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WO2009029625A1 - 4-[hétérocyclylméthyl]-8-fluoro-quinolin-2-ones utiles comme inhibiteurs de l'oxyde nitrique synthase - Google Patents

4-[hétérocyclylméthyl]-8-fluoro-quinolin-2-ones utiles comme inhibiteurs de l'oxyde nitrique synthase Download PDF

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WO2009029625A1
WO2009029625A1 PCT/US2008/074334 US2008074334W WO2009029625A1 WO 2009029625 A1 WO2009029625 A1 WO 2009029625A1 US 2008074334 W US2008074334 W US 2008074334W WO 2009029625 A1 WO2009029625 A1 WO 2009029625A1
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disease
pain
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Nicholas D. Smith
Celine Bonnefous
Sergio Duron
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Kalypsys Inc
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Kalypsys Inc
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    • 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
    • C07D401/06—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 only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • 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.
  • NOS NO synthase
  • NOS inducible NOS
  • iNOS inducible NOS
  • 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 Attorney Docket No. KO 152-401 -PC
  • NOS 2 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 130 kDa subunits. Each subunit comprises an oxygenase domain and a reductase domain. Importantly, dimerization of the iNOS synthase is required for enzyme activity. If the dimerization mechanism is disrupted, the production of nitric oxide via inducible NOS enzyme is inhibited.
  • iNOS 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.
  • NO-derived metabolites e.g., peroxynitrite
  • 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.
  • Nitric oxide and NOS activity and expression have been linked to neuropathic pain and postherpetic neuralgia, as well, conditions for which treatment options have been equivocal at best(Wu CL and Raja SN, J Pain. 2008 Jan;9(l Suppl l):S19-30).
  • Inhibitors of iNOS show promise in the treatment of these debilitating diseases.
  • several recent studies in rats administered an iNOS inhibitor demonstrate a role for peripherally-expressed iNOS in Attorney Docket No. KO 152-401 -PC
  • INOS-selective and nonselective inhibitors have long been known in the art, and have been investigated for the treatment of iNOS-mediated diseases and conditions including pain, as described above.
  • iNOS-mediated diseases and conditions including pain, as described above.
  • no NOS inhibitor has made it to market, for reasons that will not be exhaustively addressed here.
  • the earliest compounds tended to fall in to the category of active-site inhibitors, leading to unacceptable side effects.
  • Novel compounds and pharmaceutical compositions certain of which have been found to inhibit inducible NOS synthase have been discovered, together with methods of synthesizing and using the compounds including methods for the treatment of iNOS-mediated diseases in a patient by administering the compounds.
  • R 1 is selected from the group consisting of acyl, alkyl, alkylene, aminoalkyl, amidoalkyl, alkynyl, amido, amino, aminoalkyl, aryl, arylalkyl, arylalkoxy, arylamino, arylaminoalkyl, arylthio, carboxy, cycloalkyl, ester, ether, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkyl, heteroarylamino, heteroarylaminoalkyl, heterocycloalkyl, heterocycloalkylalkyl, hydrazinyl, hydrogen, imino, thio, sulfonate, sulfonylamino and sulfonylaminoalkyl, 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, halo, haloalkyl, heteroaryl, heterocycloalkyl and hydrogen, any of which may be optionally substituted; or, alternatively, R 2 may combine with R 1 to form heterocycloalkyl, which may be optionally substituted;
  • R 3 is selected from the group consisting of alkyl, amino, arylalkyl, aryl, cycloalkyl, haloalkyl, heteroarylalkyl, heterocycloalkyl and hydrogen, any of which may be optionally substituted; and
  • A, B, C and D are each independently selected from the group consisting of acyl, alkoxy, 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; or, alternatively, any two or more A, B, C and D may combine to form aryl, cycloalkyl, heteroaryl or heterocycloalkyl, any of which may be optionally substituted.
  • Certain compounds disclosed herein may possess useful iNOS inhibitory activity, and may be used in the treatment or prophylaxis of a disease or condition in which iNOS plays an active role.
  • the certain embodiments also provide pharmaceutical compositions comprising one or more compounds disclosed herein together with a pharmaceutically acceptable carrier, as well as methods of making and using the compounds and compositions.
  • Certain embodiments provide methods for inhibiting iNOS.
  • Other embodiments provide methods for treating an iNOS-mediated disorder in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound or composition according to the present invention.
  • certain compounds disclosed herein for use in the manufacture of a medicament for the treatment of a disease or condition ameliorated by the inhibition of iNOS.
  • the compounds have structural Formula II:
  • R 4 , R 5 , R 6 and R 7 are independently selected from the group consisting of hydrogen, lower alkyl, and halogen;
  • R 8 is selected from the group consisting of heteroaryl and heterocycloalkyl, either of which may be optionally substituted. [014] In further embodiments, R 6 and R 7 are hydrogen. [015] In further embodiments, R 4 is hydrogen.
  • R 8 is selected from the group consisting of lower heteroaryl and lower heterocycloalkyl, either of which may be optionally substituted. [017] In further embodiments, R 8 is selected from the group consisting of lower heteroaryl and lower heterocycloalkyl, either of which may be optionally substituted with one to three substituents selected from the group consisting of hydrogen, halogen, lower alkyl, lower monocyclic cycloalkyl, lower heteroalkyl, lower haloalkyl, lower amino, and lower alkoxy.
  • R 8 has the structure:
  • X 1 , X 2 , and X 5 are each independently selected from the group consisting of C and N;
  • X 3 is selected from the group consisting of C(R 10 ) and N;
  • X 4 is selected from the group consisting of C(R 11 ) and N
  • R 9 is selected from the group consisting of hydrogen, halogen, lower alkyl, and lower monocyclic cycloalkyl; or R 9 may combine with X 6 to form a cyclic moiety selected from the group consisting of aryl and heteroaryl; and
  • R 10 , R 11 , and R 12 are each independently selected from the group consisting of a bond, hydrogen, halogen, lower alkyl, lower alkoxy, and lower monocyclic cycloalkyl; each R 13 and R 14 is independently selected from the group consisting of hydrogen, halogen, lower alkyl, and lower monocyclic cycloalkyl; and each n is independently 0 or 1 ; and with the provisos that: the fused ring formed by X 1 , X 2 , X 5 , X 6 , and the carbon bearing R 9 may be aromatic or aliphatic; and
  • X 1 and X 6 may not both be N.
  • R has the structure:
  • R 8 has a structure selected from the group consisting of:
  • R 15 is selected from the group consisting of hydrogen, halogen, lower alkyl, and lower monocyclic cycloalkyl, and all other groups are as previously defined.
  • the compounds have structural Formula III:
  • X 1 , X 2 , and X 5 are each independently selected from the group consisting of C and N;
  • X 3 is selected from the group consisting of C(R 10 ) and N;
  • X 4 is selected from the group consisting of C(R 11 ) and N
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, lower alkyl, and halogen;
  • R 9 is selected from the group consisting of hydrogen, halogen, lower alkyl, and lower monocyclic cycloalkyl; or R 9 may combine with X 6 to form a cyclic moiety selected from the group consisting of aryl and heteroaryl;
  • R 10 , R 11 , and R 12 are each independently selected from the group consisting of a bond, hydrogen, halogen, lower alkyl, lower alkoxy, and lower monocyclic cycloalkyl; each R 13 and R 14 is independently selected from the group consisting of hydrogen, halogen, lower alkyl, and lower monocyclic cycloalkyl; and each n is independently 0 or 1 ; and with the proviso that X 1 and X 6 may not both be N.
  • R 4 is hydrogen.
  • R 5 is fluorine.
  • Claim 1 as a medicament.
  • Claim 1 as a medicament for the prevention or treatment of a disease or condition ameliorated by the inhibition of iNOS.
  • composition comprising a compound as recited in Claim 1 together with a pharmaceutically acceptable carrier.
  • a method of treatment of a iNOS-mediated disease comprising the administration of a therapeutically effective amount of a compound as recited in Claim 1 to a patient in need thereof.
  • a method of treatment of a iNOS-mediated disease comprising the administration of: a therapeutically effective amount of a compound as recited in Claim 1; and another therapeutic agent.
  • 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 group having one or more double bonds and containing from 2 to 20 carbon atoms. In certain embodiments, said alkenyl will comprise from 2 to 6 carbon atoms.
  • alkoxy refers to an alkyl ether group, wherein the term alkyl is as defined below.
  • suitable alkyl ether groups 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 group containing from 1 to 20 carbon atoms. In certain embodiments, said alkyl will comprise from 1 to 10 carbon atoms. In further embodiments, said alkyl will comprise from 1 to 6 carbon atoms. Alkyl groups may be optionally substituted as defined herein.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, noyl and the like.
  • alkylene 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 -). Unless otherwise specified, the term “alkyl” may include “alkylene” groups.
  • 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-) group wherein the term alkyl is as defined above and wherein the sulfur may be singly or doubly oxidized.
  • suitable alkyl thioether groups include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso- butylthio, sec-butylthio, tert-butylthio, methanesulfonyl, ethanesulfmyl, and the like.
  • alkynyl refers to a straight-chain or branched chain hydrocarbon group having one or more triple bonds and containing from 2 to 20 carbon atoms. In certain embodiments, said alkynyl comprises from 2 to 6 carbon atoms. In further embodiments, said alkynyl comprises 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 groups include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1- yl, 3-methylbutyn-l-yl, hexyn-2-yl, and the like.
  • alkynyl may include "alkynylene” groups.
  • 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 (CHsC(O)NH-).
  • amino as used herein, alone or in combination, refers to —
  • 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. Additionally, R and R' may combine to form heterocycloalkyl, either of which may be optionally substituted.
  • aryl as used herein, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such polycyclic ring systems are fused together.
  • aryl embraces aromatic groups such as phenyl, naphthyl, anthracenyl, and phenanthryl.
  • 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 group derived from an aryl-substituted alkanecarboxylic acid such as benzoyl, naphthyl, phenylacetyl, 3-phenylpropionyl
  • hydrocinnamoyl 4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like.
  • aryloxy refers to an aryl group attached to the parent molecular moiety through an oxy.
  • 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.
  • N-carbamyl as used herein, alone or in combination, refers to a
  • carbonyl when alone includes formyl [-C(O)H] and in combination is a -C(O)- group.
  • carboxyl or “carboxy,” as used herein, refers to -C(O)OH or the corresponding “carboxylate” anion, such as is in a carboxylic acid salt.
  • O-carboxy group refers to a RC(O)O- group, where R is as defined herein.
  • 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 or, alternatively, “carbocycle,” as used herein, alone or in combination, refers to a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl group wherein each cyclic moiety contains from 3 to 12 carbon atom ring members and which may optionally be a benzo fused ring system which is optionally substituted as defined herein.
  • said cycloalkyl will comprise from 5 to 7 carbon atoms.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, indanyl, 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 decahydronaphthalene, octahydronaphthalene as well as the multicyclic (multicentered) saturated or partially unsaturated type.
  • the latter type of isomer is exemplified in general by, bicyclo[l,l,l]pentane, camphor, adamantane, and bicyclo[3,2,l]octane.
  • esters 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 or halogen
  • haloalkoxy refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.
  • haloalkyl refers to an alkyl group having the meaning as defined above wherein one or more hydrogens are replaced with a halogen. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl groups. A monohaloalkyl group, for one example, may have an iodo, bromo, chloro or fluoro atom within the group.
  • Dihalo and polyhaloalkyl groups may have two or more of the same halo atoms or a combination of different halo groups.
  • haloalkyl groups 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 group, 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 a 3 to 7 membered unsaturated heteromonocyclic ring, or a fused monocyclic, bicyclic, or tricyclic ring system in which at least one of the fused rings is aromatic, which contains at least one atom selected from the group consisting of O, S, and N.
  • heteroaryl refers to a 3 to 7 membered unsaturated heteromonocyclic ring, or a fused monocyclic, bicyclic, or tricyclic ring system in which at least one of the fused rings is aromatic, which contains at least one atom selected from the group consisting of O, S, and N.
  • said heteroaryl will comprise from 5 to 7 carbon atoms.
  • the term also embraces fused polycyclic groups wherein heterocyclic rings are fused with aryl rings, wherein heteroaryl rings are fused with other heteroaryl rings, wherein heteroaryl rings are fused with heterocycloalkyl rings, or wherein heteroaryl rings are fused with cycloalkyl rings.
  • 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 group containing at least one heteroatom as a ring member, wherein each said heteroatom may be independently selected from the group consisting of nitrogen, oxygen, and sulfur
  • said heterocycloalkyl will comprise from 1 to 4 heteroatoms as ring members.
  • said heterocycloalkyl will comprise from 1 to 2 heteroatoms as ring members.
  • said heterocycloalkyl will comprise from 3 to 8 ring members in each ring.
  • heterocycloalkyl will comprise from 3 to 7 ring members in each ring. In yet further embodiments, said heterocycloalkyl will comprise from 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 include aziridinyl, azetidinyl, 1,3- benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, Attorney Docket No. KO 152-401 -PC
  • dihydrobenzodioxinyl dihydro[ 1 ,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-.
  • hydroxyalkyl refers to a hydroxy group attached to the parent molecular moiety through an alkyl group.
  • isocyanato refers to a -NCO 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.
  • lower aryl as used herein, alone or in combination, means phenyl or naphthyl, which may be optionally substituted as provided.
  • lower heteroaryl as used herein, alone or in combination, means either 1) monocyclic heteroaryl comprising five or six ring members, of which between one and four said members may be heteroatoms selected from the group consisting of
  • each of the fused rings comprises five or six ring members, comprising between them one to four heteroatoms selected from the group consisting of O, S, and N.
  • lower cycloalkyl as used herein, alone or in combination, means a monocyclic cycloalkyl having between three and six ring members. Lower cycloalkyls may be unsaturated. Examples of lower cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • lower heterocycloalkyl as used herein, alone or in combination, means a monocyclic heterocycloalkyl having between three and six ring members, of which between one and four may be heteroatoms selected from the group consisting of
  • lower heterocycloalkyls examples include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, and morpholinyl. Lower heterocycloalkyls may be unsaturated.
  • R and R are independently selected from the group consisting of hydrogen, lower alkyl, and lower heteroalkyl, any of which may be optionally substituted. Additionally, the R and R' of a lower amino group may combine to form a five- or six-membered heterocycloalkyl, either of which may be optionally substituted.
  • 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 to the -SO 3 H group and its anion as the sulfonic acid is used in salt formation.
  • 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 sulfmyl and sulfonyl, are included in the definition of thia and thio.
  • thiol as used herein, alone or in combination, refers to an -SH 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.
  • trimethoxy refers to a X3CO- 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.
  • the term "optionally substituted” means the anteceding group may be substituted or unsubstituted.
  • 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 alkylcarbonyl
  • Two substituents may be joined together to form a fused five-, six-, or seven-membered 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 ).
  • R or the term R' 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 Attorney Docket No. KO 152-401 -PC
  • Asymmetric centers exist in the compounds disclosed herein. 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.
  • the compounds disclosed herein may exist as geometric isomers.
  • the present invention includes all cis, trans, syn, anti,
  • 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.
  • disease as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.
  • 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 ⁇ M and more typically not more than about 50 ⁇ M, as measured in the iNOS assay described generally hereinbelow.
  • IC50 is that concentration of inhibitor which reduces the activity of an enzyme (e.g., iNOS) to half-maximal level. Certain compounds disclosed herein have been discovered to exhibit inhibition against iNOS.
  • compounds will exhibit an EC 50 with respect to iNOS of no more than about 10 ⁇ M; in further embodiments, compounds will exhibit an EC50 with respect to iNOS of no more than about 5 ⁇ M; in yet further embodiments, compounds will exhibit an EC50 with respect to iNOS of not more than about 1 ⁇ M; in yet further embodiments, compounds Attorney Docket No. KO 152-401 -PC
  • 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.
  • 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 disclosed herein 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- VHC A, 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 Attorney Docket No. KO 152-401 -PC
  • the compounds disclosed herein can exist as therapeutically acceptable salts.
  • the present invention includes compounds listed above in the form of salts, including 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 disclosed herein 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, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenyl
  • basic groups in the compounds disclosed herein 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 Attorney Docket No. KO 152-401 -PC
  • 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 disclosed herein, 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, JV,iV-dimethylaniline, N- methylpiperidine, JV-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, ⁇ /, ⁇ /-dibenzylphenethylamine, 1-ephenamine, and iV. ⁇ /'-dibenzylethylenediamme.
  • nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, trieth
  • compositions which comprise one or more of certain compounds disclosed herein, or one or more pharmaceutically acceptable salts, esters, prodrugs, amides, or solvates 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 disclosed herein may be manufactured in any manner known in the art, e.g. , by means Attorney Docket No. KO 152-401 -PC
  • 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.
  • parenteral including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary
  • intraperitoneal including 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.
  • topical including dermal, buccal, sublingual and intraocular
  • 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.
  • these methods include the step of bringing into association a compound of the subject invention or a pharmaceutically acceptable salt, ester, amide, prodrug or solvate thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients.
  • active ingredient a pharmaceutically acceptable salt, ester, amide, prodrug or solvate thereof
  • 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 compounds disclosed herein 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 Attorney Docket No. KO 152-401 -PC
  • 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.
  • 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.
  • 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
  • Formulations for parenteral administration include aqueous and nonaqueous (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 Attorney Docket No. KO 152-401 -PC
  • 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.
  • Certain compounds disclosed herein may be administered topically, that is by non-systemic administration. This includes the application of a compound disclosed herein 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 for topical administration may comprise, for example, from 0.001% to 10% w/w (by weight) of the formulation. In certain embodiments, the active ingredient may comprise as much as 10% w/w.
  • the active ingredient may comprise from 2% w/w to 5% w/w. In other embodiments, it may comprise from 0.1% to 1% w/w of the formulation.
  • Gels for topical or transdermal administration may comprise, generally, a mixture of volatile solvents, nonvolatile solvents, and water.
  • the volatile solvent component of the buffered solvent system may include lower (Cl- C6) alkyl alcohols, lower alkyl glycols and lower glycol polymers.
  • 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. In certain embodiments, 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 may 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; in certain embodiments, water is used. A common 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 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 Attorney Docket No. KO 152-401 -PC
  • 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 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 stearic 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 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, in certain embodiments, 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 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.
  • compounds may be 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.
  • the formulations described above 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.
  • Compounds may be administered orally or via injection at a dose of from 0.1 to 500 mg/kg per day. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of one or more compounds 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 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 Attorney Docket No. KO 152-401 -PC
  • the route of administration may vary depending on the condition and its severity.
  • another therapeutic agent such as 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.
  • 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).
  • 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.
  • 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.
  • Specific, non- limiting examples of possible combination therapies include use of the compounds of the invention with: a) corticosteroids including betamethasone dipropionate (augmented and nonaugemented), betamethasone valerate, clobetasol propionate, diflorasone diacetate, halobetasol propionate, amcinonide, dexosimethasone, fluocinolone acetononide, fluocinonide, halocinonide, clocortalone pivalate, 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) anaesthetic
  • lidocaine lidocaine/deoxy-D- glucose (an antiviral), prilocaine, and EMLA Cream
  • 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 fluvo
  • 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.
  • certain embodiments provide 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 disclosed herein 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.
  • certain embodiments provide therapeutic compositions comprising at least one compound disclosed herein 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.
  • nitric oxide synthase contributes to the development of neuropathic pain (Levy D, Kubes P, and Zochodne DW, J Neuropathol Exp Neurol. 2001 May;60(5):411-21).
  • 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; Kern TS, Exp Diabetes Res. 2007;2007:95-103), intractable cancer pain, complex regional pain syndrome, chemotherapy-induced neuropathy, HIV neuropathy, or entrapment neuropathy (carpel tunnel syndrome).
  • neuropathy or inflammatory pain such as reflex sympathetic dystrophy/causalgia (nerve injury), peripheral neuropathy (including diabetic neuropathy; Kern TS, Exp Diabetes Res. 2007;2007:95-103), intractable cancer pain, complex regional pain syndrome, chemotherapy-induced neuropathy, HIV neuropathy, or 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
  • Pain indications include, but are not limited to, treatment or prophylaxis of surgical or post-surgical pain for various surgical procedures including amputation, 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 inhibitors of the subject invention Attorney Docket No. KO 152-401 -PC
  • 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,
  • 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 (Cuzzocrea S., Curr Pharm Des. 2006;12(27):3551-70, including but not limited to rheumatoid arthritis (Maki-Petaja KM et al, MJ Cardiol. 2008 Jun 18.
  • 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, ulcerative colitis, and acute and chronic inflammation of the pancreas.
  • 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 organ and tissue injury injury associated with severe burns, sepsis, trauma, and hemorrhage- or resuscitation-induced hypotension, and also 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, 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
  • 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 Attorney Docket No. KO 152-401 -PC
  • 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-induced 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), Korsakoff s disease, cognitive disorders relating to a cerebral vessel disorder, hypersensitivity, 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, endotoxic shock syndrome, and atherosclerosis.
  • Still other disorders or conditions advantageously treated by the compounds of the subject invention include the prevention or treatment of hyperproliferative diseases, especially cancers, either alone or incombination of standards of care especially those agents that target tumor growth by re-instating the aberrant apoptotic machinery in the malignant cells.
  • Hematological and non-hematological malignancies which may be treated or prevented include but are not limited to multiple myeloma, acute and chronic leukemias including Acute Lymphocytic Leukemia (ALL), Chronic Lymphocytic Leukemia (CLL), and Chronic Myelogenous Leukemia(CLL), lymphomas, including Hodgkin's lymphoma and non-Hodgkin's lymphoma (low, intermediate, and high grade), as well as solid tumors and malignancies of the brain, head and neck, breast, lung, reproductive tract, upper digestive tract, pancreas, liver, renal, bladder, prostate and colorectal.
  • ALL Acute Lymphocytic Leukemia
  • CLL Chronic Lymphocytic Leukemia
  • CLL Chronic Myelogenous Leukemia
  • lymphomas including Hodgkin's lymphoma and non-Hodgkin's lymphoma (low, intermediate, and high grade)
  • the present compounds and methods can be used to treat the fibrosis, such as that 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.
  • FAP familial adenomatous polyposis
  • the compounds of the subject invention can be used in the treatment of ophthalmic diseases, such as glaucoma, retinal ganglion degeneration, ocular ischemia, corneal neovascularization, optic neuritis, retinitis, retinopathies such as glaucomatous retinopathy and/or diabetic retinopathy, uveitis, ocular photophobia, dry eye, Sjogren's syndrome, seasonal and chronic allergic conjunctivitis, and of inflammation and pain associated with chronic ocular disorders and acute injury to the eye tissue.
  • 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 provide 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.
  • Reagents (a) 3-oxobutanoate, xylene/pyridine, reflux, 3Oh. (b) (i) Br 2 , AcOH, 25°C, 22h. (ii) Acetone, (c) H 2 SO 4 , 40 0 C, 2Oh. (d) POCl 3 , 80 0 C, 3h. (e) HCOOK, MeOH, H 2 O, reflux, 18h. (f) MeONa, MeOH, reflux, 2h. (g) MnO 2 , CHCl 3 , 50 0 C, 1.5h.
  • Reagents (a) (i) 2,2,2-trichloroethane-l,l-diol, Na 2 SO 4 , H 2 O, 25°C, Ih. (ii) NH 2 OKHCl 60 0 C, 2h. (b) and H 2 SO 4 , 80 0 C, 3h. (c) (i) Ac 2 O, 130 0 C, 3h. Attorney Docket No. KO 152-401 -PC
  • Reagents (a) NBS, AIBN, CCl 4 , reflux, 3h. (b) Potassium isoindoline-1,3- dione, DMF, 25°C, 12h. (c) hydrazine hydrate, 50 0 C, 2h. (d) Isobutyryl chloride, Et 3 N, THF, 0 0 C, Ih. (e) Fe, NH 4 Cl, H 2 O, EtOH, reflux, 2h. (f) 4- (Bromomethyl)-2-chloro-7,8-difluoroquinoline, Na 2 CO 3 , DMF, 50 0 C, 2h. (g) Titanium(IV) chloride, toluene, ACN, reflux, 18h. (h) AcOH, reflux, 3h.
  • Reagents (a) 3-Methylbutan-2-one, H 2 O, KOH/EtOH, reflux, 2days. (b) 1- phenoxybenzene, 270 0 C, Ih. (c) NaBH 4 , NiCl 2 .6H 2 O, MeOH, 25°C, Ih. (d) Titanium(IV) chloride, toluene, ACN, reflux, 18h. (e) AcOH, reflux, 3h.
  • Reagents (a) NaH, DMF, 25°C, 2- 1Oh.
  • Reagents (a) Sodium azide, DMF (500 niL), 50 0 C, 12h. (b) (i) Na, EtOH, 0 0 C. (ii) Picolinaldehyde, EtOH, 0 0 C, 4h. (c) Xylene, 110 0 C, Ih. (d) (i) MeI, Mg, Et 2 O, reflux, 1.5h. (ii) ethyl H-pyrazolo[l,5-a]pyridine-2- carboxylate,0°C, lO min. (e) H 2 , Pd/C, 33°C, 2h.
  • Reagents (a) Isobutyryl chloride, Et 3 N, toluene, reflux, 12h. (b) AlCl 3 , 7,8- difluoro-2-methoxyquinoline-4-carbonyl chloride, DCM, -78°C to -10 0 C, 2.5h. (c) AlLiH 45 AlCl 3 , Et 2 O, 0 0 C to 25°C, 15 min. (d) HBr/AcOH, 50 0 C, Ih.
  • Reagents (a) Hydrazine, EtOH, reflux, 4h. (b) Raney Ni, H 2 , EtOH, 18h. (c) Cyclobutylethanone, EtOH, reflux, 18h. (d) NH 3 .H 2 O, 125°C, 18h. (e) Pd/C, H 2 , MeOH, RT, 1.5h. (f) NBS, CHCl 3 , RT, 30 min or NBS, AIBN, 55°C, 20 min. (g) (i) THF, -78°C, 30 min (ii) 7,8-difluoro-2- methoxyquinoline-4-carbaldehyde, -78°C, 2h.
  • Step 1 N-(2,3-Difluorophenyl)-3-oxobutanamide
  • Adjustment of the pH to 2 was accomplished by the addition of HCl (4N, 50 mL) and the precipitate was filtered and dried to afford 5.6 g of 7,8- difluoro-2-hydroxyquinoline-4-carboxylic acid(crude) as a yellow solid.
  • Adjustment of the pH to ⁇ 3 was accomplished by the addition of HCl (4N) and the precipitate was filtered, washed with H 2 O, and dried to afford in 2.58 g (94%) of 7,8-difluoro-2-methoxyquinoline-4-carboxylic acid as a white solid.
  • Step 1 (2-Chloro-7,8-difluoroquinolin-4-yl)methanol
  • Step 6 N-(2-((2-Chloro-7,8-difluoroquinolin-4- yl)methylamino)benzyl)isobutyramide
  • Step 7 l-((2-Chloro-7,8-difluoroquinolin-3-yl)methyl)-2-isopr ⁇ )pyl-l,2- dihydroquinazoline
  • Titanium(IV) chloride was added dropwise to a cooled solution (10 0 C) of N-(2-((2-chloro-7,8-difluoroquinolin-3-yl)methylamino)benzyl)isobutyramide (900 mg, 2.12 mmol) in toluene and ACN (60 mL) and the resulting solution was refluxed for 18h.
  • the reaction mixture was then quenched by the adding of ice/salt. A filtration was performed.
  • the resulting solution was extracted with EtOAc (2x100 mL) and the combined organic layers was concentrated under vacuum.
  • Step 8 7,8-Difluoro-4-((2-isopropylquinazolin-l(2H)-yl)methyl)quinolin-2(lH)- one
  • Step 4 2-Chloro-7,8-difluoro-4-((2-isopropyl-3,4-dihydroquinolin-l(2H)- yl)methyl)quinoline
  • Step 5 7,8-Difluoro-4-((2-isopropyl-3,4-dihydroquinolin-l(2H)- yl)methyl)quinolin-2(lH)-one
  • Step 6 7,8-Difluoro-4-(2-isopropylpyrazolo[l,5-a]pyridine-3-carbonyl)quinolin- 2(lH)-one
  • Step 7 7,8-Difluoro-4-((2-isopropylpyrazolo[l,5-a]pyridin-3-yl)methyl)quinolin- 2(lH)-one
  • Step 2 (7,8-Difluoro-2-methoxyquinolin-4-yl)(2-isopropylbenzofuran-3-yl)methanone
  • AICI 3 (350 mg, 2.63 mmol) was added dropwise to a solution of 7,8- difluoro-2-methoxyquinoline-4-carbonyl chloride (INTERMEDIATE 3, 260 mg, 1.01 mmol) and 2-isopropylbenzofuran (160 mg, 1.00 mmol, 1.00 equiv) in DCM (25 mL) cooled to -78°C. . The mixture was stirred for 30 min at -78°C, then warmed up to - 10 0 C and stirred for another 2h. The mixture was then quenched by adding 10 mL of HCl (2N) and diluted with 150 mL of EtOAc.
  • Step 5 4-((6-Cyclobutyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)methyl)-7,8-difluoroquinolin- 2(lH)-one
  • Stepl 1 -Cyclobutyl-2-(pyridin-2-yl)ethanone
  • Step 3 4-((2-Cyclobutylpyrazolo[ 1 ,5-a]pyridin-3-yl)methyl)-7,8-difluoroquinolin- 2(lH)-one
  • Step 5 (2-Cyclobutyl-8-methylimidazo[ 1 ,2-b]pyridazin-3-yl)(7,8-difluoro-2- methoxyquinolin-4-yl)methanol
  • n-BuLi (2M, 0.5 mL) was slowly added to a solution of 3-bromo-2- cyclobutyl-8-methylimidazo[l,2-b]pyridazine (150 mg, 0.57 mmol) in THF (20 mL) cooled -78°C.
  • the resulting solution was stirred at -78°C for 0.5h followed by addition of 7,8-difluoro-2-methoxyquinoline-4-carbaldehyde (INTERMEDIATE 5, 120 mg, 0.54 mmol).
  • the resulting solution was stirred at -78°C for another 2h.
  • Step 6 4-((2-Cyclobutyl-8-methylimidazo[ 1 ,2-b]pyridazin-3-yl)methyl)-7,8-difluoro- 2-methoxyquinoline
  • Step 7 4-((2-Cyclobutyl-8-methylimidazo[ 1 ,2-b]pyridazin-3-yl)methyl)-7,8- difluoroquinolin-2( 1 H)-one
  • Step 1 l,2,4-Triazin-3-amine
  • Step 2 6-Cyclobutylimidazo[ 1 ,2-b] [ 1 ,2,4]triazine
  • Step 3 7-Bromo-6-cyclobutylimidazo[ 1 ,2-b] [ 1 ,2,4]triazine
  • Step 4 (6-Cyclobutylimidazo[l,2-b][l,2,4]triazin-7-yl)(7,8-difluoro-2- methoxyquinolin-4-yl)methanol
  • Step 5 4-((6-Cyclobutylimidazo[l,2-b][l,2,4]triazin-7-yl)methyl)-7,8- difluoroquinolin-2( 1 H)-one
  • Step 1 6-Chloropyridazin-3 -amine Attorney Docket No. KO 152-401 -PC
  • Step 2 6-Chloro-2-cyclobutylimidazo[ 1 ,2-b]pyridazine
  • 6-Chloro-2-cyclobutylimidazo[l,2-b]pyridazine was synthesized as described in EXAMPLE 12, Step 3 using 2-bromo-l-cyclobutylethanone (obtained by brominating 1-cyclobutylethanone with Br 2 ) and 6-chloropyridazin-3 -amine as starting materials.
  • Step 4 3-Bromo-2-cyclobutylimidazo[ 1 ,2-b]pyridazine
  • Step 5 4-((2-Cyclobutylimidazo[ 1 ,2-b]pyridazin-3-yl)methyl)-7,8-difluoroquinolin- 2(lH)-one
  • Step 1 7-bromo-6-cyclobutyl-5H-pyrrolo[2,3-b]pyrazine
  • Step 2 4-((7-bromo-6-cyclobutyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)methyl)-7,8- difluoroquinolin-2( 1 H)-one
  • Step 2 4-((6-Cyclobutyl-7-methyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)methyl)-7,8- difluoroquinolin-2( 1 H)-one
  • Step 2 4-((2-Cyclobutyl-lH-imidazo[4,5-b]pyridin-l-yl)methyl)-7,8-difluoroquinolin- 2(lH)-one
  • 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. Sci. 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 (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
  • 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 Attorney Docket No. KO 152-401 -PC
  • 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.
  • DAN 2,3-diaminonaphthalene
  • 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.
  • 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. 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.
  • nitrate or nitrite level may be determined 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. In certain instances two regioisomers correspond to a single example #, whereby the example # is given in Table 1 with two hiNOS activity values respectively.
  • Liver microsomes are subcellular fractions that contain drug-metabolizing enzymes including the cytochrome P450s (CYPs), flavin monooxygenases and UDP glucuronyl transferases. These enzymes require exogenous cofactors for activity in this test system.
  • the co-factors used consist of an NADPH regenerating system (supporting Phase I oxidation) and UDP-GA (supporting Phase II glucuronidation).
  • the following protocol, employing murine liver microsomes may be used to determine the in vitro metabolic stability of compounds in terms of half life. Preparation:
  • Potassium phosphate buffer at pH 7.4 (incubation buffer) was prepared from 110 mL IM KPO 4 monobasic and 390 mL of IM KPO 4 dibasic (500 mL total volume), which was diluted with water to 100 mM prior to addition ofl mM EDTA, 3 mM MgCl 2 and 1.25 mM D-saccharic acid 1,4-lactone monohydrate. May be stored for up to one month at 4°C.
  • Incubation buffer was prepared from 110 mL IM KPO 4 monobasic and 390 mL of IM KPO 4 dibasic (500 mL total volume), which was diluted with water to 100 mM prior to addition ofl mM EDTA, 3 mM MgCl 2 and 1.25 mM D-saccharic acid 1,4-lactone monohydrate. May be stored for up to one month at 4°C.
  • Incubation buffer was prepared from 110 mL IM KPO 4 monobasic and 3
  • Liver microsomes male CD-I mouse liver microsomes from, e.g., BD Gentest, Woburn, MA; may be stored at -70 0 C until use) at a concentration of 20 mg/mL were diluted to 5 mg/mL in incubation buffer in a separate tube.
  • a NADPH-generating system was prepared by combining one aliquot each of the following premade ingredients:
  • test articles were 5 ⁇ M, and final concentration of DMSO solvent in the incubation were 0.4% (v/v).
  • Metabolic stability was determined based on disappearance half-life. The percent (%) test article remaining was determined at each incubation time-point, relative to the zero-time sample. These results were transformed by natural log, such that first-order decline of substrate concentrations with time produced a straight line. This line was fit with a standard linear regression algorithm, and the slope determined. If data points suggested higher order elimination kinetics (non linear), then the earliest data points were used for slope calculation. Disappearance half-life in minutes (Ty 2 ) was calculated by multiplying the inverse of this slope by the natural log of 2 ⁇ In ⁇ ). All data analysis was performed with Microsoft Excel (ver 2007). Results are reported Attorney Docket No. KO 152-401 -PC
  • Inhibition of induction of iNOS can be quantified via the LPS challenge. Inflammation, edema, and the onset of sepsis can be observed following an injection of lipopolysaccharide (LPS), a substance produced by Gram-negative bacteria. Injection of LPS has been shown to induce iNOS transcription, leading to measureable increases in both iNOS and NO.
  • LPS lipopolysaccharide
  • the level of nitric oxide in the specimen can be quantified by correlation with plasma nitrate or nitrite levels via chemiluminescence, fluorescence, spectophotometric assays, or by any method known in the art which provides adequate sensitivity and reproducibility, including those described above.
  • Rats Male Lewis rats weighing 150-250 g are often used in the studies. Rats may be fasted for up to 16 hours prior to the administration of LPS. Free access to water is maintained. Test compounds are administered with LPS or alone. Compounds are dissolved in the vehicle of 0.5% methycele/0.025% Tween 20 or 20% encapsin for oral administration. For the intravenous dosing, compounds are dissolved in saline or 0.5-3%DMSO/20% encapsin. Compounds may also be dissolved in 10% stock solution of 90% PGE-400, 5% Tween 80, 5%PVP + 90% CMC. The dosing volumes are 1-2 ml for oral and 0.3-1 ml for intravenous administration.
  • LPS is injected intravenously (under anesthesia) or intraperitoneally in sterile 0.9% saline (sodium chloride ) at a dose between 0.1-10 mg/kg in a volume not excess to 1 ml.
  • the needle is 26-30 gauge.
  • rats usually exhibit flu-like symptoms, principally involving lack of activity and diarrhea.
  • rats are sacrificed 1.5-6 hr after LPS injection and a terminal bleeding is performed under anesthesia to collect 1-3 ml blood samples and then animals are then euthanized by CO 2 .
  • mice instead of rats was adapted from the methods disclosed above, adjusting for species and weight differences, for example, using Attorney Docket No. KO 152-401 -PC
  • Compound 9 was administered at 30 mpk, and yielded 41% inhibition of NO production versus control.

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Abstract

L'invention porte sur de nouveaux composés représentés par la formule (II) et sur des compositions pharmaceutiques correspondantes dont il a été constaté qu'ils inhibent la NOS synthase inductible. Dans la formule (II) R4, R5, R6 et R7 sont choisis indépendamment dans le groupe constitué par hydrogène, alkyle inférieur et halogène; et R8 a une structure dans laquelle X1, X2, X3, X4, X6, R9, R13, R14 et n sont tels que décrits présentement.
PCT/US2008/074334 2007-08-27 2008-08-26 4-[hétérocyclylméthyl]-8-fluoro-quinolin-2-ones utiles comme inhibiteurs de l'oxyde nitrique synthase Ceased WO2009029625A1 (fr)

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