WO2007101213A2 - Novel 2-oxo-1,2,3,4-tetrahydropyrimidines, bicyclic pyrimidine diones and imidazolidine-2,4-diones useful as inducible nitric oxide synthase inhibitors - Google Patents

Novel 2-oxo-1,2,3,4-tetrahydropyrimidines, bicyclic pyrimidine diones and imidazolidine-2,4-diones useful as inducible nitric oxide synthase inhibitors Download PDF

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WO2007101213A2
WO2007101213A2 PCT/US2007/062903 US2007062903W WO2007101213A2 WO 2007101213 A2 WO2007101213 A2 WO 2007101213A2 US 2007062903 W US2007062903 W US 2007062903W WO 2007101213 A2 WO2007101213 A2 WO 2007101213A2
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group
optionally substituted
ester
alkyl
heterocycloalkyl
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WO2007101213A3 (en
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Jeffrey R. Roppe
Hui Zhuang
Xiaohong Chen
Celine Bonnefous
Joseph E. Payne
Nicholas D. Smith
Christian A. Hassig
Stewart A. Noble
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Kalypsys, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention is directed to new 2-oxo-l,2,3,4-tetrahydropyrimidine, bicyclic pyrimidine dione and imidizolidine-2,4-dione compounds and compositions and their application as pharmaceuticals for the treatment of disease.
  • Methods of inhibition of nitric oxide synthase, activity in a human or animal subject are also provided for the treatment of diseases.
  • Nitric oxide is involved in the regulation of many physiological processes as well as the pathophysiology of a number of diseases. It is synthesized enzymatically from L-arginine in numerous tissues and cell types by three distinct isoforms of the enzyme NO synthase (NOS). Two of these isoforms, endothelial NOS (eNOS) and neuronal NOS (nNOS) are expressed in a constitutive manner and are calcium/calmodulin dependent. Endothelial NOS is expressed by endothelium and other cell types and is involved in cardiovascular homeostasis. Neuronal NOS is constitutively present in both the central and peripheral nervous system where NO acts a neurotransmitter. Under normal physiological conditions, these constitutive forms of NOS generate low, transient levels of NO in response to increases in intracellular calcium concentrations. These low levels of NO act to regulate blood pressure, platelet adhesion, gastrointestinal motility, bronchomotor tone and neurotransmission.
  • NOS NO synthase
  • nNOS neuron
  • the third isoform of NOS inducible NOS (iNOS), a virtually calcium independent enzyme, is absent in resting cells, but is rapidly expressed in virtually all nucleated mammalian cells in response to stimuli such as endotoxins and/or cytokines.
  • the inducible isoform is neither stimulated by calcium nor blocked by calmodulin antagonists. It contains several tightly bound co-factors, including FMN, FAD and tetrahydrobiopterin.
  • the inducible isoform of nitric oxide synthase (NOS2 or iNOS) is expressed in virtually all nucleated mammalian cells following exposure to inflammatory cytokines or lipopolysaccharide.
  • the enzyme iNOS synthase is a homodimer composed of 13OkDa subunits. Each subunit comprises an oxygenase domain and a reductase domain.
  • the presence of iNOS in macrophages and lung epithelial cells is significant. Once present, iNOS synthesizes 100-1000 times more NO than the constitutive enzymes synthesize and does so for prolonged periods. This excessive production of NO and resulting NO-derived metabolites (e.g., peroxynitrite) elicit cellular toxicity and tissue damage which contribute to the pathophysiology of a number of diseases, disorders and conditions.
  • Nitric oxide generated by the inducible form of NOS has also been implicated in the pathogenesis of inflammatory diseases.
  • hypotension induced by lipopolysaccharide or tumor necrosis factor alpha can be reversed by NOS inhibitors.
  • Conditions which lead to cytokine-induced hypotension include septic shock, hemodialysis and interleukin therapy in cancer patients.
  • An iNOS inhibitor has been shown to be effective in treating cytokine-induced hypotension, inflammatory bowel disease, cerebral ischemia, osteoarthritis, asthma and neuropathies such as diabetic neuropathy and post-herpetic neuralgia.
  • nitric oxide localized in high amounts in inflamed tissues has been shown to induce pain locally and to enhance central as well as peripheral stimuli.
  • nitric oxide produced by an inflammatory response is thought to be synthesized by iNOS, the inhibition of iNOS dimerization produces both prophylactic and remedial analgesia in patients.
  • Novel compounds and pharmaceutical compositions that inhibit the inducible NOS synthase have been found, together with methods of synthesizing and using the compounds including methods for the treatment of Nitric oxide -mediated diseases in a patient by administering the compounds.
  • the present invention discloses a class of compounds, useful in treating iNOS-mediated disorders and conditions, defined by structural Formula I:
  • X 1 is selected from the group consisting of CH 2 , O, S or NH;
  • R 1 is selected from the group consisting of alkoxy, alkyl, alkylamino, alkylene, alkylamino, alkynyl, amino, aryl, arylalkoxy, arylamino, arylthio, cycloalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylamino, heterocycloalkyl and hydrogen, any of which may be optionally substituted;
  • R 2 is selected from the group consisting of acyl, alkoxy, alkoxyalkyl, alkyl, alkylene, alkylamino, alkynyl, alkylimino, amido, amino, aryl, carboxy, cyano, cycloalkyl, ester, haloalkyl, heteoaryl, heterocycloalkyl and hydrogen, any of which may be optionally substituted;
  • R 3a and R 3b are each independently selected from the group consisting of alkyl, amino, arylalkyl, aryl, cycloalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl and hydrogen, any of which may be optionally substituted; and R 4 and R 5 are each independently optionally substituted alkyl or hydrogen.
  • the present invention further discloses a class of compounds, useful in treating iNOS-mediated disorders and conditions, defined by structural Formula VI:
  • A is optionally substituted heteroaryl
  • R 1 and R 2 are each independently selected from the group consisting of acyl, alkyl, alkylene, alkylamino, alkynyl, amido, amino, aryl, arylalkoxy, arylamino, arylthio, carboxy, cycloalkyl, ester, ether, halo, haloalkoxy, haloalkyl, heteroaryl, heterocycloalkyl, hydrogen, thio, sulfonate and sulfonyl, any of which may be optionally substituted.
  • the present invention further discloses a class of compounds, useful in treating iNOS-mediated disorders and conditions, defined by structural Formula XI:
  • X 1 and X 2 are each independently selected from the group consisting of acyl, alkoxy, alkyl, alkylene, alkynyl, amido, amino, aminosulfonyl, aryl, arylalkoxy, arylamino, arylthio, carboxy, cycloalkyl, ester, haloalkyl, heteroaryl, heterocycloalkyl, hydrogen, thio, sulfonate and sulfonyl, any of which may be optionally substituted;
  • R 1 is selected from the group consisting of alkoxy, alkyl, alkylamino, alkylaryl, alkylheteroaryl, alkylene, alkylamino, alkynyl, amino, aryl, arylalkoxy, arylamino, arylthio, cycloalkyl, ester, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylamin
  • the present invention also provides pharmaceutical compositions comprising one or more compounds of the present invention together with a pharmaceutically acceptable carrier.
  • the present invention also provides methods for inhibiting iNOS.
  • the present invention also provides methods for treating a iNOS-mediated disorder in a human or animal subject in need of such treatment comprising administering to said subject an amount of a compound of the present invention effective to reduce or prevent said disorder in said subject.
  • the subject invention provides for novel compounds, pharmaceutical compositions and methods of making and using the compounds and compositions. These compounds possess useful iNOS inhibiting or modulating activity, and may be used in the treatment or prophylaxis of a disease or condition in which iNOS plays an active role.
  • the compounds of the present invention have structural Formula II:
  • X 1 is selected from the group consisting of O, S or NH;
  • R 1 is selected from the group consisting of alkoxy, alkyl, alkylamino, alkylene, alkylamino, alkynyl, amino, aryl, arylalkoxy, arylamino, arylthio, cycloalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylamino, heterocycloalkyl and hydrogen, any of which may be optionally substituted;
  • R 2 is selected from the group consisting of acyl, alkoxy, alkoxyalkyl, alkyl, alkylene, alkylamino, alkynyl, alkylimino, amido, amino, aryl, carboxy, cyano, cycloalkyl, ester, haloalkyl, heteoaryl, heterocycloalkyl and hydrogen, any of which may be optionally substituted;
  • R 3a is
  • R 2 is selected from the group consisting of alkyl, alkylene, alkynyl, alkylimino, cycloalkyl, haloalkyl, heterocycloalkyl and hydrogen, any of which may be optionally substituted;
  • R 3a is aryl or heteroaryl, either of which may be optionally substituted;
  • R 8 is selected from the group consisting of alkyl, alkylamino, alkylene, alkynyl, aryl, cycloalkyl, haloalkyl, heteroaryl, heterocycloalkyl and hydrogen, any of which may be optionally substituted.
  • the invention further provides for compounds of Formula VII:
  • X 1 is selected from the group consisting of NR 3 or CR 4 ;
  • X 2 is selected from the group consisting of NR 5 , O, S(O) 2 or S(O);
  • X 3 is selected from the group consisting of acyl, alkoxy, alkyl, alkylthio, alkylene, alkylamino, alkynyl, amido, amino, aminosulfonyl, aryl, arylalkoxy, arylamino, arylthio, carboxy, cycloalkyl, ester, ether, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylamino, heteroarylthio, heterocycloalkyl, hydrazinyl, imino, thio, sulfonate and sulfonylamino, any of which may be optionally substituted;
  • R 1 and R 2 are each independently selected from the group consisting of acyl, alkyl, alkylene, alkylamino, alkynyl, amido, amino, aryl, arylalkoxy, arylamino, arylthio, carboxy, cycloalkyl, ester, ether, halo, haloalkoxy, haloalkyl, heteroaryl, heterocycloalkyl, hydrogen, thio, sulfonate and sulfonyl, any of which may be optionally substituted;
  • R is selected from the group consisting of acyl, alkyl, alkylene, alkylamino, alkynyl, aryl, arylalkoxy, arylamino, arylthio, carboxy, cycloalkyl, ester, ether, haloalkyl, heteroaryl, heteroarylamino, heterocycloalkyl, hydrogen, thio, sulfonate and sulfonylamino, any of which may be optionally substituted;
  • R 4 is selected from the group consisting of acyl, alkyl, alkylene, alkylamino, alkynyl, aryl, arylalkoxy, arylamino, arylthio, carboxy, cycloalkyl, ester, ether, haloalkyl, heteroaryl, heteroarylamino, heterocycloalkyl, hydrogen, thio, sulfonate and sulfonylamino, any of which may be optionally substituted; and R 5 is selected from the group consisting of acyl, alkyl, alkylene, alkylamino, alkynyl, aryl, arylalkoxy, arylamino, arylthio, carboxy, cycloalkyl, ester, ether, haloalkyl, heteroaryl, heteroarylamino, heterocycloalkyl, hydrogen, thio, sulfonate and sulfonylamino, any of which
  • the invention further provides for compounds of Formula VIII:
  • X 3 is selected from the group consisting of -SR 6 , -S(O) 2 R 6 , -NR 7 R 8 and -OR 3 , any of which may be optionally substituted;
  • R 6 is selected from the group consisting of alkyl, alkylaryl, alkylene, alkynyl, aryl, cycloalkyl, ester, halo, haloalkyl, heteroaryl, heterocycloalkyl and hydrogen, any of which may be optionally substituted;
  • R 7 and R 8 are each independently selected from the group selected from the group consisting of acyl, alkyl, alkylene, aminoalkyl, alkynyl, arylthio, carboxy, cycloalkyl, ester, ether, halo, haloalkoxy, haloalkyl, heteroaryl, heterocycloalkyl, hydrogen, thio and sulfonyl, any of which may be optionally substituted; or, alternatively, R 5 and R 6 may combine to form optionally substituted heterocycloalkyl; and
  • R is selected from the group consisting of acyl, alkyl, alkylene, alkylamino, alkynyl, aryl, arylalkoxy, arylamino, arylthio, carboxy, cycloalkyl, ester, ether, haloalkyl, heteroaryl, heteroarylamino, heterocycloalkyl, hydrogen, thio, sulfonate and sulfonyl, any of which may be optionally substituted.
  • the invention further provides for compounds of Formula IX:
  • R 1 and R 2 are each independently selected from the group consisting of acyl, alkyl, alkylene, alkylamino, alkynyl, amido, amino, aryl, arylalkoxy, arylamino, arylthio, carboxy, cycloalkyl, ester, ether, halo, haloalkoxy, haloalkyl, heteroaryl, heterocycloalkyl, hydrogen, thio, sulfonate and sulfonyl, any of which may be optionally substituted; and
  • R 9 , R 10 and R 11 are each independently selected from the group consisting of acyl, alkoxy, alkoxyalkylaryl, alkoxyalkylheteroaryl, alkyl, alkylene, alkylamino, alkynyl, amido, amino, aminosulfonyl, aryl, arylalkoxy, arylamino, arylthio, carboxy, cycloalkyl, ester, ether, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylamino, heterocycloalkyl, hydrazinyl, hydrogen, imino, thio, sulfonate and sulfonylamino, any of which may be optionally substituted.
  • the invention further provides for compounds of Formula XII:
  • R 1 is selected from the group consisting of alkylaryl, alkylheteroaryl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl, any of which may be optionally substituted;
  • R 2 is selected from the group consisting of alkyl, cycloalkyl, haloalkyl, heterocycloalkyl and hydrogen, any of which may be optionally substituted.
  • the invention further provides for compounds of Formula XIII:
  • X 3 is selected from the group consisting of CR 3 or N;
  • X 4 is selected from the group consisting of CR 4 or N
  • X 5 is selected from the group consisting of CR 5 or N;
  • X 6 is selected from the group consisting of CR 6 or N;
  • X 7 is selected from the group consisting of CR 7 or N;
  • R 2 is selected from the group consisting of alkyl, cycloalkyl, haloalkyl, heterocycloalkyl and hydrogen, any of which may be optionally substituted; and R 3 , R 4 , R 5 R 6 and R 7 are each independently selected from the group consisting of acyl, alkoxy, alkoxyalkylaryl, alkoxyalkylheteroaryl, alkyl, alkylene, alkylamino, alkynyl, amido, amino, aminosulfonyl, aryl, arylalkoxy, arylamino, arylthio, carboxy, cycloalkyl, ester, ether, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylamino, heterocycloalkyl, hydrazinyl, hydrogen, imino, thio, sulfonate and sulfonylamino, any of which may be optionally substituted.
  • the invention provides for compounds of Formulas I- XIII administered in combination with another therapeutic agent.
  • the invention provides for compounds of Formulas I- XIII for use as a medicament.
  • the invention provides for compounds of Formulas I- XIII for use in the manufacture of a medicament for the prevention or treatment of a disease or condition ameliorated by the inhibition of iNOS.
  • the invention provides for a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of any of Formulas I- XIII together with a pharmaceutically acceptable carrier, useful for the treatment or prevention of an iNOS-mediated disease.
  • the invention provides for a method of inhibition of iNOS comprising contacting iNOS with a compound of any of Formulas I- XIII.
  • the invention provides for a method of treatment of a iNOS-mediated disease comprising the administration of a therapeutically effective amount of a compound of any of Formulas I- XIII to a patient in need thereof, wherein said disease is selected from the group consisting of psoriasis, uveitis, type 1 diabetes, septic shock, pain, migraine, rheumatoid arthritis, inflammatory bowel disease, asthma, immune complex diseases, multiple sclerosis, ischemic brain edema, toxic shock syndrome, heart failure, ulcerative colitis, atherosclerosis, glomerulonephritis, Paget's disease, osteoporosis, inflammatory sequelae of viral infections, retinitis, oxidant induced lung injury, eczema, acute allograft rejection and infection caused by invasive microorganisms which produce NO.
  • said disease is selected from the group consisting of psoriasis, uveitis, type 1 diabetes, septic shock, pain, migraine
  • acyl refers to a carbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocycle, or any other moiety were the atom attached to the carbonyl is carbon.
  • An “acetyl” group refers to a -C(O)CH 3 group.
  • An “alkylcarbonyl” or “alkanoyl” group refers to an alkyl group attached to the parent molecular moiety through a carbonyl group. Examples of such groups include methylcarbonyl and ethylcarbonyl. Examples of acyl groups include formyl, alkanoyl and aroyl.
  • alkenyl refers to a straight- chain or branched-chain hydrocarbon radical having one or more double bonds and containing from 2 to 20, preferably 2 to 6, carbon atoms.
  • suitable alkenyl radicals include ethenyl, propenyl, 2-methylpropenyl, 1,4-butadienyl and the like.
  • alkoxy refers to an alkyl ether radical, wherein the term alkyl is as defined below. Examples of suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like.
  • alkyl refers to a straight- chain or branched-chain alkyl radical containing from 1 to and including 20, preferably 1 to 10, and more preferably 1 to 6, carbon atoms. Alkyl groups may be optionally substituted as defined herein. Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, noyl and the like.
  • alkylene as used herein, alone or in combination, refers to a saturated aliphatic group derived from a straight or branched chain saturated hydrocarbon attached at two or more positions, such as methylene (-CH 2 -).
  • alkylamino refers to an alkyl group attached to the parent molecular moiety through an amino group. Suitable alkylamino groups may be mono- or dialkylated, forming groups such as, for example, N-methylamino, N-ethylamino, N,N- dimethylamino, N,N-ethylmethylamino and the like.
  • alkylidene refers to an alkenyl group in which one carbon atom of the carbon-carbon double bond belongs to the moiety to which the alkenyl group is attached.
  • alkylthio refers to an alkyl thioether
  • (R-S-) radical wherein the term alkyl is as defined above and wherein the sulfur may be singly or doubly oxidized.
  • suitable alkyl thioether radicals include methylthio, ethylthio, n- propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like.
  • alkynyl refers to a straight- chain or branched chain hydrocarbon radical having one or more triple bonds and containing from 2 to 20, preferably from 2 to 6, more preferably from 2 to 4, carbon atoms.
  • Alkynylene refers to a carbon- carbon triple bond attached at two positions such as ethynylene (-C:::C-, -C ⁇ C-).
  • alkynyl radicals include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, 3- methylbutyn- 1 -yl, hexyn-2-yl, and the like.
  • acylamino as used herein, alone or in combination, embraces an acyl group attached to the parent moiety through an amino group.
  • An example of an “acylamino” group is acetylamino (CH 3 C(O)NH-).
  • amino refers to — NRR , wherein R and R are independently selected from the group consisting of hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may themselves be optionally substituted.
  • aryl as used herein, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused.
  • aryl embraces aromatic radicals such as benzyl, phenyl, naphthyl, anthracenyl, phenanthryl, indanyl, indenyl, annulenyl, azulenyl, tetrahydronaphthyl, and biphenyl.
  • arylalkenyl or “aralkenyl,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkenyl group.
  • arylalkoxy or “aralkoxy,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkoxy group.
  • arylalkyl or “aralkyl,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkyl group.
  • arylalkynyl or “aralkynyl,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkynyl group.
  • arylalkanoyl or “aralkanoyl” or “aroyl,”as used herein, alone or in combination, refers to an acyl radical derived from an aryl-substituted alkanecarboxylic acid such as benzoyl, napthoyl, phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, A- chlorohydrocinnamoyl, and the like.
  • aryloxy refers to an aryl group attached to the parent molecular moiety through an oxy.
  • benzo and "benz,” as used herein, alone or in combination, refer to the divalent radical derived from benzene. Examples include benzothiophene and benzimidazole.
  • carbamate refers to an ester of carbamic acid (-NHCOO-) which may be attached to the parent molecular moiety from either the nitrogen or acid end, and which may be optionally substituted as defined herein.
  • O-carbamyl refers to a -OC(O)NRR', group-with R and R' as defined herein.
  • N-carbamyl as used herein, alone or in combination, refers to a ROC(O)NR'- group, with R and R' as defined herein.
  • carbonyl as used herein, when alone includes formyl [-C(O)H] and in combination is a -C(O)- group.
  • carboxy refers to -C(O)OH or the corresponding "carboxylate” anion, such as is in a carboxylic acid salt.
  • An "O-carboxy” group refers to a RC(O)O- group, where R is as defined herein.
  • a "C-carboxy” group refers to a -C(O)OR groups where R is as defined herein.
  • cyano as used herein, alone or in combination, refers to -CN.
  • cycloalkyl refers to a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl radical wherein each cyclic moiety contains from 3 to 12, preferably five to seven, carbon atom ring members and which may optionally be a benzo fused ring system which is optionally substituted as defined herein.
  • cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, octahydronaphthyl, 2,3-dihydro-lH- indenyl, adamantyl and the like.
  • Bicyclic and tricyclic as used herein are intended to include both fused ring systems, such as decahydonapthalene, octahydronapthalene as well as the multicyclic (multicentered) saturated or partially unsaturated type.
  • the latter type of isomer is exemplified in general by, bicyclo[ 1,1,1 ]pentane, camphor, adamantane, and bicyclo[3,2,l]octane.
  • esteer as used herein, alone or in combination, refers to a carboxy group bridging two moieties linked at carbon atoms.
  • ether refers to an oxy group bridging two moieties linked at carbon atoms.
  • halo refers to fluorine, chlorine, bromine, or iodine.
  • haloalkoxy refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.
  • haloalkyl refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals.
  • a monohaloalkyl radical for one example, may have an iodo, bromo, chloro or fluoro atom within the radical.
  • Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals.
  • haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
  • "Haloalkylene" refers to a haloalkyl group attached at two or more positions.
  • heteroalkyl refers to a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, fully saturated or containing from 1 to 3 degrees of unsaturation, consisting of the stated number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom(s) O, N and S may be placed at any interior position of the heteroalkyl group. Up to two heteroatoms may be consecutive, such as, for example, -CH 2 -NH-OCH 3 .
  • heteroaryl refers to 3 to 7 membered, preferably 5 to 7 membered, unsaturated heteromonocyclic rings, or fused polycyclic rings in which at least one of the fused rings is unsaturated, wherein at least one atom is selected from the group consisting of O, S, and N.
  • the term also embraces fused polycyclic groups wherein heterocyclic radicals are fused with aryl radicals, wherein heteroaryl radicals are fused with other heteroaryl radicals, or wherein heteroaryl radicals are fused with cycloalkyl radicals.
  • heteroaryl groups include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, benzothienyl, chromonyl,
  • Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl and the like.
  • heterocycloalkyl and, interchangeably, “heterocycle,” as used herein, alone or in combination, each refer to a saturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic, or tricyclic heterocyclic radical containing at least one, preferably 1 to 4, and more preferably 1 to 2 heteroatoms as ring members, wherein each said heteroatom may be independently selected from the group consisting of nitrogen, oxygen, and sulfur, and wherein there are preferably 3 to 8 ring members in each ring, more preferably 3 to 7 ring members in each ring, and most preferably 5 to 6 ring members in each ring.
  • Heterocycloalkyl and “heterocycle” are intended to include sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclic fused and benzo fused ring systems; additionally, both terms also include systems where a heterocycle ring is fused to an aryl group, as defined herein, or an additional heterocycle group.
  • Heterocycle groups of the invention are exemplified by aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[l,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihy- dropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like.
  • the heterocycle groups may be optionally substituted unless specifically prohibited.
  • hydrazinyl as used herein, alone or in combination, refers to two amino groups joined by a single bond, i.e., -N-N-.
  • hydroxy as used herein, alone or in combination, refers to -OH.
  • hydroxyalkyl refers to a hydroxy group attached to the parent molecular moiety through an alkyl group.
  • the phrase "in the main chain” refers to the longest contiguous or adjacent chain of carbon atoms starting at the point of attachment of a group to the compounds of this invention.
  • isocyanato refers to a -NCO group.
  • isothiocyanato refers to a -NCS group.
  • linear chain of atoms refers to the longest straight chain of atoms independently selected from carbon, nitrogen, oxygen and sulfur.
  • lower means containing from 1 to and including 6 carbon atoms.
  • mercaptyl as used herein, alone or in combination, refers to an RS- group, where R is as defined herein.
  • nitro refers to -NO 2 .
  • perhaloalkoxy refers to an alkoxy group where all of the hydrogen atoms are replaced by halogen atoms.
  • perhaloalkyl refers to an alkyl group where all of the hydrogen atoms are replaced by halogen atoms.
  • sulfonate refers the -SO 3 H group and its anion as the sulfonic acid is used in salt formation.
  • sulfinyl as used herein, alone or in combination, refers to -S(O)-.
  • sulfonyl as used herein, alone or in combination, refers to -S(O) 2 -.
  • thia and thio refer to a -S- group or an ether wherein the oxygen is replaced with sulfur.
  • the oxidized derivatives of the thio group namely sulfinyl and sulfonyl, are included in the definition of thia and thio.
  • thiol as used herein, alone or in combination, refers to an -SH group.
  • thiocarbonyl when alone includes thioformyl -C(S)H and in combination is a -C(S)- group.
  • N-thiocarbamyl refers to an ROC(S)NR'- group, with R and R' as defined herein.
  • O-thiocarbamyl refers to a -OC(S)NRR', group with R and R' as defined herein.
  • thiocyanato refers to a -CNS group.
  • trihalomethanesulfonamido refers to a X 3 CS(O ⁇ NR- group with X is a halogen and R as defined herein.
  • trihalomethane sulfonyl refers to a X 3 CS(O ⁇ - group where X is a halogen.
  • trimihalomethoxy refers to a X 3 CO- group where X is a halogen.
  • trimethysilyl as used herein, alone or in combination, refers to a silicone group substituted at its three free valences with groups as listed herein under the definition of substituted amino. Examples include trimethysilyl, tert-butyldimethylsilyl, triphenylsilyl and the like.
  • any definition herein may be used in combination with any other definition to describe a composite structural group.
  • the trailing element of any such definition is that which attaches to the parent moiety.
  • the composite group alkylamido would represent an alkyl group attached to the parent molecule through an amido group
  • the term alkoxyalkyl would represent an alkoxy group attached to the parent molecule through an alkyl group.
  • substituents of an "optionally substituted” group may include, without limitation, one or more substituents independently selected from the following groups or a particular designated set of groups, alone or in combination: lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester, lower carboxamid
  • Two substituents may be joined together to form a fused five-, six-, or seven-menbered carbocyclic or heterocyclic ring consisting of zero to three heteroatoms, for example forming methylenedioxy or ethylenedioxy.
  • An optionally substituted group may be unsubstituted (e.g., -CH 2 CH 3 ), fully substituted (e.g., -CF 2 CF 3 ), monosubstituted (e.g., -CH 2 CH 2 F) or substituted at a level anywhere in-between fully substituted and monosubstituted (e.g., -CH 2 CF 3 ).
  • aryl, heterocycle, R, etc. occur more than one time in a formula or generic structure, its definition at each occurrence is independent of the definition at every other occurrence.
  • certain groups may be attached to a parent molecule or may occupy a position in a chain of elements from either end as written.
  • an unsymmetrical group such as -C(O)N(R)- may be attached to the parent moiety at either the carbon or the nitrogen.
  • Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art.
  • Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art.
  • the compounds of the present invention may exist as geometric isomers.
  • the present invention includes all cis, trans, syn, anti,
  • compounds may exist as tautomers; all tautomeric isomers are provided by this invention.
  • the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
  • bonds refers to a covalent linkage between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure.
  • a bond may be single, double, or triple unless otherwise specified.
  • a dashed line between two atoms in a drawing of a molecule indicates that an additional bond may be present or absent at that position.
  • combination therapy means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.
  • iNOS inhibitor is used herein to refer to a compound that exhibits an IC 50 with respect to iNOS activity of no more than about 100 ⁇ M and more typically not more than about 50 ⁇ M, as measured in the iNOS DAN Assay described generally hereinbelow.
  • IC 50 is that concentration of inhibitor which reduces the activity of an enzyme (e.g., iNOS) to half-maximal level.
  • Representative compounds of the present invention have been discovered to exhibit inhibitory activity against iNOS.
  • Compounds of the present invention preferably exhibit an IC 50 with respect to iNOS of no more than about 10 ⁇ M, more preferably, no more than about 5 ⁇ M, even more preferably not more than about 1 ⁇ M, and most preferably, not more than about 200 nM, as measured in the iNOS assay(s) described herein.
  • terapéuticaally effective is intended to qualify the amount of active ingredients used in the treatment of a disease or disorder. This amount will achieve the goal of reducing or eliminating the said disease or disorder.
  • terapéuticaally acceptable refers to those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
  • treatment of a patient is intended to include prophylaxis.
  • patient means all mammals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, pigs, and rabbits. Preferably, the patient is a human.
  • prodrug refers to a compound that is made more active in vivo. Certain compounds of the present invention may also exist as prodrugs, as described in Hydrolysis in Drug and Prodrug Metabolism : Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley-
  • Prodrugs of the compounds described herein are structurally modified forms of the compound that readily undergo chemical changes under physiological conditions to provide the compound. Additionally, prodrugs can be converted to the compound by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to a compound when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because, in some situations, they may be easier to administer than the compound, or parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug.
  • An example, without limitation, of a prodrug would be a compound which is administered as an ester (the "prodrug"), but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound.
  • the compounds of the present invention can exist as therapeutically acceptable salts.
  • the present invention includes compounds listed above in the form of salts, in particular acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable salts may be of utility in the preparation and purification of the compound in question. Basic addition salts may also be formed and be pharmaceutically acceptable.
  • Pharmaceutical Salts Properties, Selection, and Use (Stahl, P. Heinrich. Wiley- VCHA, Zurich, Switzerland, 2002).
  • terapéuticaally acceptable salt represents salts or zwitterionic forms of the compounds of the present invention which are water or oil-soluble or dispersible and therapeutically acceptable as defined herein.
  • the salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound in the form of the free base with a suitable acid.
  • Representative acid addition salts include acetate, adipate, alginate, L- ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethansulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, me sitylene sulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phen
  • basic groups in the compounds of the present invention can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides.
  • acids which can be employed to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Salts can also be formed by coordination of the compounds with an alkali metal or alkaline earth ion.
  • the present invention contemplates sodium, potassium, magnesium, and calcium salts of the compounds of the compounds of the present invention and the like.
  • Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxy group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine.
  • a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine.
  • the cations of therapeutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, ⁇ f-dimethylaniline, iV-methylpiperidine, ⁇ f-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, ⁇ f-dibenzylphenethylamine, 1 -ephenamine, and N.N 1 - dibenzylethylenediamine.
  • Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.
  • a salt of a compound can be made by reacting the appropriate compound in the form of the free base with the appropriate acid. While it may be possible for the compounds of the subject invention to be administered as the raw chemical, it is also possible to present them as a pharmaceutical formulation. Accordingly, the subject invention provides a pharmaceutical formulation comprising a compound or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients.
  • the carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Proper formulation is dependent upon the route of administration chosen.
  • compositions of the present invention may be manufactured in a manner that is itself known, e.g. , by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.
  • the formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association a compound of the subject invention or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof ("active ingredient”) with the carrier which constitutes one or more accessory ingredients.
  • formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration.
  • the push- fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • Dragee cores are provided with suitable coatings.
  • concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • the compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use.
  • sterile liquid carrier for example, saline or sterile pyrogen-free water
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner.
  • Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. , containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.
  • Compounds of the present invention may be administered topically, that is by non-systemic administration. This includes the application of a compound of the present invention externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream.
  • systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
  • Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.
  • the active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, for instance from 1% to 2% by weight of the formulation. It may however comprise as much as 10% w/w but preferably will comprise less than 5% w/w, more preferably from 0.1% to 1% w/w of the formulation.
  • Gels for topical or transdermal administration of compounds of the subject invention may comprise, generally, a mixture of volatile solvents, nonvolatile solvents, and water.
  • the volatile solvent component of the buffered solvent system may preferably include lower (C1-C6) alkyl alcohols, lower alkyl glycols and lower glycol polymers. More preferably, the volatile solvent is ethanol.
  • the volatile solvent component is thought to act as a penetration enhancer, while also producing a cooling effect on the skin as it evaporates.
  • the nonvolatile solvent portion of the buffered solvent system is selected from lower alkylene glycols and lower glycol polymers. Preferably, propylene glycol is used.
  • the nonvolatile solvent slows the evaporation of the volatile solvent and reduces the vapor pressure of the buffered solvent system.
  • the amount of this nonvolatile solvent component, as with the volatile solvent, is determined by the pharmaceutical compound or drug being used. When too little of the nonvolatile solvent is in the system, the pharmaceutical compound may crystallize due to evaporation of volatile solvent, while an excess will result in a lack of bioavailability due to poor release of drug from solvent mixture.
  • the buffer component of the buffered solvent system may be selected from any buffer commonly used in the art; preferably, water is used.
  • the preferred ratio of ingredients is about 20% of the nonvolatile solvent, about 40% of the volatile solvent, and about 40% water.
  • chelators and gelling agents Appropriate gelling agents can include, but are not limited to, semisynthetic cellulose derivatives (such as hydroxypropylmethylcellulose) and synthetic polymers, and cosmetic agents.
  • Lotions according to the present invention include those suitable for application to the skin or eye.
  • An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops.
  • Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.
  • Creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy base.
  • the base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives or a fatty acid such as steric or oleic acid together with an alcohol such as propylene glycol or a macrogel.
  • the formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof.
  • Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.
  • Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and preferably including a surface active agent.
  • the resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-100 0 C for half an hour.
  • the solution may be sterilized by filtration and transferred to the container by an aseptic technique.
  • bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%).
  • Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.
  • Formulations for topical administration in the mouth, for example buccally or sublingually include lozenges comprising the active ingredient in a flavored basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.
  • the compounds according to the invention are conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray.
  • Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the compounds according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
  • Preferred unit dosage formulations are those containing an effective dose, as herein below recited, or an appropriate fraction thereof, of the active ingredient.
  • formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • the compounds of the invention may be administered orally or via injection at a dose of from 0.1 to 500 mg/kg per day.
  • the dose range for adult humans is generally from 5 mg to 2 g/day.
  • Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of compound of the invention which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • the compounds of the subject invention can be administered in various modes, e.g. orally, topically, or by injection.
  • the precise amount of compound administered to a patient will be the responsibility of the attendant physician.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diets, time of administration, route of administration, rate of excretion, drug combination, the precise disorder being treated, and the severity of the indication or condition being treated.
  • the route of administration may vary depending on the condition and its severity.
  • the compounds described herein may be administered in combination with another therapeutic agent.
  • another therapeutic agent such as a pharmaceutically acceptable salt, ester, or prodrug thereof.
  • an adjuvant i.e., by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced.
  • the benefit of experienced by a patient may be increased by administering one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
  • another therapeutic agent which also includes a therapeutic regimen
  • increased therapeutic benefit may result by also providing the patient with another therapeutic agent for diabetes.
  • the overall benefit experienced by the patient may simply be additive of the two therapeutic agents or the patient may experience a synergistic benefit.
  • ком ⁇ онентs include use of the compounds of the invention with: a) corticosteroids including betamethasone dipropionate (augmented and nonaugemnted), betamethasone valerate, clobetasol propionate, diflorasone diacetate, halobetasol propionate, amcinonide, dexosimethasone, fluocinolone acetononide, fluocinonide, halocinonide, clocortalone pivalate, dexosimetasone, and flurandrenalide; b) non-steroidal anti-inflammatory drugs including diclofenac, ketoprofen, and piroxicam; c) muscle relaxants and combinations thereof with other agents, including cyclobenzaprine, baclofen, cyclobenzaprine/lidocaine, baclofen/cyclobenzaprine, and cyclobenzaprine/lidocaine/ketoprofen;
  • This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather then as crystals)]; e) expectorants and combinations thereof with other agents, including guaifenesin and guaifenesin/ketoprofen/cyclobenzaprine; f) antidepressants including tricyclic antidepressants (e.g., amitryptiline, doxepin, desipramine, imipramine, amoxapine, clomipramine, nortriptyline, and protriptyline), selective serotonin/norepinephrine reuptake inhibitors including (e.g, duloxetine and mirtazepine), and selective norepinephrine reuptake inhibitors (e.g.
  • nisoxetine mapsrotiline, and reboxetine
  • selective serotonin reuptake inhibitors e.g., fluoxetine and fluvoxamine
  • anticonvulsants and combinations thereof including gabapentin, carbamazepine, felbamate, lamotrigine, topiramate, tiagabine, oxcarbazepine, carbamezipine, zonisamide, mexiletine, gabapentin/clonidine, gabapentin/carbamazepine, and carbamazepine/cyclobenzaprine
  • antihypertensives including clonidine
  • opioids including loperamide, tramadol, morphine, fentanyl, oxycodone, levorphanol, and butorphanol
  • topical counter-irritants including menthol, oil of wintergreen, camphor, eucalyptus oil and turpentine oil
  • the multiple therapeutic agents may be administered in any order or even simultaneously. If simultaneously, the multiple therapeutic agents may be provided in a single, unified form, or in multiple forms (by way of example only, either as a single pill or as two separate pills). One of the therapeutic agents may be given in multiple doses, or both may be given as multiple doses. If not simultaneous, the timing between the multiple doses may be any duration of time ranging from a few minutes to four weeks.
  • the present invention provides methods for treating iNOS-mediated disorders in a human or animal subject in need of such treatment comprising administering to said subject an amount of a compound of the present invention effective to reduce or prevent said disorder in the subject in combination with at least one additional agent for the treatment of said disorder that is known in the art.
  • the present invention provides therapeutic compositions comprising at least one compound of the present invention in combination with one or more additional agents for the treatment of iNOS-mediated disorders.
  • Compounds of the subject invention are useful in treating nitric oxide synthase -mediated disease, disorders and conditions, and are particularly suitable as inhibitors of nitric oxide synthase dimerization.
  • the compounds of the present invention are useful to treat patients with neuropathy or inflammatory pain such as reflex sympathetic dystrophy/causalgia (nerve injury), peripheral neuropathy (including diabetic neuropathy), intractable cancer pain, complex regional pain syndrome, and entrapment neuropathy (carpel tunnel syndrome).
  • the compounds are also useful in the treatment of pain associated with acute herpes zoster (shingles), postherpetic neuralgia (PHN), and associated pain syndromes such as ocular pain.
  • the compounds are further useful as analgesics in the treatment of pain such as surgical analgesia, or as an antipyretic for the treatment of fever.
  • Pain indications include, but are not limited to, post-surgical pain for various surgical procedures including post-cardiac surgery, dental pain/dental extraction, pain resulting from cancer, muscular pain, mastalgia, pain resulting from dermal injuries, lower back pain, headaches of various etiologies, including migraine, and the like.
  • the compounds are also useful for the treatment of pain-related disorders such as tactile allodynia and hyperalgesia.
  • the pain may be somatogenic (either nociceptive or neuropathic), acute and/or chronic.
  • the nitric oxide synthase inhibitors of the subject invention are also useful in conditions where NSAIDs, morphine or fentanyl opiates and/or other opioid analgesics would traditionally be administered.
  • the compounds of the subject invention can be used in the treatment or prevention of opiate tolerance in patients needing protracted opiate analgesics, and benzodiazepine tolerance in patients taking benzodiazepines, and other addictive behavior, for example, nicotine addiction, alcoholism, and eating disorders.
  • the compounds and methods of the present invention are useful in the treatment or prevention of drug withdrawal symptoms, for example treatment or prevention of symptoms of withdrawal from opiate, alcohol, or tobacco addiction.
  • the compounds of the subject invention can be used to treat insulin resistance and other metabolic disorders such as atherosclerosis that are typically associated with an exaggerated inflammatory signaling.
  • the present invention encompasses therapeutic methods using novel selective iNOS inhibitors to treat or prevent respiratory disease or conditions, including therapeutic methods of use in medicine for preventing and treating a respiratory disease or condition including: asthmatic conditions including allergen-induced asthma, exercise-induced asthma, pollution-induced asthma, cold-induced asthma, and viral-induced-asthma; chronic obstructive pulmonary diseases including chronic bronchitis with normal airflow, chronic bronchitis with airway obstruction (chronic obstructive bronchitis), emphysema, asthmatic bronchitis, and bullous disease; and other pulmonary diseases involving inflammation including bronchioectasis cystic fibrosis, pigeon fancier's disease, farmer's lung, acute respiratory distress syndrome, pneumonia, aspiration or inhalation injury, fat embolism in the lung, acidosis inflammation of the lung, acute pulmonary edema, acute mountain sickness, acute pulmonary hypertension, persistent pulmonary hypertension of the newborn, perinatal as
  • disorders or conditions which can be advantageously treated by the compounds of the present invention include inflammation.
  • the compounds of the present invention are useful as anti- inflammatory agents with the additional benefit of having significantly less harmful side effects.
  • the compounds are useful to treat arthritis, including but not limited to rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis, acute rheumatic arthritis, enteropathic arthritis, neuropathic arthritis, psoriatic arthritis, and pyogenic arthritis.
  • the compounds are also useful in treating osteoporosis and other related bone disorders.
  • These compounds can also be used to treat gastrointestinal conditions such as reflux esophagitis, diarrhea, inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis.
  • the compounds may also be used in the treatment of pulmonary inflammation, such as that associated with viral infections and cystic fibrosis.
  • compounds of invention are also useful in organ transplant patients either alone or in combination with conventional immunomodulators. Yet further, the compounds of the invention are useful in the treatment of pruritis and vitaligo.
  • the compounds of the present invention are also useful in treating tissue damage in such diseases as vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, neuromuscular junction disease including myasthenia gravis, white matter disease including multiple sclerosis, sarcoidosis, nephritis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, periodontis, hypersensitivity, swelling occurring after injury, ischemias including myocardial ischemia, cardiovascular ischemia, and ischemia secondary to cardiac arrest, and the like.
  • diseases as vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, neuromuscular junction disease including myasthenia grav
  • the compounds of the subject invention are also be useful for the treatment of certain diseases and disorders of the nervous system.
  • Central nervous system disorders in which nitric oxide inhibition is useful include cortical dementias including Alzheimer's disease, central nervous system damage resulting from stroke, ischemias including cerebral ischemia (both focal ischemia, thrombotic stroke and global ischemia (for example, secondary to cardiac arrest), and trauma.
  • Neurodegenerative disorders in which nitric oxide inhibition is useful include nerve degeneration or nerve necrosis in disorders such as hypoxia, hypoglycemia, epilepsy, and in cases of central nervous system (CNS) trauma (such as spinal cord and head injury), hyperbaric oxygen convulsions and toxicity, dementia e.g.
  • CNS central nervous system
  • pre-senile dementia and AIDS-related dementia, cachexia, Sydenham's chorea, Huntington's disease, Parkinson's Disease, amyotrophic lateral sclerosis (ALS), Korsakoffs disease, imbecility relating to a cerebral vessel disorder, sleeping disorders, schizophrenia, depression, depression or other symptoms associated with Premenstrual Syndrome (PMS), and anxiety.
  • PMS Premenstrual Syndrome
  • the compounds of the present invention are also useful in inhibiting NO production from L-arginine including systemic hypotension associated with septic and/or toxic hemorrhagic shock induced by a wide variety of agents; therapy with cytokines such as TNF, IL-I and IL-2; and as an adjuvant to short term immunosuppression in transplant therapy.
  • cytokines such as TNF, IL-I and IL-2
  • these compounds can also be used to treat allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome, and atherosclerosis.
  • Still other disorders or conditions advantageously treated by the compounds of the subject invention include the prevention or treatment of cancer, such as colorectal cancer, and cancer of the breast, lung, prostate, bladder, cervix and skin.
  • Compounds of the invention may be used in the treatment and prevention of neoplasias including but not limited to brain cancer, bone cancer, a leukemia, a lymphoma, epithelial cell-derived neoplasia (epithelial carcinoma) such as basal cell carcinoma, adenocarcinoma, gastrointestinal cancer such as lip cancer, mouth cancer, esophogeal cancer, small bowel cancer and stomach cancer, colon cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast cancer and skin cancer, such as squamous cell and basal cell cancers, prostate cancer, renal cell carcinoma, and other known cancers that effect epithelial cells throughout the body.
  • the neoplasia can be selected from gastrointestinal cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, prostate cancer, cervical cancer, lung cancer, breast cancer and skin cancer, such as squamous cell and basal cell cancers.
  • the present compounds and methods can also be used to treat the fibrosis which occurs with radiation therapy.
  • the present compounds and methods can be used to treat subjects having adenomatous polyps, including those with familial adenomatous polyposis (FAP). Additionally, the present compounds and methods can be used to prevent polyps from forming in patients at risk of FAP.
  • the compounds of the subject invention can be used in the treatment of ophthalmic diseases, such as glaucoma, retinal ganglion degeneration, occular ischemia, retinitis, retinopathies, uveitis, ocular photophobia, and of inflammation and pain associated with acute injury to the eye tissue.
  • ophthalmic diseases such as glaucoma, retinal ganglion degeneration, occular ischemia, retinitis, retinopathies, uveitis, ocular photophobia, and of inflammation and pain associated with acute injury to the eye tissue.
  • the compounds can be used to treat glaucomatous retinopathy and/or diabetic retinopathy.
  • the compounds can also be used to treat post-operative inflammation or pain as from ophthalmic surgery such as cataract surgery and refractive surgery.
  • compounds of the subject invention may be used in the treatment of menstrual cramps, dysmenorrhea, premature labor, tendonitis, bursitis, skin-related conditions such as psoriasis, eczema, burns, sunburn, dermatitis, pancreatitis, hepatitis, and the like.
  • Other conditions in which the compounds of the subject invention provides an advantage in inhibiting nitric oxide inhibition include diabetes (type I or type II), congestive heart failure, myocarditis, atherosclerosis, and aortic aneurysm.
  • the present compounds may also be used in co-therapies, partially or completely, in place of other conventional anti-inflammatory therapies, such as together with steroids, NSAIDs, COX-2 selective inhibitors, 5 -lipoxygenase inhibitors, LTB 4 antagonists and LTA 4 hydrolase inhibitors.
  • the compounds of the subject invention may also be used to prevent tissue damage when therapeutically combined with antibacterial or antiviral agents.
  • the compounds and formulations of the present invention are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.
  • This compound is commercially available.
  • This compound is commercially available.
  • This compound is commercially available.
  • This compound is commercially available.
  • This compound is commercially available.
  • This compound is commercially available.
  • This compound is commercially available.
  • Ethyl 6-methyl-2-oxo-4-m-tolyl-l,2,3,4-tetrahydropyrimidine-5-carboxylate Ethyl 3 -oxobutanoate (2.6 g, 20.00 mmol) was added to a solution of 3-methylbenzaldehyde (2 g, 16.67 mmol) in CH3CN at room temperature. To this solution was added urea (1.2 g, 20.00 mmol) followed by SiO2-NaHSO4 (300 mg, 1.67 mmol). The reaction mixture was stirred overnight at reflux. The reaction mixture was cooled and poured into ice-water (50 g) followed by filtration.
  • Ethyl 4-(5-bromo-2-hydroxyphenyl)-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate N,N- dimethyl benzenamine (280 mg, 2.31 mmol) was added to a solution of ethyl 4-(2-(benzyloxy)-5- bromophenyl)-2-oxo- l,2,3,4-tetrahydropyrimidine-5-carboxylate (500 mg, 1.16 mmol) in CH2C12 (30 mL) at room temperature. To this solution was added dropwise A1C13 (150 mg, 1.14 mmol). The reaction mixture was stirred for 0.5 h at 50 degrees C.
  • the aqueous layer was extracted with EtOAc ( 3 x 20 mL).
  • the combined organic layer was dried (Na2SO4) and concentrated to afford 0.4 g (100%) as a white solid.
  • Oxobutanoate 800 mg, 6.15 mmol was added to a solution of 3-methoxybenzaldehyde (700 mg, 5.15 mmol) in CH3CN. To this solution was then added urea (360 mg, 6.00 mmol) followed SiO2-NaHSO4 (90 mg, 0.50 mmol). The reaction mixture was stirred overnight at reflux. The reaction mixture was cooled and filtrated. The product was purified by silica gel flash column chromatography (1% MeOH in dichloromethane to 2% MeOh in dichloromethane) to afford 1.2 g (75%) as a white solid. 1 HNMR
  • Ethyl 4-(4-methoxyphenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate The compound ethyl 4-(4-methoxyphenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate was synthesized according to the procedure from Example 12 using 4-methoxybenzaldehyde (700 mg, 5.15 mmol) to afford 1 g (62%) as a white solid.
  • Ethyl 4-(3-fluorophenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate Ethyl 3- oxobutanoate (2.5 g, 19.23 mmol) was added to a solution of 3-fluorobenzaldehyde (2 g, 16.13 mmol) in CH3CN at room temperature. To this solution was added urea (1.2 g, 20.00 mmol) followed SiO2- NaHSO4 (300 mg, 1.67 mmol). The reaction mixture was stirred overnight at reflux. The reaction mixture was cooled to room temperature and filtered.
  • Ethyl 4-(4-fluorophenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate The compound ethyl 4-(4-fluorophenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate was synthesized according to the procedure from Example 14 using 4-fluorobenzaldehyde (2 g, 16.13 mmol) to afford 3.2 g (71%) as a white solid.
  • Ethyl 6-methyl-4-(4-nitrophenyl)-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate The compound Ethyl 6-methyl-4-(4-nitrophenyl)-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate was synthesized according to the procedure from Example 14 using 4-nitrobenzaldehyde (2.4 g, 15.89 mmol) to afford 4.1 g (85%) as a white solid.
  • Ethyl 6-methyl-4-(3-nitrophenyl)-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate The compound ethyl 6-methyl-4-(3-nitrophenyl)-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate was synthesized according to the procedure from Example 14 using 3-nitrobenzaldehyde (2.4 g, 15.89 mmol) to afford 3.4 g (70%) as a white solid.
  • 2-(benzyloxy)benzaldehyde The compound 2-(benzyloxy)benzaldehyde was synthesized according to the procedure rom Example 12, step 1 using 2-hydroxybenzaldehyde (5 g, 40.98 mmol) to afford 9 g (crude) as a light yellow solid.
  • Ethyl 4-[2-(benzyloxy)phenyl]-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate The compound ethyl 4-(2-(benzyloxy)phenyl)-6-methyl -2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylate was synthesized according to the procedure from Example 12 step 1 using 2-(benzyloxy)benzaldehyde (9 g, 42.45 mmol) to afford 5 g (32%) as a white solid.
  • the reaction mixture was cooled to room temperature and filtered.
  • the filter cake was washed with CHC13 (3 x 250 ml) and the filtrate was concentrated to afford 4 g (51%) as a white solid.
  • Ethyl 4-(3-hydroxyphenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate The compound ethyl 4-(3-hydroxyphenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate was synthesized according to the procedure from Example 16 except using 2-(benzyloxy)benzaldehyde as a starting material.
  • Ethyl 4-(2-bromophenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate The compound was synthesized according to the procedure from Example 8 using 2-bromobenzaldehyde as a starting material.
  • Ethyl 2-oxo-4-(2-(trifluoromethoxy)phenyl)-6-(trifluoromethyl)-l,2,3,4 tetrahydropyrimidine-5- carboxylate Ethyl 4,4,4,trifluoro-3-oxobutanoate (200mg, 1.08 mmol) was added to a solution of (trifluoromethoxy)benzaldehyde (103 mg, 0.54mmol) in CH3CN at room temperature. To this solution was added urea (64.8 mg, 1.08 mmol) followed SiO2-NaHSO4 (20mg, 0.1 mmol). The reaction mixture was stirred overnight at reflux. The reaction mixture was cooled to room temperature and filtered.
  • Ethyl 6-methyl-2-oxo-4-(pyridine-3-yl) -l,2,3,4-tetrahydropyrimidine-5-carboxylate The compound ethyl 6-methyl-2-oxo-4-(pyridine-3-yl) -l,2,3,4-tetrahydropyrimidine-5-carboxylate was synthesized according to the procedure from Example 16 except using nicotinaldehyde as a starting material. [M+H] + calcd. for C13H15N3O3, 261.2, found 261.2.
  • Ethyl 4-(2,3,-dihydrobenzo[b] [l,4]dioxin-6-yl)-6-methyl-2-ox -l,2,3,4-tetrahydropyrimidine-5- carboxylate The compound ethyl 4-(2,3,-dihydrobenzo[b][l,4]dioxin-6-yl)-6-methyl-2-ox -1,2,3,4- tetrahydropyrimidine-5-carboxylate was synthesized according to the procedure from Example 16 except using l,4-benzodioxan-6-carboxaldehyde as a starting material. [M+H] + calcd. for C16H18N2O5, 318.3, found 318. EXAMPLE 25 Ethyl 6-methyl-4-(naphthalene-2-yl)-2-ox -l,2,3,4-tetrahydropyrimidine-5-carboxylate
  • Ethyl 6-methyl-4-(naphthalene-2-yl)-2-ox -l,2,3,4-tetrahydropyrimidine-5-carboxylate The compound Ethyl 6-methyl-4-(naphthalene-2-yl)-2-ox -l,2,3,4-tetrahydropyrimidine-5-carboxylate was synthesized according to the procedure from Example 16 except using 2-naphthaldehyde as a starting material. [M+H] + calcd. for C18H18N2O3, 310.3, found 310.
  • Ethyl 6-methyl-4-(naphthalene-2-yl)-2-ox -l,2,3,4-tetrahydropyrimidine-5-carboxylate The compound Ethyl 6-methyl-4-(naphthalene-2-yl)-2-ox -l,2,3,4-tetrahydropyrimidine-5-carboxylate was synthesized according to the procedure from Example 16 except using 2-naphthaldehyde as a starting material. [M+H] + calcd. for C18H18N2O3, 310.3, found 310.
  • Ethyl 4-(3-bromophenyl)-6-cyclopropyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate The compound ethyl 4-(3-bromophenyl)-6-cyclopropyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate was synthesized according to the procedure from Example 8 except using 5-bromo-2- fluorobenzaldehyde and as a starting materials. [M+H] + calcd. for C15H15FN3O4Br, 399.0, found 399.
  • Ethyl l-allyl-4-(3-bromophenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate The compound ethyl 1 -allyl-4-(3 -bromophenyl)-6-methyl-2-oxo- 1 ,2,3 ,4-tetrahydropyrimidine-5- carboxylate was synthesized according to the procedure from Example 8 except using 5- bromobenzaldehyde and 1-allylurea as starting materials. [M+H] + calcd. for C17H19N2O3Br, 378.1, found 378.
  • Ethyl l-allyl-4-(3-bromophenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate The compound ethyl 1 -allyl-4-(3 -bromophenyl)-6-methyl-2-oxo- 1 ,2,3 ,4-tetrahydropyrimidine-5- carboxylate was synthesized according to the procedure from Example 8 except using 5- bromobenzaldehyde and methylurea as starting materials. [M+H] + calcd. for C15H17N2O3Br, 352.0, found 352.
  • Ethyl 4-(3-acetylphenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate The compound ethyl 4-(3-acetylphenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate was synthesized according to the procedure from Example 8 except using 3-acetylbenzaldehyde as a starting materials. [M+H] + calcd. for C16H18N2O4, 302.1, found 302.
  • EXAMPLE 33 Ethyl 6-methyl-2-oxo-4-(3-(trifluoromethoxy)phenyl)-l,2,3,4-tetrahydropyrimidine-5-carboxylate
  • Ethyl 6-methyl-4-(3-(5-methyl-l,2,4-oxadiazole-3-yl)phenyl)-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylate The compound ethyl 6-methyl-4-(3-(5-methyl-l,2,4-oxadiazole-3-yl)phenyl)-2-oxo- l,2,3,4-tetrahydropyrimidine-5-carboxylate was synthesized according to the procedure from Example 8 except using 3-(5-methyl-l,24-oxodiazol-3-yl)benzaldehyde as a starting materials. [M+H] + calcd. for C17H18N4O4, 342.1 found 342.1. EXAMPLE 35
  • Ethyl 6-methyl-4-(3-(2-methylthiazol-4-yl)phenyl)-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylate The compound ethyl 6-methyl-4-(3-(2-methylthiazol-4-yl)phenyl)-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate was synthesized according to the procedure from Example 8 except using 3-(2-methylthiazole-4-yl)benzaldehyde as a starting materials. [M+H] + calcd. for C18H19N3O3S, 357.1 found 357.1.
  • Ethyl 4-(3-bromo-2-methoxyphenyl)-6-methyl-2-oxo-l,2,3,4-tetradroprimidine-5-carboxylate The compound ethyl 4-(3-bromo-2-methoxyphenyl)-6-methyl-2-oxo-l,2,3,44etradroprimidine-5- carboxylate was synthesized according to the procedure from Example 8 except using 5-bromo-2- ethoxylbenzaldehyde as a starting materials. [M+H] + calcd. for C16H19N2O4BR, 382.01 found 382.
  • Ethyl 2-oxo-4-phenyl-6-(trifluoromethyl)-l,2,3,4-tetrahydropyrimidine-5-carboxylate The compound ethyl 2-oxo-4-phenyl-6-(trifluoromethyl)- 1 ,2,3,4-tetrahydropyrimidine-5-carboxylate was synthesized according to the procedure from Example 8 except using benzaldehyde and ethyl 4,4,4- trifluoro-3-oxobutanoate as starting materials. [M+H] + calcd. for C15H15N2O2F3, 312.3 found 312.3.
  • Ethyl 4-(furan-2-yl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate The compound ethyl 4-(furan-2-yl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate was synthesized according to the procedure from Example 8 except using furan-2-carbaldehyde as a starting material. [M+H] + calcd. for C12H14N2O4, 250.1 found 250.1.
  • Ethyl 6-methyl-2-oxo-4-(3-(pyridin-3-yl)phenyl)-l,2,3,4-tetrahydropyrimidine-5-carboxylate The compound ethyl 6-methyl-2-oxo-4-(3-(pyridin-3-yl)phenyl)-l,2,3,4-tetrahydropyrimidine-5-carboxylate was synthesized according to the procedure from Example 8 except using 3-(pyridin-3-yl)benzaldehyde as a starting material. [M+H] + calcd. for C19H19N3O3, 337.3 found 337.3.
  • EXAMPLE 44 Ethyl 6-methyl-2-oxo-4-(pyrimidin-5-yl)-l,2,3,4-tetrahydropyrimidine-5-carboxylate
  • Ethyl 6-methyl-2-oxo-4-(pyrimidine-5-yl)-l,2,3,4-tetrahydropyrimidine-5-carboxylate 3 The compound ethyl 6-methyl-2-oxo-4-(pyrimidine-5-yl)-l,2,3,4-tetrahydropyrimidine-5-carboxylate was synthesized according to the procedure from Example 8 except using pyrimidine-5-cabaldehyde as a starting material to yield 0.15 g (6%) as a yellow solid.
  • This compound is commercially available.
  • This compound is commercially available.
  • This compound is commercially available.
  • This compound is commercially available.
  • Ethyl 4-(3-cyanophenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate The compound Ethyl 4-(3-cyanophenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate was synthesized according to the procedure from Example 8 except using 3-cyanobenzaldehyde as a starting material. [M+H] + calcd. for C15H15N3O3, 285.1 found 285.1.
  • EXAMPLE 52 7-hexyl-3-methyl-8-(2-oxopropylthio)-lH-purine-2,6(3H,7H)-dione
  • This compound is commercially available.
  • This compound is commercially available.
  • This compound is commercially available.
  • This compound is commercially available.
  • SMILES Simplified Molecular Input Line Entry System
  • SMILES is a modern chemical notation system, developed by David Weininger and Daylight Chemical Information Systems, Inc., that is built into all major commercial chemical structure drawing software packages. Software is not needed to interpret SMILES text strings, and an explanation of how to translate SMILES into structures can be found in Weininger, D., J. Chem. Inf. Comput. ScL 1988, 28, 31-36.
  • the source of nitric oxide synthase (NOS) enzyme can be generated in several ways including induction of endogenous iNOS using cytokines and/or lipopolysaccharide (LPS) in various cell types known in the art.
  • the gene encoding the enzyme can be cloned and the enzyme can be generated in cells via heterologous expression from a transient or stable expression plasmid with suitable features for protein expression as are known in the art.
  • Enzymatic activity is calcium independent for iNOS, while the constitutive NOS isoforms, nNOS and eNOS, become active with the addition of various cofactors added to cellular media or extract as are well known in the art.
  • Enzymes specified in Table 1 were expressed in HEK293 cells transiently transfected with human iNOS.
  • nitrate and nitrite are stable metabolites within tissue culture, tissue, plasma, and urine (S Moncada, A Higgs, N Eng J Med 329, 2002 (1993)). Tracer studies in humans have demonstrated that perhaps 50% of the total body nitrate/nitrite originates from the substrate for NO synthesis, L-arginine (PM Rhodes, AM Leone, PL Francis, AD Struthers, S Moncada, Biomed Biophys Res. Commun. 209, 590 (1995); L. Castillo et al., Proc Natl Acad Sci USA 90, 193 (1993).
  • nitrate and nitrite are not measures of biologically active NO, plasma and urine samples obtained from subjects after a suitable period of fasting, and optionally after administration of a controlled diet (low nitrate/low arginine), allow the use of nitrate and nitrite as an index of NO activity (C Baylis, P Vallance, Curr Opin Nephrol Hypertens 7, 59 (1998)).
  • the level of nitrate or nitrite in the specimen can be quantified by any method known in the art which provides adequate sensitivity and reproducibility.
  • a variety of protocols have also been described for detecting and quantifying nitrite and nitrate levels in biological fluids by ion chromatography (e.g.,
  • DAN 2,3-diaminonaphthalene
  • researchers have developed a rapid, quantitative fluorometric assay that can detect from 10 nM to 10 ⁇ M nitrite and is compatible with a multi-well microplate format.
  • DAN is a highly selective photometric and fluorometric reagent for Se and nitrite ion. DAN reacts with nitrite ion and gives fluorescent naphthotriazole (MC Carre et al., Analusis 27, 835-838 (1999)). Table 1 provides the test results of various compounds of the subject invention using the DAN assay.
  • a specimen can be processed prior to determination of nitrate or nitrite as required by the quantification method, or in order to improve the results, or for the convenience of the investigator.
  • processing can involve centrifuging, filtering, or homogenizing the sample.
  • the sample is whole blood, the blood can be centrifuged to remove cells and the nitrate or nitrite assay performed on the plasma or serum fraction.
  • the sample is tissue, the tissue can be dispersed or homogenized by any method known in the art prior to determination of nitrate or nitrite. It may be preferable to remove cells and other debris by centrifugation or another method and to determine the nitrate or nitrite level using only the fluid portion of the sample, or the extracellular fluid fraction of the sample.
  • the sample can also be preserved for later determination, for example by freezing of urine or plasma samples.
  • additives may be introduced into the specimen to preserve or improve its characteristics for use in the nitrate or nitrite assay.
  • the "level" of nitrate, nitrite, or other NO-related product usually refers to the concentration (in moles per liter, micromoles per liter, or other suitable units) of nitrate or nitrite in the specimen, or in the fluid portion of the specimen.
  • concentration in moles per liter, micromoles per liter, or other suitable units
  • other units of measure can also be used to express the level of nitrate or nitrite.
  • an absolute amount in micrograms, milligrams, nanomoles, moles, or other suitable units
  • the amount refers back to a constant amount (e.g., grams, kilograms, milliliters, liters, or other suitable units) of the specimens under consideration.
  • a number of commercially available kits can be used.
  • MNOS EC 50 + indicates ⁇ 5 ⁇ M
  • Example # - indicates > 5 ⁇ M NT indicates Not Tested

Abstract

The present invention relates to novel 2-oxo-l,2,3,4-tetrahydropyrimidines, bicyclic pyrimidine diones and imidizolidine-2,4-diones and methods useful as inhibitors of nitric oxide synthase.

Description

NOVEL 2-OXO-l,2,3,4-TETRAHYDROPYRIMIDINES, BICYCLIC PYRIMIDINE DIONES AND IMIDAZOLIDINE-2,4-DIONES USEFUL AS INDUCIBLE NITRIC OXIDE SYNTHASE
INHIBITORS
This application claims the benefit of priority of United States provisional application No.
60/777,816, filed February 28, 2006, United States provisional application No. 60/777,817, filed February 28, 2006, United States provisional application No. 60/777,818, filed February 28, 2006 and United States provisional application No. 60/836,544, filed August 08, 2006, the disclosures of which are hereby incorporated by reference as if written herein in their entireties.
FIELD OF THE INVENTION
The present invention is directed to new 2-oxo-l,2,3,4-tetrahydropyrimidine, bicyclic pyrimidine dione and imidizolidine-2,4-dione compounds and compositions and their application as pharmaceuticals for the treatment of disease. Methods of inhibition of nitric oxide synthase, activity in a human or animal subject are also provided for the treatment of diseases.
BACKGROUND OF THE INVENTION
Nitric oxide (NO) is involved in the regulation of many physiological processes as well as the pathophysiology of a number of diseases. It is synthesized enzymatically from L-arginine in numerous tissues and cell types by three distinct isoforms of the enzyme NO synthase (NOS). Two of these isoforms, endothelial NOS (eNOS) and neuronal NOS (nNOS) are expressed in a constitutive manner and are calcium/calmodulin dependent. Endothelial NOS is expressed by endothelium and other cell types and is involved in cardiovascular homeostasis. Neuronal NOS is constitutively present in both the central and peripheral nervous system where NO acts a neurotransmitter. Under normal physiological conditions, these constitutive forms of NOS generate low, transient levels of NO in response to increases in intracellular calcium concentrations. These low levels of NO act to regulate blood pressure, platelet adhesion, gastrointestinal motility, bronchomotor tone and neurotransmission.
In contrast, the third isoform of NOS, inducible NOS (iNOS), a virtually calcium independent enzyme, is absent in resting cells, but is rapidly expressed in virtually all nucleated mammalian cells in response to stimuli such as endotoxins and/or cytokines. The inducible isoform is neither stimulated by calcium nor blocked by calmodulin antagonists. It contains several tightly bound co-factors, including FMN, FAD and tetrahydrobiopterin. The inducible isoform of nitric oxide synthase (NOS2 or iNOS) is expressed in virtually all nucleated mammalian cells following exposure to inflammatory cytokines or lipopolysaccharide. The enzyme iNOS synthase is a homodimer composed of 13OkDa subunits. Each subunit comprises an oxygenase domain and a reductase domain. The presence of iNOS in macrophages and lung epithelial cells is significant. Once present, iNOS synthesizes 100-1000 times more NO than the constitutive enzymes synthesize and does so for prolonged periods. This excessive production of NO and resulting NO-derived metabolites (e.g., peroxynitrite) elicit cellular toxicity and tissue damage which contribute to the pathophysiology of a number of diseases, disorders and conditions.
Nitric oxide generated by the inducible form of NOS has also been implicated in the pathogenesis of inflammatory diseases. In experimental animals, hypotension induced by lipopolysaccharide or tumor necrosis factor alpha can be reversed by NOS inhibitors. Conditions which lead to cytokine-induced hypotension include septic shock, hemodialysis and interleukin therapy in cancer patients. An iNOS inhibitor has been shown to be effective in treating cytokine-induced hypotension, inflammatory bowel disease, cerebral ischemia, osteoarthritis, asthma and neuropathies such as diabetic neuropathy and post-herpetic neuralgia.
In addition, nitric oxide localized in high amounts in inflamed tissues has been shown to induce pain locally and to enhance central as well as peripheral stimuli. Because nitric oxide produced by an inflammatory response is thought to be synthesized by iNOS, the inhibition of iNOS dimerization produces both prophylactic and remedial analgesia in patients.
Hence, in situations where the overproduction of nitric oxide is deleterious, it would be advantageous to find a specific inhibitor of iNOS to reduce the production of NO. However, given the important physiological roles played by the constitutive NOS isoforms, it is essential that the inhibition of iNOS has the least possible effect on the activity of eNOS and nNOS.
SUMMARY OF THE INVENTION
Novel compounds and pharmaceutical compositions that inhibit the inducible NOS synthase have been found, together with methods of synthesizing and using the compounds including methods for the treatment of Nitric oxide -mediated diseases in a patient by administering the compounds.
The present invention discloses a class of compounds, useful in treating iNOS-mediated disorders and conditions, defined by structural Formula I:
Figure imgf000003_0001
wherein:
X1 is selected from the group consisting of CH2, O, S or NH; R1 is selected from the group consisting of alkoxy, alkyl, alkylamino, alkylene, alkylamino, alkynyl, amino, aryl, arylalkoxy, arylamino, arylthio, cycloalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylamino, heterocycloalkyl and hydrogen, any of which may be optionally substituted;
R2 is selected from the group consisting of acyl, alkoxy, alkoxyalkyl, alkyl, alkylene, alkylamino, alkynyl, alkylimino, amido, amino, aryl, carboxy, cyano, cycloalkyl, ester, haloalkyl, heteoaryl, heterocycloalkyl and hydrogen, any of which may be optionally substituted;
R3a and R3b are each independently selected from the group consisting of alkyl, amino, arylalkyl, aryl, cycloalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl and hydrogen, any of which may be optionally substituted; and R4 and R5 are each independently optionally substituted alkyl or hydrogen.
The present invention further discloses a class of compounds, useful in treating iNOS-mediated disorders and conditions, defined by structural Formula VI:
Figure imgf000004_0001
wherein:
A is optionally substituted heteroaryl; and
R1 and R2 are each independently selected from the group consisting of acyl, alkyl, alkylene, alkylamino, alkynyl, amido, amino, aryl, arylalkoxy, arylamino, arylthio, carboxy, cycloalkyl, ester, ether, halo, haloalkoxy, haloalkyl, heteroaryl, heterocycloalkyl, hydrogen, thio, sulfonate and sulfonyl, any of which may be optionally substituted.
The present invention further discloses a class of compounds, useful in treating iNOS-mediated disorders and conditions, defined by structural Formula XI:
Figure imgf000004_0002
wherein:
X1 and X2 are each independently selected from the group consisting of acyl, alkoxy, alkyl, alkylene, alkynyl, amido, amino, aminosulfonyl, aryl, arylalkoxy, arylamino, arylthio, carboxy, cycloalkyl, ester, haloalkyl, heteroaryl, heterocycloalkyl, hydrogen, thio, sulfonate and sulfonyl, any of which may be optionally substituted; R1 is selected from the group consisting of alkoxy, alkyl, alkylamino, alkylaryl, alkylheteroaryl, alkylene, alkylamino, alkynyl, amino, aryl, arylalkoxy, arylamino, arylthio, cycloalkyl, ester, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylamino, heterocycloalkyl and hydrogen, any of which may be optionally substituted; and R2 is selected from the group consisting of acyl, alkoxy, alkoxyalkyl, alkyl, alkylene, alkylamino, alkynyl, alkylimino, amido, amino, aryl, carboxy, cyano, cycloalkyl, ester, halo, haloalkyl, heteoaryl, heterocycloalkyl and hydrogen, any of which may be optionally substituted.
The present invention also provides pharmaceutical compositions comprising one or more compounds of the present invention together with a pharmaceutically acceptable carrier. In another aspect, the present invention also provides methods for inhibiting iNOS. In broad aspect, the present invention also provides methods for treating a iNOS-mediated disorder in a human or animal subject in need of such treatment comprising administering to said subject an amount of a compound of the present invention effective to reduce or prevent said disorder in said subject. In a broad aspect, the subject invention provides for novel compounds, pharmaceutical compositions and methods of making and using the compounds and compositions. These compounds possess useful iNOS inhibiting or modulating activity, and may be used in the treatment or prophylaxis of a disease or condition in which iNOS plays an active role.
DETAILED DESCRIPTION OF THE INVENTION
In certain embodiments, the compounds of the present invention have structural Formula II:
Figure imgf000005_0001
wherein:
X1 is selected from the group consisting of O, S or NH; R1 is selected from the group consisting of alkoxy, alkyl, alkylamino, alkylene, alkylamino, alkynyl, amino, aryl, arylalkoxy, arylamino, arylthio, cycloalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylamino, heterocycloalkyl and hydrogen, any of which may be optionally substituted; R2 is selected from the group consisting of acyl, alkoxy, alkoxyalkyl, alkyl, alkylene, alkylamino, alkynyl, alkylimino, amido, amino, aryl, carboxy, cyano, cycloalkyl, ester, haloalkyl, heteoaryl, heterocycloalkyl and hydrogen, any of which may be optionally substituted; R3ais aryl or heteroaryl, either of which may be optionally substituted; and R3b is selected from the group consisting of alkyl, amino, cycloalkyl, haloalkyl, heterocycloalkyl and hydrogen, any of which may be optionally substituted. The invention further provides for compounds of Formula III:
Figure imgf000006_0001
wherein:
R2 is selected from the group consisting of alkyl, alkylene, alkynyl, alkylimino, cycloalkyl, haloalkyl, heterocycloalkyl and hydrogen, any of which may be optionally substituted; R3ais aryl or heteroaryl, either of which may be optionally substituted; and R8 is selected from the group consisting of alkyl, alkylamino, alkylene, alkynyl, aryl, cycloalkyl, haloalkyl, heteroaryl, heterocycloalkyl and hydrogen, any of which may be optionally substituted. The invention further provides for compounds of Formula VII:
Figure imgf000006_0002
wherein:
X1 is selected from the group consisting of NR3 or CR4; X2 is selected from the group consisting of NR5, O, S(O)2 or S(O); X3 is selected from the group consisting of acyl, alkoxy, alkyl, alkylthio, alkylene, alkylamino, alkynyl, amido, amino, aminosulfonyl, aryl, arylalkoxy, arylamino, arylthio, carboxy, cycloalkyl, ester, ether, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylamino, heteroarylthio, heterocycloalkyl, hydrazinyl, imino, thio, sulfonate and sulfonylamino, any of which may be optionally substituted;
R1 and R2 are each independently selected from the group consisting of acyl, alkyl, alkylene, alkylamino, alkynyl, amido, amino, aryl, arylalkoxy, arylamino, arylthio, carboxy, cycloalkyl, ester, ether, halo, haloalkoxy, haloalkyl, heteroaryl, heterocycloalkyl, hydrogen, thio, sulfonate and sulfonyl, any of which may be optionally substituted;
R is selected from the group consisting of acyl, alkyl, alkylene, alkylamino, alkynyl, aryl, arylalkoxy, arylamino, arylthio, carboxy, cycloalkyl, ester, ether, haloalkyl, heteroaryl, heteroarylamino, heterocycloalkyl, hydrogen, thio, sulfonate and sulfonylamino, any of which may be optionally substituted;
R4 is selected from the group consisting of acyl, alkyl, alkylene, alkylamino, alkynyl, aryl, arylalkoxy, arylamino, arylthio, carboxy, cycloalkyl, ester, ether, haloalkyl, heteroaryl, heteroarylamino, heterocycloalkyl, hydrogen, thio, sulfonate and sulfonylamino, any of which may be optionally substituted; and R5 is selected from the group consisting of acyl, alkyl, alkylene, alkylamino, alkynyl, aryl, arylalkoxy, arylamino, arylthio, carboxy, cycloalkyl, ester, ether, haloalkyl, heteroaryl, heteroarylamino, heterocycloalkyl, hydrogen, thio, sulfonate and sulfonylamino, any of which may be optionally substituted.
The invention further provides for compounds of Formula VIII:
Figure imgf000007_0001
wherein:
X3 is selected from the group consisting of -SR6, -S(O)2R6, -NR7R8 and -OR3, any of which may be optionally substituted; R6 is selected from the group consisting of alkyl, alkylaryl, alkylene, alkynyl, aryl, cycloalkyl, ester, halo, haloalkyl, heteroaryl, heterocycloalkyl and hydrogen, any of which may be optionally substituted;
R7 and R8 are each independently selected from the group selected from the group consisting of acyl, alkyl, alkylene, aminoalkyl, alkynyl, arylthio, carboxy, cycloalkyl, ester, ether, halo, haloalkoxy, haloalkyl, heteroaryl, heterocycloalkyl, hydrogen, thio and sulfonyl, any of which may be optionally substituted; or, alternatively, R5 and R6 may combine to form optionally substituted heterocycloalkyl; and
R is selected from the group consisting of acyl, alkyl, alkylene, alkylamino, alkynyl, aryl, arylalkoxy, arylamino, arylthio, carboxy, cycloalkyl, ester, ether, haloalkyl, heteroaryl, heteroarylamino, heterocycloalkyl, hydrogen, thio, sulfonate and sulfonyl, any of which may be optionally substituted.
The invention further provides for compounds of Formula IX:
Figure imgf000007_0002
wherein:
R1 and R2 are each independently selected from the group consisting of acyl, alkyl, alkylene, alkylamino, alkynyl, amido, amino, aryl, arylalkoxy, arylamino, arylthio, carboxy, cycloalkyl, ester, ether, halo, haloalkoxy, haloalkyl, heteroaryl, heterocycloalkyl, hydrogen, thio, sulfonate and sulfonyl, any of which may be optionally substituted; and
R9, R10 and R11 are each independently selected from the group consisting of acyl, alkoxy, alkoxyalkylaryl, alkoxyalkylheteroaryl, alkyl, alkylene, alkylamino, alkynyl, amido, amino, aminosulfonyl, aryl, arylalkoxy, arylamino, arylthio, carboxy, cycloalkyl, ester, ether, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylamino, heterocycloalkyl, hydrazinyl, hydrogen, imino, thio, sulfonate and sulfonylamino, any of which may be optionally substituted.
The invention further provides for compounds of Formula XII:
Figure imgf000008_0001
wherein:
R1 is selected from the group consisting of alkylaryl, alkylheteroaryl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl, any of which may be optionally substituted; and
R2 is selected from the group consisting of alkyl, cycloalkyl, haloalkyl, heterocycloalkyl and hydrogen, any of which may be optionally substituted. The invention further provides for compounds of Formula XIII:
Figure imgf000008_0002
wherein:
X3 is selected from the group consisting of CR3 or N;
X4 is selected from the group consisting of CR4 or N, X5 is selected from the group consisting of CR5 or N;
X6 is selected from the group consisting of CR6 or N;
X7 is selected from the group consisting of CR7 or N;
R2 is selected from the group consisting of alkyl, cycloalkyl, haloalkyl, heterocycloalkyl and hydrogen, any of which may be optionally substituted; and R3, R4, R5 R6 and R7 are each independently selected from the group consisting of acyl, alkoxy, alkoxyalkylaryl, alkoxyalkylheteroaryl, alkyl, alkylene, alkylamino, alkynyl, amido, amino, aminosulfonyl, aryl, arylalkoxy, arylamino, arylthio, carboxy, cycloalkyl, ester, ether, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylamino, heterocycloalkyl, hydrazinyl, hydrogen, imino, thio, sulfonate and sulfonylamino, any of which may be optionally substituted. The invention provides for compounds of Formulas I-XIII for use in the inhibition of iNOS for the treatment of disease.
The invention provides for compounds of Formulas I- XIII administered in combination with another therapeutic agent.
The invention provides for compounds of Formulas I- XIII for use as a medicament. The invention provides for compounds of Formulas I- XIII for use in the manufacture of a medicament for the prevention or treatment of a disease or condition ameliorated by the inhibition of iNOS.
The invention provides for a pharmaceutical composition comprising a compound of any of Formulas I- XIII together with a pharmaceutically acceptable carrier, useful for the treatment or prevention of an iNOS-mediated disease.
The invention provides for a method of inhibition of iNOS comprising contacting iNOS with a compound of any of Formulas I- XIII.
The invention provides for a method of treatment of a iNOS-mediated disease comprising the administration of a therapeutically effective amount of a compound of any of Formulas I- XIII to a patient in need thereof, wherein said disease is selected from the group consisting of psoriasis, uveitis, type 1 diabetes, septic shock, pain, migraine, rheumatoid arthritis, inflammatory bowel disease, asthma, immune complex diseases, multiple sclerosis, ischemic brain edema, toxic shock syndrome, heart failure, ulcerative colitis, atherosclerosis, glomerulonephritis, Paget's disease, osteoporosis, inflammatory sequelae of viral infections, retinitis, oxidant induced lung injury, eczema, acute allograft rejection and infection caused by invasive microorganisms which produce NO.
As used herein, the terms below have the meanings indicated.
The term "acyl," as used herein, alone or in combination, refers to a carbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocycle, or any other moiety were the atom attached to the carbonyl is carbon. An "acetyl" group refers to a -C(O)CH3 group. An "alkylcarbonyl" or "alkanoyl" group refers to an alkyl group attached to the parent molecular moiety through a carbonyl group. Examples of such groups include methylcarbonyl and ethylcarbonyl. Examples of acyl groups include formyl, alkanoyl and aroyl. The term "alkenyl," as used herein, alone or in combination, refers to a straight- chain or branched-chain hydrocarbon radical having one or more double bonds and containing from 2 to 20, preferably 2 to 6, carbon atoms. Alkenylene refers to a carbon-carbon double bond system attached at two or more positions such as ethenylene [(-CH=CH-),(-C::C-)]. Examples of suitable alkenyl radicals include ethenyl, propenyl, 2-methylpropenyl, 1,4-butadienyl and the like. The term "alkoxy," as used herein, alone or in combination, refers to an alkyl ether radical, wherein the term alkyl is as defined below. Examples of suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like.
The term "alkyl," as used herein, alone or in combination, refers to a straight- chain or branched-chain alkyl radical containing from 1 to and including 20, preferably 1 to 10, and more preferably 1 to 6, carbon atoms. Alkyl groups may be optionally substituted as defined herein. Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, noyl and the like. The term "alkylene," as used herein, alone or in combination, refers to a saturated aliphatic group derived from a straight or branched chain saturated hydrocarbon attached at two or more positions, such as methylene (-CH2-).
The term "alkylamino," as used herein, alone or in combination, refers to an alkyl group attached to the parent molecular moiety through an amino group. Suitable alkylamino groups may be mono- or dialkylated, forming groups such as, for example, N-methylamino, N-ethylamino, N,N- dimethylamino, N,N-ethylmethylamino and the like.
The term "alkylidene," as used herein, alone or in combination, refers to an alkenyl group in which one carbon atom of the carbon-carbon double bond belongs to the moiety to which the alkenyl group is attached. The term "alkylthio," as used herein, alone or in combination, refers to an alkyl thioether
(R-S-) radical wherein the term alkyl is as defined above and wherein the sulfur may be singly or doubly oxidized. Examples of suitable alkyl thioether radicals include methylthio, ethylthio, n- propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like. The term "alkynyl," as used herein, alone or in combination, refers to a straight- chain or branched chain hydrocarbon radical having one or more triple bonds and containing from 2 to 20, preferably from 2 to 6, more preferably from 2 to 4, carbon atoms. "Alkynylene" refers to a carbon- carbon triple bond attached at two positions such as ethynylene (-C:::C-, -C≡C-). Examples of alkynyl radicals include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, 3- methylbutyn- 1 -yl, hexyn-2-yl, and the like.
The terms "amido" and "carbamoyl,"as used herein, alone or in combination, refer to an amino group as described below attached to the parent molecular moiety through a carbonyl group, or vice versa. The term "C-amido" as used herein, alone or in combination, refers to a -C(=O)-NR2 group with R as defined herein. The term "N-amido" as used herein, alone or in combination, refers to a RC(=O)NH- group, with R as defined herein. The term "acylamino" as used herein, alone or in combination, embraces an acyl group attached to the parent moiety through an amino group. An example of an "acylamino" group is acetylamino (CH3C(O)NH-).
The term "amino," as used herein, alone or in combination, refers to — NRR , wherein R and R are independently selected from the group consisting of hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may themselves be optionally substituted.
The term "aryl," as used herein, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused. The term "aryl" embraces aromatic radicals such as benzyl, phenyl, naphthyl, anthracenyl, phenanthryl, indanyl, indenyl, annulenyl, azulenyl, tetrahydronaphthyl, and biphenyl. The term "arylalkenyl" or "aralkenyl," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkenyl group.
The term "arylalkoxy" or "aralkoxy," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkoxy group. The term "arylalkyl" or "aralkyl," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkyl group.
The term "arylalkynyl" or "aralkynyl," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkynyl group. The term "arylalkanoyl" or "aralkanoyl" or "aroyl,"as used herein, alone or in combination, refers to an acyl radical derived from an aryl-substituted alkanecarboxylic acid such as benzoyl, napthoyl, phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, A- chlorohydrocinnamoyl, and the like.
The term aryloxy as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an oxy.
The terms "benzo" and "benz," as used herein, alone or in combination, refer to the divalent radical
Figure imgf000011_0001
derived from benzene. Examples include benzothiophene and benzimidazole.
The term "carbamate," as used herein, alone or in combination, refers to an ester of carbamic acid (-NHCOO-) which may be attached to the parent molecular moiety from either the nitrogen or acid end, and which may be optionally substituted as defined herein.
The term "O-carbamyl" as used herein, alone or in combination, refers to a -OC(O)NRR', group-with R and R' as defined herein.
The term "N-carbamyl" as used herein, alone or in combination, refers to a ROC(O)NR'- group, with R and R' as defined herein. The term "carbonyl," as used herein, when alone includes formyl [-C(O)H] and in combination is a -C(O)- group.
The term "carboxy," as used herein, refers to -C(O)OH or the corresponding "carboxylate" anion, such as is in a carboxylic acid salt. An "O-carboxy" group refers to a RC(O)O- group, where R is as defined herein. A "C-carboxy" group refers to a -C(O)OR groups where R is as defined herein. The term "cyano," as used herein, alone or in combination, refers to -CN.
The term "cycloalkyl," as used herein, alone or in combination, refers to a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl radical wherein each cyclic moiety contains from 3 to 12, preferably five to seven, carbon atom ring members and which may optionally be a benzo fused ring system which is optionally substituted as defined herein. Examples of such cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, octahydronaphthyl, 2,3-dihydro-lH- indenyl, adamantyl and the like. "Bicyclic" and "tricyclic" as used herein are intended to include both fused ring systems, such as decahydonapthalene, octahydronapthalene as well as the multicyclic (multicentered) saturated or partially unsaturated type. The latter type of isomer is exemplified in general by, bicyclo[ 1,1,1 ]pentane, camphor, adamantane, and bicyclo[3,2,l]octane. The term "ester," as used herein, alone or in combination, refers to a carboxy group bridging two moieties linked at carbon atoms.
The term "ether," as used herein, alone or in combination, refers to an oxy group bridging two moieties linked at carbon atoms. The term "halo," or "halogen," as used herein, alone or in combination, refers to fluorine, chlorine, bromine, or iodine.
The term "haloalkoxy," as used herein, alone or in combination, refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom. The term "haloalkyl," as used herein, alone or in combination, refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. "Haloalkylene" refers to a haloalkyl group attached at two or more positions. Examples include fluoromethylene (-CFH-), difluoromethylene (-CF2 -), chloromethylene (-CHC1-) and the like. The term "heteroalkyl," as used herein, alone or in combination, refers to a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, fully saturated or containing from 1 to 3 degrees of unsaturation, consisting of the stated number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N and S may be placed at any interior position of the heteroalkyl group. Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3.
The term "heteroaryl," as used herein, alone or in combination, refers to 3 to 7 membered, preferably 5 to 7 membered, unsaturated heteromonocyclic rings, or fused polycyclic rings in which at least one of the fused rings is unsaturated, wherein at least one atom is selected from the group consisting of O, S, and N. The term also embraces fused polycyclic groups wherein heterocyclic radicals are fused with aryl radicals, wherein heteroaryl radicals are fused with other heteroaryl radicals, or wherein heteroaryl radicals are fused with cycloalkyl radicals. Examples of heteroaryl groups include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, benzothienyl, chromonyl, coumarinyl, benzopyranyl, tetrahydroquinolinyl, tetrazolopyridazinyl, tetrahydroisoquinolinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl and the like. Exemplary tricyclic heterocyclic groupsinclude carbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl and the like.
The terms "heterocycloalkyl" and, interchangeably, "heterocycle," as used herein, alone or in combination, each refer to a saturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic, or tricyclic heterocyclic radical containing at least one, preferably 1 to 4, and more preferably 1 to 2 heteroatoms as ring members, wherein each said heteroatom may be independently selected from the group consisting of nitrogen, oxygen, and sulfur, and wherein there are preferably 3 to 8 ring members in each ring, more preferably 3 to 7 ring members in each ring, and most preferably 5 to 6 ring members in each ring. "Heterocycloalkyl" and "heterocycle" are intended to include sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclic fused and benzo fused ring systems; additionally, both terms also include systems where a heterocycle ring is fused to an aryl group, as defined herein, or an additional heterocycle group. Heterocycle groups of the invention are exemplified by aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[l,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihy- dropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like. The heterocycle groups may be optionally substituted unless specifically prohibited.
The term "hydrazinyl" as used herein, alone or in combination, refers to two amino groups joined by a single bond, i.e., -N-N-. The term "hydroxy," as used herein, alone or in combination, refers to -OH.
The term "hydroxyalkyl," as used herein, alone or in combination, refers to a hydroxy group attached to the parent molecular moiety through an alkyl group.
The term "imino," as used herein, alone or in combination, refers to =N-.
The term "iminohydroxy," as used herein, alone or in combination, refers to =N(OH) and =N-O-.
The phrase "in the main chain" refers to the longest contiguous or adjacent chain of carbon atoms starting at the point of attachment of a group to the compounds of this invention.
The term "isocyanato" refers to a -NCO group.
The term "isothiocyanato" refers to a -NCS group. The phrase "linear chain of atoms" refers to the longest straight chain of atoms independently selected from carbon, nitrogen, oxygen and sulfur.
The term "lower," as used herein, alone or in combination, means containing from 1 to and including 6 carbon atoms.
The term "mercaptyl" as used herein, alone or in combination, refers to an RS- group, where R is as defined herein.
The term "nitro," as used herein, alone or in combination, refers to -NO2.
The terms "oxy" or "oxa," as used herein, alone or in combination, refer to -O-.
The term "oxo," as used herein, alone or in combination, refers to =O.
The term "perhaloalkoxy" refers to an alkoxy group where all of the hydrogen atoms are replaced by halogen atoms.
The term "perhaloalkyl" as used herein, alone or in combination, refers to an alkyl group where all of the hydrogen atoms are replaced by halogen atoms. The terms "sulfonate," "sulfonic acid," and "sulfonic," as used herein, alone or in combination, refer the -SO3H group and its anion as the sulfonic acid is used in salt formation.
The term "sulfanyl," as used herein, alone or in combination, refers to -S-.
The term "sulfinyl," as used herein, alone or in combination, refers to -S(O)-. The term "sulfonyl," as used herein, alone or in combination, refers to -S(O)2-.
The term "N-sulfonamido" refers to a RS(=O)2NR'- group with R and R' as defined herein.
The term "S-sulfonamido" refers to a -S(=O)2NRR', group, with R and R' as defined herein.
The terms "thia" and "thio," as used herein, alone or in combination, refer to a -S- group or an ether wherein the oxygen is replaced with sulfur. The oxidized derivatives of the thio group, namely sulfinyl and sulfonyl, are included in the definition of thia and thio.
The term "thiol," as used herein, alone or in combination, refers to an -SH group.
The term "thiocarbonyl," as used herein, when alone includes thioformyl -C(S)H and in combination is a -C(S)- group.
The term "N-thiocarbamyl" refers to an ROC(S)NR'- group, with R and R' as defined herein. The term "O-thiocarbamyl" refers to a -OC(S)NRR', group with R and R' as defined herein.
The term "thiocyanato" refers to a -CNS group.
The term "trihalomethanesulfonamido" refers to a X3CS(O^NR- group with X is a halogen and R as defined herein.
The term "trihalomethane sulfonyl" refers to a X3CS(O^- group where X is a halogen. The term "trihalomethoxy" refers to a X3CO- group where X is a halogen.
The term "trisubstituted silyl," as used herein, alone or in combination, refers to a silicone group substituted at its three free valences with groups as listed herein under the definition of substituted amino. Examples include trimethysilyl, tert-butyldimethylsilyl, triphenylsilyl and the like.
Any definition herein may be used in combination with any other definition to describe a composite structural group. By convention, the trailing element of any such definition is that which attaches to the parent moiety. For example, the composite group alkylamido would represent an alkyl group attached to the parent molecule through an amido group, and the term alkoxyalkyl would represent an alkoxy group attached to the parent molecule through an alkyl group.
When a group is defined to be "null," what is meant is that said group is absent. The term "optionally substituted" means the anteceding group may be substituted or unsubstituted. When substituted, the substituents of an "optionally substituted" group may include, without limitation, one or more substituents independently selected from the following groups or a particular designated set of groups, alone or in combination: lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester, lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, lower alkylamino, arylamino, amido, nitro, thiol, lower alkylthio, arylthio, lower alkylsulfinyl, lower alkylsulfonyl, arylsulfinyl, arylsulfonyl, arylthio, sulfonate, sulfonic acid, trisubstituted silyl, N3, SH, SCH3, C(O)CH3, CO2CH3, CO2H, pyridinyl, thiophene, furanyl, lower carbamate, and lower urea. Two substituents may be joined together to form a fused five-, six-, or seven-menbered carbocyclic or heterocyclic ring consisting of zero to three heteroatoms, for example forming methylenedioxy or ethylenedioxy. An optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and monosubstituted (e.g., -CH2CF3). Where substituents are recited without qualification as to substitution, both substituted and unsubstituted forms are encompassed. Where a substituent is qualified as "substituted," the substituted form is specifically intended. Additionally, different sets of optional substituents to a particuar moiety may be defined as needed; in these cases, the optional substitution will be as defined, often immediately following the phrase, "optionally substituted with."
The term R or the term R', appearing by itself and without a number designation, unless otherwise defined, refers to a moiety selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl and heterocycloalkyl, any of which may be optionally substituted. Such R and R' groups should be understood to be optionally substituted as defined herein. Whether an R group has a number designation or not, every R group, including R, R' and Rn where n=(l, 2, 3, ...n), every substituent, and every term should be understood to be independent of every other in terms of selection from a group. Should any variable, substituent, or term (e.g. aryl, heterocycle, R, etc.) occur more than one time in a formula or generic structure, its definition at each occurrence is independent of the definition at every other occurrence. Those of skill in the art will further recognize that certain groups may be attached to a parent molecule or may occupy a position in a chain of elements from either end as written. Thus, by way of example only, an unsymmetrical group such as -C(O)N(R)- may be attached to the parent moiety at either the carbon or the nitrogen.
Asymmetric centers exist in the compounds of the present invention. These centers are designated by the symbols "R" or "S," depending on the configuration of substituents around the chiral carbon atom. It should be understood that the invention encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric, and epimeric forms, as well as d-isomers and 1 -isomers, and mixtures thereof. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art. Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art. Additionally, the compounds of the present invention may exist as geometric isomers. The present invention includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. Additionally, compounds may exist as tautomers; all tautomeric isomers are provided by this invention. Additionally, the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
The term "bond" refers to a covalent linkage between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure. A bond may be single, double, or triple unless otherwise specified. A dashed line between two atoms in a drawing of a molecule indicates that an additional bond may be present or absent at that position.
The term "combination therapy" means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.
"iNOS inhibitor" is used herein to refer to a compound that exhibits an IC50 with respect to iNOS activity of no more than about 100 μM and more typically not more than about 50 μM, as measured in the iNOS DAN Assay described generally hereinbelow. "IC50" is that concentration of inhibitor which reduces the activity of an enzyme (e.g., iNOS) to half-maximal level. Representative compounds of the present invention have been discovered to exhibit inhibitory activity against iNOS.
Compounds of the present invention preferably exhibit an IC50 with respect to iNOS of no more than about 10 μM, more preferably, no more than about 5 μM, even more preferably not more than about 1 μM, and most preferably, not more than about 200 nM, as measured in the iNOS assay(s) described herein.
The phrase "therapeutically effective" is intended to qualify the amount of active ingredients used in the treatment of a disease or disorder. This amount will achieve the goal of reducing or eliminating the said disease or disorder.
The term "therapeutically acceptable" refers to those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use. As used herein, reference to "treatment" of a patient is intended to include prophylaxis. The term "patient" means all mammals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, pigs, and rabbits. Preferably, the patient is a human.
The term "prodrug" refers to a compound that is made more active in vivo. Certain compounds of the present invention may also exist as prodrugs, as described in Hydrolysis in Drug and Prodrug Metabolism : Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley-
VHCA, Zurich, Switzerland 2003). Prodrugs of the compounds described herein are structurally modified forms of the compound that readily undergo chemical changes under physiological conditions to provide the compound. Additionally, prodrugs can be converted to the compound by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to a compound when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because, in some situations, they may be easier to administer than the compound, or parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. A wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. An example, without limitation, of a prodrug would be a compound which is administered as an ester (the "prodrug"), but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound.
The compounds of the present invention can exist as therapeutically acceptable salts. The present invention includes compounds listed above in the form of salts, in particular acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable salts may be of utility in the preparation and purification of the compound in question. Basic addition salts may also be formed and be pharmaceutically acceptable. For a more complete discussion of the preparation and selection of salts, refer to Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P. Heinrich. Wiley- VCHA, Zurich, Switzerland, 2002).
The term "therapeutically acceptable salt," as used herein, represents salts or zwitterionic forms of the compounds of the present invention which are water or oil-soluble or dispersible and therapeutically acceptable as defined herein. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound in the form of the free base with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L- ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethansulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, me sitylene sulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, phosphonate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para- toluene sulfonate (p-tosylate), and undecanoate. Also, basic groups in the compounds of the present invention can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids which can be employed to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Salts can also be formed by coordination of the compounds with an alkali metal or alkaline earth ion. Hence, the present invention contemplates sodium, potassium, magnesium, and calcium salts of the compounds of the compounds of the present invention and the like.
Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxy group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine. The cations of therapeutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, λζλf-dimethylaniline, iV-methylpiperidine, λf-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, λζλf-dibenzylphenethylamine, 1 -ephenamine, and N.N1- dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.
A salt of a compound can be made by reacting the appropriate compound in the form of the free base with the appropriate acid. While it may be possible for the compounds of the subject invention to be administered as the raw chemical, it is also possible to present them as a pharmaceutical formulation. Accordingly, the subject invention provides a pharmaceutical formulation comprising a compound or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., in Remington's Pharmaceutical Sciences. The pharmaceutical compositions of the present invention may be manufactured in a manner that is itself known, e.g. , by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.
The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association a compound of the subject invention or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation. Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
Pharmaceutical preparations which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. The push- fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner. Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.
The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. , containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.
Compounds of the present invention may be administered topically, that is by non-systemic administration. This includes the application of a compound of the present invention externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, for instance from 1% to 2% by weight of the formulation. It may however comprise as much as 10% w/w but preferably will comprise less than 5% w/w, more preferably from 0.1% to 1% w/w of the formulation.
Gels for topical or transdermal administration of compounds of the subject invention may comprise, generally, a mixture of volatile solvents, nonvolatile solvents, and water. The volatile solvent component of the buffered solvent system may preferably include lower (C1-C6) alkyl alcohols, lower alkyl glycols and lower glycol polymers. More preferably, the volatile solvent is ethanol. The volatile solvent component is thought to act as a penetration enhancer, while also producing a cooling effect on the skin as it evaporates. The nonvolatile solvent portion of the buffered solvent system is selected from lower alkylene glycols and lower glycol polymers. Preferably, propylene glycol is used. The nonvolatile solvent slows the evaporation of the volatile solvent and reduces the vapor pressure of the buffered solvent system. The amount of this nonvolatile solvent component, as with the volatile solvent, is determined by the pharmaceutical compound or drug being used. When too little of the nonvolatile solvent is in the system, the pharmaceutical compound may crystallize due to evaporation of volatile solvent, while an excess will result in a lack of bioavailability due to poor release of drug from solvent mixture. The buffer component of the buffered solvent system may be selected from any buffer commonly used in the art; preferably, water is used. The preferred ratio of ingredients is about 20% of the nonvolatile solvent, about 40% of the volatile solvent, and about 40% water. There are several optional ingredients which can be added to the topical composition. These include, but are not limited to, chelators and gelling agents. Appropriate gelling agents can include, but are not limited to, semisynthetic cellulose derivatives (such as hydroxypropylmethylcellulose) and synthetic polymers, and cosmetic agents.
Lotions according to the present invention include those suitable for application to the skin or eye. An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops. Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.
Creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy base. The base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives or a fatty acid such as steric or oleic acid together with an alcohol such as propylene glycol or a macrogel. The formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof. Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included. Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and preferably including a surface active agent. The resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-1000C for half an hour. Alternatively, the solution may be sterilized by filtration and transferred to the container by an aseptic technique. Examples of bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol. Formulations for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising the active ingredient in a flavored basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia. For administration by inhalation the compounds according to the invention are conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compounds according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
Preferred unit dosage formulations are those containing an effective dose, as herein below recited, or an appropriate fraction thereof, of the active ingredient.
It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
The compounds of the invention may be administered orally or via injection at a dose of from 0.1 to 500 mg/kg per day. The dose range for adult humans is generally from 5 mg to 2 g/day. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of compound of the invention which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
The compounds of the subject invention can be administered in various modes, e.g. orally, topically, or by injection. The precise amount of compound administered to a patient will be the responsibility of the attendant physician. The specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diets, time of administration, route of administration, rate of excretion, drug combination, the precise disorder being treated, and the severity of the indication or condition being treated. Also, the route of administration may vary depending on the condition and its severity.
In certain instances, it may be appropriate to administer at least one of the compounds described herein (or a pharmaceutically acceptable salt, ester, or prodrug thereof) in combination with another therapeutic agent. By way of example only, if one of the side effects experienced by a patient upon receiving one of the compounds herein is hypertension, then it may be appropriate to administer an anti- hypertensive agent in combination with the initial therapeutic agent. Or, by way of example only, the therapeutic effectiveness of one of the compounds described herein may be enhanced by administration of an adjuvant (i.e., by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or, by way of example only, the benefit of experienced by a patient may be increased by administering one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit. By way of example only, in a treatment for diabetes involving administration of one of the compounds described herein, increased therapeutic benefit may result by also providing the patient with another therapeutic agent for diabetes. In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient may simply be additive of the two therapeutic agents or the patient may experience a synergistic benefit.
Specific, non-limiting examples of possible combination therapies include use of the compounds of the invention with: a) corticosteroids including betamethasone dipropionate (augmented and nonaugemnted), betamethasone valerate, clobetasol propionate, diflorasone diacetate, halobetasol propionate, amcinonide, dexosimethasone, fluocinolone acetononide, fluocinonide, halocinonide, clocortalone pivalate, dexosimetasone, and flurandrenalide; b) non-steroidal anti-inflammatory drugs including diclofenac, ketoprofen, and piroxicam; c) muscle relaxants and combinations thereof with other agents, including cyclobenzaprine, baclofen, cyclobenzaprine/lidocaine, baclofen/cyclobenzaprine, and cyclobenzaprine/lidocaine/ketoprofen; d) anaesthetics and combinations thereof with other agents, including lidocaine, lidocaine/deoxy-D-glucose (an antiviral), prilocaine, and EMLA Cream [Eutectic Mixture of Local Anesthetics (lidocaine 2.5% and prilocaine 2.5%; an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 1 : 1 by weight. This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather then as crystals)]; e) expectorants and combinations thereof with other agents, including guaifenesin and guaifenesin/ketoprofen/cyclobenzaprine; f) antidepressants including tricyclic antidepressants (e.g., amitryptiline, doxepin, desipramine, imipramine, amoxapine, clomipramine, nortriptyline, and protriptyline), selective serotonin/norepinephrine reuptake inhibitors including (e.g, duloxetine and mirtazepine), and selective norepinephrine reuptake inhibitors (e.g. , nisoxetine, maprotiline, and reboxetine), selective serotonin reuptake inhibitors (e.g., fluoxetine and fluvoxamine); g) anticonvulsants and combinations thereof, including gabapentin, carbamazepine, felbamate, lamotrigine, topiramate, tiagabine, oxcarbazepine, carbamezipine, zonisamide, mexiletine, gabapentin/clonidine, gabapentin/carbamazepine, and carbamazepine/cyclobenzaprine; h) antihypertensives including clonidine; i) opioids including loperamide, tramadol, morphine, fentanyl, oxycodone, levorphanol, and butorphanol; j) topical counter-irritants including menthol, oil of wintergreen, camphor, eucalyptus oil and turpentine oil; k) topical cannabinoids including selective and non-selective CB1/CB2 ligands; and other agents, such as capsaicin.
In any case, the multiple therapeutic agents (at least one of which is a compound of the present invention) may be administered in any order or even simultaneously. If simultaneously, the multiple therapeutic agents may be provided in a single, unified form, or in multiple forms (by way of example only, either as a single pill or as two separate pills). One of the therapeutic agents may be given in multiple doses, or both may be given as multiple doses. If not simultaneous, the timing between the multiple doses may be any duration of time ranging from a few minutes to four weeks. Thus, in another aspect, the present invention provides methods for treating iNOS-mediated disorders in a human or animal subject in need of such treatment comprising administering to said subject an amount of a compound of the present invention effective to reduce or prevent said disorder in the subject in combination with at least one additional agent for the treatment of said disorder that is known in the art. In a related aspect, the present invention provides therapeutic compositions comprising at least one compound of the present invention in combination with one or more additional agents for the treatment of iNOS-mediated disorders.
Compounds of the subject invention are useful in treating nitric oxide synthase -mediated disease, disorders and conditions, and are particularly suitable as inhibitors of nitric oxide synthase dimerization. The compounds of the present invention are useful to treat patients with neuropathy or inflammatory pain such as reflex sympathetic dystrophy/causalgia (nerve injury), peripheral neuropathy (including diabetic neuropathy), intractable cancer pain, complex regional pain syndrome, and entrapment neuropathy (carpel tunnel syndrome). The compounds are also useful in the treatment of pain associated with acute herpes zoster (shingles), postherpetic neuralgia (PHN), and associated pain syndromes such as ocular pain. The compounds are further useful as analgesics in the treatment of pain such as surgical analgesia, or as an antipyretic for the treatment of fever. Pain indications include, but are not limited to, post-surgical pain for various surgical procedures including post-cardiac surgery, dental pain/dental extraction, pain resulting from cancer, muscular pain, mastalgia, pain resulting from dermal injuries, lower back pain, headaches of various etiologies, including migraine, and the like. The compounds are also useful for the treatment of pain-related disorders such as tactile allodynia and hyperalgesia. The pain may be somatogenic (either nociceptive or neuropathic), acute and/or chronic. The nitric oxide synthase inhibitors of the subject invention are also useful in conditions where NSAIDs, morphine or fentanyl opiates and/or other opioid analgesics would traditionally be administered.
Furthermore, the compounds of the subject invention can be used in the treatment or prevention of opiate tolerance in patients needing protracted opiate analgesics, and benzodiazepine tolerance in patients taking benzodiazepines, and other addictive behavior, for example, nicotine addiction, alcoholism, and eating disorders. Moreover, the compounds and methods of the present invention are useful in the treatment or prevention of drug withdrawal symptoms, for example treatment or prevention of symptoms of withdrawal from opiate, alcohol, or tobacco addiction. In addition, the compounds of the subject invention can be used to treat insulin resistance and other metabolic disorders such as atherosclerosis that are typically associated with an exaggerated inflammatory signaling.
The present invention encompasses therapeutic methods using novel selective iNOS inhibitors to treat or prevent respiratory disease or conditions, including therapeutic methods of use in medicine for preventing and treating a respiratory disease or condition including: asthmatic conditions including allergen-induced asthma, exercise-induced asthma, pollution-induced asthma, cold-induced asthma, and viral-induced-asthma; chronic obstructive pulmonary diseases including chronic bronchitis with normal airflow, chronic bronchitis with airway obstruction (chronic obstructive bronchitis), emphysema, asthmatic bronchitis, and bullous disease; and other pulmonary diseases involving inflammation including bronchioectasis cystic fibrosis, pigeon fancier's disease, farmer's lung, acute respiratory distress syndrome, pneumonia, aspiration or inhalation injury, fat embolism in the lung, acidosis inflammation of the lung, acute pulmonary edema, acute mountain sickness, acute pulmonary hypertension, persistent pulmonary hypertension of the newborn, perinatal aspiration syndrome, hyaline membrane disease, acute pulmonary thromboembolism, heparin-protamine reactions, sepsis, status asthamticus and hypoxia.
Other disorders or conditions which can be advantageously treated by the compounds of the present invention include inflammation. The compounds of the present invention are useful as anti- inflammatory agents with the additional benefit of having significantly less harmful side effects. The compounds are useful to treat arthritis, including but not limited to rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis, acute rheumatic arthritis, enteropathic arthritis, neuropathic arthritis, psoriatic arthritis, and pyogenic arthritis. The compounds are also useful in treating osteoporosis and other related bone disorders. These compounds can also be used to treat gastrointestinal conditions such as reflux esophagitis, diarrhea, inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis. The compounds may also be used in the treatment of pulmonary inflammation, such as that associated with viral infections and cystic fibrosis. In addition, compounds of invention are also useful in organ transplant patients either alone or in combination with conventional immunomodulators. Yet further, the compounds of the invention are useful in the treatment of pruritis and vitaligo.
The compounds of the present invention are also useful in treating tissue damage in such diseases as vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, neuromuscular junction disease including myasthenia gravis, white matter disease including multiple sclerosis, sarcoidosis, nephritis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, periodontis, hypersensitivity, swelling occurring after injury, ischemias including myocardial ischemia, cardiovascular ischemia, and ischemia secondary to cardiac arrest, and the like.
The compounds of the subject invention are also be useful for the treatment of certain diseases and disorders of the nervous system. Central nervous system disorders in which nitric oxide inhibition is useful include cortical dementias including Alzheimer's disease, central nervous system damage resulting from stroke, ischemias including cerebral ischemia (both focal ischemia, thrombotic stroke and global ischemia (for example, secondary to cardiac arrest), and trauma. Neurodegenerative disorders in which nitric oxide inhibition is useful include nerve degeneration or nerve necrosis in disorders such as hypoxia, hypoglycemia, epilepsy, and in cases of central nervous system (CNS) trauma (such as spinal cord and head injury), hyperbaric oxygen convulsions and toxicity, dementia e.g. pre-senile dementia, and AIDS-related dementia, cachexia, Sydenham's chorea, Huntington's disease, Parkinson's Disease, amyotrophic lateral sclerosis (ALS), Korsakoffs disease, imbecility relating to a cerebral vessel disorder, sleeping disorders, schizophrenia, depression, depression or other symptoms associated with Premenstrual Syndrome (PMS), and anxiety.
Furthermore, the compounds of the present invention are also useful in inhibiting NO production from L-arginine including systemic hypotension associated with septic and/or toxic hemorrhagic shock induced by a wide variety of agents; therapy with cytokines such as TNF, IL-I and IL-2; and as an adjuvant to short term immunosuppression in transplant therapy. These compounds can also be used to treat allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome, and atherosclerosis.
Still other disorders or conditions advantageously treated by the compounds of the subject invention include the prevention or treatment of cancer, such as colorectal cancer, and cancer of the breast, lung, prostate, bladder, cervix and skin. Compounds of the invention may be used in the treatment and prevention of neoplasias including but not limited to brain cancer, bone cancer, a leukemia, a lymphoma, epithelial cell-derived neoplasia (epithelial carcinoma) such as basal cell carcinoma, adenocarcinoma, gastrointestinal cancer such as lip cancer, mouth cancer, esophogeal cancer, small bowel cancer and stomach cancer, colon cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast cancer and skin cancer, such as squamous cell and basal cell cancers, prostate cancer, renal cell carcinoma, and other known cancers that effect epithelial cells throughout the body. The neoplasia can be selected from gastrointestinal cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, prostate cancer, cervical cancer, lung cancer, breast cancer and skin cancer, such as squamous cell and basal cell cancers. The present compounds and methods can also be used to treat the fibrosis which occurs with radiation therapy. The present compounds and methods can be used to treat subjects having adenomatous polyps, including those with familial adenomatous polyposis (FAP). Additionally, the present compounds and methods can be used to prevent polyps from forming in patients at risk of FAP. The compounds of the subject invention can be used in the treatment of ophthalmic diseases, such as glaucoma, retinal ganglion degeneration, occular ischemia, retinitis, retinopathies, uveitis, ocular photophobia, and of inflammation and pain associated with acute injury to the eye tissue. Specifically, the compounds can be used to treat glaucomatous retinopathy and/or diabetic retinopathy. The compounds can also be used to treat post-operative inflammation or pain as from ophthalmic surgery such as cataract surgery and refractive surgery.
Moreover, compounds of the subject invention may be used in the treatment of menstrual cramps, dysmenorrhea, premature labor, tendonitis, bursitis, skin-related conditions such as psoriasis, eczema, burns, sunburn, dermatitis, pancreatitis, hepatitis, and the like. Other conditions in which the compounds of the subject invention provides an advantage in inhibiting nitric oxide inhibition include diabetes (type I or type II), congestive heart failure, myocarditis, atherosclerosis, and aortic aneurysm. The present compounds may also be used in co-therapies, partially or completely, in place of other conventional anti-inflammatory therapies, such as together with steroids, NSAIDs, COX-2 selective inhibitors, 5 -lipoxygenase inhibitors, LTB4 antagonists and LTA4 hydrolase inhibitors. The compounds of the subject invention may also be used to prevent tissue damage when therapeutically combined with antibacterial or antiviral agents.
Besides being useful for human treatment, the compounds and formulations of the present invention are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.
All references, patents or applications, U.S. or foreign, cited in the application are hereby incorporated by reference as if written herein.
The invention is further illustrated by the following examples.
EXAMPLE 1 Ethyl 4-(5-bromo-2-hydroxyphenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate
Figure imgf000027_0001
This compound is commercially available.
EXAMPLE 2 Ethyl 4-(4-chlorophenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate
Figure imgf000027_0002
This compound is commercially available.
EXAMPLE 3 Ethyl 4-(3-chlorophenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate
Figure imgf000027_0003
This compound is commercially available.
EXAMPLE 4 Ethyl 6-methyl-2-oxo-4-p-tolyl-l,2,3,4-tetrahydropyrimidine-5-carboxylate
Figure imgf000029_0001
This compound is commercially available.
EXAMPLE 5 Propyl 4-(3-chlorophenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate
Figure imgf000029_0002
This compound is commercially available.
EXAMPLE 6 Propyl 4-(3-bromophenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate
Figure imgf000029_0003
This compound is commercially available.
EXAMPLE 7 Ethyl 6-methyl-2-oxo-4-phenyl-l,2,3,4-tetrahydropyrimidine-5-carboxylate
Figure imgf000030_0001
This compound is commercially available.
EXAMPLE 8 Ethyl 6-methyl-2-oxo-4-m-tolyl-l,2,3,4-tetrahydropyrimidine-5-carboxylate
Figure imgf000030_0002
Ethyl 6-methyl-2-oxo-4-m-tolyl-l,2,3,4-tetrahydropyrimidine-5-carboxylate: Ethyl 3 -oxobutanoate (2.6 g, 20.00 mmol) was added to a solution of 3-methylbenzaldehyde (2 g, 16.67 mmol) in CH3CN at room temperature. To this solution was added urea (1.2 g, 20.00 mmol) followed by SiO2-NaHSO4 (300 mg, 1.67 mmol). The reaction mixture was stirred overnight at reflux. The reaction mixture was cooled and poured into ice-water (50 g) followed by filtration. The product was purified by silica gel flash column chromatography ( 1% MeOH in dichloromethane) to afford 1.6 g (35%) as a white solid. 1HNMR (OMSO-d6, 300 MHz): 1.08 (t, 3H), 2.22 (s, 3H), 2.26 (s, 3H), 3.96 (m, 2H), 5.08 (d, IH), 7.01 (m, 4H), 7.18 (m, IH), 7.67 (s, NH), 9.13 (s, NH).
EXAMPLE 9 Ethyl 4-(5-bromo-2-hydroxyphenyl)-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate
Figure imgf000030_0003
Step l
Figure imgf000031_0001
2-(benzyloxy)-5-bromobenzaldehyde: l-(bromomethyl)benzene (25.5 g, 150.00 mmol) was added to a solution of 5-bromo-2-hydroxybenzaldehyde (30 g, 150.00 mmol) at room temperature. To this solution was added K2CO3 (20.7 g, 150.00 mmol) in THF (200 ml). The reaction mixture was stirred for 5 h at reflux. The reaction progress was monitored by TLC (PE/EtOAc= 10: 1). After cooling, a filtration was performed and the filtrate was concentrated to afford 45 g (crude) of 2-(benzyloxy)-5- bromobenzaldehyde as a yellow solid.
Step 2
Figure imgf000031_0002
Ethyl 4-[2-(benzyloxy)-5-bromophenyl]-2-oxo-l,2,3,4-tetrahydropyrimidine-5carboxylate: 3-
Ethoxyacrylate was added to a solution of 2-(benzyloxy)-5-bromobenzaldehyde (2 g, 6.90 mmol) in CH3CN at room temperature. To this solution was then added urea (0.50 g, 8.28 mmol) followed by the addition of SiO2-NaHSO4 (370 mg, 2.07 mmol). The reaction mixture was stirred overnight at reflux. The reaction mixture was cooled down to room temperature and poured into ice followed by filtration. The product was purified by silica gel flash column chromatography ( 1% MeOH in dichloromethane to 2% MEOH in dichloromethane) to afford 1.0 g (34%) as a white solid.
Step 3
Figure imgf000031_0003
Ethyl 4-(5-bromo-2-hydroxyphenyl)-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate: N,N- dimethyl benzenamine (280 mg, 2.31 mmol) was added to a solution of ethyl 4-(2-(benzyloxy)-5- bromophenyl)-2-oxo- l,2,3,4-tetrahydropyrimidine-5-carboxylate (500 mg, 1.16 mmol) in CH2C12 (30 mL) at room temperature. To this solution was added dropwise A1C13 (150 mg, 1.14 mmol). The reaction mixture was stirred for 0.5 h at 50 degrees C. The reaction progress was monitored by TLC (CH2C12/MeOH = 10: 1). The reaction mixture was poured into H2O (50 mL) and then was acidified to PH=5 by the adding of HCl (IN). The aqueous layer was extracted with EtOAc ( 3 x 20 mL). The combined organic layer was dried (Na2SO4) and concentrated to afford 0.4 g (100%) as a white solid. 1HNMR (DMSO-dό, 300 MHz): 1.10 (t, 3H), 3.94 (m, 2H), 5.31 (s, OH), 6.74 (d, IH), 7.10 (s, IH), 7.21 (d, IH), 7.31 (s, IH), 9.17 (d, NH), 9.99 (s, NH).
EXAMPLE 10 Ethyl4-(3-methoxyphenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate
Figure imgf000032_0001
Ethyl4-(3-methoxyphenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate: 3-
Oxobutanoate (800 mg, 6.15 mmol) was added to a solution of 3-methoxybenzaldehyde (700 mg, 5.15 mmol) in CH3CN. To this solution was then added urea (360 mg, 6.00 mmol) followed SiO2-NaHSO4 (90 mg, 0.50 mmol). The reaction mixture was stirred overnight at reflux. The reaction mixture was cooled and filtrated. The product was purified by silica gel flash column chromatography (1% MeOH in dichloromethane to 2% MeOh in dichloromethane) to afford 1.2 g (75%) as a white solid. 1HNMR
(400MHz, DMSO) δ: 7.23 (lH,t), 6.78 (lH,d), 6.75 (lH,d), 6.75 (lH,s), 5.10 (lH,s), 3.95 (2H,m), 3.70 (3H,s), 2.21 (3H,s), 1.08 (3H,t).
EXAMPLE 11 Ethyl 4-(4-methoxyphenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate
Figure imgf000032_0002
Ethyl 4-(4-methoxyphenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate: The compound ethyl 4-(4-methoxyphenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate was synthesized according to the procedure from Example 12 using 4-methoxybenzaldehyde (700 mg, 5.15 mmol) to afford 1 g (62%) as a white solid. 1HNMR (400MHz, CDC13) δ: 7.23 (lH,t), 6.78 (lH,d), 6.75 (lH,d), 6.75 (lH,s), 5.10 (lH,s), 3.95 (2H,m), 3.70 (3H,s), 2.21 (3H,s), 1.08 (3H,t). [M+l]+ calcd for C15H19N2O4, 291.1, found 291.1.
EXAMPLE 12 Ethyl 4-(3-fluorophenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate
Figure imgf000033_0001
Ethyl 4-(3-fluorophenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate: Ethyl 3- oxobutanoate (2.5 g, 19.23 mmol) was added to a solution of 3-fluorobenzaldehyde (2 g, 16.13 mmol) in CH3CN at room temperature. To this solution was added urea (1.2 g, 20.00 mmol) followed SiO2- NaHSO4 (300 mg, 1.67 mmol). The reaction mixture was stirred overnight at reflux. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with CHC13 (250 ml) and filtrate was concentrated to afford 3.9 g (87%) as a white solid. 1HNMR (400MHz, DMSO) δ: 1.08 (3H,t), 2.23 (3H,s), 3.98 (2H,m), 5.14 (lH,s), 6.96 (lH,m), 7.07 (lH,m), 7.35 (lH,m), 7.78 (lH,s), 9.24 (lH,s). [M+H]+ calcd for C14H16FN2O3, 279.1, found 279.1.
EXAMPLE 13 Ethyl 4-(4-fluorophenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate
Figure imgf000033_0002
Ethyl 4-(4-fluorophenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate: The compound ethyl 4-(4-fluorophenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate was synthesized according to the procedure from Example 14 using 4-fluorobenzaldehyde (2 g, 16.13 mmol) to afford 3.2 g (71%) as a white solid. 1HNMR (400MHz, CDCl) δ: 1.18 (3H,t), 2.34 (3H,s), 4.08 (2H,m), 5.38 (lH,s), 5.65 (lH,s), 7.00 (2H,t), 7.28 (2H,t), 7.82 (lH,s). [M+H]+ calcd. for C14H16FN2O3, 279.1, found 279. EXAMPLE 14 Ethyl 6-methyl-4-(4-nitrophenyl)-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate
Figure imgf000034_0001
Ethyl 6-methyl-4-(4-nitrophenyl)-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate: The compound Ethyl 6-methyl-4-(4-nitrophenyl)-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate was synthesized according to the procedure from Example 14 using 4-nitrobenzaldehyde (2.4 g, 15.89 mmol) to afford 4.1 g (85%) as a white solid. 1HNMR (300MHz, DMSO) δ: 1.10 (3H,t), 2.2 7(3H,s), 4.00 (2H,m), 5.27 (lH,s), 7.51 (2H,d), 7.90 (NH,s), 8.23 (2H,d), 9.37 (NH,s). [M+H]+ calcd. for C14H16N3O5, 306.1, found 306.1.
EXAMPLE 15 Ethyl 6-methyl-4-(3-nitrophenyl)-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate
Figure imgf000034_0002
Ethyl 6-methyl-4-(3-nitrophenyl)-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate: The compound ethyl 6-methyl-4-(3-nitrophenyl)-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate was synthesized according to the procedure from Example 14 using 3-nitrobenzaldehyde (2.4 g, 15.89 mmol) to afford 3.4 g (70%) as a white solid. 1HNMR (300MHz, CDC13) δ: 1.10 (3H,t), 2.27 (3H,s), 3.99 (2H,m), 5.30 (lH,s), 7.68 (lH,m), 7.90 (lH,s), 8.08 (lH,s), 8.15 (lH,d), 9.37 (lH,s). [M+H]+ calcd. for C14H16N3O5, 306.1, found 306.1.
EXAMPLE 16 Ethyl 4-(2-hydroxyphenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate
Figure imgf000034_0003
Step l
Figure imgf000035_0001
2-(benzyloxy)benzaldehyde: The compound 2-(benzyloxy)benzaldehyde was synthesized according to the procedure rom Example 12, step 1 using 2-hydroxybenzaldehyde (5 g, 40.98 mmol) to afford 9 g (crude) as a light yellow solid.
Step 2
Figure imgf000035_0002
Ethyl 4-[2-(benzyloxy)phenyl]-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate: The compound ethyl 4-(2-(benzyloxy)phenyl)-6-methyl -2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylate was synthesized according to the procedure from Example 12 step 1 using 2-(benzyloxy)benzaldehyde (9 g, 42.45 mmol) to afford 5 g (32%) as a white solid.
Step 3
Figure imgf000035_0003
Ethyl 4-(2-hydroxyphenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate: Ethyl A- (2-(benzyloxy)phenyl)-6-methyl-2-oxo- l,2,3,4-tetrahydropyrimidine-5-carboxylate (500 mg, 1.37 mmol) was dissolved in CH3CH2OH (100 ml). To this solution was added Pd-C (0.2 g). The reaction mixture was stirred for 0.5 h at room temperature. The reaction progress was monitored by TLC (CH2C12/MeOH = 10:1). A filtration was performed. The filtrate was concentrated to afford 0.4 g (100%) as a white solid. 1H NMR (DMSO-^, 300 MHz): 1.02 (t, 3H), 2.25 (s, 3H), 3.92 (m, 2H), 5.44 (s, IH), 5.74 (s, OH), 6.70 (t, IH), 6.77 (d, IH), 6.95 (d, IH), 7.04 (m, IH), 9.06 (s, NH), 9.54 (s, NH). EXAMPLE 17 4-(5-bromo-2-hydroxyphenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylicacid
Figure imgf000036_0001
4-(5-bromo-2-hydroxyphenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylicacid: Ethyl 4-(5-bromo-2-hydroxyphenyl)-6-methyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate (3 g, 6.78 mmol) from Example 1 was dissolved in THF/H2O (10 mL). To this solution was added 1 M LiOH (20 ml) and was stirred at 50 C for 3 h. The reaction progress was monitored by TLC (CH2C12/MeOH = 10:1). The reaction mixture was diluted with H2O (100 mL) and pH was adjusted to 2~3. The aqueous layer was extracted with EtOAc (3 x 500 mL) and the combined organic layers was dried (Na2SO4) and to afford 1 g (36%) as a white solid. 1HNMR (400MHz, DMSO) δ: 2.12 (3H,S), 5.36 (1H,S), 6.76 (lH,d), 6.99 (1H,S), 7.22 (lH,d). [M-H]+ CaId. for C14H15BrN2O4, 353, found 353.
EXAMPLE 18
4-(5-bromo-2-hydroxyphenyl)-N-ethyl-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxamide
Figure imgf000036_0002
4-(5-bromo-2-hydroxyphenyl)-N-ethyl-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxamide: N-((cyclohexylimino)methylene) cyclohexanamine (1 g, 4.37 mmol) was added to a solution of 4-(5-bromo-2-hydroxyphenyl)-6-methyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylic acid (1 g, 2.45 mmol) from Example 17 in N,N-dimethylacetamide (10 ml). To this solution was added ethanamine (600 mg, 12.00 mmol) and triethylamine (1 g, 9.90 mmol). The reaction mixture was stirred at room temperature for 48 h. The reaction mixture was then diluted with H2O (10 mL) and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were dried (Na2SO4) and concentrated to afford 0.2 g (20%) as a white solid. 1HNMR (400MHz, DMSO) δ: 1.19 (3H,S), 2.01 (3H,M), 2.88 (2H,M), 5.40 (1H,S), 7.17 (lH,d), 7.06 (1H,S), 7.20(lH,d). [M+H]+ cald. for C14H16BrN2O4, 354, found 354. EXAMPLE 19
4-(5-bromo-2-hydroxyphenyl)-N-ethyl-6-isopropyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxamide
Figure imgf000037_0001
Methyl 4-(2-(benzyloxy)-5-bromophenyl) -6-isopropyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylate: 4-Methyl-3-oxopentanoate (3.1 g, 19.62mmol) was added to a solution of 2-(benzyloxy)- 5-bromobenzaldehyde (5 g, 17.24 mmol) in CH3CN from Example step 1 at room temperature . To this solution was added urea (1.3 g, 21.67 mmol) followed by SiO2-NaHSO4 (310 mg, 1.72 mmol). The reaction mixture was stirred overnight at reflux. The reaction progress was monitored by TLC (CH2C12/MeOH = 10: 1). The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with CHC13 (3 x 250 ml) and the filtrate was concentrated to afford 4 g (51%) as a white solid.
Figure imgf000037_0002
4-(5-bromo-2-hydroxyphenyl)-N-ethyl-6-isopropyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxamide: The compound 4-(5-bromo-2-hydroxyphenyl)-N-ethyl-6-isopropyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxamide was synthesized according to the procedure from Example 18 using methyl 4-(2-(benzyloxy)-5-bromophenyl)-6-isopropyl -2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylate (2 g, 4.37 mmol) to afford 0.8 g (50%) as a white solid. 1HNMR (300MHz, DMSO) δ: 1.13 (6H,d), 3.48 (3H,s), 4.13 (lH,m), 5.38 (lH,s), 6.78 (lH,d), 7.00 (lH,s), 7.21 (lH,d). [M+H]+ calcd. for C22H24BrN2O4, 468.1, found 468.1.
EXAMPLE 20
Ethyl 4-(3-hydroxyphenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate
Figure imgf000039_0001
Ethyl 4-(3-hydroxyphenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate: The compound ethyl 4-(3-hydroxyphenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate was synthesized according to the procedure from Example 16 except using 2-(benzyloxy)benzaldehyde as a starting material.
EXAMPLE 21 Ethyl 4-(2-bromophenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate
Figure imgf000039_0002
Ethyl 4-(2-bromophenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate: The compound was synthesized according to the procedure from Example 8 using 2-bromobenzaldehyde as a starting material.
EXAMPLE 22
Ethyl 2-oxo-4-(2-(trifluoromethoxy)phenyl)-6-(trifluoromethyl)-l,2,3,4 tetrahydropyrimidine-5- carboxylate
Figure imgf000039_0003
Ethyl 2-oxo-4-(2-(trifluoromethoxy)phenyl)-6-(trifluoromethyl)-l,2,3,4 tetrahydropyrimidine-5- carboxylate: Ethyl 4,4,4,trifluoro-3-oxobutanoate (200mg, 1.08 mmol) was added to a solution of (trifluoromethoxy)benzaldehyde (103 mg, 0.54mmol) in CH3CN at room temperature. To this solution was added urea (64.8 mg, 1.08 mmol) followed SiO2-NaHSO4 (20mg, 0.1 mmol). The reaction mixture was stirred overnight at reflux. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with CHC13 (250 ml) and filtrate was concentrated to afford 3.9 g (87%) as a off- white solid. [M+H]+ calcd for C14H16FN2O3, 398.25, found 398.
EXAMPLE 23 Ethyl 6-methyl-2-oxo-4-(pyridine-3-yl) -l,2,3,4-tetrahydropyrimidine-5-carboxylate
Figure imgf000040_0001
Ethyl 6-methyl-2-oxo-4-(pyridine-3-yl) -l,2,3,4-tetrahydropyrimidine-5-carboxylate: The compound ethyl 6-methyl-2-oxo-4-(pyridine-3-yl) -l,2,3,4-tetrahydropyrimidine-5-carboxylate was synthesized according to the procedure from Example 16 except using nicotinaldehyde as a starting material. [M+H]+ calcd. for C13H15N3O3, 261.2, found 261.2.
EXAMPLE 24
Ethyl 4-(2,3,-dihydrobenzo[b] [l,4]dioxin-6-yl)-6-methyl-2-ox -l,2,3,4-tetrahydropyrimidine-5- carboxylate
Figure imgf000040_0002
Ethyl 4-(2,3,-dihydrobenzo[b] [l,4]dioxin-6-yl)-6-methyl-2-ox -l,2,3,4-tetrahydropyrimidine-5- carboxylate: The compound ethyl 4-(2,3,-dihydrobenzo[b][l,4]dioxin-6-yl)-6-methyl-2-ox -1,2,3,4- tetrahydropyrimidine-5-carboxylate was synthesized according to the procedure from Example 16 except using l,4-benzodioxan-6-carboxaldehyde as a starting material. [M+H]+ calcd. for C16H18N2O5, 318.3, found 318. EXAMPLE 25 Ethyl 6-methyl-4-(naphthalene-2-yl)-2-ox -l,2,3,4-tetrahydropyrimidine-5-carboxylate
Figure imgf000041_0001
Ethyl 6-methyl-4-(naphthalene-2-yl)-2-ox -l,2,3,4-tetrahydropyrimidine-5-carboxylate: The compound Ethyl 6-methyl-4-(naphthalene-2-yl)-2-ox -l,2,3,4-tetrahydropyrimidine-5-carboxylate was synthesized according to the procedure from Example 16 except using 2-naphthaldehyde as a starting material. [M+H]+ calcd. for C18H18N2O3, 310.3, found 310.
EXAMPLE 26 Ethyl 6-methyl-4-(naphthalene-2-yl)-2-ox -l,2,3,4-tetrahydropyrimidine-5-carboxylate
Figure imgf000041_0002
Ethyl 6-methyl-4-(naphthalene-2-yl)-2-ox -l,2,3,4-tetrahydropyrimidine-5-carboxylate: The compound Ethyl 6-methyl-4-(naphthalene-2-yl)-2-ox -l,2,3,4-tetrahydropyrimidine-5-carboxylate was synthesized according to the procedure from Example 16 except using 2-naphthaldehyde as a starting material. [M+H]+ calcd. for C18H18N2O3, 310.3, found 310.
EXAMPLE 27 5-benzoyl-4-(3-bromophenyl)-6-methyl-3,4-dihydropyrimidin-2(lH)-one
Figure imgf000041_0003
5-benzoyl-4-(3-bromophenyl)-6-methyl-3,4-dihydropyrimidin-2(lH)-one: The compound 5- benzoyl-4-(3-bromophenyl)-6-methyl-3,4-dihydropyrimidin-2(lH)-one was synthesized according to the procedure from Example 16 except 3-bromobenzaldehyde and ethyl 3-oxo-3phenylpropanoate and biuret as starting materials. [M+H]+ calcd. for C18H15N2O2Br, 370.0, found 370. EXAMPLE 28 4-(5-bromo-2-fluorophenyl)-5-butyryl-6-methyl-2-oxo-3,4-dihydropyrimidine-l(2H)-carboxylate
Figure imgf000042_0001
4-(5-bromo-2-fluorophenyl)-5-butyryl-6-methyl-2-oxo-3,4-dihydropyrimidine-l(2H)-carboxylate:
The compound 4-(5-bromo-2-fluorophenyl)-5-butyryl-6-methyl-2-oxo-3,4-dihydropyrimidine-l(2H)- carboxylate was synthesized according to the procedure from Example 16 except using 5-bromo-2- fluorobenzaldehyde and as a starting materials. [M+H]+ calcd. for C15H15FN3O4Br, 399.0, found 399.
EXAMPLE 29 Ethyl 4-(3-bromophenyl)-6-cyclopropyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate
Figure imgf000042_0002
Ethyl 4-(3-bromophenyl)-6-cyclopropyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate: The compound ethyl 4-(3-bromophenyl)-6-cyclopropyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate was synthesized according to the procedure from Example 8 except using 5-bromo-2- fluorobenzaldehyde and as a starting materials. [M+H]+ calcd. for C15H15FN3O4Br, 399.0, found 399.
EXAMPLE 30 Ethyl l-allyl-4-(3-bromophenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate
Figure imgf000042_0003
Ethyl l-allyl-4-(3-bromophenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate: The compound ethyl 1 -allyl-4-(3 -bromophenyl)-6-methyl-2-oxo- 1 ,2,3 ,4-tetrahydropyrimidine-5- carboxylate was synthesized according to the procedure from Example 8 except using 5- bromobenzaldehyde and 1-allylurea as starting materials. [M+H]+ calcd. for C17H19N2O3Br, 378.1, found 378.
EXAMPLE 31 Ethyl l-allyl-4-(3-bromophenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate
Figure imgf000043_0001
Ethyl l-allyl-4-(3-bromophenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate: The compound ethyl 1 -allyl-4-(3 -bromophenyl)-6-methyl-2-oxo- 1 ,2,3 ,4-tetrahydropyrimidine-5- carboxylate was synthesized according to the procedure from Example 8 except using 5- bromobenzaldehyde and methylurea as starting materials. [M+H]+ calcd. for C15H17N2O3Br, 352.0, found 352.
EXAMPLE 32 Ethyl 4-(3-acetylphenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate:
Figure imgf000043_0002
Ethyl 4-(3-acetylphenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate: The compound ethyl 4-(3-acetylphenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate was synthesized according to the procedure from Example 8 except using 3-acetylbenzaldehyde as a starting materials. [M+H]+ calcd. for C16H18N2O4, 302.1, found 302. EXAMPLE 33 Ethyl 6-methyl-2-oxo-4-(3-(trifluoromethoxy)phenyl)-l,2,3,4-tetrahydropyrimidine-5-carboxylate
Figure imgf000044_0001
Ethyl 6-methyl-2-oxo-4-(3-(trifluoromethoxy)phenyl)-l,2,3,4-tetrahydropyrimidine-5-carboxylate:
The compound ethyl 6-methyl-2-oxo-4-(3-(trifluoromethoxy)phenyl)-l,2,3,4-tetrahydropyrimidine-5- carboxylate was synthesized according to the procedure from Example 8 except using 3- (trifluoromethoxy)benzaldehyde as a starting materials. [M+H]+ calcd. for C15H15N2O4F3, 344.1, found 344.1.
EXAMPLE 34
Ethyl 6-methyl-4-(3-(5-methyl-l,2,4-oxadiazole-3-yl)phenyl)-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylate
Figure imgf000044_0002
Ethyl 6-methyl-4-(3-(5-methyl-l,2,4-oxadiazole-3-yl)phenyl)-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylate: The compound ethyl 6-methyl-4-(3-(5-methyl-l,2,4-oxadiazole-3-yl)phenyl)-2-oxo- l,2,3,4-tetrahydropyrimidine-5-carboxylate was synthesized according to the procedure from Example 8 except using 3-(5-methyl-l,24-oxodiazol-3-yl)benzaldehyde as a starting materials. [M+H]+ calcd. for C17H18N4O4, 342.1 found 342.1. EXAMPLE 35
Ethyl 6-methyl-4-(3-(2-methylthiazol-4-yl)phenyl)-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylate
Figure imgf000045_0001
Ethyl 6-methyl-4-(3-(2-methylthiazol-4-yl)phenyl)-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylate: The compound ethyl 6-methyl-4-(3-(2-methylthiazol-4-yl)phenyl)-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate was synthesized according to the procedure from Example 8 except using 3-(2-methylthiazole-4-yl)benzaldehyde as a starting materials. [M+H]+ calcd. for C18H19N3O3S, 357.1 found 357.1.
EXAMPLE 36 Ethyl 4-(3-(lH-pyrazol-l-yl)phenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate
Figure imgf000045_0002
Ethyl 4-(3-(lH-pyrazol-l-yl)phenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate:
The compound ethyl 4-(3-(lH-pyrazol-l-yl)phenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylate was synthesized according to the procedure from Example 8 except using 3-(lH-pyrazol-l- yl)benzaldehyde as a starting materials. [M+H]+ calcd. for C17H18N4O3, 326.1 found 326.1. EXAMPLE 37 Ethyl 4-(3-bromo-2-methoxyphenyl)-6-methyl-2-oxo-l,2,3,4-tetradroprimidine-5-carboxylate
Figure imgf000046_0001
Ethyl 4-(3-bromo-2-methoxyphenyl)-6-methyl-2-oxo-l,2,3,4-tetradroprimidine-5-carboxylate: The compound ethyl 4-(3-bromo-2-methoxyphenyl)-6-methyl-2-oxo-l,2,3,44etradroprimidine-5- carboxylate was synthesized according to the procedure from Example 8 except using 5-bromo-2- ethoxylbenzaldehyde as a starting materials. [M+H]+ calcd. for C16H19N2O4BR, 382.01 found 382.
EXAMPLE 38 Ethyl 2-oxo-4-phenyl-6-(trifluoromethyl)-l,2,3,4-tetrahydropyrimidine-5-carboxylate
Figure imgf000046_0002
Ethyl 2-oxo-4-phenyl-6-(trifluoromethyl)-l,2,3,4-tetrahydropyrimidine-5-carboxylate: The compound ethyl 2-oxo-4-phenyl-6-(trifluoromethyl)- 1 ,2,3,4-tetrahydropyrimidine-5-carboxylate was synthesized according to the procedure from Example 8 except using benzaldehyde and ethyl 4,4,4- trifluoro-3-oxobutanoate as starting materials. [M+H]+ calcd. for C15H15N2O2F3, 312.3 found 312.3.
EXAMPLE 39
Ethyl l-benzyl-4-(3-bromophenyl)-6-methyl-2-oxo-l,2,3,4-twtrahydropyrimidine-5-carboxylate
Figure imgf000046_0003
Ethyl l-benzyl-4-(3-bromophenyl)-6-methyl-2-oxo-l,2,3,4-twtrahydropyrimidine-5-carboxylate:
The compound ethyl l-benzyl-4-(3-bromophenyl)-6-methyl-2-oxo-l,2,3,4-twtrahydropyrimidine-5- carboxylate was synthesized according to the procedure from Example 8 except using 3- bromobenzaldehyde and ethyl 3-oxo-3-phenylpropanoate as starting materials. [M+H]+ calcd. for C21H21N2O3Br, 429.3 found 429.3.
EXAMPLE 40 Ethyl l-benzyl-4-(3-bromophenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate
Figure imgf000047_0001
Ethyl l-benzyl-4-(3-bromophenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate:
The compound ethyl l-benzyl-4-(5-bromo2-fluorophenyl)-6-methyl-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxylate was synthesized according to the procedure from Example 8 except using 5-bromo-2-fluorobenzaldehyde and ethyl 3-oxo-3-phenylpropanoate as starting materials. [M+H]+ calcd. for C21H21N2O3Br, 429.3 found 429.3.
EXAMPLE 41 Ethyl 4-(furan-2-yl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate
Figure imgf000047_0002
Ethyl 4-(furan-2-yl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate: The compound ethyl 4-(furan-2-yl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate was synthesized according to the procedure from Example 8 except using furan-2-carbaldehyde as a starting material. [M+H]+ calcd. for C12H14N2O4, 250.1 found 250.1.
EXAMPLE 42 Ethyl 6-(4-fluorophenyl)-4-(4-isopropylphenyl)-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate
Figure imgf000048_0001
Ethyl 6-(4-fluorophenyl)-4-(4-isopropylphenyl)-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate:
The compound ethyl 6-(4-fluorophenyl)-4-(4-isopropylphenyl)-2-oxo- 1,2,3, 4-tetrahydropyrimidine-5- carboxylate was synthesized according to the procedure from Example 8 except using A- isopropylbenzaldehyde and ethyl 3-(4-fluorophenyl)-3-oxopropanoate as starting materials. [M+H]+ calcd. for C22H23N2O3F, 382.1 found 382.1.
EXAMPLE 43 Ethyl 6-methyl-2-oxo-4-(3-(pyridin-3-yl)phenyl)-l,2,3,4-tetrahydropyrimidine-5-carboxylate
Figure imgf000048_0002
Ethyl 6-methyl-2-oxo-4-(3-(pyridin-3-yl)phenyl)-l,2,3,4-tetrahydropyrimidine-5-carboxylate: The compound ethyl 6-methyl-2-oxo-4-(3-(pyridin-3-yl)phenyl)-l,2,3,4-tetrahydropyrimidine-5-carboxylate was synthesized according to the procedure from Example 8 except using 3-(pyridin-3-yl)benzaldehyde as a starting material. [M+H]+ calcd. for C19H19N3O3, 337.3 found 337.3. EXAMPLE 44 Ethyl 6-methyl-2-oxo-4-(pyrimidin-5-yl)-l,2,3,4-tetrahydropyrimidine-5-carboxylate
Figure imgf000049_0001
Step l
Figure imgf000049_0002
Pyrimidine-5-carbaldehyde 2: To a solution of 5-bromopyrimidine (1Og, 56.96 mmol) in THF (500 niL) under the an inert atmosphere of nitrogen was added butyllithium (20 ml, 3.6 M) dropwise with stirring while cooling to a temperature of -100 C. The resulting solution was allowed to stir for an additional 1 hour at -100 C, followed by adding HCl (5 ml) dropwise with stirring while keeping the temperature at - 80 C and then warmed up to room temperature. The reaction progress was monitored by TLC (EtOAc/PE = 1:1). The resulting solution was extracted with ethyl ether (3 x 500 ml) and the organic layer was combined and dried over Na2SO4 and concentrated by evaporation under vacuum using a rotatory evaportator yield 2 g (29%) of pyrmidine-5-cabaldehyde as an colorless oil.
Step2
Figure imgf000049_0003
Ethyl 6-methyl-2-oxo-4-(pyrimidine-5-yl)-l,2,3,4-tetrahydropyrimidine-5-carboxylate 3: The compound ethyl 6-methyl-2-oxo-4-(pyrimidine-5-yl)-l,2,3,4-tetrahydropyrimidine-5-carboxylate was synthesized according to the procedure from Example 8 except using pyrimidine-5-cabaldehyde as a starting material to yield 0.15 g (6%) as a yellow solid. IH NMR (400MHz, CDC13) 9.15 (IH, s), 8.76 (2H,s), 5.45 (IH, s), 4.13 (2H, m), 2.38 (3H, s) and 1.21 (3H, t). [M+H]+ calcd. for C12H14N4O3, 262.2, found 262.
EXAMPLE 45
4-(3-chlorophenyl)-N-(2-ethoxyphenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxamide
Figure imgf000050_0001
This compound is commercially available.
EXAMPLE 46
Isobutyl 4-(5-bromo-2-methoxyphenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxylate
Figure imgf000050_0002
This compound is commercially available. EXAMPLE 47 Ethyl 4-(3-bromophenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate
Figure imgf000051_0001
This compound is commercially available.
EXAMPLE 48 Isobutyl 4-(3-chlorophenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate
Figure imgf000051_0002
This compound is commercially available.
EXAMPLE 49 Isobutyl 4-(3-bromophenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate
Figure imgf000051_0003
This compound is commercially available. EXAMPLE 50 2-cyanoethyl 4-(3-bromophenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate
Figure imgf000052_0001
This compound is commercially available.
EXAMPLE 51 Ethyl 4-(3-cyanophenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate
Figure imgf000052_0002
Ethyl 4-(3-cyanophenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate: The compound Ethyl 4-(3-cyanophenyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate was synthesized according to the procedure from Example 8 except using 3-cyanobenzaldehyde as a starting material. [M+H]+ calcd. for C15H15N3O3, 285.1 found 285.1. EXAMPLE 52 7-hexyl-3-methyl-8-(2-oxopropylthio)-lH-purine-2,6(3H,7H)-dione
Figure imgf000053_0001
This compound is commercially available.
EXAMPLE 53 l-methyl-7-(thiophen-2-yl)-5-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(lH,3H)-dione
Figure imgf000053_0002
This compound is commercially available.
EXAMPLE 54 l-ethyl^-Cthiophen^-y^-S-Ctrifluoromethy^pyridoP^-dlpyrimidine^^ClH^^-dione
Figure imgf000053_0003
This compound is commercially available. EXAMPLE 55 (E)-5-(5-bromo-2-(4-fluorobenzyloxy)benzylidene)imidazolidine-2,4-dione
Figure imgf000054_0001
This compound is commercially available.
EXAMPLE 56 (E)-5-(5-bromo-2-isopropoxybenzylidene)imidazolidine-2,4-dione
Figure imgf000054_0002
This compound is commercially available.
The following compounds can generally be made using the methods described above. It is expected that these compounds when made will have activity similar to those that have been made in the examples above.
The following compounds are represented herein using the Simplified Molecular Input Line Entry System, or SMILES. SMILES is a modern chemical notation system, developed by David Weininger and Daylight Chemical Information Systems, Inc., that is built into all major commercial chemical structure drawing software packages. Software is not needed to interpret SMILES text strings, and an explanation of how to translate SMILES into structures can be found in Weininger, D., J. Chem. Inf. Comput. ScL 1988, 28, 31-36.
O=C1NC(C2=CC=CC(C)=C2)C(C(OCC)=O)=C(C)N1
O=C1NC(C2=CC=C(N(C)C)S2)C(C(OCC)=O)=C(C)N1
O=C1NC(C2=CC=C(N(C)C)O2)C(C(OCC)=O)=C(C)N1 O=C1NC(C2=CC=C(N3CCCC3)C=C2)C(C(OCC)=O)=CN1
O=C1NC(C2=CN=CN2)C(C(OCC)=O)=C(C)N1
O=C1NC(C2=CC=C(OCCO3)C3=C2)C(C(OCC)=O)=C(C)N1 O=C1NC(C2=CC=CN=C2)C(C(OCC)=O)=C(C)N1 O=C1NC(C2=CC=CC3=C2N=CC=N3)C(C(OCC)=O)=C(C)N1 O=C1NC(C2=CC=CC=C2N3CCOCC3)C(C(OCC)=O)=C(C)N1 O=C1NC(C2=CC=CO2)C(C(OCC)=O)=C(C)N1 O=C1NC(C2=CC=CC(OCC=C)=C2)C(C(OCC)=O)=C(C)N1
O=C1NC(C2=CC=CC=C2)C(C(OCC)=O)=C(C3=CC=CC=C3)N1 O=C1NC(C2=CC=CC=C2)C(C(OCC)=O)=C(C(F)(F)F)N1 O=C1NC(C2=CC=CC=C2OC(F)(F)F)C(C(OCC)=O)=C(C(F)(F)F)N1 O=C1NC(C2=CC=CC=C2SC(F)(F)F)C(C(OCC)=O)=C(C(F)(F)F)N1 O=C1NC(C2=CC=C(N3CCOCC3)S2)C(C(OCC)=O)=C(C)N1
O=C 1NC(C2=CC=C(N(C)C)C=C2C1)C(C(OCC)=O)=C(C)N 1 O=C1NC(C2=C(N3C=CC=C3)C=CS2)C(C(OCC)=O)=C(C)N1 O=ClNC(C2=CC(OCO3)=C3C=C2Br)C(C(OCC)=O)=C(C)Nl O=C1NC(C2=CC=CC(OC3=CC=C(C1)C=C3)=C2)C(C(OCC)=O)=C(C)N1 O=C1NC(C2=CC=CC(OC3=CC=C(C(C)(C)C)C=C3)=C2)C(C(OCC)=O)=C(C)N1
O=C1NC(C2=CC=CC(OC3=CC=C(OC)C=C3)=C2)C(C(OCC)=O)=C(C)N1 O=C1C2=C(N=C(SCC(C)=O)N2C)N(C)C(N1)=O O=C1C2=C(N=C(SCC(C)=O)N2CC3=CC=CC=C3)N(C)C(N1)=O O=C 1 C2=C(N=C(SCC(C)=O)N2CC)N(C)C(N1 )=O O=C 1 C2=C(N=C(SCC(C(F)(F)F)=O)N2C(C)C)N(C)C(N1 )=O
O=C1C2=C(C=C(NCC(C)=O)S2(=O)=O)N(C)C(N1)=O O=C1C2=C(N=C(SCC(C3=CC=CC=C3)=O)N2C)N(C)C(N1)=O O=C 1 C2=C(N=C(SCC(C)=O)N2CCC)N(C)C(N1 )=O O=C1C2=C(N=C(SCC(C)=O)N2CC3=CC=CS3)N(C)C(N1)=O O=C1C2=C(N=C(S(NC3=CC=CC=C3)(=O)=O)N2C)N(C)C(N1)=O
O=C1C2=C(N=C(SCC(C)=O)N2C3=CC=CC=C3)N(C)C(N1)=O O=C(NC(N/l)=O)Cl=C/C2=C(OCC3=CC=CC=N3)C=CC(Br)=C2 O=C(NC(N/l)=O)Cl=C/C2=C([N]CC3=CC=C(F)C=C3)C=CC(Br)=C2 O=C(NC(N/1)=O)C1=C/C2=C(OCC3=CC=C(F)C=C3)C=CC(OC)=C2 O=C(NC(N/1)=O)C1=C/C2=C(OCC3=CC=C(F)C=C3)C=CC(C)=C2
O=C(NC(N/l)=O)Cl=C/C2=C(OCC3=CC=C(C)C=C3)C=CC(Br)=C2 O=C(NC(N/l)=O)Cl=C/C2=C(SCC3=CC=C(F)C=C3)C=CC(Br)=C2 O=C(NC(N/l)=O)Cl=C/C2=C(OCC3=CC=C(C)C=C3C)C=CC(Br)=C2 O=C(NC(N/l)=O)Cl=C/C2=C(OCC3=CC=NC=C3)C=CC(Br)=C2 O=C(NC(N/1)=O)C1=C/C2=C(OCC3=CC=C(F)C=C3)C=C(C1)C=C2
O=C(NC(N/l)=O)Cl=C(C)/C2=C(OCC3=CC=C(F)C=C3)C=CC(Br)=C2
O=C(NC(N/l)=O)Cl=C/C2=C(OCC3=CC=C(F)C=C3)C=CC(Br)=C2
O=C(NC(N/l)=O)Cl=C/C2=C(OCC3=CC=CS3)C=CC(Br)=C2 The activity of the compounds in Examples 1-56 as iNOS inhibitors is illustrated in the following assay. The other compounds listed above, which have not yet been made and tested, are predicted to have activity in this assay as well.
Biological Activity Assay
Enzyme Source
The source of nitric oxide synthase (NOS) enzyme can be generated in several ways including induction of endogenous iNOS using cytokines and/or lipopolysaccharide (LPS) in various cell types known in the art. Alternatively, the gene encoding the enzyme can be cloned and the enzyme can be generated in cells via heterologous expression from a transient or stable expression plasmid with suitable features for protein expression as are known in the art. Enzymatic activity (nitric oxide production) is calcium independent for iNOS, while the constitutive NOS isoforms, nNOS and eNOS, become active with the addition of various cofactors added to cellular media or extract as are well known in the art.
Enzymes specified in Table 1 were expressed in HEK293 cells transiently transfected with human iNOS.
DAN Assay
A major metabolic pathway for nitric oxide is to nitrate and nitrite, which are stable metabolites within tissue culture, tissue, plasma, and urine (S Moncada, A Higgs, N Eng J Med 329, 2002 (1993)). Tracer studies in humans have demonstrated that perhaps 50% of the total body nitrate/nitrite originates from the substrate for NO synthesis, L-arginine (PM Rhodes, AM Leone, PL Francis, AD Struthers, S Moncada, Biomed Biophys Res. Commun. 209, 590 (1995); L. Castillo et al., Proc Natl Acad Sci USA 90, 193 (1993). Although nitrate and nitrite are not measures of biologically active NO, plasma and urine samples obtained from subjects after a suitable period of fasting, and optionally after administration of a controlled diet (low nitrate/low arginine), allow the use of nitrate and nitrite as an index of NO activity (C Baylis, P Vallance, Curr Opin Nephrol Hypertens 7, 59 (1998)).
The level of nitrate or nitrite in the specimen can be quantified by any method known in the art which provides adequate sensitivity and reproducibility. A variety of protocols have also been described for detecting and quantifying nitrite and nitrate levels in biological fluids by ion chromatography (e.g.,
SA Everett et al., J. Chromatogr. 706, 437 (1995); JM Monaghan et al., J. Chromatogr. 770, 143 (1997)), high-performance liquid chromatography (e.g., M KeIm et al., Cardiovasc. Res. 41, 765 (1999)), and capillary electrophoresis (MA Friedberg et al., J. Chromatogr. 781, 491 (1997)). For example, 2,3- diaminonaphthalene reacts with the nitrosonium cation that forms spontaneously from NO to form the fluorescent product l//-naphthotriazole. Using 2,3-diaminonaphthalene ("DAN"), researchers have developed a rapid, quantitative fluorometric assay that can detect from 10 nM to 10 μM nitrite and is compatible with a multi-well microplate format. DAN is a highly selective photometric and fluorometric reagent for Se and nitrite ion. DAN reacts with nitrite ion and gives fluorescent naphthotriazole (MC Carre et al., Analusis 27, 835-838 (1999)). Table 1 provides the test results of various compounds of the subject invention using the DAN assay.
A specimen can be processed prior to determination of nitrate or nitrite as required by the quantification method, or in order to improve the results, or for the convenience of the investigator. For example, processing can involve centrifuging, filtering, or homogenizing the sample. If the sample is whole blood, the blood can be centrifuged to remove cells and the nitrate or nitrite assay performed on the plasma or serum fraction. If the sample is tissue, the tissue can be dispersed or homogenized by any method known in the art prior to determination of nitrate or nitrite. It may be preferable to remove cells and other debris by centrifugation or another method and to determine the nitrate or nitrite level using only the fluid portion of the sample, or the extracellular fluid fraction of the sample. The sample can also be preserved for later determination, for example by freezing of urine or plasma samples. When appropriate, additives may be introduced into the specimen to preserve or improve its characteristics for use in the nitrate or nitrite assay.
The "level" of nitrate, nitrite, or other NO-related product usually refers to the concentration (in moles per liter, micromoles per liter, or other suitable units) of nitrate or nitrite in the specimen, or in the fluid portion of the specimen. However, other units of measure can also be used to express the level of nitrate or nitrite. For example, an absolute amount (in micrograms, milligrams, nanomoles, moles, or other suitable units) can be used, particularly if the amount refers back to a constant amount (e.g., grams, kilograms, milliliters, liters, or other suitable units) of the specimens under consideration. A number of commercially available kits can be used.
Table 1. Biological Activity
MNOS EC50 + indicates < 5 μM
Example # - indicates > 5 μM NT indicates Not Tested
1 +
2 - i +
4 -
5 +
6 +
7 -
8 -
9 +
10 -
11 -
12 +
13 -
Figure imgf000058_0001
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

Claims

CLAIMS What is claimed is:
1. A method for achieving an effect in a patient comprising the administration to a patient of a therapeutically effective amount of a compound of Formula I:
Figure imgf000060_0001
or a salt, ester, or prodrug thereof, wherein:
X1 is selected from the group consisting of CH2, O, S or NH;
R1 is selected from the group consisting of alkoxy, alkyl, alkylamino, alkylene, alkylamino, alkynyl, amino, aryl, arylalkoxy, arylamino, arylthio, cycloalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylamino, heterocycloalkyl and hydrogen, any of which may be optionally substituted;
R2 is selected from the group consisting of acyl, alkoxy, alkoxyalkyl, alkyl, alkylene, alkylamino, alkynyl, alkylimino, amido, amino, aryl, carboxy, cyano, cycloalkyl, ester, haloalkyl, heteoaryl, heterocycloalkyl and hydrogen, any of which may be optionally substituted;
R3a and R3b are each independently selected from the group consisting of alkyl, amino, arylalkyl, aryl, cycloalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl and hydrogen, any of which may be optionally substituted; and
R4 and R5 are each independently selected from the group consisting of optionally substituted alkyl and hydrogen; and wherein the effect is selected from the group consisting of inhibition of iNOS and treatment of an iNOS-mediated disease in a patient in need thereof.
2. The method as recited in Claim 1, wherein the effect is inhibition of iNOS.
3. The method as recited in Claim 1, wherein the effect is treatment of an iNOS-mediated disease.
4. The method as recited in Claim 3, wherein the compound has Formula II:
Figure imgf000060_0002
or a salt, ester, or prodrug thereof, wherein:
X1 is selected from the group consisting of O, S or NH;
R2 is selected from the group consisting of acyl, alkoxy, alkoxyalkyl, alkyl, alkylene, alkylamino, alkynyl, alkylimino, amido, amino, aryl, carboxy, cyano, cycloalkyl, ester, haloalkyl, heteoaryl, heterocycloalkyl and hydrogen, any of which may be optionally substituted;
R3ais aryl or heteroaryl, either of which may be optionally substituted; and R3b is selected from the group consisting of alkyl, amino, cycloalkyl, haloalkyl, heterocycloalkyl and hydrogen, any of which may be optionally substituted.
5. The method as recited in Claim 4, wherein the compound has Formula III:
Figure imgf000061_0001
or a salt, ester, or prodrug thereof, wherein:
R2 is selected from the group consisting of alkyl, alkylene, alkynyl, alkylimino, cycloalkyl, haloalkyl, heterocycloalkyl and hydrogen, any of which may be optionally substituted; and
R8 is selected from the group consisting of alkyl, alkylamino, alkylene, alkynyl, aryl, cycloalkyl, haloalkyl, heteroaryl, heterocycloalkyl and hydrogen, any of which may be optionally substituted.
6. The method as recited in Claim 3, wherein said disease is selected from the group consisting of psoriasis, uveitis, type 1 diabetes, septic shock, pain, migraine, rheumatoid arthritis, inflammatory bowel disease, asthma, immune complex diseases, multiple sclerosis, ischemic brain edema, toxic shock syndrome, heart failure, ulcerative colitis, atherosclerosis, glomerulonephritis, Paget's disease, osteoporosis, inflammatory sequelae of viral infections, retinitis, oxidant induced lung injury, eczema, acute allograft rejection and infection caused by invasive microorganisms which produce NO.
7. The method as recited in Claim 3, wherein said compound of Formula I is administered in combination with another therapeutic agent.
8. The method as recited in Claim 7, wherein: said disease is selected from the group consisting of psoriasis, uveitis, type 1 diabetes, septic shock, pain, migraine, rheumatoid arthritis, inflammatory bowel disease, asthma, immune complex diseases, multiple sclerosis, ischemic brain edema, toxic shock syndrome, heart failure, ulcerative colitis, atherosclerosis, glomerulonephritis, Paget's disease, osteoporosis, inflammatory sequelae of viral infections, retinitis, oxidant induced lung injury, eczema, acute allograft rejection and infection caused by invasive microorganisms which produce NO; and said other therapeutic agent is selected from the group consisting of corticosteroids, nonsteroidal anti-inflammatory drugs, muscle relaxants, anaesthetics, expectorants, antidepressants, anticonvulsants, antihypertensives, opioids, topical counter-irritants and topical cannabinoids.
9. A pharmaceutical composition comprising a compound as recited in Formula IV:
Figure imgf000062_0001
or a salt, ester, or prodrug thereof, wherein: X1 is selected from the group consisting of O, S or NH;
R1 is selected from the group consisting of alkoxy, acyl, alkyl, alkylene, alkylamino, alkynyl, amido, amino, aminosulfonyl, aryl, arylalkoxy, arylamino, arylthio, carboxy, cycloalkyl, ester, ether, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylamino, heterocycloalkyl, hydrazinyl, hydrogen, imino, thio, sulfonate and sulfonylamino, any of which may be optionally substituted;
R2 is selected from the group consisting of acyl, alkoxy, alkoxyalkyl, alkyl, alkylene, alkylamino, alkynyl, alkylimino, amido, amino, aryl, carboxy, cyano, cycloalkyl, ester, halo, haloalkyl, heteoaryl, heterocycloalkyl and hydrogen, any of which may be optionally substituted; and R3a is aryl or heteroaryl, either of which may be optionally substituted; and together with a pharmaceutically acceptable carrier.
10. The pharmaceutical composition as recited in Claim 9, wherein the compound has Formula III:
Figure imgf000062_0002
or a salt, ester, or prodrug thereof, wherein: R8 is selected from the group consisting of alkyl, alkylene, alkylamino, alkynyl, aryl, carboxy, cycloalkyl, ether, haloalkyl, heteroaryl, heterocycloalkyl and hydrogen, any of which may be optionally substituted;
R2 is selected from the group consisting of acyl, alkoxy, alkoxyalkyl, alkyl, alkylene, alkylamino, alkynyl, alkylimino, amido, amino, aryl, carboxy, cyano, cycloalkyl, ester, halo, haloalkyl, heteoaryl, heterocycloalkyl and hydrogen, any of which may be optionally substituted; and
R3ais aryl or heteroaryl, either of which may be optionally substituted.
11. The pharmaceutical composition as recited in Claim 10, useful for the treatment or prevention of an iNOS-mediated disease.
12. A method for achieving an effect in a patient comprising the administration to a patient of a therapeutically effective amount of a compound of Formula VI:
Figure imgf000063_0001
or a salt, ester, or prodrug thereof, wherein:
A is optionally substituted heteroaryl; and
R1 and R2 are each independently selected from the group consisting of acyl, alkyl, alkylene, alkylamino, alkynyl, amido, amino, aryl, arylalkoxy, arylamino, arylthio, carboxy, cycloalkyl, ester, ether, halo, haloalkoxy, haloalkyl, heteroaryl, heterocycloalkyl, hydrogen, thio, sulfonate and sulfonyl, any of which may be optionally substituted; and wherein the effect is selected from the group consisting of inhibition of iNOS and treatment of an iNOS-mediated disease in a patient in need thereof.
13. The method as recited in Claim 12, wherein the effect is inhibition of iNOS.
14. The method as recited in Claim 12, wherein the effect is treatment of an iNOS-mediated disease.
15. The method as recited in Claim 14 wherein the compound has the Formula VII:
Figure imgf000063_0002
or a salt, ester, or prodrug thereof, wherein:
X1 is selected from the group consisting of NR3 or CR4; X2 is selected from the group consisting of NR5, O, S(O)2 or S(O);
X3 is selected from the group consisting of acyl, alkoxy, alkyl, alkylthio, alkylene, alkylamino, alkynyl, amido, amino, aminosulfonyl, aryl, arylalkoxy, arylamino, arylthio, carboxy, cycloalkyl, ester, ether, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylamino, heteroarylthio, heterocycloalkyl, hydrazinyl, imino, thio, sulfonate and sulfonylamino, any of which may be optionally substituted;
R1 and R2 are each independently selected from the group consisting of acyl, alkyl, alkylene, alkylamino, alkynyl, amido, amino, aryl, arylalkoxy, arylamino, arylthio, carboxy, cycloalkyl, ester, ether, halo, haloalkoxy, haloalkyl, heteroaryl, heterocycloalkyl, hydrogen, thio, sulfonate and sulfonyl, any of which may be optionally substituted; R3 is selected from the group consisting of acyl, alkyl, alkylene, alkylamino, alkynyl, aryl, arylalkoxy, arylamino, arylthio, carboxy, cycloalkyl, ester, ether, haloalkyl, heteroaryl, heteroarylamino, heterocycloalkyl, hydrogen, thio, sulfonate and sulfonylamino, any of which may be optionally substituted; R4 is selected from the group consisting of acyl, alkyl, alkylene, alkylamino, alkynyl, aryl, arylalkoxy, arylamino, arylthio, carboxy, cycloalkyl, ester, ether, haloalkyl, heteroaryl, heteroarylamino, heterocycloalkyl, hydrogen, thio, sulfonate and sulfonylamino, any of which may be optionally substituted; and
R5 is selected from the group consisting of acyl, alkyl, alkylene, alkylamino, alkynyl, aryl, arylalkoxy, arylamino, arylthio, carboxy, cycloalkyl, ester, ether, haloalkyl, heteroaryl, heteroarylamino, heterocycloalkyl, hydrogen, thio, sulfonate and sulfonylamino, any of which may be optionally substituted.
16. The method as recited in Claim 15 wherein the compound has the Formula VIII:
Figure imgf000064_0001
or a salt, ester, or prodrug thereof, wherein:
X3 is selected from the group consisting of -SR6, -S(O)2R6, -NR7R8 and -OR3, any of which may be optionally substituted;
R6 is selected from the group consisting of alkyl, alkylaryl, alkylene, alkynyl, aryl, cycloalkyl, ester, halo, haloalkyl, heteroaryl, heterocycloalkyl and hydrogen, any of which may be optionally substituted;
R7 and R8 are each independently selected from the group selected from the group consisting of acyl, alkyl, alkylene, aminoalkyl, alkynyl, arylthio, carboxy, cycloalkyl, ester, ether, halo, haloalkoxy, haloalkyl, heteroaryl, heterocycloalkyl, hydrogen, thio and sulfonyl, any of which may be optionally substituted; or, alternatively, R5 and R6 may combine to form optionally substituted heterocycloalkyl; and
R3 is selected from the group consisting of acyl, alkyl, alkylene, alkylamino, alkynyl, aryl, arylalkoxy, arylamino, arylthio, carboxy, cycloalkyl, ester, ether, haloalkyl, heteroaryl, heteroarylamino, heterocycloalkyl, hydrogen, thio, sulfonate and sulfonyl, any of which may be optionally substituted.
17. The method as recited in Claim 14 wherein the compound has the Formula IX:
Figure imgf000065_0001
or a salt, ester, or prodrug thereof, wherein: R1 and R2 are each independently selected from the group consisting of acyl, alkyl, alkylene, alkylamino, alkynyl, amido, amino, aryl, arylalkoxy, arylamino, arylthio, carboxy, cycloalkyl, ester, ether, halo, haloalkoxy, haloalkyl, heteroaryl, heterocycloalkyl, hydrogen, thio, sulfonate and sulfonyl, any of which may be optionally substituted; and
R9, R10 and R11 are each independently selected from the group consisting of acyl, alkoxy, alkoxyalkylaryl, alkoxyalkylheteroaryl, alkyl, alkylene, alkylamino, alkynyl, amido, amino, aminosulfonyl, aryl, arylalkoxy, arylamino, arylthio, carboxy, cycloalkyl, ester, ether, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylamino, heterocycloalkyl, hydrazinyl, hydrogen, imino, thio, sulfonate and sulfonylamino, any of which may be optionally substituted.
18. The method as recited in Claim 14, wherein said disease is selected from the group consisting of psoriasis, uveitis, type 1 diabetes, septic shock, pain, migraine, rheumatoid arthritis, inflammatory bowel disease, asthma, immune complex diseases, multiple sclerosis, ischemic brain edema, toxic shock syndrome, heart failure, ulcerative colitis, atherosclerosis, glomerulonephritis, Paget's disease, osteoporosis, inflammatory sequelae of viral infections, retinitis, oxidant induced lung injury, eczema, acute allograft rejection and infection caused by invasive microorganisms which produce NO.
19. The method as recited in Claim 14, wherein said compound of Formula VI is administered in combination with another therapeutic agent.
20. The method as recited in Claim 19, wherein: said disease is selected from the group consisting of psoriasis, uveitis, type 1 diabetes, septic shock, pain, migraine, rheumatoid arthritis, inflammatory bowel disease, asthma, immune complex diseases, multiple sclerosis, ischemic brain edema, toxic shock syndrome, heart failure, ulcerative colitis, atherosclerosis, glomerulonephritis, Paget's disease, osteoporosis, inflammatory sequelae of viral infections, retinitis, oxidant induced lung injury, eczema, acute allograft rejection and infection caused by invasive microorganisms which produce NO; and said other therapeutic agent is selected from the group consisting of corticosteroids, nonsteroidal anti-inflammatory drugs, muscle relaxants, anaesthetics, expectorants, antidepressants, anticonvulsants, antihypertensives, opioids, topical counter-irritants and topical cannabinoids.
21. A pharmaceutical composition comprising a compound as recited in Formula X together with a pharmaceutically acceptable carrier.
Figure imgf000066_0001
or a salt, ester, or prodrug thereof, wherein:
A is optionally substituted heteroaryl; and
R1 and R2 are each independently selected from the group consisting of acyl, alkyl, alkylene, alkylamino, alkynyl, amido, amino, aryl, arylalkoxy, arylamino, arylthio, carboxy, cycloalkyl, ester, ether, halo, haloalkoxy, haloalkyl, heteroaryl, heterocycloalkyl, hydrogen, thio, sulfonate and sulfonyl, any of which may be optionally substituted.
22. The pharmaceutical composition as recited in Claim 21, useful for the treatment or prevention of an iNOS-mediated disease.
23. A method for achieving an effect in a patient comprising the administration to a patient of a therapeutically effective amount of a compound of Formula XI:
Figure imgf000066_0002
or a salt, ester, or prodrug thereof, wherein:
X1 and X2 are each independently selected from the group consisting of acyl, alkoxy, alkyl, alkylene, alkynyl, amido, amino, aminosulfonyl, aryl, arylalkoxy, arylamino, arylthio, carboxy, cycloalkyl, ester, haloalkyl, heteroaryl, heterocycloalkyl, hydrogen, thio, sulfonate and sulfonyl, any of which may be optionally substituted;
R1 is selected from the group consisting of alkoxy, alkyl, alkylamino, alkylaryl, alkylene, alkylamino, alkynyl, amino, aryl, arylalkoxy, arylamino, arylthio, cycloalkyl, ester, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkyl, heteroarylamino, heterocycloalkyl and hydrogen, any of which may be optionally substituted; and R2 is selected from the group consisting of acyl, alkoxy, alkoxyalkyl, alkyl, alkylene, alkylamino, alkynyl, alkylimino, amido, amino, aryl, carboxy, cyano, cycloalkyl, ester, halo, haloalkyl, heteoaryl, heterocycloalkyl and hydrogen, any of which may be optionally substituted; and wherein the effect is selected from the group consisting of inhibition of iNOS and treatment of an iNOS-mediated disease in a patient in need thereof.
24. The method as recited in Claim 23, wherein the effect is inhibition of iNOS.
25. The method as recited in Claim 23, wherein the effect is treatment of an iNOS-mediated disease.
26. The method as recited in Claim 25 wherein the compound has the Formula XII:
Figure imgf000067_0001
or a salt, ester, or prodrug thereof, wherein:
R1 is selected from the group consisting of alkylaryl, alkylheteroaryl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl, any of which may be optionally substituted; and R2 is selected from the group consisting of alkyl, cycloalkyl, haloalkyl, heterocycloalkyl and hydrogen, any of which may be optionally substituted.
27. The method as recited in Claim 26 wherein the compound has the Formula XIII:
Figure imgf000067_0002
or a salt, ester, or prodrug thereof, wherein: X3 is selected from the group consisting of CR3 or N;
X4 is selected from the group consisting of CR4 or N, X5 is selected from the group consisting of CR5 or N; X6 is selected from the group consisting of CR6 or N; X7 is selected from the group consisting of CR7 or N; R2 is selected from the group consisting of alkyl, cycloalkyl, haloalkyl, heterocycloalkyl and hydrogen, any of which may be optionally substituted; and
R3, R4, R5 R6 and R7 are each independently selected from the group consisting of acyl, alkoxy, alkoxyalkylaryl, alkoxyalkylheteroaryl, alkyl, alkylene, alkylamino, alkynyl, amido, amino, aminosulfonyl, aryl, arylalkoxy, arylamino, arylthio, carboxy, cycloalkyl, ester, ether, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylamino, heterocycloalkyl, hydrazinyl, hydrogen, imino, thio, sulfonate and sulfonylamino, any of which may be optionally substituted.
28. The method as recited in Claim 25, wherein said disease is selected from the group consisting of psoriasis, uveitis, type 1 diabetes, septic shock, pain, migraine, rheumatoid arthritis, inflammatory bowel disease, asthma, immune complex diseases, multiple sclerosis, ischemic brain edema, toxic shock syndrome, heart failure, ulcerative colitis, atherosclerosis, glomerulonephritis, Paget's disease, osteoporosis, inflammatory sequelae of viral infections, retinitis, oxidant induced lung injury, eczema, acute allograft rejection and infection caused by invasive microorganisms which produce NO.
29. The method as recited in Claim 25, wherein said compound of Formula XI is administered in combination with another therapeutic agent.
30. The method as recited in Claim 29, wherein: said disease is selected from the group consisting of psoriasis, uveitis, type 1 diabetes, septic shock, pain, migraine, rheumatoid arthritis, inflammatory bowel disease, asthma, immune complex diseases, multiple sclerosis, ischemic brain edema, toxic shock syndrome, heart failure, ulcerative colitis, atherosclerosis, glomerulonephritis, Paget's disease, osteoporosis, inflammatory sequelae of viral infections, retinitis, oxidant induced lung injury, eczema, acute allograft rejection and infection caused by invasive microorganisms which produce NO; and said other therapeutic agent is selected from the group consisting of corticosteroids, nonsteroidal anti-inflammatory drugs, muscle relaxants, anaesthetics, expectorants, antidepressants, anticonvulsants, antihypertensives, opioids, topical counter-irritants and topical cannabinoids.
31. A compound selected from the group consisting of Examples 8-44 and 51.
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