CA2563377A1

CA2563377A1 - Methods of using and compositions comprising pde4 modulators for the treatment and management of pulmonary hypertension

Methods of using and compositions comprising pde4 modulators for the treatment and management of pulmonary hypertension Download PDF

Info

Publication number: CA2563377A1
Authority: CA; Canada
Prior art keywords: carbon atoms; alkyl; substituted; amino; phenyl
Prior art date: 2004-04-23
Legal status : Abandoned

Application number

CA002563377A

Other languages

English (en)

French (fr)

Inventor

Jerome B. Zeldis

Current Assignee

Celgene Corp

Original Assignee

Individual

Priority date

2004-04-23

Filing date

2005-04-21

Publication date

2005-11-03

2005-04-21 Application filed by Individual filed Critical Individual

2005-11-03 Publication of CA2563377A1 publication Critical patent/CA2563377A1/en

Status Abandoned legal-status Critical Current

Links

208000002815 pulmonary hypertension Diseases 0.000 title claims abstract description 121
238000000034 method Methods 0.000 title claims abstract description 48
238000011282 treatment Methods 0.000 title claims description 19
239000000203 mixture Substances 0.000 title description 37
101100296719 Caenorhabditis elegans pde-4 gene Proteins 0.000 title 1
-1 hydrate) Chemical class 0.000 claims abstract description 220
101100296720 Dictyostelium discoideum Pde4 gene Proteins 0.000 claims abstract description 89
101100082610 Plasmodium falciparum (isolate 3D7) PDEdelta gene Proteins 0.000 claims abstract description 89
239000013543 active substance Substances 0.000 claims abstract description 89
150000003839 salts Chemical class 0.000 claims abstract description 40
239000012453 solvate Substances 0.000 claims abstract description 35
239000008194 pharmaceutical composition Substances 0.000 claims abstract description 34
238000002054 transplantation Methods 0.000 claims abstract description 18
210000004072 lung Anatomy 0.000 claims abstract description 13
210000001147 pulmonary artery Anatomy 0.000 claims abstract description 13
230000004872 arterial blood pressure Effects 0.000 claims abstract description 10
238000001356 surgical procedure Methods 0.000 claims abstract description 7
125000004432 carbon atom Chemical group C* 0.000 claims description 299
125000000217 alkyl group Chemical group 0.000 claims description 199
125000003545 alkoxy group Chemical group 0.000 claims description 92
125000004093 cyano group Chemical group *C#N 0.000 claims description 88
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 79
229910052739 hydrogen Inorganic materials 0.000 claims description 78
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 77
239000001257 hydrogen Substances 0.000 claims description 76
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 73
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 65
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 63
125000001424 substituent group Chemical group 0.000 claims description 56
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 44
206010064911 Pulmonary arterial hypertension Diseases 0.000 claims description 27
208000004248 Familial Primary Pulmonary Hypertension Diseases 0.000 claims description 23
201000008312 primary pulmonary hypertension Diseases 0.000 claims description 22
MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims description 20
BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 claims description 20
LMHIPJMTZHDKEW-XQYLJSSYSA-M Epoprostenol sodium Chemical compound [Na+].O1\C(=C/CCCC([O-])=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 LMHIPJMTZHDKEW-XQYLJSSYSA-M 0.000 claims description 17
GJPICJJJRGTNOD-UHFFFAOYSA-N bosentan Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2N=CC=CN=2)OCCO)=C1NS(=O)(=O)C1=CC=C(C(C)(C)C)C=C1 GJPICJJJRGTNOD-UHFFFAOYSA-N 0.000 claims description 17
125000003282 alkyl amino group Chemical group 0.000 claims description 16
PAJMKGZZBBTTOY-ZFORQUDYSA-N treprostinil Chemical compound C1=CC=C(OCC(O)=O)C2=C1C[C@@H]1[C@@H](CC[C@@H](O)CCCCC)[C@H](O)C[C@@H]1C2 PAJMKGZZBBTTOY-ZFORQUDYSA-N 0.000 claims description 16
229960001123 epoprostenol Drugs 0.000 claims description 15
DHKAFTYWTCIWJX-UHFFFAOYSA-N 3-(3,4-dimethoxyphenyl)-3-(3-oxo-1h-isoindol-2-yl)propanamide Chemical group C1=C(OC)C(OC)=CC=C1C(CC(N)=O)N1C(=O)C2=CC=CC=C2C1 DHKAFTYWTCIWJX-UHFFFAOYSA-N 0.000 claims description 14
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239000003071 vasodilator agent Substances 0.000 claims description 14
208000024891 symptom Diseases 0.000 claims description 12
PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 claims description 12
125000000000 cycloalkoxy group Chemical group 0.000 claims description 11
125000001624 naphthyl group Chemical group 0.000 claims description 11
208000037812 secondary pulmonary hypertension Diseases 0.000 claims description 11
125000002030 1,2-phenylene group Chemical group [H]C1=C([H])C([*:1])=C([*:2])C([H])=C1[H] 0.000 claims description 10
229940127291 Calcium channel antagonist Drugs 0.000 claims description 10
125000004442 acylamino group Chemical group 0.000 claims description 10
125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 10
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239000000480 calcium channel blocker Substances 0.000 claims description 9
125000004663 dialkyl amino group Chemical group 0.000 claims description 9
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239000003146 anticoagulant agent Substances 0.000 claims description 8
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LTMHDMANZUZIPE-PUGKRICDSA-N digoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)[C@H](O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O LTMHDMANZUZIPE-PUGKRICDSA-N 0.000 claims description 8
LTMHDMANZUZIPE-UHFFFAOYSA-N digoxine Natural products C1C(O)C(O)C(C)OC1OC1C(C)OC(OC2C(OC(OC3CC4C(C5C(C6(CCC(C6(C)C(O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)CC2O)C)CC1O LTMHDMANZUZIPE-UHFFFAOYSA-N 0.000 claims description 8
LVRLSYPNFFBYCZ-VGWMRTNUSA-N omapatrilat Chemical compound C([C@H](S)C(=O)N[C@H]1CCS[C@H]2CCC[C@H](N2C1=O)C(=O)O)C1=CC=CC=C1 LVRLSYPNFFBYCZ-VGWMRTNUSA-N 0.000 claims description 8
TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 claims description 8
RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 claims description 8
229960005080 warfarin Drugs 0.000 claims description 8
229960002240 iloprost Drugs 0.000 claims description 7
HIFJCPQKFCZDDL-ACWOEMLNSA-N iloprost Chemical compound C1\C(=C/CCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)C(C)CC#CC)[C@H](O)C[C@@H]21 HIFJCPQKFCZDDL-ACWOEMLNSA-N 0.000 claims description 7
239000003112 inhibitor Substances 0.000 claims description 7
229950005143 sitosterol Drugs 0.000 claims description 7
KZJWDPNRJALLNS-VJSFXXLFSA-N sitosterol 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)CC[C@@H](CC)C(C)C)[C@@]1(C)CC2 KZJWDPNRJALLNS-VJSFXXLFSA-N 0.000 claims description 7
ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 claims description 6
229930064664 L-arginine Natural products 0.000 claims description 6
235000014852 L-arginine Nutrition 0.000 claims description 6
239000005557 antagonist Substances 0.000 claims description 6
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229940097217 cardiac glycoside Drugs 0.000 claims description 6
239000002368 cardiac glycoside Substances 0.000 claims description 6
HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 claims description 6
229960001597 nifedipine Drugs 0.000 claims description 6
239000002571 phosphodiesterase inhibitor Substances 0.000 claims description 6
150000003815 prostacyclins Chemical class 0.000 claims description 6
229960003310 sildenafil Drugs 0.000 claims description 6
229930002534 steroid glycoside Natural products 0.000 claims description 6
RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 claims description 6
TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 claims description 5
RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 claims description 5
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 description 5
229960000528 amlodipine Drugs 0.000 claims description 5
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 5
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239000002947 C09CA04 - Irbesartan Substances 0.000 claims description 4
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LXFIMHZDTHLHOA-UHFFFAOYSA-N 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-(1h-pyrrol-2-yl)isoindole-1,3-dione Chemical compound C1=C(OC)C(OCC)=CC(C(CS(C)(=O)=O)N2C(C3=C(C=4NC=CC=4)C=CC=C3C2=O)=O)=C1 LXFIMHZDTHLHOA-UHFFFAOYSA-N 0.000 claims description 2
HPNGOUOSHMENJP-UHFFFAOYSA-N 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-(1h-pyrrol-2-ylmethyl)isoindole-1,3-dione Chemical compound C1=C(OC)C(OCC)=CC(C(CS(C)(=O)=O)N2C(C3=C(CC=4NC=CC=4)C=CC=C3C2=O)=O)=C1 HPNGOUOSHMENJP-UHFFFAOYSA-N 0.000 claims description 2
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GQFMVEASNXTCHG-UHFFFAOYSA-N 4-(aminomethyl)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]isoindole-1,3-dione;hydrochloride Chemical compound Cl.C1=C(OC)C(OCC)=CC(C(CS(C)(=O)=O)N2C(C3=C(CN)C=CC=C3C2=O)=O)=C1 GQFMVEASNXTCHG-UHFFFAOYSA-N 0.000 claims 1
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