WO2006058411A1 - Pyridoxal-5´-phosphate and related compounds in combination with therapeutic cadiovascular compounds for treating angina. - Google Patents
Pyridoxal-5´-phosphate and related compounds in combination with therapeutic cadiovascular compounds for treating angina. Download PDFInfo
- Publication number
- WO2006058411A1 WO2006058411A1 PCT/CA2005/001470 CA2005001470W WO2006058411A1 WO 2006058411 A1 WO2006058411 A1 WO 2006058411A1 CA 2005001470 W CA2005001470 W CA 2005001470W WO 2006058411 A1 WO2006058411 A1 WO 2006058411A1
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- WO
- WIPO (PCT)
- Prior art keywords
- composition
- alkyl
- compound
- hydrogen
- blocker
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 126
- 206010002383 Angina Pectoris Diseases 0.000 title claims abstract description 109
- 230000001225 therapeutic effect Effects 0.000 title claims abstract description 51
- 229910019142 PO4 Inorganic materials 0.000 title description 4
- 239000010452 phosphate Substances 0.000 title description 4
- 239000000203 mixture Substances 0.000 claims abstract description 121
- 238000000034 method Methods 0.000 claims abstract description 107
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 claims abstract description 62
- NGVDGCNFYWLIFO-UHFFFAOYSA-N pyridoxal 5'-phosphate Chemical compound CC1=NC=C(COP(O)(O)=O)C(C=O)=C1O NGVDGCNFYWLIFO-UHFFFAOYSA-N 0.000 claims abstract description 58
- 239000011589 pyridoxal 5'-phosphate Substances 0.000 claims abstract description 58
- 235000007682 pyridoxal 5'-phosphate Nutrition 0.000 claims abstract description 58
- 150000003839 salts Chemical class 0.000 claims abstract description 44
- 239000004036 potassium channel stimulating agent Substances 0.000 claims abstract description 36
- 229940127291 Calcium channel antagonist Drugs 0.000 claims abstract description 33
- 239000000480 calcium channel blocker Substances 0.000 claims abstract description 33
- RADKZDMFGJYCBB-UHFFFAOYSA-N Pyridoxal Chemical compound CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 claims abstract description 32
- 239000011677 pyridoxine Substances 0.000 claims abstract description 31
- 235000008160 pyridoxine Nutrition 0.000 claims abstract description 31
- 229940011671 vitamin b6 Drugs 0.000 claims abstract description 31
- 230000003647 oxidation Effects 0.000 claims abstract description 28
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 28
- NHZMQXZHNVQTQA-UHFFFAOYSA-N pyridoxamine Chemical compound CC1=NC=C(CO)C(CN)=C1O NHZMQXZHNVQTQA-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000011674 pyridoxal Substances 0.000 claims abstract description 16
- 235000008164 pyridoxal Nutrition 0.000 claims abstract description 16
- 229960003581 pyridoxal Drugs 0.000 claims abstract description 16
- 239000002876 beta blocker Substances 0.000 claims abstract description 13
- 235000014113 dietary fatty acids Nutrition 0.000 claims abstract description 13
- 229930195729 fatty acid Natural products 0.000 claims abstract description 13
- 239000000194 fatty acid Substances 0.000 claims abstract description 13
- 150000004665 fatty acids Chemical class 0.000 claims abstract description 13
- 239000011699 pyridoxamine Substances 0.000 claims abstract description 13
- 235000008151 pyridoxamine Nutrition 0.000 claims abstract description 13
- 239000003112 inhibitor Substances 0.000 claims abstract description 10
- HXACOUQIXZGNBF-UHFFFAOYSA-N 4-pyridoxic acid Chemical compound CC1=NC=C(CO)C(C(O)=O)=C1O HXACOUQIXZGNBF-UHFFFAOYSA-N 0.000 claims abstract description 9
- 230000036961 partial effect Effects 0.000 claims abstract description 8
- -1 nifeipine Chemical compound 0.000 claims description 107
- 125000000217 alkyl group Chemical group 0.000 claims description 106
- 229910052739 hydrogen Inorganic materials 0.000 claims description 66
- 239000001257 hydrogen Substances 0.000 claims description 64
- 125000003118 aryl group Chemical group 0.000 claims description 59
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 37
- 125000004423 acyloxy group Chemical group 0.000 claims description 35
- 125000003545 alkoxy group Chemical group 0.000 claims description 34
- 150000002431 hydrogen Chemical group 0.000 claims description 32
- 125000005843 halogen group Chemical group 0.000 claims description 31
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 30
- 229910002651 NO3 Inorganic materials 0.000 claims description 30
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 30
- 229940081730 Partial fatty acid oxidation inhibitor Drugs 0.000 claims description 28
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 27
- 229910052760 oxygen Inorganic materials 0.000 claims description 27
- 239000001301 oxygen Substances 0.000 claims description 27
- 238000011282 treatment Methods 0.000 claims description 24
- 239000000674 adrenergic antagonist Substances 0.000 claims description 23
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 claims description 23
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 claims description 21
- MOYKHGMNXAOIAT-JGWLITMVSA-N isosorbide dinitrate Chemical compound [O-][N+](=O)O[C@H]1CO[C@@H]2[C@H](O[N+](=O)[O-])CO[C@@H]21 MOYKHGMNXAOIAT-JGWLITMVSA-N 0.000 claims description 21
- 229960000201 isosorbide dinitrate Drugs 0.000 claims description 21
- 229960002497 nicorandil Drugs 0.000 claims description 21
- LBHIOVVIQHSOQN-UHFFFAOYSA-N nicorandil Chemical group [O-][N+](=O)OCCNC(=O)C1=CC=CN=C1 LBHIOVVIQHSOQN-UHFFFAOYSA-N 0.000 claims description 21
- 229960001722 verapamil Drugs 0.000 claims description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 20
- XKLMZUWKNUAPSZ-UHFFFAOYSA-N N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]piperazin-1-yl}acetamide Chemical group COC1=CC=CC=C1OCC(O)CN1CCN(CC(=O)NC=2C(=CC=CC=2C)C)CC1 XKLMZUWKNUAPSZ-UHFFFAOYSA-N 0.000 claims description 20
- 229910052757 nitrogen Inorganic materials 0.000 claims description 20
- 229960000213 ranolazine Drugs 0.000 claims description 20
- 125000003342 alkenyl group Chemical group 0.000 claims description 18
- 125000001624 naphthyl group Chemical group 0.000 claims description 18
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 claims description 16
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 16
- 229960003711 glyceryl trinitrate Drugs 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- 241000124008 Mammalia Species 0.000 claims description 15
- METKIMKYRPQLGS-GFCCVEGCSA-N (R)-atenolol Chemical compound CC(C)NC[C@@H](O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-GFCCVEGCSA-N 0.000 claims description 13
- RZTAMFZIAATZDJ-HNNXBMFYSA-N 5-o-ethyl 3-o-methyl (4s)-4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC(Cl)=C1Cl RZTAMFZIAATZDJ-HNNXBMFYSA-N 0.000 claims description 13
- GOEMGAFJFRBGGG-UHFFFAOYSA-N acebutolol Chemical group CCCC(=O)NC1=CC=C(OCC(O)CNC(C)C)C(C(C)=O)=C1 GOEMGAFJFRBGGG-UHFFFAOYSA-N 0.000 claims description 13
- 229960002122 acebutolol Drugs 0.000 claims description 13
- 229960000528 amlodipine Drugs 0.000 claims description 13
- 229960002274 atenolol Drugs 0.000 claims description 13
- 229960004166 diltiazem Drugs 0.000 claims description 13
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 claims description 13
- 229960003580 felodipine Drugs 0.000 claims description 13
- YWXYYJSYQOXTPL-SLPGGIOYSA-N isosorbide mononitrate Chemical compound [O-][N+](=O)O[C@@H]1CO[C@@H]2[C@@H](O)CO[C@@H]21 YWXYYJSYQOXTPL-SLPGGIOYSA-N 0.000 claims description 13
- 229960003827 isosorbide mononitrate Drugs 0.000 claims description 13
- VKQFCGNPDRICFG-UHFFFAOYSA-N methyl 2-methylpropyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)C)C1C1=CC=CC=C1[N+]([O-])=O VKQFCGNPDRICFG-UHFFFAOYSA-N 0.000 claims description 13
- VWPOSFSPZNDTMJ-UCWKZMIHSA-N nadolol Chemical compound C1[C@@H](O)[C@@H](O)CC2=C1C=CC=C2OCC(O)CNC(C)(C)C VWPOSFSPZNDTMJ-UCWKZMIHSA-N 0.000 claims description 13
- 229960004255 nadolol Drugs 0.000 claims description 13
- 229960000227 nisoldipine Drugs 0.000 claims description 13
- PHUTUTUABXHXLW-UHFFFAOYSA-N pindolol Chemical compound CC(C)NCC(O)COC1=CC=CC2=NC=C[C]12 PHUTUTUABXHXLW-UHFFFAOYSA-N 0.000 claims description 13
- 229960002508 pindolol Drugs 0.000 claims description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- IUBSYMUCCVWXPE-UHFFFAOYSA-N metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 claims description 12
- 229960002237 metoprolol Drugs 0.000 claims description 12
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 12
- 125000005425 toluyl group Chemical group 0.000 claims description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
- 125000004104 aryloxy group Chemical group 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 claims description 8
- 239000011593 sulfur Substances 0.000 claims description 8
- SGUAFYQXFOLMHL-UHFFFAOYSA-N 2-hydroxy-5-{1-hydroxy-2-[(4-phenylbutan-2-yl)amino]ethyl}benzamide Chemical compound C=1C=C(O)C(C(N)=O)=CC=1C(O)CNC(C)CCC1=CC=CC=C1 SGUAFYQXFOLMHL-UHFFFAOYSA-N 0.000 claims description 7
- 125000005110 aryl thio group Chemical group 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 229960001632 labetalol Drugs 0.000 claims description 7
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 6
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 125000003282 alkyl amino group Chemical group 0.000 claims description 5
- 125000001769 aryl amino group Chemical group 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 4
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 2
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 claims 12
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 12
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 4
- HVTMFBOSQNXQPI-UHFFFAOYSA-N [4-formyl-5-(hydroxymethyl)pyridin-2-yl] 2,3-dimethylbenzoate Chemical compound CC1=CC=CC(C(=O)OC=2N=CC(CO)=C(C=O)C=2)=C1C HVTMFBOSQNXQPI-UHFFFAOYSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 abstract description 14
- 150000003223 pyridoxals Chemical class 0.000 abstract description 11
- 238000002648 combination therapy Methods 0.000 abstract description 7
- HSBSNPYTEWODSO-UHFFFAOYSA-N P(O)(O)=O.N1=C(C)C(O)=C(CO)C(CO)=C1 Chemical class P(O)(O)=O.N1=C(C)C(O)=C(CO)C(CO)=C1 HSBSNPYTEWODSO-UHFFFAOYSA-N 0.000 abstract description 6
- 150000002823 nitrates Chemical class 0.000 abstract description 5
- 230000002526 effect on cardiovascular system Effects 0.000 abstract description 3
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 16
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- 229910052943 magnesium sulfate Inorganic materials 0.000 description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
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- DMVOXQPQNTYEKQ-UHFFFAOYSA-N biphenyl-4-amine Chemical group C1=CC(N)=CC=C1C1=CC=CC=C1 DMVOXQPQNTYEKQ-UHFFFAOYSA-N 0.000 description 3
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Classifications
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- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/275—Nitriles; Isonitriles
- A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
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- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4415—Pyridoxine, i.e. Vitamin B6
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- the angina therapeutics 0-adrenergic-blocking agents and calcium channel blockers are widely used.
- New classes of drugs are currently being experimentally administered in the treatment of angina. These new drugs include partial fatty acid oxidation inhibitors (pFOX) and potassium channel activators.
- pFOX partial fatty acid oxidation inhibitors
- potassium channel activators potassium channel activators.
- heart disease patients with stable angina may also be treated with angiotensin converting enzyme inhibitors, angiotensin receptor blockers, antiplatelet therapy, diuretics, statins, or mixtures thereof.
- the invention includes a method 'of treating angina in a mammal by concurrently administering to the mammal a therapeutically effective amount of a combination of a compound suitable for use in methods of the invention and a therapeutic angina compound. More specifically, the invention includes administering a therapeutically effective amount of at least one of pyridoxal-5 1 - phosphate, pyridoxic acid, pyridoxal, pyridoxine, pyridoxamine, 3-acylated analogues of pyridoxal, 3-acylated analogues of pyridoxal-4,5-aminal, pyridoxine phosphonate analogues, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof concurrently with a therapeutically effective amount of at least one of calcium channel blocker, /3-adrenergic-blocker, nitrate, partial fatty acid oxidation inhibitor, potassium channel activator, or mixtures thereof.
- the invention also includes compositions comprising at least one of pyridoxal-5'-phosphate, pyridoxic acid, pyridoxal, pyridoxine, pyridoxamine, 3- .
- acylated analogues of pyridoxal 3-acylated analogues of pyridoxal-4,5-aminal, pyridoxine phosphonate analogues, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof and a therapeutically effective amount of at least one of a nitrate, a partial fatty acid oxidation inhibitor, a potassium channel activator, or a mixture thereof.
- Figure 1 illustrates glucose oxidation rates in rat hearts treated with saline (control), DCA, and P5P (MC-I).
- compositions containing "a compound” includes a mixture of two or more compounds.
- Some of the compounds described herein contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms which may be defined in terms of absolute stereochemistry as (R)- or (S)-.
- the present invention is meant to include all such possible diastereomers and enantiomers as well as their racemic. and optically pure forms.
- Optically active (R)- and (S)- isomers may be prepared using chifal synthons or chiral reagents, or resolved using conventional techniques.
- the compounds described herein contain olefmic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and A geometric isomers. Likewise all tautomeric forms are intended to be included.
- the invention is directed to methods of treating angina in a mammal by concurrently administering a therapeutically effective amount of pyridoxal-5'- phosphate (also referred to herein as either PLP or P5P), pyridoxal, pyridoxine, pyridoxamine, 3-acylated analogues of pyridoxal, 3-acylated analogues of pyridoxal-4,5-aminal, pyridoxine phosphonate analogues, pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof with a therapeutic angina compound.
- pyridoxal-5'- phosphate also referred to herein as either PLP or P5P
- pyridoxal also referred to herein as either PLP or P5P
- pyridoxal also referred to herein as either PLP or P5P
- pyridoxal also referred to herein as either PLP or P5P
- pyridoxal also referred to herein as either PLP or P5P
- treating angina includes but is not limited to, reducing or relieving the symptoms of an angina attack, reducing the frequency of angina attack, altering the symptoms of an angina attack, delaying the onset of an angina attack, and reducing the duration of angina attack.
- Angina includes angina pectoris, stress-induced angina, stable angina, unstable angina, and Prinzmetal's angina.
- Methods of the invention can be utilized to treat angina pectoris, stress induced angina, stable angina, unstable angina, or Prinzmetal's angina
- Angina pectoris results when myocardial oxygen demand is increased to levels that cannot be met through increased coronary blood flow. It usually results because of stenotic atherosclerotic lesions in one or more of the epicardial coronary vessels. Accordingly, angina is typically brought oh by physical exertion or emotional stress. Most patients with stable angina can identify specific activities or situations that will predictably elicit the discomfort; walking up an incline or hurrying are common examples. Some variability in the effort threshold is not uncommon. Activity done in cold weather, after meals or early in the morning may also be more likely to evoke angina. Some patients report that activity with their arms above their heads is more likely to produce the discomfort.
- variable effort threshold for angina in some patients suggests that dynamic alterations in coronary blood flow (eg, because of an intermittent increase in coronary vasomotor tone) contribute to fixed atherosclerotic stenosis in lirniting blood flow.
- Episodes of stable angina usually begin gradually and last about 2 to about 10 minutes. Discomfort is usually relieved promptly by rest or sublingual nitroglycerin.
- angina pectoris The symptoms of angina pectoris are typically described as a substernal chest discomfort perceived as a tightness, heaviness, pressure, or a burning sensation. It is characteristically nonfocal, i.e., the patient cannot indicate the location with one finger. The discomfort may radiate to the left shoulder or the arms, or to the neck and jaw. Some patients describe their angina in more atypical terms, such as sharp, a "gas pain", discomfort only in the jaw, teeth, forearms, or back, or discomfort beginning in the epigastric region and radiating up into the chest. Other patients describe it as shortness of breath with no definite discomfort, a symptom called angina-equivalent dyspnea.
- Angina also occurs in some patients with severe aortic valvular stenosis, left ventricular hypertrophy, or pulmonary arterial hypertension in the absence of significant coronary artery stenoses. In these situations, even normal coronary blood flow may be inadequate to meet the heightened myocardial oxygen demand. Angina may also develop in persons with very dilated left ventricles, particularly when accompanied by reduced diastolic coronary perfusion pressure, as in advanced aortic regurgitation. • Angina pectoris that has recently progressed or spontaneously increased in severity, frequency, or duration-particularly if accompanied by rest pain--is considered unstable angina.
- Prinzmetal's angina is similar in character and location to stable angina and often responds to nitroglycerin. It characteristically occurs at rest, however, without obvious provocation or a preceding increase in heart rate or blood pressure. These features are explained by its underlying mechanism: transient coronary artery spasm. Often, the episodes occur in the early morning. Some patients with Prinzmetal's angina report other vasomotor-related symptoms such as migraine headache or Raynaud's phenomenon. (Textbook of Internal Medicine, Third Edition, pages 316- 317 (1997).
- a “therapeutic angina compound”, as used herein, includes angina therapeutics such as ⁇ -adrenergic blocking agents, calcium channel blockers, partial fatty acid oxidation inhibitors, potassium channel activators, and nitrates, but does not include pyridoxal-5 ' -phosphate, pyridoxal, pyridoxine, pyridoxic acid, pyridoxamine, 3-acylated analogues of pyridoxal, 3-acylated analogues of pyridoxal-4,5-aminal, pyridoxine phosphate analogues, or pharmaceutically acceptable salts thereof, even though such compounds have, been found to have therapeutic use in the treatment of angina.
- angina therapeutics such as ⁇ -adrenergic blocking agents, calcium channel blockers, partial fatty acid oxidation inhibitors, potassium channel activators, and nitrates
- pyridoxal-5 ' -phosphate pyridoxal, pyridoxine, pyridoxic acid,
- a "therapeutically effective amount" as used herein includes a prophylactic amount, for example, an amount effective for preventing the occurrence of an angina attack.
- a therapeutically effective amount includes an amount suitable for reducing or relieving the symptoms of an angina attack.
- a therapeutically effective amount includes an amount suitable for decreasing the frequency of occurrence of angina attacks.
- a therapeutically effective amount also includes an amount suitable to alter the symptoms of an angina attack.
- a therapeutically effective amount also includes an amount suitable to delay the onset of an angina attack.
- An amount effective to reduce the duration of an angina attack can also be considered a therapeutically effective amount.
- a therapeutic compound can be administered, for example, after an angina attack has occurred.
- a composition of the invention can be administered before or during the occurrence of an angina attack.
- Methods of the invention include administration of a therapeutically effective amount of a compound including any one or more of pyridoxal-5'-phosphate, pyridoxal, pyridoxine, pyridoxamine, 3-acylated analogues of pyridoxal, 3-acylated analogues of pyridoxal-4,5-aminal, pyridoxine phosphonate analogues, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof.
- a compound including any one or more of pyridoxal-5'-phosphate, pyridoxal, pyridoxine, pyridoxamine, 3-acylated analogues of pyridoxal, 3-acylated analogues of pyridoxal-4,5-aminal, pyridoxine phosphonate analogues, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof.
- a therapeutic compound includes any one or more of pyridoxal-5 '-phosphate, pyridoxal, pyridoxine, pyridoxamine, or a pharmaceutically acceptable salt thereof.
- Vitamin B 6 typically refers to pyridoxine, which is chemically known as 2-methyl-3 ⁇ hydr ⁇ xy- 4,5-di(hydroxymethyl)pyridine and is represented by formula I:
- PLP is a metabolite of vitamin B& inside cells and in blood plasma. Mammals cannot synthesize PLP de novo and must rely on dietary sources of precursors such as pyridoxine, pyridoxal, and pyridoxamine, which are metabolized to PLP. For instance, mammals produce PLP by phosphorylating pyridoxine by action of pyridoxal kinase and then oxidizing the phosphorylated product.
- PLP is a regulator of biological processes and a cofactor in more than 100 enzymatic reactions. It has been shown to be an antagonist of a purinergic receptor, thereby affecting ATP binding; it has been implicated in modulation of platelet aggregation; it is an inhibitor of certain phosphatase enzymes; and it has been implicated in the control of gene transcription. PLP is also a coenzyme in certain enzyme-catalyzed processes, for example, in glycogenolysis at the glycogen phosphorylase level, in the malate asparatate shuttle involving glycolysis and glycogenolysis at the transamination level, and in homocysteine metabolism.
- Therapeutic compounds include esters of pyridoxic acid andpyridoxic acid 4,5-lactone.
- Therapeutic compounds also include any one or more of the 3-acylated analogues of pyridoxal represented by formula V: where
- Ri is alkyl, or alkenyl, in which alkyl or alkenyl can be interrupted by nitrogen, oxygen, or sulfur, and can be unsubstituted or substituted at the terminal carbon with hydroxy, alkoxy, alkanoyloxy, alkanoyloxyaryl, alkoxyalkanoyl, alkoxycarbonyl; or Rl is dialkylcarbamoyloxy; alkoxy; dialkylamino; alkanoyloxy; alkanoyloxyaryl; alkoxyalkanoyl; alkoxycarbonyl; dialkylcarbamoyloxy; or Rl is aryl, aryloxy, arylthio, or aralkyl, in which aryl can be substituted by alkyl, alkoxy, amino, hydroxy, halo, nitro, or alkanoyloxy; or a pharmaceutically acceptable salt thereof.
- alkyl includes a straight or branched saturated aliphatic hydrocarbon radicals, such as, for example, methyl, ethyl, propyl, isopropyl (1-
- alkenyl includes an unsaturated aliphatic hydrocarbon chain having from 2 to 8 carbon atoms, such as, for example, ethenyl, 1-propenyl, 2- propenyl, 1-butenyl, 2-methyl-l-pro ⁇ enyl, and the like.
- the above alkyl or alkenyl can optionally be interrupted in the chain by a heteroatom, such as, for example, a nitrogen, sulfur, or oxygen atom, forming an alkylarninoalkyl, alkylthioalkyl, or alkoxyalkyl, for example, methylaminoethyl, ethylthiopropyl, methoxymethyl, and the like.
- a heteroatom such as, for example, a nitrogen, sulfur, or oxygen atom
- the above alkyl or alkenyl can optionally be substituted at the terminal carbon by hydroxy, alkoxy, alkanoyloxyaryl, alkanoyloxy, alkoxyalkanoyl, alkoxycarbonyl, or dialkylcarbamoyloxy.
- alkoxy i.e. alkyl-O-
- alkyl-O- alkyl as defined above joined to an oxygen atom having preferably from 1 to 4 carbon atoms in a straight or branched chain, such as, for example, methoxy, ethoxy, propoxy, isopropoxy (1- methylethoxy), butoxy, tert-butoxy (1,1-dimethylethoxy), and the like.
- dialkylamino includes two alkyl groups as defined above joined o a nitrogen atom, in which alkyl has preferably 1 to 4 carbon atoms, such as, for example, dimethylamino, diethylamino, methylethylamino, methylpropylamino, diethylamino, and the like.
- alkanoyloxy includes a group of the formula CA-C-Lo- )
- alkanoyloxy examples include methanoyloxy, ethanoyloxy, prqpanoyloxy, and the like.
- alkyl substituted at the terminal carbon by alkanoyloxy examples include 1 -ethanoyloxy- 1-methylethyl, propanoyloxy-1-methylethyl, and the like.
- alkanoyloxyaryl includes a group of the formula
- alkanoyloxyaryl examples include methanoyloxyphenyl, ethanoyloxyphenyl, propanoyloxyphenyl, and the like.
- aryl refers to unsaturated aromatic carbocyclic radicals having a single ring, such as phenyl, or multiple condensed rings, such as naphthyl or anthryl
- aryl also includes substituted aryl comprising aryl substituted on a ring by, for example, C 1 - 4 alkyl, C 1 - 4 alkoxy, amino, hydroxy, phenyl, nitro, halo, carboxyalkyl or alkanoyloxy.
- Aryl groups include, for example, phenyl, naphthyl, anthryl, biphenyl, methoxyphenyl, halophenyl, and the like.
- aryloxy includes aryl having an oxygen atom bonded to an aromatic ring, such as, for example, phenoxy and naphthoxy.
- arylthio 11 i.e. aryl-S-
- aryl having a sulfur atom bonded to an aromatic ring such as, for example, phenylthio andnaphthylthio.
- aralkyl refers to an aryl radical defined as above substituted with an alkyl radical as defined above (e.g. aryl-alkyl-).
- Aralkyl groups include, for example, phenethyl, benzyl, and naphthylmethyl..
- Aryl from any of aryl, aryloxy, arylthio, aralkyl, and alkanoyloxyaryl can be unsubstituted or can be substituted on a ring by, for example, C 1 . 4 alkyl, CM alkoxy, amino, hydroxy, nitro, halo, or alkanoyloxy.
- substituted aryl include toluyl, methoxyphenyl, ethylphenyl, and the like.
- alkoxyalkanoyl includes a group of the formula
- alkoxyalkanoyl examples include (2-acetoxy-2- • methyl) ⁇ ropanyl, 3 ⁇ eth ⁇ xy-3-propanoyl, 3-meth ⁇ xy-2-propanoyl, and the like.
- alkoxycarbonyl includes a group of the formula
- alkoxycarbonyl examples include methox ⁇ ycarbonyl, ethoxycarbonyl, propoxycarbonyl, and the like.
- dialkylcarbarnoyloxy includes a group of the formula .
- dialkylcarbamoyloxy examples include dimethylamino- methanoyloxy, 1-ethyl-l-methylaminomethanoyloxy, and the like.
- alkyl substituted at the terminal carbon by alkanoyloxy examples include dimethylamino-1- methylethyl, 1-ethyl-l-methylaminomethanoyloxy-l-methylethyl, and the like.
- halo includes bromo, chloro, and fluoro.
- Ri includes toluyl, naphthyl, phenyl, phenoxy, dimethylamino, 2,2-dimethylethyl, ethoxy, (2-acetoxy-2-methyl)propanyl, 1- ethanoyloxy-1-methylethyl, tert-buty ⁇ , acetylsalicyl, and ethanoyloxyphenyl for example.
- Ri groups for compounds of formula V are toluyl or naphthyl.
- Ri groups when joined with a carbonyl group form an acyl group l which can include toluoyl or ⁇ -naphthoyl for example.
- acyl group l which can include toluoyl or ⁇ -naphthoyl for example.
- thep-isomer is the substituent in one embodiment.
- 3-acylated analogues of pyridoxal include, but are not limited to, 2-methyl i -3-toluoyloxy-4-formyl-5-hydroxymethylpyridine and 2-methyl- ⁇ - naphthoyloxy-4-formyl-5-hydroxymethylpyridine.
- Therapeutic compounds also include any one or more of the 3-acylated analogues of pyridoxal-4,5-aminal represented by formula VI:
- Ri is alkyl, or alkenyl, in which alkyl or alkenyl can be interrupted by nitrogen, oxygen, or sulfur, and can be unsubstituted or substituted at the terminal carbon with hydroxy, alkoxy, alkanoyloxy, alkanoyloxyaryl, alkoxyalkanoyl, alkoxycarbonyl, or dialkylcarbamoyloxy; Ri is alkoxy; dialkylamino; alkanoyloxy; alkanoyloxyaryl; alkoxyalkanoyl; alkoxycarbonyl; dialkylcarbamoyloxy; Ri is aryl, aryloxy, arylthio, or aralkyl, in which aryl can be substituted by alkyl, alkoxy, amino, hydroxy, halo, nitro, or alkanoyloxy; R 2 is a secondary amino group; or a pharmaceutically acceptable salt thereof.
- alkyl alkenyl
- alkoxy dialkylamino
- alkanoyloxy alkanoyloxyaryl
- alkoxyalkanoyl alkoxycarbonyl
- dialkylcarbamoyloxy halo
- aryl aryloxy
- arylthio arylthio
- second amino includes a group of formula VII:
- R 3 R 4 NH derived from a secondary amine R 3 R 4 NH, in which R 3 and R 4 are each independently alkyl, alkenyl, cycloalkyl, aryl, or, when R 3 and R 4 are taken together, may form a ring with the nitrogen atom and which may be interrupted by a heteroatom, such as, for example, a nitrogen, sulfur, or oxygen atom.
- alkyl alkenyl
- aryl are used as defined above in forming secondary amino groups such as, for example, dimethylamino, methylethylamino, diethylamino, dialkylamino, phenylmethylamino, diphenylamino, and the like.
- cycl ⁇ alkyl refers to a saturated hydrocarbon having from 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms, such as, for example, cyclopropyl, cyclopentyl, cyclohexyl, and the like. ' . .
- a cyclic secondary amino group such as, for example, piperidino
- a group such as, for example, piperazino or morpholino can be formed.
- Ri groups include toluyl, naphthyl, phenyl, phenoxy, dnnethylamino, 2,2-dimethylethyl, ethoxy, (2-acetoxy-2-rnethyl)propanyl, 1- ethanoyloxy-1-methylethyl, tert-butyl, acetylsalicyl, and ethanoyloxyphenyl for example.
- Ri groups can include toluyl, e.g.jp-toluyl, naphthyl, tert-bvA ⁇ l, dimethylamino, acetylphenyl, hydroxyphenyl, or alkoxy, e.g., methoxy.
- Ri groups when joined with a carbonyl group form an acyl group Ri 1 C — which can include toluoyl, /?-naphthoyl, pivaloyl, dimethylcarbamoyl, acetylsalicyloyl, salicyloyl, or alkoxycarbonyl.
- R 2 the secondary amino group can be morpholino.
- 3-acylated analogues of pyridoxal-4,5-aminal include, but are not limited to, l-mor ⁇ holino-l,3-dihydro-7-(p-toluoyloxy)-6-methylfuro(3,4- c) ⁇ yridine; l-mor ⁇ holino-l,3-dihydro-7-(y5-naphthoyloxy)-6-methylfuro(3,4- c)pyridine; l-morpholmo-l,3-dihydro-7- ⁇ ivaloyloxy-6-methylfuro(3,4-c)pyridine; l-morpholino-ljS-dihydro-T-carbamoyloxy- ⁇ -methylfuroCS ⁇ - ⁇ pyridine; and 1- morpholino-ljS-dihydro-V-acetylsalicyloxy- ⁇ -methylfuroCS ⁇ - ⁇ pyridine.
- Therapeutic compounds include any one or more pyridoxal phosphonate analogues represented by the formula VHI: 01470
- Ri is hydrogen or alkyl
- R 2 is -CHO, -CH 2 OH 5 -CH 3 , -CO 2 Re in which R 6 is hydrogen, alkyl, or atyl; or R 2 is -CH 2 .O-alkyl- in which alkyl is covalently bonded to the oxygen at the 3-position instead of Ri,
- R 3 is hydrogen and R 4 is hydroxy, halo, alkoxy, alkanoyloxy, alkylamino or arylamino; or
- R3 and R 4 are halo
- R5 is hydrogen, alkyl, aryl, aralkyl, or -CO 2 R 7 in which R 7 is hydrogen, alkyl, aryl, or aralkyl; or a pharmaceutically acceptable salt thereof.
- alkyl alkoxy
- alkanoyloxy alkanoyloxy
- halo aryl
- aralkyl alkyl
- alkylamino refers to -NH-alkyl with alkyl as defined above.
- Alkylamino groups include those with 1-6 carbons in a straight or branched chain, such as, for example, methylamino, ethylamino, propylamine, and the like.
- arylamino refers to -N-aryl with aryl as defined above.
- Arylamino includes -NH-phenyl, -NH-biphenyl, -NH-4-methoxyphenyl, and the like.
- Examples of compounds of formula VIII include those where Ri is hydrogen, or those where R 2 is -CH 2 OH, or -CH 2 -O-alkyl- in which alkyl is covalently bonded to the oxygen at the 3-position instead of Ri, or those where R3 is hydrogen and R 4 is F 5 MeO- or CHsC(O)O-, or those where R5 is alkyl or aralkyl. Additional examples of compounds of formula VHI include those where R3 and R 4 are F 5 or those where R5 is t-butyl or benzyl.
- Therapeutic compounds further include any one or more pyridoxal phosphonate analogues represented by the formula IX:
- Ri is hydrogen or alkyl
- R 2 is -CHO, -CH 2 OH 5 -CH 3 or -CO 2 R 5 in which R 5 is hydrogen, alkyl, or aryl; or R 2 is -CH 2 -O-alkyl- in which alkyl is covalently bonded to the oxygen at the
- R 3 is hydrogen, alkyl, aryl, or aralkyl
- R4 is hydrogen, alkyl, aryl, aralkyl, or -CO 2 Re in which Re is ' hydrogen, alkyl, aryl, or aralkyl
- n is 1 to 6; or a pharmaceutically acceptable salt thereof.
- alkyl alkyl
- aryl aralkyl
- alkyl alkyl
- aralkyl alkyl
- examples of compounds of formula IX include those where Ri is hydrogen, or those where R 2 is -CH 2 OH, or -CH 2 .O-alkyl- in which alkyl is covalently bonded to the oxygen at the 3-position instead of Ri, or those where R 3 is hydrogen,- or those where R 4 is alkyl or hydrogen.
- Additional examples of compounds of formula IX include those where R 4 is ethyl.
- Therapeutic compounds further include any one or more pyridoxal phosphonate analogues represented by the formula X:
- Ri is hydrogen or alkyl
- R 2 is -CHO, -CH 2 OH, -CH 3 or -CO 2 R 8 in which R 8 is hydrogen, alkyl, or aryl; or R 2 is -C ⁇ 2 .O-alkyl- in which alkyl is covalently bonded to the oxygen at the
- alkyl alkoxy
- alkanoyloxy alkanoyloxy
- halo aryl
- aralkyl alkyl
- salts of the compounds of formulas I, II, HI, IV, V, VI, V ⁇ , IX, or X include acid addition satts derived from nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobrornic, hydriodic, hydrofluoric, phosphorus, and the like, as well as the salts, derived from nontoxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
- nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobrornic, hydriodic, hydrofluoric, phosphorus, and the like
- nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted
- Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, • toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like.
- salts of amino acids such as arginate and the like and gluconate, galacturonate, n-methyl glutamine, etc. (see, e.g., Berge et al., J. Pharmaceutical Science, 66: 1-19 (1977)).
- the salts of the basic compounds are prepared by contacting the free base form with a sufficient amount of a desired acid to produce the salt in the conventional manner.
- the free base form can be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner.
- the free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for purposes of the present invention.
- Pharmaceutically acceptable salts of the compounds of formulas VIII, IX, and X include metals such as alkali and alkaline earth metals. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Also included are heavy metal salts such as for example silver, zinc, cobalt, and cerium.
- Any of the above compounds may be mixed with a nitrate, partial fatty acid oxidation inhibitor, potassium channel activator, or mixtures thereof, to form a single novel composition.
- 3,4-isopropylidenepyridoxine ⁇ 5-al can be treated with a phosphonating agent, such as, a metal salt of di-tert-butyl phosphite or dibenzyl phosphite or diphenyl phosphite, to give protected alpha- hydroxyphosphonates.
- a phosphonating agent such as, a metal salt of di-tert-butyl phosphite or dibenzyl phosphite or diphenyl phosphite
- the protected alpha-hydroxyphosphonates can be treated with an acylating agent in an aprotic solvent, such as acetic anhydride in pyridine, or with an alkylating agent, such as methyl iodide and sodium hydride in tetrahydrofuran (THF), to give alpha-alkylcarbonyloxy or alpha- alkyloxyphosphonates esters respectively.
- an acylating agent in an aprotic solvent, such as acetic anhydride in pyridine
- an alkylating agent such as methyl iodide and sodium hydride in tetrahydrofuran (THF)
- the protected alpha-hydroxyphosphonates can be treated with an agent to convert the hydroxyl group to a halogen, such as conversion to a fluoro group with DAST (diethylaminosulfurtrifluoride), to prepare the alpha- halophosphonate esters.
- a halogen such as conversion to a fluoro group with DAST (diethylaminosulfurtrifluoride)
- DAST diethylaminosulfurtrifluoride
- the isopropylidene protecting group is removed from the • fully protected alpha-substituted phosphonates by reacting them with water and an acid, such as 20% water in acetic acid, to prepare the pyridoxine-alpha-substituted phosphoriate esters.
- ester groups can be removed from the phosphonate groups of the pyridoxine-alpha-substituted phosphonate esters by further treating them with acid in water, such as 20% water in acetic acid, to give the corresponding phosphonic acids as can be seen in the following scheme.
- 3,4- isopropylidenepyridoxine-5-halide can be treated with a phosphonating agent, such as, a metal salt of di-tert-butyl phosphite or dibenzyl phosphite or diphenyl phosphite, to give protected phosphonates.
- a phosphonating agent such as, a metal salt of di-tert-butyl phosphite or dibenzyl phosphite or diphenyl phosphite
- the protected phosphonates are treated with abase, such as sodium hexamethyldisilazane (NaHMDS), and a halogenating agent, such as N-fluorobenzenesulfonimide (NFSi) 5 to provide the dihalophosphonates as can be seen in the following scheme.
- a base such as sodium hexamethyldisilazane (NaHMDS)
- a halogenating agent
- 3,4- isopropylidenepyridoxine-5-al can be treated with an amine, such as p- methoxyaniline or p-aminobiphenyl 5 and a phosphonating agent, such as, a metal salt of di-tert-butyl phosphite, dibenzyl phosphite or diphenyl phosphite, to give protected aminophosphonates as can be seen in the following scheme.
- an amine such as p- methoxyaniline or p-aminobiphenyl 5
- a phosphonating agent such as, a metal salt of di-tert-butyl phosphite, dibenzyl phosphite or diphenyl phosphite
- Rl alkyl or aryl
- R 2 N-alkyl or N-aryl
- 3,4-isopropylidenepyridoxine-5- amine can be used as a starting material.
- the amine is treated with a haloalkylphosphonate diester, such as diethyl bromomethylphosphonate, to give 5'- phosphonoazaalkylpyridine diesters.
- a trialkylsilyl halide such as trimethylsilyl bromide
- the acetonide protecting group on the 3 and 4 position of the pyridoxine ring on the 3,4-iso ⁇ ropylidene ⁇ 5'- phosphonoazaalkylpyridoxine diacid can be removed by reaction with acid and water, such as 20% water in acetic acid as can be seen in the following scheme.
- 3,4-isopropylidenepyridoxine-5-al can be reacted with a metal salt of a methyl, or dihalomethyl, phosphonate diester to produce 5'-phosphonoalkylpyridoxine diesters.
- the 5'-hydroxyl group of this product is acylated by an acylating agent, such as acetic anhydride in pyridine, to provide the corresponding O-acyl derivatives respectively, or oxidized to the keto functional group by an oxidizing agent, such as manganese dioxide.
- the blocking group at the 3 and 4 positions and the phosphonate ester groups of the hydroxy, alkylcarbonyloxy and keto phosphonate diesters are hydrolyzed by reaction with acid and water, such as 20% water in acetic acid, to provide the corresponding phosphonate diesters, without the blocking group at the 3 and 4 position. These reactions are illustrated in the following scheme. 2005/001470
- R j alkyl
- R 1 alkyl
- R 2 O-CO-BIlCyI 5
- X Hs
- a therapeutic compound as defined above can be formulated into a pharmaceutical composition for use in methods of the invention.
- a pharmaceutical composition is suitable for treating angina.
- a pharmaceutical composition comprises a pharmaceutically acceptable carrier, at least one therapeutic compound of formula I, II, IH, IV, V, VI, VII, IX, or X or a pharmaceutically acceptable salt thereof, and at least one of a nitrate, a partial fatty acid oxidation inhibitor, a potassium channel activator, a calcium channel blocker, a ⁇ -adrenergic-blocker, a potassium channel activator, or a mixture thereof.
- a pharmaceutically acceptable carrier includes, but is not limited to, physiological saline, ringers, phosphate-buffered saline, and other carriers known in the art.
- compositions can also include additives, for example, stabilizers, antioxidants, colorants, excipients, binders, thickeners, dispersing agents, readsorpotion enhancers, buffers, surfactants, preservatives, emulsifiers, isotonizing agents, and diluents.
- additives for example, stabilizers, antioxidants, colorants, excipients, binders, thickeners, dispersing agents, readsorpotion enhancers, buffers, surfactants, preservatives, emulsifiers, isotonizing agents, and diluents.
- Pharmaceutically acceptable carriers and additives can be chosen such that side effects from the pharmaceutical compound are minimized and the performance of the compound is not canceled or inhibited to such an extent that treatment is ineffective.
- compositions containing a pharmaceutically acceptable carrier at least one therapeutic compound of formula I, ⁇ , ⁇ , IV, V 5 VI, Vn, IX, or X or a pharmaceutically acceptable salt thereof are known to those of skill in the art, and at least one of a nitrate, a partial fatty acid oxidation inhibitor, a potassium channel activator, a calcium channel blocker, a ⁇ - adrenergic-blocker, a potassium channel activator, or a mixture thereof.
- All methods can include the step of bringing the compound of the invention in association with the carrier and additives.
- the formulations generally are prepared by uniformly and intimately bringing the compound of the invention into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired unit dosage form.
- a solution of a therapeutic compound may be prepared by simply mixing PLP with a pharmaceutically acceptable solution, for example, buffered aqueous saline solution at a neutral or alkaline pH (because PLP. is essentially insoluble in water, alcohol, and ether), at a temperature of at least room temperature and under sterile conditions.
- a pharmaceutically acceptable solution for example, buffered aqueous saline solution at a neutral or alkaline pH (because PLP. is essentially insoluble in water, alcohol, and ether), at a temperature of at least room temperature and under sterile conditions.
- the PLP solution is , prepared immediately prior to administration to the mammal. However, if the PLP solution is prepared.at a time more than immediately prior to the administration to the mammal, the prepared solution can be stored under sterile, refrigerated conditions.
- the PLP solution can be stored in containers suitable for protecting the PLP solution from the light, such as amber-colored vials or bottles.
- a pharmaceutical composition or therapeutic compound can be administered enterally or parenterally.
- Parenteral administration includes subcutaneous, intramuscular, intradermal, intramammary, intravenous, and other administrative methods known in the art.
- Enteral administration includes solution, tablets, sustained release capsules, enteric coated capsules, and syrups.
- Compounds and compositions of the invention can also be administered nasally, s ⁇ b-lingually, and in suppository form. When administered, the pharmaceutical composition or therapeutic compound should be at or near body temperature.
- a physician of ordinary skill can readily determine a subject who may be suffering or is likely to suffer from angina. Regardless of the route of administration selected, the therapeutic compounds of formula I, II, HI 5 IV 5 V 5 VI 5 VII 5 IX 5 or X or a pharmaceutically acceptable salt thereof can be formulated into pharmaceutically acceptable unit dosage forms by conventional methods known to the pharmaceutical art. An effective but nontoxic quantity of the compound can be employed in treatment.
- the therapeutic compound of formula I 5 II, III, IV, V 5 VI 5 VII, IX 5 or X or a pharmaceutically acceptable salt thereof can be administered in enteral unit dosage forms, such as, for example s tablets, sustained-release tablets, enteric coated tablets, capsules, sustained-release capsules, enteric coated capsules, pills, powders 5 granules, solutions, and the like. They can also be administered parenterally, such as, for example, subcutaneously, intramuscularly, intradermally, intramammarally, intravenously, and other administrative methods known in the art. They can further be administered nasally, sub-lingually, or in suppository form.
- a therapeutic compound of formula I, II, III, IV, V, VI 5 VIE, IX 5 or X or a pharmaceutically acceptable salt thereof as described above is administered alone in a unit dosage form, preferably the compound is administered in admixture as a pharmaceutical composition.
- the ordinarily skilled physician will readily determine and prescribe a therapeutically effective amount of at least one therapeutic compound of formula I, II, EI, W, V, VI, VH 5 IX, or X or a pharmaceutically acceptable salt thereof to treat angina.
- the physician could employ relatively low dosages at first, subsequently increasing the dose until a maximum response is obtained.
- the particular type of angina, the severity of the symptoms, or the frequency of the attacks, the compound to be administered, the route of administration, and the characteristics of the mammal to be treated, for example, age, sex, and weight can be considered in determining the effective amount to administer.
- a therapeutic amount is in a range of about 0.1-100 mg/kg of a patient's body weight, in another embodiment, in the range of about 0.5- 50 mg/kg of a patient's body weight, per daily dose.
- the compound can be administered for periods of short or long duration. Although some individual situations can warrant to the contrary, short-term administration, for example, 30 days or less, of doses larger than 25 mg/kg of a patient's body weight is chosen when compared to long-term administration. When long-term administration, for example, months or years, is utilized, the suggested.dose generally should not exceed 25 mg/kg of a patient's body weight.
- a therapeutically effective amount of a therapeutic compound of formula I, ⁇ , m, IV, V, VI, VII, DC, or X or a pharmaceutically acceptable salt thereof for treating angina can be administered prior to, concurrently with, or after the onset of an angina attack.
- a therapeutic compound of the invention can be administered concurrently with or subsequent to compounds that are already known to be suitable for treating angina.
- Concurrent administration and “concurrently administering” as used herein includes administering a therapeutic compound and a known therapy in admixture such as, for example, in a pharmaceutical composition or in solution, or as separate components, such as, for example, separate pharmaceutical compositions or solutions administered consecutively, simultaneously, or at different times but not so distant in time such that the therapeutic compound and the known therapy cannot interact and a lower dosage amount of the active ingredient cannot be administered.
- Methods of the invention include concurrently administering ⁇ yridoxal-5'-.
- phosphate pyridoxic acid, pyridoxal, pyridoxine, pyridoxamine, 3-acylated analogues of pyridoxal, 3-acylated analogues of ⁇ yridoxal-4,5-aminal, pyridoxine phosphonate analogues with a therapeutic angina compound to treat angina.
- Therapeutic angina compounds that may be concurrently administered with a compound suitable for use in methods of the invention include a calcium channel blocker, a ⁇ -adrenergic blocker, nitrates, fatty acid oxidation inhibitors (e.g., ranolazine), potassium channel activators (e.g., nicorandil), and mixtures thereof.
- Calcium channel blockers include, but are not limited to, verapamil, diltiazem, nifedipine, felodipine, amlodipine, and nisoldipine.
- ⁇ -adrenergic blockers include, but are not limited to, acebutolol, atenolol, labetalol, metoprolol, nadolol, pindolol, and propanolol.
- Nitrates include, but are not limited to, nitroglycerine, isosorbide dinitrate, and isosorbide mononitrate.
- the dichloromethane solution was washed with saturated, aqueous NaHCC ⁇ 3 (20 mL), then saturated brine (3 x 10 mL).
- the dichloromethane layer was dried (MgSO 4 ), filtered and evaporated to give crude product as a colorless solid.
- the crude product was purified by silica gel column chromatography, using ether: hexanes (1:2) as eluent to give 1.3 g (58%).
- Example 3 Synthesis of (3-hvdroxy-4-hydroxymethyl-2-methyl-5- pyridvDhvdroxymethyl phosphonic Acid
- acetic acid 80% in water, 100 ml
- 6O 0 C acetic acid
- Another 50 ml of 80% acetic acid in water was added to the mixture and the mixture stirred at 6O 0 C for another day.
- the solid was filtered off, washed with cold water,.then methanol and dried to give a colorless solid (4.78 g, 77%).
- the dichloromethane layer was dried (MgSO 4 ), filtered and evaporated to give crude fluorophosphonate.
- the crude product was purified by silica gel column chromatography, using ethyl acetate: hexanes (1:1) as the eluent to give 350 mg (12%).
- Example 6 Synthesis of di-t-butyl (3-hydroxy-4-hvdroxymethyl-2-methyl-5- pyridvMuoromethyl phosphonate The protected di-t-butyl alpha-fluoro phosphonate from Example 5 of structure IX
- the protected di-t-butyl alpha-fluoro phosphonate from Example 5 of structure IX (200 mg, 0.5 mmol) was dissolved in acetic acid (80% in water, 15 ml) and heated at 75 0 C for 24 hours. The solvent was removed by evaporation on a rotary evaporator using toluene to codistill the water. The crude product (183 mg) was purified by column chromatography on silica using chloroform:methanol:water (65:35 :2) as eluent to give 60 mg (55%).
- the dichloromethane layer was dried (MgSO 4 ), filtered and evaporated to give crude alpha acetoxy phosph ⁇ nate as a colorless solid.
- the crude product was purified by silica gel column chromatography, using ethyl acetate: hexanes (2:1) as the eluent to give the product in good yield.
- The.solution was diluted with methylene chloride (250 mL), washed with dilute, aqueous HCL (10%, 100 mL), then saturated, aqueous NaHCO 3 , dried (MgSO 4 ) and evaporated.
- the crude product was chromatographed on silica gel using ethyl acetate/hexanes (1:1) as the eluent to give 132 mg (32%).
- Example 12 Synthesis of dibenzyl ( ⁇ 4 .3-O-isopropylidene-3-hvd.roxy-4- hydroxymethyl ⁇ -methyl-S-pyridvDdifluoromethylphosphonate
- Example 14 Synthesis of di-t-butyl ( ⁇ 4 ,3-O-iso ⁇ ro ⁇ ylidene-3-hvdroxy-4- hyo ⁇ oxymethyl-2-methyl-5-pyridyl)(4-memoxyphenylamino ' )methylphosphonate ( ⁇ 4 ,3-O-Isopropylidene-3-hydroxy-4-hydroxymethyl-2-methyl-5- ⁇ yridyl)methanal (Kortynk et al, J. Org.
- the crude imine (370 mg, 1.19 mmol) was dissolved in THF (20 mL) and added to a flask containing di-t-butyl phosphite (955 mg, 5.1 mmol) in THF (20 mL) and NaH (208 mg, 57% in oil, 4.94 mmol) and stirred at O 0 C for two hours and at room temperature for 24 hours.
- the solution was diluted with Et 2 O, washed with saturated, aqueous NaHCO3 (40 mL), brine (40 mL), dried (MgSO 4 ) and evaporated.
- Example 16 The product of Example 16, of formula XX (168 mg, 0.53 mmol) was dissolved in acetic acid (80% in water, 10 mL) and heated to 6O 0 C for 5 hours. The solvent was removed by evaporation using toluene to codistill the water. The crude product was purified by chromatography on C-18.reverse phase silica gel using methanol'.water (4:1) as eluent to give 57 mg (39%).
- Example 18 The product of Example 18, of structure XXII (300 mg, 0.84 mmol) was acetylated in pyridine (0.5 mL) and acetic anhydride (0.25 mL) at 0 0 C for 5 minutes followed by 3 hours at room temperature. The solvent was removed by evaporation using 05 001470
- Example 20 Synthesis of diethyl ( ⁇ 4 ,3-O-isopropylidene-3-hvdroxy-4- hydroxymethyl ⁇ -methyl-S-pyridyD ⁇ -hydroxy- 1 , 1 -difluoroethylphosphonate
- Example 20 The product of Example 20, of structure XXTV 5 (420 mg, 1.06 mmol) was dissolved in toluene (50 mL) and MnO 2 (651 mg, 636 mmol) added. The mixture was heated to 5O 0 C and stirred overnight. The solution was cooled, filtered (Celite) and the solvent evaporated to give the crude product. Purification by chromatography on silica gel ethyl acetate (1 :2) gave 201 mg (48%). 1 H mm * (CDCl 3 , TMS) 1.39 (q, 6H), 1.56 (d, 6H), 2.51 (s,3H), 4.34 (m, 4H), 5.08 (s, 2H) 5 8.88 (s, IH). . . .
- Example 20 The product of Example 20, of structure XXIV (489 mg, 1.26 mmol) was dissolved in acetic acid (80% in water, 20 mL) and heated at 8O 0 C for 6 hours. The solvent was removed by evaporation by codistilling with toluene to remove last traces of acetic acid. The crude product was purified by chromatography on silica . gel using dichloromethane:methanol:hexane (5:1:5) as eluent to give 171 mg (38%).
- Example 21 The product of Example 21, of structure XXV (198 mg, 0.51 mmoi) was dissolved in acetic acid (80% in water, 20 mL) and heated at 8O 0 C for 6 hours. The solvent was removed by evaporation by codistilling with toluene to remove last traces of acetic acid. The crude product was purified by chromatography on silica gel using dichloromethane:methanol:hexane (5:1 :5) as eluent to give 25 mg (14%).
- 1 HNMR (CDCl 3 , TMS) 1.38 (m, 6H) 5 2.37 (s,3H), 4.33 (m, 4H), 4.92 (s, IH) 5 7.88 (s, IH).
- Example 25 Treatment of Stress-induced angina with P5P Patients with a history of exercise induced angina are treated with P5P either before or after the onset of angina.
- Several measures are used to test the effectiveness of P5P for the treatment of angina including the time to onset of angina, exercise duration, time to lmm ST depression, and patient pain evaluation. Studies ' find that onset to angina, time to lmm ST depression, and patient pain, are all diminished, and exercise duration is increased, in patient groups treated with P5P.
- Example 26 Animal models for treatment of stress-induced angina
- the canine model of myocardial ischemia, the canine model of exertional dysfunction, and the isolated perfused rate heart model of low flow ischemia, as previously and elsewhere described, is used to determine the effectiveness of P5P, pyridoxal, pyridoxine, and the compounds synthesized in Examples 1-24, to determine effectiveness of these compounds in treatment of angina.
- Groups treated with P5P, pyridoxal, pyridoxine, and the compounds synthesized in Examples 1-24 show varying symptoms and levels of angina, however, all treatment groups exhibit significantly lower symptoms and levels of angina than untreated or sham treated control animals.
- Example 27 Effect of P5P on glucose oxidation rates or cardiac function Study Design
- Rat hearts were cannulated for isolated working heart perfusions as described previously (Lopaschuk et al., J Pharmacol Exp Ther. 1993 Jan;264(l):135-44).
- mice Male Sprague-Dawley rats (0.3-0.35 kg) were anesthetized with pentobarbital sodium (60 mg/ kg i. p.). The hearts were quickly excised, the aorta was cannulated, and a retrograde perfusion at 37°C was initiated at a hydrostatic pressure of 60 ' mm Hg. Hearts were trimmed of excess tissue, and the pulmonary ⁇ artery and the opening to the left atrium were then cannulated. After 15 min of Langendorff perfusion, hearts were switched to the working mode by clamping the aortic inflow line from the Langendorff reservoir and opening the left atrial inflow line.
- the perfusate was delivered from an oxygenator into the left atrium at a constant preload pressure of 11 mm Hg.
- the perfusate was ej ected from spontaneously beating hearts into a compliance chamber (containing 1 ml of air) and . into the aortic outflow line.
- the afterload was set at a hydrostatic pressure of 80 mm Hg. : ⁇ " • ⁇ ⁇ ⁇ . " . . '
- Coronary flow was calculated as the difference between cardiac output and aortic flow.
- Glucose oxidation was measured by perfusing the hearts with [ 14 C] glucose. The total myocardial 3 EbO production and 14 CO 2 production were determined at 10- min intervals from the 60-minute aerobic period. Glucose oxidation rates were determined by quantitative measurement of 14 CO 2 production as described previously. An imbalance between glycolysis and glucose oxidation can explain the detrimental effects of high levels of fatty acids during aerobic reperfusion of . ischemic hearts. Lopaschaulk, et al., J Pharmacol Exp Ther. 1993; 264: 135-144.).
- DCA positive control
- Example 28 Treatment of stress-induced angina with P5P combination therapies . . ⁇
- Example 25 The experiment of Example 25 is repeated, this time testing combination therapies.
- Patient groups are as follows: placebo-treated, P5P-treated, propanolol treated, P5P + propanolol treated, verapamil treated, P5P + verapamil treated, ranolazine treated, P5P + ranolazine treated, isosorbide dinitrate treated, P5P + isosorbide dinitrate treated, nicorandil treated, P5P + nicorandil treated.
- the inventors find that P5P treatment alone improves angina outcomes, confirming the . results of Example 25.
- combination treatments P5P + propanolol, P5P + verapamil, P5P + ranolazine, P5P + isosorbide dinitrate, P5P + nicorandil
- have significantly improved and advantageous angina outcomes when directly compared to treatment with their respective therapeutic angina compounds a ⁇ one i.e. propanolol, verapamil, ranolazine, isosorbide dinitrate, and nicorandil, respectively.
- Example 29 Treatment of stress4nduced angina with pyridoxine combination therapies .
- Example 28 The Experiments of Example 28 are repeated, this time using pyridoxine instead of P5P.
- Patient groups are thus as follows: placebo-treated, pyridoxine treated, propanolol treated, pyridoxine + propanolol treated, verapamil treated, pyridoxine + verapamil treated, ranolazine treated, pyridoxine + ranolazine treated, isosorbide dinitrate treated, pyridoxine + isosorbide dinitrate treated, nicorandil treated, pyridoxine + nicorandil treated.
- Example 26 The animal model experiments of Example 26 are repeated, this time with the combination treatment groups as elucidated in Examples 28, 29 and 30.
- the inventors find that combination treatments have significantly improved and advantageous angina outcomes when directly compared to treatment with their respective therapeutic angina compounds alone.
- Example 32 Effect of combination therapies on glucose oxidation rates or cardiac function
- Example 27 The experiments of Example 27 are repeated, this time with the combination treatment groups as elucidated in Examples 28, 29 and 30.
- the inventors find that combination treatments have significantly improved and advantageous angina outcomes when directly compared to treatment with their respective therapeutic angina compounds alone.
Abstract
Description
Claims
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US11/663,824 US20080311099A1 (en) | 2004-09-24 | 2005-09-26 | Pyridoxal-5-Phosphate and Related Compounds in Combination With Therapeutic Cardiovascular Compounds for Treating Angina |
EP05850112A EP1796685A1 (en) | 2004-09-24 | 2005-09-26 | Pyridoxal-5´-phosphate and related compounds in combination with therapeutic cadiovascular compounds for treating angina. |
CA002580970A CA2580970A1 (en) | 2004-09-24 | 2005-09-26 | Pyridoxal-5´-phosphate and related compounds in combination with therapeutic cardiovascular compounds for treating angina. |
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US7375112B2 (en) | 2005-01-05 | 2008-05-20 | Medicure International Inc. | Compounds and methods for regulating triglyceride levels |
WO2008135743A1 (en) * | 2007-05-02 | 2008-11-13 | Queen Mary And Westfield College | Substituted phosphonates and their use in decreasing amyloid aggregates |
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WO2001013900A2 (en) * | 1999-08-24 | 2001-03-01 | Medicure International Inc. | Compositions for the treatment of cardiovascular diseases containing pyridoxal compounds and cardiovascular compounds |
-
2005
- 2005-09-26 US US11/663,824 patent/US20080311099A1/en not_active Abandoned
- 2005-09-26 WO PCT/CA2005/001470 patent/WO2006058411A1/en active Application Filing
- 2005-09-26 EP EP05850112A patent/EP1796685A1/en not_active Withdrawn
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WO2001013900A2 (en) * | 1999-08-24 | 2001-03-01 | Medicure International Inc. | Compositions for the treatment of cardiovascular diseases containing pyridoxal compounds and cardiovascular compounds |
Non-Patent Citations (6)
Title |
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"Stedman's Medical Dictionary", 1961, WAVERLY PRESS INC., BALTIMORE, MD, pages: 101 * |
DYCK J.R.B. ET AL: "Malonyl CoA control of fatty acid oxidation in the ischemic heart", J.MOL. CELL CARDIOL., vol. 34, no. 9, September 2002 (2002-09-01), pages 1099 - 1109 * |
LOPASCHUK G.D. ET AL: "Glucose metabolism in the ischemic heart", CIRCULATION, vol. 95, 1997, pages 313 - 315 * |
PHAM V. ET AL: "Design and synthesis of novel pyridoxine 5'-phosphonates as potential antiischemic agents", J.MED.CHEM., vol. 46, no. 17, 14 August 2003 (2003-08-14), pages 3681 - 3682 * |
RUPP H. ET AL: "The use of partial fatty acid oxidation inhibitors for metabolic therapy of angina pectoris and heart failure", HERZ, vol. 27, no. 7, November 2002 (2002-11-01), pages 621 - 636 * |
STANLEY W.C.: "Partial fatty acid oxidation inhibitors for stable angina", EXPERT OPINION ON INVESTIGATIVE DRUGS, vol. 11, no. 5, May 2002 (2002-05-01), pages 615 - 629 * |
Cited By (3)
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US7375112B2 (en) | 2005-01-05 | 2008-05-20 | Medicure International Inc. | Compounds and methods for regulating triglyceride levels |
WO2008135743A1 (en) * | 2007-05-02 | 2008-11-13 | Queen Mary And Westfield College | Substituted phosphonates and their use in decreasing amyloid aggregates |
US8513219B2 (en) | 2007-05-02 | 2013-08-20 | Queen Mary & Westfield College, University Of London | Substituted phosphonates and their use in decreasing amyloid aggregates |
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US20080311099A1 (en) | 2008-12-18 |
CA2580970A1 (en) | 2006-06-08 |
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