ZA200302190B - Spiro-pyrimidine-2, 4, 6-trione metalloproteinase inhibitors. - Google Patents
Spiro-pyrimidine-2, 4, 6-trione metalloproteinase inhibitors. Download PDFInfo
- Publication number
- ZA200302190B ZA200302190B ZA200302190A ZA200302190A ZA200302190B ZA 200302190 B ZA200302190 B ZA 200302190B ZA 200302190 A ZA200302190 A ZA 200302190A ZA 200302190 A ZA200302190 A ZA 200302190A ZA 200302190 B ZA200302190 B ZA 200302190B
- Authority
- ZA
- South Africa
- Prior art keywords
- alkyl
- group
- ring
- spiro
- cio
- Prior art date
Links
- 239000003475 metalloproteinase inhibitor Substances 0.000 title description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 38
- -1 4-Ethyl-phenoxy Chemical group 0.000 claims description 35
- 125000000217 alkyl group Chemical group 0.000 claims description 34
- 125000001424 substituent group Chemical group 0.000 claims description 33
- 125000001072 heteroaryl group Chemical group 0.000 claims description 31
- 150000001875 compounds Chemical class 0.000 claims description 26
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 22
- 229910052760 oxygen Inorganic materials 0.000 claims description 22
- 239000001301 oxygen Substances 0.000 claims description 22
- 125000003118 aryl group Chemical group 0.000 claims description 21
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 18
- 125000003545 alkoxy group Chemical group 0.000 claims description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims description 15
- 229910052799 carbon Inorganic materials 0.000 claims description 14
- 229910052794 bromium Inorganic materials 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 13
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 12
- 239000000460 chlorine Substances 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 12
- 125000005010 perfluoroalkyl group Chemical group 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 239000011593 sulfur Substances 0.000 claims description 12
- 102000002274 Matrix Metalloproteinases Human genes 0.000 claims description 11
- 108010000684 Matrix Metalloproteinases Proteins 0.000 claims description 11
- 229920001774 Perfluoroether Polymers 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 125000005330 8 membered heterocyclic group Chemical group 0.000 claims description 6
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 208000035475 disorder Diseases 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 125000000304 alkynyl group Chemical group 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000002837 carbocyclic group Chemical group 0.000 claims description 2
- 150000001721 carbon Chemical group 0.000 claims description 2
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 230000005764 inhibitory process Effects 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 241000124008 Mammalia Species 0.000 claims 3
- 208000024172 Cardiovascular disease Diseases 0.000 claims 2
- 208000035473 Communicable disease Diseases 0.000 claims 2
- 208000012895 Gastric disease Diseases 0.000 claims 2
- 206010020751 Hypersensitivity Diseases 0.000 claims 2
- 208000000453 Skin Neoplasms Diseases 0.000 claims 2
- 208000026935 allergic disease Diseases 0.000 claims 2
- 230000007815 allergy Effects 0.000 claims 2
- 208000015114 central nervous system disease Diseases 0.000 claims 2
- 208000018631 connective tissue disease Diseases 0.000 claims 2
- 239000003937 drug carrier Substances 0.000 claims 2
- 208000030533 eye disease Diseases 0.000 claims 2
- 208000027866 inflammatory disease Diseases 0.000 claims 2
- 208000017169 kidney disease Diseases 0.000 claims 2
- 210000004185 liver Anatomy 0.000 claims 2
- 208000019423 liver disease Diseases 0.000 claims 2
- 208000030159 metabolic disease Diseases 0.000 claims 2
- 230000009933 reproductive health Effects 0.000 claims 2
- 208000023504 respiratory system disease Diseases 0.000 claims 2
- 208000017520 skin disease Diseases 0.000 claims 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims 2
- FPGLDNOEDDIHDV-UHFFFAOYSA-N 1-[6-(4-bromophenoxy)pyridin-3-yl]-1,7,9-triazaspiro[4.5]decane-2,6,8,10-tetrone Chemical compound C1=CC(Br)=CC=C1OC1=CC=C(N2C3(C(NC(=O)NC3=O)=O)CCC2=O)C=N1 FPGLDNOEDDIHDV-UHFFFAOYSA-N 0.000 claims 1
- XTGSXSLCZLEGOR-UHFFFAOYSA-N 1-[6-(4-fluorophenoxy)pyridin-3-yl]-1,7,9-triazaspiro[4.5]decane-2,6,8,10-tetrone Chemical compound C1=CC(F)=CC=C1OC1=CC=C(N2C3(C(NC(=O)NC3=O)=O)CCC2=O)C=N1 XTGSXSLCZLEGOR-UHFFFAOYSA-N 0.000 claims 1
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims 1
- TXWOGHSRPAYOML-UHFFFAOYSA-N cyclobutanecarboxylic acid Chemical compound OC(=O)C1CCC1 TXWOGHSRPAYOML-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims 1
- 125000004076 pyridyl group Chemical group 0.000 description 24
- 125000000714 pyrimidinyl group Chemical group 0.000 description 18
- 125000003373 pyrazinyl group Chemical group 0.000 description 17
- 125000002098 pyridazinyl group Chemical group 0.000 description 17
- 125000002883 imidazolyl group Chemical group 0.000 description 12
- 125000001786 isothiazolyl group Chemical group 0.000 description 12
- 125000000842 isoxazolyl group Chemical group 0.000 description 12
- 125000003226 pyrazolyl group Chemical group 0.000 description 12
- 125000001715 oxadiazolyl group Chemical group 0.000 description 11
- 125000002971 oxazolyl group Chemical group 0.000 description 11
- 239000002253 acid Substances 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 125000000168 pyrrolyl group Chemical group 0.000 description 7
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 6
- 125000004601 benzofurazanyl group Chemical group N1=C2C(=NO1)C(=CC=C2)* 0.000 description 6
- HAVZTGSQJIEKPI-UHFFFAOYSA-N benzothiadiazine Chemical compound C1=CC=C2C=NNSC2=C1 HAVZTGSQJIEKPI-UHFFFAOYSA-N 0.000 description 6
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 6
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 6
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 6
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 6
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 6
- 125000003838 furazanyl group Chemical group 0.000 description 6
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 6
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 6
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 6
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 6
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 6
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 6
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 6
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 6
- 125000003831 tetrazolyl group Chemical group 0.000 description 6
- 125000001544 thienyl group Chemical group 0.000 description 6
- 125000004306 triazinyl group Chemical group 0.000 description 6
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 5
- 239000011575 calcium Substances 0.000 description 5
- 125000002541 furyl group Chemical group 0.000 description 5
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 5
- 125000001041 indolyl group Chemical group 0.000 description 5
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 5
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 5
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 5
- 125000001113 thiadiazolyl group Chemical group 0.000 description 5
- 125000000335 thiazolyl group Chemical group 0.000 description 5
- 125000001425 triazolyl group Chemical group 0.000 description 5
- 229940124761 MMP inhibitor Drugs 0.000 description 4
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 4
- 210000000845 cartilage Anatomy 0.000 description 4
- 125000004612 furopyridinyl group Chemical group O1C(=CC2=C1C=CC=N2)* 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- 102100030411 Neutrophil collagenase Human genes 0.000 description 3
- 101710118230 Neutrophil collagenase Proteins 0.000 description 3
- 125000004104 aryloxy group Chemical group 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- VKUYLANQOAKALN-UHFFFAOYSA-N 2-[benzyl-(4-methoxyphenyl)sulfonylamino]-n-hydroxy-4-methylpentanamide Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)N(C(CC(C)C)C(=O)NO)CC1=CC=CC=C1 VKUYLANQOAKALN-UHFFFAOYSA-N 0.000 description 2
- 102100026802 72 kDa type IV collagenase Human genes 0.000 description 2
- 101710151806 72 kDa type IV collagenase Proteins 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- 102000008186 Collagen Human genes 0.000 description 2
- 108010035532 Collagen Proteins 0.000 description 2
- 102100027995 Collagenase 3 Human genes 0.000 description 2
- 108050005238 Collagenase 3 Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 102100027998 Macrophage metalloelastase Human genes 0.000 description 2
- 101710187853 Macrophage metalloelastase Proteins 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 102100030416 Stromelysin-1 Human genes 0.000 description 2
- 101710108790 Stromelysin-1 Proteins 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 229920001436 collagen Polymers 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000003349 osteoarthritic effect Effects 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- NDQQRRVKUBPTHQ-QBIQUQHTSA-N (2r,3r,4r,5s)-6-(methylamino)hexane-1,2,3,4,5-pentol Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO NDQQRRVKUBPTHQ-QBIQUQHTSA-N 0.000 description 1
- DKYBVKMIZODYKL-UHFFFAOYSA-N 1,3-diazinane Chemical compound C1CNCNC1 DKYBVKMIZODYKL-UHFFFAOYSA-N 0.000 description 1
- JPRPJUMQRZTTED-UHFFFAOYSA-N 1,3-dioxolanyl Chemical group [CH]1OCCO1 JPRPJUMQRZTTED-UHFFFAOYSA-N 0.000 description 1
- HKDFRDIIELOLTJ-UHFFFAOYSA-N 1,4-dithianyl Chemical group [CH]1CSCCS1 HKDFRDIIELOLTJ-UHFFFAOYSA-N 0.000 description 1
- WYLSGWZVDHQRNX-UHFFFAOYSA-N 2-(3,4-dimethoxy-n-(4-methylphenyl)sulfonylanilino)-n-(2,4-dimethylpentan-3-yl)acetamide Chemical group C1=C(OC)C(OC)=CC=C1N(CC(=O)NC(C(C)C)C(C)C)S(=O)(=O)C1=CC=C(C)C=C1 WYLSGWZVDHQRNX-UHFFFAOYSA-N 0.000 description 1
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 1
- 125000001698 2H-pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-M 3-carboxy-2,3-dihydroxypropanoate Chemical compound OC(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-M 0.000 description 1
- 125000004364 3-pyrrolinyl group Chemical group [H]C1=C([H])C([H])([H])N(*)C1([H])[H] 0.000 description 1
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000001826 4H-pyranyl group Chemical group O1C(=CCC=C1)* 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- DSLZVSRJTYRBFB-LLEIAEIESA-N D-glucaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O DSLZVSRJTYRBFB-LLEIAEIESA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 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
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 101001011896 Homo sapiens Matrix metalloproteinase-19 Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000012659 Joint disease Diseases 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 102100030417 Matrilysin Human genes 0.000 description 1
- 108090000855 Matrilysin Proteins 0.000 description 1
- 102000000380 Matrix Metalloproteinase 1 Human genes 0.000 description 1
- 108010016113 Matrix Metalloproteinase 1 Proteins 0.000 description 1
- 108010076557 Matrix Metalloproteinase 14 Proteins 0.000 description 1
- 102100030216 Matrix metalloproteinase-14 Human genes 0.000 description 1
- 102100030201 Matrix metalloproteinase-15 Human genes 0.000 description 1
- 108090000560 Matrix metalloproteinase-15 Proteins 0.000 description 1
- 102100030200 Matrix metalloproteinase-16 Human genes 0.000 description 1
- 108090000561 Matrix metalloproteinase-16 Proteins 0.000 description 1
- 102100030219 Matrix metalloproteinase-17 Human genes 0.000 description 1
- 108090000585 Matrix metalloproteinase-17 Proteins 0.000 description 1
- 102100030218 Matrix metalloproteinase-19 Human genes 0.000 description 1
- 108090000587 Matrix metalloproteinase-19 Proteins 0.000 description 1
- 102000004055 Matrix metalloproteinase-19 Human genes 0.000 description 1
- 102100029693 Matrix metalloproteinase-20 Human genes 0.000 description 1
- 108090000609 Matrix metalloproteinase-20 Proteins 0.000 description 1
- 102100030412 Matrix metalloproteinase-9 Human genes 0.000 description 1
- 108010015302 Matrix metalloproteinase-9 Proteins 0.000 description 1
- 102000003843 Metalloendopeptidases Human genes 0.000 description 1
- 108090000131 Metalloendopeptidases Proteins 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102100028848 Stromelysin-2 Human genes 0.000 description 1
- 101710108792 Stromelysin-2 Proteins 0.000 description 1
- 102100028847 Stromelysin-3 Human genes 0.000 description 1
- 108050005271 Stromelysin-3 Proteins 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 101001011890 Xenopus laevis Matrix metalloproteinase-18 Proteins 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001336 alkenes Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 150000007656 barbituric acids Chemical class 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000002527 bicyclic carbocyclic group Chemical group 0.000 description 1
- BVCRERJDOOBZOH-UHFFFAOYSA-N bicyclo[2.2.1]heptanyl Chemical group C1C[C+]2CC[C-]1C2 BVCRERJDOOBZOH-UHFFFAOYSA-N 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 1
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 1
- 125000005057 dihydrothienyl group Chemical group S1C(CC=C1)* 0.000 description 1
- 125000000532 dioxanyl group Chemical group 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 125000005553 heteroaryloxy group Chemical group 0.000 description 1
- 125000004634 hexahydroazepinyl group Chemical group N1(CCCCCC1)* 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000003965 isoxazolidinyl group Chemical group 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000003771 matrix metalloproteinase inhibitor Substances 0.000 description 1
- 229940121386 matrix metalloproteinase inhibitor Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 125000005503 thioxanyl group Chemical group 0.000 description 1
- 230000008427 tissue turnover Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000005455 trithianyl group Chemical group 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/04—Drugs for genital or sexual disorders; Contraceptives for inducing labour or abortion; Uterotonics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/06—Antiabortive agents; Labour repressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/16—Masculine contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/18—Feminine contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/16—Emollients or protectives, e.g. against radiation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/06—Antimalarials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
-
- 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
- C07D487/10—Spiro-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Immunology (AREA)
- Reproductive Health (AREA)
- Endocrinology (AREA)
- Rheumatology (AREA)
- Oncology (AREA)
- Pain & Pain Management (AREA)
- Communicable Diseases (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Dermatology (AREA)
- Diabetes (AREA)
- Pulmonology (AREA)
- Gynecology & Obstetrics (AREA)
- Hematology (AREA)
- Ophthalmology & Optometry (AREA)
- Cardiology (AREA)
- Virology (AREA)
- Pregnancy & Childbirth (AREA)
- Tropical Medicine & Parasitology (AREA)
- Heart & Thoracic Surgery (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
Description
Background of the fnvention
The present invention relates to S5-spiro-pyrimidine-2,4,6-trione metalloproteinase inhibitors and to pharmaceutical compositions and methods of treatment of inflammation, cancer and other disorders.
The compounds of the present invention are inhibitors of zinc metalloendopeptidases, especially those belonging to the class of matrix metalloproteinases (also called MMP or matrixin),
The MMP subfamily of enzymes, currently contains seventeen members (MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-8, MMP-10, MMP-11, MMP-12, MMP-13, MMP-14,
MMP-15, MMP-16, MMP-17, MMP-18, MMP-19, MMP-20). The MMP’s are most well known for their role in regulating the turn-over of extracellular matrix proteins and as such play important roles in normal physiological processes such as reproduction, development and differentiation. In addition, the MMP's are expressed in many pathological situations in which abnormal connective tissue turnover is occurring. For example, MMP-13 an enzyme with potent activity at degrading type il collagen (the principal collagen in cartilage), has been demonstrated to be overexpressed in osteoarthritic cartilage (Mitchell, et al., J. Clin. invest. 97, 761 (1996)). Other MMPs (MMP-2, MMP-3, MMP-8, MMP-9, MMP-12) are aiso overexpressed in osteoarthritic cartilage and inhibition of some or all of these MMP's is expected to slow or block the accelerated loss of cartilage typical of joint diseases such as osteoarthritis or rheumatoid arthritis.
It is recognized that different combinations of MMP's are expressed in different pathological situations. As such, inhibitors with specific selectivities for individual MMP's may be preferred for individual diseases.
Matrix metalloproteinase inhibitors are well known in the literature. Hydroxamic acid
MMP inhibitors are exemplified in European Patent Publication 606,046, published July 13, 1994. Several pyrimidine-2,4,6-trione MMP inhibitors are referred to in PCT publication WO 98/58925, published December 30, 1998. PCT publication WO 00/475865, published August 17, 2000 refers to certain aryl substituted pyrimidine-2,4,6-trione MMP inhibitors. United
States Non-provisional application 09/635156, filed August 8, 2000 (which claims priority to
United States Provisional application 60/148547 filed August 12, 1999) refers to heteroaryl ) substituted pyrimidine-2,4,6-trione MMP inhibitors. United States Provisional Application " entitled “Pyrimidine-2,4,6-trione Metalloproteinase Inhibitors”, filed October 26, 2000, refers to . certain pyrimidine-2,4,6-triones. Barbituric acids and methods for their preparation are well known in the art, see for example Goodman and Gilman's, “The Phamacological Basis of
Therapeutics,” 345-382 (Eighth Edition, McGraw Hill, 1990). Each of the above referenced publications and applications is hereby incorporated by reference in its entirety.
The present invention relates to compounds of the formula: . H 0 Tyee
N o=(
N A
0) I : wherein said "A" is a 5-7 membered heterocyclic ring selected from the group consisting of:
X-Y-Z-G
X-Y-Z-G b) X-Y-Z-G 0 | o a) | o | 0 Rs
N Re & N rR! NE R® . ’ 3 2 7 3 RE TR ZR 2 . ’ 6 6 rR R ' R'Z2 R® R RRR’ R™
Y-2- X-Y-Z-G d) X-Y-Z-G e) X26 f) 9
Lp | 2 2
N— nA _R° N"N R" $ N—R® : N Rr ox R" 11 . . - 6 rR" R ; R' I Ro : R' Rr? RS R :
X-Y-Z-G
X-Y-Z-G X-Y-Z-G i 9) | h) | ) | rR? 3
N—S0, N-SO, _R N SOR . é L” R J rR3 p R
Sy R® k= T~R® LR . : 1 R® N
R' RZ R' R2 R® R R? RS
X-Y-Z-G
No XYZ6 X-Y-2-G ) R o10 j)] R 10 R 13 rR! R R 8 12
R' N R N R
N 6 ) 7 \ 8
R Z, ' R IY) R - 5 a [3 / R’
R 1 R 1 R®
YR 5 R 5 ; R ;
RR rR* R R® RS
, m) ree n) Te 0) X-Y-Z-G 0 rs < NA 5 NK N R®
DN NR NT and Lon
SO, RZ 0 o wherein each of R', R% R®, RY, R°, R®, R’, R®, R%, R"™, R", R™ and Ris independently selected from the group consisting of hydrogen, (C4-C,)alkyl, (C4-C,)alkenyl, (C4-Cylalkynyl, (Ce-Cyo)aryl, (Ci-Cio)heteroaryl, (Cs-Cg)cycloalkyl and (C,-Cyp)heterocyclyl; wherein each of said (C-Cy)alkyl, (Cs-Cio)aryl, (Ci-Cio)heteroaryl, (Cs-Cs)cycioalkyl and (Cs-
Cio)heterocyclyl may be optionally substituted on any of the ring carbon atoms capable of forming an additional bond with 1-3 substituents per ring independently selected from halo, (C1-Cy)alkyl, (C4-Cy)alkoxy, -CN, -OH and —NH,;
X is (Ce-C1p)aryl or (Cy-Cio)heteroaryl;
Y is selected from the group consisting of a bond, oxygen, sulfur, >C=0, >S0,, >S=0, -CHy-, -CH,0-, -O(CHjy),-, -CH,S-, -S{CH,),-, -CH2S0-, -CH,S0,-, -SO(CH;),-, -S0,(CHy)e-, -NR™, -NR™(CH,)p-, -CHa[N(R')]-, -CHp(CHy)y-, -CH=CH-, -C=C-, -[N(R"'*)]-SO,- and -SON(R™)}-; n is an integer from one to four;
R™ is hydrogen or (C,-C,)alkyl;
Z is selected from the group consisting of (Ce-Cyplaryl, (Cs-Cs)cycloalkyl, (Cs-
Cqo)heterocyclyl and (C4-Cig)heteroaryl; wherein one or two carbon-carbon single bonds of said (C3-Cg)cycioalkyl or (C4-Cip)heterocyclyl may optionally be replaced by carbon-carbon double bonds; wherein each of said X or Z may be independently optionally substituted on any of the ring carbon atoms capable of forming an additional bond by one or two substituents per ring independently selected from F, Cl, Br, CN, OH, (C4-Cs)alkyl, (C4-Cs)perfluoroalkyl, (C,-
C.)perfluoroalkoxy, (C4-C4)alkoxy and (Cs-Ca)cycloalkyloxy;
G is R"-(CR™R""),-; wherein G is a substituent on any ring carbon atom of Z capable of forming an additional bond and is oriented at a position other than alpha to the point of attachment of the Z ring to Y; - p is an integer from O to 4,
R' is independently selected from the group consisting of halo, -CN, -NO,, OH, (C,- . Cs)alkenyl, (C;-C4)alkynyl, (Ci-C4)perfluoroalkyl, perfluoro(Cy-C,)alkoxy, R'®-, R"-0-, R"®-(C,-
Cyakyl-0-, R™(C=0)-, R"-(C=0)-0-, R®-0-(C=0)- R™-8-, R?(S=0)-, R"-(S0,)-, RZ (SO.)-(NR¥)-, R™-(C=0)-(NR*')-, R®-0-(C=0)-(NR®)-, (R“R®NN-, (R"R®)N-(SO,)-, (RUR®)N-(C=0)-; (R"*R®)N-(C=0)-(NR?")- and (R"*R**)N-(C=0)-O-; each of R" and R" is independently selected from hydrogen and (C4-C,)alkyl;
, or R' and R" may optionally be taken together with the carbon to which they are attached to form a 5 to 10-membered carbocyclic ring; ] R", R", R® and R®' are independently selected from the group consisting of hydrogen, (C-Cy)alkyl, (Ce-Cio)aryl, (Cs-Cs)cycloalkyl, (Ci-Cio)heteroaryl and (Ci- Cio)heterocyclyl; wherein said (Cg-Cyo)aryl, (Cs-Cg)cycloalkyl, (C-Cio)heteroaryl and (Ci-
Cio)heterocyclyl moieties may be optionally substituted on any of the ring carbon atoms capable of forming an additional bond by one to three substituents per ring independently selected from F, Cl, Br, CN, OH, (C4-Cs)alkyl, (C4-C,)perfluoroalkyl, (C,-Cs)perfiuoroalkoxy, (C+-Cy)alkoxy, amino, (C,-Cslalkyl-NH-, [(C-C,)alkyl]-N- and (Cj-Cs)cycloalkyloxy, wherein said (C3-Cs)cycloalkyl and (C4-Cio)heterocyclyl moieties may also optionally be substituted by oxo; wherein said (C:-Cio)heteroaryl and (Ci-C,o)heterocyclyl moieties may optionally be substituted on any ring nitrogen atom able to support an additional substituent by one to two substituents per ring independently selected from the group consisting of (C,-C,)alkyl and (C;-
C,)alkyl-(C=0)-; or R'® and R® may optionally be taken together with the nitrogen to which they are attached to form a 3 to 8-membered heterocyclic ring; or R* and R* may optionally be taken together with the nitrogen, the carbon or the oxygen to which they are attached to form a 3 to 8-membered heterocyclic ring;
R# is selected from the group consisting of (Cy-Cyalkyl, (Ce-Cyo)aryl, (Cs- Cg)cycloalkyl, (Cs-Cioheteroaryl and (Cq-Cio)heterocyclyl; wherein said (Ce-Cyplaryl, (Cs-
Cs)cycloalkyl, (C4-Cio)heteroaryl and (C4-Cio)heterocyclyl moieties may be optionally substituted on any of the ring carbon atoms capable of forming an additional bond by one to three substituents per ring independently selected from F, Cl, Br, CN, OH, (C,-C,)alkyl, (Cs-
C,)perfluoroalkyl, (C;-C4)perfluoroalkoxy, (C,-C,)alkoxy, amino, (C;-Cs)alkyl-NH-, [(Cy- C,)alkyll;-N- and (Cs-Cg)cycloalkyloxy, wherein said (Cs-Cs)cycloalkyl and (C4-Cip)heterocyclyl moieties may also optionally be substituted by oxo; wherein said (C4-Cio)heteroaryl and (C,-
Cio)heterocyclyl moieties may optionally be substituted on any ring nitrogen atom able to support an additional substituent by one to two substituents per ring independently selected from the group consisting of (C,-C,)alkyl and (C4-C4)alkyl-(C=0)-; or R*' and R¥ may optionally be taken together with the nitrogen, the oxygen or the sulfur to which they are attached to form a 3 to 8-membered heterocyclic ring; ’ or the pharmaceutically acceptable salts thereof.
The present invention also relates to the pharmaceutically acceptable acid addition : salts of compounds of the formula I. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, ie., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate,
» tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, para-toluenesulfonate and pamoate . [i.e., 1,1-methylene-bis-(2-hydroxy-3- naphthoate)}salts.
The invention also relates to base addition salts of formula §. The chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of formula | that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water- soluble amine addition salts such as N-methylglucamine (meglumine) and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.
The term “a bond", as used herein in the group Y, means that the groups X and Z are directly connected through a carbon-carbon bond so as to form pendent aryl rings such as diphenyl. ~
The dashed lines as used in each of the heterocyclic ring “A” of formulae a), b), c), 9), h), i), k) and I) refer to optional double bonds. The exact positions of the optional double bonds for each of the heterocyclic ring “A” of formulae a), b), ¢), g), h), i}, k) and I) are as defined in the specification. Whenever the dashed line extends over two carbon atoms, one skilled in the art will understand that two carbons are tetravalent and that the extra substituent(s) (i.e., any of R', R%, R* R* R%, R®, R, R%, R", R"", R", or R"®) may be absent.
The term "alkyl", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched moieties, or combinations thereof.
Alkyl groups, wherever they occur, may be optionally substituted by a suitable substituent. } The term "alkenyl", as used herein, unless otherwise indicated, includes hydrocarbon radicals containing at least one olefin linkage and having straight, branched moieties, or combinations thereof.
The term "alkynyl", as used herein, unless otherwise indicated, includes hydrocarbon radicals containing at least one carbon-carbon triple bond linkage and having straight, branched moieties or combinations thereof.
The term "cycloalkyl", as used herein, unless otherwise indicated, includes a mono or bicyclic carbocyclic ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl, cyclohexenyl, bicyclo[2.2.1}heptanyl, bicyclo[3.2.1]octany! and bicyclo[5.2.0Jnonanyl, etc.); optionally containing 1or 2 double bonds ) and optionally substituted by 1 to 3 suitable substituents as defined below such as fluoro, chloro, trifluoromethyl, (C;-Cs)alkoxy, (Ce-Cio)aryloxy, trifluoromethoxy, difluoromethoxy or (C+-Cs)alkyl, more preferably fiuoro, chloro, methyl, ethyl and methoxy.
: The term "alkoxy", as used herein, includes O-alkyl groups wherein "alkyl" is as defined above. ‘ The term "halo", as used herein, unless otherwise indicated, includes fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
The term "aryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one aor more hydrogens, such as phenyl or naphthyl, optionally substituted by 1 to 3 suitable substituents such as fluoro, chloro, cyano, nitro, trifluoromethyl, (C4-Cg)alkoxy, (Ce-Cio)aryloxy, (Cs-Cg)cycloalkyloxy, trifluoromethoxy,- difluoromethoxy, or (C4-Cg)alkyl. :
The term "heteroaryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic heterocyclic compound by removal of one or more hydrogens, such as benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-1-benzopyranyi, benzothiadiazine, benzothiazinyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl,” furazanyl, furopyridinyl, fury), imidazolyl, indazoly!, indolinyl, indolizinyl, indotyl, 3H- indolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazotyl, oxazofyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyridazinyi, pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl, guinazolinyl, quinolinyl, quinoxalinyi, tetrazolyl, thiazoly!, thiadiazoiyl, thienyl, triazinyl and trizzolyl, wherein said (C;-Cio)neteroany is optionally substituted on any of the ring carbon atoms capable of forming an additional band by one or two substituents independently selected from F, Ci, Br, CN, OH, (C,-Cslalkyl, (C4-C,)perfluoroalkyl, (C4-C,)perfiuoroalkoxy, (C4-Cslatkoxy and (Cs-Cp)cycloalkyloxy. The foregoing groups, can be C-attached or N- attached where such is possible. For instance, pyrrolyl can be pyrrol-1-yt (N-attached) or pyrrol-3-yl (C-attached).
The term "heterocyclyl", as used herein, unless otherwise indicated, includes an organic radical derived from a non-aromatic heterocyclic compound by removal of one or more hydrogens, such as 3-azabicyclo[3.1.0lhexanyl, 3-azabicyclo[4.1.0]-heptanyl, azetidinyl, dihydrofuranyl, dihydropyranyl, dihydrothienyl, dioxanyl, 1,3-dioxolanyl, 1,4-dithianyl, hexahydroazepinyl, hexahydropyrimidine, imidazolidinyl, imidazolinyl, isoxazolidinyl, morpholinyl, oxazolidinyl, piperazinyl, piperidinyl, 2H-pyranyl, 4H-pyranyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, ~~ 2-pyrrolinyl, 3-pyrrolinyl, quinolizinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, tetrahydrothienyl, tetrahydrothiapyranyl, thiomorpholinyl, thioxanyl and trithianyl, The foregoing groups, can be C-attached or N-attached where such is possible. For example, piperidiny! can be piperidin-1-yl (N-attached) or piperidin-4- ) yi (C-attached). The foregoing groups, as derived from the compounds listed above, can be optionally substituted where such is possible by a suitable substituent, such as oxo, F, Cl, Br,
CN, OH, (Cy-Cui)alkyl, (C-Cy)perfluoroalkyl, (C4-C,)perfluoroalkoxy, (Cq-Cy)alkoxy, or (Ca-
Cg)cycloalkyloxy. :
. The phrase “a suitable substituent’ is intended to mean a chemically and pharmaceutically acceptable functional group i.e., a moiety that does not negate the inhibitory . activity of the inventive compounds. Such suitable substituents may be routinely selected by those skilled in the art. lllustrative examples of suitable substituents include, but are not limited to halo groups, perfluoroalkyl groups, perfluoroalkoxy groups, alkyl groups, hydroxy groups, 0X0 groups, mercapto groups, alkylthio groups, alkoxy groups, aryl or heteroaryl groups, aryloxy or heteroaryloxy groups, aralkyl or heteroaralkyf groups, aralkoxy or heteroaralkoxy groups, carboxy groups, amino groups, alkyl- and dialkylamino groups, carbamoyl groups, alkylcarbonyl groups, alkoxycarbonyl groups, alkylaminocarbonyl groups dialkylamino carbonyl groups, aryicarbonyl groups, aryloxycarbonyl groups, alkylsulfonyl groups, an aryisuifonyl groups and the iike.
The phrase "at a position other than alpha to the point of attachment of the Z ring to
Y", as used herein, unless otherwise indicated, is intended to mean a chemically and pharmaceutically acceptable orientation of the bond connecting group Z to G (Z-G bond) relative to the bond connecting group Y to Z (Y-Z bond). Such relative orientation may be meta, wherein the Z-G bond is in the 1,3 position relative to the Y-Z bond. Another relative orientation may be para, wherein the Z-G bond is in the 1,4 position relative to the Y-Z bond.
Some compounds of formula | contain chiral centers and therefore exist in different enantiomeric forms. This invention relates to all optical isomers, enantiomers, diastereomers and stereoisomers of the compounds of formula | and mixtures thereof. The compounds of the invention also exist in different tautomeric forms. This invention relates to all tautomers of formula I. Those skilled in the art are well aware that the pyrimidine-2,4,6-frione nucleus exists as a mixture of tautomers in solution. The various ratios of the tautomers in solid and liquid form is dependent on the various substituents on the molecule as well as the particular crystallization technique used to isolate a compound. in one embodiment of the invention, the heterocyclic ring “A” of the compounds of the formula 1 is selected from the formulae a) or b):
X-Y-2-G X-Y-Z-G a) | o b) | o
N R her R? RZ RS rR; wherein X is (Cg-Cyg)aryl, preferably phenyl. Within this embodiment, Y is selected from the . group consisting of a bond, oxygen, >C=0, -CH,-, -CH,0-, -O(CHy),-, -CH,CH,-, -CH=CH- and -C=C-; wherein n is 1or 2; preferably Y is selected from the group consisting of oxygen, -OCH_- and -CH,0-; more preferably Y is oxygen.
In another embodiment of the invention, the heterocyclic ring “A” has the formulae a) or b), wherein X is (Cg-Cqo)aryl, preferably phenyl. Within this embodiment, Y is selected from
. the group consisting of sulfur, >SO,, >S$=0, -CH,S-, -S(CHa)n-, -CH2S0-, -CH,S0,-, -SOCH;- and -SO,(CHy,)-; wherein n is 1 or 2; preferably Y is sulfur or >SO.. . In another embodiment of the invention, the heterocyclic ring “A” has the formulae a) or b), wherein X is (C¢-C1g)aryl, preferably phenyl. Within this embodiment, Y is selected from the group consisting of CHz[N(R')}-, >NR™, -NR"(CH,)n-, -SO,[N(R™)]- and -[N(R")}-SOz-, wherein R' is hydrogen or methyl; and nis 1 or 2.
In another embodiment of the invention, the heterocyclic ring “A” has the formulae a) or b), wherein X is (C4-Cio)heteroaryl selected from the group consisting of benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl, furazanyl, furopyridinyl, furyl, imidazolyl, indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl and triazolyl, wherein said (Cs-
C.o)heteroaryl is optionally substituted on any of the ring carbon atoms capable of forming an additional bond by one or two substituents independently selected from F, Cl, Br, CN, OH, (C;-
Cyalkyl, (C4-Cy)perfluoroalkyl, (C4-Cy)perfluoroalkoxy, (C4-C4)atkoxy and (Cs-Cs)cycloalkyloxy; preferably X is selected from the group consisting of imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyi, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl; more preferably X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; most preferably X is pyridinyl. Within this embodiment, Y is a bond, oxygen, sulfur, -CH,-, >80O,, -OCH,- or -CH,0-; preferably Y is oxygen, -OCH,- or -CH,0-; more preferably Y is oxygen.
In another embodiment of the invention, the heterocyclic ring “A” has the formulae a) or b), wherein X is (C4-Cso)heteroaryl selected from the group consisting of benzimidazoiyl, benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl,” furazanyl, furopyridinyl, furyl, imidazolyl, indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl and triazolyl, wherein said (C4-
Cio)heteroaryl is optionally substituted on any of the ring carbon atoms capable of forming an additional bond by one or two substituents independently selected from F, Cl, Br, CN, OH, (C,-
C,)alkyl, (C4-C,)perfiuoroalkyl, (C4-Cy)perfluoroalkoxy, (C4-Cs)alkoxy and (Ca-Ca)cycloalkyloxy; ’ preferably X is selected from the group consisting of imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl, more preferably
X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; most preferably X is pyridinyl. Within this embodiment, Y is selected from the group consisting of sulfur, >SO,, >8=0, -CH,S-, -S(CH,),-
. , “CH2S80-, -CH,S0;-, -SOCH,- and -SO,(CHj),-; wherein n is 1 or 2; preferably Y is sulfur or >80,. . In another embodiment of the invention, the heterocyclic ring “A” has the formulae a) or b), wherein X is (C,-Cqo)heteroaryi selected from the group consisting of benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl, furazanyl, furopyridinyl, furyl, imidazolyl, indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl and triazolyl, wherein said (C:-
Cio)heteroaryl is optionally substituted on any of the ring carbon atoms capable of forming an additional bond by one or two substituents independently selected from F, Cl, Br, CN, OH, (C,-
Ca)alkyl, (C4-Cq)perfiuoroalkyl, (C4-C,)perfluoroalkoxy, (C4-C,)alkoxy and (C3-Cs)cycloalkyloxy; preferably X is selected from the group consisting of imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl; more preferably
X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; most preferably X is pyridinyl. Within this embodiment Y is selected from the group consisting of CH,[N(R*)}-, >NR"™, -NR(CHy)-, -
SOIN(R™)]- and -[N(R'*)]-SO-, wherein Ris hydrogen or methyl; and n is 1 or 2.
In another embodiment of the invention, the heterocyclic ring “A” has the formula a), wherein X is (Cs-Cio)heteroaryl selected from the group consisting of benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl, furazanyl, furopyridiny!, furyl, imidazolyl, indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phthalazinyl, pteridiny, purinyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl and triazolyl, wherein said (C,-
Cio)heteroaryl is optionally substituted on any of the ring carbon atoms capable of forming an additional bond by one or two substituents independently selected from F, CI, Br, CN, OH, (Cy-
Ca)alkyl, (C4-Cy)perfiuoroalkyl, (C,-C,)perfluoroalkoxy, (C4-C4)alkoxy and (C3-Cs)cycloalkyloxy; preferably X is selected from the group consisting of imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl; more preferably ’ X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; most preferably X is pyridinyl. Within this embodiment, Y is selected from the group consisting of a bond, oxygen, sulfur, -CH,-, >S0,, ) -OCH_;- and -CH,O-; preferably Y-is oxygen, -OCH,- or -CH,O-; more preferably Y is oxygen.
In another embodiment of the invention, the heterocyclic ring “A” has the formula a), as defined in the aforesaid paragraph, wherein in the heterocyclic ring “A” the dashed line is a double bond.
. In another embodiment of the invention, the heterocyclic ring “A” has the formula b), wherein X is (C4-Cyo)heteroaryl selected from the group consisting of benzimidazolyl, . benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine, benzothiaziny}, benzothiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl, furazanyl, furopyridiny!, furyl, imidazolyl, indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl and triazolyl, wherein said (Cs-
Cio)heteroaryl is optionally substituted on any of the ring carbon atoms capable of forming an additional bond by one or two substituents independently selected from F, CI, Br, CN, OH, (C;-
C.)alkyl, (C4-Cy)perfluoroalkyl, (C4-Cy)perfluoroalkoxy, (Cs-C,)alkoxy and (Ca-Cg)cycloalkyloxy; preferably X is selected from the group consisting of imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl; more preferably
X is pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; most preferably X is pyridinyl. Within this embodiment, Y is selected from the group consisting of a bond, oxygen, sulfur, -CHa-, >SO,, -OCH,- and -CH,0-; preferably Y is oxygen, ~-OCH,- or -CH,0-; more preferably Y is oxygen.
In another embodiment of the invention, the heterocyclic ring “A” has the formula b), as defined in the aforesaid paragraph, wherein in the heterocyclic ring "A" the dashed line is a double bond.
In another embodiment of the invention, the heterocyclic ring "A" has the formula ¢):
X-Y-Z-G c) | 0 R* 3
RVR RR wherein X is (C1-Cyg)heteroaryl selected from the group consisting of imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrazolyl; preferably X is selected from the group consisting of pyrazinyl, pyridazinyl, pyridyl and pyrimidinyl; more preferably X is pyridinyl. Within this embodiment, Y is selected from the group consisting of a bond, oxygen, sulfur, -CH,-, >S0,, -OCH,- and -CH,0-; preferably Y is : oxygen, -OCH,- or -CH,0O-; more preferably Y is oxygen.
In another embodiment of the invention, the heterocyclic ring "A" has the formula ¢), " wherein in the heterocyclic ring “A” the dashed line is a double bond, such that the heterocyclic ring “A” of formula c is selected from the group consisting of:
Claims (14)
1. A compound of the formula: . H 0) Yee N o=( N A 0) ! wherein said “A” is a 5-7 membered heterocyclic ring selected from the group consisting of: X-Y-Z-G X-Y-Z-G Xree a) b) ©) | Or o 0 R® NX R? N R* N WR? A LOR JR R
2 . 1 6 6 R' R ' R R? RS R : R' R? Rr® R : X-Y-2- X-Y-Z-G d) . X-Y-Z-G e) v6 f) 0 R° o | P af Nn NA re NTN R" § N—R® N R" IX Rr 6 10’ Rr" ; 1 0 R"2R° R : R R rR? R R X-Y-Z-G X-Y-Z-G X-Y-2-G i g) | h) | ) R* 80, _R SOR? $ EN ES | IF" 7 3 . ’ 7 “uy R 1 i ; R' < R' R® R Rr R® R? RS X-Y-Z-G X-Y-Z- ) Xvze K) EG ) R' 10 R' p10 13 Rr" R R R® R"2 N Rs N 7 N \ 8 R A JJ TR } R A 5 : / 7 R 1 R® 1 A 1 2 : R 5 ; R 1p Yo m) er n) Ta 0 X-YZG o 0 | 1 ENA oo N4 N So DN N° NYT Jo SO, : and R" . 0) 'e) : wherein each of R, R%, R’, R%, R®, R®, R, R, R°, R", R", R” and R" is independently selected from the group consisting of hydrogen, (C;-Cs)alkyl, (C1-C,)alkenyl, (C4-Cu)alkynyl, (Ce-Cro)aryl, (Ci-Cio)heteroaryl, (Cs-Cs)cycloalkyl and (C:-Cig)heterocyciyl; wherein each of said (C-Cs)alkyl, (Ce-Cig)aryl, (C4-Cio)heteroaryl, (Cs-Cg)cycloalkyl and (Cq- Cio)heterocyclyl may be optionally substituted on any of the ring carbon atoms capable of forming an additional bond with 1-3 substituents per ring independently selected from halo, (C4-Cy)alkyl, (C4-Cs)alkoxy, -CN, -OH and —NH,; xX is (Ce-Cyp)aryl or (C4-Cyg)heteroaryl; Y is selected from the group consisting of a bond, oxygen, sulfur, >C=0, >S0,, >8=0, -CHg-, ~CH;0-, -O(CHy)p~, -CH,S-, -S(CH,),-, -CH2S0-, -CH,S0,-, -SO(CH,)r, -80(CHa)n-, -NR™, -NR'(CHy)p-, ~-CHoIN(R")}-, -CHa(CHy)ym, -CH=CH-, ~C=C-, -[N(R")}-SO, and -SO,IN(R™)}-; n is an integer from one to four; - R' is hydrogen or (C,-C,)alkyl; Z is selected from the group consisting of (Cs-Cyg)aryl, (Cs-Cs)cycloalkyl, (Cs- Ciolheterocyclyl and (C,-Cyglheteroaryl; wherein one or two carbon-carbon single bonds of said (Cs-Cg)cycloalkyl or (C-Cqp)heterocyclyl may optionally be replaced by carbon-carbon double bonds; wherein each of said X or Z may be independently optionally substituted on any of the ring carbon atoms capable of forming an additional bond by one or two substituents per ring independently selected from F, Cl, Br, CN, OH, (C;-Cyalkyl, (C,-Cg)perfiuoroalkyi, (C;-
C.)perfluoroalkoxy, (C-C,)alkoxy and (C3-Cg)cycioalkyloxy; G is R™-(CR"™R"),-; wherein G is a substituent on any ring carbon atom of Z capable of forming an additional bond and is oriented at a position other than alpha to the point of attachment of the Z ring to Y; } p is an integer from 0 to 4; R' is independently selected from the group consisting of halo, -CN, -NO,, OH, (C,- Cu)alkenyl, (Cs-Cs)alkynyl, (C4-Cq)perfluoroalkyl, perfluoro(Ci-Cq)alkoxy, R™-, R™-0-, R™(C,- C,akyl-0-, R*(C=0)., R"™(C=0)-0-, R®-0-(C=0)- R™-8-, R*(S=0)-, R®-(S0,)-, RZ (SO-(NR¥")-, R™-(C=0)-(NR”')., RZ-O-(C=O-NR*')., (RUR®IN-, (RYR®N-(SO,)-, (R™R®)N-(C=0)-; (R"*R®)N-(C=0)-(NR*")- and (R"*R®)N-(C=0)-O-; each of R*® and R" are independently selected from hydrogen and (C;-C,)alkyl;
or R'® and RY may optionally be taken together with the carbon to which they are v attached to form a 5 to 10-membered carbocyclic ring; R*, R™ R® and R* are independently selected from the group consisting of ‘ hydrogen, (Ci-C,)alkyl, (Ce-Ciolaryl, (Cs-Ce)cycloalkyl, (Cs-Cio)heteroaryl and (C+- Caiplheterocyclyl; wherein said (Cg-Cip)aryl, (Cs-Cg)cycloalkyl, (Cs-Cip)heteroaryl and {Cy Cio)heterocyclyl moieties may be optionally substituted on any of the ring carbon atoms capable of forming an additional bond by one to three substituents per ring independently selected from F, Cl, Br, CN, OH, (C:-Cs)alkyl, (C;-Cy)perfluoroalkyl, (C4-C4)perfluoroatkoxy, (Cy-Cs)atkoxy, amino, (C-Cylatkyl-NH-, [(C(-Cs)alkyl]-N- and (C;-Cs)cycioalkyloxy; wherein said (Cs-Cg)cycloalkyl and (C4-Cyg)heteracyclyl moieties may also optionally be substituted by oxo; wherein said {C{-Cio)heteroaryl and (C,-Cig)heterocyclyl moieties may optionally be substituted on any ring nitrogen atom able to support an additional substituent hy one to two substituents per ring independently selected from the group consisting of (C,-C,)alkyl and (Cy- Ca4)alkyl-(C=0)-; or R'® and R® may optionally be taken together with the nitrogen to which they are attached to form a 3 to 8-membered heterocyclic ring; or R" and R*' may optionally be taken together with the nitrogen, the carbon or the oxygen to which they are attached to form a 3 to 8-membered heterocyclic ring; R# is selected from the group consisting of (C,-Cilalkyl, (Ce-Cio)aryl, (Ca- Cg)cycloalkyl, (Cy-Cqo)heteroaryl and (Cy-Cioheterocyclyl; wherein said (Ce-Cip)aryl, (Ca- Cg)oycloalkyl, (Cs-Ciglheteroaryt and (C4-Cio)heterocyclyl moieties may be optionally substituted on any of the ring carbon atoms capable of forming an additional bond by one to three substituents per ring independently selected from F, Cl, Br, CN, OH, (C;-C,)alky}, (C;- Cas)perfluoroalkyl, (C-Cy)perfluoroalkoxy, (C4-Cslalkoxy, amino, (Ci-Cslalkyl-NH-, [(Cy- C,)alkyl]-N- and (Cs-Cg)cycloalkyloxy, wherein said (C;-Cs)cycloalkyl and (C4-Cio)heterocyclyl moieties may also optionally be substituted by oxo; wherein said (C-Cyp)heteroaryl and (C,- Cqo)heterocyclyl moieties may optionally be substituted on any ring nitrogen atom able to support an additional substituent by one to two substituents per ring independently selected from the group consisting of (C-Cy)alkyl and (C4-C)alkyl-(C=0)-; or R*' and R® may optionally be taken together with the nitrogen, the oxygen or the sulfur to which they are attached to form a 3 to 8-membered heterocyclic ring; or a pharmaceutically acceptable salt thereof. 2, The compound according to claim 1 wherein said “A” is selected from the . group consisting of
X-Y-Z:G 0 X-Y-Z-G k) Xy-za . I) R Ro ; | rR" | R eS RY N Rr® y RE , N R® ! rR / rR’ RY R® R' a2 R® cand RR :
3. The compound according to claim 1 wherein said X is (Cg-Cyg)aryl.
4. The compound according to claim 1 wherein said X is (C4-Cyo)heteroaryl.
5. The compound according to claim 1 wherein said Y is oxygen.
5. The compound according to claim 1 wherein said G is R™-(CR™R"),; wherein p is 0.
7. The compound according fo claim 1 wherein said G is R"(CR"R"), wherein p is an integer from 1 fo 4.
8. A compound according to claim 1, wherein said compound is selected from the group consisting of: 1-[6-(4-Fluoro-phenoxy)-pyridin-3-yl}-1,7,9-triaza-spiro[4.5]decane-2,6,8, 10-tetraone; 1-[6-(4-Fluoro-phenoxy)-pyridin-3-yl}-1,8,10-trizza-spiro[5.5]undecane-2,7,9,11- tetraone; 4~{5-(2,6,8,10-Tetraoxo-1,7,9-triaza-spiro{4.5)dec-1-yl)-pyridin-2-yloxy}-benzonitrile; 1-[6-(4-[1,3,4Joxadiazol-2-yl-phenoxy)-pyridin-3-yi]-1.7 9-triaza-spiro[4.5]decane- 2,6,8,10-tetraone; 1-[6~(4-Ethyl-phenoxy)-pyridin-3-yi]-1.7,9-taza-spiro[4.5]decane-2,6,8,10-tetraone; N-{4-[5-(2,6,8,10-Tetraoxo-1,7,9-triaza-spiro[4.5]dec-1-yl}-pyridin-2-yloxy}-benzyl)- acetamide; N-{4-[5-(2,6,8,10-Tetraoxo-1,7,9-triaza-spiro[4.5]dec-1-yl}-pyridin-2-yloxy}-benzyl}- propionarnide; N-{4-[5~(2,6,8,10-Tetraoxo-1,7,9-triaza-spiraf4,5]dec-1-yl)-pyridin-2-yloxy}-benzyl)- butyramide; Pentanoic acid 4-[S-(2,6,8,10-tetraoxo-1,7,8-triaza-spiro[4.5]dec-1-yl)-pyridin-2-yloxy}- benzylamide; Cyclobutanecarboxylic acid 4-[5-(2.6,8,10-tefraoxo-1,7,9-triaza-spiro[4.5]dec-1-yl)- . pyridin-2-yloxy]-benzylamide; 1-[6-(4-Bromo-phenoxy)-pyridin-3-yl}-1,7,9-triaza-spiro[4.5]decane-2,6,8,10-tetraone; , 1-[6-(4-pyrazol-1-yimethyl-phenoxy)-pyridin-3-yi]-1,7,9-triaza-spiro[4.5]decane- 2,6,8,10-tetraone; . and a pharmaceutically acceptable salt thereof.
9. A pharmaceutical composition for the treatment of a condition selected from the group consisting of connective tissue disorders, inflammatory disorders, immunology/allergy disorders, infectious diseases, respiratory diseases, cardiovascular diseases, eye diseases, metabolic diseases, central nervous system disorders, liver/kidney diseases, reproductive health disorders, gastric disorders, skin disorders and cancers in a mammal, including a human, comprising an amount of a compound of claim 1 effective in such treatment and a pharmaceutically acceptable carrier.
10. Use of a compound of claim 1, in the manufacture of a medicament for treating a condition selected from the group consisting of connective tissue disorders, inflammatory disorders, immunology/allergy disorders, infectious diseases, respiratory diseases, cardiovascular diseases, eye diseases, metabolic diseases, central nervous system disorders, liver/kidney diseases, reproductive health disorders, gastric disorders, skin disorders and cancers in a mammal, including a human.
11. A pharmaceutical composition for the treatment of a condition which can be treated by the inhibition of matrix metalloproteinases in a mammal, including a human, comprising an amount of a compound of claim 1 effective in such treatment and a pharmaceutically acceptable carrier.
12. The compound according to claim 1, substantially as herein described and exemplified.
13. A pharmaceutical composition according to claim 9 or 11, substantially as herein described and exemplified.
14. Use according to claim 10, substantially as herein described and exemplified. AMENDED SHEET
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US24338900P | 2000-10-26 | 2000-10-26 |
Publications (1)
Publication Number | Publication Date |
---|---|
ZA200302190B true ZA200302190B (en) | 2004-04-28 |
Family
ID=22918584
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ZA200302190A ZA200302190B (en) | 2000-10-26 | 2003-03-19 | Spiro-pyrimidine-2, 4, 6-trione metalloproteinase inhibitors. |
Country Status (32)
Country | Link |
---|---|
EP (1) | EP1332146A2 (en) |
JP (1) | JP2004518635A (en) |
KR (1) | KR20040004412A (en) |
CN (1) | CN1501937A (en) |
AP (1) | AP2001002318A0 (en) |
AR (1) | AR035069A1 (en) |
AU (1) | AU2002210813A1 (en) |
BG (1) | BG107653A (en) |
BR (1) | BR0114913A (en) |
CA (1) | CA2425283A1 (en) |
CZ (1) | CZ20031083A3 (en) |
EA (1) | EA005762B1 (en) |
EC (1) | ECSP034567A (en) |
EE (1) | EE200300196A (en) |
GT (1) | GT200100213A (en) |
HN (1) | HN2001000244A (en) |
HR (1) | HRP20030332A2 (en) |
HU (1) | HUP0301577A3 (en) |
IL (1) | IL154948A0 (en) |
IS (1) | IS6762A (en) |
MA (1) | MA26957A1 (en) |
MX (1) | MXPA03003735A (en) |
NO (1) | NO20031853L (en) |
OA (1) | OA12529A (en) |
PA (1) | PA8531401A1 (en) |
PE (1) | PE20020589A1 (en) |
PL (1) | PL366201A1 (en) |
SK (1) | SK4972003A3 (en) |
SV (1) | SV2003000705A (en) |
TN (1) | TNSN01149A1 (en) |
WO (1) | WO2002034753A2 (en) |
ZA (1) | ZA200302190B (en) |
Families Citing this family (36)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DOP2002000333A (en) | 2001-02-14 | 2002-09-30 | Warner Lambert Co | DERIVATIVES OF ISOFTALIC ACID AS INHIBITORS OF METALOPROTEINASES OF THE MATRIX |
DE60236851D1 (en) | 2001-02-14 | 2010-08-12 | Warner Lambert Co | Pyrimidinmatrixmetalloproteinaseinhibitoren |
DOP2002000332A (en) | 2001-02-14 | 2002-08-30 | Warner Lambert Co | MATRIX METALOPROTEINAS PYRIDINE INHIBITORS |
PA8539501A1 (en) | 2001-02-14 | 2002-09-30 | Warner Lambert Co | TRIAZOLO COMPOUNDS AS MMP INHIBITORS |
BR0207865A (en) | 2001-02-14 | 2004-03-23 | Warner Lambert Co | Benzothiadiazines matrix metalloproteinase inhibitors |
US6924276B2 (en) | 2001-09-10 | 2005-08-02 | Warner-Lambert Company | Diacid-substituted heteroaryl derivatives as matrix metalloproteinase inhibitors |
JP4164028B2 (en) | 2001-10-12 | 2008-10-08 | ワーナー−ランバート カンパニー リミテッド ライアビリティー カンパニー | Alkyne matrix metalloproteinase inhibitors |
US6962922B2 (en) | 2001-10-12 | 2005-11-08 | Warner-Lambert Company Llc | Alkynylated quinazoline compounds |
US6894057B2 (en) | 2002-03-08 | 2005-05-17 | Warner-Lambert Company | Oxo-azabicyclic compounds |
AU2003228701A1 (en) * | 2002-04-25 | 2003-11-10 | Bristol-Myers Squibb Company | Spirobarbituric acid derivatives useful as inhibitors of matrix metalloproteases |
JP2005527598A (en) * | 2002-04-26 | 2005-09-15 | ファイザー・プロダクツ・インク | Triaryl-oxy-aryl-spiro-pyrimidine-2,4,6-trione metalloproteinase inhibitors |
EP1501833B1 (en) * | 2002-04-26 | 2005-11-02 | Pfizer Products Inc. | N-substituted-heteroaryloxy-aryl-spiro-pyrimidine-2,4,6-trione metalloproteinase inhibitors |
WO2004014923A1 (en) | 2002-08-13 | 2004-02-19 | Warner-Lambert Company Llc | Pyrimidinone fused bicyclic metalloproteinase inhibitors |
AU2003250466A1 (en) | 2002-08-13 | 2004-02-25 | Warner-Lambert Company Llc | 3-isoquinolinone derivatives as matrix metalloproteinase inhiitors |
AU2003249540A1 (en) | 2002-08-13 | 2004-02-25 | Warner-Lambert Company Llc | Fused bicyclic metalloproteinase inhibitors |
CA2497658A1 (en) | 2002-08-13 | 2004-02-19 | Warner-Lambert Company Llc | Chromone derivatives as matrix metalloproteinase inhibitors |
EP1537098A1 (en) * | 2002-08-13 | 2005-06-08 | Warner-Lambert Company LLC | Monocyclic derivatives as matrix metalloproteinase inhibitors |
PA8578101A1 (en) | 2002-08-13 | 2004-05-07 | Warner Lambert Co | HETEROBIARILO DERIVATIVES AS METALOPROTEINASE IN MATRIX INHIBITORS |
MXPA05001786A (en) | 2002-08-13 | 2005-04-25 | Warner Lambert Co | Azaisoquinoline derivatives as matrix metalloproteinase inhibitors. |
AU2003253186A1 (en) | 2002-08-13 | 2004-02-25 | Warner-Lambert Company Llc | Fused tetrahydropyridine derivatives as matrix metalloproteinase inhibitors |
JP2006500351A (en) | 2002-08-13 | 2006-01-05 | ワーナー−ランバート・カンパニー、リミテッド、ライアビリティ、カンパニー | Pyrimidine-2,4-dione derivatives as matrix metalloproteinase-13 inhibitors |
WO2004014908A1 (en) | 2002-08-13 | 2004-02-19 | Warner-Lambert Company Llc | Heterobicylcic metalloproteinase inhibitors |
US7208490B2 (en) | 2002-10-07 | 2007-04-24 | Pharmacia & Upjohn Company Llc | Tricyclic tetrahydroquinoline antibacterial agents |
GB0223249D0 (en) * | 2002-10-08 | 2002-11-13 | Amersham Plc | Improved imaging agents |
WO2004084903A1 (en) * | 2003-03-27 | 2004-10-07 | F. Hoffmann-La Roche Ag | Use of a trioxopyrimidine for the treatment and prevention of ocular pathologic angiogenesis |
WO2004084902A1 (en) * | 2003-03-28 | 2004-10-07 | F. Hoffmann-La Roche Ag | Use of a trioxopyrimidine for the treatment of chronic wounds |
FR2858232B1 (en) * | 2003-07-29 | 2006-03-03 | Pierre Potier | USE OF A BIGUANIDE DERIVATIVE TO PROTECT THE SKIN FROM UVB RADIATION |
CA2561828C (en) * | 2004-04-01 | 2012-05-22 | F. Hoffmann-La Roche Ag | Use of a trioxopyrimidine for the treatment and prevention of bronchial inflammatory diseases |
DOP2006000268A (en) | 2005-12-22 | 2007-07-31 | Pfizer Prod Inc | ANTIBACTERIAL AGENTS |
US8153166B2 (en) * | 2006-06-08 | 2012-04-10 | Chih-Hsiung Lin | Composition for prophylaxis or treatment of urinary system infection and method thereof |
CN102285934B (en) * | 2009-01-08 | 2013-08-14 | 四川大学 | Spirocycle dienone derivates as well as preparation method and application thereof |
HUE037530T2 (en) * | 2012-12-10 | 2018-09-28 | Chugai Pharmaceutical Co Ltd | Hydantoin derivative |
KR101594506B1 (en) * | 2014-03-20 | 2016-02-17 | 한국화학연구원 | A Composition for Treating Bone-Related Diseases |
BR112016003511B8 (en) | 2014-06-09 | 2023-10-03 | Chugai Pharmaceutical Co Ltd | Pharmaceutical composition containing hydantoin derivatives and use thereof |
AU2019387367A1 (en) | 2018-11-30 | 2021-06-10 | Nuvation Bio Inc. | Diarylhydantoin compounds and methods of use thereof |
CN110092790B (en) * | 2019-06-11 | 2020-07-24 | 东北农业大学 | Alkaloid compound and preparation method and application thereof |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3714093A (en) * | 1970-05-19 | 1973-01-30 | American Home Prod | Spiro [heterocycloalkyl-2'(1'h)-quinazoline]-4'(3'h)-ones |
CN1295227C (en) * | 1997-06-21 | 2007-01-17 | 罗赫诊断器材股份有限公司 | Barbituric acid derivs with antimetastatic and antitumor activity |
US6265578B1 (en) * | 1999-02-12 | 2001-07-24 | Hoffmann-La Roche Inc. | Pyrimidine-2,4,6-triones |
PA8498701A1 (en) * | 1999-08-12 | 2002-08-26 | Pfizer Prod Inc | PYRIMIDINE-2,4,6-METALOPROTEINASE INHIBITING TRIONES |
-
2001
- 2001-10-23 EA EA200300306A patent/EA005762B1/en not_active IP Right Cessation
- 2001-10-23 CA CA002425283A patent/CA2425283A1/en not_active Abandoned
- 2001-10-23 CZ CZ20031083A patent/CZ20031083A3/en unknown
- 2001-10-23 EP EP01978721A patent/EP1332146A2/en not_active Withdrawn
- 2001-10-23 CN CNA018179231A patent/CN1501937A/en active Pending
- 2001-10-23 AP APAP/P/2001/002318A patent/AP2001002318A0/en unknown
- 2001-10-23 HU HU0301577A patent/HUP0301577A3/en unknown
- 2001-10-23 IL IL15494801A patent/IL154948A0/en unknown
- 2001-10-23 JP JP2002537743A patent/JP2004518635A/en not_active Withdrawn
- 2001-10-23 OA OA1200300123A patent/OA12529A/en unknown
- 2001-10-23 BR BR0114913-0A patent/BR0114913A/en not_active IP Right Cessation
- 2001-10-23 EE EEP200300196A patent/EE200300196A/en unknown
- 2001-10-23 MX MXPA03003735A patent/MXPA03003735A/en unknown
- 2001-10-23 KR KR10-2003-7005753A patent/KR20040004412A/en not_active Application Discontinuation
- 2001-10-23 WO PCT/IB2001/001986 patent/WO2002034753A2/en not_active Application Discontinuation
- 2001-10-23 PL PL01366201A patent/PL366201A1/en not_active Application Discontinuation
- 2001-10-23 AU AU2002210813A patent/AU2002210813A1/en not_active Abandoned
- 2001-10-23 SK SK497-2003A patent/SK4972003A3/en unknown
- 2001-10-24 HN HN2001000244A patent/HN2001000244A/en unknown
- 2001-10-24 AR ARP010104977A patent/AR035069A1/en unknown
- 2001-10-25 SV SV2001000705A patent/SV2003000705A/en unknown
- 2001-10-25 GT GT200100213A patent/GT200100213A/en unknown
- 2001-10-25 PE PE2001001060A patent/PE20020589A1/en not_active Application Discontinuation
- 2001-10-25 TN TNTNSN01149A patent/TNSN01149A1/en unknown
- 2001-10-26 PA PA20018531401A patent/PA8531401A1/en unknown
-
2003
- 2003-03-19 ZA ZA200302190A patent/ZA200302190B/en unknown
- 2003-03-20 BG BG107653A patent/BG107653A/en unknown
- 2003-03-27 IS IS6762A patent/IS6762A/en unknown
- 2003-04-22 MA MA27117A patent/MA26957A1/en unknown
- 2003-04-24 NO NO20031853A patent/NO20031853L/en not_active Application Discontinuation
- 2003-04-25 EC EC2003004567A patent/ECSP034567A/en unknown
- 2003-04-28 HR HR20030332A patent/HRP20030332A2/en not_active Application Discontinuation
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
ZA200302190B (en) | Spiro-pyrimidine-2, 4, 6-trione metalloproteinase inhibitors. | |
ZA200302192B (en) | Pyrimidine-2, 4, 6-trione metalloproteinase inhibitors. | |
Griffith | [9] Depletion of glutathione by inhibition of biosynthesis | |
DE69613365D1 (en) | ESTER OF 5-AMINOLEVULINIC ACID AS A MEANS FOR PHOTOSENSITIZATION IN CHEMOTHERAPY | |
AU2003284632A1 (en) | Isoquinoline compounds and medicinal use thereof | |
CA2429067A1 (en) | Preventive or therapeutic medicines for diabetes containing fused-heterocycle compounds or their salts | |
KR20020063173A (en) | Pyrrole derivatives as phosphodiesterase ⅶ inhibitors | |
ES2270154T3 (en) | DERIVATIVES OF 3H-QUINAZOLIN-4-ONA. | |
KR910015562A (en) | Drugs for the treatment of brain failure diseases, novel 2- (1-piperazinyl) -4-phenylcycloalkano pyrimidine derivatives, and preparations thereof | |
JP2001501918A (en) | IL-8 receptor antagonist | |
EP1095015B1 (en) | Sulfonylamino carboxylic acid n-arylamides as guanylate cyclase activators | |
DE69020394T2 (en) | Aldose reductase inhibitor. | |
HUT56548A (en) | Process for producing n-(2-substituted alkyl)-n'-)imidazol-4-ylalkyl)-guanidine derivatives and pharmaceutical compositions comprising such compounds as active ingredient | |
ES2243313T3 (en) | DERIVATIVES OF ISOXAZOL AS INHIBITORS OF PHOSPHODIESTERASE VII. | |
DE2944037C2 (en) | ||
SI21188A (en) | Crystalline glucosamine sulphate metal salts | |
WO2000072845A1 (en) | Il-8 receptor antagonists | |
US4137326A (en) | Use of magnesium monospartate hydrochloride complex | |
Atwal et al. | Aryl cyanoguanidine potassium channel openers | |
US4086354A (en) | Novel anti-hypertensive compositions | |
DE2527291A1 (en) | ACYLDER DERIVATIVES | |
US3557285A (en) | Methods for providing muscle relaxation with 1-(substituted) - 5-amino-tetrazoles | |
IE61325B1 (en) | Crystalline salts of [3s(z)]-2[[[1-(2-amino-4-thiazolyl)-2-[[2,2-dimethyl-4-oxo-1 -(sulfooxy)-3-azetidinyl]amino]-2-oxoethylidene] amino]oxy]acetic acid | |
US4647588A (en) | 2-(substituted sulfamyl)-6-nitrobenzoic acid amides and pharmaceutical compositions | |
PL318014A1 (en) | Novel 2-[(2,6-dichlorophenyl)amino]phenyloaacetoxyacetic salts with cations of organic bases |