NZ622964B2 - Novel rock kinase inhibitors - Google Patents
Novel rock kinase inhibitors Download PDFInfo
- Publication number
- NZ622964B2 NZ622964B2 NZ622964A NZ62296412A NZ622964B2 NZ 622964 B2 NZ622964 B2 NZ 622964B2 NZ 622964 A NZ622964 A NZ 622964A NZ 62296412 A NZ62296412 A NZ 62296412A NZ 622964 B2 NZ622964 B2 NZ 622964B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- 20alkyl
- group
- halo
- aryl
- phenyl
- Prior art date
Links
- 239000011435 rock Substances 0.000 title claims abstract description 73
- 239000003757 phosphotransferase inhibitor Substances 0.000 title abstract description 6
- -1 3-fluoropyridin-4-yl Chemical group 0.000 claims abstract description 349
- 150000001875 compounds Chemical class 0.000 claims abstract description 155
- 201000010099 disease Diseases 0.000 claims abstract description 73
- 239000000203 mixture Substances 0.000 claims abstract description 72
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 44
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 44
- 239000003814 drug Substances 0.000 claims abstract description 33
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 26
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 23
- 201000001880 sexual dysfunction Diseases 0.000 claims abstract description 17
- 231100000872 sexual dysfunction Toxicity 0.000 claims abstract description 17
- 200000000018 inflammatory disease Diseases 0.000 claims abstract description 11
- WPYMKLBDIGXBTP-UHFFFAOYSA-M benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-M 0.000 claims abstract description 10
- 125000003118 aryl group Chemical group 0.000 claims description 83
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 60
- 125000001424 substituent group Chemical group 0.000 claims description 56
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 54
- 125000001072 heteroaryl group Chemical group 0.000 claims description 53
- 239000001257 hydrogen Substances 0.000 claims description 48
- 229910052739 hydrogen Inorganic materials 0.000 claims description 48
- 125000005843 halogen group Chemical group 0.000 claims description 38
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 34
- 150000002148 esters Chemical group 0.000 claims description 34
- 229910052736 halogen Chemical group 0.000 claims description 33
- 230000002265 prevention Effects 0.000 claims description 32
- 150000002431 hydrogen Chemical class 0.000 claims description 31
- 125000004043 oxo group Chemical group O=* 0.000 claims description 29
- 125000003368 amide group Chemical group 0.000 claims description 27
- 239000004202 carbamide Substances 0.000 claims description 27
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 27
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 27
- 150000002367 halogens Chemical group 0.000 claims description 27
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 27
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 27
- 150000003573 thiols Chemical class 0.000 claims description 27
- KXDHJXZQYSOELW-UHFFFAOYSA-M carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 26
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 26
- 125000004442 acylamino group Chemical group 0.000 claims description 23
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 20
- 125000004122 cyclic group Chemical group 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 17
- 229910052799 carbon Inorganic materials 0.000 claims description 14
- 208000009745 Eye Disease Diseases 0.000 claims description 13
- 125000001153 fluoro group Chemical group F* 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 239000011780 sodium chloride Substances 0.000 claims description 12
- 206010020772 Hypertension Diseases 0.000 claims description 11
- 108091000081 Phosphotransferases Proteins 0.000 claims description 11
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 11
- 241000282414 Homo sapiens Species 0.000 claims description 10
- 230000000694 effects Effects 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 230000000414 obstructive Effects 0.000 claims description 10
- 206010016654 Fibrosis Diseases 0.000 claims description 9
- 206010020751 Hypersensitivity Diseases 0.000 claims description 9
- 208000001083 Kidney Disease Diseases 0.000 claims description 9
- 208000005392 Spasm Diseases 0.000 claims description 9
- 201000005794 allergic hypersensitivity disease Diseases 0.000 claims description 9
- 230000001684 chronic Effects 0.000 claims description 9
- 230000004761 fibrosis Effects 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 9
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 claims description 8
- 208000003432 Bone Disease Diseases 0.000 claims description 8
- 229940035295 Ting Drugs 0.000 claims description 8
- 230000000926 neurological Effects 0.000 claims description 8
- 230000002062 proliferating Effects 0.000 claims description 8
- 206010052779 Transplant rejections Diseases 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 239000012453 solvate Substances 0.000 claims description 7
- 201000011528 vascular disease Diseases 0.000 claims description 7
- 208000008787 Cardiovascular Disease Diseases 0.000 claims description 6
- 210000001508 Eye Anatomy 0.000 claims description 6
- QPJVMBTYPHYUOC-UHFFFAOYSA-N Methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 claims description 6
- 210000000329 Myocytes, Smooth Muscle Anatomy 0.000 claims description 6
- 208000005918 Urinary Bladder Disease Diseases 0.000 claims description 6
- 201000008848 bladder disease Diseases 0.000 claims description 6
- 230000002757 inflammatory Effects 0.000 claims description 6
- 150000002596 lactones Chemical class 0.000 claims description 6
- 230000004770 neurodegeneration Effects 0.000 claims description 6
- 206010014004 Ear disease Diseases 0.000 claims description 5
- 208000010412 Glaucoma Diseases 0.000 claims description 5
- 208000002780 Macular Degeneration Diseases 0.000 claims description 5
- 238000000338 in vitro Methods 0.000 claims description 5
- 201000003958 nose disease Diseases 0.000 claims description 5
- 238000007634 remodeling Methods 0.000 claims description 5
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- 208000002691 Choroiditis Diseases 0.000 claims description 4
- 208000008760 Optic Nerve Disease Diseases 0.000 claims description 4
- 206010061323 Optic neuropathy Diseases 0.000 claims description 4
- 210000003800 Pharynx Anatomy 0.000 claims description 4
- 208000003971 Posterior Uveitis Diseases 0.000 claims description 4
- 230000003915 cell function Effects 0.000 claims description 4
- 230000003412 degenerative Effects 0.000 claims description 4
- 230000004054 inflammatory process Effects 0.000 claims description 4
- 201000011056 retinal disease Diseases 0.000 claims description 4
- 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 claims description 3
- 206010061218 Inflammation Diseases 0.000 claims description 3
- 206010022941 Iridocyclitis Diseases 0.000 claims description 3
- 208000007014 Retinitis Pigmentosa Diseases 0.000 claims description 3
- 206010038932 Retinopathy Diseases 0.000 claims description 3
- 206010038923 Retinopathy Diseases 0.000 claims description 3
- 230000033115 angiogenesis Effects 0.000 claims description 3
- 201000004612 anterior uveitis Diseases 0.000 claims description 3
- 230000005549 barrier dysfunction Effects 0.000 claims description 3
- 230000004663 cell proliferation Effects 0.000 claims description 3
- 229940095102 methyl benzoate Drugs 0.000 claims description 3
- 125000005475 oxolanyl group Chemical group 0.000 claims description 3
- 125000005418 aryl aryl group Chemical group 0.000 claims description 2
- 230000035874 hyperreactivity Effects 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- SIOXPEMLGUPBBT-UHFFFAOYSA-M picolinate Chemical compound [O-]C(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-M 0.000 claims description 2
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 claims 26
- 125000006647 (C3-C15) cycloalkyl group Chemical group 0.000 claims 19
- 125000003860 C1-C20 alkoxy group Chemical group 0.000 claims 10
- OSTIHFXUTPZJQL-UHFFFAOYSA-N fluoro benzoate Chemical compound FOC(=O)C1=CC=CC=C1 OSTIHFXUTPZJQL-UHFFFAOYSA-N 0.000 claims 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 1
- QHKJIJXBJCOABP-UHFFFAOYSA-N 1-benzofuran-2-carboxamide Chemical compound C1=CC=C2OC(C(=O)N)=CC2=C1 QHKJIJXBJCOABP-UHFFFAOYSA-N 0.000 claims 1
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims 1
- 102000030951 Phosphotransferases Human genes 0.000 claims 1
- 230000000968 intestinal Effects 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 abstract description 35
- 230000001225 therapeutic Effects 0.000 abstract description 16
- 230000000069 prophylaxis Effects 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 206010038683 Respiratory disease Diseases 0.000 abstract description 3
- 125000000217 alkyl group Chemical group 0.000 description 25
- 229940079593 drugs Drugs 0.000 description 17
- 125000000753 cycloalkyl group Chemical group 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 13
- 125000000623 heterocyclic group Chemical group 0.000 description 12
- 150000003254 radicals Chemical class 0.000 description 11
- 102000004308 Carboxylic Ester Hydrolases Human genes 0.000 description 10
- 108090000863 Carboxylic Ester Hydrolases Proteins 0.000 description 10
- 102000001253 Protein Kinases Human genes 0.000 description 10
- 125000003545 alkoxy group Chemical group 0.000 description 10
- 125000004076 pyridyl group Chemical group 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 9
- 125000001544 thienyl group Chemical group 0.000 description 9
- 102100009225 ACHE Human genes 0.000 description 8
- 102000003914 Cholinesterases Human genes 0.000 description 8
- 108090000322 Cholinesterases Proteins 0.000 description 8
- 102000004157 Hydrolases Human genes 0.000 description 8
- 108090000604 Hydrolases Proteins 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 8
- 125000002947 alkylene group Chemical group 0.000 description 8
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 8
- 125000002541 furyl group Chemical group 0.000 description 8
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 8
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 description 8
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 8
- 239000000758 substrate Substances 0.000 description 8
- 125000005871 1,3-benzodioxolyl group Chemical group 0.000 description 7
- 206010021972 Inflammatory bowel disease Diseases 0.000 description 7
- 125000004429 atoms Chemical group 0.000 description 7
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 7
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 7
- 125000002993 cycloalkylene group Chemical group 0.000 description 7
- 125000001041 indolyl group Chemical group 0.000 description 7
- 150000002500 ions Chemical class 0.000 description 7
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 7
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 210000001519 tissues Anatomy 0.000 description 7
- 125000000183 1,4-thiazinyl group Chemical group S1C(C=NC=C1)* 0.000 description 6
- 108010022752 Acetylcholinesterase Proteins 0.000 description 6
- 229940022698 Acetylcholinesterase Drugs 0.000 description 6
- 206010006451 Bronchitis Diseases 0.000 description 6
- 210000004185 Liver Anatomy 0.000 description 6
- 210000004072 Lung Anatomy 0.000 description 6
- 125000003943 azolyl group Chemical group 0.000 description 6
- 230000000875 corresponding Effects 0.000 description 6
- 125000002883 imidazolyl group Chemical group 0.000 description 6
- 239000002207 metabolite Substances 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 210000000056 organs Anatomy 0.000 description 6
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 6
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 6
- 125000000547 substituted alkyl group Chemical group 0.000 description 6
- 125000000335 thiazolyl group Chemical group 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 125000000355 1,3-benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 5
- 125000005955 1H-indazolyl group Chemical group 0.000 description 5
- 229960004373 Acetylcholine Drugs 0.000 description 5
- 102100012919 BCHE Human genes 0.000 description 5
- 108010053652 Butyrylcholinesterase Proteins 0.000 description 5
- 206010046851 Uveitis Diseases 0.000 description 5
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 5
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- 229940048961 cholinesterase Drugs 0.000 description 5
- 230000014509 gene expression Effects 0.000 description 5
- 125000004438 haloalkoxy group Chemical group 0.000 description 5
- 125000005842 heteroatoms Chemical group 0.000 description 5
- 125000001786 isothiazolyl group Chemical group 0.000 description 5
- 125000000842 isoxazolyl group Chemical group 0.000 description 5
- 230000000670 limiting Effects 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 125000002971 oxazolyl group Chemical group 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 125000003226 pyrazolyl group Chemical group 0.000 description 5
- 125000000714 pyrimidinyl group Chemical group 0.000 description 5
- 125000000168 pyrrolyl group Chemical group 0.000 description 5
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 5
- 230000001839 systemic circulation Effects 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- 208000006673 Asthma Diseases 0.000 description 4
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 4
- 206010011401 Crohn's disease Diseases 0.000 description 4
- JNWBBCNCSMBKNE-UHFFFAOYSA-N HATU Chemical compound F[P-](F)(F)(F)(F)F.C1=CN=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 JNWBBCNCSMBKNE-UHFFFAOYSA-N 0.000 description 4
- 206010058359 Hypogonadism Diseases 0.000 description 4
- 208000007906 Intestinal Disease Diseases 0.000 description 4
- 210000000936 Intestines Anatomy 0.000 description 4
- 210000003734 Kidney Anatomy 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 208000009025 Nervous System Disease Diseases 0.000 description 4
- 206010029305 Neurological disorder Diseases 0.000 description 4
- 210000003932 Urinary Bladder Anatomy 0.000 description 4
- JKEKMBGUVUKMQB-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium;tetrafluoroborate Chemical compound F[B-](F)(F)F.C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 JKEKMBGUVUKMQB-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- 238000004166 bioassay Methods 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 210000004027 cells Anatomy 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 230000001808 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 125000001188 haloalkyl group Chemical group 0.000 description 4
- 230000028709 inflammatory response Effects 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 125000005990 isobenzothienyl group Chemical group 0.000 description 4
- 125000004430 oxygen atoms Chemical group O* 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 230000002685 pulmonary Effects 0.000 description 4
- 125000003373 pyrazinyl group Chemical group 0.000 description 4
- 238000001356 surgical procedure Methods 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 230000000699 topical Effects 0.000 description 4
- 125000004529 1,2,3-triazinyl group Chemical group N1=NN=C(C=C1)* 0.000 description 3
- 125000004530 1,2,4-triazinyl group Chemical group N1=NC(=NC=C1)* 0.000 description 3
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 3
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 3
- 206010002855 Anxiety Diseases 0.000 description 3
- 206010057666 Anxiety disease Diseases 0.000 description 3
- 210000004369 Blood Anatomy 0.000 description 3
- 206010006458 Bronchitis chronic Diseases 0.000 description 3
- 102100008787 CEL Human genes 0.000 description 3
- 102100011049 CES1 Human genes 0.000 description 3
- 101710026891 CES1 Proteins 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- 208000007451 Chronic Bronchitis Diseases 0.000 description 3
- 230000037242 Cmax Effects 0.000 description 3
- 210000001072 Colon Anatomy 0.000 description 3
- 206010012438 Dermatitis atopic Diseases 0.000 description 3
- 206010012601 Diabetes mellitus Diseases 0.000 description 3
- 206010014561 Emphysema Diseases 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 210000003128 Head Anatomy 0.000 description 3
- 206010022557 Intermediate uveitis Diseases 0.000 description 3
- 206010025650 Malignant melanoma Diseases 0.000 description 3
- 210000003739 Neck Anatomy 0.000 description 3
- 208000004296 Neuralgia Diseases 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 208000001132 Osteoporosis Diseases 0.000 description 3
- 210000001672 Ovary Anatomy 0.000 description 3
- 102100010404 PLA2G4A Human genes 0.000 description 3
- 210000002381 Plasma Anatomy 0.000 description 3
- 206010035664 Pneumonia Diseases 0.000 description 3
- 210000002307 Prostate Anatomy 0.000 description 3
- 206010037162 Psoriatic arthropathy Diseases 0.000 description 3
- 208000002815 Pulmonary Hypertension Diseases 0.000 description 3
- 206010039073 Rheumatoid arthritis Diseases 0.000 description 3
- 206010039083 Rhinitis Diseases 0.000 description 3
- 206010039491 Sarcoma Diseases 0.000 description 3
- 210000003491 Skin Anatomy 0.000 description 3
- 208000006641 Skin Disease Diseases 0.000 description 3
- 210000001685 Thyroid Gland Anatomy 0.000 description 3
- 210000004291 Uterus Anatomy 0.000 description 3
- 206010047139 Vasoconstriction Diseases 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 230000036506 anxiety Effects 0.000 description 3
- 201000008937 atopic dermatitis Diseases 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 230000004064 dysfunction Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 150000004677 hydrates Chemical class 0.000 description 3
- 125000001183 hydrocarbyl group Chemical group 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 201000001441 melanoma Diseases 0.000 description 3
- 239000003607 modifier Substances 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000004433 nitrogen atoms Chemical group N* 0.000 description 3
- 201000008482 osteoarthritis Diseases 0.000 description 3
- 125000001715 oxadiazolyl group Chemical group 0.000 description 3
- 201000007407 panuveitis Diseases 0.000 description 3
- 238000006366 phosphorylation reaction Methods 0.000 description 3
- 230000000865 phosphorylative Effects 0.000 description 3
- 201000004681 psoriasis Diseases 0.000 description 3
- 201000001263 psoriatic arthritis Diseases 0.000 description 3
- 230000001105 regulatory Effects 0.000 description 3
- 201000002793 renal fibrosis Diseases 0.000 description 3
- 230000000268 renotropic Effects 0.000 description 3
- 102000000568 rho-Associated Kinases Human genes 0.000 description 3
- 108010041788 rho-Associated Kinases Proteins 0.000 description 3
- 230000016160 smooth muscle contraction Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000007962 solid dispersion Substances 0.000 description 3
- 230000004936 stimulating Effects 0.000 description 3
- 125000003107 substituted aryl group Chemical group 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 125000004306 triazinyl group Chemical group 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- 230000025033 vasoconstriction Effects 0.000 description 3
- 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 description 2
- 125000004511 1,2,3-thiadiazolyl group Chemical group 0.000 description 2
- BBVIDBNAYOIXOE-UHFFFAOYSA-N 1,2,4-oxadiazole Chemical compound C=1N=CON=1 BBVIDBNAYOIXOE-UHFFFAOYSA-N 0.000 description 2
- 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 description 2
- 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 description 2
- 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 description 2
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical compound C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 2
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-Dimethylaminophenol Substances CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- 102100011382 ABHD2 Human genes 0.000 description 2
- 101700004207 ACER Proteins 0.000 description 2
- 230000037082 AUClast Effects 0.000 description 2
- 206010000349 Acanthosis Diseases 0.000 description 2
- 206010002556 Ankylosing spondylitis Diseases 0.000 description 2
- 210000001742 Aqueous Humor Anatomy 0.000 description 2
- 210000004556 Brain Anatomy 0.000 description 2
- 102100001457 CES2 Human genes 0.000 description 2
- 108010051152 Carboxylesterase Proteins 0.000 description 2
- 102000013392 Carboxylesterase Human genes 0.000 description 2
- 229960001231 Choline Drugs 0.000 description 2
- 210000000349 Chromosomes Anatomy 0.000 description 2
- 206010009887 Colitis Diseases 0.000 description 2
- 206010009900 Colitis ulcerative Diseases 0.000 description 2
- 206010012689 Diabetic retinopathy Diseases 0.000 description 2
- 210000001035 Gastrointestinal Tract Anatomy 0.000 description 2
- 230000036499 Half live Effects 0.000 description 2
- 208000009326 Ileitis Diseases 0.000 description 2
- 208000008384 Ileus Diseases 0.000 description 2
- 241000229754 Iva xanthiifolia Species 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 210000002464 Muscle, Smooth, Vascular Anatomy 0.000 description 2
- 102000016349 Myosin Light Chains Human genes 0.000 description 2
- 108010067385 Myosin Light Chains Proteins 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 210000000496 Pancreas Anatomy 0.000 description 2
- 208000005775 Parakeratosis Diseases 0.000 description 2
- 102000001708 Protein Isoforms Human genes 0.000 description 2
- 108010029485 Protein Isoforms Proteins 0.000 description 2
- 208000005069 Pulmonary Fibrosis Diseases 0.000 description 2
- 101700020165 RHOA Proteins 0.000 description 2
- 102100009534 TNF Human genes 0.000 description 2
- 230000036335 Tissue distribution Effects 0.000 description 2
- 206010044008 Tonsillitis Diseases 0.000 description 2
- 208000004371 Toothache Diseases 0.000 description 2
- 206010068760 Ulcers Diseases 0.000 description 2
- 125000003158 alcohol group Chemical group 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 102000004965 antibodies Human genes 0.000 description 2
- 108090001123 antibodies Proteins 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 125000005129 aryl carbonyl group Chemical group 0.000 description 2
- 125000004104 aryloxy group Chemical group 0.000 description 2
- 125000005874 benzothiadiazolyl group Chemical group 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 230000000271 cardiovascular Effects 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- CRBHXDCYXIISFC-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CC[O-] CRBHXDCYXIISFC-UHFFFAOYSA-N 0.000 description 2
- ZPUCINDJVBIVPJ-BARDWOONSA-N cocaine Natural products O([C@@H]1C[C@H]2CC[C@H](N2C)[C@@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-BARDWOONSA-N 0.000 description 2
- 125000006165 cyclic alkyl group Chemical group 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 201000003883 cystic fibrosis Diseases 0.000 description 2
- 230000004059 degradation Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 230000001809 detectable Effects 0.000 description 2
- 239000008157 edible vegetable oil Substances 0.000 description 2
- 239000002158 endotoxin Substances 0.000 description 2
- 230000002708 enhancing Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 230000000366 juvenile Effects 0.000 description 2
- 102000004882 lipase Human genes 0.000 description 2
- 108090001060 lipase Proteins 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000001404 mediated Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 230000004220 muscle function Effects 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 230000003000 nontoxic Effects 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003287 optical Effects 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- 230000003389 potentiating Effects 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 229940002612 prodrugs Drugs 0.000 description 2
- PAQZWJGSJMLPMG-UHFFFAOYSA-N propylphosphonic anhydride Substances CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 2
- 125000004944 pyrazin-3-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 2
- 125000002098 pyridazinyl group Chemical group 0.000 description 2
- 239000011535 reaction buffer Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000011769 retinyl palmitate Substances 0.000 description 2
- 101700065091 rho1 Proteins 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 2
- 125000004434 sulfur atoms Chemical group 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing Effects 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 125000001113 thiadiazolyl group Chemical group 0.000 description 2
- 125000005307 thiatriazolyl group Chemical group S1N=NN=C1* 0.000 description 2
- 125000004305 thiazinyl group Chemical group S1NC(=CC=C1)* 0.000 description 2
- VYGQUTWHTHXGQB-FFHKNEKCSA-N trans-Retinyl palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C VYGQUTWHTHXGQB-FFHKNEKCSA-N 0.000 description 2
- 231100000397 ulcer Toxicity 0.000 description 2
- 230000036269 ulceration Effects 0.000 description 2
- 201000006704 ulcerative colitis Diseases 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- 230000029663 wound healing Effects 0.000 description 2
- 101710017995 xacC Proteins 0.000 description 2
- 101700041488 zds1 Proteins 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2R,3R,4S,5R,6S)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2S,3R,4S,5R,6R)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2R,3R,4S,5R,6R)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- AXVIQHWRLSFEAC-KNYJJKDQSA-N (2R,3S,4S,5S)-2,3,4,5,6-pentahydroxy-7-oxooctanal Chemical compound CC(=O)C(O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O AXVIQHWRLSFEAC-KNYJJKDQSA-N 0.000 description 1
- SBTVLCPCSXMWIQ-UHFFFAOYSA-N (3,5-dimethylphenyl) carbamate Chemical compound CC1=CC(C)=CC(OC(N)=O)=C1 SBTVLCPCSXMWIQ-UHFFFAOYSA-N 0.000 description 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 1
- COLOHWPRNRVWPI-UHFFFAOYSA-N 1,1,1-trifluoroethane Chemical group [CH2]C(F)(F)F COLOHWPRNRVWPI-UHFFFAOYSA-N 0.000 description 1
- SLLFVLKNXABYGI-UHFFFAOYSA-N 1,2,3-benzoxadiazole Chemical compound C1=CC=C2ON=NC2=C1 SLLFVLKNXABYGI-UHFFFAOYSA-N 0.000 description 1
- UGUHFDPGDQDVGX-UHFFFAOYSA-N 1,2,3-thiadiazole Chemical compound C1=CSN=N1 UGUHFDPGDQDVGX-UHFFFAOYSA-N 0.000 description 1
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1,2,3-triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 1
- YGTAZGSLCXNBQL-UHFFFAOYSA-N 1,2,4-thiadiazole Chemical compound C=1N=CSN=1 YGTAZGSLCXNBQL-UHFFFAOYSA-N 0.000 description 1
- 125000004506 1,2,5-oxadiazolyl group Chemical group 0.000 description 1
- UDGKZGLPXCRRAM-UHFFFAOYSA-N 1,2,5-thiadiazole Chemical compound C=1C=NSN=1 UDGKZGLPXCRRAM-UHFFFAOYSA-N 0.000 description 1
- 125000004517 1,2,5-thiadiazolyl group Chemical group 0.000 description 1
- JIHQDMXYYFUGFV-UHFFFAOYSA-N 1,3,5-Triazine Chemical compound C1=NC=NC=N1 JIHQDMXYYFUGFV-UHFFFAOYSA-N 0.000 description 1
- 125000003363 1,3,5-triazinyl group Chemical group N1=C(N=CN=C1)* 0.000 description 1
- 125000004227 1,3-benzoxazol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N=C(*)OC2=C1[H] 0.000 description 1
- IGERFAHWSHDDHX-UHFFFAOYSA-N 1,3-dioxanyl Chemical group [CH]1OCCCO1 IGERFAHWSHDDHX-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- HKDFRDIIELOLTJ-UHFFFAOYSA-N 1,4-dithianyl Chemical group [CH]1CSCCS1 HKDFRDIIELOLTJ-UHFFFAOYSA-N 0.000 description 1
- MNCMBBIFTVWHIP-UHFFFAOYSA-N 1-anthracen-9-yl-2,2,2-trifluoroethanone Chemical group C1=CC=C2C(C(=O)C(F)(F)F)=C(C=CC=C3)C3=CC2=C1 MNCMBBIFTVWHIP-UHFFFAOYSA-N 0.000 description 1
- 125000006083 1-bromoethyl group Chemical group 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 1H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 1
- 125000002152 1H-pyrrolizinyl group Chemical group C1(C=CN2C=CC=C12)* 0.000 description 1
- MVXVYAKCVDQRLW-UHFFFAOYSA-N 1H-pyrrolo[2,3-b]pyridine Chemical compound C1=CN=C2NC=CC2=C1 MVXVYAKCVDQRLW-UHFFFAOYSA-N 0.000 description 1
- XLKDJOPOOHHZAN-UHFFFAOYSA-N 1H-pyrrolo[2,3-c]pyridine Chemical compound C1=NC=C2NC=CC2=C1 XLKDJOPOOHHZAN-UHFFFAOYSA-N 0.000 description 1
- XWIYUCRMWCHYJR-UHFFFAOYSA-N 1H-pyrrolo[3,2-b]pyridine Chemical compound C1=CC=C2NC=CC2=N1 XWIYUCRMWCHYJR-UHFFFAOYSA-N 0.000 description 1
- SRSKXJVMVSSSHB-UHFFFAOYSA-N 1H-pyrrolo[3,2-c]pyridine Chemical compound N1=CC=C2NC=CC2=C1 SRSKXJVMVSSSHB-UHFFFAOYSA-N 0.000 description 1
- AWBOSXFRPFZLOP-UHFFFAOYSA-N 2,1,3-benzoxadiazole Chemical compound C1=CC=CC2=NON=C21 AWBOSXFRPFZLOP-UHFFFAOYSA-N 0.000 description 1
- AUVALWUPUHHNQV-UHFFFAOYSA-M 2-carboxy-6-propylphenolate Chemical class CCCC1=CC=CC(C([O-])=O)=C1O AUVALWUPUHHNQV-UHFFFAOYSA-M 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000006088 2-oxoazepinyl group Chemical group 0.000 description 1
- 125000004638 2-oxopiperazinyl group Chemical group O=C1N(CCNC1)* 0.000 description 1
- 125000004637 2-oxopiperidinyl group Chemical group O=C1N(CCCC1)* 0.000 description 1
- 125000006087 2-oxopyrrolodinyl group Chemical group 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- YHWMFDLNZGIJSD-UHFFFAOYSA-N 2H-1,4-oxazine Chemical compound C1OC=CN=C1 YHWMFDLNZGIJSD-UHFFFAOYSA-N 0.000 description 1
- ZAISDHPZTZIFQF-UHFFFAOYSA-N 2H-1,4-thiazine Chemical compound C1SC=CN=C1 ZAISDHPZTZIFQF-UHFFFAOYSA-N 0.000 description 1
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 108010000816 3-oxoadipate enol-lactonase Proteins 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- PNBJAWCXUSYQNY-UHFFFAOYSA-N 4-(2-thiophen-2-ylthiophen-3-yl)but-3-ynyl acetate Chemical compound C1=CSC(C=2SC=CC=2)=C1C#CCCOC(=O)C PNBJAWCXUSYQNY-UHFFFAOYSA-N 0.000 description 1
- 108010015134 4-pyridoxolactonase Proteins 0.000 description 1
- 125000001826 4H-pyranyl group Chemical group O1C(=CCC=C1)* 0.000 description 1
- 125000002471 4H-quinolizinyl group Chemical group C=1(C=CCN2C=CC=CC12)* 0.000 description 1
- RGIIXLVKXLFDLP-UHFFFAOYSA-N 5-(3,4-diacetoxybut-1-ynyl)-2,2'-bithiophene Chemical compound S1C(C#CC(OC(C)=O)COC(=O)C)=CC=C1C1=CC=CS1 RGIIXLVKXLFDLP-UHFFFAOYSA-N 0.000 description 1
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 description 1
- 108010029731 6-phosphogluconolactonase Proteins 0.000 description 1
- 102000001762 6-phosphogluconolactonase Human genes 0.000 description 1
- 101710025088 66 Proteins 0.000 description 1
- 102100001042 AOAH Human genes 0.000 description 1
- 102100004323 ASPG Human genes 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 235000006491 Acacia senegal Nutrition 0.000 description 1
- 229940068372 Acetyl salicylate Drugs 0.000 description 1
- 108010013043 Acetylesterase Proteins 0.000 description 1
- 206010000565 Acquired immunodeficiency syndrome Diseases 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 206010064930 Age-related macular degeneration Diseases 0.000 description 1
- 208000002205 Allergic Conjunctivitis Diseases 0.000 description 1
- 102000037198 Anion channels Human genes 0.000 description 1
- 108091006430 Anion channels Proteins 0.000 description 1
- MWPLVEDNUUSJAV-UHFFFAOYSA-N Anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 1
- 206010059512 Apoptosis Diseases 0.000 description 1
- 206010003011 Appendicitis Diseases 0.000 description 1
- 229940114079 Arachidonic Acid Drugs 0.000 description 1
- YZXBAPSDXZZRGB-DOFZRALJSA-N Arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 206010003246 Arthritis Diseases 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N Benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- 230000036912 Bioavailability Effects 0.000 description 1
- 210000004204 Blood Vessels Anatomy 0.000 description 1
- 206010061590 Blood disease Diseases 0.000 description 1
- 210000000988 Bone and Bones Anatomy 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 210000000481 Breast Anatomy 0.000 description 1
- YRIBGSCJIMXMPJ-UHFFFAOYSA-N Butyrylcholine Chemical compound CCCC(=O)OCC[N+](C)(C)C YRIBGSCJIMXMPJ-UHFFFAOYSA-N 0.000 description 1
- 102000024261 Butyrylcholinesterase Human genes 0.000 description 1
- 102100003814 CASP3 Human genes 0.000 description 1
- 101700024634 CDK16 Proteins 0.000 description 1
- 101700045507 CES2 Proteins 0.000 description 1
- 102100001446 CES3 Human genes 0.000 description 1
- 101700069118 CXE2 Proteins 0.000 description 1
- JHLNERQLKQQLRZ-UHFFFAOYSA-N Calcium silicate Chemical compound [Ca+2].[Ca+2].[O-][Si]([O-])([O-])[O-] JHLNERQLKQQLRZ-UHFFFAOYSA-N 0.000 description 1
- 206010007554 Cardiac failure Diseases 0.000 description 1
- 102000004046 Caspase 2 Human genes 0.000 description 1
- 108090000552 Caspase 2 Proteins 0.000 description 1
- 108090000397 Caspase 3 Proteins 0.000 description 1
- 208000005024 Castleman Disease Diseases 0.000 description 1
- HOKIDJSKDBPKTQ-PXWWUCIGSA-O Cephalosporin C Chemical compound S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CCC[C@H]([NH3+])C(O)=O)[C@H]12 HOKIDJSKDBPKTQ-PXWWUCIGSA-O 0.000 description 1
- 101710032139 Ces2c Proteins 0.000 description 1
- 229950009533 Cetraxate Drugs 0.000 description 1
- 230000037250 Clearance Effects 0.000 description 1
- 206010010744 Conjunctivitis allergic Diseases 0.000 description 1
- 208000010247 Contact Dermatitis Diseases 0.000 description 1
- 210000004087 Cornea Anatomy 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 210000004292 Cytoskeleton Anatomy 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- VGXYDZCCQDSGLZ-YMYYPMOMSA-N Desferritriacetylfusigen Chemical compound CC(=O)NC1CCCN(O)C(=O)\C=C(C)\CCOC(=O)C(NC(C)=O)CCCN(O)C(=O)\C=C(C)\CCOC(=O)C(NC(C)=O)CCCN(O)C(=O)\C=C(C)\CCOC1=O VGXYDZCCQDSGLZ-YMYYPMOMSA-N 0.000 description 1
- 206010013774 Dry eye Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 108030007212 EC 3.4.21.79 Proteins 0.000 description 1
- 229940022766 EGTA Drugs 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 101700036757 ERN1 Proteins 0.000 description 1
- 102100016655 ERN1 Human genes 0.000 description 1
- 101700014948 ERN2 Proteins 0.000 description 1
- 101710026920 ESD Proteins 0.000 description 1
- 102100002095 ESD Human genes 0.000 description 1
- 208000004232 Enteritis Diseases 0.000 description 1
- 210000003743 Erythrocytes Anatomy 0.000 description 1
- 229940012356 Eye Drops Drugs 0.000 description 1
- 206010015958 Eye pain Diseases 0.000 description 1
- 210000000744 Eyelids Anatomy 0.000 description 1
- NGOGFTYYXHNFQH-UHFFFAOYSA-N Fasudil Chemical compound C=1C=CC2=CN=CC=C2C=1S(=O)(=O)N1CCCNCC1 NGOGFTYYXHNFQH-UHFFFAOYSA-N 0.000 description 1
- 206010057671 Female sexual dysfunction Diseases 0.000 description 1
- 101710007478 GJE1 Proteins 0.000 description 1
- 108091000058 GTP-Binding Proteins Proteins 0.000 description 1
- 102000030007 GTP-Binding Proteins Human genes 0.000 description 1
- 102100004391 GZMB Human genes 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 208000005577 Gastroenteritis Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- XKMLYUALXHKNFT-UUOKFMHZSA-N Guanosine-5'-triphosphate Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XKMLYUALXHKNFT-UUOKFMHZSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N HEPES Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 206010019280 Heart failure Diseases 0.000 description 1
- 208000005209 Hematologic Disease Diseases 0.000 description 1
- 210000003494 Hepatocytes Anatomy 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 229940088597 Hormone Drugs 0.000 description 1
- 206010020648 Hyperkeratosis Diseases 0.000 description 1
- 206010020649 Hyperkeratosis Diseases 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- 101700085586 IRE1A Proteins 0.000 description 1
- 101700019719 IRE1B Proteins 0.000 description 1
- 210000004969 Inflammatory Cells Anatomy 0.000 description 1
- 208000003456 Juvenile Arthritis Diseases 0.000 description 1
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 description 1
- 102100004188 LIPC Human genes 0.000 description 1
- 102100017525 LIPE Human genes 0.000 description 1
- 102100011688 LPL Human genes 0.000 description 1
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 1
- 241001523179 Lasia <small-headed fly> Species 0.000 description 1
- 206010024324 Leukaemias Diseases 0.000 description 1
- 229940040461 Lipase Drugs 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 101710007526 MAP3K14 Proteins 0.000 description 1
- 101710028361 MARVELD2 Proteins 0.000 description 1
- 210000002540 Macrophages Anatomy 0.000 description 1
- 206010057672 Male sexual dysfunction Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 230000036740 Metabolism Effects 0.000 description 1
- 230000035633 Metabolized Effects 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241001024304 Mino Species 0.000 description 1
- 210000004413 Myocytes, Cardiac Anatomy 0.000 description 1
- 108010037801 Myosin-Light-Chain Phosphatase Proteins 0.000 description 1
- 125000000815 N-oxide group Chemical group 0.000 description 1
- 150000001204 N-oxides Chemical class 0.000 description 1
- 101700076120 NCEH1 Proteins 0.000 description 1
- 102100008107 NCEH1 Human genes 0.000 description 1
- 210000002241 Neurites Anatomy 0.000 description 1
- 229910004755 ORb Inorganic materials 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 230000035536 Oral bioavailability Effects 0.000 description 1
- 206010025310 Other lymphomas Diseases 0.000 description 1
- 241000283898 Ovis Species 0.000 description 1
- 108009000578 Oxidative Stress Proteins 0.000 description 1
- 102100017524 PNLIPRP2 Human genes 0.000 description 1
- 102100019180 PON3 Human genes 0.000 description 1
- 102100019781 PPP1CB Human genes 0.000 description 1
- 101700044505 PUB33 Proteins 0.000 description 1
- 101700045570 PUB34 Proteins 0.000 description 1
- 101700046887 PUB35 Proteins 0.000 description 1
- 101700066160 PUB51 Proteins 0.000 description 1
- 101700067511 PUB52 Proteins 0.000 description 1
- 101700068819 PUB53 Proteins 0.000 description 1
- 101700086326 PUB70 Proteins 0.000 description 1
- 206010033616 Pancreatic disease Diseases 0.000 description 1
- DHHVAGZRUROJKS-UHFFFAOYSA-N Phentermine Chemical compound CC(C)(N)CC1=CC=CC=C1 DHHVAGZRUROJKS-UHFFFAOYSA-N 0.000 description 1
- 108010058868 Phospholipases A1 Proteins 0.000 description 1
- 108010058864 Phospholipases A2 Proteins 0.000 description 1
- 230000036823 Plasma Levels Effects 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 206010036346 Posterior capsule opacification Diseases 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M Potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 208000005107 Premature Birth Diseases 0.000 description 1
- 206010036590 Premature baby Diseases 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N Procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 208000002158 Proliferative Vitreoretinopathy Diseases 0.000 description 1
- 210000003324 RBC Anatomy 0.000 description 1
- 102100006021 RGN Human genes 0.000 description 1
- 101700034252 ROCK1 Proteins 0.000 description 1
- 102100000534 ROCK1 Human genes 0.000 description 1
- 101700011174 ROCK2 Proteins 0.000 description 1
- 102100000533 ROCK2 Human genes 0.000 description 1
- 102100000549 RPE65 Human genes 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010038910 Retinitis Diseases 0.000 description 1
- 206010038934 Retinopathy proliferative Diseases 0.000 description 1
- 102100000993 SIAE Human genes 0.000 description 1
- 210000002966 Serum Anatomy 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 206010042316 Subarachnoid haemorrhage Diseases 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 229920001949 Transfer RNA Polymers 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H Tricalcium phosphate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 108010001801 Tumor Necrosis Factor-alpha Proteins 0.000 description 1
- 206010047163 Vasospasm Diseases 0.000 description 1
- 210000004127 Vitreous Body Anatomy 0.000 description 1
- GPLOTACQBREROW-WQLSNUALSA-N [(2R,3R)-5,7-dihydroxy-2-[3,4,5-trihydroxy-6-oxo-8-[(2R,3R)-3,5,7-trihydroxy-3,4-dihydro-2H-chromen-2-yl]benzo[7]annulen-1-yl]-3,4-dihydro-2H-chromen-3-yl] 3,4,5-trihydroxybenzoate Chemical compound O([C@@H]1CC2=C(O)C=C(O)C=C2O[C@@H]1C=1C2=CC(=CC(=O)C(O)=C2C(O)=C(O)C=1)[C@H]1OC2=CC(O)=CC(O)=C2C[C@H]1O)C(=O)C1=CC(O)=C(O)C(O)=C1 GPLOTACQBREROW-WQLSNUALSA-N 0.000 description 1
- XZJKQEQKZAYDRM-UHFFFAOYSA-N [N+](=O)([O-])N(N)N Chemical compound [N+](=O)([O-])N(N)N XZJKQEQKZAYDRM-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 108010093941 acetylxylan esterase Proteins 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 108010075015 actinomycin lactonase Proteins 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 108010058834 acylcarnitine hydrolase Proteins 0.000 description 1
- 230000002730 additional Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000000240 adjuvant Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 101710044068 aiiM Proteins 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 1
- 125000005094 alkyl carbonyl amino alkyl group Chemical group 0.000 description 1
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 description 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 1
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 125000005360 alkyl sulfoxide group Chemical group 0.000 description 1
- 125000004422 alkyl sulphonamide group Chemical group 0.000 description 1
- 125000004419 alkynylene group Chemical group 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium Chemical class [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- 210000003433 aortic smooth muscle cell Anatomy 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 201000001320 atherosclerosis Diseases 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 230000001908 autoinhibitory Effects 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 1
- 101700027839 bah Proteins 0.000 description 1
- 101710027477 bcpC Proteins 0.000 description 1
- 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004238 benzotriazol-4-yl group Chemical group [H]N1N=NC2=C(*)C([H])=C([H])C([H])=C12 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- BVCRERJDOOBZOH-UHFFFAOYSA-N bicyclo[2.2.1]heptanyl Chemical group C1C[C+]2CC[C-]1C2 BVCRERJDOOBZOH-UHFFFAOYSA-N 0.000 description 1
- 230000035514 bioavailability Effects 0.000 description 1
- 238000010256 biochemical assay Methods 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 125000002529 biphenylenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C12)* 0.000 description 1
- 108010042769 bis(2-ethylhexyl)phthalate esterase Proteins 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 1
- 125000004181 carboxyalkyl group Chemical group 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 108010057927 carboxymethylenebutenolidase Proteins 0.000 description 1
- 210000002317 cardiac myocyte Anatomy 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- FHRSHSOEWXUORL-HDJSIYSDSA-N cetraxate zwitterion Chemical compound C1C[C@@H](C[NH3+])CC[C@@H]1C(=O)OC1=CC=C(CCC([O-])=O)C=C1 FHRSHSOEWXUORL-HDJSIYSDSA-N 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 108010025790 chlorophyllase Proteins 0.000 description 1
- 230000035512 clearance Effects 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229960003920 cocaine Drugs 0.000 description 1
- 239000012612 commercial material Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000010192 crystallographic characterization Methods 0.000 description 1
- 108010005400 cutinase Proteins 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 1
- 125000004980 cyclopropylene group Chemical group 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 230000003436 cytoskeletal Effects 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000003111 delayed Effects 0.000 description 1
- 230000002939 deleterious Effects 0.000 description 1
- NLNLACOJSWLNHE-DYNITIQCSA-N deoxylimonoic acid Chemical compound C=1([C@@H]2OC(=O)CC3=C([C@H](CC[C@]32C)[C@]23[C@H](CC(=O)OC2)OC(C)(C)[C@@H]3CC(O)=O)C)C=COC=1 NLNLACOJSWLNHE-DYNITIQCSA-N 0.000 description 1
- 239000007933 dermal patch Substances 0.000 description 1
- 201000004624 dermatitis Diseases 0.000 description 1
- 231100000406 dermatitis Toxicity 0.000 description 1
- 231100000080 dermatitis contact Toxicity 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 125000000597 dioxinyl group Chemical group 0.000 description 1
- 201000009910 diseases by infectious agent Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- LBKPGNUOUPTQKA-UHFFFAOYSA-N ethyl N-phenylcarbamate Chemical compound CCOC(=O)NC1=CC=CC=C1 LBKPGNUOUPTQKA-UHFFFAOYSA-N 0.000 description 1
- KONIYTHNVWYBMP-UHFFFAOYSA-N ethylcyclohexane Chemical group [CH2-]C[C+]1CCCCC1 KONIYTHNVWYBMP-UHFFFAOYSA-N 0.000 description 1
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- SFNALCNOMXIBKG-UHFFFAOYSA-N ethylene glycol monododecyl ether Chemical compound CCCCCCCCCCCCOCCO SFNALCNOMXIBKG-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 108060000072 faeA Proteins 0.000 description 1
- 229960002435 fasudil Drugs 0.000 description 1
- 108010063260 fatty acyl ethyl ester synthase Proteins 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 125000003838 furazanyl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 108010010539 gluconolactonase Proteins 0.000 description 1
- 125000003106 haloaryl group Chemical group 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 235000003642 hunger Nutrition 0.000 description 1
- 108010008510 hydroxybutyrate-dimer hydrolase Proteins 0.000 description 1
- UFBBWLWUIISIPW-UHFFFAOYSA-N imidazo[2,1-b][1,3]thiazole Chemical compound C1=CSC2=NC=CN21 UFBBWLWUIISIPW-UHFFFAOYSA-N 0.000 description 1
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229910001867 inorganic solvent Inorganic materials 0.000 description 1
- 239000003049 inorganic solvent Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 101700052395 ire-1 Proteins 0.000 description 1
- 125000003384 isochromanyl group Chemical group C1(OCCC2=CC=CC=C12)* 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 1
- 125000003965 isoxazolidinyl group Chemical group 0.000 description 1
- 125000003971 isoxazolinyl group Chemical group 0.000 description 1
- 108010080576 juvenile hormone esterase Proteins 0.000 description 1
- 201000002215 juvenile rheumatoid arthritis Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 101700039502 ligI Proteins 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 201000009673 liver disease Diseases 0.000 description 1
- 238000011068 load Methods 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 239000002609 media Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000035786 metabolism Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000002773 monoterpene derivatives Chemical class 0.000 description 1
- 229930003658 monoterpenes Natural products 0.000 description 1
- 235000002577 monoterpenes Nutrition 0.000 description 1
- 210000000663 muscle cells Anatomy 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 150000002829 nitrogen Chemical class 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000036220 oral bioavailability Effects 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- KVGZZAHHUNAVKZ-UHFFFAOYSA-N p-dioxin Chemical compound O1C=COC=C1 KVGZZAHHUNAVKZ-UHFFFAOYSA-N 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 108020004410 pectinesterase Proteins 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 101700057279 phaZ Proteins 0.000 description 1
- 239000000546 pharmaceutic aid Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000275 pharmacokinetic Effects 0.000 description 1
- 230000036231 pharmacokinetics Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002644 phorbol ester Substances 0.000 description 1
- 150000003905 phosphatidylinositols Chemical class 0.000 description 1
- 238000003566 phosphorylation assay Methods 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000004928 piperidonyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 200000000002 platelet activation Diseases 0.000 description 1
- 108010040046 poly-beta-hydroxybutyrate depolymerase Proteins 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 108010090668 polyneuridine aldehyde esterase Proteins 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 229930010796 primary metabolites Natural products 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 201000007914 proliferative diabetic retinopathy Diseases 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 1
- 125000004940 pyridazin-4-yl group Chemical group N1=NC=C(C=C1)* 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 125000004159 quinolin-2-yl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C([H])C(*)=NC2=C1[H] 0.000 description 1
- 230000002829 reduced Effects 0.000 description 1
- 108700000006 regulatory domains Proteins 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 235000019172 retinyl palmitate Nutrition 0.000 description 1
- 229940108325 retinyl palmitate Drugs 0.000 description 1
- 101700080288 sce3 Proteins 0.000 description 1
- 230000001568 sexual Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000006104 solid solution Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000037351 starvation Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 125000004426 substituted alkynyl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000004083 survival Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002459 sustained Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000002195 synergetic Effects 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000004885 tandem mass spectrometry Methods 0.000 description 1
- 108010038851 tannase Proteins 0.000 description 1
- 125000006092 tetrahydro-1,1-dioxothienyl group Chemical group 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- IWVMCIAPBOORJL-UHFFFAOYSA-N thieno[2,3-b]furan Chemical compound C1=CSC2=C1C=CO2 IWVMCIAPBOORJL-UHFFFAOYSA-N 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- 125000005309 thioalkoxy group Chemical group 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- 230000001256 tonic Effects 0.000 description 1
- 230000001131 transforming Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- VCXBSHBJVUIQHJ-UHFFFAOYSA-N trimethyl(2-phenoxyethyl)azanium Chemical compound C[N+](C)(C)CCOC1=CC=CC=C1 VCXBSHBJVUIQHJ-UHFFFAOYSA-N 0.000 description 1
- 108010050564 tropinesterase Proteins 0.000 description 1
- 125000005289 uranyl group Chemical group 0.000 description 1
- 108010086346 uronolactonase Proteins 0.000 description 1
- 230000002227 vasoactive Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229950004578 vitamin A palmitate Drugs 0.000 description 1
- 230000035513 volume of distribution Effects 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 108010062040 wax-ester hydrolase Proteins 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- 230000002034 xenobiotic Effects 0.000 description 1
- 239000002676 xenobiotic agent Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/04—Drugs for disorders of the respiratory system for throat disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/06—Anti-spasmodics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The present disclosure relates to compounds of formula I as defined in the specification as kinase inhibitors, more specifically ROCK inhibitors, compositions, in particular pharmaceuticals, comprising such inhibitors, and to uses of such inhibitors in the treatment and prophylaxis of disease. In particular, the present disclosure relates to new ROCK inhibitors, compositions, in particular pharmaceuticals, comprising such inhibitors, and to uses of such inhibitors in the treatment and prophylaxis of disease. In addition, the disclosure relates to methods of treatment and use of said compounds in the manufacture of a medicament for the application to a number of therapeutic indications including sexual dysfunction, inflammatory diseases, ophthalmic diseases and respiratory diseases. In one embodiment the compound is methyl 4-({3-[2-(aminomethyl)-5-[(3-fluoropyridin-4-yl)carbamoyl]phenyl]phenyl}amido) benzoate. rticular, the present disclosure relates to new ROCK inhibitors, compositions, in particular pharmaceuticals, comprising such inhibitors, and to uses of such inhibitors in the treatment and prophylaxis of disease. In addition, the disclosure relates to methods of treatment and use of said compounds in the manufacture of a medicament for the application to a number of therapeutic indications including sexual dysfunction, inflammatory diseases, ophthalmic diseases and respiratory diseases. In one embodiment the compound is methyl 4-({3-[2-(aminomethyl)-5-[(3-fluoropyridin-4-yl)carbamoyl]phenyl]phenyl}amido) benzoate.
Description
/067016
NOVEL ROCK KINASE INHIBITORS
Field of the invention
The present invention relates to new kinase inhibitors, more specifically ROCK inhibitors,
compositions, in particular pharmaceuticals, comprising such inhibitors, and to uses of such
tors in the treatment and prophylaxis of e. In particular, the present invention s to
new ROCK inhibitors, compositions, in particular pharmaceuticals, comprising such inhibitors, and
to uses of such inhibitors in the treatment and prophylaxis of disease.
1O Background of the invention
The serine/threonine protein kinase ROCK consists in humans of two isoforms ROCK | and ROCK
N. ROCK | is encoded on chromosome 18 whereas ROCK II, also called Rho-kinase, is located on
chromosome 12. They both have a molecular weight close to 160kDa. They share an overall
homology of 65% while being 95% homologous in their kinase domains. Despite their sequence
similarity, they differ by their tissue distributions. The t levels of expression for ROCK l are
ed in heart, lung and skeletal tissues whereas ROCK N is mostly expressed in brain. Recent
data indicate that these two isoforms are partially on redundant, ROCK I being more involved
in immunological events, ROCK N in smooth muscle function. The term ROCK refers to ROCK |
, p160ROCK, or Rho-kinase B) and ROCK N or or Rho-kinase or).
ROCK activity has been shown to be enhanced by GTPase RhoA that is a member of the Rho
(Ras homologous) GTP-binding proteins. The active GTP-bound state of RhoA interacts with Rho-
binding domain (RBD) of ROCK that is d in an autoinhibitory yl-terminal loop. Upon
binding, the interactions between the ROCK negative regulatory domain and the kinase domain are
disrupted. The process enables the kinase to acquire an open conformation in which it is fully
active. The open conformation is also induced by the binding of lipid activators such as arachidonic
acid to the PH domain in the kinase yl-terminal domain. Another activation mechanism has
been described during apoptosis and involves the cleavage of carboxyl terminus by caspase-3 and
-2 (or granzyme B) for ROCK | and II, respectively.
ROCK plays an important role in various cellular functions such as smooth muscle contraction,
3O actin cytoskeleton organization, platelet activation, downregulation of myosin phosphatase cell
adhesion, -migration, -pro|iferation and survival, in-induced ses of aortic smooth
muscle cells, hypertrophy of cardiomyocytes, bronchial smooth muscle contraction, smooth muscle
contraction and cytoskeletal reorganization of non- muscle cells, activation of volume- regulated
anion channels, neurite tion, wound healing, cell transformation and gene expression. ROCK
also acts in several signaling pathways that are involved in auto-immunity and inflammation. ROCK
has been shown to play a part in the activation of NF-KB, a critical molecule that leads to the
production of TNF and other inflammatory cytokines. ROCK inhibitors are reported to act against
TNF-alpha and lL-6 production in lipopolysaccharide (LPS)—stimulated THP-1 macrophages.
Therefore, ROCK inhibitors provide a useful therapy to treat autoimmune and inflammatory
es as well as oxidative stress.
In sion, ROCK is a major control point in smooth muscle cell on and a key signaling
component involved in inflammatory processes in various inflammatory cells as well as fibrosis and
remodeling in many diseased organs. In addition, ROCK has been implicated in various es
and disorders including eye diseases; airway diseases; cardiovascular and ar diseases;
inflammatory diseases; neurological and CNS disorders: erative diseases; kidney diseases;
sexual dysfunction; blood diseases; bone diseases; diabetes; benign prostatic lasia,
1O transplant rejection, liver disease, systemic lupus erythematosus, spasm, hypertension, chronic
obstructive r disease, premature birth, infection, allergy, obesity, pancreatic disease and
AIDS.
ROCK appears to be a safe target, as exemplified by knockout models and a large number of
academic studies. These KO mice data, in combination with post-marketing surveillance studies
with Fasudil, a moderately potent ROCK inhibitor used for the treatment of vasospasm after
subarachnoid hemorrhage, te that ROCK is a genuine and significant drug target.
ROCK inhibitors would be useful as therapeutic agents for the treatment of ers implicated in
the ROCK pathway. Accordingly, there is a great need to develop ROCK inhibitors that are useful
in treating various diseases or conditions associated with ROCK tion, particularly given the
inadequate treatments currently available for the majority of these ers. Some non-limiting
examples include eye diseases (Age-related macular degeneration (dry or wet AMD), diabetic
retinopathy, uveitis, glaucoma), or respiratory diseases (asthma, COPD...).
Several different classes of ROCK inhibitors are known. The current focus is oncology and
cardiovascular applications. Until now, the outstanding therapeutic potential of ROCK inhibitors has
only been explored to a limited extent, e ROCK is such a potent and widespread
biochemical regulator, that systemic inhibition of ROCK leads to strong biological effects that are
considered as being side s for the treatment of most of the diseases. Indeed, the medical use
of ROCK tors for rdiological indications is hampered by the pivotal role of ROCK in the
regulation of the tonic phase of smooth muscle cell contraction. Systemically available ROCK
3O inhibitors induce a marked decrease in blood pressure. Therefore, ROCK inhibitors with different
properties are highly required.
For the target specific treatment of ers by regulating smooth muscle function and/or
atory processes and/or remodeling, it is highly desired to deliver a ROCK inhibitor to the
target organ and to avoid significant amounts of these drugs to enter other organs. Therefore, local
or topical application is desired. Typically, topical administration of drugs has been applied for the
treatment of airway-, eye, sexual dysfunction and skin disorders. In addition, local injection /
ration into diseased tissues further extend the potential medical use of locally applied ROCK
inhibitors. Given n criteria are fulfilled, these local applications allow high drug concentration
WO 30365
to be reached in the target tissue. In addition, the incorporation of ROCK inhibitors into ts
and stents can further expand the medical application towards the local treatment of CV diseases
such as atherosclerosis, coronary es and heart failure.
Despite the fact that direct local application is preferred in medical practice, there are concerns
regarding drug levels reached into the systemic circulation. For e the treatment of airway
diseases by local delivery by for instance inhalation, poses the risk of systemic re due to
large amounts entering the GI tract and/or systemic absorption through the lungs. For the treatment
of eye diseases by local delivery, also significant amounts enter the GI tract and/or systemic
circulation due to the low bility of the cornea, low capacity for fluid, efficient drainage and
1O presence of blood vessels in the eyelids. Also for dermal ations, local injections and
implantable medical devices, there is a severe risk of leakage into the systemic circulation.
Therefore, in addition to local ation, the compounds should preferably have additional
properties to avoid significant systemic exposure.
Soft drugs are biologically active compounds that are inactivated once they enter the systemic
circulation. This vation can be achieved in the liver and/or in blood. These compounds, once
applied y to the target tissue / organ exert their desired effect locally. When they leak out of
this tissue / organ into the systemic circulation, they are very rapidly inactivated. Thus, soft drugs of
choice are sufficiently stable in the target tissue / organ to exert the desired biological effect, but
are rapidly degraded in the liver or in the blood to biologically inactive compounds. In addition, it is
highly preferable that the soft drugs of choice have retention at their biological target. This property
will limit the number of applications and is highly desired to reduce the total load of drug and
metabolites and in on will significantly increase the patient compliance.
In conclusion, there is a continuing need to design and develop soft ROCK inhibitors for the
ent of a wide range of disease states. The compounds described herein and
pharmaceutically acceptable compositions thereof are useful for treating or ing the severity
of a y of disorders or conditions associated with ROCK activation. More specifically, the
compounds of the invention are preferably used in the prevention and/or treatment of at least one
disease or disorder, in which ROCK is involved, such as es linked to smooth muscle cell
function, inflammation, fibrosis, excessive cell proliferation, excessive angiogenesis,
3O eactivity, barrier dysfunction, neurodegeneration and remodeling. For example, the
compounds of the invention may be used in the tion and/or treatment of diseases and
disorders such as:
- Eye es or disorders: including but not limited to retinopathy, optic neuropathy, glaucoma
and degenerative retinal diseases such as macular degeneration, proliferative
vitreoretinopathy, proliferative diabetic retinopathy retinitis pigmentosa and inflammatory eye
es (such as anterior uveitis, panuveitis, intermediate uveitis and posterior uveitis),
glaucoma filtration surgery failure, dry eye, allergic conjunctivitis, posterior capsule
opacification, alities of corneal wound healing and ocular pain.
- Airway diseases; including but not limited to pulmonary fibrosis, emphysema, chronic
bronchitis, asthma, fibrosis, pneumonia, cytsic fibrosis, chronic obstructive pulmonary
disease (COPD); bronchitis and rhinitis and respiratory distress syndrome
- Throat, Nose and Ear diseases: including but not limited to sinus ms, g problems,
toothache, tonsillitis, ulcer and rhinitis,
- Skin diseases: including but not limited to hyperkeratosis, parakeratosis, hypergranulosis,
acanthosis, dyskeratosis, spongiosis and ulceration.
- Intestinal diseases; including but not limited to inflammatory bowel disease (IBD), colitis,
enteritis, ileus, ileitis, appendicitis and s disease.
1O - vascular and vascular diseases: including but not limited to, pulmonary hypertension
and pulmonary vasoconstriction,.
- Inflammatory diseases: ing but not limited to contact dermatitis, atopic dermatitis,
psoriasis, rheumatoid arthritis, juvenile toid arthritis, ankylosing spondylitis, psoriatic
arthritis, inflammatory bowel disease, Crohn's e and ulcerative colitis.
- Neurological disorders: ing but not limited to neuropathic pain. The present compounds
are therefore suitable for preventing neurodegeneration and stimulating neurogeneration in
s neurological disorders.
- Proliferative diseases: such as but not limited to cancer of head
, , colon, intestine, skin,
and neck, nerve, uterus, kidney, lung, ovary, as, prostate, or thyroid gland; Castleman
disease; sarcoma; oma; and melanoma.
- Kidney diseases: including but not limited to renal fibrosis or renal dysfunction
- Sexual dysfunction: is meant to include both male and female sexual dysfunction caused by a
defective vasoactive response. The soft ROCK inhibitors of the present ion may also
be used to treat sexual dysfunction arising from a variety of causes. For example, in an
embodiment, the soft ROCK inhibitors may be used to treat sexual dysfunction associated
with hypogonadism and more particularly, wherein the hypogonadism is associated with
reduced levels of androgen hormones. In another embodiment, the soft ROCK inhibitors may
be used to treat sexual dysfunction associated with a variety of causes including, but not
limited to, bladder e, hypertension, es, or pelvic surgery. In addition, the soft
3O ROCK inhibitors may be used to treat sexual dysfunction ated with treatment using
certain drugs, such as drugs used to treat hypertension, depression or anxiety.
- Bone diseases: including but not limited to osteoporosis and osteoarthritis
- In on, the compounds of the invention may be used in the prevention and/or treatment of
diseases and disorders such as benign prostatic hyperplasia, transplant rejection, spasm,
chronic obstructive bladder e, and allergy.
SUMMARY OF THE INVENTION
We have surprisingly found that the compounds described herein act as inhibitors of ROCK, in
particular as soft ROCK inhibitors. The nds of the t invention are rapidly converted
into functionally inactive compounds for e by carboxylic ester hydrolases (EC 3.1 .1) such as
cholinesterases or carboxylesterases. Carboxylic ester hydrolases (EC 3.1.1) represent a large
group of enzymes involved in the degradation of carboxylic esters into alcohols and carboxylic
acids. As such, enzymes displaying this tic activity are of potential interest for the design of
soft kinase inhibitors. EC 3.1.1 includes the following sub-classes:
EC 3.1.1.1 carboxylesterase; EC 3.1.1.2 terase; EC 3.1.1.3 triacylglycerol lipase; EC 3.1.1.4 ;
1O phospholipase A2; EC 3.1.1.5 ospholipase; EC 3.1.1.6 acetylesterase; EC 3.1.1.7
acetylcholinesterase; EC 3.1.1.8 cholinesterase; EC 10 tropinesterase; EC 11
pectinesterase; EC 3.1.1.13 sterol esterase; EC 3.1.1.14 chlorophyllase; EC 3.1.1.15 L-
arabinonolactonase; EC 3.1.1.17 gluconolactonase; EC 3.1.1.19 uronolactonase; EC 20
tannase; EC 3.1.1.21 retinyl-palmitate esterase; EC 3.1.1.22 hydroxybutyrate-dimer hydrolase; EC
3.1.1.23 acylglycerol lipase; EC 3.1.1.24 3-oxoadipate enol-lactonase; EC 3.1.1.25 1,4-lactonase;
EC 3.1.1.26 galactolipase; EC 3.1.1.27 4-pyridoxolactonase; EC 3.1.1.28 acylcarnitine hydrolase;
EC 3.1.1.29 cyl-tRNA hydrolase; EC 3.1.1.30 D-arabinonolactonase; EC 31 6-
phosphogluconolactonase; EC 32 phospholipase A1; EC 3.1.1.33 6-acetylglucose
deacetylase; EC 3.1.1.34 lipoprotein lipase; EC 3.1.1.35 dihydrocoumarin hydrolase; EC 3.1.1.36
2O limonin-D-ring-lactonase; EC 3.1.1.37 steroid-lactonase; EC 38 triacetate-lactonase; EC
3.1.1.39 actinomycin lactonase; EC 3.1.1.40 orsellinate-depside hydrolase; EC 41
cephalosporin-C ylase; EC 3.1.1.42 chlorogenate hydrolase; EC 3.1.1.43 o-acid
esterase; EC 3.1.1.44 4-methyloxaloacetate esterase; EC 3.1.1.45 carboxymethylenebutenolidase;
EC 3.1.1.46 deoxylimonate A-ring-lactonase; EC 3.1.1.47 lacetylglycerophosphocholine
esterase; EC 3.1.1.48 fusarinine-C ornithinesterase; EC 3.1.1.49 sinapine esterase; EC 3.1.1.50
wax-ester hydrolase; EC 3.1.1.51 phorbol-diester hydrolase; EC 3.1.1.52 phosphatidylinositol
deacylase; EC 3.1.1.53 sialate O-acetylesterase; EC 3.1.1.54 acetoxybutynylbithiophene
ylase; EC 3.1.1.55 acetylsalicylate deacetylase; EC 3.1.1.56 methylumbelliferyl-acetate
deacetylase; EC 3.1.1.57 2-pyrone-4,6-dicarboxylate lactonase; EC 3.1.1.58 N-
3O acetylgalactosaminoglycan deacetylase; EC 3.1.1.59 juvenile-hormone esterase; EC 3.1.1.60
bis(2-ethylhexyl)phthalate esterase; EC 3.1.1.61 protein-glutamate methylesterase; EC 3.1.1.63
-retinyl-palmitate hydrolase; EC 3.1.1.64 all-trans-retinyl-palmitate hydrolase; EC 3.1.1.65 L-
rhamnono-1,4-lactonase; EC 3.1.1.66 5-(3,4-diacetoxybutynyl)-2,2'-bithiophene deacetylase; EC
3.1.1.67 fatty-acyl-ethyl-ester synthase; EC 3.1.1.68 xylono-1,4-lactonase; EC 3.1.1.70 cetraxate
benzylesterase; EC 3.1.1.71 acetylalkylglycerol acetylhydrolase; EC 3.1.1.72 acetylxylan esterase;
EC 73 feruloyl esterase; EC 3.1.1.74 cutinase; EC 75 poly(3-hydroxybutyrate)
depolymerase; EC 3.1.1.76 poly(3-hydroxyoctanoate) depolymerase; EC 3.1.1.77 acyloxyacyl
hydrolase; EC 3.1.1.78 polyneuridine-aldehyde esterase; EC 3.1.1.79 hormone-sensitive lipase;
EC 3.1.1.80 acetylajmaline esterase; EC 81 quorum-quenching N-acyl-homoserine
lactonase; EC 82 pheophorbidase; EC 83 monoterpene s-lactone hydrolase; EC
3.1.1.84 cocaine esterase; EC 3.1.1.85 ylglycerate hydrolases.
Cholinesterases are enzymes that are primarily known for their role in the degradation of the
ransmitter acetylcholine. Acetylcholinesterase (EC 3.1.1.7) is also known as Choline
esterase l, true cholinesterase, RBC cholinesterase, erythrocyte cholinesterase, or acetylcholine
acetylhydrolase. As suggested by some of its alternative names, acetylcholinesterase is not only
found in brain, but also in the ocyte fraction of blood. In addition to its action on acetylcholine,
acetylcholinesterase hydrolyzes a variety of acetic esters, and also catalyzes transacetylations.
Acetylcholinesterase usually displays a preference for substrates with short acid chains, as the
1O acetyl group of acetylcholine. Butyrylcholinesterase (EC 8) is also known as
benzoylcholinesterase, choline esterase ll, non-specific cholinesterase, pseudocholinesterase,
plasma cholinesterase or acylcholine acylhydrolase, While being found primarily in liver,
butyrylcholinesterase is also present in plasma. As indicated by some of its alternative names, it is
less specific than acetylcholinesterase and will typically carry out the hydrolysis of substrates with
larger acid chains (such as the butyryl group of butyrylcholine or the benzoyl group of
benzolylcholine) at a faster rate than acetylcholinesterase. In addition to its action on acetylcholine,
butyrylcholinesterase is known to participate in the metabolism of several ester drugs, such as
procaine.
Carboxylesterases (CES) represent a multigene family and show ubiquitous expression profiles,
with high levels in liver, intestine and lungs. A majority of carboxylesterases can be classified either
in carboxylesterase 1 (CES 1) or carboxylesterase 2 (CESZ) families. Interestingly, these different
CES es show differences in tissue distribution and substrate specificity. Human CES1 is
widely distributed in many tissues, but is found in low levels in the ine. CES1 preferentially
hydrolyzes esters with relatively small alcohol groups and larger acid groups. As a l e,
hCES1 preferentially catalyzes the hydrolysis of the methyl ester of e. Human CESZ is
predominantly found in ine, liver and kidney. CESZ preferentially hydrolyzes esters with
r alcohol groups, and larger acid groups. As a typical example, human CESZ zes the
hydrolysis of the l ester of cocaine. Another interesting ation about CES enzymes is
the lack of carboxylesterase activity in human plasma. Overall, carboxylesterases can play a major
3O role in the bioconversion of ester-containing drugs and xenobiotics.
Unless a context dictates otherwise, asterisks are used herein to indicate the point at which a
mono- or bivalent radical depicted is connected to the structure to which it relates and of which the
radical forms part.
Viewed from a first aspect, the invention provides a compound of Formula | or a stereoisomer,
tautomer, racemic, salt, hydrate, or solvate thereof,
YI / o
R3 \R2
X NH2
N / O
Wherein,
X is hydrogen or halogen;
A is —NH-C(=O)— or —NH-;
Y is N or C;
R3 is selected from the group sing hydrogen, C1_20alkyl and 03.15cycloalkyl;
R1 is selected from the group comprising hydrogen, C1_20alkyl, lkoxy, and halogen; and
R2 is selected from the group consisting of C1_20alkyl, C3_20alkenyl, C3_20alkynyl, 03.15cycloalkyl, aryl,
1O heteroaryl, and 03.19heterocyclyl; wherein said C1_20alkyl, C3_20alkenyl, lkynyl, 03.15cycloalkyl,
aryl, heteroaryl, and C3_19heterocyclyl is optionally substituted with one or more substituents
selected from the group consisting of halo, hydroxyl, oxo, carbonyl, amino, amido, cyano, aryl,
heteroaryl, ycloalkyl, C3_19heterocyclyl, C1_20alkylamino, Cq_6alkyl, di(C1_20alkyl)amino, C1.
goalkoxy, halo-C1_20alkoxy, halo-C1_Zoalkyl, thiol, C1_20alkylthio, carboxylic acid, acylamino, C1_20alkyl
esters, carbamate, thioamido, urea, and sulfonamido;
or R2 taken together with R1 forms a cyclic ester (lactone) comprising from 4 to 9 carbon atoms in
the cyclic ester ring.
Viewed from a further aspect, the invention es the use of a compound of the invention, or a
composition comprising such a compound, for inhibiting the activity of at least one kinase, in vitro
or in vivo.
Viewed from a further aspect, the invention provides the use of a compound of the invention, or a
composition comprising such a compound, for inhibiting the activity of at least one ROCK kinase,
for example ROCKII and/or ROCKI ms.
Viewed from a r aspect, the invention provides a pharmaceutical and/or veterinary
composition sing a compound of the invention.
Viewed from a still further aspect, the invention provides a compound of the invention for use in
human or veterinary medicine.
Viewed from a still further aspect, the invention provides the use of a compound of the ion in
the preparation of a medicament for the prevention and/or treatment of at least one disease and/or
disorder selected from the group comprising eye diseases; airway diseases; , nose and ear
diseases; intestinal diseases; cardiovascular and vascular diseases; inflammatory diseases;
neurological and CNS ers: proliferative diseases; kidney diseases; sexual dysfunction; bone
diseases; benign prostatic hyperplasia, transplant rejection, spasm, chronic obstructive r
disease, and allergy.
ED DESCRIPTION OF THE INVENTION
The present invention will now be further described. In the following passages, different s of
the invention are defined in more detail. Each aspect so defined may be combined with any other
aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as
being red or advantageous may be combined with any other feature or features ted as
being red or advantageous.
Unless a context dictates otherwise, asterisks are used herein to indicate the point at which a
mono- or bivalent radical depicted is connected to the structure to which it relates and of which the
radical forms part.
Undefined (racemic) asymmetric centers that may be present in the nds of the present
invention are interchangeably indicated by drawing a wavy bonds or a straight bond in order to
visualize the undefined steric character of the bond.
As already mentioned hereinbefore, in a first aspect the present invention provides compounds of
Formulal
Y' / o
R3 \ R2
X NH2
N / O
Wherein, X, R1, A, Y, R2 and R3 are as defined hereinbefore, including the stereo-isomeric forms,
solvates, and pharmaceutically acceptable addition salts thereof.
When describing the compounds of the invention, the terms used are to be construed in
accordance with the following tions, unless a context es otherwise:
The term " by itself or as part of another substituent refers to a fully saturated hydrocarbon of
Formula CXH2X+1 wherein x is a number greater than or equal to 1. Generally, alkyl groups of this
invention comprise from 1 to 20 carbon atoms. Alkyl groups may be linear or branched and may be
substituted as indicated herein. When a subscript is used herein following a carbon atom, the
subscript refers to the number of carbon atoms that the named group may contain. Thus, for
1O example, C1_4alkyl means an alkyl of one to four carbon atoms. Examples of alkyl groups are
methyl (also shortened as Me), ethyl, n-propyl (also shortened as nPr), i-propyl, butyl, and its
isomers (e.g. n-butyl, i-butyl and t-butyl); pentyl and its isomers, hexyl and its isomers, heptyl and
its isomers, octyl and its s, nonyl and its isomers; decyl and its isomers. C1-C6 alkyl includes
all linear, branched, or cyclic alkyl groups with between 1 and 6 carbon atoms, and thus includes
, ethyl, n-propyl, i-propyl, butyl and its isomers (e.g. n-butyl, i-butyl and t-butyl); pentyl and its
s, hexyl and its isomers, cyclopentyl, 2-, 3-, or 4-methylcyclopentyl, cyclopentylmethylene,
and cyclohexyl.
The term "optionally substituted alkyl" refers to an alkyl group optionally substituted with one or
more substituents (for example 1 to 4 substituents, for example 1, 2, 3, or 4 substituents or 1 to 2
tuents) at any available point of attachment. Non-limiting es of such substituents
include halo, hydroxyl, oxo, carbonyl, nitro, amino, amido, oxime, imino, azido, hydrazino, cyano,
aryl, heteroaryl, lkyl, heterocyclyl, alkylamino, alkoxy, haloalkoxy, haloalkyl, thiol, alkylthio,
carboxylic acid, ino, alkyl esters, carbamate, thioamido, urea, sulfonamido and the like.
The term “alkylamino”, as used herein refers to an amino group substituted with one or more alkyl
chain(s). This definition includes quaternary ammonium derivatives.
The term yl", as used herein, unless otherwise indicated, means straight-chain, cyclic, or
branched-chain hydrocarbon radicals containing at least one carbon-carbon double bond.
Examples of alkenyl radicals include ethenyl, E- and Z-propenyl, isopropenyl, E- and Z-butenyl, E-
and Z-isobutenyl, E- and Z-pentenyl, E- and Z-hexenyl, E,E-, E,Z-, Z,E-, Z,Z-hexadienyl, and the
3O like. An optionally substituted alkenyl refers to an l having ally one or more
substituents (for example 1, 2, 3 or 4), selected from those defined above for substituted alkyl.
The term "alkynyl", as used herein, unless othen/vise indicated, means straight-chain or branched-
chain hydrocarbon radicals containing at least one carbon-carbon triple bond. Examples of alkynyl
radicals include ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, pentynyl, hexynyl, and the like.
An ally substituted alkynyl refers to an l having ally one or more substituents
selected from those defined above for substituted alkyl.
-1 0-
The term “cycloalkyl” by itself or as part of another substituent is a cyclic alkyl group, that is to say,
a monovalent, saturated, or unsaturated hydrocarbyl group having 1, 2, or 3 cyclic ure.
Cycloalkyl includes all ted or partially saturated (containing 1 or 2 double bonds)
hydrocarbon groups containing 1 to 3 rings, including monocyclic, bicyclic, or polycyclic alkyl
groups. Cycloalkyl groups may comprise 3 or more carbon atoms in the ring and generally,
according to this invention comprise from 3 to 15 atoms. The further rings of multi-ring cycloalkyls
may be either fused, bridged and/or joined through one or more spiro atoms. Cycloalkyl groups
may also be considered to be a subset of homocyclic rings discussed hereinafter. Examples of
cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
1O cycloheptyl, cyclooctyl, cyclononyl, adamantanyl, bicyclo(2.2.1)heptanyl and cyclodecyl with
cyclopropyl, cyclopentyl, cyclohexyl, adamantanyl, and o(2.2.1)heptanyl being particularly
preferred. An nally substituted cycloalkyl” refers to a cycloalkyl having optionally one or more
substituents (for example 1 to 3 substituents, for example 1, 2, 3 or 4 substituents), selected from
those defined above for substituted alkyl. When the suffix "ene" is used in ction with a cyclic
group, after also referred to as “Cycloalkylene”, this is intended to mean the cyclic group as
defined herein having two single bonds as points of attachment to other groups. lkylene
groups of this invention preferably se the same number of carbon atoms as their cycloalkyl
radical counterparts.
Where alkyl groups as defined are divalent, i.e., with two single bonds for attachment to two other
groups, they are termed "alkylene" groups. Non-limiting examples of alkylene groups includes
methylene, ne, methylmethylene, trimethylene, propylene, tetramethylene, ethylethylene, 1,2-
dimethylethylene, pentamethylene and hexamethylene. Similarly, where alkenyl groups as defined
above and alkynyl groups as defined above, respectively, are divalent radicals having single bonds
for attachment to two other groups, they are termed ylene" and "alkynylene" respectively.
Generally, alkylene groups of this invention preferably se the same number of carbon atoms
as their alkyl counterparts. Where an alkylene or cycloalkylene biradical is present, tivity to
the molecular structure of which it forms part may be through a common carbon atom or different
carbon atom, ably a common carbon atom. To illustrate this applying the asterisk
nomenclature of this invention, a C3 alkylene group may be for example *-CHZCH2CH2-*, *-CH(-
3O CHZCH3)-*, or *-CHZCH(-CH3)-*. Likewise a C3 cycloalkylene group may be
Where a cycloalkylene group is present, this is preferably a C3-C6 cycloalkylene group, more
ably a C3 cycloalkylene (i.e. cyclopropylene group) wherein its connectivity to the structure of
which it forms part is through a common carbon atom. Cycloalkylene and alkylene cals in
compounds of the invention may be, but preferably are not, substituted.
-1 1 _
The terms ocyclyl" or "heterocyclo" as used herein by itself or as part of another group refer
to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3 to 13 member
monocyclic, 7 to 17 member bicyclic, or 10 to 20 member tricyclic ring systems, or containing a
total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom-
containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4
heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen
and sulfur heteroatoms may optionally be oxidized and the nitrogen atoms may optionally be
quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring
or ring system, where valence allows. The rings of multi-ring heterocycles may be fused, d
1O and/or joined through one or more spiro atoms. An optionally substituted heterocyclyl refers to a
heterocyclyl having optionally one or more substituents (for example 1 to 4 substituents, or for
example 1, 2, 3 or 4), selected from those defined for substituted aryl.
Exemplary heterocyclic groups e piperidinyl, azetidinyl, imidazolinyl, imidazolidinyl,
isoxazolinyl, idinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidyl, succinimidyl, 3H-
indolyl, isoindolinyl, nyl, isochromanyl, xanthenyl, 2H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-
inyl, pyrrolidinyl, 4H-quinolizinyl, 4aH-carbazolyl, 2-oxopiperazinyl, piperazinyl,
perazinyl, 2-pyrazolinyl, zolinyl, pyranyl, dihydro-2H-pyranyl, 4H-pyranyl, 3,4-dihydro-
2H-pyranyl, phthalazinyl, oxetanyl, thietanyl, olanyl, 1,3-dioxanyl, 2,5-dioximidazolidinyl,
piperidonyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, indolinyl, tetrahydropyranyl,
tetrahydrofuranyl, tetrehydrothienyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, rpholinyl,
rpholinyl sulfoxide, rpholinyl sulfone, oxolanyl, 1,4-oxathianyl, 1,4-dithianyl,
1,3,5-trioxanyl, 6H-1,2,5-thiadiazinyl, 2H-1,5,2—dithiazinyl, 2H-oxocinyl, 1H-pyrrolizinyl, tetrahydro-
1,1-dioxothienyl, N- formylpiperazinyl, and linyl.
The term “aryl" as used herein refers to a polyunsaturated, aromatic hydrocarbyl group having a
single ring (i.e. phenyl) or multiple aromatic rings fused together (e.g. naphthalene or anthracene)
or linked covalently, typically containing 6 to 10 atoms; wherein at least one ring is aromatic. The
aromatic ring may optionally include one to three additional rings (either cycloalkyl, heterocyclyl, or
heteroaryl) fused thereto. Aryl is also intended to include the partially hydrogenated derivatives of
the carbocyclic systems enumerated herein. Non-limiting examples of aryl comprise phenyl,
3O biphenylyl, biphenylenyl, 5- or 6-tetralinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-azulenyl, 1- or 2-naphthyl, 1-,
2-, or 3-indenyl, 1-, 2-, or 9-anthryl, 1- 2-, 3-, 4-, or 5-acenaphtylenyl, 3-, 4-, or 5-acenaphtenyl, 1-,
2-, 3-, 4-, or 10-phenanthryl, 1- or 2-pentalenyl, 1, 2-, 3-, or 4-fluorenyl, 4- or 5-indanyl, 5-, 6-, 7-, or
ahydronaphthyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, dibenzo[a,d]cylcoheptenyl,
and 1-, 2-, 3-, 4-, or 5-pyrenyl.
The aryl ring can optionally be substituted by one or more substituents. An “optionally substituted
aryl” refers to an aryl having optionally one or more substituents (for example 1 to 5 substituents,
for example 1, 2, 3 or 4) at any available point of attachment. Non-limiting examples of such
substituents are selected from halogen, hydroxyl, oxo, nitro, amino, hydrazine, aminocarbonyl,
azido, cyano, alkyl, cycloalkyl, l, alkynyl, cycloalkylalkyl, mino, alkoxy, -SOZ-NH2, aryl,
-1 2-
heteroaryl, l, haloalkyl, koxy, alkoxycarbonyl, alkylaminocarbonyl, arylalkyl,
alkylsulfonamide, heterocyclyl, alkylcarbonylaminoalkyl, aryloxy, alkylcarbonyl, arylcarbonyl,
arbonyl, alkylsulfoxide, -SOZRa, alkylthio, carboxyl, and the like, wherein Ra is alkyl or
cycloal kyl.
Where a carbon atom in an aryl group is ed with a heteroatom, the resultant ring is referred
to herein as a aryl ring.
The term “heteroaryl” as used herein by itself or as part of another group refers but is not limited to
to 12 carbon-atom aromatic rings or ring systems containing 1 to 3 rings which are fused together
or linked covalently, typically containing 5 to 8 atoms; at least one of which is aromatic in which one
1O or more carbon atoms in one or more of these rings can be replaced by oxygen, nitrogen or sulfur
atoms where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen
heteroatoms may optionally be quaternized. Such rings may be fused to an aryl, cycloalkyl,
heteroaryl or heterocyclyl ring. Non-limiting es of such heteroaryl, include: pyrrolyl, furanyl,
thiophenyl, lyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl,
thiadiazolyl, tetrazolyl, azolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl,
yl, thiazinyl, triazinyl, imidazo[2,1-b][1,3]thiazolyl, thieno[3,2—b]furanyl, thieno[3,2—b]thiophenyl,
thieno[2,3-d][1,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[1,5-a]pyridinyl, indolyl, zinyl,
isoindolyl, benzofuranyl, benzopyranyl, 1(4H)-benzopyranyl, 1(2H)—benzopyranyl, 3,4-dihydro-
1(2H)—benzopyranyl, 3,4-dihydro-1(2H)—benzopyranyl, isobenzofuranyl, benzothiophenyl,
zothiophenyl, indazolyl, benzimidazolyl, 1,3-benzoxazolyl, 1,2—benzisoxazolyl, 2,1-
benzisoxazolyl, 1,3-benzothiazolyl, 1,2—benzoisothiazolyl, 2,1-benzoisothiazolyl, benzotriazolyl,
1,2,3-benzoxadiazolyl, 2,1 ,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl, benzothiadiazolyl,
pyridinyl, purinyl, imidazo[1,2—a]pyridinyl, 6-oxo-pyridazin-1(6H)—yl, yridin-1(2H)-yl, 6-
oxo-pyridazin-1(6H)—yl, 2-oxopyridin-1(2H)-yl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl,
quinazolinyl, quinoxalinyl, 7-azaindolyl, 6-azaindolyl, 5-azaindolyl, 4-azaindolyl.
The term “pyrrolyl” (also called azolyl) as used herein includes pyrrolyl, pyrrolyl and pyrrol
yl. The term “furanyl” (also called "furyl") as used herein includes furanyl and furanyl (also
called furanyl and furanyl). The term “thiophenyl” (also called "thienyl") as used herein
includes thiophenyl and enyl (also called thienyl and thienyl). The term “pyrazolyl”
3O (also called 1H-pyrazolyl and azolyl) as used herein includes pyrazolyl, pyrazolyl,
pyrazolyl and pyrazolyl. The term “imidazolyl” as used herein includes imidazolyl, imidazol-
2-yl, imidazolyl and imidazolyl. The term “oxazolyl” (also called 1,3-oxazolyl) as used herein
includes oxazolyl; oxazolyl and oxazolyl. The term “isoxazolyl” (also called 1,2—oxazolyl),
as used herein includes isoxazolyl, isoxazolyl, and isoxazolyl. The term “thiazolyl” (also
called 1,3-thiazolyl),as used herein includes lyl, thiazolyl and thiazolyl (also called 2-
thiazolyl, zolyl and 5-thiazolyl). The term “isothiazolyl” (also called 1,2—thiazolyl) as used
herein includes isothiazolyl, isothiazolyl, and isothiazolyl. The term olyl” as used
herein includes 1H-triazolyl and 4H-1,2,4-triazolyl, “1H-triazolyl” includes 1H-1,2,3-triazolyl, 1H-
1,2,3-triazolyl, 1H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 1H-1,2,4-triazolyl and 1H-1,2,4-
-1 3-
triazolyl. “4H-1,2,4-triazolyl” includes 4H-1,2,4-triazolyl, and 4H-1,2,4-triazolyl. The term
“oxadiazolyl” as used herein includes 1,2,3-oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazol
yl, oxadiazolyl, 1,2,5-oxadiazolyl and 1,3,4-oxadiazolyl. The term “thiadiazolyl” as
used herein includes 1,2,3-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,4-
thiadiazolyl, 1,2,5-thiadiazolyl (also called furazanyl) and 1,3,4-thiadiazolyl. The term
zolyl” as used herein includes 1H-tetrazolyl, 1H-tetrazolyl, 2H-tetrazolyl, and 2H-
tetrazolyl. The term “oxatriazolyl” as used herein includes 1,2,3,4-oxatriazolyl and 12,35-
azolyl. The term “thiatriazolyl” as used herein includes 1,2,3,4-thiatriazolyl and 12,35-
thiatriazolyl. The term “pyridinyl” (also called "pyridyl") as used herein es pyridinyl,
1O pyridinyl and pyridinyl (also called 2-pyridyl, 3-pyridyl and 4-pyridyl). The term “pyrimidyl” as
used herein includes pyrimidyl, pyrimidyl, pyrimidyl and dyl. The term “pyrazinyl”
as used herein includes pyrazinyl and pyrazinyl. The term azinyl as used herein
es pyridazinyl and zinyl. The term nyl” (also called "1,4-oxazinyl") as used
herein includes 1,4-oxazinyl and 1,4-oxazinyl. The term “dioxinyl” (also called "1,4-dioxinyl”)
as used herein includes 1,4-dioxinyl and 1,4-dioxinyl. The term “thiazinyl” (also called "1,4-
thiazinyl”) as used herein includes 1,4-thiazinyl, 1,4-thiazinyl, 1,4-thiazinyl, 1,4-thiazinyl
and 1,4-thiazinyl. The term “triazinyl” as used herein includes 1,3,5-triazinyl, 1,2,4-triazinyl,
triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl and 1,2,3-triazinyl. The term “imidazo[2,1-
b][1,3]thiazolyl” as used herein includes imidazo[2,1-b][1,3]thiazoiyl, imidazo[2,1-b][1,3]thiazol
yl, imidazo[2, 1-b][1,3]thiazolyl and imidazo[2,1-b][1,3]thiazolyl. The term “thieno[3,2—
b]furanyl” as used herein includes thieno[3,2—b]furanyl, thieno[3,2—b]furanyl, thieno[3,2—
b]furanyl, and thieno[3,2—b]furanyl. The term “thieno[3,2—b]thiophenyl” as used herein includes
thieno[3,2—b]thienyl, thieno[3,2—b]thienyl, thieno[3,2—b]thienyl and thieno[3,2—b]thienyl.
The term “thieno[2,3-d][1,3]thiazolyl” as used herein includes thieno[2,3-d][1,3]thiazolyl,
thieno[2,3-d][1,3]thiazolyl and thieno[2,3-d][1,3]thiazolyl. The term “thieno[2,3-d]imidazolyl” as
used herein includes thieno[2,3-d]imidazolyl, thieno[2,3-d]imidazolyl and thieno[2,3-
azolyl. The term “tetrazolo[1,5-a]pyridinyl” as used herein includes tetrazolo[1,5-a]pyridine-
-yl, tetrazolo[1,5-a]pyridineyl, tetrazolo[1,5-a]pyridineyl, and tetrazolo[1,5-a]pyridineyl. The
term “indolyl” as used herein includes indolyl, indolyl, indolyl,-indolyl, indolyl, 6-
3O yl and indolyl. The term “indolizinyl” as used herein includes indolizinyl, indolizinyl,
indolizinyl, indolizinyl, indolizinyl, indolizinyl, and indolizinyl. The term “isoindolyl” as
used herein includes isoindolyl, isoindolyl, isoindolyl, isoindolyl, isoindolyl, isoindol
yl and isoindolyl. The term “benzofuranyl” (also called benzo[b]furanyl) as used herein includes
benzofuranyl, benzofuranyl, benzofuranyl, benzofuranyl, benzofuranyl and
uranyl. The term “isobenzofuranyl” (also called benzo[c]furanyl) as used herein includes
isobenzofuranyl, isobenzofuranyl, isobenzofuranyl, isobenzofuranyl, isobenzofuranyl
and isobenzofuranyl. The term “benzothiophenyl” (also called benzo[b]thienyl) as used herein
includes 2-benzo[b]thiophenyl, o[b]thiophenyl, o[b]thiophenyl, 5-benzo[b]thiophenyl,
6-benzo[b]thiophenyl and benzo[b]thiophenyl (also called hienyl, hienyl,
40 hienyl, benzothienyl, benzothienyl and benzothienyl). The term
“isobenzothiophenyl” (also called benzo[c]thienyl) as used herein includes isobenzothienyl,
zothienyl, isobenzothienyl, isobenzothienyl, isobenzothienyl and isobenzothien
yl. The term “indazolyl” (also called azolyl or 2-azaindolyl) as used herein includes 1H-
indazolyl, 1H-indazolyl, 1H-indazolyl, 1H-indazolyl, 1H-indazolyl, 1H-indazolyl, 2H-
indazolyl, 2H-indazolyl, 2H-indazolyl, azolyl, azolyl, and 2H-indazolyl.
The term “benzimidazolyl” as used herein includes benzimidazolyl, benzimidazolyl,
benzimidazolyl, benzimidazolyl, benzimidazolyl and benzimidazolyl. The term “1,3-
benzoxazolyl” as used herein es 1,3-benzoxazol-2—yl, 1,3-benzoxazolyl, 1,3-benzoxazol
yl, 1,3-benzoxazolyl and 1,3-benzoxazolyl. The term “1,2—benzisoxazolyl” as used herein
1O includes 1,2—benzisoxazolyl, 1,2—benzisoxazolyl, 1,2—benzisoxazolyl, 1,2—benzisoxazolyl
and 1,2—benzisoxazolyl. The term “2,1-benzisoxazolyl” as used herein includes 2,1-
benzisoxazolyl, 2,1-benzisoxazolyl, 2,1-benzisoxazolyl, 2,1-benzisoxazolyl and 2,1-
benzisoxazolyl. The term “1 ,3-benzothiazolyl” as used herein includes 1,3-benzothiazolyl, 1,3-
benzothiazolyl, 1,3-benzothiazolyl, 1,3-benzothiazolyl and 1,3-benzothiazolyl. The term
“1 zoisothiazolyl” as used herein includes 1,2—benzisothiazolyl, 1,2—benzisothiazolyl, 1,2-
benzisothiazolyl, 1,2—benzisothiazolyl and 1,2—benzisothiazolyl. The term “2,1-
benzoisothiazolyl” as used herein includes 2,1-benzisothiazolyl, nzisothiazolyl, 2,1-
othiazolyl, nzisothiazolyl and 2,1-benzisothiazolyl. The term “benzotriazolyl”
as used herein includes benzotriazolyl, benzotriazol4-yl, benzotriazolyl, benzotriazolyl and
benzotriazolyl. The term “1 ,2,3-benzoxadiazolyl” as used herein es 1,2,3-benzoxadiazol
yl, 1,2,3-benzoxadiazolyl, 1,2,3-benzoxadiazolyl and 1,2,3-benzoxadiazolyl. The term
“2,1,3-benzoxadiazolyl” as used herein includes 2,1,3-benzoxadiazolyl, 2,1,3-benzoxadiazol
yl, 2,1,3-benzoxadiazol-6—yl and 2,1,3-benzoxadiazolyl. The term “1,2,3-benzothiadiazolyl” as
used herein includes 1,2,3-benzothiadiazolyl, 1,2,3-benzothiadiazolyl, 1,2,3-benzothiadiazol-
6-yl and benzothiadiazolyl. The term “2,1,3-benzothiadiazolyl” as used herein includes
2,1,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl and 2,1,3-
benzothiadiazolyl. The term “thienopyridinyl” as used herein includes thieno[2,3-b]pyridinyl,
thieno[2,3-c]pyridinyl, thieno[3,2—c]pyridinyl and thieno[3,2—b]pyridinyl. The term “purinyl” as used
herein includes purinyl, purinyl, purinyl and purinyl. The term “imidazo[1,2—a]pyridinyl”,
3O as used herein es imidazo[1,2—a]pyridinyl, imidazo[1,2—a]pyridinyl, imidazo[1,2—a]pyridin-
4-yl, imidazo[1,2—a]pyridinyl, imidazo[1,2—a]pyridinyl and imidazo[1,2—a]pyridinyl. The term
“1,3-benzodioxolyl”, as used herein includes 1,3-benzodioxolyl, 1,3-benzodioxolyl, 1,3-
benzodioxolyl, and 1,3-benzodioxolyl. The term “quinolinyl” as used herein includes quinolin-
2—yl, quinolinyl, inyl, quinolinyl, quinolinyl, quinolinyl and quinolinyl. The term
inolinyl” as used herein includes isoquinolinyl, isoquinolinyl, isoquinolinyl, isoquinolin-
-yl, isoquinolinyl, isoquinolinyl and isoquinolinyl. The term “cinnolinyl” as used herein
includes cinnolinyl, cinnolinyl, cinnolinyl, cinnolinyl, cinnolinyl and cinnolinyl. The
term “quinazolinyl” as used herein includes quinazolinyl, quiriazolinyl, olinyl,
quinazolinyl, quinazolinyl and quinazolinyl. The term “quinoxalinyl”. as used herein es
40 quinoxalinyl, quinoxalinyl, and quinoxalinyl. The term “7-azaindolyl” as used herein refers
WO 30365 2012/067016
-1 5-
to 1H-Pyrrolo[2,3-b]pyridinyl and es 7-azaindolyl, 7-azaindolyl, 7-azaindolyl, 7-
azaindolyl, 7-azaindolyl, 7-azaindolyl. The term “6-azaindolyl” as used herein refers to 1HPyrrolo
[2,3-c]pyridinyl and includes 6—azaindolyl, 6—azaindolyl, 6-azaindolyl, 6-azaindol
yl, 6—azaindolyl, 6—azaindolyl. The term “5-azaindolyl” as used herein refers to 1H-Pyrrolo[3,2—
c]pyridinyl and includes 5-azaindolyl, 5-azaindolyl, 5-azaindolyl, 5-azaindolyl, 5-
azaindolyl, 5-azaindolyl. The term “4-azaindolyl” as used herein refers to 1H-Pyrrolo[3,2—
dinyl and includes ndolyl, 4-azaindolyl, 4-azaindolyl, 4-azaindolyl, 4-
azaindolyl, 4-azaindolyl.
For example, miting examples of heteroaryl can be 2— or 3-furyl, 2— or 3-thienyl, 1-, 2— or 3-
1O pyrrolyl, 1-, 2—, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 2—, 4- or 5-oxazolyl,
3-, 4- or 5-isothiazolyl, 2—, 4- or zolyl, 1,2,3-triazol, or yl, 1,2,4-triazol, , or
yl, 1H-tetrazol, oryl, 2H-tetrazol, or yl, 1,2,3-0xadiazol or yl, 1,2,4-oxadiazol or -
-yl, 1,2,5-0xadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazol or yl, 1,2,4-thiadiazol or yl,
1,2,5-thiadiazol or yl, 1,3,4-thiadiazolyl, 1- or 5-tetrazolyl, 2—, 3- or 4-pyridyl, 3- or 4-
pyridazinyl, 2—, 4-, 5- or 6-pyrimidyl, 2—, 3-, 4-, 5- 6—2H-thiopyranyl, 2—, 3- or 4-4H-thiopyranyl, 4-
azaindol, 2—, 3-, 5-, or 7-yl, 5-azaindol, or 2—, 3-, 4-, 6-, or 7-yl, ndol-1, 2—, 3-, 4-, 5-, or 7-
yl, 7-azaindol, 2—, 3-, 4, 5-, or 6-yl, 2—, 3-, 4-, 5-, 6- or 7-benzofuryl, 1-, 3-, 4- or 5-isobenzofuryl,
2—, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 3-, 4- or 5-isobenzothienyl, 1-, 2—, 3-, 4-, 5-, 6- or 7-indolyl, 2-
or 3-pyrazinyl, 1,4-oxazin or yl, 1,4-dioxin or yl, 1,4-thiazin or yl, 1,2,3-triazinyl,
1,2,4-triazinyl, 1,3,5-triazin, or yl, thieno[2,3-b]furan, , , or yl, benzimidazolyl,
yl, yl, yl, yl, or yl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 3-, 4-, 5-, 6- or 7-
benzisoxazolyl, 2—, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisothiazolyl, 1,3-benzothiazol-
2—yl, yl, yl, yl or yl, 1,3-benzodioxolyl, yl, yl, or yl, benzotriazolyl, yl, yl,
yl or yl1-, nthrenyl, 3-, 4- or 5-isobenzofuranyl, 1-, 2—, 3-, 4- or 9-xanthenyl, 1-, 2—, 3- or
4-phenoxathiinyl, 2—, 3-pyrazinyl, 1-, 2—, 3-, 4-, 5-, 6-, 7- or 8-indolizinyl, 2—, 3-, 4- or 5-isoindolyl, 1H-
indazolyl, 3-yl, yl, yl, yl, or yl, 2H-indazolyl, 3-yl, yl, yl, yl, or yl,
imidazo[2,1-b][1,3]thiazoiyl, imidazo[2,1-b][1,3]thiazolyl, imidazo[2, 1-b][1,3]thiazolyl or
imidazo[2,1-b][1,3]thiazolyl, imidazo[1,2—a]pyridinyl, imidazo[1,2—a]pyridinyl, imidazo[1,2—
a]pyridinyl, imidazo[1,2—a]pyridinyl, o[1,2—a]pyridinyl or imidazo[1,2—a]pyridinyl,
3O tetrazolo[1 ,5-a]pyridineyl, tetrazolo[1 ,5-a]pyridineyl, tetrazolo[1,5-a]pyridineyl, or
tetrazolo[1,5-a]pyridineyl, 2—, 6-, 7- or 8-purinyl, 4-, 5- or 6-phthalazinyl, 2—, 3- or 4-naphthyridinyl,
2—, 5- or 6-quinoxalinyl, 2—, 4-, 5-, 6-, 7- or 8-quinazolinyl, 1-, 2—, 3- or 4-quinolizinyl, 2—, 3-, 4-, 5-, 6-,
7-, or 8-quinolinyl(quinolyl), 2—, 4-, 5-, 6-, 7- or 8-quinazolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-
isoquinolinyl(isoquinolyl), 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl,2-, 4-, 6- or 7-pteridinyl, 1-, 2—, 3-, 4- or 9-
carbazolyl, 1-, 2—, 3-, 4-, 5-, 6-, 7-, 8- or olinyl, 1-, 2—, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-
thridinyl, 1-, 2—, 3- or 4-acridinyl, 1-, 2—, 3-, 4-, 5-, 6-, 7-, 8- or 9-perimidinyl, 2—, 3-, 4-, 5-, 6-,
7-, 8-, 9- or 10-(1,7)phenanthrolinyl, 1- or 2—phenazinyl, 1-, 2—, 3-, 4-, or 10-phenothiazinyl, 3- or 4-
nyl, 1-, 2—, 3-, 4-, or 10-phenoxazinyl, or additionally substituted tives thereof.
-1 5-
An “optionally substituted heteroaryl” refers to a heteroaryl having optionally one or more
substituents (for example 1 to 4 substituents, for example 1, 2, 3 or 4), selected from those defined
above for substituted aryl.
The term “oxo” as used herein refers to the group =0.
The term “alkoxy" or “alkyloxy” as used herein refers to a l having the Formula -ORb wherein
Rb is alkyl. ably, alkoxy is C1-C10 , C1-C6 alkoxy, or C1-C4 alkoxy. miting
examples of suitable alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-
butoxy, tert-butoxy, pentyloxy and hexyloxy. Where the oxygen atom in an alkoxy group is
substituted with sulfur, the ant radical is referred to as thioalkoxy. “Haloalkoxy” is an alkoxy
1O group wherein one or more hydrogen atoms in the alkyl group are substituted with halogen. Non-
limiting examples of suitable haloalkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy,
2,2,2—trifluoroethoxy, 1,1,2,2—tetrafluoroethoxy, roethoxy, 2—chloroethoxy, fluoroethoxy,
2,2,2—trichloroethoxy; trichloromethoxy, 2—bromoethoxy, pentafluoroethyl, 3,3,3-trichloropropoxy,
4,4,4-trichlorobutoxy.
The term "aryloxy" as used herein denotes a group -O-aryl, wherein aryl is as defined above.
The term “arylcarbonyl” or "aroyl" as used herein denotes a group -C(O)—aryl, wherein aryl is as
defined above.
The term “cycloalkylalkyl” by itself or as part of another substituent refers to a group having one of
the aforementioned cycloalkyl groups attached to one of the aforementioned alkyl chains.
Examples of such cycloalkylalkyl radicals include cyclopropylmethyl, cyclobutylmethyl,
cyclopentylmethyl, cyclohexylmethyl, 1-cyclopentylethyl, 1-cyclohexylethyl, 2—cyclopentylethyl, 2-
cyclohexylethyl, cyclobutylpropyl, entylpropyl, 3-cyclopentylbutyl, exylbutyl and the
like.
The term “heterocyclyl-alkyl” by itself or as part of another substituents refers to a group having one
of the aforementioned heterocyclyl group attached to one of the aforementioned alkyl group, i.e., to
a group —Rd-RC wherein Rd is alkylene or alkylene tuted by alkyl group and Rc is a
heterocyclyl group.
The term "carboxy" or “carboxyl” or “hydroxycarbonyl” by itself or as part of another substituent
refers to the group -C02H. Thus, a carboxyalkyl is an alkyl group as defined above having at least
one substituent that is -COZH.
The term "alkoxycarbonyl" by itself or as part of another substituent refers to a carboxy group
linked to an alkyl l i.e. to form —C(=O)ORe, wherein R9 is as defined above for alkyl.
The term “alkylcarbonyloxy” by itself or as part of another tuent refers to a —O-C(=O)Re
wherein R9 is as defined above for alkyl.
-1 7-
The term “alkylcarbonylamino” by itself or as part of another substituent refers to an group of
Formula -NH(C=O)R or -NR'(C=O)R, wherein R and R’ are each independently alkyl or substituted
alkyl.
The term “thiocarbonyl” by itself or as part of r substituent refers to the group -C(=S)—.
The term “alkoxy” by itself or as part of r substituent refers to a group consisting of an
oxygen atom attached to one optionally substituted straight or branched alkyl group, cycloalkyl
group, l, or cycloalkylalkyl group. Non-limiting examples of suitable alkoxy group e
methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, hexanoxy,
and the like.
1O The term “halo” or en” as a group or part of a group is generic for fluoro, , bromo, or
iodo.
The term "haloalkyl" alone or in combination, refers to an alkyl radical having the meaning as
defined above wherein one or more hydrogens are replaced with a halogen as defined above. Non-
limiting examples of such haloalkyl radicals e chloromethyl, 1-bromoethyl, fluoromethyl,
difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and the like.
The term "haloaryl" alone or in combination, refers to an aryl radical having the meaning as defined
above wherein one or more hydrogens are replaced with a halogen as defined above.
The term “haloalkoxy” alone or in combination refers to a group of Formula -O-alkyl wherein the
alkyl group is substituted by 1, 2, or 3 halogen atoms. For example, "haloalkoxy" includes -OCF3, —
OCHFz, 'OCHzF, -CF3, 'O-CHz-CF3, -O-CH2—CHF2, and -O-CH2—CH2F.
Whenever the term “substituted” is used in the t invention, it is meant to indicate that one or
more hydrogens on the atom indicated in the expression using “substituted” is replaced with a
selection from the ted group, provided that the indicated atom’s normal valency is not
exceeded, and that the substitution results in a chemically stable compound, Le. a compound that
is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and
formulation into a therapeutic agent.
As used herein the terms such as “alkyl, aryl, or lkyl, each being optionally substituted with”
or “alkyl, aryl, or cycloalkyl, optionally substituted with” refers to optionally substituted alkyl,
ally tuted aryl and optionally substituted cycloalkyl.
3O As described herein, some of the compounds of the invention may contain one or more
tric carbon atoms that serve as a chiral center, which may lead to different optical forms
(e.g. enantiomers or diastereoisomers). The invention comprises all such l forms in all
possible configurations, as well as mixtures thereof.
More lly, from the above, it will be clear to the skilled person that the compounds of the
invention may exist in the form of different isomers and/or tautomers, including but not limited to
geometrical isomers, conformational isomers, E/Z-isomers, stereochemical isomers (i.e.
-1 8-
enantiomers and diastereoisomers) and isomers that correspond to the presence of the same
substituents on different positions of the rings present in the compounds of the invention. All such
possible s, tautomers and mixtures thereof are included within the scope of the invention.
Whenever used in the present invention the term “compounds of the invention” or a similar term is
meant to include the compounds of general Formula | and any subgroup thereof. This term also
refers to the compounds as depicted in Tables 1 to 11, their derivatives, es, salts, solvates,
hydrates, stereoisomeric forms, racemic mixtures, tautomeric forms, optical isomers, ues,
pro-drugs, esters, and metabolites, as well as their quaternized nitrogen analogues. The N-oxide
forms of said compounds are meant to comprise compounds wherein one or several nitrogen
1O atoms are oxidized to the so-called N-oxide.
As used in the specification and the appended claims, the singular forms "a", "an", and "the"
include plural referents unless the context clearly dictates otherwise. By way of example, "a
compound" means one compound or more than one compound.
The terms described above and others used in the specification are well understood to those in the
art.
In a further embodiment, the present invention provides compounds of formula I as bed
herein, wherein;
R3 is selected from the group comprising hydrogen, Cq_6alkyl, and C3_6cycloalkyl, in ular
hydrogen or C1_3alkyl; more in ular hydrogen.
In a preferred embodiment, the present invention provides nds of formula I, n;
X is hydrogen or n; in particular halogen; more in particular fluoro;
A is —NH-C(=O)— or —C(=O)—NH-;
Y is N or C;
R3 is selected from the group comprising en, C1_20alkyl, and 03.15cycloalkyl; in particular
hydrogen or C1_6alkyl; more in ular hydrogen or C1_6alkyl; even more in particular hydrogen;
R1 is selected from the group comprising en, Cmoalkyl, C1_20alkoxy, and halogen; in
particular hydrogen, C1_6alkyl, and halogen; more in particular hydrogen, methyl, and halogen; and
R2 is selected from the group consisting of C1_20alkyl, C3_20alkenyl, C3_20alkynyl, 03.15cycloalkyl, aryl,
heteroaryl, and 03.19heterocyclyl; wherein said Cmoalkyl, C3_20alkenyl, C3_20alkynyl, 03.15cycloalkyl,
aryl, heteroaryl, and eterocyclyl is optionally substituted with one or more substituents
selected from the group consisting of halo, hydroxyl, oxo, carbonyl, amino, amido, cyano, aryl,
heteroaryl, ycloalkyl, C3_19heterocyclyl, C1_20alkylamino, Cq_6alkyl, di(C1_20alkyl)amino, C1.
-1 9-
goalkoxy, halo-C1_20alkoxy, halo-C1_Zoalkyl, thiol, C1_20alkylthio, carboxylic acid, acylamino, Cmoalkyl
esters, carbamate, thioamido, urea, and sulfonamido;
Or R2 taken together with R1 form a cyclic ester (Iactone) comprising from 4 to 9 carbon atoms in
the cyclic ester ring.
In an even r embodiment, the present invention provides compounds of formula I as
described herein, wherein;
R1 is selected from the group comprising hydrogen, C1_6alkyl, C1_6alkoxy, and halogen; in particular
hydrogen, C1_6alkyl, and halogen; more in particular hydrogen, methyl, and halogen.
1O In an even further red embodiment, the present invention provides compounds of formula I as
described herein, wherein;
R1 is selected from the group sing hydrogen, Cmoalkyl, C1_20alkoxy, and halogen; in
particular hydrogen, methyl, and n; more in particular R1 is methyl or fluoro; and
R2 is selected from the group ting of C1_20alkyl, C3_20alkenyl, C3_20alkynyl, 03.15cycloalkyl, aryl,
heteroaryl, and 03.19heterocyclyl; wherein said Cmoalkyl, C3_20alkenyl, and C3_20alkynyl is optionally
substituted with one or more substituents selected from the group ting of halo, hydroxyl, oxo,
carbonyl, amino, amido, cyano, aryl, heteroaryl, C1_6alkyl, 03.15cycloalkyl, C3_19heterocyclyl, C1.
goalkylamino, di(C1_20alkyl)amino, C1_20alkoxy, 1_20alkoxy, halo-C1_Zoalkyl, thiol, C1_20alkylthio,
carboxylic acid, acylamino, yl esters, carbamate, ido, urea, and sulfonamido;
in particular R2 is selected from the group consisting of lkyl, C3_20alkenyl, C3_20alkynyl, C3.
15cycloalkyl, aryl, heteroaryl, and C3_19heterocyclyl; wherein said Cmoalkyl is optionally substituted
with one or more substituents selected from the group ting of halo, yl, oxo, carbonyl,
amino, amido, cyano, aryl, heteroaryl, 03.15cycloalkyl, C3_19heterocyclyl, C1_20alkylamino, di(C1_
goalkyl)amino, C1_20alkoxy, halo-C1_Zoalkoxy, halo-C1_Zoalkyl, thiol, C1_20alkylthio, carboxylic acid,
ino, yl esters, carbamate, thioamido, urea, and sulfonamido.
or R2 taken together with R1 form a cyclic ester (Iactone) comprising from 4 to 5 carbon atoms in
the cyclic ester ring.
In a further ment, the present invention provides compounds of formula I as described
3O herein, wherein;
R1 is selected from the group comprising hydrogen, Cmoalkyl, C1_20alkoxy, and n; in
particular hydrogen, methyl or halogen, more in particular methyl or fluoro; and
R2 is selected from the group consisting of Cmoalkyl, C3_20alkenyl, C3_20alkynyl, and aryl; wherein
said Cmoalkyl, C3_20alkenyl, C3_20alkynyl, and aryl is optionally substituted with one or more
substituents selected from the group consisting of halo, hydroxyl, oxo, carbonyl, amino, amido,
cyano, aryl, heteroaryl, Cq_6alkyl, 03.15cycloalkyl, 03.19heterocyclyl, C1_20alkylamino, di(C1_
goalkyl)amino, lkoxy, halo-C1_Zoalkoxy, halo-C1_Zoalkyl, thiol, C1_20alkylthio, carboxylic acid,
acylamino, Cmoalkyl esters, carbamate, thioamido, urea, and sulfonamido;
in particular R2 is selected from the group consisting of Cmoalkyl, C3_20alkenyl, C3_20alkynyl, and
aryl; wherein said Cmoalkyl is optionally substituted with one or more tuents selected from
the group consisting of halo, yl, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, C3.
15cycloalkyl, C3_19heterocyclyl, Cmoalkylamino, di(C1_20alkyl)amino, oxy, halo-C1_Zoalkoxy,
halo-C1_Zoalkyl, thiol, lkylthio, ylic acid, acylamino, Cmoalkyl esters, ate,
ido, urea, and sulfonamido;
1O or R2 taken together with R1 form a cyclic ester (lactone) sing from 4 to 5 carbon atoms in
the cyclic ester ring.
In another preferred embodiment, the present invention provides nds of formula I as
described herein, wherein;
R1 is selected from the group comprising hydrogen, yl, lkoxy, and halogen; in
particular hydrogen, methyl or halogen, more in particular methyl or fluoro; and
R2 is ed from the group consisting of Cq_6alkyl, Cg_6alkenyl, Cg_6alkynyl, and aryl; n said
C1_6alkyl, C3_6alkenyl, Cg_6alkynyl, and aryl is ally substituted with one or more substituents
selected from the group consisting of halo, hydroxyl, oxo, carbonyl, amino, amido, cyano, aryl,
heteroaryl, C1_6alkyl, 03.15cycloalkyl, C3_19heterocyclyl, C1_20alkylamino, di(C1_20alkyl)amino, C1.
goalkoxy, halo-C1_20alkoxy, halo-C1_Zoalkyl, thiol, C1_20alkylthio, carboxylic acid, acylamino, Cmoalkyl
, carbamate, thioamido, urea, and sulfonamido;
in particular selected from the group consisting of C1_6alkyl, C3_6alkenyl, and Cg_6alkynyl; wherein
said Cq_6alkyl, C3_6alkenyl, and Cg_6alkynyl is optionally substituted with one or more substituents
selected from the group consisting of halo, hydroxyl, oxo, carbonyl, amino, amido, cyano, aryl,
heteroaryl, C1_6alkyl, 03.15cycloalkyl, C3_19heterocyclyl, C1_20alkylamino, di(C1_20alkyl)amino, C1.
goalkoxy, halo-C1_20alkoxy, halo-C1_Zoalkyl, thiol, C1_20alkylthio, carboxylic acid, acylamino, Cmoalkyl
esters, carbamate, thioamido, urea, and sulfonamido;
more in particular R2 is C1_6alkyl optionally substituted with a substituent selected from the group
3O consisting of halo, hydroxyl, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, Cq_6alkyl, C3.
15cycloalkyl, C3_19heterocyclyl, Cmoalkylamino, di(C1_20alkyl)amino, Cmoalkoxy, halo-C1_Zoalkoxy,
halo-C1_Zoalkyl, thiol, C1_20alkylthio, carboxylic acid, acylamino, Cmoalkyl esters, carbamate,
thioamido, urea, and sulfonamido;
or R2 taken together with R1 form a cyclic ester (lactone) comprising from 4 to 5 carbon atoms in
the cyclic ester ring.
-21 _
In a particular embodiment, the present invention provides nds of a I as described
herein, wherein;
said one or more al substituents for R2 are selected from the group consisting of halo,
hydroxyl, nitro, amino, cyano, aryl, heteroaryl, 03.15cycloalkyl, C3_19heterocyclyl, C1_20alkylamino,
di(C1_20alkyl)amino, C1_20alkoxy, and halo-C1_Zoalkyl; in particular from the group consisting of cyano,
C3_6cycloalkyl, C3_6heterocyclyl, C1_6alkoxy, di(C1_6alkyl)amino, aryl, and aryl; more in
particular from C3_6heterocyclyl, and C1_6alkoxy.
It is also an object of the invention to provide those compounds of formula I wherein one or more of
1O the following ction apply:
0 X is halogen; in particular fluoro;
- A is —C(=O)—NH-;
- Y is C;
0 R3 is hydrogen;
0 R1 is selected from the group comprising hydrogen, Cmoalkyl, and halogen; in particular
hydrogen, C1_6alkyl, and halogen; more in particular hydrogen, methyl and fluoro
- R1 is hydrogen;
0 R1 is fluoro;
- R2 is selected from the group ting of C1_20alkyl, C3_20alkenyl, C3_20alkynyl, C3.
oalkyl, aryl, heteroaryl, and 03.19heterocyclyl; wherein said C1_20alkyl, C3_20alkenyl,
and C3_20alkynyl is optionally substituted with one or more tuents selected from the
group consisting of halo, hydroxyl, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, C1.
6alkyl, 03.15cycloalkyl, C3_19heterocyclyl, lkylamino, di(C1_20alkyl)amino, C1_20alkoxy,
halo-C1_Zoalkoxy, halo-C1_Zoalkyl, thiol, C1_20alkylthio, carboxylic acid, acylamino, Cmoalkyl
esters, carbamate, thioamido, urea, and sulfonamido; in particular R2 is selected from the
group consisting of Cmoalkyl, lkenyl, C3_20alkynyl, 03.15cycloalkyl, aryl, heteroaryl, and
C3_19heterocyclyl; wherein said Cmoalkyl is optionally substituted with one or more
substituents selected from the group ting of halo, hydroxyl, oxo, carbonyl, amino,
amido, cyano, aryl, heteroaryl, 03.15cycloalkyl, C3_19heterocyclyl, C1_20alkylamino, di(C1_
3O goalkyl)amino, C1_20alkoxy, halo-C1_Zoalkoxy, halo-C1_Zoalkyl, thiol, C1_20alkylthio, carboxylic
acid, acylamino, Cmoalkyl esters, carbamate, thioamido, urea, and sulfonamido;
- R2 is selected from the group consisting of C1_20alkyl, C3_20alkenyl, C3_20alkynyl, and aryl;
wherein said lkyl, lkenyl, C3_20alkynyl, and aryl is optionally substituted with one
or more substituents selected from the group consisting of halo, hydroxyl, oxo, carbonyl,
amino, amido, cyano, aryl, heteroaryl, Cq_6alkyl, ycloalkyl, C3_19heterocyclyl, C1.
lamino, di(C1_20alkyl)amino, C1_20alkoxy, halo-C1_20alkoxy, halo-C1_Zoalkyl, thiol, C1.
goalkylthio, carboxylic acid, acylamino, Cmoalkyl esters, carbamate, thioamido, urea, and
sulfonamido; in particular R2 is selected from the group consisting of C1_20alkyl, C3.
WO 30365 2012/067016
goalkenyl, C3_20alkynyl, and aryl; wherein said Cmoalkyl is optionally substituted with one or
more substituents selected from the group consisting of halo, yl, oxo, carbonyl,
amino, amido, cyano, aryl, heteroaryl, 03.15cycloalkyl, C3_19heterocyclyl, C1_20alkylamino,
di(C1_20alkyl)amino, oxy, halo-C1_Zoalkoxy, halo-C1_Zoalkyl, thiol, C1_20alkylthio,
carboxylic acid, acylamino, Cmoalkyl esters, carbamate, thioamido, urea, and sulfonamido;
R2 is selected from the group consisting of Cq_6alkyl, C3_6alkenyl, Cg_6alkynyl, and aryl;
wherein said Cq_6alkyl, C3_6alkenyl, Cg_6alkynyl, and aryl is optionally substituted with one or
more substituents selected from the group consisting of halo, hydroxyl, oxo, carbonyl,
amino, amido, cyano, aryl, heteroaryl, Cq_6alkyl, 03.15cycloalkyl, C3_19heterocyclyl, C1.
1O goalkylamino, di(C1_20alkyl)amino, lkoxy, 1_20alkoxy, halo-C1_Zoalkyl, thiol, C1.
goalkylthio, carboxylic acid, acylamino, Cmoalkyl esters, carbamate, thioamido, urea, and
sulfonamido; in particular selected from the group consisting of C1_6alkyl, C3_6alkenyl, and
Cg_6alkynyl; wherein said C1_6alkyl, C3_6alkenyl, and kynyl is optionally substituted with
one or more substituents ed from the group consisting of halo, hydroxyl, oxo,
carbonyl, amino, amido, cyano, aryl, heteroaryl, C1_6alkyl, 03.15cycloalkyl, C3_19heterocyclyl,
C1_20alkylamino, di(C1_20alkyl)amino, Cmoalkoxy, halo-C1_Zoalkoxy, halo-C1_Zoalkyl, thiol, C1.
goalkylthio, carboxylic acid, acylamino, Cmoalkyl esters, carbamate, ido, urea, and
sulfonamido; more in particular R2 is C1_6alkyl optionally tuted with a substituent
selected from the group consisting of halo, hydroxyl, oxo, carbonyl, amino, amido, cyano,
aryl, heteroaryl, Cq_6alkyl, 03.15cycloalkyl, C3_19heterocyclyl, C1_20alkylamino, di(C1_
goalkyl)amino, C1_20alkoxy, halo-C1_Zoalkoxy, 1_Zoalkyl, thiol, C1_20alkylthio, carboxylic
acid, acylamino, Cmoalkyl esters, carbamate, thioamido, urea, and sulfonamido; even
more in particular R2 is C1_6alkyl.
said one or more optional substituents for R2 are selected from the group consisting of
halo, hydroxyl, nitro, amino, cyano, aryl, heteroaryl, 03.15cycloalkyl, C3_19heterocyclyl, C1.
goalkylamino, di(C1_20alkyl)amino, C1_20alkoxy, and 1_Zoalkyl; in particular from the
group consisting of cyano, cloalkyl, terocyclyl, C1_6alkoxy, di(C1_6alkyl)amino,
aryl, and heteroaryl; more in particular from C3_6heterocyclyl, and C1_6alkoxy;
said one or more optional substituents for R2 are selected from C3_19heterocyclyl and C1.
3O goalkoxy; more in particular from oxolanyl and methoxy;
R1 and R2 taken er form a cyclic ester comprising 4 carbon atoms in the cyclic ester
ring.
In another particular embodiment, the present invention provides a compound selected from the
group consisting of:
methyl 4-({3- [2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl}amido)
benzoate;
methyl 4-({3-[2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl}amido)—3-
fluorobenzoate;
0 methyl 4-({3-[2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl}amido)—2—
fluorobenzoate;
- propyl 4-({3-[2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl}amido)—3-
fluorobenzoate;
- methyl 4-({3-[2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl}amido)—2—
methylbenzoate;
- propyl 4-({3-[2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl}amido)—2—
methylbenzoate;
- methyl 4-({3-[2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl}carbamoyl)
1O benzoate;
- methyl 6-({3-[2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl}carbamoyl)
pyridinecarboxylate;
- 2—methoxyethyl 4-({3- [2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl}
amido)benzoate;
- oxolanylmethyl 4-({3- [2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl}
amido)benzoate;
- 4-(aminomethyl)-N-(3-fluoropyridinyl){3-[(1-oxo-1,3-dihydrobenzofuranyl)
carbamoyl]phenyl}benzamide; and
- N-{3-[2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl}oxo-1,3-dihydro-
2-benzofurancarboxamide.
The nds of the present invention can be prepared according to the reaction schemes
ed in the examples hereinafter, but those skilled in the art will appreciate that these are only
rative for the invention and that the compounds of this invention can be prepared by any of
several standard synthetic processes ly used by those skilled in the art of organic
chemistry.
In a red embodiment, the compounds of the t invention are useful as kinase inhibitors,
either in vitro or in vivo, more in particular for the inhibition of at least one ROCK kinase, ed
from ROCKl and ROCKll, in particular soft ROCK inhibitors. Accordingly the present invention
3O provides the compounds as defined herein, or a composition comprising said compound(s) for use
as a medicine.
The present invention further provides the use of a compound as defined before or the use of
a composition comprising said compound, as a human or veterinary medicine, in particular for
prevention and/or treatment of at least one disease or disorder, in which ROCK is ed, such as
diseases linked to smooth muscle cell function, mation, fibrosis, excessive cell proliferation,
excessive angiogenesis, hyperreactivity, barrier dysfunction, neurodegeneration, and remodeling.
In a further embodiment, the invention provides the use of a compound as defined hereinbefore, or
the use of a composition comprising said compound in the tion and/or treatment of at least
one disease or disorder selected from the group comprising eye diseases; airway diseases; throat,
nose and ear diseases; intestinal diseases; vascular and ar diseases; inflammatory
diseases; neurological and CNS disorders: proliferative es; kidney diseases; sexual
dysfunction; bone diseases; benign prostatic hyperplasia, transplant rejection, spasm,
hypertension, chronic obstructive bladder disease, and allergy.
In a preferred embodiment, the invention es the use of a nd as defined hereinbefore
or the use of a composition comprising said compound in the prevention and/or treatment of eyes
1O diseases including but not limited to pathy, optic neuropathy, glaucoma and degenerative
retinal diseases such as macular degeneration, retinitis pigmentosa and inflammatory eye diseases
(such as or uveitis, panuveitis, intermediate uveitis and posterior uveitis), and/or for
preventing, treating and/or alleviating complications and/or symptoms associated therewith.
In another embodiment, the invention provides the use of a compound as defined hereinbefore or
the use of a composition comprising said compound in the prevention and/or treatment of airway
diseases; including but not limited to ary fibrosis, emphysema, chronic bronchitis, asthma,
fibrosis, pneumonia, cystic fibrosis, chronic obstructive pulmonary e (COPD); bronchitis and
is and respiratory distress syndrome, and/or for preventing, treating and/or alleviating
complications and/or symptoms associated therewith.
In a further ment, the invention provides the use of a compound as defined hereinbefore or
the use of a composition comprising said compound in the prevention and/or treatment of
cardiovascular and vascular diseases: including but not d to pulmonary hypertension and
pulmonary vasoconstriction, and/or for preventing, treating and/or alleviating complications and/or
symptoms ated therewith and/or alleviating complications and/or symptoms associated
therewith.
In a further ment, the invention provides the use of a compound as defined hereinbefore or
the use of a composition comprising said compound in the prevention and/or treatment of throat,
nose and ear diseases: including but not limited to sinus ms, hearing problems, toothache,
tonsillitis, ulcer and is,
3O In a further embodiment, the invention es the use of a compound as defined before or
the use of a composition comprising said compound in the prevention and/or treatment of skin
diseases: including but not limited to eratosis, parakeratosis, hypergranulosis, acanthosis,
dyskeratosis, spongiosis and ulceration.
In a further embodiment, the invention provides the use of a compound as defined hereinbefore or
the use of a composition comprising said compound in the prevention and/or treatment of intestinal
diseases; including but not limited to inflammatory bowel disease (IBD), colitis, gastroenteritis,
ileus, ileitis, icitis and Crohn’s disease.
2012/067016
In yet another embodiment, the invention es the use of a compound as defined before
or the use of a composition comprising said compound in the tion and/or treatment of
inflammatory diseases: including but not d to t dermatitis, atopic dermatitis, psoriasis,
rheumatoid arthritis, juvenile rheumatoid tis, sing litis, psoriatic arthritis,
inflammatory bowel disease, Crohn's disease and ulcerative colitis, and/or for preventing, treating
and/or ating complications and/or symptoms and/or inflammatory responses associated
therewith.
In another embodiment, the invention es the use of a compound as defined hereinbefore or
the use of a composition sing said compound in the prevention, treatment and/or
1O management of neurological and CNS disorders: including but not limited to neuropathic pain. The
present compounds are therefore suitable for preventing neurodegeneration and stimulating
neurogeneration in various neurological disorders, and/or for preventing, treating and/or alleviating
complications and/or symptoms associated therewith.
In r embodiment, the invention provides the use of a compound as defined hereinbefore or
the use of a composition comprising said compound in the prevention and/or treatment of
proliferative diseases: such as but not limited to cancer of breast, colon, intestine, skin, head and
neck, nerve, uterus, kidney, lung, ovary, pancreas, prostate, or thyroid gland; man disease;
sarcoma; malignoma; and melanoma; and/or for preventing, treating and/or alleviating
complications and/or symptoms and/or inflammatory responses ated therewith.
In r embodiment, the invention provides the use of a compound as d hereinbefore or
the use of a composition comprising said compound in the prevention and/or treatment of kidney
diseases: including but not d to renal fibrosis or renal dysfunction; and/or for preventing,
treating and/or alleviating complications and/or symptoms and/or inflammatory responses
associated therewith.
In another embodiment, the invention provides the use of a compound as defined hereinbefore or
the use of a composition comprising said compound in the prevention and/or treatment of sexual
dysfunction: including but not limited to hypogonadism, bladder disease, hypertension, diabetes, or
pelvic surgery; and/or to treat sexual dysfunction associated with treatment using n drugs,
such as drugs used to treat hypertension, depression or anxiety.
3O In another embodiment, the invention provides the use of a compound as defined hereinbefore or
the use of a composition comprising said compound in the prevention and/or treatment of bone
diseases: including but not limited to osteoporosis and osteoarthritis; and/or for preventing, treating
and/or alleviating complications and/or symptoms and/or inflammatory responses associated
therewith.
In another embodiment, the invention provides the use of a compound as d before or
the use of a composition comprising said compound in the prevention and/or treatment of diseases
and disorders such as benign prostatic hyperplasia, transplant rejection, spasm, chronic obstructive
bladder e, and allergy, and/or for preventing, treating and/or alleviating complications and/or
symptoms associated therewith.
In a preferred embodiment the present invention provides the use of a compound as defined
hereinbefore or the use of a ition comprising said compound in the prevention and/or
treatment of eye diseases.
METHOD OF TREATMENT
The present invention further provides a method for the prevention and/or treatment of at least one
disease or disorder ed from the group comprising eye diseases; airway es;
1O cardiovascular and vascular diseases; inflammatory diseases; neurological and CNS disorders:
proliferative diseases; kidney diseases; sexual dysfunction; bone diseases; benign prostatic
hyperplasia; transplant ion; spasm; hypertension; c obstructive bladder disease; and
allergy; said method comprising stering to a subject in need f a therapeutic effective
amount of a compound or a composition as defined herein.
In a preferred embodiment, the ion provides a method for the prevention and/or treatment of
eye diseases including but not limited to retinopathy, optic neuropathy, ma and degenerative
retinal diseases such as macular degeneration, retinitis tosa and inflammatory eye diseases
(such as anterior uveitis, panuveitis, intermediate uveitis and posterior uveitis), said method
comprising administering to a subject in need thereof a therapeutic effective amount of a
nd or a composition as defined .
In another embodiment, the invention provides a method for the prevention and/or treatment of
ain/vay diseases including but not d to pulmonary fibrosis, emphysema, chronic bronchitis,
asthma, fibrosis, pneumonia, cystic fibrosis, chronic obstructive pulmonary disease (COPD)
bronchitis, rhinitis, and respiratory distress syndrome; said method comprising stering to a
subject in need thereof a therapeutic effective amount of a compound or a composition as defined
herein.
In another embodiment, the invention provides a method for the prevention and/or treatment of
cardiovascular and vascular diseases: including but not limited to pulmonary hypertension and
pulmonary vasoconstriction; said method comprising administering to a subject in need thereof a
3O therapeutic effective amount of a compound or a composition as d herein.
In another embodiment, the invention provides a method for the prevention and/or treatment of
inflammatory diseases: including but not d to contact itis, atopic dermatitis, psoriasis,
rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis,
inflammatory bowel disease, Crohn's disease and ulcerative s; said method comprising
stering to a subject in need thereof a therapeutic effective amount of a nd or a
composition as defined herein.
In another ment, the invention es a method for the tion and/or treatment of
neurological and CNS disorders: including but not limited to neuropathic pain. The present
compounds are therefore suitable for preventing neurodegeneration and stimulating
neurogeneration in various neurological disorders; said method comprising administering to a
subject in need thereof a therapeutic effective amount of a compound or a composition as d
herein.
In another embodiment, the invention provides a method for the tion and/or treatment of
proliferative es: such as but not limited to cancer of , colon, intestine, skin, head and
neck, nerve, uterus, kidney, lung, liver, ovary, pancreas, prostate, or thyroid gland; Castleman
1O disease; leukemia; sarcoma; lymphoma; oma; and melanoma; said method comprising
administering to a subject in need thereof a therapeutic effective amount of a compound or a
composition as defined herein.
In another embodiment, the invention es a method for the prevention and/or treatment of
kidney diseases: including but not limited to renal fibrosis or renal dysfunction; said method
comprising administering to a subject in need thereof a therapeutic effective amount of a
compound or a composition as defined herein.
In another embodiment, the invention provides a method for the prevention and/or treatment of
sexual ction: including but not limited to hypogonadism, bladder e, hypertension,
diabetes, or pelvic surgery; and/or to treat sexual dysfunction associated with treatment using
certain drugs, such as drugs used to treat hypertension, depression or anxiety; said method
comprising administering to a subject in need thereof a therapeutic ive amount of a
compound or a composition as defined herein.
In another embodiment, the invention provides a method for the prevention and/or treatment of
bone es: including but not limited to osteoporosis and osteoarthritis; said method comprising
stering to a subject in need thereof a therapeutic effective amount of a compound or a
composition as defined herein.
In another embodiment, the invention provides a method for the prevention and/or treatment of
diseases and disorders such as benign prostatic hyperplasia, lant ion, spasm, chronic
obstructive bladder disease, and allergy; said method comprising stering to a subject in need
3O thereof a therapeutic ive amount of a compound or a composition as defined herein.
In a preferred embodiment, the invention provides a method for the prevention and/or treatment of
eye diseases; said method comprising administering to a subject in need thereof a therapeutic
effective amount of a compound or a composition as defined herein.
In the invention, particular preference is given to compounds of Formula | or any subgroup thereof
that in the inhibition assay for ROCK described below t ROCK with an IC5O value of less than
uM, preferably less than 1 uM, even more preferably less than 0.1uM.
Said inhibition may be effected in vitro and/or in vivo, and when effected in vivo, is preferably
effected in a selective manner, as defined above.
The term "ROCK-mediated condition" or "disease", as used herein, means any disease or other
deleterious condition in which is known to play a role. The term "ROCK-mediated condition" or
"disease" also means those es or conditions that are alleviated by treatment with a ROCK
inhibitor. Accordingly, another embodiment of the present invention relates to treating or ing
the severity of one or more diseases in which ROCK is known to play a role.
For pharmaceutical use, the compounds of the invention may be used as a free acid or base,
and/or in the form of a pharmaceutically acceptable acid-addition and/or base-addition salt (e.g.
1O obtained with non-toxic organic or inorganic acid or base), in the form of a hydrate, solvate and/or
complex, and/or in the form or a pro-drug or pre-drug, such as an ester. As used herein and unless
otherwise stated, the term “solvate” includes any combination which may be formed by a
compound of this invention with a suitable inorganic solvent (e.g. hydrates) or organic solvent, such
as but not limited to alcohols, s, esters and the like. Such salts, hydrates, solvates, etc. and
the preparation thereof will be clear to the skilled person.
The pharmaceutically acceptable salts of the compounds ing to the ion, i.e. in the form
of water-, oil-soluble, or dispersible products, include the conventional non-toxic salts or the
quaternary ammonium salts which are formed, e.g., from nic or organic acids or bases.
lly, for pharmaceutical use, the compounds of the inventions may be formulated as a
pharmaceutical preparation or ceutical composition comprising at least one nd of
the invention and at least one pharmaceutically acceptable r, diluent or excipient and/or
adjuvant, and ally one or more further pharmaceutically active compounds.
By means of non-limiting es, such a formulation may be in a form suitable for oral
administration, for parenteral stration (such as by intramuscular or subcutaneous injection),
for topical administration (including ocular), for administration by inhalation, by a skin patch, by an
implant, by a suppository, etc.. Such suitable administration forms — which may be solid, olid
or liquid, ing on the manner of administration — as well as methods and carriers, diluents
and excipients for use in the preparation thereof, will be clear to the skilled person.
Some preferred, but non-limiting examples of such preparations e tablets, pills, powders,
3O lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments,
creams, lotions, soft and hard gelatin capsules, suppositories, eye drops, sterile injectable solutions
and sterile packaged s (which are usually reconstituted prior to use) for administration as a
bolus and/or for continuous administration, which may be formulated with carriers, excipients, and
diluents that are suitable per se for such formulations, such as lactose, dextrose, e, sorbitol,
mannitol, starches, gum acacia, calcium phosphate, alginates, anth, gelatin, calcium silicate,
microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, le) water,
methylcellulose, methyl- and propylhydroxybenzoates, talc, magnesium stearate, edible oils,
vegetable oils and mineral oils or suitable mixtures thereof. The formulations can optionally contain
other pharmaceutically active substances (which may or may not lead to a synergistic effect with
the compounds of the invention) and other nces that are commonly used in pharmaceutical
formulations, such as lubricating agents, g agents, emulsifying and suspending agents,
sing agents, desintegrants, bulking agents, fillers, preserving agents, sweetening agents,
ing agents, flow regulators, release agents, etc. The compositions may also be formulated so
as to provide rapid, sustained or delayed release of the active compound(s) contained therein, for
e using liposomes or hydrophilic ric matrices based on natural gels or synthetic
polymers. In order to enhance the solubility and/or the stability of the compounds of a
pharmaceutical composition according to the invention, it can be advantageous to employ Cl-, [3- or
1O y-cyclodextrins or their derivatives.ln on, co-solvents such as alcohols may improve the
lity and/or the ity of the compounds. In the preparation of aqueous compositions,
addition of salts of the compounds of the invention can be more suitable due to their increased
water solubility.
For ophthalmic application, solutions, gels, tablets and the like are often prepared using a
physiological saline solution, gel or excipient as a major vehicle. Ophthalmic formulations should
preferably be prepared at a comfortable pH with an appropriate buffer system.
More in particular, the compositions may be formulated in a pharmaceutical formulation comprising
a therapeutically effective amount of particles consisting of a solid dispersion of the compounds of
the invention and one or more pharmaceutically acceptable water-soluble polymers.
The term "a solid dispersion" defines a system in a solid state (as opposed to a liquid or gaseous
state) sing at least two components, wherein one component is dispersed more or less
evenly throughout the other component or components. When said dispersion of the components is
such that the system is chemically and physically uniform or homogenous throughout or ts of
one phase as defined in thermodynamics, such a solid dispersion is referred to as "a solid
on". Solid solutions are preferred physical systems because the components n are
y readily bioavailable to the organisms to which they are stered.
It may further be convenient to formulate the compounds in the form of nanoparticles which have a
surface modifier ed on the surface thereof in an amount sufficient to maintain an effective
average particle size of less than 1000 nm. Suitable surface modifiers can preferably be selected
3O from known organic and inorganic pharmaceutical excipients. Such excipients include various
polymers, low molecular weight oligomers, natural ts and surfactants. Preferred surface
modifiers include nonionic and anionic surfactants.
The preparations may be prepared in a manner known per se, which usually involves mixing at
least one compound according to the invention with the one or more pharmaceutically able
carriers, and, if desired, in combination with other pharmaceutical active compounds, when
ary under aseptic conditions.
The compounds can be administered by a variety of routes including the oral, rectal, ocular,
transdermal, subcutaneous, intramuscular or intranasal routes, ing mainly on the specific
2012/067016
preparation used and the condition to be treated or prevented. The at least one compound of the
ion will generally be administered in an “effective ”, by which is meant any amount of
a compound of the Formula | or any subgroup thereof that, upon le administration, is
sufficient to achieve the desired therapeutic or prophylactic effect in the individual to which it is
administered.
In accordance with the method of the present invention, said pharmaceutical composition can be
administered separately at different times during the course of therapy or concurrently in divided or
single combination forms. The present invention is therefore to be understood as embracing all
such regimes of simultaneous or alternating treatment and the term "administering" is to be
1O interpreted accordingly.
In preferred embodiments, the nds and itions of the invention are used locally, for
instance topical or in both absorbed and sorbed applications.
The compositions are of value in the veterinary field, which for the purposes herein not only
includes the prevention and/or treatment of diseases in animals, but also — for economically
important animals such as cattle, pigs, sheep, chicken, fish, etc. — enhancing the growth and/or
weight of the animal and/or the amount and/or the quality of the meat or other ts obtained
from the animal. Thus, in a further aspect, the invention relates to a composition for veterinary use
that contains at least one compound of the invention and at least one suitable r (Le. a carrier
suitable for veterinary use). The invention also relates to the use of a compound of the invention in
the preparation of such a composition.
The invention will now be rated by means of the following synthetic and ical examples,
which do not limit the scope of the invention in any way.
A. Physicochemical ties of the compounds
A. 1. Compound purity
Unless indicated otherwise, the purity of the compounds was confirmed by liquid
chromatography/mass spectrometry (LC/MS).
A.2. Attribution of the configuration:
3O The Cahn-lngold-Prelog system was used to attribute the absolute configuration of chiral center, in
which the four groups on an asymmetric carbon are ranked to a set of sequences rules. Reference
is made to Cahn; lngold; Prelog Angew. Chem. Int. Ed. Engl. 1966, 5, 385-415.
A.3. Stereochemistrv:
It is known by those skilled in the art that specific enantiomers (or diastereoisomers) can be
obtained by different methods such as, but not limited to chiral resolution (for example, salts formed
2012/067016
with optically active acids or bases may be used to form diastereoisomeric salts that can facilitate
the tion of optically active isomers of the compounds of Formula | or any subgroup thereof),
assymetric synthesis or preparative chiral chromatography (using different column such as
Chiralcel OD-H 3,5-dimethylphenylcarbamate, 46 x 250 or 100 x 250 mm, 5 pm), Chiralcel OJ
methylbenzoate, 46 x 250 or 100 x 250 mm, 5 pm), Chiralpak AD (tris-3,5-
dimethylphenylcarbamate, 46 x 250 mm, 10 um) and Chiralpak AS (tris-(S)
phenylethylcarbamate, 46 x 250 mm, 10 pm) from Chiral Technologies Europe (lllkirch, France)).
Whenever it is convenient, stereoisomers can be obtained starting from commercial materials with
known configuration (such compounds e aminoacid for instance).
1O B. Compound synthesis
B. 1. Compounds of the invention
The compounds of the invention can be made according to the ing general procedures:
R1 O
O o \ 0/
0 /
OH 0
R1 0 i Y
R3 /
\ o 3
+ R
I a
/ —>
X NH HN Y F NH
H A 2
N A
|\ O O
X |\ o o
N / O N / O K
Intermediate
R1 O
o \ OH
o N Y/ 0
H R1
R3 o \ o/
x NH N Y
\ GAO 3
d,c N/ O
R1 0
0 I\ o’
O N Y
x NH2
N/ 0
Reaction a: To a solution or suspension of the ylic acid intermediate in an organic solvent
such as DMF or DCM at room temperature were added an appropriate coupling reagent (e.g
TBTU/HOBt, HATU or T3P) and a base such as DIEA or DMAP. After 5 min the selected amine
was added and the mixture stirred at the appropriate temperature (e.g rt or 60°C) until completion
of the reaction. After an riate work up, the residue could be purified following different
methods such as flash chromatography eluted for instance with DCM/EtOAc or precipitation in a
solvent (e.g DCM or water) to give the expected product as a white powder.
Reaction b: To a solution or suspension of the ester intermediate in an organic t (e.g THF,
Dioxane or Acetonitrile) was added dropwise an aqueous solution of an appropriate base such as
LiOH. The resulting e was stirred at room temperature until completion of the reaction. Then
the on mixture was acidified until pH 4 using an appropriate acid such as HCI (0.5M in water)
or KHSO4 (0.5M in water). The white suspension was ted by filtration, washed with water and
an riate organic solvent such as AcOEt or DCM, and dried under vacuum to give the
1O expected t as a white powder.
Reaction c: h a solution or suspension of the Boc-protected amine in an organic solvent (e.g
DCM, AcOEt, diethyl ether or e) was bubbled HCI (gas) at room temperature for 5 to 10 min.
The resulting mixture was stirred at an appropriate temperature (e.g 0°C or rt) until completion of
the reaction. Then the white suspension was collected by filtration, washed with an organic solvent
such as diethyl ether and dried under vacuum to give the HCI salt of the expected product as a
white powder.
Reaction d: To a solution or suspension of the carboxylic acid intermediate in an organic t
(e.g THF, DMF or DCM) at room temperature were added an appropriate coupling reagent (e.g
TBTU/HOBt, HATU, DIC or T3P) and a base such as DIEA or DMAP. After 5 min the selected
alcohol was added and the mixture stirred at the appropriate temperature (e.g rt or 60°C) until
completion of the on. After an appropriate work up, the residue was purified by flash
chromatography using an appropriate eluent such as DCM/EtOAc or Heptane/EtOAc to give the
expected product as a white powder.
If A = -NHC(O)—, the final compounds can be made from the required aniline intermediate and the
appropriate carboxylic acid, following similar protocols.
For the ation of the required intermediate(s), reference is made to the PCT application
W02011/107608.
In the table that is set forth below, exemplary compounds of the invention are set out in tabulated
form. In this table, an arily assigned compound number and structural information are set out.
Table1
A 1R;
ORsYl / Osz
x NH2
“I.“
— iI--—_
IN“I--——
--'CIOIN“I--——
--I-_'H
--I-_——“H
———_l-———_I—-——
_I—-——
«CH:ll:l:v'l'l
Compound 11:
F Q O
— O
o NH2
Compound 11 is obtained by first coupling the Intermediate carboxylic acid (as described in the
general scheme / Intermediate described in /107608) with the corresponding commercially
available lactone and then removing Boc protection as described in the general scheme (step c).
Compound 12:
nd 12 is obtained by first coupling the Intermediate aniline (as described in
W02011/107608) with the corresponding commercially available lactone and then removing Boc
protection as described in the general scheme (step c).
WO 30365
C. In vitro and in vivo assays
C. 1. ROCK inhibitory activity screening
C. 1.1 . Kinase inhibition (ROCKI or ROCK/l)
On-target activity against ROCK was measured in a biochemical assay, using the following
reagents: Base Reaction buffer; 20 mM Hepes (pH 7.5), 10 mM MgCIZ, 1mM EGTA, 0.02% Brij35,
0.02 mg/ml BSA, 0.1 mM , 2 mM DTT, 1% DMSO. ed cofactors are added
individually to each kinase reaction. The reaction procedure first ed the ation of a
peptide substrate in a freshly prepared reaction buffer. Required cofactors were then added to the
substrate solution. ROCK (1nM final tration) was then delivered to the substrate solution.
1O After gentle mix, DMSO solutions of the test compounds were added to the . Substrate mix
33P-ATP (specific activity 0.01 uCi/ul final) was then delivered into the reaction mixture to initiate
the reaction. The kinase reaction was incubated for 120 min. at room temperature. Reactions were
then spotted onto P81 ion exchange paper (Whatman # 3698-915). Filters were washed
ively in 0.1% oric acid. A radiometric count was then performed and IC5O values were
uently ined.
When evaluated under such conditions, compounds of the invention inhibit ROCK2 with an |C50 <
100nM.
C. 1.2. Myosin Light Chain Phosphorylation assay
Rat smooth muscle cell line A7r5 is used. The endogenous expression of ROCK results in a
tutive phosphorylation of the regulatory myosin light chain at T18/S19. A7r5 cells were plated
in DMEM supplemented with 10%FCS in multiwall cell culture plates. After serum starvation
overnight, cells were ted with compounds in serum-free medium.
Quantification of MLC-T18/S19 phosphorylation is assessed in 96 well-plates via ELISA using a
phspho-MLC-T18/S19 specific antibody and a secondary detection antibody. Raw data were
converted into percent substrate phosphorylation relative to high controls, which were set to 100%.
IC5O values were determined using GraphPad Prism 5.01 software using a nonlinear regression
curve fit with variable hill slope. The EC50 values are below 500nM for the compounds of the
invenfion.
C. 2. Pharmacological Characterization
3O 0.2. 1. Stability assay in human hepatocytes.
Compounds are incubated at a concentration of 1 uM with human cytes (2 106 cells/ml in
buffer solution). At fixed time points (ex: 1, 30, 60 & 120 minutes), an incubation mixture (200ul) is
cooled down on ice and 100u| of acetonitrile is added. After vortex-mixing, the sample is
centrifuged for 5 minutes at 16000rpm. The remnant of compound in each sample is determined by
LC-PDA-MS/MS analysis and half-life of the compound is subsequently calculated. Formation of
the acid metabolite resulting from ester hydrolysis can be performed simultaneously. Peak areas
for appearance of the acid are first recorded, and the corresponding concentrations are then back-
calculated from ation curve.
When evaluated under such conditions, compounds of the invention are rapidly degraded in the
corresponding acid (primary metabolite). For instance, compound 1 has a t1/2 of 14 minutes, as
illustrated in table in Table 2:
Table2
de 1 (% remaining) Acid (corresponding %)
4.8 +/- 0.1 99.7 +/- 0.8
2.4 +/- 1.3 99.3 +/- 0.8
C. 2. 2. Stability assay in rabbit s or vitreous humor
Compounds are incubated at a concentration of 1 uM in rabbit aqueous humor (AH) or rabbit
1O vitreous (VH). Samples are taken at fixed time points and the remnant of compound is determined
by LC-MS/MS after protein precipitation. Half-life values for compounds of the invention are
provided in table 3.
Table 3
C. 2.3. Pharmacokinetics after intravenous and oral administration in mice.
The bioavailability of compound 1 was evaluated after intravenous and oral dosing in male CD-1
mice. The nd was dosed at 0.1 mg/kg intravenously and 1 mg/kg . Plasma levels
were ined by LC-MS/MS and pharmacokinetic parameters were ted by a non-
compartmental model using WinNonlin v5.2.1 software.
After intravenous dosing of compound 1 at 0.1 mg/kg, Cmax of 16.3 ng/mL was reached. The
clearance and volume of distribution were 15.4 g and 100 L/kg, respectively. The intravenous
exposure as ed by AUClast was found to be 4.82 i 0.276 hr*ng/mL. The corresponding
metabolite was detectable till 1 hour post dose with maximum concentration of 16.3 ng/mL.
Metabolite had 1.47-fold higher exposure (7.10 i 0.920 hr*ng/mL) compared to parent compound.
Following oral dosing of nd 1 at 1 mg/kg, a Cmax of 22.4 i 22 ng/mL, was observed at 15
minutes post dose. AUClast was found to be 6.20 i 5.50 hr*ng/mL. The percent oral bioavailability
was found to be 12.9%. Following oral dosing of Compound 1, its metabolite was detectable at 15
min only with Cmax of 4.53 i 3.83 ng/mL. These data confirm that Compound 1 is y
metabolized and excreted from the body very rapidly.
Claims (14)
1. A compound of Formula I or a isomer, tautomer, racemic, salt, hydrate, or solvate thereof, Y O R3 R2 X NH H 2 N O Wherein, X is hydrogen or halogen; A is –NH-C(=O)- or –C(=O)-NH-; Y is N or C; R3 is selected from the group comprising en, C1-20alkyl and C3-15cycloalkyl; R1 is selected from the group comprising hydrogen, C1-20alkyl, C1-20alkoxy, and halogen; and R2 is selected from the group consisting of C1-20alkyl, C3-20alkenyl, C3-20alkynyl, C3-15cycloalkyl, aryl, heteroaryl, and C3-19heterocyclyl; wherein said C1-20alkyl, C3-20alkenyl, C3-20alkynyl, C3-15cycloalkyl, aryl, heteroaryl, and C3-19heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, C3- 15cycloalkyl, C3-19heterocyclyl, C1-20alkylamino, C1-6alkyl, di(C1-20alkyl)amino, C1-20alkoxy, halo-C1- xy, halo-C1-20alkyl, thiol, C1-20alkylthio, ylic acid, ino, C1-20alkyl esters, carbamate, thioamido, urea, and sulfonamido; or R2 taken together with R1 forms a cyclic ester ne) comprising from 4 to 9 carbon atoms in the cyclic ester ring.
2. The compound of formula I according to claim 1, n; R3 is selected from the group comprising hydrogen, C1-6alkyl, and C3-6cycloalkyl, in particular hydrogen or C1-3alkyl; more in particular hydrogen.
3. The compound of a I according to claim 1, wherein; X is halogen; more in particular fluoro; A is =O)- or –C(=O)-NH-; Y is N or C; R3 is ed from the group comprising hydrogen, C1-20alkyl, and C3-15cycloalkyl; in particular hydrogen or C1-6alkyl; more in particular hydrogen or C1-6alkyl; even more in particular hydrogen; R1 is ed from the group sing hydrogen, C1-20alkyl, C1-20alkoxy, and halogen; in ular hydrogen, C1-6alkyl, and halogen; more in particular hydrogen, methyl, and halogen; and R2 is selected from the group consisting of C1-20alkyl, C3-20alkenyl, lkynyl, C3-15cycloalkyl, aryl, heteroaryl, and C3-19heterocyclyl; wherein said C1-20alkyl, C3-20alkenyl, C3-20alkynyl, C3-15cycloalkyl, aryl, heteroaryl, and C3-19heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, oxo, yl, amino, amido, cyano, aryl, heteroaryl, C3- 15cycloalkyl, C3-19heterocyclyl, C1-20alkylamino, C1-6alkyl, di(C1-20alkyl)amino, C1-20alkoxy, halo-C1- 20alkoxy, halo-C1-20alkyl, thiol, C1-20alkylthio, carboxylic acid, acylamino, C1-20alkyl esters, carbamate, thioamido, urea, and sulfonamido; or R2 taken together with R1 form a cyclic ester (lactone) comprising from 4 to 9 carbon atoms in the cyclic ester ring.
4. The nd of formula I ing to claim 1, wherein; R1 is selected from the group comprising hydrogen, C1-6alkyl, C1-6alkoxy, and halogen; in particular hydrogen, C1-6alkyl, and halogen; more in particular hydrogen, methyl, and halogen.
5. The compound of formula I according to claim 1, n; R1 is selected from the group comprising hydrogen, C1-20alkyl, C1-20alkoxy, and halogen; in particular hydrogen, methyl, and halogen; more in particular R1 is methyl or ; and R2 is selected from the group ting of lkyl, C3-20alkenyl, C3-20alkynyl, C3-15cycloalkyl, aryl, heteroaryl, and C3-19heterocyclyl; wherein said C1-20alkyl, is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, C1-6alkyl, C3-15cycloalkyl, C3-19heterocyclyl, C1-20alkylamino, di(C1-20alkyl)amino, C1- 20alkoxy, halo-C1-20alkoxy, halo-C1-20alkyl, thiol, C1-20alkylthio, ylic acid, acylamino, C1-20alkyl esters, carbamate, thioamido, urea, and sulfonamido; or R2 taken together with R1 form a cyclic ester ne) comprising from 4 to 5 carbon atoms in the cyclic ester ring.
6. The compound of formula I according to claim 1, wherein one or more of the following restrictions apply: • X is halogen; in particular fluoro; • A is –C(=O)-NH-; • Y is C; • R3 is hydrogen; • R1 is selected from the group comprising hydrogen, C1-20alkyl, and halogen; in ular hydrogen, C1-6alkyl, and n; more in particular hydrogen, methyl and fluoro • R1 is hydrogen; • R1 is fluoro; • R2 is ed from the group ting of lkyl, C3-20alkenyl, C3-20alkynyl, ycloalkyl, aryl, heteroaryl, and C3-19heterocyclyl; n said C1-20alkyl, C3-20alkenyl, and C3-20alkynyl is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, C1-6alkyl, C3-15cycloalkyl, C3-19heterocyclyl, lkylamino, di(C1-20alkyl)amino, lkoxy, halo-C1-20alkoxy, halo-C1- 20alkyl, thiol, C1-20alkylthio, carboxylic acid, acylamino, C1-20alkyl esters, carbamate, thioamido, urea, and sulfonamido; in particular R2 is selected from the group consisting of C1-20alkyl, C3- 20alkenyl, C3-20alkynyl, C3-15cycloalkyl, aryl, heteroaryl, and C3-19heterocyclyl; wherein said C1- 20alkyl is optionally substituted with one or more tuents selected from the group consisting of halo, hydroxyl, oxo, carbonyl, amino, amido, cyano, aryl, aryl, C3- 15cycloalkyl, C3-19heterocyclyl, C1-20alkylamino, di(C1-20alkyl)amino, C1-20alkoxy, halo-C1- 20alkoxy, halo-C1-20alkyl, thiol, C1-20alkylthio, carboxylic acid, acylamino, C1-20alkyl esters, carbamate, thioamido, urea, and sulfonamido; • R2 is selected from the group consisting of C1-20alkyl, lkenyl, lkynyl, and aryl; wherein said C1-20alkyl, C3-20alkenyl, C3-20alkynyl, and aryl is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, C1-6alkyl, C3-15cycloalkyl, C3-19heterocyclyl, C1-20alkylamino, di(C1-20alkyl)amino, C1-20alkoxy, halo-C1-20alkoxy, halo-C1-20alkyl, thiol, C1-20alkylthio, carboxylic acid, acylamino, C1-20alkyl esters, carbamate, thioamido, urea, and sulfonamido; in particular R2 is selected from the group consisting of C1-20alkyl, C3-20alkenyl, C3-20alkynyl, and aryl; wherein said C1-20alkyl is optionally substituted with one or more substituents ed from the group consisting of halo, yl, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, C3-15cycloalkyl, C3-19heterocyclyl, C1-20alkylamino, di(C1-20alkyl)amino, C1-20alkoxy, halo-C1- 20alkoxy, halo-C1-20alkyl, thiol, C1-20alkylthio, carboxylic acid, acylamino, C1-20alkyl esters, carbamate, thioamido, urea, and sulfonamido; • R2 is selected from the group consisting of C1-6alkyl, C3-6alkenyl, C3-6alkynyl, and aryl; wherein said C1-6alkyl, C3-6alkenyl, C3-6alkynyl, and aryl is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, C1-6alkyl, C3-15cycloalkyl, C3-19heterocyclyl, C1-20alkylamino, di(C1-20alkyl)amino, lkoxy, halo-C1-20alkoxy, halo-C1-20alkyl, thiol, C1-20alkylthio, carboxylic acid, acylamino, C1-20alkyl esters, carbamate, thioamido, urea, and sulfonamido; in ular selected from the group consisting of C1-6alkyl, C3-6alkenyl, and C3-6alkynyl; wherein said C1- 6alkyl, C3-6alkenyl, and C3-6alkynyl is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, C1-6alkyl, C3-15cycloalkyl, C3-19heterocyclyl, C1-20alkylamino, di(C1-20alkyl)amino, C1- 20alkoxy, halo-C1-20alkoxy, halo-C1-20alkyl, thiol, C1-20alkylthio, carboxylic acid, ino, C1- 2 is C 20alkyl esters, carbamate, ido, urea, and sulfonamido; more in ular R 1-6alkyl optionally substituted with a substituent selected from the group consisting of halo, hydroxyl, oxo, carbonyl, amino, amido, cyano, aryl, heteroaryl, C1-6alkyl, C3-15cycloalkyl, C3- 19heterocyclyl, C1-20alkylamino, di(C1-20alkyl)amino, C1-20alkoxy, 1-20alkoxy, halo-C1- 20alkyl, thiol, C1-20alkylthio, carboxylic acid, acylamino, C1-20alkyl , carbamate, thioamido, urea, and sulfonamido; even more in particular R2 is C1-6alkyl. • said one or more optional substituents for R2 are selected from the group consisting of halo, hydroxyl, nitro, amino, cyano, aryl, heteroaryl, C3-15cycloalkyl, C3-19heterocyclyl, C1- 20alkylamino, di(C1-20alkyl)amino, C1-20alkoxy, and halo-C1-20alkyl; in particular from the group consisting of cyano, C3-6cycloalkyl, terocyclyl, C1-6alkoxy, di(C1-6alkyl)amino, aryl, and heteroaryl; more in particular from C3-6heterocyclyl, and C1-6alkoxy; • said one or more optional substituents for R2 are selected from C3-19heterocyclyl and C1- 20alkoxy; more in ular from oxolanyl and methoxy; • R1 and R2 taken together form a cyclic ester sing 4 carbon atoms in the cyclic ester ring.
7. The compound according to claim 1, selected from the group consisting of • methyl 4-({3- [2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl}amido) benzoate; • methyl 4-({3-[2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl}amido) fluorobenzoate; • methyl [2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl}amido) fluorobenzoate; • propyl 4-({3-[2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl}amido) fluorobenzoate; • methyl 4-({3-[2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl}amido) methylbenzoate; • propyl 4-({3-[2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl}amido) methylbenzoate; • methyl [2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl}carbamoyl) benzoate; • methyl 6-({3-[2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl}carbamoyl) pyridinecarboxylate; • 2-methoxyethyl 4-({3- [2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl} amido)benzoate; • oxolanylmethyl 4-({3- [2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl} amido)benzoate; • 4-(aminomethyl)-N-(3-fluoropyridinyl){3-[(1-oxo-1,3-dihydrobenzofuranyl) carbamoyl]phenyl}benzamide; and • N-{3-[2-(aminomethyl)[(3-fluoropyridinyl)carbamoyl]phenyl]phenyl}oxo-1,3-dihydro benzofurancarboxamide.
8. A compound according to any one of claims 1 to 7 for use as a medicine.
9. A ition comprising a nd as defined in any one of claims 1 to 7, for use as a human or veterinary medicine.
10. A compound according to any one of claims 1 to 7, or a composition according to claim 9, for use in the prevention and/or treatment of a disease or disorder, in which ROCK is involved, such as diseases linked to smooth muscle cell function, inflammation, fibrosis, excessive cell proliferation, excessive angiogenesis, hyperreactivity, barrier dysfunction, neurodegeneration, and remodeling.
11. A compound according to any one of claims 1 to 7, or a composition according to claim 9, for use in the prevention and/or treatment of at least one disease or disorder selected from the group comprising eye diseases; airway diseases; throat, nose and ear diseases; intestinal es; cardiovascular and vascular diseases; inflammatory diseases; neurological and CNS disorders: proliferative es; kidney diseases; sexual dysfunction; bone diseases; benign prostatic hyperplasia, transplant rejection, spasm, hypertension, chronic obstructive bladder disease, and allergy.
12. A compound according to any one of claims 1 to 7, or a composition according to claim 9, for use in the prevention and/or treatment of an eye e; including but not limited to retinopathy, optic neuropathy, glaucoma, degenerative retinal diseases such as macular degeneration, retinitis pigmentosa and inflammatory eye es (such as anterior uveitis, itis, intermediate s and posterior uveitis), and/or for ting, ng and/or alleviating complications and/or symptoms ated therewith.
13. Use of a compound according to any one of claims 1 to 7, or a composition according to claim 9, for inhibiting the activity of at least one kinase in vitro.
14. Use of a nd according to any one of claims 1 to 7, or a composition according to claim 9, for the preparation of a medicament for the prevention and/or treatment of at least one e or disorder ed from the group comprising eye diseases; airway diseases; cardiovascular and vascular diseases; inflammatory diseases; neurological and CNS disorders: proliferative diseases; kidney diseases; sexual dysfunction; bone diseases; benign prostatic hyperplasia; transplant rejection; spasm; hypertension; chronic obstructive bladder disease; and allergy.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP11179491 | 2011-08-31 | ||
EP11179491.3 | 2011-08-31 | ||
PCT/EP2012/067016 WO2013030365A1 (en) | 2011-08-31 | 2012-08-31 | Novel rock kinase inhibitors |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ622964A NZ622964A (en) | 2015-03-27 |
NZ622964B2 true NZ622964B2 (en) | 2015-06-30 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2898674C (en) | Pyridine derivatives as soft rock inhibitors | |
AU2012300833B2 (en) | Novel soft ROCK inhibitors | |
AU2012247455A1 (en) | Novel ROCK inhibitors | |
DK2914590T3 (en) | NEW ROCK INHIBITORS | |
WO2013030216A1 (en) | Novel soft rock inhibitors | |
NZ622964B2 (en) | Novel rock kinase inhibitors | |
NZ622959B2 (en) | Biphenylcarboxamides as rock kinase inhibitors | |
NZ622953B2 (en) | Novel soft rock inhibitors |