ZA200505227B - Thienopyridazinones and their use in modulation of autoimmune disease - Google Patents
Thienopyridazinones and their use in modulation of autoimmune disease Download PDFInfo
- Publication number
- ZA200505227B ZA200505227B ZA200505227A ZA200505227A ZA200505227B ZA 200505227 B ZA200505227 B ZA 200505227B ZA 200505227 A ZA200505227 A ZA 200505227A ZA 200505227 A ZA200505227 A ZA 200505227A ZA 200505227 B ZA200505227 B ZA 200505227B
- Authority
- ZA
- South Africa
- Prior art keywords
- compound according
- independently selected
- formula
- compound
- methyl
- Prior art date
Links
- 208000023275 Autoimmune disease Diseases 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims description 89
- 150000003839 salts Chemical class 0.000 claims description 32
- 125000000217 alkyl group Chemical group 0.000 claims description 28
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 28
- 229910052757 nitrogen Inorganic materials 0.000 claims description 21
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 10
- 125000005842 heteroatom Chemical group 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 9
- 125000004982 dihaloalkyl group Chemical group 0.000 claims description 9
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 9
- 239000005864 Sulphur Chemical group 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000004043 oxo group Chemical group O=* 0.000 claims description 8
- 239000001301 oxygen Chemical group 0.000 claims description 8
- 125000000464 thioxo group Chemical group S=* 0.000 claims description 8
- 125000004385 trihaloalkyl group Chemical group 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 125000004122 cyclic group Chemical group 0.000 claims description 6
- 125000001188 haloalkyl group Chemical group 0.000 claims description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 6
- 125000006413 ring segment Chemical group 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 239000012453 solvate Substances 0.000 claims description 5
- 238000002560 therapeutic procedure Methods 0.000 claims description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- JGOOQALRLGHKIY-UHFFFAOYSA-N 1h-thieno[2,3-d]pyrimidine-2,4-dione Chemical compound O=C1NC(=O)NC2=C1C=CS2 JGOOQALRLGHKIY-UHFFFAOYSA-N 0.000 claims description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 125000001589 carboacyl group Chemical group 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 49
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 29
- 239000000243 solution Substances 0.000 description 20
- 235000019439 ethyl acetate Nutrition 0.000 description 17
- 239000000203 mixture Substances 0.000 description 16
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 14
- 201000010099 disease Diseases 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 12
- -1 Cz4alkanoyl Chemical group 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 238000004949 mass spectrometry Methods 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 239000012442 inert solvent Substances 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 206010039083 rhinitis Diseases 0.000 description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 7
- 229910052786 argon Inorganic materials 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 239000000377 silicon dioxide Substances 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 239000008194 pharmaceutical composition Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000011282 treatment Methods 0.000 description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 5
- 208000006673 asthma Diseases 0.000 description 5
- PHEDXBVPIONUQT-RGYGYFBISA-N phorbol 13-acetate 12-myristate Chemical compound C([C@]1(O)C(=O)C(C)=C[C@H]1[C@@]1(O)[C@H](C)[C@H]2OC(=O)CCCCCCCCCCCCC)C(CO)=C[C@H]1[C@H]1[C@]2(OC(C)=O)C1(C)C PHEDXBVPIONUQT-RGYGYFBISA-N 0.000 description 5
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- FDLDWKIEWAWOSL-UHFFFAOYSA-N ethyl acetate;2-methylpentane Chemical compound CCCC(C)C.CCOC(C)=O FDLDWKIEWAWOSL-UHFFFAOYSA-N 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- PGHMRUGBZOYCAA-ADZNBVRBSA-N ionomycin Chemical compound O1[C@H](C[C@H](O)[C@H](C)[C@H](O)[C@H](C)/C=C/C[C@@H](C)C[C@@H](C)C(/O)=C/C(=O)[C@@H](C)C[C@@H](C)C[C@@H](CCC(O)=O)C)CC[C@@]1(C)[C@@H]1O[C@](C)([C@@H](C)O)CC1 PGHMRUGBZOYCAA-ADZNBVRBSA-N 0.000 description 4
- PGHMRUGBZOYCAA-UHFFFAOYSA-N ionomycin Natural products O1C(CC(O)C(C)C(O)C(C)C=CCC(C)CC(C)C(O)=CC(=O)C(C)CC(C)CC(CCC(O)=O)C)CCC1(C)C1OC(C)(C(C)O)CC1 PGHMRUGBZOYCAA-UHFFFAOYSA-N 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
- 208000030507 AIDS Diseases 0.000 description 3
- 201000004624 Dermatitis Diseases 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 210000001744 T-lymphocyte Anatomy 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 208000010668 atopic eczema Diseases 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 210000003491 skin Anatomy 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- NOIXNOMHHWGUTG-UHFFFAOYSA-N 2-[[4-[4-pyridin-4-yl-1-(2,2,2-trifluoroethyl)pyrazol-3-yl]phenoxy]methyl]quinoline Chemical group C=1C=C(OCC=2N=C3C=CC=CC3=CC=2)C=CC=1C1=NN(CC(F)(F)F)C=C1C1=CC=NC=C1 NOIXNOMHHWGUTG-UHFFFAOYSA-N 0.000 description 2
- VHBFEIBMZHEWSX-UHFFFAOYSA-N 2-isothiocyanatopropane Chemical compound CC(C)N=C=S VHBFEIBMZHEWSX-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 2
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical class [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 206010014950 Eosinophilia Diseases 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-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
- 206010062016 Immunosuppression Diseases 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 241000721454 Pemphigus Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 230000000172 allergic effect Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Substances OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 2
- 229910052681 coesite Inorganic materials 0.000 description 2
- 229910052906 cristobalite Inorganic materials 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 230000001506 immunosuppresive effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 206010025135 lupus erythematosus Diseases 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
- 238000004519 manufacturing process Methods 0.000 description 2
- HYDCQMJFDPQCJH-UHFFFAOYSA-N methyl 3-bromo-2-oxobutanoate Chemical compound COC(=O)C(=O)C(C)Br HYDCQMJFDPQCJH-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N methyl pentane Natural products CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 229910052682 stishovite Inorganic materials 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 229910052905 tridymite Inorganic materials 0.000 description 2
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- SSJXIUAHEKJCMH-PHDIDXHHSA-N (1r,2r)-cyclohexane-1,2-diamine Chemical compound N[C@@H]1CCCC[C@H]1N SSJXIUAHEKJCMH-PHDIDXHHSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- RXNZFHIEDZEUQM-UHFFFAOYSA-N 2-bromo-1,3-thiazole Chemical compound BrC1=NC=CS1 RXNZFHIEDZEUQM-UHFFFAOYSA-N 0.000 description 1
- DORVKAJYRZXVMJ-UHFFFAOYSA-N 2-bromobutanediamide Chemical compound NC(=O)CC(Br)C(N)=O DORVKAJYRZXVMJ-UHFFFAOYSA-N 0.000 description 1
- KJWZZVVMLOPVTC-UHFFFAOYSA-N 2-hydroxy-1,2-oxazolidine Chemical compound ON1CCCO1 KJWZZVVMLOPVTC-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- PXRKCOCTEMYUEG-UHFFFAOYSA-N 5-aminoisoindole-1,3-dione Chemical compound NC1=CC=C2C(=O)NC(=O)C2=C1 PXRKCOCTEMYUEG-UHFFFAOYSA-N 0.000 description 1
- XDJFCEHWNCBCRE-INIZCTEOSA-N 6-[(3,5-dimethyl-1-pyridin-2-ylpyrazol-4-yl)methyl]-5-[(4s)-4-hydroxy-1,2-oxazolidine-2-carbonyl]-3-methyl-1-propan-2-ylthieno[2,3-d]pyrimidine-2,4-dione Chemical compound C([C@@H](O)C1)ON1C(=O)C=1C=2C(=O)N(C)C(=O)N(C(C)C)C=2SC=1CC(=C1C)C(C)=NN1C1=CC=CC=N1 XDJFCEHWNCBCRE-INIZCTEOSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000035285 Allergic Seasonal Rhinitis Diseases 0.000 description 1
- 208000035939 Alveolitis allergic Diseases 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 201000008283 Atrophic Rhinitis Diseases 0.000 description 1
- 208000009137 Behcet syndrome Diseases 0.000 description 1
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 208000015943 Coeliac disease Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 206010010744 Conjunctivitis allergic Diseases 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010014989 Epidermolysis bullosa Diseases 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- 208000027445 Farmer Lung Diseases 0.000 description 1
- 206010016228 Fasciitis Diseases 0.000 description 1
- 208000005577 Gastroenteritis Diseases 0.000 description 1
- 208000030836 Hashimoto thyroiditis Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 201000003838 Idiopathic interstitial pneumonia Diseases 0.000 description 1
- 206010021245 Idiopathic thrombocytopenic purpura Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000009388 Job Syndrome Diseases 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 206010024227 Lepromatous leprosy Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010028735 Nasal congestion Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010029164 Nephrotic syndrome Diseases 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 206010036774 Proctitis Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 1
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 208000033464 Reiter syndrome Diseases 0.000 description 1
- 206010039088 Rhinitis atrophic Diseases 0.000 description 1
- 208000036284 Rhinitis seasonal Diseases 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- 208000009359 Sezary Syndrome Diseases 0.000 description 1
- 208000021388 Sezary disease Diseases 0.000 description 1
- 208000021386 Sjogren Syndrome Diseases 0.000 description 1
- 201000009594 Systemic Scleroderma Diseases 0.000 description 1
- 206010042953 Systemic sclerosis Diseases 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- 206010047112 Vasculitides Diseases 0.000 description 1
- 206010047115 Vasculitis Diseases 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000005263 alkylenediamine group Chemical group 0.000 description 1
- 208000002205 allergic conjunctivitis Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 208000004631 alopecia areata Diseases 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 201000009151 chronic rhinitis Diseases 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 238000006392 deoxygenation reaction Methods 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
- 229940113088 dimethylacetamide Drugs 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
- 208000035475 disorder Diseases 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 231100000321 erythema Toxicity 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 208000022195 farmer lung disease Diseases 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000003784 fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000004970 halomethyl group Chemical group 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 206010051040 hyper-IgE syndrome Diseases 0.000 description 1
- 230000003463 hyperproliferative effect Effects 0.000 description 1
- 230000004047 hyperresponsiveness Effects 0.000 description 1
- 230000001969 hypertrophic effect Effects 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 208000033065 inborn errors of immunity Diseases 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910052909 inorganic silicate Inorganic materials 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000003965 isoxazolidinyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- 201000010260 leiomyoma Diseases 0.000 description 1
- 201000011486 lichen planus Diseases 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 208000008585 mastocytosis Diseases 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- MOBBVQRTKHTLCX-UHFFFAOYSA-N methyl 3,6-dimethyl-2,4-dioxo-1-propan-2-ylthieno[2,3-d]pyrimidine-5-carboxylate Chemical compound CC(C)N1C(=O)N(C)C(=O)C2=C1SC(C)=C2C(=O)OC MOBBVQRTKHTLCX-UHFFFAOYSA-N 0.000 description 1
- MBBQAVVBESBLGH-UHFFFAOYSA-N methyl 4-bromo-3-hydroxybutanoate Chemical compound COC(=O)CC(O)CBr MBBQAVVBESBLGH-UHFFFAOYSA-N 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- 201000005962 mycosis fungoides Diseases 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 208000028529 primary immunodeficiency disease Diseases 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- NWELCUKYUCBVKK-UHFFFAOYSA-N pyridin-2-ylhydrazine Chemical compound NNC1=CC=CC=N1 NWELCUKYUCBVKK-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- QDGHXQFTWKRQTG-UHFFFAOYSA-N pyrimidin-2-ylhydrazine Chemical compound NNC1=NC=CC=N1 QDGHXQFTWKRQTG-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 208000002574 reactive arthritis Diseases 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- DOQQTKLDEQSKIE-UHFFFAOYSA-N silver;isocyanate Chemical compound [Ag+].[N-]=C=O DOQQTKLDEQSKIE-UHFFFAOYSA-N 0.000 description 1
- 201000005671 spondyloarthropathy Diseases 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- IIHPVYJPDKJYOU-UHFFFAOYSA-N triphenylcarbethoxymethylenephosphorane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=CC(=O)OCC)C1=CC=CC=C1 IIHPVYJPDKJYOU-UHFFFAOYSA-N 0.000 description 1
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 239000010937 tungsten Substances 0.000 description 1
- 208000001319 vasomotor rhinitis Diseases 0.000 description 1
- 201000005539 vernal conjunctivitis Diseases 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Description
Thienopyridazinones and their use in modulatdéon of autoimmune disease
The present invention relates to thienopyridazinones, processes for their preparation, pharmaceutical compositions containing them and their use in therapy. The invention also relates to their use in the modulation of autoimmune disease.
T-cells play an important role in the immune response, however in auto-immune disease
T-cells are inappropriately activated against particular tissues and proliferate, eg causing the inflammation associated with rheumatoid arthritis. Inhibition of the proliferation of
T-cells is beneficial in the modulation of autoimmune disease. The present invention relates to compounds which are beneficial in the modulation of autoimmune disease.
In accordance with the present invention, there is provided a compound of formula (1): 0 OH ? N
CO . af
SN IN O
Ams ¢ 0 iy Ar-Ar®
R
@ wherein:
R! and R? each independently represent C;.¢alkyl, Csalkenyl, Cs.scycloalkylCi.salkyl or
Cagcycloalkyl, each of which may be optionally substituted by 1 to 3 halogen atoms;
Q is CR*R® where R* is hydrogen, fluorine or Cj.¢ alkyl and R® is hydrogen, fluorine or hydroxy;
Arisa5-to 10-membered aromatic ring system wherein up to 4 ring atoms may be heteroatoms independently selected from nitrogen, oxygen and sulphur, the ring system being optionally substituted by one or more substituents independently selected from
C1alkyl (optionally substituted by 1, 2 or 3 hydroxy groups), C)4alkoxy, halogen, haloalkyl, dihaloalkyl, or trihaloalkyl, (wherein alkyl groups suitably contain from 1 to 4 carbon atoms) C).alkoxyC,.alkyl, C)4alkylthio, C;4alkoxycarbonyl, C,4alkanoyl, oxo, thioxo, nitro, cyano, NERHR' and ~(CH2)pNRYR’, hydroxy, C.4alkylsulphonyl, C;salkylsulphinyl, carbamoyl,
C).4alkylcarbamoyl, di-(Cyalkyl)carbamoyl, carboxy, SO,NE®R®R%;
Ar is 2 5 or 6 membered aromatic ring containing up to 4 hetero atoms independently selected from nitrogen, sulphur or oxygen, and which may be optionally substituted by s one or more groups independently selected from C4alkyl (optionally substituted by 1,2 or 3 hydroxy groups), C;4alkoxy, halogen, haloalkyl, dihaloalkyl, or trihaloalkyl, (wherein alkyl groups suitably contain from 1 to 4 carbon atoms) C,.alkoxyC;4alkyl,
C, alkylthio, C, alkoxycarbonyl, Cz4alkanoyl, oxo, thioxo, nitro, cyano, NR*R’ and © {(CH;)pNR®R’, hydroxy, Cjalkylsulphonyl, C;4alkylsulphinyl, carbamoyl, C;. salkylcarbamoyl, di-(C)alkyl)carbamoyl, carboxy, SO.NR¥R’; pisltoé4;
RS and R’ each independently represent a hydrogen atom, Ci4alkanoyl or C;4alkyl group, or together with the nitrogen atom to which they are attached form a 5- to 7- membered saturated heterocyclic ring optionally containing a further O, S, NH or Nalkyl group;
R® and R® each independently represent a hydrogen atom, Ci4alkanoyl or C;4alkyl group, or together with the nitrogen atom to which they are attached form a 5- to 7- membered saturated heterocyclic ring optionally containing a further O, §, NH or Nalkyl group; and pharmaceutically acceptable salts and solvates thereof, provided that the compound is other than 5-[(4S)-4-Hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-3-methyl-6-[5- methyl-3-phenyl-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4( 1H,3H)-dione, 6-[3,5-Dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl]-5-[(45)-4-hydroxyisoxazolidin-2- ylcarbonyl}-1 -isobutyl-3-methylthieno[2,3-d)pyrimidine-2,4(1 H,3 H)-dione or : 6-[3,5-Dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl}-5-[ (45)-4-hydroxyisoxazolidin-2- ylcarbonyl}-3-methyl-1-propyithieno(2,3-dpyrimidine-2,4(1H,3H)-dione or a pharmaceutically acceptable salt or solvate thereof.
Suitably R! is Cy. alkyl or Cs. cycloalkyl, and in particular Cy. alkyl. More preferably
R! is ethyl, propyl, butyl or cyclopropyl. Most preferably R'is ethyl, isobutyl, isopropyl or cyclopropyl.
3 N
More preferably R! is C,4 alkyl such as isobutyl or isopropyl. Co
Preferably R? is Cy alkyl such as ethyl or methyl, more preferably methyl . s Suitably Q is CR*R® where R® is hydrogen, Ci. alkyl and R® is hydrogen. Preferably Q is CR'R® where R* and R® are both hydrogen.
Examples of 5-10 membered mono- or bi-cyclic aromatic ring systems for Ar include thienyl, furanyl, pyrrolyl, pyrrolopyridino, imidazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, triazinyl, oxazolyl, thiazolyl, isoxazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazoly], tetrazolyl and quinolyl. - :
Examples of 5- to 7-membered saturated heterocyclic rings formed by R® and R’ and R® and R® include morpholine, piperidine, N-alkyl piperidine, pierazine, pyrrolidine and the like. Preferably Arisa 5 or 6-membered aromatic ring system wherein up to 2 ring atoms may be heteroatoms independently selected from nitrogen, oxygen and sulphur, the ring system being optionally substituted by one or more substituents independently selected from C,alkyl, C,4alkoxy, halogen, haloC, alkyl, dihaloC,4alkyl, tri haloC, alkyl, oxo, thioxo, cyano, or C;4alkylsulphonyl.
More preferably Ar is S-membered aromatic ring containing two nitrogen atoms and substituted as above.
A particular example of Ar is an optionally substituted pyrazole ring. Preferably Ar is a substituted pyrazole ring.
Most preferably Ar is a pyrazole ring di-substituted by C; alkyl, especially methyl. _. For instance, Ar is suitably a group of sub-formula (i) 3
R™
I,
R' N _N
Ar . (i where R'® and R!! are independently selected from H, C,.¢alkyl, haloC, alkyl, dihaloC salkyl, or trihaloC)salkyl, and Ar” is as defined above.
In R' and RY are selected from H or C;.salkyl, such as methyl. In particular, both R'’ and R" is Cy.alkyl such as methyl.
AF is suitably a 5 or 6-membered aromatic ring system wherein up to 3 ring atoms may be heteroatoms independently selected from nitrogen, oxygen and sulphur, the ring system being optionally substituted by one or more substituents independently selected from C,4alkyl, Ci4alkoxy, halogen, dihaloalkyl, trihaloalkyl, oxo, thioxo, cyano,
C4alkylsulphonyl. :
Preferably Ar? is other than phenyl. In particular Ar” includes at least one heteroatom.
Examples of haloalkyl groups are haloC;4alkyl groups which include halomethyl groups such as fluoroethyl groups. Examples of dihaloalkyl groups are dihaloC, alkyl groups including difluoromethy! and dichloromethyl. Examples of trihaloalkyl groups are trihaloC;4alkyl groups such as trifluoromethyl.
In a preferred embodiment, Ar” is 5-membered aromatic ring containing a nitrogen and sulphur atom and substituted as above. Most preferably Ar” is a thiazole ring substituted by halogen, especially fluoro.
In an alternative embodiment of the invention, Ar? is pyridine or pyrimidine. The rings carry at least one substituent, but are preferably unsubstituted.
Preferably Ar” is pyridiny] or pyrimidinyl. ; Preferred compounds of formula (I) include: 6-[[3,5-dimethyl-1-(2-pyrimidinyl)-1H-pyrazol-4-yljmethyl]-5-[[ (48)-4-hydroxy-2- isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d}pyrimidine- 2,4(1H,3H)-dione, and 6-[[3,5-dimethyl-1-(2-pyridinyl)-1H-pyrazol-4-yl]methyl]-5-[[(4S)-4-hydroxy-2- isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine- 2,4(1H,3H)-dione, and pharmaceutically acceptable salts thereof.
Other preferred compounds of formula (I) include (8)-2-[[6-[[3,5-Dimethy}-1-(2- thiazolyl)-1H-pyrazol-4-yljmethyl]-1,2,3,4-tetrahydro-3-methyl-1-(1-methylethyl)-2,4- dioxothieno[2,3-d]pyrimidin-5-yl]carbonyl]-4-isoxazolidinol and pharmaceutically acceptable salts thereof.
Alkyl groups, whether alone or as part of another group, can be straight chained or branched. Unless otherwise stated, they may contain from 1 to 6, and preferably from 1 to 4 carbon atoms.
It will be understood that a compound of the formula (J) or a salt thereof may exhibit the phenomenon of tautomerism and that the drawings within this specification represent only one of the possible tautomeric forms. It is to be understood that the invention encompasses any tautomeric form.
Certain compounds of formula (1) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (1) and mixtures thereof including racemates. These also : form an aspect of the present invention.
Salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formuia I and their pharmaceutically acceptable salts. Pharmaceutically acceptable salts of the invention may, for example, include acid addition salts of the compounds of formula I as hereinbefore defined which are sufficiently basic to form such salts. Such acid addition salts include for example salts with inorganic or organic acids affording pharmaceutically acceptable anions such as with hydrogen halides (especially hydrochloric or hydrobromic acid of which hydrochloric acid is particularly preferred) or with sulphuric or phosphoric acid, or with trifluoroacetic, citric or maleic acid.
Suitable salts include hydrochlorides, hydrobromides, phosphates, sulphates, hydrogen sulphates, alkylsulphonates, arylsulphonates, acetates, benzoates, citrates, maleates, . fumarate, succinates, lactates and tartrates. In addition where the compounds of formula I are sufficiently acidic, pharmaceutically acceptable salts may be formed with an inorganic or organic base which affords a pharmaceutically acceptable cation. Such salts with inorganic or organic bases include for example an alkali metal salt, such as a sodium or potassium salt, an alkaline earth metal salt such as a calcium or magnesium salt, an ammonium salt or for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
Preferred salts include an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulfonate or p- toluenesulfonate, or an alkali metal salt such as a sodium or potassium salt.
In a further aspect the invention provides a process for the preparation of a compound of formula (I) which comprises: (a) reaction of a compound of formula (II): ’
O—P oO / 0 N,
R2 Oo
BEN
0“ NS Y Co
RX 0
Oo (in in which R! and R? are as defined in formula (T) or are protected derivatives thereof, and
X and Y are selected from C).alkyl (optionally substituted by 1,2 or 3 hydroxy groups),
Ci4alkoxy, haloalkyl, dihaloalkyl, trihaloalkyl, C,4alkoxyC;alkyl,
C) alkoxycarbonyl, (CH,)pNR®)R, with a compound of formula (IIT): :
AP-G1-G2 (III) where Ar is as defined in formula (T) or are protected derivatives thereof and G1 is NH, ~ G2is NH, SH or OH, or
: (b) reacting a compound of formula (IV): : oo 0 2 CO,H
R\
N | AN :
PS Ss ¢ oN Ar-AF
R' (dV) in which R', R?, Ar and Ar” are as defined in formula (I) or are protected derivatives : thereof, with a compound of formula (V)
OP
HN, 0 .
Ww) in which P is a protecting group, or (c) for compounds of formula (T) where Ar has an NH group, reacting a compound of formula (VI):
O OH
Oo
RA. NT
N | A 0
Pa oN Ar ~ R' (VD) in which R' and R? and as defined in formula (I) and Ar is as defined in formula (I) provided Ar has an NH group, or are protected derivatives thereof, with a compound of - formula (VII):
Ar-L (VI)
in which A¥ is as defined in formula (I) or is a protected derivative thereof and L is 2 leaving group, 5s and optionally thereafter process (a), (b) or (c) in any order e removing any protecting groups o forming a pharmaceutically acceptable salt.
Reaction of compounds (II) and (III) is suitably carried out in an inert solvent eg ethanol, at a temperature of from 0°C to 100°C, preferably 10°C to 50°C, optionally in the presence of a catalytic quantity of an acid eg trifluoroacetic acid.
Reaction of compounds (IV) and (V) is carried out by conversion of the carboxylic acid function to an activated form by reaction with a coupling agent eg EDCI and 1-hydroxybenzotriazole, in an inert solvent eg dichloromethane, in the presence of a base, preferably triethylamine or ethyldiisopropylamine, at a temperature of from 0°C to 100°C, preferably 10°C to 50°C, in the presence of compound (V).
Reaction of compounds (VI) and (VII) is carried out either by heating in an inert solvent such as NMP in the presence of a base, for example a metal carbonate, under microwave irradiation; or by use of catalytic (or stoicheiometric) Buchwald conditionsusing a Cu(I) salt with a diamine ligand in a solvent such as dioxan at a temperature of about 100°C.
The group L is any suitable leaving group, preferably L is halogen.
Compounds of formula (IT) can be prepared by reacting a compound of formula (VIII):
JOP : : (0 (1)
LO N,
RA 0)
Bes 0” °N” SS L
Ly
R
(VII)
in which R’, R? and P are as defined above and L is a leaving group with a nucleophilic fragment of a the group Ar such as a zinc salt of a beta-diketone. L is preferably a halogen such as bromo.
Compounds of formula (VIII) can be prepared from compounds of formula (IX):
O0—P 0) / 0) N,
RAL © )
XC
07 NTS : in which R!, R? and P are as defined above by, for example, bromination using N- : bromosuccinamide in an inert solvent such as chloroform under a light source at a temperature of from 15°C to 80°C, preferably at 50°C to 70°C.
Compounds of formula (IX) can be prepared by protection of the corresponding alcohols of formula (X):
OH oo] 0 N.
R2 0)
Tord 07 °N~ 7S . : iy &X in which R', R? and P are as defined above by, for example, reacting with a trialkylsilyl halide in an inert solvent such as dichloromethane at a temperature of from 0°C to 60°C, preferably 10°C to 30°C, in the presence of a base such as imidazole.
; EE _
Compounds of formula (X) can be prepared from acids of formula (XI): 6) 0] Oo
RAL
LIS
0“ °N~ 7S . lg
R sO in which R!, R? and P are as defined above by forming an acid chloride by treating with a reagent such as oxalyl chloride in an inert solvent such as dichloromethane at a temperature of from 0°C to 60°C, preferably 10°C to 30°C, followed by treatment of the resulting acid chloride with the hydroxyisooxazolidine in a solvent such as dichloromethane at a temperature of from 0°C to 60°C, preferably 10°C to 30°C in the presence of a base such as triethylamine.
Compounds of formula (XI) are prepared from the corresponding esters using standard conditions.
Compounds of formula (IV) can be prepared from compounds of formula (XII): 0] , CO,R®
R\
LAs
Oo N S Ar
R' in which R', R? and Ar are as defined above, provided that Ar contains an NH group, and R?is an ester forming group by, for example, reacting with a compound of formula (XII)
Ar’-halogen (XIII)
"in which AP is as defined above or by reaction with a compound Ar* where Ar is as : defined above provided that Ar contains a nitrogen centre.
Reaction of compounds (XII) and (XIII) can be carried out in an inert solvent such as. dioxan at a temperature of 10°C to 120°C in the presence of a copper (I) salt and an alkylene diamine. The group RY is an ester forming group such as alkyl, especially methyl.
Reaction of compounds (XII) and Ar? can be carried out in a solvent such as dimethyl acetamide at a temperature of 10°C to 200°C in the presence of a base such as potassium carbonate optionally with microwave irradiation. :
A compound of formula (XII) can be prepared from a compound of formula (XV): . (0) B ’
RN
AAS o} N S
R | -
XV) in which R', R? and R* are as defined above by reaction with a strong base such as lithium diisopropylamide in a solvent such as THF at —78°C to 0°C followed by the addition of a compound of formula (XVI):
Ar-CHO (XVI)
Compounds of formula (IV) are prepared from compounds of formula Xv):
Oo 2 CO,R™
RN
J | NOH 0 N S Arad
R'
XVI)
053 in which R', R%, R®, Ar and Ar” are as defined above, either by deoxygenation using a strong acid such as TFA in the presence of a hydride source such as triethylsilane, optionally in a solvent such as dichloromethane at a temperature of 10°C to 40°C, or by activation of the hydroxy! group by esterification with ana ctivated carboxylic acid such as trifluoroacetic anhydride or methane sulphonyl chloride in an inert solvent such as ethyl acetate followed by hydrogenolysis, for example using palladium on carbon at1 to 5 bar at 10°C to 80°C.
Compounds of formula (XVII) are prepared from compounds of formula (XV) as defined above by reacxting with compounds (XVIII):
Ar-Ar-CHO (XVII) in which Ar and Ar* are as ddefined above using conditions analogous to those above for the reaction of compounds (XV) and (XVI).
Compounds of formula (VI) may be made from compounds of formula (XII) by hydrolysis of the ester function (using an alkali metal or alkaline earth hydroxide in a solvent containg water eg aqueous ethanol or aqueous methanol) at a temperature of from 0°C to 100°C, or using aqueous mineral acid in an inert solvent at a temperature of from 20°C to 100°C, and then coupling the acid residue with a compound of formula (V) in the presence of a condensing agent eg PyBrOP in an inert solvent eg THF in the presence of a base such as triethylamine at a temperature of from 0°C to 30°C.
Starting materials as defined above are available commercially or can be prepared using routine chemistry known in the art.
The compounds of the invention are useful because they possess pharmacological activity in human and non-human animals. They are indicated as pharmaceuticals for . use in the (prophylactic) treatment of autoimmune, inflammatory, proliferative and hyperproliferative diseases and immunologically mediated diseases including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS).
Examples of these conditions are: (1) (the respiratory tract) airways diseases including chronic obstructive pulmonary disease (COPD); asthma, such as bronchial, allergic, intrinsic, extrinsic and dust asthma, particularly chronic or inveterate asthma (e.g. late asthma and airways . hyper-responsiveness); bronchitis; acute, allergic, atrophic rhinitis and chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca and rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous and pseudomembranous rhinitis and scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) and vasomotor rhinitis; sarcoidosis, farmer’s lung and related diseases, fibroid lung and idiopathic interstitial pneumonia; (2) (bone and joints) rheumatoid arthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis and Reiter’s disease), Behcet's disease, Sjogren’s syndrome and systemic sclerosis; (3) (skin) psoriasis, atopical dermatitis, contact dermatitis and other eczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Pemphigus, bullous Pemphigus,
Epidermolysis bullosa, urticaria, angiodermas, vasculitides, erythemas, cutaneous eosinophilias, uveitis, Alopecia areata and vernal conjunctivitis; (4) (gastrointestinal tract) Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, Crohn’s disease, ulcerative colitis, food-related allergies which have effects remote from the gut, e.g., migraine, rhinitis and eczema; (5) (other tissues and systemic disease) multiple sclerosis, atherosclerosis, Acquired
Immunodeficiency Syndrome (AIDS), lupus erythematosus, systemic lupus, erythematosus, Hashimoto’s thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, lepromatous leprosy, sezary syndrome and idiopathic thrombocytopenia pupura; (6) (allograft rejection) acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin and cornea; and chronic graft versus 30 . host disease; and . (7) cancer.
Accordingly, the present invention provides a compound of formula (1) or a pharmaceutically acceptable salt thereof as hereinbefore defined for use in therapy.
In another aspect, the invention provides the use of a compound of formula (1ora pharmaceutically acceptable salt thereof as hereinbefore defined in the manufacture of a medicament for use in therapy. }
In the context of the present specification, the tern "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be construed accordingly.
Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question. Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.
The invention further provides a method of effecting immunosuppression (e.g. in the treatment of allograft rejection) which comprises administering to a patient a : therapeutically effective amount of a compound of formula (1) or a pharmaceutically acceptable salt thereof as hereinbefore defined. 20 .
The invention still further provides a method of treating, or reducing the risk of, an airways disease (e.g. asthma or COPD) in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (1) or a pharmaceutically-acceptable salt thereof as hereinbefore defined.
For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. However, in general, for effecting immunosuppression, the daily 30 . dosage of the compound of formula (1) will be in the range from 0.1 mg/kg, preferably . from 0.3 mg/kg, more preferably from 0.5 mg/kg and still more preferably from mg/kg up to and including 30 mg/kg. For the treatment of airways diseases, the daily dosage of the compound of formula (1) will typically be in the range from 0.001 mg/kg to 30 : mg/kg.
The compounds of formula (1) and pharmaceutically-acceptable salts thereof may be used on their own but will generally be administered in the form of a pharmaceutical
15 Jf composition in which the formula (1) compound/salt/solvate (active ingredient) is in association with a pharmaceutically-acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably less than 80 %w, e.g. from 0.10 to 70 %w, and even more preferably less than 50 %w, of active ingredient, all percentages by weight being based on total composition.
Thus, the present invention also provides a pharmaceutical composition comprising a compound of formula (1) or a pharmaceutically acceptable salt thereof as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (1) ora pharmaceutically acceptable salt thereof as hereinbefore defined, with a pharmaceutically acceptable adjuvant, diluent or carrier.
The pharmaceutical composition of the invention may be administered topically (e.g. to the lung and/or airways or to the skin) in the form of solutions, suspensions, heptafluoroalkane aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules, or by parenteral administration in the form of solutions or suspensions, or by subcutaneous administration or by rectal administration in the form of suppositories or transdermally.
The ability of compounds which can inhibit PMA/ionomycin-stimulated peripheral blood mononuclear cell proliferation can be assessed, for example using the procedure set out below.
The invention will now be illustrated in the following Examples in which, unless otherwise stated: . (i) evaporations were carried out by rotary evaporation in vacuo and work-up procedures were carried out after removal of residual solids such as drying agents by filtration; (ii) operations were carried out at ambient temperature, that is in the range 18-25°C and under an atmosphere of an inert gas such as argon or nitrogen;
(iif) yields are given for illustration only and are not necessarily the maximum attainable; (iv) the structures of the end-products of the formula I were confirmed by nuclear (generally proton) magnetic resonance (NMR) and mass spectral techniques; proton magnetic resonance chemical shift values were measured on the delta scale and peak multiplicities are shown as follows: s, singlet; d, doublet; t, triplet; m, multiplet; br, broad; g, quartet, quin, quintet; (Vv) intermediates were not generally fully characterised and purity was assessed by thin layer chromatography (TLC), high-performance liquid chromatography (HPLC), mass spectrometry (MS), infra-red (IR) or NMR analysis; So
Abbreviations : : 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone DDQ
Dimethylformamide DMF * Tetrahydrofuran : THF
The following examples illustrate the invention.
Example 1 6-[13.5-dimethy}-1-(2-pyrimidinyl)-1H-pyrazol-4-ylj methyl}-5-[[(4S)-4-hydroxy-2- isoxazolidinyl]carbonyi]-3-methyl-1-(1-methylethyl)thieno[2.3-dlpyrimidine- 2,4(1H 3H)-dione
OH o © No) o oP NTS Co
PY 4 } N . > N
A,
Ng a) Ethyl methyl 2-methyl-S-(N.N-methylethylamino)-thiophene-3.4-dicarboxylate
Ethoxycarbonylmethylene triphenyl phosphorane (33.8 g) in dry THF (200 ml) was treated with isopropyl isothiocyanate (10.1 g) at 65°C for 16 h under nitrogen. The mixture was cooled to -78°C and methyl 3-bromo-2-oxo-butanoate was added. The reaction was allowed to warm slowly to room temperature. After 24h at room temperature more methyl 3-bromo-2-oxo-butanoate (2.8 g) was added and the mixture was warmed to 60°C for 16 h. The cooled reaction was poured into water (1.5L) and extracted into ether. Drying and evaporation gave an oil which was chromatographed (Si04/10:1 isohexane-ethyl acetate then 5:1 isohexane-ethyl acetate) to afford the sub- title compound (23.5 g)- 8 Hepa 1.23-1.35(9H, m), 2.26(3H,3), 3.46(1H, m), 3.82(3H, 5), 42(2H, 9), 7.42(1H, br.s) b) Methyl 1,2.3.4-tetrahydro-3.6-dimethyl-1-(1-methylethyl)-2.4-dioxo-thieno[2.3- d]pyrimidine-5-carboxylate
Silver cyanate (13.5 g) suspended in anhydrous toluene (90 ml) under nitrogen was treated dropwise with acetyl chloride (5.34 mI) and stirred vigorously for 30 min. The product of step a) (23 g) dissolved in anhydrous toluene (15 ml) was added and the mixture was stirred for 72 h. Ether (360 ml) was added and the insoluble material was 1s filtered off and washed with a small volume of ether. The combined organic solutions were washed with saturated sodium bicarbonate solution, dried and evaporated. The residue was treated with a solution of sodium methoxide in methanol (25wt%, 64 ml) at room temperature for 72 h. The reaction was cooled in ice and treated with : trimethylsilyl chloride (50.8 ml) and stirred at room temperature overnight. All volatiles were removed in vacuo and the residue partitioned between water and ethyl acetate.
Drying and evaporation of the organic solution left a residue, which was chromatographed (Si02/2:1 isohexane-ethyl acetate then 3:2 isohexane-ethyl acetate) to isolate the major component (12.2 g). This was taken in dry DMF (150 ml) with potassium carbonate (6.95 g) and methyl iodide (7.1 g) for 72 h at room temperature.
The mixture was poured into water (2L), acidified and extracted into ether. Washing with brine, drying and evaporation gave a solid which was boiled in isohexane (200 ml) containing ethyl acetate (3 ml). On cooling the precipitated pale yellow solid was collected and dried, to afford the sub-title compound (10.5 g).
MS (APCI) [M+H]' 297 5 'Hepen 1.6(6H, d), 2.44(3H,s), 3.37(3H, 5), 3.95(3H, 5), 4.66(1H, br) © ¢) 1,2.3,4-Tetrahydro-3.6-dimethyl-1-(1-methylethyl)-2.4-dioxo-thieno[2.3- d]pyrimidine-S-carboxylic acid
To a solution of the product of step b) (3.81 g) in THF (50 ml) and methanol (5 ml) was added 1N NaOH (25.7 ml) and the mixture stirred under nitrogen for 18 hr. It was acidified with 2.5N HCI and extracted with DCM, the organic extracts washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give the sub-title compound as a solid (3.40 g) 40 MS (ESI) 283 [M+H]"
d) 5-[[(48)-4-Hydroxy-2-isoxazolidinyljcarbonyl]-3,6-dimethyl-1-(1- methylethyl)thieno[2,3-dlpyrimidine-2.4(1H.3H)-dione
To a suspension of the product of part c) (3.40 g) in DCM (50 ml) was added oxalyl chloride (1.16 ml) and DMF (10 pl) and the mixture stirred under nitrogen for 2 br. The acid chloride solution was added to a suspension of (:S)-4-isoxazolidinol hydrochloride (1.51 g) and triethylamine (3.52 mi) in DCM (20 ml) at 0°C under nitrogen and the mixture stirred at room temperature for 3 hr. It was washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography over silica, eluting with ethyl acetate to give the sub-title compound as a solid (2.52 g).
MS (ESI) 354 [M+H]' : & "Hpmso 1.50-1.52 (6H, m), 2.30-2.34 (3H, m), 3.18-3.19 (3H, m), 3.42-4.08 (4H, m), 4.59-4.74 (2H, m), 5.49-5.50 (1H, m) e) 5-[[(48)-4-[[(1.1-Dimethylethyl)dimethylsilylloxy]-2-isoxazolidiny] jcarbonyl]-3,6- dimethyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2.4(1H.3H)-dione
To a solution of the product of part d) (2.52 g) in DCM (30 ml) was added imidazole - (0.53 g) and tert-butyldimethylsilyl chloride (1.18 g) and the mixture stirred under nitrogen for 24 hr. It was acidified with IN HCI and extracted with DCM, the organic extracts washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography over silica, eluting with i-hexane/ethyl acetate (3:1) followed by i- hexane/ethyl acetate (1:1) to give the sub-title compound (2.42 g). 8 'Hpmso 0.09 (6H, d), 0.86 (9H, s), 1.50 (6H, d), 2.31-2.34 (3H, m), 3.18-3.19 (3H, m), 3.44-4.15 (4H, m), 4.50-4.97 (2H, m) f) 6-Bromomethyl-5-[[(4S)-4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2- : isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)thieno[2.3-d]pyrimidine- 2,41H.3H)-dione to a solution of the product of part ¢) (2.42 g) in chloroform (100 ml) was added N- : bromosuccinimide (1.01 g) and the mixture heated under reflux whilst being irradiated © with a 300W tungsten lamp for 2 hr. It was cooled, washed with IN NaOH solution, washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give the sub-title compound (2.83 g)
MS (ESI) 546 and 548 [M+H]" g) 6-(2-Acetyl-3-o0xobutyl)-5-[[(4S)-4-[[(1.1-dimethylethyldimethylsilyljoxy]-2- isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyhthieno{2,3-d]pyrimidine- 40 2,4(1H.3H)-dione
A solution of the product of part f) (2.83 g) and zinc acetylacetonate hydrate (1.47 g) in chloroform (50 ml) was heated under reflux for 1 hr. It was cooled, washed with sodium bicarbonate solution, filtered through celite, washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give the sub-title s compound (2.93 g) -
MS (ESI) 566 [M+H]" h) 5-[[(4S)-4-[[(1.1-DimethylethyldimethylsilylJoxy]-2-isoxazolidinyl]carbonyl]-6- [[3.5-dimethyl-1-(2-pyrimidinyl)-1H-pyrazol-4-yllmethyl}-3-methyl-1-(1- methylethyl)thieno[2,3-dlpyrimidine-2.4(1H.3H)-dione
To a solution of the product of part g) (0.73 g) in chloroform (25 ml) was added pyrimidin-2-ylhydrazine (0.27 g) and the mixture stirred for 48 hr. It was washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced : pressure. The residue was purified by column chromatography over silica, eluting with i-hexane/ethyl acetate (1:1) followed by i-hexane/ethyl acetate (1:4) to give the sub-title compound (0.43 g).
MS (ESI) 640 [M+H]" : _ i) 6-[[3,5-Dimethyl-1-(2-pyrimidinyl)-1H-pyrazol-4-ylimethyl]-5-[{(4S)4-hydroxy-2- isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)thieno[2.3-d]pyrimidine- 2,4(1H,3H)-dione
A solution of the product of part h) (0.43 g) and trifluoroacetic acid (0.5 ml) in DCM (10 ml) was stirred for 72 hr. It was concentrated in vacuo, diluted with sodium bicarbonate solution, and extracted with ethyl acetate, the organic extracts washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography over silica, eluting with ethyl acetate then ethyl acetate/methano! (9:1) to give the title compound (30 mg).
MS (APCI) 526 [M+H]" 8 'Hpwmso 1.44-1.46 (6H, m), 2.16-2.19 (3H, m), 2.53-2.55 (3H, m), 3.17-3.19 (3H, m), 3.48-4.14 (6H, m), 4.38 (1H, s, br), 4.60-4.80 (1H, m), 5.48-5.52 (1H, m), 7.46 (1H, dv), ‘8.87 (2H, t)
Example 2 Co 6-]3.5-dimethy}-1-(2-pyridinyl)-1H-pyrazol-4-ylimethyl)-5-[{(4S)-4-hydroxy-2- isoxazolidinyllcarbonyl]-3-methyi-1-(1-methylethylthieno[2.3-dlpyrimidine- 2.4(1H 3H)-dione :
S
JOH ’ o ° VD
Xx 0“ NT 7S )
PY { N : 8) 5-[[(4S)}-4-[[(1,1-Dimethylethyl)Mimethylsilylloxy]-2-isoxazolidinyljcarbonyl]-6- [[3.5-dimethyl-1-(2-pyridiny])-1H-pyrazol-4-ylimethyl]-3-methyl-1-(1- methylethyl)thieno[2 3-dlpyrimidine-2 4(1H 3H)-diope
To a solution of the product of example 1 part g) (0.73 g) in chloroform (25 ml) was added pyridin-2-ylhydrazine (0.28 g) and the mixture stirred for 48 br. It was washed . with water, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography over silica, eluting with i-hexane followed by i-hexane/ethyl acetate (1:1) to give the sub-title compound (0.28 g). :
MS (ESI) 639 [M+H]" b) 6-[[3,5-Dimethyl-1-(2-pyridinyl)- 1 H-pyrazol-4-yllmethyl]-5-[[(4S)-4-hydroxy-2- isoxazolidinyl]carbonyl]-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine- 2.4(1H3H)-dione
A solution of the product of part a) (0.28 g) and triffuoroacetic acid (0.5 ml) in DCM (10 ml) was stirred for 72 hr. It was concentrated in vacuo, diluted with sodium bicarbonate solution, and extracted with ethyl acetate, the organic extracts washed with water, dried . over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue Was purified by column chromatography over silica, eluting with ethyl acetate then ethyl acetate/methanol (49:1) to give the title compound (88 mg).
MS (APCI) 525 [M+H]" 8 '"Hpmso 1.44-1.47 (6H, m), 2.17-2.19 (3H, m), 2.56-2.58 (3H, m), 3.47-4.14 (6H, m), 4.38 (1H, s, br), 4.60-4.80 (1H, m), 5.51-5.52 (1H, m), 7.30-7.34 (1H, m), 7.80 (1H, d), 7.95 (1H, dt), 8.45-8.47 (1H, m)
Example 3 (S)-2-[[6-[[3,5-Dimethyl-1-(2-thiazolyl}-1H-pyrazol-4-yl] methyl]-1,2,3 4-tetrahydro- 3-methyl-1-(1-methylethyl)-2,4-dioxothieno[2,3-d] pyrimidin-S-yl] carbonyl]-4- isoxazolidinol oH o WN
Nn A 0
SB J
A NY
4
A mixture of (S)-2-[[6-[(3,5-dimethy]-1H-pyrazol-4-yl)methyl]-1,2,3,4-tetrahydro-3- methyl-1-(1-methylethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]carbonyl]-4- isoxazolidinol (237mg), 2-bromothiazole (237mg), copper(l)iodide (20mg), trans- cyclohexane-1,2-diamine (15mg) and potassium carbonate (145mg) were heated at 100°C in 1,4-dioxane(1ml) for 24hrs. The reaction mixture was concentrated to dryness and purified by chromatography on SiO2 (Biotage cartridge) (eluting with EtOAc to 5%
MeOH in EtOAc) and subsequently reverse phase chromatography to give the title compound as a white solid (110mg).
MS (APCI +ve) M+H = 531.1 8 'Hpwmso,120°C 1.47 (6H, d), 2.17 (3H, s), 2.60 (3H, s), 3.20 (3H, s), 3.46 (1H, d), 3.75 (1H, d), 3.89-3.95 (2H, m), 3.89 (2H, s), 4.46 (1H, sep), 4.70 (1H, s), 5.08 (1H, 8), 7.38 (1H, d), 7.56 (1H, d).
Pharmacological Data
Inhibition of PMA/ionomycin-stimulated peripheral blood mononuclear cell proliferation
The assay for PMA/ionomycin-stimulated PBMC proliferation was performed in 96- well flat-bottomed microtitre plates. Compounds were prepared as 10mM stock solutions in dimethyl sulfoxide. A 50-fold dilution of this was prepared in RPMI and serial dilutions were prepared from this solution. 10p! of the 50-fold diluted stock, or dilutions of it, were added to the well to give concentrations in the assay starting at 9.5uM and going down. Into each well was placed 1 x 10° PBMC, prepared from human peripheral blood from a single donor, in RPMI1640 medium supplemented with 10% human serum, 2mM glutamine and penicillin/streptomycin. Phorbol myristate acetate (PMA) (0.5ng/ml final concentration) and ionomycin (500ng/ml final concentration) were added to these cells in supplemented RPMI1640 medium (as above) so that the final volume of the assay was 0.2ml. The cells were incubated at 37°C in a bumidified atmosphere at 5% carbon dioxide for 72 hours. H-Thymidine (0.51Ci) was added for the final 6 hours of the ) incubation. The level of radioactivity incorporated by the cells was then determined and this is a measure of proliferation.
The compounds of the Examples were found to exhibit an IAs; value of less than 1 x 10 M in the above test. Of the specific examples, examples 1 had a PIAso of 8.3 and
Example 3 had a P1As of 9.07 in the above test.
Claims (13)
1. A compound of formula (1): o 0) OH RAL | J TL 0~ S oN © Ar-AF © 5 ) wherein: R! and R? each independently represent C, alkyl, Cs alkenyl, Cs.scycloalkylC.salkyl or Csecycloalkyl, each of which may be optionally substituted by 1 to 3 halogen atoms; Q is CR*R® where R* is hydrogen, fluorine or Cy. alkyl and R® is hydrogen, fluorine or hydroxy; Arisa 5- to 10-membered aromatic ring system wherein up to 4 ring atoms may be heteroatoms independently selected from nitrogen, oxygen and sulphur, the ring system being optionally substituted by one or more substituents independently selected from C14alkyl (optionally substituted by 1, 2 or 3 hydroxy groups), Cialkoxy, halogen, haloalkyl, dihaloalkyl, or trihaloalkyl, (wherein alkyl groups suitably contain from 1 to 4 carbon atoms) C;.salkoxyC4alkyl, C) alkylthio, Ci4alkoxycarbonyl, C;4alkanoyl, oxo, thioxo, nitro, cyano, -N(R®R” and ~(CHa)pNR¥R?, hydroxy, C;4alkylsulphonyl, Cy4alkylsulphinyl, carbamoyl, C, 4alkylcarbamoyl, di-(C;.salkyl)carbamoyl, carboxy, SO;NRYR’; Aris a 5 or 6 membered aromatic ring containing up to 4 hetero atoms independently selected from nitrogen, sulphur or oxygen, and which may be optionally substituted by one or more groups independently selected from C,4alkyl (optionally substituted by 1,2 or 3 hydroxy groups), C;alkoxy, halogen, haloalkyl, dihaloalkyl, or trihaloalkyl, (wherein alkyl groups suitably contain from 1 to 4 carbon atoms) C;alkoxyCi4alkyl, Cj4alkylthio, C,4alkoxycarbonyl, C;4alkanoyl, oxo, thioxo, nitro, cyano, NRSR’ and ~(CH)pNRYR®, hydroxy, C; 4alkylsulphonyl, Ci4alkylsulphinyl, carbamoyl, Cy. salkylcarbamoyl, di-(Cy4alkyl)carbamoyl, carboxy, SO;NR)R’;
pislito4; RS and R’ each independently represent a hydrogen atom, C,«alkanoyl or C;4alkyl group, or together with the nitrogen atom to which they are attached form a 5- to 7- membered saturated heterocyclic ring optionally containing a further O, S, NH or Nalkyl group; : R® and R® each independently represent a hydrogen atom, C;4alkanoy] or Ci4alkyl group, or together with the nitrogen atom to which they are attached form a 5-to 7- membered saturated heterocyclic ring optionally containing a further O, S, NH or Nalkyl group; or a pharmaceutically acceptable salt or solvates thereof, provided that the compound is other than 5-[(4S)-4-Hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-3-methyl-6-[5- methyl-3-phenyl-1H-pyrazol-4-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3 H)-dione, 6-[3,5-Dimethyl-1 -phenyl-1H-pyrazol-4-ylmethyl}-5-[(4S5)-4-hydroxyisoxazolidin-2- ylcarbonyl]-1-isobutyl-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione or 6-{3,5-Dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl]-5-[(4S)-4-hydroxyisoxazolidin-2- ylcarbonyl}-3-methyl-1-propylthienof2,3-d]pyrimidine-2,4(1H,3 H)-dione or a pharmaceutically acceptable salt or solvate thereof.
2. A compound according to claim 1 in which R'is Cs alkyl.
3. A compound according to claim 1 or 2 in which R? is methyl,
4. A compound according to any one of claim 1 to 3 in which Q is CHa.
-5. A compound according to any one of claims 1 to 4 in which Arisa 5 or 6- membered aromatic ring system wherein up to 2 ring atoms may be heteroatoms independently selected from nitrogen, oxygen and sulphur, the ring system being optionally substituted by one or more substituents independently selected from C14alkyl,, Ci4alkoxy, halogen, dihaloalkyl, trihaloalkyl, oxo, thioxo, cyano and C,. salkylsulphonyl. : : ’
6. A compound according to claim 5 wherein Ar is a group of sub-formula (i) R' : R" NC AP aU) where R'® and R*' are independently selected from H, C.salkyl, or baloC, salkyl and Ar” is as defined above.
7. A compound according to any one of the preceding claims wherein Ar” is other than phenyl.
8. A compound according to claim 7 wherein Ar contains at least one heteroatom.
9. A compound according to any one of claims 1 to 6 in which Ar” is a 5 or 6- membered aromatic ring system wherein up to 3 ring atoms may be heteroatoms independently selected from nitrogen, oxygen and sulphur, the ring system being optionally substituted by one or more substituents independently selected from Ciaalkyl, C,4alkoxy, halogen, dihaloalkyl, tribaloalkyl, oxo, thioxo, cyano and C;. . salkylsulphonyl.
10. A compound according to claim 9 wherein AY is pyridiny] or pyrimidinyl. -
11. A compound according to claim 9 wherein Ar is thiazolyl.
12. A compound of formula (I) selected from: (S)-2-[[6-[[3,5-Dimethyl-1-(2-thiazolyl)-14-pyrazol-4-ylJmethyl]-1,2,3,4-tetrahydro-3- - methyl-1-(1-methylethyl)-2,4-dioxothieno[2,3-d]}pyrimidin-5-yl]carbonyl]-4- isoxazolidinol and pharmaceutically acceptable salts thereof. .
13. A compound as defined in any one of claims 1 to 12 for use in therapy.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE0300117A SE0300117D0 (en) | 2003-01-17 | 2003-01-17 | Novel Compounds |
Publications (1)
Publication Number | Publication Date |
---|---|
ZA200505227B true ZA200505227B (en) | 2006-11-29 |
Family
ID=20290152
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ZA200505227A ZA200505227B (en) | 2003-01-17 | 2005-06-28 | Thienopyridazinones and their use in modulation of autoimmune disease |
Country Status (4)
Country | Link |
---|---|
CN (1) | CN100354282C (en) |
SE (1) | SE0300117D0 (en) |
UA (1) | UA82497C2 (en) |
ZA (1) | ZA200505227B (en) |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SE9702001D0 (en) * | 1997-05-28 | 1997-05-28 | Astra Pharma Prod | Novel compounds |
-
2003
- 2003-01-17 SE SE0300117A patent/SE0300117D0/en unknown
-
2004
- 2004-01-15 CN CNB2004800024049A patent/CN100354282C/en not_active Expired - Fee Related
- 2004-01-15 UA UAA200506373A patent/UA82497C2/en unknown
-
2005
- 2005-06-28 ZA ZA200505227A patent/ZA200505227B/en unknown
Also Published As
Publication number | Publication date |
---|---|
CN1738825A (en) | 2006-02-22 |
CN100354282C (en) | 2007-12-12 |
UA82497C2 (en) | 2008-04-25 |
SE0300117D0 (en) | 2003-01-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2512441C (en) | Thienopyrimidinediones and their use in the modulation of autoimmune disease | |
EP1412362B1 (en) | THIENO¬2,3-d|PYRIMIDINEDIONES AS INHIBITORS OF T-CELLS PROLIFERATION | |
EP1414825B1 (en) | Thienopyrimidinediones and their use in the modulation of autoimmune disease | |
EP1107973B1 (en) | NOVEL THIENO[2,3-d]PYRIMIDINEDIONES, PROCESS FOR THEIR PREPARATION AND USE THEREOF IN THERAPY | |
EP1587809B1 (en) | Thienopyridazinone derivative as modulators of autoimmune diseases | |
AU2002319469A1 (en) | Thienopyrimidinediones and their use in the modulation of autoimmune disease | |
US20080221131A1 (en) | Thienopyrimidinediones and their use in modulation of autoimmune disease | |
ZA200505227B (en) | Thienopyridazinones and their use in modulation of autoimmune disease |