WO2010011917A1 - Inhibiteurs doubles de seh et 11β-hsd1 - Google Patents

Inhibiteurs doubles de seh et 11β-hsd1 Download PDF

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Publication number
WO2010011917A1
WO2010011917A1 PCT/US2009/051678 US2009051678W WO2010011917A1 WO 2010011917 A1 WO2010011917 A1 WO 2010011917A1 US 2009051678 W US2009051678 W US 2009051678W WO 2010011917 A1 WO2010011917 A1 WO 2010011917A1
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Prior art keywords
methyl
phenyl
trifluoromethyl
triazol
oct
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PCT/US2009/051678
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English (en)
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WO2010011917A8 (fr
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Joseph Paul Marino
Carl A. Brooks
Patrick Eidam
John Jeffrey Mcatee
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Glaxosmithkline Llc
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Publication of WO2010011917A8 publication Critical patent/WO2010011917A8/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Definitions

  • the invention is directed to bicycle[2.2.2]oct-1-yl compounds, pharmaceutical compositions containing them and their use in the treatment of a variety of conditions mediated by the sEH enzyme and/or the 1 1 ⁇ -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 Biophys., 47, 87-98, 2007], heart failure [Xu et al., Proc. Natl Acad. Sc/._l/.S.A,103, 18733-18738, 2006], renal dysfunction / end organ damage [Zhao et al., J. Am. Soc. Nephrol., 15, 1244-1253, 2004; Imig et al., Hypertension, 46, 975-981 , 2005], stroke [Koerner et al., J.
  • 11 beta-hvdroxysteroid dehydrogenase type 1 11 beta-hydroxysteroid dehydrogenase type 1 (“11 ⁇ -HSD1") is an intracellular enzyme that converts inactive glucocorticoids (e.g. cortisone) to active glucocorticoids (e.g. Cortisol).
  • glucocorticoids activate both glucocorticoid receptors and mineralocorticoid receptors in multiple tissues they can affect endocrine, metabolic, cardiovascular, and immune function. See E.g.
  • 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 11 ⁇ -HSD2 cause a decrease in 11 ⁇ -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 bicycle[2.2.2]oct-1-yl compounds. Specifically, the invention is directed to compounds according to Formula I and pharmaceutically acceptable salts thereof:
  • the compounds of the invention are sEH and 1 1 ⁇ -HSD1 dual inhibitors and can be used in the treatment of diseases mediated by the sEH enzyme or the 1 1 ⁇ -HSD1 enzyme, such as hypertension. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting sEH or 11 ⁇ -HSD1 and treatment of conditions associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.
  • this invention provides for the use of the compounds of
  • 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 invention is directed to compounds according to Formula (I):
  • A is phenyl or pyridyl; which is unsubstituted or substituted by one, two, three, four or five Ri groups;
  • Ri is selected from the group consisting of: halo, CN, Ra, ORb, C(O)ORc, C(O)NRcRc,
  • R 2 and R 3 are independently hydrogen or C 1-3 alkyl; m is O, 1 or 2;
  • R 4 and R 5 are independently hydrogen or C 1-6 alkyl;
  • R 6 is hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl;
  • n is 1 or 2;
  • x is 0 - 5;
  • R ⁇ is phenyl unsubstituted or substituted by one to five substituents selected from the group consisting of: halo, CN, Ra, ORb, C(O)ORc, C(O)NRcRc, NRcRc, NRcC(O)Rb, NRcS(O 2 )Ra, SRb, S(O 2 )Ra, and S(O 2 )NRcRc;
  • R 8 and R 9 are hydrogen or methyl, provided only one may be methyl; each Ra is independently Ci -6 alkyl or Ci -6 haloalkyl; each Rb is independently H, Ci -6 alkyl or Ci -6 haloalkyl; and each Rc is independently H or Ci -6 alkyl; or a pharmaceutically acceptable salt thereof.
  • 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.
  • Cycloalkyl refers to a monovalent saturated or unsaturated hydrocarbon ring having the specified number of member atoms.
  • C 3-6 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 includes cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl.
  • 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.
  • 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.
  • “Pharmaceutically acceptable” refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • Substituted in reference to a group indicates that one or more hydrogen atom attached to a member atom within the group is replaced with a substituent selected from the group of defined substituents. 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. one that does not spontaneously undergo transformation such as by rearrangement, cyclization, or elimination and that is sufficiently robust to survive isolation from a reaction mixture). When it is stated that a group may contain one or more substituents, one or more (as appropriate) member atoms within the group may be substituted. In addition, a single member atom within the group 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.
  • 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.
  • 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 an acidic functional group and are therefore capable of forming pharmaceutically-acceptable base addition salts by treatment with a suitable base.
  • 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.
  • 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.
  • 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.
  • A is phenyl or pyridyl; which is unsubstituted or substituted by one, two, three, four or five R 1 groups;
  • R 1 is selected from the group consisting of: halo, CN, Ra, ORb, C(O)ORc, C(O)NRcRc, NRcRc, NRcC(O)Rb, NRcS(O 2 )Ra, SRb, S(O 2 )Ra, S(O 2 )NRcRc, piperdinyl, pyrrolidinyl, morpholinyl, and phenyl; R 2 and R 3 are independently hydrogen or C 1-3 alkyl; m is O, 1 or 2; X is
  • R 4 and R 5 are independently hydrogen or C 1-6 alkyl
  • R 6 is hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl; n is 1 or 2; x is O - 5;
  • R 7 is phenyl unsubstituted or substituted by one to three substituents selected from the group consisting of: halo, CN, Ra, ORb, C(O)ORc, C(O)NRcRc, NRcRc,
  • Re and Rg are hydrogen or methyl, provided only one may be methyl; each Ra is independently C 1-6 alkyl or C 1-6 haloalkyl; each Rb is independently H, C 1-6 alkyl or C 1-6 haloalkyl; and each Rc is independently H or C 1-6 alkyl.
  • A is phenyl which is or substituted by one or two R 1 groups;
  • R 1 is selected from the group consisting of: halo, Ra, and ORb,;
  • R 2 and R 3 are hydrogen;
  • m is O or 1 ;
  • X is
  • R 4 and R 5 are hydrogen;
  • R 6 is C 1-6 alkyl; n is 1 ;
  • R 7 is phenyl unsubstituted or substituted by one to three substituents selected from the group consisting of: halo, CN, Ra, ORb, C(O)ORc, C(O)NRcRc, NRcRc, NRcC(O)Rb, NRcS(O 2 )Ra, SRb, S(O 2 )Ra, and S(O 2 )NRcRc;
  • R 8 and R 9 are hydrogen; each Ra is independently Ci -6 alkyl or Ci -6 haloalkyl;
  • each Rb is independently H, Ci -6 alkyl or Ci -6 haloalkyl; and each Rc is independently H or Ci -6 alkyl.
  • 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 1.7).
  • Compounds such as 1.2 were prepared from a requisite amide, such as 1.1, and a tetrazole. Hydrolysis of intermediate 1.2 with an aqueous base provides intermediate 1.3. Treatment of intermediate 1.3 with an amine, a trialkylamine base and a coupling reagent such as BOP furnished the desired amide (1.4). Nitrile 1.5 was then formed by treatment of the amide 1.4 with TFAA. The nitrile was then reduced to the primary amine 1.6. Finally, ureas such as 1.7 were formed by condensing the amine 1.6 with an isocyanate.
  • Scheme 2 represents a general reaction scheme for preparing certain compounds according to Formula I (depicted as compound 2.7).
  • Compounds such as 2.2 were prepared from a requisite amide, such as 2.1, and a tetrazole. Hydrolysis of intermediate
  • intermediate 2.3 Treatment of intermediate 2.3 with an amine, a trialkylamine base and a coupling reagent such as BOP furnished the desired amide (2.4). Nitrile 2.5 was then formed by treatment of the amide 2.4 with TFAA. The nitrile was then reduced to the primary amine 2.6. Finally, ureas such as 2.7 were formed by condensing the amine 2.6 with an isocyanate, which was formed in situ from triphosgene and an appropriate amine.
  • Scheme 3 represents a general reaction scheme for preparing certain compounds according to Formula I (depicted as compound 3.7).
  • Compounds such as 3.2 were prepared from a requisite amide, such as 3.1, and a tetrazole. Reduction of methylester
  • intermediate 3.3 Treatment of intermediate 3.3 with sulfonylchloride and a trialkylamine base furnished the desired mesylate (3.4). Displacement of the mesylate with a nitrile was accomplished using sodium cyanide to provide the desired nitrile 3.5. The nitrile was then hydrolyzed to the carboxylic acid 3.6 using aqueous acid. Finally, amides such as 3.7 were formed by treatment of acid 3.6 with an amine, a trialkylamine base and a coupling reagent such as BOP.
  • Scheme 4 represents a general reaction scheme for preparing certain compounds according to Formula I (depicted as compound 4.7).
  • Compounds such as 4.2 were prepared from a requisite amide, such as 4.1, and a tetrazole. Hydrolysis of intermediate
  • intermediate 4.2 with an aqueous base provides intermediate 4.3.
  • Nitrile 4.5 was then formed by treatment of the amide 4.4 with TFAA. The nitrile was then reduced to the primary amine 4.6.
  • amides such as 4.7 were formed by treatment of amine 4.6 with a carboxylic acid, a trialkylamine base and a coupling reagent such as BOP.
  • the naming program used is ACD Name Pro 6.02.
  • BOP is an abbreviation for (Benzotriazol-i-yloxy)tris (dimethylamino)phosphonium hexafluorophosphate
  • 0 C is an abbreviation for degrees Celsius
  • HATU is an abbreviation for Dimethylsulfoxide
  • L is an abbreviation for liter or liters
  • LC-MS is an abbreviation for Liquid chromatography-Mass spectrometry
  • mmol is an abbreviation for millimole or millimolar
  • 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
  • St is an abbreviation for saturated
  • THF trifluoroacetic acid
  • THF tetrahydrofuran
  • Intermediate 1 Methyl 4- ⁇ 4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3- yl ⁇ bicyclo[2.2.2]octane-1 -carboxylate
  • Hexafluorophosphate (1.079 g, 2.440 mmol) were added and the resultant mixture was stirred for 30 minutes.
  • the reaction mixture was concentrated to 20% original volume and then partitioned between water and dichloromethane. The layers were separated and the aqueous extracted twice more. The combined organic layers were washed with 2 x water, brine and concentrated in vacuo to afford a red oil.
  • the oil was purified by 2 x 2Og SCX SPE. 4 Volumes of methanol followed by 3 volumes of 2N ammonia in methanol were collected. The ammonia fractions combined and concentrated to afford the title compound as a light orange solid. (750mg, 1.982 mmol, 97 % yield)
  • Example 6 was prepared using the general procedure similar to that described above in Example 4 substituting the appropriate phenyl isocyanate in place of 1-fluoro-4- isocyanatobenzene (Scheme 1 ).
  • Example 7 was prepared using the general procedure similar to that described above in Example 4 substituting the appropriate phenyl isocyanate in place of 1-fluoro-4- isocyanatobenzene (Scheme 1 ). (24 mg, 0.033 mmol, 8 % yield)
  • Example 9 was prepared using the general procedure similar to that described above in Example 3 substituting the appropriate phenyl isocyanate in place of isocyanatobenzene (Scheme 1 ).
  • Example 10 was prepared using the general procedure similar to that described above in
  • Example 11 was prepared using the general procedure similar to that described above in Example 3 substituting the appropriate phenyl isocyanate in place of isocyanatobenzene (Scheme 1 ). (27mg, 0.041 mmol, 19 % yield)
  • Example 12 was prepared using the general procedure similar to that described above in
  • Example 13 was prepared using the general procedure similar to that described above in Example 3 substituting the appropriate phenyl isocyanate in place of isocyanatobenzene (Scheme 1 ). (58mg, 0.085 mmol, 39 % yield)
  • Example 14 was prepared using the general procedure similar to that described above in
  • Example 15 was prepared using the general procedure similar to that described above in
  • Example 16 was prepared using the general procedure similar to that described above in Example 3 substituting the appropriate phenyl isocyanate in place of isocyanatobenzene (Scheme 1 ).
  • Example 17 was prepared using the general procedure similar to that described above in Example 3 substituting the appropriate phenyl isocyanate in place of isocyanatobenzene (Scheme 1 ).
  • Example 20 was prepared using the general procedure similar to that described above in
  • Example 22 was prepared using the general procedure similar to that described above in
  • Example 25 was prepared using the general procedure similar to that described above in
  • Example 26 was prepared using the general procedure similar to that described above in
  • Example 27 was prepared using the general procedure similar to that described above in
  • Example 28 was prepared using the general procedure similar to that described above in
  • Example 29 was prepared using the general procedure similar to that described above in
  • Example 30 was prepared using the general procedure similar to that described above in Example 23 substituting the appropriate benzylamine in place of ⁇ [2- (trifluoromethyl)phenyl]methyl ⁇ amine (Scheme 2).
  • Example 31 was prepared using the general procedure similar to that described above in
  • Example 32 was prepared using the general procedure similar to that described above in
  • Example 33 was prepared using the general procedure similar to that described above in
  • Example 34 was prepared using the general procedure similar to that described above in Example 23 substituting the appropriate benzylamine in place of ⁇ [2- (trifluoromethyl)phenyl]methyl ⁇ amine (Scheme 2). (23mg, 0.030 mmol, 1 1 % yield)
  • Example 35 was prepared using the general procedure similar to that described above in Example 23 substituting the appropriate benzylamine in place of ⁇ [2- (trifluoromethyl)phenyl]methyl ⁇ amine (Scheme 2). (37mg, 0.052 mmol, 19 % yield)
  • Example 36 was prepared using the general procedure similar to that described above in
  • Example 37 was prepared using the general procedure similar to that described above in
  • Example 38 was prepared using the general procedure similar to that described above in
  • Example 39 was prepared using the general procedure similar to that described above in
  • Example 40 was prepared using the general procedure similar to that described above in
  • Example 48 2-(4- ⁇ 4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl ⁇ bicyclo[2.2.2]oct-1 - yl)- ⁇ /-(phenylmethyl)acetamide
  • Example 48 was prepared using the general procedure similar to that described above in
  • Example 49 was prepared using the general procedure described above in Example 47 substituting the appropriate benzylamine in place of aniline (Scheme 3).
  • Example 50 was prepared using the general procedure similar to that described above in
  • Example 52 was prepared using the general procedure similar to that described above in
  • Example 54 ⁇ /-[(2-chloro-4-cyanophenyl)methyl]-2-(4- ⁇ 4-methyl-5-[2-(trifluoromethyl)phenyl]-4H- 1 ,2,4-triazol-3-yl ⁇ bicyclo[2.2.2]oct-1 -yl)acetamide
  • Example 54 was prepared using the general procedure similar to that described above in
  • Example 56 was prepared using the general procedure similar to that described above in
  • Example 62 ⁇ /-[(4- ⁇ 4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1 ,2,4-triazol-3-yl ⁇ bicyclo[2.2.2]oct-1 - yl)methyl]-W-[2-(trifluoromethyl)phenyl]urea
  • 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, 1 1 ⁇ -HSD1 and / or 11 ⁇ -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, 1 1 ⁇ -HSD1 and 1 1 ⁇ -HSD2 inhibitory activity are provided below.
  • the compounds according to Formula I are sEH inhibitors and 11 ⁇ -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 0,000 nM and an IC 50 against 1 1 ⁇ -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 IC 50 against sEH from 0.1 nM to 1 ,000 nM and an IC 50 against 1 1 ⁇ - 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 IC 50 against sEH from 0.1 nM to 100 nM and an IC 50 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 nM to 10 nM and an IC50 against 1 1 ⁇ -HSD1 from 0.1 nM to 10 nM.
  • the invention is directed to a compound according to Formula I wherein the compound exhibits a selectivity ratio (based on IC 50 ) 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 IC 50 ) 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 IC 50 ) 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 11 ⁇ -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 IC 50 ) equal to or greater than 10:1 for 11 ⁇ -HSD1 over 11 ⁇ -HSD2.
  • the invention is directed to a compound according to Formula I wherein the compound exhibits a selectivity ratio (based on IC 50 ) 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 IC 50 ) 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
  • Production of 6-methoxy-2-naphthaldehyde is monitored at excitation of 360 nm and an emission of 465 nm.
  • the assay is used in a quenched assay format by sequentially adding enzyme (5 ⁇ L; 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 ⁇ L; 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 ⁇ L; 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 ⁇ L; 10 u
  • 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 ⁇ L; 3.33 mM ZnSO4 (sEH assay) or 5OmM ZnSO4 (mEH assay) in water.
  • Stop solution 5 ⁇ L; 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.
  • 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. Cell-based sEH inhibitor assay 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:
  • sample dilution buffer ex. Add 220 ⁇ l_
  • Inhibition of 1 1 ⁇ -HSD1 activity can be measured in a scintillation proximity assay (SPA) based format described by Mundt et al. (ASSAY and Drug Development Technologies Vol. 3 No. 4 (2005) pp. 367-375).
  • the assay measures the ⁇ -NADPH dependent reductase activity of Human 1 1 ⁇ -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.
  • 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 ⁇ l_ 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 ⁇ l_.
  • the assay is incubated for 3 hours at 37 °C before quenching the reaction with 25 ⁇ l_ of 10 ⁇ M 18 ⁇ -glycyrrhetinic acid, a potent natural product inhibitor of 1 1 ⁇ -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 : where cpm, min, and max refer to counts per minute of reaction in presence of compound,
  • Example 44 All of the tested compounds, except Example 44, were found to have an IC 50 against sEH from 0.1 nM to 2,512 nM.
  • Example 44 was found to have an IC 50 greater than 3,981 nM. It is not known whether or not Example 44 would inhibit sEH activity at concentrations above 3,981 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 11 ⁇ -HSD1 inhibition offers some clinical benefit even though the underlying pathology is not (even in part) attributable to sEH and/or 11 ⁇ -HSD1 involvement.
  • Such conditions include hypertension, organ failure / damage (including heart failure, renal failure, 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.
  • sEH is indirectly involved in the regulation of platelet function through its effect on EETs. Drugs that inhibit platelet aggregation are believed to decrease the risk of atherthrombotic events, such as myocardial infarction and stroke, in patients with established cardiovascular atherosclerotic disease.
  • 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.
  • 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 ⁇ -
  • compositions 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.
  • the pharmaceutical 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.
  • 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.
  • oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets
  • parenteral administration such as sterile solutions, suspensions, and powders for reconstitution
  • transdermal administration such as transdermal patches
  • rectal administration such as suppositories
  • 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 des composés de bicycle[2.2.2]oct-1-yle, des compositions pharmaceutiques les contenant et leur utilisation pour le traitement de diverses maladies médiées par l’enzyme sEH et/ou l’enzyme 11β-HSD1.
PCT/US2009/051678 2008-07-25 2009-07-24 Inhibiteurs doubles de seh et 11β-hsd1 WO2010011917A1 (fr)

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Cited By (11)

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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
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation 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
CN104926746A (zh) * 2015-07-14 2015-09-23 佛山市赛维斯医药科技有限公司 含苯并异恶唑和末端胺基苄基类结构的化合物及其用途
CN104926743A (zh) * 2015-07-14 2015-09-23 佛山市赛维斯医药科技有限公司 含苯并异恶唑和末端苄基类结构的化合物及其用途
CN104926744A (zh) * 2015-07-14 2015-09-23 佛山市赛维斯医药科技有限公司 一类含苯并异恶唑和末端苄基类结构的化合物及其用途
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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
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
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation 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
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
CN104926746A (zh) * 2015-07-14 2015-09-23 佛山市赛维斯医药科技有限公司 含苯并异恶唑和末端胺基苄基类结构的化合物及其用途
CN104926743A (zh) * 2015-07-14 2015-09-23 佛山市赛维斯医药科技有限公司 含苯并异恶唑和末端苄基类结构的化合物及其用途
CN104926744A (zh) * 2015-07-14 2015-09-23 佛山市赛维斯医药科技有限公司 一类含苯并异恶唑和末端苄基类结构的化合物及其用途
CN104926742A (zh) * 2015-07-14 2015-09-23 佛山市赛维斯医药科技有限公司 一类含苯并异恶唑和硝基苯基类结构的化合物及其用途

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