WO2009070497A1 - Inhibiteurs de ehs et de 11β-hsd1 et leur utilisation - Google Patents

Inhibiteurs de ehs et de 11β-hsd1 et leur utilisation Download PDF

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WO2009070497A1
WO2009070497A1 PCT/US2008/084289 US2008084289W WO2009070497A1 WO 2009070497 A1 WO2009070497 A1 WO 2009070497A1 US 2008084289 W US2008084289 W US 2008084289W WO 2009070497 A1 WO2009070497 A1 WO 2009070497A1
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tricyclo
sulfonyl
dec
methyl
carboxamide
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PCT/US2008/084289
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English (en)
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Joseph Paul Jr. Marino
John Jeffrey Mcatee
David G. Washburn
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Smithkline Beecham Corporation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
    • C07D207/48—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/96—Sulfur atom
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the invention is directed to sEH and 1 1 ⁇ -HSD1 inhibitors and their use in the treatment of a variety of conditions mediated by the sEH enzyme or the 11 ⁇ -HSD1 enzyme.
  • Epoxide functional groups may be found in drugs, xenobiotic materials, and endogenous biomolecules.
  • Epoxide hydrolases found in both plants and animals, are enzymes that convert epoxides to diols by hydrolysis.
  • soluble epoxide hydrolase (“sEH") is primarily responsible for the metabolism of arachidonic acid derivatives known as epoxyeicosatrienoic acids ("EETs”).
  • EETs epoxyeicosatrienoic acids
  • DHETs dihydroxyeicosatrienoic acids
  • microsomal epoxide hydrolase catalyzes the hydrolysis of a broad range of epoxide substrates including carcinogenic polycyclic aromatic hydrocarbons and reactive epoxides, thus it provides an important detoxification pathway.
  • Polymorphisms in mEH may lead to differences in bioactivation of pro- carcinogens and several human epidemiological studies suggest that mEH genotype is associated with altered cancer risk. Fretland & Omiecinski, Chemico-Biol. Int., 129, 41- 59, 2000.
  • EET levels are protective in numerous disorders including hypertension [Ce// Biochem Biophvs.. 47, 87-98, 2007], heart failure [Xu et al., Proc. Natl Acad. Sci. I/. S. A, 103, 18733-18738, 2006], renal dysfunction / end organ damage [Zhao et al., J. Am. Soc. Nephrol.. 15, 1244-1253, 2004; Imi ⁇ et al.. Hypertension. 46, 975-981 , 2005], stroke [Koerner et al., J. Neurosci..
  • 11 beta-hvdroxysteroid dehydrogenase type 1 11 beta-hydroxysteroid dehydrogenase type 1 (“1 1 ⁇ -HSD1 ") is an intracellular enzyme that converts inactive glucocorticoids (e.g. cortisone) to active glucocorticoids (e.g. Cortisol).
  • inactive glucocorticoids e.g. cortisone
  • active glucocorticoids e.g. Cortisol
  • 11 ⁇ -HSD1 can lead to cardiovascular and metabolic disorders.
  • liver-specific overexpression of 11 ⁇ -HSD1 in mice leads to insulin resistance, dyslipidemia and hypertension [Paterson et al., Proc Natl Acad U.S.A., 101 , 7088-7093, 2004].
  • 11 beta-hydroxysteroid dehydrogenase type 2 (“11 ⁇ -HSD2”) catalyzes the pre-receptor dehydrogenation of active glucocorticoids to an inactive form.
  • 11 ⁇ -HSD2 is highly expressed in epithelial tissues and protects the mineralocorticoid receptor from active glucocorticoids (Draper et al., J Endo, 186, 251-271 , 2005). Mutations in the gene that encodes 1 1 ⁇ -HSD2 cause a decrease in 1 1 ⁇ -HSD2 activity and are associated with hypertension and metabolic disorders in humans (White et al., Endocr Rev 18, 135-156, 1997).
  • the invention is directed to novel sEH and 11 ⁇ -HSD1 inhibitors and their use in the treatment of diseases mediated by the sEH enzyme or the 1 1 ⁇ -HSD1 enzyme. Specifically, the invention is directed to compounds according to Formula I:
  • A, W, and n are defined below, and to pharmaceutically-acceptable salts thereof.
  • this invention provides for the use of the compounds of Formula (I) for the treatment or prevention of hypertension, organ failure / damage (including heart failure, renal failure, cardiac and renal fibrosis, and liver failure), peripheral vascular disease (including ischemic limb disease, intermittent claudication, endothelial dysfunction, erectile dysfunction, Raynaud's disease, and diabetic vasculopathies e.g.
  • organ failure / damage including heart failure, renal failure, cardiac and renal fibrosis, and liver failure
  • peripheral vascular disease including ischemic limb disease, intermittent claudication, endothelial dysfunction, erectile dysfunction, Raynaud's disease, and diabetic vasculopathies e.g.
  • Atherosclerosis atherosclerosis
  • atherothrombotic disorders including coronary artery disease, coronary vasospasm, angina, stroke, myocardial ischemia, myocardial infarction, and hyperlipidemia
  • metabolic disorders including diabetes, metabolic syndrome, hyperglycemia, and obesity
  • inflammation inflammatory disorders (including arthritis, inflammatory pain, overactive bladder, asthma, and COPD)
  • cognitive disorders including cognitive impairment, dementia, and depression
  • glaucoma including osteoporosis, and polycystic ovary syndrome.
  • the compounds of this invention may be administered alone or in conjunction with one or more other therapeutic agents, eg. agents being selected from the group consisting of may be administered alone or in conjunction with one or more other therapeutic agents, eg. agents being selected from the group consisting of endothelin receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, angiotension Il receptor antagonists, vasopeptidase inhibitors, diuretics, digoxin, beta blocker, aldosterone antagonists, iontropes, NSAIDS, nitric oxide donors, calcium channel modulators, muscarinic antagonists, steroidal anti-inflammatory drugs, bronchodilators, Leukotriene antagonist, HMG-CoA reductase inhibitors, dual non-selective ⁇ - adrenoceptor and ⁇ -
  • agents being selected from the group consisting of may be administered alone or
  • the invention is directed to compounds according to Formula I:
  • A is A1 , A2, or A3 wherein
  • W is S(O 2 )R2 or C(O)NR2R2;
  • X, Y, and Z are each selected from the group consisting of: Rc, Rd, Rg, or Rh; or two of X, Y, and Z taken together with the carbon atom to which they are attached form a saturated bridged or fused polycyclic ring having from 5 to 15 member atoms wherein said ring optionally contains one to four heteroatoms as member atoms in the ring and wherein said ring is optionally substituted with one or more substituents selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, ORa, SRa, NRbRb, C(O)ORa, and C(O)NRaRa, and the other of X, Y and Z is selected from the group consisting of: H, Rc, Rd, Rg, or Rh; or X, Y, and Z taken together with the carbon atom to which they are attached form a saturated bridged or fused polycycl
  • the compounds according to Formula I may contain one or more asymmetric centers (also referred to as a chiral center) and may, therefore, exist as individual enantiomers, diastereomers, or other stereoisomeric forms, or as mixtures thereof.
  • Chiral centers such as chiral carbon atoms, may also be present in a substituent such as an alkyl group.
  • the stereochemistry of a chiral center present in Formula I, or in any chemical structure illustrated herein, is not specified the structure is intended to encompass any stereoisomer and all mixtures thereof.
  • compounds according to Formula I containing one or more chiral center may be used as racemic mixtures, enantiomerically enriched mixtures, or as enantiomerically pure individual stereoisomers.
  • Individual stereoisomers of a compound according to Formula I which contain one or more asymmetric center may be resolved by methods known to those skilled in the art. For example, such resolution may be carried out (1 ) by formation of diastereoisomeric salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer-specific reagent, for example by enzamatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral enviornment, for example, on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent.
  • stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.
  • the compounds according to Formula I may also contain double bonds or other centers of geometric asymmetry. Where the stereochemistry of a center of geometric asymmetry present in Formula I, or in any chemical structure illustrated herein, is not specified, the structure is intended to encompass the trans (E) geometric isomer, the cis (Z) geometric isomer, and all mixtures thereof. Likewise, all tautomeric forms are also included in Formula I whether such tautomers exist in equilibrium or predominately in one form.
  • compounds according to Formula (I) may contain a basic functional group and are therefore capable of forming pharmaceutically acceptable acid addition salts by treatment with a suitable acid. Suitable acids include pharmaceutically acceptable inorganic acids and organic acids.
  • Representative pharmaceutically acceptable acids include hydrogen chloride, hydrogen bromide, nitric acid, sulfuric acid, sulfonic acid, phosphoric acid, acetic acid, hydroxyacetic acid, phenylacetic acid, propionic acid, butyric acid, valeric acid, maleic acid, acrylic acid, fumaric acid, malic acid, malonic acid, tartaric acid, citric acid, salicylic acid, benzoic acid, tannic acid, formic acid, stearic acid, lactic acid, ascorbic acid, p-toluenesulfonic acid, oleic acid, lauric acid, and the like.
  • compounds according to Formula I may contain an acidic functional group and are therefore capable of forming pharmaceutically-acceptable base addition salts by treatment with a suitable base.
  • pharmaceutically-acceptable salts of the compounds according to Formula I may be prepared. Indeed, in certain embodiments of the invention, pharmaceutically-acceptable salts of the compounds according to Formula I may be preferred over the respective free base or free acid because such salts impart greater stability or solubility to the molecule thereby facilitating formulation into a dosage form. Accordingly, the invention is further directed to pharmaceutically-acceptable salts of the compounds according to Formula I.
  • pharmaceutically-acceptable salts refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. These pharmaceutically-acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.
  • the term "compounds of the invention” means both the compounds according to Formula I and the pharmaceutically-acceptable salts thereof.
  • a compound of the invention also appears herein and refers to both a compound according to Formula I and its pharmaceutically-acceptable salts.
  • compounds of the invention can exist in crystalline, semi- crystalline and amorphous forms, as well as mixtures thereof.
  • pharmaceutically-acceptable solvates of a compound of the invention may be formed wherein solvent molecules are incorporated into the solid-state structure during crystallization.
  • Solvates may involve water or nonaqueous solvents, or mixtures thereof.
  • the solvent content of such solvates can vary in response to environment and upon storage. For example, water may displace another solvent over time depending on relative humidity and temperature.
  • Solvates wherein water is the solvent that is incorporated into the solid-state structure are typically referred to as "hydrates.”
  • Solvates wherein more than one solvent is incorporated into the solid-state structure are typically referred to as “mixed solvates”.
  • Solvates include "stoichiometric solvates” as well as compositions containing variable amounts of solvent (referred to as “non-stoichiometric solvates”).
  • Stoichiometric solvates wherein water is the solvent that is incorporated into the solid-state structure are typically referred to as “stoichiometric hydrates", and non-stoichiometric solvates wherein water is the solvent that is incorporated into the solid-state structure are typically referred to as “non-stoichiometric hydrates”.
  • the invention includes both stoichiometric and non- stoichiometric solvates.
  • crystalline forms of a compound of the invention may contain solvent molecules, which are not incorporated into the solid-state structure.
  • solvent molecules may become trapped in the crystals upon isolation.
  • solvent molecules may be retained on the surface of the crystals.
  • the invention includes such forms.
  • polymorphs may exhibit polymorphism (i.e. the capacity to occur in different crystalline packing arrangements). These different crystalline forms are typically known as “polymorphs.”
  • the invention includes all such polymorphs. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different IR spectra and X-ray powder diffraction patterns, which may be used for identification. Polymorphs may also exhibit different melting points, which may be used for identification.
  • polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in the production of different polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.
  • Alkyl refers to a monovalent saturated hydrocarbon chain having the specified number of member atoms.
  • C1-C8 alkyl refers to an alkyl group having from 1 to 8 member atoms.
  • Alkyl groups may be optionally substituted with one or more substituents as defined herein.
  • Alkyl groups may be straight or branched. Representative branched alkyl groups have one, two, or three branches.
  • Alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and t-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl.
  • Aryl refers to a monovalent aromatic hydrocarbon ring.
  • Aryl groups are monocyclic ring systems or bicyclic ring systems.
  • Monocyclic aryl ring refers to phenyl.
  • Bicyclic aryl ring refers to napthyl, biphenyl, and to rings wherein phenyl is fused to a cycloalkyl ring having 5, 6, or 7 member atoms.
  • Aryl groups may be optionally substituted with one or more substituents as defined herein.
  • Cycloalkyl refers to a monovalent saturated or unsaturated hydrocarbon ring having the specified number of member atoms.
  • C3-C6 cycloalkyl refers to a cycloalkyl group having from 3 to 6 member atoms.
  • Unsaturated Cycloalkyl groups have one or more carbon-carbon double bonds within the ring. Cycloalkyl groups are not aromatic. Cycloalkyl groups having from 3 to 7 member atoms or less are monocyclic ring systems. Cycloalkyl groups having at least 7 member atoms may be monocyclic, bridged or fused bicyclic ring systems. Cycloalkyl groups may be optionally substituted with one or more substituents as defined herein.
  • Cycloalkyl includes cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptanyl, and cycloheptenyl.
  • Enantiomerically enriched refers to products whose enantiomeric excess is greater than zero.
  • enantiomerically enriched refers to products whose enantiomeric excess is greater than 50% ee, greater than 75% ee, and greater than 90% ee.
  • Enantiomeric excess or "ee” is the excess of one enantiomer over the other expressed as a percentage. As a result, since both enantiomers are present in equal amounts in a racemic mixture, the enantiomeric excess is zero (0% ee). However, if one enantiomer was enriched such that it constitutes 95% of the product, then the enantiomeric excess would be 90% ee (the amount of the enriched enantiomer, 95%, minus the amount of the other enantiomer, 5%).
  • Enantiomerically pure refers to products whose enantiomeric excess is 99% ee or greater.
  • Hydrof-life refers to the time required for half of a quantity of a substance to be converted to another chemically distinct specie in vitro or in vivo.
  • Halo refers to the halogen radical fluoro, chloro, bromo, or iodo.
  • Haloalkyl refers to an alkyl group that is substituted with one or more halo substituents. Haloalkyl includes trifluoromethyl.
  • Heteroaryl refers to a monovalent aromatic ring containing from 1 to 4 heteroatoms as member atoms in the ring. Heteroaryl groups containing more than one heteroatom may contain different heteroatoms. Heteroaryl groups may be optionally substituted with one or more substituents as defined herein. Unless otherwise specified, heteroaryl groups are monocyclic ring systems or are fused, spiro, or bridged bicyclic ring systems. Monocyclic heteroaryl rings have 5 or 6 member atoms. Bicyclic heteroaryl rings have from 7 to 1 1 member atoms.
  • Bicyclic heteroaryl rings include those rings wherein phenyl and a monocyclic heterocycloalkyl ring are attached forming a fused, spiro, or bridged bicyclic ring system, and those rings wherein a monocyclic heteroaryl ring and a monocyclic cycloalkyl, cycloalkenyl, heterocycloalkyl, or heteroaryl ring are attached forming a fused, spiro, or bridged bicyclic ring system.
  • Heteroaryl includes pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, furanyl, furazanyl, thienyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, tetrazolyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pteridinyl, cinnolinyl, benzimidazolyl, benzopyranyl, benzoxazolyl, benzisoxazolyl, benzofuranyl, iso
  • Heteroatom refers to a nitrogen, sulphur, or oxygen atom.
  • Heterocycloalkyl refers to a saturated or unsaturated ring containing from 1 to
  • heterocycloalkyl rings are not aromatic. Heterocycloalkyl groups containing more than one heteroatom may contain different heteroatoms. Heterocycloalkyl groups may be optionally substituted with one or more substituent as defined herein. Unless otherwise specified, heterocycloalkyl groups are monocyclic, bridged, or fused ring systems. Monocyclic heterocycloalkyl rings have from 4 to 7 member atoms. Bridged or bicyclic heterocycloalkyl rings have from 7 to 11 member atoms. In certain embodiments, heterocycloalkyl is saturated. In other embodiments, heterocycloalkyl is unsaturated but not aromatic.
  • Heterocycloalkyl includes pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, pyranyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothienyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, azepinyl, 1 ,3-dioxolanyl, 1 ,3- dioxanyl, 1 ,4-dioxanyl, 1 ,3-oxathiolanyl, 1 ,3-oxathianyl, 1 ,3-dithianyl, azetidinyl, azabicylo[3.2.1]octyl, azabicylo[3.3.1]nonyl, azabicylo[4.3
  • Member atoms refers to the atom or atoms that form a chain or ring. Where more than one member atom is present in a chain and within a ring, each member atom is covalently bound to an adjacent member atom in the chain or ring. Atoms that make up a substituent group on a chain or ring are not member atoms in the chain or ring.
  • Optionally substituted indicates that a group, such as alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heteroaryl, may be unsubstituted or substituted with one or more substituents as defined herein.
  • “Substituted” in reference to a group indicates that a hydrogen atom attached to a member atom within a group is replaced. It should be understood that the term “substituted” includes the implicit provision that such substitution be in accordance with the permitted valence of the substituted atom and the substituent and that the substitution results in a stable compound (i.e.
  • a single atom may be substituted with more than one substituent as long as such substitution is in accordance with the permitted valence of the atom.
  • Suitable substituents are defined herein for each substituted or optionally substituted group.
  • A is A 1 , A 2 , or A 3 ;
  • W is S(O 2 )R 2 or C(O)NR 2 R 2 ;
  • p is 1 or 2;
  • X, Y, Z together form adamantyl which may be substituted with one or more substituents selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, ORa, SRa, NRbRb, C(O)ORa, and C(O)NRaRa;
  • Ri is hydrogen;
  • One R 2 is hydrogen; and the other R 2 is phenyl, pyridyl, furyl, thienyl, benzofuryl, benzothienyl, benzothiazolyl, cyclohexyl, pyrido-oxazinyl, phenyl-ethyl, napthyl, or C 2-6 alkyl; all of which may be substituted or unsubstituted by one, two or three substituents chosen from: halo, C 1-6 alkyl, NRbRb, C(O)NRbRb
  • A is A 2 , or A 3 ; W iS S(O 2 )R 2 Or C(O)NR 2 R 2 ; p is 1 or 2;
  • R 1 is hydrogen
  • R 2 is H 1 ; and the other R 2 is phenyl, which may be substituted or unsubstituted by one, two or three substituents chosen from: halo, C 1-6 alkyl, NH 2 , NHC(O)CH 3 , CF 3 , OCF 3 , phenyl, C 1-6 alkoxy, OH, CN, , NO 2 ,
  • n 1 or 2; or a pharmaceutically acceptable salt thereof.
  • A is A 2 ;
  • W is S(O 2 )R 2 ;
  • p is 1 ;
  • X, Y, Z together form unsubstituted adamantyl;
  • R 1 is hydrogen;
  • One R 2 is H 1 ; and the other R 2 is phenyl, which may be substituted or unsubstituted by one, two or three substituents chosen from: halo, C 1-6 alkyl, NH 2 , NHC(O)CH 3 , CF 3 , OCF 3 , phenyl, C 1-6 alkoxy, OH, CN; -NRbRb, and n is 1 or 2; or a pharmaceutically acceptable salt thereof.
  • Compounds of Formula (I) include:
  • the compounds according to Formula I are prepared using conventional organic syntheses. Suitable synthetic routes are depicted below in the following general reaction schemes. All functional groups are as defined in Formula I unless otherwise defined. Starting materials and reagents depicted below in the general reaction schemes are commercially available or can be made from commercially available starting materials using methods known by those skilled in the art.
  • a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions.
  • the protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound.
  • suitable protecting groups and methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley & Sons, NY (1999).
  • a substituent may be specifically selected to be reactive under the reaction conditions used. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is either useful as an intermediate compound or is a desired substituent in a target compound.
  • Scheme 1 represents a general reaction scheme for preparing certain compounds according to Formula I (depicted as compound 1.4).
  • a reagent W which may be a sulfonyl chloride (commercially available or made from commercially available starting materials using methods known to those skilled in the art) and a base (such as NaOH) in a solvent (such as THF and water) at temperatures between O 0 C to 8O 0 C provides intermediate 1.2.
  • Scheme 2 represents a general reaction scheme for preparing certain compounds according to Formula I (depicted as compound 2.5).
  • Intermediate 2.1 commercially available or made from commercially available starting materials using methods known to those skilled in the art
  • an amine 2.2 commercially available or made from commercially available starting materials using methods known to those skilled in the art
  • a coupling reagent such as HATU
  • a base such as triethylamine
  • a solvent such as methylene chloride
  • Treatment of intermediate 2.3 with an acid (such as HCI) in a solvent (such as dioxane) provides intermediate 2.4.
  • reagent W which may be a sulfonyl chloride or an isocyanate (commercially available or made from commercially available starting materials using methods known to those skilled in the art) and a base (such as triethylamine) in a solvent (such as methylene chloride) at temperatures between -1O 0 C to 8O 0 C provides compounds according to Formula I wherein A is A1 (depicted as compound 2.5).
  • Scheme 3 represents a general reaction scheme for preparing compounds according to Formula I wherein A is A2 (depicted as compound 3.5), and PG is a protecting group such as a Boc or Cbz group.
  • Scheme 4 represents a general reaction scheme for preparing compounds according to Formula I wherein A is A3 (depicted as compound 4.5).
  • Scheme 5 represents a general reaction scheme for preparing compounds according to Formula I wherein A is A3 (depicted as compound 4.5).
  • Scheme 5 represents a reaction scheme for the synthesis of certain compounds according to Formula I (depicted as compounds 5.2 and 5.4).
  • Treatment of compound 5.1 with BBr 3 in a solvent (such as methylene chloride) provides 5.2.
  • a solvent such as methylene chloride
  • treatment of compound 5.3 with Pd/C, and H 2 in a solvent such as ethanol
  • MS and liquid chromatography MS were recorded on a MDS Sciex liquid chromatography / mass spectroscopy system. All mass spectra were performed under electrospray ionization (ESI), chemical ionization (Cl), electron impact (El) or by fast atom bombardment (FAB) methods.
  • HPLC data was recorded on an Agilent 1 100 series HPLC system with C-18 reverse phase column (Eclipse XDB-C18, 4.6 x 250 mm, 5 micron) running a gradient of 1-99% MeCN/H2O (+0.1% TFA) over 12 minutes.
  • BOP is an abbreviation for (Benzotriazol-i-yloxy)tris (dimethylamino)phosphonium hexafluorophosphate
  • DMF is an abbreviation for dimethylformamide
  • DMSO is an abbreviation for Dimethylsulfoxide
  • HATU is an abbreviation for 2-(1 H-7-azabenzotriazol-1-yl)-1 ,1 ,3,3-tetramethyl uronium hexafluorophosphate methanaminium
  • HPLC is an abbreviation for High Pressure Liquid Chromatography
  • g is an abbreviation for gram or grams
  • L is an abbreviation for liter or liters
  • LC-MS is an abbreviation for Liquid chromatography-Mass spectrometry
  • N is an abbreviation for Normal and refers to the number of equivalents of reagent per liter of solution
  • Ph is an abbreviation for phenyl
  • Step 1 Preparation of ⁇ (2/?)-1-r(3-methylphenyl)sulfonyll-2-pyrrolidinyl ⁇ acetic acid
  • a 100 mL round bottom flask was equipped with a magnetic stir bar and charged with a solution of (2/?)-2-pyrrolidinylacetic acid (875 mg, 5.3 mmol) dissolved in 3.2M NaOH (6.2 mL, 19.8 mmol) and THF (15 mL).
  • the solution was cooled to 0 0 C in an ice bath, and then a solution of 3-methylbenzenesulfonyl chloride (1.4 mL, 9.5 mmol) in THF (15 mL) was added slowly.
  • the reaction was allowed to stir at 0 0 C and monitored by LC/MS until the reaction was complete (5 h).
  • the solution was acidified with 1 N HCI to reach a pH of 6 to 7 and THF was removed under reduced pressure.
  • Step 2 Preparation of 2- ⁇ (2R)-1-r(3-methylphenyl)sulfonyll-2-pyrrolidinyl ⁇ -N-tricvclo
  • reaction mixture was filtered and purified by reverse-phase HPLC (SunfireTM Prep
  • Step 1 Preparation of 1 ,1-dimethylethyl 2-r2-oxo-2-(tricvclor3.3.1.1 3 ' 7 1dec-2-ylamino) ethyli-1-pyrrolidinecarboxylate
  • Step 2 Preparation of 2-(2-pyrrolidinyl)- ⁇ /-tricvclor3.3.1.1 3 ' 7 ldec-1-ylacetamide 1 ,1-dimethylethyl-2-[2-oxo-2-(tricyclo[3.3.1.1 3 ' 7 ]dec-2-ylamino)ethyl]-1 -pyrrolidine carboxylate (165 mg) was dissolved in dioxane (2 ml.) and treated with 4M HCI (2 ml.) in dioxane at RT. The reaction was stirred at RT for 30 minutes. The reaction mixture was then concentrated and extracted with CH 2 CI 2 . The organics were collected and washed with aqueous Na 2 CO 3 and brine.
  • Step 3 Preparation of N-tricvclora.S.i .i ⁇ ldec-i-yl-2-d- ⁇ -ftrifluoromethvnphenyll sulfonyl ⁇ -2-pyrrolidinyl)acetamide
  • Step 1 Preparation of 2-(2-pyrrolidinyl)-/ ⁇ /-tricvclor3.3.1.1 3 ' 7 ldec-1-ylacetamide hydrochloride salt
  • Step 2 Preparation of N-r(2.4-dichlorophenvnmethyll-2-r2-oxo-2-(tricvclor3.3.1.1 3 ' 7 ldec-1- ylamino)ethyll-1-pyrrolidinecarboxamide
  • Step 1 Preparation of 1 ,1-dimethylethyl 2- ⁇ [(tricvclo[3.3.1.13,71dec-1- ylcarbonyl)aminolmethyl ⁇ -1-piperidinecarboxylate
  • Step 2 Preparation of N-(2-piperidinylmethyl)tricvclor3.3.1.13,7ldecane-1-carboxamide Hydrochloride Salt 1 ,1-dimethylethyl 2- ⁇ [(tricyclo[3.3.1.13,7]dec-1-ylcarbonyl)amino]methyl ⁇ -1- piperidinecarboxylate (9.1 g, 24.2 mmol) was dissolved in CH 2 CI 2 (25 ml.) and 4M HCI in dioxane (30.2 ml_). Solution stirred over night. Solid precipitate was filtered to give a tacky solid which was redissolved, stirred and sonicated in MeOH/hexanes and chilled. Solid precipitate was filtered to yield white solid as hydrochloride salt (5.0 g, 14.4 mmol, 59.5%). MS (ES+): m/e 277 [M + H] + .
  • Step 3 Preparation of N-[[1-[(3-chloro-4-hvdroxyphenyl)sulfonyl1-2-piperidinyl1methyl1- tricvclo[3.3.1.13,71decane-1-carboxamide N-(2-piperidinylmethyl)tricyclo[3.3.1.13,7]decane-1-carboxamide (200 mg, 0.64 mmol) was dissolved in CH 2 CI 2 (1 ml.) in a 13 x 100 mm test tube. Et 3 N (270 uL, 1.9 mmol) was added followed by 3-chloro-4-(methyloxy)benzenesulfonyl chloride (154 mg, 0.64 mmol).
  • Step 1 Preparation of 1 ,1-dimethylethyl 4-( ⁇ r(tricvclo[3.3.1.1 3 ' 7 ldec-1- ylamino)carbonyl1amino ⁇ methyl)-1-piperidinecarboxylate
  • Step 2 Preparation of ⁇ /-(4-piperidinylmethyl)- ⁇ /'-tricvclor3.3.1.1 3 ' 7 ldec-1-ylurea
  • reaction mixture was concentrated, diluted with water and CH2CI2 (30 ml.) and washed with NaHCO3 (saturated solution). The organics were collected, dried over
  • Step 3 Preparation of ⁇ /1-r(3-chloro-2-methylphenyl)sulfonyll-N-r(tricvclor3.3.1.13,7ldec- 1-ylamino)carbonyl1-4-piperidinemethanamine
  • N-( ⁇ 1-[(3-chloro-4-hydroxyphenyl)sulfonyl]-2- piperidinyl ⁇ methyl)tricyclo[3.3.1.13,7]decane-1-carboxamide (125 mg, 0.25 mmol) was dissolved in CH 2 CI 2 (2 ml.) and 1 M BBr 3 in CH 2 CI 2 (2.08 ml_, 2.08 mmol) was added under a N 2 atmosphere into a 4 ml. capped vial. The solution stirred 3 h. H 2 O (0.25 ml.) was added dropwise (vigorous exotherm) and the mixture stirred 1 h.
  • the compounds according to Formula I are sEH inhibitors and 11 ⁇ -HSD1 inhibitors.
  • the compounds according to Formula I therefore, are useful in the treatment of conditions involving sEH activity and/or 1 1 ⁇ -HSD1 activity.
  • the biological activity of the compounds according to Formula I against sEH, mEH, 11 ⁇ -HSD1 and / or 1 1 ⁇ -HSD2 can be determined using any suitable assay for determining the relevant activity of a candidate compound, as well as suitable tissue and / or in vivo models. Suitable assays for determining sEH, mEH, 11 ⁇ -HSD1 and 11 ⁇ -HSD2 inhibitory activity are provided below.
  • the compounds according to Formula I are sEH inhibitors and 1 1 ⁇ -HSD1 inhibitors.
  • the invention is directed to a compound according to Formula I wherein the compound has an IC50 against sEH from 0.1 nM to 10,000 nM and an IC50 against 11 ⁇ -HSD1 from 0.1 nM to 10,000 nM.
  • the invention is directed to a compound according to Formula I wherein the compound has an IC50 against sEH from 0.1 nM to 1 ,000 nM and an IC50 against 11 ⁇ - HSD1 from 0.1 nM to 1 ,000 nM.
  • the invention is directed to a compound according to Formula I wherein the compound has an IC50 against sEH from 0.1 nM to 100 nM and an IC50 against 11 ⁇ -HSD1 from 0.1 nM to 100 nM.
  • the invention is directed to a compound according to Formula I wherein the compound has an IC50 against sEH from 0.1 n M to 10 nM and an IC50 against 1 1 ⁇ - HSD1 from 0.1 nM to 1 O nM.
  • mEH provides an important detoxification pathway in mammals.
  • the invention is directed to a compound according to Formula I wherein the compound exhibits a selectivity ratio (based on IC50) equal to or greater than 10:1 for sEH over mEH.
  • the invention is directed to a compound according to Formula I wherein the compound exhibits a selectivity ratio (based on IC50) equal to or greater than 100:1 for sEH over mEH.
  • the invention is directed to a compound according to Formula I wherein the compound exhibits a selectivity ratio (based on IC50) equal to or greater than 1000:1 for sEH over mEH.
  • 1 1 ⁇ -HSD2 catalyzes the conversion of active glucocorticoids to an inactive form in mammals.
  • Compounds that exhibit pharmacological selectivity for 1 1 ⁇ -HSD1 over 11 ⁇ -HSD2 therefore are desirable in the methods of treatment described below.
  • the invention is directed to a compound according to Formula I wherein the compound exhibits a selectivity ratio (based on IC50) equal to or greater than 10:1 for 1 1 ⁇ -HSD1 over 11 ⁇ -HSD2.
  • the invention is directed to a compound according to Formula I wherein the compound exhibits a selectivity ratio (based on IC50) equal to or greater than 100:1 for 11 ⁇ -HSD1 over 11 ⁇ -HSD2. In another embodiment the invention is directed to a compound according to Formula I wherein the compound exhibits a selectivity ratio (based on IC50) equal to or greater than 1000:1 for 11 ⁇ -HSD1 over 11 ⁇ -HSD2.
  • Inhibition of sEH or mEH activity can be measured in a fluorescent assay based upon the format described by Wolf et al. (Analytical Biochemistry Vol. 355 (2006) pp. 71- 80).
  • PHOME (3-Phenyl-oxiranyl)-acetic acid cyano-(6- methoxy-naphthalen-2-yl)-methyl ester
  • the assay is used in a quenched assay format by sequentially adding enzyme (5 uL; 200 pM sEH or 150 nM mEH in 25 mM Hepes at pH 7.0, 0.01% CHAPS (w/v), 0.005% Casein (w/v); 10 minute ambient pre-incubation after addition) then PHOME substrate (5 ul; 10 uM PHOME substrate in 25 mM Hepes at pH 7.0, 0.01% CHAPS (w/v), 0.005% Casein (w/v)) to a 384 well assay plate (Greiner 784076) pre-stamped with 25-100 nl_ compound at the desired concentration.
  • enzyme 5 uL; 200 pM sEH or 150 nM mEH in 25 mM Hepes at pH 7.0, 0.01% CHAPS (w/v), 0.005% Casein (w/v); 10 minute ambient pre-incubation after addition
  • PHOME substrate (5 ul; 10 uM P
  • the reaction is incubated for 30 minutes (sEH assay) or 60 minutes (mEH assay) at room temperature, then quenched by the addition of stop solution (5 uL; 3.33 mM ZnSO4 (sEH assay) or 5OmM ZnSO4 (mEH assay) in water.
  • Stop solution 5 uL; 3.33 mM ZnSO4 (sEH assay) or 5OmM ZnSO4 (mEH assay) in water.
  • Microtiter plates are centrifuged after each addition for 30 seconds at 500 rpm.
  • the fluorescence is measured on an EnVision plate reader platform (Perkin Elmer) using a 360 nm excitation filter, 460 nm emission filter, and 400 nm dichroic filter.
  • Cell based sEH inhibition is measured using the 14,15-DHET immunoassay ELISA kit available from Detroit R&D (Cat. No. DH1 ), according to the following procedure:
  • HEK293 cells are transduced by sEH BacMam virus to increase sEH expression (other cell lines may be suitable) as follows: One day before the experiment, 1.5 million HEK293 cells (BioCat ID 80556) are seated in 3 ml. of DMEM/F12 ⁇ with L- Glutamine, 15 mM HEPES, pH 7.30), with 10% fetal bovine serum ⁇ from SAFC
  • reaction mixture is diluted 3-fold with provided sample dilution buffer (ex. Add 220 ⁇ L to the 1 10 ⁇ L reaction mixture), mixed well, and spun for 5 min at 500 rpm.
  • Compounds are first prepared in neat DMSO at a concentration of 0.5 mM, then diluted as required to achieve the desired assay concentration. For inhibition curves, compounds are diluted using a three fold serial dilution and tested at 9 concentrations (e.g. 10 ⁇ M-1.5 nM). Curves are analysed using ActivityBase and XLfit, and results are expressed as plC50 values.
  • the assay measures the ⁇ -NADPH dependent reductase activity of Human 11 ⁇ -HSD1 upon cortisone substrate to yield the active glucocorticoid Cortisol.
  • Microsomal membranes are prepared from frozen cell pellets of Super 9 (in- house generated variant of Sf9 insect cells) infected for approximately 72 hours with baculovirus encoding for human 11 B-HSD1.
  • Ten volumes of ice-cold, lysis solution (2OmM sodium phosphate buffer pH7.0, 5% glycerol, 1 mM EDTA, and Protease Inhibitor Cocktail III at 1 :500 [Calbiochem, San Diego, CA]) is added per gram of cell pellet, and the pellet kept on ice until it can be loosened from the tube.
  • the slurry is transferred to a glass Waring blender, and the following process repeated four times: homogenization for 15 seconds on high followed by a 5 minute incubation on ice.
  • the homogenate is centrifuged at 600xg for 10 minutes at 4 0 C; the supernatant from this spin is transferred to ultracentrifuge tubes which are spun at 100000xg for one hour at 4 0 C.
  • the cell pellet is resuspended in ice-cold 4OmM phosphate buffer, pH7.5 with 5% glycerol and 1 mM EDTA, aliquoted, and stored at - 8O 0 C.
  • the total protein recovered is determined with commercial protein assay kit using bovine albumin as the standard.
  • Assays are initiated by incubating 0.5 uL of compound sample in the presence of 15 ugs/mL of Sf9 microsomes, 1 mM ⁇ -NADPH, and 16 nM [ 3 H]cortisone ([S]/K m ⁇ 10) in buffer containing 50 mM HEPES, 100 mM KCI, 5 mM NaCI, 2 mM MgCI 2 , 0.02% Brij-35 (w/v) pH 7.4 in a reaction volume of 50 uL.
  • the assay is incubated for 3 hours at 37 °C before quenching the reaction with 25 uL of 10 uM 18 ⁇ -glycyrrhetinic acid, a potent natural product inhibitor of 11 ⁇ -HSD1 , and 8 mg/ml_ Protein-A-coated Yttrium silicate SPA beads pre-absorbed with 2.1 ug/mL monoclonal Cortisol antibody in the presence of Superblock ® Blocking Buffer (Pierce, Rockford, IL). Microtiter plates are sealed and incubated overnight before detection of scintillation on a ViewLux Plate Imager for 10 minutes using a clear filter.
  • Compounds are first prepared in neat DMSO at a concentration of 10 mM, then diluted as required to achieve the desired assay concentration. For inhibition curves, compounds are diluted using a three fold serial dilution and tested at 1 1 concentrations (e.g. 50 ⁇ M-0.8 nM or 25 ⁇ M-0.42 nM or 2.5 ⁇ M to 42 pM). Curves are analysed using ActivityBase and XLfit, and results are expressed as plC50 values.
  • Compounds (0 - 100 ⁇ M) are pre-incubated with recombinant microsomal human 11 ⁇ -HSD2 (10 ⁇ g/ml) and 1 mM NAD + in assay buffer (50 mM Hepes, pH 7.4, 100 mM KCI, 5 mM NaCI, 0.2 mM MgCI 2 , and 2% DMSO) at ambient temperature for 20 min.
  • Reactions are initiated with the addition of 10 nM [ 3 H]- cortisol (36.5 nCi; [cortisol]/K m ⁇ 1 ), incubated at ambient temperature for 60 min (which is within the linear response time of the assay), and quenched with the addition of 20 ⁇ M glycyrrhetinic acid. Remaining [ 3 H]-cortisol is assayed by addition of 0.7 mg (to a final concentration of 0.6 mg/ml) Protein A-YSi SPA beads (GE Healthcare) pre-complexed with a murine anti-cortisol monoclonal antibody (East Coast Bio, East Berwick, ME).
  • Reaction mixtures are incubated with SPA beads for at least 16 hours at ambient temperature, and cpm is measured on a Microbeta Trilux scintillation plate counter (PerkinElmer, Waltham, MA). Percent inhibition (%/) is calculated at each compound concentration using Equation 1 : n) where cpm, min, and max refer to counts per minute of reaction in presence of compound, 10 ⁇ M glycyrrhetinic acid, and 2% DMSO, respectively.
  • IC50 values (the concentration of compound that yields 50% enzyme inhibition) are calculated by plotting %/ versus logarithm of the compound concentration, and fitting the data to a four- parameter Hill equation (Equation 2): n / T i t°P - bottom . _.
  • Example 24 All of the compounds exemplified above except Example 24 were tested for activity as sEH inhibitors. Where the assay for a particular compound had been performed two or more times, the following conclusion regarding their activities is based on the average of individual experiments: All of the tested compounds except Example 3 and Example 5 were found to have an IC50 against sEH from 0.1 nM to 10,000 nM. Example 3 was found to have an IC50 of 19,953 nM. Example 5 was to have an IC50 greater than 25,119 nM. It is not known whether or not Example 5 would inhibit sEH activity at concentrations above 25,119 nM.
  • the compounds of the invention inhibit the sEH enzyme and the 11 ⁇ -HSD1 enzyme and can be useful in the treatment of conditions wherein the underlying pathology is (at least in part) attributable to sEH and/or 1 1 ⁇ -HSD1 involvement or in conditions wherein sEH and/or 1 1 ⁇ -HSD1 inhibition offers some clinical benefit even though the underlying pathology is not (even in part) attributable to sEH and/or 11 ⁇ - HSD1 involvement.
  • organ failure / damage including heart failure, renal failure, cardiac and renal fibrosis, and liver failure
  • peripheral vascular disease including ischemic limb disease, intermittent claudication, endothelial dysfunction, erectile dysfunction, Raynaud's disease, and diabetic vasculopathies e.g.
  • the invention is directed to methods of treating such conditions.
  • Essential hypertension is commonly associated with the development of significant end organ damage such as renal, endothelial, myocardial, and erectile dysfunction. Such conditions occur “secondary" to the elevated systemic arterial blood pressure. Secondary conditions may be prevented by treatment of the underlying ("primary") cause. Accordingly, in another aspect the invention is directed to methods of preventing such secondary conditions.
  • Heart failure is a complex heterogenous disorder characterized by reduced cardiac output, resulting in the inability of the heart to meet perfusion demands of the body. Cardiac proinflammatory cytokine recruitment and maladaptive cardiac hypertrophy, fibrosis and apoptosis/necrosis are factors associated with the progression of heart failure. Compounds of the invention are directed to methods of treating such conditions.
  • the invention is directed to methods of preventing atherothrombotic events, such as myocardial infarction and stroke in patients with a history of recent myocardial infarction, stroke, transient ischemic attacks, unstable angina, or atherosclerosis.
  • the methods of treating and the methods of preventing described above comprise administering a safe and effective amount of a compound of the invention to a patient in need thereof.
  • treatment in reference to a condition means: (1 ) the amelioration or prevention of the condition being treated or one or more of the biological manifestations of the condition being treated, (2) the interference with (a) one or more points in the biological cascade that leads to or is responsible for the condition being treated or (b) one or more of the biological manifestations of the condition being treated, or (3) the alleviation of one or more of the symptoms or effects associated with the condition being treated.
  • prevention of a condition includes prevention of the condition.
  • prevention is not an absolute term. In medicine, “prevention” is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.
  • safe and effective amount in reference to a compound of the invention or other pharmaceutically-active agent means an amount of the compound sufficient to significantly induce a positive modification in the condition to be treated but low enough to avoid serious side effects (at a reasonable benefit/risk ratio) within the scope of sound medical judgment.
  • a safe and effective amount of a compound of the invention will vary with the particular compound chosen (e.g. consider the potency, efficacy, and half-life of the compound); the route of administration chosen; the condition being treated; the severity of the condition being treated; the age, size, weight, and physical condition of the patient being treated; the medical history of the patient being treated; the duration of the treatment; the nature of concurrent therapy; the desired therapeutic effect; and like factors, but can nevertheless be determined by the skilled artisan.
  • patient refers to a human or other animal.
  • the compounds of the invention may be administered by any suitable route of administration, including both systemic administration and topical administration.
  • Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation.
  • Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion.
  • Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion.
  • Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages.
  • Topical administration includes application to the skin as well as intraocular, otic, intravaginal, and intranasal administration.
  • the compounds of the invention may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan.
  • suitable dosing regimens including the amount administered and the duration such regimens are administered, for a compound of the invention depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the particular route of administration chosen, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change. Typical daily dosages range from 1 mg to 1000 mg.
  • a prodrug of a compound of the invention is a functional derivative of the compound which, upon administration to a patient, eventually liberates the compound of the invention in vivo.
  • Administration of a compound of the invention as a prodrug may enable the skilled artisan to do one or more of the following: (a) modify the onset of the compound in vivo; (b) modify the duration of action of the compound in vivo; (C) modify the transportation or distribution of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome or overcome a side effect or other difficulty encountered with the compound.
  • Typical functional derivatives used to prepare prodrugs include modifications of the compound that are chemically or enzymatically cleaved in vivo. Such modifications, which include the preparation of phosphates, amides, esters, thioesters, carbonates, and carbamates, are well known to those skilled in the art.
  • the compounds of this invention may be administered alone or in conjunction with one or more other therapeutic agents, eg. agents being selected from the group consisting of may be administered alone or in conjunction with one or more other therapeutic agents, eg.
  • agents being selected from the group consisting of endothelin receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, angiotension Il receptor antagonists, vasopeptidase inhibitors, diuretics, digoxin, beta blocker, aldosterone antagonists, iontropes, NSAIDS, nitric oxide donors, calcium channel modulators, muscarinic antagonists, steroidal anti-inflammatory drugs, bronchodilators, Leukotriene antagonist, HMG-CoA reductase inhibitors, dual non-selective ⁇ - adrenoceptor and ⁇ -
  • ACE angiotensin converting enzyme
  • the compounds of the invention will normally, but not necessarily, be formulated into a pharmaceutical composition prior to administration to a patient. Accordingly, in another aspect the invention is directed to pharmaceutical compositions comprising a compound of the invention and a pharmaceutically-acceptable excipient.
  • compositions of the invention may be prepared and packaged in bulk form wherein a safe and effective amount of a compound of the invention can be extracted and then given to the patient such as with powders, syrups, and solutions for injection.
  • the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a safe and effective amount of a compound of the invention.
  • the pharmaceutical compositions of the invention typically contain from 1 mg to 1000 mg.
  • compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. For example, in certain embodiments the pharmaceutical compositions of the invention contain two compounds of the invention. In addition, the pharmaceutical compositions of the invention may optionally further comprise one or more additional pharmaceutically active compounds. Conversely, the pharmaceutical compositions of the invention typically contain more than one pharmaceutically-acceptable excipient. However, in certain embodiments, the pharmaceutical compositions of the invention contain one pharmaceutically-acceptable excipient. As used herein, "pharmaceutically-acceptable excipient” means a pharmaceutically acceptable material, composition or vehicle involved in giving form or consistency to the pharmaceutical composition.
  • each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided.
  • each excipient must of course be of sufficiently high purity to render it pharmaceutically- acceptable.
  • the compound of the invention and the pharmaceutically-acceptable excepient or excepients will typically be formulated into a dosage form adapted for administration to the patient by the desired route of administration.
  • dosage forms include those adapted for (1 ) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as aerosols and solutions; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels. Suitable pharmaceutically-acceptable excipients will vary depending upon the particular dosage form chosen.
  • suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition.
  • certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the carrying or transporting the compound or compounds of the invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body.
  • Certain pharmaceutically- acceptable excipients may be chosen for their ability to enhance patient compliance.
  • Suitable pharmaceutically-acceptable excipients include the following types of excipients: Diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweetners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents.
  • excipients include the following types of excipients: Diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweetners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chelating agents
  • Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically-acceptable excipients in appropriate amounts for use in the invention.
  • resources that are available to the skilled artisan which describe pharmaceutically-acceptable excipients and may be useful in selecting suitable pharmaceutically-acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).
  • the pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
  • the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a safe and effective amount of a compound of the invention and a diluent or filler.
  • Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate.
  • the oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g.
  • the oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose.
  • the oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesuim stearate, calcium stearate, and talc.

Abstract

L'invention concerne de nouveaux inhibiteurs de EHs et de 11β-HSD1 et leur utilisation dans le traitement de maladies à médiation par l'enzyme EHs ou l'enzyme 11β-HSD1. Précisément, l'invention concerne des composés selon la formule (I) : dans laquelle A, W et n sont tels que définis ci-dessous; et des sels pharmaceutiquement acceptables de ceux-ci. Les composés de l'invention sont des inhibiteurs de EHs et de 11β-HSD1 et peuvent être utilisés dans le traitement de maladies à médiation par l'enzyme EHs ou l'enzyme 11β-HSD1, telles que l'hypertension. Par conséquent, l'invention concerne en outre des compositions pharmaceutiques comprenant un composé de l'invention. L'invention concerne encore également des procédés d'inhibition de EHs ou de 11β-HSD1 et de traitement d'affections associées à celles-ci à l'aide d'un composé de l'invention ou d'une composition pharmaceutique comprenant un composé de l'invention.
PCT/US2008/084289 2007-11-28 2008-11-21 Inhibiteurs de ehs et de 11β-hsd1 et leur utilisation WO2009070497A1 (fr)

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WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
US8173805B2 (en) 2007-10-11 2012-05-08 GlaxoSmithKline, LLC sEH inhibitors and their use
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
WO2013115294A1 (fr) * 2012-01-31 2013-08-08 東レ株式会社 Dérivé de diazaspiro-urée et son utilisation pharmaceutique
WO2015046405A1 (fr) * 2013-09-26 2015-04-02 東レ株式会社 Analgésique
WO2015046404A1 (fr) * 2013-09-26 2015-04-02 東レ株式会社 Agent thérapeutique ou agent prophylactique pour l'hypertension pulmonaire
CN104817487A (zh) * 2015-05-06 2015-08-05 中国药科大学 一类可抑制表皮生长因子受体的哌啶基乙酰胺类化合物及其应用

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8173805B2 (en) 2007-10-11 2012-05-08 GlaxoSmithKline, LLC sEH inhibitors and their use
US8212032B2 (en) 2007-10-11 2012-07-03 Glaxosmithkline Llc. sEH inhibitors and their use
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
WO2013115294A1 (fr) * 2012-01-31 2013-08-08 東レ株式会社 Dérivé de diazaspiro-urée et son utilisation pharmaceutique
WO2015046405A1 (fr) * 2013-09-26 2015-04-02 東レ株式会社 Analgésique
WO2015046404A1 (fr) * 2013-09-26 2015-04-02 東レ株式会社 Agent thérapeutique ou agent prophylactique pour l'hypertension pulmonaire
CN104817487A (zh) * 2015-05-06 2015-08-05 中国药科大学 一类可抑制表皮生长因子受体的哌啶基乙酰胺类化合物及其应用
CN104817487B (zh) * 2015-05-06 2017-10-31 中国药科大学 一类可抑制表皮生长因子受体的哌啶基乙酰胺类化合物及其应用

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