CN117337292A - 作为cGAS抑制剂的具有N-连接环状取代基的吡啶衍生物 - Google Patents
作为cGAS抑制剂的具有N-连接环状取代基的吡啶衍生物 Download PDFInfo
- Publication number
- CN117337292A CN117337292A CN202280032800.4A CN202280032800A CN117337292A CN 117337292 A CN117337292 A CN 117337292A CN 202280032800 A CN202280032800 A CN 202280032800A CN 117337292 A CN117337292 A CN 117337292A
- Authority
- CN
- China
- Prior art keywords
- formula
- methyl
- compound
- prodrugs
- pharmaceutically acceptable
- 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.)
- Pending
Links
- 102100031256 Cyclic GMP-AMP synthase Human genes 0.000 title claims description 86
- 101710118064 Cyclic GMP-AMP synthase Proteins 0.000 title claims description 85
- 239000003112 inhibitor Substances 0.000 title description 29
- 150000003222 pyridines Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 230
- 229940002612 prodrug Drugs 0.000 claims abstract description 66
- 239000000651 prodrug Substances 0.000 claims abstract description 66
- 150000003839 salts Chemical class 0.000 claims abstract description 64
- 201000010099 disease Diseases 0.000 claims abstract description 28
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 28
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims abstract description 20
- 208000029523 Interstitial Lung disease Diseases 0.000 claims abstract description 19
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims abstract description 16
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims abstract description 16
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 claims abstract description 15
- 208000036971 interstitial lung disease 2 Diseases 0.000 claims abstract description 15
- 201000009594 Systemic Scleroderma Diseases 0.000 claims abstract description 14
- 206010042953 Systemic sclerosis Diseases 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims description 110
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 54
- -1 t-Butoxycarbonyl Chemical group 0.000 claims description 52
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 42
- 125000004432 carbon atom Chemical group C* 0.000 claims description 38
- 230000005764 inhibitory process Effects 0.000 claims description 32
- 108010050904 Interferons Proteins 0.000 claims description 29
- 102000014150 Interferons Human genes 0.000 claims description 29
- 229940079322 interferon Drugs 0.000 claims description 26
- 125000003118 aryl group Chemical group 0.000 claims description 25
- 125000004122 cyclic group Chemical group 0.000 claims description 25
- 239000013543 active substance Substances 0.000 claims description 24
- 229910052736 halogen Inorganic materials 0.000 claims description 23
- 150000002367 halogens Chemical class 0.000 claims description 23
- 125000005842 heteroatom Chemical group 0.000 claims description 19
- 125000000623 heterocyclic group Chemical group 0.000 claims description 19
- 206010064930 age-related macular degeneration Diseases 0.000 claims description 18
- 208000002780 macular degeneration Diseases 0.000 claims description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims description 17
- 208000011580 syndromic disease Diseases 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- 229910052717 sulfur Inorganic materials 0.000 claims description 14
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 13
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 12
- 125000006239 protecting group Chemical group 0.000 claims description 12
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 11
- 230000003176 fibrotic effect Effects 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 125000001188 haloalkyl group Chemical group 0.000 claims description 9
- 125000001072 heteroaryl group Chemical group 0.000 claims description 9
- 208000025721 COVID-19 Diseases 0.000 claims description 8
- 102000004127 Cytokines Human genes 0.000 claims description 8
- 208000018737 Parkinson disease Diseases 0.000 claims description 8
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 8
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 7
- 229940124748 beta 2 agonist Drugs 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 125000003566 oxetanyl group Chemical group 0.000 claims description 7
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 6
- 208000005692 Bloom Syndrome Diseases 0.000 claims description 6
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 6
- 206010019280 Heart failures Diseases 0.000 claims description 6
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 claims description 6
- 230000003510 anti-fibrotic effect Effects 0.000 claims description 6
- 229940121363 anti-inflammatory agent Drugs 0.000 claims description 6
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 6
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 6
- 239000000812 cholinergic antagonist Substances 0.000 claims description 6
- 125000004969 haloethyl group Chemical group 0.000 claims description 6
- 125000004970 halomethyl group Chemical group 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 230000000750 progressive effect Effects 0.000 claims description 6
- 108090000695 Cytokines Proteins 0.000 claims description 5
- 108010008165 Etanercept Proteins 0.000 claims description 5
- 239000000048 adrenergic agonist Substances 0.000 claims description 5
- 229940124630 bronchodilator Drugs 0.000 claims description 5
- 239000000168 bronchodilator agent Substances 0.000 claims description 5
- 229960000403 etanercept Drugs 0.000 claims description 5
- RTGDFNSFWBGLEC-SYZQJQIISA-N mycophenolate mofetil Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 claims description 5
- 229960004866 mycophenolate mofetil Drugs 0.000 claims description 5
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 claims description 4
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 4
- 229940122245 Janus kinase inhibitor Drugs 0.000 claims description 4
- 208000037847 SARS-CoV-2-infection Diseases 0.000 claims description 4
- 229960002964 adalimumab Drugs 0.000 claims description 4
- 239000000739 antihistaminic agent Substances 0.000 claims description 4
- 229960003270 belimumab Drugs 0.000 claims description 4
- 239000003246 corticosteroid Substances 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 4
- 150000002617 leukotrienes Chemical class 0.000 claims description 4
- 208000030159 metabolic disease Diseases 0.000 claims description 4
- 201000008383 nephritis Diseases 0.000 claims description 4
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 claims description 4
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 claims description 4
- 239000004745 nonwoven fabric Substances 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 208000019553 vascular disease Diseases 0.000 claims description 4
- 102000009410 Chemokine receptor Human genes 0.000 claims description 3
- 108050000299 Chemokine receptor Proteins 0.000 claims description 3
- 102000019034 Chemokines Human genes 0.000 claims description 3
- 108010012236 Chemokines Proteins 0.000 claims description 3
- 108091008036 Immune checkpoint proteins Proteins 0.000 claims description 3
- 102000037982 Immune checkpoint proteins Human genes 0.000 claims description 3
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 3
- 230000003266 anti-allergic effect Effects 0.000 claims description 3
- 229940125715 antihistaminic agent Drugs 0.000 claims description 3
- 239000011324 bead Substances 0.000 claims description 3
- 201000011529 cardiovascular cancer Diseases 0.000 claims description 3
- 108010057085 cytokine receptors Proteins 0.000 claims description 3
- 239000002955 immunomodulating agent Substances 0.000 claims description 3
- 229940047124 interferons Drugs 0.000 claims description 3
- 229960000485 methotrexate Drugs 0.000 claims description 3
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 3
- 201000002793 renal fibrosis Diseases 0.000 claims description 3
- 229950007943 risankizumab Drugs 0.000 claims description 3
- 150000003527 tetrahydropyrans Chemical class 0.000 claims description 3
- 239000003970 toll like receptor agonist Substances 0.000 claims description 3
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical group C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 claims description 2
- 208000021386 Sjogren Syndrome Diseases 0.000 claims description 2
- 229960001334 corticosteroids Drugs 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 2
- 201000010235 heart cancer Diseases 0.000 claims description 2
- 208000024348 heart neoplasm Diseases 0.000 claims description 2
- XZXHXSATPCNXJR-ZIADKAODSA-N nintedanib Chemical compound O=C1NC2=CC(C(=O)OC)=CC=C2\C1=C(C=1C=CC=CC=1)\NC(C=C1)=CC=C1N(C)C(=O)CN1CCN(C)CC1 XZXHXSATPCNXJR-ZIADKAODSA-N 0.000 claims description 2
- 229960004378 nintedanib Drugs 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims 1
- 150000003147 proline derivatives Chemical class 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 description 105
- 239000011541 reaction mixture Substances 0.000 description 83
- 239000000203 mixture Substances 0.000 description 81
- 238000004128 high performance liquid chromatography Methods 0.000 description 66
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 52
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 52
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 49
- 239000000243 solution Substances 0.000 description 43
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 42
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Chemical compound OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 40
- 210000004027 cell Anatomy 0.000 description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 31
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 30
- 108020004414 DNA Proteins 0.000 description 26
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 26
- 239000002904 solvent Substances 0.000 description 25
- 235000019439 ethyl acetate Nutrition 0.000 description 23
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 22
- 238000000338 in vitro Methods 0.000 description 22
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 21
- 239000002585 base Substances 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 21
- 230000037361 pathway Effects 0.000 description 21
- 238000000746 purification Methods 0.000 description 21
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 20
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 19
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
- 101710196623 Stimulator of interferon genes protein Proteins 0.000 description 17
- 238000004458 analytical method Methods 0.000 description 17
- 239000012074 organic phase Substances 0.000 description 17
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 17
- 230000001225 therapeutic effect Effects 0.000 description 17
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 16
- 238000003556 assay Methods 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 241000282414 Homo sapiens Species 0.000 description 15
- 239000002253 acid Substances 0.000 description 15
- 210000004369 blood Anatomy 0.000 description 15
- 239000008280 blood Substances 0.000 description 15
- 230000000694 effects Effects 0.000 description 15
- 101001074035 Homo sapiens Zinc finger protein GLI2 Proteins 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 102100035558 Zinc finger protein GLI2 Human genes 0.000 description 14
- 238000004440 column chromatography Methods 0.000 description 14
- 230000002829 reductive effect Effects 0.000 description 14
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 14
- 239000003643 water by type Substances 0.000 description 14
- 102000053602 DNA Human genes 0.000 description 13
- 239000000460 chlorine Substances 0.000 description 13
- 238000005259 measurement Methods 0.000 description 13
- 229920006395 saturated elastomer Polymers 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- 229910052786 argon Inorganic materials 0.000 description 11
- 239000012043 crude product Substances 0.000 description 11
- 230000000144 pharmacologic effect Effects 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
- 230000001413 cellular effect Effects 0.000 description 10
- 239000012071 phase Substances 0.000 description 10
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 10
- 239000002244 precipitate Substances 0.000 description 10
- 239000000377 silicon dioxide Substances 0.000 description 10
- 239000011734 sodium Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- 101000776648 Homo sapiens Cyclic GMP-AMP synthase Proteins 0.000 description 9
- 125000004093 cyano group Chemical group *C#N 0.000 description 9
- 102000048017 human cGAS Human genes 0.000 description 9
- 230000002401 inhibitory effect Effects 0.000 description 9
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 9
- 238000004007 reversed phase HPLC Methods 0.000 description 9
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 238000004809 thin layer chromatography Methods 0.000 description 8
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 8
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 230000004913 activation Effects 0.000 description 7
- 125000002947 alkylene group Chemical group 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 150000004702 methyl esters Chemical class 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 7
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 description 7
- 208000023275 Autoimmune disease Diseases 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 6
- 241000700605 Viruses Species 0.000 description 6
- 150000007513 acids Chemical class 0.000 description 6
- 125000000304 alkynyl group Chemical group 0.000 description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 6
- 238000004364 calculation method Methods 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000011157 data evaluation Methods 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 6
- 239000007937 lozenge Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 239000001301 oxygen Substances 0.000 description 6
- 244000052769 pathogen Species 0.000 description 6
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- 239000011593 sulfur Chemical group 0.000 description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 5
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 5
- 102000043138 IRF family Human genes 0.000 description 5
- 108091054729 IRF family Proteins 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- 125000002619 bicyclic group Chemical group 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 230000003834 intracellular effect Effects 0.000 description 5
- ZCYXXKJEDCHMGH-UHFFFAOYSA-N nonane Chemical compound CCCC[CH]CCCC ZCYXXKJEDCHMGH-UHFFFAOYSA-N 0.000 description 5
- BKIMMITUMNQMOS-UHFFFAOYSA-N normal nonane Natural products CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 5
- 238000003359 percent control normalization Methods 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000000454 talc Substances 0.000 description 5
- 235000012222 talc Nutrition 0.000 description 5
- 229910052623 talc Inorganic materials 0.000 description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 4
- 239000012981 Hank's balanced salt solution Substances 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 4
- 102000002227 Interferon Type I Human genes 0.000 description 4
- 108010014726 Interferon Type I Proteins 0.000 description 4
- 239000012124 Opti-MEM Substances 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 230000002159 abnormal effect Effects 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 150000001602 bicycloalkyls Chemical group 0.000 description 4
- 125000001246 bromo group Chemical group Br* 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 125000001309 chloro group Chemical group Cl* 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 125000001153 fluoro group Chemical group F* 0.000 description 4
- 230000014509 gene expression Effects 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- 125000002346 iodo group Chemical group I* 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 206010025135 lupus erythematosus Diseases 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 229940098779 methanesulfonic acid Drugs 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 229920000136 polysorbate Polymers 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 4
- HLTDBMHJSBSAOM-UHFFFAOYSA-N 2-nitropyridine Chemical compound [O-][N+](=O)C1=CC=CC=N1 HLTDBMHJSBSAOM-UHFFFAOYSA-N 0.000 description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 3
- ROADCYAOHVSOLQ-UHFFFAOYSA-N 3-oxetanone Chemical compound O=C1COC1 ROADCYAOHVSOLQ-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 3
- 239000007821 HATU Substances 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 229910010082 LiAlH Inorganic materials 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 108020005196 Mitochondrial DNA Proteins 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 239000004698 Polyethylene Substances 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 238000006069 Suzuki reaction reaction Methods 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- 238000004378 air conditioning Methods 0.000 description 3
- 150000001340 alkali metals Chemical class 0.000 description 3
- 125000004450 alkenylene group Chemical group 0.000 description 3
- 239000000043 antiallergic agent Substances 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 239000012131 assay buffer Substances 0.000 description 3
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 3
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 3
- PKFDLKSEZWEFGL-MHARETSRSA-N c-di-GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]3[C@@H](O)[C@H](N4C5=C(C(NC(N)=N5)=O)N=C4)O[C@@H]3COP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 PKFDLKSEZWEFGL-MHARETSRSA-N 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 125000002843 carboxylic acid group Chemical group 0.000 description 3
- 230000004637 cellular stress Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- PMMYEEVYMWASQN-IMJSIDKUSA-N cis-4-Hydroxy-L-proline Chemical compound O[C@@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-IMJSIDKUSA-N 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 3
- 239000000824 cytostatic agent Substances 0.000 description 3
- 230000001085 cytostatic effect Effects 0.000 description 3
- 230000003111 delayed effect Effects 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 238000001952 enzyme assay Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 230000001747 exhibiting effect Effects 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000001530 fumaric acid Substances 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 238000007477 logistic regression Methods 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 102000007863 pattern recognition receptors Human genes 0.000 description 3
- 108010089193 pattern recognition receptors Proteins 0.000 description 3
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 3
- 235000011056 potassium acetate Nutrition 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- ONIBWKKTOPOVIA-UHFFFAOYSA-M prolinate Chemical compound [O-]C(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-M 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- XJJBXZIKXFOMLP-UHFFFAOYSA-N tert-butyl pyrrolidine-2-carboxylate Chemical compound CC(C)(C)OC(=O)C1CCCN1 XJJBXZIKXFOMLP-UHFFFAOYSA-N 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 3
- 239000011534 wash buffer Substances 0.000 description 3
- DUBNHZYBDBBJHD-UHFFFAOYSA-L ziram Chemical compound [Zn+2].CN(C)C([S-])=S.CN(C)C([S-])=S DUBNHZYBDBBJHD-UHFFFAOYSA-L 0.000 description 3
- CXNPLSGKWMLZPZ-GIFSMMMISA-N (2r,3r,6s)-3-[[(3s)-3-amino-5-[carbamimidoyl(methyl)amino]pentanoyl]amino]-6-(4-amino-2-oxopyrimidin-1-yl)-3,6-dihydro-2h-pyran-2-carboxylic acid Chemical compound O1[C@@H](C(O)=O)[C@H](NC(=O)C[C@@H](N)CCN(C)C(N)=N)C=C[C@H]1N1C(=O)N=C(N)C=C1 CXNPLSGKWMLZPZ-GIFSMMMISA-N 0.000 description 2
- BENKAPCDIOILGV-BQBZGAKWSA-N (2s,4s)-4-hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(O)=O BENKAPCDIOILGV-BQBZGAKWSA-N 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- XLCGXYGEJFLVQY-UHFFFAOYSA-N 1-([1]benzofuro[3,2-d]pyrimidin-4-yl)pyrrolidin-1-ium-2-carboxylate Chemical class OC(=O)C1CCCN1C1=NC=NC2=C1OC1=CC=CC=C12 XLCGXYGEJFLVQY-UHFFFAOYSA-N 0.000 description 2
- 125000004809 1-methylpropylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])C([H])([H])[*:2] 0.000 description 2
- UMUJDMACQDCTNC-UHFFFAOYSA-N 1-o-tert-butyl 3-o-methyl 2-methylpiperidine-1,3-dicarboxylate Chemical compound COC(=O)C1CCCN(C(=O)OC(C)(C)C)C1C UMUJDMACQDCTNC-UHFFFAOYSA-N 0.000 description 2
- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 description 2
- PMWGIVRHUIAIII-UHFFFAOYSA-N 2,2-difluoropropanoic acid Chemical compound CC(F)(F)C(O)=O PMWGIVRHUIAIII-UHFFFAOYSA-N 0.000 description 2
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 description 2
- JUIKUQOUMZUFQT-UHFFFAOYSA-N 2-bromoacetamide Chemical compound NC(=O)CBr JUIKUQOUMZUFQT-UHFFFAOYSA-N 0.000 description 2
- REXUYBKPWIPONM-UHFFFAOYSA-N 2-bromoacetonitrile Chemical compound BrCC#N REXUYBKPWIPONM-UHFFFAOYSA-N 0.000 description 2
- UNCQVRBWJWWJBF-UHFFFAOYSA-N 2-chloropyrimidine Chemical compound ClC1=NC=CC=N1 UNCQVRBWJWWJBF-UHFFFAOYSA-N 0.000 description 2
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- YNNVWKYTJJOGEQ-UHFFFAOYSA-N 3-(1-aminoethyl)oxetan-3-ol Chemical compound CC(C1(COC1)O)N YNNVWKYTJJOGEQ-UHFFFAOYSA-N 0.000 description 2
- JGIYBKFOIUVCQB-UHFFFAOYSA-N 3-[(2-chloroacetyl)amino]-1-benzofuran-2-carboxamide Chemical compound C1=CC=C2C(NC(=O)CCl)=C(C(=O)N)OC2=C1 JGIYBKFOIUVCQB-UHFFFAOYSA-N 0.000 description 2
- KPLPXBCQZSGRGU-UHFFFAOYSA-N 3-amino-1-benzofuran-2-carbonitrile Chemical compound C1=CC=C2C(N)=C(C#N)OC2=C1 KPLPXBCQZSGRGU-UHFFFAOYSA-N 0.000 description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[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
- BGLPECHZZQDNCD-UHFFFAOYSA-N 4-(cyclopropylamino)-2-[4-(4-ethylsulfonylpiperazin-1-yl)anilino]pyrimidine-5-carboxamide Chemical compound C1CN(S(=O)(=O)CC)CCN1C(C=C1)=CC=C1NC1=NC=C(C(N)=O)C(NC2CC2)=N1 BGLPECHZZQDNCD-UHFFFAOYSA-N 0.000 description 2
- PJJGZPJJTHBVMX-UHFFFAOYSA-N 5,7-Dihydroxyisoflavone Chemical compound C=1C(O)=CC(O)=C(C2=O)C=1OC=C2C1=CC=CC=C1 PJJGZPJJTHBVMX-UHFFFAOYSA-N 0.000 description 2
- LSLYOANBFKQKPT-DIFFPNOSSA-N 5-[(1r)-1-hydroxy-2-[[(2r)-1-(4-hydroxyphenyl)propan-2-yl]amino]ethyl]benzene-1,3-diol Chemical compound C([C@@H](C)NC[C@H](O)C=1C=C(O)C=C(O)C=1)C1=CC=C(O)C=C1 LSLYOANBFKQKPT-DIFFPNOSSA-N 0.000 description 2
- YMXQSNGTVXQMLC-UHFFFAOYSA-N 5-bromo-3-fluoro-2-nitropyridine Chemical compound [O-][N+](=O)C1=NC=C(Br)C=C1F YMXQSNGTVXQMLC-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 241000208340 Araliaceae Species 0.000 description 2
- MBUVEWMHONZEQD-UHFFFAOYSA-N Azeptin Chemical compound C1CN(C)CCCC1N1C(=O)C2=CC=CC=C2C(CC=2C=CC(Cl)=CC=2)=N1 MBUVEWMHONZEQD-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 description 2
- IHDRGXRQBCPQAO-STQMWFEESA-N C#CC(C=C1N2CCOCC2)=CN=C1O[C@@H](C1)CN[C@@H]1C(O)=O Chemical compound C#CC(C=C1N2CCOCC2)=CN=C1O[C@@H](C1)CN[C@@H]1C(O)=O IHDRGXRQBCPQAO-STQMWFEESA-N 0.000 description 2
- GTIHJJKTNNBSGX-UHFFFAOYSA-N CC(C1(COC1)CCC1)N1C(OC(C)(C)C)=O Chemical compound CC(C1(COC1)CCC1)N1C(OC(C)(C)C)=O GTIHJJKTNNBSGX-UHFFFAOYSA-N 0.000 description 2
- JPQKGMUQDURMFD-UHFFFAOYSA-N CC(C1(COC1)O)[N+]([O-])=O Chemical compound CC(C1(COC1)O)[N+]([O-])=O JPQKGMUQDURMFD-UHFFFAOYSA-N 0.000 description 2
- ORHHEXXUBNUONC-UHFFFAOYSA-N CCC(C=C1)=CC(OCC#N)=C1C#N Chemical compound CCC(C=C1)=CC(OCC#N)=C1C#N ORHHEXXUBNUONC-UHFFFAOYSA-N 0.000 description 2
- GMSNHHLFEUHJCO-UHFFFAOYSA-N CCc1ccc2c(N)c(oc2c1)C#N Chemical compound CCc1ccc2c(N)c(oc2c1)C#N GMSNHHLFEUHJCO-UHFFFAOYSA-N 0.000 description 2
- CDTVVTCSHBHOTN-UHFFFAOYSA-N COc1cc(ccc1C#N)C(F)F Chemical compound COc1cc(ccc1C#N)C(F)F CDTVVTCSHBHOTN-UHFFFAOYSA-N 0.000 description 2
- JVYBGIZYBOMUIQ-QMMMGPOBSA-N C[C@@H](CC1(CC2)N=N1)N2C(OC(C)(C)C)=O Chemical compound C[C@@H](CC1(CC2)N=N1)N2C(OC(C)(C)C)=O JVYBGIZYBOMUIQ-QMMMGPOBSA-N 0.000 description 2
- LERNTVKEWCAPOY-VOGVJGKGSA-N C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 Chemical compound C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 LERNTVKEWCAPOY-VOGVJGKGSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- LUKZNWIVRBCLON-GXOBDPJESA-N Ciclesonide Chemical compound C1([C@H]2O[C@@]3([C@H](O2)C[C@@H]2[C@@]3(C[C@H](O)[C@@H]3[C@@]4(C)C=CC(=O)C=C4CC[C@H]32)C)C(=O)COC(=O)C(C)C)CCCCC1 LUKZNWIVRBCLON-GXOBDPJESA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 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 2
- LELOWRISYMNNSU-UHFFFAOYSA-N Hydrocyanic acid Natural products N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- ZJVFLBOZORBYFE-UHFFFAOYSA-N Ibudilast Chemical compound C1=CC=CC2=C(C(=O)C(C)C)C(C(C)C)=NN21 ZJVFLBOZORBYFE-UHFFFAOYSA-N 0.000 description 2
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 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
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 108060001084 Luciferase Proteins 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Meloxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- PVLJETXTTWAYEW-UHFFFAOYSA-N Mizolastine Chemical compound N=1C=CC(=O)NC=1N(C)C(CC1)CCN1C1=NC2=CC=CC=C2N1CC1=CC=C(F)C=C1 PVLJETXTTWAYEW-UHFFFAOYSA-N 0.000 description 2
- UCHDWCPVSPXUMX-TZIWLTJVSA-N Montelukast Chemical compound CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC(O)=O)CC1 UCHDWCPVSPXUMX-TZIWLTJVSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- PBANMIWKJNHXOK-UHFFFAOYSA-N NC(C(OC1=C2C=CC(C(F)F)=C1)=C2N)=O Chemical compound NC(C(OC1=C2C=CC(C(F)F)=C1)=C2N)=O PBANMIWKJNHXOK-UHFFFAOYSA-N 0.000 description 2
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 2
- JAUOIFJMECXRGI-UHFFFAOYSA-N Neoclaritin Chemical compound C=1C(Cl)=CC=C2C=1CCC1=CC=CN=C1C2=C1CCNCC1 JAUOIFJMECXRGI-UHFFFAOYSA-N 0.000 description 2
- WGQGCLHXUPGUSZ-HIFRSBDPSA-N OC(=O)[C@@H]1CCCC[C@@H]1NC(=O)c1c[nH]n2c1nc(cc2=O)-c1ccccc1 Chemical compound OC(=O)[C@@H]1CCCC[C@@H]1NC(=O)c1c[nH]n2c1nc(cc2=O)-c1ccccc1 WGQGCLHXUPGUSZ-HIFRSBDPSA-N 0.000 description 2
- SGNQZTCLNRMKBT-UHFFFAOYSA-N Oc1cc(ccc1C#N)C(F)F Chemical compound Oc1cc(ccc1C#N)C(F)F SGNQZTCLNRMKBT-UHFFFAOYSA-N 0.000 description 2
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 2
- 235000003140 Panax quinquefolius Nutrition 0.000 description 2
- 101150003085 Pdcl gene Proteins 0.000 description 2
- VQDBNKDJNJQRDG-UHFFFAOYSA-N Pirbuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=N1 VQDBNKDJNJQRDG-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- GIIZNNXWQWCKIB-UHFFFAOYSA-N Serevent Chemical compound C1=C(O)C(CO)=CC(C(O)CNCCCCCCOCCCCC=2C=CC=CC=2)=C1 GIIZNNXWQWCKIB-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 239000004012 Tofacitinib Substances 0.000 description 2
- YEEZWCHGZNKEEK-UHFFFAOYSA-N Zafirlukast Chemical compound COC1=CC(C(=O)NS(=O)(=O)C=2C(=CC=CC=2)C)=CC=C1CC(C1=C2)=CN(C)C1=CC=C2NC(=O)OC1CCCC1 YEEZWCHGZNKEEK-UHFFFAOYSA-N 0.000 description 2
- 239000005870 Ziram Substances 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001345 alkine derivatives Chemical class 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 150000001413 amino acids Chemical group 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 229960004574 azelastine Drugs 0.000 description 2
- 229960003060 bambuterol Drugs 0.000 description 2
- ANZXOIAKUNOVQU-UHFFFAOYSA-N bambuterol Chemical compound CN(C)C(=O)OC1=CC(OC(=O)N(C)C)=CC(C(O)CNC(C)(C)C)=C1 ANZXOIAKUNOVQU-UHFFFAOYSA-N 0.000 description 2
- NBMKJKDGKREAPL-DVTGEIKXSA-N beclomethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O NBMKJKDGKREAPL-DVTGEIKXSA-N 0.000 description 2
- 229940092705 beclomethasone Drugs 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 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
- 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 2
- CXNPLSGKWMLZPZ-UHFFFAOYSA-N blasticidin-S Natural products O1C(C(O)=O)C(NC(=O)CC(N)CCN(C)C(N)=N)C=CC1N1C(=O)N=C(N)C=C1 CXNPLSGKWMLZPZ-UHFFFAOYSA-N 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 150000001642 boronic acid derivatives Chemical class 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229960004436 budesonide Drugs 0.000 description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 2
- 229960000590 celecoxib Drugs 0.000 description 2
- 229950006295 cerdulatinib Drugs 0.000 description 2
- 229960001803 cetirizine Drugs 0.000 description 2
- 239000012320 chlorinating reagent Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 229960003728 ciclesonide Drugs 0.000 description 2
- 229960001117 clenbuterol Drugs 0.000 description 2
- STJMRWALKKWQGH-UHFFFAOYSA-N clenbuterol Chemical compound CC(C)(C)NCC(O)C1=CC(Cl)=C(N)C(Cl)=C1 STJMRWALKKWQGH-UHFFFAOYSA-N 0.000 description 2
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 2
- 125000006165 cyclic alkyl group Chemical group 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 210000000172 cytosol Anatomy 0.000 description 2
- 230000007123 defense Effects 0.000 description 2
- 229960001271 desloratadine Drugs 0.000 description 2
- 229960003957 dexamethasone Drugs 0.000 description 2
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 2
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 230000009266 disease activity Effects 0.000 description 2
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 229960001971 ebastine Drugs 0.000 description 2
- MJJALKDDGIKVBE-UHFFFAOYSA-N ebastine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)CCCN1CCC(OC(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 MJJALKDDGIKVBE-UHFFFAOYSA-N 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 230000003511 endothelial effect Effects 0.000 description 2
- 229960003449 epinastine Drugs 0.000 description 2
- WHWZLSFABNNENI-UHFFFAOYSA-N epinastine Chemical compound C1C2=CC=CC=C2C2CN=C(N)N2C2=CC=CC=C21 WHWZLSFABNNENI-UHFFFAOYSA-N 0.000 description 2
- MNJVRJDLRVPLFE-UHFFFAOYSA-N etoricoxib Chemical compound C1=NC(C)=CC=C1C1=NC=C(Cl)C=C1C1=CC=C(S(C)(=O)=O)C=C1 MNJVRJDLRVPLFE-UHFFFAOYSA-N 0.000 description 2
- 229960004945 etoricoxib Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229960001022 fenoterol Drugs 0.000 description 2
- 229960003592 fexofenadine Drugs 0.000 description 2
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 229960000676 flunisolide Drugs 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229960002714 fluticasone Drugs 0.000 description 2
- MGNNYOODZCAHBA-GQKYHHCASA-N fluticasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(O)[C@@]2(C)C[C@@H]1O MGNNYOODZCAHBA-GQKYHHCASA-N 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 229960002848 formoterol Drugs 0.000 description 2
- BPZSYCZIITTYBL-UHFFFAOYSA-N formoterol Chemical compound C1=CC(OC)=CC=C1CC(C)NCC(O)C1=CC=C(O)C(NC=O)=C1 BPZSYCZIITTYBL-UHFFFAOYSA-N 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 235000008434 ginseng Nutrition 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 2
- 125000006038 hexenyl group Chemical group 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 150000004678 hydrides Chemical class 0.000 description 2
- 229960002591 hydroxyproline Drugs 0.000 description 2
- 229960002491 ibudilast Drugs 0.000 description 2
- 229960001680 ibuprofen Drugs 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 230000036039 immunity Effects 0.000 description 2
- 229960000905 indomethacin Drugs 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 230000015788 innate immune response Effects 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 229960003088 loratadine Drugs 0.000 description 2
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 229960003464 mefenamic acid Drugs 0.000 description 2
- 229960001929 meloxicam Drugs 0.000 description 2
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 230000006676 mitochondrial damage Effects 0.000 description 2
- 230000002438 mitochondrial effect Effects 0.000 description 2
- 229960001144 mizolastine Drugs 0.000 description 2
- 229960001664 mometasone Drugs 0.000 description 2
- QLIIKPVHVRXHRI-CXSFZGCWSA-N mometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CCl)(O)[C@@]1(C)C[C@@H]2O QLIIKPVHVRXHRI-CXSFZGCWSA-N 0.000 description 2
- 229960005127 montelukast Drugs 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 229960002009 naproxen Drugs 0.000 description 2
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 230000009437 off-target effect Effects 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].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.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 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- 230000001717 pathogenic effect Effects 0.000 description 2
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 2
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 2
- YNPNZTXNASCQKK-UHFFFAOYSA-N phenanthrene Chemical compound C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 2
- 229960005414 pirbuterol Drugs 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 229960004583 pranlukast Drugs 0.000 description 2
- UAJUXJSXCLUTNU-UHFFFAOYSA-N pranlukast Chemical compound C=1C=C(OCCCCC=2C=CC=CC=2)C=CC=1C(=O)NC(C=1)=CC=C(C(C=2)=O)C=1OC=2C=1N=NNN=1 UAJUXJSXCLUTNU-UHFFFAOYSA-N 0.000 description 2
- 229960002288 procaterol Drugs 0.000 description 2
- FKNXQNWAXFXVNW-BLLLJJGKSA-N procaterol Chemical compound N1C(=O)C=CC2=C1C(O)=CC=C2[C@@H](O)[C@@H](NC(C)C)CC FKNXQNWAXFXVNW-BLLLJJGKSA-N 0.000 description 2
- MIXMJCQRHVAJIO-TZHJZOAOSA-N qk4dys664x Chemical compound O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O MIXMJCQRHVAJIO-TZHJZOAOSA-N 0.000 description 2
- 230000008929 regeneration Effects 0.000 description 2
- 238000011069 regeneration method Methods 0.000 description 2
- 230000008439 repair process Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229960004017 salmeterol Drugs 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 235000015424 sodium Nutrition 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 238000007910 systemic administration Methods 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 229960000278 theophylline Drugs 0.000 description 2
- 229960000257 tiotropium bromide Drugs 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 229960003989 tocilizumab Drugs 0.000 description 2
- 229960001350 tofacitinib Drugs 0.000 description 2
- UJLAWZDWDVHWOW-YPMHNXCESA-N tofacitinib Chemical compound C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)C1=NC=NC2=C1C=CN2 UJLAWZDWDVHWOW-YPMHNXCESA-N 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 2
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 2
- 230000001960 triggered effect Effects 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 241000701447 unidentified baculovirus Species 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- 238000013389 whole blood assay Methods 0.000 description 2
- 229960004764 zafirlukast Drugs 0.000 description 2
- MWLSOWXNZPKENC-SSDOTTSWSA-N zileuton Chemical compound C1=CC=C2SC([C@H](N(O)C(N)=O)C)=CC2=C1 MWLSOWXNZPKENC-SSDOTTSWSA-N 0.000 description 2
- 229960005332 zileuton Drugs 0.000 description 2
- XWTYSIMOBUGWOL-UHFFFAOYSA-N (+-)-Terbutaline Chemical compound CC(C)(C)NCC(O)C1=CC(O)=CC(O)=C1 XWTYSIMOBUGWOL-UHFFFAOYSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 description 1
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 1
- 125000006590 (C2-C6) alkenylene group Chemical group 0.000 description 1
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 description 1
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- SCZNXLWKYFICFV-UHFFFAOYSA-N 1,2,3,4,5,7,8,9-octahydropyrido[1,2-b]diazepine Chemical compound C1CCCNN2CCCC=C21 SCZNXLWKYFICFV-UHFFFAOYSA-N 0.000 description 1
- CSNIZNHTOVFARY-UHFFFAOYSA-N 1,2-benzothiazole Chemical class C1=CC=C2C=NSC2=C1 CSNIZNHTOVFARY-UHFFFAOYSA-N 0.000 description 1
- 125000004815 1,2-dimethylethylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([*:2])C([H])([H])[H] 0.000 description 1
- 125000004824 1,3-dimethylpropylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])C([H])([*:2])C([H])([H])[H] 0.000 description 1
- IBXMKLPFLZYRQZ-UHFFFAOYSA-N 1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1C=CC(=O)C=CC1=CC=CC=C1 IBXMKLPFLZYRQZ-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000006019 1-methyl-1-propenyl group Chemical group 0.000 description 1
- 125000006021 1-methyl-2-propenyl group Chemical group 0.000 description 1
- 125000004806 1-methylethylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000002152 1H-pyrrolizinyl group Chemical class C1(C=CN2C=CC=C12)* 0.000 description 1
- QHQZEEGNGSZBOL-UHFFFAOYSA-N 2-(aminomethyl)-2-(hydroxymethyl)propane-1,3-diol Chemical compound NCC(CO)(CO)CO QHQZEEGNGSZBOL-UHFFFAOYSA-N 0.000 description 1
- YBDSNEVSFQMCTL-UHFFFAOYSA-N 2-(diethylamino)ethanethiol Chemical compound CCN(CC)CCS YBDSNEVSFQMCTL-UHFFFAOYSA-N 0.000 description 1
- LSVICRMDTZSTDC-UHFFFAOYSA-N 2-acetyloxybenzoic acid Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O.CC(=O)OC1=CC=CC=C1C(O)=O LSVICRMDTZSTDC-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- LONXFNWBWBLJNP-UHFFFAOYSA-N 2-chloro-5-nitropyrazine Chemical compound [O-][N+](=O)C1=CN=C(Cl)C=N1 LONXFNWBWBLJNP-UHFFFAOYSA-N 0.000 description 1
- IVXNIUMDPHLSBV-UHFFFAOYSA-N 2-fluoro-4-iodo-3-methoxypyridine Chemical compound COC1=C(F)N=CC=C1I IVXNIUMDPHLSBV-UHFFFAOYSA-N 0.000 description 1
- SDTMFDGELKWGFT-UHFFFAOYSA-N 2-methylpropan-2-olate Chemical compound CC(C)(C)[O-] SDTMFDGELKWGFT-UHFFFAOYSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- 125000004924 2-naphthylethyl group Chemical group C1=C(C=CC2=CC=CC=C12)CC* 0.000 description 1
- TWBPWBPGNQWFSJ-UHFFFAOYSA-N 2-phenylaniline Chemical group NC1=CC=CC=C1C1=CC=CC=C1 TWBPWBPGNQWFSJ-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- FXOYSSLDDDZIJN-UHFFFAOYSA-N 3-amino-1-benzofuran-2-carboxamide Chemical compound C1=CC=C2C(N)=C(C(=O)N)OC2=C1 FXOYSSLDDDZIJN-UHFFFAOYSA-N 0.000 description 1
- MTJGVAJYTOXFJH-UHFFFAOYSA-N 3-aminonaphthalene-1,5-disulfonic acid Chemical compound C1=CC=C(S(O)(=O)=O)C2=CC(N)=CC(S(O)(=O)=O)=C21 MTJGVAJYTOXFJH-UHFFFAOYSA-N 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- YTEIHWVCQJZNEN-UHFFFAOYSA-N 3-pyridin-4-ylpyridine Chemical compound C1=CN=CC(C=2C=CN=CC=2)=C1 YTEIHWVCQJZNEN-UHFFFAOYSA-N 0.000 description 1
- PZSMUPGANZGPBF-UHFFFAOYSA-N 4-[5-(dithiolan-3-yl)pentanoylamino]butanoic acid Chemical compound OC(=O)CCCNC(=O)CCCCC1CCSS1 PZSMUPGANZGPBF-UHFFFAOYSA-N 0.000 description 1
- PCWRBBLXAOCSQC-UHFFFAOYSA-N 4-bromo-1-cyclopropylpyrazole Chemical compound C1=C(Br)C=NN1C1CC1 PCWRBBLXAOCSQC-UHFFFAOYSA-N 0.000 description 1
- ATNPXZIVQPMNAU-UHFFFAOYSA-N 4-bromo-3-methoxy-n,n-dimethylpyridin-2-amine Chemical compound COC1=C(Br)C=CN=C1N(C)C ATNPXZIVQPMNAU-UHFFFAOYSA-N 0.000 description 1
- HKZMXPYRQCDFCR-UHFFFAOYSA-N 4-bromo-n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC(Br)=CC=N1 HKZMXPYRQCDFCR-UHFFFAOYSA-N 0.000 description 1
- WOZVPMDTZPJZAR-UHFFFAOYSA-N 4-ethyl-2-hydroxybenzonitrile Chemical compound CCC1=CC=C(C#N)C(O)=C1 WOZVPMDTZPJZAR-UHFFFAOYSA-N 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- 125000004938 5-pyridyl group Chemical group N1=CC=CC(=C1)* 0.000 description 1
- TVEXGJYMHHTVKP-UHFFFAOYSA-N 6-oxabicyclo[3.2.1]oct-3-en-7-one Chemical compound C1C2C(=O)OC1C=CC2 TVEXGJYMHHTVKP-UHFFFAOYSA-N 0.000 description 1
- OHCGIXVHHALVQI-UHFFFAOYSA-N 9-methyl-2,5-dioxa-8-azaspiro[3.5]nonane Chemical compound CC1C2(COC2)OCCN1 OHCGIXVHHALVQI-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 208000009304 Acute Kidney Injury Diseases 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- HJCMDXDYPOUFDY-WHFBIAKZSA-N Ala-Gln Chemical compound C[C@H](N)C(=O)N[C@H](C(O)=O)CCC(N)=O HJCMDXDYPOUFDY-WHFBIAKZSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 102100035631 Bloom syndrome protein Human genes 0.000 description 1
- 108091009167 Bloom syndrome protein Proteins 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 239000005885 Buprofezin Substances 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- LPHYTISTLYHFCU-UHFFFAOYSA-N CC(C(CO)(CO)CCC1)N1C(OC(C)(C)C)=O Chemical compound CC(C(CO)(CO)CCC1)N1C(OC(C)(C)C)=O LPHYTISTLYHFCU-UHFFFAOYSA-N 0.000 description 1
- UPZJKUOKVMXQFC-UHFFFAOYSA-N CC(C(NC1=C(C#N)OC2=C1C=CC=C2)=O)(F)F Chemical compound CC(C(NC1=C(C#N)OC2=C1C=CC=C2)=O)(F)F UPZJKUOKVMXQFC-UHFFFAOYSA-N 0.000 description 1
- NDJUOFKHBDRFOV-UHFFFAOYSA-N CC(C)[Si](C(C)C)(C(C)C)C#CC(C=C1N2C(C)C3(COC3)OCC2)=CN=C1[N+]([O-])=O Chemical compound CC(C)[Si](C(C)C)(C(C)C)C#CC(C=C1N2C(C)C3(COC3)OCC2)=CN=C1[N+]([O-])=O NDJUOFKHBDRFOV-UHFFFAOYSA-N 0.000 description 1
- CBQKSHSPXQTNRA-UHFFFAOYSA-N CC(C1(COC1)OCC1)N1C1=CC(Br)=CN=C1[N+]([O-])=O Chemical compound CC(C1(COC1)OCC1)N1C1=CC(Br)=CN=C1[N+]([O-])=O CBQKSHSPXQTNRA-UHFFFAOYSA-N 0.000 description 1
- NVPHHDLPKASABY-UHFFFAOYSA-N CC(C1(COC1)OCC1)N1C1=CC(F)=CN=C1F Chemical compound CC(C1(COC1)OCC1)N1C1=CC(F)=CN=C1F NVPHHDLPKASABY-UHFFFAOYSA-N 0.000 description 1
- VRBXIEKGFURPLJ-UHFFFAOYSA-N CC1NCCCC11COC1 Chemical compound CC1NCCCC11COC1 VRBXIEKGFURPLJ-UHFFFAOYSA-N 0.000 description 1
- SXTWYVFBOFVNAX-UHFFFAOYSA-N CC1NCCCC1C(OC)=O.CC(O)=O Chemical compound CC1NCCCC1C(OC)=O.CC(O)=O SXTWYVFBOFVNAX-UHFFFAOYSA-N 0.000 description 1
- 241001678559 COVID-19 virus Species 0.000 description 1
- IYQOGOPRBGSURN-UHFFFAOYSA-N COc1c(F)nccc1Br Chemical compound COc1c(F)nccc1Br IYQOGOPRBGSURN-UHFFFAOYSA-N 0.000 description 1
- HXPJYRZMUNJNPP-QEJZJMRPSA-N C[C@@H](C1(COC1)OCC1)N1C1=CC(C#C)=CN=C1O[C@@H](C1)CN[C@@H]1C(O)=O Chemical compound C[C@@H](C1(COC1)OCC1)N1C1=CC(C#C)=CN=C1O[C@@H](C1)CN[C@@H]1C(O)=O HXPJYRZMUNJNPP-QEJZJMRPSA-N 0.000 description 1
- GOVCWAXAGKPMQB-IEZWGBDMSA-N C[C@@H](C1(COC1)OCC1)N1C1=CC(C#C)=CN=C1O[C@@H](C[C@H]1C(O)=O)CN1C(OC(C)(C)C)=O Chemical compound C[C@@H](C1(COC1)OCC1)N1C1=CC(C#C)=CN=C1O[C@@H](C[C@H]1C(O)=O)CN1C(OC(C)(C)C)=O GOVCWAXAGKPMQB-IEZWGBDMSA-N 0.000 description 1
- KYECFWYMZBNBBY-YFKPBYRVSA-N C[C@@H](C1)NCCC11N=N1 Chemical compound C[C@@H](C1)NCCC11N=N1 KYECFWYMZBNBBY-YFKPBYRVSA-N 0.000 description 1
- LKRXOVYRLWSAHR-QMMMGPOBSA-N C[C@@H](CN(CC1)C#N)N1C1=CC(Br)=CN=C1[N+]([O-])=O Chemical compound C[C@@H](CN(CC1)C#N)N1C1=CC(Br)=CN=C1[N+]([O-])=O LKRXOVYRLWSAHR-QMMMGPOBSA-N 0.000 description 1
- HJYGPQZUYXJCRV-ZETCQYMHSA-N C[C@@H](CNCC1)N1C1=CC(Br)=CN=C1[N+]([O-])=O Chemical compound C[C@@H](CNCC1)N1C1=CC(Br)=CN=C1[N+]([O-])=O HJYGPQZUYXJCRV-ZETCQYMHSA-N 0.000 description 1
- RLZFQTKFIWLPTD-FJXQXJEOSA-N C[C@@H](CNCC1)N1C1=CC(Br)=CN=C1[N+]([O-])=O.Cl Chemical compound C[C@@H](CNCC1)N1C1=CC(Br)=CN=C1[N+]([O-])=O.Cl RLZFQTKFIWLPTD-FJXQXJEOSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 102000053642 Catalytic RNA Human genes 0.000 description 1
- 108090000994 Catalytic RNA Proteins 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- 208000037051 Chromosomal Instability Diseases 0.000 description 1
- 241000207199 Citrus Species 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 108030002637 Cyclic GMP-AMP synthases Proteins 0.000 description 1
- 244000110556 Cyclopia subternata Species 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
- XUIIKFGFIJCVMT-GFCCVEGCSA-N D-thyroxine Chemical compound IC1=CC(C[C@@H](N)C(O)=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-GFCCVEGCSA-N 0.000 description 1
- 108010053770 Deoxyribonucleases Proteins 0.000 description 1
- 102000016911 Deoxyribonucleases Human genes 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- QEVGZEDELICMKH-UHFFFAOYSA-N Diglycolic acid Chemical compound OC(=O)COCC(O)=O QEVGZEDELICMKH-UHFFFAOYSA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 239000004150 EU approved colour Substances 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 108060002716 Exonuclease Proteins 0.000 description 1
- DAWJNFVHVJJBQB-UHFFFAOYSA-N FC(C(N1CC2=CON=C2CC1)=C1)=NC=C1Cl Chemical compound FC(C(N1CC2=CON=C2CC1)=C1)=NC=C1Cl DAWJNFVHVJJBQB-UHFFFAOYSA-N 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- SQSZANZGUXWJEA-UHFFFAOYSA-N Gandotinib Chemical compound N1C(C)=CC(NC2=NN3C(CC=4C(=CC(Cl)=CC=4)F)=C(C)N=C3C(CN3CCOCC3)=C2)=N1 SQSZANZGUXWJEA-UHFFFAOYSA-N 0.000 description 1
- 201000004311 Gilles de la Tourette syndrome Diseases 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 101000959794 Homo sapiens Interferon alpha-2 Proteins 0.000 description 1
- 101000643024 Homo sapiens Stimulator of interferon genes protein Proteins 0.000 description 1
- 101000830956 Homo sapiens Three-prime repair exonuclease 1 Proteins 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 102100040018 Interferon alpha-2 Human genes 0.000 description 1
- 206010023421 Kidney fibrosis Diseases 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 1
- 229930064664 L-arginine Natural products 0.000 description 1
- 235000014852 L-arginine Nutrition 0.000 description 1
- 239000002144 L01XE18 - Ruxolitinib Substances 0.000 description 1
- 241001424413 Lucia Species 0.000 description 1
- 239000005089 Luciferase Substances 0.000 description 1
- 208000004852 Lung Injury Diseases 0.000 description 1
- 102000014944 Lysosome-Associated Membrane Glycoproteins Human genes 0.000 description 1
- 108010064171 Lysosome-Associated Membrane Glycoproteins Proteins 0.000 description 1
- 101710175243 Major antigen Proteins 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Natural products C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 1
- ZKGNPQKYVKXMGJ-UHFFFAOYSA-N N,N-dimethylacetamide Chemical compound CN(C)C(C)=O.CN(C)C(C)=O ZKGNPQKYVKXMGJ-UHFFFAOYSA-N 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
- JOOXLOJCABQBSG-UHFFFAOYSA-N N-tert-butyl-3-[[5-methyl-2-[4-[2-(1-pyrrolidinyl)ethoxy]anilino]-4-pyrimidinyl]amino]benzenesulfonamide Chemical compound N1=C(NC=2C=C(C=CC=2)S(=O)(=O)NC(C)(C)C)C(C)=CN=C1NC(C=C1)=CC=C1OCCN1CCCC1 JOOXLOJCABQBSG-UHFFFAOYSA-N 0.000 description 1
- 102000003945 NF-kappa B Human genes 0.000 description 1
- 108010057466 NF-kappa B Proteins 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 208000033626 Renal failure acute Diseases 0.000 description 1
- 108700008625 Reporter Genes Proteins 0.000 description 1
- 241000219061 Rheum Species 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 102100038192 Serine/threonine-protein kinase TBK1 Human genes 0.000 description 1
- 101710106944 Serine/threonine-protein kinase TBK1 Proteins 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 102100035533 Stimulator of interferon genes protein Human genes 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 239000012505 Superdex™ Substances 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 102100040347 TAR DNA-binding protein 43 Human genes 0.000 description 1
- 101710150875 TAR DNA-binding protein 43 Proteins 0.000 description 1
- PZBFGYYEXUXCOF-UHFFFAOYSA-N TCEP Chemical compound OC(=O)CCP(CCC(O)=O)CCC(O)=O PZBFGYYEXUXCOF-UHFFFAOYSA-N 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- 102100024855 Three-prime repair exonuclease 1 Human genes 0.000 description 1
- 208000000323 Tourette Syndrome Diseases 0.000 description 1
- 208000016620 Tourette disease Diseases 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 206010069363 Traumatic lung injury Diseases 0.000 description 1
- 101150012828 UPC2 gene Proteins 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 241001660687 Xantho Species 0.000 description 1
- 108010084455 Zeocin Proteins 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- ANGKOCUUWGHLCE-HKUYNNGSSA-N [(3s)-1,1-dimethylpyrrolidin-1-ium-3-yl] (2r)-2-cyclopentyl-2-hydroxy-2-phenylacetate Chemical class C1[N+](C)(C)CC[C@@H]1OC(=O)[C@](O)(C=1C=CC=CC=1)C1CCCC1 ANGKOCUUWGHLCE-HKUYNNGSSA-N 0.000 description 1
- WKHOPHIMYDJVSA-UHFFFAOYSA-N [3-[2-(tert-butylamino)-1-hydroxyethyl]-5-(2-methylpropanoyloxy)phenyl] 2-methylpropanoate Chemical compound CC(C)C(=O)OC1=CC(OC(=O)C(C)C)=CC(C(O)CNC(C)(C)C)=C1 WKHOPHIMYDJVSA-UHFFFAOYSA-N 0.000 description 1
- ISYOFZCEMBXHOL-UHFFFAOYSA-M [Li].CC(C)[Mg]Cl Chemical compound [Li].CC(C)[Mg]Cl ISYOFZCEMBXHOL-UHFFFAOYSA-M 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 201000011040 acute kidney failure Diseases 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 210000005006 adaptive immune system Anatomy 0.000 description 1
- 108091005764 adaptor proteins Proteins 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000808 adrenergic beta-agonist Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- DQPBABKTKYNPMH-UHFFFAOYSA-N amino hydrogen sulfate Chemical compound NOS(O)(=O)=O DQPBABKTKYNPMH-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 210000000612 antigen-presenting cell Anatomy 0.000 description 1
- 229940111121 antirheumatic drug quinolines Drugs 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- 238000006254 arylation reaction Methods 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 230000006472 autoimmune response Effects 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 150000001556 benzimidazoles Chemical class 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 150000001562 benzopyrans Chemical class 0.000 description 1
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical class C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 230000003454 betamimetic effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 229960004620 bitolterol Drugs 0.000 description 1
- FZGVEKPRDOIXJY-UHFFFAOYSA-N bitolterol Chemical compound C1=CC(C)=CC=C1C(=O)OC1=CC=C(C(O)CNC(C)(C)C)C=C1OC(=O)C1=CC=C(C)C=C1 FZGVEKPRDOIXJY-UHFFFAOYSA-N 0.000 description 1
- 238000004159 blood analysis Methods 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 125000005620 boronic acid group Chemical group 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- PRLVTUNWOQKEAI-VKAVYKQESA-N buprofezin Chemical compound O=C1N(C(C)C)\C(=N\C(C)(C)C)SCN1C1=CC=CC=C1 PRLVTUNWOQKEAI-VKAVYKQESA-N 0.000 description 1
- 125000005569 butenylene group Chemical group 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 235000019577 caloric intake Nutrition 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229960001386 carbuterol Drugs 0.000 description 1
- KEMXXQOFIRIICG-UHFFFAOYSA-N carbuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(NC(N)=O)=C1 KEMXXQOFIRIICG-UHFFFAOYSA-N 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000000423 cell based assay Methods 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- DREIJXJRTLTGJC-ZLBJMMTISA-N chembl3137308 Chemical compound C([C@H]1C[C@@](O)(C2)C3)C2C[C@H]3[C@H]1NC1=C2C=CNC2=NC=C1C(=O)N DREIJXJRTLTGJC-ZLBJMMTISA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 235000019504 cigarettes Nutrition 0.000 description 1
- 235000020971 citrus fruits Nutrition 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 239000003433 contraceptive agent Substances 0.000 description 1
- 230000002254 contraceptive effect Effects 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 150000001907 coumarones Chemical class 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229940109275 cyclamate Drugs 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 239000000409 cytokine receptor agonist Substances 0.000 description 1
- 239000000430 cytokine receptor antagonist Substances 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
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- 230000004041 dendritic cell maturation Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- HKBUFTCADGLKAS-UHFFFAOYSA-N diazonio(trimethylsilylmethyl)azanide Chemical compound C[Si](C)(C)C[N-][N+]#N HKBUFTCADGLKAS-UHFFFAOYSA-N 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- QKIUAMUSENSFQQ-UHFFFAOYSA-N dimethylazanide Chemical compound C[N-]C QKIUAMUSENSFQQ-UHFFFAOYSA-N 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- REWLCYPYZCHYSS-UHFFFAOYSA-N ditert-butyl-[3,6-dimethoxy-2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane Chemical compound COC1=CC=C(OC)C(C=2C(=CC(=CC=2C(C)C)C(C)C)C(C)C)=C1P(C(C)(C)C)C(C)(C)C REWLCYPYZCHYSS-UHFFFAOYSA-N 0.000 description 1
- 230000007783 downstream signaling Effects 0.000 description 1
- 230000036267 drug metabolism Effects 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000000119 electrospray ionisation mass spectrum Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 231100001129 embryonic lethality Toxicity 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000012202 endocytosis Effects 0.000 description 1
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- KZGWPHUWNWRTEP-UHFFFAOYSA-N ethynyl-tri(propan-2-yl)silane Chemical group CC(C)[Si](C#C)(C(C)C)C(C)C KZGWPHUWNWRTEP-UHFFFAOYSA-N 0.000 description 1
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 102000013165 exonuclease Human genes 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 229950003487 fedratinib Drugs 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 229950006663 filgotinib Drugs 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000002875 fluorescence polarization Methods 0.000 description 1
- 235000019264 food flavour enhancer Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229950008908 gandotinib Drugs 0.000 description 1
- 238000003209 gene knockout Methods 0.000 description 1
- 229960005219 gentisic acid Drugs 0.000 description 1
- 229960005150 glycerol Drugs 0.000 description 1
- 229960002462 glycopyrronium bromide Drugs 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 229950002451 ibuterol Drugs 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 230000000899 immune system response Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 150000002473 indoazoles Chemical class 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 150000002478 indolizines Chemical class 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- OEXHQOGQTVQTAT-JRNQLAHRSA-N ipratropium Chemical class O([C@H]1C[C@H]2CC[C@@H](C1)[N@@+]2(C)C(C)C)C(=O)C(CO)C1=CC=CC=C1 OEXHQOGQTVQTAT-JRNQLAHRSA-N 0.000 description 1
- 150000002518 isoindoles Chemical class 0.000 description 1
- 238000002955 isolation Methods 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
- 150000002537 isoquinolines Chemical class 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 229960001120 levocabastine Drugs 0.000 description 1
- ZCGOMHNNNFPNMX-KYTRFIICSA-N levocabastine Chemical compound C1([C@@]2(C(O)=O)CCN(C[C@H]2C)[C@@H]2CC[C@@](CC2)(C#N)C=2C=CC(F)=CC=2)=CC=CC=C1 ZCGOMHNNNFPNMX-KYTRFIICSA-N 0.000 description 1
- 229920005610 lignin Polymers 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- DBTNVRCCIDISMV-UHFFFAOYSA-L lithium;magnesium;propane;dichloride Chemical compound [Li+].[Mg+2].[Cl-].[Cl-].C[CH-]C DBTNVRCCIDISMV-UHFFFAOYSA-L 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 229940127212 long-acting beta 2 agonist Drugs 0.000 description 1
- 229940125389 long-acting beta agonist Drugs 0.000 description 1
- 230000004777 loss-of-function mutation Effects 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 231100000515 lung injury Toxicity 0.000 description 1
- 210000003712 lysosome Anatomy 0.000 description 1
- 230000001868 lysosomic effect Effects 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000008384 membrane barrier Effects 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- GPKUICFDWYEPTK-UHFFFAOYSA-N methoxycyclohexatriene Chemical compound COC1=CC=C=C[CH]1 GPKUICFDWYEPTK-UHFFFAOYSA-N 0.000 description 1
- ZORUKIWYFWDAKK-UHFFFAOYSA-N methyl 2-methylpiperidine-3-carboxylate Chemical compound COC(=O)C1CCCNC1C ZORUKIWYFWDAKK-UHFFFAOYSA-N 0.000 description 1
- KLHWBYHFWALOIJ-UHFFFAOYSA-N methyl 2-methylpyridine-3-carboxylate Chemical compound COC(=O)C1=CC=CN=C1C KLHWBYHFWALOIJ-UHFFFAOYSA-N 0.000 description 1
- IGKIFXSXUCBPOT-UHFFFAOYSA-N methyl 4-amino-6-anilino-1,3,5-triazine-2-carboxylate Chemical compound COC(=O)c1nc(N)nc(Nc2ccccc2)n1 IGKIFXSXUCBPOT-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- BLWYXBNNBYXPPL-UHFFFAOYSA-N methyl pyrrolidine-2-carboxylate Chemical compound COC(=O)C1CCCN1 BLWYXBNNBYXPPL-UHFFFAOYSA-N 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 229950008814 momelotinib Drugs 0.000 description 1
- ZVHNDZWQTBEVRY-UHFFFAOYSA-N momelotinib Chemical compound C1=CC(C(NCC#N)=O)=CC=C1C1=CC=NC(NC=2C=CC(=CC=2)N2CCOCC2)=N1 ZVHNDZWQTBEVRY-UHFFFAOYSA-N 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- HAASCECTXNYFCI-UHFFFAOYSA-N morpholine-2-carbonitrile Chemical compound N#CC1CNCCO1 HAASCECTXNYFCI-UHFFFAOYSA-N 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- RIJLVEAXPNLDTC-UHFFFAOYSA-N n-[5-[4-[(1,1-dioxo-1,4-thiazinan-4-yl)methyl]phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide Chemical compound C1CC1C(=O)NC(=NN12)N=C1C=CC=C2C(C=C1)=CC=C1CN1CCS(=O)(=O)CC1 RIJLVEAXPNLDTC-UHFFFAOYSA-N 0.000 description 1
- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
- CJYQZTZSYREQBD-UHFFFAOYSA-N n-fluorobenzenesulfonamide Chemical compound FNS(=O)(=O)C1=CC=CC=C1 CJYQZTZSYREQBD-UHFFFAOYSA-N 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
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000004971 nitroalkyl group Chemical group 0.000 description 1
- MCSAJNNLRCFZED-UHFFFAOYSA-N nitroethane Chemical compound CC[N+]([O-])=O MCSAJNNLRCFZED-UHFFFAOYSA-N 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 description 1
- 229950011410 pacritinib Drugs 0.000 description 1
- HWXVIOGONBBTBY-ONEGZZNKSA-N pacritinib Chemical compound C=1C=C(C=2)NC(N=3)=NC=CC=3C(C=3)=CC=CC=3COC\C=C\COCC=2C=1OCCN1CCCC1 HWXVIOGONBBTBY-ONEGZZNKSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 229950005157 peficitinib Drugs 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 230000008447 perception Effects 0.000 description 1
- 229950011087 perflunafene Drugs 0.000 description 1
- UWEYRJFJVCLAGH-IJWZVTFUSA-N perfluorodecalin Chemical compound FC1(F)C(F)(F)C(F)(F)C(F)(F)[C@@]2(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)[C@@]21F UWEYRJFJVCLAGH-IJWZVTFUSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- CWCMIVBLVUHDHK-ZSNHEYEWSA-N phleomycin D1 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC[C@@H](N=1)C=1SC=C(N=1)C(=O)NCCCCNC(N)=N)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C CWCMIVBLVUHDHK-ZSNHEYEWSA-N 0.000 description 1
- FGYSUIMDQWOPPQ-UHFFFAOYSA-N phosphane;trifluoromethanesulfonic acid Chemical compound [PH4+].[O-]S(=O)(=O)C(F)(F)F FGYSUIMDQWOPPQ-UHFFFAOYSA-N 0.000 description 1
- ISWRGOKTTBVCFA-UHFFFAOYSA-N pirfenidone Chemical compound C1=C(C)C=CC(=O)N1C1=CC=CC=C1 ISWRGOKTTBVCFA-UHFFFAOYSA-N 0.000 description 1
- 229960003073 pirfenidone Drugs 0.000 description 1
- 210000005134 plasmacytoid dendritic cell Anatomy 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000007126 proinflammatory cytokine response Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- YYVGYULIMDRZMJ-UHFFFAOYSA-N propan-2-ylsilane Chemical compound CC(C)[SiH3] YYVGYULIMDRZMJ-UHFFFAOYSA-N 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- MWWATHDPGQKSAR-UHFFFAOYSA-N propyne Chemical group CC#C MWWATHDPGQKSAR-UHFFFAOYSA-N 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000003195 pteridines Chemical class 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- QLULGIRFKAWHOJ-UHFFFAOYSA-N pyridin-4-ylboronic acid Chemical compound OB(O)C1=CC=NC=C1 QLULGIRFKAWHOJ-UHFFFAOYSA-N 0.000 description 1
- 150000008518 pyridopyrimidines Chemical class 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- JOZPEVMCAKXSEY-UHFFFAOYSA-N pyrimido[5,4-d]pyrimidine Chemical class N1=CN=CC2=NC=NC=C21 JOZPEVMCAKXSEY-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229960002720 reproterol Drugs 0.000 description 1
- WVLAAKXASPCBGT-UHFFFAOYSA-N reproterol Chemical compound C1=2C(=O)N(C)C(=O)N(C)C=2N=CN1CCCNCC(O)C1=CC(O)=CC(O)=C1 WVLAAKXASPCBGT-UHFFFAOYSA-N 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 108091092562 ribozyme Proteins 0.000 description 1
- IXTCZMJQGGONPY-XJAYAHQCSA-N rofleponide Chemical compound C1([C@@H](F)C2)=CC(=O)CC[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3O[C@@H](CCC)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O IXTCZMJQGGONPY-XJAYAHQCSA-N 0.000 description 1
- 229950004432 rofleponide Drugs 0.000 description 1
- 229960000215 ruxolitinib Drugs 0.000 description 1
- HFNKQEVNSGCOJV-OAHLLOKOSA-N ruxolitinib Chemical compound C1([C@@H](CC#N)N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)CCCC1 HFNKQEVNSGCOJV-OAHLLOKOSA-N 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229960002052 salbutamol Drugs 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 230000009758 senescence Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 229940125390 short-acting beta agonist Drugs 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 238000001542 size-exclusion chromatography Methods 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- RMBAVIFYHOYIFM-UHFFFAOYSA-M sodium methanethiolate Chemical compound [Na+].[S-]C RMBAVIFYHOYIFM-UHFFFAOYSA-M 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- WPLOVIFNBMNBPD-ATHMIXSHSA-N subtilin Chemical compound CC1SCC(NC2=O)C(=O)NC(CC(N)=O)C(=O)NC(C(=O)NC(CCCCN)C(=O)NC(C(C)CC)C(=O)NC(=C)C(=O)NC(CCCCN)C(O)=O)CSC(C)C2NC(=O)C(CC(C)C)NC(=O)C1NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C1NC(=O)C(=C/C)/NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C2NC(=O)CNC(=O)C3CCCN3C(=O)C(NC(=O)C3NC(=O)C(CC(C)C)NC(=O)C(=C)NC(=O)C(CCC(O)=O)NC(=O)C(NC(=O)C(CCCCN)NC(=O)C(N)CC=4C5=CC=CC=C5NC=4)CSC3)C(C)SC2)C(C)C)C(C)SC1)CC1=CC=CC=C1 WPLOVIFNBMNBPD-ATHMIXSHSA-N 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000009492 tablet coating Methods 0.000 description 1
- 239000002700 tablet coating Substances 0.000 description 1
- 238000004885 tandem mass spectrometry Methods 0.000 description 1
- 229960000195 terbutaline Drugs 0.000 description 1
- HQMYWQCBINPHBB-QMMMGPOBSA-N tert-butyl (2s)-2-methyl-4-oxopiperidine-1-carboxylate Chemical compound C[C@H]1CC(=O)CCN1C(=O)OC(C)(C)C HQMYWQCBINPHBB-QMMMGPOBSA-N 0.000 description 1
- FMLPQHJYUZTHQS-QMMMGPOBSA-N tert-butyl (3s)-3-methylpiperazine-1-carboxylate Chemical compound C[C@H]1CN(C(=O)OC(C)(C)C)CCN1 FMLPQHJYUZTHQS-QMMMGPOBSA-N 0.000 description 1
- LCZVKKUAUWQDPX-UHFFFAOYSA-N tert-butyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]amino]ethyl]amino]acetate Chemical compound CC(=O)OC1=CC=CC=C1CN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1=CC=CC=C1OC(C)=O LCZVKKUAUWQDPX-UHFFFAOYSA-N 0.000 description 1
- FESDUDPSRMWIDL-UHFFFAOYSA-N tert-butyl n,n'-di(propan-2-yl)carbamimidate Chemical compound CC(C)NC(OC(C)(C)C)=NC(C)C FESDUDPSRMWIDL-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 229940034208 thyroxine Drugs 0.000 description 1
- XUIIKFGFIJCVMT-UHFFFAOYSA-N thyroxine-binding globulin Natural products IC1=CC(CC([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-UHFFFAOYSA-N 0.000 description 1
- LERNTVKEWCAPOY-DZZGSBJMSA-N tiotropium Chemical class O([C@H]1C[C@@H]2[N+]([C@H](C1)[C@@H]1[C@H]2O1)(C)C)C(=O)C(O)(C=1SC=CC=1)C1=CC=CS1 LERNTVKEWCAPOY-DZZGSBJMSA-N 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 235000010215 titanium dioxide Nutrition 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 229960005294 triamcinolone Drugs 0.000 description 1
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- 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
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
-
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
-
- 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
- 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
- C07D401/14—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 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
- C07D413/04—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 directly linked by a ring-member-to-ring-member bond
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Pulmonology (AREA)
- Endocrinology (AREA)
- Transplantation (AREA)
- Mycology (AREA)
- Microbiology (AREA)
- Ophthalmology & Optometry (AREA)
- Physical Education & Sports Medicine (AREA)
- Rheumatology (AREA)
- Heart & Thoracic Surgery (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Cardiology (AREA)
- Psychology (AREA)
- Pain & Pain Management (AREA)
- Gastroenterology & Hepatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
本发明涉及作为cGAS抑制剂的新的式(I)的脯氨酸衍生物,其中其中R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11及G根据权利要求1中所定义,及这些化合物的前药或药学上可接受的盐其用于治疗例如系统性红斑狼疮、全身性硬化(SSc)、非酒精性脂肪性肝炎(NASH)、间质性肺病(ILD)及特发性肺纤维化(IPF)等疾病。
Description
背景技术
1.1 cGAS抑制剂
先天性免疫被认为是防御宿主细胞抵抗入侵病原体并启动适应性免疫系统信号传导的第一线细胞应激反应。这些过程为通过保守病原体相关分子模式(PAMP)经由多种模式识别受体(PRR)感知且随后活化细胞因子及I型干扰素基因表现而触发。主要抗原呈递细胞(诸如单核球、巨噬细胞及树突细胞)产生I型干扰素,且对于引发适应性T细胞及B细胞免疫系统反应至关重要。主要PRR在细胞表面、溶酶体膜内部或其他细胞区室中检测到异常,即定位错误、不成熟或未修饰的核酸(Barbalat等人,Annu.Rev.Immunol.29,185-214(2011))。
“环状GMP-AMP合酶(Cyclic GMP-AMP Synthase)”(cGAS,UniProtKB–Q8N884))为异常双链DNA(dsDNA)的主要传感器,该异常双链DNA源自病原体或核或线粒体细胞dsDNA的误定位或误处理(Sun等人,Science 339,786-791(2013);Wu等人,Science 339,826-830(2013);Ablasser等人,Nature 498,380-384(2013))。dsDNA与cGAS的结合活化GTP及ATP的反应,以形成环状二核苷酸GMP-AMP(称为cGAMP)。cGAMP然后到达并活化内质网膜锚定的衔接蛋白”干扰素基因的刺激物”(Stimulator of Interferon Genes,STING)。活化的STING招募并活化TANK结合激酶1(TANK-binding kinase 1,TBK1),其进而使干扰素调节因子(interferon regulatory factors,IRF)的转录因子家族磷酸化,从而诱导细胞因子及I型干扰素mRNA表现。
CGA在dsDNA感测中的关键作用已在不同病原菌(Hansen等人,EMBOJ.33,1654(2014))、病毒(Ma等人,PNAS112,E4306(2015))及反转录病毒(Gao等人,Science 341,903-906(2013))中得到确立。另外,cGAS在各种其他生物过程(例如细胞衰老(Yang等人,PNAS114,E4612(2017),Glück等人,Nat.Cell Biol.19,1061-1070(2017)))及潜在癌细胞监测中破裂的微核的识别(Mackenzie等人,Nature 548,461-465(2017);Harding等人,Nature 548,466-470(2017))中为必需的。
尽管cGAS路径对于宿主防御抵抗入侵病原体为重要的,但细胞应激及遗传因素还可例如通过核泄漏或线粒体泄漏导致产生异常细胞dsDNA效应,且藉此触发自体炎症反应。艾卡迪-古铁雷斯综合征(Aicardi-Goutieres syndrome)(AGS;Crow等人,Nat.Genet.38,917-920(2006))(一种狼疮样严重自体炎症免疫介导的病症)为由TREX1(一种负责降解胞质液中的异常DNA的主要DNA外切核酸酶)的功能丧失型突变引起。TREX1缺陷小鼠中敲除cGAS可预防其他致死性自体免疫反应,此支持cGAS作为干扰素病的驱动因子(Gray等人,J.Immunol.195,1939-1943(2015);Gao等人,PNAS112,E5699-E5705(2015))。同样,由DNAse2(一种负责在胞吞作用期间降解溶酶体中的过量DNA的内核酸酶)缺陷引起的胚胎致死性通过cGAS(Gao等人,PNAS112,E5699-E5705(2015))或STING(Ahn等人,PNAS109,19386-19391(2012))的额外敲除而被完全挽救。这些观察结果支持cGAS作为药物靶,且抑制cGAS可为预防自体炎症及治疗诸如涉及抗dsDNA抗体的系统性红斑狼疮(SLE)等疾病提供治疗策略(Pisetsky等人,Nat.Rev.Rheumatol.12,102-110(2016))。
1.2现有技术
由于观察到抑制cGAS-路径可为预防自体炎症及治疗例如自体免疫疾病提供治疗策略,故已进行许多开发cGAS抑制剂的努力。
例如,在WO 2019/241787中,4-氨基-6-(苯基氨基)-1,3,5-三嗪-2-甲酸甲酯(例如CU-32及CU-76)已公开为cGAS-抑制剂,其”活体外hcGAS IC50-值”略低于1μM(IC50(CU-32)=0.66μM且IC50(CU-76)=0.27μM)。
在Hall等人,PLoS ONE 12(9);e0184843(2017)中,化合物PF-06928215已公开作为cGAS抑制剂,如通过荧光偏振分析所量测,其”活体外hcGAS IC50-值”为0.049μM。然而,化合物PF-06928215作为cGAS抑制剂未显示可接受的细胞活性。
在WO 2020/142729中,(苯并呋喃并[3,2-d]嘧啶-4-基)吡咯烷-2-甲酸衍生物已公开作为用于自体免疫病症(例如艾卡迪-古铁雷斯综合征(AGS)、红斑狼疮、硬皮症、炎症性肠病及非酒精性脂肪性肝炎(NASH))的疗法的cGAS抑制剂。然而,本发明的化合物与WO2020/142729的(苯并呋喃并[3,2-d]嘧啶-4-基)吡咯烷-2-甲酸衍生物的不同之处在于其在吡咯烷环的4-位的完全不同的取代模式。
最近提供的cGAS抑制剂(例如WO 2020/142729中的那些)通常显示不足细胞cGAS抑制功效(在细胞分析中量测的关于cGAS/STING路径的抑制的IC50值通常大于1μM,通常大于5μM)。然而,至关重要的是提供治疗性cGAS抑制剂,其不仅显示令人满意的生物化学(活体外)抑制功效(“hcGAS IC50”),且亦显示令人满意的细胞抑制功效(例如,通过在病毒刺激的THP-1细胞中显示IFN诱导的抑制(THP1(vir)IC50)),以确保该化合物能够在患者中显示治疗效应。可预测成功开发cGAS抑制剂作为治疗剂的其他重要性质为在人类全血中满足cGAS选择性(相对于脱靶活性)及可接受的抑制功效。
令人惊讶的是,现已发现式(I)及式(I’)的化合物同时显示以下三种性质:
·令人满意的”关于cGAS抑制的生物化学(活体外)IC50值”(hcGAS IC50≤100nM、较优选≤50nM、具体而言≤10nM),
·“病毒刺激的THP-1细胞中令人满意的IFN诱导的抑制”(THP1IC50(vir)≤1μM、较优选≤500nM、更优选≤100nM、具体而言≤50nM)
及
·令人满意的对cGAS抑制的选择性
(THP1 IC50(cGAMP)/THP1 IC50(vir)的比率≥10、更优选≥50、更优选≥500、具体而言≥1000)。
另外,式(I)及式(I’)的化合物在dsDNA刺激的人类全血分析中关于IFN诱导的抑制还显示可接受的IC50值,较优选关于cGAS抑制的人类全血IC50值(hWB IC50)≤5000nM、更优选≤1000nM、具体而言≤100nM。
具有此特定药理学特性的本发明的cGAS抑制剂组合了优良活体外抑制功效及优优良细胞抑制功效与对cGAS抑制的高选择性,具有在患者中亦展现良好治疗效应的高机率。由于其高细胞抑制功效,具有此特定药理学特性的化合物应能够通过细胞膜屏障,且因此到达其细胞内靶位置,且由于其排他地抑制cGAS的选择性,这些化合物不应该显示不希望的脱靶效应,例如cGAS下游信号传导路径内某处的副作用或细胞毒性效应。
发明内容
本发明涉及式(I)化合物,
其中
R1选自甲基、乙基、卤代甲基、卤代乙基及卤素,
其中
G选自O、NR8、CH2、C及CR8R9,
其中
R2选自H、卤素、环丙基、C1-3-烷基、C2-5-炔基、-S-甲基及CN,
或其中R2为环状基团,其中所述环状基团选自:苯基及包含1、2、3或4个各自独立地选自N、S及O的杂原子的五至六元杂芳基,且其中所述环状基团由一个或两个相同或不同的取代基R10取代,
其中
R3为H或甲基
R4为H或甲基
R5选自H、甲基、-CN、-亚甲基-OH及-CF3,
或R5不存在,
R6选自H、甲基、-CN、-亚甲基-OH及-CF3,
或R5及R6与其之间的C原子一起形成选自氧杂环丁烷、四氢呋喃及环丙烷的环
R7选自H、卤素、(C1-3)-烷基及卤代-(C1-3)-烷基
R8选自CN、H及甲基,
R9选自H、甲基及卤素
或R9不存在,
其中每一R10独立地选自:氢、卤素、卤烷基、-甲基、-乙基、-NH-CO-甲基、-N(CH3)2、-CH2-OH、-NH(CH3)、-O-(C1-3-烷基)、-CN、-S-CH3、-CO-NH2、-CH2-NH(CH3)、-CH2-NH2、-SO-(CH3)、环丙基及-O-R11,
其中每一R11独立地选自具有一个或两个各自独立地选自N、O及S的杂原子的五或六元芳香族或非芳香族杂环,
或G为CR8R9,R5及R9不存在,且R8及R6及R8与R6之间的两个C原子形成包含一个、两个或三个各自独立地选自N、S及O的杂原子的环状五元芳香族或非芳香族杂环,
或G为CR8R9且R8及R9与R8及R9之间的C原子一起形成双吖丙啶环,
及这些化合物的前药或药学上可接受的盐。
本发明的较优选实施例涉及上文所提及的化合物,其属于式(I’)的范围
其中R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11及G如上文所提及定义
及这些化合物的前药或药学上可接受的盐。
本发明的另一较优选实施例是指上文提及的式(I)或式(I’)的化合物,
其中R7为H、F、Cl、甲基、乙基、卤代甲基或卤代乙基,
及这些化合物的前药或药学上可接受的盐。
在另一较优选实施例中,本发明涉及上文提及的式(I)或式(I’)的化合物,
其中R1为卤代甲基、卤代乙基或甲基,
及这些化合物的前药或药学上可接受的盐。
本发明的又一较优选实施例是指上文提及的式(I)或式(I’)的化合物,
其中R1为选自-CF3、-CHF2及-CH2F的氟甲基,
及这些化合物的前药或药学上可接受的盐。
在另一较优选实施例中,本发明涉及上文提及的式(I)或式(I’)的化合物,其中R3及R4中的至少一者为甲基
及这些化合物的前药或药学上可接受的盐。
本发明的另一较优选实施例涉及上文所提及的式(I)或式(I’)的化合物,其中R3及R4中的一者为甲基且另一者为H
及这些化合物的前药或药学上可接受的盐。
在另一较优选实施例中,本发明涉及上文提及的式(I)或式(I’)的化合物,其中G为O
及这些化合物的前药或药学上可接受的盐。
本发明的另一较优选实施例涉及上文所提及的式(I)或式(I’)的化合物,其中G为O
且其中R3及R4中的一者为甲基且另一者为H,
及这些化合物的前药或药学上可接受的盐。
在另一较优选实施例中,本发明涉及上文提及的式(I)或式(I’)的化合物,
其中G为O,
其中R4为甲基且R3为H,
且其中R5及R6一起形成氧杂环丁烷环
及这些化合物的前药或药学上可接受的盐。
本发明的另一较优选实施例涉及上文所提及的式(I)或式(I’)的化合物,
其中R2选自:H、乙炔基、1-丙炔基、-S-甲基及卤素,
及这些化合物的前药或药学上可接受的盐。
在另一较优选实施例中,本发明是指上文提及的式(I)或式(I’)的化合物,
其中R2为乙炔基,
及这些化合物的前药或药学上可接受的盐。
本发明的另一较优选实施例涉及上文所提及的式(I)或式(I’)的化合物,
其中R4为甲基且R3为H,
其中G为O,
其中R5及R6一起形成氧杂环丁烷环,
其中R2选自:H、乙炔基、1-丙炔基、-S-甲基及卤素,
及这些化合物的前药或药学上可接受的盐。
在另一较优选实施例中,本发明是指上文提及的式(I)或式(I’)的化合物,
其中R2为环状基团,其中所述环状基团选自:苯基或包含1、2或3个选自N、S及O的杂原子的五至六元杂芳基,且其中所述环状基团由一个或两个相同或不同的取代基R10取代,
其中每一R10独立地选自:氢、卤素、卤烷基、-甲基、-乙基、-NH-CO-甲基、-N(CH3)2、-CH2-OH、-NH(CH3)、-O-CH3、-CN、-S-CH3、-CO-NH2、-CH2-NH(CH3)、-CH2-NH2、-SO-(CH3)、环丙基及-O-R11,
其中每一R11独立地选自具有一个或两个各自独立地选自N及O的杂原子的五或六元芳香族或非芳香族杂环,
及这些化合物的前药或药学上可接受的盐。
本发明的又一较优选实施例是指上文提及的式(I)或式(I’)的化合物,
其中R2为选自吡唑基、吡啶基、咪唑基、苯基及异噁唑基的环状基团,
其中所述环状基团由一个或两个相同或不同的取代基R10取代
其中每一R10独立地选自:氢、卤素、卤烷基、-甲基、-乙基、-NH-CO-甲基、-N(CH3)2、-CH2-OH、-NH(CH3)、-O-CH3、-CN、-S-CH3、-CO-NH2、-CH2-NH(CH3)、-CH2-NH2、-SO-(CH3)、环丙基及-O-R11,
其中每一R11为四氢吡喃
及这些化合物的前药或药学上可接受的盐。
在另一较优选实施例中,本发明是指上文提及的式(I)或式(I’)的化合物,
其中G为O,
其中R3及R4中的一者为甲基且另一者为H,
其中R2为选自吡唑基、吡啶基、咪唑基、苯基及异噁唑基的环状基团,
其中所述环状基团由一个或两个相同或不同的取代基R10取代
其中每一R10独立地选自:氢、卤素、卤烷基、-甲基、-乙基、-NH-CO-甲基、-N(CH3)2、-CH2-OH、-NH(CH3)、-O-CH3、-CN、-S-CH3、-CO-NH2、-CH2-NH(CH3)、-CH2-NH2、-SO-(CH3)、环丙基及-O-R11,
其中每一R11为四氢吡喃,
及这些化合物的前药或药学上可接受的盐。
在另一较优选实施例中,本发明是指上文提及的式(I)或式(I’)的化合物,
其中R2为选自吡唑基、吡啶基、咪唑基、苯基及异噁唑基的环状基团,
其中所述环状基团由一个或两个相同或不同的取代基R10取代
其中每一R10独立地选自:氢、卤素、卤烷基、-甲基、-乙基、-NH-CO-甲基、-N(CH3)2、-CH2-OH、-NH(CH3)、-O-CH3、-CN、-S-CH3、-CO-NH2、-CH2-NH(CH3)、-CH2-NH2、-SO-(CH3)、环丙基及-O-R11,
其中每一R11为四氢吡喃,
其中G为O,
其中R3及R4中的一者为甲基且另一者为H,
且其中R5及R6一起形成氧杂环丁烷环,
及这些化合物的前药或药学上可接受的盐。
在另一较优选实施例中,本发明是指上文提及的式(I)或式(I’)的化合物,
其中G为CR8R9,
其中R8及R6及R8与R6之间的两个C原子形成包含一个或两个各自独立地选自N及O的杂原子的环状五元芳香族杂环,其选自环状异噁唑基环、环状吡唑基环、环状吡咯基环及环状呋喃基环,
且其中R9及R5不存在,
及这些化合物的前药或药学上可接受的盐。
本发明的另一特别优选实施例涉及式(I)或式(I’)的化合物,其选自:
/>
/>
/>
/>及
及这些化合物的前药或药学上可接受的盐。
在另一实施例中,本发明涉及上文所提及的式(I)或式(I’)的化合物,其用于治疗可通过抑制cGAS进行治疗的疾病。
在较优选实施例中,本发明是指上文提及的式(I)或式(I’)的化合物,其用于治疗选自以下的疾病:系统性红斑狼疮(SLE)、干扰素病、艾卡迪-古铁雷斯综合征、年龄相关性黄斑退化(AMD)、肌肉萎缩性脊髓侧索硬化症(ALS)、炎症性肠病(IBD)、慢性阻塞性肺病(COPD)、布卢姆氏综合征(Bloom’s syndrome)、薛格连氏综合征(Sjogren’s syndrome)、帕金森氏病(Parkinsons disease)、心脏衰竭及癌症、全身性硬化(SSc)、非酒精性脂肪肝炎(NASH)、间质性肺病(ILD),较优选进行性纤维化间质性肺病(PF-ILD),具体而言特发性肺纤维化(IPF)。
在更优选实施例中,本发明涉及上文所提及的式(I)或式(I’)的化合物,其用于治疗选自以下的疾病:系统性红斑狼疮(SLE)、干扰素病、艾卡迪-古铁雷斯综合征、年龄相关性黄斑退化(AMD)、肌肉萎缩性脊髓侧索硬化症(ALS)、炎症性肠病(IBD)、慢性阻塞性肺病(COPD)、布卢姆氏综合征、薛格连氏综合征及帕金森氏病。
在另一更优选实施例中,本发明涉及上文提及的式(I)或式(I’)的化合物,其用于治疗选自以下的纤维化疾病:全身性硬化(SSc)、干扰素病、非酒精性脂肪性肝炎(NASH)、间质性肺病(ILD),较优选进行性纤维化间质性肺病(PF-ILD),具体而言特发性肺纤维化(IPF)。
在另一更优选实施例中,本发明涉及上文提及的式(I)或式(I’)的化合物,其用于治疗选自以下的疾病:年龄相关性黄斑退化(AMD)、心脏衰竭、COVID-19/SARS-CoV-2感染、肾炎症、肾纤维化、代谢障碍、血管疾病、心血管疾病及癌症。
在另一实施例中,本发明涉及药物组合物,其包含上文提及的式(I)或式(I’)的化合物中的至少一者及任选的一种或多种药学上可接受的载剂及/或赋形剂。
在另一较优选实施例中,本发明是指下式的中间体:式(IV)
根据合成方案1,
或式(V)
根据合成方案1,
或式(X)
根据合成方案2,
或式(XI)
根据合成方案2,
其中G、R1、R2、R3、R4、R5、R6及R7如上文所提及所述定义
且其中X为F或NO2,
且其中PG为保护基团,其选自:叔丁氧基羰基(BOC)、苄基氧基羰基(Cbz)、芴基亚甲氧基羰基(Fmoc)、烯丙基氧基羰基(Alloc)、苄基(Bn)、对-甲氧基苄基(PMB)、3,4-甲氧基苄基(DMPM)、对-甲氧基苯基(PMP)、甲苯磺酰基(Ts)、氯甲酸三氯乙酯(Troc)、乙酰基(Ac)或苯甲酰基(Bn)。
在又一较优选实施例中,本发明涉及上文所提及的式(I)或式(I’)的化合物中的任一者的前药,
其中此前药属式(A)的范围
或属式(A’)的范围
其中G、R1、R2、R3、R4、R5、R6及R7如上文所提及所述定义
且其中R12为C1-4-烷基、芳基、-CH2-芳基、NH-SO2-C1-3-烷基。
具体而言,本发明涉及上文所提及的式(A)或式(A’)的前药,其中R12为甲基。
在另一较优选实施例中,本发明涉及式(I)或式(I’)的化合物与一种或多种选自以下的活性剂的组合:抗炎症剂、抗纤维变性剂、抗过敏剂/抗组织胺、支气管扩张剂、β2激动剂/β模拟物、肾上腺素性激动剂、抗胆碱剂、甲氨蝶呤(methotrexate)、吗替麦考酚酯(mycophenolate mofetil)、白三烯调节剂、JAK抑制剂、抗白介素抗体、非特异性免疫治疗剂(例如干扰素或其他细胞因子/趋化因子)、细胞因子/趋化因子受体调节剂、toll样受体激动剂、免疫检查点调节剂、抗TNF抗体(例如阿达木单抗(Adalimumab))、抗BAFF抗体(例如贝利木单抗(Belimumab)及依那西普(Etanercept))。
在进一步特别优选实施例中,本发明涉及式(I)或式(I’)的化合物及一种或多种选自由比非尼酮(Pirfenidon)及尼达尼布(Nintedanib)组成的组的抗纤维变性剂的组合。
在进一步特别优选实施例中,本发明涉及式(I)或式(I’)的化合物与一种或多种选自由NSAID及皮质类固醇组成的组的抗炎症剂的组合。
在进一步特别优选实施例中,本发明涉及式(I)或式(I’)的化合物与一种或多种选自以下的活性剂的组合:支气管扩张剂、β2激动剂/β模拟物、肾上腺素性激动剂及抗胆碱剂。
在进一步特别优选实施例中,本发明涉及式(I)或式(I’)的化合物与一种或多种选自以下的抗白介素抗体的组合:抗IL23抗体(例如利散吉珠单抗(Risankizumab))、抗IL17抗体、抗IL1抗体、抗IL4抗体、抗IL13抗体、抗lL-5抗体、抗IL-6抗体(例如托珠单抗(Tocilizumab))、抗IL-12抗体及抗IL-15抗体。
在另一较优选实施例中,本发明涉及药物组合物,其包含式(I)或式(I’)的化合物与上文提及的活性剂中的任一者的组合。
具体实施方式
所用的术语及定义
除非另外陈述,否则所有取代基皆彼此独立。若(例如)多个C1-6-烷基为基团处的可能取代基,则在三个取代基的情形下,例如,C1-6-烷基可彼此独立地表示甲基、正丙基及叔丁基。
术语“C1-6-烷基”(包括作为其他基团的部分的那些)意指具有1至6个碳原子的具支链及无支链烷基,且术语“C1-3-烷基”意指具有1至3个碳原子的具支链及无支链烷基。“C1-4-烷基”相应地表示具有1至4个碳原子的具支链及无支链烷基。具有1至4个碳原子的烷基为较优选的。这些基团的实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基及己基。缩写Me、Et、n-Pr、i-Pr、n-Bu、i-Bu、t-Bu等也可任选地用于上文提及的基团。除非另外陈述,否则定义丙基、丁基、戊基及己基包括所述基团的所有可能的异构形式。因此,例如,丙基包括正丙基及异丙基,丁基包括异丁基、仲丁基及叔丁基等。
术语“C1-6-亚烷基”(包括作为其他基团的部分的那些)意指具有1至6个碳原子的具支链及无支链亚烷基,且术语“C1-4-亚烷基”意指具有1至4个碳原子的具支链及无支链亚烷基。具有1至4个碳原子的亚烷基为较优选的。这些基团的实例包括亚甲基、亚乙基、亚丙基、1-甲基亚乙基、亚丁基、1-甲基亚丙基、1,1-二甲基亚乙基、1,2-二甲基亚乙基、亚戊基、1,1-二甲基亚丙基、2,2-二甲基亚丙基、1,2-二甲基亚丙基、1,3-二甲基亚丙基及亚己基。除非另外陈述,否则定义亚丙基、亚丁基、亚戊基及亚己基包括具有相同碳数的所述基团的所有可能的异构形式。因此,例如,丙基还包括1-甲基亚乙基,且亚丁基包括1-甲基亚丙基、1,1-二甲基亚乙基、1,2-二甲基亚乙基等。
若碳链由与亚烷基链的一个或两个碳原子一起形成具有3、5或6个碳原子的碳环的基团取代,则此尤其包括环的以下实例:
术语“C2-6-烯基”(包括作为其他基团的部分的那些)意指具有2至6个碳原子的具支链及无支链烯基,且术语“C2-4-烯基”意指具有2至4个碳原子的具支链及无支链烯基,前提为其具有至少一个双键。具有2至4个碳原子的烯基为较优选的。实例包括:乙烯基(ethenyl或vinyl)、丙烯基、丁烯基、戊烯基或己烯基。除非另外陈述,否则定义丙烯基、丁烯基、戊烯基及己烯基包括所述基团的所有可能的异构形式。因此,例如,丙烯基包括1-丙烯基及2-丙烯基,丁烯基包括1-、2-及3-丁烯基、1-甲基-1-丙烯基、1-甲基-2-丙烯基等。
术语“C2-5-炔基”(包括作为其他基团的部分的那些)意指具有2至5个碳原子的具支链及无支链炔基,且术语“C2-4-炔基”意指具有2至4个碳原子的具支链及无支链炔基,前提为其具有至少一个三键。具有2至4个碳原子的炔基为较优选的。
术语“C2-6-亚烯基”(包括作为其他基团的部分的那些)意指具有2至6个碳原子的具支链及无支链亚烯基,且术语“C2-4-亚烯基”意指具有2至4个碳原子的具支链及无支链亚烯基。具有2至4个碳原子的亚烯基为较优选的。这些基团的实例包括:亚乙烯基、亚丙烯基、1-甲基亚乙烯基、亚丁烯基、1-甲基亚丙烯基、1,1-二甲基亚乙烯基、1,2-二甲基亚乙烯基、亚戊烯基、1,1-二甲基亚丙烯基、2,2-二甲基亚丙烯基、1,2-二甲基亚丙烯基、1,3-二甲基亚丙烯基及亚己烯基。除非另外陈述,否则定义亚丙烯基、亚丁烯基、亚戊烯基及亚己烯基包括具有相同碳数的所述基团的所有可能的异构形式。因此,例如,丙烯基还包括1-甲基亚乙烯基,且亚丁烯基包括1-甲基亚丙烯基、1,1-二甲基亚乙烯基、1,2-二甲基亚乙烯基。
术语“芳基”(包括作为其他基团的部分的那些)意指具有6或10个碳原子的芳香族环体系。实例包括苯基或萘基,较优选芳基为苯基。除非另外陈述,否则芳香族基团可由一个或多个选自以下的基团取代:甲基、乙基、异丙基、叔丁基、羟基、氟、氯、溴及碘。
术语“芳基-C1-6-亚烷基”(包括作为其他基团的部分的那些)意指具有1至6个碳原子的具支链及无支链亚烷基,其由具有6或10个碳原子的芳香族环体系取代。实例包括苄基、1-或2-苯基乙基及1-或2-萘基乙基。除非另外陈述,否则芳香族基团可由一个或多个选自以下的基团取代:甲基、乙基、异丙基、叔丁基、羟基、氟、氯、溴及碘。
术语“杂芳基-C1-6-亚烷基”(包括作为其他基团的部分的那些)意指(即使其已经包括在”芳基-C1-6-亚烷基”之下)具有1至6个碳原子的具支链及无支链亚烷基,其由杂芳基取代。
若无另外特别定义,则此类杂芳基包括包括五或六元杂环芳香族基团或5-10元二环杂芳基环,其可含有一个、两个、三个或四个选自氧、硫及氮的杂原子,且含有如此多的共轭双键以至于形成芳香族体系。以下为五或六元杂环芳香族基团及二环杂芳基环的实例:
除非另外陈述,否则这些杂芳基可由一个或多个选自以下的基团取代:甲基、乙基、异丙基、叔丁基、羟基、氨基、硝基、烷氧基、氟、氯、溴及碘。
以下为杂芳基-C1-6-亚烷基的实例:
术语“C1-6-卤烷基”(包括作为其他基团的部分的那些)意指具有1至6个碳原子的具支链及无支链烷基,其由一个或多个卤素原子取代。术语“C1-4-卤烷基”意指具有1至4个碳原子的具支链及无支链烷基,其由一个或多个卤素原子取代。具有1至4个碳原子的烷基为较优选的。实例包括:CF3、CHF2、CH2F、CH2CF3。
若无另外特别定义,则术语“C3-7-环烷基”(包括作为其他基团的部分的那些)意指具有3至7个碳原子的环状烷基。实例包括:环丙基、环丁基、环戊基、环己基及环庚基。除非另外陈述,否则环状烷基可由一个或多个选自以下的基团取代:甲基、乙基、异丙基、叔丁基、羟基、氟、氯、溴及碘。
若无另外特别定义,则术语“C3-10-环烷基”还意指具有3至7个碳原子的单环烷基亦及具有7至10个碳原子的二环烷基、或由至少一个C1-3-碳桥桥接的单环烷基。
除非另有说明,否则术语“杂环(heterocyclic rings或heterocycle)”意指五、六或七元饱和、部分饱和或不饱和杂环,其可含有一个、两个或三个选自氧、硫及氮的杂原子,而该环可经由碳原子或经由氮原子(若存在一者)连接至分子。尽管由术语“杂环(heterocyclic rings或heterocycles)”包括,但术语“饱和杂环”是指五、六或七元饱和环。实例包括:
尽管由术语“杂环”或”杂环基”包括,但除非另有明确定义,否则术语“部分饱和杂环基”是指五、六或七元部分饱和环,其含有一个或两个双键,而未产生如此多的双键以致于形成芳香族体系。实例包括:
尽管由术语“杂环(heterocyclic rings或heterocycles)”包括,但除非另有明确定义,否则术语“杂环芳香族环”、”不饱和杂环基”或”杂芳基”是指五或六元杂环芳香族基团、或五-十元二环杂芳基环,其可含有一个、两个、三个或四个选自氧、硫及氮的杂原子,且含有如此多的共轭双键以致于形成芳香族体系。五或六元杂环芳香族基团的实例包括:
除非另外提及,否则杂环(heterocyclic ring或heterocycle)可提供有酮基。实例包括:
尽管由术语“环烷基”涵盖,但术语“二环烷基”通常表示八、九或十元二环碳环。实例包括:
尽管已经由术语“杂环”包括,但除非未另外明确定义,否则术语“二环杂环”通常表示八、九或十元二环,其可含有一个或多个选自氧、硫及氮的杂原子,较优选1-4、更优选1-3、甚至更优选1-2、具体而言一个杂原子。环可经由环的碳原子或经由环的氮原子(若存在一者)连接至分子。实例包括:
尽管已经由术语“芳基”包括,但术语“二环芳基”表示5-10元二环芳基环,其含有足够共轭双键以形成芳香族体系。二环芳基的一个实例为萘基。
尽管已经包括在”杂芳基”下,但除非另外明确定义,否则术语“二环杂芳基”表示5-10元二环杂芳基环,其可含有一个、两个、三个或四个选自氧、硫及氮的杂原子,且含有足够共轭双键以形成芳香族体系。
尽管由术语“二环烷基”或“二环芳基”包括,但术语“稠合环烷基”或“稠合芳基”表示二环,其中分离环的桥表示直接单键。以下为稠合二环烷基的实例:
尽管由术语“二环杂环”或”二环杂芳基”包括,但术语“稠合二环杂环”或”稠合二环杂芳基”表示二环5-10元杂环,其含有一个、两个、三个或四个选自氧、硫及氮的杂原子,且其中分离环的桥表示直接单键。此外,“稠合二环杂芳基”含有足够共轭双键以形成芳香族体系。实例包括吡咯嗪、吲哚、吲嗪、异吲哚、吲唑、嘌呤、喹啉、异喹啉、苯并咪唑、苯并呋喃、苯并吡喃、苯并噻唑、苯并噻唑、苯并异噻唑、吡啶并嘧啶、喋啶、嘧啶并嘧啶,
“卤素”在本发明的范围内表示氟、氯、溴或碘。除非说明相反的情况,否则认为氟、氯及溴为较优选卤素。
如先前所提及,式(I)或(I’)的化合物可转化成其盐,尤其对于医药用途,转化成其生理及药理上可接受的盐。词组”药学上可接受的”在本文中用以指在合理医学判断范围内适用于与人类及动物组织接触且无过度毒性、刺激性、过敏反应或其他问题或并发症且与合理益处/风险比相称的那些化合物、材料、组合物及/或剂型。一方面,这些盐可作为式(I)或(I’)的化合物与无机或有机酸的生理及药理上可接受的酸加成盐存在。另一方面,式(I)或(I’)的化合物可通过与无机碱反应转化为生理及药理上可接受的盐,其中碱金属或碱土金属阳离子作为相对离子。酸加成盐可使用(例如)盐酸、氢溴酸、硫酸、磷酸、甲磺酸、对-甲苯磺酸、乙酸、富马酸、琥珀酸、乳酸、柠檬酸、酒石酸或马来酸来制备。也可使用上文提及的酸的混合物。为了制备式(I)或(I’)的化合物的碱金属及碱土金属盐,较优选使用碱金属及碱土金属氢氧化物及氢化物,其中碱金属(具体而言钠、钾、镁、钙、锌及二乙醇胺)的氢氧化物及氢化物为较优选的,而氢氧化钠及氢氧化钾为特别优选的。
本发明涉及所述化合物,任选地呈个别光学异构物、非镜像异构物、非镜像异构物的混合物、个别镜像异构物或外消旋物的混合物的形式,呈互变异构物的形式以及呈游离碱或与药理学上可接受的酸的相应酸加成盐(例如与氢卤酸(例如盐酸或氢溴酸)或有机酸(例如草酸、反丁烯二酸、二甘醇酸或甲磺酸)的酸加成盐)的形式。
根据本发明的式(I)或(I’)的化合物可任选的以非镜像异构异构物的混合物存在,但也可以纯非镜像异构物获得。较优选者为具有式(I’)的特定立体化学的化合物。
4合成方法
根据本发明的化合物及其中间体可使用本领域技术人员已知且阐述于例如有机合成文献中的合成方法来获得。
此外,本发明提供制备式(I)或式(I’)的化合物的方法。
最佳反应条件及反应时间可端视所用特定反应物而变。除非另有规定,否则本领域技术人员可容易地选择溶剂、温度、压力及其他反应条件。具体程序提供于合成实例部分中。通常,若需要,可通过薄层色谱(TLC)或液相色谱质谱(LC-MS)监测反应过程,且可通过硅胶上色谱、HPLC及/或通过重结晶纯化中间体及产物。以下实例为说明性的,且如本领域技术人员将认识到,特定试剂或条件可针对个别化合物任选地进行修改,而无需过多实验。以下方法中所用的起始材料及中间体有市售或由本领域技术人员自市售材料容易地制备。
式(I)化合物可通过方案1-4中概述的方法来制备,其中R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11及G如上文所提及定义,且其中PG为较优选保护基团,其选自:叔丁氧基羰基(BOC)、苄基氧基羰基(Cbz)、芴基亚甲氧基羰基(Fmoc)及烯丙基氧基羰基(Alloc):
方案1:
如方案1中所阐释,(2S,4S)-4-羟基吡咯烷-2-甲酸(III)与氯-嘧啶(II)在适宜碱(例如二异丙基乙胺、碳酸钾或氢化钠)存在下在适宜溶剂(例如DMSO)中的反应提供式(IV)的羟脯氨酸衍生物。羟脯氨酸(IV)与式(V)的吡啶(其中X为F或NO2)在适宜碱(例如NaH)存在下在适宜溶剂(例如DMA、DMF或NMP)中的反应提供式(I)化合物。
方案2:
如方案2中所阐释,氟硝基吡啶(VI)与环状胺(VII)在适宜碱(例如K2CO3)存在下在适宜溶剂(例如乙腈)中的反应提供式(VIII)的硝基吡啶。此硝基吡啶(VIII)可与式(IX)的羟脯氨酸在适宜碱(例如NaH)存在下在适宜溶剂(例如DMF、NMP或DMA)中反应,以提供式(X)的化合物,其中保护基团PG可为(例如)叔丁氧基羰基(BOC)。在标准条件下(X)的保护基团PG的去除提供式(XI)的脯氨酸衍生物,即,若PG为BOC,则去保护可使用TFA在适宜溶剂(例如乙腈)中实施。化合物(XI)与式(II)的氯-嘧啶在适宜碱(例如二异丙基乙胺、碳酸钾或氢化钠)存在下在适宜溶剂(例如DMSO或DMF)中的反应提供式(I)化合物。
遵循此通用反应方案2,取代基R2可在自反应顺序开始即就位于化合物(VI)中且保持不变直至获得化合物(I)(即,若R2为H、Br、Cl、芳基或炔基),或其可在稍后阶段在合成期间经由铃木偶合(Suzuki coupling)或一些本领域技术人员已知的其他芳基化反应来引入。举例而言,式(VI)、(VIII)、(X)或(I)的化合物(其中R2为Br、I或OTf)可与适宜硼酸芳基酯(酯/酸)在适宜碱(例如Na2CO3、K3PO4或KOH)及适宜催化剂(例如Pd(dppf)Cl2或Pd(PPh3)4(使用适宜配体,例如Xphos))存在下在适宜溶剂(例如二噁烷或DMF)中反应,以得到各别化合物,其中R2为芳基。
或者,式(VI)、(VIII)、(X)或(I)的化合物(其中R2为卤素或OTf)可与硼化试剂(例如双(频哪醇)二硼)在适宜催化剂(例如Pd(dppf)Cl2)及适宜碱(例如乙酸钾)存在下反应,以提供硼酸酯。此硼酸酯可与适宜芳基-卤化物在适宜碱(例如Na2CO3,K3PO4或KOH)及适宜催化剂(例如Pd(dppf)Cl2或Pd(PPh3)4(使用适宜配体,例如Xphos)存在下在适宜溶剂(例如二噁烷或DMF)中在铃木偶合中反应,以得到各别化合物,其中R2为芳基。
或者,式(VI)、(VIII)、(X)或(I)的化合物(其中R2为卤素)可与适宜炔烃(例如乙炔基参(丙-2-基)硅烷)在适宜催化剂(例如PdCl2(PPh3)2及碘化铜(I))存在下及在适宜碱(例如DIPEA)存在下在适宜溶剂(例如THF)中反应,以提供各别化合物,其中R2为炔烃。
可在呈此顺序的具体反应期间用适宜保护基团(例如烷基酯)保护脯氨酸基序的羧酸官能基(即在式(X)或(I)的化合物),即,叔丁基酯为适宜保护基团以在R2引入芳基部分。
式(II)化合物可如方案3中所阐释来制备。
方案3:
式(XII)的甲腈与式(XIII)的酸酐或相应酸在适宜溶剂(例如吡啶)中的反应提供酰胺(XIV)。在与适宜氯化试剂(例如五氯化磷)在适宜溶剂(例如环丁砜)中反应时,酰胺(XIV)环化以形成式(II)化合物。
在替代合成顺序中,式(XV)的化合物与2-溴乙酰胺在适宜碱(例如K2CO3或KOH)存在下在适宜溶剂(例如乙醇)中反应,以提供式(XVII)的化合物。化合物(XVII)与式(XVIII)的二甲基酰胺在适宜氯化试剂(例如氧氯化磷)存在下反应且形成式(II)化合物。
在另一替代合成顺序中,式(XV)的化合物与溴乙腈在适宜碱(例如K2CO3)存在下在适宜溶剂(例如DMF)中反应,以产生式(XIX)的化合物。此化合物在适宜碱(例如叔丁醇盐)存在下在适宜溶剂(例如THF)中环化以形成甲腈(XII),且可转化成式(XIV)的化合物且随后转化成上述式(II)的化合物。
式(VII)化合物有市售或可根据文献程序制备或如实验部分中所例示而阐述。由式(XXIII)化合物例示的式(VII)化合物可如方案4中所阐释来制备:
方案4:
/>
氧杂环丁-3-酮(XXII)与式(XXIII)的硝基烷烃在适宜溶剂(例如甲醇)中反应且形成式(XXIV)化合物。在氢及适宜催化剂(例如Pd(OH)2/C)存在下在适宜溶剂(例如乙醇)中化合物(XXIV)的氢化提供式(XXV)化合物。化合物(XXV)与氯乙酰氯在适宜碱(例如三乙胺)存在下在适宜溶剂(例如乙腈)中的反应提供化合物(XXVI),其在适宜溶剂(例如叔戊基醇)中在用适宜碱(例如叔丁醇盐)处理下环化以形成式(XXVII)的内酰胺。在适宜溶剂(例如二乙醚)中用适宜还原试剂(例如氢化锂铝)还原化合物(XXVII)提供式(XXVIII)的吗啉化合物。
通过本领域技术人员已知且下文实例中阐释的方法进一步修饰式(I)化合物可用于制备本发明的额外化合物。
所存在的合成途径可依赖于保护基团的使用。举例而言,所存在的潜在反应性基团(例如羟基、羰基、羧基、氨基、烷基氨基或亚氨基)可在反应期间由常用保护基团保护,这些保护基团在反应后再次裂解。各别官能基的适宜保护基团及其去除为本领域技术人员所熟知且阐述于有机合成的文献中:例如于”Protecting Groups,第3版”,PhilipJ.Kocienski,Thieme,2005或”Protective Groups in Organic Synthesis,第4版”,PeterG.M.Wuts,Theodora W.Greene,John Wiley and Sons,2007中。
如下文所提及,可将通式(I)化合物拆分为其非镜像异构物(ds)。因此,例如,可将顺式/反式混合物拆分成其顺式及反式异构物。
可通过(例如)色谱将顺式/反式混合物拆分为其顺式及反式异构物。通式(I)化合物的非镜像异构混合物可通过利用其不同物理-化学性质使用本身已知的方法(例如色谱及/或分段结晶)拆分成其非镜像异构物。
较优选通过在手性相上柱色谱或通过自光学活性溶剂结晶或通过与光学活性物质反应来拆分外消旋中间体,该光学活性物质与外消旋化合物形成盐或诸如酯或酰胺等衍生物。碱性化合物可与镜像异构纯的酸形成盐,且酸性化合物可与镜像异构纯的碱形成盐。非镜像异构衍生物为与镜像异构纯的辅助化合物(例如酸、其活化衍生物或醇)形成。由此获得的盐或衍生物的非镜像异构混合物的分离可通过利用其不同物理-化学性质(例如溶解度差异)来达成;游离镜像体可通过适宜试剂的作用自纯非镜像异构盐或衍生物释放。常用于此一目的的光学活性酸以及适合用作辅助残基的光学活性醇为本领域技术人员已知。
如上文所提及,式(I)化合物可转化为盐,尤其对于医药用途转化为药学上可接受的盐。如本文所用的”药学上可接受的盐”是指所公开化合物的衍生物,其中母化合物通过形成其药学上可接受的酸或碱盐而经修饰,词组“药学上可接受的”在本文中用于指在合理医学判断范围内适用于与人类及动物组织接触且无过度毒性、刺激性、过敏反应或其他问题或并发症且与合理益处/风险比相称的那些化合物、材料、组合物及/或剂型。药学上可接受的盐的实例包括(但不限于)碱性残基(例如胺)的无机酸盐或有机酸盐;酸性残基(例如羧酸)的碱性盐或有机盐;及诸如此类。
举例而言,这些盐包括来自苯磺酸、苯甲酸、柠檬酸、乙磺酸、富马酸、龙胆酸、氢溴酸、盐酸、马来酸、苹果酸、丙二酸、苦杏仁酸、甲磺酸、4-甲基-苯磺酸、磷酸、柳酸、琥珀酸、硫酸及酒石酸的盐。
其他药学上可接受的盐可与来自氨、L-精氨酸、钙、2,2’-亚氨基双乙醇、L-离氨酸、镁、N-甲基-D-葡萄糖胺、钾、钠及参(羟基甲基)-氨基乙烷的阳离子形成。
本发明的药学上可接受的盐可通过常用化学方法自含有碱性或酸性部分的母化合物来合成。通常,这些盐可通过使这些化合物的游离酸或碱形式与足量的适当碱或酸于水或有机稀释剂(如醚、乙酸乙酯、乙醇、异丙醇或乙腈、或其混合物)中进行反应来制备。
除上文所提及的其他酸外的(例如)可用于纯化或分离本发明化合物的盐(例如三氟乙酸盐)也构成本发明的一部分。
根据本发明的化合物还可有利地使用下文实例中所述的方法来获得,这些方法还可与本领域技术人员自文献中获知的方法组合用于此目的。
一般技术评论
术语“环境温度”及”室温”可互换使用并指定约20℃、例如15℃至25℃的温度。
通常,已获得所制备化合物的1H-NMR谱及/或质谱。除非另外陈述,否则所有色谱操作皆为在室温下实施。
中间体的合成
中间体1.1.I
N-(2-氰基-1-苯并呋喃-3-基)-2,2,2-三氟乙酰胺
于RT下向3-氨基-1-苯并呋喃-2-甲腈(4.00g,25.3mmol)于吡啶(40.0mL)中的混合物中添加TFAA(5.31g,25.3mmol)。将混合物于25℃搅拌12h,然后在减压下浓缩,用20mL水稀释且用EtOAc萃取。用盐水洗涤合并的有机层,经由Na2SO4干燥,过滤,并在减压下浓缩。通过柱色谱(硅胶;PE/EtOAc=20/1至5/1)纯化残余物。
ESI-MS:254.9[M+H]+
Rt(HPLC):0.56min(方法A)
以下中间体为根据上述通用程序(中间体1.1.I)来制备:
中间体1.1.III
N-(2-氰基-1-苯并呋喃-3-基)-2,2-二氟丙酰胺
于RT下向2,2-二氟丙酸(300mg,2.73mmol)及DIPEA(1.41mL,8.18mmol)于2.00mLDMF中的混合物中添加HATU(1.04g,2.73mmol),之后添加3-氨基-1-苯并呋喃-2-甲腈(474mg,3.00mmol)。将反应物于RT下搅拌1.5h后,向反应混合物中添加2.0mL 2,2-二氟丙酸(300mg,2.73mmol)、DIPEA(1.41mL,8.18mmol)及HATU(1.04g,2.73mmol)的混合物且继续搅拌。向反应混合物中添加DCM及水且萃取产物。分离各相且在真空中浓缩,且通过RP-HPLC(X-Bridge C18,ACN/H2O/TFA)纯化粗产物。
ESI-MS:249[M-H]-
Rt(HPLC):0.53min(方法A)
中间体1.2.I
6-氯-4-(三氟甲基)-8-氧杂-3,5-二氮杂三环[7.4.0.02,7]十三-1(9),2(7),3,5,10,12-六烯
向N-(2-氰基-1-苯并呋喃-3-基)-2,2,2-三氟乙酰胺(中间体1.1.I,4.00g,15.7mmol)于环丁砜(10.0mL)中的溶液中添加五氯化磷(13.1g,63.0mmol)。将混合物于110℃搅拌16h。将反应混合物倾倒至冰水中且用EtOAc萃取。将合并的有机层用盐水洗涤,经Na2SO4干燥,过滤,并在减压下浓缩。通过柱色谱(硅胶;PE/EtOAc=20/1至10/1)纯化残余物。
ESI-MS:273[M+H]+
Rt(HPLC):0.71min(方法A)
以下化合物为根据上述通用程序(中间体1.2.I)来制备:
中间体1.3.I
(2S,4S)-4-羟基-1-[4-(三氟甲基)-8-氧杂-3,5-二氮杂三环[7.4.0.02,7]-十三-1(9),2(7),3,5,10,12-己烯-6-基]吡咯烷-2-甲酸
于110℃向(2S,4S)-4-羟基吡咯烷-2-甲酸(1.44g,11.0mmol)于DMSO(25.0mL)中的预加热混合物中添加DIPEA(3.90g,30.0mmol)及6-氯-4-(三氟甲基)-8-氧杂-3,5-二氮杂三环[7.4.0.02,7]十三-1(9),2(7),3,5,10,12-六烯(中间体1.2.I,2.73g,10.0mmol)。于110℃继续搅拌10min,之后将反应混合物逐滴添加至水中并用4M HCl酸化。过滤沉淀并干燥。
ESI-MS:368[M+H]+
Rt(HPLC):0.50min(方法A)
以下化合物为根据上述通用程序(中间体1.3.I)来制备:
/>
中间体2.1
3-(1-硝基乙基)氧杂环丁-3-醇
将硝基乙烷(27.3g,364mmol)于50mL甲醇中的混合物冷却至0℃。在冷却下逐滴添加TEA(9.74mL,69.4mmol),之后逐滴添加氧杂环丁-3-酮(25.0g,347mmol)。去除冷却,将反应混合物于RT下搅拌1h且然后浓缩。通过柱色谱(硅胶;CH/EtOAc=75/25至50/50)纯化残余物。
ESI-MS:r 146[M-H]-
Rt(EI):3.38min
中间体2.2
3-(1-氨基乙基)氧杂环丁-3-醇
将3-(1-硝基乙基)氧杂环丁-3-醇(中间体2.1,24.5g,157mmol)、280mL乙醇及Pd(OH)2/C 5mol%(5.52g,7.87mmol)的混合物在Parr装置中在氢气压力(50psi)下放置16h。过滤反应混合物且在减压下浓缩且不经进一步纯化即用于下一步骤。
ESI-MS:118[M+H]+
Rf(TLC):0.20(PE/EtOAc=0/1)
中间体2.3
2-氯-N-[1-(3-羟基氧杂环丁-3-基)乙基]乙酰胺
将3-(1-氨基乙基)氧杂环丁-3-醇(中间体2.2,32.4g,262mmol)于500mL ACN中的混合物冷却至0℃且添加TEA(44.2mL,315mmol),之后逐滴添加氯乙酰氯(23.0mL,289mmol)。使混合物达到RT且搅拌3h。通过过滤去除沉淀且用50mL甲醇稀释滤液且在真空中浓缩。通过柱色谱(硅胶;DCM/甲醇=97/3至85/15)纯化残余物。
ESI-MS:194[M+H]+
Rt(HPLC):0.27min(方法E)
以下化合物为根据上述通用程序(中间体2.3)来制备:
中间体2.4
9-甲基-2,5-二氧杂-8-氮杂螺[3.5]壬-7-酮
于RT下在氩气下,在30min内向叔丁醇钾(1.01g,9.03mmol)于12.0mL叔戊基醇中的搅拌、脱气溶液中添加2-氯-N-[1-(3-羟基氧杂环丁-3-基)乙基]乙酰胺(中间体2.3,1.24g,6.02mmol)于24.0mL叔戊基醇中的脱气溶液。完成添加后,将反应混合物于RT下再搅拌1h。然后,添加MeOH(5.0mL)及水(0.5mL)且将混合物于RT下搅拌20min。蒸发挥发性物质之后,将残余物吸收于DCM中且通过柱色谱(硅胶;DCM/甲醇=99/1至90/10)纯化。
ESI-MS:158[M+H]+
Rt(HPLC):0.24min(方法E)
以下化合物为根据上述通用程序(中间体2.4)来制备:
中间体2.5
9-甲基-2,5-二氧杂-8-氮杂螺[3.5]壬烷
在氩气下,向9-甲基-2,5-二氧杂-8-氮杂螺[3.5]壬-7-酮(中间体2.4,3.80g,23.0mmol)于90.0mL THF中的脱气混合物中逐滴添加LiAlH4于二乙醚中的1.0M溶液,同时保持温度低于0℃。添加完成后,使反应混合物升温至RT且于此温度下再搅拌16h。
将反应混合物冷却至0℃,用60mL无水二乙醚稀释且连续用1.33mL水、1.33mL 4NNaOH水溶液且最后用4mL水处理。使反应混合物达到室温且再搅拌15min。将混合物经硫酸钠干燥,然后过滤且在真空中蒸发溶剂。将所得残余物与ACN共蒸发两次以去除残余水。
ESI-MS:144[M+H]+
Rt(HPLC):0.17min(方法E)
以下化合物为根据上述通用程序(中间体2.5)来制备:
中间体2.6.I
8-(5-溴-2-硝基吡啶-3-基)-9-甲基-2,5-二氧杂-8-氮杂螺[3.5]壬烷
向5-溴-3-氟-2-硝基吡啶(1.00g,4.53mmol)于20.0mL ACN中的混合物中添加K2CO3(1.88g,13.58mmol)及9-甲基-2,5-二氧杂-8-氮杂螺[3.5]-壬烷(中间体2.5,777mg,5.43mmol)。将混合物加热至60℃且搅拌16.5h。用EtOAc稀释反应物且添加水。分离各相,且用EtOAc萃取水相。将合并的有机相经Na2SO4干燥,并浓缩。
ESI-MS:344/346[M+H]+
Rt(HPLC):0.85min(方法B)
以下化合物为根据上述通用程序(中间体2.6.I)来制备:
/>
/>
/>
中间体2.7.I
9-甲基-8-(2-硝基-5-{2-[三(丙-2-基)硅基]乙炔基}吡啶-3-基)-2,5-二氧杂-8-氮杂螺[3.5]壬烷
在氩气下向8-(5-溴-2-硝基吡啶-3-基)-9-甲基-2,5-二氧杂-8-氮杂螺[3.5]壬烷(中间体2.6.I,584mg,1.70mmol)于6.80mL THF中的脱气溶液中添加DIPEA(2.31mL,12.8mmol),之后添加(三异丙基硅基)-乙炔(0.780mL,3.40mmol)、PdCl2(PPh3)2(60mg,0.085mmol)及碘化铜(I)(49mg,0.25mmol)。将混合物于80℃搅拌1h。将反应混合物用ACN稀释,过滤且在减压下浓缩。通过柱色谱(硅胶;CH/EtOAc=50/50至60/40)纯化残余物。
ESI-MS:446[M+H]+
Rt(HPLC):0.66min(方法G)
以下化合物为根据上述通用程序(中间体2.7.I)来制备:
/>
中间体3.1.I(a)
(a):(2S,4S)-4-({5-溴-3-[(9S)-9-甲基-2,5-二氧杂-8-氮杂螺[3.5]壬-8-基]吡啶-2-基}氧基)-1-[4-(二氟甲基)-8-氧杂-3,5-二氮杂三环[7.4.0.02,7]-十三-1(9),2(7),3,5,10,12-己烯-6-基]吡咯烷-2-甲酸
于RT下向(2S,4S)-1-[4-(二氟甲基)-8-氧杂-3,5-二氮杂三环[7.4.0.02,7]-十三-1(9),2(7),3,5,10,12-己烯-6-基]-4-羟基吡咯烷-2-甲酸(中间体1.3.II,1.00g,2.72mmol)及8-(5-溴-2-硝基吡啶-3-基)-9-甲基-2,5-二氧杂-8-氮杂螺[3.5]壬烷(中间体2.6.I,2.00g,5.44mmol)于20mL DMA中的混合物中添加NaH(326mg,8.16mmol)。将混合物于RT下搅拌过夜。添加水并用TFA酸化混合物。通过过滤收集沉淀且在真空中干燥。通过RP-HPLC(Sunfire C18,ACN/H2O/TFA)纯化粗产物,以提供两种非镜像异构物(a)及(b)。非镜像异构物(a)继续用于下一步骤。
ESI-MS:646/648[M+H]+
Rt(HPLC):1.03min(方法C)-非镜像异构物(a)
1.08min(方法C)-非镜像异构物(b)
以下化合物为根据上述通用程序(中间体3.1.I)来制备:
中间体3.2
(2S,4S)-4-({5-溴-3-[(9S)-9-甲基-2,5-二氧杂-8-氮杂螺[3.5]壬-8-基]吡啶-2-基}氧基)-1-[4-(二氟甲基)-8-氧杂-3,5-二氮杂三环[7.4.0.02,7]-十三-1(9),2(7),3,5,10,12-己烯-6-基]吡咯烷-2-甲酸叔丁基酯
向2.30mL THF中的(2S,4S)-4-({5-溴-3-[(9S)-9-甲基-2,5-二氧杂-8-氮杂螺[3.5]壬-8-基]吡啶-2-基}氧基)-1-[4-(二氟甲基)-8-氧杂-3,5-二氮杂三环[7.4.0.02,7]十三-1(9),2(7),3,5,10,12-己烯-6-基]吡咯烷-2-甲酸(中间体3.1.I(a),110mg,0.170mmol)中添加2-叔丁基-1,3-二异丙基异脲(162μL,0.68mmol)。将反应混合物于70℃在微波炉中搅拌1h。过滤沉淀且在减压下浓缩滤液。通过柱色谱(硅胶;CH/EtOAc=93/7至60/40)纯化残余物。
ESI-MS:702/704[M+H]+
Rt(HPLC):0.87min(方法A)
中间体3.3
(2S,4S)-1-[4-(二氟甲基)-8-氧杂-3,5-二氮杂三环[7.4.0.02,7]-十三-1(9),2(7),3,5,10,12-己烯-6-基]-4-({3-[(9S)-9-甲基-2,5-二氧杂-8-氮杂螺[3.5]壬-8-基]-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶-2-基}氧基)吡咯烷-2-甲酸叔丁基酯
在氩气下向2.00mL二噁烷中的(2S,4S)-4-({5-溴-3-[(9S)-9-甲基-2,5-二氧杂-8-氮杂螺[3.5]壬-8-基]吡啶-2-基}氧基)-1-[4-(二氟甲基)-8-氧杂-3,5-二氮杂三环[7.4.0.02,7]十三-1(9),2(7),3,5,10,12-己烯-6-基]吡咯烷-2-甲酸叔丁基酯(中间体3.2,132mg,0.150mmol)中添加双(频哪醇)-二硼(113mg,0.445mmol)、Pd(dppf)Cl2(12.0mg,0.0160mmol)及乙酸钾(58.0mg,0.591mmol)。将反应混合物在90℃搅拌过夜。用水稀释反应混合物并用DCM/甲醇萃取。使用相分离器处理有机相且在减压下浓缩。
ESI-MS:750[M+H]+
Rt(HPLC):0.90min(方法A)
中间体3.4.I
(2S,4S)-1-[4-(二氟甲基)-8-氧杂-3,5-二氮杂三环[7.4.0.02,7]十三-1(9),2(7),3,5,10,12-己烯-6-基]-4-({N,N-二甲基-5-[(9S)-9-甲基-2,5-二氧杂-8-氮杂螺[3.5]壬-8-基]-[3,4'-联吡啶]-2'-基}氧基)吡咯烷-2-甲酸叔丁基酯
在氩气下向2.00mL二噁烷中的(2S,4S)-1-[4-(二氟甲基)-8-氧杂-3,5-二氮杂三环[7.4.0.02,7]十三-1(9),2(7),3,5,10,12-己烯-6-基]-4-({3-[(9S)-9-甲基-2,5-二氧杂-8-氮杂螺[3.5]壬-8-基]-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶-2-基}氧基)吡咯烷-2-甲酸叔丁基酯(中间体3.3,105mg,0.0700mmol)中添加4-溴-N,N-二甲基吡啶-2-胺(22.0mg,0.109mmol),Pd(PPh3)4(9.7mg,0.0080mmol)、第3代Xphos(6.0mg,0.0070mmol)及碳酸钠溶液2mol/L(105μL,0.210mmol)。将反应混合物于100℃1.5h。将反应混合物用ACN/水稀释,过滤且通过RP-HPLC(Xbridge-C18,ACN/H2O/0.1% NH4OH)纯化。
ESI-MS:744[M+H]+
Rt(HPLC):0.64min(方法A)
以下化合物为根据上述通用程序(中间体3.4.I)来制备:
中间体4.1
4-溴-3-甲氧基-N,N-二甲基吡啶-2-胺
向3.00mL THF中的4-溴-2-氟-3-甲氧基吡啶(200mg,0.97mmol)中添加二甲胺(3.64mL,7.28mmol)。将反应混合物于50℃搅拌过夜且然后在减压下浓缩,以得到标题化合物。
ESI-MS:231/233[M+H]+
Rt(HPLC):0.30min(方法A)
中间体5.1
4-碘-3-甲氧基-N-甲基吡啶-2-胺
向8.00mL THF中的2-氟-4-碘-3-甲氧基吡啶(500mg,1.98mmol)中添加甲胺于THF中的2.0M溶液(7.90mL,15.8mmol)。将反应混合物于55℃搅拌48h,然后在减压下浓缩。
ESI-MS:265[M+H]+
Rt(HPLC):0.26min(方法A)
中间体6.1
8-(2,5-二氟吡啶-3-基)-9-甲基-2,5-二氧杂-8-氮杂螺[3.5]壬烷
在氩气氛下,将8-(5-溴-2-氟吡啶-3-基)-9-甲基-2,5-二氧杂-8-氮杂螺[3.5]壬烷(中间体7.1.III,668mg;2.00mmol)于THF(13.4mL)中的脱气溶液冷却至0℃。然后,逐滴添加异丙基氯化镁氯化锂复合物于THF中的溶液(1.92mL;2.5mmol)。使反应混合物达到室温且搅拌2.5h。添加额外于THF中的异丙基氯化镁氯化锂复合物(0.45mL;0.59mmol)且再继续搅拌1.5h。在真空中浓缩混合物,然后吸收于DCM(5.00mL)中且冷却中-78℃中。于-78℃在搅拌下逐滴添加N-氟苯磺酰胺(863mg,2.60mmol)于DCM(7.50mL)及全氟十氢萘(2.50mL)的混合物中的溶液。完成添加后,将反应混合物升温至0℃,搅拌30min,然后升温至RT且再搅拌1h。将反应混合物倾倒至饱和NH4Cl溶液中且搅拌5min。经由硅藻土过滤混合物,且在相分离后,用DCM萃取水相且用硫酸钠干燥合并的有机相,过滤且蒸发。将残余物溶解于ACN/H2O中,过滤且通过RP-HPLC纯化。
ESI-MS:257[M+H]+
Rt(HPLC):0.45min(方法A)
中间体7.1.I
5-氯-2-氟-3-{4H,5H,6H,7H-[1,2]噁唑并[4,3-c]吡啶-5-基}吡啶
向2.00mL DMF中的5-氯-2-硝基-3-{4H,5H,6H,7H-[1,2]噁唑并[4,3-c]吡啶-5-基}吡啶(中间体2.6.VII,210mg,0.750mmol)中添加TBAF于THF中的1.0M溶液(1.50mL,1.50mmol)。将反应混合物于RT下搅拌30min,然后于50℃搅拌3h。再次,添加TBAF(1.50mL,1.50mmol)且将反应混合物于50℃搅拌5h。向反应混合物中添加ACN/水,通过过滤收集沉淀且通过RP-HPLC(Xbridge C18,ACN/H2O/TFA)纯化。
ESI-MS:254/256[M+H]+
Rt(HPLC):0.77min(方法E)
以下化合物为根据上述通用程序(中间体7.1.I)来制备:
中间体8.1
(2S,4S)-4-{[5-乙炔基-3-(吗啉-4-基)吡啶-2-基]氧基}吡咯烷-2-甲酸
向3.00 mL DMA中的(2S,4S)-1-(叔丁氧基羰基)-4-羟基吡咯烷-2-甲酸(202 mg,0.83 mmol)中添加NaH(99.8 mg,2.50 mmol)。将此混合物于RT下搅拌30 min,之后添加4-{2-硝基-5-[2-(三甲基硅基)乙炔基]-吡啶-3-基}吗啉(中间体2.7.II,127 mg,0.42mmol)于2.00 mL DMA中的溶液。在将反应混合物于RT下搅拌2 h后,将其用ACN稀释并用TFA酸化。通过过滤收集沉淀且通过RP-HPLC(Sunfire,ACN/H2O/TFA)纯化。将残余物稀释于10.0 mL DCM中且添加1.00 ml TFA。将反应混合物于RT下搅拌过夜且浓缩,以得到标题化合物。
ESI-MS:318[M+H]+
Rt(HPLC):0.67 min(方法C)
中间体9.1(a)
(2S,4S)-1-[(叔丁氧基)羰基]-4-({5-乙炔基-3-[(9S)-9-甲基-2,5-二氧杂-8-氮杂螺[3.5]壬-8-基]吡啶-2-基}氧基)吡咯烷-2-甲酸
向(2S,4S)-1-[(叔丁氧基)羰基]-4-羟基吡咯烷-2-甲酸(800 mg,3.30 mmol)及9-甲基-8-(2-硝基-5-{2-[三(丙-2-基)硅基]乙炔基}吡啶-3-基)-2,5-二氧杂-8-氮杂螺[3.5]壬烷(中间体2.7.I,1.55 g,3.30 mmol)于31.0 mL NMP中的混合物中添加NaH(660mg,16.5 mmol)。将反应混合物于RT下搅拌1 h 20 min。将反应混合物用水淬灭,用1N HCl酸化,过滤且用EtOAc萃取三次。合并有机相且经硫酸钠干燥,过滤并蒸发。将粗产物溶解于10 mL THF中,添加2 mL TBAF溶液(1.0M,于THF中)且将反应混合物于50℃搅拌1h。将反应混合物用EtOAc稀释且用NH4Cl饱和溶液萃取。合并有机相且经硫酸钠干燥,过滤并蒸发。通过HPLC(Xbridge,ACN/H2O/TFA)纯化残余物。
ESI-MS:474[M+H]+
Rt(HPLC):0.63min(方法A)-非镜像异构物(a)
0.66min(方法A)-非镜像异构物(b)
中间体9.2
(2S,4S)-4-({5-乙炔基-3-[(9S)-9-甲基-2,5-二氧杂-8-氮杂螺[3.5]壬-8-基]吡啶-2-基}氧基)吡咯烷-2-甲酸
向3.00mL ACN中的(2S,4S)-1-[(叔丁氧基)羰基]-4-({5-乙炔基-3-[(9S)-9-甲基-2,5-二氧杂-8-氮杂螺[3.5]壬-8-基]吡啶-2-基}氧基)吡咯烷-2-甲酸(中间体9.1(a),40mg,0.080mmol)中添加TosOH(35mg,0.18mmol)。将反应混合物于RT下搅拌48h。蒸发反应混合物且不经进一步纯化即用于下一步骤。
ESI-MS:374[M+H]+
Rt(HPLC):0.36min(方法A)
中间体10.1
4-(二氟甲基)-2-甲氧基苯甲腈
向3.00mL DCM中的4-甲酰基-2-甲氧基苯甲腈(806mg,5.00mmol)中缓慢添加双(2-甲氧基乙基)氨基三氟化硫(于甲苯中的50%溶液,3.13mL,8.50mmol)及乙醇(1.00mmol,57.6μL)。将反应混合物于RT下搅拌过夜。再次,添加双(2-甲氧基乙基)氨基三氟化硫(920μL,2.5mmol),之后添加乙醇(20.0μL,0.5mmol)。将此混合物于RT下搅拌1h后,将其倾倒至饱和NaHCO3水溶液中且搅拌5min。分离各相,且用DCM萃取水相。合并有机相,用水洗涤,干燥并蒸发。粗产物原样用于下一步骤中。
Rt(HPLC):0.49min(方法A)
中间体10.2
4-(二氟甲基)-2-羟基苯甲腈
将2-(二乙基氨基)乙烷硫醇(300mg,1.77mmol)于3.00mL DMF中的混合物冷却至0℃且添加叔丁醇钠(340mg,3.54mmol)。将反应混合物于0℃搅拌5min。然后去除冷却浴且使混合物达到RT。于RT下添加4-(二氟甲基)-2-甲氧基苯甲腈(中间体10.1,50.0mg,0.270mmol)于2.00mL DMF中的溶液且在搅拌下将所得混合物加热至160℃并保持1.5h。然后,将反应混合物冷却至0℃且用1N HCl水溶液酸化。用EtOAc萃取反应混合物,将合并的有机层干燥且蒸发。通过RP-HPLC(Xbridge,ACN/H2O/TFA)纯化粗产物。
ESI-MS:170[M+H]+
Rt(HPLC):0.41min(方法A)
中间体10.3.I
3-氨基-6-(二氟甲基)-1-苯并呋喃-2-甲酰胺
向5.00mL乙醇中的4-(二氟甲基)-2-羟基苯甲腈(120mg,0.71mmol)中添加K2CO3(中间体10.2,150mg,1.09mmol)及2-溴乙酰胺(119mg,0.87mmol)。将反应混合物加热回流2h。使反应混合物达到RT且添加KOH(95.1mg,1.44mmol)。然后,将混合物加热回流2h。冷却至RT后,用水稀释反应混合物。在真空中蒸发乙醇,通过过滤收集沉淀,用水洗涤且干燥。
ESI-MS:227[M+H]+
Rt(HPLC):0.39min(方法A)
以下化合物为根据上述通用程序(中间体10.3.I)来制备:
中间体10.4.I
6-氯-11-(二氟甲基)-4-甲基-8-氧杂-3,5-二氮杂三环[7.4.0.02,7]十三-1(9),2(7),3,5,10,12-六烯
于0℃在氩气氛下,将氧氯化磷(92.0μL,1.01mmol)及DMA(39.0μL,0.40mmol)的混合物搅拌30min。将混合物用0.5mL氧氯化磷稀释且然后逐滴添加至3-氨基-6-(二氟甲基)-1-苯并呋喃-2-甲酰胺(中间体10.3.I,76.0mg,0.34mmol)中。在完成添加后,将混合物加热至50℃并搅拌3h。再次,添加氧氯化磷(184μL,2.02mmol)且将反应混合物于50℃搅拌过夜。将反应混合物冷却至RT,用冰水稀释且用NaHCO3水溶液中和。将混合物用DCM萃取,干燥有机相,过滤并蒸发。
ESI-MS:269[M+H]+
Rt(HPLC):0.62min(方法A)
以下化合物为根据上述通用程序(中间体10.4.I)来制备:
中间体11.1
(2S)-1-(5-溴-2-硝基吡啶-3-基)-2-甲基六氢吡嗪
/>
向4.00mL ACN中的5-溴-3-氟-2-硝基吡啶(200mg,0.91mmol)中添加(3S)-3-甲基六氢吡嗪-1-甲酸叔丁基酯(272mg,1.36mmol)及TEA(635μL,4.53mmol)。将反应混合物于80℃搅拌2.75h。将反应混合物用EtOAc淬灭且用半饱和NH4Cl溶液、半饱和NaHCO3l溶液及饱和NaCl溶液萃取。干燥有机相,过滤并浓缩。将残余物稀释于二噁烷中的4N HCl中,于RT下搅拌45min且浓缩,以得到呈盐形式的标题化合物。
ESI-MS:301/303[M+H]+
Rt(HPLC):0.70min(方法C)
中间体11.2
(3S)-4-(5-溴-2-硝基吡啶-3-基)-3-甲基六氢吡嗪-1-甲腈
向2.00mL DCM中的(2S)-1-(5-溴-2-硝基吡啶-3-基)-2-甲基六氢吡嗪盐酸盐(中间体11.1,80.0mg,0.24mmol)中添加DIPEA(103μL,0.592mmol)及溴化氰(3mol/L,于DCM中,86.9μL,0.261mmol)。将反应混合物于RT下搅拌过夜。再次,向反应混合物中添加溴化氰(3mol/L,于DCM中,86.9μL,0.261mmol)且于RT下继续搅拌1h。将反应混合物用半饱和NaHCO3水溶液淬灭。分离各相且用DCM萃取。将合并的有机相经相分离器干燥且蒸发。
ESI-MS:326/328[M+H]+
Rt(HPLC):0.83min(方法C)
中间体12.1
(5S)-5-甲基-1,2,6-三氮杂螺[2.5]辛-1-烯-6-甲酸叔丁基酯
于0℃,向(2S)-2-甲基-4-侧氧基六氢吡啶-1-甲酸叔丁基酯(1.00g,4.69mmol)中添加6.70mL氨(7N,于甲醇中)。搅拌反应混合物且使其达到RT过夜。然后将混合物冷却至-20℃且逐份添加羟基胺-O-磺酸(1.33g,11.7mmol)。使反应混合物达到RT并搅拌1h。过滤掉沉淀,用甲醇洗涤且在真空中浓缩滤液。将浓缩物吸收于EtOAc/TEA(20mL72 mL)中且用10% Na2CO3水溶液(15mL)萃取。将有机相用水萃取且经相分离器干燥。
将有机层用10mL甲醇稀释且随后冷却至-10℃。添加碘(1.31g,5.16mmol)且使反应混合物达到RT。将反应混合物用5%亚硫酸钠溶液淬灭且用10%NaCl水溶液萃取。将有机相经Na2SO4干燥,过滤并蒸发。通过HPLC(Sunfire,ACN/H2O/TFA)纯化产物。
ESI-MS:248[M+Na]+
Rt(HPLC):1.09min(方法C)
中间体12.2
(5S)-5-甲基-1,2,6-三氮杂螺[2.5]辛-1-烯
向5.00mL DCM中的(5S)-5-甲基-1,2,6-三氮杂螺[2.5]辛-1-烯-6-甲酸叔丁基酯(中间体12.1,440mg,1.95mmol)中添加TFA(0.50mL 3.00mmol)。将反应混合物于RT下搅拌6h,然后浓缩且不经进一步纯化即用于下一步骤。
ESI-MS:126[M+H]+
Rt(HPLC):0.11min(方法C)
中间体13.1
2-甲基六氢吡啶3-甲酸甲基酯乙酸盐
向80.0mL乙酸中的2-甲基吡啶-3-甲酸甲基酯(10.0g,66.2mmol)中添加Pd(OH)2/C(1.00g)且将混合物于80℃在3巴下氢化12h。过滤反应混合物且在减压下浓缩且不经进一步纯化即用于下一步骤。
ESI-MS:158[M+H]+
Rt(HPLC):0.27min(方法N)
中间体13.2
2-甲基六氢吡啶-1,3-二甲酸1-叔丁基酯3-甲基酯
向90.0mL THF中的2-甲基六氢吡啶-3-甲酸甲基酯(中间体13.1,15.0g,60.4mmol)中添加TEA(8.49mL,60.4mmol)及二碳酸二-叔丁基酯(13.2g,60.4mmol)且将反应混合物于RT下搅拌1.5h。将反应混合物用EtOAc稀释且用半饱和NaHCO3溶液萃取。将有机相经Na2SO4干燥,过滤并蒸发。通过柱色谱(硅胶;CH/EtOAc=99/1至1/99)纯化粗产物。
ESI-MS:258[M+H]+
Rt(HPLC):0.65min(方法F)
中间体13.3
2-甲基六氢吡啶-1,3,3-三甲酸1-叔丁基酯3,3-二甲基酯
于-78℃在氩气下向二异丙基氨基锂(2mol/L,11.1mL,22.2mmol)于32.5mL THF中的溶液中添加2-甲基六氢吡啶-1,3-二甲酸1-叔丁基酯3-甲基酯(中间体13.2,5.00g,18.5mmol)于20.0mL THF中的溶液中。使反应混合物达到-20℃并搅拌30min。然后将反应混合物冷却至-78℃且向反应混合物中逐滴添加氯甲酸甲酯(2.25mL,27.7mmol)于10.0mLTHF中的溶液。在添加期间,保持温度低于-65℃。完全添加后,使反应混合物达到RT且于RT下搅拌2h。将反应混合物用饱和NH4Cl溶液淬灭且于RT下搅拌10min。将混合物用水稀释并用DCM萃取。合并有机层且经硫酸钠干燥,过滤并在真空中浓缩。通过柱色谱(硅胶;CH/EtOAc=95/5至60/40)纯化残余物。
ESI-MS:316[M+H]+
Rf(TLC):0.29(CH/EtOAc=20/80)
中间体13.4
3,3-双(羟基甲基)-2-甲基六氢吡啶-1-甲酸叔丁基酯
于RT下在氩气下向2-甲基六氢吡啶-1,3,3-三甲酸1-叔丁基酯3,3-二甲基酯(中间体13.3,5.60g,16.9mmol)于44.8mL THF中的脱气溶液中逐滴添加LiAlH4(2.3mol/L,于2-甲基四氢呋喃中,14.6mL,33.7mmol)且将此混合物于RT下搅拌1.5h。将反应混合物冷却至0℃,用80.0mL二乙醚稀释且小心地用1.25mL水、然后1.25mL 4N NaOH及最后用3.75mL水处理。使反应混合物达到RT且搅拌15min。将混合物经Na2SO4干燥,过滤且蒸发。通过柱色谱(硅胶;CH/EtOAc=75/25至0/100)纯化残余物。
ESI-MS:260[M+H]+
Rf(TLC):0.14(CH/EtOAc=50/50)
中间体13.5
5-甲基-2-氧杂-6-氮杂螺[3.5]壬烷-6-甲酸叔丁基酯
向6.00mL THF中的3,3-双(羟基甲基)-2-甲基六氢吡啶-1-甲酸叔丁基酯(中间体13.4,259mg,1.00mmol)中添加三苯基膦(525mg,2.00mmol)。将反应混合物于RT下搅拌5min。然后添加福美锌(Ziram)(483mg,1.50mmol)及偶氮二甲酸二异丙基酯(413μL,2.00mmol)且将混合物于70℃搅拌16h。将反应混合物用EtOAc稀释,经硅藻土垫过滤且用EtOAc洗涤。将滤液用5%NH3水溶液洗涤。干燥有机相,过滤并蒸发。通过柱色谱(硅胶;DCM/EtOAc=95/5至70/30)纯化残余物。通过HPLC(Sunfire,ACN/H2O/TFA)纯化残余物。
ESI-MS:242[M+H]+
Rt(HPLC):0.80min(方法E)
中间体13.6
5-甲基-2-氧杂-6-氮杂螺[3.5]壬烷
向2.00mL DCM中的5-甲基-2-氧杂-6-氮杂螺[3.5]壬烷-6-甲酸叔丁基酯(中间体13.5,134mg,0.56mmol)中添加TFA(500mL,6.48mmol)。将反应混合物于RT下搅拌30min,然后在减压下浓缩且不经进一步纯化即用于下一步骤。
ESI-MS:142[M+H]+
Rt(HPLC):0.17min(方法E)
中间体14.1
2-(氰基甲氧基)-4-乙基苯甲腈
向4-乙基-2-羟基-苯甲腈(2.34g,16.2mmol)及碳酸钾(4.83g,35.0mmol)于40.0mL DMF中的混合物中添加溴乙腈(1.22mL,17.5mmol)且将反应混合物于50℃搅拌过夜。将反应混合物倾倒至水中并用DCM萃取。在真空中浓缩有机相且粗产物不经进一步纯化即用于下一步骤。
中间体14.2
3-氨基-6-乙基-1-苯并呋喃-2-甲腈
向2-(氰基甲氧基)-4-乙基苯甲腈(中间体14.1,1.79g,10.0mmol)于40.0mL THF中的混合物中添加叔丁醇钾(108mg,0.964mmol),且将混合物于RT下搅拌过夜。在真空中蒸发溶剂且通过柱色谱纯化产物且原样用于下一步骤。
中间体14.3
N-(2-氰基-6-乙基-1-苯并呋喃-3-基)-2,2,2-三氟乙酰胺
将3-氨基-6-乙基-1-苯并呋喃-2-甲腈(中间体14.2,1.40g,7.51mmol)于20mLTFAA中的混合物于50℃搅拌3h。将溶剂在减压下蒸发至干燥。将残余物吸收于乙酸乙酯中且将有机相用水洗涤且在真空中浓缩。粗产物不经进一步纯化即用于下一步骤。
中间体14.4
6-氯-11-乙基-4-(三氟甲基)-8-氧杂-3,5-二氮杂三环[7.4.0.02,7]十三-1(13),2,4,6,9,11-六烯
于45℃向N-(2-氰基-6-乙基-1-苯并呋喃-3-基)-2,2,2-三氟乙酰胺(中间体14.3,2.00g,7.09mmol)于5.0mL环丁砜中的混合物中添加五氯化磷(5.90g,28.3mmol)。将混合物于110℃搅拌16h,然后倾倒至水中并用EtOAc萃取。用盐水洗涤合并的有机层,并蒸发。通过柱色谱(硅胶;CH/EtOAc=100/0至95/5)纯化残余物。
ESI-MS:301/303[M+H]+
Rt(HPLC):0.79min(方法A)
中间体15.1
3-(2-氯乙酰氨基)-1-苯并呋喃-2-甲酰胺
将3-氨基苯并呋喃-2-甲酰胺(3.52g,176mmol)于氯乙酰氯(6.00mL,75mmol)中的混合物于60℃搅拌10min。添加氯乙酰氯(4.00mL,50mmol)且于60℃继续搅拌20min。将反应混合物倾倒至水中,通过过滤收集沉淀,重新悬浮于水中,过滤且用水洗涤。粗产物不经进一步纯化即原样用于下一步骤。
ESI-MS:253[M+H]+
Rt(HPLC):0.41min(方法A)
中间体15.2
4-(羟基甲基)-8-氧杂-3,5-二氮杂三环[7.4.0.02,7]十三-1(9),2(7),3,10,12-戊烯-6-酮
将3-(2-氯乙酰氨基)-1-苯并呋喃-2-甲酰胺(中间体15.1,5.80g,23.0mmol)于2MNaOH水溶液中的混合物于60℃搅拌10min。冷却至RT后,继续搅拌10h,然后通过添加浓盐酸将pH调整至1。通过过滤收集沉淀,并用水洗涤并干燥。
ESI-MS:217[M+H]+
Rt(HPLC):0.59min(方法C)
中间体15.3
6-氯-4-(氯甲基)-8-氧杂-3,5-二氮杂三环[7.4.0.02,7]十三-1(9),2(7),3,5,10,12-六烯
在搅拌下向4-(羟基甲基)-8-氧杂-3,5-二氮杂三环[7.4.0.02,7]十三-1(9),2(7),3,10,12-戊烯-6-酮(中间体15.2,5.00g,17.3mmol)中添加氧氯化磷(30mL,328mmol)且将所得混合物在回流下加热1.5h。将反应混合物冷却至RT且在真空中浓缩。向残余物中添加乙酸乙酯,且通过添加碳酸氢钠饱和水溶液中和混合物。将混合物经硅藻土过滤,分离各相且将有机相经硫酸镁干燥且蒸发。通过急速柱色谱(环己烷/EtOAc=88/12 0/100)纯化粗产物。
ESI-MS:253[M+H]+
Rt(HPLC):1.07min(方法C)
中间体16.1
(2S,4S)-4-({3-[(9S)-9-甲基-2,5-二氧杂-8-氮杂螺[3.5]壬-8-基]-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶-2-基}氧基)-1-[4-(三氟甲基)-8-氧杂-3,5-二氮杂三环[7.4.0.02,7]-十三-1(9),2(7),3,5,10,12-己烯-6-基]吡咯烷-2-甲酸
在氩气氛下向实施例1.10(1.50g,2.26mmol)、双-(频哪醇)-二硼(630mg,2.48mmol)及乙酸钾(670mg,6.93mmol)的混合物于30mL二噁烷中的脱气混合物中添加Pd(dppf)Cl2(165mg,0.226mmol)。将反应混合物加热至90℃并保持3h,然后冷却至RT,倾倒至水中且用二乙醚/THF萃取。合并有机相,经硫酸钠干燥,并在减压下浓缩。通过急速柱色谱(EtOAc/MeOH=10:1)纯化粗产物。
ESI-MS:712[M+H]+
Rt(HPLC):1.05min(方法A)
最终化合物的制备
实施例1.01(通用途径)
(2S,4S)-4-{[5-氯-3-(2-氰基吗啉-4-基)吡啶-2-基]氧基}-1-[4-(三氟甲基)-8-氧杂-3,5-二氮杂三环[7.4.0.02,7]十三-1(13),2,4,6,9,11-己烯-6-基]吡咯烷-2-甲酸
向2.00mL DMA中的(2S,4S)-4-羟基-1-[4-(三氟甲基)-8-氧杂-3,5-二氮杂三环[7.4.0.02,7]十三-1(9),2(7),3,5,10,12-己烯-6-基]吡咯烷-2-甲酸(中间体1.3.I,58.0mg,0.15mmol)中添加4-(5-氯-2-硝基吡啶-3-基)吗啉-2-甲腈(中间体2.6.III,80.6mg,0.30mmol,2.0eq)及NaH(18.0mg,0.45mmol,3.0eq)。将反应混合物于80℃搅拌20min。将反应混合物用ACN/水稀释,用TFA酸化,过滤且通过HPLC(ACN/H2O/TFA)纯化。获得呈两种非镜像异构物的混合物形式的产物。
ESI-MS:589[M+H]+
Rt(HPLC):1.05min(方法H)
下表中所列示的化合物为根据上述通用程序(实施例1.01)来制备。在表中指示的情况下,实施例化合物分离为非镜像异构混合物(ds-混合物)或纯非镜像异构物(Rt为针对分离的非镜像异构物(实施例及第2非镜像异构物(第2ds)二者给出)。
/>
/>
/>
/>
/>
/>
/>
/>
如下文所阐释经由小分子X射线确认实施例1.10的绝对立体化学:
如下文所阐释经由小分子X射线确认实施例1.28的绝对立体化学:
实施例2.01(通用途径)
(2S,4S)-1-[4-(二氟甲基)-8-氧杂-3,5-二氮杂三环[7.4.0.02,7]十三-1(13),2,4,6,9,11-己烯-6-基]-4-{[5-乙炔基-3-(吗啉-4-基)吡啶-2基]氧基}-吡咯烷-2-甲酸
向1.50mL DMSO中的6-氯-4-(二氟甲基)-8-氧杂-3,5-二氮杂三环[7.4.0.02,7]十三-1(9),2(7),3,5,10,12-六烯(中间体1.2.II,30.0mg,0.12mmol)中添加(2S,4S)-4-{[5-乙炔基-3-(吗啉-4-基)吡啶-2-基]氧基}吡咯烷-2-甲酸(中间体8.1,55.9mg,0.13mmol)及DIPEA(60.8μL,0.35mmol)。将反应混合物于110℃搅拌1h。将反应混合物用ACN稀释,用TFA酸化,过滤且通过HPLC(ACN/H2O/TFA)纯化。
ESI-MS:536[M+H]+
Rt(HPLC):1.08min(方法C)
以下实施例为根据上述通用程序(实施例2.1)来制备:
/>
/>
实施例3.01(通用途径)
(2S,4S)-4-({5-[(3S)-3-甲基吗啉-4-基]-[3,4'-联吡啶]-6-基}氧基)-1-[4-(三氟甲基)-8-氧杂-3,5-二氮杂三环[7.4.0.02,7]十三-1(9),2(7),3,5,10,12-己烯-6-基]吡咯烷-2-甲酸
在氩气下,向(2S,4S)-4-({5-溴-3-[(3S)-3-甲基吗啉-4-基]吡啶-2-基}氧基)-1-[4-(三氟甲基)-8-氧杂-3,5-二氮杂三环[7.4.0.02,7]十三-1(9),2(7),3,5,10,12-己烯-6-基]吡咯烷-2-甲酸(中间体3.1.II,50.0mg,0.08mmol)、(吡啶-4-基)硼酸(24.7mg,0.20mmol)、Na2CO3溶液(2.0M,100μL,0.20mmol)、第3代Xphos(3.40mg)及Pd(PPh3)4(4.64mg)中的混合物中添加2.00mL二噁烷。将反应混合物于100℃搅拌2h。过滤反应混合物,用ACN/甲醇稀释且通过HPLC(Xbridge,ACN/H2O/TFA)纯化。
ESI-MS:621[M+H]+
Rt(HPLC):0.818min(方法B)
以下实施例为根据上述通用程序(实施例3.01)来制备。所用的硼酸酯或硼酸有市售或可容易地如文献(Boronic Acids:Preparation and Applications in OrganicSynthesis,Medicine and Materials,1及2,第2版,ISBN 9783527325986)中所述来制备。
/>
/>
/>
/>
/>
/>
/>
/>
实施例4.01(通用途径)
(2S,4S)-1-[4-(二氟甲基)-8-氧杂-3,5-二氮杂三环[7.4.0.02,7]十三-1(9),2(7),3,5,10,12-己烯-6-基]-4-({N,N-二甲基-5-[(9S)-9-甲基-2,5-二氧杂-8-氮杂螺[3.5]壬-8-基]-[3,4'-联吡啶]-2'-基}氧基)吡咯烷-2-甲酸
经1天的时段向2.00mL DCM中的(2S,4S)-1-[4-(二氟甲基)-8-氧杂-3,5-二氮杂三环[7.4.0.02,7]十三-1(9),2(7),3,5,10,12-己烯-6-基]-4-({N,N-二甲基-5-[(9S)-9-甲基-2,5-二氧杂-8-氮杂螺[3.5]壬-8-基]-[3,4'-联吡啶]-2'-基}氧基)吡咯烷-2-甲酸叔丁基酯(中间体3.4.I,13mg,0.020mmol)中添加三氟乙酸(650μL,8.49mmol)。将反应混合物于RT下搅拌过夜且然后在减压下浓缩。通过HPLC(Xbridge,ACN/H2O/TFA)纯化粗产物。
ESI-MS:688[M+H]+
Rt(HPLC):0.51min(方法A)
以下实施例为根据上述通用程序(实施例4.1)来制备:
/>
实施例5.01
(2S,4S)-1-[4-(二氟甲基)-8-氧杂-3,5-二氮杂三环[7.4.0.02,7]十三-1(9),2(7),3,5,10,12-己烯-6-基]-4-({2'-甲烷亚磺酰基-5-[(9S)-9-甲基-2,5-二氧杂-8-氮杂螺[3.5]壬-8-基]-[3,4'-联吡啶]-6-基}氧基)吡咯烷-2-甲酸
于-15℃向(2S,4S)-1-[4-(二氟甲基)-8-氧杂-3,5-二氮杂三环-[7.4.0.02,7]十三-1(9),2(7),3,5,10,12-己烯-6-基]-4-({5-[(9S)-9-甲基-2,5-二氧杂-8-氮杂螺[3.5]壬-8-基]-2'-(甲基硫基)-[3,4'-联吡啶]-6-基}氧基)-吡咯烷-2-甲酸(实施例3.16,25.0mg,0.04mmol)于1.00mL DCM中的冷却溶液中添加间-氯过氧苯甲酸(7.30mg,0.03mmol)。将反应混合物于-15℃搅拌10min且随后通过HPLC(Xbridge,ACN/H2O/TFA)纯化。
ESI-MS:707[M+H]+
Rt(HPLC):0.85min(方法H)
实施例6.01
(2S,4S)-4-({3-[(9S)-9-甲基-2,5-二氧杂-8-氮杂螺[3.5]壬-8-基]-5-(丙-1-炔-1-基)吡啶-2-基}-氧基)-1-[4-(三氟甲基)-8-氧杂-3,5-二氮杂三环[7.4.0.02,7]十三-1(9),2(7),3,5,10,12己烯-6-基]吡咯烷-2-甲酸
向(2S,4S)-4-({5-溴-3-[(9S)-9-甲基-2,5-二氧杂-8-氮杂螺[3.5]壬-8-基]吡啶-2-基}氧基)-1-[4-(三氟甲基)-8-氧杂-3,5-二氮杂三环[7.4.0.02,7]十三-1(9),2(7),3,5,10,12-己烯-6-基]吡咯烷-2-甲酸(实施例1.10,150mg,0.230mmol)于5.00mL THF中的脱气溶液中添加碘化铜(I)(4.3mg,0.023mmol),之后添加Pd(dppf)Cl2(33mg,0.050mmol))。搅拌几分钟后,添加甲基乙炔于THF中的1M溶液(1.35mL,1.35mmol)且将混合物加热至75℃并保持4h。将反应混合物用ACN稀释,用乙酸酸化,过滤且通过HPLC(Xbridge,ACN/H2O/TFA)纯化。
ESI-MS:624[M+H]+
Rt(HPLC):1.08min(方法E)
以下实施例为根据上述通用程序(实施例6.01)来制备:
/>
实施例7.01
(2S,4S)-4-({3-[(9S)-9-甲基-2,5-二氧杂-8-氮杂螺[3.5]壬-8-基]-5-(嘧啶-5-基)吡啶-2--基}氧基)-1-[4-(三氟甲基)-8-氧杂-3,5-二氮杂三环[7.4.0.02,7]十三-1(9),2(7),3,5,10,12-己烯-6-基]吡咯烷-2-甲酸
向(2S,4S)-4-({3-[(9S)-9-甲基-2,5-二氧杂-8-氮杂螺[3.5]壬-8-基]-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶-2-基}氧基)-1-[4-(三氟甲基)-8-氧杂-3,5-二氮杂三环-[7.4.0.02,7]-十三-1(9),2(7),3,5,10,12-己烯-6-基]吡咯烷-2-甲酸(中间体16.1,220mg,0.309mmol)、碳酸钾溶液(2.0mol/L,0.463mL,0.928mmol)及4-溴-1-环丙基-1H-吡唑(119mg,618mmol)于5.00mL二噁烷中的脱气混合物中添加第3代Xphos(15mg,0.018mmol)。将反应混合物加热至80℃并保持2h,然后冷却至RT且用乙酸乙酯稀释。添加饱和氯化铵水溶液及水。分离各相并用乙酸乙酯萃取水层。将合并的有机层用饱和氯化铵溶液洗涤且经硫酸钠干燥,过滤,蒸发且通过HPLC(Sunfire,ACN/H2O/TFA)纯化。
ESI-MS:692[M+H]+
Rt(HPLC):1.01min(E)
以下实施例为根据上述通用程序(实施例7.01)来制备:
/>
实施例8.01
(2S,4S)-4-{[5-(1-甲基-1H-1,2,3-三唑-4-基)-3-[(9S)-9-甲基-2,5-二氧杂-8-氮杂螺[3.5]壬-8-基]吡啶-2-基]氧基}-1-[4-(三氟甲基)-8-氧杂-3,5-二氮杂三环[7.4.0.02,7]十三-1(9),2(7),3,5,10,12-己烯-6-基]吡咯烷-2-甲酸
将实施例1.12(75mg,0.12mmol)、三甲基硅基甲基叠氮化物(16mg,0.012mmol)、硫酸铜(II)(20mg,0.12mmol)及L-抗坏血酸钠盐(49mg,0.24mmol)于1.00mL DMSO及0.10mL水的混合物中的混合物于RT下搅拌1h。然后,添加1M TBAF溶液(240μL)且将反应混合物于室温下搅拌1h。将反应混合物用ACN/H2O稀释,用TFA酸化,过滤且通过HPLC纯化。
ESI-MS:667[M+H]+
Rt(HPLC):0.87min(方法P)
实施例9.01
(2S,4S)-1-[4-(二氟甲基)-8-氧杂-3,5-二氮杂三环[7.4.0.02,7]十三-1(9),2(7),3,5,10,12-己烯-6-基]-4-({3-[(9S)-9-甲基-2,5-二氧杂-8-氮杂螺[3.5]壬-8-基]-5-(甲基硫基)吡啶-2-基}氧基)吡咯烷-2-甲酸
将(2S,4S)-4-({5-溴-3-[(9S)-9-甲基-2,5-二氧杂-8-氮杂螺[3.5]壬-8-基]吡啶-2-基}氧基)-1-[4-(二氟甲基)-8-氧杂-3,5-二氮杂三环[7.4.0.02,7]-十三-1(9),2(7),3,5,10,12-己烯-6-基]吡咯烷-2-甲酸(中间体3.1.I(a),160mg,0.25mmol)、XANTPHOS(20mg,0.035mmol)、甲烷硫醇钠(0.25mL,0.59mmol)、DIPEA(0.100mL,0.58mmol)及Pd2(dba)3(16mg,0.017mmol)于8.00mL二噁烷中的脱气混合物于110℃加热过夜。冷却至RT后,向反应混合物中添加乙酸乙酯及水。分离有机层,干燥,在真空中浓缩且通过HPLC(SunfireC-18,H2O/ACN/TFA)纯化。
ESI-MS: 614[M+H]+
Rt(HPLC): 1.01min(方法C)
实施例10.01
(2S,4S)-4-({3-[(9S)-9-甲基-2,5-二氧杂-8-氮杂螺[3.5]壬-8-基]-5-(1H-吡唑-1-基)吡啶-2-基}氧基)-1-[4-(三氟甲基)-8-氧杂-3,5-二氮杂三环[7.4.0.02,7]十三--1(9),2(7),3,5,10,12-己烯-6-基]吡咯烷-2-甲酸
在氩气氛下向(2S,4S)-4-({5-溴-3-[(9S)-9-甲基-2,5-二氧杂-8-氮杂螺[3.5]壬-8-基]吡啶-2-基}氧基)-1-[4-(三氟甲基)-8-氧杂-3,5-二氮杂三环[7.4.0.02,7]-十三-1(9),2(7),3,5,10,12-己烯-6-基]吡咯烷-2-甲酸(实施例1.10,30mg,0.045mmol)、LiHMDS(1M,于THF中,0.120mL,0.120mmol)及吡唑(5.00mg,0.073mmol)于1.50mL二噁烷中的脱气混合物中添加tBuBrettPhos(5.00mg,0.006mmol),且将混合物于80℃加热5h。冷却至RT后,将混合物用甲醇稀释,在真空中浓缩且通过HPLC纯化。
ESI-MS:652[M+H]+
Rt(HPLC):1.01min(方法P)
前药的制备:
前药P01
(2S,4S)-4-({3-[(9S)-9-甲基-2,5-二氧杂-8-氮杂螺[3.5]壬-8-基]吡啶-2-基}氧基)-1-[4-(二氟甲基)-8-氧杂-3,5-二氮杂三环[7.4.0.02,7]十三-1(9),2(7),3,5,10,12-己烯-6-基]吡咯烷-2-甲酸甲基酯
向1.0mL THF中的(2S,4S)-4-({3-[(9S)-9-甲基-2,5-二氧杂-8-氮杂螺[3.5]壬-8-基]-吡啶-2-基}-氧基)1-[4-(二氟-甲基)-8-氧杂-3,5-二氮杂三环[7.4.0.02,7]十三-1(13),2,4,6,9,11-己烯-6-基]吡咯烷-2-甲酸(实施例4.04,15mg,0.020mmol)中添加O-甲基-N,N'-二异丙基脲(41μL,0.25mmol)。将反应混合物于RT下搅拌60h,然后用ACN/水稀释且通过HPLC(ACN/H2O/TFA)纯化。
ESI-MS:582[M+H]+
Rt(HPLC):0.69min(方法A)
以下化合物为根据上述通用程序(前药P01)来制备:
缩写列表
ACN 乙腈
aq. 水性
℃ 摄氏度
CH 环己烷
DBU 二氮杂二环[5.4.0]十一-7-烯
DCM 二氯甲烷
DIPEA 二异丙基乙胺
DMA 二甲基乙酰胺
DMF N,N-二甲基甲酰胺
ds 非镜像异构物
ESI-MS 电喷雾离子化质谱
EtOAc 乙酸乙酯
eq 当量
FA 甲酸
FC 急速色谱,若未给出其他详情,则使用SiO2
h 小时
HCl 氯化氢
HATU 六氟磷酸[二甲基氨基-(1,2,3-三唑并[4,5-b]吡啶-3-基氧基)-亚甲基]-二甲基-铵
HPLC 高效液相色谱
K2CO3 碳酸钾
KOH 氢氧化钾
L 公升
LiAlH4 氢化锂铝
LiHMDS 六甲基二硅烷胺化锂
MeOH 甲醇
min 分钟
mL 毫升
M 摩尔
MS 质谱
n.d. 未测定
NH4OH NH3于水中的溶液
Pd2(dba)3 参(二亚苄基丙酮)二钯(0)
Pd(dppf)Cl2 (1,1′-双-(二苯基膦基)-二茂铁)二氯钯(II)
Pd(PPh3)4 四(三苯基膦)钯(0)
Pd(OH)2/C 碳载氢氧化钯20%
RT 室温(约20℃)
Sol 溶剂
tBuBrettPhos (丙-2-烯-1-基)钯鎓[3,6-二甲氧基-2',4',6'-参(丙-2-基)-[1,1'-联苯]-2-基]磷烷三氟甲烷磺酸二-叔丁基酯
TBS 叔丁基-二甲基硅基
TBAF 四丁基氟化铵
TEA 三乙胺
TFA 三氟乙酸
TFAA 三氟乙酸酐
THF 四氢呋喃
TIPS 三异丙基硅基
TMS 三甲基硅烷基
TosOH 对甲苯磺酸单水合物
TLC 薄层色谱
RP-HPLC 反相HPLC
Rf 延迟因子(TLC)
Rt 滞留时间(分钟)
Vol% 体积百分比
第3代Xphos (2-二环己基膦基-2’,4’,6’-三异丙基-1,1'-联苯)[2-(2'-氨基-1,1'-联苯)]甲烷磺酸钯(II)
吉阑(Ziram) 二甲基二硫代胺基甲酸锌盐
分析型HPLC方法:
方法A
时间(min) | Vol%水(包括0.1%TFA) | Vol%ACN | 流速[mL/min] |
0.00 | 99 | 1 | 1.6 |
0.02 | 99 | 1 | 1.6 |
1.00 | 0 | 100 | 1.6 |
1.10 | 0 | 100 | 1.6 |
分析柱:XBridge BEH C18_2.1x30mm,1.7μm;柱温度:60℃
方法B
分析柱:Stable Bond(Agilent)1.8μm;3.0x30mm;柱温度:60℃
方法C
分析柱:Sunfire(Waters)2.5μm;3.0x30mm;柱温度:60℃
方法D
分析柱:XBridge C18_3.0x30mm_2.5μm(Waters);柱温度:60℃
方法E
分析柱:Sunfire C18(Waters)2.5μm;3.0x30mm;柱温度:60℃
方法F
时间(min) | Vol%水(包括0.1%NH3) | Vol%ACN | 流速[mL/min] |
0.00 | 95 | 5 | 1.3 |
0.02 | 95 | 5 | 1.3 |
1.00 | 0 | 100 | 1.3 |
1.30 | 0 | 100 | 1.3 |
分析柱:XBridge BEH(Waters)C18_2.1x30mm,2.5μm;柱温度:60℃
方法G
时间(min) | Vol%水(包括0.1%TFA) | Vol%ACN | 流速[mL/min] |
0.00 | 50 | 50 | 1.6 |
0.02 | 50 | 50 | 1.6 |
1.00 | 0 | 100 | 1.6 |
1.10 | 0 | 100 | 1.6 |
分析柱:XBridge BEH(Waters)C18_2.1x30mm,1.7μm;柱温度:60℃
方法H
分析柱:Sunfire C18(Waters)2.5μm;3.0x30mm;柱温度:60℃
方法I
时间(min) | Vol%水(包括0.1%NH3) | Vol%ACN | 流速[mL/min] |
0.00 | 97 | 3 | 2.2 |
0.20 | 97 | 3 | 2.2 |
1.20 | 0 | 100 | 2.2 |
1.25 | 0 | 100 | 3.0 |
1.40 | 0 | 100 | 3.0 |
分析柱:XBridge(Waters)C18_3.0x30mm,2.5μm;柱温度:60℃
方法J
分析柱:Sunfire C18(Waters)2.5μm;3.0x30mm;柱温度:60℃
方法K
分析柱:Xbridge C18(Waters)2.5μm;3.0x30mm;柱温度:60℃
方法L
时间(min) | Vol.%二氧化碳 | Vol.%甲醇 | 流速[mL/min] |
0.00 | 97 | 3 | 1.3 |
2.50 | 55 | 45 | 1.3 |
3.50 | 55 | 45 | 1.3 |
3.51 | 97 | 3 | 1.3 |
4.00 | 97 | 3 | 1.3 |
分析柱:Acquity UPC2 Torus 2-PIC(Waters)1.7μm;3.0×100mm;柱温度:30℃
方法M
时间(min) | Vol.%水(包括0.1%FA) | Vol.%ACN | 流速[mL/min] |
0.00 | 97 | 3 | 2.2 |
0.20 | 97 | 3 | 2.2 |
1.20 | 0 | 100 | 2.2 |
1.25 | 0 | 100 | 3.0 |
1.40 | 0 | 100 | 3.0 |
分析柱:Sunfire C18(Waters)2.5μm;3.0x30mm;柱温度:60℃
方法N
分析柱:XSelect HSS PFP(Waters)1.8μm;2.1x30mm;柱温度:60℃
方法O
分析柱:Acquity UPLC BEH C18(Waters)1.7μm;2.1×100mm;柱温度:40°
方法P
柱:Sunfire C18(Waters)2.5μm;3.0x30mm;CT:60℃
实施例
5.1实施例化合物
已合成如表1中概述的以下式(I)或式(I’)的实施例化合物且就其关于其抑制cGAS活性的功效的药理学性质进行测试。
具体而言,关于cGAS抑制的“生物化学(活体外)IC50值”(hcGAS IC50)、”关于在病毒刺激的THP1细胞中IFN诱导的抑制的“IC50值”(THP(vir)IC50)、“关于在cGAMP刺激的THP1细胞中IFN诱导的抑制的IC50值”(THP(cGAMP)IC50)及“关于在dsDNA刺激的人类全血中IFN诱导的抑制的IC50值”(hWB IC50)已根据下文第6节中所述的分析方法通过实验测定。结果概述于表1中。
如表1中概述的式(I)或式(I’)的实施例化合物同时显示以下三种性质:
·令人满意的“关于cGAS抑制的生物化学(活体外)IC50值”(hcGAS IC50≤100nM、较优选≤50nM、具体而言≤10nM),
·令人满意的“关于cGAS抑制的细胞IC50值”(THP1(vir)IC50≤1μM、较优选≤500nM、更优选≤100nM、具体而言≤50nM)
及
·令人满意的对cGAS抑制的选择性
(THP1(cGAMP)IC50/THP1(vir)IC50的比率≥10、更优选≥50、更优选≥500、具体而言≥1000)。
另外,式(I)或式(I’)的实施例化合物亦显示关于dsDNA刺激的人类全血中IFN诱导的抑制的可接受的IC50值(hWB IC50)。
表1:本发明的实施例化合物的药理学性质
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
5.2实施例化合物与现有技术化合物的比较
5.2.1WO 2020/142729的化合物
在WO 2020/142729中,已公开具有潜在类似结构的cGAS抑制剂。在WO 2020/142729的第44及45页,已公开关于cGAS抑制的“生物化学(活体外)IC50值”(对应于”hcGASIC50”)。因此,“生物化学(活体外)IC50值”小于100nM的化合物命名为”组A”,“生物化学(活体外)IC50值”大于100nM且小于500nM的化合物命名为“组B”,“生物化学(活体外)IC50值”大于500nM且小于1μM的化合物命名为“组C”,“生物化学(活体外)IC50值”大于1μM且小于10μM的化合物命名为“组D”,且“生物化学(活体外)IC50值”大于10μM的化合物命名为“组E”(参见WO 2020/142729的第44页)。
在WO 2020/142729的第45页,公开仅化合物编号25可命名为具有“小于100nM的生物化学(活体外)IC50值”的“组A”。WO 2020/142729的所有其他实施例化合物显示大于100nM的“生物化学(活体外)IC50值”。
5.2.2本发明的实施例与WO 2020/142729的实施例之间的比较
已合成WO 2020/142729的所选现有技术化合物且然后已就其关于其抑制cGAS/STING路径的功效的药理学性质进行测试。具体而言,关于cGAS抑制的“生物化学(活体外)IC50值”(hcGAS IC50)、“关于在病毒刺激的THP1细胞中IFN诱导的抑制的细胞IC50值”(THP1(vir)IC50)、“关于在cGAMP刺激的THP1细胞中IFN诱导的抑制的细胞IC50值”(THP1(cGAMP)IC50)及“关于在人类全血中的IFN诱导的抑制的IC50值”(hWB)已根据下文第6节中所述的分析方法通过实验针对WO 2020/142729的结构上最紧密的实施例进行测定(参见表2)。
表2:WO 2020/142729的实施例化合物的选择的药理学性质
/>
如表1中概述废热本发明的实施例化合物的药理学性质与WO 2020/142729的化合物的各别药理学性质可彼此进行比较,此乃因其为根据如下文第6节中所述的相同分析程序通过实验来测定。
自表2中所示数据可明了,WO 2020/142729的所有实施例化合物皆显示显著大于100nM的“生物化学(活体外)IC50值”(=hcGAS IC50)–唯一例外为WO 2020/142729的实施例编号25(在WO 2020/142729中,命名为具有小于100nM的“生物化学(活体外)IC50值”(=hcGAS IC50)的“组A”)。与其相比,本发明的实施例化合物皆具有小于100nM的“生物化学(活体外)IC50值”(hcGAS IC50)。然而,具有55nM的“生物化学(活体外)IC50值”(hcGASIC50)的WO 2020/142729的实施例编号25完全不符合由THP1(vir)IC50低于1μM所示的“令人满意的细胞抑制功效”的选择标准,此乃因WO 2020/142729的实施例编号25的THP1(vir)IC50为17μM。
5.3前药
已知具有羧酸基团的活性剂的酯可代表可行前药,其可即显示与各别活性剂相比改善的口服吸收/生物利用度。具有羧酸基团的活性剂的常用前药为例如甲基酯、乙基酯、异丙基酯等(参见Beaumont等人,Current Drug Metabolism,2003,第4卷,第6期,461-485)。
此外,Nakamura等人,Bioorganic&Medicinal Chem.,第15卷,第24期,第7720-7725页(2007),阐述具有游离羧酸基团的特定活性剂的N-酰基磺酰胺衍生物及N-酰基磺酰脲衍生物也具有成为可行前药的潜力。
另外,已发现实验提示,即式(I)或式(I’)的实施例化合物的甲基酯也代表式(I)或式(I’)的cGAS抑制剂的可行前药。
化合物P01、P02、P03及P04分别为实施例化合物4.04、1.10、1.12及3.14的甲基酯,且因此可代表各别实施例化合物的可行前药。
已合成P01、P02、P03及P04,并测试其抑制cGAS/STING路径的功效的药理学性质。随后,将实验确定的前药P01、P02、P03及P04的药理学性质与如表3中概述的各别实施例化合物4.04、1.10、1.12及3.14的相应药理学性质进行比较。
实施例化合物与其相应前药之间的此比较显示,实施例化合物的hcGAS IC50值总是在10nM左右或甚至小于10nM,而相应前药的hcGAS IC50值总是非常大,这意味着通常大于9000nM。对于在实施例化合物及其相应前药之间总是保持在相同范围内的各别THP1(vir)IC50值,从未观察到一方面实施例化合物与另一方面其相应前药之间的如此大的差异(关于实施例4.04及其相应前药P01,参见表3)。
对该观察结果的一种可能解释为,实施例化合物(其代表”药物”)均具有游离羧基,这似乎对抑制cGAS活性至关重要,而在所有“前药”中,羧基由羧基-甲基酯基团掩蔽。因此,前药在“活体外人类cGAS酶分析”(参见下文第6.1节)中失去其抑制功效,此乃因在此分析中不存在裂解羧基-甲基酯基团的细胞内酶。因此,在该“活体外人类cGAS酶分析”中,前药显示非常大的“生物化学(活体外)IC50值”(=hcGAS IC50),而相应实施例化合物(其代表药物或活性剂)显示小的“生物化学(活体外)IC50值”(=hcGAS IC50)。
在“人类cGAS细胞及反细胞分析”(参见下文第6.2节)中,存在裂解羧基-甲基酯基团的内源性细胞酶。因此,不仅实施例化合物本身(其意指药物或活性剂本身)显示小的THP1(vir)IC50值,而且相应前药亦显示相对小的“THP1(vir)IC50值”,此乃因在此“人类cGAS细胞分析”中,前药的甲基酯可由内源性细胞内酶裂解成再次显示抑制功效的相应药物/活性剂。
此种解释连同表3中所示的量测结果表明,式(I)或式(I’)的化合物的甲基酯衍生物似乎确实代表式(I)或式(I’)的化合物的可行前药,其本身无关于活体外人类生物化学cGAS抑制的抑制功效。然而,当甲基酯由内源细胞内酶裂解时,形成式(I)或式(I’)的化合物(活性剂),其再次展现关于cGAS/STING路径的抑制功效。
表3:选择的本发明的实施例化合物(=活性剂)及其各别甲酯前药之间的比较:
/>
/>
6生物实验
本发明化合物的活性可使用以下活体外cGAS酶及细胞分析来展现:
6.1方法:人类cGAS酶分析(hcGAS IC50(活体外))
在用以活化人类cGAS酶的45个碱基对双链DNA及作为受质的GTP及ATP存在下培育该人类cGAS酶。通过量测化合物对酶反应产物cGAMP的形成的效应(其通过质谱方法来量测)来确定化合物活性。
酶制备:
使具有N-末端6x-His-卷标及SUMO-卷标的人类cGAS(氨基酸1-522)在大肠杆菌BL21(DE3)pLysS(Novagen)细胞中于18℃表现16小时。使细胞在含有25mM Tris(pH 8)、300mM NaCl、10mM咪唑、10%甘油、蛋白酶抑制剂混合剂(cOmpleteTM,无EDTA,Roche)及DNA酶(5μg/mL)的缓冲液中溶解。通过在Ni-NTA琼脂糖树脂上的亲和色谱分离cGAS蛋白,并通过使用在20mM Tris(pH 7.5)、500mM KCl及1mM TCEP中平衡的Superdex 200柱(GEHealthcare)的粒径筛析色谱进一步纯化。将纯化的蛋白质浓缩至1.7mg/mL并在-80℃储存。
分析方法
将化合物递送于10mM DMSO溶液中,连续稀释并使用Echo声学分配器转移至384孔分析板(Greiner#781201)。通常,在最终分析体积中使用8种浓度,最高浓度为10μM,之后为约1:5稀释步骤。将最终分析体积中的DMSO浓度设定为1%。384孔分析板含有22种测试化合物(第1-22列)及第23及24列中的DMSO。
化合物转移后,将15μL酶-DNA-工作溶液(12nM cGAS、分析缓冲液中的0.32μM 45个碱基对DNA、10mM Tris pH 7.5/10mM KCl/5mM MgCl2/1mM DTT)经由MultiDrop Combi分配器添加至自第1-23列的每一孔中。在第24列中,添加15μl不含酶/DNA的分析缓冲液作为低对照。
然后将板在室温下预培育60min。
其后,使用Multidrop Combi将10μL GTP(ThermoFisher#R0461)-ATP(Promega#V915B)添加至分析板(第1-24列,各自30μM最终浓度)中。
将板在室温下再次培育90min。
培育后,在含有作质谱的内标准品的5nM环-二-GMP(Sigma#SML1228)的分析缓冲液中由80μL 0.1%甲酸终止反应。总体积/孔为105μL。
Rapidfire MS检测
将板以4000rpm、4℃离心5min。
RapidFire自动取样器与二元泵(Agilent 1290)及Triple Quad 6500(ABSciex,Toronto,Canada)耦联。此系统配备有10μL环、C18[12μL床体积]柱(Agilent,零件号G9210A),其含有10mM NH4Ac(aq)水(pH7.4)作为溶析液A(泵1以1.5mL/min,泵2以1.25mL/min)及10mM于v/v/v 47.5/47.5/5ACN/MeOH/H2O中的NH4Ac(pH7.4)作为溶析液B(泵3以1.25mL/min)。抽吸时间:250ms;加载时间:3000ms;溶析时间:3000ms;洗涤体积:500μL。
MS为用HESI离子源以正离子模式操作,源温度为550℃,帘气=35,气体1=65,且气体2=80。SRM模式下的单位质量分辨率。确定cGAMP及DicGMP的以下跃迁及MS参数(DP:去簇电压,及CE:碰撞能):
分析物:cGAMP,675.1/524,DP=130,CE=30且
内标准品:环-二-GMP,690.1/540,DP=130,CE=30。
监测cGAMP的形成并评估为与环-二GMP的比率。
数据评估及计算:
对于数据评估及计算,将低对照的量测值设定为0%对照,而将高对照的量测值设定为100%对照。使用标准4参数逻辑回归公式计算IC50值。计算:[y=(a-d)/(1+(x/c)^b)+d],a=低值,d=高值;x=conc M;c=IC50 M;b=斜率
6.2方法:人类cGAS细胞分析及cGAMP刺激的反细胞分析(THP1(vir)IC50及THP1(cGAMP)IC50)
使用表现IRF依赖性Lucia荧光素酶报导基因的THP1-DualTM细胞(InvivoGen#thpd-nfis)作为两种分析的基础。对于细胞cGAS活性的检测,由递送cGAS酶刺激双链DNA的杆状病毒(pFastbac-1,Invitrogen,无编码插入物)感染刺激细胞(THP1(vir)IC50的量测)。
对于反分析,由cGAMP(SigmaAldrich#SML1232)刺激细胞以活化独立于cGAS且直接位于cGAS下游的相同路径(THP1(cGAMP)IC50的量测)。
通过量测由DNA刺激的cGAS酶活性(THP1(vir)IC50的量测)或直接由cGAMP(THP1(cGAMP)IC50的量测,反分析)诱导的Lucia荧光素酶活性来监测路径活性。
分析方法
将化合物递送于10mM DMSO溶液中,连续稀释并使用Echo声学分配器转移至384孔分析板(Greiner#781201)。通常,在最终分析体积中使用8种浓度,最高浓度为10μM,之后为约1:5稀释步骤。将最终分析体积中的DMSO浓度设定为1%。384孔分析板含有21种测试化合物(第1-22列)及第23及24列中的DMSO。
通过以300g/10min离心收获根据制造商的条件培养的细胞,且然后将重新悬浮并稀释至新鲜细胞培养基中的1.66E5细胞/ml(RPMI 1640(Gibco#A10491-01)、10% FCS(Gibco#10500)、1x GlutaMax(Gibco#35050-061)、1x Pen/Strep溶液(Gibco#15140-122)、100μg/ml诺莫辛(Normocin)(InvivoGen#ant-nr)、100μg/ml吉欧霉素(Zeocin)(InvivoGen#ant-zn)、10μg/ml杀稻瘟菌素S(Blasticidin S)(Life Technologies#A11139-03))。然后将杆状病毒溶液以1:200(根据病毒批次而变化)添加至细胞中(THP1(vir)IC50的量测)。或者,对于反分析,将cGAMP以10μM的最终浓度添加至细胞中(THP1(cGAMP)IC50的量测)。
将30μL细胞/病毒混合物经由MultiDrop Combi分配器(5000个细胞/孔)添加至自第1-23列的复合板的每一孔中。在第24列中,添加30μl/5000个无病毒的细胞/孔作为低对照。
然后将板于37℃在加湿培育器中培育18h。
其后,使用MultiDrop Combi将15μL QuantiLuc检测试剂(InvivoGen#rep-qlcg5)添加至每一孔中。添加后立即使用EnVision读取器(US发光读取模式)进行量测。
数据评估及计算:
对于数据评估及计算,将低对照的量测值设定为0%对照,而将高对照的量测值设定为100%对照。使用标准4参数逻辑回归公式计算IC50值。计算:[y=(a-d)/(1+(x/c)^b)+d],a=低值,d=高值;x=conc M;c=IC50 M;b=斜率
6.3方法:人类全血分析(人类WB IC50)
对于细胞cGAS活性的检测,通过用双链DNA进行转染来刺激人类全血。通过量测IFNα2α的产生来监测路径活性。
分析方法
化合物以10mM DMSO溶液的形式递送,并连续稀释并转移至96孔细胞培养板(Corning#3595),使用Echo声学分配器在每一孔中预先填充20μlOptiMEM(Gibco,#11058-021)。通常,在最终分析体积中使用8种浓度,最高浓度为10μM,之后为约1:5稀释步骤。将最终分析体积中的DMSO浓度设定为0.1%。96孔分析板包含10种测试化合物及对照孔中的DMSO。
并行收集来自3个或更多健康供体(男性或女性,除了避孕药及甲状腺素之外,7天内无药物治疗)的人类全血作为柠檬酸钠血液(例如,3.8%,于来自Sarstedt的Monovettes中)。收集后将全血在室温下保持最长3小时,直至用于分析。
将160μl全血样品转移至填充有化合物/OptiMEM的96孔分析板的每一孔中。用来自不同供体的血液一式两份制备所有分析板。将血液板在室温下保持60分钟,并以450rpm连续振荡,用盖覆盖,但不密封。
在OptiMEM中制备DNA-Fugene混合物(Herring DNA,Sigma Aldrich#D6898-1G,Fugene(5x1mL),Promega#E2312),并于RT下培育10min(125ng DNA/20μl及Fugene比率为9.6:1)。向每一孔中添加20μl DNAFugene混合物,产生125ng DNA/孔/200μl,且Fugene比率为9.6:1。向所有低对照孔中添加20μl OptiMEM及9.6:1Fugene。
在用区域密封件及盖覆盖分析板之后,将血液板在室温下保持30分钟并以450rpm连续振荡,之后在培育器中于37℃过夜培育22h,而不振荡。
对于人类血浆中的IFNα-2α的检测,根据制造商的说明,将生物素化的捕获抗体(抗体组IFNA2,Meso Scale Diagnostics#B21VH-3,包括涂层及捕获抗体)在稀释剂100(Meso Scale Diagnostics#R50AA-4)中以1:17.5稀释。用25μl稀释的捕获抗体涂覆U-PlexMSD GOLD 96孔小斑点链霉亲和素SECTOR板(Meso Scale Diagnostics#L45SA-5)。在室温下在700rpm的连续振荡下,将涂覆的板培育60min。将MSD IFNα-2α板用150μl洗涤缓冲液(1x HBSS,0.05%Tween)洗涤三次。
在室温及700rpm连续振荡下用100μl封阻溶液/孔(1x HBSS,具有0.2%Tween、2%BSA)封阻板60min后,恰好在继续人类血浆之前通过倾倒尽可能干燥地清空板。
将全血分析板以1600rpm离心10分钟。用移液机器人将25μl上清液自每一全血板转移至相应IFNα-2α板。用微板密封件密封板,并在700rpm连续振荡下再次在室温下保持2小时。
接下来,将MSD IFNα-2α板用150μl洗涤缓冲液(1x HBSS,0.05% Tween)洗涤三次,之后向板的每一孔中添加25μl MSD磺基-TAG IFNα-2α抗体溶液(在稀释剂3(MesoScale Diagnostics#R50AP-2)中以1:100稀释)。
其后,用微板密封件密封板,并在700rpm连续振荡下再次在室温下保持2小时。最后,将MSD IFNα-2α板用150μl洗涤缓冲液(1x HBSS,0.05% Tween)洗涤3次。向每一孔中添加150μl 2x读取缓冲液,且用MSD Sector S600读取仪使用供货商条形码立即量测板。
数据评估及计算:
对于数据评估及计算而言,每一孔的%对照计算为基于通过使用以下公式的高对照(DNA刺激的对照)及低对照(未刺激的对照)的平均值:
[计数(样品)-计数(低))/(计数(高)-计数(低))]*100
使用标准4参数逻辑回归公式计算IC50值。计算:[y=(a-d)/(1+(x/c)^b)+d],a=低值,d=高值;x=conc M;c=IC50 M;b=斜率
7适应症
已发现,式(I)或式(I’)的化合物的特征在于其在治疗领域的应用范围。应特别提及的是根据本发明的式(I)或式(I’)的化合物基于其作为cGAS抑制剂的医药活性而较优选使用的那些应用。尽管cGAS路径对于宿主防御入侵病原体(例如,病毒感染及一些细胞内细菌的入侵)为重要的,但细胞应激及遗传因素也可引起异常细胞dsDNA的产生(例如,通过核或线粒体渗漏),并由此触发自体炎症反应。因此,cGAS抑制剂具有欲用于治疗多种自体炎症及自体免疫疾病的强治疗潜力。
An等人,Arthritis Rheumatol.2017年4月;69(4):800-807公开,外周血单核细胞(PBMC)中的cGAS表现在患有自体免疫疾病系统性红斑狼疮(SLE)的患者中比在正常对照中更高。通过串联质谱法的cGAMP的靶向量测在15%的测试SLE患者中检测到cGAMP,但正常或类风湿性关节炎对照中未检测到。与无cGAMP的SLE患者相比,具有cGAMP的SLE患者中疾病活动性更高。而较高的cGAS表现可能为暴露于I型干扰素(IFN)的结果,但在具有增加的疾病活动性的SLE患者中检测到cGAMP指示cGAS路径可能涉及疾病表现。
Park等人,Ann Rheum Dis.2018年10月;77(10):1507-1515,也公开cGAS路径涉及SLE的发展。
Thim-Uam等人,iScience 2020年9月4日;23(9),101530(doi:10.1016/j.isci.2020.101530)公开,STING路径经由活化常用树突状细胞成熟及浆细胞样树突细胞分化介导狼疮。
Gao等人,Proc.Natl.Acad.Sci.U S A.2015年10月20日;112(42):E5699-705阐述,由自体DNA活化cGAS导致某些自体免疫疾病,例如干扰素病。
Tonduti等人,Expert Rev.Clin.Immunol.2020年2月;16(2):189-198公开,cGAS抑制剂在艾卡迪-古铁雷斯综合征(其为一种狼疮样严重自体炎症免疫介导的疾病)中具有特别治疗潜力。
在Yu等人,Cell 2020年10月29日;183(3):636-649,阐述肌肉萎缩性脊髓侧索硬化症(ALS)中TDP-43触发的粒线体DNA与cGAS/STING路径的活化之间的联系。
Ryu等人,Arthritis Rheumatol.2020年11月;72(11):1905-1915也显示,生物活性血浆线粒体DNA与特定纤维化疾病(例如全身性硬化(SSc)或肺间质疾病(ILD)、进行性纤维化间质性肺病(PF-ILD)及特发性肺纤维化(IPF))的疾病进展相关。
在Schuliga等人,Clin.Sci.(Lond).2020年4月17日;134(7):889-905中,阐述自体DNA以cGAS依赖性方式使IPF肺纤维母细胞衰老永久化。
将其他纤维化疾病(例如非酒精性脂肪性肝炎(NASH))的病因与cGAS/STING路径联系起来的其他科学线索阐述于以下中:Yu等人,J.Clin.Invest.2019年2月1日;129(2):546-555,及Cho等人,Hepatology.2018年10月;68(4):1331-1346。
Nascimento等人,Sci.Rep.2019年10月16日;9(1):14848公开,自体DNA释放及STING依赖性感知会驱动小鼠中由于香烟烟雾而炎症,暗示cGAS-STING路径与慢性阻塞性肺病(COPD)之间的联系。
Ma等人,Sci.Adv.2020年5月20日;6(21):eaaz6717公开,溃疡性结肠炎及炎症性肠病(IBD)可通过控制cGAS介导的炎症而得以抑制。
Gratia等人,J.Exp.Med.2019年5月6日;216(5):1199-1213显示,布卢姆综合征蛋白抑制cGAS对微核的先天免疫感应。因此,cGAS抑制剂在治疗布卢姆氏综合征中具有治疗潜力。
Kerur等人,Nat.Med.2018年1月;24(1):50-61阐述,cGAS在年龄相关性黄斑退化(AMD)中的非典型炎症小体活化中起重要作用。
此外,式(I)或式(I’)的cGAS抑制剂在癌症治疗中也具有治疗潜力(参见Hoong等人,Oncotarget.2020年7月28日;11(30):2930-2955,及Chen等人,Sci.Adv.2020年10月14日;6(42):eabb8941)。
另外,式(I)或式(I’)的cGAS抑制剂在治疗心脏衰竭中也具有治疗潜力(Hu等人,Am.J.Physiol.Heart Circ.Physiol.2020年6月1日;318(6):H1525-H1537)。
存在帕金森氏病与cGAS/STING路径之间的相关性(Sliter等人,Nature.2018年9月;561(7722):258-262)及薛格连氏综合征与cGAS/STING路径之间的相关性(Papinska等人,J.Dent.Res.2018Jul;97(8):893-900)的进一步科学线索。
此外,式(I)或式(I’)的cGAS抑制剂在治疗COVID-19/SARS-CoV-2感染中亦具有治疗潜力,如以下中所显示:Di Domizio等人,Nature.2022年1月19日.doi:10.1038/s41586-022-04421-w:“The cGAS-STING pathway drives type I IFN immunopathology inCOVID-19”,及Neufeldt等人,Commun Biol.2022年1月12日;5(1):45.doi:10.1038/s42003-021-02983-5:“SARS-CoV-2infection induces a pro-inflammatory cytokineresponse through cGAS-STING and NF-kappaB”。
另外,式(I)或式(I’)的cGAS抑制剂在治疗肾炎症及肾纤维化中具有治疗潜力,如以下中所显示:Chung等人,Cell Metab.2019 30:784-799:“Mitochondrial Damage andActivation of the STING Pathway Lead to Renal Inflammation and Fibrosis”,及Maekawa等人,Cell Rep.2019 29:1261-1273:“Mitochondrial Damage CausesInflammation via cGAS-STING Signaling in Acute Kidney Injury”。
此外,式(I)或式(I’)的cGAS抑制剂在治疗癌症中具有治疗潜力,如以下中所显示:Bakhoum等人,Nature.2018年1月25日;553(7689):467-472:“Chromosomalinstability drives metastasis through a cytosolic DNA response”,及Liu等人,Nature.2018年11月;563(7729):131-136:“Nuclear cGAS suppresses DNArepair andpromotes tumorigenesis”。
另外,式(I)或式(I’)的cGAS抑制剂在治疗代谢障碍中具有治疗潜力,此乃因STINGgt动物显示在亚慢性高热量摄入(HFD)时脂肪组织中巨噬细胞浸润减少,且STINGgt及IRF 3-缺乏导致血糖及胰岛素降低以及体重减轻(Mao等人,Arterioscler Thromb VascBiol,2017;37(5):920-929)。
此外,式(I)或式(I’)的cGAS抑制剂在治疗血管疾病中具有治疗潜力,并导致血管修复/再生,此乃因将线粒体DNA释放至内皮细胞的胞质液中会导致cGAS/STING路径活化及抑制内皮增殖。此外,cGAS基因敲除恢复炎症性肺损伤的小鼠模型中的内皮修复/再生(Huang等人,Immunity,2020,2017年3月;52(3):475-486.e5.doi:10.1016/j.immuni.2020,02.002)。
另外,式(I)或式(I’)的cGAS抑制剂在治疗年龄相关及肥胖相关的心血管疾病中具有治疗潜力(Hamann等人,Immun Ageing,2020年3月14日;17:7;doi:10.1186/s12979-020-00176-y.eCollection 2020)。
因此,作为cGAS抑制剂的式(I)或式(I’)的化合物可用于治疗自体炎症及自体免疫疾病,例如系统性红斑狼疮(SLE)、干扰素病、艾卡迪-古铁雷斯综合征、年龄相关性黄斑退化(AMD)、肌肉萎缩性脊髓侧索硬化症(ALS)、炎症性肠病(IBD)、慢性阻塞性肺病(COPD)、布卢姆氏综合征、薛格连氏综合征及帕金森氏病。
另外,作为cGAS抑制剂的式(I)或式(I’)的化合物可用于纤维化疾病(例如全身性硬化(SSc)、干扰素病、非酒精性脂肪肝炎(NASH)、间质性肺病(ILD),较优选进行性纤维化间质性肺病(PF-ILD),具体而言特发性肺纤维化(IPF))的疗法中。
此外,作为cGAS抑制剂的式(I)或式(I’)的化合物可用于年龄相关性黄斑退化(AMD)、心脏衰竭、COVID-19/SARS-CoV-2感染、肾炎症、肾纤维化、代谢障碍、血管疾病、心血管疾病及癌症的疗法中。
8组合
式(I)或式(I’)的化合物可单独或与一种或多种其他药理学活性剂组合向患者给药。
在本发明的较优选实施例中,式(I)或式(I’)的化合物可与一种或多种选自以下的药理学活性剂组合:抗炎症剂、抗纤维变性剂、抗过敏剂/抗组织胺、支气管扩张剂、β2激动剂/β模拟物、肾上腺素性激动剂、抗胆碱剂、甲氨蝶呤、吗替麦考酚酯、白三烯调节剂、JAK抑制剂、抗白介素抗体、非特异性免疫治疗剂(例如干扰素或其他细胞因子/趋化因子)、细胞因子/趋化因子受体调节剂(即细胞因子受体激动剂或拮抗剂)、toll样受体激动剂(=TLR激动剂)、免疫检查点调节剂、抗TNF抗体(阿达木单抗(Adalimumab))及抗BAFF剂(贝利木单抗及依那西普)。
抗纤维变性剂较优选选自比非尼酮及酪氨酸激酶抑制剂(例如尼达尼布),其中尼达尼布特别优选。
抗炎症剂的较优选实施例为NSAID及皮质类固醇。
NSAID较优选选自布洛芬(ibuprofen)、萘普生(naproxen)、双氯芬酸(diclofenac)、美洛西卡(meloxicam)、塞来昔布(celecoxib)、乙酰基柳酸(acetylsalicylic acid)(AspirinTM)、吲哚美辛(indomethacin)、甲芬那酸(mefenamicacid)及依托昔布(etoricoxib)。
皮质类固醇较优选选氟尼缩松(Flunisolide)、倍氯米松(Beclomethasone)、曲安奈德(Triamcinolone)、布地奈德(Budesonide)、氟替卡松(Fluticasone)、莫米松(Mometasone)、环索奈德(Ciclesonide)、罗氟奈德(Rofleponide)及地塞米松(Dexametasone)。
抗过敏剂/抗组织胺较优选选自依匹斯汀(Epinastine)、西替利嗪(Cetirizine)、氮卓斯汀(Azelastine)、Fexofenadine(非索非那定)、左卡巴斯汀(Levocabastine)、氯雷他定(Loratadine)、依巴斯汀(Ebastine)、地氯雷他定(Desloratidine)及咪唑斯汀(Mizolastine)。
β2激动剂/β模拟物可为长效β2激动剂(LABA)或短效β激动剂(SABA)。特别优选β2激动剂/β模拟物选自班布特罗(Bambuterol)、比托特罗(Bitolterol)、卡布特罗(Carbuterol)、克伦特罗(Clenbuterol)、非诺特罗(Fenoterol)、福莫特罗(Formoterol)、海索那林(Hexoprenalin)、异丁特罗(Ibuterol)、吡布特罗(Pirbuterol)、丙卡特罗(Procaterol)、瑞普特罗(Reproterol)、沙美特罗(Salmeterol)、磺酰特罗(Sulfonterol)、特布他林(Terbutalin)、托鲁布特罗(Tolubuterol)、奥达特罗(Olodaterol)及沙丁胺醇(Salbutamol),具体而言奥达特罗。
抗胆碱剂较优选选自异丙托铵盐(ipratropium salt)、噻托铵盐(tiotropiumsalt)、格隆铵盐(glycopyrronium salt)及茶碱(theophylline),其中噻托溴铵(tiotropium bromide)特别优选。
白三烯调节剂较优选选自孟鲁司特(Montelukast)、普鲁司特(Pranlukast)、扎鲁司特(Zafirlukast)、伊布地司特(Ibudilast)及齐留通(Zileuton)。
JAK抑制剂较优选选自巴瑞替尼(Baricitinib)、赛度替尼(Cerdulatinib)、菲卓替尼(Fedratinib)、非戈替尼(Filgotinib)、甘地替尼(Gandotinib)、来他替尼(Lestaurtinib)、莫洛替尼(Momelotinib)、帕克替尼(Pacritinib)、培非替尼(Peficitinib)、鲁索替尼(Ruxolitinib)、托法替尼(Tofacitinib)及乌帕替尼(Upadacitinib)。
抗白介素抗体较优选选自抗IL23抗体(例如利散吉珠单抗(Risankizumab))、抗IL17抗体、抗IL1抗体、抗IL4抗体、抗IL13抗体、抗lL-5抗体、抗IL-6抗体(例如托珠单抗(Tocilizumab))、抗IL-12抗体、抗IL-15抗体。
9制剂
本发明的化合物可通过任何适宜给药途径(包括全身给药及局部给药)来给药。全身给药包括经口给药、非经肠给药、经皮给药、直肠给药及通过吸入给药。非经肠给药是指除了经肠、经皮或通过吸入以外的给药途径,且通常为通过注射或输注。非经肠给药包括静脉内、肌内、胸骨内及皮下注射或输注。吸入是指给药至患者的肺中,无论为经由口或经由鼻道吸入。局部给药包括施加至皮肤。本发明的化合物可经由滴眼剂给药以治疗薛格连氏综合征。
适宜给药形式系例如锭剂、胶囊、溶液、糖浆、乳剂或可吸入粉末或气溶胶。在每种情况下,药学上有效化合物的含量应在占总组合物的0.1至90wt.%、较优选0.5至50wt.%的范围内,即其量足以达到下文指定的剂量范围。
制剂可以锭剂、粉末、胶囊中的粉末(例如硬明胶胶囊)、溶液或悬浮液的形式经口给药。当通过吸入给药时,活性物质组合可以粉末、水溶液或水性乙醇溶液或使用推进剂气体制剂来给予。
因此,较优选地,医药制剂的特征在于根据上述较优选实施例的一种或多种式(I)或式(I’)的化合物的含量。
若式(I)或式(I’)的化合物为经口给药则特别优选,且若其为每天给药一次或两次,则也特别优选。可通过(例如)将活性物质与已知赋形剂混合来获得适宜锭剂,这些赋形剂为(例如)惰性稀释剂,例如碳酸钙、磷酸钙或乳糖;崩解剂,例如玉米淀粉或海藻酸;黏合剂,例如淀粉或明胶;润滑剂,例如硬脂酸镁或滑石粉;及/或延迟释放试剂,例如羧甲基纤维素、邻苯二甲酸乙酸纤维素或聚乙酸乙烯酯。锭剂也可包含一些层。
因此,可通过用通常用于锭剂涂覆的物质(例如可力酮(kollidone)或虫胶、阿拉伯树胶、滑石、二氧化钛或糖)涂覆以类似于锭剂的方式产生的核来制备包衣锭剂。为达成延时释放或防止不兼容性,核也可由许多层组成。类似地,锭剂包衣可由许多层组成以达成延迟释放,可能使用用于锭剂的上述赋形剂。
含有本发明的活性物质或其组合的糖浆可另外含有甜味剂,例如糖精、环己氨基磺酸盐(cyclamate)、甘油或糖;及增味剂,例如矫味剂,例如香草醛或柑橘提取物。其也可包含悬浮液佐剂或增稠剂(例如羧甲基纤维素钠)、湿润剂(例如,脂肪醇与环氧乙烷的缩合产物)或防腐剂(例如对羟基苯甲酸酯)。
含有一种或多种活性物质或活性物质组合的胶囊可(例如)通过将活性物质与惰性载剂(例如乳糖或山梨醇)混合并将其装入明胶胶囊中来制备。适宜栓剂可(例如)通过将其与出于此目的提供的载剂(例如中性脂肪或聚乙二醇或其衍生物)混合来制备。
可使用的赋形剂包括(例如)水;药学上可接受的有机溶剂,例如石蜡(例如,石油馏分)、植物油(例如,花生油或芝麻油)、单官能或多官能醇(例如,乙醇或甘油);载剂,例如天然矿物粉末(例如,高岭土、黏土、滑石、白垩)、合成矿物粉末(例如,高度分散的硅酸及硅酸盐)、糖(例如,蔗糖、乳糖及葡萄糖)、乳化剂(例如,木质素、亚硫酸盐废液、甲基纤维素、淀粉及聚乙烯吡咯烷酮)及润滑剂(例如,硬脂酸镁、滑石、硬脂酸及月桂基硫酸钠)。
对于经口给药而言,除上述载剂外,锭剂当然也可含有诸如柠檬酸钠、碳酸钙及磷酸二钙等添加剂以及诸如淀粉(较优选马铃薯淀粉)、明胶及诸如此类等各种添加剂。此外,诸如硬脂酸镁、月桂基硫酸钠及滑石等润滑剂可同时用于制锭制程。在水性悬浮液的情形下,除上述赋形剂以外,活性物质还可与各种增味剂或着色剂组合。
Claims (33)
1.一种式(I)化合物,
其中
R1选自甲基、乙基、卤代甲基、卤代乙基及卤素,
其中
G选自O、NR8、CH2、C及CR8R9,
其中
R2选自H、卤素、环丙基、C1-3-烷基、-C2-5-炔基、-S-甲基及CN,
或其中R2为环状基团,其中所述环状基团选自:苯基或包含1、2、3或4个各自独立地选自N、S及O的杂原子的五至六元杂芳基,其中所述环状基团由一个或两个相同或不同的取代基R10取代,
其中
R3为H或甲基,
R4为H或甲基,
R5选自H、甲基、-CN、-亚甲基-OH及-CF3,
或R5可不存在,
R6选自H、甲基、-CN、-亚甲基-OH及-CF3,
或R5及R6与其之间的C原子一起形成选自氧杂环丁烷、四氢呋喃及环丙烷的环,
R7选自H、卤素、(C1-3)-烷基及卤代-(C1-3)-烷基,
R8选自CN、H及甲基,
R9选自H、甲基及卤素
或R9可不存在,
其中每一R10独立地选自:氢、卤素、卤烷基、-甲基、-乙基、-NH-CO-甲基、-N(CH3)2、-CH2-OH、-NH(CH3)、-O-(C1-3-烷基)、-CN、-S-CH3、-CO-NH2、-CH2-NH(CH3)、-CH2-NH2、-SO-(CH3)、环丙基及-O-R11,
其中R11为具有一个或两个各自独立地选自N、O及S的杂原子的五或六元杂环,
或G为CR8R9,R5及R9不存在,且R8及R6与R8及R6之间的两个C原子形成包含一个、两个或三个各自独立地选自N、S及O的杂原子的环状五元芳香族或非芳香族杂环,
或G为CR8R9,且R8及R9与R8及R9之间的C原子一起形成双吖丙啶环,
及其前药或药学上可接受的盐。
2.根据权利要求1所述的化合物,其具有式(I’):
其中R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11及G根据权利要求1中所定义,
及其前药或药学上可接受的盐。
3.根据权利要求1所述的式(I)或权利要求2所述的式(I’)的化合物,其中R7选自H、F、Cl、甲基、乙基、卤代甲基及卤代乙基,
及其前药或药学上可接受的盐。
4.根据权利要求1所述的式(I)或权利要求2所述的式(I’)的化合物,其中R1选自卤代甲基、卤代乙基及甲基,
及其前药或药学上可接受的盐。
5.根据权利要求3所述的化合物,其中R1为选自-CF3、-CHF2及-CH2F的氟甲基,
及其前药或药学上可接受的盐。
6.根据权利要求1所述的式(I)或权利要求2所述的式(I’)的化合物,其中R3及R4中的至少一者为甲基,
及其前药或药学上可接受的盐。
7.根据权利要求1所述的式(I)或权利要求2所述的式(I’)的化合物,其中R3及R4中的一者为甲基且另一者为H,
及其前药或药学上可接受的盐。
8.根据权利要求1所述的式(I)或权利要求2所述的式(I’)的化合物,其中G为O
及其前药或药学上可接受的盐。
9.根据权利要求1所述的式(I)或权利要求2所述的式(I’)的化合物,
其中G为O,
且其中R3或R4中的一者为甲基且另一者为H
及其前药或药学上可接受的盐。
10.根据权利要求8所述的化合物,
其中R4为甲基且R3为H,
其中R5及R6与其之间C原子一起形成氧杂环丁烷环,
及其前药或药学上可接受的盐。
11.根据权利要求1所述的式(I)或权利要求2所述的式(I’)的化合物,
其中R2选自:H、乙炔基、1-丙炔基、-S-甲基、卤素,
及其前药或药学上可接受的盐。
12.根据权利要求1所述的式(I)或权利要求2所述的式(I’)的化合物,其中R2为乙炔基
及其前药或药学上可接受的盐。
13.根据权利要求1所述的式(I)或权利要求2所述的式(I’)的化合物,其中R4为甲基且R3为H,
其中G为O,
其中R5及R6一起形成氧杂环丁烷环
其中R2选自:H、乙炔基、1-丙炔基、-S-甲基、卤素,
及其前药或药学上可接受的盐。
14.根据权利要求1所述的式(I)或权利要求2所述的式(I’)的化合物,
其中R2为环状基团,其中该环状基团选自:苯基或包含1、2或3个选自N、S及O的杂原子的五至六元杂芳基,其中所述环状基团由一个或两个相同或不同的取代基R10取代,
其中每一R10独立地选自:氢、卤素、卤烷基、-甲基、-乙基、-NH-CO-甲基、-N(CH3)2、-CH2-OH、-NH(CH3)、-O-CH3、-CN、-S-CH3、-CO-NH2、-CH2-NH(CH3)、-CH2-NH2、-SO-(CH3)、环丙基及-O-R11,
其中每一R11选自具有一个或两个各自独立地选自N及O的杂原子的五或六元杂环,
及其前药或药学上可接受的盐。
15.根据权利要求14所述的化合物,其中R2为选自吡唑基、吡啶基、咪唑基、苯基及异噁唑基的环状基团,
其中所述环状基团由一个或两个相同或不同的取代基R10取代,
其中每一R10独立地选自:氢、卤素、卤烷基、-甲基、-乙基、-NH-CO-甲基、-N(CH3)2、-CH2-OH、-NH(CH3)、-O-CH3、-CN、-S-CH3、-CO-NH2、-CH2-NH(CH3)、-CH2-NH2、-SO-(CH3)、环丙基及-O-R11,
其中每一R11为四氢吡喃,
及其前药或药学上可接受的盐。
16.根据权利要求15所述的化合物,
其中G为O,
其中R3或R4中的一者为甲基且另一者为H,
及其前药或药学上可接受的盐。
17.根据权利要求16所述的化合物,
其中R4为甲基且R3为H,
其中R5及R6与其之间C原子一起形成氧杂环丁烷环,
及其前药或药学上可接受的盐。
18.根据权利要求1所述的式(I)或权利要求2所述的式(I’)的化合物,其中
G为CR8R9
且其中
R8及R6与R8及R6之间的两个C原子形成包含一个或两个各自独立地选自N及O的杂原子的环状五元芳香族杂环,其选自环状异噁唑基环、环状吡唑基环、环状吡咯基环及环状呋喃基环,
其中R9及R5不存在,
及其前药或药学上可接受的盐。
19.根据权利要求1所述的式(I)或权利要求2所述的式(I’)的化合物,其选自:
及其前药或药学上可接受的盐。
20.一种中间体,其具有式(IV)
或式(V)
或式(X)
或式(XI)
其中G、R1、R2、R3、R4、R5、R6及R7根据权利要求1中所定义且其中X为F或NO2,
且其中PG为保护基团,其选自:叔丁氧基羰基(BOC)、苄基氧基羰基(Cbz)、芴基亚甲氧基羰基(Fmoc)及烯丙基氧基羰基(Alloc)。
21.一种根据权利要求1至19中任一项所述的化合物中的任一者的前药,其具有
式(A)
或式(A’)
其中R12为C1-4-烷基、芳基、-CH2-芳基、NH-SO2-C1-3-烷基。
22.根据权利要求21所述的式(A)或式(A’)的前药,其中R12为甲基。
23.一种根据权利要求1至19中任一项所述的式(I)或式(I’)的化合物,其用于治疗可通过cGAS的抑制得以治疗的疾病。
24.一种根据权利要求1至19中任一项所述的式(I)或式(I’)的化合物,其用于治疗疾病,所述疾病选自:系统性红斑狼疮(SLE)、干扰素病、艾卡迪-古铁雷斯综合征(Aicardi-Goutières syndrome)、年龄相关性黄斑退化(AMD)、肌肉萎缩性脊髓侧索硬化症(ALS)、炎症性肠病(IBD)、慢性阻塞性肺病(COPD)、布卢姆氏综合征(Bloom’s syndrome)、薛格连氏综合征(Sjogren’ssyndrome)、帕金森氏病(Parkinsons disease)、心脏衰竭及癌症、全身性硬化(SSc)、非酒精性脂肪肝炎(NASH)、间质性肺病(ILD),较优选进行性纤维化间质性肺病(PF-ILD),具体而言特发性肺纤维化(IPF)。
25.一种根据权利要求1至19中任一项所述的式(I)或式(I’)的化合物,其用于治疗疾病,所述疾病选自:系统性红斑狼疮(SLE)、干扰素病、艾卡迪-古铁雷斯综合征、年龄相关性黄斑退化(AMD)、肌肉萎缩性脊髓侧索硬化症(ALS)、炎症性肠病(IBD)、慢性阻塞性肺病(COPD)、布卢姆氏综合征、薛格连氏综合征及帕金森氏病。
26.一种根据权利要求1至19中任一项所述的式(I)或式(I’)的化合物,其用于治疗选自以下的纤维化疾病:全身性硬化(SSc)、非酒精性脂肪性肝炎(NASH)、干扰素病、间质性肺病(ILD),较优选进行性纤维化间质性肺病(PF-ILD),具体而言特发性肺纤维化(IPF)。
27.一种根据权利要求1至19中任一项所述的式(I)或式(I’)的化合物,其用于治疗疾病,所述疾病选自:年龄相关性黄斑退化(AMD)、心脏衰竭、COVID-19/SARS-CoV-2感染、肾炎症、肾纤维化、代谢障碍、血管疾病、心血管疾病及癌症。
28.一种药物组合物,其包含根据权利要求1至19中任一项所述的式(I)或式(I’)的化合物及任选的一种或多种药学上可接受的载剂及/或赋形剂。
29.一种药物组合物,其包含根据权利要求1至19中任一项所述的式(I)或式(I’)的化合物与一种或多种选自以下的活性剂的组合:抗炎症剂、抗纤维变性剂、抗过敏剂/抗组织胺、支气管扩张剂、β2激动剂/β模拟物、肾上腺素性激动剂、抗胆碱剂、甲氨蝶呤(methotrexate)、吗替麦考酚酯(mycophenolate mofetil)、白三烯调节剂、JAK抑制剂、抗白介素抗体;非特异性免疫治疗剂,例如干扰素或其他细胞因子/趋化因子;细胞因子/趋化因子受体调节剂、toll样受体激动剂、免疫检查点调节剂;抗TNF抗体,例如阿达木单抗(Adalimumab);抗BAFF抗体,例如贝利木单抗(Belimumab)及依那西普(Etanercept)。
30.根据权利要求29所述的药物组合物,其中该式(I)或式(I’)的化合物与一种或多种选自由比非尼酮(Pirfenidon)及尼达尼布(Nintedanib)组成的组的抗纤维变性剂组合。
31.根据权利要求29所述的药物组合物,其中该式(I)或式(I’)的化合物与一种或多种选自由NSAID及皮质类固醇组成的组的抗炎症剂组合。
32.根据权利要求29所述的药物组合物,其中该式(I)或式(I’)的化合物与一种或多种选自支气管扩张剂、β2激动剂/β模拟物、肾上腺素性激动剂及抗胆碱剂的活性剂组合。
33.根据权利要求29所述的药物组合物,其中该式(I)或式(I’)的化合物与一种或多种选自以下的抗白介素抗体组合:抗IL-23,例如利散吉珠单抗(Risankizumab);抗IL-17抗体、抗IL-1抗体、抗IL-4抗体、抗IL-13抗体、抗lL-5抗体;抗IL-6抗体,例如托珠单抗(Tocilizumab);抗IL-12抗体及抗IL-15抗体。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP21173689.7 | 2021-05-12 | ||
EP21173689 | 2021-05-12 | ||
PCT/EP2022/062480 WO2022238327A1 (en) | 2021-05-12 | 2022-05-09 | Pyridine derivatives with n-linked cyclic substituents as cgas inhibitors |
Publications (1)
Publication Number | Publication Date |
---|---|
CN117337292A true CN117337292A (zh) | 2024-01-02 |
Family
ID=75919222
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202280032800.4A Pending CN117337292A (zh) | 2021-05-12 | 2022-05-09 | 作为cGAS抑制剂的具有N-连接环状取代基的吡啶衍生物 |
Country Status (18)
Country | Link |
---|---|
US (1) | US20230000878A1 (zh) |
EP (1) | EP4337326A1 (zh) |
JP (1) | JP2024519306A (zh) |
KR (1) | KR20240007205A (zh) |
CN (1) | CN117337292A (zh) |
AR (1) | AR125846A1 (zh) |
AU (1) | AU2022274298A1 (zh) |
BR (1) | BR112023019221A2 (zh) |
CA (1) | CA3215920A1 (zh) |
CL (1) | CL2023003023A1 (zh) |
CO (1) | CO2023015149A2 (zh) |
CR (1) | CR20230520A (zh) |
DO (1) | DOP2023000240A (zh) |
EC (1) | ECSP23076856A (zh) |
IL (1) | IL307793A (zh) |
MX (1) | MX2023013233A (zh) |
TW (1) | TW202313624A (zh) |
WO (1) | WO2022238327A1 (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20240189315A1 (en) * | 2022-11-09 | 2024-06-13 | Boehringer Ingelheim International Gmbh | Cyclic Pyridine Derivatives as cGAS Inhibitors |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP5008569B2 (ja) * | 2004-10-22 | 2012-08-22 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | C−fmsキナーゼのインヒビターとしての芳香族アミド |
AR074343A1 (es) * | 2008-11-14 | 2011-01-12 | Amgen Inc | Derivados de piridina y pirimidina como inhibidores de la fosfodiesterasa 10 |
US20110190269A1 (en) * | 2010-02-01 | 2011-08-04 | Karlheinz Baumann | Gamma secretase modulators |
UY36294A (es) * | 2014-09-12 | 2016-04-29 | Novartis Ag | Compuestos y composiciones como inhibidores de quinasa |
WO2019241787A1 (en) | 2018-06-15 | 2019-12-19 | The Regents Of The University Of Colorado A Body Corporate | Novel cyclic gmp-amp synthase (cgas) inhibitors and their method of use |
US20220073532A1 (en) | 2019-01-04 | 2022-03-10 | Bellbrook Labs, Llc | Inhibitors of cgas activity as therapeutic agents |
-
2022
- 2022-05-09 AU AU2022274298A patent/AU2022274298A1/en active Pending
- 2022-05-09 CN CN202280032800.4A patent/CN117337292A/zh active Pending
- 2022-05-09 MX MX2023013233A patent/MX2023013233A/es unknown
- 2022-05-09 CR CR20230520A patent/CR20230520A/es unknown
- 2022-05-09 WO PCT/EP2022/062480 patent/WO2022238327A1/en active Application Filing
- 2022-05-09 BR BR112023019221A patent/BR112023019221A2/pt unknown
- 2022-05-09 CA CA3215920A patent/CA3215920A1/en active Pending
- 2022-05-09 EP EP22728219.1A patent/EP4337326A1/en active Pending
- 2022-05-09 IL IL307793A patent/IL307793A/en unknown
- 2022-05-09 KR KR1020237042267A patent/KR20240007205A/ko unknown
- 2022-05-09 JP JP2023567205A patent/JP2024519306A/ja active Pending
- 2022-05-10 US US17/741,009 patent/US20230000878A1/en active Pending
- 2022-05-11 AR ARP220101256A patent/AR125846A1/es unknown
- 2022-05-11 TW TW111117563A patent/TW202313624A/zh unknown
-
2023
- 2023-10-11 EC ECSENADI202376856A patent/ECSP23076856A/es unknown
- 2023-10-11 CL CL2023003023A patent/CL2023003023A1/es unknown
- 2023-10-27 DO DO2023000240A patent/DOP2023000240A/es unknown
- 2023-11-07 CO CONC2023/0015149A patent/CO2023015149A2/es unknown
Also Published As
Publication number | Publication date |
---|---|
AU2022274298A1 (en) | 2023-09-28 |
ECSP23076856A (es) | 2023-12-29 |
TW202313624A (zh) | 2023-04-01 |
BR112023019221A2 (pt) | 2023-11-21 |
AR125846A1 (es) | 2023-08-16 |
IL307793A (en) | 2023-12-01 |
CR20230520A (es) | 2024-02-13 |
CO2023015149A2 (es) | 2023-11-20 |
CA3215920A1 (en) | 2022-11-17 |
MX2023013233A (es) | 2023-11-16 |
JP2024519306A (ja) | 2024-05-10 |
KR20240007205A (ko) | 2024-01-16 |
EP4337326A1 (en) | 2024-03-20 |
CL2023003023A1 (es) | 2024-03-15 |
US20230000878A1 (en) | 2023-01-05 |
WO2022238327A1 (en) | 2022-11-17 |
DOP2023000240A (es) | 2023-11-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10954236B2 (en) | Tyrosine amide derivatives as Rho-Kinase inhibitors | |
KR102642203B1 (ko) | 급속 진행형 섬유육종 폴리펩티드의 표적화 분해를 위한 다중 고리 화합물 및 방법 | |
KR102268155B1 (ko) | 테트라히드로피라졸로피리미딘 화합물 | |
US9434743B2 (en) | Indazole derivatives | |
US9475816B2 (en) | Substituted-1,4-dihydropyrazolo[4,3-b]indoles | |
KR20170005870A (ko) | Jak 억제제인 5-클로로-2-다이플루오로메톡시페닐 피라졸로피리미딘 화합물 | |
AU2016305590A1 (en) | Bicyclic-fused heteroaryl or aryl compounds | |
KR20140026627A (ko) | 인다졸 | |
TW202241906A (zh) | 吲唑化合物 | |
US20210154179A1 (en) | Substituted pyridines and methods of use | |
CN117337292A (zh) | 作为cGAS抑制剂的具有N-连接环状取代基的吡啶衍生物 | |
CA3216507A1 (en) | Pyridine derivatives with c-linked cyclic substituents as cgas inhibitors | |
CN117337291A (zh) | 作为cGAS抑制剂的具有C-连接环状取代基的吡啶衍生物 | |
US20240208997A1 (en) | Cyclic benzimidazole derivatives as cgas inhibitors | |
US20240189315A1 (en) | Cyclic Pyridine Derivatives as cGAS Inhibitors | |
US20230391774A1 (en) | Novel Compounds | |
CA3202134A1 (en) | Dihydrofuropyridine derivatives as rho- kinase inhibitors | |
TW202317106A (zh) | 作為egfr抑制劑之取代胺基吡啶化合物 |
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 |