CA2588949A1

CA2588949A1 - Compounds with mixed pde-inhibitory and .beta.-adrenergic antagonist or partial agonist activity for treatment of heart failure

Compounds with mixed pde-inhibitory and .beta.-adrenergic antagonist or partial agonist activity for treatment of heart failure Download PDF

Info

Publication number: CA2588949A1
Authority: CA; Canada
Prior art keywords: compound; radicals; group; propoxy; phenyl
Prior art date: 2004-11-30
Legal status : Abandoned

Application number

CA002588949A

Other languages

English (en)

French (fr)

Inventor

Malcolm George Taylor

Burkhard Klenke

Peter D. Suzdak

Reza Mazhari

Current Assignee

Artesian Therapeutics Inc

Original Assignee

Individual

Priority date

2004-11-30

Filing date

2005-11-08

Publication date

2006-06-08

2005-11-08 Application filed by Individual filed Critical Individual

2006-06-08 Publication of CA2588949A1 publication Critical patent/CA2588949A1/en

Status Abandoned legal-status Critical Current

Links

150000001875 compounds Chemical class 0.000 title claims abstract description 178
206010019280 Heart failures Diseases 0.000 title claims description 17
230000000694 effects Effects 0.000 title description 22
239000000674 adrenergic antagonist Substances 0.000 title description 5
239000004031 partial agonist Substances 0.000 title description 2
238000000034 method Methods 0.000 claims abstract description 46
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 22
239000008194 pharmaceutical composition Substances 0.000 claims abstract description 17
230000002401 inhibitory effect Effects 0.000 claims abstract description 16
208000035475 disorder Diseases 0.000 claims abstract description 13
208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 6
102000004861 Phosphoric Diester Hydrolases Human genes 0.000 claims abstract description 6
108090001050 Phosphoric Diester Hydrolases Proteins 0.000 claims abstract description 6
208000019695 Migraine disease Diseases 0.000 claims abstract description 5
208000006011 Stroke Diseases 0.000 claims abstract description 5
206010015037 epilepsy Diseases 0.000 claims abstract description 5
206010027599 migraine Diseases 0.000 claims abstract description 5
-1 2-amino-1-hydroxyeth-1-yl radical Chemical class 0.000 claims description 197
150000003254 radicals Chemical class 0.000 claims description 58
239000000203 mixture Substances 0.000 claims description 50
229910052739 hydrogen Inorganic materials 0.000 claims description 45
YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 claims description 30
125000000217 alkyl group Chemical group 0.000 claims description 19
241001465754 Metazoa Species 0.000 claims description 16
125000001424 substituent group Chemical group 0.000 claims description 14
229910052727 yttrium Inorganic materials 0.000 claims description 11
125000003342 alkenyl group Chemical group 0.000 claims description 10
229910052721 tungsten Inorganic materials 0.000 claims description 10
229910052720 vanadium Inorganic materials 0.000 claims description 10
125000003118 aryl group Chemical group 0.000 claims description 9
125000004093 cyano group Chemical group *C#N 0.000 claims description 9
201000010099 disease Diseases 0.000 claims description 9
239000003937 drug carrier Substances 0.000 claims description 9
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 9
125000004043 oxo group Chemical group O=* 0.000 claims description 9
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
239000001257 hydrogen Substances 0.000 claims description 8
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 7
125000004450 alkenylene group Chemical group 0.000 claims description 7
125000002947 alkylene group Chemical group 0.000 claims description 7
230000004094 calcium homeostasis Effects 0.000 claims description 7
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
206010007558 Cardiac failure chronic Diseases 0.000 claims description 6
206010007559 Cardiac failure congestive Diseases 0.000 claims description 6
125000004414 alkyl thio group Chemical group 0.000 claims description 6
125000006588 heterocycloalkylene group Chemical group 0.000 claims description 6
KQMJLUHMRFZKEY-NRFANRHFSA-N n-[2-[4-[(2s)-3-(tert-butylamino)-2-hydroxypropoxy]phenyl]ethyl]-2-[4-(6-oxo-4,5-dihydro-1h-pyridazin-3-yl)phenoxy]acetamide Chemical compound C1=CC(OC[C@@H](O)CNC(C)(C)C)=CC=C1CCNC(=O)COC1=CC=C(C=2CCC(=O)NN=2)C=C1 KQMJLUHMRFZKEY-NRFANRHFSA-N 0.000 claims description 6
HZXRRWYLGCNFEB-UHFFFAOYSA-N n-[2-[4-[3-(tert-butylamino)-2-hydroxypropoxy]phenyl]ethyl]-2-[2-chloro-4-(6-oxo-4,5-dihydro-1h-pyridazin-3-yl)phenoxy]acetamide Chemical compound C1=CC(OCC(O)CNC(C)(C)C)=CC=C1CCNC(=O)COC1=CC=C(C=2CCC(=O)NN=2)C=C1Cl HZXRRWYLGCNFEB-UHFFFAOYSA-N 0.000 claims description 6
FLJSKMRBQZTAQT-UHFFFAOYSA-N n-[[4-[3-(tert-butylamino)-2-hydroxypropoxy]phenyl]methyl]-2-[2-chloro-4-(6-oxo-4,5-dihydro-1h-pyridazin-3-yl)phenoxy]acetamide Chemical compound C1=CC(OCC(O)CNC(C)(C)C)=CC=C1CNC(=O)COC1=CC=C(C=2CCC(=O)NN=2)C=C1Cl FLJSKMRBQZTAQT-UHFFFAOYSA-N 0.000 claims description 6
GTVQURYUYGYVDR-UHFFFAOYSA-N 2-[2-chloro-4-(6-oxo-4,5-dihydro-1h-pyridazin-3-yl)phenoxy]-n-[[4-[2-hydroxy-3-(propan-2-ylamino)propoxy]phenyl]methyl]acetamide Chemical compound C1=CC(OCC(O)CNC(C)C)=CC=C1CNC(=O)COC1=CC=C(C=2CCC(=O)NN=2)C=C1Cl GTVQURYUYGYVDR-UHFFFAOYSA-N 0.000 claims description 5
LPFKKNRVAFTENR-UHFFFAOYSA-N 3-[3-chloro-4-[2-[4-[2-hydroxy-3-(propan-2-ylamino)propoxy]phenyl]ethoxy]phenyl]-4,5-dihydro-1h-pyridazin-6-one Chemical compound C1=CC(OCC(O)CNC(C)C)=CC=C1CCOC1=CC=C(C=2CCC(=O)NN=2)C=C1Cl LPFKKNRVAFTENR-UHFFFAOYSA-N 0.000 claims description 5
LPHTUGOMETZXKX-QFIPXVFZSA-N 3-[4-[3-[2-[4-[(2s)-3-(tert-butylamino)-2-hydroxypropoxy]phenyl]ethoxy]propoxy]-3-chlorophenyl]-4,5-dihydro-1h-pyridazin-6-one Chemical compound C1=CC(OC[C@@H](O)CNC(C)(C)C)=CC=C1CCOCCCOC1=CC=C(C=2CCC(=O)NN=2)C=C1Cl LPHTUGOMETZXKX-QFIPXVFZSA-N 0.000 claims description 5
WUMDEDHGYLBFTD-UHFFFAOYSA-N 3-[4-[3-[[4-[3-(tert-butylamino)-2-hydroxypropoxy]phenyl]methoxy]propoxy]-3-chlorophenyl]-4,5-dihydro-1h-pyridazin-6-one Chemical compound C1=CC(OCC(O)CNC(C)(C)C)=CC=C1COCCCOC1=CC=C(C=2CCC(=O)NN=2)C=C1Cl WUMDEDHGYLBFTD-UHFFFAOYSA-N 0.000 claims description 5
206010020772 Hypertension Diseases 0.000 claims description 5
206010003119 arrhythmia Diseases 0.000 claims description 5
230000006793 arrhythmia Effects 0.000 claims description 5
ALQSLSCVJSPTIL-UHFFFAOYSA-N 2-[2-chloro-4-(6-oxo-4,5-dihydro-1h-pyridazin-3-yl)phenoxy]-n-[2-[4-[2-hydroxy-3-(propan-2-ylamino)propoxy]phenyl]ethyl]acetamide Chemical compound C1=CC(OCC(O)CNC(C)C)=CC=C1CCNC(=O)COC1=CC=C(C=2CCC(=O)NN=2)C=C1Cl ALQSLSCVJSPTIL-UHFFFAOYSA-N 0.000 claims description 4
241000124008 Mammalia Species 0.000 claims description 4
229910052760 oxygen Inorganic materials 0.000 claims description 4
UVSBDRRJOCXMPP-QFIPXVFZSA-N 3-[3-chloro-4-[3-[2-[4-[(2s)-2-hydroxy-3-(propan-2-ylamino)propoxy]phenyl]ethoxy]propoxy]phenyl]-4,5-dihydro-1h-pyridazin-6-one Chemical compound C1=CC(OC[C@@H](O)CNC(C)C)=CC=C1CCOCCCOC1=CC=C(C=2CCC(=O)NN=2)C=C1Cl UVSBDRRJOCXMPP-QFIPXVFZSA-N 0.000 claims description 3
FIKNZEFYNKNAKF-UHFFFAOYSA-N 3-[3-chloro-4-[3-[[4-[2-hydroxy-3-(propan-2-ylamino)propoxy]phenyl]methoxy]propoxy]phenyl]-4,5-dihydro-1h-pyridazin-6-one Chemical compound C1=CC(OCC(O)CNC(C)C)=CC=C1COCCCOC1=CC=C(C=2CCC(=O)NN=2)C=C1Cl FIKNZEFYNKNAKF-UHFFFAOYSA-N 0.000 claims description 3
FYDFMFOMILPYLA-UHFFFAOYSA-N 3-[4-[2-[4-[3-(tert-butylamino)-2-hydroxypropoxy]phenyl]ethoxy]-3-chlorophenyl]-4,5-dihydro-1h-pyridazin-6-one Chemical compound C1=CC(OCC(O)CNC(C)(C)C)=CC=C1CCOC1=CC=C(C=2CCC(=O)NN=2)C=C1Cl FYDFMFOMILPYLA-UHFFFAOYSA-N 0.000 claims description 3
AHNNKJCYHBXTGM-UHFFFAOYSA-N 3-[4-[2-[[4-[3-(tert-butylamino)-2-hydroxypropoxy]-9h-carbazol-1-yl]-methylamino]ethoxy]-3-chlorophenyl]-4,5-dihydro-1h-pyridazin-6-one Chemical compound C=1C=C(OCC(O)CNC(C)(C)C)C(C2=CC=CC=C2N2)=C2C=1N(C)CCOC(C(=C1)Cl)=CC=C1C1=NNC(=O)CC1 AHNNKJCYHBXTGM-UHFFFAOYSA-N 0.000 claims description 3
206010002383 Angina Pectoris Diseases 0.000 claims description 3
125000004406 C3-C8 cycloalkylene group Chemical group 0.000 claims description 3
210000001992 atrioventricular node Anatomy 0.000 claims description 3
206010020871 hypertrophic cardiomyopathy Diseases 0.000 claims description 3
238000001990 intravenous administration Methods 0.000 claims description 3
125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 claims description 3
230000001105 regulatory effect Effects 0.000 claims description 3
125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 3
125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 3
LWMPOMSZJGBJOT-UHFFFAOYSA-N 3-[3-chloro-4-[2-[[4-[2-hydroxy-3-[2-(2-methoxyphenoxy)ethylamino]propoxy]-9h-carbazol-1-yl]-methylamino]ethoxy]phenyl]-4,5-dihydro-1h-pyridazin-6-one Chemical compound COC1=CC=CC=C1OCCNCC(O)COC(C=1C2=CC=CC=C2NC=11)=CC=C1N(C)CCOC1=CC=C(C=2CCC(=O)NN=2)C=C1Cl LWMPOMSZJGBJOT-UHFFFAOYSA-N 0.000 claims description 2
UGZYTKOPRHIGTQ-UHFFFAOYSA-N 5-[2-[3-[4-[2-hydroxy-3-(propan-2-ylamino)propoxy]phenoxy]propoxy]pyridin-4-yl]-6-methyl-2-oxo-1h-pyridine-3-carbonitrile Chemical compound C1=CC(OCC(O)CNC(C)C)=CC=C1OCCCOC1=CC(C2=C(NC(=O)C(C#N)=C2)C)=CC=N1 UGZYTKOPRHIGTQ-UHFFFAOYSA-N 0.000 claims description 2
125000003277 amino group Chemical group 0.000 claims description 2
150000005840 aryl radicals Chemical class 0.000 claims description 2
230000033228 biological regulation Effects 0.000 claims description 2
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241000179948 Sarcophaga beta Species 0.000 claims 3
125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 2
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
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YBRMEBLELNNTJM-UHFFFAOYSA-N 2-[2-chloro-4-(6-oxo-4,5-dihydro-1h-pyridazin-3-yl)phenoxy]-n-[[4-(oxiran-2-ylmethoxy)phenyl]methyl]acetamide Chemical compound ClC1=CC(C=2CCC(=O)NN=2)=CC=C1OCC(=O)NCC(C=C1)=CC=C1OCC1CO1 YBRMEBLELNNTJM-UHFFFAOYSA-N 0.000 description 4
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