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WO2009086429A1 - Soluble epoxide hydrolase inhibitors - Google Patents

Soluble epoxide hydrolase inhibitors Download PDF

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Publication number
WO2009086429A1
WO2009086429A1 PCT/US2008/088244 US2008088244W WO2009086429A1 WO 2009086429 A1 WO2009086429 A1 WO 2009086429A1 US 2008088244 W US2008088244 W US 2008088244W WO 2009086429 A1 WO2009086429 A1 WO 2009086429A1
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WIPO (PCT)
Prior art keywords
substituted
compound
fluoro
group
alkyl
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PCT/US2008/088244
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French (fr)
Inventor
Sampath-Kumar Anandan
Richard D. Gless, Jr.
Bhasker R. Aavula
Dinesh V. Patel
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Arete Therapeutics, Inc.
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Publication of WO2009086429A1 publication Critical patent/WO2009086429A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/26—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of rings other than six-membered aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/30—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
    • C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/18—Systems containing only non-condensed rings with a ring being at least seven-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/93—Spiro compounds
    • C07C2603/94—Spiro compounds containing "free" spiro atoms

Definitions

  • This invention relates to the field of pharmaceutical chemistry.
  • compounds that inhibit soluble epoxide hydrolase (sEH) are provided herein.
  • compounds that inhibit soluble epoxide hydrolase (sEH) are provided herein, pharmaceutical compositions containing such compounds, methods for preparing the compounds and formulations, and methods for treating patients with such compounds and compositions.
  • the compounds, compositions, and methods are useful for treating a variety of sEH mediated diseases, including hypertensive, cardiovascular, inflammatory, metabolic syndrome, and diabetic- related diseases.
  • the arachidonate cascade is a ubiquitous lipid signaling cascade in which arachidonic acid is liberated from the plasma membrane lipid reserves in response to a variety of extra-cellular and/or intra-cellular signals. The released arachidonic acid is then available to act as a substrate for a variety of oxidative enzymes that convert arachidonic acid to signaling lipids that play critical roles in, for example, inflammation, and other disease conditions. Disruption of the pathways leading to the lipids remains an important strategy for many commercial drugs used to treat a multitude of inflammatory disorders. For example, non-steroidal anti-inflammatory drugs (NSAIDs) disrupt the conversion of arachidonic acid to prostaglandins by inhibiting cyclooxygenases (COXl and COX2). New asthma drugs, such as SINGULAIRTM disrupt the conversion of arachidonic acid to leukotrienes by inhibiting lipoxygenase (LOX).
  • NSAIDs non-steroidal anti-inflammatory drugs
  • COXl and COX2 cyclo
  • cytochrome P450-dependent enzymes convert arachidonic acid into a series of epoxide derivatives known as epoxyeicosatrienoic acids (EETs). These EETs are particularly prevalent in the vascular endothelium (cells that make up arteries and vascular beds), kidney, and lung. In contrast to many of the end products of the prostaglandin and leukotriene pathways, the EETs have a variety of anti-inflammatory and anti-hypertensive properties and are known to be potent vasodilators and mediators of vascular permeability.
  • EETs epoxyeicosatrienoic acids
  • EETs While EETs have potent effects in vivo, the epoxide moiety of the EETs is rapidly hydrolyzed into the less active dihydroxyeicosatrienoic acid (DHET) form by an enzyme called soluble epoxide hydrolase (sEH). Inhibition of sEH has been found to significantly reduce blood pressure in hypertensive animals (see, e.g., Yu et al. Circ. Res. 87:992-8 (2000) and Sinai et al. J. Biol. Chem.
  • R is selected from the group consisting of cycloalkyl, substituted cycloalkyl, phenyl and substituted phenyl;
  • L is -NH- or -CR'R"- where R' and R" are independently hydrogen or alkyl or R' and R" together form a C 3 -C 6 cycloalkyl ring;
  • Z is C, O, or NR 4 where R 4 is hydrogen or C 1 -C 4 alkyl and where when Z is O or
  • X is absent;
  • the dotted line Z112 is a single bond or a double bond;
  • the wavy line is a cis or a trans configuration when the dotted line is a double bond and m and n are 1 ; when the dotted line is a single bond and Z is C, then m and n are 2;
  • p is O, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
  • q is 0 or 1; each of X and Y is independently selected from the group consisting of hydrogen,
  • R 1 is selected from the group consisting of -CH 2 OR 2 , -COR 2 , -COOR 2 , -CONR 2 R 3 ,
  • R is selected from the group consisting of cycloalkyl, substituted cycloalkyl, phenyl and substituted phenyl; p is O, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
  • R 1 is selected from the group consisting of -CH 2 OR 2 , -COR 2 , -COOR 2 , -CONR 2 R 3 , -OR 2 , and carboxylic acid isostere;
  • R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or R 2 and R 3 together with the nitrogen atom bound thereto form a heterocycloalkyl ring having 3 to 9 ring atoms, and wherein said ring is optionally substituted with alkyl, substituted alkyl, heterocyclic, oxo or carboxy; and each of X a , X b , Y a , and Y b is independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, substituted C 1 -C 4 alkyl, and halo, provided that at least one of Y a and Y b is halo or C 1 -C 4 alkyl.
  • R is selected from the group consisting of cycloalkyl, substituted cycloalkyl, phenyl and substituted phenyl; p is O, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
  • X and Y independently are selected from the group consisting of hydrogen, C 1 -C 4 alkyl, substituted C 1 -C 4 alkyl, and halo;
  • R 1 is selected from the group consisting of -CH 2 OR 2 , -COR 2 , -COOR 2 , -CONR 2 R 3 , and carboxylic acid isostere;
  • R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or R 2 and R 3 together with the nitrogen atom bound thereto form a heterocycloalkyl ring having 3 to 9 ring atoms, and wherein said ring is optionally substituted with alkyl, substituted alkyl, heterocyclic, oxo or carboxy.
  • Formula (IV) or a stereoisomer, or pharmaceutically acceptable salt thereof:
  • R is selected from the group consisting of cycloalkyl, substituted cycloalkyl, phenyl and substituted phenyl;
  • R 1 is selected from the group consisting of -CH 2 OR 2 , -COR 2 , -COOR 2 , -CONR 2 R 3 , and carboxylic acid isostere; and R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or R 2 and R 3 together with the nitrogen atom bound thereto form a heterocycloalkyl ring having 3 to 9 ring atoms, and wherein said ring is optionally substituted with alkyl, substituted alkyl, heterocyclic, oxo or carboxy; p is O, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
  • Z is O or NR 4 where R 4 is hydrogen or C 1 -C 4 alkyl
  • Y a and Y b independently are selected from the group consisting of hydrogen, halo, or C 1 -C 4 alkyl.
  • Y a and Y b independently are selected from the group consisting of hydrogen, halo, or C 1 -C 4 alkyl.
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Formula I-IV or a stereoisomer or pharmaceutically acceptable salt thereof, for treating a soluble epoxide hydrolase mediated disease.
  • a method for treating a soluble epoxide hydrolase mediated disease comprising administering to a patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Formula I-IV or a stereoisomer or pharmaceutically acceptable salt thereof.
  • EETs cis-Epoxyeicosatrienoic acids
  • EH alpha/beta hydrolase fold family that add water to 3 membered cyclic ethers termed epoxides.
  • Soluble epoxide hydrolase (“sEH”) is an enzyme which in endothelial, smooth muscle and other cell types converts EETs to dihydroxy derivatives called dihydroxyeicosatrienoic acids (“DHETs").
  • DHETs dihydroxyeicosatrienoic acids
  • the cloning and sequence of the murine sEH is set forth in Grant et al, J. Biol. Chem. 268(23):17628-17633 (1993).
  • the cloning, sequence, and accession numbers of the human sEH sequence are set forth in Beetham et al., Arch.
  • COPD Chronic Obstructive Pulmonary Disease
  • COPD is also sometimes known as “chronic obstructive airway disease”, “chronic obstructive lung disease”, and “chronic airways disease.”
  • COPD is generally defined as a disorder characterized by reduced maximal expiratory flow and slow forced emptying of the lungs. COPD is considered to encompass two related conditions, emphysema and chronic bronchitis. COPD can be diagnosed by the general practitioner using art recognized techniques, such as the patient's forced vital capacity (“FVC”), the maximum volume of air that can be forcibly expelled after a maximal inhalation. In the offices of general practitioners, the FVC is typically approximated by a 6 second maximal exhalation through a spirometer.
  • FVC forced vital capacity
  • obstructive pulmonary disease and “obstructive lung disease” refer to obstructive diseases, as opposed to restrictive diseases. These diseases particularly include COPD, bronchial asthma, and small airway disease.
  • obstructive pulmonary disease and “obstructive lung disease” refer to obstructive diseases, as opposed to restrictive diseases. These diseases particularly include COPD, bronchial asthma, and small airway disease.
  • COPD COPD
  • bronchial asthma bronchial asthma
  • small airway disease a disease of the lungs characterized by permanent destructive enlargement of the airspaces distal to the terminal bronchioles without obvious fibrosis.
  • Chronic bronchitis is a disease of the lungs characterized by chronic bronchial secretions which last for most days of a month, for three months, a year, for two years, etc..
  • Small airway disease refers to diseases where airflow obstruction is due, solely or predominantly to involvement of the small airways. These are defined as airways less than 2 mm in diameter and correspond to small cartilaginous bronchi, terminal bronchioles, and respiratory bronchioles. Small airway disease (SAD) represents luminal obstruction by inflammatory and fibrotic changes that increase airway resistance. The obstruction may be transient or permanent.
  • SAD Small airway disease
  • ILDs Interstitial lung diseases
  • interstitium As discussed on the website of the American Lung Association, the tissue between the air sacs of the lung is the interstitium, and this is the tissue affected by fibrosis in the disease. Persons with such restrictive lung disease have difficulty breathing in because of the stiffness of the lung tissue but, in contrast to persons with obstructive lung disease, have no difficulty breathing out.
  • the definition, diagnosis and treatment of interstitial lung diseases are well known in the art and discussed in detail by, for example, Reynolds, H. Y., in Harrison's Principles of Internal Medicine, supra, at pp. 1460-1466. Reynolds notes that, while ILDs have various initiating events, the immunopathological responses of lung tissue are limited and the ILDs therefore have common features. [0025] "Idiopathic pulmonary fibrosis," or "IPF,” is considered the prototype ILD.
  • BAL Bronchoalveolar lavage
  • Diabetic neuropathy refers to acute and chronic peripheral nerve dysfunction resulting from diabetes.
  • Diabetic nephropathy refers to renal diseases resulting from diabetes.
  • Alkyl refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and preferably 1 to 6 carbon atoms. Alternatively, alkyl refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 4 carbon atoms.
  • This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH 3 -), ethyl (CH 3 CH 2 -), n-propyl (CH 3 CH 2 CH 2 -), isopropyl ((CHs) 2 CH-), /i-butyl (CH 3 CH 2 CH 2 CH 2 -), isobutyl ((CH 3 ) 2 CHCH 2 -), sec-butyl ((CH 3 )(CH 3 CH 2 )CH-), f-butyl ((CHs) 3 C-), n-pentyl (CH 3 CH 2 CH 2 CH 2 CH 2 -), and neopentyl ((CH 3 ) 3 CCH 2 -).
  • linear and branched hydrocarbyl groups such as methyl (CH 3 -), ethyl (CH 3 CH 2 -), n-propyl (CH 3 CH 2 CH 2 -), isopropyl ((CHs) 2 CH-), /
  • Alkynyl refers to straight or branched monovalent hydrocarbyl groups having from 2 to 6 carbon atoms and preferably 2 to 3 carbon atoms and having at least 1 and preferably from 1 to 2 sites of acetylenic (-C ⁇ C-) unsaturation.
  • alkynyl groups include acetylenyl (-C ⁇ CH), and propargyl (-CIH ⁇ C ⁇ CH).
  • Substituted alkyl refers to an alkyl group having from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkyloxy,
  • Substituted alkenyl refers to alkenyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkyloxy,
  • Substituted alkynyl refers to alkynyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkyloxy
  • Alkoxy refers to the group -O-alkyl wherein alkyl is defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy.
  • Substituted alkoxy refers to the group -O-(substituted alkyl) wherein substituted alkyl is defined herein.
  • Acyl refers to the groups H-C(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclic-C(O)-, and substituted heterocyclic-C(O)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, substituted
  • Acylamino refers to the groups -NR 17 C(O)alkyl, -NR 17 C(O)substituted alkyl, -NR 17 C(O)cycloalkyl, -NR 17 C(O)substituted cycloalkyl, -NR 17 C(O)cycloalkenyl, -NR 17 C(O)substituted cycloalkenyl, -NR 17 C(O)alkenyl, -NR 17 C(O)alkenyl, -NR 17 C(O)substituted alkenyl, -NR 17 C(O)alkynyl, -NR 17 C(O)substituted alkynyl, -NR 17 C(O)aryl, -NR 17 C(O)substituted aryl, -NR 17 C(O)heteroaryl, -NR 17 C(O)substituted heteroaryl, -NR 17 C(O)
  • Acyloxy refers to the groups alkyl-C(O)O-, substituted alkyl-C(O)O-, alkenyl-C(O)O-, substituted alkenyl-C(O)O-, alkynyl-C(O)O-, substituted alkynyl-C(O)O-, aryl-C(O)O-, substituted aryl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, cycloalkenyl-C(O)O-, substituted cycloalkenyl-C(O)O-, heteroaryl-C(O)O-, substituted heteroaryl-C(O)O-, heterocyclic-C(O)O-, and substituted heterocyclic-C(O)O- wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkyn
  • Substituted amino refers to the group -NR 18 R 19 where R 18 and R 19 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -SO 2 -alkyl, -SO 2 -substituted alkyl, -SO 2 -alkenyl, -SO 2 -substituted alkenyl, -SO 2 -cycloalkyl, -SO 2 -substituted cycloalkyl, -SC ⁇ -cycloalkenyl, -S ⁇ 2 -substituted cycloalkenyl,-
  • R When R is hydrogen and R 19 is alkyl, the substituted amino group is sometimes referred to herein as alkylamino. When R 18 and R 19 are alkyl, the substituted amino group is sometimes referred to herein as dialkylamino.
  • R 18 and R 19 When referring to a monosubstituted amino, it is meant that either R 18 or R 19 is hydrogen but not both.
  • R 18 nor R 19 When referring to a disubstituted amino, it is meant that neither R 18 nor R 19 are hydrogen.
  • Aminocarbonyl refers to the group -C(O)NR 20 R 21 where R 20 and R 21 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 20 and R 21 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted
  • Aminothiocarbonyl refers to the group -C(S)NR 20 R 21 where R 20 and R 21 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 20 and R 21 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl
  • Aminocarbonylamino refers to the group -NR 17 C(O)NR 20 R 21 where R 17 is hydrogen or alkyl and R 20 and R 21 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 20 and R 21 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted
  • Aminothiocarbonylamino refers to the group -NR 17 C(S)NR 20 R 21 where R 17 is hydrogen or alkyl and R 20 and R 21 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 10 and R 11 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,
  • Aminocarbonyloxy refers to the group -0-C(O)NR 20 R 21 where R 20 and R 21 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 20 and R 21 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl
  • Aminosulfonyl refers to the group -SO 2 NR 20 R 21 where R 20 and R 21 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 20 and R 21 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl
  • Aminosulfonyloxy refers to the group -0-SO 2 NR 20 R 21 where R 20 and R 21 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 20 and R 21 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, substituted cycloal
  • Aminosulfonylamino refers to the group -NR 17 -SO 2 NR 20 R 21 where R 17 is hydrogen or alkyl and R 20 and R 21 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R and R are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,
  • Aryl refers to a monovalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-l,4-benzoxazin-3(4H)-one-7-yl, and the like) provided that the point of attachment is at an aromatic carbon atom.
  • Preferred aryl groups include phenyl and naphthyl.
  • Substituted aryl refers to aryl groups which are substituted with 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano,
  • Aryloxy refers to the group -O-aryl, where aryl is as defined herein, that includes, by way of example, phenoxy and naphthoxy.
  • Substituted aryloxy refers to the group -O-(substituted aryl) where substituted aryl is as defined herein.
  • Arylthio refers to the group -S-aryl, where aryl is as defined herein.
  • Substituted arylthio refers to the group -S-(substituted aryl), where substituted aryl is as defined herein.
  • Carboxy or “carboxyl” refers to -COOH or salts thereof.
  • Isosteres are different compounds that have different molecular formulae but exhibit the same or similar properties.
  • tetrazole is an isostere of carboxylic acid because it mimics the properties of carboxylic acid even though they both have very different molecular formulae. Tetrazole is one of many possible isosteric replacements for carboxylic acid.
  • carboxylic acid isosteres contemplated by the present invention include -SO 3 H, -SO 2 NHR k' , -PO 2 (R k' ) 2 , -CN, -PO 3 (R k' ) 2 , -OR k , -SR k' , -NHCOR k' , -N(R k' ) 2 , -CONH(O)R k' , -CONHNHSO 2 R k' , -COHNSO 2 R k' , -SO 2 NHCOR k' , -SO 2 NHNHCOR k' , and -CONR k CN, where R k is selected from hydrogen, hydroxyl, halo, haloalkyl, thiocarbonyl, alkoxy, alkenoxy, aryloxy, cyano, nitro, imino, alkylamino, aminoalkyl, thiol, thioal
  • carboxylic acid isosteres can include 5-7 membered carbocycles or heterocycles containing any combination of CH 2 , O, S, or N in any chemically stable oxidation state, where any of the atoms of said ring structure are optionally substituted in one or more positions.
  • the following structures are non-limiting examples of preferred carboxylic acid isosteres contemplated by this invention.
  • Carboxyl ester or “carboxy ester” refers to the groups -C(O)O-alkyl, -C(O)O-substituted alkyl, -C(O)O-alkenyl, -C(O)O-substituted alkenyl, -C(O)O-alkynyl, -C(O)O-substituted alkynyl, -C(O)O-aryl, -C(O)O-substituted aryl, -C(O)O-cycloalkyl, -C(O)O-substituted cycloalkyl, -C(O)O-cycloalkenyl, -C(O)O-substituted cycloalkenyl, -C(O)O-heteroaryl, -C(O)O-substituted heteroaryl, -C(O)O-
  • (Carboxyl ester)amino refers to the group -NR 17 -C(O)O-alkyl, -NR 17 -C(0)0- substituted alkyl, -NR 17 -C(O)O-alkenyl, -NR 17 -C(O)O-substituted alkenyl, -NR 17 -C(O)O-alkynyl, -NR 17 -C(O)O-substituted alkynyl, -NR 17 -C(O)O-aryl, -NR 17 -C(O)O-substituted aryl, -NR 17 -C(O)O-cycloalkyl, -NR 17 -C(O)O-substituted cycloalkyl, -NR 17 -C(O)O-cycloalkenyl, -NR 17 -C(O)O-substituted cycloalkenyl, -NR 17
  • R 17 is alkyl or hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
  • (Carboxyl ester)oxy refers to the group -O-C(O)O-alkyl, substituted
  • Cyano refers to the group -CN.
  • Cycloalkyl refers to cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings including fused, bridged, and spiro ring systems. One or more of the rings can be aryl, heteroaryl, or heterocyclic provided that the point of attachment is through the non-aromatic, non-heterocyclic ring carbocyclic ring.
  • suitable cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl.
  • Other examples of cycloalkyl groups include bicycle[2,2,2,]octanyl, norbornyl, and spirobicyclo groups such as spiro [4.5] dec- 8 -yl:
  • Substituted cycloalkyl and “substituted cycloalkenyl” refers to a cycloalkyl or cycloalkenyl group having from 1 to 5 or preferably 1 to 3 substituents selected from the group consisting of oxo, thione, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl, carboxy
  • Substituted cycloalkyloxy refers to -O-(substituted cycloalkyl).
  • Cycloalkylthio refers to -S-cycloalkyl.
  • Substituted cycloalkylthio refers to -S-(substituted cycloalkyl).
  • Cycloalkenyloxy refers to -O -cycloalkenyl.
  • Substituted cycloalkenyloxy refers to -O-(substituted cycloalkenyl).
  • Cycloalkenylthio refers to -S-cycloalkenyl.
  • Substituted cycloalkenylthio refers to -S-(substituted cycloalkenyl).
  • Halo or "halogen” refers to fluoro, chloro, bromo and iodo and preferably is fluoro or chloro.
  • Haloalkyl refers to alkyl groups substituted with 1 to 5, 1 to 3, or 1 to 2 halo groups, wherein alkyl and halo are as defined herein.
  • Haloalkoxy refers to alkoxy groups substituted with 1 to 5, 1 to 3, or 1 to 2 halo groups, wherein alkoxy and halo are as defined herein.
  • Haloalkylthio refers to alkylthio groups substituted with 1 to 5, 1 to 3, or 1 to 2 halo groups, wherein alkylthio and halo are as defined herein.
  • “Hydroxy” or “hydroxyl” refers to the group -OH.
  • Heteroaryl refers to an aromatic group of from 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur within the ring.
  • Such heteroaryl groups can have a single ring (e.g., pyridinyl or furyl) or multiple condensed rings (e.g. , indolizinyl or benzothienyl) wherein the condensed rings may or may not be aromatic and/or contain a heteroatom provided that the point of attachment is through an atom of the aromatic heteroaryl group.
  • the nitrogen and/or the sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N ⁇ O), sulfmyl, and/or sulfonyl moieties.
  • Preferred heteroaryls include pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl.
  • "Substituted heteroaryl" refers to heteroaryl groups that are substituted with from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of the same group of substituents defined for substituted aryl.
  • Heteroaryloxy refers to -O-heteroaryl.
  • Substituted heteroaryloxy refers to the group -O-(substituted heteroaryl).
  • Heteroarylthio refers to the group -S-heteroaryl.
  • Substituted heteroarylthio refers to the group -S-(substituted heteroaryl).
  • Heterocycle or “heterocyclic” or “heterocycloalkyl” or “heterocyclyl” refers to a saturated or partially saturated, but not aromatic, group having 3 to 16 ring atoms with from 1 to 12 ring carbon atoms and from 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen. Heterocycle encompasses single ring or multiple condensed rings, including fused bridged and spiro ring systems. In fused ring systems, one or more the rings can be cycloalkyl, aryl, or heteroaryl provided that the point of attachment is through the non-aromatic heterocyclic ring.
  • the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, sulfmyl, and/or sulfonyl moieties.
  • “Substituted heterocyclic” or “substituted heterocycloalkyl” or “substituted heterocyclyl” refers to heterocyclyl groups that are substituted with from 1 to 5 or preferably 1 to 3 of the same substituents as defined for substituted cycloalkyl.
  • Heterocyclyloxy refers to the group -O-heterocycyl.
  • Substituted heterocyclyloxy refers to the group -O-(substituted heterocycyl).
  • Heterocyclylthio refers to the group -S-heterocycyl.
  • Substituted heterocyclylthio refers to the group -S-(substituted heterocycyl).
  • heterocycle and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline,
  • Neitro refers to the group -NO 2 .
  • Spiro ring systems refers to bicyclic ring systems that have a single ring carbon atom common to both rings.
  • Sulfonyl refers to the divalent group -S(O) 2 -.
  • Substituted sulfonyl refers to the group -SO 2 -alkyl, -SO 2 -substituted alkyl, -SO 2 -alkenyl, -SO 2 -substituted alkenyl, -SO 2 -cycloalkyl, -SO 2 -substituted cycloalkyl, -SO 2 -cycloalkenyl, -SO 2 -substituted cycloalkenyl, -SO 2 -aryl, -SO 2 -substituted aryl, -SO 2 -heteroaryl, -SO 2 -substituted heteroaryl, -SO 2 -heterocyclic, -SO 2 -substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,
  • Substituted sulfonyl includes groups such as methyl-S02-, phenyl-SO 2 -, and 4-methylphenyl-SO 2 -.
  • alkylsulfonyl refers to -SO 2 -alkyl.
  • haloalkylsulfonyl refers to -SO 2 -haloalkyl where haloalkyl is defined herein.
  • (substituted sulfonyl)amino refers to -NH(substituted sulfonyl), and the term “(substituted sulfonyl)aminocarbonyl” refers to -C(O)NH(substituted sulfonyl), wherein substituted sulfonyl is as defined herein.
  • Sulfonyloxy refers to the group -OSO 2 -alkyl, -OSO 2 -substituted alkyl, -OSO 2 -alkenyl, -OSO 2 -substituted alkenyl, -OSO 2 -cycloalkyl, -OSO 2 -substituted cycloalkyl, -OSO 2 -cycloalkenyl, -OSO 2 -substituted cycloalkenyl,-OSO 2 -aryl, -OSO 2 -substituted aryl, -OSO 2 -heteroaryl, -OSO 2 -substituted heteroaryl,
  • alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
  • Thioacyl refers to the groups H-C(S)-, alkyl-C(S)-, substituted alkyl-C(S)-, alkenyl-C(S)-, substituted alkenyl-C(S)-, alkynyl-C(S)-, substituted alkynyl-C(S)-, cycloalkyl-C(S)-, substituted cycloalkyl-C(S)-, cycloalkenyl-C(S)-, substituted cycloalkenyl-C(S)-, aryl-C(S)-, substituted aryl-C(S)-, heteroaryl-C(S)-, substituted heteroaryl-C(S)-, heterocyclic-C(S)-, and substituted heterocyclic-C(S)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, substituted
  • Thiol refers to the group -SH.
  • Alkylthio refers to the group -S-alkyl wherein alkyl is as defined herein.
  • Substituted alkylthio refers to the group -S-(substituted alkyl) wherein substituted alkyl is as defined herein.
  • Compound or “compounds” as used herein is meant to include the stereoiosmers and pharmaceutically acceptable salts of the indicated formulas.
  • Steps or “stereoisomers” refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.
  • Prodrug refers to any derivative of a compound of the embodiments that is capable of directly or indirectly providing a compound of the embodiments or an active metabolite or residue thereof when administered to a subject.
  • Particularly favored derivatives and prodrugs are those that increase the bioavailability of the compounds of the embodiments when such compounds are administered to a subject (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.
  • Prodrugs include ester forms of the compounds of the invention. Examples of ester prodrugs include formate, acetate, propionate, butyrate, acrylate, and ethylsuccinate derivatives.
  • a general overview of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
  • “Patient” refers to mammals and includes humans and non-human mammals.
  • “Pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts of a compound, which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, and oxalate.
  • Treating" or “treatment” of a disease in a patient refers to (1) preventing the disease from occurring in a patient that is predisposed or does not yet display symptoms of the disease; (2) inhibiting the disease or arresting its development; or (3) ameliorating or causing regression of the disease.
  • substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment.
  • substituent “arylalkyloxycarbonyl” refers to the group (aryl)-(alkyl)-O-C(O)-.
  • impermissible substitution patterns e.g., methyl substituted with 5 fluoro groups.
  • impermissible substitution patterns are well known to the skilled artisan.
  • the present invention provides a compound of Formula (I) or a steroisomer, or pharmaceutically acceptable salt thereof:
  • R is selected from the group consisting of cycloalkyl, substituted cycloalkyl, phenyl and substituted phenyl;
  • L is -NH- or -CR'R"- where R' and R" are independently hydrogen or alkyl or R' and R" together form a C3-C6 cycloalkyl ring;
  • Z is C, O, or NR 4 where R 4 is hydrogen or C 1 -C 4 alkyl and where when Z is O or
  • X is absent; the dotted line ⁇ 111 is a single bond or a double bond; the wavy line is a cis or a trans configuration when the dotted line is a double bond and m and n are 1 ; when the dotted line is a single bond and Z is C, then m and n are 2; p is 0-10; q is 0 or 1 ; each of X and Y is independently selected from the group consisting of hydrogen,
  • R 1 is selected from the group consisting of -CH 2 OR 2 , -COR 2 , -COOR 2 , -CONR 2 R 3 ,
  • R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or R 2 and R 3 together with the nitrogen atom bound thereto form a heterocycloalkyl ring having 3 to 9 ring atoms, and wherein said ring is optionally substituted with alkyl, substituted alkyl, heterocyclic, oxo or carboxy; provided that when the dotted line z ⁇ zz is the single bond; Z is C; and q is 0, then at least one of Y is halo or C 1 -C 4 alkyl; and provided that when dotted line ⁇ 111 is the double bond, R 1 is not OH. [0117] In one preferred embodiment, when Z is C and q is
  • R 1 is selected from the group consisting of -CH 2 OR 2 , - COR 2 , -COOR 2 , -CONR 2 R 3 , and carboxylic acid isostere.
  • R is cycloalkyl or substituted cycloalkyl.
  • the substituted cycloalkyl is substituted with 1 to 3 substituents independently selected from the group consisting of halo and alkyl.
  • the substituted cycloalkyl is substituted with 1 to 3 substituents independently selected from the group consisting of fluoro and methyl.
  • R is selected from the group consisting of cyclohexyl, substituted cyclohexyl, cyclooctyl, spiro[4.5]decan-8-yl, and 4-methylbicyclo[2.2.2]octan- 1-yl.
  • the substituted cyclohexyl is substituted with 1 to 3 substituents independently selected from the group consisting of halo or alkyl.
  • the substituted cyclohexyl is substituted with 1 to 3 substituents independently selected from the group consisting of fluoro or methyl.
  • R is adamantyl. In one embodiment, R is substituted adamantyl.
  • R is phenyl. In another embodiment, R is substituted phenyl. In one embodiment, R is phenyl substituted with 1 to 5 substituents independently selected from the group consisting of hydrogen, halo, alkyl, acyl, acyloxy, carboxyl ester, acylamino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonylamino, (carboxyl ester)amino, aminosulfonyl, (substituted sulfonyl)amino, haloalkyl, haloalkoxy, haloalkylthio, cyano, and alkylsulfonyl.
  • R is phenyl substituted with 1 to 5 substituents independently selected from the group consisting of fluoro, trifluomethyl, and trifluoromethoxy.
  • R is selected from the group consisting of 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl,
  • L is -NH-.
  • L is -CR'R"- where R' and R" are independently H or alkyl or R' and R" together form a C3-C6 cycloalkyl ring. In one preferred embodiment, L is -CH 2 -.
  • p is 2, 3, 4, 5, 6, 7, or 8. In one preferred embodiment, p is 4. [0129] In one embodiment, q is 0. [0130] In one embodiment, q is 1.
  • dotted line zz ⁇ z is the single bond; Z is C; and q is 0, then at least one of Y is fluoro.
  • dotted line z ⁇ z is the single bond; Z is C; and q is 0, then X is hydrogen and at least one of Y is fluoro.
  • dotted line z ⁇ zz is the single bond; Z is C; and q is 0, then X is hydrogen and at least one of Y is alkyl, such as methyl or t-butyl.
  • R is -CH 2 OR where R is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • R 1 is -COOR 2 where R 2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • R 1 is -COR 2 where R 2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • R 1 is -CONR 2 R 3 , where R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl,
  • R 1 is -OR 2 where R 2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • R is selected from the group consisting of cycloalkyl, substituted cycloalkyl, phenyl and substituted phenyl; p is 0-10; R 1 is selected from the group consisting of -CH 2 OR 2 , -COR 2 , -COOR 2 , -CONR 2 R 3 ,
  • R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or R 2 and R 3 together with the nitrogen atom bound thereto form a heterocycloalkyl ring having 3 to 9 ring atoms, and wherein said ring is optionally substituted with alkyl, substituted alkyl, heterocyclic, oxo or carboxy; and each of X a , X b , Y a , and Y b is independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, substituted C 1 -C 4 alkyl, and halo, provided that at least one of Y a and Y b is halo or C 1 -C 4 alky
  • R is cycloalkyl or substituted cycloalkyl.
  • R is selected from the group consisting of cyclohexyl, substituted cyclohexyl, cyclooctyl, spiro[4.5]decan-8-yl, and 4-methylbicyclo[2.2.2]octan- 1-yl.
  • R is adamantyl. In one embodiment, R is substituted adamantyl.
  • R is phenyl. In another embodiment, R is substituted phenyl. In one embodiment, R is selected from the group consisting of phenyl,
  • R is phenyl substituted with 1 to 5 substituents independently selected from the group consisting of fluoro, trifluomethyl, and trifluoromethoxy.
  • X a , X b , and Y a are hydrogen and Y b is halo.
  • X a , X b , and Y a are hydrogen and Y b is fluoro.
  • X a and X b are hydrogen, Y a is halo and Y b is halo. In one preferred embodiment, Y a and Y b are fluoro. [0146] In one embodiment, X a , X b , and Y a are hydrogen and Y b is alkyl. In one embodiment, X a , X b , and Y a are hydrogen, and Y b is methyl. In one embodiment, Y b is t- butyl.
  • X a and X b are hydrogen and Y a andY b are alkyl. In one embodiment, X a and X b are hydrogen andY a and Y b are methyl. [0148] In one embodiment, Y a , Y b , and X a are hydrogen and X b is alkyl. In one embodiment, Y a , Y b , and X a are hydrogen and X b is methyl.
  • Y a and Y b are hydrogen and X a andX b are alkyl. In one embodiment,X a and X b are methyl.
  • R 1 is selected from the group consisting Of -CH 2 OR 2 , -COR 2 , -COOR 2 , -CONR 2 R 3 , and carboxylic acid isostere.
  • R is -CH 2 OR where R is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • R 1 is -CH 2 OR 2 where R 2 is selected from the group consisting of hydrogen and methyl.
  • R is -COOR where R is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • R 1 is -COOR 2 where R 2 is selected from the group consisting of hydrogen, methyl, ethyl, /-propyl, ter/-butyl, 2,2,2-trimethylethyl, and dimethylaminoethyl.
  • R 1 is -COR 2 where R 2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • R is -COR where R is selected from the group consisting of hydrogen and methyl.
  • R is -CONR R , where R and R are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or R and R together with the nitrogen atom bound thereto form a heterocycloalkyl ring having 3 to 9 ring atoms, and wherein said ring is optionally substituted with alkyl, substituted alkyl, heterocyclic, oxo or carboxy.
  • R 1 is -CONR 2 R 3 , where R 2 and R 3 independently are selected from the group consisting of hydrogen and methyl.
  • R 1 is -CH 2 OR 2 where R 2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • R is adamantyl or substituted adamantyl; p is 2, 4, or 8;
  • R 1 is selected from the group consisting of -CH 2 OR 2 , -COR 2 , -COOR 2 , -CONR 2 R 3 ,
  • R 2 and R 3 are independently selected from the group consisting of hydrogen and alkyl; and each of X a , X b , Y a , and Y b is independently selected from the group consisting of hydrogen, methyl, and halo, provided that at least one of Y a and Y b is fluoro or methyl.
  • R is phenyl or substituted phenyl; p is 2, 4, or 8;
  • R 1 is selected from the group consisting of -CH 2 OR 2 , -COR 2 , -COOR 2 , -CONR 2 R 3 , -OR 2 , and carboxylic acid isostere;
  • R 2 and R 3 are independently selected from the group consisting of hydrogen and alkyl; and each of X a , X b , Y a , and Y b is independently selected from the group consisting of hydrogen, methyl, and halo, provided that at least one of Y a and Y b is fluoro or methyl.
  • R is selected from the group consisting of cycloalkyl, substituted cycloalkyl, phenyl and substituted phenyl; p is 0-10;
  • X and Y independently are selected from the group consisting of hydrogen, C 1 -C 4 alkyl, substituted C 1 -C 4 alkyl, and halo;
  • R 1 is selected from the group consisting of -CH 2 OR 2 , -COR 2 , -COOR 2 , -CONR 2 R 3 , and carboxylic acid isostere; and R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or R 2 and R 3 together with the nitrogen atom bound thereto form a heterocycloalkyl ring having 3 to 9 ring atoms, and wherein said ring is optionally substituted with alkyl, substituted alkyl, heterocyclic, oxo or carboxy.
  • R is cycloalkyl. In one embodiment, R is substituted cycloalkyl.
  • R is selected from the group consisting of cyclohexyl, substituted cyclohexyl, cyclooctyl, spiro[4.5]decan-8-yl, and 4-methylbicyclo[2.2.2]octan- 1-yl.
  • R is adamantyl. In one embodiment, R is substituted adamantyl.
  • R is phenyl. In one embodiment, R is substituted phenyl.
  • R is selected from the group consisting of phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 3 -fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, and 4-trifluoromethoxyphenyl.
  • R is phenyl substituted with 1 to 5 substituents independently selected from the group consisting of fluoro, trifluomethyl, and trifluoromethoxy.
  • p is 3, 4, or 5. In one preferred embodiment, p is 4.
  • X is hydrogen.
  • Y is hydrogen, fluoro, or methyl.
  • R 1 is -CH 2 OR 2 where R 2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • R 1 is -CH 2 OR 2 where R 2 is selected from the group consisting of hydrogen or methyl.
  • R 1 is -COOR 2 where R 2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • R 2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • R is -COOR where R is selected from the group consisting of hydrogen, methyl, ethyl, /-propyl, ter/-butyl, 2,2,2-trimethylethyl, and dimethylaminoethyl.
  • R is -COR where R is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • R 1 is -COR 2 where R 2 is selected from the group consisting of hydrogen and methyl.
  • R is -CONR R , where R and R are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or R and R together with the nitrogen atom bound thereto form a heterocycloalkyl ring having 3 to 9 ring atoms, and wherein said ring is optionally substituted with alkyl, substituted alkyl, heterocyclic, oxo or carboxy.
  • R 1 is -CONR 2 R 3 , where R 2 and R 3 are independently selected from the group consisting of hydrogen and methyl.
  • R is adamantyl or substituted adamantyl; p is 4;
  • X is hydrogen
  • Y is hydrogen, halo, or methyl
  • R 1 is selected from the group consisting of -CH 2 OR 2 , -COR 2 , -COOR 2 , -CONR 2 R 3 , and carboxylic acid isostere; and R 2 and R 3 are independently selected from the group consisting of hydrogen and alkyl.
  • R is phenyl or substituted phenyl; p is 4; X is hydrogen;
  • Y is hydrogen, halo, or methyl
  • R 1 is selected from the group consisting of -CH 2 OR 2 , -COR 2 , -COOR 2 , -CONR 2 R 3 , or carboxylic acid isostere; and R 2 and R 3 are independently selected from the group consisting of hydrogen and alkyl.
  • R is selected from the group consisting of cycloalkyl, substituted cycloalkyl, phenyl and substituted phenyl;
  • R 1 is selected from the group consisting of -CH 2 OR 2 , -COR 2 , -COOR 2 , -CONR 2 R 3 , and carboxylic acid isostere;
  • R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or R 2 and R 3 together with the nitrogen atom bound thereto form a heterocycloalkyl ring having 3 to 9 ring atoms, and wherein said ring is optionally substituted with alkyl, substituted alkyl, heterocyclic, oxo or carboxy; p is 0-10;
  • Z is O or NR 4 where R 4 is hydrogen or C 1 -C 4 alkyl
  • Y a and Y b independently are selected from the group consisting of hydrogen, halo, or C 1 -C 4 alkyl.
  • R is cycloalkyl. In one embodiment, R is substituted cycloalkyl. [0177] In one embodiment, R is adamantyl. In one embodiment, R is substituted adamantyl.
  • R is phenyl. In one embodiment, R is substituted phenyl.
  • R is phenyl substituted with 1 to 5 substituents independently selected from the group consisting of fluoro, trifluomethyl, and trifluoromethoxy.
  • R is selected from the group consisting of phenyl, 4- fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 3 -fluorophenyl, 3-chlorophenyl, 3- bromophenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, and 4-trifluoromethoxyphenyl.
  • /? is 4, 6, or 8.
  • p is 4.
  • Z is O.
  • Z is NCH 3 .
  • Y a and Y b independently are fluoro.
  • Y a and Y b independently are hydrogen or methyl. In one preferred embodiment, both Y a and Y b are hydrogen,
  • R is -CH 2 OR where R is selected from the group consisting of hydrogen or methyl.
  • R is -COOR where R is selected from the group consisting of hydrogen, methyl, ethyl, /-propyl, tert-butyi, 2,2,2-trimethylethyl, and dimethylamino ethyl .
  • R 1 is -CONR 2 R 3 , where R 2 and R 3 independently are selected from the group consisting of hydrogen or methyl.
  • R 1 is -COR 2 where R 2 is selected from the group consisting of hydrogen and methyl.
  • R is phenyl or substituted phenyl;
  • R 1 is selected from the group consisting of -CH 2 OR 2 , -COR 2 , -COOR 2 , -CONR 2 R 3 , and carboxylic acid isostere; and
  • R 2 and R 3 are independently selected from the group consisting of hydrogen and alkyl; p is 4 or 8;
  • Z is O, NH, or NCH 3 ;
  • Y a and Y b independently are selected from the group consisting of hydrogen or fluoro.
  • R is adamantyl or substituted adamantyl
  • R 1 is selected from the group consisting of -CH 2 OR 2 , -COR 2 , -COOR 2 , -CONR 2 R 3 , and carboxylic acid isostere;
  • R 2 and R 3 are independently selected from the group consisting of hydrogen and alkyl; p is 4 or 8;
  • the invention provides a prodrug of the compounds of formula I, II, III, or IV.
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of any one of Formula (I), (II), (Ilia), (HIb), or (IV) or of Tables 1, 2, or 3 or a stereoisomer or pharmaceutically acceptable salt thereof, for treating a soluble expoxide hydrolase mediated disease.
  • a method for inhibiting a soluble epoxide hydrolase comprising contacting the soluble epoxide hydrolase with an effective amount of a compound of the invention or a stereoisomer or pharmaceutically acceptable salt thereof.
  • a method for treating a soluble expoxide hydrolase mediated disease comprising administering to a patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of any one of Formula (I), (II), (Ilia), (HIb), or (IV) or of Tables 1, 2, or 3 or a stereoisomer or pharmaceutically acceptable salt thereof.
  • inhibitors of soluble epoxide hydrolase can reduce hypertension (see, e.g., U.S. Pat. No. 6,531,506).
  • Such inhibitors can be useful in controlling the blood pressure of persons with undesirably high blood pressure, including those who suffer from diabetes.
  • compounds of the invention are administered to a subject in need of treatment for hypertension, specifically renal, hepatic, or pulmonary hypertension; inflammation, specifically renal inflammation, hepatic inflammation, vascular inflammation, and lung inflammation; adult respiratory distress syndrome; diabetic complications; end stage renal disease; Raynaud syndrome; and arthritis.
  • ARDS adult respiratory distress syndrome
  • ARDS is a pulmonary disease that has a mortality rate of 50% and results from lung lesions that are caused by a variety of conditions found in trauma patients and in severe burn victims.
  • ARDS which is defined in part by the development of alveolar edema, represents a clinical manifestation of pulmonary disease resulting from both direct and indirect lung injury. While previous studies have detailed a seemingly unrelated variety of causative agents, the initial events underlying the pathophysiology of ARDS are not well understood. ARDS was originally viewed as a single organ failure, but is now considered a component of the multisystem organ failure syndrome (MOFS).
  • MOFS multisystem organ failure syndrome
  • SIRS systematic inflammatory response syndrome
  • ARDS The ARDS ailments are seen in a variety of patients with severe burns or sepsis. Sepsis in turn is one of the SIRS symptoms. In ARDS, there is an acute inflammatory reaction with high numbers of neutrophils that migrate into the interstitium and alveoli. If this progresses there is increased inflammation, edema, cell proliferation, and the end result is impaired ability to extract oxygen. ARDS is thus a common complication in a wide variety of diseases and trauma. The only treatment is supportive. There are an estimated 150,000 cases per year and mortality ranges from 10% to 90%.
  • the leukotoxin diol produced by the action of the soluble epoxide hydrolase appears to be a specific inducer of the mitochondrial inner membrane permeability transition (MPT).
  • MPT mitochondrial inner membrane permeability transition
  • ARDS ARDS
  • SIRS SIRS
  • the compounds of the invention can reduce damage to the kidney, and especially damage to kidneys from diabetes, as measured by albuminuria.
  • the compounds of the invention can reduce kidney deterioration (nephropathy) from diabetes even in individuals who do not have high blood pressure.
  • the conditions of therapeutic administration are as described above.
  • EETs cis-Epoxyeicosantrienoic acids
  • EETs can be used in conjunction with the compounds of the invention to further reduce kidney damage.
  • EETs which are epoxides of arachidonic acid, are known to be effectors of blood pressure, regulators of inflammation, and modulators of vascular permeability. Hydrolysis of the epoxides by sEH diminishes this activity. Inhibition of sEH raises the level of EETs since the rate at which the EETs are hydrolyzed into DHETs is reduced.
  • raising the level of EETs interferes with damage to kidney cells by the microvasculature changes and other pathologic effects of diabetic hyperglycemia. Therefore, raising the EET level in the kidney is believed to protect the kidney from progression from microalbuminuria to end stage renal disease.
  • EETs are well known in the art. EETs useful in the methods of the present invention include 14,15-EET, 8,9-EET and 11,12-EET, and 5,6 EETs, in that order of preference. Preferably, the EETs are administered as the methyl ester, which is more stable.
  • the EETs are regioisomers, such as 8S,9R- and 14R,15S-EET. 8,9-EET, 11,12-EET, and 14R,15S-EET, are commercially available from, for example, Sigma- Aldrich (catalog nos. E5516, E5641, and E5766, respectively, Sigma-Aldrich Corp., St. Louis, Mo).
  • EETs produced by the endothelium have anti-hypertensive properties and the EETs 11,12-EET and 14,15-EET may be endothelium-derived hyperpolarizing factors (EDHFs). Additionally, EETs such as 11,12-EET have pro fibrinolytic effects, anti-inflammatory actions and inhibit smooth muscle cell proliferation and migration. In the context of the present invention, these favorable properties are believed to protect the vasculature and organs during renal and cardiovascular disease states.
  • Inhibition of sEH activity can be effected by increasing the levels of EETs. This permits EETs to be used in conjunction with one or more sEH inhibitors to reduce nephropathy in the methods of the invention. It further permits EETs to be used in conjunction with one or more sEH inhibitors to reduce hypertension, or inflammation, or both.
  • medicaments of EETs can be made which can be administered in conjunction with one or more sEH inhibitors, or a medicament containing one or more sEH inhibitors can optionally contain one or more EETs.
  • the EETs can be administered concurrently with the sEH inhibitor, or following administration of the sEH inhibitor. It is understood that, like all drugs, inhibitors have half lives defined by the rate at which they are metabolized by or excreted from the body, and that the inhibitor will have a period following administration during which it will be present in amounts sufficient to be effective. IfEETs are administered after the inhibitor is administered, therefore, it is desirable that the EETs be administered during the period in which the inhibitor will be present in amounts to be effective to delay hydrolysis of the EETs. Typically, the EET or EETs will be administered within 48 hours of administering an sEH inhibitor.
  • the EET or EETs are administered within 24 hours of the inhibitor, and even more preferably within 12 hours. In increasing order of desirability, the EET or EETs are administered within 10, 8, 6, 4, 2, hours, 1 hour, or one half hour after administration of the inhibitor. Most preferably, the EET or EETs are administered concurrently with the inhibitor.
  • the EETs, the compound of the invention, or both are provided in a material that permits them to be released over time to provide a longer duration of action.
  • Slow release coatings are well known in the pharmaceutical art; the choice of the particular slow release coating is not critical to the practice of the present invention.
  • EETs are subject to degradation under acidic conditions. Thus, if the EETs are to be administered orally, it is desirable that they are protected from degradation in the stomach.
  • EETs for oral administration may be coated to permit them to passage through the acidic environment of the stomach into the basic environment of the intestines.
  • Such coatings are well known in the art. For example, aspirin coated with so-called “enteric coatings” is widely available commercially. Such enteric coatings may be used to protect EETs during passage through the stomach.
  • An exemplary coating is set forth in the Examples .
  • the present invention can be used with regard to any and all forms of diabetes to the extent that they are associated with progressive damage to the kidney or kidney function.
  • the chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels.
  • the long-term complications of diabetes include retinopathy with potential loss of vision; nephropathy leading to renal failure; peripheral neuropathy with risk of foot ulcers, amputation, and Charcot joints.
  • the person has metabolic syndrome and blood pressure below 130/85.
  • Dyslipidemia or disorders of lipid metabolism is another risk factor for heart disease. Such disorders include an increased level of LDL cholesterol, a reduced level of HDL cholesterol, and an increased level of triglycerides.
  • An increased level of serum cholesterol, and especially of LDL cholesterol, is associated with an increased risk of heart disease.
  • the kidneys are also damaged by such high levels. It is believed that high levels of triglycerides are associated with kidney damage. In particular, levels of cholesterol over 200 mg/dL, and especially levels over 225 mg/dL, would suggest that sEH inhibitors and, optionally, EETs, should be administered.
  • triglyceride levels of more than 215 mg/dL, and especially of 250 mg/dL or higher, would indicate that administration of sEH inhibitors and, optionally, of EETs, would be desirable.
  • the administration of compounds of the present invention with or without the EETs can reduce the need to administer statin drugs (HMG-COA reductase inhibitors) to the patients, or reduce the amount of the statins needed.
  • candidates for the methods, uses, and compositions of the invention have triglyceride levels over 215 mg/dL and blood pressure below 130/85. In some embodiments, the candidates have triglyceride levels over 250 mg/dL and blood pressure below 130/85. In some embodiments, candidates for the methods, uses and compositions of the invention have cholesterol levels over 200 mg/dL and blood pressure below 130/85. In some embodiments, the candidates have cholesterol levels over 225 mg/dL and blood pressure below 130/85.
  • VSM vascular smooth muscle
  • compounds of Formula (I), (II), (Ilia), (HIb), or (IV) or of Tables 1, 2, or 3 inhibit proliferation of vascular smooth muscle (VSM) cells without significant cell toxicity, (e.g. specific to VSM cells). Because VSM cell proliferation is an integral process in the pathophysiology of atherosclerosis, these compounds are suitable for slowing or inhibiting atherosclerosis. These compounds are useful to subjects at risk for atherosclerosis, such as individuals who have diabetes and those who have had a heart attack or a test result showing decreased blood circulation to the heart. The conditions of therapeutic administration are as described above.
  • the methods of the invention are particularly useful for patients who have had percutaneous intervention, such as angioplasty to reopen a narrowed artery, to reduce or to slow the narrowing of the reopened passage by restenosis.
  • the artery is a coronary artery.
  • the compounds of the invention can be placed on stents in polymeric coatings to provide a controlled localized release to reduce restenosis.
  • Polymer compositions for implantable medical devices, such as stents, and methods for embedding agents in the polymer for controlled release are known in the art and taught, for example, in U.S. Pat. Nos.
  • the coating releases the inhibitor over a period of time, preferably over a period of days, weeks, or months.
  • the particular polymer or other coating chosen is not a critical part of the present invention.
  • the methods of the invention are useful for slowing or inhibiting the stenosis or restenosis of natural and synthetic vascular grafts.
  • the synthetic vascular graft comprises a material which releases a compound of the invention over time to slow or inhibit VSM proliferation and the consequent stenosis of the graft.
  • Hemodialysis grafts are a particularly preferred embodiment.
  • the methods of the invention can be used to slow or to inhibit stenosis or restenosis of blood vessels of persons who have had a heart attack, or whose test results indicate that they are at risk of a heart attack.
  • Removal of a clot such as by angioplasty or treatment with tissue plasminogen activator (tPA) can also lead to reperfusion injury, in which the resupply of blood and oxygen to hypoxic cells causes oxidative damage and triggers inflammatory events.
  • tPA tissue plasminogen activator
  • the compounds and compositions are administered prior to or following angioplasty or administration of tPA.
  • compounds of the invention are administered to reduce proliferation of VSM cells in persons who do not have hypertension.
  • compounds of the invention are used to reduce proliferation of VSM cells in persons who are being treated for hypertension, but with an agent that is not an sEH inhibitor.
  • the compounds of the invention can be used to interfere with the proliferation of cells which exhibit inappropriate cell cycle regulation.
  • the cells are cells of a cancer.
  • the proliferation of such cells can be slowed or inhibited by contacting the cells with a compound of the invention.
  • the determination of whether a particular compound of the invention can slow or inhibit the proliferation of cells of any particular type of cancer can be determined using assays routine in the art.
  • the levels of EETs can be raised by adding EETs.
  • VSM cells contacted with both an EET and a compound of the invention exhibited slower proliferation than cells exposed to either the EET alone or to the compound of the invention alone.
  • the slowing or inhibition of VSM cells of a compound of the invention can be enhanced by adding an EET along with a compound of the invention.
  • this can conveniently be accomplished by embedding the EET in a coating along with a compound of the invention so that both are released once the stent or graft is in position.
  • Chronic obstructive pulmonary disease encompasses two conditions, emphysema and chronic bronchitis, which relate to damage caused to the lung by air pollution, chronic exposure to chemicals, and tobacco smoke.
  • Emphysema as a disease relates to damage to the alveoli of the lung, which results in loss of the separation between alveoli and a consequent reduction in the overall surface area available for gas exchange.
  • Chronic bronchitis relates to irritation of the bronchioles, resulting in excess production of mucin, and the consequent blocking by mucin of the airways leading to the alveoli. While persons with emphysema do not necessarily have chronic bronchitis or vice versa, it is common for persons with one of the conditions to also have the other, as well as other lung disorders.
  • sEH soluble epoxide hydrolase
  • EETs can be used in conjunction with sEH inhibitors to reduce damage to the lungs by tobacco smoke or, by extension, by occupational or environmental irritants. These findings indicate that the co-administration of sEH inhibitors and of EETs can be used to inhibit or slow the development or progression of COPD, emphysema, chronic bronchitis, or other chronic obstructive lung diseases which cause irritation to the lungs.
  • the invention In addition to inhibiting or reducing the progression of chronic obstructive airway conditions, the invention also provides new ways of reducing the severity or progression of chronic restrictive airway diseases. While obstructive airway diseases tend to result from the destruction of the lung parenchyma, and especially of the alveoli, restrictive diseases tend to arise from the deposition of excess collagen in the parenchyma. These restrictive diseases are commonly referred to as "interstitial lung diseases", or "ILDs", and include conditions such as idiopathic pulmonary fibrosis. The methods, compositions, and uses of the invention are useful for reducing the severity or progression of ILDs, such as idiopathic pulmonary fibrosis.
  • ILDs interstitial lung diseases
  • Macrophages play a significant role in stimulating interstitial cells, particularly fibroblasts, to lay down collagen. Without wishing to be bound by theory, it is believed that neutrophils are involved in activating macrophages, and that the reduction of neutrophil levels found in the studies reported herein demonstrate that the methods and uses of the invention will also be applicable to reducing the severity and progression of ILDs.
  • the ILD is idiopathic pulmonary fibrosis.
  • the ILD is one associated with an occupational or environmental exposure.
  • exemplary ILDs are asbestosis, silicosis, coal worker's pneumoconiosis, and berylliosis.
  • the ILD is sarcoidosis of the lungs. ILDs can also result from radiation in medical treatment, particularly for breast cancer, and from connective tissue or collagen diseases such as rheumatoid arthritis and systemic sclerosis.
  • the invention is used to reduce the severity or progression of asthma. Asthma typically results in mucin hypersecretion, resulting in partial airway obstruction. Additionally, irritation of the airway results in the release of mediators which result in airway obstruction. While the lymphocytes and other immunomodulatory cells recruited to the lungs in asthma may differ from those recruited as a result of COPD or an ILD, it is expected that the invention will reduce the influx of immunomodulatory cells, such as neutrophils and eosinophils, and ameliorate the extent of obstruction.
  • immunomodulatory cells such as neutrophils and eosinophils
  • sEH inhibitors and the administration of sEH inhibitors in combination with EETs, will be useful in reducing airway obstruction due to asthma.
  • sEH inhibitors In each of these diseases and conditions, it is believed that at least some of the damage to the lungs is due to agents released by neutrophils which infiltrate into the lungs. The presence of neutrophils in the airways is thus indicative of continuing damage from the disease or condition, while a reduction in the number of neutrophils is indicative of reduced damage or disease progression.
  • a reduction in the number of neutrophils in the airways in the presence of an agent is a marker that the agent is reducing damage due to the disease or condition, and is slowing the further development of the disease or condition.
  • the number of neutrophils present in the lungs can be determined by, for example, bronchoalveolar lavage.
  • the invention provides a method for enhancing smooth muscle function by administering to the subject predisposed to a disorder, disease or condition associated therewith an effective amount of a sEH inhibitor of this invention.
  • This aspect of the method is unrelated to hypertension.
  • the method enhances the smooth muscle relaxation of non- vascular smooth muscle.
  • This non- vascular smooth muscle in some aspects comprises the male or female reproductive tract, bladder or gastrointestinal tract of said subject.
  • Impairments in smooth muscle relaxation are associated with several disorders including, but not limited to, erectile dysfunction, overactive bladder, uterine contractions and irritable bowel syndrome.
  • Smooth muscles can be divided into “multi-unit” and “visceral” types or into
  • vascular smooth muscle may contract phasically with rapid contraction and relaxation, or tonically with slow and sustained contraction.
  • the reproductive, digestive, respiratory, and urinary tracts, skin, eye, and vasculature all contain this tonic muscle type.
  • contractile and relaxation function of vascular smooth muscle is critical to regulating the lumenal diameter of the small arteries-arterioles called resistance vessels.
  • the resistance arteries contribute significantly to setting the level of blood pressure.
  • Smooth muscle contracts slowly and may maintain the contraction for prolonged periods in blood vessels, bronchioles, and some sphincters.
  • nonvascular smooth muscle contracts in a rhythmic peristaltic fashion, rhythmically forcing foodstuffs through the digestive tract as the result of phasic contraction.
  • a smooth muscle disorder is characterized by an otherwise healthy smooth muscle which over or under responds to stimuli.
  • Said stimuli are capable of inducing smooth muscle contraction or relaxation as described above.
  • Said stimuli includes, but are not limited to, direct stimulation by the autonomic nervous system, chemical, biological or physical stimulation by neighbouring cells and hormones within the medium that surround the muscle.
  • Erectile dysfunction or male impotence is characterized by the regular or repeated inability to obtain or maintain an erection.
  • erectile dysfunction is analyzed including, but not limited to: a) obtaining full erections at some times, such as when asleep, when the mind and psychological issues if any are less present, tends to suggest the physical structures are functionally working; b) obtaining erections which are either not rigid or full (lazy erection), or are lost more rapidly than would be expected (often before or during penetration), can be a sign of a failure of the mechanism which keeps blood held in the penis, and may signify an underlying clinical condition; and c) other factors leading to erectile dysfunction are diabetes mellitus (causing neuropathy) or hypogonadism (decreased testosterone levels due to disease affecting the testicles or the pituitary gland).
  • Diseases associated with ED include, but are not limited to; vascular diseases such as atherosclerosis, peripheral vascular disease, myocardial infarction, arterial hypertension, vascular diseases resulting from radiaon therapy or prostate cancer treatment, blood vessel and nerve trauma; systemic diseases such as diabetes mellitus, scleroderma, renal failure, liver cirrhosis, idiopathic hemochromatosis, cancer treatment, dyslipidemia and hypertension; neurogenic diseases such as, epilepsy, stroke, multiple sclerosis, Guillain- Barre syndrome, Alzheimers disease and trauma; respiratory dieases such as, chronic obstructive pulmonary diease and sleep apnea; hematologic diseases such as sickle cell anemia and leukemias; endocrine conditions such as, hyperthyroidism, hypothyroidism, hypogonadism and diabetes; penile conditions such as, peyronie disease, epispadias and priapism; and psychiatric conditions such
  • Additional states which are associated with ED include nutritional states such as, malnutrition and zinc deficiency; surgical procedures such as, procedures on the brain and spinal cord, retroperitoneal or pelvic lymph node dissection, aortioliac or aorto femoral bypass, abdominal perineal resection, surical removal of the prostate, proctocolectomy, transurethral resection of the prostate, and cryosergery of the prostate; and treat with medication such as, antidepressants, antipsychotics, antihypertensives, antiulcer agents, 5-alpha reductase inhibitors and cholesterol-lowering agents.
  • nutritional states such as, malnutrition and zinc deficiency
  • surgical procedures such as, procedures on the brain and spinal cord, retroperitoneal or pelvic lymph node dissection, aortioliac or aorto femoral bypass, abdominal perineal resection, surical removal of the prostate, proctocolectomy, transurethral resection of the prostate, and cry
  • Overactive bladder is defined by the International Continence Society as a uro logical condition defined by a set of symptoms: urgency, with and without urge incontinence, usually with frequency and nocturia.
  • urgency with and without urge incontinence, usually with frequency and nocturia.
  • nocturia The etiology of OAB is still unclear, however it is often associated with detrusuor overactivity, a pattern of bladder muscle contraction observed during urodynamic.
  • IBS Irritable bowel syndrome
  • spastic colon is a functional bowel disorder characterized by abdominal pair and altered bowel habits in the absence of specific and unique organic pathology.
  • IBS is a clinically defined disease, wherein one set of criteria is that the subject must have recurrent abdominal pain or discomfort at least 3 days per month during the previous 3 months that is associated with 2 or more of the following: relieved by defecation, onset associated with a change in stool frequency and onset associated with a change in stool form or appearance. Additional symptoms included altered stool frequency, altered stool form, altered stool passage (straining and/or urgency), mucorrhea and abdominal bloating or subjective distention.
  • Uterine Contraction is the tightening and shortening of the smooth muscles comprising the uterus. Irregular contractions, increased frequency or increased contraction strength of the uterus can be associated with the pre-menstral syndrome (PMS) or during premature or normal labor delivery of a fetus.
  • PMS pre-menstral syndrome
  • the invention provides a method for treating a smooth muscle disorder in a subject, wherein the smooth muscle disorder is characteriaed by an otherwise healthy smooth muscle which over or under responds to stimuli by administering to the subject an effective amount of a sEH inhibitor.
  • the subject is suffering from a smooth muscle disorder selected from, but not limited to, erectile dysfunction, overactive bladder, uterine contractions, irritiable bowel syndrome, non- inflammatory irritable bowel syndrome, migraine, general gastrointestinal tract motility.
  • a subject is unable to be treated with an effective amount of a phosphodiesterase type 5 inhibitor.
  • phosphodiesterase type 5 inhibitors include, but are not limited to, sildenafil, tadalafil, vardenafil, udenaf ⁇ l and avanafil.
  • the subject of the above embodiments are unable to be treated with a phosphodiesterase type 5 inhibitor due to a preexisting diease, disorder or condition including, but not limited to, congestive heart failure, heart disease, stroke, hypotention, diabetes or any combination thereof.
  • a subject is unable to be treated with an effective amount of an anticholinergic.
  • anticholinergics include, but are not limited to, dicycloverine, tolterodine, oxybutynin, trospium and solifenacin.
  • Inhibitors of soluble epoxide hydrolase (“sEH”) and EETs administered in conjunction with inhibitors of sEH have been shown to reduce brain damage from strokes. Based on these results, we expect that inhibitors of sEH taken prior to an ischemic stroke will reduce the area of brain damage and will likely reduce the consequent degree of impairment. The reduced area of damage should also be associated with a faster recovery from the effects of the stroke.
  • Hemorrhagic stroke differs from ischemic stroke in that the damage is largely due to compression of tissue as blood builds up in the confined space within the skull after a blood vessel ruptures, whereas in ischemic stroke, the damage is largely due to loss of oxygen supply to tissues downstream of the blockage of a blood vessel by a clot.
  • Ischemic strokes are divided into thrombotic strokes, in which a clot blocks a blood vessel in the brain, and embolic strokes, in which a clot formed elsewhere in the body is carried through the blood stream and blocks a vessel there.
  • embolic strokes in which a clot formed elsewhere in the body is carried through the blood stream and blocks a vessel there.
  • the damage is due to the death of brain cells. Based on the results observed in our studies, we would expect at least some reduction in brain damage in all types of stroke and in all subtypes.
  • sEH inhibitors administered to persons with any one or more of the following conditions or risk factors high blood pressure, tobacco use, diabetes, carotid artery disease, peripheral artery disease, atrial fibrillation, transient ischemic attacks (TIAs), blood disorders such as high red blood cell counts and sickle cell disease, high blood cholesterol, obesity, alcohol use of more than one drink a day for women or two drinks a day for men, use of cocaine, a family history of stroke, a previous stroke or heart attack, or being elderly, will reduce the area of brain damaged by a stroke. With respect to being elderly, the risk of stroke increases for every 10 years.
  • sEH inhibitors As an individual reaches 60, 70, or 80, administration of sEH inhibitors has an increasingly larger potential benefit. As noted in the next section, the administration of EETs in combination with one or more sEH inhibitors can be beneficial in further reducing the brain damage.
  • the sEH inhibitors and, optionally, EETs are administered to persons who use tobacco, have carotid artery disease, have peripheral artery disease, have atrial fibrillation, have had one or more transient ischemic attacks (TIAs), have a blood disorder such as a high red blood cell count or sickle cell disease, have high blood cholesterol, are obese, use alcohol in excess of one drink a day if a woman or two drinks a day if a man, use cocaine, have a family history of stroke, have had a previous stroke or heart attack and do not have high blood pressure or diabetes, or are 60, 70, or 80 years of age or more and do not have hypertension or diabetes.
  • TAAs transient ischemic attacks
  • Clot dissolving agents such as tissue plasminogen activator (tPA) have been shown to reduce the extent of damage from ischemic strokes if administered in the hours shortly after a stroke.
  • tPA tissue plasminogen activator
  • tPA is approved by the FDA for use in the first three hours after a stroke.
  • sEH inhibitors optionally with EETs
  • administration of sEH inhibitors, optionally with EETs can also reduce brain damage if administered within 6 hours after a stroke has occurred, more preferably within 5, 4, 3, or 2 hours after a stroke has occurred, with each successive shorter interval being more preferable.
  • the inhibitor or inhibitors are administered 2 hours or less or even 1 hour or less after the stroke, to maximize the reduction in brain damage.
  • Persons of skill are well aware of how to make a diagnosis of whether or not a patient has had a stroke. Such determinations are typically made in hospital emergency rooms, following standard differential diagnosis protocols and imaging procedures.
  • the sEH inhibitors and, optionally, EETs are administered to persons who have had a stroke within the last 6 hours who: use tobacco, have carotid artery disease, have peripheral artery disease, have atrial fibrillation, have had one or more transient ischemic attacks (TIAs), have a blood disorder such as a high red blood cell count or sickle cell disease, have high blood cholesterol, are obese, use alcohol in excess of one drink a day if a woman or two drinks a day if a man, use cocaine, have a family history of stroke, have had a previous stroke or heart attack and do not have high blood pressure or diabetes, or are 60, 70, or 80 years of age or more and do not have hypertension or diabetes.
  • TAAs transient ischemic attacks
  • Inhibitors of soluble epoxide hydrolase (“sEH”) and EETs administered in conjunction with inhibitors of sEH have been shown to treat one or more conditions associated with metabolic syndrome as provided for in U.S. Provisional Application Serial No. 60/887,124, U.S. Patent Application Publication US2008/0221105, and U.S. Patent Application Serial No. 12/264,816, all of which are incorporated herein by reference in their entirety.
  • Metabolic syndrome is characterized by a group of metabolic risk factors present in one person.
  • the metabolic risk factors include central obesity (excessive fat tissue in and around the abdomen), atherogenic dyslipidemia (blood fat disorders — mainly high triglycerides and low HDL cholesterol), insulin resistance or glucose intolerance or impaired glucose tolerance, prothrombotic state (e.g., high fibrinogen or plasminogen activator inhibitor in the blood), and high blood pressure (130/85 mmHg or higher).
  • Metabolic syndrome in general, can be diagnosed based on the presence of three or more of the following clinical manifestations in one subject: a) Abdominal obesity characterized by a elevated waist circumference equal to or greater than 40 inches (102 cm) in men and equal to or greater than 35 inches (88 cm) in women; b) Elevated triglycerides equal to or greater than 150 mg/dL; c) Reduced levels of high-density lipoproteins of less than 40 mg/dL in women and less than 50 mg/dL in men; d) High blood pressure equal to or greater than 130/85 mm Hg; and e) Elevated fasting glucose equal to or greater than 100 mg/dL.
  • Another risk factor includes reduced ratios of high-density lipoprotein (HDL) to low-density lipoprotein (LDL) of less than 0.4, or alternatively less than 0.3, or alternatively less than 0.2, or alternatively less than 0.1, or alternatively less than 0.4 but equal to or greater than 0.3, or alternatively less than 0.3 but equal to or greater than 0.2 or alternatively less than 0.2 but equal to or greater than 0.1.
  • HDL high-density lipoprotein
  • LDL low-density lipoprotein
  • metabolic syndrome refers to early intervention in subjects predisposed to, but not yet manifesting, metabolic syndrome. These subjects may have a genetic disposition associated with metabolic syndrome and/or they may have certain external acquired factors associated with metabolic syndrome, such as excess body fat, poor diet, and physical inactivity. Additionally, these subjects may exhibit one or more of the conditions associated with metabolic syndrome. These conditions can be in their incipient form.
  • the invention provides a method for inhibiting the onset of metabolic syndrome by administering to the subject predisposed thereto an effective amount of a sEH inhibitor.
  • Another aspect provides a method for treating one or more conditions associated with metabolic syndrome in a subject where the conditions are selected from incipient diabetes, obesity, glucose intolerance, high blood pressure, elevated serum cholesterol, and elevated triglycerides.
  • This method comprises administering to the subject an amount of an sEH inhibitor effective to treat the condition or conditions manifested in the subject.
  • two or more of the noted conditions are treated by administering to the subject an effective amount of an sEH inhibitor.
  • the conditions to be treated include treatment of hypertension.
  • sEH inhibitors are also useful in treating metabolic conditions comprising obesity, glucose intolerance, hypertension, high blood pressure, elevated levels of serum cholesterol, and elevated levels of triglycerides, reduced HDL to LDL ratios, or combinations thereof, regardless if the subject is manifesting, or is predisposed to, metabolic syndrome.
  • another aspect of the invention provides for methods for treating a metabolic condition in a subject, comprising administering to the subject an effective amount of a sEH inhibitor, wherein the metabolic condition is selected from the group consisting of conditions comprising obesity, glucose intolerance, high blood pressure, elevated serum cholesterol, and elevated triglycerides, reduced HDL to LDL ratios, and combinations thereof.
  • a sEH inhibitor selected from the group consisting of conditions comprising obesity, glucose intolerance, high blood pressure, elevated serum cholesterol, and elevated triglycerides, reduced HDL to LDL ratios, and combinations thereof.
  • IGT and IFG are transitional states from a state of normal glycemia to diabetes.
  • IGT is defined as two-hour glucose levels of 140 to 199 mg per dL (7.8 to 11.0 mmol) on the 75 -g oral glucose tolerance test (OGTT)
  • IFG is defined as fasting plasma glucose (FG) values of 100 to 125 mg per dL (5.6 to 6.9 mmol per L) in fasting patients. These glucose levels are above normal but below the level that is diagnostic for diabetes.
  • Intra diabetes refers to a state where a subject has elevated levels of glucose or, alternatively, elevated levels of glycosylated hemoglobin, but has not developed diabetes.
  • a standard measure of the long term severity and progression of diabetes in a patient is the concentration of glycosylated proteins, typically glycosylated hemoglobin. Glycosylated proteins are formed by the spontaneous reaction of glucose with a free amino group, typically the N-terminal amino group, of a protein.
  • HbAIc is one specific type of glycosylated hemoglobin (Hb), constituting approximately 80% of all glycosylated hemoglobin, in which the N-terminal amino group of the Hb A beta chain is glycosylated.
  • HbAIc irreversible and the blood level depends on both the life span of the red blood cells (average 120 days) and the blood glucose concentration.
  • a buildup of glycosylated hemoglobin within the red cell reflects the average level of glucose to which the cell has been exposed during its life cycle.
  • the HbAIc level is proportional to average blood glucose concentration over the previous four weeks to three months. Therefore HbAIc represents the time-averaged blood glucose values, and is not subject to the wide fluctuations observed in blood glucose values, a measurement most typically taken in conjunction with clinical trials of candidate drugs for controlling diabetes.
  • the invention provides methods and compositions that treat, reduce or ameliorate the diseases or the symptoms of diseases related to endothelial dysfunction using one or more compound(s) of Formula I-IV.
  • the endothelium is a cellular layer lining the walls of blood vessels of a mammal. It is a highly specialized interface between blood and underlying tissues and has a number of functions, including: control of haemostasis by inhibiting platelet aggregation (antithrombotic and regulating the coagulation and f ⁇ brolinolytic systems); control of vascular tone, and hence blood flow; control of blood vessel smooth muscle growth; and selective permeability to cells and proteins. [0272] Normally, the endothelium maintains vascular homeostasis by responding to physiological stimuli, for example, changes in blood flow, oxygen tension etc., by adaptive alteration of function.
  • Dysfunctional endothelium has an impaired response to such physiological stimuli, and can ultimately lead to medical disorders.
  • a number of subsets of endothelial dysfunction have been recognized, including Endothelial Activation, and Endothelial-mediated Vasodilatory Dysfunction (see De Caterina "Endothelial dysfunctions: common denominators in vascular disease”. Current Opinions in Lipidology 11 :9-23, (2000)).
  • Endothelial activation may lead to the initiation of atherosclerosis and is a process whereby there is an inappropriate up-regulation and expression of cell attraction and cell adhesion molecules on endothelial cells. This particularly involves the Macrophage
  • MCP-I Chemoattractant Protein- 1
  • chemoattractants for lymphocytes IP-10, MIG, I- TAG
  • VCAM-I Vascular Cell Adhesion Molecule- 1
  • IL-I IL-6, TNF ⁇ , and ICAM-I
  • monocytes and lymphocytes adhere. Once adherent, the leucocytes enter the artery wall.
  • the monocytes and lymphocytes are recruited to the intima (sub-endothelial layers) of the blood vessels by these cell attraction and cell adhesion molecules of the activated endothelium during the early stages of atherosclerosis (see Libby, P. "Changing concepts of atherogenesis," Journal of Internal Medicine 247:349-358, (2000))
  • Endothelial-mediated Vasodilatory Dysfunction is characterized by a reduction or loss of endothelium-dependent vasodilation and involves "decreased nitric oxide bioavailability" (decreased production, increased destruction and/or decreased sensitivity to nitric oxide). (De Caterina (2000), cited above). Nitric oxide induces vasodilation by relaxing the smooth muscle cells of the blood vessel wall.
  • Endothelial-mediated Vasodilatory Dysfunction can be measured as a reduction in vasodilation in response to acetylcholine, or as a reduced vasodilatory response following occlusion of arterial blood flow (reactive hyperaemia) for example using a sphygmomanometer cuff.
  • decreased endothelial nitric oxide bioavailability can also result in an increase in the production of vaso-constriction and hypertension. Platelet aggregation is inhibited by nitric oxide, hence a decrease in nitric oxide bioavailability can lead to an increase in platelet aggregation and consequent thrombosis.
  • a variety of diseases related to endothelial dysfunction that can be treated in the present invention, include, by way of example only, vascular inflammation, such as, atherosclerosis plaque progression/rupture and acute coronary syndrome; vasospasm, such as, coronary-angina and cerebral-subarachnoid hemorrhage; nephropathy, such as, microalbuminuria; diabetic vasculopathy; and autoimmune vasculitis.
  • vascular inflammation such as, atherosclerosis plaque progression/rupture and acute coronary syndrome
  • vasospasm such as, coronary-angina and cerebral-subarachnoid hemorrhage
  • nephropathy such as, microalbuminuria
  • diabetic vasculopathy and autoimmune vasculitis.
  • the autoimmune vasculitis relates to scleroderma, lupus, behcet syndrome,takayashu arteritis, churg-strauss syndrome, cutaneous vasculitis, and thrombangitis obliterans (Reynaud's syndrome).
  • autoimmune vasculitis is associated with sickle cell anemia and beta thalasemia.
  • Sickle cell anemia is characterized by several aspects that make it a disease that may be positively impacted by inhibition of sEH. Although the anemia is congenital, the acute sickling events lead to the actual issues with the disease including vascular inflammation, stroke and renal damage. Vascular inflammation may be considered a key characteristic of this disease. Stroke is a co-morbidity in sickle cell anemia that has potential to be positively impacted by sEH inhibitors. Additionally, it is also characterized by leading to a wide range of glomerular and tubulointerstitial nephropathies. Finally, an sEH inhibitor can be anti-thrombotic which can positively impact the primary mortality.
  • the compounds of the present invention will, in some instances, be used in combination with other therapeutic agents to bring about a desired effect. Selection of additional agents will, in large part, depend on the desired target therapy (see, e.g., Turner, N. et al. Prog. Drug Res. (1998) 51 : 33-94; Haffner, S. Diabetes Care (1998) 21 : 160-178; and DeFronzo, R. et al. (eds), Diabetes Reviews (1997) Vol. 5 No. 4). A number of studies have investigated the benefits of combination therapies with oral agents (see, e.g., Mahler, R., J. Clin. Endocrinol. Metab.
  • Combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound of Formula (I), (II), (Ilia), (HIb), or (IV) or of Tables 1, 2, or 3 or a stereoisomer or pharmaceutically acceptable salt thereof and one or more additional active agents, as well as administration of the compound and each active agent in its own separate pharmaceutical dosage formulation.
  • the compound of Formula (I), (II), (Ilia), (HIb), or (IV) or of Tables 1, 2, or 3 or a stereoisomer or pharmaceutically acceptable salt thereof and one or more additional active agents can be administered at essentially the same time (i.e., concurrently), or at separately staggered times (i.e., sequentially). Combination therapy is understood to include all these regimens.
  • the compounds of this invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities.
  • the actual amount of the compound of this invention, i.e., the active ingredient will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors.
  • the drug can be administered more than once a day, preferably once or twice a day. All of these factors are within the skill of the attending clinician.
  • Therapeutically effective amounts of the compounds may range from approximately 0.05 to 50 mg per kilogram body weight of the recipient per day; preferably about 0.1-25 mg/kg/day, more preferably from about 0.5 to 10 mg/kg/day. Thus, for administration to a 70 kg person, the dosage range would most preferably be about 35-70 mg per day.
  • compounds of this invention will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), parenteral (e.g., intramuscular, intravenous or subcutaneous), or intrathecal administration.
  • routes oral, systemic (e.g., transdermal, intranasal or by suppository), parenteral (e.g., intramuscular, intravenous or subcutaneous), or intrathecal administration.
  • the preferred manner of administration is oral using a convenient daily dosage regimen that can be adjusted according to the degree of affliction.
  • Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
  • Another preferred manner for administering compounds of this invention is inhalation. This is an effective method for delivering a therapeutic agent directly to the respiratory tract (see U. S. Patent 5,607,91
  • the choice of formulation depends on various factors such as the mode of drug administration and bioavailability of the drug substance.
  • the compound can be formulated as liquid solution, suspensions, aerosol propellants or dry powder and loaded into a suitable dispenser for administration.
  • suitable dispenser for administration There are several types of pharmaceutical inhalation devices-nebulizer inhalers, metered dose inhalers (MDI) and dry powder inhalers (DPI).
  • MDI metered dose inhalers
  • DPI dry powder inhalers
  • Nebulizer devices produce a stream of high velocity air that causes the therapeutic agents (which are formulated in a liquid form) to spray as a mist that is carried into the patient's respiratory tract.
  • MDFs typically are formulation packaged with a compressed gas.
  • the device Upon actuation, the device discharges a measured amount of therapeutic agent by compressed gas, thus affording a reliable method of administering a set amount of agent.
  • DPI dispenses therapeutic agents in the form of a free flowing powder that can be dispersed in the patient's inspiratory air-stream during breathing by the device.
  • the therapeutic agent In order to achieve a free flowing powder, the therapeutic agent is formulated with an excipient such as lactose.
  • a measured amount of the therapeutic agent is stored in a capsule form and is dispensed with each actuation.
  • 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules.
  • U.S. Patent No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
  • compositions are comprised of in general, a compound of the invention in combination with at least one pharmaceutically acceptable excipient.
  • Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound.
  • excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
  • Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
  • Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • Preferred liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose, and glycols.
  • Compressed gases may be used to disperse a compound of this invention in aerosol form.
  • Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
  • Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).
  • the amount of the compound in a formulation can vary within the full range employed by those skilled in the art.
  • the formulation will contain, on a weight percent (wt%) basis, from about 0.01-99.99 wt% of the compound of based on the total formulation, with the balance being one or more suitable pharmaceutical excipients.
  • the compound is present at a level of about 1-80 wt%. Representative pharmaceutical formulations containing compounds of the invention are described below.
  • Injectable formulation [0293] The following ingredients are mixed to form an injectable formulation.
  • a suppository of total weight 2.5 g is prepared by mixing the compound of the invention with Witepsol® H- 15 (triglycerides of saturated vegetable fatty acid; Riches-Nelson, Inc., New York), and has the following composition:
  • the compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. [0296] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.
  • the compounds of this invention may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this invention, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.
  • the starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof.
  • many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA).
  • the synthesis of the compounds of the invention can also be exemplified by, but is not limited to, as shown in Scheme 1.
  • the dotted line, the wavy line, R, R 1 , X, Y, m, n, and p are as defined herein.
  • Amines 1.1 react with the appropriate isocyanates 1.2 to form corresponding urea or thiourea of formula I.
  • the formation of the urea is conducted using a polar solvent such as DMF (dimethylformamide) at 0 to 10 0 C.
  • Isocyanates 1.2 can be either known compounds or compounds that can be prepared from known compounds by conventional synthetic procedures.
  • Compounds 1.4 are then treated with any suitable oxidizing agent known in the art, to give aldehydes 1.5.
  • 1.4 can be treated with pyridinium chlorochromate (PCC) and neutral alumina (AI 2 O 3 ) in the presence of a suitable solvent, such as, dichloromethane (DCM) to give 1.5.
  • PCC pyridinium chlorochromate
  • AI 2 O 3 neutral alumina
  • 1.5 can be recovered by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration and the like; or, alternatively, used in the next step without purification and/or isolation.
  • Compounds 1.5 are then treated with triethyl-2-fiuoro-2-phosphonoacetate 1.6 to give compounds 1.7.
  • This is typically performed in dry tetrahydrofuran (THF) or another suitable solvent known to one skilled in the art, typically at, but not limited to, room temperature in the presence of n-butyllithium (n-BuLi), or another suitable base known to one skilled in the art.
  • n-BuLi n-butyllithium
  • 1.7 can be recovered by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration and the like; or, alternatively, used in the next step without purification and/or isolation.
  • the intermediate 1.8 can be treated with appropriate isocyanate compounds 1.9 or 2.0 to form the corresponding adamantyl compounds 2.1 or phenyl compounds 2.2.
  • Scheme 3 shows p-fluorophenyl or unsubstituted adamantyl for illustration purposes only. Any suitably substituted or unsubstituted phenyl or adamantyl can be used in Scheme 3 to yield the compounds of the invention.
  • the reaction with isocyanates is conducted using DCM in the presence of triethylamine (TEA) at room temperature, or alternatively, a polar solvent such as DMF (dimethylformamide) at 0 to 10 0 C.
  • TAA triethylamine
  • Isocyanate compounds 1.9 or 2.0 can be either known compounds or compounds that can be prepared from known compounds by conventional synthetic procedures. Upon reaction completion, 2.1 and/or 2.2 can be recovered by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration and the like; or, alternatively, used in the next step without purification and/or isolation.
  • Compounds 2.1 or 2.2 can then be reduced using any suitable reducing agent known in the art, to give compounds 2.3 or 2.4, respectively.
  • 2.1 or 2.2 can be hydrogenated with palladium/carbon (Pd/C) in the presence of a suitable solvent known in the art such as, methanol, at suitable temperature such as, room temperature.
  • a suitable solvent known in the art such as, methanol
  • 2.3 and/or 2.4 can be recovered by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration and the like.
  • the ester group of the adamantyl compounds 2.1 or phenyl compounds 2.2 can be hydrolyzed (not shown in Scheme 3) to give the corresponding acid compounds.
  • esters can be hydrolyzed using lithium hydroxide (LiOH) in the presence of a suitable solvent such as, but not limited to THF/methanol/water.
  • a suitable solvent such as, but not limited to THF/methanol/water.
  • the resulting acids can then be reduced with reducing agents as described above to give the corresponding adamantyl or phenyl compounds of the invention.
  • Boc fert-butoxycarbonyl
  • 6-Amino-l-hexanol 1 (9.00 g, 7.67 mmol) was taken in 300 niL of THF/Water (1 :1) and to it was added tBoc anhydride (18.0 g, 8.44 mmol) followed by sodium carbonate (19.0 g, 19.2 mmol). The reaction mixture was then stirred at room temperature for 3 hours. After completion of the reaction, the resulting mixture was poured into water and extracted with ethyl acetate (2 x 300 mL). The combined organic layers were washed with water and brine and dried over sodium sulfate. Evaporation of the organic layer gave 16 g (96%) of compound 2 which was essentially pure and was used without further purification.
  • rO3191 ZVethyl 2-fluoro-8-(3-adamantylureido)oct-2-enoate of Example 2 (2.0 g, 0.66 mmol) was taken in 20 niL of methanol and to it was added 350 mg of Pd/C (10%), and the reaction mixture was stirred at room temperature for 1.5 hours under a hydrogen atmosphere. After the reaction was complete, it was filtered through celite, the celite layer was washed with methanol, and the combined organic layers evaporated under reduced pressure.
  • reaction mixture was extracted with EtOAc (4 x 100 mL), and the combined organic extracts were washed with water (2 x 50 mL) and brine (100 mL). The organic layer was dried over anhydrous Na 2 SO 4 , filtered and evaporated under reduced pressure to provide Boc-1 (17.4 g, 93%) as a colorless liquid.
  • ester 46 (2.5 g, 6.9 mmol) in ethanol (50 mL) was added 10% aqueous NaOH solution (100 mL) at room temperature and stirring was continued for 3 h. After complete consumption of starting material as monitored by TLC, the solvent was evaporated under reduced pressure. The residue was acidified and stirred for 10 min. The precipitated solid was filtered, washed with diethyl ether (4 x 50 mL) and dried under vacuum to afford acid 45 (1.36 g, 59.1%) as white solid. TLC: Ethyl Acetate (R f : 0.2). M.P: 72.6-74.8°C.
  • MsEH mouse sEH
  • HsEH human sEH
  • the expressed proteins were purified from cell lysate by affinity chromatography. Wixtrom et al., Anal. Biochem., 169:71-80 (1988). Protein concentration was quantified using the Pierce BCA assay using bovine serum albumin as the calibrating standard.
  • the preparations were at least 97% pure as judged by SDS-PAGE and scanning densitometry. They contained no detectable esterase or glutathione transferase activity which can interfere with the assay.
  • the assay was also evaluated with similar results in crude cell lysates or homogenate of tissues.
  • Protocol [0357] In a black 96 well plate, fill all the wells with 150 ⁇ L of buffer A.

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Abstract

Disclosed are amide and urea compounds and compositions that inhibit soluble epoxide hydrolase (sEH), methods for preparing the compounds and compositions, and methods for treating patients with such compounds and compositions. The compounds, compositions, and methods are useful for treating a variety of sEH mediated diseases, including hypertensive, cardiovascular, inflammatory, and diabetic-related diseases.

Description

SOLUBLE EPOXIDE HYDROLASE INHIBITORS
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit under 35 U. S. C. § 119(e) of provisional Patent Application Serial No. 61/017,380, filed on December 28, 2007, which is incorporated herein by reference in its entirety.
BACKGROUND OF THE INVENTION
Field of the Invention
[0002] This invention relates to the field of pharmaceutical chemistry. Provided herein are compounds that inhibit soluble epoxide hydrolase (sEH), pharmaceutical compositions containing such compounds, methods for preparing the compounds and formulations, and methods for treating patients with such compounds and compositions. The compounds, compositions, and methods are useful for treating a variety of sEH mediated diseases, including hypertensive, cardiovascular, inflammatory, metabolic syndrome, and diabetic- related diseases.
State of the Art
[0003] The arachidonate cascade is a ubiquitous lipid signaling cascade in which arachidonic acid is liberated from the plasma membrane lipid reserves in response to a variety of extra-cellular and/or intra-cellular signals. The released arachidonic acid is then available to act as a substrate for a variety of oxidative enzymes that convert arachidonic acid to signaling lipids that play critical roles in, for example, inflammation, and other disease conditions. Disruption of the pathways leading to the lipids remains an important strategy for many commercial drugs used to treat a multitude of inflammatory disorders. For example, non-steroidal anti-inflammatory drugs (NSAIDs) disrupt the conversion of arachidonic acid to prostaglandins by inhibiting cyclooxygenases (COXl and COX2). New asthma drugs, such as SINGULAIR™ disrupt the conversion of arachidonic acid to leukotrienes by inhibiting lipoxygenase (LOX).
[0004] Certain cytochrome P450-dependent enzymes convert arachidonic acid into a series of epoxide derivatives known as epoxyeicosatrienoic acids (EETs). These EETs are particularly prevalent in the vascular endothelium (cells that make up arteries and vascular beds), kidney, and lung. In contrast to many of the end products of the prostaglandin and leukotriene pathways, the EETs have a variety of anti-inflammatory and anti-hypertensive properties and are known to be potent vasodilators and mediators of vascular permeability.
[0005] While EETs have potent effects in vivo, the epoxide moiety of the EETs is rapidly hydrolyzed into the less active dihydroxyeicosatrienoic acid (DHET) form by an enzyme called soluble epoxide hydrolase (sEH). Inhibition of sEH has been found to significantly reduce blood pressure in hypertensive animals (see, e.g., Yu et al. Circ. Res. 87:992-8 (2000) and Sinai et al. J. Biol. Chem. 275:40504-10 (2000)), to reduce the production of proinflammatory nitric oxide (NO), cytokines, and lipid mediators, and to contribute to inflammatory resolution by enhancing lipoxin A4 production in vivo (see. Schmelzer et al. Proc. Nat'lAcad. Sci. USA 102(28):9772-7 (2005)).
[0006] Various small molecule compounds have been found to inhibit sEH and elevate EET levels (Morisseau et al. Annu. Rev. Pharmacol. Toxicol. 45:311-33 (2005)). The availability of more potent compounds capable of inhibiting sEH and its inactivation of EETs would be highly desirable for treating a wide range of disorders that are mediated by conversion of sEH to EET 's including inflammation and hypertension.
SUMMARY OF THE INVENTION
[0007] Disclosed are compounds and their pharmaceutical compositions, their preparation, related intermediates, and their uses for treating diseases mediated by soluble epoxide hydrolase (sEH). In accordance with one embodiment of the invention, provided are compounds represented by Formula (I) or a stereoisomer, or pharmaceutically acceptable salt thereof:
Figure imgf000003_0001
wherein
R is selected from the group consisting of cycloalkyl, substituted cycloalkyl, phenyl and substituted phenyl; L is -NH- or -CR'R"- where R' and R" are independently hydrogen or alkyl or R' and R" together form a C3-C6 cycloalkyl ring; Z is C, O, or NR4 where R4 is hydrogen or C1-C4 alkyl and where when Z is O or
NR4 then X is absent; the dotted line Z112 is a single bond or a double bond; the wavy line is a cis or a trans configuration when the dotted line is a double bond and m and n are 1 ; when the dotted line is a single bond and Z is C, then m and n are 2; p is O, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; q is 0 or 1; each of X and Y is independently selected from the group consisting of hydrogen,
C1-C4 alkyl, substituted C1-C4 alkyl, and halo; R1 is selected from the group consisting of -CH2OR2, -COR2, -COOR2, -CONR2R3,
OR2, and carboxylic acid isostere; and R2 and R3 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or R2 and R3 together with the nitrogen atom bound thereto form a heterocycloalkyl ring having 3 to 9 ring atoms, and wherein said ring is optionally substituted with alkyl, substituted alkyl, heterocyclic, oxo or carboxy; provided that when the dotted line :==z is the single bond; Z is C; and q is 0, then at least one of Y is halo or C1-C4 alkyl; and provided that when dotted line zz∑z is the double bond, R1 is not OH. [0008] In one preferred embodiment, when Z is C and q is 1, then each of X and Y independently is hydrogen or C1-C4 alkyl.
[0009] In another embodiment, provided are compounds represented by Formula (II), or a stereoisomer, or pharmaceutically acceptable salt thereof:
Figure imgf000004_0001
wherein
R is selected from the group consisting of cycloalkyl, substituted cycloalkyl, phenyl and substituted phenyl; p is O, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
R1 is selected from the group consisting of -CH2OR2, -COR2, -COOR2, -CONR2R3, -OR2, and carboxylic acid isostere;
R2 and R3 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or R2 and R3 together with the nitrogen atom bound thereto form a heterocycloalkyl ring having 3 to 9 ring atoms, and wherein said ring is optionally substituted with alkyl, substituted alkyl, heterocyclic, oxo or carboxy; and each of Xa, Xb, Ya, and Yb is independently selected from the group consisting of hydrogen, C1-C4 alkyl, substituted C1-C4 alkyl, and halo, provided that at least one of Ya and Yb is halo or C1-C4 alkyl.
[0010] In another embodiment, provided are compounds represented by Formula (Ilia) or (HIb), or a stereoisomer, or pharmaceutically acceptable salt thereof:
Figure imgf000005_0001
wherein
R is selected from the group consisting of cycloalkyl, substituted cycloalkyl, phenyl and substituted phenyl; p is O, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
X and Y independently are selected from the group consisting of hydrogen, C1-C4 alkyl, substituted C1-C4 alkyl, and halo; R1 is selected from the group consisting of -CH2OR2, -COR2, -COOR2, -CONR2R3, and carboxylic acid isostere; and
R2 and R3 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or R2 and R3 together with the nitrogen atom bound thereto form a heterocycloalkyl ring having 3 to 9 ring atoms, and wherein said ring is optionally substituted with alkyl, substituted alkyl, heterocyclic, oxo or carboxy. [0011] In another embodiment, provided are compounds represented by Formula (IV), or a stereoisomer, or pharmaceutically acceptable salt thereof:
Figure imgf000006_0001
wherein
R is selected from the group consisting of cycloalkyl, substituted cycloalkyl, phenyl and substituted phenyl;
R1 is selected from the group consisting of -CH2OR2, -COR2, -COOR2, -CONR2R3, and carboxylic acid isostere; and R2 and R3 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or R2 and R3 together with the nitrogen atom bound thereto form a heterocycloalkyl ring having 3 to 9 ring atoms, and wherein said ring is optionally substituted with alkyl, substituted alkyl, heterocyclic, oxo or carboxy; p is O, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
Z is O or NR4 where R4 is hydrogen or C1-C4 alkyl; and
Ya and Yb independently are selected from the group consisting of hydrogen, halo, or C1-C4 alkyl. [0012] In another embodiment, provided are compounds of Tables 1, 2, and 3 or a stereoisomer or pharmaceutically acceptable salt thereof.
[0013] In another embodiment, provided is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Formula I-IV or a stereoisomer or pharmaceutically acceptable salt thereof, for treating a soluble epoxide hydrolase mediated disease.
[0014] In yet another embodiment, provided is a method for treating a soluble epoxide hydrolase mediated disease, the method comprising administering to a patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Formula I-IV or a stereoisomer or pharmaceutically acceptable salt thereof.
[0015] These and other embodiments of the invention are further described in the detailed description that follows.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0016] As used herein, the following definitions shall apply unless otherwise indicated.
[0017] "cis-Epoxyeicosatrienoic acids" ("EETs") are biomediators synthesized by cytochrome P450 epoxygenases.
[0018] "Epoxide hydrolases" ("EH;" EC 3.3.2.3) are enzymes in the alpha/beta hydrolase fold family that add water to 3 membered cyclic ethers termed epoxides.
[0019] "Soluble epoxide hydrolase" ("sEH") is an enzyme which in endothelial, smooth muscle and other cell types converts EETs to dihydroxy derivatives called dihydroxyeicosatrienoic acids ("DHETs"). The cloning and sequence of the murine sEH is set forth in Grant et al, J. Biol. Chem. 268(23):17628-17633 (1993). The cloning, sequence, and accession numbers of the human sEH sequence are set forth in Beetham et al., Arch.
Biochem. Biophys. 305(l):197-201 (1993). The amino acid sequence of human sEH and the nucleic acid sequence encoding the human sEH are also set forth in U.S. Pat. No. 5,445,956, which is incorporated by reference in its entirety. The evolution and nomenclature of the gene is discussed in Beetham et al, DNA Cell Biol. 14(1):61-71 (1995). Soluble epoxide hydrolase represents a single highly conserved gene product with over 90% homology between rodent and human (Arand et al., FEBS Lett., 338:251-256 (1994)).
[0020] "Chronic Obstructive Pulmonary Disease" or "COPD" is also sometimes known as "chronic obstructive airway disease", "chronic obstructive lung disease", and "chronic airways disease." COPD is generally defined as a disorder characterized by reduced maximal expiratory flow and slow forced emptying of the lungs. COPD is considered to encompass two related conditions, emphysema and chronic bronchitis. COPD can be diagnosed by the general practitioner using art recognized techniques, such as the patient's forced vital capacity ("FVC"), the maximum volume of air that can be forcibly expelled after a maximal inhalation. In the offices of general practitioners, the FVC is typically approximated by a 6 second maximal exhalation through a spirometer. The definition, diagnosis and treatment of COPD, emphysema, and chronic bronchitis are well known in the art and discussed in detail by, for example, Honig and Ingram, in Harrison's Principles of Internal Medicine, (Fauci et al., Eds), 14th Ed., 1998, McGraw-Hill, New York, pp.
1451-1460 (hereafter, "Harrison's Principles of Internal Medicine"). As the names imply, "obstructive pulmonary disease" and "obstructive lung disease" refer to obstructive diseases, as opposed to restrictive diseases. These diseases particularly include COPD, bronchial asthma, and small airway disease. [0021] "Emphysema" is a disease of the lungs characterized by permanent destructive enlargement of the airspaces distal to the terminal bronchioles without obvious fibrosis.
[0022] "Chronic bronchitis" is a disease of the lungs characterized by chronic bronchial secretions which last for most days of a month, for three months, a year, for two years, etc..
[0023] "Small airway disease" refers to diseases where airflow obstruction is due, solely or predominantly to involvement of the small airways. These are defined as airways less than 2 mm in diameter and correspond to small cartilaginous bronchi, terminal bronchioles, and respiratory bronchioles. Small airway disease (SAD) represents luminal obstruction by inflammatory and fibrotic changes that increase airway resistance. The obstruction may be transient or permanent. [0024] "Interstitial lung diseases (ILDs)" are restrictive lung diseases involving the alveolar walls, perialveolar tissues, and contiguous supporting structures. As discussed on the website of the American Lung Association, the tissue between the air sacs of the lung is the interstitium, and this is the tissue affected by fibrosis in the disease. Persons with such restrictive lung disease have difficulty breathing in because of the stiffness of the lung tissue but, in contrast to persons with obstructive lung disease, have no difficulty breathing out. The definition, diagnosis and treatment of interstitial lung diseases are well known in the art and discussed in detail by, for example, Reynolds, H. Y., in Harrison's Principles of Internal Medicine, supra, at pp. 1460-1466. Reynolds notes that, while ILDs have various initiating events, the immunopathological responses of lung tissue are limited and the ILDs therefore have common features. [0025] "Idiopathic pulmonary fibrosis," or "IPF," is considered the prototype ILD.
Although it is idiopathic in that the cause is not known, Reynolds, supra, notes that the term refers to a well defined clinical entity.
[0026] "Bronchoalveolar lavage," or "BAL," is a test which permits removal and examination of cells from the lower respiratory tract and is used in humans as a diagnostic procedure for pulmonary disorders such as IPF. In human patients, it is usually performed during bronchoscopy.
[0027] "Diabetic neuropathy" refers to acute and chronic peripheral nerve dysfunction resulting from diabetes.
[0028] "Diabetic nephropathy" refers to renal diseases resulting from diabetes. [0029] "Alkyl" refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and preferably 1 to 6 carbon atoms. Alternatively, alkyl refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 4 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CHs)2CH-), /i-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), f-butyl ((CHs)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-).
[0030] "Alkenyl" refers to straight or branched hydrocarbyl groups having from 2 to 6 carbon atoms and preferably 2 to 4 carbon atoms and having at least 1 and preferably from 1 to 2 sites of vinyl (>C=C<) unsaturation. Such groups are exemplified, for example, by vinyl, allyl, and but-3-en-l-yl. Included within this term are the cis and trans isomers or mixtures of these isomers.
[0031] "Alkynyl" refers to straight or branched monovalent hydrocarbyl groups having from 2 to 6 carbon atoms and preferably 2 to 3 carbon atoms and having at least 1 and preferably from 1 to 2 sites of acetylenic (-C≡C-) unsaturation. Examples of such alkynyl groups include acetylenyl (-C≡CH), and propargyl (-CIH^C≡CH).
[0032] "Substituted alkyl" refers to an alkyl group having from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, hetero aryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein.
[0033] "Substituted alkenyl" refers to alkenyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein and with the proviso that any hydroxy or thiol substitution is not attached to a vinyl (unsaturated) carbon atom.
[0034] "Substituted alkynyl" refers to alkynyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cyclo alkylthio, substituted cyclo alkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein and with the proviso that any hydroxy or thiol substitution is not attached to an acetylenic carbon atom.
[0035] "Alkoxy" refers to the group -O-alkyl wherein alkyl is defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy.
[0036] "Substituted alkoxy" refers to the group -O-(substituted alkyl) wherein substituted alkyl is defined herein.
[0037] "Acyl" refers to the groups H-C(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclic-C(O)-, and substituted heterocyclic-C(O)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Acyl includes the "acetyl" group CH3C(O)-.
[0038] "Acylamino" refers to the groups -NR17C(O)alkyl, -NR17C(O)substituted alkyl, -NR17C(O)cycloalkyl, -NR17C(O)substituted cycloalkyl, -NR17C(O)cycloalkenyl, -NR17C(O)substituted cycloalkenyl, -NR17C(O)alkenyl, -NR17C(O)substituted alkenyl, -NR17C(O)alkynyl, -NR17C(O)substituted alkynyl, -NR17C(O)aryl, -NR17C(O)substituted aryl, -NR17C(O)heteroaryl, -NR17C(O)substituted heteroaryl, -NR17C(O)heterocyclic, and -NR17C(O)substituted heterocyclic wherein R17 is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0039] "Acyloxy" refers to the groups alkyl-C(O)O-, substituted alkyl-C(O)O-, alkenyl-C(O)O-, substituted alkenyl-C(O)O-, alkynyl-C(O)O-, substituted alkynyl-C(O)O-, aryl-C(O)O-, substituted aryl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, cycloalkenyl-C(O)O-, substituted cycloalkenyl-C(O)O-, heteroaryl-C(O)O-, substituted heteroaryl-C(O)O-, heterocyclic-C(O)O-, and substituted heterocyclic-C(O)O- wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. [0040] "Amino" refers to the group -NH2.
[0041] "Substituted amino" refers to the group -NR18R19 where R18 and R19 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -SO2-alkyl, -SO2-substituted alkyl, -SO2-alkenyl, -SO2-substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cycloalkyl, -SC^-cycloalkenyl, -Sθ2-substituted cycloalkenyl,-SO2-aryl, -Sθ2-substituted aryl, -Sθ2-heteroaryl, -Sθ2-substituted heteroaryl, -Sθ2-heterocyclic, and -Sθ2-substituted heterocyclic and wherein R18 and R19 are optionally joined, together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, provided that R18 and R19 are both not hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. When R is hydrogen and R19 is alkyl, the substituted amino group is sometimes referred to herein as alkylamino. When R18 and R19 are alkyl, the substituted amino group is sometimes referred to herein as dialkylamino. When referring to a monosubstituted amino, it is meant that either R18 or R19 is hydrogen but not both. When referring to a disubstituted amino, it is meant that neither R18 nor R19 are hydrogen.
[0042] "Aminocarbonyl" refers to the group -C(O)NR20R21 where R20 and R21 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R20 and R21 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0043] "Aminothiocarbonyl" refers to the group -C(S)NR20R21 where R20 and R21 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R20 and R21 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0044] "Aminocarbonylamino" refers to the group -NR17C(O)NR20R21 where R17 is hydrogen or alkyl and R20 and R21 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R20 and R21 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0045] "Aminothiocarbonylamino" refers to the group -NR17C(S)NR20R21 where R17 is hydrogen or alkyl and R20 and R21 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R10 and R11 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0046] "Aminocarbonyloxy" refers to the group -0-C(O)NR20R21 where R20 and R21 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R20 and R21 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0047] "Aminosulfonyl" refers to the group -SO2NR20R21 where R20 and R21 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R20 and R21 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0048] "Aminosulfonyloxy" refers to the group -0-SO2NR20R21 where R20 and R21 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R20 and R21 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0049] "Aminosulfonylamino" refers to the group -NR17-SO2NR20R21 where R17 is hydrogen or alkyl and R20 and R21 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R and R are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0050] "Amidino" refers to the group -C(=NR22)NR20R21 where R20, R21, and R22 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R20 and R21 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0051] "Aryl" or "Ar" refers to a monovalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-l,4-benzoxazin-3(4H)-one-7-yl, and the like) provided that the point of attachment is at an aromatic carbon atom. Preferred aryl groups include phenyl and naphthyl.
[0052] "Substituted aryl" refers to aryl groups which are substituted with 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, hetero aryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein.
[0053] "Aryloxy" refers to the group -O-aryl, where aryl is as defined herein, that includes, by way of example, phenoxy and naphthoxy. [0054] "Substituted aryloxy" refers to the group -O-(substituted aryl) where substituted aryl is as defined herein.
[0055] "Arylthio" refers to the group -S-aryl, where aryl is as defined herein.
[0056] "Substituted arylthio" refers to the group -S-(substituted aryl), where substituted aryl is as defined herein. [0057] "Carbonyl" refers to the divalent group -C(O)- which is equivalent to -C(=O)-. [0058] "Carboxy" or "carboxyl" refers to -COOH or salts thereof.
[0059] "Isosteres" are different compounds that have different molecular formulae but exhibit the same or similar properties. For example, tetrazole is an isostere of carboxylic acid because it mimics the properties of carboxylic acid even though they both have very different molecular formulae. Tetrazole is one of many possible isosteric replacements for carboxylic acid. Other carboxylic acid isosteres contemplated by the present invention include -SO3H, -SO2NHRk', -PO2(Rk')2, -CN, -PO3(Rk')2, -ORk, -SRk', -NHCORk', -N(Rk')2, -CONH(O)Rk', -CONHNHSO2Rk', -COHNSO2Rk', -SO2NHCORk', -SO2NHNHCORk', and -CONRk CN, where Rk is selected from hydrogen, hydroxyl, halo, haloalkyl, thiocarbonyl, alkoxy, alkenoxy, aryloxy, cyano, nitro, imino, alkylamino, aminoalkyl, thiol, thioalkyl, alkylthio, sulfonyl, alkyl, alkenyl, alkynyl, aryl, aralkyl (-(alkyl)-(aryl)), cycloalkyl, heteroaryl, heterocycle, and CO2Rm where Rm is hydrogen, alkyl or alkenyl. In addition, carboxylic acid isosteres can include 5-7 membered carbocycles or heterocycles containing any combination of CH2, O, S, or N in any chemically stable oxidation state, where any of the atoms of said ring structure are optionally substituted in one or more positions. The following structures are non-limiting examples of preferred carboxylic acid isosteres contemplated by this invention.
Figure imgf000018_0001
[0060] "Carboxyl ester" or "carboxy ester" refers to the groups -C(O)O-alkyl, -C(O)O-substituted alkyl, -C(O)O-alkenyl, -C(O)O-substituted alkenyl, -C(O)O-alkynyl, -C(O)O-substituted alkynyl, -C(O)O-aryl, -C(O)O-substituted aryl, -C(O)O-cycloalkyl, -C(O)O-substituted cycloalkyl, -C(O)O-cycloalkenyl, -C(O)O-substituted cycloalkenyl, -C(O)O-heteroaryl, -C(O)O-substituted heteroaryl, -C(O)O-heterocyclic, and -C(O)O-substituted heterocyclic wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0061] "(Carboxyl ester)amino" refers to the group -NR17-C(O)O-alkyl, -NR17-C(0)0- substituted alkyl, -NR17-C(O)O-alkenyl, -NR17-C(O)O-substituted alkenyl, -NR17-C(O)O-alkynyl, -NR17-C(O)O-substituted alkynyl, -NR17-C(O)O-aryl, -NR17-C(O)O-substituted aryl, -NR17-C(O)O-cycloalkyl, -NR17-C(O)O-substituted cycloalkyl, -NR17-C(O)O-cycloalkenyl, -NR17-C(O)O-substituted cycloalkenyl,
-NR17-C(O)O-heteroaryl, -NR17-C(O)O-substituted heteroaryl, -NR17-C(O)O-heterocyclic, and -NR17-C(O)O-substituted heterocyclic wherein R17 is alkyl or hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0062] "(Carboxyl ester)oxy" refers to the group -O-C(O)O-alkyl, substituted
-O-C(O)O-alkyl, -O-C(O)O-alkenyl, -O-C(O)O-substituted alkenyl, -O-C(O)O-alkynyl, -O-C(O)O-substituted alkynyl, -O-C(O)O-aryl, -O-C(O)O-substituted aryl, -O-C(O)O-cycloalkyl, -O-C(O)O-substituted cycloalkyl, -O-C(O)O-cycloalkenyl, -O-C(O)O-substituted cycloalkenyl, -O-C(O)O-heteroaryl, -O-C(O)O-substituted heteroaryl, -O-C(O)O-heterocyclic, and -O-C(O)O-substituted heterocyclic wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0063] "Cyano" refers to the group -CN. [0064] "Cycloalkyl" refers to cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings including fused, bridged, and spiro ring systems. One or more of the rings can be aryl, heteroaryl, or heterocyclic provided that the point of attachment is through the non-aromatic, non-heterocyclic ring carbocyclic ring. Examples of suitable cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl. Other examples of cycloalkyl groups include bicycle[2,2,2,]octanyl, norbornyl, and spirobicyclo groups such as spiro [4.5] dec- 8 -yl:
Figure imgf000019_0001
[0065] "Cycloalkenyl" refers to non-aromatic cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings and having at least one >C=C< ring unsaturation and preferably from 1 to 2 sites of >C=C< ring unsaturation.
[0066] "Substituted cycloalkyl" and "substituted cycloalkenyl" refers to a cycloalkyl or cycloalkenyl group having from 1 to 5 or preferably 1 to 3 substituents selected from the group consisting of oxo, thione, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein. [0067] "Cycloalkyloxy" refers to -O-cycloalkyl.
[0068] "Substituted cycloalkyloxy" refers to -O-(substituted cycloalkyl).
[0069] "Cycloalkylthio" refers to -S-cycloalkyl.
[0070] "Substituted cycloalkylthio" refers to -S-(substituted cycloalkyl).
[0071] "Cycloalkenyloxy" refers to -O -cycloalkenyl. [0072] "Substituted cycloalkenyloxy" refers to -O-(substituted cycloalkenyl).
[0073] "Cycloalkenylthio" refers to -S-cycloalkenyl.
[0074] "Substituted cycloalkenylthio" refers to -S-(substituted cycloalkenyl).
[0075] "Guanidino" refers to the group -NHC(=NH)NH2.
[0076] "Substituted guanidino" refers to -NR23C(=NR23)N(R23)2 where each R23 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and two R23 groups attached to a common guanidino nitrogen atom are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, provided that at least one R23 is not hydrogen, and wherein said substituents are as defined herein.
[0077] "Halo" or "halogen" refers to fluoro, chloro, bromo and iodo and preferably is fluoro or chloro.
[0078] "Haloalkyl" refers to alkyl groups substituted with 1 to 5, 1 to 3, or 1 to 2 halo groups, wherein alkyl and halo are as defined herein. [0079] "Haloalkoxy" refers to alkoxy groups substituted with 1 to 5, 1 to 3, or 1 to 2 halo groups, wherein alkoxy and halo are as defined herein.
[0080] "Haloalkylthio" refers to alkylthio groups substituted with 1 to 5, 1 to 3, or 1 to 2 halo groups, wherein alkylthio and halo are as defined herein. [0081] "Hydroxy" or "hydroxyl" refers to the group -OH.
[0082] "Heteroaryl" refers to an aromatic group of from 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur within the ring. Such heteroaryl groups can have a single ring (e.g., pyridinyl or furyl) or multiple condensed rings (e.g. , indolizinyl or benzothienyl) wherein the condensed rings may or may not be aromatic and/or contain a heteroatom provided that the point of attachment is through an atom of the aromatic heteroaryl group. In one embodiment, the nitrogen and/or the sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N→O), sulfmyl, and/or sulfonyl moieties. Preferred heteroaryls include pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl. [0083] "Substituted heteroaryl" refers to heteroaryl groups that are substituted with from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of the same group of substituents defined for substituted aryl.
[0084] "Heteroaryloxy" refers to -O-heteroaryl.
[0085] "Substituted heteroaryloxy" refers to the group -O-(substituted heteroaryl). [0086] "Heteroarylthio" refers to the group -S-heteroaryl.
[0087] "Substituted heteroarylthio" refers to the group -S-(substituted heteroaryl).
[0088] "Heterocycle" or "heterocyclic" or "heterocycloalkyl" or "heterocyclyl" refers to a saturated or partially saturated, but not aromatic, group having 3 to 16 ring atoms with from 1 to 12 ring carbon atoms and from 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen. Heterocycle encompasses single ring or multiple condensed rings, including fused bridged and spiro ring systems. In fused ring systems, one or more the rings can be cycloalkyl, aryl, or heteroaryl provided that the point of attachment is through the non-aromatic heterocyclic ring. In one embodiment, the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, sulfmyl, and/or sulfonyl moieties. [0089] "Substituted heterocyclic" or "substituted heterocycloalkyl" or "substituted heterocyclyl" refers to heterocyclyl groups that are substituted with from 1 to 5 or preferably 1 to 3 of the same substituents as defined for substituted cycloalkyl.
[0090] "Heterocyclyloxy" refers to the group -O-heterocycyl. [0091] "Substituted heterocyclyloxy" refers to the group -O-(substituted heterocycyl).
[0092] "Heterocyclylthio" refers to the group -S-heterocycyl.
[0093] "Substituted heterocyclylthio" refers to the group -S-(substituted heterocycyl).
[0094] Examples of heterocycle and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to as thiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine, and tetrahydrofuranyl.
[0095] "Nitro" refers to the group -NO2. [0096] "Oxo" refers to the atom (=0) or (-0 ). [0097] "Spiro ring systems" refers to bicyclic ring systems that have a single ring carbon atom common to both rings.
[0098] "Sulfonyl" refers to the divalent group -S(O)2-.
[0099] "Substituted sulfonyl" refers to the group -SO2-alkyl, -SO2-substituted alkyl, -SO2-alkenyl, -SO2-substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cycloalkyl, -SO2-cycloalkenyl, -SO2-substituted cycloalkenyl, -SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted heteroaryl, -SO2-heterocyclic, -SO2-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Substituted sulfonyl includes groups such as methyl-S02-, phenyl-SO2-, and 4-methylphenyl-SO2-. The term "alkylsulfonyl" refers to -SO2-alkyl. The term "haloalkylsulfonyl" refers to -SO2-haloalkyl where haloalkyl is defined herein. The term "(substituted sulfonyl)amino" refers to -NH(substituted sulfonyl), and the term "(substituted sulfonyl)aminocarbonyl" refers to -C(O)NH(substituted sulfonyl), wherein substituted sulfonyl is as defined herein.
[0100] "Sulfonyloxy" refers to the group -OSO2-alkyl, -OSO2-substituted alkyl, -OSO2-alkenyl, -OSO2-substituted alkenyl, -OSO2-cycloalkyl, -OSO2-substituted cycloalkyl, -OSO2-cycloalkenyl, -OSO2-substituted cycloalkenyl,-OSO2-aryl, -OSO2-substituted aryl, -OSO2-heteroaryl, -OSO2-substituted heteroaryl,
-OSO2-heterocyclic, -OSO2-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. [0101] "Thioacyl" refers to the groups H-C(S)-, alkyl-C(S)-, substituted alkyl-C(S)-, alkenyl-C(S)-, substituted alkenyl-C(S)-, alkynyl-C(S)-, substituted alkynyl-C(S)-, cycloalkyl-C(S)-, substituted cycloalkyl-C(S)-, cycloalkenyl-C(S)-, substituted cycloalkenyl-C(S)-, aryl-C(S)-, substituted aryl-C(S)-, heteroaryl-C(S)-, substituted heteroaryl-C(S)-, heterocyclic-C(S)-, and substituted heterocyclic-C(S)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0102] "Thiol" refers to the group -SH. [0103] "Thiocarbonyl" refers to the divalent group -C(S)- which is equivalent to -C(=S)-.
[0104] "Thione" refers to the atom (=S).
[0105] "Alkylthio" refers to the group -S-alkyl wherein alkyl is as defined herein.
[0106] "Substituted alkylthio" refers to the group -S-(substituted alkyl) wherein substituted alkyl is as defined herein. [0107] "Compound" or "compounds" as used herein is meant to include the stereoiosmers and pharmaceutically acceptable salts of the indicated formulas.
[0108] "Stereoisomer" or "stereoisomers" refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers. [0109] "Prodrug" refers to any derivative of a compound of the embodiments that is capable of directly or indirectly providing a compound of the embodiments or an active metabolite or residue thereof when administered to a subject. Particularly favored derivatives and prodrugs are those that increase the bioavailability of the compounds of the embodiments when such compounds are administered to a subject (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species. Prodrugs include ester forms of the compounds of the invention. Examples of ester prodrugs include formate, acetate, propionate, butyrate, acrylate, and ethylsuccinate derivatives. A general overview of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
[0110] "Patient" refers to mammals and includes humans and non-human mammals. [0111] "Pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts of a compound, which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, and oxalate.
[0112] "Treating" or "treatment" of a disease in a patient refers to (1) preventing the disease from occurring in a patient that is predisposed or does not yet display symptoms of the disease; (2) inhibiting the disease or arresting its development; or (3) ameliorating or causing regression of the disease. [0113] Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment. For example, the substituent "arylalkyloxycarbonyl" refers to the group (aryl)-(alkyl)-O-C(O)-.
[0114] It is understood that in all substituted groups defined above, polymers arrived at by defining substituents with further substituents to themselves are not intended for inclusion herein. In such cases, the maximum number of such substitutions is three. For example, serial substitutions of substituted aryl groups with two other substituted aryl groups are limited to -substituted aryl-(substituted aryl)-substituted aryl.
[0115] Similarly, it is understood that the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluoro groups). Such impermissible substitution patterns are well known to the skilled artisan.
[0116] Accordingly, the present invention provides a compound of Formula (I) or a steroisomer, or pharmaceutically acceptable salt thereof:
Figure imgf000025_0001
wherein
R is selected from the group consisting of cycloalkyl, substituted cycloalkyl, phenyl and substituted phenyl; L is -NH- or -CR'R"- where R' and R" are independently hydrogen or alkyl or R' and R" together form a C3-C6 cycloalkyl ring; Z is C, O, or NR4 where R4 is hydrogen or C1-C4 alkyl and where when Z is O or
NR4 then X is absent; the dotted line ^111 is a single bond or a double bond; the wavy line is a cis or a trans configuration when the dotted line is a double bond and m and n are 1 ; when the dotted line is a single bond and Z is C, then m and n are 2; p is 0-10; q is 0 or 1 ; each of X and Y is independently selected from the group consisting of hydrogen,
C1-C4 alkyl, substituted C1-C4 alkyl, and halo; R1 is selected from the group consisting of -CH2OR2, -COR2, -COOR2, -CONR2R3,
-OR2, and carboxylic acid isostere; and R2 and R3 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or R2 and R3 together with the nitrogen atom bound thereto form a heterocycloalkyl ring having 3 to 9 ring atoms, and wherein said ring is optionally substituted with alkyl, substituted alkyl, heterocyclic, oxo or carboxy; provided that when the dotted line z∑zz is the single bond; Z is C; and q is 0, then at least one of Y is halo or C1-C4 alkyl; and provided that when dotted line ^111 is the double bond, R1 is not OH. [0117] In one preferred embodiment, when Z is C and q is 1, then each of X and Y independently is hydrogen or C1-C4 alkyl.
[0118] In another embodiment, R1 is selected from the group consisting of -CH2OR2, - COR2, -COOR2, -CONR2R3, and carboxylic acid isostere.
[0119] Various embodiments relating to the compounds of Formula (I) or a stereoisomer or pharmaceutically acceptable salts thereof, are listed below. These embodiments can be combined with each other or with any other embodiments described in this application. In some aspects, provided are compounds of Formula (I) or a stereoisomer or pharmaceutically acceptable salts thereof, having one or more of the following features.
[0120] In one embodiment, R is cycloalkyl or substituted cycloalkyl. In one embodiment, the substituted cycloalkyl, is substituted with 1 to 3 substituents independently selected from the group consisting of halo and alkyl. In one embodiment, the substituted cycloalkyl, is substituted with 1 to 3 substituents independently selected from the group consisting of fluoro and methyl.
[0121] In one embodiment, R is selected from the group consisting of cyclohexyl, substituted cyclohexyl, cyclooctyl, spiro[4.5]decan-8-yl, and 4-methylbicyclo[2.2.2]octan- 1-yl. In one embodiment, the substituted cyclohexyl, is substituted with 1 to 3 substituents independently selected from the group consisting of halo or alkyl. In one embodiment, the substituted cyclohexyl, is substituted with 1 to 3 substituents independently selected from the group consisting of fluoro or methyl.
[0122] In one embodiment, R is adamantyl. In one embodiment, R is substituted adamantyl.
[0123] In one embodiment, R is phenyl. In another embodiment, R is substituted phenyl. In one embodiment, R is phenyl substituted with 1 to 5 substituents independently selected from the group consisting of hydrogen, halo, alkyl, acyl, acyloxy, carboxyl ester, acylamino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonylamino, (carboxyl ester)amino, aminosulfonyl, (substituted sulfonyl)amino, haloalkyl, haloalkoxy, haloalkylthio, cyano, and alkylsulfonyl.
[0124] In one embodiment, R is phenyl substituted with 1 to 5 substituents independently selected from the group consisting of fluoro, trifluomethyl, and trifluoromethoxy.
[0125] In one embodiment, R is selected from the group consisting of 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl,
4-trifluoromethoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 3 -fluorophenyl, 3-chlorophenyl and 3-bromophenyl.
[0126] In one embodiment, L is -NH-.
[0127] In one embodiment, L is -CR'R"- where R' and R" are independently H or alkyl or R' and R" together form a C3-C6 cycloalkyl ring. In one preferred embodiment, L is -CH2-.
[0128] In one embodiment, p is 2, 3, 4, 5, 6, 7, or 8. In one preferred embodiment, p is 4. [0129] In one embodiment, q is 0. [0130] In one embodiment, q is 1.
[0131] In one embodiment, when the dotted line zz∑z is the single bond; Z is C; and q is 0, then at least one of Y is fluoro. In one preferred embodiment, when the dotted line :==z is the single bond; Z is C; and q is 0, then at least one of Y is alkyl, such as methyl or t-butyl. In one embodiment, when the dotted line z∑∑z is the single bond; Z is C; and q is 0, then X is hydrogen and at least one of Y is fluoro. In one embodiment, when the dotted line z∑zz is the single bond; Z is C; and q is 0, then X is hydrogen and at least one of Y is alkyl, such as methyl or t-butyl.
1 0 0
[0132] In one embodiment, R is -CH2OR where R is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
[0133] In one embodiment, R1 is -COOR2 where R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
[0134] In one embodiment, R1 is -COR2 where R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
[0135] In one embodiment, R1 is -CONR2R3, where R2 and R3 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl,
0 'X and substituted heteroaryl; or R and R together with the nitrogen atom bound thereto form a heterocycloalkyl ring having 3 to 9 ring atoms, and wherein said ring is optionally substituted with alkyl, substituted alkyl, heterocyclic, oxo or carboxy.
[0136] In one embodiment, R1 is -OR2 where R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
[0137] In one embodiment, provided is a compound represented by Formula (II) or a stereoisomer, or pharmaceutically acceptable salt thereof:
Figure imgf000028_0001
wherein R is selected from the group consisting of cycloalkyl, substituted cycloalkyl, phenyl and substituted phenyl; p is 0-10; R1 is selected from the group consisting of -CH2OR2, -COR2, -COOR2, -CONR2R3,
-OR2 and carboxylic acid isostere; R2 and R3 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or R2 and R3 together with the nitrogen atom bound thereto form a heterocycloalkyl ring having 3 to 9 ring atoms, and wherein said ring is optionally substituted with alkyl, substituted alkyl, heterocyclic, oxo or carboxy; and each of Xa, Xb, Ya, and Yb is independently selected from the group consisting of hydrogen, C1-C4 alkyl, substituted C1-C4 alkyl, and halo, provided that at least one of Ya and Yb is halo or C1-C4 alkyl.
[0138] Various embodiments relating to the compounds or stereoisomer or pharmaceutically acceptable salts thereof, of Formula (II) are listed below. These embodiments can be combined with each other or with any other embodiments described in this application. In some aspects, provided are compounds of Formula (II) having one or more of the following features.
[0139] In one embodiment, R is cycloalkyl or substituted cycloalkyl.
[0140] In one embodiment, R is selected from the group consisting of cyclohexyl, substituted cyclohexyl, cyclooctyl, spiro[4.5]decan-8-yl, and 4-methylbicyclo[2.2.2]octan- 1-yl.
[0141] In one embodiment, R is adamantyl. In one embodiment, R is substituted adamantyl.
[0142] In one embodiment, R is phenyl. In another embodiment, R is substituted phenyl. In one embodiment, R is selected from the group consisting of phenyl,
3 -trifluoromethylphenyl, 4-trifluoromethylphenyl, 3 -trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 3 -fluorophenyl, 3-chlorophenyl and 3-bromophenyl.
[0143] In one embodiment, R is phenyl substituted with 1 to 5 substituents independently selected from the group consisting of fluoro, trifluomethyl, and trifluoromethoxy. [0144] In one embodiment, Xa, Xb, and Ya are hydrogen and Yb is halo. In one preferred embodiment, Xa, Xb, and Ya are hydrogen and Yb is fluoro.
[0145] In one embodiment, Xa and Xb are hydrogen, Ya is halo and Yb is halo. In one preferred embodiment, Ya and Yb are fluoro. [0146] In one embodiment, Xa, Xb, and Ya are hydrogen and Yb is alkyl. In one embodiment, Xa, Xb, and Ya are hydrogen, and Yb is methyl. In one embodiment, Yb is t- butyl.
[0147] In one embodiment, Xa and Xb are hydrogen and Ya andYb are alkyl. In one embodiment, Xa and Xb are hydrogen andYa and Yb are methyl. [0148] In one embodiment, Ya, Yb, and Xa are hydrogen and Xb is alkyl. In one embodiment, Ya, Yb, and Xa are hydrogen and Xb is methyl.
[0149] In one embodiment, Ya and Yb are hydrogen and Xa andXb are alkyl. In one embodiment,Xa and Xb are methyl.
[0150] In one embodiment, p is 2, 3, 4, 5, 6, 7, or 8. In one preferred embodiment, p is 4. [0151] In one embodiment, R1 is selected from the group consisting Of -CH2OR2, -COR2, -COOR2, -CONR2R3, and carboxylic acid isostere.
1 0 0
[0152] In one embodiment, R is -CH2OR where R is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In one preferred embodiment, R1 is -CH2OR2 where R2 is selected from the group consisting of hydrogen and methyl.
1 0 0
[0153] In one embodiment, R is -COOR where R is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In one preferred embodiment, R1 is -COOR2 where R2 is selected from the group consisting of hydrogen, methyl, ethyl, /-propyl, ter/-butyl, 2,2,2-trimethylethyl, and dimethylaminoethyl.
[0154] In one embodiment, R1 is -COR2 where R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In one preferred embodiment, R is -COR where R is selected from the group consisting of hydrogen and methyl.
[0155] In one embodiment, R is -CONR R , where R and R are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or R and R together with the nitrogen atom bound thereto form a heterocycloalkyl ring having 3 to 9 ring atoms, and wherein said ring is optionally substituted with alkyl, substituted alkyl, heterocyclic, oxo or carboxy. In one preferred embodiment, R1 is -CONR2R3, where R2 and R3 independently are selected from the group consisting of hydrogen and methyl.
[0156] In one embodiment, R1 is -CH2OR2 where R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
[0157] In one embodiment, provided is a compound represented by Formula (II) or a stereoisomer, or pharmaceutically acceptable salt thereof, wherein
R is adamantyl or substituted adamantyl; p is 2, 4, or 8;
R1 is selected from the group consisting of -CH2OR2, -COR2, -COOR2, -CONR2R3,
-OR2, and carboxylic acid isostere; R2 and R3 are independently selected from the group consisting of hydrogen and alkyl; and each of Xa, Xb, Ya, and Yb is independently selected from the group consisting of hydrogen, methyl, and halo, provided that at least one of Ya and Yb is fluoro or methyl. [0158] In one embodiment, provided is a compound represented by Formula (II) or a stereoisomer, or pharmaceutically acceptable salt thereof, wherein
R is phenyl or substituted phenyl; p is 2, 4, or 8;
R1 is selected from the group consisting of -CH2OR2, -COR2, -COOR2, -CONR2R3, -OR2, and carboxylic acid isostere; R2 and R3 are independently selected from the group consisting of hydrogen and alkyl; and each of Xa, Xb, Ya, and Yb is independently selected from the group consisting of hydrogen, methyl, and halo, provided that at least one of Ya and Yb is fluoro or methyl.
[0159] In one embodiment, provided is a compound represented by Formula (Ilia) or (HIb), or a stereoisomer, or pharmaceutically acceptable salt thereof:
Figure imgf000032_0001
wherein
R is selected from the group consisting of cycloalkyl, substituted cycloalkyl, phenyl and substituted phenyl; p is 0-10;
X and Y independently are selected from the group consisting of hydrogen, C1-C4 alkyl, substituted C1-C4 alkyl, and halo;
R1 is selected from the group consisting of -CH2OR2, -COR2, -COOR2, -CONR2R3, and carboxylic acid isostere; and R2 and R3 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or R2 and R3 together with the nitrogen atom bound thereto form a heterocycloalkyl ring having 3 to 9 ring atoms, and wherein said ring is optionally substituted with alkyl, substituted alkyl, heterocyclic, oxo or carboxy. [0160] Various embodiments relating to the compounds or stereoisomer or pharmaceutically acceptable salts thereof, of Formula (Ilia) and (HIb) are listed below. These embodiments can be combined with each other or with any other embodiments described in this application. In some aspects, provided are compounds of Formula (Ilia) and (HIb) having one or more of the following features.
[0161] In one embodiment, R is cycloalkyl. In one embodiment, R is substituted cycloalkyl.
[0162] In one embodiment, R is selected from the group consisting of cyclohexyl, substituted cyclohexyl, cyclooctyl, spiro[4.5]decan-8-yl, and 4-methylbicyclo[2.2.2]octan- 1-yl.
[0163] In one embodiment, R is adamantyl. In one embodiment, R is substituted adamantyl.
[0164] In one embodiment, R is phenyl. In one embodiment, R is substituted phenyl.
[0165] In one embodiment, R is selected from the group consisting of phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 3 -fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, and 4-trifluoromethoxyphenyl.
[0166] In one embodiment, R is phenyl substituted with 1 to 5 substituents independently selected from the group consisting of fluoro, trifluomethyl, and trifluoromethoxy. [0167] In one embodiment, p is 3, 4, or 5. In one preferred embodiment, p is 4.
[0168] In one embodiment, X is hydrogen. In one preferred embodiment, Y is hydrogen, fluoro, or methyl.
[0169] In one embodiment, R1 is -CH2OR2 where R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In one preferred embodiment, R1 is -CH2OR2 where R2 is selected from the group consisting of hydrogen or methyl.
[0170] In one embodiment, R1 is -COOR2 where R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In
1 0 0 one embodiment, R is -COOR where R is selected from the group consisting of hydrogen, methyl, ethyl, /-propyl, ter/-butyl, 2,2,2-trimethylethyl, and dimethylaminoethyl.
1 0 0
[0171] In one embodiment, R is -COR where R is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In one embodiment, R1 is -COR2 where R2 is selected from the group consisting of hydrogen and methyl.
1 0 'X 0 'X
[0172] In one embodiment, R is -CONR R , where R and R are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or R and R together with the nitrogen atom bound thereto form a heterocycloalkyl ring having 3 to 9 ring atoms, and wherein said ring is optionally substituted with alkyl, substituted alkyl, heterocyclic, oxo or carboxy. In one embodiment, R1 is -CONR2R3, where R2 and R3 are independently selected from the group consisting of hydrogen and methyl.
[0173] In one embodiment, provided is a compound represented by Formula (Ilia) or (HIb), or a stereoisomer, or pharmaceutically acceptable salt thereof, wherein
R is adamantyl or substituted adamantyl; p is 4;
X is hydrogen;
Y is hydrogen, halo, or methyl;
R1 is selected from the group consisting of -CH2OR2, -COR2, -COOR2, -CONR2R3, and carboxylic acid isostere; and R2 and R3 are independently selected from the group consisting of hydrogen and alkyl.
[0174] In one embodiment, provided is a compound represented by Formula (Ilia) or (HIb), or a stereoisomer, or pharmaceutically acceptable salt thereof, wherein
R is phenyl or substituted phenyl; p is 4; X is hydrogen;
Y is hydrogen, halo, or methyl;
R1 is selected from the group consisting of -CH2OR2, -COR2, -COOR2, -CONR2R3, or carboxylic acid isostere; and R2 and R3 are independently selected from the group consisting of hydrogen and alkyl.
[0175] In one embodiment, provided is a compound represented by Formula (IV), or a stereoisomer, or pharmaceutically acceptable salt thereof:
Figure imgf000035_0001
wherein
R is selected from the group consisting of cycloalkyl, substituted cycloalkyl, phenyl and substituted phenyl; R1 is selected from the group consisting of -CH2OR2, -COR2, -COOR2, -CONR2R3, and carboxylic acid isostere; and R2 and R3 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or R2 and R3 together with the nitrogen atom bound thereto form a heterocycloalkyl ring having 3 to 9 ring atoms, and wherein said ring is optionally substituted with alkyl, substituted alkyl, heterocyclic, oxo or carboxy; p is 0-10;
Z is O or NR4 where R4 is hydrogen or C1-C4 alkyl; and
Ya and Yb independently are selected from the group consisting of hydrogen, halo, or C1-C4 alkyl.
[0176] In one embodiment, R is cycloalkyl. In one embodiment, R is substituted cycloalkyl. [0177] In one embodiment, R is adamantyl. In one embodiment, R is substituted adamantyl.
[0178] In one embodiment, R is phenyl. In one embodiment, R is substituted phenyl.
[0179] In one embodiment, R is phenyl substituted with 1 to 5 substituents independently selected from the group consisting of fluoro, trifluomethyl, and trifluoromethoxy.
[0180] In one embodiment, R is selected from the group consisting of phenyl, 4- fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 3 -fluorophenyl, 3-chlorophenyl, 3- bromophenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, and 4-trifluoromethoxyphenyl. [0181] In one embodiment,/? is 4, 6, or 8.
[0182] In one embodiment, p is 4.
[0183] In one embodiment, Z is O.
[0184] In one embodiment, Z is NCH3.
[0185] In one embodiment, Ya and Yb independently are fluoro. [0186] In one embodiment, Ya and Yb independently are hydrogen or methyl. In one preferred embodiment, both Ya and Yb are hydrogen,
1 0 0
[0187] In one embodiment, R is -CH2OR where R is selected from the group consisting of hydrogen or methyl.
1 0 0
[0188] In one embodiment, R is -COOR where R is selected from the group consisting of hydrogen, methyl, ethyl, /-propyl, tert-butyi, 2,2,2-trimethylethyl, and dimethylamino ethyl .
[0189] In one embodiment, R1 is -CONR2R3, where R2 and R3 independently are selected from the group consisting of hydrogen or methyl.
[0190] In one embodiment, R1 is -COR2 where R2 is selected from the group consisting of hydrogen and methyl.
[0191] In one embodiment, provided is a compound represented by Formula (IV), or a stereoisomer, or pharmaceutically acceptable salt thereof, wherein
R is phenyl or substituted phenyl; R1 is selected from the group consisting of -CH2OR2, -COR2, -COOR2, -CONR2R3, and carboxylic acid isostere; and R2 and R3 are independently selected from the group consisting of hydrogen and alkyl; p is 4 or 8;
Z is O, NH, or NCH3; and
Ya and Yb independently are selected from the group consisting of hydrogen or fluoro.
[0192] In one embodiment, provided is a compound represented by Formula (IV), or a stereoisomer, or pharmaceutically acceptable salt thereof, wherein
R is adamantyl or substituted adamantyl;
R1 is selected from the group consisting of -CH2OR2, -COR2, -COOR2, -CONR2R3, and carboxylic acid isostere; and
R2 and R3 are independently selected from the group consisting of hydrogen and alkyl; p is 4 or 8;
Z is O, NH, or NCH3; and Ya and Yb independently are selected from the group consisting of hydrogen or fluoro. [0193] In one embodiment, the invention provides a prodrug of the compounds of formula I, II, III, or IV.
[0194] In one embodiment, there is provided a compound selected from the group consisting of:
(Z)-l-(7-fluoro-8-hydroxyoct-6-enyl)-3-(adamantyl)urea; (Z)-methyl 2-fluoro-8-(3-adamantylureido)oct-2-enoate;
(Z)-ethyl 2-fluoro-8-(3-adamantylureido)oct-2-enoate;
(Z)-isopropyl 2-fluoro-8-(3-adamantylureido)oct-2-enoate;
(Z)-2-fluoro-8-(3-adamantylureido)oct-2-enoic acid;
(Z)-2-fluoro-8-(3-adamantylureido)oct-2-enamide; (Z)-l-(7-fluoro-8-methoxyoct-6-enyl)-3-adamantylurea;
(Z)-t-butyl 2-fluoro-8-(3-adamantylureido)oct-2-enoate; (Z)-I -(7-fluoro-8-hydroxyoct-6-enyl)-3-(4-(trifluoromethyl)phenyl)urea;
(Z)-I -(7-fluoro-8-hydroxyoct-6-enyl)-3-(4-(trifluoromethoxy)phenyl)urea;
(Z)-l-(7-fluoro-8-hydroxyoct-6-enyl)-3-(4-fluorophenyl)urea;
(Z)-2-fluoro-8-(3-(4-fluorophenyl)ureido)oct-2-enamide; (Z)-ethyl 2-fluoro-8-(3-(4-fluorophenyl)ureido)oct-2-enoate;
(Z)-2-fluoro-8-(3-(4-fluorophenyl)ureido)oct-2-enoic acid;
(Z)-2-fluoro-8-(3-(4-(trifluoromethoxy)phenyl)ureido)oct-2-enoic acid;
(Z)-2-fluoro-8-(3-(4-(trifluoromethoxy)phenyl)ureido)oct-2-enamide;
(Z)-ethyl 2-fluoro-8-(3-(4-(trifluoromethoxy)phenyl)ureido)oct-2-enoate; (Z)-ethyl 2-fluoro-8-(3-(4-(trifluoromethyl)phenyl)ureido)oct-2-enoate;
2-fluoro-6-(3-adamantylureido)hexanoic acid;
Ethyl 2-fluoro-6-(3-adamantylureido)hexanoate;
1 -(7-fluoro-8-hydroxyoctyl)-3 -(adamantyl)urea; l-(7,7-difluoro-8-hydroxyoctyl)-3-(adamantyl)urea; ethyl 2,2-difluoro-8-(3-adamantylureido)octanoate; methyl 2-fluoro-8-(3-adamantylureido)octanoate; ethyl 2-fluoro-8-(3-adamantylureido)octanoate; isopropyl 2-fluoro-8-(3-adamantylureido)octanoate;
2-fluoro-8-(3-adamantylureido)octanoic acid; t-butyl 2-fluoro-8-(3-adamantylureido)octanoate;
2-fluoro-8-(3-adamantylureido)octanamide; l-(7-fluoro-8-methoxyoctane)-3-adamantylurea; l-(7-fluoro-8-oxononyl)-3-adamantylurea;
2-fluoro-12-(3-adamantylureido)dodecanoic acid; Ethyl 2-fluoro-12-(3-adamantylureido)dodecanoate;
2-fluoro-10-(3-adamantylureido)decanoic acid;
Ethyl 2-fluoro- 10-(3-adamantylureido)decanoate; ethyl 2-fluoro-8-(3-(4-fluorophenyl)ureido)octanoate;
2-fluoro-8-(3-(4-fluorophenyl)ureido)octanoic acid; 2-fluoro-8-(3-(4-fluorophenyl)ureido)octanamide;
2-fluoro-8-(3-(4-(trifluoromethoxy)phenyl)ureido)octanoic acid; ethyl 2-fluoro-8-(3-(4-(trifluoromethoxy)phenyl)ureido)octanoate; ethyl 2-fluoro-8-(3-(4-(trifluoromethyl)phenyl)ureido)octanoate; ethyl 2-fluoro-8-(3-(4-fluorophenyl)ureido)octanoate;
8-(3-(4,4-dimethylcyclohexyl)ureido)-2-fluorooctanoic acid; ethyl 8-(3-(4,4-dimethylcyclohexyl)ureido)-2-fluorooctanoate; 8-(3-cyclooctylureido)-2-fluorooctanoic acid; ethyl 8-(3-cyclooctylureido)-2-fluorooctanoate;
8-(3-(4,4-difluorocyclohexyl)ureido)-2-fluorooctanoic acid; ethyl 8-(3-(4,4-difluorocyclohexyl)ureido)-2-fluorooctanoate;
2-fluoro-8-(3-spiro[4.5]decan-8-ylureido)octanoic acid; ethyl 2-fluoro-8-(3-spiro[4.5]decan-8-ylureido)octanoate;
2-fluoro-8-(3-(4-methylbicyclo[2.2.2]octan- 1 -yl)ureido)octanoic acid; ethyl 2-fluoro-8-(3-(4-methylbicyclo[2.2.2]octan- 1 -yl)ureido)octanoate; methyl 2,2-dimethyl-l l-(3-(4-(trifluoromethyl)phenyl)ureido)undecanoate;
2,2-dimethyl- 11 -(3-(4-(trifluoromethyl)phenyl)ureido)undecanoic acid; 1 -(8-hydroxy-8-methylnonyl)-3 -adamantylurea;
1 -(8-hydroxy-9,9-dimethyldecyl)-3- adamantylurea;
(E)-ethyl 8-(3-adamantylureido)oct-2-enoate; ethyl 2-methyl-8-(3-adamantylureido)octanoate;
1 -(5 -(2-hydroxyethoxy)pentyl)-3 -adamantylurea; methyl 2-(methyl(9-(3 -(4-(trifluoromethyl)phenyl)ureido)nonyl)amino)acetate; methyl 2-(methyl(9-(3 -adamantylureido)nonyl)amino)acetate;
2-(methyl(9-(3-(4-(trifluoromethyl)phenyl)ureido)nonyl)amino)acetamide;
2-(methyl(9-(3-adamantylureido)nonyl)amino)acetamide; ethyl 2,2-difluoro-2-(5-(3-adamantylureido)pentyloxy)acetate; 3,3-dimethyl-5-oxo-5-(6-(3-(4-
(trifluoromethyl)phenyl)ureido)hexylamino)pentanoic acid; and
3,3-dimethyl-5-oxo-5-(6-(3-adamantylureido)hexylamino)pentanoic acid, or a stereoisomer, or pharmaceutically acceptable salt thereof.
[0195] In some embodiments, there is provided a compound selected from Tables 1, 2, or 3 or a stereoisomer, or a pharmaceutically acceptable salt thereof. Table 1
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Table 2
Figure imgf000044_0002
Figure imgf000045_0001
Table 3
Figure imgf000045_0002
[0196] In one embodiment, provided is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of any one of Formula (I), (II), (Ilia), (HIb), or (IV) or of Tables 1, 2, or 3 or a stereoisomer or pharmaceutically acceptable salt thereof, for treating a soluble expoxide hydrolase mediated disease.
[0197] In another embodiment, provided is a method for inhibiting a soluble epoxide hydrolase, comprising contacting the soluble epoxide hydrolase with an effective amount of a compound of the invention or a stereoisomer or pharmaceutically acceptable salt thereof.
[0198] In another embodiment, provided is a method for treating a soluble expoxide hydrolase mediated disease, the method comprising administering to a patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of any one of Formula (I), (II), (Ilia), (HIb), or (IV) or of Tables 1, 2, or 3 or a stereoisomer or pharmaceutically acceptable salt thereof.
[0199] It has previously been shown that inhibitors of soluble epoxide hydrolase ("sEH") can reduce hypertension (see, e.g., U.S. Pat. No. 6,531,506). Such inhibitors can be useful in controlling the blood pressure of persons with undesirably high blood pressure, including those who suffer from diabetes.
[0200] In preferred embodiments, compounds of the invention are administered to a subject in need of treatment for hypertension, specifically renal, hepatic, or pulmonary hypertension; inflammation, specifically renal inflammation, hepatic inflammation, vascular inflammation, and lung inflammation; adult respiratory distress syndrome; diabetic complications; end stage renal disease; Raynaud syndrome; and arthritis.
Methods to Treat ARDS and SIRS
[0201] Adult respiratory distress syndrome (ARDS) is a pulmonary disease that has a mortality rate of 50% and results from lung lesions that are caused by a variety of conditions found in trauma patients and in severe burn victims. Ingram, R. H. Jr., "Adult Respiratory Distress Syndrome," Harrison's Principals of Internal Medicine, 13, p. 1240,
1995. With the possible exception of glucocorticoids, there have not been therapeutic agents known to be effective in preventing or ameliorating the tissue injury, such as microvascular damage, associated with acute inflammation that occurs during the early development of ARDS. [0202] ARDS, which is defined in part by the development of alveolar edema, represents a clinical manifestation of pulmonary disease resulting from both direct and indirect lung injury. While previous studies have detailed a seemingly unrelated variety of causative agents, the initial events underlying the pathophysiology of ARDS are not well understood. ARDS was originally viewed as a single organ failure, but is now considered a component of the multisystem organ failure syndrome (MOFS). Pharmacologic intervention or prevention of the inflammatory response is presently viewed as a more promising method of controlling the disease process than improved ventilatory support techniques. See, for example, Demling, Annu. Rev. Med., 46, pp. 193-203, 1995. [0203] Another disease (or group of diseases) involving acute inflammation is the systematic inflammatory response syndrome, or SIRS, which is the designation recently established by a group of researchers to describe related conditions resulting from, for example, sepsis, pancreatitis, multiple trauma such as injury to the brain, and tissue injury, such as laceration of the musculature, brain surgery, hemorrhagic shock, and imrnune- mediated organ injuries (JAMA, 268(24):3452-3455 (1992)).
[0204] The ARDS ailments are seen in a variety of patients with severe burns or sepsis. Sepsis in turn is one of the SIRS symptoms. In ARDS, there is an acute inflammatory reaction with high numbers of neutrophils that migrate into the interstitium and alveoli. If this progresses there is increased inflammation, edema, cell proliferation, and the end result is impaired ability to extract oxygen. ARDS is thus a common complication in a wide variety of diseases and trauma. The only treatment is supportive. There are an estimated 150,000 cases per year and mortality ranges from 10% to 90%.
[0205] The exact cause of ARDS is not known. However it has been hypothesized that over-activation of neutrophils leads to the release of linoleic acid in high levels via phospho lipase A2 activity. Linoleic acid in turn is converted to 9,10-epoxy-12- octadecenoate enzymatically by neutrophil cytochrome P-450 epoxygenase and/or a burst of active oxygen. This lipid epoxide, or leukotoxin, is found in high levels in burned skin and in the serum and bronchial lavage of burn patients. Furthermore, when injected into rats, mice, dogs, and other mammals it causes ARDS. The mechanism of action is not known. However, the leukotoxin diol produced by the action of the soluble epoxide hydrolase appears to be a specific inducer of the mitochondrial inner membrane permeability transition (MPT). This induction by leukotoxin diol, the diagnostic release of cytochrome c, nuclear condensation, DNA laddering, and CPP32 activation leading to cell death were all inhibited by cyclosporin A, which is diagnostic for MPT induced cell death. Actions at the mitochondrial and cell level were consistent with this mechanism of action suggesting that the inhibitors of this invention could be used therapeutically with compounds which block MPT.
[0206] Thus in one embodiment provided is a method for treating ARDS. In another embodiment, provided is a method for treating SIRS.
Methods for Inhibiting Progression of Kidney Deterioration (Nephropathy) and Reducing Blood Pressure:
[0207] In another aspect of the invention, the compounds of the invention can reduce damage to the kidney, and especially damage to kidneys from diabetes, as measured by albuminuria. The compounds of the invention can reduce kidney deterioration (nephropathy) from diabetes even in individuals who do not have high blood pressure. The conditions of therapeutic administration are as described above.
[0208] cis-Epoxyeicosantrienoic acids ("EETs") can be used in conjunction with the compounds of the invention to further reduce kidney damage. EETs, which are epoxides of arachidonic acid, are known to be effectors of blood pressure, regulators of inflammation, and modulators of vascular permeability. Hydrolysis of the epoxides by sEH diminishes this activity. Inhibition of sEH raises the level of EETs since the rate at which the EETs are hydrolyzed into DHETs is reduced. Without wishing to be bound by theory, it is believed that raising the level of EETs interferes with damage to kidney cells by the microvasculature changes and other pathologic effects of diabetic hyperglycemia. Therefore, raising the EET level in the kidney is believed to protect the kidney from progression from microalbuminuria to end stage renal disease.
[0209] EETs are well known in the art. EETs useful in the methods of the present invention include 14,15-EET, 8,9-EET and 11,12-EET, and 5,6 EETs, in that order of preference. Preferably, the EETs are administered as the methyl ester, which is more stable. Persons of skill will recognize that the EETs are regioisomers, such as 8S,9R- and 14R,15S-EET. 8,9-EET, 11,12-EET, and 14R,15S-EET, are commercially available from, for example, Sigma- Aldrich (catalog nos. E5516, E5641, and E5766, respectively, Sigma-Aldrich Corp., St. Louis, Mo).
[0210] EETs produced by the endothelium have anti-hypertensive properties and the EETs 11,12-EET and 14,15-EET may be endothelium-derived hyperpolarizing factors (EDHFs). Additionally, EETs such as 11,12-EET have pro fibrinolytic effects, anti-inflammatory actions and inhibit smooth muscle cell proliferation and migration. In the context of the present invention, these favorable properties are believed to protect the vasculature and organs during renal and cardiovascular disease states.
[0211] Inhibition of sEH activity can be effected by increasing the levels of EETs. This permits EETs to be used in conjunction with one or more sEH inhibitors to reduce nephropathy in the methods of the invention. It further permits EETs to be used in conjunction with one or more sEH inhibitors to reduce hypertension, or inflammation, or both. Thus, medicaments of EETs can be made which can be administered in conjunction with one or more sEH inhibitors, or a medicament containing one or more sEH inhibitors can optionally contain one or more EETs.
[0212] The EETs can be administered concurrently with the sEH inhibitor, or following administration of the sEH inhibitor. It is understood that, like all drugs, inhibitors have half lives defined by the rate at which they are metabolized by or excreted from the body, and that the inhibitor will have a period following administration during which it will be present in amounts sufficient to be effective. IfEETs are administered after the inhibitor is administered, therefore, it is desirable that the EETs be administered during the period in which the inhibitor will be present in amounts to be effective to delay hydrolysis of the EETs. Typically, the EET or EETs will be administered within 48 hours of administering an sEH inhibitor. Preferably, the EET or EETs are administered within 24 hours of the inhibitor, and even more preferably within 12 hours. In increasing order of desirability, the EET or EETs are administered within 10, 8, 6, 4, 2, hours, 1 hour, or one half hour after administration of the inhibitor. Most preferably, the EET or EETs are administered concurrently with the inhibitor.
[0213] In preferred embodiments, the EETs, the compound of the invention, or both, are provided in a material that permits them to be released over time to provide a longer duration of action. Slow release coatings are well known in the pharmaceutical art; the choice of the particular slow release coating is not critical to the practice of the present invention.
[0214] EETs are subject to degradation under acidic conditions. Thus, if the EETs are to be administered orally, it is desirable that they are protected from degradation in the stomach. Conveniently, EETs for oral administration may be coated to permit them to passage through the acidic environment of the stomach into the basic environment of the intestines. Such coatings are well known in the art. For example, aspirin coated with so-called "enteric coatings" is widely available commercially. Such enteric coatings may be used to protect EETs during passage through the stomach. An exemplary coating is set forth in the Examples .
[0215] While the anti-hypertensive effects of EETs have been recognized, EETs have not been administered to treat hypertension because it was thought endogenous sEH would hydrolyse the EETs too quickly for them to have any useful effect. Surprisingly, it was found during the course of the studies underlying the present invention that exogenously administered inhibitors of sEH succeeded in inhibiting sEH sufficiently that levels of EETs could be further raised by the administration of exogenous EETs. These findings underlie the co-administration of sEH inhibitors and of EETs described above with respect to inhibiting the development and progression of nephropathy. This is an important improvement in augmenting treatment. While levels of endogenous EETs are expected to rise with the inhibition of sEH activity caused by the action of the sEH inhibitor, and therefore to result in at least some improvement in symptoms or pathology, it may not be sufficient in all cases to inhibit progression of kidney damage fully or to the extent intended. This is particularly true where the diseases or other factors have reduced the endogenous concentrations of EETs below those normally present in healthy individuals. Administration of exogenous EETs in conjunction with an sEH inhibitor is therefore expected to be beneficial and to augment the effects of the sEH inhibitor in reducing the progression of diabetic nephropathy.
[0216] The present invention can be used with regard to any and all forms of diabetes to the extent that they are associated with progressive damage to the kidney or kidney function. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels. The long-term complications of diabetes include retinopathy with potential loss of vision; nephropathy leading to renal failure; peripheral neuropathy with risk of foot ulcers, amputation, and Charcot joints.
[0217] In addition, persons with metabolic syndrome are at high risk of progression to type 2 diabetes, and therefore at higher risk than average for diabetic nephropathy. It is therefore desirable to monitor such individuals for microalbuminuria, and to administer an sEH inhibitor and, optionally, one or more EETs, as an intervention to reduce the development of nephropathy. The practitioner may wait until microalbuminuria is seen before beginning the intervention. Since a person can be diagnosed with metabolic syndrome without having a blood pressure of 130/85 or higher, both persons with blood pressure of 130/85 or higher and persons with blood pressure below 130/85 can benefit from the administration of sEH inhibitors and, optionally, of one or more EETs, to slow the progression of damage to their kidneys. In some preferred embodiments, the person has metabolic syndrome and blood pressure below 130/85. [0218] Dyslipidemia or disorders of lipid metabolism is another risk factor for heart disease. Such disorders include an increased level of LDL cholesterol, a reduced level of HDL cholesterol, and an increased level of triglycerides. An increased level of serum cholesterol, and especially of LDL cholesterol, is associated with an increased risk of heart disease. The kidneys are also damaged by such high levels. It is believed that high levels of triglycerides are associated with kidney damage. In particular, levels of cholesterol over 200 mg/dL, and especially levels over 225 mg/dL, would suggest that sEH inhibitors and, optionally, EETs, should be administered. Similarly, triglyceride levels of more than 215 mg/dL, and especially of 250 mg/dL or higher, would indicate that administration of sEH inhibitors and, optionally, of EETs, would be desirable. The administration of compounds of the present invention with or without the EETs, can reduce the need to administer statin drugs (HMG-COA reductase inhibitors) to the patients, or reduce the amount of the statins needed. In some embodiments, candidates for the methods, uses, and compositions of the invention have triglyceride levels over 215 mg/dL and blood pressure below 130/85. In some embodiments, the candidates have triglyceride levels over 250 mg/dL and blood pressure below 130/85. In some embodiments, candidates for the methods, uses and compositions of the invention have cholesterol levels over 200 mg/dL and blood pressure below 130/85. In some embodiments, the candidates have cholesterol levels over 225 mg/dL and blood pressure below 130/85.
Methods of Inhibiting the Proliferation of Vascular Smooth Muscle Cells: [0219] In other embodiments, compounds of Formula (I), (II), (Ilia), (HIb), or (IV) or of Tables 1, 2, or 3 inhibit proliferation of vascular smooth muscle (VSM) cells without significant cell toxicity, (e.g. specific to VSM cells). Because VSM cell proliferation is an integral process in the pathophysiology of atherosclerosis, these compounds are suitable for slowing or inhibiting atherosclerosis. These compounds are useful to subjects at risk for atherosclerosis, such as individuals who have diabetes and those who have had a heart attack or a test result showing decreased blood circulation to the heart. The conditions of therapeutic administration are as described above.
[0220] The methods of the invention are particularly useful for patients who have had percutaneous intervention, such as angioplasty to reopen a narrowed artery, to reduce or to slow the narrowing of the reopened passage by restenosis. In some preferred embodiments, the artery is a coronary artery. The compounds of the invention can be placed on stents in polymeric coatings to provide a controlled localized release to reduce restenosis. Polymer compositions for implantable medical devices, such as stents, and methods for embedding agents in the polymer for controlled release, are known in the art and taught, for example, in U.S. Pat. Nos. 6,335,029; 6,322,847; 6,299,604; 6,290,722; 6,287,285; and 5,637,113. In preferred embodiments, the coating releases the inhibitor over a period of time, preferably over a period of days, weeks, or months. The particular polymer or other coating chosen is not a critical part of the present invention.
[0221] The methods of the invention are useful for slowing or inhibiting the stenosis or restenosis of natural and synthetic vascular grafts. As noted above in connection with stents, desirably, the synthetic vascular graft comprises a material which releases a compound of the invention over time to slow or inhibit VSM proliferation and the consequent stenosis of the graft. Hemodialysis grafts are a particularly preferred embodiment.
[0222] In addition to these uses, the methods of the invention can be used to slow or to inhibit stenosis or restenosis of blood vessels of persons who have had a heart attack, or whose test results indicate that they are at risk of a heart attack. [0223] Removal of a clot such as by angioplasty or treatment with tissue plasminogen activator (tPA) can also lead to reperfusion injury, in which the resupply of blood and oxygen to hypoxic cells causes oxidative damage and triggers inflammatory events. In some embodiments, provided are methods for administering the compounds and compositions of the invention for treating reperfusion injury. In some such embodiments, the compounds and compositions are administered prior to or following angioplasty or administration of tPA.
[0224] In one group of preferred embodiments, compounds of the invention are administered to reduce proliferation of VSM cells in persons who do not have hypertension. In another group of embodiments, compounds of the invention are used to reduce proliferation of VSM cells in persons who are being treated for hypertension, but with an agent that is not an sEH inhibitor.
[0225] The compounds of the invention can be used to interfere with the proliferation of cells which exhibit inappropriate cell cycle regulation. In one important set of embodiments, the cells are cells of a cancer. The proliferation of such cells can be slowed or inhibited by contacting the cells with a compound of the invention. The determination of whether a particular compound of the invention can slow or inhibit the proliferation of cells of any particular type of cancer can be determined using assays routine in the art.
[0226] In addition to the use of the compounds of the invention, the levels of EETs can be raised by adding EETs. VSM cells contacted with both an EET and a compound of the invention exhibited slower proliferation than cells exposed to either the EET alone or to the compound of the invention alone. Accordingly, if desired, the slowing or inhibition of VSM cells of a compound of the invention can be enhanced by adding an EET along with a compound of the invention. In the case of stents or vascular grafts, for example, this can conveniently be accomplished by embedding the EET in a coating along with a compound of the invention so that both are released once the stent or graft is in position.
Methods of Inhibiting the Progression of Obstructive Pulmonary Disease, Interstitial Lung Disease, or Asthma:
[0227] Chronic obstructive pulmonary disease, or COPD, encompasses two conditions, emphysema and chronic bronchitis, which relate to damage caused to the lung by air pollution, chronic exposure to chemicals, and tobacco smoke. Emphysema as a disease relates to damage to the alveoli of the lung, which results in loss of the separation between alveoli and a consequent reduction in the overall surface area available for gas exchange. Chronic bronchitis relates to irritation of the bronchioles, resulting in excess production of mucin, and the consequent blocking by mucin of the airways leading to the alveoli. While persons with emphysema do not necessarily have chronic bronchitis or vice versa, it is common for persons with one of the conditions to also have the other, as well as other lung disorders.
[0228] Some of the damage to the lungs due to COPD, emphysema, chronic bronchitis, and other obstructive lung disorders can be inhibited or reversed by administering inhibitors of the enzyme known as soluble epoxide hydrolase, or "sEH". The effects of sEH inhibitors can be increased by also administering EETs. The effect is at least additive over administering the two agents separately, and may indeed be synergistic.
[0229] The studies reported herein show that EETs can be used in conjunction with sEH inhibitors to reduce damage to the lungs by tobacco smoke or, by extension, by occupational or environmental irritants. These findings indicate that the co-administration of sEH inhibitors and of EETs can be used to inhibit or slow the development or progression of COPD, emphysema, chronic bronchitis, or other chronic obstructive lung diseases which cause irritation to the lungs.
[0230] Animal models of COPD and humans with COPD have elevated levels of immunomodulatory lymphocytes and neutrophils. Neutrophils release agents that cause tissue damage and, if not regulated, will over time have a destructive effect. Without wishing to be bound by theory, it is believed that reducing levels of neutrophils reduces tissue damage contributing to obstructive lung diseases such as COPD, emphysema, and chronic bronchitis. Administration of sEH inhibitors to rats in an animal model of COPD resulted in a reduction in the number of neutrophils found in the lungs. Administration of EETs in addition to the sEH inhibitors also reduced neutrophil levels. The reduction in neutrophil levels in the presence of sEH inhibitor and EETs was greater than in the presence of the sEH inhibitor alone.
[0231] While levels of endogenous EETs are expected to rise with the inhibition of sEH activity caused by the action of the sEH inhibitor, and therefore to result in at least some improvement in symptoms or pathology, it may not be sufficient in all cases to inhibit progression of COPD or other pulmonary diseases. This is particularly true where the diseases or other factors have reduced the endogenous concentrations of EETs below those normally present in healthy individuals. Administration of exogenous EETs in conjunction with an sEH inhibitor is therefore expected to augment the effects of the sEH inhibitor in inhibiting or reducing the progression of COPD or other pulmonary diseases.
[0232] In addition to inhibiting or reducing the progression of chronic obstructive airway conditions, the invention also provides new ways of reducing the severity or progression of chronic restrictive airway diseases. While obstructive airway diseases tend to result from the destruction of the lung parenchyma, and especially of the alveoli, restrictive diseases tend to arise from the deposition of excess collagen in the parenchyma. These restrictive diseases are commonly referred to as "interstitial lung diseases", or "ILDs", and include conditions such as idiopathic pulmonary fibrosis. The methods, compositions, and uses of the invention are useful for reducing the severity or progression of ILDs, such as idiopathic pulmonary fibrosis. Macrophages play a significant role in stimulating interstitial cells, particularly fibroblasts, to lay down collagen. Without wishing to be bound by theory, it is believed that neutrophils are involved in activating macrophages, and that the reduction of neutrophil levels found in the studies reported herein demonstrate that the methods and uses of the invention will also be applicable to reducing the severity and progression of ILDs.
[0233] In some preferred embodiments, the ILD is idiopathic pulmonary fibrosis. In other preferred embodiments, the ILD is one associated with an occupational or environmental exposure. Exemplars of such ILDs, are asbestosis, silicosis, coal worker's pneumoconiosis, and berylliosis. Further, occupational exposure to any of a number of inorganic dusts and organic dusts is believed to be associated with mucus hypersecretion and respiratory disease, including cement dust, coke oven emissions, mica, rock dusts, cotton dust, and grain dust (for a more complete list of occupational dusts associated with these conditions, see Table 254-1 of Speizer, "Environmental Lung Diseases," Harrison's Principles of Internal Medicine, infra, at pp. 1429-1436). In other embodiments, the ILD is sarcoidosis of the lungs. ILDs can also result from radiation in medical treatment, particularly for breast cancer, and from connective tissue or collagen diseases such as rheumatoid arthritis and systemic sclerosis. It is believed that the methods, uses and compositions of the invention can be useful in each of these interstitial lung diseases. [0234] In another set of embodiments, the invention is used to reduce the severity or progression of asthma. Asthma typically results in mucin hypersecretion, resulting in partial airway obstruction. Additionally, irritation of the airway results in the release of mediators which result in airway obstruction. While the lymphocytes and other immunomodulatory cells recruited to the lungs in asthma may differ from those recruited as a result of COPD or an ILD, it is expected that the invention will reduce the influx of immunomodulatory cells, such as neutrophils and eosinophils, and ameliorate the extent of obstruction. Thus, it is expected that the administration of sEH inhibitors, and the administration of sEH inhibitors in combination with EETs, will be useful in reducing airway obstruction due to asthma. [0235] In each of these diseases and conditions, it is believed that at least some of the damage to the lungs is due to agents released by neutrophils which infiltrate into the lungs. The presence of neutrophils in the airways is thus indicative of continuing damage from the disease or condition, while a reduction in the number of neutrophils is indicative of reduced damage or disease progression. Thus, a reduction in the number of neutrophils in the airways in the presence of an agent is a marker that the agent is reducing damage due to the disease or condition, and is slowing the further development of the disease or condition. The number of neutrophils present in the lungs can be determined by, for example, bronchoalveolar lavage.
Treatment of Smooth Muscle Disorders [0236] In another aspect the invention provides a method for enhancing smooth muscle function by administering to the subject predisposed to a disorder, disease or condition associated therewith an effective amount of a sEH inhibitor of this invention. This aspect of the method is unrelated to hypertension. In a further aspect, the method enhances the smooth muscle relaxation of non- vascular smooth muscle. This non- vascular smooth muscle in some aspects comprises the male or female reproductive tract, bladder or gastrointestinal tract of said subject.
[0237] Impairments in smooth muscle relaxation are associated with several disorders including, but not limited to, erectile dysfunction, overactive bladder, uterine contractions and irritable bowel syndrome. [0238] Smooth muscles can be divided into "multi-unit" and "visceral" types or into
"phasic" and "tonic" types based on the characteristics of the contractile patterns. Smooth muscles may contract phasically with rapid contraction and relaxation, or tonically with slow and sustained contraction. The reproductive, digestive, respiratory, and urinary tracts, skin, eye, and vasculature all contain this tonic muscle type. By way of example, contractile and relaxation function of vascular smooth muscle is critical to regulating the lumenal diameter of the small arteries-arterioles called resistance vessels. The resistance arteries contribute significantly to setting the level of blood pressure. Smooth muscle contracts slowly and may maintain the contraction for prolonged periods in blood vessels, bronchioles, and some sphincters. By way of another example, in the digestive tract, nonvascular smooth muscle contracts in a rhythmic peristaltic fashion, rhythmically forcing foodstuffs through the digestive tract as the result of phasic contraction.
[0239] A smooth muscle disorder is characterized by an otherwise healthy smooth muscle which over or under responds to stimuli. Said stimuli are capable of inducing smooth muscle contraction or relaxation as described above. Said stimuli includes, but are not limited to, direct stimulation by the autonomic nervous system, chemical, biological or physical stimulation by neighbouring cells and hormones within the medium that surround the muscle.
[0240] Erectile dysfunction (ED) or male impotence is characterized by the regular or repeated inability to obtain or maintain an erection. There are several ways that erectile dysfunction is analyzed including, but not limited to: a) obtaining full erections at some times, such as when asleep, when the mind and psychological issues if any are less present, tends to suggest the physical structures are functionally working; b) obtaining erections which are either not rigid or full (lazy erection), or are lost more rapidly than would be expected (often before or during penetration), can be a sign of a failure of the mechanism which keeps blood held in the penis, and may signify an underlying clinical condition; and c) other factors leading to erectile dysfunction are diabetes mellitus (causing neuropathy) or hypogonadism (decreased testosterone levels due to disease affecting the testicles or the pituitary gland).
[0241] There are many causes of ED and are usually multifactorial in a single subject, including but not limited to, organic, physiologic, endocrine, and psychogenic factors. One of the physiological causes of erectile dysfunction is the inability of the smooth muscle comprising the penis to relax thereby allowing the infiltration of blood into the penis. Disorders which result in the insufficiency or defective relaxation of the smooth muscle can result in ED.
[0242] Diseases associated with ED include, but are not limited to; vascular diseases such as atherosclerosis, peripheral vascular disease, myocardial infarction, arterial hypertension, vascular diseases resulting from radiaon therapy or prostate cancer treatment, blood vessel and nerve trauma; systemic diseases such as diabetes mellitus, scleroderma, renal failure, liver cirrhosis, idiopathic hemochromatosis, cancer treatment, dyslipidemia and hypertension; neurogenic diseases such as, epilepsy, stroke, multiple sclerosis, Guillain- Barre syndrome, Alzheimers disease and trauma; respiratory dieases such as, chronic obstructive pulmonary diease and sleep apnea; hematologic diseases such as sickle cell anemia and leukemias; endocrine conditions such as, hyperthyroidism, hypothyroidism, hypogonadism and diabetes; penile conditions such as, peyronie disease, epispadias and priapism; and psychiatric conditions such as depression, widower syndrome, performance anxiety and posttraumatic stress disorder. Additional states which are associated with ED include nutritional states such as, malnutrition and zinc deficiency; surgical procedures such as, procedures on the brain and spinal cord, retroperitoneal or pelvic lymph node dissection, aortioliac or aorto femoral bypass, abdominal perineal resection, surical removal of the prostate, proctocolectomy, transurethral resection of the prostate, and cryosergery of the prostate; and treat with medication such as, antidepressants, antipsychotics, antihypertensives, antiulcer agents, 5-alpha reductase inhibitors and cholesterol-lowering agents.
[0243] Overactive bladder (OAB) is defined by the International Continence Society as a uro logical condition defined by a set of symptoms: urgency, with and without urge incontinence, usually with frequency and nocturia. The etiology of OAB is still unclear, however it is often associated with detrusuor overactivity, a pattern of bladder muscle contraction observed during urodynamic.
[0244] Irritable bowel syndrome (IBS) also known as "spastic colon" is a functional bowel disorder characterized by abdominal pair and altered bowel habits in the absence of specific and unique organic pathology. IBS is a clinically defined disease, wherein one set of criteria is that the subject must have recurrent abdominal pain or discomfort at least 3 days per month during the previous 3 months that is associated with 2 or more of the following: relieved by defecation, onset associated with a change in stool frequency and onset associated with a change in stool form or appearance. Additional symptoms included altered stool frequency, altered stool form, altered stool passage (straining and/or urgency), mucorrhea and abdominal bloating or subjective distention. [0245] Uterine Contraction is the tightening and shortening of the smooth muscles comprising the uterus. Irregular contractions, increased frequency or increased contraction strength of the uterus can be associated with the pre-menstral syndrome (PMS) or during premature or normal labor delivery of a fetus.
[0246] In another aspect, the invention provides a method for treating a smooth muscle disorder in a subject, wherein the smooth muscle disorder is characteriaed by an otherwise healthy smooth muscle which over or under responds to stimuli by administering to the subject an effective amount of a sEH inhibitor. In yet a further aspect the subject is suffering from a smooth muscle disorder selected from, but not limited to, erectile dysfunction, overactive bladder, uterine contractions, irritiable bowel syndrome, non- inflammatory irritable bowel syndrome, migraine, general gastrointestinal tract motility.
[0247] In a further aspect of the above embodiments, a subject is unable to be treated with an effective amount of a phosphodiesterase type 5 inhibitor. Examples of phosphodiesterase type 5 inhibitors include, but are not limited to, sildenafil, tadalafil, vardenafil, udenafϊl and avanafil. In a further aspect, the subject of the above embodiments are unable to be treated with a phosphodiesterase type 5 inhibitor due to a preexisting diease, disorder or condition including, but not limited to, congestive heart failure, heart disease, stroke, hypotention, diabetes or any combination thereof.
[0248] In a further aspect of the above embodiments, a subject is unable to be treated with an effective amount of an anticholinergic. Examples of anticholinergics include, but are not limited to, dicycloverine, tolterodine, oxybutynin, trospium and solifenacin.
Prophylactic and Therapeutic Methods to Reduce Stroke Damage: [0249] Inhibitors of soluble epoxide hydrolase ("sEH") and EETs administered in conjunction with inhibitors of sEH have been shown to reduce brain damage from strokes. Based on these results, we expect that inhibitors of sEH taken prior to an ischemic stroke will reduce the area of brain damage and will likely reduce the consequent degree of impairment. The reduced area of damage should also be associated with a faster recovery from the effects of the stroke.
[0250] While the pathophysiologies of different subtypes of stroke differ, they all cause brain damage. Hemorrhagic stroke differs from ischemic stroke in that the damage is largely due to compression of tissue as blood builds up in the confined space within the skull after a blood vessel ruptures, whereas in ischemic stroke, the damage is largely due to loss of oxygen supply to tissues downstream of the blockage of a blood vessel by a clot. Ischemic strokes are divided into thrombotic strokes, in which a clot blocks a blood vessel in the brain, and embolic strokes, in which a clot formed elsewhere in the body is carried through the blood stream and blocks a vessel there. In both hemorrhagic stroke and ischemic stroke, the damage is due to the death of brain cells. Based on the results observed in our studies, we would expect at least some reduction in brain damage in all types of stroke and in all subtypes.
[0251] A number of factors are associated with an increased risk of stroke. Given the results of the studies underlying the present invention, sEH inhibitors administered to persons with any one or more of the following conditions or risk factors: high blood pressure, tobacco use, diabetes, carotid artery disease, peripheral artery disease, atrial fibrillation, transient ischemic attacks (TIAs), blood disorders such as high red blood cell counts and sickle cell disease, high blood cholesterol, obesity, alcohol use of more than one drink a day for women or two drinks a day for men, use of cocaine, a family history of stroke, a previous stroke or heart attack, or being elderly, will reduce the area of brain damaged by a stroke. With respect to being elderly, the risk of stroke increases for every 10 years. Thus, as an individual reaches 60, 70, or 80, administration of sEH inhibitors has an increasingly larger potential benefit. As noted in the next section, the administration of EETs in combination with one or more sEH inhibitors can be beneficial in further reducing the brain damage.
[0252] In some preferred uses and methods, the sEH inhibitors and, optionally, EETs, are administered to persons who use tobacco, have carotid artery disease, have peripheral artery disease, have atrial fibrillation, have had one or more transient ischemic attacks (TIAs), have a blood disorder such as a high red blood cell count or sickle cell disease, have high blood cholesterol, are obese, use alcohol in excess of one drink a day if a woman or two drinks a day if a man, use cocaine, have a family history of stroke, have had a previous stroke or heart attack and do not have high blood pressure or diabetes, or are 60, 70, or 80 years of age or more and do not have hypertension or diabetes.
[0253] Clot dissolving agents, such as tissue plasminogen activator (tPA), have been shown to reduce the extent of damage from ischemic strokes if administered in the hours shortly after a stroke.For example, tPA is approved by the FDA for use in the first three hours after a stroke. Thus, at least some of the brain damage from a stoke is not instantaneous, but rather occurs over a period of time or after a period of time has elapsed after the stroke. It is contemplated that administration of sEH inhibitors, optionally with EETs, can also reduce brain damage if administered within 6 hours after a stroke has occurred, more preferably within 5, 4, 3, or 2 hours after a stroke has occurred, with each successive shorter interval being more preferable. Even more preferably, the inhibitor or inhibitors are administered 2 hours or less or even 1 hour or less after the stroke, to maximize the reduction in brain damage. Persons of skill are well aware of how to make a diagnosis of whether or not a patient has had a stroke. Such determinations are typically made in hospital emergency rooms, following standard differential diagnosis protocols and imaging procedures.
[0254] In some preferred uses and methods, the sEH inhibitors and, optionally, EETs, are administered to persons who have had a stroke within the last 6 hours who: use tobacco, have carotid artery disease, have peripheral artery disease, have atrial fibrillation, have had one or more transient ischemic attacks (TIAs), have a blood disorder such as a high red blood cell count or sickle cell disease, have high blood cholesterol, are obese, use alcohol in excess of one drink a day if a woman or two drinks a day if a man, use cocaine, have a family history of stroke, have had a previous stroke or heart attack and do not have high blood pressure or diabetes, or are 60, 70, or 80 years of age or more and do not have hypertension or diabetes.
Metabolic Syndrome
[0255] Inhibitors of soluble epoxide hydrolase ("sEH") and EETs administered in conjunction with inhibitors of sEH have been shown to treat one or more conditions associated with metabolic syndrome as provided for in U.S. Provisional Application Serial No. 60/887,124, U.S. Patent Application Publication US2008/0221105, and U.S. Patent Application Serial No. 12/264,816, all of which are incorporated herein by reference in their entirety.
[0256] Metabolic syndrome is characterized by a group of metabolic risk factors present in one person. The metabolic risk factors include central obesity (excessive fat tissue in and around the abdomen), atherogenic dyslipidemia (blood fat disorders — mainly high triglycerides and low HDL cholesterol), insulin resistance or glucose intolerance or impaired glucose tolerance, prothrombotic state (e.g., high fibrinogen or plasminogen activator inhibitor in the blood), and high blood pressure (130/85 mmHg or higher).
[0257] Metabolic syndrome, in general, can be diagnosed based on the presence of three or more of the following clinical manifestations in one subject: a) Abdominal obesity characterized by a elevated waist circumference equal to or greater than 40 inches (102 cm) in men and equal to or greater than 35 inches (88 cm) in women; b) Elevated triglycerides equal to or greater than 150 mg/dL; c) Reduced levels of high-density lipoproteins of less than 40 mg/dL in women and less than 50 mg/dL in men; d) High blood pressure equal to or greater than 130/85 mm Hg; and e) Elevated fasting glucose equal to or greater than 100 mg/dL.
[0258] Another risk factor includes reduced ratios of high-density lipoprotein (HDL) to low-density lipoprotein (LDL) of less than 0.4, or alternatively less than 0.3, or alternatively less than 0.2, or alternatively less than 0.1, or alternatively less than 0.4 but equal to or greater than 0.3, or alternatively less than 0.3 but equal to or greater than 0.2 or alternatively less than 0.2 but equal to or greater than 0.1.
[0259] It is desirable to provide early intervention to prevent the onset of metabolic syndrome so as to avoid the medical complications brought on by this syndrome.
Prevention or inhibition of metabolic syndrome refers to early intervention in subjects predisposed to, but not yet manifesting, metabolic syndrome. These subjects may have a genetic disposition associated with metabolic syndrome and/or they may have certain external acquired factors associated with metabolic syndrome, such as excess body fat, poor diet, and physical inactivity. Additionally, these subjects may exhibit one or more of the conditions associated with metabolic syndrome. These conditions can be in their incipient form.
[0260] Accordingly, one aspect, the invention provides a method for inhibiting the onset of metabolic syndrome by administering to the subject predisposed thereto an effective amount of a sEH inhibitor.
[0261] Another aspect provides a method for treating one or more conditions associated with metabolic syndrome in a subject where the conditions are selected from incipient diabetes, obesity, glucose intolerance, high blood pressure, elevated serum cholesterol, and elevated triglycerides. This method comprises administering to the subject an amount of an sEH inhibitor effective to treat the condition or conditions manifested in the subject. In one embodiment of this aspect, two or more of the noted conditions are treated by administering to the subject an effective amount of an sEH inhibitor. In this aspect, the conditions to be treated include treatment of hypertension.
[0262] sEH inhibitors are also useful in treating metabolic conditions comprising obesity, glucose intolerance, hypertension, high blood pressure, elevated levels of serum cholesterol, and elevated levels of triglycerides, reduced HDL to LDL ratios, or combinations thereof, regardless if the subject is manifesting, or is predisposed to, metabolic syndrome.
[0263] Accordingly, another aspect of the invention provides for methods for treating a metabolic condition in a subject, comprising administering to the subject an effective amount of a sEH inhibitor, wherein the metabolic condition is selected from the group consisting of conditions comprising obesity, glucose intolerance, high blood pressure, elevated serum cholesterol, and elevated triglycerides, reduced HDL to LDL ratios, and combinations thereof.
[0264] In general, levels of glucose, serum cholesterol, triglycerides, obesity, HDL to LDL ratios, and blood pressure are well known parameters and are readily determined using methods known in the art.
[0265] Several distinct categories of glucose intolerance exist, including for example, type 1 diabetes mellitus, type 2 diabetes mellitus, gestational diabetes mellitus (GDM), impaired glucose tolerance (IGT), and impaired fasting glucose (IFG). IGT and IFG are transitional states from a state of normal glycemia to diabetes. IGT is defined as two-hour glucose levels of 140 to 199 mg per dL (7.8 to 11.0 mmol) on the 75 -g oral glucose tolerance test (OGTT), and IFG is defined as fasting plasma glucose (FG) values of 100 to 125 mg per dL (5.6 to 6.9 mmol per L) in fasting patients. These glucose levels are above normal but below the level that is diagnostic for diabetes. Rao, et al, Amer. Fam. Phys. 69:1961-1968 (2004). [0266] Current knowledge suggests that development of glucose intolerance or diabetes is initiated by insulin resistance and is worsened by the compensatory hyperinsulinemia. The progression to type 2 diabetes is influenced by genetics and environmental or acquired factors including, for example, a sedentary lifestyle and poor dietary habits that promote obesity. Patients with type 2 diabetes are usually obese, and obesity is also associated with insulin resistance .
[0267] "Incipient diabetes" refers to a state where a subject has elevated levels of glucose or, alternatively, elevated levels of glycosylated hemoglobin, but has not developed diabetes. A standard measure of the long term severity and progression of diabetes in a patient is the concentration of glycosylated proteins, typically glycosylated hemoglobin. Glycosylated proteins are formed by the spontaneous reaction of glucose with a free amino group, typically the N-terminal amino group, of a protein. HbAIc is one specific type of glycosylated hemoglobin (Hb), constituting approximately 80% of all glycosylated hemoglobin, in which the N-terminal amino group of the Hb A beta chain is glycosylated.
[0268] Formation of HbAIc irreversible and the blood level depends on both the life span of the red blood cells (average 120 days) and the blood glucose concentration. A buildup of glycosylated hemoglobin within the red cell reflects the average level of glucose to which the cell has been exposed during its life cycle. Thus the amount of glycosylated hemoglobin can be indicative of the effectiveness of therapy by monitoring long-term serum glucose regulation. The HbAIc level is proportional to average blood glucose concentration over the previous four weeks to three months. Therefore HbAIc represents the time-averaged blood glucose values, and is not subject to the wide fluctuations observed in blood glucose values, a measurement most typically taken in conjunction with clinical trials of candidate drugs for controlling diabetes.
[0269] Obesity can be monitored by measuring the weight of a subject or by measuring the Body Mass Index (BMI) of a subject. BMI is determined by dividing the subject's weight in kilograms by the square of his/her height in metres (BMI = kg /m2). Alternatively, obesity can be monitored by measuring percent body fat. Percent body fat can be measured by methods known in the art including by weighing a subject underwater, by a skinfold test, in which a pinch of skin is precisely measured to determine the thickness of the subcutaneous fat layer, or by bioelectrical impedance analysis. Endothelial dysfunction
[0270] In one embodiment, the invention provides methods and compositions that treat, reduce or ameliorate the diseases or the symptoms of diseases related to endothelial dysfunction using one or more compound(s) of Formula I-IV.
[0271] The endothelium is a cellular layer lining the walls of blood vessels of a mammal. It is a highly specialized interface between blood and underlying tissues and has a number of functions, including: control of haemostasis by inhibiting platelet aggregation (antithrombotic and regulating the coagulation and fϊbrolinolytic systems); control of vascular tone, and hence blood flow; control of blood vessel smooth muscle growth; and selective permeability to cells and proteins. [0272] Normally, the endothelium maintains vascular homeostasis by responding to physiological stimuli, for example, changes in blood flow, oxygen tension etc., by adaptive alteration of function. Dysfunctional endothelium has an impaired response to such physiological stimuli, and can ultimately lead to medical disorders. A number of subsets of endothelial dysfunction have been recognized, including Endothelial Activation, and Endothelial-mediated Vasodilatory Dysfunction (see De Caterina "Endothelial dysfunctions: common denominators in vascular disease". Current Opinions in Lipidology 11 :9-23, (2000)).
[0273] Endothelial activation may lead to the initiation of atherosclerosis and is a process whereby there is an inappropriate up-regulation and expression of cell attraction and cell adhesion molecules on endothelial cells. This particularly involves the Macrophage
Chemoattractant Protein- 1 (MCP-I), chemoattractants for lymphocytes (IP-10, MIG, I- TAG), the Vascular Cell Adhesion Molecule- 1 (VCAM-I), IL-I, IL-6, TNFα, and ICAM-I, to which the monocytes and lymphocytes adhere. Once adherent, the leucocytes enter the artery wall. The monocytes and lymphocytes are recruited to the intima (sub-endothelial layers) of the blood vessels by these cell attraction and cell adhesion molecules of the activated endothelium during the early stages of atherosclerosis (see Libby, P. "Changing concepts of atherogenesis," Journal of Internal Medicine 247:349-358, (2000))
[0274] Endothelial-mediated Vasodilatory Dysfunction is characterized by a reduction or loss of endothelium-dependent vasodilation and involves "decreased nitric oxide bioavailability" (decreased production, increased destruction and/or decreased sensitivity to nitric oxide). (De Caterina (2000), cited above). Nitric oxide induces vasodilation by relaxing the smooth muscle cells of the blood vessel wall. Endothelial-mediated Vasodilatory Dysfunction can be measured as a reduction in vasodilation in response to acetylcholine, or as a reduced vasodilatory response following occlusion of arterial blood flow (reactive hyperaemia) for example using a sphygmomanometer cuff. As well as leading to a reduction in vasodilation, decreased endothelial nitric oxide bioavailability can also result in an increase in the production of vaso-constriction and hypertension. Platelet aggregation is inhibited by nitric oxide, hence a decrease in nitric oxide bioavailability can lead to an increase in platelet aggregation and consequent thrombosis. These are just a few examples of how decreased nitric oxide bioavailability resulting from Endothelial-mediated Vasodilatory Dysfunction can have pathological consequences.
[0275] A variety of diseases related to endothelial dysfunction that can be treated in the present invention, include, by way of example only, vascular inflammation, such as, atherosclerosis plaque progression/rupture and acute coronary syndrome; vasospasm, such as, coronary-angina and cerebral-subarachnoid hemorrhage; nephropathy, such as, microalbuminuria; diabetic vasculopathy; and autoimmune vasculitis. In one embodiment, the autoimmune vasculitis relates to scleroderma, lupus, behcet syndrome,takayashu arteritis, churg-strauss syndrome, cutaneous vasculitis, and thrombangitis obliterans (Reynaud's syndrome). In one embodiment, autoimmune vasculitis is associated with sickle cell anemia and beta thalasemia.
[0276] Sickle cell anemia is characterized by several aspects that make it a disease that may be positively impacted by inhibition of sEH. Although the anemia is congenital, the acute sickling events lead to the actual issues with the disease including vascular inflammation, stroke and renal damage. Vascular inflammation may be considered a key characteristic of this disease. Stroke is a co-morbidity in sickle cell anemia that has potential to be positively impacted by sEH inhibitors. Additionally, it is also characterized by leading to a wide range of glomerular and tubulointerstitial nephropathies. Finally, an sEH inhibitor can be anti-thrombotic which can positively impact the primary mortality.
[0277] US Application No. 12/ , , entitled, "Soluble epoxide hydrolase inhibitors for the treatment of endothelial dysfunction," which claims priority to US Provsional application Nos. 61/017,376 and 61/045,216 with an Attorney Docket No. 074019-1752, is incorporated herein by reference in its entirety.
Combination Therapy
[0278] As noted above, the compounds of the present invention will, in some instances, be used in combination with other therapeutic agents to bring about a desired effect. Selection of additional agents will, in large part, depend on the desired target therapy (see, e.g., Turner, N. et al. Prog. Drug Res. (1998) 51 : 33-94; Haffner, S. Diabetes Care (1998) 21 : 160-178; and DeFronzo, R. et al. (eds), Diabetes Reviews (1997) Vol. 5 No. 4). A number of studies have investigated the benefits of combination therapies with oral agents (see, e.g., Mahler, R., J. Clin. Endocrinol. Metab. (1999) 84: 1165-71; United Kingdom Prospective Diabetes Study Group: UKPDS 28, Diabetes Care (1998) 21 : 87-92; Bardin, C. W.,(ed), Current Therapy In Endocrinology And Metabolism, 6th Edition (Mosby-Year Book, Inc., St. Louis, Mo. 1997); Chiasson, J. et al., Ann. Intern. Med. (1994) 121 : 928-935; Coniff, R. et al., Clin. Ther. (1997) 19: 16-26; Coniff, R. et al., Am. J. Med. (1995) 98: 443-451; and Iwamoto, Y. et al., Diabet. Med. (1996) 13 365-370; Kwiterovich, P. Am. J. Cardiol (1998) 82(12A): 3U-17U).
[0279] Combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound of Formula (I), (II), (Ilia), (HIb), or (IV) or of Tables 1, 2, or 3 or a stereoisomer or pharmaceutically acceptable salt thereof and one or more additional active agents, as well as administration of the compound and each active agent in its own separate pharmaceutical dosage formulation. For example, a compound of Formula (I), (II), (Ilia), (HIb), or (IV) or of Tables 1, 2, or 3 or a stereoisomer or pharmaceutically acceptable salt thereof and one or more angiotensin receptor blockers, angiotensin converting enzyme inhibitors, calcium channel blockers, diuretics, alpha blockers, beta blockers, centrally acting agents, vasopeptidase inhibitors, renin inhibitors, endothelin receptor agonists, AGE (advanced glycation end-products) crosslink breakers, sodium/potassium ATPase inhibitors, endothelin receptor agonists, endothelin receptor antagonists, angiotensin vaccine, and the like; can be administered to the human subject together in a single oral dosage composition, such as a tablet or capsule, or each agent can be administered in separate oral dosage formulations. Where separate dosage formulations are used, the compound of Formula (I), (II), (Ilia), (HIb), or (IV) or of Tables 1, 2, or 3 or a stereoisomer or pharmaceutically acceptable salt thereof and one or more additional active agents can be administered at essentially the same time (i.e., concurrently), or at separately staggered times (i.e., sequentially). Combination therapy is understood to include all these regimens.
Administration and Pharmaceutical Composition [0280] In general, the compounds of this invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. The actual amount of the compound of this invention, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors. The drug can be administered more than once a day, preferably once or twice a day. All of these factors are within the skill of the attending clinician.
[0281] Therapeutically effective amounts of the compounds may range from approximately 0.05 to 50 mg per kilogram body weight of the recipient per day; preferably about 0.1-25 mg/kg/day, more preferably from about 0.5 to 10 mg/kg/day. Thus, for administration to a 70 kg person, the dosage range would most preferably be about 35-70 mg per day.
[0282] In general, compounds of this invention will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), parenteral (e.g., intramuscular, intravenous or subcutaneous), or intrathecal administration. The preferred manner of administration is oral using a convenient daily dosage regimen that can be adjusted according to the degree of affliction. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions. Another preferred manner for administering compounds of this invention is inhalation. This is an effective method for delivering a therapeutic agent directly to the respiratory tract (see U. S. Patent 5,607,915).
[0283] The choice of formulation depends on various factors such as the mode of drug administration and bioavailability of the drug substance. For delivery via inhalation the compound can be formulated as liquid solution, suspensions, aerosol propellants or dry powder and loaded into a suitable dispenser for administration. There are several types of pharmaceutical inhalation devices-nebulizer inhalers, metered dose inhalers (MDI) and dry powder inhalers (DPI). Nebulizer devices produce a stream of high velocity air that causes the therapeutic agents (which are formulated in a liquid form) to spray as a mist that is carried into the patient's respiratory tract. MDFs typically are formulation packaged with a compressed gas. Upon actuation, the device discharges a measured amount of therapeutic agent by compressed gas, thus affording a reliable method of administering a set amount of agent. DPI dispenses therapeutic agents in the form of a free flowing powder that can be dispersed in the patient's inspiratory air-stream during breathing by the device. In order to achieve a free flowing powder, the therapeutic agent is formulated with an excipient such as lactose. A measured amount of the therapeutic agent is stored in a capsule form and is dispensed with each actuation.
[0284] Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area, i.e., decreasing particle size. For example, U.S. Pat. No.
4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules. U.S. Patent No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
[0285] The compositions are comprised of in general, a compound of the invention in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound. Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art. [0286] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.
[0287] Compressed gases may be used to disperse a compound of this invention in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc. Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).
[0288] The amount of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt%) basis, from about 0.01-99.99 wt% of the compound of based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 1-80 wt%. Representative pharmaceutical formulations containing compounds of the invention are described below.
Formulation Examples
[0289] The following are representative pharmaceutical formulations containing a compound of the present invention.
Tablet formulation
[0290] The following ingredients are mixed intimately and pressed into single scored tablets.
Figure imgf000070_0001
Capsule formulation
[0291] The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule.
Figure imgf000071_0001
Suspension formulation
[0292] The following ingredients are mixed to form a suspension for oral administration (q.s. = sufficient amount).
Figure imgf000071_0002
Injectable formulation [0293] The following ingredients are mixed to form an injectable formulation.
Figure imgf000071_0003
Suppository formulation
[0294] A suppository of total weight 2.5 g is prepared by mixing the compound of the invention with Witepsol® H- 15 (triglycerides of saturated vegetable fatty acid; Riches-Nelson, Inc., New York), and has the following composition:
Figure imgf000072_0001
General Synthetic Methods
[0295] The compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. [0296] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.
[0297] Furthermore, the compounds of this invention may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this invention, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like. [0298] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Others may be prepared by procedures, or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).
[0299] Various starting materials, intermediates, and compounds of the invention may be isolated and purified where appropriate using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography. Characterization of these compounds may be performed using conventional methods such as by melting point, mass spectrum, nuclear magnetic resonance, and various other spectroscopic analyses.
Scheme 1
Figure imgf000073_0001
[0300] Alternatively, the synthesis of the compounds of the invention can also be exemplified by, but is not limited to, as shown in Scheme 1. The dotted line, the wavy line, R, R1, X, Y, m, n, and p are as defined herein. Amines 1.1 react with the appropriate isocyanates 1.2 to form corresponding urea or thiourea of formula I. Typically, the formation of the urea is conducted using a polar solvent such as DMF (dimethylformamide) at 0 to 10 0C. Isocyanates 1.2 can be either known compounds or compounds that can be prepared from known compounds by conventional synthetic procedures.
Scheme 2
H2N
Figure imgf000074_0001
Deprotecting agent
Figure imgf000074_0002
Figure imgf000074_0003
1.8 1.7
[0301] In Scheme 2,/? is as defined herein. The synthesis of the compounds of the invention can be exemplified by, but is not limited to, the preparation of the intermediate 1.8, as shown in Scheme 2. Amine 1.3 can be protected with any amine protecting group known in the art (for example, 2,4-dimethoxy-benzyl (DMB), tert-butoxycarbonyl (Boc) etc.) to give compounds 1.4. For example, amine 1.3 can be treated with t-Boc anhydride in the presence of a base, such as sodium carbonate, and a suitable solvent such as, THF to give compounds 1.4. Upon reaction completion, 1.4 can be recovered by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration and the like; or, alternatively, used in the next step without purification and/or isolation.
[0302] Compounds 1.4 are then treated with any suitable oxidizing agent known in the art, to give aldehydes 1.5. For example, 1.4 can be treated with pyridinium chlorochromate (PCC) and neutral alumina (AI2O3) in the presence of a suitable solvent, such as, dichloromethane (DCM) to give 1.5. Upon reaction completion, 1.5 can be recovered by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration and the like; or, alternatively, used in the next step without purification and/or isolation.
[0303] Compounds 1.5 are then treated with triethyl-2-fiuoro-2-phosphonoacetate 1.6 to give compounds 1.7. This is typically performed in dry tetrahydrofuran (THF) or another suitable solvent known to one skilled in the art, typically at, but not limited to, room temperature in the presence of n-butyllithium (n-BuLi), or another suitable base known to one skilled in the art. Upon reaction completion, 1.7 can be recovered by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration and the like; or, alternatively, used in the next step without purification and/or isolation.
[0304] Compounds 1.7 are then deprotected using a suitable deprotecting agent known in the art to give the intermediate 1.8. For example, deprotection can be achieved, in addition to other methods known to one skilled in the art, by treatment of 1.7 with SOCl2 in a suitable solvent such as dichloromethane (DCM) (preferred method for PG = 2,4- dimethoxy-benzyl (DMB)). Alternatively, 1.7 can be deprotected with TFA neat or in a suitable solvent known to one skilled in the art such as, DCM to give the compounds 1.8 (preferred method for PG = fert-butoxycarbonyl (Boc)). Upon reaction completion, 1.8 can be recovered by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration and the like; or, alternatively, used in the next step without purification and/or isolation.
[0305] The synthesis of the compounds of the invention can be exemplified by, but is not limited to, the use of the intermediate 1.8 to prepare the compounds of the invention, as shown in Scheme 3.
Scheme 3
Figure imgf000076_0001
2.1 2.2
Reducing Reducing agent agent
Figure imgf000076_0002
2.3 2.4
[0306] The intermediate 1.8 can be treated with appropriate isocyanate compounds 1.9 or 2.0 to form the corresponding adamantyl compounds 2.1 or phenyl compounds 2.2. Without limiting the scope of the present invention, Scheme 3 shows p-fluorophenyl or unsubstituted adamantyl for illustration purposes only. Any suitably substituted or unsubstituted phenyl or adamantyl can be used in Scheme 3 to yield the compounds of the invention. Typically, the reaction with isocyanates is conducted using DCM in the presence of triethylamine (TEA) at room temperature, or alternatively, a polar solvent such as DMF (dimethylformamide) at 0 to 10 0C. Isocyanate compounds 1.9 or 2.0 can be either known compounds or compounds that can be prepared from known compounds by conventional synthetic procedures. Upon reaction completion, 2.1 and/or 2.2 can be recovered by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration and the like; or, alternatively, used in the next step without purification and/or isolation.
[0307] Compounds 2.1 or 2.2 can then be reduced using any suitable reducing agent known in the art, to give compounds 2.3 or 2.4, respectively. For example, 2.1 or 2.2 can be hydrogenated with palladium/carbon (Pd/C) in the presence of a suitable solvent known in the art such as, methanol, at suitable temperature such as, room temperature. Upon reaction completion, 2.3 and/or 2.4 can be recovered by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration and the like. Alternatively, the ester group of the adamantyl compounds 2.1 or phenyl compounds 2.2 can be hydrolyzed (not shown in Scheme 3) to give the corresponding acid compounds.
The hydrolysis of esters is well known in the art. For example, the ester can be hydrolyzed using lithium hydroxide (LiOH) in the presence of a suitable solvent such as, but not limited to THF/methanol/water. The resulting acids can then be reduced with reducing agents as described above to give the corresponding adamantyl or phenyl compounds of the invention.
[0308] Other modifications to arrive at compounds of this invention are well within the skill of the art. For example, the adamantyl group in the schemes can be replaced with any other cycloalkyl group to give the corresponding compounds of the invention.
[0309] The following examples are provided to illustrate certain aspects of the present invention and to aid those of skill in the art in practicing the invention. These examples are in no way to be considered to limit the scope of the invention.
EXAMPLES
[0310] The invention is further understood by reference to the following examples, which are intended to be purely exemplary of the invention. The present invention is not limited in scope by the exemplified embodiments, which are intended as illustrations of single aspects of the invention only. Any methods that are functionally equivalent are within the scope of the invention. Various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications fall within the scope of the appended claims. [0311] Unless otherwise stated all temperatures are in degrees Celsius. Also, in these examples and elsewhere, abbreviations have the following meanings:
Al2O3 = alumina bs = broad singlet
Boc = fert-butoxycarbonyl
BuLi = butyl lithium
CDCl3 = deuterated chloroform d = doublet
DCM = dichloromethane
DMF = dimethylformamide
DMSO = dimethyl sulfoxide g = gram
LiOH = lithium hydroxide m = multiplet
M = molarity
MeOH = methanol mg = milligram mL = milliliter mmol = millimole
Na2CO3 = sodium carbonate
NMR = nuclear magnetic resonance
Pd/C = palladium over carbon
PCC - pyridinium chlorochromate rt = room temperature s = singlet t = triplet
THF = tetrahydrofuran
TFA = trifluoroacetic acid
TEA = triethylamine
TLC = thin layer chromatography q = quartet
Example 1 Synthesis of Intermediate 5
Boc2O PCC
H7N BocHN
Na2CO3 AI2O31DCM THF/H2O
BocHN
Figure imgf000079_0001
TFA ,OEt
H7N
DCM ,rt
5 O
[0312] 6-Amino-l-hexanol 1 (9.00 g, 7.67 mmol) was taken in 300 niL of THF/Water (1 :1) and to it was added tBoc anhydride (18.0 g, 8.44 mmol) followed by sodium carbonate (19.0 g, 19.2 mmol). The reaction mixture was then stirred at room temperature for 3 hours. After completion of the reaction, the resulting mixture was poured into water and extracted with ethyl acetate (2 x 300 mL). The combined organic layers were washed with water and brine and dried over sodium sulfate. Evaporation of the organic layer gave 16 g (96%) of compound 2 which was essentially pure and was used without further purification.
[0313] Compound 2 (16 g) was dissolved in 500 mL of DCM and to it was added 24.0 g of PCC and 60 g of neutral alumina. The reaction mixture was stirred at room temperature, and the progress of the reaction was monitored by TLC. The reaction was complete after 6 hours. The reaction mixture was filtered, and the filtrate was washed with water several times. The organic layer was evaporated under reduced pressure, and the crude product was purified by flash chromatography using ethyl acetate:hexane (1 :3) as eluent to give 3 (14.4 g, 91%) as colourless oil.
[0314] Compound 3 (5.00 g, 2.74mmol) was dissolved in 7OmL of dry THF and cooled to -78°C, and to it was added 12 mL of n-BuLi (1.6 M in hexane) and the solution stirred for 1 hour at -78°C. Triethyl-2-fluoro-2-phosphonoacetate (6.60 g, 2.74 mmol) dissolved in
2OmL of dry THF was added slowly to the reaction mixture via a cannula and the reaction mixture was allowed to warm to room temperature. The reaction mixture was then stirred at room temperature for 6 hours, poured into saturated ammonium chloride solution (20OmL), and extracted with ethyl acetate (2 x 30OmL). After evaporation of the organic layer, the crude product was purified by flash chromatography using ethyl acetate:hexane (1 :4) as eluent to afford 4 (6.Og, 68%).
[0315] Compound 4 (6.00 g, 1.78 mmol) was taken in 50 mL of DCM and to it was added 15 mL of TFA. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with DCM. The organic layer was washed with water and sodium bicarbonate solution, and, after drying over sodium sulfate, solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography using ethyl acetate:hexane (2:3) as eluent to give intermediate 5 (4.0 g, 95%).
[0316] 1H NMR (DMSO-d6): δ 5.90-6.00(m, IH); 5.00 (bs, 2H); 4.20 (q ,2H); 3.20 (t, 2H); 2.60 (m, 2H); 1.60-1.80 (m , 6H); 1.40 (t, 3H). Mass: 204 (M+ 1, 100%). Example 2
Synthesis of (Z)-ethyl 2-fluoro-8-(3-adamantylureido)oct-2-enoate
Figure imgf000080_0001
[0317] Intermediate 5 of Example 1 (2.0 g, 1.0 mmol) was dissolved in 50 mL of DCM and to it was added adamantyl isocyanate (1.7g, 1.0 mmol) followed by triethylamine (2 mL, 2 mmol). The reaction mixture was stirred at room temperature for 6 hours. After completion of the reaction, the DCM layer was phase separated and washed with water several times. Evaporation of solvent gave the crude product which was purified by flash chormatography using ethyl acetate :hexane (2:3) as eluent to give (Z)-ethyl 2-fluoro-8-(3- adamantylureido)oct-2-enoate (3.4 g, 88%) as white solid. [0318] 1H NMR (CDCl3): δ 5.90-6.00 (m, IH); 4.20 (q, 2H); 4.00 (bs, 2H); 3.20 (t, 2H); 2.60 (m, 2H); 2.00-1.80 (m, 6H); 1.70-1.40 (15H); 1.40 (t, 3H). Mass: 381 (M+1,100%). Example 3 Synthesis of ethyl 2-fluoro-8-(3-adamantylureido)octanoate
Figure imgf000081_0001
rO3191 (ZVethyl 2-fluoro-8-(3-adamantylureido)oct-2-enoate of Example 2 (2.0 g, 0.66 mmol) was taken in 20 niL of methanol and to it was added 350 mg of Pd/C (10%), and the reaction mixture was stirred at room temperature for 1.5 hours under a hydrogen atmosphere. After the reaction was complete, it was filtered through celite, the celite layer was washed with methanol, and the combined organic layers evaporated under reduced pressure. The crude product was purified by flash chromatography using ethyl acetate:hexane (2:3) as eluent to give ethyl 2-fluoro-8-(3-adamantylureido)octanoate (1.7 g, 93%) as a white solid.
[0320] 1H NMR (CDCl3): δ 5.10-5.00 (m, IH); 4.20 (q, 2H); 4.00 (bs, 2H); 3.20 (t, 2H); 2.60 (m, 2H); 2.00-1.80 (m, 7H); 1.70-1.40 (m, 15H); 1.40 (t, 3H). Mass: 383 (M+1,100%). Example 4
Synthesis of (Z)-ethyl 2-fluoro-8-(3-(4-fluorophenyl)ureido)oct-2-enoate
Figure imgf000081_0002
[0321] Intermediate 5 of Example 1 (1 g, 0.5mmol) was dissolved in 30 mL of DCM and to it was added 4-fluorophenyl isocyanate (700mg, 0.600 mmol) followed by triethylamine (1 mL, 1 mmol). The reaction mixture was stirred at room temperature for 4 hours . After completion of the reaction, the DCM layer was phase separated and washed with water several times and the solvent evaporated. The crude product was purified by flesh chromatography using ethyl acetate :hexane (2:3) as eluent to give (Z)-ethyl 2-fluoro-8-(3- (4-fluorophenyl)ureido)oct-2-enoate (1.4 g, 85%) as syrup. [0322] 1H NMR (CDCl3): δ 7.20 (m, 2H); 7.00 (m, 2H); 6.40 (bs, IH); 5.90-6.00 (m, IH); 4.80 (bs, IH); 4.20 (q, 2H); 3.20 (t, 2H); 2.60 (m, 2H); 1.60-1.80 (m ,6H); 1.40 (t, 3H). Mass: 341 (M+1,100%).
Example 5 Synthesis of (Z)-2-fluoro-8-(3-(4-fluorophenyl)ureido)oct-2-enoic acid
Figure imgf000082_0001
[0323] (Z)-ethyl 2-fluoro-8-(3-(4-fluorophenyl)ureido)oct-2-enoate of Example 4 (150 mg, 0.43 mmol) was taken in 10 ml of methanol/ THF/water mixture and to it was added lOOmg of LiOH. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was filtered through celite, the celite layer washed with methanol, and the combined organic layer evaporated under reduced pressure. The crude product was purified by flash chromatography using ethyl acetate:hexane (2:3) as eluent to afford (Z)-2-fluoro-8-(3-(4-fluorophenyl)ureido)oct-2-enoic acid (lOOmg, 89%) as white solid.
[0324] 1H NMR (DMSO-d6): δ 8.40(bs, IH); 7.40 (d, 2H); 7.00 (d, 2H); 6.00 (m, IH); 5.20-5.00 (m, IH); 3.10 (t, 2H); 2.60 (m, 2H); 1.60-1.40 (m, 7H). Mass: 313 (M+1,100%).
Example 6 Synthesis of 2-fluoro-8-(3-(4-fluorophenyl)ureido)octanoic acid
Figure imgf000082_0002
[0325] (Z)-2-fluoro-8-(3-(4-fluorophenyl)ureido)oct-2-enoic acid of Example 5(100 mg, 0.330 mmol) was taken in 10 mL of methanol and to it was added 50 mg of Pd/C (10%). The reaction mixture was stirred at room temperature for 1 hour under hydrogen atmosphere. After completion of the reaction, the reaction mixture was filtered through celite, the celite layer washed with methanol, and the combined organic layers evaporated under reduced pressure. The crude product was purified by flash chromatography using ethyl acetate :hexane (2:3) as eluent to give 2-fluoro-8-(3-(4-fluorophenyl)ureido)octanoic acid (100 mg, 99%) as white solid.
[0326] 1H NMR (DMSO-d6): δ 8.40 (bs,lH); 7.40 (d, 2H); 7.00 (d, 2H); 6.00 (bs,lH); 5.20-5.00 (m, IH); 3.10 (t, 2H); 2.60 (m, 2H); 1.60-1.40 (m, 9H). Mass: 315 (M+1,100%).
Example 7 Synthesis of ethyl 2-fluoro-8-(3-(4-fluorophenyl)ureido)octanoate
Figure imgf000083_0001
[0327] (Z)-ethyl 2-fluoro-8-(3-(4-fluorophenyl)ureido)oct-2-enoate of Example 4 (150 mg, 0.43 mmol) was taken in 10 mL of methanol and to it was added 50 mg of Pd/C (10%). The reaction mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. After completion of the reaction, the reaction mixture was filtered through celite, the celite layer washed with methanol, and the combined organic layers evaporated under reduced pressure. The crude product was purified by flash chromatography using ethyl acetate:hexane (2:3) as eluent to give ethyl 2-fluoro-8-(3-(4- fluorophenyl)ureido)octanoate (140 mg, 93%) as white solid.
[0328] 1H NMR (DMSO-d6): δ 8.40 (bs, IH); 7.4 0(d, 2H); 7.00 (d, 2H); 6.00 (bs, IH); 5.20-5.00 (m, IH); 4.20 (q, 2H); 3.10 (t, 2H); 2.60 (m, 2H); 1.60-1.40 (m, 9H), 1.30 (t, 2H). Mass: 343 (M+1,100%).
Example 8
Preparation of racemic 8-(3-Cyclooctylureido)-2-fluorooctanoic Acid (45)
(BoC)2O
HoN
Figure imgf000084_0001
Figure imgf000084_0002
Procedure:
Synthesis of tert-Buty\ 6-Hydroxyhexylcarbamate (8-1):
[0329] To a stirred solution of 6-amino-l-hexanol (10.0 g, 85.4 mmol) in THF (200 rnL) was added a 10% aqueous Na2CO3 solution (50 rnL) and the mixture was cooled to O0C. After being stirred for 10 min, Boc anhydride (12.0 g, 564 mmol) was added dropwise over a period of 15 min to the reaction mixture. After completion of addition, the reaction mixture was allowed to warm to room temperature and stirring was continued for 1 h. After complete consumption of starting material as monitored by TLC, the reaction mixture was extracted with EtOAc (4 x 100 mL), and the combined organic extracts were washed with water (2 x 50 mL) and brine (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to provide Boc-1 (17.4 g, 93%) as a colorless liquid.
[0330] TLC : 30% Ethyl Acetate/Hexane (Rf: 0.6).
Synthesis of tert-Buty\ 6-Oxohexylcarbamate (8-2): [0331] To a mixture of PCC (25.8 g, 120 mmol) and neutral alumina (120 g) in dry DCM (200 mL) was added Boc-1 (17.4 g, 80.1 mmol) at room temperature under an N2 atmosphere and the resulting mixture was stirred for an additional 2 h. After complete consumption of starting material as monitored by TLC, the reaction mixture was filtered through a pad of celite. The filtrate was evaporated under reduced pressure, and crude material was purified by silica gel column chromatography eluting with 10% ethyl acetate/hexane to afford aldehyde 8-2 (15 g, 87%) as a thick yellow syrup.
[0332] TLC: 30% Ethyl acetate/Hexane (Rf: 0.7).
Synthesis of (Z)-Ethyl 8-(tørt-Butoxycarbonylamino)-2-fluorooct-2-enoate (8-3):
[0333] To a solution of triethyl 2-fluoro-2-phosphanoacetate (20.2 g, 83.7 mmol) in THF (150 mL) was added n-BuLi (8.00 g, 104 mmol) dropwise over a period of 30 min at -780C under an N2 atmosphere. After being stirred for 45 minutes at -780C, a solution of aldehyde 8-2 (15.0 g, 69.7 mmol) in THF (40 mL) was added dropwise to reaction mixture at -78 0C under an N2 atmosphere and stirring was continued allowing the reaction to warm to room temperature over 16 h. After complete consumption of starting material as monitored by TLC, the reaction mixture was diluted with EtOAc (400 mL) and washed with water (2 x 100 mL) and brine (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with 15% ethyl acetate/hexane to provide olefin 8-3 (12 g, 56%) as a thick syrup. [0334] TLC: 30% Ethyl acetate/Hexane (Rf: 0.8).
Synthesis of (Z)-Ethyl 8-Amino-2-fluorooct-2-enoate (8-4):
[0335] A solution of olefin 8-3 (1.5 g, 4.9 mmol) in TFA (10 mL) was stirred for 15 min at room temperature under an N2 atmosphere. After complete consumption of starting material as monitored by TLC, the solvent was evaporated under reduced pressure to afford amine 8-4 (0.95 g, 95%) as thick syrup. [0336] TLC : 50% Ethyl Acetate/Hexane (Rf: 0.2).
Synthesis of 4-Nitrophenyl cyclooctylcarbamate (8-5):
[0337] To a stirred solution of cyclooctylamine (0.20 g, 1.5 mmol) in DCM (15 rnL) was added 4-nitrophenyl carbamate (0.38 g, 1.8 mmol) at 0-50C followed by addition of N- methyl morpholine (0.23 gm,2.25 mmol) under an inert atmosphere, and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with DCM (100 mL), washed with brine and dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to afford carbamate 8-5 (0.35g, 78%) as a yellow solid.
[0338] TLC: 50% Ethyl Acetate/Hexane (Rf: 0.8). Synthesis of (Z)-Ethyl 8-(3-cy clooctylureido^-fluorooct^-enoate (8-6) :
[0339] To a solution of amine 8-4 (1.5 g, 7.3 mmol) in DCM (100 mL) was added TEA (1.49 g, 14.7 mmol) and carbamate 8-5 (1.9 g, 8.1 mmol) at room temperature under an N2 atmosphere and stirring was continued for 2 h. The reaction mixture was diluted with DCM (200 mL), washed with water (50 mL) and brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The crude productl was purified by silica gel column chromatography eluting with 50% MeOH/DCM to provide 8-6 (0.43 g, 17%) as a light yellow liquid.
[0340] TLC: Ethyl Acetate (Rf: 0.2).
Synthesis of ethyl 8-(3-Cyclooctylureido)-2-fluorooctanoate (46): [0341] To a solution of 8-6 (3.40 g, 94.4 mmol) in methanol (100 mL) was added 10% Pd/C (20 mg) under an N2 atmosphere, and the mixture was subjected to hydrogenation (at balloon pressure) at room temperature for 2 h. The reaction mixture was filtered through a pad of celite; and filtrate was evaporated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with 20% ethyl acetate/hexane to provide ester 46 (2.5 g, 73%) as a thick, light yellow syrup.
[0342] TLC : 50% Ethyl Acetate/Hexane (Rf: 0.4).
Synthesis of 8-(3-Cyclooctylureido)-2-fluorooctanoic Acid (45):
[0343] To a stirred solution of ester 46 (2.5 g, 6.9 mmol) in ethanol (50 mL) was added 10% aqueous NaOH solution (100 mL) at room temperature and stirring was continued for 3 h. After complete consumption of starting material as monitored by TLC, the solvent was evaporated under reduced pressure. The residue was acidified and stirred for 10 min. The precipitated solid was filtered, washed with diethyl ether (4 x 50 mL) and dried under vacuum to afford acid 45 (1.36 g, 59.1%) as white solid. TLC: Ethyl Acetate (Rf: 0.2). M.P: 72.6-74.8°C. 1HNMR (500 MHz) (DMSO-d6): δ (ppm) 1.20-1.90 (m, 24H), 2.90- 3.00 (m, 2H), 3.50-3.60 (m, IH), 4.70-5.00 (dm, IH), 5.60-5.70 (m, 2H); Mass: 331 (M+l); HPLC (purity): 98.1%.
Example 9 Preparation of 8-(3-cyclooctylureido)-2-fluorooctanoic acid enantiomers (45a and 45b)
Figure imgf000087_0001
Synthesis l-Cyclooctyl-3-((9R)-7-fluoro-8-oxo-9-phenyldecyl) Urea (9-la & 9-lb):
[0344] To a stirred solution of acid 45 (2.0 g, 6.0 mmol) in THF (10 mL) was added 2,4,6- trichloro benzoylchloride (1.47 g, 6.00 mmol) dropwise at 0 - 1O0C under an N2 atmosphere. After stirring for 1 h at room temperature, the reaction mixture was cooled to 0-100C. S (-)- Phenyl ethanol (0.74 g, 6.0 mmol) and DMAP (0.36 g, 3.0 mmol) were introduced into reaction mixture at 0-100C. After completion of addition the reaction mixture was allowed to warm to RT and stirring was continued for 16 h. The reaction mixture was diluted with water (50 mL), extracted with EtOAc (4 x 50 mL). The combined organic phases were washed with saturated NaHCO3 solution, water, and brine and dried over anhydrous
Na2SO4. The organic layer was evaporated under reduced pressure, and the crude material was purified by silica gel column chromatography to afford a diastereomeric mixture of compound 9-la and 9-lb (1.20 g, 45.6%) as a solid, which was separated by chiral preparative HPLC to afford optically pure isomer 9-la (0.35 g, 13%) and 9-lb. (0.5Og, 19%)
[0345] TLC: 10% MeOH/DCM (Rf: 0.7).
Synthesis 8-(3-Cyclooctylureido)-2-fluorooctanoic Acid (45a): [0346] To a stirred solution of compound 9-la (0.90 g, 2.7 mmol) in MeOH (50 niL) was added 10% Pd/C (30 mg) under a nitrogen atmosphere, and the reaction mixture was stirred at room temperature for 2 h under a hydrogen atmosphere. After consumption of the starting precursor as monitored by TLC, the reaction mixture was filtered through a pad of celite and filtrate was evaporated under reduced pressure. The crude material was purified by silica gel column chromatography to afford 45a (0.40 g, 59%) as an off white solid. TLC: 10% MeOH/DCM (Rf: 0.1) M.P: 192.6-195.7°C. HPLC (Purity): 97.9%; Mass: 331 (M+l); [α]D 25 -3.24 (0.95, DMSO). 1HNMR (500 MHz) (DMSO-d6): δ (ppm) 1.18-1.85 (m, 25H), 2.90-3.00 (m, 2H), 4.85-5.00 (dm, IH), 5.60-5.78 (m, 2H), 13.2 (br, s, IH).
Synthesis 8-(3-Cyclooctylureido)-2-fluorooctanoic Acid (3b): [0347] To a stirred solution of compound 9-lb (1.2 g, 2.7 mmol) in MeOH (50 mL) was added 10% Pd/C (50 mg) under nitrogen atmosphere and the reaction mixture was stirred at room temperature for 2 h under a hydrogen atmosphere. After consumption of the starting precursor as monitored by TLC), the reaction mixture was filtered through a pad of celite and filtrate was evaporated under reduced pressure. The crude material was purified by silica gel column chromatography to afford 45b (0.50 g, 54%) as an off white solid. TLC: 10% MeOH/DCM (Rf: 0.1). M.P: 180.1-185.90C. HPLC (Purity): 98.1%; Mass: 331 (M+l); [α]D 25 +2.37 (0.95, DMSO). 1HNMR (500 MHz) (DMSO-d6): δ (ppm) 1.18-1.85 (m, 25H), 2.90-3.00 (m, 2H), 4.90-5.00 (dm, IH), 5.60-5.78 (m, 2H), 13.2 (br, s, IH).
[0348] The following compounds were made using methods similar to those disclosed above: (Z)- 1 -(7-fluoro-8-hydroxyoct-6-enyl)-3-(adamantyl)urea ( 1 )
(Z)-methyl 2-fluoro-8-(3-adamantylureido)oct-2-enoate (2)
(Z)-2-fluoro-8-(3-adamantylureido)oct-2-enoic acid (5)
(Z)-2-fluoro-8-(3-adamantylureido)oct-2-enamide (6) (Z)-2-fluoro-8-(3-(4-fluorophenyl)ureido)oct-2-enamide (12)
(Z)-2-fluoro-8-(3-(4-(trifluoromethoxy)phenyl)ureido)oct-2-enoic acid (15)
(Z)-2-fluoro-8-(3-(4-(trifluoromethoxy)phenyl)ureido)oct-2-enamide (16)
(Z)-ethyl 2-fluoro-8-(3-(4-(trifluoromethoxy)phenyl)ureido)oct-2-enoate (17)
(Z)-ethyl 2-fluoro-8-(3-(4-(trifluoromethyl)phenyl)ureido)oct-2-enoate (18) 2-fluoro-6-(3-adamantylureido)hexanoic acid (19)
Ethyl 2-fluoro-6-(3-adamantylureido)hexanoate (20)
1 -(7-fluoro-8-hydroxyoctyl)-3 -(adamantyl)urea (21)
1 -(7,7-difluoro-8-hydroxyoctyl)-3-(adamantyl)urea (22) ethyl 2,2-difluoro-8-(3-adamantylureido)octanoate (23) 2-fluoro-8-(3-adamantylureido)octanoic acid (27) t-butyl 2-fluoro-8-(3-adamantylureido)octanoate (28)
2-fluoro-8-(3-adamantylureido)octanamide (29)
1 -(7-fluoro-8-methoxyoctane)-3-adamantylurea (30) l-(7-fluoro-8-oxononyl)-3-adamantylurea (31) 2-fluoro-12-(3-adamantylureido)dodecanoic acid (32)
Ethyl 2-fluoro-12-(3-adamantylureido)dodecanoate (33)
2-fluoro-10-(3-adamantylureido)decanoic acid (34)
Ethyl 2-fluoro-10-(3-adamantylureido)decanoate (35)
2-fluoro-8-(3-(4-fluorophenyl)ureido)octanamide (38) 2-fluoro-8-(3-(4-(trifluoromethoxy)phenyl)ureido)octanoic acid (39) ethyl 2-fluoro-8-(3-(4-(trifluoromethoxy)phenyl)ureido)octanoate (40) ethyl 2-fluoro-8-(3-(4-(trifluoromethyl)phenyl)ureido)octanoate (41) ethyl 2-fluoro-8-(3-(4-fluorophenyl)ureido)octanoate (42)
8-(3-(4,4-dimethylcyclohexyl)ureido)-2-fluorooctanoic acid (43) ethyl 8-(3-(4,4-dimethylcyclohexyl)ureido)-2-fluorooctanoate (44) ethyl 8-(3-cyclooctylureido)-2-fluorooctanoate (46) ethyl 8-(3-(4,4-difluorocyclohexyl)ureido)-2-fluorooctanoate (48) methyl 2,2-dimethyl-l l-(3-(4-(trifluoromethyl)phenyl)ureido)undecanoate (53)
2,2-dimethyl-l l-(3-(4-(trifluoromethyl)phenyl)ureido)undecanoic acid (54) l-(8-hydroxy-8-methylnonyl)-3-adamantylurea (55)
1 -(8-hydroxy-9,9-dimethyldecyl)-3-adamantylurea (56) (E)-ethyl 8-(3-adamantylureido)oct-2-enoate (57) ethyl 2-methyl-8-(3-adamantylureido)octanoate (58)
1 -(5 -(2-hydroxyethoxy)pentyl)-3 -adamantylurea (59) methyl 2-(methyl(9-(3 -(4-(trifluoromethyl)phenyl)ureido)nonyl)amino)acetate (60) methyl 2-(methyl(9-(3-adamantylureido)nonyl)amino)acetate (61) 2-(methyl(9-(3-(4-(trifluoromethyl)phenyl)ureido)nonyl)amino)acetamide (62)
2-(methyl(9-(3-adamantylureido)nonyl)amino)acetamide (63) ethyl 2,2-difluoro-2-(5 -(3 -adamantylureido)pentyloxy)acetate (64)
3,3-dimethyl-5-oxo-5-(6-(3-(4-
(trifluoromethyl)phenyl)ureido)hexylamino)pentanoic acid (65), and 3,3-dimethyl-5-oxo-5-(6-(3-adamantylureido)hexylamino)pentanoic acid (66).
[0349] The following compounds can be made using methods similar to those disclosed above:
(Z)-isopropyl 2-fluoro-8-(3-adamantylureido)oct-2-enoate (4) (Z)- 1 -(7-fluoro-8-methoxyoct-6-enyl)-3-adamantylurea (7) (Z)-t-butyl 2-fluoro-8-(3-adamantylureido)oct-2-enoate (8)
(Z)-l-(7-fluoro-8-hydroxyoct-6-enyl)-3-(4-(trifluoromethyl)phenyl)urea (9) (Z)-l-(7-fluoro-8-hydroxyoct-6-enyl)-3-(4-(trifluoromethoxy)phenyl)urea (10) (Z)-l-(7-fluoro-8-hydroxyoct-6-enyl)-3-(4-fluorophenyl)urea (11) methyl 2-fluoro-8-(3-adamantylureido)octanoate (24) isopropyl 2-fluoro-8-(3-adamantylureido)octanoate (26)
8-(3-(4,4-difluorocyclohexyl)ureido)-2-fluorooctanoic acid (47) 2-fluoro-8-(3-spiro[4.5]decan-8-ylureido)octanoic acid (49) ethyl 2-fluoro-8-(3-spiro[4.5]decan-8-ylureido)octanoate (50) 2-fluoro-8-(3-(4-methylbicyclo[2.2.2]octan-l-yl)ureido)octanoic acid (51); and ethyl 2-fluoro-8-(3-(4-methylbicyclo[2.2.2]octan-l-yl)ureido)octanoate (52). Biological Example
Fluorescent assay for mouse and human soluble epoxide hydrolase
[0350] Recombinant mouse sEH (MsEH) and human sEH (HsEH) were produced in a baculovirus expression system as previously reported. Grant et al., J. Biol. Chem., 268:17628-17633 (1993); Beetham et al., Arch. Biochem. Biophys., 305:197-201 (1993). The expressed proteins were purified from cell lysate by affinity chromatography. Wixtrom et al., Anal. Biochem., 169:71-80 (1988). Protein concentration was quantified using the Pierce BCA assay using bovine serum albumin as the calibrating standard. The preparations were at least 97% pure as judged by SDS-PAGE and scanning densitometry. They contained no detectable esterase or glutathione transferase activity which can interfere with the assay. The assay was also evaluated with similar results in crude cell lysates or homogenate of tissues.
[0351] The IC50S for each inhibitor were according to the following procedure: Substrate:
Figure imgf000091_0001
[0352] Cyano(2-methoxynaphthalen-6-yl)methyl (3-phenyloxiran-2-yl)methyl carbonate
(CMNPC; Jones P. D. et. al.; Analytical Biochemistry 2005; 343: pp. 66-75)
Solutions:
[0353] Bis/Tris HCl 25 mM pH 7.0 containing 0.1 mg/mL of BSA (buffer A) [0354] CMNPC at 0.25 mM in DMSO.
[0355] Mother solution of enzyme in buffer A (Mouse sEH at 6 μg/mL and Human sEH at 5 μg/mL).
[0356] Inhibitor dissolved in DMSO at the appropriate concentration.
Protocol: [0357] In a black 96 well plate, fill all the wells with 150 μL of buffer A.
[0358] Add 2 μL of DMSO in well A2 and A3, and then add 2 μL of inhibitor solution in Al and A4 through Al 2. [0359] Add 150 μL of buffer A in row A, then mix several time and transfer 150 μL to row B. Repeat this operation up to row H. The 150 μL removed from row H is discarded.
[0360] Add 20 μL of buffer A in column 1 and 2, then add 20 μL of enzyme solution to column 3 to 12.
[0361] Incubate the plate for 5 minutes in the plate reader at 300C.
[0362] During incubation prepare the working solution of substrate by mixing 3.68 mL of buffer A (4x0.920 mL) with 266μL (2x133 μL) of substrate solution).
[0363] At t=0, add 30 μL of working substrate solution with multi-channel pipette labeled "Briggs 303" and start the reading ([S]finai: 5 μM).
[0364] Read with ex: 330 nm (20 nm) and em: 465 nm (20 nm) every 30 second for 10 minutes. The velocities are used to analyze and calculate the IC50S.
Table Ia
Figure imgf000092_0001
Figure imgf000093_0001

Claims

WHAT IS CLAIMED IS:
1. A compound of Formula (I) or a stereoisomer, or pharmaceutically acceptable salt thereof:
Figure imgf000094_0001
wherein
R is selected from the group consisting of cycloalkyl, substituted cycloalkyl, phenyl and substituted phenyl;
L is -NH- or -CR'R"- where R' and R" are independently hydrogen or alkyl or R' and R" together form a C3-C6 cycloalkyl ring;
Z is C, O, or NR4 where R4 is hydrogen or C1-C4 alkyl and where when Z is O or NR4 then X is absent; the dotted line ^111 is a single bond or a double bond; the wavy line is a cis or a trans configuration when the dotted line is a double bond and m and n are 1; when the dotted line is a single bond and Z is C, then m and n are 2; p is 0-10; q is 0 or 1 ; each of X and Y is independently selected from the group consisting of hydrogen, C1-C4 alkyl, substituted C1-C4 alkyl, and halo;
R1 is selected from the group consisting of -CH2OR2, -COR2, -COOR2, -CONR2R3, -OR2, and carboxylic acid isostere; and
R2 and R3 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or R2 and R3 together with the nitrogen atom bound thereto form a heterocycloalkyl ring having 3 to 9 ring atoms, and wherein said ring is optionally substituted with alkyl, substituted alkyl, heterocyclic, oxo or carboxy; provided that when the dotted line z∑zz is the double bond, then R1 is not OH; and provided that when the dotted line ^111 is the single bond; Z is C; and q is 0, then at least one of Y is halo or C1-C4 alkyl.
2. The compound of claim 1, wherein R is cycloalkyl or substituted cycloalkyl.
3. The compound of claim 2, wherein R is selected from the group consisting of cyclohexyl, substituted cyclohexyl, cyclooctyl, spiro[4.5]decan-8-yl, and A- methylbicyclo[2.2.2]octan-l-yl.
4. The compound of claim 2, wherein R is adamantyl or substituted adamantyl.
5. The compound of claim 1 , wherein R is phenyl or substituted phenyl.
6. The compound of claim 5, wherein R is phenyl substituted with 1 to 5 substituents independently selected from the group consisting of hydrogen, halo, alkyl, acyl, acyloxy, carboxyl ester, acylamino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonylamino, (carboxyl ester)amino, aminosulfonyl, (substituted sulfonyl)amino, haloalkyl, haloalkoxy, haloalkylthio, cyano, and alkylsulfonyl.
7. The compound of claim 5, wherein R is phenyl substituted with 1 to 5 substituents independently selected from the group consisting of fluoro, trifluomethyl, and trifluoromethoxy.
8. The compound of claim 5, wherein R is selected from the group consisting of phenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 3 -fluorophenyl, 3-chlorophenyl and 3-bromophenyl.
9. The compound of claim 1, wherein L is -NH-.
10. The compound of claim 1, wherein L is -CR'R"- where R' and R" are independently H or alkyl or R' and R" together form a C3-C6 cycloalkyl ring.
11. The compound of claim 10, wherein L is -CH2-.
12. The compound of claim 1, wherein/? is 2, 3, 4, 5, 6, 7, or 8.
13. The compound of claim 12, wherein/? is 4.
14. The compound of claim 1, wherein q is 0.
15. The compound of claim 1 , wherein q is 1.
16. The compound of claim 1 , wherein when the dotted line z∑∑z is the single bond; Z is C; and q is 0, then at least one of Y is fluoro or methyl.
17. The compound of claim 1 , wherein when Z is C and q is 1 , then each of X and Y independently is hydrogen or C1-C4 alkyl.
1 0 0
18. The compound of claim 1 , wherein R is -CH2OR where R is as defined in claim 1.
1 0 0 0 19. The compound of claim 1 , wherein R is -COOR or -COR where R is as defined in claim 1.
20. The compound of claim 1, wherein R1 is -CONR2R3, where R2 and R3 are as defined in claim 1.
21. The compound of claim 1 , wherein the compound is of Formula (II), or a stereoisomer or pharmaceutically acceptable salt thereof:
Figure imgf000096_0001
wherein
R, R1, and p are as defined in claim 1; and each of Xa, Xb, Ya, and Yb is independently selected from the group consisting of hydrogen, C1-C4 alkyl, substituted C1-C4 alkyl, and halo, provided that at least one of Ya and Yb is halo or C1-C4 alkyl.
22. The compound of claim 21 , wherein R is cycloalkyl or substituted cycloalkyl.
23. The compound of claim 22, wherein R is selected from the group consisting of cyclohexyl, substituted cyclohexyl, cyclooctyl, spiro[4.5]decan-8-yl, and 4-methylbicyclo[2.2.2]octan-l-yl.
24. The compound of claim 22, wherein R is adamantyl or substituted adamantyl.
25. The compound of claim 21 , wherein R is phenyl or substituted phenyl.
26. The compound of claim 25, wherein R is selected from the group consisting of phenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 3 -fluorophenyl, 3-chlorophenyl and 3-bromophenyl.
27. The compound of claim 25, wherein R is phenyl substituted with 1 to 5 substituents independently selected from the group consisting of fluoro, trifluomethyl, and trifluoromethoxy.
28. The compound of claim 21 , wherein Xa, Xb, and Ya are hydrogen and Yb is halo.
29. The compound of claim 28, wherein Yb is fluoro.
30. The compound of claim 21 , wherein Xa and Xb are hydrogen, Ya is halo and Yb is halo.
31. The compound of claim 30, wherein Ya and Yb are fluoro.
32. The compound of claim 21 , wherein Xa, Xb, and Ya are hydrogen and Yb is alkyl.
33. The compound of claim 32, wherein Yb is methyl.
34. The compound of claim 21 , wherein Xa and Xb are hydrogen and Ya andYb are alkyl.
35. The compound of claim 34, wherein Ya and Yb are methyl.
36. The compound of claim 21, wherein/? is 2, 3, 4, 5, 6, 7, or 8.
37. The compound of claim 36, wherein/? is 4.
38. The compound of claim 21, wherein R1 is -CH2OR2 where R2 is selected from the group consisting of hydrogen or methyl.
39. The compound of claim 21, wherein R1 is -COOR2 where R2 is selected from the group consisting of hydrogen, methyl, ethyl, /-propyl, ter/-butyl, 2,2,2-trimethylethyl, and dimethylaminoethyl.
40. The compound of claim 21 , wherein R1 is -CONR2R3, where R2 and R3 independently are selected from the group consisting of hydrogen or methyl.
41. The compound of claim 21, wherein R is -COR where R is selected from the group consisting of hydrogen and methyl.
42. The compound of claim 1, wherein the compound is of Formula (Ilia) or (HIb), or a stereoisomer or pharmaceutically acceptable salt thereof:
Figure imgf000098_0001
wherein R, p, X, Y, and R1 are as defined in claim 1.
43. The compound of claim 42, wherein R is cycloalkyl or substituted cycloalkyl.
44. The compound of claim 43, wherein R is selected from the group consisting of cyclohexyl, substituted cyclohexyl, cyclooctyl, spiro[4.5]decan-8-yl, and 4- methylbicyclo[2.2.2]octan-l-yl.
45. The compound of claim 43, wherein R is adamantyl or substituted adamantyl.
46. The method of claim 42, wherein R is phenyl or substituted phenyl.
47. The compound of claim 46, wherein R is phenyl substituted with 1 to 5 substituents independently selected from the group consisting of fluoro, trifluomethyl, and trifluoromethoxy.
48. The compound of claim 46, wherein R is selected from the group consisting of phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 3 -fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, and 4-trifluoromethoxyphenyl.
49. The compound of claim 42, wherein/? is 3, 4, or 5.
50. The compound of claim 42, wherein p is 4.
51. The compound of claim 42, wherein X is hydrogen.
52. The compound of claim 42, wherein Y is hydrogen, fluoro, or methyl.
1 0 0 53. The compound of claim 42, wherein R is -CH2OR where R is selected from the group consisting of hydrogen or methyl.
1 0 0
54. The compound of claim 42, wherein R is -COOR where R is selected from the group consisting of hydrogen, methyl, ethyl, /-propyl, tert-butyi, 2,2,2-trimethylethyl, and dimethylaminoethyl.
55. The compound of claim 42, wherein R1 is -CONR2R3, where R2 and R3 independently are selected from the group consisting of hydrogen and methyl.
56. The compound of claim 42, wherein R1 is -COR2 where R2 is selected from the group consisting of hydrogen and methyl.
57. The compound of claim 1, wherein the compound is of Formula (IV), or a stereoisomer or pharmaceutically acceptable salt thereof:
Figure imgf000100_0001
wherein
R, R1, R4, and p are as defined in claim 1; Z is O or NR4 ; and Ya and Yb independently are selected from the group consisting of hydrogen, halo, or Ci-C4 alkyl.
58. The compound of claim 57, wherein R is cycloalkyl or substituted cycloalkyl.
59. The compound of claim 58, wherein R is adamantyl or substituted adamantyl.
60. The method of claim 57, wherein R is phenyl or substituted phenyl.
61. The compound of claim 60, wherein R is phenyl substituted with 1 to 5 substituents independently selected from the group consisting of fluoro, trifluomethyl, and trifluoromethoxy.
62. The compound of claim 60, wherein R is selected from the group consisting of phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 3 -fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, and 4-trifluoromethoxyphenyl.
63. The compound of claim 57, wherein/? is 4, 6, or 8.
64. The compound of claim 57, wherein/? is 4.
65. The compound of claim 57, wherein Z is O.
66. The compound of claim 57, wherein Z is NCH3.
67. The compound of claim 57, wherein Ya and Yb independently are fluoro.
68. The compound of claim 57, wherein Ya and Yb independently are hydrogen or methyl.
69. The compound of claim 57, wherein R1 is -CH2OR2 where R2 is selected from the group consisting of hydrogen or methyl.
70. The compound of claim 57, wherein R1 is -COOR2 where R2 is selected from the group consisting of hydrogen, methyl, ethyl, /-propyl, ter/-butyl, 2,2,2-trimethylethyl, and dimethylaminoethyl.
71. The compound of claim 57, wherein R1 is -CONR2R3, where R2 and R3 independently are selected from the group consisting of hydrogen or methyl.
72. The compound of claim 57, wherein R is -COR where R is selected from the group consisting of hydrogen and methyl.
73. A compound selected from the group consisting of:
(Z)-l-(7-fluoro-8-hydroxyoct-6-enyl)-3-(adamantyl)urea;
(Z)-methyl 2-fluoro-8-(3-adamantylureido)oct-2-enoate; (Z)-ethyl 2-fluoro-8-(3-adamantylureido)oct-2-enoate;
(Z)-isopropyl 2-fluoro-8-(3-adamantylureido)oct-2-enoate;
(Z)-2-fluoro-8-(3-adamantylureido)oct-2-enoic acid;
(Z)-2-fluoro-8-(3-adamantylureido)oct-2-enamide;
(Z)- 1 -(7-fluoro-8-methoxyoct-6-enyl)-3-adamantylurea; (Z)-/-butyl 2-fluoro-8-(3-adamantylureido)oct-2-enoate;
(Z)-l-(7-fluoro-8-hydroxyoct-6-enyl)-3-(4-(trifluoromethyl)phenyl)urea;
(Z)-I -(7-fluoro-8-hydroxyoct-6-enyl)-3-(4-(trifluoromethoxy)phenyl)urea;
(Z)-I -(7-fluoro-8-hydroxyoct-6-enyl)-3-(4-fluorophenyl)urea;
(Z)-2-fluoro-8-(3-(4-fluorophenyl)ureido)oct-2-enamide; (Z)-ethyl 2-fluoro-8-(3-(4-fluorophenyl)ureido)oct-2-enoate;
(Z)-2-fluoro-8-(3-(4-fluorophenyl)ureido)oct-2-enoic acid;
(Z)-2-fluoro-8-(3-(4-(trifluoromethoxy)phenyl)ureido)oct-2-enoic acid;
(Z)-2-fluoro-8-(3-(4-(trifluoromethoxy)phenyl)ureido)oct-2-enamide;
(Z)-ethyl 2-fluoro-8-(3-(4-(trifluoromethoxy)phenyl)ureido)oct-2-enoate; (Z)-ethyl 2-fluoro-8-(3-(4-(trifluoromethyl)phenyl)ureido)oct-2-enoate;
2-fluoro-6-(3-adamantylureido)hexanoic acid;
Ethyl 2-fluoro-6-(3-adamantylureido)hexanoate;
1 -(7-fluoro-8-hydroxyoctyl)-3 -(adamantyl)urea; 1 -(7,7-difluoro-8-hydroxyoctyl)-3-(adamantyl)urea; ethyl 2,2-difluoro-8-(3 -adamantylureido)octanoate; methyl 2-fluoro-8-(3-adamantylureido)octanoate; ethyl 2-fluoro-8-(3-adamantylureido)octanoate; isopropyl 2-fluoro-8-(3-adamantylureido)octanoate; 2-fluoro-8-(3-adamantylureido)octanoic acid; t-butyl 2-fluoro-8-(3 -adamantylureido)octanoate;
2-fluoro-8-(3-adamantylureido)octanamide; l-(7-fluoro-8-methoxyoctane)-3-adamantylurea; l-(7-fluoro-8-oxononyl)-3-adamantylurea; 2-fluoro-12-(3-adamantylureido)dodecanoic acid;
Ethyl 2-fluoro- 12-(3 -adamantylureido)dodecanoate;
2-fluoro-10-(3-adamantylureido)decanoic acid;
Ethyl 2-fluoro- 10-(3-adamantylureido)decanoate; ethyl 2-fluoro-8-(3-(4-fluorophenyl)ureido)octanoate; 2-fluoro-8-(3-(4-fluorophenyl)ureido)octanoic acid;
2-fluoro-8-(3-(4-fluorophenyl)ureido)octanamide;
2-fluoro-8-(3-(4-(trifluoromethoxy)phenyl)ureido)octanoic acid; ethyl 2-fluoro-8-(3-(4-(trifluoromethoxy)phenyl)ureido)octanoate; ethyl 2-fluoro-8-(3-(4-(trifluoromethyl)phenyl)ureido)octanoate; ethyl 2-fluoro-8-(3-(4-fluorophenyl)ureido)octanoate;
8-(3-(4,4-dimethylcyclohexyl)ureido)-2-fluorooctanoic acid; ethyl 8-(3-(4,4-dimethylcyclohexyl)ureido)-2-fluorooctanoate;
8-(3-cyclooctylureido)-2-fluorooctanoic acid;
(S)-8-(3-cyclooctylureido)-2-fluorooctanoic acid; (R)-8-(3-cyclooctylureido)-2-fluorooctanoic acid; ethyl 8-(3-cyclooctylureido)-2-fluorooctanoate;
8-(3-(4,4-difluorocyclohexyl)ureido)-2-fluorooctanoic acid; ethyl 8-(3-(4,4-difluorocyclohexyl)ureido)-2-fluorooctanoate;
2-fluoro-8-(3-spiro[4.5]decan-8-ylureido)octanoic acid; ethyl 2-fluoro-8-(3 -spiro [4.5 ] decan-8-ylureido)octanoate;
2-fluoro-8-(3-(4-methylbicyclo[2.2.2]octan- 1 -yl)ureido)octanoic acid; ethyl 2-fluoro-8-(3-(4-methylbicyclo[2.2.2]octan- 1 -yl)ureido)octanoate; methyl 2,2-dimethyl-l l-(3-(4-(trifluoromethyl)phenyl)ureido)undecanoate;
2,2-dimethyl- 11 -(3-(4-(trifluoromethyl)phenyl)ureido)undecanoic acid;
1 -(8-hydroxy-8-methylnonyl)-3 -adamantylurea;
1 -(8-hydroxy-9,9-dimethyldecyl)-3- adamantylurea; (E)-ethyl 8-(3-adamantylureido)oct-2-enoate; ethyl 2-methyl-8-(3-adamantylureido)octanoate;
1 -(5 -(2-hydroxyethoxy)pentyl)-3 -adamantylurea; methyl 2-(methyl(9-(3-(4-(trifluoromethyl)phenyl)ureido)nonyl)amino)acetate; methyl 2-(methyl(9-(3 -adamantylureido)nonyl)amino)acetate; 2-(methyl(9-(3 -(4-(trifluoromethyl)phenyl)ureido)nonyl)amino)acetamide;
2-(methyl(9-(3-adamantylureido)nonyl)amino)acetamide; ethyl 2,2-difluoro-2-(5-(3-adamantylureido)pentyloxy)acetate;
3,3-dimethyl-5-oxo-5-(6-(3-(4-
(trifluoromethyl)phenyl)ureido)hexylamino)pentanoic acid; and 3,3-dimethyl-5-oxo-5-(6-(3-adamantylureido)hexylamino)pentanoic acid, or a stereoisomer or pharmaceutically acceptable salt thereof.
74. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound or a stereoisomer or pharmaceutically acceptable salt thereof of any one of Claims 1-73 for treating a soluble epoxide hydrolase mediated disease.
75. Use of a compound or the stereoisomer of any one of Claims 1 -74 in the manufacture of a medicament.
76. The use of claim 75, wherein the medicament is for treating a soluble epoxide hydrolase mediated disease.
77. A method for treating a soluble epoxide hydrolase mediated disease, said method comprising administering to a patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound or a stereoisomer or pharmaceutically acceptable salt thereof of any one of Claims 1-73.
78. The method of claim 76 or 77 wherein the disease is selected from the group consisting of hypertension, inflammation, adult respiratory distress syndrome, diabetic complications, end stage renal disease, Raynaud syndrome, arthritis, obstructive pulmonary disease, interstitial lung disease, and asthma.
79. A method for inhibiting a soluble epoxide hydrolase, comprising contacting the soluble epoxide hydrolase with an effective amount of a compound or a stereoisomer or pharmaceutically acceptable salt thereof of any one of Claims 1-73.
PCT/US2008/088244 2007-12-28 2008-12-23 Soluble epoxide hydrolase inhibitors WO2009086429A1 (en)

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WO2015176135A1 (en) * 2014-05-22 2015-11-26 The University Of Sydney Omega-3 analogues
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