NZ531343A - Pyrrolo pyrimidines as agents for the inhibition of cystein proteases - Google Patents
Pyrrolo pyrimidines as agents for the inhibition of cystein proteasesInfo
- Publication number
- NZ531343A NZ531343A NZ531343A NZ53134302A NZ531343A NZ 531343 A NZ531343 A NZ 531343A NZ 531343 A NZ531343 A NZ 531343A NZ 53134302 A NZ53134302 A NZ 53134302A NZ 531343 A NZ531343 A NZ 531343A
- Authority
- NZ
- New Zealand
- Prior art keywords
- acoet
- heterocyclyl
- lower alkyl
- hexane
- aryl
- Prior art date
Links
- 230000005764 inhibitory process Effects 0.000 title description 6
- 239000003795 chemical substances by application Substances 0.000 title description 3
- 102000035195 Peptidases Human genes 0.000 title description 2
- 108091005804 Peptidases Proteins 0.000 title description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 title description 2
- 150000004944 pyrrolopyrimidines Chemical class 0.000 title description 2
- 239000004365 Protease Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 145
- 150000003839 salts Chemical class 0.000 claims abstract description 26
- 102000004171 Cathepsin K Human genes 0.000 claims abstract description 21
- 108090000625 Cathepsin K Proteins 0.000 claims abstract description 21
- 150000002148 esters Chemical class 0.000 claims abstract description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 18
- 201000010099 disease Diseases 0.000 claims abstract description 17
- -1 lower-alkylsulphonyl Chemical group 0.000 claims description 207
- 125000000217 alkyl group Chemical group 0.000 claims description 88
- 238000000034 method Methods 0.000 claims description 69
- 125000005843 halogen group Chemical group 0.000 claims description 37
- 125000003118 aryl group Chemical group 0.000 claims description 34
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 claims description 26
- 238000002360 preparation method Methods 0.000 claims description 25
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 23
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 19
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- 125000004043 oxo group Chemical group O=* 0.000 claims description 13
- 229920006395 saturated elastomer Polymers 0.000 claims description 13
- 125000001424 substituent group Chemical group 0.000 claims description 13
- 125000000623 heterocyclic group Chemical group 0.000 claims description 12
- 125000004104 aryloxy group Chemical group 0.000 claims description 11
- CYJAWBVQRMVFEO-UHFFFAOYSA-N piperazine-2,6-dione Chemical compound O=C1CNCC(=O)N1 CYJAWBVQRMVFEO-UHFFFAOYSA-N 0.000 claims description 11
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 9
- 125000003435 aroyl group Chemical group 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
- 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
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 229910052757 nitrogen 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
- 229910020008 S(O) Inorganic materials 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 claims description 6
- 238000011321 prophylaxis Methods 0.000 claims description 6
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 5
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000000304 alkynyl 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
- 125000002619 bicyclic group Chemical group 0.000 claims description 4
- 125000002837 carbocyclic group Chemical group 0.000 claims description 4
- 230000008878 coupling Effects 0.000 claims description 4
- 238000010168 coupling process Methods 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
- 125000005257 alkyl acyl group Chemical group 0.000 claims description 3
- 125000005251 aryl acyl group Chemical group 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 125000003003 spiro group Chemical group 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
- 125000004453 alkoxycarbonyl 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
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 230000001225 therapeutic effect Effects 0.000 claims description 2
- IZOKUQXPKFAZPF-UHFFFAOYSA-N 9-(cyclohexylmethyl)-8-[[4-(4-ethoxyphenyl)piperazin-1-yl]methyl]purine-2-carbonitrile Chemical compound C1=CC(OCC)=CC=C1N1CCN(CC=2N(C3=NC(=NC=C3N=2)C#N)CC2CCCCC2)CC1 IZOKUQXPKFAZPF-UHFFFAOYSA-N 0.000 claims 1
- 208000001132 Osteoporosis Diseases 0.000 abstract description 8
- 206010028980 Neoplasm Diseases 0.000 abstract description 6
- 239000003112 inhibitor Substances 0.000 abstract description 6
- 201000008482 osteoarthritis Diseases 0.000 abstract description 6
- 206010039073 rheumatoid arthritis Diseases 0.000 abstract description 6
- 206010061218 Inflammation Diseases 0.000 abstract description 4
- 230000004054 inflammatory process Effects 0.000 abstract description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 659
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 588
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 437
- 239000000203 mixture Substances 0.000 description 160
- 239000011541 reaction mixture Substances 0.000 description 138
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 124
- 239000000243 solution Substances 0.000 description 123
- 229910001868 water Inorganic materials 0.000 description 115
- 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 101
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 100
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 100
- 238000005481 NMR spectroscopy Methods 0.000 description 88
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 88
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 88
- 239000002904 solvent Substances 0.000 description 86
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 79
- IIHQNAXFIODVDU-UHFFFAOYSA-N pyrimidine-2-carbonitrile Chemical compound N#CC1=NC=CC=N1 IIHQNAXFIODVDU-UHFFFAOYSA-N 0.000 description 78
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 69
- 239000000284 extract Substances 0.000 description 66
- 238000010898 silica gel chromatography Methods 0.000 description 65
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 61
- 239000000047 product Substances 0.000 description 60
- 238000005160 1H NMR spectroscopy Methods 0.000 description 59
- 239000012044 organic layer Substances 0.000 description 59
- 239000007858 starting material Substances 0.000 description 59
- 239000000741 silica gel Substances 0.000 description 53
- 229910002027 silica gel Inorganic materials 0.000 description 53
- 229960001866 silicon dioxide Drugs 0.000 description 53
- 229910000027 potassium carbonate Inorganic materials 0.000 description 51
- 230000002829 reductive effect Effects 0.000 description 51
- 235000019341 magnesium sulphate Nutrition 0.000 description 50
- 239000012043 crude product Substances 0.000 description 47
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 44
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 38
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 35
- 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
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 31
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 30
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 29
- 101150041968 CDC13 gene Proteins 0.000 description 26
- 229940086542 triethylamine Drugs 0.000 description 26
- 239000012299 nitrogen atmosphere Substances 0.000 description 25
- 235000015320 potassium carbonate Nutrition 0.000 description 25
- 235000011181 potassium carbonates Nutrition 0.000 description 25
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 25
- 239000002253 acid Substances 0.000 description 23
- 238000004440 column chromatography Methods 0.000 description 20
- 238000004587 chromatography analysis Methods 0.000 description 19
- 125000004093 cyano group Chemical group *C#N 0.000 description 19
- 238000000746 purification Methods 0.000 description 19
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 19
- 239000000725 suspension Substances 0.000 description 19
- LELOWRISYMNNSU-UHFFFAOYSA-N Hydrocyanic acid Natural products N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 18
- JJTNLWSCFYERCK-UHFFFAOYSA-N 7h-pyrrolo[2,3-d]pyrimidine Chemical compound N1=CN=C2NC=CC2=C1 JJTNLWSCFYERCK-UHFFFAOYSA-N 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
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- 229940093499 ethyl acetate Drugs 0.000 description 15
- 239000000706 filtrate 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
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 13
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 11
- 125000004432 carbon atom Chemical group C* 0.000 description 11
- 229910000104 sodium hydride Inorganic materials 0.000 description 11
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 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 9
- 238000001914 filtration Methods 0.000 description 9
- 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 9
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 241000124008 Mammalia Species 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- 238000011282 treatment Methods 0.000 description 8
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 7
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 7
- 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 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical class C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 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
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Chemical class COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 125000004076 pyridyl group Chemical group 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 125000003106 haloaryl group Chemical group 0.000 description 5
- 229910052736 halogen Inorganic materials 0.000 description 5
- 150000002367 halogens Chemical class 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- 150000002466 imines Chemical class 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 5
- 125000004999 nitroaryl group Chemical group 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
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 5
- HCNCYKRNISOPIX-UHFFFAOYSA-N 4-(2-fluoro-4-hydroxyphenyl)piperazine-1-carboxylic acid Chemical compound C1CN(C(=O)O)CCN1C1=CC=C(O)C=C1F HCNCYKRNISOPIX-UHFFFAOYSA-N 0.000 description 4
- 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 4
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- 101000761509 Homo sapiens Cathepsin K Proteins 0.000 description 4
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical class C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
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- 102000049698 human CTSK Human genes 0.000 description 4
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- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Chemical class C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
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- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 4
- 150000003254 radicals Chemical class 0.000 description 4
- 238000004007 reversed phase HPLC Methods 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 125000001425 triazolyl group Chemical group 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- CYNYIHKIEHGYOZ-UHFFFAOYSA-N 1-bromopropane Chemical compound CCCBr CYNYIHKIEHGYOZ-UHFFFAOYSA-N 0.000 description 3
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- VWYHJCRJHOEEEK-UHFFFAOYSA-N 2-(difluoromethyl)-1h-pyridin-4-one Chemical compound OC1=CC=NC(C(F)F)=C1 VWYHJCRJHOEEEK-UHFFFAOYSA-N 0.000 description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 3
- VURIYIYAKMLWMZ-UHFFFAOYSA-N 4-benzylpiperazine-2,6-dione Chemical compound C1C(=O)NC(=O)CN1CC1=CC=CC=C1 VURIYIYAKMLWMZ-UHFFFAOYSA-N 0.000 description 3
- SIKXIUWKPGWBBF-UHFFFAOYSA-N 5-bromo-2,4-dichloropyrimidine Chemical compound ClC1=NC=C(Br)C(Cl)=N1 SIKXIUWKPGWBBF-UHFFFAOYSA-N 0.000 description 3
- 125000004938 5-pyridyl group Chemical group N1=CC=CC(=C1)* 0.000 description 3
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 3
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- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical compound OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 description 1
- NGKSKVYWPINGLI-UHFFFAOYSA-N prop-2-ynylbenzene Chemical compound C#CCC1=CC=CC=C1 NGKSKVYWPINGLI-UHFFFAOYSA-N 0.000 description 1
- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 1
- WHMDPDGBKYUEMW-UHFFFAOYSA-N pyridine-2-thiol Chemical compound SC1=CC=CC=N1 WHMDPDGBKYUEMW-UHFFFAOYSA-N 0.000 description 1
- 125000005554 pyridyloxy group Chemical group 0.000 description 1
- 150000003235 pyrrolidines Chemical class 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 201000004409 schistosomiasis Diseases 0.000 description 1
- 238000013077 scoring method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 description 1
- 229960002218 sodium chlorite Drugs 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 229910052979 sodium sulfide Inorganic materials 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- 125000001174 sulfone group Chemical group 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- UUKKQQKEPIXSKN-UHFFFAOYSA-N tert-butyl 4-(6-fluoropyridin-3-yl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1=CC=C(F)N=C1 UUKKQQKEPIXSKN-UHFFFAOYSA-N 0.000 description 1
- NWSNCNVCDPBGAR-UHFFFAOYSA-N tert-butyl 4-[[2-cyano-7-(2,2-dimethylpropyl)pyrrolo[2,3-d]pyrimidin-6-yl]methyl]-3,5-dioxopiperazine-1-carboxylate Chemical compound C=1C2=CN=C(C#N)N=C2N(CC(C)(C)C)C=1CN1C(=O)CN(C(=O)OC(C)(C)C)CC1=O NWSNCNVCDPBGAR-UHFFFAOYSA-N 0.000 description 1
- FQKMRIJPQXEDTO-UHFFFAOYSA-N tert-butyl n-(4-prop-2-ynylphenyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=C(CC#C)C=C1 FQKMRIJPQXEDTO-UHFFFAOYSA-N 0.000 description 1
- DEGRJODPOICGRU-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate;hydrochloride Chemical compound Cl.CC(C)(C)OC(=O)N1CCNCC1 DEGRJODPOICGRU-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000005309 thioalkoxy group Chemical group 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 150000003628 tricarboxylic acids Chemical class 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- 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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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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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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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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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)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
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- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Life Sciences & Earth Sciences (AREA)
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- Hematology (AREA)
- Urology & Nephrology (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 (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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 (1)
| Publication Number | Publication Date |
|---|---|
| NZ531343A true NZ531343A (en) | 2006-01-27 |
Family
ID=9921234
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NZ531343A NZ531343A (en) | 2001-08-30 | 2002-08-29 | Pyrrolo pyrimidines as agents for the inhibition of cystein proteases |
Country Status (29)
| Country | Link |
|---|---|
| US (2) | US7452886B2 (enExample) |
| EP (1) | EP1423391B8 (enExample) |
| JP (1) | JP4629334B2 (enExample) |
| KR (1) | KR100695845B1 (enExample) |
| CN (1) | CN100372849C (enExample) |
| AR (1) | AR036374A1 (enExample) |
| AT (1) | ATE326469T1 (enExample) |
| AU (1) | AU2002333760B2 (enExample) |
| BR (1) | BR0212226A (enExample) |
| CA (1) | CA2458684C (enExample) |
| CY (1) | CY1105573T1 (enExample) |
| DE (1) | DE60211530T2 (enExample) |
| DK (1) | DK1423391T3 (enExample) |
| EC (1) | ECSP044998A (enExample) |
| ES (1) | ES2262888T3 (enExample) |
| GB (1) | GB0121033D0 (enExample) |
| HU (1) | HUP0401301A3 (enExample) |
| IL (3) | IL160367A0 (enExample) |
| MX (1) | MXPA04001935A (enExample) |
| MY (1) | MY157368A (enExample) |
| NO (1) | NO328890B1 (enExample) |
| NZ (1) | NZ531343A (enExample) |
| PE (1) | PE20030418A1 (enExample) |
| PL (1) | PL368280A1 (enExample) |
| PT (1) | PT1423391E (enExample) |
| RU (1) | RU2331644C2 (enExample) |
| TW (1) | TWI297690B (enExample) |
| WO (1) | WO2003020721A1 (enExample) |
| ZA (1) | ZA200401042B (enExample) |
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| 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 |
| EP1619193A4 (en) * | 2003-04-18 | 2010-08-11 | Ono Pharmaceutical Co | SPIROPIPERIDINE COMPOUND AND MEDICINAL USE THEREOF |
| WO2004096227A1 (en) * | 2003-04-28 | 2004-11-11 | Novartis Ag | Pharmaceutical compositon comprising a cathepsin s inhibitor and an opioid |
| EP1797883A3 (en) * | 2003-04-28 | 2007-08-01 | Novartis AG | Pharmaceutical composition comprising a cathepsin S inhibitor and an opioid |
| ATE434612T1 (de) * | 2003-04-30 | 2009-07-15 | Bayer Cropscience Ag | Insektizide (dihalopropenyl)phenylalkyl substituierte dihydrobenzofuran- und dihydrobenzopyran-derivate |
| WO2005011703A1 (en) * | 2003-08-04 | 2005-02-10 | Akzo Nobel N.V. | 2-cyano-1,3,5-triazine-4,6-diamine derivatives |
| CA2579609A1 (en) | 2003-09-10 | 2005-03-17 | Virochem Pharma Inc. | Spirohydantoin compounds and methods for the modulation of chemokine receptor activity |
| WO2005080356A1 (en) | 2004-02-18 | 2005-09-01 | Astrazeneca Ab | Tetrazole compounds and their use as metabotropic glutamate receptor antagonits |
| EP1724264A1 (en) * | 2004-03-10 | 2006-11-22 | Ono Pharmaceutical Co., Ltd. | 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. |
| CA2564953A1 (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 |
| RU2424234C2 (ru) * | 2005-08-05 | 2011-07-20 | Ибриженикс Са | Новые ингибиторы цистеиновых протеаз и их терапевтическое применение |
| 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 |
| TW200732314A (en) * | 2005-10-26 | 2007-09-01 | Smithkline Beecham Corp | Substituted thiazoles and their use |
| PT1961744E (pt) | 2005-11-18 | 2013-05-15 | Ono Pharmaceutical Co | Composto que contém um grupo básico e sua utilização |
| EA200870019A1 (ru) * | 2005-12-05 | 2008-12-30 | Инсайт Корпорейшн | Лактамовые соединения и способы их применения |
| 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 |
| BRPI0818448A2 (pt) | 2007-10-19 | 2015-05-12 | Astrazeneca Ab | Composto, composição farmacêutica, uso de um composto, e, métodos para o tratamento ou prevenção de um distúrbio madiano pelo receptor mglur5. |
| WO2009155475A1 (en) | 2008-06-20 | 2009-12-23 | Novartis Ag | Paediatric compositions for treating1 multiple sclerosis |
| TW201035094A (en) | 2009-01-16 | 2010-10-01 | Organon Nv | 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivatives |
| 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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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL270922A (enExample) | 1960-11-02 | |||
| 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 |
| CA2223081C (en) * | 1995-06-07 | 2001-03-06 | Pfizer Inc. | Heterocyclic ring-fused pyrimidine derivatives |
| BR9808281A (pt) * | 1997-03-19 | 2000-05-16 | Basf Ag | Compostos, composições farmacêuticas, processo para tratar doenças proliferativas e/ou distúrbios do sistema imune e para preparar um composto, e, uso de um composto |
| DE69934311D1 (de) * | 1998-06-30 | 2007-01-18 | Lilly Co Eli | BICYCLISCHE sPLA 2-INHIBITOREN |
| NZ510588A (en) * | 1998-09-18 | 2003-08-29 | Abbott Gmbh & Co | Pyrrolopyrimidines as protein kinase inhibitors |
| OA12118A (en) * | 1999-12-10 | 2006-05-04 | Pfizer Prod Inc | PyrroloÄ2,3-dÜpyrimidine compounds. |
| US20030225036A1 (en) * | 2000-03-20 | 2003-12-04 | Aleksandr Kolesnikov | Non-amidine containing protease inhibitors |
| KR100711042B1 (ko) | 2000-04-28 | 2007-04-24 | 다나베 세이야꾸 가부시키가이샤 | 환상 화합물 |
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