CA2678256A1

CA2678256A1 - Methodes de traitement de maladies vasculaires caracterisees par une insuffisance en monoxyde d'azote

Methodes de traitement de maladies vasculaires caracterisees par une insuffisance en monoxyde d'azote Download PDF

Info

Publication number: CA2678256A1
Authority: CA; Canada
Prior art keywords: nitric oxide; compound; nitrosated; hypertension; antioxidant
Prior art date: 2000-10-27
Legal status : Abandoned

Application number

CA002678256A

Other languages

English (en)

Inventor

Joseph Loscalzo

Joseph A. Vita

Michael D. Loberg

Manuel Worcel

Current Assignee

Boston University

Nitromed Inc

Original Assignee

Individual

Priority date

2000-10-27

Filing date

2001-05-02

Publication date

2002-05-02

2000-10-27 Priority claimed from PCT/US2000/029582 external-priority patent/WO2001035509A1/fr

2000-10-27 Priority claimed from US09/697,317 external-priority patent/US6635273B1/en

2001-05-02 Application filed by Individual filed Critical Individual

2002-05-02 Publication of CA2678256A1 publication Critical patent/CA2678256A1/fr

Status Abandoned legal-status Critical Current

Links

MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 title claims abstract description 444
238000000034 method Methods 0.000 title claims abstract description 145
208000019553 vascular disease Diseases 0.000 title claims abstract description 25
150000001875 compounds Chemical class 0.000 claims abstract description 150
239000000203 mixture Substances 0.000 claims abstract description 122
239000003963 antioxidant agent Substances 0.000 claims abstract description 96
-1 hydralazine compound Chemical class 0.000 claims abstract description 96
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239000012730 sustained-release form Substances 0.000 claims abstract description 58
238000013268 sustained release Methods 0.000 claims abstract description 57
208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 56
102000008299 Nitric Oxide Synthase Human genes 0.000 claims abstract description 43
108010021487 Nitric Oxide Synthase Proteins 0.000 claims abstract description 43
239000000066 endothelium dependent relaxing factor Substances 0.000 claims abstract description 43
238000012546 transfer Methods 0.000 claims abstract description 42
238000009472 formulation Methods 0.000 claims abstract description 40
239000000758 substrate Substances 0.000 claims abstract description 40
RPTUSVTUFVMDQK-UHFFFAOYSA-N hydrallazine Natural products C1=CC=C2C(NN)=NN=CC2=C1 RPTUSVTUFVMDQK-UHFFFAOYSA-N 0.000 claims abstract description 34
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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 35
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ZUXNZUWOTSUBMN-UHFFFAOYSA-N hydralazine hydrochloride Chemical compound Cl.C1=CC=C2C(NN)=NN=CC2=C1 ZUXNZUWOTSUBMN-UHFFFAOYSA-N 0.000 claims description 30
101710129690 Angiotensin-converting enzyme inhibitor Proteins 0.000 claims description 29
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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 26
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CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 14
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RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 claims description 14
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HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 12
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ACTIUHUUMQJHFO-UPTCCGCDSA-N coenzyme Q10 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UPTCCGCDSA-N 0.000 claims description 12
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FQWRAVYMZULPNK-UHFFFAOYSA-N N(5)-[(Z)-amino(hydroxyimino)methyl]ornithine Chemical compound OC(=O)C(N)CCCNC(N)=NO FQWRAVYMZULPNK-UHFFFAOYSA-N 0.000 claims description 10
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KWDSFGYQALRPMG-UHFFFAOYSA-N delta-N-Hydroxy-L-orginin Natural products OC(=O)C(N)CCCN(O)C(N)=N KWDSFGYQALRPMG-UHFFFAOYSA-N 0.000 claims description 10
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125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
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206010052337 Diastolic dysfunction Diseases 0.000 claims description 9
ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 claims description 9
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ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 8
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125000004183 alkoxy alkyl group Chemical group 0.000 claims description 8
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229910052700 potassium Inorganic materials 0.000 claims description 8
239000011591 potassium Substances 0.000 claims description 8
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
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ICRHORQIUXBEPA-UHFFFAOYSA-N thionitrous acid Chemical compound SN=O ICRHORQIUXBEPA-UHFFFAOYSA-N 0.000 claims description 8
102000016938 Catalase Human genes 0.000 claims description 7
ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 claims description 7
102000006587 Glutathione peroxidase Human genes 0.000 claims description 7
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XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 7
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QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
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WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 6
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NPCOQXAVBJJZBQ-UHFFFAOYSA-N reduced coenzyme Q9 Natural products COC1=C(O)C(C)=C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)C(O)=C1OC NPCOQXAVBJJZBQ-UHFFFAOYSA-N 0.000 claims description 6
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QNTNKSLOFHEFPK-UPTCCGCDSA-N ubiquinol-10 Chemical compound COC1=C(O)C(C)=C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)C(O)=C1OC QNTNKSLOFHEFPK-UPTCCGCDSA-N 0.000 claims description 6
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