusion injury; and
(11) kidney malfunction, such as proteinuria, and in particular, albuminuria, and subsequent edema resulting therefrom, macrophage infiltration, and the like.
The compounds may also be used in a method for reducing the risks of adverse sequelae associated with metabolic syndrome in a human or other mammalian patient in need of such treatment which comprises administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
The compounds may also be used in a method for treating atherosclerosis, for reducing the risk of developing atherosclerosis, for delaying the onset of atherosclerosis, and/or reducing the risk of sequelae of atherosclerosis in a human or other mammalian patient in need of such treatment or at risk of developing atherosclerosis or sequelae of atherosclerosis, which comprises administering to the patient a therapeutically effective amount of a compound of
Formula I. Sequelae of atherosclerosis include for example angina, claudication, heart attack, stroke, etc. The compounds are especially useful in the treatment of the following diseases, by administering a therapeutically effective amount (for the specific disease) of the compound, or a pharmaceutically acceptable salt thereof, to a patient in need of treatment:
(1) type 2 diabetes, and especially insulin resistance resulting from type 2 diabetes; (2) hypertension;
(3) atherosclerosis; and
(4) metabolic syndrome.
Another aspect of the invention that is of interest relates to a method of treating atherosclerosis in a human patient in need of such treatment comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective for treating atherosclerosis. Another aspect of the invention that is of interest relates to a method of treating diabetes, and in particular, type 2 diabetes, in a human patient in need of such treatment comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective for treating diabetes. Another aspect of the invention that is of interest relates to a method of treating metabolic syndrome in a human patient in need of such treatment comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective for treating metabolic syndrome.
Another aspect of the invention that is of interest relates to a method of treating high blood pressure in a human patient in need of such treatment comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective for treating hypertension.
Another aspect of the invention that is of interest relates to a method of treating inflammatory pain or CN S -mediated pain in a human patient in need of such treatment comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective for treating pain.
Another aspect of the invention that is of interest relates to a method of treating disorders of the eye in a human patient in need of such treatment comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective for alleviating eye disorders.
Another aspect of the invention that is of interest relates to a method of treating cardiac hypertrophy and renal failure in a human patient in need of such treatment comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective for anti-inflammatory end organ protection. Another aspect of the invention that is of particular interest relates to a method of treating or preventing atherosclerosis, diabetes, hypertension, metabolic syndrome or a related condition in a human patient in need of such treatment, comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof administered in an amount that is effective to treat or prevent atherosclerosis, diabetes, hypertension, metabolic syndrome or a related condition.
Compounds of the present invention are inhibitors of the enzyme, soluble epoxide hydrolase (sEH). The compounds of this invention are useful in treating or controlling diseases, disorders or conditions which are mediated by sEH and EETs (Larsen, Campbell and Gutterman TRENDS in Pharmacol Sci. 2007, 28(1), 32). One aspect of the present invention provides a method for the treatment and control of diseases that can be mediated by administration of an sEH inhibitor, such as type 2 diabetes or hypertension. Compounds of the present invention may be useful in treating or controlling many sEH mediated diseases and conditions, including, but not limited to, (1) diabetes mellitus, and especially non-insulin dependent type 2 diabetes mellitus (NIDDM), (2) hyperglycemia, (3) low glucose tolerance, (4) pre-diabetes or insulin resistance, (5) obesity, (6) hypertension, (7) dyslipidemia, (8) hyperlipidemia, (9) hypercholesterolemia, (10) atherosclerosis and its sequelae, (11) kidney failure, (12) cardiac hypertrophy, (13) pancreatitis, (14) vascular restenosis, (15) inflammatory pain, (16) CNS- mediated pain, (17) glaucoma, (18) macular degeneration, (19) retinopathy, (20) thrombosis, (21) metabolic syndrome, and (22) Raynaud's syndrome.
Another aspect of the invention provides a method of treating inflammatory conditions, including acute respiratory distress syndrome (ARDS), ischemϊa/reperfusion injury and related diseases.
The present compounds can be used to lower glucose and insulin in non-diabetic patients who have impaired glucose tolerance and/or are in a pre-diabetic condition by the administration to a patient in need of treatment a therapeutically effective amount of a compound having Formula I, or pharmaceutically acceptable salt thereof. The present compounds can be used to treat obesity in a patient in need of such treatment by administering to the patient a therapeutically effective amount of a compound of Formula I, or pharmaceutically acceptable salt thereof.
The present compounds can be used to treat or reduce the risk of developing atherosclerosis in a patient in need of such treatment by administering to the patient a therapeutically effective amount of a compound of Formula 1 „ or a pharmaceutically acceptable salt thereof.
The present compounds can be used to treat or reduce hyperglycemia in a diabetic patient in need of such treatment by administering to the patient a therapeutically effective amount of a compound of Formula 1, or a pharmaceutically acceptable salt thereof. The present compounds can be used to treat or reduce blood pressure and provide kidney end organ protection in a hypertensive patient in need of such treatment by administering to the patient a therapeutically effective amount of a compound of Formula 1 , or a pharmaceutically acceptable salt thereof.
One aspect of the invention provides a method for the treatment and control of mixed or diabetic dyslipidemia, and/or atherosclerosis, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound having formula I. The compound may be used alone or advantageously may be administered with a cholesterol biosynthesis inhibitor, particularly an HMG-CoA reductase inhibitor such as lovastatin, simvastatin, rosuvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, or ZD-4522. The compound may also be used advantageously in combination with other lipid lowering drugs such as cholesterol absorption inhibitors (for example stanol esters, sterol glycosides such as tiqueside, and azetidinones such as ezetimibe), ACAT inhibitors (such as avasimibe), CETP inhibitors (such as torcetrapib), niacin, niacin receptor agonists, bile acid sequestrants, microsomal triglyceride transport inhibitors, and bile acid reuptake inhibitors. These combination treatments may also be effective for the treatment or control of one or more related conditions selected from the group consisting of hypercholesterolemia, atherosclerosis, hyperlipidemia, hypertriglyceridemia, dyslipidemia, high LDL~c levels, and low HDL-c levels.
Another aspect of the invention that is of interest relates to a method of treating or controlling one or more of: mixed or diabetic dyslipidemia, hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, and/or hypertriglyceridemia., type 2 diabetes, hyperglycemia, insulin resistance and related conditions, hypertension, and/or kidney failure, and inflammatory pain which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound having formula I in combination with a compound selected from the group consisting of: a DPP -4 antagonist; a glucagon receptor antagonist; a glucokinase activator; a GPRl 19 agonist; a GPR 40 modulator; a GPR 120 agonist; an insulin sensitizer; a sulfonylurea or other insulin secretogogue; a SPPARγM such as those disclosed in WO 2006/099077 Al; an α-glucosidase inhibitor; an SGLT inhibitor; a GLP-I, GLP-I analogue or mimetic or a GLP-I receptor agonist; a GIP, GIP mimetic or GIP receptor agonist; a PACAP5 a PACAP mimetic or PACAP receptor agonist; an HMG Co-A reductase inhibitor; a bile acid sequestrant; (niacin) nicotinic acid or a nicotinyl alcohol; a PPAR α agonist; a PPARα/γ dual agonist; a PPAR pan agonist; inhibitors of cholesterol absorption; acyl CoA:cholesterol acyltransferase inhibitors; antioxidants; PPARδ agonists; antiobesity agents such as NPYl or NPY5 antagonists CBl receptor inverse agonists, ileal bile acid transporter inhibitors; aspirin, NSAIDs, glucocorticoids, azulfidine, selective COX-2 inhibitors; antihypertensive agents such as ACE inhibitors, All receptor blockers, beta blockers and calcium channel blocking drugs; diuretics; inhibitors of 11 β- HSD-I ; inhibitors of CETP and inhibitors of fructose 156-bisphosphatase.
Pharmaceutical Compositions
Another aspect of the present invention provides pharmaceutical compositions which comprise a compound of Formula I and a pharmaceutically acceptable carrier. The pharmaceutical compositions of the present invention comprise a compound of Formula I or a pharmaceutically acceptable salt as an active ingredient, as well as a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids. A pharmaceutical composition may also comprise a prodrug, or a pharmaceutically acceptable salt thereof, if a prodrug is administered.
The compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy. In general, compositions suitable for oral administration are preferred.
In practical use, the compounds of Formula I can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalHne cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained. The active compounds can also be administered intranasally as, for example, liquid drops or spray.
The tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor. Compounds of formula I may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
The following are examples of pharmaceutical dosage forms containing a compound of Formula I:
Figure imgf000031_0001
REPRESENTATIVE SCHEMES AND EXAMPLES
The following Schemes and Examples are provided to more fully illustrate the present invention. Representative compounds of Formula I have been prepared by the following reaction Schemes below. It is understood that other synthetic approaches to these structure classes are conceivable to one skilled in the art. Therefore these reaction Schemes, as well as the Examples, should not be construed as limiting the scope of the invention. Unless stated otherwise:
(i) all operations were carried out at room (it) or ambient temperature, that is, at a temperature in the range 18-250C; (ii) evaporation of solvent was carried out using a rotary evaporator under reduced pressure (4.5-30 mniHg) with a bath temperature of up to 5O0C;
(iii) the course of reactions was followed by thin layer chromatography (TLC) and/or tandem high performance liquid chromatography (HPLC) followed by mass spectroscopy (MS), herein termed LCMS, and any reaction times are given for illustration only; (iv) yields, if given, are for illustration only;
(v) the structure of all final compounds was assured by at least one of the following techniques: low resolution MS (LRMS) or proton nuclear magnetic resonance (IH NMR) spectrometry, and the purity was assured by at least one of the following techniques: TLC or HPLC; (vi) 1 H NMR spectra were recorded on either a Varian Unity™ or a Varian
Inova™ instrument at 500 or 600 MHz using the indicated solvent; when line-listed, NMR data is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to residual solvent peaks (multiplicity and number of hydrogens); conventional abbreviations used for signal shape are: s. singlet; d. doublet (apparent); t. triplet (apparent); m. multiplet; br. broad; etc.;
(vii) MS data were recorded on a Waters Micromass unit, interfaced with a Hewlett-Packard (Agilent 1100™) HPLC instrument, and operating on MassLynx/OpenLynx software; electrospray ionization was used with positive (ES+) or negative ion (ES-) detection; the method for LCMS ES+ was 1-2 mL/min, 10-95% B linear gradient over 5.5 min (B = 0.05% TFA-acetonitrile, A = 0.05% TFA-water), and the method for LCMS ES- was 1-2 mL/min, 10- 95% B linear gradient over 5.5 min (B = 0.1% formic acid - acetonitrile, A = 0.1% formic acid - water). Waters XTerra Cl 8 - 3.5 urn - 50 x 3.0 mmID and diode array detection;
(viii) automated purification of compounds by preparative reverse phase RP- HPLC was performed on a Gilson system using a YMC-Pack Pro Cl 8 column (150 x 20 mm i.d.) eluting at 20 mL/min with 0 - 50% acetonitrile in water (0.1 % TFA);
(ix) column chromatography was carried out on a glass silica gel column using Kieselgel 60™, 0.063-0.200 mm (Merck), or a Biotage cartridge system;
(x) chemical symbols have their usual meanings; the following abbreviations have also been used v (volume), w (weight), b.p. (boiling point), m.p. (melting point), L (litre(s)), mL (milliUtres), g (gram(s)), mg (milligrams(s)), mol (moles), mmol (millimoles), eq or equiv (equivalents)), IC50 (molar concentration which results in 50% of maximum possible inhibition), EC50 (molar concentration which results in 50% of maximum possible efficacy), uM (micromolar), nM (nanomolar).
The various organic group transformations and protecting groups utilized herein can be performed by a number of procedures other than those described below. References for other synthetic procedures that can be utilized for the preparation of intermediates or compounds disclosed herein can be found in, for example, M.B. Smith, J. March Advanced Organic Chemistry, 5th Edition, Wiley-ϊnterscience (2001); R.C. Larock Comprehensive Organic Transformations, A Guide to Functional Group Preparations, 2nd Edition, VCH Publishers, Inc. (1999); T.L. Gilchrist Heterocyclic Chemistry, 3rd Edition, Addison Wesley Longman Ltd. (1997); J. A. Joule, K. Mills, G.F. Smith Heterocyclic Chemistry, 3rd Edition, Stanley Thornes Ltd. (1998); G.R. Newkome, W.W. Paudler Contemporary Heterocyclic Chemistry, John Wiley and Sons (1982);or Wuts, P. G. M.; Greene, T. W.; Protective Groups in Organic Synthesis, 3rd Edition, John Wiley and Sons, (1999), all six incorporated herein by reference in their entirety.
Scheme I
Figure imgf000033_0001
Example I- 1
Figure imgf000033_0002
N"(cyclohexylmethyl)-5-[2-fluoro-6-(trifluoromethyl)phenyl]pyridin-2-amine
Step A: 2-fluoro-5-f2-flιιoro-6-('triflυororoetlwπphenvl]pvridme
2-Bromo-l-fluoro-3-(trifluoromethyl)benzene (2500 mg, 10.29 mmol), (6-fluoropyridin-3-yI) boronic acid (1812 mg, 12.86 mmol) and bis(tri-t-butylphosphine)palladium(0) (526 mg) were added into a 20 mL pressure vessel followed by adition of dioxane, and CS2CO3 (6704 mg), purged with N2, capped and stirred at 320 0C for 2 h. The reaction mixture was cooled, filtered, and concentrated. The residue was purified by silica gel chromatography (5 to 15% EtOAc in hexane). LRMS: m/z found: 260.3 (M+l).
Step B: N-CcyclohexylmethyD-S-P-fluoro-ά-ftrifiuoromethvπphenyljpyridin^-amine 2-Fluoro-5-[2-fluoro-6-(trifluorometliyl)phenyl]pyridme {1700 mg, 6.56 mmol) and 1- cyclohexylmethanamine (2.56 niL, 19.68 mmol) were mixed in NMP, stirred at 200 0C for 1 h, cooled to room temperature, diluted with water, extracted with EtOAc twice. The combined organic extracts were washed with brine, dried over Na2SO^ filtered, concentrated. The residue was purified by silica gel chromatography (5 to 20% EtOAc in hexane). LRMS: m/z found: 353.5 (M+l). 1H NMR (500 MHz, CDCl3): δ 8.02 (s, 1 H), 7.59 (d, J = 8.0, 1 H) 7.51-7.45 (m, 1 H), 7.40-7.32 (m, 2 H), 6.47(d, J = 9.0, 1 H), 4.74 (s, 1 H), 3.19 (t, J - 6.5, 2 H), 2.08-1.62 (m, 6 H), 1.394.19 (m, 3 H), 1.10-1.02 (m, 2 H).
The following compounds in Table 2 were made according to Scheme I where intermediates in the scheme were modified according to literature methods.
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0002
δ
Figure imgf000037_0001
Figure imgf000038_0002
Scheme II
Figure imgf000038_0001
Example II- 1
Figure imgf000039_0001
1 - [4-(6- { [2-(2-chloro-6-fluorophenyI)ethyl] amino } pyridin- 3 -yl)-3 - (trifluoromethyl)benzoyl]piperidine-4-carboxylic acid
Step A: 4-(6-fluoropwidin-3-yl)-3-(trifluoromethyl)benzamide
4-Bromo-3-(trifluoromethyl)benzamide (400 mg, 1.492 mmol), (6-fluoropyridin-3-yl) boronic acid (263 mg, 1.865 rαmol) and bis(tri-t-butylphosphine)palladium (0) (82 mg) were added into a 20 niL pressure vessel followed by adition of dioxane, and CS2CO3 (1000 mg), purged with nitrogen, capped and stirred at 100 0C overnight. The reaction mixture was filtered, and concentrated. The residue was purified by silica gel chromatography (3 to 10% MeOH in CH2Cl2). LRMS: m/z found: 285.4 (M+ 1).
Step B : , 4-(6- { [2-(2-chloro-6-fluorophenyl)ethyl] amino } pyridm-3-y l)-3 - (trifluoromethyl)benzamide
4-(6-fluoropyridin-3-yl)-3-(trifluoromethyl)benzamide (470 mg, 1.65 mmol) and 2-(2-chloro-6- fluorophenyl) ethanamine (574 mg, 3.31 mmol) were mixed in NMP. The reaction mixture was stirred at 200 0C for 1 h, cooled to room temperature, diluted with water, extracted with EtOAc twice. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (4% to 8% MeOH in CH2Cl2). LRMS: m/z found: 438.39 (M+l)
Step C: ethyl H4-(6-f r2-(2-chloro-6-fluorophenyl)ethyll amino }pyridin-3-vD-3- (trifluoromethyl)benzoyl]ρiperidine-4-carboxylate
4-(6-{[2-(2-chloro-6-fluorophenyl)ethyl]amino}pyridin-3-yl)-3-(trifluoromethyl)benzamide (170 mg, 0.388 mmol), and ethyl ρiρeridine-4-carboxylate (0.299 mL, 1.941 mmol) were mixed in NMP. The mixture was stirred at 185 0C overnight, cooled to room temperature, diluted with water, extracted with EtOAc, and concentrated. The residue was purified by reverse phase chromatography (10%-90% MeCWH2O, both containing 0.05 % TFA). LRMS: m/z found: 578.55 (M+l). Step D: 1 -[4~(6- ( r2-(2-chloro-6-fluorophenyl)ethyl1 amino }pyridin-3-yi)-3 - (trifIuoromethyl)benzovl]piperidme-4-carboxylic acid
Ethyl 1 - [4-(6- { [2-(2-chloro-6-fluorophenyl)ethyl] amino } pyridin-3 -yl)-3 - (trifluoromethyl)benzoyl]piperidme-4~carboxylate (60 mg, 0.104 mmol) was dissolved in a mixture of solvents (0.6 mL of dioxane, 0.6 mL of MeOH and 0.6 mL water) followed by addition of Li OH (12.43 mg, 0.519 mmol). The mixture was stirred at 45 0C for 15mm, concentrated in vacuo. The residue was diluted with EtOAc5 washed with IN HCL The organic layer was concentrated. The residue was purified by reverse phase chromatography (10%-90% MeCN/H2Os both containing 0.05 % TFA). LRMS: m/z found: 550.51 (M+l). 1HNMR (500 MHz, CD3OD): δ 7.93-7.88 (m, 3 H), 7.79 (d, J = 7.5, 1 H)3 7.58 (d, J = 8.0, 1 H), 7.35-7.29 (m, 2 H), 7.15-7.09 (m, 2 H), 4.50 (d, J = 8.0, 1 H), 3.77 (t, J = 7.O5 2 H), 3.72-3.68 (m, 2 H)3 3.27 (t, J - 7.O3 2 H), 3.20-3.16 (m, 2 H)3 2.72-2.67 (m, 2 H), 2.15-2.11 (m, 1 H), 1.96-1.92 (m, 1 H), 1.79-1.66 (m, 2 H).
The following compounds in Table 3 were made according to Scheme II where intermediates in the scheme were modified according to literature methods.
Figure imgf000040_0001
Figure imgf000041_0003
Scheme HI
Figure imgf000041_0001
Figure imgf000041_0002
N-(cyclohexylmethyl)-5- [3 -pyridin- 3 -yl- 5 -(trifluorometliyl)- 1 H-pyrazol- 1 -yl] pyr idin-2-amine Step A: dZ")-4A4-lrifluoro-l-pvτidin-3-vlbut-l-ene-1.3,3-triol To a cold (O0C) NaOMe (270 mgf 5 mmol) ether (6 mL) solution was slowly added 1 -ρyridin-3- ylethanone (0.550 mL, 5 mmol), and ethyl trifluoroacetate (0.595 mL, 5.00 mmol) via syringes. The mixture was then stirred at reflux for 2 h, cooled to room temperature, diluted with water, washed with ether(3x). The aqueous layer was acidified to pH 5 using acetic acid. The resulting solid was filtered, rinsed with cold ether and dried. LRMS: m/z found: 236.3 (M+ 1).
Step B: 1 -(6-fluoropyridin-3-yl)-3-pyridin-3-yl-5-ftrifiuoromethyl)-4,5-dihydro-l H-pγrazol-5-ol
A solution of 2-chloro-5-hydrazinopyridine (136 mg, 0.95 mmol) and acetic acid (0.29 mL, 5,00 mmol) in ethanol (2 mL) is added to a stirred solution of (lZ)-45454-trifluoro-l-pyridin-3-ylbut-l- ene-l,3,3-triol (160 mg, 0,68 mmol) in ethanol (2 mL) in a pressure tube. The reaction mixture is heated at 90 0C (oil bath temp) overnight, cooled and concentrated. The residue was purified by silica gel chromatography (2% to 10% MeOH in CH2Cl2). LRMS: m/z found: 343.5 (M+l).
Step C^-fcvclohexylmethvD-S-rS-pyridin-β-yl-S-ftrifluoromethYD-lH-pyrazol-l-yllpyridiB^- amine
1 -(6-fluoropyridin-3 -yl)- 3 -pyridin-3 -yl- 5 -(trifluoromethyl)-4, 5 -dihydro- 1 H-pyrazol- 5 -ol (17 mg, 0.050 mmol) and 1 -cyclohexylrnethanamine (28.1 mg, 0.248 mmol) were mixed in NMP (0.05 mL), stirred at 165 0C for 3 h. The reaction mixture was purified by prep TLC
(solvent: DCM/MeOH=97/3). LRMS: m/z found: 402.7 (M+l). 1H NMR (500 MHz, CDCl3): δ 9.52 (s, 1 H)5 7.59 (d, J= 8.0, 1 H) 8.67-8.63 (m, 1 H), 8.24 (s, 1 H), 8.18 (d, J = 9.0, 1 H), 7.55 (d, J = 8.5, 1 H), 7.39 (t, J= 8.O5 1 H), 7.17 (s, 1 H), 6.47 (d, J = 9.0, 1 H)5 4.94 (s, 1 H), 3.18 (t, J = 6.5, 2 H)5 1.88-1.64 (m, 6 H), 1.36-1.19 (m, 3 H), 1.05-1.01 (m, 2 H),
sEH human enzyme assay Preparation of recombinant sEH human enzyme
The DNA for expressing sEH was designed based on a rhesus monkey sEH cDNA, modified to optimize for expression both in E. coli and insect cells. The designed DNA fragment encodes a protein sequence that is identical to full length human sEH, and the DNA was synthesized in vitro. The DNA was then subcloned into the pETlOO vector that will generate a fusion protein with an N-terminal His-tag. The recombinant protein was expressed in E. coli. The sEH enzyme was affinity purified by a Ni+4" column. His-tag was removed by Enter Kinase (EK) digestion. The purified enzyme aliquots were frozen and held at -80 0C for later use.
Fluorescence based enzyme in vitro assay For each assay (100 ul), an aliquot of enzymes (about 1 nM final concentration) was incubated with a fluorescence substrate, S7 (lOuM final concentration), in sEH assay buffer (25 mM HEPES, pH7.0, O.lmg/ml BSA) in a 96-well plate. The kinetic reaction reading (Ex330/Em465) was conducted using a plate reader, Spectra max (Molecular Devices) at 25 0C.
DHET production assay
HEK293 (human kidney) cells were seeded at 4.2X104 cells/well (10OuI) in 96- well plate in DMEM medium (high glucose) containing 10% FBS, 100 units/ml Penicillin and 100 ug/ml Streptomycin at 370C in a humidified atmosphere of 10% CO2. After 24 h} the medium was changed to the same medium but without FBS for 1 h. The compound, diluted in DMSO, was added to each well for 1 h. Then, the substrate EET (3 uM final cone.) was added to each well for 2 h. At the end of the incubation period, 80 ul of medium was transferred to a new 96 well plate followed by LC-MS/MS analysis for the production of DHET.
Study Protocol: Oral dosing of Enzyme Inhibitor for 14 days in male ZDF rats
Seven weeks old, male ZDF rats (purchased from Charles River Labs) are conditioned with vehicle (0.5% methocel) for one week before the study is initiated. One week later, animals are prescreened and divided into 5 groups (n=8) based on the average baseline blood glucose levels and body weight. All the rats are then orally dosed (at a volume of 5 ml/kg) once daily with vehicle, inhibitor or rosiglitazone for continuous 14 days. The animals are fed Purina diet 5008 (ad lib.) throughout the study. Body weight and food intake are monitored twice a week. Ambient (fed) blood glucose levels are measured by glucometer (by tail clip) on day 1 , 7 and 10 in the morning before dosing. On day 13, the animals treated with Vehicle 1, Inhibitor and rosiglitazone (n^6/group) are subjected to an oral glucose tolerance test (glucose: 2g/kg) following overnight fast and one hr after receiving vehicle or compound. Blood glucose levels are measured at -60 (prior to compound dosing), 0 (prior to oral glucose), 20, 40, 60 and 120 min after glucose challenge. On day 14, two hours after the last dose, (fed) blood samples are collected from all the animals through cardiac puncture under CO2 euthanasia. Whole blood target engagement, drug levels, plasma glucose, insulin, lipids, cytokines and other hormones are determined. Liver, skeletal muscle (Gastrocnemius), epididymal white adipose tissues and kidneys (cut longitudinally) from some animals are collected, wrapped into foils and frozen into liquid nitrogen immediately. Tissue target engagement, biomarkers and drug levels are measured.
Formulation: Vehicle 1 : 0.5% methocel (with 10% vol. of cone. HCl and 20% vol. of 5N NaOH, pH~7) Inhibitor Compound: dissolve the compound in 10% volume of cone HCl (~10N), add 70% volume of 0.5% methocel (at pH 3), mix well and then add 20% volume of 5N NaOH and mix. Adjust pH to neutral (pH 7). Vehicle 2: 0.5% methocel Rosiglitazone: in 0.5% methocel.
Table 3. IC50 [nM] for human sEH enzyme inhibition
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0002
Figure imgf000047_0001
Figure imgf000048_0001
All patents, patent applications and publications that are cited herein are hereby incorporated by reference in their entirety. While certain preferred embodiments have been described herein in detail, numerous alternative embodiments are seen as falling within the scope of the invention.

Claims

WHAT IS CLAIMED IS:
1. A compound in accordance with structural formula I:
Figure imgf000049_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein: one of W and X represents a carbon or nitrogen atom, and the other represents a carbon atom; Ring A represents an Aryl group or a 5-6 membered Heteroaryl group containing
1-3 N atoms and 0-1 O or S atom;
Ring B represents a member selected from the group consisting of: a) a 3-7 membered monocyclic or bridged bicyclic aliphatic carbocycle; b) a 5-6 membered heterocycle, containing 1-2 heteroatoms, 0-1 of which is selected from oxygen and sulfur, and 0-2 of which are nitrogen atoms; c) a 6-10 membered aromatic group, and d) a 5-6 membered heteroaryl ring containing 1-2 nitrogen atoms, and 0-1 oxygen or sulfur atom;
R1 is halo, C1^6 alkyl, haloCμealkyl or phenyl; each R2 is H or is selected from the group consisting of halo;
Figure imgf000049_0002
haloCi-
≤alkyl; CO2R8; C(O)NH2; C(O)NHC 1-8alkyl; S(O)2NHCi_8alkyl; NHC(O)NHCI-8alkyl; OCi- 6alkyl-CO2Ra; C(O)-Hetcy optionally substituted with 1-3 halo atoms and one group selected from Ci^alkyl, haloC^alkyl and CO2Ra; phenyl and HAR, said Phenyl and HAR being optionally substituted with 1-3 halogen atoms and 1-2 members selected from the group consisting of: C1-6 alkyl, haloCi.6aIkyl5 CO2Ra, (CH2) i-6CO2Ra, OC1-6alkyl and OhaloC1-6alkyl; each Ra is selected from the group consisting of H and Cμealkyl; each R3 is selected from the group consisting of: H, halo, Ci-6alkyl,
Figure imgf000049_0003
haloCμ6alkyl5 OhaloCi-6alkyl C(O)C i-6alky I5 C(O)haloCi-6alkyl, C(O)Aryl, NHC(O)Aryl, S(O)2haloCj.6alkyl5 S(O)2Aryl, S(O)2NHCμ8alkyl, NHC(O)NHC 1-8alkyl, NHC(O)C, -8alkyl, C(O)HAR and CO2R3, the Aryl and HAR portions of C(O)Aryl, S(O)2AIyI, NHC(O)Aryl and C(O)HAR being optionally substituted with 1-3 halo groups and 1-2 Ci-6alkyl or haloCμgalkyl groups; j represents an integer of from 0-4; and R4 is selected from the group consisting of H, halo, Ci-galkyl and phenyl, such that no more than two R4 groups represent phenyl.
2. A compound in accordance with claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein W and X each represent a carbon atom.
3. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein ring A represents a phenyl or pyridyl ring.
4. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein ring A represents a phenyl ring.
5. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein ring B represents a 3-7 membered monocyclic or bridged bicyclic aliphatic carbocycle.
6. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein ring B represents a 5-6 membered heterocycle, containing 1 -2 heteroatoms, 0-1 of which is selected from oxygen and sulfur, and 0-2 of which are nitrogen atoms.
7. A compound in accordance with claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein ring B represents a 6-10 membered aromatic group.
8. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein ring B represents a 5-6 membered heteroaryl ring containing 1-2 nitrogen atoms, and 0-1 oxygen or sulfur atom.
9. A compound in accordance with claim I5 or a pharmaceutically acceptable salt or solvate thereof, wherein ring B represents a member selected from the group consisting of: cyclohexane, piperidine, piperazine, pyrrolidine, phenyl and pyridine.
10. A compound in accordance with claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein ring B represents a member selected from the group consisting of: cyclohexane, piperidine, piperazine, phenyl and pyridine.
1 1. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R1 represents halo or haloC1-6alkyl.
12. A compound in accordance with claim 11 , or a pharmaceutically acceptable salt or solvate thereof, wherein R1 represents haloCt^alkyl.
13. A compound in accordance with claim 12, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 represents trifluoromethyl.
14. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 is selected from the group consisting of H; HAR; C(O)- Hetcy optionally substituted with halo, C1-3alkyl, CF3 or CO2R3; O-C1-6alkyl-CO2Ra wherein Ra is H or Ci-4alkyl; phenyl optionally substituted with Cμgalkyl or CO2Ra; C(O)NHC 1-8alkyl and C(O)NH2.
15. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 is selected from the group consisting of H; phenyl optionally substituted with Ci^alkyl or CO2Ra; HAR which is selected from pyridyl and tetrazolyl; C(O)-Hetcy wherein the Hetcy represents a piperidinyl group, optionally substituted with CO2H; O-CI-3alkyl- CO2H; C(O)NH2; and C(O)NHC Malkyl wherein the alkyl portion represents -CHi-cycJohexyL
16. A compound in accordance with claim 15, or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 represents H.
17. A compound in accordance with claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is selected from the group consisting of: H; halo selected from Cl and F; CO2Ra wherein Ra represents H or C Malkyl; C^alkyl; haloC1-6alkyl wherein the halo portion is F; OhaloC^alkyl wherein the halo portion is F; C(O)C i-ealkyl, C(O)haloCi-6alkyl wherein the halo portion is F; C(O)-Phenyl; NHC(O)~Phenyl; S(O)2ImIoC1- 6alkyl wherein the halo portion is F; SO2 Phenyl; SO2NHC1-8alkyl; NHC(O)NHC ^alkyl; NHC(O)C μ8alkyl; C(O)HAR and, the Phenyl and HAR portions of C(O)Phenyl, SO2Phenyl, NHC(O)Phenyl and C(O)HAR being optionally substituted with 1-3 halo groups selected from F and Cl, and 1-2 Ci-ealkyl or haloC^ealkyl groups the halo portions of which are F.
18. A compound in accordance with claim 17, or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 represents hydrogen.
19. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein: W and X each represent a carbon atom;
Rng A represents a phenyl or pyridyl ring;
Ring B represents a member selected from the group consisting of: a) a 3-7 membered monocyclic or bridged bicyclic aliphatic carbocycle; b) a 5-6 membered heterocycle, containing 1-2 heteroatoms, 0-1 of which is selected from oxygen and sulfur, and 0-2 of which are nitrogen atoms; c) a 6- 10 membered aromatic group, and d) a 5-6 membered heteroaryl ring containing 1-2 nitrogen atoms, and 0-1 oxygen or sulfur atom; R1 represents halo or haloC j -ealkyl; each R2 is selected from the group consisting of H; HAR; C(O)-Hetcy optionally substituted with halo, CL-3alkyl, CF3 or C O2Ra; O-Cμ6alkyl-CO2Ra wherein Ra is H or.CMalkyl; phenyl optionally substituted with Chalky, or CO2Ra; C(O)NHC 1-8alkyl and C(O)NH2. each R3 is selected from the group consisting of: H; halo selected from Cl and F; CO2R3 wherein Ra represents H or C1 ^alkyl; Chalky!; haloCi-6alkyl wherein the halo portion is F; OhaloCμealkyl wherein the halo portion is F; C(O)C i^alkyl, C(O)haloCi-6alkyl wherein the halo portion is F; C(O)-Phenyl; NHC(O)-Phenyl; S(O)2haloC1-6alkyl wherein the halo portion is F; SO2 Phenyl; SO2NHCi-8alkyl; NHC(O)NHC 1-8alkyl; NHC(O)C 1-8alkyl; C(O)HAR and, the Phenyl and HAR portions of C(O)Phenyl, SO2Phenyls NHC(O)Phenyl and C(O)HAR being optionally substituted with 1-3 halo groups selected from F and Ci, and 1-2
Figure imgf000052_0001
or haloCμ ealkyl groups the halo portions of which are F, or two R3groups taken together represent a fused phenyl ring and the remaining R3 group is as defined above.
20. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
W and X each represent a carbon atom;
Ring A represents a phenyl or pyridyl ring;
Ring B represents a member selected from the group consisting of: a) a 3-7 membered monocyclic or bridged bicyclic aliphatic carbocycle; b) a 5-6 membered heterocycle, containing 1-2 heteroatoms, 0-1 of which is selected from oxygen and sulfur, and 0-2 of which are nitrogen atoms; c) a 6-10 membered aromatic group, and d) a 5-6 membered heteroaryl ring containing 1-2 nitrogen atoms, and 0-1 oxygen or sulfur atom;
R1 represents trifluoromethyl or chloro; each R2 is selected from the group consisting of H; HAR; C(O)-Hetcy optionally substituted with haϊo, C^aikyl, CF3 or CO2Ra; O-Cϊ.<;aIlcyl-CO2Ra wherein Ra is H or CMalkyl; phenyl optionally substituted with C^alkyl or CO2R3; C(O)NHC1-galkyl and C(O)NH2; each R3 is selected from the group consisting of: H; halo selected from Cl and F; CO2Ra wherein Ra represents H or C1 ^
Figure imgf000053_0001
alkyl; Cs-βalkyl; wherein the halo portion is F; OhaloCi.fialkyl wherein the halo portion is F; C(O)Ci-6alkyl, C(O)haloCi_6alkyl wherein the halo portion is F; C(O)-Phenyl; NHC(O)-PhenyI; S(O)2haloCi-6alkyl wherein the halo portion is F; SO2 Phenyl; SO2NHCi.8alkyl; NHC(O)NΗC,-8alkyl; NHC(O)C1-8alkyl; C(O)HAR and, the Phenyl and HAR portions of C(O)Phenyl, SO2Phenyl, NHC(O)Phenyl and C(O)HAR being optionally substituted with 1- 3 halo groups selected from F and Cl, and 1-2 C]-Salkyl or haloCμgalkyl groups the halo portions of which are F.
21. A compound in accordance with claim 1 as set forth in Table 1 below:
Figure imgf000053_0002
Figure imgf000054_0001
a pharmacetucially acceptable salt or solvate thereof.
22. A pharmaceutical composition comprised of a compound in accordance with claim 1 , or a pharmaceutically acceptable salt or solvate thereof, in combination with a pharmaceutically acceptable carrier.
23. A method of treating diabetes in a mammalian patient in need of such treatment comprising administering to the patient a compound in accordance with claim 1, or a pharmaceutically acceptable salt or solvate thereof, in an amount that is effective for treating diabetes.
24. A method of treating pain in a mammalian patient in need of such treatment comprising administering to the patient a compound in accordance with claim 1 , or a pharmaceutically acceptable salt or solvate thereof, in an amount that is effective for treating pain.
25. A method of treating atherosclerosis in a mammalian patient in need of such treatment comprising administering to the patient a compound in accordance with claim 1 , or a pharmaceutically acceptable salt or solvate thereof, in an amount that is effective for treating atherosclerosis.
26. A method of treating hypertension in a mammalian patient in need of such treatment comprising administering to the patient a compound in accordance with claim 1 , or a pharmaceutically acceptable salt or solvate thereof, in an amount that is effective for treating hypertension.
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