DE60211530T2 - Pyrrolopyrimidine als mittel zur inhibierung von cysteinproteasen - Google Patents
Pyrrolopyrimidine als mittel zur inhibierung von cysteinproteasen Download PDFInfo
- Publication number
- DE60211530T2 DE60211530T2 DE60211530T DE60211530T DE60211530T2 DE 60211530 T2 DE60211530 T2 DE 60211530T2 DE 60211530 T DE60211530 T DE 60211530T DE 60211530 T DE60211530 T DE 60211530T DE 60211530 T2 DE60211530 T2 DE 60211530T2
- Authority
- DE
- Germany
- Prior art keywords
- mmol
- lower alkyl
- pyrrolo
- acoet
- heterocyclyl
- 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.)
- Expired - Lifetime
Links
- 230000002401 inhibitory effect Effects 0.000 title description 3
- 102000035195 Peptidases Human genes 0.000 title description 2
- 108091005804 Peptidases Proteins 0.000 title description 2
- 239000004365 Protease Substances 0.000 title 1
- 239000010143 cystone Substances 0.000 title 1
- 150000004944 pyrrolopyrimidines Chemical class 0.000 title 1
- -1 R 4 is H Chemical group 0.000 claims description 275
- 150000001875 compounds Chemical class 0.000 claims description 140
- 125000000217 alkyl group Chemical group 0.000 claims description 88
- 238000000034 method Methods 0.000 claims description 65
- 125000003118 aryl group Chemical group 0.000 claims description 39
- 229910052736 halogen Inorganic materials 0.000 claims description 33
- 150000002367 halogens Chemical class 0.000 claims description 33
- 125000003545 alkoxy group Chemical group 0.000 claims description 27
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 24
- 238000002360 preparation method Methods 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 24
- 229920006395 saturated elastomer Polymers 0.000 claims description 24
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 21
- 125000001424 substituent group Chemical group 0.000 claims description 20
- 102000004171 Cathepsin K Human genes 0.000 claims description 19
- 108090000625 Cathepsin K Proteins 0.000 claims description 19
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 claims description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 18
- 150000002148 esters Chemical class 0.000 claims description 16
- 201000010099 disease Diseases 0.000 claims description 15
- 125000000623 heterocyclic group Chemical group 0.000 claims description 13
- 229910052717 sulfur Inorganic materials 0.000 claims description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- CYJAWBVQRMVFEO-UHFFFAOYSA-N piperazine-2,6-dione Chemical compound O=C1CNCC(=O)N1 CYJAWBVQRMVFEO-UHFFFAOYSA-N 0.000 claims description 12
- 125000004104 aryloxy group Chemical group 0.000 claims description 11
- 125000005843 halogen group Chemical group 0.000 claims description 9
- 125000004043 oxo group Chemical group O=* 0.000 claims description 9
- 239000002243 precursor Substances 0.000 claims description 9
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 claims description 8
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 8
- 125000003435 aroyl group Chemical group 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 claims description 8
- 229940091173 hydantoin Drugs 0.000 claims description 8
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 claims description 8
- 125000003342 alkenyl group Chemical group 0.000 claims description 7
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 6
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 6
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 238000011321 prophylaxis Methods 0.000 claims description 6
- 125000000304 alkynyl group Chemical group 0.000 claims description 5
- 229910052721 tungsten Inorganic materials 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 125000003368 amide group Chemical group 0.000 claims description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 125000002837 carbocyclic group Chemical group 0.000 claims description 4
- 230000008878 coupling Effects 0.000 claims description 4
- 238000005859 coupling reaction Methods 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 238000007363 ring formation reaction Methods 0.000 claims description 4
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 4
- 125000002619 bicyclic group Chemical group 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 238000010168 coupling process Methods 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 125000005251 aryl acyl group Chemical group 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000006413 ring segment Chemical group 0.000 claims description 2
- 125000003003 spiro group Chemical group 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 230000001225 therapeutic effect Effects 0.000 claims description 2
- 125000005257 alkyl acyl group Chemical group 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 348
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 299
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 199
- 239000000203 mixture Substances 0.000 description 158
- 239000000243 solution Substances 0.000 description 137
- 239000011541 reaction mixture Substances 0.000 description 136
- 239000012267 brine Substances 0.000 description 113
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 113
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 102
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 78
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 78
- 239000000284 extract Substances 0.000 description 69
- 238000010898 silica gel chromatography Methods 0.000 description 66
- 239000012074 organic phase Substances 0.000 description 63
- 239000000047 product Substances 0.000 description 62
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 59
- 239000007858 starting material Substances 0.000 description 59
- 230000002829 reductive effect Effects 0.000 description 56
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 54
- 239000000741 silica gel Substances 0.000 description 52
- 229910002027 silica gel Inorganic materials 0.000 description 52
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 51
- 235000019341 magnesium sulphate Nutrition 0.000 description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 51
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 50
- 239000012043 crude product Substances 0.000 description 45
- 239000002904 solvent Substances 0.000 description 39
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 34
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 34
- 235000019439 ethyl acetate Nutrition 0.000 description 34
- 229910052938 sodium sulfate Inorganic materials 0.000 description 34
- 235000011152 sodium sulphate Nutrition 0.000 description 34
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 33
- SVNIABUZGXNWNA-UHFFFAOYSA-N 6-(bromomethyl)-7-(2,2-dimethylpropyl)pyrrolo[2,3-d]pyrimidine-2-carbonitrile Chemical compound N1=C(C#N)N=C2N(CC(C)(C)C)C(CBr)=CC2=C1 SVNIABUZGXNWNA-UHFFFAOYSA-N 0.000 description 30
- 238000003756 stirring Methods 0.000 description 28
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- 239000012299 nitrogen atmosphere Substances 0.000 description 26
- 229910000027 potassium carbonate Inorganic materials 0.000 description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 22
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- 238000004440 column chromatography Methods 0.000 description 21
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 20
- 239000000725 suspension Substances 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- 238000004587 chromatography analysis Methods 0.000 description 17
- 238000000746 purification Methods 0.000 description 17
- 239000003480 eluent Substances 0.000 description 16
- 239000007787 solid Substances 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 239000000706 filtrate Substances 0.000 description 15
- 239000011734 sodium Substances 0.000 description 15
- 238000001704 evaporation Methods 0.000 description 14
- 230000008020 evaporation Effects 0.000 description 14
- 238000001816 cooling Methods 0.000 description 13
- 239000005457 ice water Substances 0.000 description 13
- 0 CC(C1)C(*(C)=CC(*2CC(C)(C)C)=CC(C=*C3C)=C2*=C3C#*)=CC=C1N Chemical compound CC(C1)C(*(C)=CC(*2CC(C)(C)C)=CC(C=*C3C)=C2*=C3C#*)=CC=C1N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 12
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 11
- 125000004432 carbon atom Chemical group C* 0.000 description 11
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 11
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 11
- 238000011282 treatment Methods 0.000 description 11
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 10
- 238000010992 reflux Methods 0.000 description 10
- 229910000104 sodium hydride Inorganic materials 0.000 description 10
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- KZXZPTCXNTWWCS-UHFFFAOYSA-N 5-bromo-4-(2,2-dimethylpropylamino)pyrimidine-2-carbonitrile Chemical compound CC(C)(C)CNC1=NC(C#N)=NC=C1Br KZXZPTCXNTWWCS-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- ONNNJLDEPAZHLQ-UHFFFAOYSA-N 6-[(4-aminophenyl)methyl]-7-(2,2-dimethylpropyl)pyrrolo[2,3-d]pyrimidine-2-carbonitrile Chemical compound C=1C2=CN=C(C#N)N=C2N(CC(C)(C)C)C=1CC1=CC=C(N)C=C1 ONNNJLDEPAZHLQ-UHFFFAOYSA-N 0.000 description 7
- 241000124008 Mammalia Species 0.000 description 7
- 208000001132 Osteoporosis Diseases 0.000 description 7
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical class C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical class C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 125000004076 pyridyl group Chemical group 0.000 description 6
- 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 6
- XQWHIIQIVZJEMR-UHFFFAOYSA-N 7-(2,2-dimethylpropyl)-6-(piperazin-1-ylmethyl)pyrrolo[2,3-d]pyrimidine-2-carbonitrile Chemical compound C=1C2=CN=C(C#N)N=C2N(CC(C)(C)C)C=1CN1CCNCC1 XQWHIIQIVZJEMR-UHFFFAOYSA-N 0.000 description 5
- HCJRBZZBADWUJG-UHFFFAOYSA-N 7-(2,2-dimethylpropyl)-6-[(1-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl]pyrrolo[2,3-d]pyrimidine-2-carbonitrile Chemical compound CN1C(=O)N(CC=2N(C3=NC(=NC=C3C=2)C#N)CC(C)(C)C)C(=O)C11CCNCC1 HCJRBZZBADWUJG-UHFFFAOYSA-N 0.000 description 5
- SYHBEDCSCPDPHK-UHFFFAOYSA-N 7-(2,2-dimethylpropyl)-6-[(4-oxopiperidin-1-yl)methyl]pyrrolo[2,3-d]pyrimidine-2-carbonitrile Chemical compound C=1C2=CN=C(C#N)N=C2N(CC(C)(C)C)C=1CN1CCC(=O)CC1 SYHBEDCSCPDPHK-UHFFFAOYSA-N 0.000 description 5
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 150000002466 imines Chemical class 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 5
- 201000008482 osteoarthritis Diseases 0.000 description 5
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Chemical class COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 238000004007 reversed phase HPLC Methods 0.000 description 5
- 206010039073 rheumatoid arthritis Diseases 0.000 description 5
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- DPWSMMSNJFCJNW-LLVKDONJSA-N (5r)-1-[(4-chlorophenyl)methyl]-5-propan-2-ylimidazolidine-2,4-dione Chemical compound O=C1NC(=O)[C@@H](C(C)C)N1CC1=CC=C(Cl)C=C1 DPWSMMSNJFCJNW-LLVKDONJSA-N 0.000 description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 4
- XQRLXUYZKZXSBN-UHFFFAOYSA-N 1-benzyl-4-hydroxypiperidine-4-carbonitrile Chemical compound C1CC(O)(C#N)CCN1CC1=CC=CC=C1 XQRLXUYZKZXSBN-UHFFFAOYSA-N 0.000 description 4
- CYNYIHKIEHGYOZ-UHFFFAOYSA-N 1-bromopropane Chemical compound CCCBr CYNYIHKIEHGYOZ-UHFFFAOYSA-N 0.000 description 4
- FUPPPVQJOVHZSX-UHFFFAOYSA-N 1-oxa-8-thia-3-azaspiro[4.5]decane-2,4-dione Chemical compound O1C(=O)NC(=O)C11CCSCC1 FUPPPVQJOVHZSX-UHFFFAOYSA-N 0.000 description 4
- VURIYIYAKMLWMZ-UHFFFAOYSA-N 4-benzylpiperazine-2,6-dione Chemical compound C1C(=O)NC(=O)CN1CC1=CC=CC=C1 VURIYIYAKMLWMZ-UHFFFAOYSA-N 0.000 description 4
- DRETZBXCDQMKEU-UHFFFAOYSA-N 7-(2,2-dimethylpropyl)-6-[(2,6-dioxopiperazin-1-yl)methyl]pyrrolo[2,3-d]pyrimidine-2-carbonitrile Chemical compound C=1C2=CN=C(C#N)N=C2N(CC(C)(C)C)C=1CN1C(=O)CNCC1=O DRETZBXCDQMKEU-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
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- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical class C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
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- 125000001931 aliphatic group Chemical group 0.000 description 4
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- 239000007864 aqueous solution Substances 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- WFNRSIKLRUTKMJ-UHFFFAOYSA-N n-[4-[[2-cyano-7-(2,2-dimethylpropyl)pyrrolo[2,3-d]pyrimidin-6-yl]methyl]phenyl]methanesulfonamide Chemical compound C=1C2=CN=C(C#N)N=C2N(CC(C)(C)C)C=1CC1=CC=C(NS(C)(=O)=O)C=C1 WFNRSIKLRUTKMJ-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
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 150000003254 radicals Chemical class 0.000 description 4
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 4
- RUVRAIGXERUAHV-UHFFFAOYSA-N tert-butyl 3,5-dioxopiperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(=O)NC(=O)C1 RUVRAIGXERUAHV-UHFFFAOYSA-N 0.000 description 4
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- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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- A—HUMAN NECESSITIES
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
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- Life Sciences & Earth Sciences (AREA)
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- Transplantation (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (3)
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| GB0121033 | 2001-08-30 | ||
| GBGB0121033.5A GB0121033D0 (en) | 2001-08-30 | 2001-08-30 | Organic compounds |
| PCT/EP2002/009663 WO2003020721A1 (en) | 2001-08-30 | 2002-08-29 | Pyrrolo pyrimidines as agents for the inhibition of cystein proteases |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE60211530D1 DE60211530D1 (de) | 2006-06-22 |
| DE60211530T2 true DE60211530T2 (de) | 2006-12-21 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE60211530T Expired - Lifetime DE60211530T2 (de) | 2001-08-30 | 2002-08-29 | Pyrrolopyrimidine als mittel zur inhibierung von cysteinproteasen |
Country Status (29)
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| HU (1) | HUP0401301A3 (enExample) |
| IL (3) | IL160367A0 (enExample) |
| MX (1) | MXPA04001935A (enExample) |
| MY (1) | MY157368A (enExample) |
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| SE0201980D0 (sv) * | 2002-06-24 | 2002-06-24 | Astrazeneca Ab | Novel compounds |
| GB0220187D0 (en) * | 2002-08-30 | 2002-10-09 | Novartis Ag | Organic compounds |
| CN102526079B (zh) | 2002-09-24 | 2014-06-18 | 诺华股份有限公司 | 治疗脱髓鞘疾病的鞘氨醇-1-磷酸受体激动剂 |
| AR043692A1 (es) * | 2003-02-06 | 2005-08-10 | Novartis Ag | 2-cianopirrolopirimidinas y sus usos farmaceuticos |
| GB0304640D0 (en) | 2003-02-28 | 2003-04-02 | Novartis Ag | Organic compounds |
| JP4710606B2 (ja) * | 2003-04-18 | 2011-06-29 | 小野薬品工業株式会社 | スピロピペリジン化合物およびその医薬用途 |
| EP1797883A3 (en) * | 2003-04-28 | 2007-08-01 | Novartis AG | Pharmaceutical composition comprising a cathepsin S inhibitor and an opioid |
| MXPA05011593A (es) * | 2003-04-28 | 2005-12-15 | Novartis Ag | Composicion farmaceutica que comprende un inhibidor de catepsina s y un opioide. |
| JP2006525336A (ja) * | 2003-04-30 | 2006-11-09 | エフ エム シー コーポレーション | フェニル置換した環状誘導体 |
| WO2005011703A1 (en) * | 2003-08-04 | 2005-02-10 | Akzo Nobel N.V. | 2-cyano-1,3,5-triazine-4,6-diamine derivatives |
| EP1786816A4 (en) * | 2003-09-10 | 2009-11-04 | Virochem Pharma Inc | SPIROHYDANTOIN COMPOUNDS AND METHODS FOR MODULATING CHEMOKINE RECEPTOR ACTIVITY |
| BRPI0507498A (pt) | 2004-02-18 | 2007-07-10 | Astrazeneca Ab | composto, composição farmacêutica, uso do composto, e, métodos para tratar distúrbios mediados por mglur 5 e para inibir ativação de receptores de mglur 5 |
| US20070197510A1 (en) * | 2004-03-10 | 2007-08-23 | Kazuyuki Ohmoto | Nitriles and medicinal compositions containing the same as the active ingredient |
| ES2251292B1 (es) * | 2004-04-20 | 2007-07-01 | Inke, S.A. | Procedimiento para la obtencion de un compuesto farmaceuticamente activo y de sus intermedios de sintesis. |
| WO2005111042A1 (en) * | 2004-05-03 | 2005-11-24 | Janssen Pharmaceutica N.V. | Novel indole derivatives as selective androgen receptor modulators (sarms) |
| TW200614993A (en) | 2004-06-11 | 2006-05-16 | Akzo Nobel Nv | 4-phenyl-pyrimidine-2-carbonitrile derivatives |
| US7951816B2 (en) | 2004-08-27 | 2011-05-31 | Ono Pharmaceutical Co., Ltd. | Compound containing basic group and use thereof |
| KR100651849B1 (ko) * | 2005-02-01 | 2006-12-01 | 엘지전자 주식회사 | 세탁기 |
| AU2006277678B2 (en) * | 2005-08-05 | 2012-04-19 | Hybrigenics Sa | Novel cysteine protease inhibitors and their therapeutic applications |
| EP1933860A2 (en) | 2005-09-01 | 2008-06-25 | Ares Trading S.A. | Treatment of optic neuritis |
| TW200745055A (en) * | 2005-09-23 | 2007-12-16 | Organon Nv | 4-Phenyl-6-substituted-pyrimidine-2-carbonitrile derivatives |
| US7326715B2 (en) | 2005-09-23 | 2008-02-05 | N.V. Organon | 4-Phenyl-6-substituted-pyrimidine-2-carbonitrile derivatives |
| AR056720A1 (es) * | 2005-10-26 | 2007-10-17 | Smithkline Beecham Corp | Compuesto de tiazol substtuido composicion farmaceuticamente que lo comprende y su uso para preparar un medicamento |
| PT1961744E (pt) | 2005-11-18 | 2013-05-15 | Ono Pharmaceutical Co | Composto que contém um grupo básico e sua utilização |
| WO2007067504A2 (en) * | 2005-12-05 | 2007-06-14 | Incyte Corporation | Lactam compounds and methods of using the same |
| US7687515B2 (en) | 2006-01-17 | 2010-03-30 | N.V. Organon | 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivatives |
| US8618122B2 (en) | 2006-05-16 | 2013-12-31 | Ono Pharmaceutical Co., Ltd. | Compound having acidic group which may be protected, and use thereof |
| JP2010503656A (ja) | 2006-09-13 | 2010-02-04 | アストラゼネカ アクチボラグ | スピロ−オキサゾリジノン化合物と代謝共役型グルタミン酸受容体ポテンシエーターとしてのその使用 |
| TW200911803A (en) * | 2007-07-16 | 2009-03-16 | Organon Nv | 6-phenyl-1H-imidazo [4,5-c] pyridine-4-carbonitrile derivatives |
| US7932251B2 (en) | 2007-07-16 | 2011-04-26 | N.V. Organon | 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivatives |
| TW200934771A (en) | 2007-10-19 | 2009-08-16 | Astrazeneca Ab | New compounds |
| EP2303250A1 (en) | 2008-06-20 | 2011-04-06 | Novartis AG | Paediatric compositions for treating1 multiple sclerosis |
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| US8026236B2 (en) | 2009-01-16 | 2011-09-27 | N.V. Organon | 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivatives |
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| WO2017203468A1 (en) | 2016-05-25 | 2017-11-30 | Inbiomotion S.L. | Therapeutic treatment of breast cancer based on c-maf status |
| AU2018372762B2 (en) | 2017-11-22 | 2025-08-21 | Inbiomotion S.L. | Therapeutic treatment of breast cancer based on c-maf status |
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| CN120053645A (zh) | 2018-06-01 | 2025-05-30 | 因赛特公司 | 治疗pi3k相关病症的给药方案 |
| EP3946332A1 (en) | 2019-04-05 | 2022-02-09 | Université de Bretagne Occidentale | Protease-activated receptor-2 inhibitors for the treatment of sensory neuropathy induced by a marine neurotoxic poisoning |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1251074B (de) * | 1960-11-02 | 1967-09-28 | J R Geigy A -G , Basel (Schweiz) | Selektives Herbizid |
| CH627919A5 (de) | 1977-04-14 | 1982-02-15 | Ciba Geigy Ag | Herbizide mittel. |
| US5958930A (en) * | 1991-04-08 | 1999-09-28 | Duquesne University Of The Holy Ghost | Pyrrolo pyrimidine and furo pyrimidine derivatives |
| ES2109796T3 (es) * | 1994-05-03 | 1998-01-16 | Ciba Geigy Ag | Derivados de pirrolopirimidilo con efecto antiproliferante. |
| US5683999A (en) * | 1995-03-17 | 1997-11-04 | The Dupont Merck Pharmaceutical Company | Cyclic urea HIV protease inhibitors |
| ATE247469T1 (de) * | 1995-06-07 | 2003-09-15 | Pfizer | Heterocyclische kondensierte pyrimidin-derivate |
| ES2202827T3 (es) * | 1997-03-19 | 2004-04-01 | ABBOTT GMBH & CO. KG | Pirrolo(2,3-d)pirimidinas y su uso como inhibidores de la tirosina kinasa. |
| DE69934311D1 (de) * | 1998-06-30 | 2007-01-18 | Lilly Co Eli | BICYCLISCHE sPLA 2-INHIBITOREN |
| PL346700A1 (en) * | 1998-09-18 | 2002-02-25 | Basf Ag | Pyrrolopyrimidines as protein kinase inhibitors |
| GEP20053479B (en) * | 1999-12-10 | 2005-03-25 | Pfizer Prod Inc | Pyrrolo[2,3-d]Pyrimidine Compounds, Pharmaceutical Composition Containing the Same and Use |
| CA2402516A1 (en) * | 2000-03-20 | 2001-09-27 | Roopa Rai | Non-amidine containing protease inhibitors |
| CN1657523A (zh) | 2000-04-28 | 2005-08-24 | 田边制药株式会社 | 环状化合物 |
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