EP1797100A1 - Esters de nitrate et leur utilisation pour limiter les dommages cellulaires - Google Patents

Esters de nitrate et leur utilisation pour limiter les dommages cellulaires

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Publication number
EP1797100A1
EP1797100A1 EP05787832A EP05787832A EP1797100A1 EP 1797100 A1 EP1797100 A1 EP 1797100A1 EP 05787832 A EP05787832 A EP 05787832A EP 05787832 A EP05787832 A EP 05787832A EP 1797100 A1 EP1797100 A1 EP 1797100A1
Authority
EP
European Patent Office
Prior art keywords
unsubstituted
substituted
group
nitrate
nhr
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP05787832A
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German (de)
English (en)
Other versions
EP1797100A4 (fr
Inventor
Gregory R. J. Thatcher
Brian M. Bennett
James N. Reynolds
Roland J. Boegman
Khem Jhamandas
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Queens University at Kingston
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Queens University at Kingston
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Publication date
Priority claimed from US10/943,264 external-priority patent/US20050137191A1/en
Application filed by Queens University at Kingston filed Critical Queens University at Kingston
Publication of EP1797100A1 publication Critical patent/EP1797100A1/fr
Publication of EP1797100A4 publication Critical patent/EP1797100A4/fr
Pending legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/66—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/32—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/56—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
    • C07D339/02—Five-membered rings
    • C07D339/04—Five-membered rings having the hetero atoms in positions 1 and 2, e.g. lipoic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
    • C07D339/08—Six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—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 only aliphatic carbon atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/10—Spiro-condensed systems

Definitions

  • This invention relates to nitrate esters and use thereof in mitigating cellular damage. Particularly, this invention relates to selected organic nitrates, most particularly those bearing a sulfur or phosphorus atom ⁇ or ⁇ to the nitrate group, having therapeutic utility as agents that protect tissues from oxidative injury.
  • nitrate ester glyceryl trinitrate (GTN) or nitroglycerin, has been used as a vasodilator in the treatment of angina pectoris for over a hundred years, and the dominant contemporary belief is that GTN exerts its therapeutic effect through in vivo release of nitric oxide (NO).
  • NO nitric oxide
  • Other organic nitrates such as isosorbide dinitrate, have also been identified as effective and clinically important vasodilators.
  • NO itself has been identified as Endothelium Derived Relaxing Factor (EDRF) and several classes of compounds, for example nitrosothiols, in addition to organic nitrates, have been proposed as NO donors or NO prodrugs.
  • EDRF Endothelium Derived Relaxing Factor
  • GT ⁇ is firstly a potent vasodilator and secondly possesses potential neuroprotective properties.
  • GT ⁇ has been found to suppress renal oxidant damage caused by potassium bromate (Rahman et al., Redox Rep. 4: 263-9, 1999).
  • nitrate esters having the formula
  • each of m and n is, independently, an integer from O to 10; each of R , R , R , 17 is, independently, hydrogen, a nitrate group, or A;
  • R 1 is hydrogen or A; where A is selected from: a substituted or unsubstituted aliphatic group having from 1 to 24 carbon atoms in the chain, which optionally contains 1 to 4 O, S, NR 6 , and/or unsaturations in the chain, optionally bearing from 1 to 4 hydroxy, nitrate, amino, aryl, or heterocyclic groups; an unsubstituted or substituted cyclic aliphatic moiety having from 3 to 7 carbon atoms in the aliphatic ring, which optionally contains 1 to 2 O, S, NR 6 , and/or unsaturations in the ring, optionally bearing from 1 to 4 hydroxy, nitrate, amino, aryl, or heterocyclic groups; an unsubstituted or substituted aliphatic moiety comprising a linkage from 0 to 5 carbon atoms between R 1 and R 3 and/or between R 17 and R 4 , which optionally contains 1 to 2 O, S, NR 6 , and/or uns
  • M is H, Na + , K + , NH 4 + , or N + H k R 1 ' ⁇ 4-k) where k is 0 to 3;
  • one of m, n, or p must be equal to at least one.
  • the compound of the invention is:
  • G 1 is Me, OMe, Cl, NO 2 , Br, or H;
  • G 2 is CO 2 Et,
  • the compound is:
  • the compound is:
  • n 2 or 3.
  • the compound is:
  • the compound is:
  • the compound is:
  • the invention features a compound having the formula:
  • nitrate groups containing from 1 to 3 nitrate groups and an S atom in proximity to a nitrate group, wherein each of m and n is, independently, an integer from O to 10;
  • R 1 is a hydrogen or A
  • each of R »2 , n R5 , and R , 18 is, independently, hydrogen or A
  • each of R 3 , R 4 , and R 17 is independently, a hydrogen, a nitrate group, or
  • each of R 6 , R 7 , R 8 , R 9 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 is, independently, A, a hydrogen, a nitrate group, or a C 1 -C 24 alkyl or acyl group, optionally containing 1-4 ONO 2 substituents or a CpC 6 linkage to R 1 , R 2 , R 3 , or R 4 in cyclic derivatives; each of R 7 and R 11 is, independently, a substituted or unsubstituted C 1 - Cg alkyl or acyl group;
  • each of R 18 and R 3 is, independently, a hydrogen, a nitrate group, or a C 1 -C 4 alkyl chain, which may include one O, linking R 18 and R 3 together to form a pentosyl, a hexosyl, a cyclopentyl, or a cyclohexyl ring, said ring optionally bearing from 1-4 hydroxyl substituents; each of R 17 and R 4 is, independently, a hydrogen, a nitrate group, a C 1 - C 4 alkyl group, optionally bearing from 1-3 nitrate groups, or an acyl group (- C(O)R 5 ); each of R 5 , R 6 , R 8 , R 9 ,
  • the compound is:
  • the compound is:
  • the compound is:
  • the compound is:
  • the compound is:
  • the compound is:
  • the invention features a compound having the formula:
  • the invention features a composition that includes a pharmaceutically acceptable carrier and a compound having the general formula:
  • each of m and n is, independently, an integer from O to 10;
  • R 1 is a hydrogen or A;
  • 2 , r R> 5 , and R , 18 is, independently, hydrogen or A;
  • each of R » 3 , ⁇ R4 , and R , 17 is independently, a hydrogen, a nitrate group, or
  • each of R 6 , R 7 , R 8 , R 9 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 is, independently, A, a hydrogen, a nitrate group, or a C 1 -C 24 alkyl or acyl group, optionally containing 1-4 ONO 2 substituents or a C 1 -C 6 linkage to R 1 , R 2 , R 3 , or R 4 in cyclic derivatives; each of R 7 and R 11 is, independently, a substituted or unsubstituted Q- C 8 alkyl or acyl group;
  • each of R 18 and R 3 is, independently, a hydrogen, a nitrate group, or a C 1 -C 4 alkyl chain, which may include one O, linking R 18 and R 3 together to form a pentosyl, a hexosyl, a cyclopentyl, or a cyclohexyl ring, said ring optionally bearing from 1-4 hydroxyl substituents; each of R 17 and R 4 is, independently, a hydrogen, a nitrate group, a Q- C 4 alkyl group, optionally bearing from 1-3 nitrate groups, or an acyl group (- C(O)R 5 ); each of R 5 , R 6 , R 8 , R 9
  • the invention features a composition that includes a pharmaceutically acceptable carrier and one of the following compounds:
  • the invention features a method for preventing or mitigating tissue and/or cellular damage in a subject by modulating intercellular and/or intracellular free radical concentration in the subject by administering to the subject an effective amount of a compound containing at least one aliphatic nitrate group and at least one sulfur atom in proximity to the nitrate group.
  • sulfur atom in proximity or "proximal functional group” is meant a sulfur atom or functional group that is connected through bonds in a ⁇ , ⁇ , or ⁇ relationship to a nitrate ester group (i.e., the atom connectivity is 1,2, or 1,3, or 1,4).
  • the functional group may also be referred to as "proximally located” or “situated in proximity.”
  • Proximal functional groups also include those groups that have a through-space intramolecular juxtaposition with a nitrate group that is within 3 A.
  • the tissue and/or cellular damage can be associated with aging, septic shock, ischemia/reperfusion injury, ulcers, gastritis, ulcerative colitis, Crohn's disease, diabetes, rheumatoid arthritis, asthma, cirrhosis of the liver, allograft rejection, encephalomyelitis, meningitis, pancreatitis, peritonitis, vasculitis, lymphocytic choriomeningitis, glomerulonephritis, uveitis, glaucoma, blepharitis, chalazion, allergic eye disease, corneal ulcer, keratitis, cataracts, age-related macular degeneration, optic neuritis, ileitis, hemorrhagic shock, anaphylactic shock, bacterial infection, viral infection, fungal infection, parasitic infection, hemodialysis, chronic fatigue syndrome, stroke, toxic shock syndrome, adult respiratory distress syndrome, cachexia, myocarditis, ecze
  • the tissue and/or cellular damage can associated with neurological diseases such as, for example, Parkinson's disease; Alzheimer's disease; Huntington's disease; multiple sclerosis; amyotrophic lateral sclerosis; AIDS-induced dementia; epilepsy; alcoholism; alcohol withdrawal; drug-induced seizures; viral/bacterial/fever-induced seizures; trauma to the head; hypoglycemia; hypoxia due to myocardial infarction; cerebral vascular occlusion; cerebral vascular hemorrhage; hemorrhage; or environmental excitotoxins of plant, animal, or marine origin.
  • neurological diseases such as, for example, Parkinson's disease; Alzheimer's disease; Huntington's disease; multiple sclerosis; amyotrophic lateral sclerosis; AIDS-induced dementia; epilepsy; alcoholism; alcohol withdrawal; drug-induced seizures; viral/bacterial/fever-induced seizures; trauma to the head; hypoglycemia; hypoxia due to myocardial infarction; cerebral vascular occlusion; cerebral vascular hemor
  • tissue and/or cellular damage can be associated with cytokine therapy, wherein a nitrate ester of the invention is administered to the subject before, during, and/or after the administration of the therapeutic cytokine.
  • the compound has the formula:
  • n is an integer from 0 to 10; each of R 3>4>17 is, independently, hydrogen, a nitrate group, or A;
  • R 1 is hydrogen or A
  • A is selected from: a substituted or unsubstituted C 1 -C 24 alkyl group, optionally containing 1 to 4 O, S, NR 6 , and/or unsaturations in the chain, optionally bearing from 1 to 4 hydroxy, nitrate, Cl, F, amino or unsubstituted or substituted aryl, or unsubstituted or substituted heterocyclic groups; an unsubstituted or substituted cyclic moiety having from 3 to 7 carbon atoms in the ring, which optionally containing 1 to 2 O, S, NR 6 , and/or unsaturations in the ring, optionally bearing from 1 to 4 hydroxy, nitrate, Cl, F, amino or unsubstituted or substituted aryl, or unsubstituted or substituted heterocyclic groups; an unsubstituted or substituted moiety constituting a linkage from 0 to 5 carbons, to or between any of R 1 , R 3 , R 17 and R 4 ,
  • R 2 , R 5 , R 18 are optionally hydrogen, A, or X-Y;
  • each of R 6 , R 7 , R 8 , R 9 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 is, independently, a C 1 -C 24 alkyl group, optionally containing 1-4 ONO 2 substituents, a C 1 -C 24 acyl group, optionally containing 1-4 ONO 2 substituents, a CpC 6 ring-forming connection to any of R ! -R 4 , a hydrogen, a nitrate group, or A; and
  • M is H, Na + , K + , NH 4 + , N + H k R 1 ⁇ 4 . k) where k is 0-3;
  • the compound contains at least 2 nitrate groups.
  • the nitrate is beta or gamma to said sulfur atom.
  • the compound in another embodiment, can be any of the compounds that were cited individually as an embodiment of either the first or second aspect of the invention.
  • the compound is:
  • the compound is:
  • alkyl and the prefix “alk-” are inclusive of both straight chain and branched chain saturated or unsaturated groups, and of cyclic groups, i.e., cycloalkyl and cycloalkenyl groups.
  • acyclic alkyl groups are from 1 to 6 carbons and contain at least one C-H bond.
  • the number of carbons in an alkyl group refers to the total number of carbons contained in the group.
  • Cyclic groups can be monocyclic or polycyclic and preferably have from 3 to 8 ring carbon atoms.
  • Exemplary cyclic groups include cyclopropyl, cyclopentyl, cyclohexyl, and adamantyl groups.
  • alkyl groups may be substituted or unsubstituted.
  • substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen, hydroxyl, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups.
  • aryl is meant a carbocyclic aromatic ring or ring system. Unless otherwise specified, aryl groups are from 6 to 18 carbons. . Examples of aryl groups include phenyl, naphthyl, biphenyl, fluorenyl, and indenyl groups.
  • heterocycle is meant an aromatic or non-aromatic ring system that contains at least one ring heteroatom (e.g., O, S, N).
  • heteroaryl refers to an aromatic heterocyclic ring or ring system that contains at least one ring heteroatom (e.g., O, S, N). Unless otherwise specified, heteroaryl rings contain from 1 to 9 carbons.
  • heteroaryl groups include furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, oxatriazolyl, pyridyl, pyridazyl, pyrimidyl, pyrazyl, triazyl, benzofuranyl, isobenzofuranyl, benzothienyl, indole, indazolyl, indolizinyl, benzisoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, naphtyridinyl, phthalazinyl, phenanthrolinyl, purinyl, and carbazolyl rings or ring systems.
  • non-aromatic heterocyclic groups are from 2 to 9 carbons and can include, for example, dihydropyrrolyl, tetrahydropyrrolyl, piperazinyl, pyranyl, dihydropyranyl, tetrahydropyranyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothiophene, tetrahydrothiophene, and morpholinyl groups.
  • heterocycle specifically excludes ⁇ -lactam rings.
  • aryl, heteroaryl, or heterocyclic groups may be unsubstituted or substituted by one or more substituents selected from the group consisting Of Ci -6 alkyl, hydroxy, halo, nitro, C 1-6 alkoxy, Ci -6 alkylthio, trifluoromethyl, C 1-6 acyl, arylcarbonyl, heteroarylcarbonyl, nitrile, C 1-6 alkoxycarbonyl, arylalkyl (wherein the alkyl group has from 1 to 6 carbon atoms) and heteroarylalkyl (wherein the alkyl group has from 1 to 6 carbon atoms).
  • halide or “halogen” or “halo” is meant bromine, chlorine, iodine, or fluorine.
  • alkyl and the prefix “alk-” are inclusive of both straight chain and branched chain saturated or unsaturated groups, and of cyclic groups, i.e., cycloalkyl and cycloalkenyl groups. Unless otherwise specified, acyclic alkyl groups are from 1 to 6 carbons. Cyclic groups can be monocyclic or polycyclic and preferably have from 3 to 8 ring carbon atoms. Exemplary cyclic groups include cyclopropyl, cyclopentyl, cyclohexyl, and adamantyl groups.
  • Alkyl groups may be substituted or unsubstituted.
  • substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen, hydroxyl, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups.
  • alkoxy is meant a chemical substituent of the formula -OR, where R is an alkyl group.
  • aryloxy is meant a chemical substituent of the formula -OR', where R' is an aryl group.
  • alkaryl is meant a chemical substituent of the formula -RR', where R is an alkyl group and R' is an aryl group,
  • alkheteraryl is meant a chemical substituent of the formula RR", where R is an alkyl group and R" is a heteroaryl group.
  • aliphatic nitrate is a nitrate group that is connected to a non-aromatic carbon.
  • antioxidant is a compound that attenuates or prevents oxidation of a target biomolecule through the inhibition of the initiation or propagation steps that constitute oxidative and peroxidative processes.
  • “Mitigating neurodegeneration” as used herein involves affecting neuroprotection, inhibiting or preventing neurodegeneration, and/or ameliorating the manifestations or impact of neurodegeneration. Such amelioration includes effecting cognition enhancement, as is quantified by tests known in the art (e.g., Venault et al., 1992, incorporated herein by reference).
  • “Modulating” a biological process as used herein encompasses both increasing (positively modulating) and decreasing (negatively modulating) such activity, and thus inhibition, potentiation, agonism, and antagonism of the biological process.
  • Compounds may be constructed according to formulas of the invention in which an S atom is appropriately proximally placed with respect to a nitrate functional group, but in which a carbonyl group intervenes to form a thioester linkage. Such compounds do not form part of the invention if cleavage of this thioester bond produces two entirely separate molecules, one containing the nitrate funtionality, and another the S-functionality.
  • An example of such a compound is one containing the motif, O 2 NOCH 2 C(CH 3 ) 2 C(O)S-(organic radical), which would liberate on thioester cleavage an aliphatic nitrate that does not contain a S-functionality.
  • Figure 1 is a synthetic scheme showing the use of Bunte salt IVd in the preparation of compounds Va, IVr, Vbb, and Vbc.
  • Figure 6 is a graph showing a comparison of 50 ⁇ M GTN (stippled bars) and 50 ⁇ M Va (hatched bars) on coronary perfusion pressure in isolated perfused rat heart after left coronary artery occlusion (LCAO) for 45 min followed by reperfusion for 90 min.
  • Hearts were perfused with drugs for ten min prior to and throughout the period of LCAO.
  • Figure 7 is an immunocytochemical analysis of tyrosine hydroxylase immunoreactivity in the substantia nigra of rats.
  • Figure 7 A is an analysis of a brain section in which the animal was administered the neurotoxic compound 6- hydroxydopamine (6-OHDA).
  • Figure 7B is an analysis of a brain section in which the animal was administered only vehicle control (dimethyl sulfoxide).
  • Figure 7C is an analysis of a brain section in which the animal was treated with compound Va before and after administration of 6-OHDA.
  • Figure 7D is an analysis of a brain section in which the animal was administered only vehicle control.
  • Va varied
  • ImM cysteine
  • Va + PhSH Va + PhSH (1 mM)
  • This invention pertains to methods and compositions useful for treating neurodegeneration or preventing or mitigating tissue and/or cellular damage by administering to a subject a therapeutic nitrate ester.
  • Neuroprotection and/or cognition enhancement can be affected, for example, by modulating an interaction with guanylyl cyclase (GCase, the enzyme responsible for cGMP production in various areas of the brain), modulating a glutamate or non- glutamate neuroreceptor or attenuating free radical damage.
  • GCase guanylyl cyclase
  • the attenuation of free radical concentration by a nitrate ester of the invention can also be useful for preventing or mitigating tissue and/or cellular damage.
  • neurodegeneration is mitigated by stimulating cerebral GCase.
  • One of the major targets for the novel organic nitrates of the invention is GCase activation, resulting in the production of cGMP.
  • Experimental evidence obtained in a number of in vitro model systems supports the notion that elevated levels of cGMP help to prevent apoptotic (programmed) cell death.
  • a cGMP-dependent mechanism significantly increases the survival of trophic factor-deprived PC 12 cells and rat sympathetic neurons (Farinelli et al., 1996), and of primary cultures of rat embryonic motor neurons (Estevez et al., 1998).
  • the mechanism of action for selected organic nitrates in preventing apoptotic cell death may be inhibition of caspase-3 activation indirectly through elevations in cGMP levels or directly via protein S-nitrosylation of the enzyme by an NO-intermediate (Kim et al., 1997).
  • Caspase-3 is a member of the cysteine protease family of enzymes that are essential for the execution step in apoptosis (Cohen, 1997; Nicholson and Thornberry, 1997).
  • caspase-3 Activation of caspase-3 is required for apoptotic cell death in trophic factor-deprived PC 12 cells (Haviv et al., 1997) and in glutamate- mediated apoptotic cell death of cultured cerebellar granule neurons (Du et al., 1997).
  • caspase-3 activity is induced and may be responsible for the apoptotic component of delayed neuronal cell death (Chen et al., 1998; Namura et al., 1998; Ni et al., 1998).
  • Inhibitors of caspase-3 significantly decrease the apoptotic component of delayed neuronal cell death in response to ischemic injury both in vitro (Gottron et al., 1997) and in vivo (Endres et al., 1998).
  • a secreted region of the Alzheimer's disease ⁇ -amyloid precursor protein lowers intracellular calcium levels and provides neuroprotective effects on target cells through increases in cGMP levels and activation of protein kinase G (Barger et al., 1995; Furukawa et al., 1996).
  • nitrated molecules that have the capacity to activate GCase directly or via release of an NO-containing intermediate are used to modulate GCase activity.
  • cognition enhancement is achieved by stimulating cerebral GCase.
  • GCase and cGMP are involved in the formation and retention of new information.
  • cGMP has been directly implicated in both long-term potentiation (LTP) and long-term depression (LTD), which are proposed cellular models for learning and memory (Arancio et al., 1995; Wu et al., 1998).
  • LTP long-term potentiation
  • LTD long-term depression
  • elevation of hippocampal cGMP levels leading to increased protein kinase G activity has been shown to be important for retention and consolidation of new learning (Bernabeu et al., 1996, 1997).
  • stimulation of cerebral GCase activity is expected to improve learning and memory performance in individuals in whom cognitive abilities are impaired by injury, disease, or aging.
  • Cerebral ischemia results in marked increases in the release of the excitatory amino acid glutamate in the affected brain region (Bullock et al., 1998; Huang et al., 1998; Yang et al., 1998).
  • the amount of glutamate released during ischemia is positively correlated with the extent of brain injury.
  • these selected organic nitrates can be used for treatment of conditions including but not limited to: stroke; Parkinson's disease; Alzheimer's disease; Huntingdon's disease; multiple sclerosis; amyotrophic lateral sclerosis; AIDS-induced dementia; epilepsy; alcoholism; alcohol withdrawal; drug-induced seizures; viral/bacterial/fever-induced seizures; trauma to the head; hypoglycemia; hypoxia; myocardial infarction; cerebral vascular occlusion; cerebral vascular hemorrhage; hemorrhage; environmental excitotoxins of plant, animal, or marine origin; and the like.
  • selected organic nitrates developed to act as modulators of GABA A receptor function, will be to improve memory performance and cognition in patient populations. It will be appreciated, therefore, that these selected organic nitrates can be used for treatment of conditions including but not limited to: stroke; dementias of all type; trauma; drug-induced brain damage; and aging.
  • neurodegeneration is mitigated by inhibition of free radical damage.
  • Reoxygenation and reperfusion after a period of ischemia contributes significantly to the development of brain injury.
  • Oxygen radicals, especially superoxide and peroxynitrite, formed in the period after an ischemic event may initiate processes such as breakdown of membrane lipids (lipid peroxidation), leading to loss of cell membrane integrity and inhibition of mitochondrial function (Macdonald and Stoodley, 1998; Gaetani et al, 1998).
  • Oxidative stress is also believed to be one factor involved in initiation of apoptotic neuronal cell death (Tagami et al., 1998).
  • 6-OHDA is a neurotoxin selectively taken up into dopaminergic neurons, resulting in a selective killing of these neurons, via a mechanism involving oxidative stress that is evident by 4 days after injection of the toxin.
  • MAO-B monoamine oxidase type B
  • deprenyl can prevent 6-OHDA-induced killing of dopaminergic neurons.
  • deprenyl as a positive control in this study.
  • Loss of dopaminergic innervation to the striatum results in an upregulation of postsynaptic dopamine receptors, and the development of dopamine receptor supersensitivity 2-3 weeks after 6-OHDA lesioning of the substantia nigra.
  • the invention features nitrated molecules which have the capacity to inhibit production of free radicals and/or which act as free radical scavengers.
  • Free radical overproduction is associated with a wide range of disease states and/or indications, such as, for example, aging, septic shock, ischemia, overexpression of cytokines, ulcers, inflammatory bowel disease (e.g., gastritis, ulcerative colitis or Crohn's disease), diabetes, arthritis (e.g., rheumatoid arthritis), asthma, cirrhosis, allograft rejection (e.g., transplant rejection), encephalomyelitis, meningitis, pancreatitis, peritonitis, vasculitis, lymphocytic choriomeningitis, glomerulonephritis, ophthalmologic diseases (e.g., uveitis, glaucoma, blepharitis, chalazion, allergic eye disease, corneal ulcer, keratitis, cataract, retinal disorders, age-related macular degeneration, optic neuritis, and the like), ileitis, inflammation induced by overproduction
  • coli infection e.g., HIV
  • fungal e.g., Candidiosis and histoplasmosis
  • parasitic e.g., Leishmaniasis and Schistosomiasis
  • hemodialysis chronic fatigue syndrome, stroke, cancers, including metastatic cancers (e.g., breast cancer, bladder cancer, lung cancer, colon cancer, or cancer of the other organs, or skin or other noncutaneous portions of the body), cardiovascular diseases associated with overproduction of inflammatory cytokines (e.g., heart disease, cardiopulmonary bypass, ischemic/reperfusion injury, and the like), ischemic/reperfusion associated with overproduction of inflammatory cytokines, toxic shock syndrome, adult respiratory distress syndrome, cachexia, myocarditis, autoimmune disorders, eczema, psoriasis, heart failure, dermatitis, urticaria, cerebral ischemia, systemic lupus erythematosis, AIDS, neurodegenerative disorders (e.g., chronic cyto
  • the compounds or methods of the present invention may find use in cytokine therapy (with consequent induction of free radical overproduction) which, for example, is commonly used in the treatment of cancers, including metastatic cancers (e.g., breast cancer, bladder cancer, lung cancer, colon cancer, or cancer of the other organs, or skin or other noncutaneous portions of the body), autoimmune disease, and in AIDS patients.
  • cytokine therapy with consequent induction of free radical overproduction
  • cancers including metastatic cancers (e.g., breast cancer, bladder cancer, lung cancer, colon cancer, or cancer of the other organs, or skin or other noncutaneous portions of the body), autoimmune disease, and in AIDS patients.
  • Systemic hypotension due to the induction of free radical overproduction is a dose-limiting side effect of cytokine therapy.
  • a large patient population exists which will benefit from the invention methods.
  • any organic nitrate in which vasodilatory potency is reduced and neuroprotective potency increased represents a new and useful therapeutic agent for use in neuroprotection, particularly in treatment of conditions including but not limited to: stroke; Parkinson's disease; Alzheimer's disease; Huntington's disease; multiple sclerosis; amylotrophic lateral sclerosis; AIDS-induced dementia; epilepsy; alcoholism; alcohol withdrawal; drug-induced seizures; viral/bacterial/fever- induced seizures; trauma to the head; hypoglycemia; hypoxia; myocardial infarction; cerebral vascular occlusion; cerebral vascular hemorrhage; hemorrhage; environmental excitotoxins of plant, animal, or marine origin.
  • GTN itself, proposed as a neuroprotective agent, has no clinical utility as a neuroprotective agent in therapy owing to its extraordinarily high vasodilatory potency.
  • GTN 1,2,3-trinitratopropane
  • cognition enhancement represents a new and useful treatment for cognition enhancement, particularly in treatment of conditions including but not limited to: stroke; dementias of all type, trauma, drug-induced brain damage, and aging.
  • the therapeutic compounds of the invention comprise at least one nitrate group.
  • the nitrate groups(s) can optionally be covalently bound to a carrier moiety or molecule (e.g., an aromatic group, an aliphatic group, peptide, steroid, nucleoside, peptidomimetic, steroidomimetic, or nucleoside analogue, or the like).
  • a carrier moiety or molecule e.g., an aromatic group, an aliphatic group, peptide, steroid, nucleoside, peptidomimetic, steroidomimetic, or nucleoside analogue, or the like.
  • the carrier moiety or molecule can enable the compound to traverse biological membranes and to be biodistributed preferentially, without excessive or premature metabolism.
  • the carrier moiety or molecule can enable the compound to exert amplified neuroprotective effects and/or cognition enhancement through synergism with the nitrate functionality.
  • the invention provides a method of treating a neurological condition and/or preventing an undesirable mental condition (e.g., memory loss) including the step of administering to a subject an effective amount of a therapeutic compound capable of mitigating neurodegeneration which has at least one nitrate group.
  • a therapeutic compound capable of mitigating neurodegeneration which has at least one nitrate group.
  • the therapeutic compound is capable of effecting neuroprotection.
  • the therapeutic compound is capable of effecting cognition enhancement.
  • the therapeutic compound has the formula (Formula I):
  • E, F, G are organic radicals which may contain inorganic counterions; so that a neurological condition is treated.
  • the invention provides a pharmaceutical composition including a physiologically acceptable carrier and a compound having the formula (Formula I):
  • E, F, G are organic radicals which may contain inorganic counterions.
  • the composition is employed for mitigating neurodegeneration, effecting neuroprotection and /or effecting cognition enhancement.
  • the composition may also be employed for preventing or mitigating tissue and/or cellular damage in a subject by modulating intercellular and/or intracellular free radical concentration in the subject.
  • therapeutic compounds of the invention that effect neuroprotection and/or effect cognition enhancement in a subject to which the therapeutic compound is administered have the formula (Formula II):
  • compositions comprising a compound of Formula II in admixture with a pharmaceutically acceptable carrier therefor are provided by the invention.
  • the invention further provides methods of mitigating neurodegeneration, effecting neuroprotection and/or effecting cognition enhancement in a subject comprising the step of administering a compound of Formula II to a subject such that said mitigation and /or said neuroprotection an/or cognition enhancement occurs.
  • preferred therapeutic compounds for effecting neuroprotection and/or cognition enhancement in a subject to which the compound is administered include compounds in which R 19 is X-Y.
  • R 19 is X-Y and R 5 , R 6 , R 8 , R 9 , R 12 , R 13 , R 14 , R 15 , R 16 are the same or different alkyl groups containing 1-24 carbon atoms which may contain 1-4 ONO 2 substituents, or C 1 or C 2 connections to R 1 - R 3 in cyclic derivatives;
  • R 1 and R 3 are the same or different and selected from H, C r C 4) alkyl chains, which may inlude one O, linking R 1 and R 3 to form pentosyl, hexosyl, cyclopentyl, or cycohexyl rings, which rings optionally bear hydroxyl substituents;
  • R 2 and R 4 are the same or different and selected from H, a nitrate group, C
  • R 19 is X-Y
  • R 19 is X-Y
  • R 19 is X-Y
  • X and/or Y contains a sulfur-containing functional group.
  • the compound of the invention comprises a heterocyclic functionality, more preferably, a nucleoside or nucleobase.
  • the compound of the invention comprises a carbocyclic functionality, more preferably, a steroidal or carbohydrate moiety.
  • a therapeutic compound of the invention is represented by the formula (Formula III):
  • R 6 - R 9 and R 1 ' - R 16 are the same or different alkyl or acyl groups containing 1-24 carbon atoms which may contain 1-4 ONO 2 substituents, or C 1 - C6 connections to R 1 - R 4 in cyclic derivatives.
  • a therapeutic compound of the invention is represented by the formula III in which the compound contains from 1 to 3 nitrate groups and an S atom in proximity to a nitrate group, where each of m and n is, independently, an integer from 0 to 10; R 1 is a hydrogen or A; each of R 2 , R 5 , and R 18 is, independently, hydrogen or A; each of R 3 , R 4 , and R 17 , is independently, a hydrogen, a nitrate group, or A; each of R 6 , R 7 , R 8 , R 9 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 is, independently, A, a hydrogen, a nitrate group, or a C 1 -C 24 alkyl or acyl group, optionally containing 1-4 ONO 2 substituents or a C 1 -C 6 linkage to R 1 , R 2 ,
  • compositions comprising a compound of Formula III in admixture with a pharmaceutically acceptable carrier therefor are provided by the invention.
  • the invention further provides methods of mitigating neurodegeneration, effecting neuroprotection and/or effecting cognition enhancement in a subject comprising the step of administering a compound of Formula III to a subject such that said mitigation and /or said neuroprotection and/or cognition enhancement occurs.
  • a therapeutic compound of the invention can be represented by the formula (Formula IV):
  • R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , Rn, R 12 , Ri 3 , Rj 4 , Ri 5 , and Ri 6 are as defined above.
  • R 2 and R 4 are optionally H, a nitrate group or a connection to R 5 -R 9 and Ri i-Ri 6 in cyclic derivatives.
  • compositions comprising a compound of Formula IV in admixture with a pharmaceutically acceptable carrier therefor are provided by the invention.
  • the invention further provides methods of mitigating neurodegeneration, effecting neuroprotection and/or effecting cognition enhancement in a subject comprising the step of administering a compound of Formula IV to a subject such that said mitigation and /or said neuroprotection and/or cognition enhancement occurs.
  • a compound of the invention can be represented by the formula (Formula V):
  • R 2 is optionally H or a connection to R 5 in cyclic derivatives
  • R 4 is H or a nitrate group
  • R 5 is as described above.
  • compositions comprising a compound of Formula V in admixture with a pharmaceutically acceptable carrier therefor are provided by the invention.
  • the invention further provides methods of mitigating neurodegeneration, effecting neuroprotection and/or effecting cognition enhancement in a subject comprising the step of administering a compound of Formula V to a subject such that said mitigation and /or said neuroprotection and/or cognition enhancement occurs.
  • Examples and preferred embodiments of compounds of the invention according to formula V are as follows:
  • the invention features one of the following nitrate esters:
  • the invention features a method for preventing or mitigating tissue and/or cellular damage in a subject by modulating intercellular and/or intracellular free radical concentration in the subject.
  • the method includes administering to the subject an effective amount of a compound containing at least one aliphatic nitrate group and at least one sulfur atom in proximity to said nitrate, such as, for example, a compound of formula I.
  • the nitrate of this method contains at least 2 nitrate groups.
  • the nitrate is beta or gamma to a sulfur atom.
  • Yet another embodiment features compounds of formula III for preventing or mitigating tissue and/or cellular damage
  • m is an integer from O to 10;
  • n is an integer from O to 10;
  • each of R 3>4>17 is, independently, hydrogen, a nitrate group, or A;
  • R 1 is hydrogen or A, with A is selected from: a substituted or unsubstituted C 1 -C 24 alkyl group, optionally containing 1 to 4 O, S, NR 6 , and/or unsaturations in the chain, optionally bearing from 1 to 4 hydroxy, nitrate, Cl, F, amino or unsubstituted or substituted aryl, or unsubstituted or substituted heterocyclic groups; an unsubstituted or substituted cyclic moiety having from 3 to 7 carbon atoms in the ring, which optionally contains O, S, NR 6 , and/or unsaturations in the ring, optionally bearing from 1 to 4 hydroxy, nitrate, Cl
  • R 2 , R 5 , R 18 are optionally hydrogen, A, or X-Y;
  • each of R 6 , R 7 , R 8 , R 9 , R 10 , R 1 ', R 12 , R 13 , R 14 , R 15 , and R 16 is, independently, a C 1 -C 24 alkyl group, optionally containing 1-4 ONO 2 substituents, a CpC 24 acyl group, optionally containing 1-4 ONO 2 substituents, a CpC 6 ring- forming connection to any of R'-R 4 , a hydrogen, a nitrate group, or A; and
  • Preferred compounds include any of the compounds of formulas II, III, IV, and V that have been individually described herein. Other preferred compounds include:
  • Particularly preferred compounds for preventing or mitigating tissue and/or cellular damage are:
  • a therapeutic compound of the invention comprises a cation (i.e., in certain embodiments, one of X or Y includes a cation, e.g., in the compound of formula IVd).
  • M can be a pharmaceutically acceptable alkali metal (e.g. Li, Na, K), ammonium, alkaline earth metal (e.g. Ca, Ba, Mg), higher valency cation, or polycationic counter ion (e.g., polyammonium cation) (see e.g., Berge et al., 1977).
  • alkali metal e.g. Li, Na, K
  • ammonium e.g. Ca, Ba, Mg
  • alkaline earth metal e.g. Ca, Ba, Mg
  • polycationic counter ion e.g., polyammonium cation
  • an anionic portion of the compound to a salt- forming cation will vary depending on the charge of the anionic portion of the compound and the charge of the counterion.
  • Preferred pharmaceutically acceptable salts include a sodium, potassium, or calcium salt, but other salts are also contemplated within their pharmaceutically acceptable range.
  • a therapeutic compound of the invention can be administered in a pharmaceutically acceptable vehicle.
  • pharmaceutically acceptable vehicle includes any and all solvents, excipients, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like which are compatible with the activity of the compound and are physiologically acceptable to the subject.
  • An example of a pharmaceutically acceptable vehicle is buffered normal saline (0.15 M NaCl).
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the therapeutic compound, use thereof in the compositions suitable for pharmaceutical administration is contemplated. Supplementary active compounds can also be incorporated into the compositions.
  • Carrier or substituent moieties useful in the present invention may also include moieties which allow the therapeutic compound to be selectively delivered to a target organ.
  • delivery of the therapeutic compound to the brain may be enhanced by a carrier moiety using either active or passive transport (a "targeting moiety").
  • the carrier molecule may be a redox moiety, as described in, for example, U.S. Patents 4,540,654 and 5,389,623, both to Bodor. These patents disclose drugs linked to dihydropyridine moieties which can enter the brain, where they are oxidized to a charged pyridinium species which is trapped in the brain. Thus drugs accumulate in the brain.
  • carrier moieties include compounds, such as amino acids or thyroxine, which can be passively or actively transported in vivo. Such a carrier moiety can be metabolically removed in vivo, or can remain intact as part of an active compound. Structural mimics of amino acids (and other actively transported moieties) including peptidomimetics, are also useful in the invention.
  • peptidomimetic is intended to include peptide analogues which serve as appropriate substitutes for peptides in interactions with, for example, receptors and enzymes. The peptodomimetic must possess not only affinity, but also efficacy and substrate function.
  • a peptidomimetic exhibits functions of a peptide, without restriction of structure to amino acid constituents.
  • Peptidomimetics and methods for their preparation and use are described in Morgan et al. (1989), the contents of which are incorporated herein by reference.
  • Many targeting moieties are known, and include, for example, asialoglycoproteins (see e.g., Wu, U.S. Patent 5,166,320) and other ligands which are transported into cells via receptor-mediated endocytosis (see below for further examples of targeting moieties which may be covalently or non-covalently bound to a target molecule).
  • neurodegeneration in a subject is mitigated, and/or neuroprotection and/or cognition enhancement is effected, by administering a therapeutic compound of the invention to the subject.
  • the invention also features methods for preventing or mitigating tissue and/or cellular damage in a subject by administering a therapeutic compound of the invention to the subject, thereby modulating intercellular and/or intracellular free radical concentration.
  • subject is intended to include living organisms in which the particular neurological condition to be treated can occur. Examples of subjects include humans, apes, monkeys, cows, sheep, goats, dogs, cats, mice, rats, and transgenic species thereof.
  • biochemical cascade initiated by cerebral ischemia is generally accepted to be identical in mammalian species (Mattson and Scheff, 1994; Higashi et al., 1995).
  • pharmacological agents that are neuroprotective in animal models such as those described herein are believed to be predictive of clinical efficacy in humans, after appropriate adjustment of dosage.
  • memory-deficit patterns between brain-damaged rats and humans, which indicates that the rat can serve as an excellent animal model to evaluate the efficacy of pharmacological treatments or brain damage upon memory (Kesner, 1990).
  • tissue plasminogen activator which is administered at a dose of 0.9 mg/kg by intravenous injection (Wittkowsky, 1998).
  • This drug is also effective in protecting the rat brain subjected to cerebral ischemia by occlusion of the middle cerebral artery, when administered at a dose of 10 mg/kg intravenously (Jiang et al., 1998).
  • the rat model of focal cerebral ischemia used in the development of the novel organic nitrate esters described herein has been shown to be shown to be predictive of clinical efficacy with at least one other class of pharmacological agents.
  • the invention further encompasses methods of the invention employed ex vivo or in vitro.
  • the Examples describe studies utilizing tissue homogenates according to the invention.
  • diagnostic tests or studies of efficacy of selected compounds may conveniently be performed ex vivo or in vitro, including in animal models. Such tests, studies and assays are within the scope of the invention.
  • compositions may be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy (20th ed.), ed. A.R. Gennaro, Lippincott Williams & Wilkins, 2000, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York).
  • Administration of the compositions of the present invention to a subject to be treated can be carried out using known procedures, at dosages and for periods of time effective to mitigate neurodegeneration, to effect neuroprotection, to effect cognition enhancement, and/or to prevent or mitigate tissue and/or cellular damage in the subject.
  • an effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the amount of neurodegeneration that has already occurred at the clinical site in the subject, the age, sex, and weight of the subject, and the ability of the therapeutic compound to mitigate neurodegeneration, to effect neuroprotection, to effect cognition enhancement, and/or to prevent or mitigate tissue and/or cellular damage in the subject.
  • Dosage regimens can be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
  • a non-limiting example of an effective dose range for a therapeutic compound of the invention (e.g., Va) is between 0.5 and 500 mg/kg of body weight per day.
  • preferred concentrations for the active compound are between 5 and 500 mM, more preferably between 10 and 100 mM, and still more preferably between 20 and 50 mM.
  • the therapeutic compounds of the invention can be effective when administered orally. Accordingly, a preferred route of administration is oral administration. Alternatively, the active compound may be administered by other suitable routes such as transdermal, subcutaneous, intraocular, intravenous, intramuscular or intraperitoneal administration, and the like (e.g., by injection). Depending on the route of administration, the active compound may be coated in a material to protect the compound from the action of acids, enzymes and other natural conditions which may inactivate the compound.
  • the compounds of the invention can be formulated to ensure proper distribution in vivo.
  • the blood-brain barrier excludes many highly hydrophilic compounds.
  • the therapeutic compounds of the invention cross the BBB, they can be formulated, for example, in liposomes.
  • liposomes For methods of manufacturing liposomes, see, e.g., U.S. Patents 4,522,811 ; 5,374,548; and 5,399,331.
  • the liposomes may comprise one or more moieties which are selectively transported into specific cells or organs ("targeting moieties"), thus providing targeted drug delivery (see, e.g., Ranade et al., 1989).
  • Exemplary targeting moieties include folate and biotin (see, e.g., U.S. Patent 5,416,016 to Low et al.); mannosides (Umezawa et al., 1988); antibodies (Bloeman et al., 1995; Owais et al., 1995); and surfactant protein A receptor (Briscoe et al., 1995).
  • the therapeutic compounds of the invention are formulated in liposomes; in a more preferred embodiment, the liposomes include a targeting moiety.
  • anionic groups such as phosphonate or carboxylate can be esterified to provide compounds with desirable pharmocokinetic, pharmacodynamic, biodistributive, or other properties.
  • anionic groups such as phosphonate or carboxylate can be esterified to provide compounds with desirable pharmocokinetic, pharmacodynamic, biodistributive, or other properties.
  • Exemplary compounds include IVl and pharmaceutically acceptable salts or esters thereof.
  • the therapeutic compound may be administered to a subject in an appropriate carrier, for example, liposomes, or a diluent.
  • suitable diluents include saline and aqueous buffer solutions.
  • Liposomes include water- in-oil-in- water CGF emulsions as well as conventional liposomes (Strejan et al., 1984).
  • the therapeutic compound may also be administered parenterally (e.g., intramuscularly, intravenously, intraperitoneally, intraspinally, or intracerebrally).
  • Dispersions can be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.
  • Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the composition must be sterile and must be fluid to the extent that easy syringability exists.
  • the vehicle can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.
  • Sterile injectable solutions can be prepared by incorporating the therapeutic compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filter sterilization.
  • dispersions are prepared by incorporating the therapeutic compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and freeze-drying which yield a powder of the active ingredient (i.e., the therapeutic compound) optionally plus any additional desired ingredient from a previously sterile- filtered solution thereof.
  • the therapeutic compound can be orally administered, for example, with an inert diluent or an assimilable edible carrier.
  • the therapeutic compound and other ingredients may also be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or incorporated directly into the subject's diet.
  • the therapeutic compound may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • the percentage of the therapeutic compound in the compositions and preparations may, of course, be varied. The amount of the therapeutic compound in such therapeutically useful compositions is such that a suitable dosage will be obtained.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle.
  • the specification for the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such a therapeutic compound for the treatment of neurological conditions in subjects.
  • Therapeutic compositions can be administered in time-release or depot form, to obtain sustained release of the therapeutic compounds over time.
  • the therapeutic compounds of the invention can also be administered transdermally (e.g., by providing the therapeutic compound, with a suitable carrier, in patch form).
  • Active compounds are administered at a therapeutically effective dosage sufficient to mitigate neurodegeneration, to effect neuroprotection, to effect cognition enhancement, and/or to prevent or mitigate tissue and/or cellular damage in a subject.
  • a "therapeutically effective dosage” preferably mitigates neurodegeneration by about 20%, more preferably by about 40%, even more preferably by about 60%, and still more preferably by about 80% relative to untreated subjects.
  • the ability of a compound to mitigate neurodegeneration can be evaluated in model systems that may be predictive of efficacy in mitigating neurodegeneration in human diseases, such as animal model systems known in the art (including, e.g., the method of transient middle cerebral artery occlusion in the rat) or by in vitro methods, (including, e.g., the assays described herein).
  • animal model systems known in the art (including, e.g., the method of transient middle cerebral artery occlusion in the rat) or by in vitro methods, (including, e.g., the assays described herein).
  • the ability of a compound of the invention to mitigate neurodegeneration will, in certain embodiments, be evaluated by observation of one or more symptoms or signs associated with neurodegeneration in vivo.
  • the ability of a compound to mitigate neurodegeneration may be associated with an observable improvement in a clinical manifestation of the underlying neurodegeneration-related disease state or condition, or a slowing or delay in progression of symptoms of the condition.
  • monitoring of clinical manifestations of disease can be useful in evaluating the neurodegeneration-mitigating efficacy of a compound of the invention.
  • neurodegeneration can be associated with conditions including but not limited to: stroke; Parkinson's disease; Alzheimer's disease; Huntington's disease; multiple sclerosis; amylotrophic lateral sclerosis; AIDS-induced dementia; epilepsy; alcoholism; alcohol withdrawal; drug-induced seizures; viral/bacterial/fever-induced seizures; trauma to the head; hypoglycemia; hypoxia; myocardial infarction; cerebral vascular occlusion; cerebral vascular hemorrhage; hemorrhage; environmental excitotoxins of plant; animal, or marine origin; dementias of all type; trauma; drug-induced brain damage; and aging; or result from surgical procedures such as cardiac bypass.
  • Novel compounds according to the invention can be synthesized by methods set forth herein or in U.S. Patent Nos. 5,807,847; 5,883,122; 6,310,052; and 6,365,579, for example.
  • Various compounds for use in the methods of the invention are commercially available and/or can be synthesized by standard techniques.
  • nitrate esters can be prepared from the corresponding alcohol, oxirane or alkene by standard methods, that include: nitration of alcohols and oxiranes, mixed aqueous/organic solvents using mixtures of nitric and sulfuric acid and/or their salts, with temperature control (see Yang et al., 1996); nitration of alcohols and oxiranes in acetic anhydride using nitric acid or its salts with or without added acid catalyst, with temperature control (see, e.g., Louw et al., 1976); nitration of an alcohol with a nitronium salt, e.g. a tetrafluoroborate; nitration of an alkene with thallium nitrate in an appropriate solvent (see Ouellette et al., 1976).
  • compound IVr proceeded from the Bunte salt, 2,3-dinitrooxypropane-l-thiosulfonate (compound IVd), which was prepared from l,2-dinitrooxy-3-bromopropane as follows: 3- bromopropane-l,2-diol was added dropwise into a cold mixture Of HNO 3 (68- 70%, 4.0eq) and H 2 SO 4 (95%, 4.0 eq) in CH 2 Cl 2 (50 mL) at room temperature over 30 min.
  • HNO 3 68- 70%, 4.0eq
  • H 2 SO 4 95%, 4.0 eq
  • the organic layer was separated, washed, dried and concentrated to yield a yellow oil which was purified by flash chromatography on SiO 2 to give 3-bromopropane-l,2-diol dinitrate in 45% yield (29).
  • the Bunte salt was prepared by reacting 3-bromopropane-l,2-diol dinitrate with an equimolar portion Of Na 2 S 2 O 3 in 3: 1 MeOH/H 2 O at 50°C for 10 hours and subsequently purifying by flash chromatography on SiO 2 (29).
  • the Bunte salt was oxidized with a small molar excess Of H 2 O 2 (30%) in EtOH:H 2 O mixture (1 :1) with a catalytic amount OfH 2 SO 4 for 2 days.
  • Alkyl bromides or alkyl mercaptans were obtained commercially or by adaptation of literature procedures.
  • Bunte salts were obtained from the appropriate alkyl bromide by reaction with sodium thiosulfate, as described above for compound IVd.
  • Bunte salts (9.67 mmoles) were dissolved in distilled water (1OmL).
  • a solution of mercaptan (6.46 mmoles) in IM NaOH (7mL) was added dropwise.
  • the resulting emulsion was stirred for 1 to 15 minutes and then extracted with dichlorometane or ethylacetate.
  • the combined organic extracts were washed with H 2 O, dried over MgSO4 and concentrated under vacuum.
  • Tables 1 and 2 list characterization data determined for other compounds of the invention.
  • Rat hearts were excised and mounted for retrograde aortic perfusion at a constant flow rate of 6-8 mL/min/g heart weight.
  • the coronary perfusion pressure was monitored by a pressure transducer connected to the perfusion line.
  • the left coronary artery was occluded for 45 minutes, after which the occlusion was released and the heart reperfused for 90 minutes.
  • the LCA was re-occluded and 0.5 mL of 1% Evan's Blue dye was slowly infused into the heart, via the aotic cannula, to stain the area of myocardium perfused by the patent right coronary artery.
  • AAR area-at-risk for infarction was determined by negative staining.
  • Acute ischemic damage was assessed by measuring the release of the cytosolic enzyme, LDH, into the perfusate, and by quantitation of infarct size by staining for viable tissue using 2,3,5-triphenyltetrazolium chloride (TTC) followed by computerized planimmetry.
  • Infarct size was expressed as infarct area (negative staining after TTC staining) as a percent of the area-at-risk (negative staining after Evan's Blue dye).
  • Synaptosome Assay The methodology for measurement of thiobarbituric acid reactive substances (TBARS) from synaptosomes was adapted from that of Keller et al. Neuroscience 80: 685-696, 1997.
  • Adult Sprague-Dawley rats 250-30Og were anesthetized with halothane for 20 sec. and decapitated.
  • the brain was removed and the cerebral cortex separated from white matter.
  • the cerebral cortex was homogenized in a solution containing sucrose 0.32 M, EDTA 2mM and TRIS-HCl 10 mM, pH 7.2, using a Teflon pestle.
  • the tissue was 5% w/v in the homogenizing buffer.
  • the homogenate was centrifuged for 10 minutes at 310 g at 4°C. The supernatant was then centrifuged for 10 minutes at 20,000 g at 4°C. The pellet was collected, resuspended in Locke's buffer (154 mM NaCl, 5.6 mM KCl, 2.3 mM CaCl 2 -2H 2 O, 1.0 mM MgCl 2 -6H 2 O, 3.6 mM NaHCO 3 , 5 mM glucose, 5 mM HEPES, pH 7.2) and centrifuged for 10 minutes at 20,000 g at 4°C. The procedure of washing the pellet was repeated 2-3 times in order to reduce transition metal ion concentrations.
  • Locke's buffer 154 mM NaCl, 5.6 mM KCl, 2.3 mM CaCl 2 -2H 2 O, 1.0 mM MgCl 2 -6H 2 O, 3.6 mM NaHCO 3 , 5 mM glucose,
  • Lipid peroxidation synaptosome experimental results. Preliminary lipid peroxidation experiments explored the time course of synaptosome lipid peroxidation, incubating homogenate with FeSO 4 (lO ⁇ M - 150 ⁇ M) in Locke's buffer, for time intervals from 15 minutes to 180 minutes (data not shown). Under these experimental conditions, the level of peroxidation, as measured by TBARS, was seen to be below saturation at 30 minutes using 50 ⁇ M FeSO 4 . The ability of this system to provide concentration dependent lipid peroxidation data was demonstrated using the antioxidant ⁇ -tocopherol ( ⁇ TH), and ascorbic acid (AH), which is known to act as a prooxidant in Fe(II)-induced lipid peroxidation systems (see Figure 8). These conditions thus were chosen for all further synaptosome experiments.
  • ⁇ TH antioxidant ⁇ -tocopherol
  • AH ascorbic acid
  • the Fe/synaptosome/TBARS system was designed to provide concentration-response curves for inhibition of lipid peroxidation, which might be quantified by EC 50 values.
  • Absolute EC 50 values measured in such systems are highly dependent on experimental conditions, and therefore must be benchmarked against well-studied antioxidants, such as Trolox, a water soluble chroman carboxylate derivative of ⁇ TH (see Figure 9).
  • Thiols can display mixed pro- and antioxidant activity towards lipid peroxidation.
  • transition metals either added to lipid preparations, or adventitious metal ions present in tissue homogenates
  • thiols may act as prooxidants.
  • the vic-dithiol, dihydrolipoic acid (LAH 2 , ⁇ , solid line in Figure 10) yielded a concentration dependent prooxidant effect, akin to ascorbic acid, whereas the oxidized disulfide lipoic acid (LA, A , dashed line in Figure 10) showed very modest inhibition of lipid peroxidation at the highest concentration applied.
  • the antioxidant trolox yielded a potent concentration dependent reduction in TBARS products with EC 50 - 6.8 x 10 "5 M (Figure 9), which can be contrasted to the effect of lipoic acid (LA) or dihydrolipoic acid (LAH 2 , see Figure 10).
  • LA lipoic acid
  • LAH 2 dihydrolipoic acid
  • Figure 11 the concentration of GTN have any significant effect in the presence of added LAH 2 (ImM)
  • Figure 11 did not significant effect on lipid peroxidation with any thiol used (e.g. cysteine, PhSH), over the effect of the thiol itself (see GTN with LAH 2 , ⁇ , solid line in Figure 11).
  • compound Va did inhibit lipid peroxidation at higher concentrations in the presence Of LAH 2 .
  • compound Va inhibited TBARS formation with the water soluble thiol, cysteine, and the more lipophilic thiophenol (PhSH) (see Va + cysteine, ⁇ , solid line or Va + PhSH, A, solid line in Figure 12).
  • PhSH water soluble thiol, cysteine, and the more lipophilic thiophenol
  • compound Va showed some prooxidant activity in the presence of cysteine.
  • Concentration response curves were derived from TBARS data for the NO donor NONOate, Sper/NO (spermine NONOate, dashed line), and for DE A/NO (diethylamine NONOate, solid line) (see Figure 14).
  • Gaetani P., A. Pasqualin, R. Rodriguez y Baena, E. Borasio, F. Marzatico, "Oxidative stress in the human brain after subarachnoid hemorrhage", J. Neurosurg. 89 (1998) 748-754.
  • Tagami M, K. Yamagata, K. Ikeda, Y. Nara, H. Fujino, A. Kubota, F. Numano, Y. Yamori, "Vitamin E prevents apoptosis in cortical neurons during hypoxia and oxygen reperfusion", Lab. Invest. 78 (1998) 1415-1429.

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Abstract

L'invention concerne des esters de nitrate et des méthodes pour limiter la neurodégénérescence, influer sur la neuroprotection, sur l'amélioration cognitive et/ou prévenir ou limiter les dommages tissulaires et/ou cellulaires chez un sujet. Les états neurologiques ou cognitifs ou les dommages induits par des radicaux libres sont traités par administration à un sujet d'une quantité efficace d'un composé thérapeutique comprenant un ester de nitrate ou un de ses sels pharmaceutiquement acceptables.
EP05787832A 2004-09-17 2005-09-16 Esters de nitrate et leur utilisation pour limiter les dommages cellulaires Pending EP1797100A4 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US10/943,264 US20050137191A1 (en) 1996-06-04 2004-09-17 Nitrate esters and their use for mitigating cellular damage
PCT/CA2005/001417 WO2006029532A1 (fr) 1996-06-04 2005-09-16 Esters de nitrate et leur utilisation pour limiter les dommages cellulaires

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000054756A2 (fr) * 1999-03-15 2000-09-21 Queen's University At Kingston Esters de nitrate et leur utilisation dans le traitement d'etats neurologiques
WO2001049275A2 (fr) * 1999-12-29 2001-07-12 Queen's University At Kingston Procedes et dispositifs destines a reduire la douleur

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000054756A2 (fr) * 1999-03-15 2000-09-21 Queen's University At Kingston Esters de nitrate et leur utilisation dans le traitement d'etats neurologiques
WO2001049275A2 (fr) * 1999-12-29 2001-07-12 Queen's University At Kingston Procedes et dispositifs destines a reduire la douleur

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO2006029532A1 *

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