CN107001344B - 用于治疗病症的哌嗪衍生物 - Google Patents
用于治疗病症的哌嗪衍生物 Download PDFInfo
- Publication number
- CN107001344B CN107001344B CN201580031650.5A CN201580031650A CN107001344B CN 107001344 B CN107001344 B CN 107001344B CN 201580031650 A CN201580031650 A CN 201580031650A CN 107001344 B CN107001344 B CN 107001344B
- Authority
- CN
- China
- Prior art keywords
- compound
- pyridyl
- group
- substituent
- alkylthio
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000011282 treatment Methods 0.000 title claims abstract description 68
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 61
- 208000035475 disorder Diseases 0.000 title claims abstract description 43
- 150000004885 piperazines Chemical class 0.000 title description 2
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 215
- 201000011461 pre-eclampsia Diseases 0.000 claims abstract description 26
- 230000000926 neurological effect Effects 0.000 claims abstract description 18
- 208000012902 Nervous system disease Diseases 0.000 claims abstract description 14
- 208000025966 Neurological disease Diseases 0.000 claims abstract description 14
- 238000011122 anti-angiogenic therapy Methods 0.000 claims abstract description 14
- 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 10
- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 8
- -1 cyano, carboxyl Chemical group 0.000 claims description 90
- 125000001424 substituent group Chemical group 0.000 claims description 35
- 208000002780 macular degeneration Diseases 0.000 claims description 27
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 25
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 24
- 125000001072 heteroaryl group Chemical group 0.000 claims description 23
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 23
- 230000002265 prevention Effects 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 22
- 239000003814 drug Substances 0.000 claims description 21
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 20
- 206010029113 Neovascularisation Diseases 0.000 claims description 20
- 206010064930 age-related macular degeneration Diseases 0.000 claims description 19
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen(.) Chemical compound [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 19
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 18
- 208000005590 Choroidal Neovascularization Diseases 0.000 claims description 17
- 206010060823 Choroidal neovascularisation Diseases 0.000 claims description 17
- 231100000673 dose–response relationship Toxicity 0.000 claims description 17
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 239000003795 chemical substances by application Substances 0.000 claims description 15
- 150000003254 radicals Chemical class 0.000 claims description 15
- 241000124008 Mammalia Species 0.000 claims description 14
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 11
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 10
- 230000000699 topical effect Effects 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 238000001727 in vivo Methods 0.000 claims description 9
- 210000002919 epithelial cell Anatomy 0.000 claims description 8
- 238000002347 injection Methods 0.000 claims description 8
- 239000007924 injection Substances 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 8
- 238000011200 topical administration Methods 0.000 claims description 8
- 206010065390 Inflammatory pain Diseases 0.000 claims description 7
- 125000001041 indolyl group Chemical group 0.000 claims description 7
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 claims description 7
- 230000001404 mediated effect Effects 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 239000001301 oxygen Substances 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 230000004083 survival effect Effects 0.000 claims description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 6
- 238000000338 in vitro Methods 0.000 claims description 6
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 claims description 5
- 102000016549 Vascular Endothelial Growth Factor Receptor-2 Human genes 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 4
- 230000001605 fetal effect Effects 0.000 claims description 4
- 210000003754 fetus Anatomy 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 4
- 230000008774 maternal effect Effects 0.000 claims description 4
- 239000012528 membrane Substances 0.000 claims description 4
- 125000005493 quinolyl group Chemical group 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 3
- 208000007135 Retinal Neovascularization Diseases 0.000 claims description 3
- 230000007812 deficiency Effects 0.000 claims description 3
- 230000000324 neuroprotective effect Effects 0.000 claims description 3
- 230000003018 neuroregenerative effect Effects 0.000 claims description 3
- 238000011275 oncology therapy Methods 0.000 claims description 3
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims 7
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims 7
- 239000004480 active ingredient Substances 0.000 claims 3
- 125000004414 alkyl thio group Chemical group 0.000 claims 2
- 229910052799 carbon Inorganic materials 0.000 claims 2
- 125000006164 6-membered heteroaryl group Chemical group 0.000 claims 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 1
- 150000002926 oxygen Chemical class 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- 208000002193 Pain Diseases 0.000 abstract description 25
- 238000000034 method Methods 0.000 abstract description 21
- VURLRACCOCGFDB-UHFFFAOYSA-N 5-pyridin-4-yl-N-[2-[4-(pyridin-2-ylmethyl)piperazin-1-yl]-5-(trifluoromethyl)phenyl]furan-2-carboxamide Chemical compound FC(F)(F)C1=CC(NC(=O)C2=CC=C(O2)C2=CC=NC=C2)=C(C=C1)N1CCN(CC2=CC=CC=N2)CC1 VURLRACCOCGFDB-UHFFFAOYSA-N 0.000 description 55
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 33
- 102000009524 Vascular Endothelial Growth Factor A Human genes 0.000 description 33
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 32
- 101000826081 Homo sapiens SRSF protein kinase 1 Proteins 0.000 description 31
- 102100023010 SRSF protein kinase 1 Human genes 0.000 description 31
- 239000000243 solution Substances 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 210000004027 cell Anatomy 0.000 description 26
- 241000252794 Sphinx Species 0.000 description 24
- 239000000203 mixture Substances 0.000 description 23
- 210000001519 tissue Anatomy 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 230000000694 effects Effects 0.000 description 21
- 102100022807 Potassium voltage-gated channel subfamily H member 2 Human genes 0.000 description 20
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
- 201000010099 disease Diseases 0.000 description 18
- 239000003112 inhibitor Substances 0.000 description 17
- XUMBMVFBXHLACL-UHFFFAOYSA-N Melanin Chemical compound O=C1C(=O)C(C2=CNC3=C(C(C(=O)C4=C32)=O)C)=C2C4=CNC2=C1C XUMBMVFBXHLACL-UHFFFAOYSA-N 0.000 description 16
- 239000003798 L01XE11 - Pazopanib Substances 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- CUIHSIWYWATEQL-UHFFFAOYSA-N pazopanib Chemical compound C1=CC2=C(C)N(C)N=C2C=C1N(C)C(N=1)=CC=NC=1NC1=CC=C(C)C(S(N)(=O)=O)=C1 CUIHSIWYWATEQL-UHFFFAOYSA-N 0.000 description 15
- 229960000639 pazopanib Drugs 0.000 description 15
- 230000033115 angiogenesis Effects 0.000 description 14
- 125000004429 atom Chemical group 0.000 description 14
- 125000005330 8 membered heterocyclic group Chemical group 0.000 description 13
- 101001047090 Homo sapiens Potassium voltage-gated channel subfamily H member 2 Proteins 0.000 description 13
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 13
- 239000007788 liquid Substances 0.000 description 13
- 239000000651 prodrug Substances 0.000 description 13
- 229940002612 prodrug Drugs 0.000 description 13
- 230000002829 reductive effect Effects 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 206010028980 Neoplasm Diseases 0.000 description 12
- 241000283973 Oryctolagus cuniculus Species 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 239000003889 eye drop Substances 0.000 description 12
- 230000014509 gene expression Effects 0.000 description 12
- 125000000623 heterocyclic group Chemical group 0.000 description 12
- 208000020016 psychiatric disease Diseases 0.000 description 12
- 210000003583 retinal pigment epithelium Anatomy 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 241001465754 Metazoa Species 0.000 description 11
- 241000699670 Mus sp. Species 0.000 description 11
- 102100037044 Serine/arginine-rich splicing factor 1 Human genes 0.000 description 11
- 125000003118 aryl group Chemical group 0.000 description 11
- 230000005764 inhibitory process Effects 0.000 description 11
- 230000002207 retinal effect Effects 0.000 description 11
- 239000011734 sodium Substances 0.000 description 11
- 101000663222 Homo sapiens Serine/arginine-rich splicing factor 1 Proteins 0.000 description 10
- 230000027455 binding Effects 0.000 description 10
- 125000004430 oxygen atom Chemical group O* 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- 108090000623 proteins and genes Proteins 0.000 description 10
- 210000001525 retina Anatomy 0.000 description 10
- 239000012453 solvate Substances 0.000 description 10
- 208000011580 syndromic disease Diseases 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 230000001772 anti-angiogenic effect Effects 0.000 description 9
- 238000009472 formulation Methods 0.000 description 9
- 208000035719 Maculopathy Diseases 0.000 description 8
- 241000699666 Mus <mouse, genus> Species 0.000 description 8
- 101000615178 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) Serine/threonine-protein kinase SKY1 Proteins 0.000 description 8
- 239000013543 active substance Substances 0.000 description 8
- 206010012601 diabetes mellitus Diseases 0.000 description 8
- 125000005842 heteroatom Chemical group 0.000 description 8
- 230000007823 neuropathy Effects 0.000 description 8
- 201000001119 neuropathy Diseases 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 210000003786 sclera Anatomy 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 229940012356 eye drops Drugs 0.000 description 7
- 230000006870 function Effects 0.000 description 7
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 7
- DWFGGOFPIISJIT-UHFFFAOYSA-N n-[2-piperidin-1-yl-5-(trifluoromethyl)phenyl]pyridine-4-carboxamide Chemical compound C=1C=NC=CC=1C(=O)NC1=CC(C(F)(F)F)=CC=C1N1CCCCC1 DWFGGOFPIISJIT-UHFFFAOYSA-N 0.000 description 7
- 230000004770 neurodegeneration Effects 0.000 description 7
- 208000033808 peripheral neuropathy Diseases 0.000 description 7
- 230000026731 phosphorylation Effects 0.000 description 7
- 238000006366 phosphorylation reaction Methods 0.000 description 7
- 230000001023 pro-angiogenic effect Effects 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- 125000003627 8 membered carbocyclic group Chemical group 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical class O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 210000004185 liver Anatomy 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 5
- 206010012689 Diabetic retinopathy Diseases 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 238000009825 accumulation Methods 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 230000006399 behavior Effects 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
- 210000003161 choroid Anatomy 0.000 description 5
- 229940125797 compound 12 Drugs 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 125000005843 halogen group Chemical group 0.000 description 5
- 230000004968 inflammatory condition Effects 0.000 description 5
- 238000004949 mass spectrometry Methods 0.000 description 5
- 208000022821 personality disease Diseases 0.000 description 5
- 125000004193 piperazinyl group Chemical group 0.000 description 5
- 210000000557 podocyte Anatomy 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 125000003373 pyrazinyl group Chemical group 0.000 description 5
- 125000004076 pyridyl group Chemical group 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- NATRYEXANYVWAW-UHFFFAOYSA-N 1-(pyridin-2-ylmethyl)piperazine Chemical compound C=1C=CC=NC=1CN1CCNCC1 NATRYEXANYVWAW-UHFFFAOYSA-N 0.000 description 4
- YCTLYYCPUQMSLM-UHFFFAOYSA-N 1-[2-nitro-4-(trifluoromethyl)phenyl]-4-(pyridin-2-ylmethyl)piperazine Chemical compound [O-][N+](=O)C1=CC(C(F)(F)F)=CC=C1N1CCN(CC=2N=CC=CC=2)CC1 YCTLYYCPUQMSLM-UHFFFAOYSA-N 0.000 description 4
- 208000024827 Alzheimer disease Diseases 0.000 description 4
- 206010006187 Breast cancer Diseases 0.000 description 4
- 208000026310 Breast neoplasm Diseases 0.000 description 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 4
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 4
- 208000020406 Creutzfeldt Jacob disease Diseases 0.000 description 4
- 208000003407 Creutzfeldt-Jakob Syndrome Diseases 0.000 description 4
- 208000010859 Creutzfeldt-Jakob disease Diseases 0.000 description 4
- 208000001089 Multiple system atrophy Diseases 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- 206010060862 Prostate cancer Diseases 0.000 description 4
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 4
- 102000001708 Protein Isoforms Human genes 0.000 description 4
- 108010029485 Protein Isoforms Proteins 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 230000002159 abnormal effect Effects 0.000 description 4
- 230000002491 angiogenic effect Effects 0.000 description 4
- 230000001149 cognitive effect Effects 0.000 description 4
- 150000004677 hydrates Chemical class 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 230000003902 lesion Effects 0.000 description 4
- 229940076783 lucentis Drugs 0.000 description 4
- 208000004296 neuralgia Diseases 0.000 description 4
- 208000021722 neuropathic pain Diseases 0.000 description 4
- 125000006574 non-aromatic ring group Chemical group 0.000 description 4
- 230000035515 penetration Effects 0.000 description 4
- 230000035699 permeability Effects 0.000 description 4
- 125000003386 piperidinyl group Chemical group 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Substances CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 4
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 230000002792 vascular Effects 0.000 description 4
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 description 3
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 3
- 208000019901 Anxiety disease Diseases 0.000 description 3
- 206010003694 Atrophy Diseases 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical group C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 201000004569 Blindness Diseases 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- 206010016654 Fibrosis Diseases 0.000 description 3
- 208000010412 Glaucoma Diseases 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 101001018978 Homo sapiens MAP kinase-interacting serine/threonine-protein kinase 2 Proteins 0.000 description 3
- 101000826077 Homo sapiens SRSF protein kinase 2 Proteins 0.000 description 3
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 201000004681 Psoriasis Diseases 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 102100023015 SRSF protein kinase 2 Human genes 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 208000006673 asthma Diseases 0.000 description 3
- 230000037444 atrophy Effects 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 244000309464 bull Species 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 206010013663 drug dependence Diseases 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 231100000025 genetic toxicology Toxicity 0.000 description 3
- 230000001738 genotoxic effect Effects 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 208000014674 injury Diseases 0.000 description 3
- 238000000021 kinase assay Methods 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- FBPIDMAELBIRLE-UHFFFAOYSA-N methyl 5-bromofuran-2-carboxylate Chemical compound COC(=O)C1=CC=C(Br)O1 FBPIDMAELBIRLE-UHFFFAOYSA-N 0.000 description 3
- 230000036651 mood Effects 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 230000035935 pregnancy Effects 0.000 description 3
- 238000000751 protein extraction Methods 0.000 description 3
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical group C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 3
- QLULGIRFKAWHOJ-UHFFFAOYSA-N pyridin-4-ylboronic acid Chemical compound OB(O)C1=CC=NC=C1 QLULGIRFKAWHOJ-UHFFFAOYSA-N 0.000 description 3
- 230000035945 sensitivity Effects 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- YKGYLSBMOUSMDS-UHFFFAOYSA-N tert-butyl 4-(pyridin-2-ylmethyl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1CC1=CC=CC=N1 YKGYLSBMOUSMDS-UHFFFAOYSA-N 0.000 description 3
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 3
- 230000004304 visual acuity Effects 0.000 description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 description 2
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 2
- JPMRGPPMXHGKRO-UHFFFAOYSA-N 2-(chloromethyl)pyridine hydrochloride Chemical compound Cl.ClCC1=CC=CC=N1 JPMRGPPMXHGKRO-UHFFFAOYSA-N 0.000 description 2
- FRTVHNVKHNCHOY-UHFFFAOYSA-N 2-[4-(pyridin-2-ylmethyl)piperazin-1-yl]-5-(trifluoromethyl)aniline Chemical compound NC1=CC(C(F)(F)F)=CC=C1N1CCN(CC=2N=CC=CC=2)CC1 FRTVHNVKHNCHOY-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- 208000007848 Alcoholism Diseases 0.000 description 2
- 238000010953 Ames test Methods 0.000 description 2
- 231100000039 Ames test Toxicity 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- 208000020925 Bipolar disease Diseases 0.000 description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 2
- 101100328957 Caenorhabditis elegans clk-1 gene Proteins 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 241000283707 Capra Species 0.000 description 2
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 2
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 2
- 206010013801 Duchenne Muscular Dystrophy Diseases 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 108700024394 Exon Proteins 0.000 description 2
- 208000037149 Facioscapulohumeral dystrophy Diseases 0.000 description 2
- 208000008069 Geographic Atrophy Diseases 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 241000725303 Human immunodeficiency virus Species 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 208000004454 Hyperalgesia Diseases 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 102100033610 MAP kinase-interacting serine/threonine-protein kinase 2 Human genes 0.000 description 2
- 206010025421 Macule Diseases 0.000 description 2
- 208000002720 Malnutrition Diseases 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 206010030113 Oedema Diseases 0.000 description 2
- 206010034277 Pemphigoid Diseases 0.000 description 2
- 206010034719 Personality change Diseases 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 2
- 102000004257 Potassium Channel Human genes 0.000 description 2
- 102000001253 Protein Kinase Human genes 0.000 description 2
- 208000028017 Psychotic disease Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 2
- 208000017442 Retinal disease Diseases 0.000 description 2
- 206010038923 Retinopathy Diseases 0.000 description 2
- 206010038933 Retinopathy of prematurity Diseases 0.000 description 2
- 206010040047 Sepsis Diseases 0.000 description 2
- 208000009415 Spinocerebellar Ataxias Diseases 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 206010043189 Telangiectasia Diseases 0.000 description 2
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical group C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 2
- 206010052779 Transplant rejections Diseases 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 208000018756 Variant Creutzfeldt-Jakob disease Diseases 0.000 description 2
- 206010047139 Vasoconstriction Diseases 0.000 description 2
- 230000001594 aberrant effect Effects 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 201000007930 alcohol dependence Diseases 0.000 description 2
- 206010053552 allodynia Diseases 0.000 description 2
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 239000004037 angiogenesis inhibitor Substances 0.000 description 2
- 239000004599 antimicrobial Substances 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- 239000012131 assay buffer Substances 0.000 description 2
- 125000003725 azepanyl group Chemical group 0.000 description 2
- 125000002393 azetidinyl group Chemical group 0.000 description 2
- 125000004931 azocinyl group Chemical group N1=C(C=CC=CC=C1)* 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000003542 behavioural effect Effects 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 235000013361 beverage Nutrition 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 208000005881 bovine spongiform encephalopathy Diseases 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 230000007882 cirrhosis Effects 0.000 description 2
- 208000019425 cirrhosis of liver Diseases 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 208000010877 cognitive disease Diseases 0.000 description 2
- 201000000159 corneal neovascularization Diseases 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 208000033679 diabetic kidney disease Diseases 0.000 description 2
- 125000000532 dioxanyl group Chemical group 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 230000009429 distress Effects 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000009510 drug design Methods 0.000 description 2
- 238000002001 electrophysiology Methods 0.000 description 2
- 230000007831 electrophysiology Effects 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000004438 eyesight Effects 0.000 description 2
- 208000008570 facioscapulohumeral muscular dystrophy Diseases 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 238000013534 fluorescein angiography Methods 0.000 description 2
- 238000011010 flushing procedure Methods 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 201000006321 fundus dystrophy Diseases 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000003349 gelling agent Substances 0.000 description 2
- 238000003197 gene knockdown Methods 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 201000011066 hemangioma Diseases 0.000 description 2
- 206010020718 hyperplasia Diseases 0.000 description 2
- 125000001841 imino group Chemical group [H]N=* 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 230000000302 ischemic effect Effects 0.000 description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 2
- 208000017169 kidney disease Diseases 0.000 description 2
- 239000012669 liquid formulation Substances 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- 230000001071 malnutrition Effects 0.000 description 2
- 235000000824 malnutrition Nutrition 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- WDWNQUVOYIQGSU-UHFFFAOYSA-N methyl 5-pyridin-4-ylfuran-2-carboxylate Chemical compound O1C(C(=O)OC)=CC=C1C1=CC=NC=C1 WDWNQUVOYIQGSU-UHFFFAOYSA-N 0.000 description 2
- 201000006938 muscular dystrophy Diseases 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 230000002107 myocardial effect Effects 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 230000009826 neoplastic cell growth Effects 0.000 description 2
- 201000003142 neovascular glaucoma Diseases 0.000 description 2
- 230000007658 neurological function Effects 0.000 description 2
- 239000004090 neuroprotective agent Substances 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 238000010606 normalization Methods 0.000 description 2
- 208000015380 nutritional deficiency disease Diseases 0.000 description 2
- 125000004043 oxo group Chemical group O=* 0.000 description 2
- 230000008533 pain sensitivity Effects 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 230000002085 persistent effect Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 102000020233 phosphotransferase Human genes 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 108020001213 potassium channel Proteins 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000000750 progressive effect Effects 0.000 description 2
- 108060006633 protein kinase Proteins 0.000 description 2
- 201000001474 proteinuria Diseases 0.000 description 2
- 230000008433 psychological processes and functions Effects 0.000 description 2
- 125000002098 pyridazinyl group Chemical group 0.000 description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 2
- 239000000700 radioactive tracer Substances 0.000 description 2
- 229960003876 ranibizumab Drugs 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 208000037803 restenosis Diseases 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 208000012672 seasonal affective disease Diseases 0.000 description 2
- 201000005608 severe pre-eclampsia Diseases 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 208000009056 telangiectasis Diseases 0.000 description 2
- 125000001984 thiazolidinyl group Chemical group 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000000472 traumatic effect Effects 0.000 description 2
- 230000025033 vasoconstriction Effects 0.000 description 2
- 230000004393 visual impairment Effects 0.000 description 2
- 230000029663 wound healing Effects 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical group C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 1
- MHSLDASSAFCCDO-UHFFFAOYSA-N 1-(5-tert-butyl-2-methylpyrazol-3-yl)-3-(4-pyridin-4-yloxyphenyl)urea Chemical compound CN1N=C(C(C)(C)C)C=C1NC(=O)NC(C=C1)=CC=C1OC1=CC=NC=C1 MHSLDASSAFCCDO-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 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
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000004398 2-methyl-2-butyl group Chemical group CC(C)(CC)* 0.000 description 1
- 125000004918 2-methyl-2-pentyl group Chemical group CC(C)(CCC)* 0.000 description 1
- 125000004922 2-methyl-3-pentyl group Chemical group CC(C)C(CC)* 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 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
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000004917 3-methyl-2-butyl group Chemical group CC(C(C)*)C 0.000 description 1
- 125000004919 3-methyl-2-pentyl group Chemical group CC(C(C)*)CC 0.000 description 1
- 125000004921 3-methyl-3-pentyl group Chemical group CC(CC)(CC)* 0.000 description 1
- JHNLZOVBAQWGQU-UHFFFAOYSA-N 380814_sial Chemical compound CS(O)(=O)=O.O=P(=O)OP(=O)=O JHNLZOVBAQWGQU-UHFFFAOYSA-N 0.000 description 1
- 239000003477 4 aminobutyric acid receptor stimulating agent Substances 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 125000004920 4-methyl-2-pentyl group Chemical group CC(CC(C)*)C 0.000 description 1
- WLCZTRVUXYALDD-IBGZPJMESA-N 7-[[(2s)-2,6-bis(2-methoxyethoxycarbonylamino)hexanoyl]amino]heptoxy-methylphosphinic acid Chemical compound COCCOC(=O)NCCCC[C@H](NC(=O)OCCOC)C(=O)NCCCCCCCOP(C)(O)=O WLCZTRVUXYALDD-IBGZPJMESA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 239000000774 AMPA receptor agonist Substances 0.000 description 1
- 206010000117 Abnormal behaviour Diseases 0.000 description 1
- 206010000125 Abnormal dreams Diseases 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 1
- 229940123702 Adenosine A2a receptor antagonist Drugs 0.000 description 1
- 208000008811 Agoraphobia Diseases 0.000 description 1
- 208000031277 Amaurotic familial idiocy Diseases 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- 208000000044 Amnesia Diseases 0.000 description 1
- 208000031091 Amnestic disease Diseases 0.000 description 1
- 208000029197 Amphetamine-Related disease Diseases 0.000 description 1
- 206010002329 Aneurysm Diseases 0.000 description 1
- 208000003120 Angiofibroma Diseases 0.000 description 1
- 206010002650 Anorexia nervosa and bulimia Diseases 0.000 description 1
- 108091023037 Aptamer Proteins 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 208000036640 Asperger disease Diseases 0.000 description 1
- 201000006062 Asperger syndrome Diseases 0.000 description 1
- 102000007370 Ataxin2 Human genes 0.000 description 1
- 108010032951 Ataxin2 Proteins 0.000 description 1
- 108010078286 Ataxins Proteins 0.000 description 1
- 102000014461 Ataxins Human genes 0.000 description 1
- 208000027448 Attention Deficit and Disruptive Behavior disease Diseases 0.000 description 1
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 description 1
- 206010003805 Autism Diseases 0.000 description 1
- 208000020706 Autistic disease Diseases 0.000 description 1
- 208000037157 Azotemia Diseases 0.000 description 1
- 208000008035 Back Pain Diseases 0.000 description 1
- 208000037663 Best vitelliform macular dystrophy Diseases 0.000 description 1
- 229940123031 Beta adrenoreceptor agonist Drugs 0.000 description 1
- 208000006386 Bone Resorption Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- 208000021465 Brief psychotic disease Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 101100113692 Caenorhabditis elegans clk-2 gene Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 208000016615 Central areolar choroidal dystrophy Diseases 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 206010008025 Cerebellar ataxia Diseases 0.000 description 1
- 206010008096 Cerebral atrophy Diseases 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 241000282994 Cervidae Species 0.000 description 1
- 108091006146 Channels Proteins 0.000 description 1
- 208000010693 Charcot-Marie-Tooth Disease Diseases 0.000 description 1
- 208000033810 Choroidal dystrophy Diseases 0.000 description 1
- 206010008874 Chronic Fatigue Syndrome Diseases 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 101150085102 Clk3 gene Proteins 0.000 description 1
- 208000022497 Cocaine-Related disease Diseases 0.000 description 1
- 208000028698 Cognitive impairment Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 208000013586 Complex regional pain syndrome type 1 Diseases 0.000 description 1
- 206010056489 Coronary artery restenosis Diseases 0.000 description 1
- 208000011990 Corticobasal Degeneration Diseases 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 208000011231 Crohn disease Diseases 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-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
- 206010011878 Deafness Diseases 0.000 description 1
- 206010012239 Delusion Diseases 0.000 description 1
- 208000024254 Delusional disease Diseases 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 206010012441 Dermatitis bullous Diseases 0.000 description 1
- 206010012468 Dermatitis herpetiformis Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- LTMHDMANZUZIPE-AMTYYWEZSA-N Digoxin Natural products O([C@H]1[C@H](C)O[C@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@](C)([C@H](O)C4)[C@H](C4=CC(=O)OC4)CC5)CC3)CC2)C[C@@H]1O)[C@H]1O[C@H](C)[C@@H](O[C@H]2O[C@@H](C)[C@H](O)[C@@H](O)C2)[C@@H](O)C1 LTMHDMANZUZIPE-AMTYYWEZSA-N 0.000 description 1
- JRWZLRBJNMZMFE-UHFFFAOYSA-N Dobutamine Chemical compound C=1C=C(O)C(O)=CC=1CCNC(C)CCC1=CC=C(O)C=C1 JRWZLRBJNMZMFE-UHFFFAOYSA-N 0.000 description 1
- 201000010374 Down Syndrome Diseases 0.000 description 1
- 102100028554 Dual specificity tyrosine-phosphorylation-regulated kinase 1A Human genes 0.000 description 1
- 102100023115 Dual specificity tyrosine-phosphorylation-regulated kinase 2 Human genes 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 208000030814 Eating disease Diseases 0.000 description 1
- 208000032096 Encephalitic infection Diseases 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- 206010014824 Endotoxic shock Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010015218 Erythema multiforme Diseases 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 208000001860 Eye Infections Diseases 0.000 description 1
- 208000019454 Feeding and Eating disease Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 208000024412 Friedreich ataxia Diseases 0.000 description 1
- 201000011240 Frontotemporal dementia Diseases 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 208000011688 Generalised anxiety disease Diseases 0.000 description 1
- 241000699694 Gerbillinae Species 0.000 description 1
- 208000010055 Globoid Cell Leukodystrophy Diseases 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 208000009396 Group II Malformations of Cortical Development Diseases 0.000 description 1
- 208000035895 Guillain-Barré syndrome Diseases 0.000 description 1
- 201000005624 HELLP Syndrome Diseases 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- 206010019196 Head injury Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 208000013875 Heart injury Diseases 0.000 description 1
- 208000031220 Hemophilia Diseases 0.000 description 1
- 208000009292 Hemophilia A Diseases 0.000 description 1
- 102000008055 Heparan Sulfate Proteoglycans Human genes 0.000 description 1
- 229920002971 Heparan sulfate Polymers 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 206010019663 Hepatic failure Diseases 0.000 description 1
- 208000003923 Hereditary Corneal Dystrophies Diseases 0.000 description 1
- 208000009889 Herpes Simplex Diseases 0.000 description 1
- 208000007514 Herpes zoster Diseases 0.000 description 1
- 206010020112 Hirsutism Diseases 0.000 description 1
- 241001272567 Hominoidea Species 0.000 description 1
- 101000838016 Homo sapiens Dual specificity tyrosine-phosphorylation-regulated kinase 1A Proteins 0.000 description 1
- 101001049990 Homo sapiens Dual specificity tyrosine-phosphorylation-regulated kinase 2 Proteins 0.000 description 1
- 101001064870 Homo sapiens Lon protease homolog, mitochondrial Proteins 0.000 description 1
- 101000826079 Homo sapiens SRSF protein kinase 3 Proteins 0.000 description 1
- 101000577652 Homo sapiens Serine/threonine-protein kinase PRP4 homolog Proteins 0.000 description 1
- 101000595531 Homo sapiens Serine/threonine-protein kinase pim-1 Proteins 0.000 description 1
- 101001001648 Homo sapiens Serine/threonine-protein kinase pim-2 Proteins 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 208000034767 Hypoproteinaemia Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 206010065042 Immune reconstitution inflammatory syndrome Diseases 0.000 description 1
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 1
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 208000032578 Inherited retinal disease Diseases 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- DHUZAAUGHUHIDS-ONEGZZNKSA-N Isomyristicin Chemical compound COC1=CC(\C=C\C)=CC2=C1OCO2 DHUZAAUGHUHIDS-ONEGZZNKSA-N 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- 208000002260 Keloid Diseases 0.000 description 1
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 1
- 208000028226 Krabbe disease Diseases 0.000 description 1
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 1
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical class NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical class NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 102000004856 Lectins Human genes 0.000 description 1
- 108090001090 Lectins Proteins 0.000 description 1
- 241000288903 Lemuridae Species 0.000 description 1
- 208000009829 Lewy Body Disease Diseases 0.000 description 1
- 201000002832 Lewy body dementia Diseases 0.000 description 1
- 208000008930 Low Back Pain Diseases 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- 239000007993 MOPS buffer Substances 0.000 description 1
- 208000002569 Machado-Joseph Disease Diseases 0.000 description 1
- 208000001344 Macular Edema Diseases 0.000 description 1
- 208000003863 Marijuana Abuse Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 206010027525 Microalbuminuria Diseases 0.000 description 1
- 208000009857 Microaneurysm Diseases 0.000 description 1
- 206010049567 Miller Fisher syndrome Diseases 0.000 description 1
- 102000010909 Monoamine Oxidase Human genes 0.000 description 1
- 108010062431 Monoamine oxidase Proteins 0.000 description 1
- 208000019022 Mood disease Diseases 0.000 description 1
- 208000026072 Motor neurone disease Diseases 0.000 description 1
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 1
- 206010068871 Myotonic dystrophy Diseases 0.000 description 1
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 description 1
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 206010029164 Nephrotic syndrome Diseases 0.000 description 1
- 108010025020 Nerve Growth Factor Proteins 0.000 description 1
- 102000007072 Nerve Growth Factors Human genes 0.000 description 1
- 208000028389 Nerve injury Diseases 0.000 description 1
- 206010029240 Neuritis Diseases 0.000 description 1
- 206010057852 Nicotine dependence Diseases 0.000 description 1
- 208000014060 Niemann-Pick disease Diseases 0.000 description 1
- 206010029412 Nightmare Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 208000001294 Nociceptive Pain Diseases 0.000 description 1
- 102000007999 Nuclear Proteins Human genes 0.000 description 1
- 108010089610 Nuclear Proteins Proteins 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 206010029888 Obliterative bronchiolitis Diseases 0.000 description 1
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 description 1
- 208000022873 Ocular disease Diseases 0.000 description 1
- 208000021957 Ocular injury Diseases 0.000 description 1
- 208000026251 Opioid-Related disease Diseases 0.000 description 1
- 208000003435 Optic Neuritis Diseases 0.000 description 1
- 208000010191 Osteitis Deformans Diseases 0.000 description 1
- 206010033266 Ovarian Hyperstimulation Syndrome Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000027868 Paget disease Diseases 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 208000027099 Paranoid disease Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 208000031481 Pathologic Constriction Diseases 0.000 description 1
- 208000034038 Pathologic Neovascularization Diseases 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-L PdCl2(PPh3)2 Substances [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 206010034912 Phobia Diseases 0.000 description 1
- 241000233805 Phoenix Species 0.000 description 1
- 208000000609 Pick Disease of the Brain Diseases 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 208000037062 Polyps Diseases 0.000 description 1
- 208000036757 Postencephalitic parkinsonism Diseases 0.000 description 1
- 208000010366 Postpoliomyelitis syndrome Diseases 0.000 description 1
- 102000029797 Prion Human genes 0.000 description 1
- 108091000054 Prion Proteins 0.000 description 1
- 206010037423 Pulmonary oedema Diseases 0.000 description 1
- 206010037649 Pyogenic granuloma Diseases 0.000 description 1
- 201000001947 Reflex Sympathetic Dystrophy Diseases 0.000 description 1
- 208000005587 Refsum Disease Diseases 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 102000009661 Repressor Proteins Human genes 0.000 description 1
- 108010034634 Repressor Proteins Proteins 0.000 description 1
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 1
- 201000007737 Retinal degeneration Diseases 0.000 description 1
- 206010038848 Retinal detachment Diseases 0.000 description 1
- 208000032430 Retinal dystrophy Diseases 0.000 description 1
- 208000007014 Retinitis pigmentosa Diseases 0.000 description 1
- 206010038934 Retinopathy proliferative Diseases 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 102100023017 SRSF protein kinase 3 Human genes 0.000 description 1
- 208000030988 Schizoid Personality disease Diseases 0.000 description 1
- 208000020186 Schizophreniform disease Diseases 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 208000000810 Separation Anxiety Diseases 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- 102100028868 Serine/threonine-protein kinase PRP4 homolog Human genes 0.000 description 1
- 102100036077 Serine/threonine-protein kinase pim-1 Human genes 0.000 description 1
- 102100036120 Serine/threonine-protein kinase pim-2 Human genes 0.000 description 1
- 208000009106 Shy-Drager Syndrome Diseases 0.000 description 1
- 206010041250 Social phobia Diseases 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 208000027520 Somatoform disease Diseases 0.000 description 1
- 206010041347 Somnambulism Diseases 0.000 description 1
- 201000003622 Spinocerebellar ataxia type 2 Diseases 0.000 description 1
- 208000027073 Stargardt disease Diseases 0.000 description 1
- 208000037065 Subacute sclerosing leukoencephalitis Diseases 0.000 description 1
- 206010042297 Subacute sclerosing panencephalitis Diseases 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 206010048327 Supranuclear palsy Diseases 0.000 description 1
- 108090000054 Syndecan-2 Proteins 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 208000034841 Thrombotic Microangiopathies Diseases 0.000 description 1
- 208000025569 Tobacco Use disease Diseases 0.000 description 1
- 208000018452 Torsade de pointes Diseases 0.000 description 1
- 208000002363 Torsades de Pointes Diseases 0.000 description 1
- 208000000323 Tourette Syndrome Diseases 0.000 description 1
- 208000016620 Tourette disease Diseases 0.000 description 1
- 101710120037 Toxin CcdB Proteins 0.000 description 1
- 208000031674 Traumatic Acute Stress disease Diseases 0.000 description 1
- 229940123445 Tricyclic antidepressant Drugs 0.000 description 1
- 206010044688 Trisomy 21 Diseases 0.000 description 1
- BGDKAVGWHJFAGW-UHFFFAOYSA-N Tropicamide Chemical compound C=1C=CC=CC=1C(CO)C(=O)N(CC)CC1=CC=NC=C1 BGDKAVGWHJFAGW-UHFFFAOYSA-N 0.000 description 1
- 208000026911 Tuberous sclerosis complex Diseases 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 108091008605 VEGF receptors Proteins 0.000 description 1
- 206010049060 Vascular Graft Occlusion Diseases 0.000 description 1
- 201000004810 Vascular dementia Diseases 0.000 description 1
- 102100022748 Wilms tumor protein Human genes 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 201000004525 Zellweger Syndrome Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 208000002552 acute disseminated encephalomyelitis Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000006022 acute inflammation Effects 0.000 description 1
- 208000038016 acute inflammation Diseases 0.000 description 1
- 208000026345 acute stress disease Diseases 0.000 description 1
- 230000002730 additional effect Effects 0.000 description 1
- 239000002467 adenosine A2a receptor antagonist Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 208000030597 adult Refsum disease Diseases 0.000 description 1
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 description 1
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 1
- 238000012382 advanced drug delivery Methods 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003288 aldose reductase inhibitor Substances 0.000 description 1
- 229940090865 aldose reductase inhibitors used in diabetes Drugs 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000009285 allergic inflammation Effects 0.000 description 1
- 208000028004 allergic respiratory disease Diseases 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000006986 amnesia Effects 0.000 description 1
- 239000002870 angiogenesis inducing agent Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 229940065524 anticholinergics inhalants for obstructive airway diseases Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 208000024823 antisocial personality disease Diseases 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 206010003074 arachnoiditis Diseases 0.000 description 1
- 125000000637 arginyl group Chemical class N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- 238000013528 artificial neural network Methods 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 230000000386 athletic effect Effects 0.000 description 1
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 description 1
- 201000004562 autosomal dominant cerebellar ataxia Diseases 0.000 description 1
- 229940120638 avastin Drugs 0.000 description 1
- 208000022804 avoidant personality disease Diseases 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical class C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-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
- 230000008827 biological function Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 208000028683 bipolar I disease Diseases 0.000 description 1
- 208000002352 blister Diseases 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000024279 bone resorption Effects 0.000 description 1
- 208000030963 borderline personality disease Diseases 0.000 description 1
- 201000003848 bronchiolitis obliterans Diseases 0.000 description 1
- 208000023367 bronchiolitis obliterans with obstructive pulmonary disease Diseases 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 208000000594 bullous pemphigoid Diseases 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229930003827 cannabinoid Natural products 0.000 description 1
- 239000003557 cannabinoid Substances 0.000 description 1
- 201000001843 cannabis dependence Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003543 catechol methyltransferase inhibitor Substances 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 210000003986 cell retinal photoreceptor Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000030570 cellular localization Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000000064 cholinergic agonist Substances 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 201000006145 cocaine dependence Diseases 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 208000021921 corneal disease Diseases 0.000 description 1
- 206010011005 corneal dystrophy Diseases 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 208000026725 cyclothymic disease Diseases 0.000 description 1
- 201000010206 cystoid macular edema Diseases 0.000 description 1
- 230000001120 cytoprotective effect Effects 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 231100000895 deafness Toxicity 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 231100000868 delusion Toxicity 0.000 description 1
- 208000030964 dependent personality disease Diseases 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 230000003205 diastolic effect Effects 0.000 description 1
- 239000002027 dichloromethane extract Substances 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000015872 dietary supplement Nutrition 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000002022 differential scanning fluorescence spectroscopy Methods 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 229960005156 digoxin Drugs 0.000 description 1
- MOAVUYWYFFCBNM-PUGKRICDSA-N digoxin(1-) Chemical compound C[C@H]([C@H]([C@H](C1)O)O)O[C@H]1O[C@H]([C@@H](C)O[C@H](C1)O[C@H]([C@@H](C)O[C@H](C2)O[C@@H](CC3)C[C@@H](CC4)[C@@]3(C)[C@@H](C[C@H]([C@]3(C)[C@H](CC5)C([CH-]O6)=CC6=O)O)[C@@H]4[C@]35O)[C@H]2O)[C@H]1O MOAVUYWYFFCBNM-PUGKRICDSA-N 0.000 description 1
- LTMHDMANZUZIPE-UHFFFAOYSA-N digoxine Natural products C1C(O)C(O)C(C)OC1OC1C(C)OC(OC2C(OC(OC3CC4C(C5C(C6(CCC(C6(C)C(O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)CC2O)C)CC1O LTMHDMANZUZIPE-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 231100000676 disease causative agent Toxicity 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 235000014632 disordered eating Nutrition 0.000 description 1
- 238000002224 dissection Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229960001089 dobutamine Drugs 0.000 description 1
- 229940052760 dopamine agonists Drugs 0.000 description 1
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 208000024732 dysthymic disease Diseases 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 206010014801 endophthalmitis Diseases 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 125000006125 ethylsulfonyl group Chemical group 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 208000030533 eye disease Diseases 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 230000003176 fibrotic effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000005558 fluorometry Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 208000029364 generalized anxiety disease Diseases 0.000 description 1
- 208000007565 gingivitis Diseases 0.000 description 1
- 230000001434 glomerular Effects 0.000 description 1
- 210000003904 glomerular cell Anatomy 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 201000006138 hallucinogen dependence Diseases 0.000 description 1
- 208000016354 hearing loss disease Diseases 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 230000011132 hemopoiesis Effects 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 230000002267 hypothalamic effect Effects 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000010166 immunofluorescence Methods 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 208000035231 inattentive type attention deficit hyperactivity disease Diseases 0.000 description 1
- 201000001371 inclusion conjunctivitis Diseases 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 208000017532 inherited retinal dystrophy Diseases 0.000 description 1
- 230000000290 insulinogenic effect Effects 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 230000004410 intraocular pressure Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000002608 ionic liquid Substances 0.000 description 1
- NQXWGWZJXJUMQB-UHFFFAOYSA-K iron trichloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].Cl[Fe+]Cl NQXWGWZJXJUMQB-UHFFFAOYSA-K 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 208000012947 ischemia reperfusion injury Diseases 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000001117 keloid Anatomy 0.000 description 1
- 229960003299 ketamine Drugs 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 229910052743 krypton Inorganic materials 0.000 description 1
- DNNSSWSSYDEUBZ-UHFFFAOYSA-N krypton atom Chemical compound [Kr] DNNSSWSSYDEUBZ-UHFFFAOYSA-N 0.000 description 1
- 206010023497 kuru Diseases 0.000 description 1
- 230000004301 light adaptation Effects 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 208000007903 liver failure Diseases 0.000 description 1
- 231100000835 liver failure Toxicity 0.000 description 1
- 210000001853 liver microsome Anatomy 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 208000018769 loss of vision Diseases 0.000 description 1
- 231100000864 loss of vision Toxicity 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
- 229940092110 macugen Drugs 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 208000024714 major depressive disease Diseases 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 208000027202 mammary Paget disease Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- HRLIOXLXPOHXTA-UHFFFAOYSA-N medetomidine Chemical compound C=1C=CC(C)=C(C)C=1C(C)C1=CN=C[N]1 HRLIOXLXPOHXTA-UHFFFAOYSA-N 0.000 description 1
- 229960002140 medetomidine Drugs 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 210000003584 mesangial cell Anatomy 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 208000005264 motor neuron disease Diseases 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 208000029766 myalgic encephalomeyelitis/chronic fatigue syndrome Diseases 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000014399 negative regulation of angiogenesis Effects 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000008764 nerve damage Effects 0.000 description 1
- 230000002232 neuromuscular Effects 0.000 description 1
- 230000003955 neuronal function Effects 0.000 description 1
- 230000002981 neuropathic effect Effects 0.000 description 1
- 239000003900 neurotrophic factor Substances 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 230000030648 nucleus localization Effects 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 208000030459 obsessive-compulsive personality disease Diseases 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 208000031237 olivopontocerebellar atrophy Diseases 0.000 description 1
- 201000005040 opiate dependence Diseases 0.000 description 1
- 208000024196 oppositional defiant disease Diseases 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 238000012261 overproduction Methods 0.000 description 1
- 238000002638 palliative care Methods 0.000 description 1
- 208000019906 panic disease Diseases 0.000 description 1
- 208000002851 paranoid schizophrenia Diseases 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 208000030062 persistent idiopathic facial pain Diseases 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- JTJMJGYZQZDUJJ-UHFFFAOYSA-N phencyclidine Chemical compound C1CCCCN1C1(C=2C=CC=CC=2)CCCCC1 JTJMJGYZQZDUJJ-UHFFFAOYSA-N 0.000 description 1
- 229950010883 phencyclidine Drugs 0.000 description 1
- OCYSGIYOVXAGKQ-FVGYRXGTSA-N phenylephrine hydrochloride Chemical compound [H+].[Cl-].CNC[C@H](O)C1=CC=CC(O)=C1 OCYSGIYOVXAGKQ-FVGYRXGTSA-N 0.000 description 1
- 229960003733 phenylephrine hydrochloride Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000000649 photocoagulation Effects 0.000 description 1
- 230000007180 physiological regulation Effects 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 208000030761 polycystic kidney disease Diseases 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 108010040003 polyglutamine Proteins 0.000 description 1
- 229920000155 polyglutamine Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 208000028173 post-traumatic stress disease Diseases 0.000 description 1
- 208000000170 postencephalitic Parkinson disease Diseases 0.000 description 1
- 208000022076 postinfectious encephalitis Diseases 0.000 description 1
- 208000001685 postmenopausal osteoporosis Diseases 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000002250 progressing effect Effects 0.000 description 1
- 206010036807 progressive multifocal leukoencephalopathy Diseases 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- ALDITMKAAPLVJK-UHFFFAOYSA-N prop-1-ene;hydrate Chemical group O.CC=C ALDITMKAAPLVJK-UHFFFAOYSA-N 0.000 description 1
- 229960005439 propantheline bromide Drugs 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 208000005333 pulmonary edema Diseases 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- 201000003651 pulmonary sarcoidosis Diseases 0.000 description 1
- 210000001747 pupil Anatomy 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000011535 reaction buffer Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000004263 retinal angiogenesis Effects 0.000 description 1
- 230000004264 retinal detachment Effects 0.000 description 1
- 208000004644 retinal vein occlusion Diseases 0.000 description 1
- 210000001210 retinal vessel Anatomy 0.000 description 1
- 201000007714 retinoschisis Diseases 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229940109850 royal jelly Drugs 0.000 description 1
- 238000011076 safety test Methods 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- 208000022610 schizoaffective disease Diseases 0.000 description 1
- 230000000698 schizophrenic effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 208000025874 separation anxiety disease Diseases 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 239000000952 serotonin receptor agonist Substances 0.000 description 1
- 210000004911 serous fluid Anatomy 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 201000001716 specific phobia Diseases 0.000 description 1
- 208000020431 spinal cord injury Diseases 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 230000036262 stenosis Effects 0.000 description 1
- 208000037804 stenosis Diseases 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 201000004595 synovitis Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 230000035488 systolic blood pressure Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical group C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 206010043778 thyroiditis Diseases 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 206010044325 trachoma Diseases 0.000 description 1
- 229940125725 tranquilizer Drugs 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
- 229960004791 tropicamide Drugs 0.000 description 1
- 208000009999 tuberous sclerosis Diseases 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 229920001664 tyloxapol Polymers 0.000 description 1
- MDYZKJNTKZIUSK-UHFFFAOYSA-N tyloxapol Chemical compound O=C.C1CO1.CC(C)(C)CC(C)(C)C1=CC=C(O)C=C1 MDYZKJNTKZIUSK-UHFFFAOYSA-N 0.000 description 1
- 229960004224 tyloxapol Drugs 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 208000009852 uremia Diseases 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 230000007998 vessel formation Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 201000007790 vitelliform macular dystrophy Diseases 0.000 description 1
- 208000020938 vitelliform macular dystrophy 2 Diseases 0.000 description 1
- 230000006614 vitellogenesis Effects 0.000 description 1
- 208000006542 von Hippel-Lindau disease Diseases 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000012130 whole-cell lysate Substances 0.000 description 1
Images
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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- 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
- 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
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
- A61P35/00—Antineoplastic agents
-
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
- C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D269/00—Heterocyclic compounds containing rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms according to more than one of groups C07D261/00 - C07D267/00
- C07D269/02—Heterocyclic compounds containing rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms according to more than one of groups C07D261/00 - C07D267/00 having the hetero atoms in positions 1 and 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- 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
- C07D405/04—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 directly linked by a ring-member-to-ring-member bond
-
- 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
- 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
- C07D405/14—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 three or more hetero rings
-
- 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
- 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
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Urology & Nephrology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Pain & Pain Management (AREA)
- Ophthalmology & Optometry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Furan Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
描述了抗血管生成治疗、通透性过高病症的治疗、神经性病症和神经变性病症的治疗、疼痛治疗、降低先兆子痫的风险的方法以及用于此类方法的化合物。
Description
发明领域
本发明涉及抗血管生成治疗以及用于抗血管生成治疗的化合物,特 别是以新生血管形成(neovascularisation)为特征的诸如年龄相关性黄斑 变性的病症的抗血管生成治疗。
本发明还涉及通透性过高(hyperpermeability)病症的治疗以及用于治 疗通透性过高病症的化合物。
本发明还涉及神经性病症和神经变性病症的治疗以及用于治疗神经 性病症和神经变性病症如阿尔茨海默病的化合物。
本发明还涉及疼痛治疗以及用于治疗疼痛的化合物。
本发明还涉及降低先兆子痫的风险的方法以及用于此类方法的化合 物。
发明背景
年龄相关性黄斑变性(AMD)是一种影响黄斑中间区域的导致视力丧 失的疾病,其是年龄超过50岁的人群失明的主要原因(Bressler,2004)。 渗出性AMD是AMD的最严重的形式(Ferris等人,1984),其主要由黄 斑下方的脉络膜循环产生并且以脉络膜新生血管化(CNV)为特征。CNV 是新血管由脉络膜到视网膜色素上皮(RPE)的异常生长(Patz等人,1977), 其被认为由于在RPE下方的血液和浆液的渗漏而导致视力丧失,所述渗 漏最终导致光感受器丧失、视网膜脱落和密集的黄斑瘢痕(Fine等人, 2000;Campochiaro等人,2006)。血管内皮生长因子(VEGF)是血管生成 和血管渗漏的关键因子(Dvorak等人,1995),其在CNV进展中被上调 (D’Amore,1994;Spilsbury等人,2000;Anderson等人,2002;Das等人, 2003),并已成为治疗渗出性AMD的主要治疗靶标。
VEGF是被可变剪接(alternatively spliced)以形成多种亚型的家族的 复合体基因(Leung等人,1989;Jingjing等人,1999),每一亚型在生物性 质、活性和功能方面不同(Houck等人,1991)。大部分细胞通常表达 VEGF121、VEGF165和VEGF189亚型,而VEGF145和VEGF206是相对罕见 的。大部分VEGF亚型包含外显子1-5(除了VEGF111外(Mineur等人,2007)),但与编码硫酸肝素(HS)结合域的外显子6和7的部分不同。这 些外显子用途的改变使可变剪接的亚型的生物性质发生改变,所述生物 性质例如它们与细胞表面硫酸肝素蛋白聚糖结合以及释放血管生成因子 的能力(Tischer等人,1991;Neufeld等人,1999)。
在2002年,从近端剪接位点(PSS)到远端剪接位点(DSS)的66个碱 基下游显示出第八外显子的差异剪接(Bates等人,2002;Woolard等人, 2004)。该区域中的可变剪接产生了第二亚型家族(VEGFxxxb),以其抗血 管生成性质而闻名(Perrin等人,2005)。WO 03/102105(其内容全部援引 加入本文)描述了可变剪接的亚型及其治疗意义。
在病理学血管生成过程中,促血管生成亚型被选择性上调(Bates等 人,2002;Varey等人,2008;Pritchard-Jones等人,2007),表明VEGFxxx和VEGFxxxb可以具有单独的调节途径。已表明在眼内注射之后,这些 抗血管生成亚型如VEGF165b和VEGF121b在视网膜和脉络膜的新生血管 形成的动物模型中有效地抗血管生成(Hua等人,2008),并且导致内皮 和视网膜上皮细胞的细胞保护作用(Magnussen等人,2010)。
FDA在2004年12月批准的治疗血管生成AMD的第一种疗法是 VEGF165、VEGF189和VEGF206特异性适体培加尼布钠(Macugen)。在临 床试验期间,培加尼布剂量依赖性降低严重视敏度下降的风险,并减缓 新生血管AMD的进展(Gragoudas等人,2004),但未导致视力的显著改 善。在2006年,雷珠单抗(Ranibizumab)(Lucentis)(一种新的人源化抗 VEGF抗体片段)被FDA批准用于新生血管AMD的治疗。该批准是基于 三个临床试验的结果,其中在1年时,约95%的每月用0.5mg Lucentis 治疗的患者维持视敏度(定义为降低<15个字母),并且≤40%的患者改善 了视力(定义为增加≥15个字母),与其相比,在假对照治疗组中为11% (Rosenfeld等人,2006;Brown等人,2006;Brown等人,2009)。当前的 治疗方案需要每月通过眼内注射给药Lucentis(Brown等人,2009; Schmidt-Erfuth等人,2011)。此类眼内注射导致眼内压增加(Good等人, 2010)以及眼内炎和其他严重副作用的风险(虽然很小)(Jager等人,2004)。 此外,证明bevicizumab(阿瓦斯丁(Avastin))(一种Lucentis衍生于其的 抗VEGF抗体)与VEGF165等效力地结合VEGF165b,由此靶向促血管生 成VEGF亚型和抗血管生成VEGF亚型(Varey等人,2008)。
因为VEGF的抗血管生成亚型和血管生成亚型源自相同的基因,所 以对亚型家族的控制取决于对可变剪接的控制。我们最近已经确定了一 些控制VEGF在近端剪接位点处的剪接的途径,涉及RNA结合蛋白质 SRSF1(Nowak等人,2008;Amin等人,2011)及其激酶SRPK1(Sanford 等人,2005)作为细胞使用近端剪接位点并因此产生VEGF的促血管生成 亚型的决定的关键需求(Nowak等人,2008;Nowak等人,2010)。SRPK1 的敲减(Knockdown)有效地降低了肿瘤中VEGF介导的体内血管生成, 并且SRPK1和SRPK2的抑制降低了体内血管生成(Amin等人,2011)。
WO2008/11077、WO2009/106855、WO2010/058227、WO2011/036429 和WO2011/148200(其公开内容援引加入本文)描述了引导有利于 VEGFxxxb亚型的表达的药剂的治疗及其他生理学用途。SRPK抑制剂在 基本上可以构成此类药剂。
WO2005/063293描述了一类SRPK抑制剂,包括SRPIN340及其衍 生物和类似物。
WO2014/060763(PCT/GB2013/052716)(其内容通过援引并入本文) 描述了靶向SRPK1的SRPK抑制剂,其尤其用作抗血管生成剂、神经保 护剂、用于治疗或预防通透性过高病症的药剂、用作用于治疗疼痛的药 剂、以及用作用于降低先兆子痫的风险或治疗先兆子痫的药剂。
用于引导VEGFxxxb亚型的表达的药剂的开发在治疗例如新生血管 性AMD方面以及在涉及VEGFxxxb的所有其他疾病方面均代表了新纪元。
本发明部分地基于靶向SRPK1的新的小分子抑制剂,其特别用作抗 血管生成剂、神经保护剂、用于治疗或预防通透性过高病症的药剂、用 作用于治疗疼痛的药剂,以及用作用于降低先兆子痫的风险或治疗先兆 子痫的药剂。
本发明还至少部分地基于下述令人惊讶的发现,即,已知抑制 SRPK1(例如SRPIN340及其衍生物和类似物)的这些低分子量化合物可 局部地或以剂量依赖性的方式用于抑制CNV进展。
发明概述
在第一方面,本发明提供式(I)的化合物、或其药学上可接受的盐、 溶剂合物、水合物或前药,其用于眼新生血管形成的剂量依赖性治疗或 预防:
其中:
n=1、2、3或0;
R1=H;4-元至8-元碳环基团,其可具有一个或多个取代基;包含 一个氧原子的4-元至8-元杂环基团,其可具有一个或多个取代基;包含 一个氮原子的4-元至8-元杂环基团,其可具有一个或多个取代基;包含 一个氮原子和一个氧原子的4-元至8-元杂环基团,其可具有一个或多个 取代基;包含两个氮原子的4-元至8-元杂环基团,其可具有一个或多个 取代基;包含三个氮原子的4-元至8-元杂环基团,其可具有一个或多个 取代基;或稠合芳族杂环基团,其可具有一个或多个取代基;
X=CH、O、NH或N;
Y=CH、O、NH或N;
Z=O、S、N或NH;以及
R2=H;C1-6烷基;苯基;4-元至8-元杂环基团或稠合芳族杂环基团, 其中的每一者可具有一个或多个取代基。
优选地,剂量依赖性是S型效力/剂量关系,例如附图的图4C所示类 型的S型效力/剂量关系。表述“眼新生血管形成”在其范围内包括以眼新 生血管形成为特征的疾病和病症,包括例如脉络膜新生血管化,如年龄 相关性黄斑变性。术语“眼新生血管形成”在其范围内还包括以视网膜新 生血管化为特征的疾病和病症。
在第二方面,本发明提供用于眼新生血管形成的局部治疗或预防的 式(I)的化合物或者其药学上可接受的盐、溶剂合物、水合物或前药。
本发明的所述第一和第二方面还提供通过向需要此类治疗的个体给 药式(I)的化合物来治疗或预防眼新生血管形成的相应方法,以及式(I)的 化合物在制备用于眼新生血管形成的治疗或预防(作为剂量依赖性治疗 和/或作为局部治疗)的药物中的相应用途。
令人惊讶且基于现有技术预料不到的是,在本发明中使用的化合物 能够剂量依赖性地治疗或预防眼新生血管形成,或者局部地治疗或预防 眼新生血管形成。剂量依赖性治疗不是固有地可预测的,但对于有效治 疗是高度期望且有益的。
可以特别提及式(I)的具体化合物和式(I)的化合物的优选或例示的子 集,以用于本发明。
可以提及用于本发明的方法的式(I)的化合物的其他实例是其中R1为 可具有一个或多个取代基的包含一个氮原子的4-元至8-元杂环基团的化 合物。此类化合物的实例包括其中R1为包含一个氮原子的6-元杂环芳族 基团(例如2-吡啶基、3-吡啶基或4-吡啶基)的化合物。此类化合物的其他 实例包括其中R1为各自可具有一个或多个取代基的包含两个或三个氮原 子的6-元杂环芳族环(例如嘧啶环、哒嗪环、吡嗪环或三嗪环)的化合物。此类化合物的其他实例包括其中R1为各自可具有一个或多个取代基的包 含一个氮原子的6-元杂环非芳族基团(例如哌啶基或哌嗪基)的化合物。
在一个实例中,式(I)的化合物包括其中R1为本文所述的含氮的6-元 杂芳基环或苯基且n、X、Y、Z和R2的任何组合如本文所述的化合物。例 如,存在被提及的化合物,其中R1为如本文所述的含氮的6-元杂芳基环 或苯基;R2为H,C1-6烷基,苯基,4-元至8-元杂环基团或稠合芳族杂环 基团,其中的每一者可具有一个或多个取代基;X=Y=CH;Z=O且n= 1。
式(I)的这些化合物以及它们的药学上可接受的盐、溶剂合物、水合 物或前药是新的,并且作为化合物本身(以及它们在眼新生血管形成的剂 量依赖性治疗或预防和/或眼新生血管形成的剂量依赖性治疗或预防中 的用途),它们构成本发明的又一方面。
包含所述新化合物的药物组合物以及所述新化合物和包含其的药物 组合物在抗血管生成治疗(包括治疗和预防以异常或过度的血管生成为 特征的病症和疾病)、通透性过高病症的治疗、神经性病症和神经变性病 症的治疗、非炎性疼痛的治疗及降低先兆子痫的风险的方法中的用途构 成本发明的其他方面。
因此,本发明还提供(i)治疗或预防如本文所定义的以异常或过度的 血管生成为特征的病症和疾病的方法;(ii)治疗或预防如本文所定义的 通透性过高病症的方法;(iii)治疗或预防如本文所定义的神经性病症和 神经变性病症的方法;(iv)治疗或预防非炎性疼痛的方法;以及(v)降 低先兆子痫的风险的方法,所述方法包括向有此需要的患者给药式(I)的 化合物。
特别提及的式(I)的化合物包括其中n=1或2的化合物。
特别提及的式(I)的化合物包括其中X=Y=CH且Z=O的化合物;其 中X和Y中的一者=CH且X和Y中的另一者=N且Z=O的化合物;或者其 中X=Y=N且Z=O的化合物。
特别提及的式(I)的化合物包括其中X=Y=CH且Z=S的化合物;其 中X和Y中的一者=CH且X和Y中的另一者=N且Z=S的化合物;或者其 中X=Y=N且Z=S的化合物。
特别提及的式(I)的化合物包括其中X=Y=CH且Z=NH的化合物; 其中X和Y中的一者=CH且X和Y中的另一者=N且Z=NH的化合物;或 者其中X=Y=N且Z=NH的化合物。
作为式(I)的化合物的优选实例,可以提及其中R1为可具有一个或多 个取代基的2-吡啶基、3-吡啶基或4-吡啶基(如未取代的3-吡啶基(即,其 中所述吡啶基的氮杂原子与5-元环呈间位))的化合物。
作为式(I)的化合物的优选实例,可以提及其中R1为可具有一个或多 个取代基(如甲氧基取代基)的苯基的化合物。
作为式(I)的化合物的优选实例,可以提及其中R1为可具有一个或多 个取代基的稠合芳族杂环基团的化合物。例如,可以提及其中R1为吲哚 基、异吲哚基、苯并咪唑基、喹啉基或异喹啉基的那些化合物。
作为式(I)的化合物的优选实例,可以提及其中R2为可具有一个或多 个取代基的2-吡啶基、3-吡啶基或4-吡啶基或者为嘧啶基的化合物。在其 中R2为可具有一个或多个取代基的2-吡啶基、3-吡啶基或4-吡啶基的式(I) 的化合物中,所述可具有一个或多个取代基的2-吡啶基、3-吡啶基或4- 吡啶基可以例如是未取代的3-吡啶基(即,其中所述吡啶基的氮杂原子与 5-元环呈间位)。
作为式(I)的化合物的优选实例,可以提及其中R2为可具有一个或多 个取代基的苯基或者为稠合芳族杂环基团的化合物,其中所述稠合芳族 杂环基团可以包括吲哚基、异吲哚基、苯并咪唑基、喹啉基或异喹啉基。
作为式(I)的化合物的优选实例,可以提及其中R2为氢或C1-6烷基(如 甲基或乙基)的化合物。
为了用于本发明的第一方面和第二方面,可以提及作为特别优选的 是(a)其中n=1;X=Y=CH且Z=O;R1为2-吡啶基、3-吡啶基或4-吡啶 基取代基;R2为苯基取代基或者2-吡啶基、3-吡啶基或4-吡啶基取代基, 或者可具有一个或多个取代基的苯基取代基或者2-吡啶基、3-吡啶基或 4-吡啶基的上述式(I)的化合物;以及(b)它们的药学上可接受的盐、溶剂 合物、水合物或前药。所述式(I)的化合物的实例包括其式如表1或表2所 示的化合物。
式(I)的化合物以及它们的药学可接受的盐、溶剂合物、水合物和前 药还可以下列特征中的一个或多个(所述特征,无论是单独地或以任意组 合形式地,可与本文所述或WO 2005/063293所述的任意实例和优选项相 结合以用于所述化合物)为特征:
1.n=1;
2.R1可以表示苯基、2-吡啶基、3-吡啶基或4-吡啶基、或嘧啶基;
3.Z=O;
4.X=Y=CH;
5.R2可以表示四氢吡喃基、苯基或者2-吡啶基、3-吡啶基或4-吡啶基。
由式(I)表示的化合物包括例如:
(1)其中上述n=1或2的此类化合物;
(2)其中上述n=1的此类化合物;
(3)其中上述R1为可具有一个或多个取代基的4-元至8-元碳环基团; 可具有一个或多个取代基的包含一个氧原子的4-元至8-元杂环基团或者 可具有一个或多个取代基的包含一个或两个氮原子的4-元至8-元杂环基 团的此类化合物;
(4)其中上述R1为2-吡啶基、3-吡啶基或4-吡啶基的此类化合物;
(5)其中上述X和Y独立地选自CH或N的此类化合物;
(6)其中上述X和Y均=CH的此类化合物;
(7)其中上述Z=O、S或NH的此类化合物;
(8)其中上述Z=O的此类化合物;
(9)其中上述R2为氢;C1-6烷基;可具有一个或多个取代基的4-元 至8-元碳环;可具有一个或多个取代基的含氮的4-元至8-元杂芳基环; 或可具有一个或多个取代基的含氧的4-元至8-元杂芳基环;或稠合芳族 杂环基团的此类化合物;
(10)其中上述R2为氢、具有一个或多个取代基的甲基或含氮的6- 元杂芳基环的此类化合物;
(11)其中上述R2为可具有一个或多个取代基的吡啶基环或嘧啶基 环的此类化合物;
(12)其中上述R2为2-吡啶基、3-吡啶基或4-吡啶基环的此类化合 物。
在上述化合物中,n按次序优选为(1)至(2),并且(2)是优选的;R1按次序优选为(3)至(4),并且(4)是更优选的;X和Y按次序优选为(5)至 (6),并且(6)是更优选的;Z按次序优选为(7)至(8),并且(8)是更优选的; R2按次序优选为(9)至(12),并且(12)是更优选的。
发明详述
本发明的化合物是SRPK1特异性抑制剂,因此可以用于治疗或预防 其中涉及SRPK1的任何疾病或病症的方法。现将描述此类病症和治疗。
抗血管生成治疗
本发明的化合物可以用于抗血管生成治疗。抗血管生成治疗优选包 括与异常血管生成或促血管生成VEGF亚型(VEGFxxx)的异常过量产生 相关的任何疾病或病症的治疗或预防。此类疾病或病症包括例如:血管 疾病(例如,血管收缩和以血管收缩为特征的病症,以及心血管疾病)、 恶性和良性瘤形成(例如,血管生成依赖性癌症,例如肿瘤性癌症)、肿瘤转移、炎性病症、糖尿病、糖尿病性视网膜病变和糖尿病的其他并发 症(例如糖尿病性新生血管形成)、沙眼、晶状体后增生、新生血管性青 光眼、年龄相关性黄斑变性、血管瘤、植入角膜组织的免疫排斥、与眼 损伤或感染相关的角膜血管生成、奥斯勒-韦伯综合征(Osler-Webber Syndrome)、心肌血管生成、伤口肉芽形成(wound granulation)、毛细血管扩张、血友病关节(hemophiliac joints)、血管纤维瘤、毛细血管扩张、 银屑病、硬皮症、脓性肉芽肿、潮红、肥胖症、关节炎(例如类风湿性关 节炎)、血细胞生成、血管发生、齿龈炎、动脉粥样硬化、子宫内膜异位 症、新生内膜过度增生、银屑病、多毛症和增殖性视网膜病变。本发明 的抗血管生成治疗还可以包括对健康个体进行的非治疗性处理,例如出 于美容目的来抑制血管形成。对于与异常血管生成相关的疾病和病症以 及抗血管生成治疗的其他细节参见WO 2008/110777,其内容通过援引加 入本文。
特别地,本发明的化合物可以用于治疗或预防眼新生血管形成,所 述眼新生血管可以包括视网膜新生血管化、脉络膜新生血管化或年龄相 关性黄斑变性。此外,本发明的化合物可以用于治疗或预防恶性瘤形成 或癌症,例如前列腺癌和乳腺癌。
微血管通透性过高病症、上皮细胞存活的病症和上皮滤过膜窗孔(fenestrations)的病症
作为SRPK1抑制剂的本发明化合物还可以用作治疗其中涉及可变 剪接的VEGFxxxb亚型的其他病症的治疗剂。例如,在WO 2010/058227 (其内容通过援引加入本文)中已表明VEGFxxxb对多种微血管通透性过高 病症、上皮细胞存活的病症和上皮滤过膜窗孔的病症是有活性的。
微血管通透性过高病症、VEGFxxx亚型的促血管生成促通透性限制 的调节障碍、上皮细胞存活和通透性的病症和/或上皮滤过膜窗孔的性质 (例如数密度和/或尺寸)方面的病症是多种严重的医学病况的基础。
此类病症的实例包括例如蛋白尿、尿毒症、微量白蛋白尿、低白蛋 白血症、肾超滤(renal hyperfiltration)、肾病综合征、肾衰竭、肺性高血 压、毛细血管通透性过高、微动脉瘤、水肿和糖尿病的血管并发症。
此类糖尿病的血管并发症的实例包括例如糖尿病性视网膜病变(增 殖性和非增殖性的)和糖尿病性肾病。糖尿病的血管并发症可与I型糖尿 病和II型糖尿病相关。
蛋白质从血液中损失可能导致其他并发症,例如血栓形成尤其是脑 中的血栓形成,以及对感染的易感性。天然蛋白质从血液中损失可能严 重削弱癌症治疗的效力。
微血管通透性过高病症可以特别是肾病症,例如GFB的通透性病症, 例如足细胞的通透性病症。
其中支持上皮细胞存活的治疗会是有效的疾病的实例如下:
急性肺纤维化疾病、成人呼吸窘迫综合征、成人呼吸窘迫综合征、 晚期癌症、过敏性呼吸道疾病、肺泡损伤、血管生成、关节炎、腹水、 哮喘、烧伤后的哮喘或水肿、动脉粥样硬化、自身免疫性疾病、骨质吸 收、与表皮下水疱形成相关的大疱性病症(包括大疱性类天疱疮)、心血 管病况、与肾小球或肾小球系膜细胞的增殖相关的某些肾疾病、慢性和 过敏性炎症、慢性肺疾病、慢性阻塞性肺疾病、硬化、角膜血管生成、 角膜疾病、冠状和脑侧枝血管形成、冠状动脉再狭窄、心脏病后的损伤、 疱疹样皮炎、糖尿病、糖尿病性肾病、糖尿病性视网膜病变、内毒素性 休克、多形性红斑、纤维化、肾小球肾炎、血管球性肾炎(glomerulonophritis)、移植物排斥、革兰氏阴性脓毒症、血管瘤、肝硬化、 肝功能衰竭、带状疱疹、宿主抗移植物反应(肾脏、肝脏、心脏和皮肤的 局部缺血再灌注损伤和同种异体移植排斥)、感染的受损伤口愈合、单纯 疱疹感染、来自人免疫缺陷病毒(HIV)的感染、炎症、癌症、炎性肠炎(克 罗恩病和溃疡性结肠炎)、炎性病况、支架内再狭窄、支架内狭窄、局部缺血、局部缺血性视网膜静脉闭塞、局部缺血性视网膜病变、卡波济氏 肉瘤、瘢痕疙瘩、在急性炎症期间的肝脏疾病、肺同种异体移植物排斥(闭 塞性支气管炎)、淋巴样恶性肿瘤、早产儿黄斑变性视网膜病变、骨髓增 生异常综合征、心肌血管生成、新生血管性青光眼、非胰岛素依赖型糖 尿病(NIDDM)、闭塞性细支气管炎、眼部病况或疾病、与视网膜血管增 生相关的眼疾病、奥斯勒-韦伯-朗迪病(Osier-Weber-Rendu disease)、骨关 节炎、卵巢过度刺激综合征、佩吉特氏病、胰腺炎、类天疱疮、多囊性 肾病、息肉、绝经后骨质疏松症、先兆子痫、银屑病、肺水肿、肺纤维 化、肺结节病、再狭窄、再狭窄、视网膜病变(包括糖尿病性视网膜病变)、 早产儿视网膜病变和年龄相关性黄斑变性;类风湿关节炎、类风湿关节 炎、潮红、结节病、脓毒症、中风、滑膜炎、系统性红斑狼疮、甲状腺 炎(throiditis)、血栓性微血管综合征(thrombic micoangiopathy syndromes)、 移植排斥、创伤、肿瘤相关的血管生成、血管移植物再狭窄、血管移植 物再狭窄、von Hippel Lindau病、伤口愈合。
本发明可以用于治疗黄斑营养不良。其包括:斯特格病/眼底黄色斑 点症;斯特格样(Stargardt-like)黄斑营养不良;斯特格样黄斑营养不良; 常染色体显性“牛眼”黄斑营养不良;Best黄斑营养不良;成人卵黄状变 性;Pattern营养不良;Doyne蜂窝状视网膜营养不良;北卡罗莱纳州黄 斑营养不良;类似MCDR1的常染色体显性黄斑营养不良;与耳聋有关的北卡罗莱纳州样黄斑营养不良;渐进性双焦脉络膜视网膜萎缩;索斯 比眼底营养不良;中央晕轮状脉络膜营养不良;显性囊样黄斑营养不良; 青少年视网膜劈裂症;隐性黄斑营养障碍;非家族隐性黄斑营养障碍。
特别地,所述病症可以是视网膜上皮的病症,例如地图样萎缩 (geographicatrophy)或年龄相关性黄斑变性。
对于微血管通透性过高病症、上皮细胞存活的病症和上皮滤过膜窗 孔的病症及其治疗的其他细节参见WO 2010/058227,其内容援引加入本 文。
神经性病症和神经变性病症
作为SRPK1抑制剂的本发明化合物还可以用作治疗其中涉及可变 剪接的VEGFxxxb亚型的其他病症的治疗剂。例如,在WO 2009/106855 (其内容通过援引加入本文)中已表明VEGFxxxb具有神经保护和神经再生 作用。
本发明所要治疗或预防的神经性病症包括神经性疼痛以及糖尿病性 神经病和其他神经病。
本发明所要治疗或预防的神经变性病症包括认知型和非认知型神经 变性、神经肌肉变性、运动感觉神经变性、眼神经变性。
预期VEGFxxxb家族的蛋白质的活性主动地预防和主动地逆转所述 病况和病症。
此外,因为轻度认知功能障碍通常与某类健康人群(例如老年人、处 于压力下的人、疲劳或疲惫的人)的正常状态相关,因此本发明还适用于 健康人群的非治疗性处理以调节或正常化他们的认知功能和行为,包括 思考、记忆、学习、集中和推理。
此外,因为神经再生可以有助于正常化具有精神病学或行为学异常 的个体的脑神经网络(无论这些是否可被诊断为一种或多种确定的精神 病学病症),所以本发明还适用于具有神经病学病症的人的治疗性处理以 及身体健康的人的非治疗性处理以将他们的认知和行为调节到正常状态。
例如,本发明提供了对下述病症的治疗或预防:疼痛(例如,神经性 疼痛)、痴呆、年龄相关性认知损伤、阿尔茨海默病、阿尔茨海默型老年 性痴呆(SDAT)、Lewy体痴呆、血管性痴呆、帕金森氏病、脑炎后帕金 森症、抑郁症、精神分裂症、肌营养不良(包括面肩肱型肌营养不良(FSH)、 杜氏肌营养不良、贝克肌营养不良和布鲁斯肌营养不良)、富克斯营养不良、强直性肌营养不良、角膜营养不良、反射性交感神经营养不良综合 征(RSDSA)、神经血管营养不良、重症肌无力、兰伯特伊顿病、亨廷顿 氏病、运动神经元疾病(包括肌萎缩性侧索硬化症(ALS)、多发性硬化、 位置性低血压、创伤性神经病或神经变性如中风后或意外事故后(例如, 创伤性头部损伤或脊髓损伤))、Batten病、科凯恩综合征、唐氏综合征、 皮质基底神经节变性、多系统萎缩症、大脑萎缩、橄榄体脑桥小脑萎缩、 齿状核红核萎缩、苍白球丘脑下部核萎缩、脊髓延髓萎缩、视神经炎、 硬化性全脑炎(SSPE)、注意力缺陷紊乱、病毒感染后脑炎、脊髓灰质炎 后综合征、华氏综合征、朱伯特综合征、格林-巴利综合征、无脑回畸形、 烟雾病、神经元移行异常、自闭症综合征(autistic syndrome)、多聚谷氨 酰胺疾病、尼曼-皮克病、进行性多灶性白质脑病、假性脑瘤、雷弗苏姆 病、Zellweger综合征、核上性麻痹、弗里德赖希共济失调、2型脊髓小 脑性共济失调、Rhett综合征、Shy-Drager综合征、结节性硬化症、匹克 氏病、慢性疲劳综合征、神经病(包括遗传性神经病、糖尿病性神经病和 有丝分裂性神经病)、基于朊病毒的神经变性(包括克雅氏病(CJD)、变异 型CJD、新变异型CJD)、牛海绵状脑病(BSE)、GSS、FFI、库鲁病和阿 尔佩斯综合症、约瑟夫病、急性播散性脑脊髓炎、蛛网膜炎、中枢神经 系统血管病变、肢体神经元功能(extremity neuronalfunction)丧失、夏科- 马里-图思病、球形细胞脑白质营养不良、脑白质营养不良、心衰易感性、 哮喘、癫痫、听觉神经变性、黄斑变性、色素性视网膜炎和青光眼诱导 的视神经变性。
一般而言,精神障碍不被诊断为“精神病学病症”,除非相关的行为 或思想使个体产生显著的痛苦或破坏他或她的日常机能。因此,在可诊 断的病症与类似但不那么严重或不那么有破坏性的心理功能之间存在着 边界线,对其的处理应认为是非治疗性的(参见下文)。
本发明所关注的精神病学病症的实例包括但不限于:焦虑症(例如, 急性应激障碍、惊恐病、广场恐怖症、社交恐怖症、特异恐怖症、强迫 性障碍、性焦虑症、创伤后应激障碍、躯体变形障碍和广泛性焦虑症)、 儿童期病症(例如,注意力缺陷多动障碍(ADHD)、Asperger障碍、孤独 症障碍、行为障碍、对立违抗性障碍、分离焦虑障碍和图雷特氏障碍)、进食障碍(例如,神经性厌食症和神经性贪食症)、情绪障碍(例如,抑郁 症、严重抑郁障碍、双相型障碍(躁狂抑郁症)、季节性情感障碍(SAD)、 循环情感性障碍和心境恶劣障碍)、睡眠障碍、认知精神病症(例如,谵 妄、遗忘症)、人格障碍(例如,偏执型人格障碍、分裂样人格障碍、精 神分裂型人格障碍、反社会型人格障碍、边缘型人格障碍、表演型人格 障碍、自恋型人格障碍、回避型人格障碍、依赖型人格障碍和强迫型人 格障碍)、精神病症(例如,精神分裂症、妄想症、短时精神障碍、精神 分裂症样精神障碍、情感性分裂症和感应性精神病症)、以及物质相关性 障碍(例如,酒精依赖、安非他明依赖、大麻依赖、可卡因依赖、致幻剂依赖、吸入剂依赖、尼古丁依赖、阿片类药物依赖、苯环利定依赖和镇 静剂依赖)。
对于神经性和神经变性病症及其治疗的其他细节参见WO 2009/106855,其内容通过援引加入本文。
疼痛的治疗
作为SRPK1抑制剂的本发明化合物还可以用作治疗其中涉及可变 剪接的VEGFxxxb亚型的其他病症的治疗剂。例如,在WO 2011/148200 (其内容通过援引加入本文)中已表明VEGFxxxb在哺乳动物中具有对 VEGFR2-介导的非炎性疼痛的镇痛作用。
本发明所要治疗或预防的VEGFR2-介导的非炎性疼痛包括这样的 非炎性神经性和伤害性疼痛,其中所述疼痛的诱因或传递涉及VEGFR2 受体。例如,预期本发明的化合物对非炎性异常性疼痛和疼痛有活性(抗 异常性疼痛和镇痛活性)。该类型的疼痛状态包括无论是间歇形式或持久 形式的慢性疼痛。此类疼痛状态可以包括例如腰痛,神经痛,非典型疼 痛如非典型性面痛,术后、损伤后(例如,手术后或引起神经损伤的外伤 后)出现的疼痛、与癌症相关的疼痛、或者与癌症治疗如细胞毒性治疗或 放射治疗相关的疼痛,或者与糖尿病相关的神经病(糖尿病性神经病、胰 岛素神经炎),或者与其他全身性或自身免疫性疾病或病理或者其治疗、 酒精中毒或HIV感染相关的神经病,老化相关的神经病,或原因不明的 神经病。
预测VEGFR2激动剂(例如VEGFxxxb家族)的蛋白质的活性主动地预 防和主动地逆转VEGFR2-介导的非炎性疼痛。
然而,鉴于VEGFxxxb家族的蛋白质的抗血管生成活性,本发明的 化合物的用途会被限于在可能的血管生成抑制不会对患者有害的情形中 的疼痛。
在本发明中使用的化合物可以与一种或多种不同的疼痛治疗剂一起 使用,从而使得使用所述一种或多种不同的疼痛治疗剂治疗(或共同治疗) 的个体对疼痛的敏感性正常化。术语“正常化”意指使个体的疼痛敏感性 移向正常水平,并且可以包括敏感性的增强,条件是所述一种或多种不 同的疼痛治疗剂导致感觉方面或对疼痛的敏感性方面的过度降低。所述 一种或多种不同的疼痛治疗剂可以选自当前已知的或尚未设计出的疼痛 治疗剂。此类选择会完全在本领域普通技术人员的技能范围内。此类联 合治疗能够根据个体的特定病症和需求精细控制个体的疼痛敏感性并且 使总体副作用最小化。
对于疼痛及其治疗的其他细节参见WO 2011/148200,其内容通过援 引加入本文。
先兆子痫的风险的降低
作为SRPK1抑制剂的本发明化合物还可以用作治疗其中涉及可变 剪接的VEGFxxxb亚型的其他病症的治疗剂。例如,在WO 2011/036429 (其内容通过援引加入本文)中已表明,怀孕的雌性哺乳动物中降低的 VEGFxxxb水平增加雌性哺乳动物出现先兆子痫的风险。因此,本发明的 化合物可以用于增加怀孕的雌性哺乳动物中的VEGFxxxb水平,从而降 低雌性哺乳动物出现先兆子痫或与其相关的并发症的风险,或降低雌性 哺乳动物的胎儿患有与母体先兆子痫相关的胎儿或新生儿缺陷的风险。
人类中的先兆子痫可以早至怀孕20周出现。在怀孕约34周之前出 现的先兆子痫通常称为“早期先兆子痫”或“早发型先兆子痫”。在怀孕约 34周之后出现的先兆子痫通常称为“晚期先兆子痫”或“晚发型先兆子痫”。
此外,根据英国皇家妇产科医师学会(United Kingdom Royal College ofObstetricians and Gynaecologists)建立的标准,先兆子痫可以分类为“重 度先兆子痫”。在这些标准下,患有“重度先兆子痫”的患者会具有大于 169mmHg的收缩期血压(BP)或大于109mmHg的舒张期BP和大于1 g/24h的蛋白尿;或会表现出HELLP综合征(溶血、升高的肝酶以及低血 小板计数)的出现。
对于先兆子痫以及降低怀孕的雌性哺乳动物出现先兆子痫或与其相 关的并发症的风险、或降低雌性哺乳动物的胎儿患有与母体先兆子痫相 关的胎儿或新生儿缺陷的风险的方法的其他细节参见WO 2011/036429, 其内容通过援引加入本文。
活性化合物
本发明的化合物可以由式(I)来定义并且已被证明为激酶SRPK1和 SRPK2中的一种或二者的抑制剂,因此可用于本文所述的治疗。
可以通过任何已知的方法合成本发明的化合物。可以根据需要来调 整WO 2005/063293所公开的合适的方法。化合物12的示例性合成在下 文实施例中描述。
联合给药
若需要,本发明的化合物可以与一种或多种其他的活性剂联合给药, 例如所述其他活性剂是选自但不限于以下的一种或多种药剂:胆碱酯酶 抑制剂、多巴胺激动剂(例如L-多巴)、COMT抑制剂、MAO-B抑制剂、 抗胆碱能药物、乙酰胆碱激动剂、血清素激动剂、AMPA受体激动剂、 GABA受体激动剂、NMDA受体激动剂、β-肾上腺素受体激动剂、地高 辛、多巴酚丁胺、抗炎剂、神经营养因子、他汀类药剂、腺苷A2a受体 拮抗剂、醛糖还原酶抑制剂、免疫调节剂、大麻素激动剂、干扰素或三 环抗抑郁药剂。
定义
在本文的式(I)的定义中:
“C1-6烷基”是指包含1个至6个碳原子的直链或支链烷基,其可以 是通过从由1至6个碳组成的脂族烃去除任意的氢原子而得到的单价基 团。具体地,C1-6烷基包括例如甲基、乙基、1-丙基、2-丙基、2-甲基-1- 丙基、2-甲基-2-丙基、1-丁基、2-丁基、1-戊基、2-戊基、3-戊基、2-甲 基-1-丁基、3-甲基-1-丁基、2-甲基-2-丁基、3-甲基-2-丁基、2,2-二甲基 -1-丙基、1-己基、2-己基、3-己基、2-甲基-1-戊基、3-甲基-1-戊基、4- 甲基-1-戊基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、2-甲基-3- 戊基、3-甲基-3-戊基、2,3-二甲基-1-丁基、3,3-二甲基-1-丁基、2,2-二甲 基-1-丁基、2-乙基-1-丁基、3,3-二甲基-2-丁基和2,3-二甲基-2-丁基;
“杂环”或“杂环基团”是指在环内可包含双键的芳族或非芳族环,其 中构成所述环的原子中的至少一个(例如一个或两个)是杂原子;
“含氮杂环”或“包含一个或多个氮原子的杂环基团”是指在环内可包 含双键的芳族或非芳族环,其中构成所述环的原子中的至少一个(例如一 个或两个)是氮原子;
”含氧杂环”或“包含一个或多个氧原子的杂环基团”是指在环内可包 含双键的芳族或非芳族环,其中构成所述环的原子中的至少一个(例如一 个或两个)是氧原子;
“杂原子”是指硫原子、氧原子或氮原子;
“含氮的5-元至10元杂芳基环”或“含氮的5-元至10-元杂芳族基团” 是指这样的芳族环,其中5至10个原子构成所述环,其中构成所述环的 原子中的至少一个是氮原子,并且还可以包含一个或多个除氮原子之外 的杂原子。具体地,含氮的5-元至10-元杂芳基环包括例如吡啶环、吲 哚环、异吲哚环、哒嗪环、嘧啶环、吡嗪环、喹啉环、异喹啉环和苯并 咪唑环。
“含氮的5-元至10-元杂芳基”是指通过从上文定义的“5-元至10-元 杂芳基环”去除一个或两个任意的氢原子而得到的单价或二价基团。具体 地,含氮的5-元至10-元杂芳基包括例如吡啶基、吲哚基、异吲哚基、 哒嗪基、嘧啶基、吡嗪基、喹啉基、异喹啉基和苯并咪唑基;
“含氮的4-元至8元杂芳基环”或“含氮的4-元至8-元杂芳族基团”是 指这样的芳族环,其中4至8个原子构成所述环,其中构成所述环的原 子中的至少一个是氮原子,并且还可以包含一个或多个除氮原子之外的 杂原子。具体地,含氮的4-元至8-元杂芳基环包括例如吡啶环、哒嗪环、 嘧啶环和吡嗪环;
“含氮的4-元至8-元杂芳基”是指通过从上文定义的“4-元至8-元杂 芳基环”去除一个或两个任意的氢原子而得到的单价或二价基团。具体地, 含氮的4-元至8-元杂芳基环包括例如吡啶基、哒嗪基、嘧啶基和吡嗪基;
“含氧的5-元至10-元杂芳基环”是指这样的芳族环,其中5至10个 原子构成所述环,其中构成所述环的原子中的至少一个是氧原子,并且 还可以包含一个或多个除了氧原子之外的杂原子。具体地,含氧的5-元 至10-元杂芳基环包括例如吡喃环;
“含氧的4-元至8-元杂芳基”是指这样的芳族环,其中4至8个原子 构成所述环,其中构成所述环的原子中的至少一个是氧原子,并且还可 以包含一个或多个除了氧原子之外的杂原子,例如为吡喃基;
“4-元至8-元非芳族杂环”是指满足下列定义的非芳族环:
1. 4至8个原子构成所述环;
2.构成所述环的原子中的一个或两个是杂原子;
3.在所述环中可以包含一个或两个双键;
4.在所述环中可以包含一个至三个羰基;以及
5.所述环是单环。
4-元至8-元非芳族杂环优选是包含作为杂原子的氮原子的含氮的4- 元至8-元杂环。
具体地,4-元至8-元非芳族杂环包括例如吖丁啶环、吡咯烷环、哌 啶环、氮杂环庚烷环、吖辛因环、四氢呋喃环、四氢吡喃环、吗啉环、 硫吗啉环、哌嗪环、噻唑烷环、二噁烷环、咪唑啉环和噻唑啉环。所述“4- 元至8-元杂环”优选包括吡咯烷环、哌啶环、吗啉环和哌嗪环;
“4-元至8-元非芳族杂环基团”是指通过从上文定义的“4-元至8-元非 芳族杂环”去除一个或两个任意的氢原子而得到的单价或二价基团。具体 地,所述4-元至8-元杂环基团包括例如吖丁啶基、吡咯烷基、哌啶基、 氮杂环庚烷基、吖辛因基、四氢呋喃基、四氢吡喃基、吗啉基、硫吗啉 基、哌嗪基、噻唑烷基、二噁烷基、咪唑基和噻唑基;
“稠合芳族杂环”是指其中杂环部分与诸如苯环的芳族环稠合(例如 邻位稠合)的环结构。所述杂环部分是上文定义的杂环。
“稠合芳族杂环基团”是指其中杂环部分与环(例如,诸如苯环的芳族 环)稠合(例如邻位稠合)的环结构。所述杂环部分是上文定义的杂环基。
稠合芳族杂环基团包括例如吲哚基、二氢吲哚基、异吲哚基、异二 氢吲哚基和1,2,3,4-四氢喹啉。
“4-元至8-元碳环”是指饱和或不饱和的碳环,例如呋喃环、四氢呋 喃环、吡喃环或四氢吡喃环;
“4-元至8-元碳环基团”是指通过从上文定义的4-元至8-元碳环去除 一个或两个任意的氢原子而得到的单价或二价基团。具体地,“4-元至8- 元碳环基团”可以是指呋喃基、四氢呋喃基、吡喃基、四氢吡喃基;
在本文中,“卤代C1-6烷基”是指其中在上文定义的“C1-6烷基”中的至 少一个任意的氢原子被上文定义的“卤原子”代替的基团。卤代C1-6烷基 包括例如三氟甲基、二氟甲基和单氟甲基。
在本文中,短语“可具有一个或多个取代基”表示某一基团或化合物 可以任选地具有在可取代位置处的一个或多个取代基的任意选择或组合。 具体地,所述取代基可以包括例如选自以下中的一个或多个的原子或基 团:卤素,羟基,羟甲基,羟乙基,巯基,硝基,氰基,甲酰基,羧基, 三氟甲基,三氟甲氧基,氨基,氧代,亚氨基,C1-6烷基(例如甲基),C1-6烷氧基(例如甲氧基),C1-6烷硫基(例如甲硫基),C2-6烯基,C2-6炔基, C1-6烷氧基羰基,C1-6烷基磺酰基,C6-10芳基,苄基,杂芳基,苯基,或 者被卤素、羟基、羟甲基、羟乙基、巯基、硝基、氰基、甲酰基、羧基、 三氟甲基、三氟甲氧基、氨基、氧代、亚氨基、C1-6烷基(例如甲基)、C1-6烷硫基(例如甲硫基)、C2-6烯基、C2-6炔基、C1-6烷氧基羰基、C1-6烷基磺 酰基或C1-6烷氧基(例如甲氧基)中的一个或多个取代的C6-10芳基、苄基、 苯基或杂芳基。
“C2-6烯基”是指包含2至6个碳的直链或支链烯基。具体地,C2-6烯 基包括例如乙烯基、烯丙基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、 3-丁烯基、戊烯基和己烯基;
“C2-6炔基”是指包含2至6个碳的直链或支链炔基。具体地,C2-6炔 基包括例如乙炔基、1-丙炔基、2-丙炔基、丁炔基、戊炔基和己炔基。
“C1-6烷氧基”是指与上文定义的“C1-6烷基”连接的氧基。具体地,C1-6烷氧基包括例如甲氧基、乙氧基、1-丙氧基、2-丙氧基、2-甲基-1-丙氧 基、2-甲基-2-丙氧基、1-丁氧基、2-丁氧基、1-戊氧基、2-戊氧基、3-戊 氧基、2-甲基-1-丁氧基、3-甲基-1-丁氧基、2-甲基-2-丁氧基、3-甲基-2- 丁氧基、2,2-二甲基-1-丙氧基、1-己氧基、2-己氧基、3-己氧基、2-甲基 -1-戊氧基、3-甲基-1-戊氧基、4-甲基-1-戊氧基、2-甲基-2-戊氧基、3-甲 基-2-戊氧基、4-甲基-2-戊氧基、2-甲基-3-戊氧基、3-甲基-3-戊氧基、2,3- 二甲基-1-丁氧基、3,3-二甲基-1-丁氧基、2,2-二甲基-1-丁氧基、2-乙基-1- 丁氧基、3,3-二甲基-2-丁氧基和2,3-二甲基-2-丁氧基;
“C1-6烷硫基”是指与上文定义的“C1-6烷基”连接的硫基。具体地,“C1-6烷硫基”包括例如甲硫基、乙硫基、1-丙硫基、2-丙硫基、丁硫基和戊硫 基;
“C1-6烷氧基羰基”是指与上文定义的“C1-6烷氧基”连接的羰基。具体 地,C1-6烷氧基羰基包括例如甲氧基羰基、乙氧基羰基、1-丙氧基羰基和 2-丙氧基羰基;
“C1-6烷基磺酰基”是指与上文定义的“C1-6烷基”连接的磺酰基。具体 地,C1-6烷基磺酰基包括例如甲基磺酰基、乙基磺酰基、1-丙基磺酰基和 2-丙基磺酰基。
“卤原子”是指氟原子、氯原子、溴原子或碘原子;
“C6-10芳基”是指包含6至10个碳原子的芳族环烃基。具体地,C6-10芳基包括例如苯基、1-萘基和2-萘基。
“盐”不受特别的限制,只要其是由本发明的化合物形成的药学上可 接受的盐。此类盐包括例如无机酸盐、有机盐、无机碱盐、有机碱盐以 及酸性或碱性氨基酸盐。优选的无机酸盐的实例包括:盐酸盐、氢溴酸 盐、硫酸盐、硝酸盐和磷酸盐。优选的有机盐的实例包括:乙酸盐、琥 珀酸盐、延胡索酸盐、马来酸盐、酒石酸盐、柠檬酸盐、乳酸盐、硬脂 酸盐、苯甲酸盐、甲磺酸盐和对甲苯磺酸盐。
优选的无机碱盐的实例包括:碱金属盐,例如钠盐和钾盐;碱土金 属盐,例如钙盐和镁盐;铝盐;以及铵盐。优选的有机碱盐的实例包括: 二乙胺盐、二乙醇胺盐、葡甲胺盐以及N,N'-二苄基乙二胺盐。
优选的酸性氨基酸盐的实例包括:天冬氨酸盐和谷氨酸盐。优选的 碱性氨基酸盐的实例包括:精氨酸盐、赖氨酸盐和鸟氨酸盐。
当在空气中放置时,本发明的化合物有时吸收水份,并且有时与吸 收的水结合或转化成水合物。本发明也包括此类水合物。
此外,本发明的化合物有时吸收一些其他溶剂而转化成溶剂合物。 本发明也包括此类溶剂合物。
任何有机溶剂原则上均可以用于制备本发明的化合物的溶剂合物。
溶剂合物可以还包含水与一种或多种有机溶剂。
因此,例如,所述溶剂可以选自酮、醇、醚、酯、芳族溶剂,以及 若可能的话,选自它们彼此的混合物、它们与其他有机溶剂和/或与水的 混合物。
式(I)的化合物的药学上可接受的前药形式可用于本发明。“药学上可 接受的前药”表示化合物的下述前药,其在合理的医学和兽医判断的范围 内适用于与人类和低等动物的组织接触而没有过度的毒性、刺激、过敏 反应等,与合理的受益/风险比相称、并且对于它们的期望用途是有效的, 以及若可能的话是所述化合物的两性离子形式。术语“前药”表示例如通 过在血液中水解而在体内迅速转变以产生上述式的母体化合物的化合物。 可以迅速转变的官能团通过代谢分裂而在体内形成一类可与羧基反应的 基团。由于化合物的可代谢分裂的基团体内分裂的容易性,因此携带此 类基团的化合物用作前药。对前药的深入探讨在以下文献中提供:Design of Prodrugs,H.Bundgaard,ed.,Elsevier,1985;Methods in Enzymology,K. Widder等人,Ed.,Academic Press,42,p.309-396,1985;ATextbook of Drug Design and Development,Krogsgaard-Larsen and H.Bundgaard,ed., Chapter 5;Design and Applications of Prodrugs p.113-191,1991; AdvancedDrug Delivery Reviews,H.Bundgard,8,p.l-38,1992;Journal of PharmaceuticalSciences,77,p.285,1988;Chem.Pharm.Bull.,N.Nakeya 等人,32,p.692,1984;Pro-drugsas Novel Delivery Systems,T.Higuchi and V.Stella,Vol.14of the A.C.S.SymposiumSeries,and Bioreversible Carriers in Drug Design,Edward B.Roche,ed.,AmericanPharmaceutical Association and Pergamon Press,1987,其通过援引加入本文。
组合物及给药
本发明的化合物可以以包含所述活性剂和任意合适的其他组分的组 合物形式给药。所述组合物可以例如是适用于局部给药(例如滴眼剂、乳 膏剂或洗剂)或肠胃外给药(例如注射、植入或输注)的药物组合物(药物)。 或者,所述组合物可以例如为食品、食品补充剂、饮料或饮料补充剂。
在本发明的上下文中的术语“药物组合物”或“药物”意指包含活性剂 并额外地包含一种或多种药学上可接受的载体的组合物。根据给药方式 和剂型的性质,组合物还可以包含选自例如稀释剂、辅剂、赋形剂、载 剂、防腐剂、填充剂、崩解剂、湿润剂、乳化剂、助悬剂、甜味剂、调 味剂、芳香剂、抗菌剂、抗真菌剂、润滑剂和分散剂的成分。组合物可 以采用例如以下的形式:片剂、糖锭剂、散剂、酏剂、糖浆剂、包括混 悬剂在内的液体制剂、喷雾剂、吸入剂、片剂、锭剂、乳剂、溶液剂、 扁囊剂、颗粒剂、胶囊剂和栓剂、以及用于注射的液体制剂(包括脂质体 制剂)。技术和配方通常在最新版Remington,The Science and Practiceof Pharmacy,Mack Publishing Co.,Easton,PA中得到。
液体形式制剂包括溶液剂、混悬剂和乳剂。作为实例可以提及用于 肠胃外注射或局部给药的水溶液剂或水-丙二醇溶液剂。液体制剂还可以 在聚乙二醇水溶液中配制为溶液剂。
本发明还包括固体形式制剂,其旨在使用前即刻转化成用于局部给 药、口服给药或肠胃外给药的液体形式制剂。此类液体形式包括溶液剂、 混悬剂和乳剂。这些特定的固体形式制剂最适宜地以单位剂量形式提供, 并且由此用于提供单一的液体剂量单位。或者,可以提供足够的固体, 从而在转化成液体形式之后,可以通过例如使用注射器、茶匙或其他测 定体积的容器或装置来测量预定体积的液体形式制剂,从而获得多个单 独的液体剂量。旨在转化成液体形式的固体形式制剂除了包含活性物质 之外,还可以包含调味剂、着色剂、稳定剂、缓冲剂、人造和天然甜味 剂、分散剂、增稠剂、增溶剂等。用于制备液体形式制剂的液体可以是 水、等渗水、乙醇、甘油、丙二醇等及其混合物。理所当然地,根据给药途径来选择所用的液体,例如包含大量的乙醇的液体制剂不适于局部 用途或肠胃外用途。
组合物可以是旨在局部施用的制剂。制剂可以是凝胶化制剂以在局 部施用之后控制活性剂的释放并因此控制活性剂的利用度。制剂可以包 含一种或多种胶凝剂,例如羟丙基甲基纤维素。制剂可以包含一种或多 种表面活性剂,例如非离子液体聚合物,其实例包括泰罗沙伯(Tyloxapol) 和来自BASF的泊洛沙姆。制剂可以包含一种或多种增溶剂, 例如右旋糖或山梨醇。制剂可以包含一种或多种抗微生物剂或防腐剂, 例如苯扎氯铵。前述指定的胶凝剂、表面活性剂、增溶剂和抗微生物剂 仅以实例形式列出,并且会认识到实现这些功能的其他药剂是已知的。
剂量可以根据患者需求、治疗的病况的严重性和采用的化合物而变 化。用于特定情况的合适剂量的确定在本领域技术人员的范围内。通常 以小于化合物的最佳剂量的较小剂量来开始治疗。此后,通过小幅增加 来提高剂量,直至达到所处环境的最佳效果。为简便起见,若需要,可 将总的日剂量分开并在一天中分批给药。
给药活性剂的剂量方案可以例如包括在例如1天至14天的给药时段 内至多1μg、例如至多500ng、例如至多50ng、例如小于20ng的活性 剂的总剂量。例如,可以给药小于18ng、17ng、16ng、15ng、14ng、 13ng、12ng、11ng或10ng的总剂量。
可以以治疗有效量来给药式(I)的化合物或其药学上可接受的盐、溶 剂合物、水合物或前药。用于治疗CNV的局部给药的式(I)的化合物的 治疗有效量可以为至少约5μg/10μl递送载剂。或者,治疗有效量可以 为至少约100μg/mL,例如至少约200μg/mL、至少约300μg/mL、至少 约400μg/mL、至少约500μg/mL、至少约600μg/mL、至少约700μg/mL、 至少约800μg/mL、至少约900μg/mL或至少约1000μg/mL。或者,治 疗有效量可以为至少约1mg/mL,例如至少约2mg/mL、至少约3mg/mL、 至少约4mg/mL、至少约5mg/mL。或者,治疗有效量可以小于约5mg/mL, 例如小于约4mg/mL、小于约3mg/mL、小于约2mg/mL、小于约1mg/mL。 可以每天给药治疗有效量,持续例如1天至14天的给药时段。治疗有效 量可以是可被分开并在一天内分批给药(例如每天两次)的总的日剂量。
用于哺乳动物个体的抗血管生成治疗、或用于治疗或预防微血管通 透性过高病症、或用于调节VEGFxxx亚型的促血管生成促通透性性质、 或用于在不增加通透性的情况下支持上皮细胞存活、或用于降低上皮滤 过膜窗孔的性质(例如数密度和/或尺寸)、或用于治疗或预防神经性病症 和神经变性病症、或用作体内或体外神经保护剂或神经再生剂、或用于 治疗或预防VEGFR2-介导的非炎性疼痛、或用于降低雌性哺乳动物出现 先兆子痫或与其相关的并发症的风险、或降低雌性哺乳动物的胎儿患有 与母体先兆子痫相关的胎儿或新生儿缺陷的风险的式(I)的化合物的治疗 有效量可以根据要治疗的个体的体重来计算,并且可以为至少约20 mg/kg,例如至少约30mg/kg、至少约40mg/kg、至少约50mg/kg、至少约60mg/kg、至少约70mg/kg、至少约80mg/kg、至少约90mg/kg、 至少约100mg/kg。或者,治疗有效量可以小于约100mg/kg,例如小于 约90mg/kg、小于约80mg/kg、小于约70mg/kg、小于约60mg/kg、小 于约50mg/kg、小于约40mg/kg、小于约30mg/kg、或小于约20mg/kg, 例如小于约10mg/kg、小于约5mg/kg。
“治疗或预防”
本文所用的表述“治疗或预防”以及类似术语是指旨在去除或避免病 症或缓解其症状的健康护理的所有形式,包括预防性、治愈性和缓解性 护理,如根据普遍的医学和精神病学实践可得的任何测试所判断的。表 述“治疗或预防”包括具有实现特定结果的合理预期但通常不总如此进行 的干预。表述“治疗或预防”包括在减缓或制止病症进展方面成功的干预。
某些神经学和精神病学病症被认为是“谱群(spectrum)”病症,其中个 体可能表现出一系列可能的症状中的一些或全部,或可能仅表现出病症 的轻微形式。此外,许多神经学和精神病学病症是进行性的,以相对轻 微的异常症状开始并进展至更严重的异常症状。本发明包括无论哪种类 型和阶段的所有神经学和精神病学病况的治疗和预防。
“易感性”
本文所用的表述“易感性”以及类似术语特别是指高于正常的出现医 学或精神病学病症或人格改变的风险的个体,如使用所述个体或病症的 已知风险因子所评估的。此类个体可以例如分类为具有出现一种或多种 特定病症或人格改变的实质风险,达到会被开处方药和/或会对该个体进 行特殊的饮食、生活方式或类似建议的程度。
“非治疗性方法”
本文所用的表述“非治疗性方法”特别是指对在神经或心理方面处于 正常范围内的个体进行的干预,以正常化或者增强或改善神经或心理类 型的功能。可以适当地非治疗性处理的神经系统功能可以包括例如认知 (包括思考、推理、记忆、回忆、想象和学习)、集中和注意,特别是趋 向病症级别的较轻微端(milder end of the scale of conditions)的,以及轻微 的异常行为或人格特质。可以适当地非治疗性处理的心理学功能可包括 例如人类行为、情绪、人格和社会功能,例如悲痛、焦虑、抑郁、情绪 化、阴郁、青春期情绪、中断睡眠模式、非常逼真的梦(vivid dream)、梦 魇和梦游。
在可诊断的神经学和精神病学病症与正常范围内的(不可诊断的)神 经学和精神病学功能之间存在界线。因此,除了上文给出的可根据本发 明的非治疗性方法处理的神经学和精神病学功能的实例之外,由于相关 行为或思想对个体不产生显著的痛苦或不破坏他或她的日常机能而不可 诊断的神经学和精神病学病症的轻微形式也被认为是根据本发明可非治 疗性处理的状况。
“正常化”
本文所用的表述“正常化”及类似术语特别是指趋向特征为一般正常 神经学或精神病学健康的情况的生理调节,无论是否实际达到了表征为 正常的情况。
哺乳动物
除了用于人类治疗,本发明还可用于一系列哺乳动物。此类哺乳动 物包括例如在动物园中的非人灵长目动物(例如类人猿、猴和狐猴),伴 侣动物如猫或狗,役用和竞技动物如狗、马和矮种马,农畜如猪、绵羊、 山羊、鹿、公牛和牛,以及实验室动物如啮齿目动物(例如、兔、大鼠、 小鼠、仓鼠、沙鼠或豚鼠)。
当要治疗的病症或功能为人类所独有时,则会理解要治疗的哺乳动 物是人类。同样分别适用于任何其他哺乳动物纲物种,条件是要治疗的 病症或功能为该物种所独有。
附图简述
现仅通过例示方式并参考附图来描述本发明的实施方案,其中:
图1示出式(I)的化合物12至14(分别称为SPHINX31、SPHINX32 和SPHINX33)针对SRPK1的活性;
图2示出SPHINX31相对于参考化合物SPHINX和SPHINX7在 SRPK1脱阻抑(DDS)细胞中对SRSF1磷酸化的作用;
图3示出SPHINX31相对于参考化合物SPHINX和SPHINX7在DDS 细胞中的剂量响应曲线;
图4A和4B示出SPHINX31在激光诱导的小鼠CNV模型中相对于 参考化合物SRPIN340和SPHINX7的作用;
图4C示出SPHINX31在激光诱导的小鼠CNV模型中的剂量响应曲 线;
图4D示出荧光素血管造影术的照片,其显示在使用SPHINX31或 参照化合物SPHINX7治疗之后在激光诱导的小鼠CNV模型中的典型的 病变尺寸;
图5示出SPHINX31的hERG抑制曲线;
图7示出使用差示扫描荧光测定法计算的等效结合亲和性;
图8示出本发明的化合物的盐酸盐在体外以盐剂量依赖性方式抑制 SRPK1活性,并且与未缀合的SPHINX化合物一样有效;
图9示出SPHINX31在PC-3细胞中也抑制SRSF1磷酸化(以1μM SPHINX31);
图10A和10B示出SPHINX31在PC-3癌细胞(图10a)和 MDA-MB-231癌细胞(图10b)中阻断SRSF1的核定位;
图11示出SPHINX化合物以剂量依赖方式增加抗血管生成 VEGF165b在Denys Drash(DDS)足细胞和正常足细胞中的表达;
图12示出SPHINX化合物增加抗血管生成VEGF165b在MCF7乳腺 癌细胞(左手边图表)和MDA-MB-231乳腺癌细胞(右手边图表)中的表达;
图13示出SPHINX化合物以剂量依赖方式增加抗血管生成 VEGF165b在RPE细胞中的表达;
图14A示出用于测试本发明的化合物是否能够渗透穿过巩膜的渗透 室。帕唑帕尼用作对照;图14B示出在兔眼组织中于0小时、4小时或 24小时之后在下室(“玻璃体”)中的化合物浓度;图14C示出在4小时之 后的视网膜浓度,其为在兔眼组织中施用的浓度的百分比形式;图14D 示出在24小时之后在巩膜组织中的化合物浓度,其为在猪眼组织中施用 的浓度的百分比形式;图14E示出在24小时之后在RPE/脉络膜组织中 的化合物浓度,其为在猪眼组织中施用的浓度的百分比形式;图14F示 出在24小时之后在视网膜组织中的化合物浓度,其为在猪眼组织中施用 的浓度的百分比形式;图14G示出在24小时之后在下室(“玻璃体”)中的 化合物浓度,其为在猪眼组织中施用的浓度的百分比形式;
图15示出在添加SPHINX31之后24小时在小鼠的视网膜中的化合 物的大量蓄积;
图16示出在体内兔研究中,SPHINX31相对于帕唑帕尼的更大的视 网膜渗透;
图17示出SPHINX31结合至黑色素显著低于帕唑帕尼结合至黑色 素;
图18示出在人血浆中化合物相对于溴丙胺太林的稳定性;
图19示出SPHINX31及其代谢物SPHINX46在爱姆斯试验(Ames test)中均不诱导基因毒性;
图20示出在使用对照或SPHINX31以2μg/ml通过局部滴眼剂给药 进行治疗之后24小时采集的小鼠中的Ganzfeld ERG记录;
图21示出在使用对照或SPHINX31以2μg/ml通过局部滴眼剂给药 进行治疗之后24小时采集的小鼠中的Ganzfeld ERG记录;
图22A示出SPHINX化合物对通过可变剪接而表达基因的RPE细 胞(其不连接于SRPK1)的作用;图22B示出SPHINX化合物对通过可变 剪接而表达基因的RPE细胞(其连接于SRPK1)的作用;以及
图23示出SPHINX化合物对MKNK2(通过SRPK1依赖性可变剪接 的RPE表达的基因)的作用。图23A示出MKNK2基因的可变剪接;以 及图23B和23C示出SPHINX对这种可变剪接的作用。
方法
合成方案
在下文路线1中示出化合物的一般合成方法,并且在下文路线2中 示出化合物12(在本文还称为SPHINX31)的示例性合成。这些化合物可 以以多种途径合成,但这种则是最短且最有效的。用于合成本文描述的 其他化合物的这种方案的变型也在本领域技术人员做此事的范围内。
路线1:一般合成
路线2:化合物12(SPHINX31)的合成途径
SPHINX31实验
4-(吡啶-2-基甲基)哌嗪-1-甲酸叔丁酯(3)
在室温下,将2-(氯甲基)吡啶盐酸盐(2)(1.97g,10.58mmol)以固体 形式一次性加入1-Boc-哌嗪(1)(2.24g,13.67mmol)和碳酸钾(4.98g, 36.02mmol)在无水DMF(12mL)中的悬浮液中。将悬浮液在室温搅拌16 小时,然后倾倒于碳酸氢钠饱和水溶液。将混合物用乙酸乙酯(×3)萃取。 将有机提取物合并,并且用水和盐水清洗,然后干燥(Na2SO4)。在减压下去除溶剂,并且通过快速色谱法在失活硅胶上(用60%乙酸乙酯/正己 烷洗脱)纯化粗产物,以得到呈无色胶形式的产物(3)(2.98g,98%),并 且所有分析材料与文献(E.Carceller,M.Merlos,M.Giral,C.Almansa,J. Bartroli,J.Garcia-Rafanell,J.Forn;J.Med.Chem.,1993,36,2984–2997)中 报道的相匹配。1H NMR(300MHz;CDCl3)δ1.44(s,9H),2.42–2.45(m, 4H),3.43–3.46(m,4H),3.65(s,2H),7.14–7.18(m,1H),7.38(d,J=7.8 Hz,1H),7.61–7.67(m,1H),8.55–8.57(m,1H)。
1-(吡啶-2-基甲基)哌嗪(4)
在0℃(冰)下,将三氟乙酸(21.5mL,280.96mmol)滴加到Boc-哌嗪 (3)(2.98g,10.76mmol)在二氯甲烷(21.5mL)中的溶液中。将溶液在0℃ 搅拌10分钟,然后移除冰浴,并且将溶液在室温搅拌4小时。将溶液用 碳酸氢钠饱和水溶液中和至pH 9。将二氯甲烷层去除,并且将剩余的水 溶液用二氯甲烷(×2)萃取。将有机提取物合并,并且用碳酸氢钠饱和水 溶液、水和盐水清洗,然后干燥(Na2SO4)。在减压下去除溶剂以得到呈 浅黄色油形式的产物(4)(1.91g,99%),其具有足够的纯度以用于下一步, 并且所有分析数据与文献(E.Carceller,M.Merlos,M.Giral,C.Almansa,J. Bartroli,J.Garcia-Rafanell,J.FornJ.Med.Chem.,1993,36,2984–2997)中 报道的相匹配。1H NMR(300MHz;CDCl3)δ1.95(s,1H),2.44–2.47(m, 4H),2.88–2.91(m,4H),3.62(s,2H),7.13(dd,J=7.6and 1.2Hz,1H), 7.38(d,J=7.8Hz,1H),7.59–7.65(m,1H),8.52–8.55(m,1H)。
1-(2-硝基-4-(三氟甲基)苯基)-4-(吡啶-2-基甲基)哌嗪(5)
将哌嗪(4)(7.01g,39.56mmol)、4-氯-3-硝基三氟甲苯(6)(6.1mL, 41.51mmol)和固体碳酸氢钠(8.31g,98.91mmo)在无水THF(39.5mL)中 的溶液加热回流16小时。使溶液冷却至室温,并且通过硅藻土(Celite) 短垫过滤反应溶液,用乙酸乙酯洗脱。在减压下去除溶剂以得到呈橙色 胶形式的产物(5)(10.72g,74%),其具有足够的纯度以用于下一步。偶尔当粗产物不纯时,可以通过快速色谱法在失活硅胶上(用2%甲醇/乙酸 乙酯洗脱)纯化,以得到产物。1H NMR(500MHz;CDCl3)δ2.67–2.69(m, 4H),3.20–3.22(m,4H),3.73(s,2H),7.15(d,J=8.8Hz,1H),7.17–7.20 (m,1H),7.39(d,J=7.8Hz,1H),7.63–7.68(m,2H),8.03(br s,1H),8.59 (d,J=4.8Hz,1H);13C NMR(75MHz;CDCl3)δ50.9,52.9,64.5,120.6,122.1(q,JC-F=34.7Hz),122.4,123.4(q,JC-F=270.8Hz),123.5,124.3(q, JC-F=3.9Hz),130.2(q,JC-F=3.5Hz),136.6,140.6,148.1,149.6,158.0;IR (NaCl,纯的)1625cm-1;HRMS(ESI-MS):m/z C17H17F3N4O2Na[M+Na]+的 理论值389.1201,实测值389.1185。
2-(4-(吡啶-2-基甲基)哌嗪-1-基)-5-(三氟甲基)苯胺(7)
在室温下,将水合肼(35.5mL,731.84mmol)滴加到哌嗪(5)(10.72g, 29.25mmol)、六水合氯化铁(III)(1.59g,5.87mmol)和炭(1.17g)在甲醇 (290mL)中的溶液中。将溶液在回流下加热2小时。使溶液冷却至室温, 然后通过硅藻土短垫过滤,用乙酸乙酯洗脱。在减压下去除溶剂。将残 余物用水稀释并且用乙酸乙酯(×3)萃取。将有机萃取物合并,并且干燥 (Na2SO4)。在减压下去除溶剂以得到呈白色固体形式的产物7(9.35g, 95%),其具有足够的纯度以用于下一步。Mp 126–127℃;1H NMR(300 MHz;CDCl3)δ2.67–2.69(m,4H),2.97–3.00(m,4H),3.74(s,2H),4.07 (br s,2H),6.92–7.04(m,3H),7.16–7.20(m,1H),7.44(d,J=7.8Hz,1H), 7.64–7.70(m,1H),8.57–8.60(m,1H);13C NMR(75MHz;CDCl3)δ50.7, 54.0,64.8,111.6(q,J=3.9Hz),115.5(q,J=4.1Hz),119.7,122.3,123.4, 124.6(q,JC-F=271.2Hz),126.5(q,JC-F=32.2Hz),136.6,141.7,142.2, 149.5,158.5;IR(NaCl,纯的)3187,3283cm-1;HRMS(ESI-MS):m/z C17H20F3N4[M+Na]+的理论值337.1640,实测值337.1594。
5-溴呋喃-2-甲酸甲酯(8)
在室温下,将浓硫酸(0.56mL,10.51mmol)滴加到甲酸(9)(20.0g, 0.105mol)在甲醇(1050mL)中的溶液中。将溶液在回流下加热17小时。 使溶液冷却至室温,并且在减压下去除甲醇。将残余物用水稀释,并且 使用固体碳酸氢钠将溶液的pH调节至pH 9。将混合物用乙酸乙酯(×3) 萃取。将有机提取物合并,并且用水和盐水清洗,然后干燥(Na2SO4)。 在减压下去除溶剂以得到呈白色固体形式的产物8(19.47g,91%),其具 有足够的纯度以用于下一步,并且所有分析数据与文献(Y.Zhu,H.Yan, L.Lu,D.Liu,G.Rong,J.MaoJ.Org.Chem.,2013,78,9898–9905)中报道 的相匹配。Mp 67–68℃;1H NMR(300MHz;CDCl3)δ3.90(s,3H),6.46 (d,J=3.5Hz,1H),7.13(d,J=3.5Hz,1H)。
5-(吡啶-4-基)呋喃-2-甲酸甲酯(10)
用酯8(2.17g,10.58mmol)、4-吡啶基硼酸(11)(1.00g,8.14mmol)、 PdCl2(PPh3)2(0.29g,0.41mmol)、2M碳酸氢钠水溶液(10.2mL,22.4 mmol)和1,2-二甲氧基乙烷(81mL)填充烧瓶。将烧瓶进行冷冻-泵-解冻循 环(freeze-pump-thawed)(×3),用氩气回填,并且在回流下加热17小时。 将溶液冷却至室温,并且在减压下去除DME。使用2M盐酸水溶液将 残余物的pH调节至pH 1。将溶液用二氯甲烷(×3)萃取。将二氯甲烷萃 取物丢弃。将剩余的水溶液用固体碳酸氢钠中和至pH 9,并且用乙酸乙 酯(×3)萃取。将各有机提取物合并,并且用水和盐水清洗,然后干燥 (Na2SO4)。在减压下去除溶剂以得到呈白色固体形式的产物10(1.41g, 85%),其具有足够的纯度以用于下一步,并且所有分析数据与文献(H.Y. Fu,H.Doucet,Eur.J.Org.Chem.,2011,7163–7173)中报道的相匹配。Mp 95–97℃;1H NMR(400MHz;CDCl3)δ3.94(s,3H),6.95(d,J=3.6Hz, 1H),7.27(d,J=3.5Hz,1H),7.62–7.64(m,2H),8.66–8.68(m,2H)。
N-(2-(4-(吡啶-2-基甲基)哌嗪-1-基)-5-三氟甲基)苯基)-5-(吡啶-4-基) 呋喃-2-甲酰胺(SPHINX31)(12)
在室温下,将三甲基铝在甲苯中的2M溶液(0.84mL,1.68mmol)滴 加到苯胺7(0.189g,0.56mmol)在二氯甲烷(1.1mL)中的溶液中。将溶液 在室温搅拌1小时,此后,在室温下,滴加酯10(0.114g,0.56mmol)在 二氯甲烷(0.6mL)中的溶液。将反应溶液在室温再搅拌16小时。在室温 下,滴加罗谢尔(Rochelle)盐水溶液以停止反应,并且使溶液在室温下再 搅拌15分钟。将混合物用碳酸氢铵饱和水溶液稀释,并且用二氯甲烷(× 3)萃取。将有机提取物合并,并且用水和盐水清洗,然后干燥(Na2SO4)。 在减压下去除溶剂以得到呈白色固体形式的产物(0.19g,67%),其具有 足够的纯度以用于下一步。偶尔当粗产物不纯时,可以通过快速色谱法 在失活硅胶上(用5%甲醇/乙酸乙酯洗脱)纯化,以得到产物。Mp157– 159℃;1H NMR(300MHz,CDCl3)δ2.85(br s,4H),3.04(br s,4H),3.78 (s,2H),7.06(d,J=3.7Hz,1H),7.20(m,1H),7.31-7.41(m,4H),7.65-7.72 (m,3H),8.60(d,J=4.5Hz,1H),8.80-8.87(m,3H),9.65(br s,1H);13C NMR(100MHz,CDCl3)δ52.2,54.5,65.0,111.3,116.7(q,JC-F=4.5Hz), 117.7,118.5,121.1,121.3(q,JC-F=4.5Hz),122.5,123.5,124.1(q,JC-F= 272Hz),128.0(q,JC-F=34Hz),133.5,136.7,148.6,149.7,150.8,153.2,155.7,157.9;HRMS(ESI):C27H24F3N5O2(MH+)的理论值508.19603,实 测值508.19315;IR:(纯的)1669,3332cm-1
所有化合物的分析数据在表4中提供。
体外激酶测定
通过Kinase-Glo测定(Promega;Koresawa and Okabe,2004)来筛选候 选化合物,其结果示于表1和表2中。向10μM SRSF1 RS肽 (NH2-RSPSYGRSRSRSRSRSRSRSRSNSRSRSY-OH(SEQ ID NO:1))和 0.1μg纯化SRPK1激酶中添加包含9.6mM MOPS pH7和0.2nM EDTA pH8的反应缓冲液。将候选化合物从10μM系列稀释至0.5nM,并添加 到反应混合物中,还增添不含SRPK1激酶和不含化合物的孔作为对照。 所有孔包含1%DMSO。添加1微摩尔ATP,孔减去ATP用作背景对照。 然后,将板在30℃孵育10分钟。向每个孔添加等体积的Kinase-Glo(Promega,25μl),并使用Fluostar Optima(BMG Labtech)读取板的荧光。
SRSF1磷酸化的抑制
使用递增浓度的SPHINX31或者参考化合物SPHINX7或SPHINX 来处理Denys Drash足细胞,其也称为DDS细胞(DDS=Denys Drash综 合征),具有WT1突变而不能抑制SRPK1表达。
使用全细胞溶解产物(细胞核和细胞质)蛋白提取和核蛋白提取物。 然后,使用小鼠抗-SRPK1(抗-SRPK1;BD 611072;1:1000)、兔抗 -panVEGF(Santa Cruz A20 sc-152;1:500)、小鼠抗-VEGFxxxb(MAB3045; R&D;1:500)、山羊抗-SRSF1(SC10255;1:500)、小鼠抗-SRSF1(AK96) (Santa Cruz SC-33562)或兔抗-GAPDH(Sigma G9545,1:2000)来对提取物进行免疫印迹法。对于免疫沉淀磷酸-SRSF1研究,将细胞溶解产物与小 鼠抗-SRSF1(SantaCruz SC-33562)或抗-Pan-磷酸-SR抗体(Santa Cruz, SC-13509)和蛋白G免疫磁珠(Invitrogen)一起孵育。为了检测磷酸化的 SRSF1,使用抗-SRSF1或抗-Pan-磷酸-SR抗体(1:500)对洗脱液进行免疫 印迹法。
在10μM的DMSO(载剂)、化合物12(SPHINX31)或参考化合物的 存在下,用10nM EGF处理PC3前列腺癌细胞1小时。将细胞溶解,并 如上所述进行免疫印迹法。
激光病变诱导方案
通过腹膜内注射50mg/kg氯胺酮和0.5mg/kg美托咪啶的混合物来 麻醉6至8周龄的C57/B6小鼠(B&K Laboratories)和成年Norway-Brown 大鼠(Harlan Laboratories)。用2.5%盐酸去氧肾上腺素和1%托吡卡胺使 瞳孔扩大。使用氪红光激光器(小鼠:250mW,0.01s,75μm,大鼠:200mW, 0.01s,75μm,IRIS Medical 810nm Oculight Slx激光器)在每只眼中的视网 膜血管之间以距离为1-2视盘直径的视乳头周围分布形式递送四个光凝 固病变。在研究中仅包括在治疗时具有视网膜下肿泡的激光病变。在激 光光凝固之后即刻使动物的双眼接受玻璃体内注射(第0天和第7天), 或者在一只眼中每天两次给药参考化合物SRPIN340、SPHINX7或 SPHINX31的局部滴眼剂并在另一只眼中给药对照载剂。在第4天或第 14天拣选动物,并且对于视网膜解剖和蛋白质提取而言,不固定眼部, 或对于同工凝集素B4而言,固定眼部并摘除以及进行脉络膜染色,并 进行检查,或通过荧光素血管造影术来成像。
在局部给药期间,测试化合物制成基于凝胶的药物递送载剂,以辅 助药物暴露于眼部的持续时间(Doukas等人,2008),0.05%DMSO用于 溶解化合物,然后将其添加到对照载剂中。
hERG抑制
使用IonWorks膜片钳电生理学测试化合物对人乙醚a go-go相关基 因(hERG)K+通道的抑制。使用3-倍连续稀释(Essen Biosciences)生成8- 点浓度响应曲线。
如Federov等人(2011)所述的那样进行差示扫描荧光测定。
如Varey等人(2008)和Carter等人(2014)所述的那样进行亚型特异性 ELISA。
在等张测定缓冲液(pH 7.4)中使用改良Ussing室组件测量巩膜渗透 性。将从兔或猪切除的眼组织放置在室内,以使巩膜侧朝向供体室并且 使视网膜侧朝向受体室。将室填充等体积的测定缓冲液,所述测定缓冲 液有(供体侧)或没有(受体侧)1μg/ml化合物。在4或24小时之后,将组 织从室移除,并且对受体侧(“玻璃体”)采样。将组织切成巩膜、脉络膜 /RPE和视网膜,并均质化。添加示踪物(SPHINX7),并且通过Gammons 等人(2013)所述的乙腈提取来提取组织。然后,通过Gammons等人(2013) 所述的质谱法分析化合物。
兔药代动力学研究
通过以200μl滴眼剂形式在一个眼中50μg SPHINX31以及50μg 帕唑帕尼,对兔每天三次治疗,持续6天。在最后一次滴眼之后12小时, 将兔处死,采集血液和肝脏,并且从脉络膜/巩膜切除视网膜,进行切口, 铺平,并且拍照。将两个眼腔室切成17个不同的区域。对所有样品称重。 通过反相提取从上述的视网膜和脉络膜/巩膜样品以及肝脏和血浆提取化合物,并且通过质谱法测定在眼的不同区域中、在血液中及在肝脏中 的量。对每一样品,计算每克组织的SPHINX31和帕唑帕尼的量,并求 平均值。
小鼠视网膜电图毒性试验
通过每个眼睛2μg SPHINX31(滴眼剂形式)对小鼠进行治疗,持续6 天,并且使用Micron IV Ganzfield ERG系统,如制造商说明书所推荐的 那样进行ERG。
黑色素结合测定
在37℃,将10μg/ml SPHINX31或帕唑帕尼在10μg/ml黑色素中孵 育1小时。然后,将溶液以15kg旋转15分钟,并且收集上清液,并在 乙腈中提取化合物。然后,对其进行质谱法以进行定量。
结果
新SRPK1抑制剂的鉴定
为了鉴定新的SRPK1抑制剂,在体外激酶测定中筛选多种抑制剂 (Promega;Koresawa and Okabe,2004)。先前鉴定的SRPK抑制剂SPHINX 和SPHINX7用作阳性对照,以用于鉴定新候选化合物。激酶测定显示 表1中的化合物12至14(分别称为SPHINX31-33)与先前报道的化合物 相比在功效方面具有10-20倍的增加,产生3.2-17nM的IC50值(图1)。
用由表2中所示的结构产生的新化合物进行用于鉴定新化合物的机 制和效力的构效关系研究。由这些化合物实现额外的活性,对于化合物 61下降至亚nM效力。使用底物DiscoverX结合亲和性测定的SPHINX31 针对所有已知激酶的蛋白激酶组筛选证实,仅有的显示结合的其他激酶 是密切相关的Clk1和Clk4,其在1μM下显示27%和14%的结合(图6)。使用差示扫描荧光测定,我们确定SPHINX31对SRPK1(ΔTm 12.8℃) 的结合亲和性是对SRPK2((ΔTm 6.7℃)或Clk1(ΔTm 6.7℃)的结合亲和 性的44倍高,并且是对Clk4(ΔTm5.7℃)结合亲和性的88倍高。对Clk2、 Clk3、PIM1、PIM2、DYRK1、DYRK2、PRPF4B和SRPK3的结合活性 是忽略不计的(ΔTm<3℃)(图7)。化合物(SPHINX31、32和33)的盐形式 也是有效的抑制剂,并且更加易溶于水(图8)。
为了确定这些化合物是否能够在细胞中抑制SRPK1活性,使用递增 浓度的化合物12(称为SPHINX31)处理具有组成性活性SRPK1(由 SRPK1阻遏蛋白中的突变引发)的DenysDrash足细胞。图2显示递增量 的SPHINX31增加对SRSF1磷酸化的抑制,并且图3示出通过用SPHINX31处理SRSF1磷酸化被剂量依赖性地抑制。
此情形在先前显示对SRPK1抑制敏感的前列腺癌细胞(PC3)中得到 重复,并且SRSF1磷酸化再次被抑制(图9)。还通过在PC3前列腺癌细 胞和MDA-MB231中的免疫荧光来测定对SRSF1定位(已知是SRPK1磷 酸化的结果)的作用(图10a(PC3细胞)和10b MDA-MB231))。SPHINX31 处理抑制在两种细胞类型中的细胞定位。
还研究了对下游剪接活性的影响,并且数据表明化合物在Denys Drash足细胞和正常足细胞中以剂量依赖方式将剪接从VEGF-A165a转换 成VEGF-A165b(图11)。使用亚型特异性ELISA,在乳腺癌细胞(MCF7 和MDA-MB231)中表明情形同样如此(图12)。在已被表明是血管生成性 眼疾病中VEGF的主要来源的RPE细胞(图13)中,SPHINX31显示出在 VEGF165b中的剂量依赖性增加,并且EC50为20nM(图13)。
为了确定SPHINX31是否能够穿过更大动物的巩膜,将兔巩膜夹在 两个室之间,并且向巩膜添加SPHINX31或帕唑帕尼(VEGFR2 TKI),并 且将盐水添加至下室且将化合物添加至上室。在0、4或24小时之后, 将来自下室(玻璃体)和视网膜组织的流体分离,并且将化合物通过乙腈 提取和HPLC纯化。图14示出,在4小时,SPHINX31能够以显著的浓 度在视网膜和玻璃体中被检测到,而帕唑帕尼则不能。在24小时,二者 在玻璃体中均被检测到,但SPHINX31多于帕唑帕尼。我们还确定了 SPHINX31是否能够穿过猪眼。尽管帕唑帕尼在巩膜中和在RPE/脉络膜 层中蓄积,但其没有渗透视网膜。相反,SPHINX31穿入视网膜和玻璃体。
我们还研究了在使用5μg/ml SPHINX31的10μl滴眼剂处理之后, 式(I)的化合物在小鼠的多种组织中的蓄积。在30分钟、1小时、4小时、 8小时或24小时后处死小鼠。将眼睛移除,并且将眼组织切开。对样品 进行提取,并且添加对照化学示踪物以修正提取效率,并且对样品进行 质谱法以测定每mg组织的化合物的量。图15A示出SPHINX31在眼的 不同组织中的蓄积。图15B示出SPHINX31在其他组织中的蓄积。这些 结果表明在添加SPHINX31之后24小时,化合物在视网膜中的显著蓄 积。
为了确定SPHINX31是否能够到达具有大眼睛的动物的视网膜,将 兔每天暴露于150μg SPHINX31或帕唑帕尼(图16)。在6天之后,将动 物处死并且采集眼睛。然后,测定来自眼睛的后半部分的巩膜和视网膜 的单独的切片的帕唑帕尼或SPHINX31。对于帕唑帕尼或SPHINX31二 者,均可见视网膜渗透,但SPHINX31的浓度是化合物的IC50的10倍, 而对于帕唑帕尼,浓度则与IC50相近。
我们先前已经表明,滴眼剂形式的SRPIN340(IC50 1μM)或SPHINX (IC50 0.44μM)对SRPK1抑制在脉络膜新生血管化的小鼠模型中是抗血管 生成的,并且在10μg/ml有最大作用,因为这些化合物是相对亲脂性的 并且具有进入眼中的高渗透。因此,我们在相同模型中测试了滴眼剂形 式的SPHINX31的作用。SPHINX31发挥出对脉络膜新生血管化的剂量依赖性抑制,并且在2μg/ml有更大的功效,并且IC50为0.24μg/ml(图 4)。
已经关注到化合物在眼中可以被黑色素隔离。因此,我们测量了化 合物的黑色素结合,并且确定SPHINX31与黑色素的结合显著小于帕唑 帕尼与黑色素的结合(图17)。我们还测试了当暴露于人肝脏微粒体时这 些化合物的半衰期。这表明化合物的半衰期如下文表3中所示。
化合物编号 | 半衰期(分钟) |
12 | 61.50 |
20 | 17.00 |
21 | 62.50 |
维拉帕米 | 11.75 |
表3
然而,化合物在血浆中是稳定的(图18),表明它们更有可能会被肝 脏摄取并在此处分解。
为了测试式(I)的化合物是否对于向患者给药是安全的,我们开始这 些化合物的体外基础安全测试。对SPHINX7、SPHINX和SPHINX31的 细胞毒性的剂量依赖性揭示了SPHINX31没有作用,而参考化合物 SPHINX7在大于10μM的剂量下是有毒性的。
我们还使用膜片钳电生理学测试这些化合物是否能够抑制人乙醚a go-go相关基因(hERG)钾通道。通常筛选新药物候选者抑制‘hERG’钾通 道的能力,这归因于在hERG通道的药理学阻断与药物诱导的持久QT 综合征和尖端扭转性室性心律失常之间的确立的关联(Hancox等人, 2008;Gintant,2008)。SPHINX不抑制hERG,如先前已经描述的 (Gammons等人,2013)。
在局部施用于眼的过程中测试的所有式(I)的化合物的血浆水平都极 低(低于1pM的检测水平),因此在作为滴眼剂的这些化合物的体内使 用过程中不可能出现在心脏中的实质性hERG通道阻断。已知的化合物 SRPIN340和SPHINX不抑制hERG这一发现表明,可能具有对SRPK1 的显著药理学作用而没有实质的hERG活性(Gammons等人,2013)。因此, 我们测试了SPHINX31,其抑制hERG且IC50为0.3μM,是其对SRPK1 的IC50值(3.2nM)的100倍(Figure 5)。
我们还在基因毒性的爱姆斯试验中测试了SPHINX31及其代谢物(称 为SPHINX46,在图19中),并且两种化合物未诱导基因毒性(图19)。
为了确定是否存在对神经功能的毒性作用的任何指征,对正常小鼠 给药2μg/mlSPHINX31,并且在Phoenix Ganzfeld ERG系统上测定视网膜 电图。在用递增强度的绿光(图20A、20C、20E、20G)(以活化M-视锥细 胞和视杆细胞)或UV光(图20B、20D、20F、20H)(以活化S-视锥细胞和 视杆细胞)进行刺激之后,在适应黑暗的动物中采集暗视ERG记录。在用绿光(图20A)和UV光(图20B)以3.756cd.s.m2进行刺激之后,随时间的平 均ERG振幅。在不同强度的绿光(图20C、20E)或UV光(图20D、20F)下的 ERG振幅呈现为A波(图20C、20D)和B波(图20E、20F)。A波:B波之比 不受SPHINX31处理的影响(图20G、图20H)。在ERG记录之后,将眼睛 摘除、切开、均质化并添加SPHINX7以测量提取效率,然后通过质谱法 进行分析(图20I、图20J)。在视网膜(当归一化成提取效率时,为施用的 滴眼剂的剂量的0.165%)和脉络膜(施用的剂量的0.0175%)中检测到 SPHINX31。示出在对照眼中的SPHINX31水平,以用于作为背景水平进 行比较。在10分钟光适应以及使用强度为30cd.m.s2的白光进行连续背景 刺激之后,采集明视ERG记录以从视杆细胞响应分离出视锥细胞响应。 在120和1920cd.s.m2绿光(以活化M-视锥细胞和视杆细胞)、UV光(以活化 S-视锥细胞和视杆细胞)或白光下,ERG振幅为A波(A)和B波(B)。没有见 到对暗视或明视活性的影响,表明没有见到可视的功能毒性作用(图20、 21)。
还通过检查在RPE细胞中表达的大量基因的可变剪接来筛选脱靶剪 接作用,并且没有见到一般剪接的变化(图22),然而VEGFR剪接稍微改 变。在这些细胞系中改变了已知的SRPK1靶标MKNK2(图23)。
在该研究中提供的数据表明用于降低与AMD相关的促血管生成性 VEGF介导的CNV的新小分子量化合物抑制剂。此外,我们还表明本发 明的化合物渗透到大动物模型的眼的后部中,在小鼠中在局部给药之后 有效地降低CNV以降低肿瘤生长,并且基于迄今进行的试验是安全的。
表1:在SRPK1抑制测定中测试的式(I)的化合物的IC50数据
测试的额外的化合物在下文表2中提供:
表2:在SRPK1抑制测定中测试的式(1)的化合物的IC50数据
表4:合成的化合物的分析数据
参考文献
Bressler,S.,Bressler,N.M.,Clemons,T.,Ferris,F.L.,Milton,R.C., Klien,R.,Klien,B.and Age-Related Eye Dis Study,G.(2004)'Ocular risk factors fordeveloping neovascular AMD in the fellow eyes of patients with unilateralneovascular AMD',Investigative Ophthalmology&Visual Science, 45,U924-U924.
Ferris,F.L.,Fine,S.L.and Hyman,L.(1984)'Age-related maculardegeneration and blindness due to neovascular maculopathy',Archives ofOphthalmology,102(11),1640-1642.
Patz,A.,Fine,S.L.,Finkelstein,D.and Yassur,Y.(1977)'Diseases ofmacula-diagnosis and management of choroidal neovascularization',Transactions American Academy of Ophthalmology and Otolaryngology, 83(3),468-475.
Fine,S.L.,Berger,J.W.,Maguire,M.G.and Ho,A.C.(2000)'Drug therapy:Age-related macular degeneration',New England Journal of Medicine,342(7),483-492.
Campochiaro,P.A.,Nguyen,Q.D.,Shah,S.M.,Klein,M.L.,Holz,E., Frank,R.N.,Saperstein,D.A.,Gupta,A.,Stout,J.T.,Macko,J., DiBartolomeo,R.and Wei,L.L.(2006)'Adenoviral vector-delivered pigment epithelium-derived factor forneovascular age-related macular degeneration:Results of a phase I clinicaltrial',Human Gene Therapy,17(2), 167-176.
Dvorak,H.F.,Brown,L.F.,Detmar,M.and Dvorak,A.M.(1995) 'Vascular-permeability factor vascular endothelial growth-factor, microvascularhyperpermeability,and angiogenesis',American Journal of Pathology,146(5),1029-1039.
D’Amore,P.A.,Shima,D.T.,Adamis,A.P.,Yeo,K.T.,Yeo,T.K., Allende,R.andFolkman,J.(1994)'differential regulation of VEGF/VPF and basic FGF byhypoxia',Faseb Journal,8(4),A116-A116.
Spilsbury,K.,Garrett,K.L.,Shen,W.Y.,Constable,I.J.and Rakoczy, P.E.(2000)'Overexpression of vascular endothelial growth factor(VEGF) in theretinal pigment epithelium leads to the development of choroidalneovascularization',American Journal of Pathology,157(1),135-144.
Anderson,D.H.,Mullins,R.F.,Hageman,G.S.and Johnson,L.V. (2002)'Perspective-A role for local inflammation in the formation of drusen in theaging eye',American Journal of Ophthalmology,134(3), 411-431.
Das,A.,Fanslow,W.,Cerretti,D.,Warren,E.,Talarico,N.and McGuire,P.(2003)'Angiopoietin/Tek interactions regulate MMP-9 expression and retinalneovascularization',Laboratory Investigation,83(11), 1637-1645.
Leung,D.W.,Cachianes,G.,Kuang,W.J.,Goeddel,D.V.and Ferrara, N.(1989)'Vascular endothelial growth-factor is a secreted angiogenic mitogen',Science,246(4935),1306-1309.
Jingjing,L.,Xue,Y.,Agarwal,N.and Roque,R.S.(1999)'Human Muller cellsexpress VEGF183,a novel spliced variant of vascular endothelial growthfactor',Iovs,40(3),752-759.
Houck,K.A.,Ferrara,N.,Winer,J.,Cachianes,G.,Li,B.and Leung,D. W.(1991)'The vascular endothelial growth-factor family-identification of a 4thmolecular-species and characterization of alternative splicing of rna',Molecular Endocrinology,5(12),1806-1814.
Mineur,P.,Colige,A.C.,Deroanne,C.F.,Dubail,J.,Kesteloot,F., Habraken,Y.,Noel,A.,Voo,S.,Waltenberger,J.,Lapiere,C.M.,Nusgens,B. V.and Lambert,C.A.(2007)'Newly identified biologically active and proteolysis-resistant VEGF-Aisoform VEGF111 is induced by genotoxic agents',Journal of Cell Biology,179(6),1261-1273.
Tischer,E.,Gospodarowicz,D.,Mitchell,R.,Silva,M.,Schilling,J., Lau,K.,Crisp,T.,Fiddes,J.C.and Abraham,J.A.(1989)'Vascular endothelial growth-factor-a new member of the platelet-derived growth-factor gene family',Biochemical and Biophysical Research Communications,165(3),1198-1206.
Neufeld,G.,Cohen,T.,Gengrinovitch,S.and Poltorak,Z.(1999) 'Vascularendothelial growth factor(VEGF)and its receptors',Faseb Journal, 13(1),9-22.
Bates,D.O.,Cui,T.G.,Doughty,J.M.,Winkler,M.,Sugiono,M., Shields,J.D.,Peat,D.,Gillatt,D.and Harper,S.J.(2002)'VEGF(165)b,an inhibitory splicevariant of vascular endothelial growth factor,is down-regulated in renal cellcarcinoma',Cancer Research,62(14), 4123-4131.
Woolard,J.,Wang,W.Y.,Bevan,H.S.,Qiu,Y.,Morbidelli,L., Pritchard-Jones,R.O.,Cui,T.G.,Sugiono,M.,Waine,E.,Perrin,R.,Foster, R.,Digby-Bell,J.,Shields,J.D.,Whittles,C.E.,Mushens,R.E.,Gillatt,D. A.,Ziche,M.,Harper,S.J.andBates,D.O.(2004)'VEGF(165)b,an inhibitory vascular endothelial growth factorsplice variant:Mechanism of action,in vivo effect on angiogenesis andendogenous protein expression', Cancer Research,64(21),7822-7835.
Perrin,R.M.,Konopatskaya,O.,Qiu,Y.,Harper,S.,Bates,D.O.and Churchill,A.J.(2005)'Diabetic retinopathy is associated with a switch in splicing fromanti-to pro-angiogenic isoforms of vascular endothelial growth factor',Diabetologia,48(11),2422-2427.
Varey,A.H.R.,Rennel,E.S.,Qiu,Y.,Bevan,H.S.,Perrin,R.M., Raffy,S.,Dixon,A.R.,Paraskeva,C.,Zaccheo,O.,Hassan,A.B.,Harper,S. J.and Bates,D.O.(2008)'VEGF(165)b,an antiangiogenic VEGF-A isoform, binds and inhibitsbevacizumab treatment in experimental colorectal carcinoma:balance of pro-andantiangiogenic VEGF-A isoforms has implications for therapy',British Journalof Cancer,98(8),1366-1379.
Pritchard-Jones,R.O.,Dunn,D.B.A.,Qiu,Y.,Varey,A.H.R., Orlando,A.,Rigby,H.,Harper,S.J.and Bates,D.O.(2007)'Expression of VEGF(xxx)b,theinhibitory isoforms of VEGF,in malignant melanoma', British Journal ofCancer,97(2),223-230.
Hua,J.,Spee,C.,Kase,S.,Rennel,E.S.,Magnussen,A.L.,Qiu,Y., Varey,A.,Dhayade,S.,Churchill,A.J.,Harper,S.J.,Bates,D.O.and Hinton,D.R.(2010)'Recombinant Human VEGF(165)b Inhibits Experimental ChoroidalNeovascularization',Investigative Ophthalmology &Visual Science,51(8),4282-4288.
Magnussen,A.L.,Rennel,E.S.,Hua,J.,Bevan,H.S.,Long,N.B., Lehrling,C.,Gammons,M.,Floege,J.,Harper,S.J.,Agostini,H.T.,Bates, D.O.and Churchill,A.J.(2010)'VEGF-A(165)b Is Cytoprotective and Antiangiogenic in the Retina',Investigative Ophthalmology&Visual Science, 51(8),4273-4281.
Gragoudas,E.S.(2004)'VEGF inhibition study in ocularneovascularization-1(VISION-1):Efficacy results from phase II/III Macugen(TM)(Pegaptanib sodium)clinical trials',Iovs,45(Suppl.1), U924.
Rosenfeld,P.J.,Rich,R.M.and Lalwani,G.A.(2006)'Ranibizumab: Phase IIIclinical trial results',Ophthalmology clinics of North America, 19(3),361-72.
Brown,D.M.,Kaiser,P.K.,Michels,M.,Soubrane,G.,Heier,J.S., Kim,R.Y.,Sy,J.P.,Schneider,S.and Grp,A.S.(2006)'Ranibizumab versus verteporfin forneovascular age-related macular degeneration',New England Journal ofMedicine,355(14),1432-1444.
Brown,D.M.,Michels,M.,Kaiser,P.K.,Heier,J.S.,Sy,J.P.and Ianchulev,T.(2009)'Ranibizumab versus Verteporfin Photodynamic Therapy for NeovascularAge-Related Macular Degeneration:Two-Year Results of the ANCHOR Study',Ophthalmology,116(1),57-65.
Schmidt-Erfurth,U.,Eldem,B.,Guymer,R.,Korobelnik,J.-F., Schlingemann,R.O.,Axer-Siegel,R.,Wiedemann,P.,Simader,C., Gekkieva,M.,Weichselberger,A.andGrp,E.S.(2011)'Efficacy and Safety of Monthly versus Quarterly RanibizumabTreatment in Neovascular Age-related Macular Degeneration:The EXCITE Study',Ophthalmology, 118(5).
Good,T.J.and Kahook,M.Y.(2010)'The role of endothelin in thepathophysiology of glaucoma',Expert Opinion on Therapeutic Targets, 14(6),647-654.
Jager,R.D.,Aiello,L.P.,Patel,S.C.and Cunningham,E.T.(2004) 'Risks ofintravitreous injection:A comprehensive review',Retina-the Journal of Retinaland Vitreous Diseases,24(5),676-698.
Nowak,D.G.,Amin,E.M.,Rennel,E.S.,Hoareau-Aveilla,C., Gammons,M.,Damodoran,G.,Hagiwara,M.,Harper,S.J.,Woolard,J., Ladomery,M.R.and Bates,D.O.(2010)'Regulation of Vascular Endothelial Growth Factor(VEGF)Splicing fromPro-angiogenic to Anti-angiogenic Isoforms a novel therapeutic strategy forangiogenesis', Journal of Biological Chemistry,285(8),5532-5540.
Amin,E.M.,Oltean,S.,Hua,J.,Gammons,M.V.R., Hamdollah-Zadeh,M.,Welsh,G.I.,Cheung,M.-K.,Ni,L.,Kase,S.,Renne, E.S.,Symonds,K.E.,Nowak,D.G.,Royer-Pokora,B.,Saleem,M.A., Hagiwara,M.,Schumacher,V.A.,Harper,S.J.,Hinton,D.R.,Bates,D.O. and Ladomery,M.R.(2011)'WT1 Mutants Reveal SRPK1 to Be aDownstream Angiogenesis Target by Altering VEGF Splicing',Cancer Cell, 20(6),768-780.
Sanford,J.R.,Ellis,J.D.,Cazalla,D.and Caceres,J.F.(2005a) 'Reversiblephosphorylation differentially affects nuclear and cytoplasmic functons ofsplicing factor 2/alternative splicing factor',Proceedings of the NationalAcademy of Sciences of the United States of America,102(42), 15042-15047.
Nowak,D.G.,Woolard,J.,Amin,E.M.,Konopatskaya,O.,Saleem,M. A.,Churchill,A.J.,Ladomery,M.R.,Harper,S.J.and Bates,D.O.(2008) 'Expression ofpro-and anti-angiogenic isoforms of VEGF is differentially regulated bysplicing and growth factors',Journal of Cell Science,121(20), 3487-3495.
Doukas,J.,Mahesh,S.,Umeda,N.,Kachi,S.,Akiyama,H.,Yokoi,K., Cao,J.,Chen,Z.,Dellamary,L.,Tam,B.,Racanelli-Layton,A.,Hood,J., Martin,M.,Noronha,G.,Soll,R.and Campochiaro,P.A.(2008)'Topical administration of a multi-targeted kinase inhibitor suppresses choroidal neovascularization and retinaledema',Journal of Cellular Physiology, 216(1),29-37.
Fukuhara,T.,Hosoya,T.,Shimizu,S.,Sumi,K.,Oshiro,T.,Yoshinaka, Y.,Suzuki,M.,Yamamoto,N.,Herzenberg,L.A.and Hagiwara,M.(2006) 'Utilization ofhost SR protein kinases and RNA-splicing machinery during viral replication',Proceedings of the National Academy of Sciences of the United States ofAmerica,103(30),11329-11333.
Rennel,E.S.,Regula,J.T.,Harper,S.J.,Thomas,M.,Klein,C.and Bates,D.O.(2011)'A Human Neutralizing Antibody Specific to Ang-2 Inhibits OcularAngiogenesis',Microcirculation,18(7).
Aubol,B.E.,Chakrabarti,S.,Ngo,J.,Shaffer,J.,Nolen,B.,Fu,X.D., Ghosh,G.and Adams,J.A.(2003)'Processive phosphorylation of alternative splicingfactor/splicing factor 2',Proceedings of the National Academy of Sciences ofthe United States of America,100(22),12601-12606.
Velazquez-Dones,A.,Hagopian,J.C.,Ma,C.T.,Zhong,X.Y.,Zhou,H. L.,Ghosh,G.,Fu,X.D.and Adams,J.A.(2005)'Mass spectrometric and kinetic analysis ofASF/SF2 phosphorylation by SRPK1 and Clk/Sty', Journal of BiologicalChemistry,280(50),41761-41768.
Ngo,J.C.K.,Chakrabarti,S.,Ding,J.H.,Velazquez-Dones,A.,Nolen, B.,Aubol,B.E.,Adams,J.A.,Fu,X.D.and Ghosh,G.(2005)'Interplay between SRPK andClk/Sty kinases in phosphorylation of the splicing factor ASF/SF2 isregulated by a docking motif in ASF/SF2',Molecular Cell,20(1), 77-89.
Xu,J.,Dou,T.,Liu,C.,Fu,M.,Huang,Y.,Gu,S.,Zhou,Y.and Xie,Y. (2011)'Theevolution of alternative splicing exons in vascular endothelial growth factorA',Gene,487(2).
Caires,K.C.,de Avila,J.M.,Cupp,A.S.and McLean,D.J.(2012) 'VEGFAFamily Isoforms Regulate Spermatogonial Stem Cell Homeostasis in Vivo',Endocrinology,153(2).
Zhao,M.,Shi,X.,Liang,J.,Miao,Y.,Xie,W.,Zhang,Y.and Li,X. (2011)'Expression of pro-and anti-angiogenic isoforms of VEGF in the mouse model ofoxygen-induced retinopathy',Experimental Eye Research, 93(6),921-926.
Harris,S.,Craze,M.,Newton,J.,Fisher,M.,Shima,D.T.,Tozer,G.M. andKanthou,C.(2012)'Do Anti-Angiogenic VEGF(VEGFxxxb)Isoforms Exist?A CautionaryTale',Plos One,7(5).
McFee,R.M.,Rozell,T.G.and Cupp,A.S.(2012)'The balance ofproangiogenic and antiangiogenic VEGFA isoforms regulate follicledevelopment',Cell and Tissue Research,349(3).
Ishida,S.,Usui,T.,Yamashiro,K.,Kaji,Y.,Amano,S.,Ogura,Y.,Hida, T.,Oguchi,Y.,Ambati,J.,Miller,J.W.,Gragoudas,E.S.,Ng,Y.S., D'Amore,P.A.,Shima,D.T.and Adamis,A.P.(2003)'VEGF(164)-mediated inflammation is required forpathological,but not physiological, ischemia-induced retinalneovascularization',Journal of Experimental Medicine,198(3),483-489.
Geroski,D.H.and Edelhauser,H.F.(2000)'Drug delivery for posteriorsegment eye disease',Investigative Ophthalmology&Visual Science,41(5), 961-964.
Keyt,B.A.,Nguyen,H.V.,Berleau,L.T.,Duarte,C.M.,Park,J.,Chen, H.andFerrara,N.(1996)'Identification of vascular endothelial growth factordeterminants for binding KDR and FLT-1 receptors-Generation of receptor-selective VEGF variants by site-directed mutagenesis',Journal of BiologicalChemistry,271(10),5638-5646.
Stalmans,I.,Ng,Y.S.,Rohan,R.,Fruttiger,M.,Bouche,A.,Yuce,A.,Fujisawa,H.,Hermans,B.,Shani,M.,Jansen,S.,Hicklin,D.,Anderson,D. J.,Gardiner,T.,Hammes,H.P.,Moons,L.,Dewerchin,M.,Collen,D., Carmeliet,P.and D'Amore,P.A.(2002)'Arteriolar and venular patterning in retinas of mice selectivelyexpressing VEGF isoforms',Journal of Clinical Investigation,109(3).
Gammons,M.V.,Dick,A.D.,Harper,S.J.,Bates,D.O.(2013)SRPK1 InhibitionModulates VEGF Splicing to Reduce Pathological Neovascularization in a RatModel of Retinopathy of Prematurity Invest. Ophthalmol.Vis.Sci.vol.54(8)5797-5806.
Gammons,M.V.,Fedorov,O.,Ivison,D.,Du,C.,Clark,T.,Hopkins,C.,Hagiwara,M.,Dick,A.D.,Cox,R.,Harper,S.J.,Hancox,J.C.and Bates, D.O.(2013)Topical Antiangiogenic SRPK1 Inhibitors Reduce Choroidal Neovascularizationin Rodent Models of Exudative AMD Invest. Ophthalmol.Vis.Sci.54(9)6052-6062.
Federov O,Niesen FH,Knapp S.Kinase Inhibitor Selectivity ProfilingUsing Differential Scanning Fluorimetry.In:Kuster B,ed.Kinase Inhibitors:Methods and Protocols:Springer,2011:109-18.
Carter JG,Gammons MV,Damodaran G,Churchill AJ,Harper SJ, Bates DO.(2015)The carboxyl terminus of VEGF-A is a potential target for anti-angiogenic therapy.Angiogenesis 18(1).
Claims (46)
1.式(I)的化合物或其药学上可接受的盐:
其中:
n=1、2或3;
X=CH;
Y=CH;
Z=O;以及
R1=苯基,其可具有一个或多个C1-6烷氧基、C1-6烷硫基、卤素、氰基或羧基取代基;包含一个氮原子的6元杂芳族基团,其可具有一个或多个C1-6烷氧基、C1-6烷硫基、卤素、氰基或羧基取代基;或包含两个氮原子的6元杂芳族基团,其可具有一个或多个C1-6烷氧基、C1-6烷硫基、卤素、氰基或羧基取代基;并且
R2=H或可具有一个或多个C1-6烷氧基、OH或氨基取代基的C1-6烷基;
或者
R1=吲哚基、异吲哚基、苯并咪唑基、喹啉基或异喹啉基,其可具有一个或多个C1-6烷氧基、C1-6烷硫基、卤素、氰基或羧基取代基;并且
R2=含氮的6元杂芳基。
2.式(I)的化合物或其药学上可接受的盐:
其中:
n=1、2或3;
R1=苯基,其可具有一个或多个C1-6烷氧基、C1-6烷硫基、卤素、氰基或羧基取代基;具有一个氮原子的6元杂芳族基团,其可具有一个或多个C1-6烷氧基、C1-6烷硫基、卤素、氰基或羧基取代基;包含两个氮原子的6元杂芳族基团,其可具有一个或多个C1-6烷氧基、C1-6烷硫基、卤素、氰基或羧基取代基;
X=CH或N;
Y=CH或N;
Z=O、S或NH;以及
R2=苯基、含氮的6元杂芳基、含氧的4元至8元非芳族杂环、或者吲哚基、异吲哚基、苯并咪唑基、喹啉基或异喹啉基,这些基团各自可具有一个或多个C1-6烷氧基、C1-6烷硫基、卤素、氰基、羧基、羟甲基或羟乙基取代基。
3.如权利要求1或2所述的化合物,其中R1表示包含一个氮原子的6元杂芳族基团,其可具有一个或多个C1-6烷氧基或C1-6烷硫基取代基。
4.如权利要求3所述的化合物,其中R1表示包含一个氮原子的6元杂芳族基团,其可具有一个甲氧基或甲硫基取代基。
5.如权利要求1或2所述的化合物,其中R1表示各自可具有一个或多个C1-6烷氧基或C1-6烷硫基取代基的2-吡啶基、3-吡啶基或4-吡啶基。
6.如权利要求5所述的化合物,其中R1表示各自可具有一个甲氧基或甲硫基取代基的2-吡啶基、3-吡啶基或4-吡啶基。
7.如权利要求1所述的化合物,其中R1表示可具有一个或多个C1-6烷氧基或C1-6烷硫基取代基的嘧啶基。
8.如权利要求7所述的化合物,其中R1表示可具有一个甲氧基或甲硫基取代基的嘧啶基。
9.如权利要求8所述的化合物,其中R1表示具有一个甲硫基取代基的嘧啶基。
10.如权利要求1或2所述的化合物,其中R1表示可具有一个或多个C1-6烷氧基或C1-6烷硫基取代基的苯基。
11.如权利要求10所述的化合物,其中R1表示可具有一个甲氧基或甲硫基取代基的苯基。
12.如权利要求2所述的化合物,其中R2表示可具有一个或多个C1-6烷氧基、C1-6烷硫基、羟甲基或羟乙基取代基的含氮的6元杂芳环。
13.如权利要求12所述的化合物,其中R2表示可具有一个甲氧基或甲硫基取代基的含氮的6元杂芳环。
14.如权利要求12所述的化合物,其中R2表示各自可具有一个或多个C1-6烷氧基、C1-6烷硫基、羟甲基或羟乙基取代基的2-吡啶基、3-吡啶基或4-吡啶基。
15.如权利要求14所述的化合物,其中R2表示各自可具有一个甲氧基或甲硫基取代基的2-吡啶基、3-吡啶基或4-吡啶基。
16.如权利要求2所述的化合物,其中R2表示可具有一个或多个C1-6烷氧基、C1-6烷硫基、羟甲基或羟乙基取代基的含氧的4元至8元非芳族杂环。
17.如权利要求2所述的化合物,其中R2表示可具有一个或多个C1-6烷氧基、C1-6烷硫基、羟甲基或羟乙基取代基的苯基。
18.如权利要求17所述的化合物,其中R2表示可具有一个甲氧基、甲硫基、羟甲基或羟乙基取代基的苯基。
19.如权利要求18所述的化合物,其中R2表示可具有一个羟甲基取代基的苯基。
20.如权利要求1所述的化合物,其中R2表示H或可具有一个或OH取代基的C1-6烷基。
21.如权利要求20所述的化合物,其中R2表示可具有一个OH取代基的甲基。
22.如权利要求16所述的化合物,其中R2表示可具有一个甲氧基、甲硫基、羟甲基或羟乙基取代基的四氢呋喃基或四氢吡喃基。
23.如权利要求22所述的化合物,其中R2表示可具有一个甲氧基、甲硫基、羟甲基或羟乙基取代基的四氢吡喃基。
24.如权利要求23所述的化合物,其中R2表示四氢吡喃基。
25.如权利要求2所述的化合物,其中X=Y=CH并且其中Z=O。
26.如权利要求1或2所述的化合物,其中n=1或2。
27.如权利要求1所述的化合物,其中n=1或2;R1表示各自可具有一个或多个C1-6烷氧基或C1-6烷硫基取代基的2-吡啶基、3-吡啶基、4-吡啶基或苯基;以及R2表示H或者可具有一个或多个OH取代基的C1-6烷基。
28.如权利要求1所述的化合物,其中n=1或2;R1表示各自可具有一个甲氧基或甲硫基取代基的2-吡啶基、3-吡啶基、4-吡啶基或苯基;以及R2表示H或者可具有一个OH取代基的甲基。
29.如权利要求2所述的化合物,其中n=1或2;R1表示各自可具有一个或多个C1-6烷氧基或C1-6烷硫基取代基的2-吡啶基、3-吡啶基、4-吡啶基或苯基;R2表示各自可具有一个或多个C1-6烷氧基、C1-6烷硫基、羟甲基或羟乙基取代基的2-吡啶基、3-吡啶基、4-吡啶基或四氢吡喃基;X=Y=CH并且Z=O。
30.如权利要求2所述的化合物,其中n=1或2;R1表示各自可具有一个甲氧基或甲硫基取代基的2-吡啶基、3-吡啶基、4-吡啶基或苯基;R2表示各自可具有一个甲氧基或甲硫基取代基的2-吡啶基、3-吡啶基或4-吡啶基,或者四氢吡喃基;X=Y=CH并且Z=O。
31.如权利要求1至30中任一项所述的化合物或其药学上可接受的盐在制备用于眼新生血管形成的剂量依赖性治疗或预防的药物中的用途。
32.如权利要求1至30中任一项所述的化合物或其药学上可接受的盐在制备用于眼新生血管形成的局部治疗或预防的药物中的用途。
33.如权利要求32所述的用途,其中所述眼新生血管形成的局部治疗或预防是剂量依赖性治疗或预防。
34.如权利要求31至33中任一项所述的用途,其中所述眼新生血管形成是脉络膜新生血管化。
35.如权利要求31至33中任一项所述的用途,其中所述眼新生血管形成是年龄相关性黄斑变性。
36.如权利要求31至33中任一项所述的用途,其中所述眼新生血管形成是视网膜新生血管化。
37.如权利要求1至30中任一项所述的化合物或其药学上可接受的盐在制备用于哺乳动物个体的抗血管生成治疗的药物中的用途。
38.如权利要求37所述的用途,其中所述抗血管生成治疗包括癌症治疗。
39.如权利要求37所述的用途,其中所述抗血管生成治疗是剂量依赖性治疗。
40.如权利要求1至30中任一项所述的化合物或其药学上可接受的盐在制备用于治疗或预防微血管通透性过高病症、或用于调节VEGFxxx亚型的促血管生成促通透性性质、或用于在不增加通透性的情况下支持上皮细胞存活、或用于降低上皮滤过膜窗孔的性质的药物中的用途。
41.如权利要求1至30中任一项所述的化合物或其药学上可接受的盐在制备用于治疗或预防神经性病症和神经变性病症或用作体内或体外的神经保护剂或神经再生剂的药物中的用途。
42.如权利要求1至30中任一项所述的化合物或其药学上可接受的盐在制备用于治疗或预防VEGFR2介导的非炎性疼痛的药物中的用途。
43.如权利要求1至30中任一项所述的化合物或其药学上可接受的盐在制备用于降低雌性哺乳动物出现先兆子痫或与其相关的并发症的风险、或用于降低雌性哺乳动物的胎儿患有与母体先兆子痫相关的胎儿或新生儿缺陷的风险的药物中的用途。
44.药物组合物,其包含权利要求1至30中任一项所述的式(I)的化合物、任选存在的一种或多种其他活性成分以及药学上可接受的载体。
45.药物组合物,其包含权利要求1至30中任一项所述的式(I)的化合物、任选存在的一种或多种其他活性成分以及药学上可接受的载体,所述药物组合物为适于眼内注射的形式。
46.药物组合物,其包含权利要求1至30中任一项所述的式(I)的化合物、任选存在的一种或多种其他活性成分以及药学上可接受的载体,所述药物组合物为适于向眼局部给药的形式。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB1406956.1A GB201406956D0 (en) | 2014-04-17 | 2014-04-17 | Compounds |
GB1406956.1 | 2014-04-17 | ||
PCT/GB2015/051172 WO2015159103A1 (en) | 2014-04-17 | 2015-04-17 | Piperazine derivatives for treating disorders |
Publications (2)
Publication Number | Publication Date |
---|---|
CN107001344A CN107001344A (zh) | 2017-08-01 |
CN107001344B true CN107001344B (zh) | 2021-02-26 |
Family
ID=50928932
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201580031650.5A Active CN107001344B (zh) | 2014-04-17 | 2015-04-17 | 用于治疗病症的哌嗪衍生物 |
Country Status (8)
Country | Link |
---|---|
US (3) | US9695160B2 (zh) |
EP (1) | EP3131886B1 (zh) |
JP (1) | JP6579714B2 (zh) |
CN (1) | CN107001344B (zh) |
AU (1) | AU2015248656B2 (zh) |
ES (1) | ES2836105T3 (zh) |
GB (1) | GB201406956D0 (zh) |
WO (1) | WO2015159103A1 (zh) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2858511T3 (es) * | 2012-10-17 | 2021-09-30 | Exonate Ltd | Compuestos útiles para tratar neovascularización ocular |
GB201518365D0 (en) * | 2015-10-16 | 2015-12-02 | Exonate Ltd | Compounds |
DK3600312T3 (da) | 2017-03-26 | 2023-07-31 | Takeda Pharmaceuticals Co | Piperidinyl- og piperazinylsubstituerede heteroaromatiske carboxamider som modulatorer af gpr6 |
AU2018341084B2 (en) * | 2017-09-27 | 2023-04-13 | Exonate Limited | SRPK1 inhibitors |
CN108912116A (zh) * | 2018-08-15 | 2018-11-30 | 翟学旭 | 一种含氮杂环类衍生物及其在视网膜疾病中的应用 |
WO2021148420A1 (en) * | 2020-01-22 | 2021-07-29 | F. Hoffmann-La Roche Ag | Novel heterocyclic compounds |
GB202010829D0 (en) | 2020-07-14 | 2020-08-26 | Exonate Ltd | Compounds for treatment of neovascular diseases |
CN118119609A (zh) | 2021-07-15 | 2024-05-31 | 豪夫迈·罗氏有限公司 | 咪唑衍生物及其作为抗生素的用途 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101837125A (zh) * | 2003-12-26 | 2010-09-22 | 萩原正敏 | Sr蛋白质的磷酸化控制方法以及以包含sr蛋白质活性控制剂的试剂为有效成分的抗病毒剂 |
WO2014060763A1 (en) * | 2012-10-17 | 2014-04-24 | The University Of Bristol | Compounds useful for treating ocular neovasculan |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2840314B1 (fr) | 2002-06-03 | 2004-08-20 | Inst Francais Du Petrole | Methode d'isolation thermique, procede de preparation d'un gel isolant et gel isolant obtenu |
WO2008054702A1 (en) * | 2006-10-31 | 2008-05-08 | Schering Corporation | Anilinopiperazine derivatives and methods of use thereof |
GB0704678D0 (en) | 2007-03-09 | 2007-04-18 | Univ Bristol | Pro- and anti-angiogenic treatments |
GB0803912D0 (en) | 2008-02-29 | 2008-05-07 | Univ Bristol | Novel Uses of VEGFxxxb |
JP2012509306A (ja) | 2008-11-22 | 2012-04-19 | ザ ユニバーシティ オブ ブリストル | VEGFxxxbの新規な使用 |
WO2011036429A1 (en) | 2009-09-25 | 2011-03-31 | The University Of Bristol | Detection of risk of pre-eclampsia |
GB201009173D0 (en) | 2010-05-28 | 2010-07-14 | Univ Bristol | Treatment of pain |
-
2014
- 2014-04-17 GB GBGB1406956.1A patent/GB201406956D0/en not_active Ceased
-
2015
- 2015-04-17 EP EP15718262.7A patent/EP3131886B1/en active Active
- 2015-04-17 CN CN201580031650.5A patent/CN107001344B/zh active Active
- 2015-04-17 AU AU2015248656A patent/AU2015248656B2/en active Active
- 2015-04-17 ES ES15718262T patent/ES2836105T3/es active Active
- 2015-04-17 WO PCT/GB2015/051172 patent/WO2015159103A1/en active Application Filing
- 2015-04-17 US US15/304,678 patent/US9695160B2/en active Active
- 2015-04-17 JP JP2017505735A patent/JP6579714B2/ja active Active
-
2017
- 2017-05-31 US US15/609,596 patent/US9796707B2/en active Active
- 2017-09-19 US US15/708,315 patent/US9932330B2/en active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101837125A (zh) * | 2003-12-26 | 2010-09-22 | 萩原正敏 | Sr蛋白质的磷酸化控制方法以及以包含sr蛋白质活性控制剂的试剂为有效成分的抗病毒剂 |
WO2014060763A1 (en) * | 2012-10-17 | 2014-04-24 | The University Of Bristol | Compounds useful for treating ocular neovasculan |
Non-Patent Citations (1)
Title |
---|
stn;stn;《STNEXT》;20110529;正文第2-4页具体化合物结构 * |
Also Published As
Publication number | Publication date |
---|---|
US9796707B2 (en) | 2017-10-24 |
WO2015159103A1 (en) | 2015-10-22 |
US20170267670A1 (en) | 2017-09-21 |
US20170050956A1 (en) | 2017-02-23 |
US9695160B2 (en) | 2017-07-04 |
EP3131886A1 (en) | 2017-02-22 |
EP3131886B1 (en) | 2020-09-09 |
US20180044331A1 (en) | 2018-02-15 |
GB201406956D0 (en) | 2014-06-04 |
US9932330B2 (en) | 2018-04-03 |
ES2836105T3 (es) | 2021-06-24 |
JP6579714B2 (ja) | 2019-09-25 |
JP2017518360A (ja) | 2017-07-06 |
AU2015248656B2 (en) | 2019-10-10 |
AU2015248656A1 (en) | 2016-11-24 |
CN107001344A (zh) | 2017-08-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN107001344B (zh) | 用于治疗病症的哌嗪衍生物 | |
CN108738319B (zh) | 用于抗血管生成治疗或预防的化合物 | |
JP6738512B2 (ja) | 眼血管形成(ocular neovasculan)を治療するのに有用な化合物 | |
CN111448193B (zh) | Srpk1抑制剂 | |
KR20230052890A (ko) | 신생혈관 질환의 치료를 위한 화합물 | |
CN116323601A (zh) | 作为转化生长因子-β 受体I/ALK5抑制剂的2-(3-吡啶-2-基-4-喹啉-4-基-吡唑-1-基)-乙酰胺衍生物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
TA01 | Transfer of patent application right | ||
TA01 | Transfer of patent application right |
Effective date of registration: 20200303 Address after: British county Applicant after: Aconet Co., Ltd Address before: England County Applicant before: THE UNIVERSITY OF NOTTINGHAM Applicant before: NEWSOUTH INNOVATIONS Pty Ltd. |
|
GR01 | Patent grant | ||
GR01 | Patent grant |