CA2530389A1

CA2530389A1 - Pyrazine and pyridine derivatives as rho kinase inhibitors

Pyrazine and pyridine derivatives as rho kinase inhibitors Download PDF

Info

Publication number: CA2530389A1
Authority: CA; Canada
Prior art keywords: phenyl; ethyl; hydroxy; pyridin; benzyl
Prior art date: 2003-07-02
Legal status : Abandoned

Application number

CA002530389A

Other languages

English (en)

French (fr)

Inventor

Veronique Birault

John C. Harris

Current Assignee

Galapagos NV

Original Assignee

Individual

Priority date

2003-07-02

Filing date

2004-07-01

Publication date

2005-01-13

2003-07-02 Priority claimed from GBGB0315494.5A external-priority patent/GB0315494D0/en

2004-07-01 Application filed by Individual filed Critical Individual

2005-01-13 Publication of CA2530389A1 publication Critical patent/CA2530389A1/en

Status Abandoned legal-status Critical Current

Links

239000003590 rho kinase inhibitor Substances 0.000 title description 2
KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 title 2
PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 title 1
150000003222 pyridines Chemical class 0.000 title 1
150000001875 compounds Chemical class 0.000 claims abstract description 143
238000000034 method Methods 0.000 claims abstract description 31
238000011282 treatment Methods 0.000 claims abstract description 21
230000001225 therapeutic effect Effects 0.000 claims abstract description 14
206010028980 Neoplasm Diseases 0.000 claims abstract description 11
201000011510 cancer Diseases 0.000 claims abstract description 10
206010020772 Hypertension Diseases 0.000 claims abstract description 9
208000030507 AIDS Diseases 0.000 claims abstract description 8
206010003210 Arteriosclerosis Diseases 0.000 claims abstract description 8
206010003225 Arteriospasm coronary Diseases 0.000 claims abstract description 8
208000003890 Coronary Vasospasm Diseases 0.000 claims abstract description 8
208000011775 arteriosclerosis disease Diseases 0.000 claims abstract description 8
201000011634 coronary artery vasospasm Diseases 0.000 claims abstract description 8
239000003814 drug Substances 0.000 claims abstract description 8
238000004519 manufacturing process Methods 0.000 claims abstract description 8
208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 7
208000010228 Erectile Dysfunction Diseases 0.000 claims abstract description 7
208000010412 Glaucoma Diseases 0.000 claims abstract description 7
208000001132 Osteoporosis Diseases 0.000 claims abstract description 7
208000006011 Stroke Diseases 0.000 claims abstract description 7
208000006673 asthma Diseases 0.000 claims abstract description 7
201000001881 impotence Diseases 0.000 claims abstract description 7
-1 2-pyridin-4-yl-ethyl Chemical group 0.000 claims description 239
IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
108091000080 Phosphotransferase Proteins 0.000 claims description 14
229910052757 nitrogen Inorganic materials 0.000 claims description 14
102000020233 phosphotransferase Human genes 0.000 claims description 13
230000000694 effects Effects 0.000 claims description 12
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims description 10
238000003556 assay Methods 0.000 claims description 10
125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 8
125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 8
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
125000005842 heteroatom Chemical group 0.000 claims description 8
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 8
239000001301 oxygen Chemical group 0.000 claims description 8
229910052760 oxygen Chemical group 0.000 claims description 8
239000008194 pharmaceutical composition Substances 0.000 claims description 7
125000003852 3-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(Cl)=C1[H])C([H])([H])* 0.000 claims description 6
125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 6
125000006291 3-hydroxybenzyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(=C1[H])C([H])([H])* 0.000 claims description 5
125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 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 5
125000004432 carbon atom Chemical group C* 0.000 claims description 5
FQUYSHZXSKYCSY-UHFFFAOYSA-N 1,4-diazepane Chemical compound C1CNCCNC1 FQUYSHZXSKYCSY-UHFFFAOYSA-N 0.000 claims description 4
125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 4
125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 4
125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 4
125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 4
125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 claims description 4
QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 claims description 4
125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 4
125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims description 4
125000004861 4-isopropyl phenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 4
125000004863 4-trifluoromethoxyphenyl group Chemical group [H]C1=C([H])C(OC(F)(F)F)=C([H])C([H])=C1* 0.000 claims description 4
XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 4
RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 4
230000002159 abnormal effect Effects 0.000 claims description 4
125000004122 cyclic group Chemical group 0.000 claims description 4
239000001257 hydrogen Substances 0.000 claims description 4
229910052739 hydrogen Inorganic materials 0.000 claims description 4
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 4
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
125000004193 piperazinyl group Chemical group 0.000 claims description 4
238000011321 prophylaxis Methods 0.000 claims description 4
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
125000004548 quinolin-3-yl group Chemical group N1=CC(=CC2=CC=CC=C12)* 0.000 claims description 4
125000000547 substituted alkyl group Chemical group 0.000 claims description 4
125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 4
238000006467 substitution reaction Methods 0.000 claims description 3
ILWFNKLXPUKLEP-UHFFFAOYSA-N 1-chloro-4-(chloromethyl)-2-fluorobenzene Chemical group FC1=CC(CCl)=CC=C1Cl ILWFNKLXPUKLEP-UHFFFAOYSA-N 0.000 claims description 2
125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
YCWRFIYBUQBHJI-UHFFFAOYSA-N 2-(4-aminophenyl)acetonitrile Chemical group NC1=CC=C(CC#N)C=C1 YCWRFIYBUQBHJI-UHFFFAOYSA-N 0.000 claims description 2
125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 2
LJGHYPLBDBRCRZ-UHFFFAOYSA-N 3-(3-aminophenyl)sulfonylaniline Chemical group NC1=CC=CC(S(=O)(=O)C=2C=C(N)C=CC=2)=C1 LJGHYPLBDBRCRZ-UHFFFAOYSA-N 0.000 claims description 2
125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 2
125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
125000006500 3-trifluoromethoxy benzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC(F)(F)F)=C1[H])C([H])([H])* 0.000 claims description 2
125000006281 4-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)C([H])([H])* 0.000 claims description 2
125000000242 4-chlorobenzoyl group Chemical group ClC1=CC=C(C(=O)*)C=C1 0.000 claims description 2
125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
125000003143 4-hydroxybenzyl group Chemical group [H]C([*])([H])C1=C([H])C([H])=C(O[H])C([H])=C1[H] 0.000 claims description 2
125000004864 4-thiomethylphenyl group Chemical group 0.000 claims description 2
125000004244 benzofuran-2-yl group Chemical group [H]C1=C(*)OC2=C([H])C([H])=C([H])C([H])=C12 0.000 claims description 2
TUWZZXGAUMSUOB-UHFFFAOYSA-N benzyl piperidine-1-carboxylate Chemical compound C1CCCCN1C(=O)OCC1=CC=CC=C1 TUWZZXGAUMSUOB-UHFFFAOYSA-N 0.000 claims description 2
UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 claims description 2
125000004551 isoquinolin-3-yl group Chemical group C1=NC(=CC2=CC=CC=C12)* 0.000 claims description 2
125000004552 isoquinolin-4-yl group Chemical group C1=NC=C(C2=CC=CC=C12)* 0.000 claims description 2
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
125000004549 quinolin-4-yl group Chemical group N1=CC=C(C2=CC=CC=C12)* 0.000 claims description 2
239000000126 substance Substances 0.000 claims description 2
238000002560 therapeutic procedure Methods 0.000 claims description 2
125000004531 indol-5-yl group Chemical group [H]N1C([H])=C([H])C2=C([H])C(*)=C([H])C([H])=C12 0.000 claims 1
108010041788 rho-Associated Kinases Proteins 0.000 abstract description 29
102000000568 rho-Associated Kinases Human genes 0.000 abstract description 29
239000003112 inhibitor Substances 0.000 abstract description 13
102000001253 Protein Kinase Human genes 0.000 abstract description 11
108060006633 protein kinase Proteins 0.000 abstract description 11
239000011435 rock Substances 0.000 abstract description 2
238000012216 screening Methods 0.000 abstract description 2
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238000004128 high performance liquid chromatography Methods 0.000 description 15
150000003839 salts Chemical class 0.000 description 12
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150000001412 amines Chemical class 0.000 description 11
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102100027609 Rho-related GTP-binding protein RhoD Human genes 0.000 description 6
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125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 5
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