ZA200601501B - Bicyclic imino acid derivatives used as inhibitors of matrixmetalloproteinases - Google Patents
Bicyclic imino acid derivatives used as inhibitors of matrixmetalloproteinases Download PDFInfo
- Publication number
- ZA200601501B ZA200601501B ZA200601501A ZA200601501A ZA200601501B ZA 200601501 B ZA200601501 B ZA 200601501B ZA 200601501 A ZA200601501 A ZA 200601501A ZA 200601501 A ZA200601501 A ZA 200601501A ZA 200601501 B ZA200601501 B ZA 200601501B
- Authority
- ZA
- South Africa
- Prior art keywords
- het ring
- alkyl
- once
- substituted
- ring
- Prior art date
Links
- 239000002253 acid Substances 0.000 title claims description 7
- 102000002274 Matrix Metalloproteinases Human genes 0.000 title description 17
- 108010000684 Matrix Metalloproteinases Proteins 0.000 title description 17
- 239000003112 inhibitor Substances 0.000 title description 5
- -1 benzothiofuranyl Chemical group 0.000 claims description 58
- 125000000217 alkyl group Chemical group 0.000 claims description 42
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 38
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 31
- 150000001875 compounds Chemical class 0.000 claims description 23
- 125000003118 aryl group Chemical group 0.000 claims description 17
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 14
- 229910052717 sulfur Chemical group 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 125000004434 sulfur atom Chemical group 0.000 claims description 11
- 229910014585 C2-Ce Inorganic materials 0.000 claims description 9
- 208000032825 Ring chromosome 2 syndrome Diseases 0.000 claims description 9
- 208000035217 Ring chromosome 1 syndrome Diseases 0.000 claims description 8
- 208000032826 Ring chromosome 3 syndrome Diseases 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 125000001624 naphthyl group Chemical group 0.000 claims description 7
- 208000002991 Ring chromosome 4 syndrome Diseases 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 201000008482 osteoarthritis Diseases 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- VVWUWTAURHNLGY-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolin-2-ium-1-carboxylate Chemical compound C1CCCC2C(C(=O)O)NCCC21 VVWUWTAURHNLGY-UHFFFAOYSA-N 0.000 claims description 4
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 230000006378 damage Effects 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 201000001320 Atherosclerosis Diseases 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 claims description 3
- 125000002785 azepinyl group Chemical group 0.000 claims description 3
- 125000002393 azetidinyl group Chemical group 0.000 claims description 3
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 claims description 3
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 claims description 3
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 claims description 3
- 125000004623 carbolinyl group Chemical group 0.000 claims description 3
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 claims description 3
- 125000004230 chromenyl group Chemical group O1C(C=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000004856 decahydroquinolinyl group Chemical group N1(CCCC2CCCCC12)* 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 208000010125 myocardial infarction Diseases 0.000 claims description 3
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 3
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 claims description 3
- 125000002471 4H-quinolizinyl group Chemical group C=1(C=CCN2C=CC=CC12)* 0.000 claims description 2
- 206010019280 Heart failures Diseases 0.000 claims description 2
- 206010027476 Metastases Diseases 0.000 claims description 2
- 206010003246 arthritis Diseases 0.000 claims description 2
- 125000004069 aziridinyl group Chemical group 0.000 claims description 2
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 claims description 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 claims description 2
- 210000002808 connective tissue Anatomy 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 230000029663 wound healing Effects 0.000 claims description 2
- 150000003254 radicals Chemical class 0.000 claims 22
- 150000003857 carboxamides Chemical class 0.000 claims 14
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims 10
- 125000004076 pyridyl group Chemical group 0.000 claims 8
- 125000000714 pyrimidinyl group Chemical group 0.000 claims 8
- 125000001544 thienyl group Chemical group 0.000 claims 7
- 125000002541 furyl group Chemical group 0.000 claims 6
- 125000000168 pyrrolyl group Chemical group 0.000 claims 5
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims 4
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 claims 4
- 125000002757 morpholinyl group Chemical group 0.000 claims 4
- 125000000335 thiazolyl group Chemical group 0.000 claims 4
- APNFMEVVIUSJSX-UHFFFAOYSA-N 2-(2-methylphenyl)phenol Chemical compound CC1=CC=CC=C1C1=CC=CC=C1O APNFMEVVIUSJSX-UHFFFAOYSA-N 0.000 claims 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims 3
- 125000004429 atom Chemical group 0.000 claims 3
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims 3
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims 3
- 125000004193 piperazinyl group Chemical group 0.000 claims 3
- 125000003386 piperidinyl group Chemical group 0.000 claims 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims 3
- 239000000126 substance Substances 0.000 claims 3
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims 3
- 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 claims 2
- 125000004511 1,2,3-thiadiazolyl group Chemical group 0.000 claims 2
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 claims 2
- 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 claims 2
- 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 claims 2
- 125000004517 1,2,5-thiadiazolyl group Chemical group 0.000 claims 2
- 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 claims 2
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 claims 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims 2
- 206010028980 Neoplasm Diseases 0.000 claims 2
- 239000002585 base Substances 0.000 claims 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims 2
- TXCDCPKCNAJMEE-UHFFFAOYSA-N dibenzofuran Chemical compound C1=CC=C2C3=CC=CC=C3OC2=C1 TXCDCPKCNAJMEE-UHFFFAOYSA-N 0.000 claims 2
- 125000000532 dioxanyl group Chemical group 0.000 claims 2
- 150000002148 esters Chemical class 0.000 claims 2
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 claims 2
- 125000005677 ethinylene group Chemical group [*:2]C#C[*:1] 0.000 claims 2
- 125000002632 imidazolidinyl group Chemical group 0.000 claims 2
- 125000002636 imidazolinyl group Chemical group 0.000 claims 2
- 125000002883 imidazolyl group Chemical group 0.000 claims 2
- 125000001041 indolyl group Chemical group 0.000 claims 2
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 claims 2
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 claims 2
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 claims 2
- 125000003965 isoxazolidinyl group Chemical group 0.000 claims 2
- 125000000842 isoxazolyl group Chemical group 0.000 claims 2
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 claims 2
- 125000004930 octahydroisoquinolinyl group Chemical group C1(NCCC2CCCC=C12)* 0.000 claims 2
- 125000001715 oxadiazolyl group Chemical group 0.000 claims 2
- 125000000160 oxazolidinyl group Chemical group 0.000 claims 2
- 125000002971 oxazolyl group Chemical group 0.000 claims 2
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 claims 2
- 125000004625 phenanthrolinyl group Chemical group N1=C(C=CC2=CC=C3C=CC=NC3=C12)* 0.000 claims 2
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 claims 2
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 claims 2
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 claims 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims 2
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 claims 2
- 238000011321 prophylaxis Methods 0.000 claims 2
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 claims 2
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 claims 2
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims 2
- 125000003373 pyrazinyl group Chemical group 0.000 claims 2
- 125000002755 pyrazolinyl group Chemical group 0.000 claims 2
- 125000003226 pyrazolyl group Chemical group 0.000 claims 2
- 125000001422 pyrrolinyl group Chemical group 0.000 claims 2
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 claims 2
- 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 claims 2
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 claims 2
- 238000011282 treatment Methods 0.000 claims 2
- 125000004306 triazinyl group Chemical group 0.000 claims 2
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 claims 2
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 claims 1
- 125000004506 1,2,5-oxadiazolyl group Chemical group 0.000 claims 1
- 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 claims 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims 1
- 125000005955 1H-indazolyl group Chemical group 0.000 claims 1
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 claims 1
- LQQNUOBJNUFKPS-UHFFFAOYSA-N 2-(6-phenoxypyridin-3-yl)sulfonyl-3,4,4a,5,6,7,8,8a-octahydro-1h-isoquinoline-1-carboxylic acid Chemical compound OC(=O)C1C2CCCCC2CCN1S(=O)(=O)C(C=N1)=CC=C1OC1=CC=CC=C1 LQQNUOBJNUFKPS-UHFFFAOYSA-N 0.000 claims 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 claims 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims 1
- 208000036487 Arthropathies Diseases 0.000 claims 1
- 206010006895 Cachexia Diseases 0.000 claims 1
- 206010058112 Chondrolysis Diseases 0.000 claims 1
- 208000017667 Chronic Disease Diseases 0.000 claims 1
- 230000005526 G1 to G0 transition Effects 0.000 claims 1
- 206010061218 Inflammation Diseases 0.000 claims 1
- 208000012659 Joint disease Diseases 0.000 claims 1
- 206010065433 Ligament rupture Diseases 0.000 claims 1
- 206010072970 Meniscus injury Diseases 0.000 claims 1
- 208000000112 Myalgia Diseases 0.000 claims 1
- 208000031481 Pathologic Constriction Diseases 0.000 claims 1
- 206010040070 Septic Shock Diseases 0.000 claims 1
- 206010041591 Spinal osteoarthritis Diseases 0.000 claims 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 1
- 208000025865 Ulcer Diseases 0.000 claims 1
- 208000027418 Wounds and injury Diseases 0.000 claims 1
- 150000007513 acids Chemical class 0.000 claims 1
- 230000001154 acute effect Effects 0.000 claims 1
- 239000000654 additive Substances 0.000 claims 1
- 230000000996 additive effect Effects 0.000 claims 1
- 239000003513 alkali Substances 0.000 claims 1
- 150000001413 amino acids Chemical class 0.000 claims 1
- 208000022531 anorexia Diseases 0.000 claims 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 claims 1
- 125000003943 azolyl group Chemical group 0.000 claims 1
- 230000004097 bone metabolism Effects 0.000 claims 1
- 201000011510 cancer Diseases 0.000 claims 1
- 206010008118 cerebral infarction Diseases 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 238000004587 chromatography analysis Methods 0.000 claims 1
- 230000001684 chronic effect Effects 0.000 claims 1
- 206010061428 decreased appetite Diseases 0.000 claims 1
- 239000012024 dehydrating agents Substances 0.000 claims 1
- 238000001212 derivatisation Methods 0.000 claims 1
- 230000008030 elimination Effects 0.000 claims 1
- 238000003379 elimination reaction Methods 0.000 claims 1
- 125000004185 ester group Chemical group 0.000 claims 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims 1
- 125000003838 furazanyl group Chemical group 0.000 claims 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 claims 1
- 230000002757 inflammatory effect Effects 0.000 claims 1
- 230000004054 inflammatory process Effects 0.000 claims 1
- 208000014674 injury Diseases 0.000 claims 1
- 229910052500 inorganic mineral Inorganic materials 0.000 claims 1
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 claims 1
- 125000003384 isochromanyl group Chemical group C1(OCCC2=CC=CC=C12)* 0.000 claims 1
- 125000005438 isoindazolyl group Chemical group 0.000 claims 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims 1
- 125000001786 isothiazolyl group Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000011707 mineral Substances 0.000 claims 1
- 235000010755 mineral Nutrition 0.000 claims 1
- 238000012986 modification Methods 0.000 claims 1
- 230000004048 modification Effects 0.000 claims 1
- 230000002107 myocardial effect Effects 0.000 claims 1
- 210000004417 patella Anatomy 0.000 claims 1
- 208000028169 periodontal disease Diseases 0.000 claims 1
- 125000005954 phenoxathiinyl group Chemical group 0.000 claims 1
- 239000002243 precursor Substances 0.000 claims 1
- 239000000047 product Substances 0.000 claims 1
- 125000002098 pyridazinyl group Chemical group 0.000 claims 1
- 238000000926 separation method Methods 0.000 claims 1
- 230000036303 septic shock Effects 0.000 claims 1
- 238000006884 silylation reaction Methods 0.000 claims 1
- 239000011593 sulfur Chemical group 0.000 claims 1
- 235000001508 sulfur Nutrition 0.000 claims 1
- 229960005349 sulfur Drugs 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
- 125000001113 thiadiazolyl group Chemical group 0.000 claims 1
- 125000004627 thianthrenyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3SC12)* 0.000 claims 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims 1
- 230000036269 ulceration Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 description 8
- 230000008569 process Effects 0.000 description 5
- 102000008186 Collagen Human genes 0.000 description 4
- 108010035532 Collagen Proteins 0.000 description 4
- 229940124761 MMP inhibitor Drugs 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- 229920001436 collagen Polymers 0.000 description 4
- 239000011159 matrix material Substances 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 3
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 3
- 230000003143 atherosclerotic effect Effects 0.000 description 3
- 210000004204 blood vessel Anatomy 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- 210000002744 extracellular matrix Anatomy 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 102000029816 Collagenase Human genes 0.000 description 2
- 108060005980 Collagenase Proteins 0.000 description 2
- 206010061216 Infarction Diseases 0.000 description 2
- 102000000380 Matrix Metalloproteinase 1 Human genes 0.000 description 2
- 108010016113 Matrix Metalloproteinase 1 Proteins 0.000 description 2
- 102000005741 Metalloproteases Human genes 0.000 description 2
- 108010006035 Metalloproteases Proteins 0.000 description 2
- 102000016611 Proteoglycans Human genes 0.000 description 2
- 108010067787 Proteoglycans Proteins 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000007574 infarction Effects 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000007634 remodeling Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 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 1
- 102100026802 72 kDa type IV collagenase Human genes 0.000 description 1
- 101710151806 72 kDa type IV collagenase Proteins 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 102100027995 Collagenase 3 Human genes 0.000 description 1
- 108050005238 Collagenase 3 Proteins 0.000 description 1
- 206010056370 Congestive cardiomyopathy Diseases 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 201000010046 Dilated cardiomyopathy Diseases 0.000 description 1
- 102000016942 Elastin Human genes 0.000 description 1
- 108010014258 Elastin Proteins 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 108060003393 Granulin Proteins 0.000 description 1
- 102000007547 Laminin Human genes 0.000 description 1
- 108010085895 Laminin Proteins 0.000 description 1
- 102100030412 Matrix metalloproteinase-9 Human genes 0.000 description 1
- 108010015302 Matrix metalloproteinase-9 Proteins 0.000 description 1
- 206010028391 Musculoskeletal Pain Diseases 0.000 description 1
- 208000034827 Neointima Diseases 0.000 description 1
- 102100030411 Neutrophil collagenase Human genes 0.000 description 1
- 101710118230 Neutrophil collagenase Proteins 0.000 description 1
- 206010035148 Plague Diseases 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 102100030416 Stromelysin-1 Human genes 0.000 description 1
- 101710108790 Stromelysin-1 Proteins 0.000 description 1
- 206010064390 Tumour invasion Diseases 0.000 description 1
- 208000007814 Unstable Angina Diseases 0.000 description 1
- 208000033774 Ventricular Remodeling Diseases 0.000 description 1
- 241000607479 Yersinia pestis Species 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 230000009400 cancer invasion Effects 0.000 description 1
- 108020001778 catalytic domains Proteins 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 208000018631 connective tissue disease Diseases 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229920002549 elastin Polymers 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000007257 malfunction Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical group CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 230000008692 neointimal formation Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000007505 plaque formation Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000008844 regulatory mechanism Effects 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000015590 smooth muscle cell migration Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000012622 synthetic inhibitor Substances 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000034365 zymogen activation Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
-
- 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
- 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
- A61P19/00—Drugs for skeletal disorders
-
- 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
- A61P19/08—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
-
- 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
- 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
- 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
- A61P35/04—Antineoplastic agents specific for metastasis
-
- 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
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/24—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Rheumatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Cardiology (AREA)
- Oncology (AREA)
- Heart & Thoracic Surgery (AREA)
- Vascular Medicine (AREA)
- Neurology (AREA)
- Hospice & Palliative Care (AREA)
- Urology & Nephrology (AREA)
- Communicable Diseases (AREA)
- Immunology (AREA)
- Biomedical Technology (AREA)
- Pain & Pain Management (AREA)
- Dermatology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
Bicyclic imino acid derivatives used as inhibitors of matrix- ® metalloproteinases
The invention relates to n ovel derivatives of saturated bicyclic imino acids, such as, in particular, decahydroisoquinoline-1-carboxylic acid, to methods for preparing them, and to the use thereof as pharmaceuticals.
In diseases such as osteoarthritis and rheumatism, destruction of the joint takes place, with this destruction being caused, in particular, by the proteolytic breakdown of collagen due to collagenases. Collagenases belong to the metalioproteinase (MP) or matrix metalloproteinase (MMP) superfamily. The MMPs form a group of Zn-dependent enzymes which are involved in the biological breakdown of the extracellular matrix (D. Yip et al. in Investigational New Drags 17 (1999), 387-399 and Michaelides et al. in
Current Pharmaceutical Design 5 (1999) 787 — 819). These MMPs are, in particular, able to break down fibrillar and nonfibrillar collagen and also proteoglycans, both of which are important matrix constituents. MMPs are involved in processes of wound healing, tumor invasion and metastasis migration, and also in amgiogenesis, multiple sclerosis and heart failure (Michaelides, page 788; see above). In particular, they play an important role in the breakdown of the joint matrix in arthrosis and arthritis, whether this be osteoarthrosis, osteoarthritis or rheumatoid arthritis.
I'he activity of the MMPs iis furthermore essential for many of the processes which play a role in atherosclerotic plague formation, such as the infiltration of inflammatory cells amd smooth muscle cell migration, as well as proliferation and angiogenesis (S.J. George, Exp. Opin. Invest. Drugs (2000), 9 (5), 993-1007). Furthermore, the degradation of matrix by MMPs can cause anything from plaque instabilities through to ruptures, with these conditions being able to give rise to the clinical symptoms of atherosclerosis, unstable angina pectoris, myocardial infarction or stroke (E.J.M. Creemers et al., Circulation Res. 89, 201-210 (2001)). All in all, the
MMP family as a whole is able to break down all the components of the extracellular matrix of the blood vessels; in normal blood vessels, therefore, their activity is to a very great degree subject to regulatory mechanisms.
The increase in MMP activity during plaque formation and plaque instability is caused by an increase in cytokine-stimulated and growth factor- stimulated gene transcription, an increase in zymogen activation and an imbalance in the MIMP/TIMP (tissue inhibitors of metalloproteases) ratio. 1t therefore seems plausible that an MMP inhibition or the reattainment of the-
C MMP-TIMP balance, would be helpful in treating atherosclerotic diseases. It is likewise becoming ever more clear that an increase in MMP activity is at least partially responsible for other cardiovascular diseases in addition toe atherosclerosis, such as restenosis, dilated cardiomyopathy and thes previously mentioned myocardial infarction. it has been shown that administering synthetic inhibitors to experimental animal models of these diseases is able to achieve marked improvements, for example in regard to the formation of atherosclerotic lesions, neointima formation, left ventricular remodeling, pump performance malfunction or infarction healing. In various preclinical studies using MMP inhibitors, detailed tissue analyses indicated a reduction in collagen damage, an improvement in extracellular matrix remodeling and an improvement in the structure and function of cardiac muscle and blood vessels. Among these processes, matrix remodeling processes and MIMP-regulated fibroses, in particular, are regarded as being important components in the progression of heart diseases (infarction) (Drugs 61, 1239-1252 (2001)).
Under physiological conditions, MMPs cleave matrix proteins such ass collagen, laminin, proteoglycans, elastin or gelatine, and also process (i.e. activate or inactivate), by means of cleavage, a large number of othear proteins and enzy mes, which means that they play an important role in th-e entire body, with this role being particularly significant in the connective tissue and bones.
A large number of different MMP inhibitors are known (EP 0 606 046, WCQ 94/28889; WO 96/27583; cf. reviews such as Current Medicinal Chemistry 8, 425-74 (2001) as well). Following the first clinical studies in humans, it has now been found that MMPs give rise to side-effects. The side-effects &o be mentioned are musculoskeletal pain or anthralgias. The prior art makes it clear that it is expected that more selective inhibitors would be able &o reduce these side-effects (Yip, page 387, see above). Specificity towards
MMP-1 is particularly to be emphasized in this connection since these unwanted side-effects evidently appear to an increased extent when MMP- 1 is inhibited.
A disadvantage of the known MMP inhibitors is therefore that they frequently lack specificity. Most MMP inhibitors inhibit many MMPs simultareously because the catalytic domains of the MMPs possess similar structurees. As a consequence, the inhibitors also unde-sirably affect the [ enzyme=s which have a vital function (Massova |, et al., Thue FASEB Journal (1998) 112, 1075-1095).
In the endeavor to find effective compounds for treating connective tissue disease s, it has now been found that the derivatives whict are employed in accordamnce with the invention are powerful inhibitors of the matrix metalloproteinases MMP-2, MMP-3, MMP-8, MMP-9 armd MMP-13 while only hawing a weak inhibitory effect on MMP-1.
The invention therefore relates to a compound of the formula ni n2 R2 0 : ua) A—ring;—B——ringz-D——rings~E ring,
R4 0
R5 R1
R3 X Cn
Oo and/or to all the stereoisomeric forms of the compound of the formula and/or to mixtures of these forms in any ratio, and/or to a physiologically tolerated salt of the compound of the formula I, wherein
Ais -CCo-Cy)-alkylene,
B, D and E are identical or different and are, independen tly of each other, -(C=0-C4)-alkylene or the radical -B1-B2-B3- in which
B1 is -(CHa),-, in which nis the integer zero, 1 or 2,
B3 is -(CH2)m-, in which m is the integer zero, 1 or 2, withh the proviso that the sum of n and m amounts to zero, 1 or 2, and
B2 is 1) -C(O)- 2) -(C2-C4)-alkenylene, 3) -S(0)o-, where o is the integers zero, 1 or 2, 4) -N(R6)-, in which R6 is hydrogen atom, meth yl or ethyl, 5) -N(R6)-C(Y)-, in which Y is oxygen atom or sulfur atom and
R6 is defined as above,
6) -C(Y)-N(R6)-, in which Y is oxygen atom or sulfur atom and
RG is defined as above, @® 7) -N(R6)-SO2-, in which R6 is defined as abosve, 8) -S0.-N(R6)-, in which R6 is defined as abo-ve, 9) -N(R6)-SO,-N(R86)-, in which R6 is defined as above, 10) -N(R6)-C(Y)-N(R6)-, in which Y is oxygen atom or sulfur atom and R6 is defined as above, 11) -O-C(O)-N(R6)-, 12) -NH-C(O)-O-, 13) -O-, 14) -C(O)-O-, 15) -O-C(O)-, 16) -0O-C(0O)-O-, 17) -O-CH,-C(O)-, 18) -O-CH,-C(O)-O-, 19) -O-CH2-C(0)-N(R6)-, in which R6 is defined as above, 20) -C(O)-CHz-0O-, 21) -O-C(O)-CH2-O-, 22) -N(R6)-C(0)-CH2-0O-, in which R6 is defined as above, 23) -O-(CH):-O-, in which n is the integer 2 or 3, or 24) -O-(CH2)m-N(R6)-, in which m is the intege=r 2 or 3 and R6 is defined as above, 25) -N(R6)-(CH2)m-O-, in which m is the intege=r 2 or 3 and R6 is defined as above, 26) -N(R6)-N(R6)-, in which R6 is defined as above, 27) -N=N-, 28) -N(R6)-CH-N-, in which R6 is defined as atoove, 29) -N=CH-N(R6)-, in which R6 is defined as aloove, 30) -N(R6)-C(R7)=N-, in which R6 is defined ass above and R7 is ~NH-RS, 31) -N=C(R7)-N(R6)-, in which R6 is defined ass above and R7 is -NH-R8, or 32) -(C-Cg)-alkynylene, ring1, ring2 and ring3 are identical or different and are , independently of eachother, 1) covalent bond, 2) -(C¢-C14)-aryl, in which aryl is unsubstituted or substituted, independently of each other, once, twice or three times, by G, or
3) 4- to 15-membered Het ring, in which Het ring is unsubstituted or substituted , independently of each other, ( once, twice or three times, by" G, ring4 is 5 1) -(Cs-C14)-aryl, in which aryl is unsubstituted or substituted, independently of each other, ©nce, twice or three times, by G, 2) 4- to 15-membered Het ring, in which the Het ring is unsubstituted or substituted, independently of each other, once, twice or three times, by G, or 3) is one of the following radicals
H H and these radicals are unsubstituted or substituted once by
G,
Gis 1) hydrogen atom, 2) halogen, 3) =0, 4) -(C1-Ce)-alkyl, in which alkyl is unsubstituted or substituted, once, twice or three times, by halogen, -(C;-Cg)-cycloalkyl, - (C2-Ceg)-alkynyl, -(Cs-C14)-aryl or Het ring, 5) -(Cs-Cha)-aryl, 6) Het ring, 7) -C(0)-0-R10, in which R10 is a) -(C1-Ce)-alkyl, in which alkyl is unsubstituted or substituted, once or twice, by -(C3-Cg)-cycloalkyl, -(C2-Ce)-alkynyl, -CCs-C14)-aryl or Het ring, or b) -(Ce-C14)-aryl or H et ring, 8) -C(S)-0-R10, in which R10 is defined as above, 9) -C(0O)-NH-R11, in which R11 is a) -(C4-Ce)-alkyl, in “which alkyl is unsubstituted or substituted, once or twice, by -(C3-Cg)-cycloalkyl, -(Cg-C14)-aryl or Het ring, or b) -(Ce-C14)-aryl or Heet ring, 10) -C(S8)-NH-R11, in which R11 iss defined as above, 11) -O-R12,in which R12 is a) hydrogen atom, b) -(C1-Ce)-anlkyl, in which alkyl is unsubstituted or @ substitute d, once, twice or three times, by halogen, -(C;-Cg)-cycioalkyl, -(C2-Ce)-alkynyl, - (Cs-C1a)-aryl or Het ring, c) -(Ce-C1a)- aryl, d) Het ring, e) -C(0)-0O-R13, in which R13 is e)) -€C4-Cg)-alkkyl, in which alkyl is wnsubstituted or substituted, once or twice, by -(C3-Cs)-cycloalkyl, -(C2-Cs)- alkynyl, -(Cg-C14)-aryl, or Het ring, or e)2) -qCg-C14)-aryl or Het ring, f) -C(S)-0-R13, in which R13 is defined as above, a) -C(O)-NHI-R14, in which R14 is g)t) -{C+-Cg)-alkyl, in which alkyl is unsubstituted or substituted, once or twice, by -(C;-Cs)-cycloalkyl, -(C2-Ce)- alkynyl, -(Ce-C1a)-aryl or Het ring, or g)2) - (Ce-C14)-aryl or Het ring, or h) -C(S)-NH -R14, in which R14 is defined as above, 12) -C(O)-R10, in which R10 is defined as above, 13) -S(0)-R12, in whichm R12 is defined as above and p is the integers zero, 1 or 2, 14) -NO,, 15) -CN, or 16) -N(R15)-R12,in whic hR15 is 16)1) hydrogen atom, 16)2) -(C4-Cg)-alkyl, or 16)3) -SO.-(C4-Cep-alkyl, in which alkyl is unsubstituted or substituted, once or twice, by -(C3-Cg)-cycloalkyl, - (C2-Cs)-alkymyl, -(Ce-C14)-aryl or Het ring, and R12 is defined as above, or 17) -SO2-N(R12)-R1, in which R12 is defined as above and R1 is defined as below,
Xis -OH or -NH-OH, n1is the integer zero, 1, 2 or 3, n2is the integer zero, 1, 2, 3 or 4, with the proviso that the sum of n1 and n2 amounts to 1, 2, 3,4, 5, 6 or7,
R1, R2, R3, R4 and R5 are identical or different and are, independently of each other, @® 1) hydroge n atom, 2) -(C+1-Cs)—alkyl, in which alkyl is unsubstituted or substituted, once or twice, by -(C3-Cs)-cycloalkyl, -(C,-Cg)-alkynyl, -(C e-
C1a)-aryl or Het ring, 3. -C(0)-O -R8, in which R8 is 3)1) hydrogen atom, 3)2) -(C1-Ces)-alkyl, in which alkyl is unsubstituted or substituted, once or twice, by -(C3-Ce)-cycioalkyl, -(C2-Ce)-alkynyl, -(Ce-C14)-aryl or Het ring, or substituted once to five times, by fluorine, or 3)3) -(C¢-Cia)-aryl or Het ring, 4) -O-R8, i n which R8 has the abovementioned meaning, or 5) -(C3-C¢) -cycloalkyl.
The invention also rel ates to the compound of the formula | where
Ais -(Co-Cs)-alkyleme,
B, D and E are identical or different and are, independently of each other, -(Co-C4)-alkylene or the radical -B1-B2-B3- in which
B1is -(CH2)»—, in which n is the integer zero, 1 or 2,
B3is -(CH2)m—, in which m is the integer zero, 1 or 2, with the proviso that the sum of n and m amounts to zero, 1 or 2, and
B2 is 1) -C(O)- 2) -(C2-Cs)-alkenylene, 3) -S(0)o-, where o is the integers zero, 1 or 2, 4) -N(R6)-, in which R6 is hydrogen atom, methyl or ethyl, 5) -N(R6)-<C(Y)-, in which Y is oxygen atom or sulfur atom ard
R6 is defined as above, 6) -C(Y)-N (R6)-, in which Y is oxygen atom or sulfur atom amd
R6 is defined as above, 7) -N(R6)--SO--, in which R6 is defined as above, 8) -S0O,-N¢R6)-, in which R6 is defined as above, : 9) -N(R6)- SO,-N(R6)-, in which R6 is defined as above, 10) -N(R6)- C(Y)-N(R6)-, in which Y is oxygen atom or sulfur atom and R6 is defined as above, 11) -O-C(O)-N(R6)-, 12) -NH-C(Q)-0-,
13) -O-, 14) -C(0)-O-, ® 15) -0-C(O), 16) -0O-C(O)-O-, 17) -0O-CH=-C(O)-, 18) -0O-CHz=-C(0)-O-, 19) -O-CHz-C(O)-N(R6)-, in which R6 is defined as above, 20) -C(O)-CHz-O-, 21) -O-C(O)-CH2-O-, 22) -N(R6)-C(0)-CH,-O-, in which R6 is defined as above, 23) -O-(CH 2)-O-, in which n is the integer 2 or 3, or 24) -O-(CH 2)m-N(R6)-, in which m is the integer 2 or 3 and R6 is defined as above, 25) -N(R8)—(CH2)m-O-, in which m is the integer 2 or 3 and R6 is defined as above, 26) -N(R6)-N(R6)-, in which R6 is defined as above, 27) -N=N-, 28) -N(R6)-CH=N-, in which R6 is defined as above, 29) -N=CH -N(R6)-, in which R6 is defined as above, 30) -N(R6)-C(R7)=N-, in which R6 is defined as above and R7 is -NH-R 6, 31) -N=C(R7)-N(R6)-, in which R6 is defined as above and R7 is —NH-R 6, or 32) -(C,-Cg)-alkynylene, ring1, ring2 and ring3 are identical or different and are, independertly of each other, 1) covalent bond, 2) phenyl or naphthyl and are unsubstituted or substituted, indepe ndently of each other, once, twice or three times, by G, or 3) 4- to 15-membered Het ring, in which the Het ring is a radical from the series acridinyl, azepinyl, azetidinyl, azir idinyl, benzimidazalinyl, benzimidazolyl, benzofuaranyl, benzot hiofuranyl, benzothiophenyl, benzoxazolyl, benzot hiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, quinazolinyl, quinolinyl, 4H-quinol izinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, cinn olinyl, deca-hydroquinolinyl, dibenzofuranyl, dibenzothioplhenyl,
Claims (9)
- Patent claims® 1. A compound of the formula 2 ni 0 R2 I LL LS A—ring,—B—ring;~D——rings"E rng, No R4 R1 RO R3 Jy (1) 5 O and/or all the stereoisomeric forms of the compound of the formula 1 : and/or mixtures of these forms in any ratio, and/or a physiologically tolerated salt of the compound of the formula |, wherein Ais -(Co—-C,)-alkylene, B, D and E are identical or different and are, independently of each other, -(Co—Cs)-alkylene or the radical -B1-B2-B3- in which B1is -(CHby).-, in which n is the integer zero, 1 or 2, B3is -(CH2)m-, in which m is the integer zero, 1 or 2, with the proviso that the sum of n and m amounts to zero, 1 or 2, and B2 is 1) -C(O)- 2) -(C2—C4)-alkenylene, 3) -S(O),-, where o is the integers zero, 1 or 2, 4) -N(R6)-, in which R6 is hydrogen atom, methyl or ethyl, 5) -N(R6)-C(Y)-, in which Y is oxygen atom or sulfur atom and R6 is defined as above, 6) -C(Y’)-N(R6)-, in which Y is oxygen atom or sulfur atom and R6 is defined as above, 7) -N(R6)-SO--, in which R6 is defined as above, 8) -SO--N(R6)-, in which R6 is defined as above, 9) -N(R6)-S02-N(R6)-, in which R6 is defined as above, 10) -N(R6)-C(Y)-N(R6)-, in which Y is oxygen atom or sulfur atorm and RG is defined as above, 11) -O-C(O)-N(R6)-, 12) -NH-C(O)-O-, 13) -O-,14) -C(0O)-O-,15) -O-C(O)-,[ 16) -O-C(0O)-O-, 17) -O-CH,-C(O)-, 18) -O-CH2-C(O)-O-,19) -O-CH»-C(O)-N(R8)-, im which R6 is defined as above,20) -C(O)-CH,-O-,21) -0O-C(O)-CH,-O-,22) -N(R6)-C(O)-CH,-O-, im which R6 is defined as above,23) -O-(CH),-O-, in which nis the integer 2 or 3, or24) -O-(CH2)n-N(R6)-, in wrhich m is the integer 2 or 3 and R6 is defined as above,25) -N(R6)-(CH2)m-O-, in wrhich m is the integer 2 or 3 and R6 is : defined as above,26) -N(R6)-N(R6)-, in which R6 is defined as above,27) -N=N-,28) -N(R6)-CH=N-, in which R6 is defined as above,29) -N=CH-N(R6)-, in whic h R6 is defined as above,30) -N(R6)-C(R7)=N-, in which R6 is defined as above and R7 is—NH-RS,31) -N=C(R7)-N(R6)-, in which R6 is defined as above and R7 is —NH-R6, or32) -(CxCe)-alkynylene,ring, ring2 and ring3 are identical or different and are,independently of each other,1) covalent bond,
- 2) -(Cs-C1s)-aryl, in whic h aryl is unsubstituted or substituted, independently of each other, once, twice or three times, by G, or
- 3) 4- to 15-membered Het ring, in which Het ring is unsubstituted or subsstituted, independently of each other, once, twice or three tirmes, by G, ring4 is 1) -(Ce-Cias)-aryl, in whicsh aryl is unsubstituted or substituted, independently of each other, once, twice or three times, by G,2) 4- to 15-membered Het ring, in which the Het ring is unsubstituted or subsstituted, independently of each other, once, twice or three tirmes, by G, or3) is one of the following radicals® oo =X =o H H and thesse radicals are unsubstituted or substituted once by G, : Gis 1) hsydrogen atom, 2) healogen, 3) =0, 4) -{C4-Ce)-alkyl, in which alkyl is unsubstituted or substituted, once, twice or three times, by halogen, -(C3-Cs)-cycloalkyl, -(C2-Cg)-alkynyl, -(Ce-C1a)-aryl or Het ring, 5) -€(Cg-Cis)-aryl, 6) Het ring, 7) -C(0)-0-R10, in which R10 is a) -(Ci-Ce)-alkyl, in which alkyl is unsubstituted or substituted, once or twice, by -(C3-Cg)-cycloalkyl, -(C,-Cs)-alkynyl, -(Cs-C14)-aryl or Het ring, or bb) -(Ces-Cis)-aryl or Het ring, 8) -€C(S)-0-R10, in which R10 is defined as above, 9) -C(0)-NH-R11, in which R11 is a) -(C4-Ce)-alkyl, in which alkyl is unsubstituted or substituted, once or twice, by -(C3-Cg)-cycloalkyl, -(Cs-C14)-aryl or Het ring, or b) -(Cs-Cis)-aryl or Het ring, 10) -C(S)-NH-R11, in which R11 is defined as above, 11) -O-R12, in which R12 is a) hydrogen atom, b) -(C4-Ce)-alkyl, in which alkyl is unsubstituted or substituted, once, twice or three times, by halogen, -(Cs-Cg)-cycloalkyl, -(C.-Ce)-alkynyl, -(Cs-C14)-aryl or Het ring, c) -(Ce-C14)-aryi, d) Hetring, e) -C(0)-0-R13, in which R13 is e)1) -(Ci-Celalkyl, in which alkyl is unsubstituted or substituted, once or ( twice, by -(Cs-Cg)-cycloalkyl, -(C2-Cs)- alkyny{, -(Cs-C14)-aryl, or Het ring, or e)2) -(Cs-C 14)-aryl or Het ring, fy) -C(S)-O-R13, i n which R13 is defined as above, g) -C(O)-NH-R14 , in which R14 is ay) -(C4-Cg)-alkyl, in which alkyl is unsub stituted or substituted, once or twice, by -(C3-Ce)-cycloalkyl, -(C2-Cs)- alkyny~l, -(C¢-C14)-aryl or Het ring, or g)2) -(Ce-C=14)-aryl or Het ring, or h) -C(S)-NH-R14 , in which R14 is defined as above, 12) -C(0)-R10, in which R10 is defined as above, 13) -S(0),-R12, in which R12 is defined as above and p is the integers zero, 1 or 2, 14) -NOg, 15) -CN, 16) -N(R15)-R12, in whic hR15 is 16)1) hydrogen atom, 16)2) -(C4-Ce)-alkyl, or 16)3) -S0O--(C4-Cg)-alkyl, in which alkyl is unsubstituted or substituted, once or twice, by -(C3-Cg)- cycloalkyl, -(C2-Cs)-alkynyl, -(Cs-C1s)-aryl or Het ring, and R12 is defined as above, or 17) -SO2-N(R12)-R1, in which R12 is defined as above and R1 is defined as below, Xis -OH or -NH-OH, n1is the integer zero, 1, 2 or 3, n2is the integer zero, 1, 2, 3 or 4, with the proviso that the sum of n1 and n2 amounts to 1, 2, 3,4, 5,6 or 7, R1, R2, R3, R4 and R5 are identical or different and are, independently of each oth er, 1) hydrogen atom, 2) -(C4-Cg)-alkyl, in which a lkyl is unsubstituted or substituted, once or twice, by -(Cs-Cs)-cycloalkyl, -(C2-Cg)-alkynyl, -(Ce- Cis)-aryl or Het ring, 3) -C(0)-0-R8, in which R8 &s 3)1) hydrogen atom,3)2) -(C1-Cg)-alkyl, in which alkyl is unsu bstituted or substituted, once or twice, by -(C3;-C=g)-cycloalkyl, ) -(C2-Ce)-alkynyl, -(Ce-C14)-aryl or Het ring, or substituted once to five times, by fluorine, or 3)3) -(Ce-C1as)-aryl or Het ring, 4) -O-R8, in which R8 has the abovementioned meaning, or 5) -(Cs-Ce)-cycloalkyl.2. A cormpound of the formula | as claimed in claim 1, Ais -(Co-Cs)-alkylene, B, D and E are identical or different and are, independently of each other, —(Co-C4)-alkylene or the radical -B1-B2-B3- in which B1is -(CH2)n-, in which n is the integer zero, 1 or 2, : B3is -(CHz)m-, in which m is the integer zero, 1 or 2, with th e proviso that the sum of n and m amounts to zero.. 1 or 2, and B2 is 1) -C(O)- 2) -(C,-C4)-alkenylene, 3) -S(0)o-, where o is the integers zero, 1 or 2, 4) -N(R6)-, in which R6 is hydrogen atom, methyl or ethyl, 5) -N(R6)-C(Y)-, in which Y is oxygen atom or sul fur atom and R6 is defined as above, 6) -C(Y)-N(R6)-, in which Y is oxygen atom or sul fur atom and R6 is defined as above, 7) -N(R6)-SO,-, in which R6 is defined as above, : 8) -S0,-N(R6)-, in which R6 is defined as above, 9) -N(R6)-SO,-N(R6)-, in which R6 is defined as ab ove, 10) -N(R6)-C(Y)-N(R6)-, in which Y is oxygen atom Or sulfur atom and R6 is defined as above, 11) -0-C(O)-N(R6)-, 12) -NH-C(O)-O-, 13) -O-, 14) -C(0)-0O-, 15) -0-C(O)-, 16) -0-C(0)-0-, 17) -O-CH,-C(O)-, 18) -0-CH,-C(0)-0O-, 19) -O-CH,-C(0O)-N(R6)-, in which R6 is defined as aabove, 20) -C(0)-CH2-O-,21) -O-C(O)-CH,-0-, 22) -N(R6)-C(0O)-CH2-O-, in which R6 is defined as above,[ 23) -O-(CH),-0-, in which n is the integer 2 or 3, or 24) -O-(CH2)m-N(R8)-, in which m is the integer 2 or 3 and R6 is defined as above, 25) -N(R6)-(CH2)m-O-, in which m is the integer 2 or 3 and R6 is defined as above, 26) -N(R6)-N(R6)-, in which R6 is defined as above, 27) -N=N-, 28) -N(R6)-CH=N-, in which R6 is defined as above, 29) -N=CH-N(R6)-, in which R6 is defined as above, 30) -N(R6)-C(R7)=N-, in which R6 is defined as above and R7 is -NH-RS, : 31) -N=C(R7)-N(R6)-, in which R6 is defined as above and R7 is -NH-R6, or32) -(C,-Cg)-alkynylene, ring1 ., ring2 and ring3 are identical or different and are, independently of ea«ch other, 1) covalent bond,2) phenyl or naphthyl and are unsubstituted or substituted, independently of each other, once, twice or &hree times, by G, or3) 4- to 15-membered Het ring, in which the Hest ring is a radical from the series acridinyl, azepinyl, aze tidinyl, aziridinyl,benzimidazalinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl,quinoxalinyl, quinuclidinyl, chromanyl, chro menyl, cinnolinyl, deca-hydroquinolinyl, dibenzofuranyl, d ibenzothiophenyl, dihydrofuran[2,3-b]tetrahydrofuranyl, dihydrofuranyl, dioxolyl, dioxanyl, 2H,6H-1,5,2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-irmdazolyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isobenzofuraryl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolidinyl, 2-isothiazolinyl, isothiazolyl, isoxazolyl, isoxazolidinyl, 2-isoxazolinyl, = morpholinyl, naphthyridinyl, octahydroisoquinolinyl, ox adiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4- oxadiazoly!l, oxazolidinyl, oxazolyl, oxothiolanyl, pyrimidinyl, ® phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperaziny|, piperidinyl , pteridinyl, purinyl, pyranyl, pyrazinyl, pyroazolid inyl, pyrazolinyl, pyrazolyl, pyridaziny=l, pyridooxazzolyl, pyridoimidazolyl, pyridothiazoly=l, pyridothiophenyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidiny~l, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofurany~l, tetrahydro isoquinolinyl, tetrahydroquinolinyl, tetrahydro- pyridinyl, 6H-1,2,5-thiadazinyl, 1,2,3-thiadiazolyl, 1,2,4-thia- diazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthreny~i, thiazolyl, thienyl, thienothiazolyl, thienooxazoly~l, : thienoimid azolyl, thiomorpholinyl, thiophenyl, triazinyl, 1,2,3- triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl arsd xanthenyl, and these radicals are unsubstituted ofr substituted, independently of each other, once, twice or three times, by G, ring4 is 1) -(Cs-Cra)-aryl, in which aryl is a radical from the series pheny~l, naphthyl, 1-naphthyl, 2-naphthyl, anthryl and fluorenyl, an d these radicals are unsubstituted or substituted, independently of each other, once, twice or three times, by G, 2) 4- to 15-mxembered Het ring, in which the Het ring is a radical from the series acridinyl, azepinyl, azetidinyl, aziridinyi, benzimida zalinyl, benzimidazolyl, benzofurany~l, benzothiofuranyi, benzothiophenyl, benzoxazoly-I, benzothia=olyl, benzotriazolyl, benzotetrazoly~l, benzisoxa=zolyl, benzisothiazolyl, carbazolyl, 4aH-carbazoly-l, carbolinyl, quinazolinyl, quinolinyl, 4H-quinoliziny1, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, cinnoliny=1, deca-hydroquinolinyl, dibenzofuranyl, dibenzothiopheny-l, dihydrofuran[2,3-b]tetrahydrofuranyl, dihydrofuranyl, dioxoly-l, dioxanyl, 2H,6H-1,5,2-dithiazinyl, furanyl, furazany-l, imidazolidi nyl, imidazolinyl, imidazolyl, 1H-indazolyl, indoliny-l, indoliziny!, indolyl, 3H-indolyl, isobenzofuranyl, isochromany-I, isoindazolwl, isoindolinyl, isoindolyl, isoquinolinyyl (benzimidaazolyl), isothiazolidinyl, 2-isothiazolinyl, isothiazoly-1, isoxazolyl, isoxazolidinyl, 2-isoxazolinyl, 2'-methylbiphenyl-2-ol, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5- [ oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxothiolanyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiiny!, phenoxazinyl, phthalazinyl, pipe razinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridothiophenyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pryrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydro- pyridinyl, 6H-1,2 5-thiadazinyl, 1,2,3-thiadiazolyl, 1,2,4-thia- diazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, : thiazolyl, thienwl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thwiomorpholinyl, thiophenyl, triazinyl, 1,2,3- triazolyl, 1,2,4-tria=zolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl, and are unsubstituted or substituted, independently of each other, once, twice or three times, by G, or 3) is one of the following radicals H H and thesc radicals are unsubstituted or substituted once by G, Gis 1) hydrogen atom, 2) halogen, 3) =0, : 4) -(C1-Ce)-alky l, in which alkyl is unsubstituted or substituted, once, twice or three times, by halogen, -(C3-Cs)-cycloalkyl, -(C2-Cg)-alkynyl, -(Ce-Cis)-aryl or Het ring, whesre aryl and Het ring are defined as above, 5) -(Ce-C14)-aryll, where aryl is defined as above, 6) Het ring, where Het ring is defined as above, 7) -C(0)-0-R10», in which R10 is a) -(Cq-Ce»-alkyl, in which alkyl is unsubstituted or substitu ted, once or twice, by -(C3-Cg)-cycloalkyl,-(C2-Ce)-alkynyl, -(Ce-C14)-aryl or Heat ring, where aryl and Het ring are defined as abowe, or ( b) -(Ce-Cua)-aryl or Het ring, where aryl and Het ring are defined as above, 8) -C(8)-0-R10, where R10 is defined as abowe, 9) -C(O)-NH-R11, in which R11 is a) -(C4+-Cg)-alkyl, in which alkyl is unsubstituted or substituted, once or twice, by -(C3-Cs)-cycloalkyl, -(C2-Ce)-alkynyl, -(C¢-C14)-ary! or Heat ring, where aryl and Het ring are defined as abowe, or b) -(Ce-C14)-aryl or Het ring, where aryl and Het ring are defined as above,10) -C(S)-NH-R11, in which R11 is defined as above, : 11) -O-R12, in which R12 is a) hydrogen atom,b) -(C+-Ce)-alkyl, in which alkyl is unsubstituted or substituted, once, twice or three times, by halogen, -(C;-Cs)-cycloalkyl, -(C2-Ce)-alkynyl, - (Cs-C1a)-aryl or Het ring, where aryl and Het ring are defined as above,c) -(Ce-C14)-aryl, where aryl is defined as above,d) Het ring, where Het ring is defined as above,e) -C(0)-0-R13, in which R13 is e)l ) -(C4-Ce)-alkyl, in which alkyl is unsubstituted or substituted, once or twice, by -(C3-Ce)-cycloalkyl, -(C2-Ce)- alkynyl, -(Ce-C14)-aryl, or Hest ring, where aryl and Het ring are defined as above, or€)2) -(Ce-Cis)-aryl or Het ring, where aryl andHet ring are defined as abowe,f) -C(S)-0-R13, in which R13 is defined as above,a) -C(O)-NH-R14, in which R14 is a) -(C+-Ce)-alkyl, in which alkyl is unsubstituted or substituted, once or twice, by -(C3-Cs)-cycloalkyl, -(C2-Cg)- alkynyl, -(Ce-C1s)-aryl or Heat ring, where aryl and Het ring are defined as above, or g)2) -(Ce-Cis)-aryl or Het ring, where aryl and Het ring are defined as abowe, or h) -C(S)-NH-R14, in which R14 is defined as above, 12) -C(0)-R10, in which R10 is defined as above, C 13) -S(0),-R12, in which R12 is defined as above and p is the integers zero, 1 or 2, 14) -NO,, 15) -CN, or 16) -N(R15)-R12, in which R15 is 16)1) hydrogen atom, 16)2) -(C4-Cg)-alkyl or 16)3) -SO,-(C4-Ce)-alkyl, in which alkyl is unsubstituted or substituted, once or twice, by -(C3-Ce)-cycloalkyl, - (C2-Cs)-alkynyl, -(Cs-C1a)-aryl or Het ring, and R12 is defined as above, : 17) -S0,-N(R12)-R1, in which R12 is defined as above and R1 is defined as below, Xis -OH or -NH-OH, n1tis the integer 1 or 2, n2 is the integer 2 or 3, R1, R2, R3, R4 and R5 are identical or differe nt and are, independently of each other, 1) hydrogen atom, 2) -(C+-Ce)-alkyl, in which alkyl is unsubstituted o r substituted, once or twice, by -(C3-Ce)-cycloalkyl, -(C2-Cs)-alkynyl, -(Ce- Cia4)-aryl or Het ring, 3) -C(0)-0O-R8, in which R8 is 3)1) hydrogen atom, 3)2) -(C+-Ce)-alkyl, in which alkyl is unsubstituted or substituted, once or twice, by -(C3-Cg)-cycloalkyl, -(Co-Ce)-alkynyl, -(Ce-Cia)-aryl or Het ring, or is substituted once to five times by fluorine, or 3)3) -(Ce-C1s)-aryl or Het ring, 4) -0-R8, in which R8 has the abovementioned meaning, or 5) -(C3-Cg)-cycloalkyl.3. A compound of the formula | as claimed in claim 1 or 2, wherein Ais -(Cy-Cs)-alkylene, B, DD and E are identical or different and are, independently of each othesr, -(Co-Cq4)-alkylene or the radical -B1-B2-B3- in which B1is -(CHz).-, in which n is the integer zero, 1 or 2,B3is -(CHz)m-, in which m is the integer zero, 1 or 2, with the proviso that the sum of n and m amounts to zero, 1 or 2, ® and B2is 1) -(Co-C2)-alkylene, 2) ethenylene, 3) ethynylene, 4) -C(O)- 5) -N(R6)-C(O)-, in which R6 is hydrogen atom, methyl or ethyl, 6) -C(O)-N(R6)-, in which R6 is defined as above, 7) -O-, or 8) -S-, ring1, ring2 and rimg3 are identical or different and are, independently of each other, 1) covalent bond, 2) phenyl or naphthyl and are unsubstituted or substituted, independently off each other, once or twice, by G, or 3) Het ring, in whi ch the Het ring is a radical from the series dihydrofuranyl, furanyl, pyridinyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiaazolyl or thiophenyl, and the radicals are unsubstituted ow substituted, independently of each other, once or twice, by G, ring4 is 1) phenyl or naphthyl and is unsubstituted or substituted, independently of each other, once or twice, by G,2) Het ring, in which the liet ring is a radical from the series benzofuranyl, dihydrofuranyl, dibenzofuranyl, dibenzothiopherwyl, furanyl, 2'-methylbiphenyl-2-ol, morpholinyl, piperazinyl, piperidinyl, pyridinyl, pyrimidinyl,pyridothiophenyl , pyrrolyl, pyrrolidinyl, thiazolyl or thiophenyl and is unsubstituted or substituted, independently of each other, once or twice, by G, or3) the following rad icalOTTO and this radical iss unsubstituted or substituted once by G,Gis 1) hydrogen atom, 2) Br, Clor F, ® 3) -(C4-Cy)-alkyl, im which alkyl is unsubstituted or substituted once or twice by F, phenyl, -Cs-cycioalkyl or Het ring, where Het ring is defined as above, 4) phenyl, 5) Het ring, where Het ring is defined as above, 6) -C(0)-0-R10, in which R10 is a) -(C4-Cs)-alkwyl, in which alkyl is unsubstituted or substituted, once or twice, by cyclopropyl, phenyl or Het ring, where Het ring is defined as above, b) phenyl, or Cc) Het ring, wheere Het ring is defined as above, 7) -C(O)-NH-R11, in which R11 is a) -(C1-Ce)-alkwyl, in which alkyl is unsubstituted or substituted, once or twice, by cyclopropyl, phenyl or Het ring, where Het ring is defined as above, b) phenyl, or c) Het ring, wheere Het ring is defined as above, 8) -0-R12,in which R12 is a) hydrogen atom,b) -(C1-Ce)-alkwyl, in which alkyl is unsubstituted or substituted, once, twice or three times, by halogen, cysclopropyl, phenyl or Het ring, whereHet ring is dlefined as above,Cc) phenyl,d) Het ring, whaere Het ring is defined as above,e) -C(0)-0O-R1 3, in which R13 is e)l) -(C+-Ce)-alkkyl, in which alkyl is unssubstituted or substituted, once or twice, by cyclopropyl, phenyl or Het ring, where Het ring is defined as above, or e)2) phenyl or Het ring, where Het ring is defined as above,f) -C(S)-0-R13, in which R13 is defined as above,or a) -C(O)-NH-R:14, in which R14 is g)t) -(C4-Cg)-alkkyl, in which alkyl is unssubstituted or substituted, once or twice, by phenyl or Het ring, where Het ring is defined as above, or ¢ a)2) phenyl or Het ring, where Het ring is defined as above, 9) -C(0)-R10, in which R10 is defined as above, 10) -S(O),-R12, in which R12 is defined as above a nd p is the integers 1 or 2, 11) -NO., 12) -CN, or 13) -N(R15)-R12, in which R15 is 13)1) hydrogen atom, or 13)2) -(C4-Ce)-alkyl and R12 is defined as above , Xis -OH or -NH-OH, n1is the integer 1 or 2, n2is the integer 2 or 3, R1, R2 and R3 are in each case hydrogen atom, R4 and R5 are identical or different and are, independently of each other, 1) hydrogen atom, 2) methyl, 3) ethyl, or 4) -OH.
- 4. A cornpound of the formula | as claimed in one or more of claims 1 to 3, wherein Ais -(Co-Cs)-alkylene, B, D and E are identical or different and are, independently of each other, -(Co-C4)-alkylene or the radical -B1-B2-B3- in which B1is -(CH2).-, in which n is the integer zero, 1 or 2, B3is -(CH2)m-, in which m is the integer zero, 1 or 2, with the proviso that the sum of n and m amounts to zero, 1 or 2, and B2is 1) -(Co-Cp)-alkylene, 2) ethenylene, or 3) ethynylene, ring1, ring2 and ring3 are identical or different and are, indepesndently of each other, 1) covalent bond,a) -(C1-Csq)-alkyl, in which alkyl is unsubstituted or substituted, once or twice, by cyclopropyl, phenyl ® or Het ring, where Het ring is defined as above, b) phenyl or naphthyl, or c) Het ring, where Het ring is defined as above, 8) -0O-R12,in which R12 is a) hydrogen atom, b) -(C1=Ce)-alkyl, in which alkyl is unsubstituted or substituted, once, twice or three times, by halo gen, cyclopropyl, phenyl or Het ring, where Het ring is defined as above, c) phenyl, d) Het ring, where Het ring is defined as above, e) -C(O)-0-R13, in which R13 is e)1) -(C1-Ce)-alkyl, in which alkyl is unsubstituted or substituted, once or twice, by cyclopropyl, phenyl, naphthyl, or Het ring, where Het ring is defined as above, or e)2) phenyl or Het ring, where Het ring is defined as above, f) -C(S)-0-R13, in which R13 is defined as above, or g) -C(O)-NH-R14, in which R14 is g)1) -(C1-Ce)-alkyl, in which alkyl is unsubstituted or substituted, once or twice, by phenyl or Het ring, where Het ring is defined as above, or g)2) phenyl or Het ring, where Het ring is defined as above, 9) -C(0O)-R10, in which R10 is defined as above, 10) -S(0),-R12Z, in which R12 is defined as above and p is the integers 1 or 2, 11) -NO., 12) -CN, or 13) -N(R15)-R12, in which R15 is 13)1) hydrogen atom, or 13)2) -(C41~Ce)-alkyl and R12 is defined as above, Xis -OH or -NH-OH,n1is the integer 2, n2 is the integer 3, ® R1, R2, R3, R4 and R5 are in each case hydrogen atom.
- 5. A compound of the formula | as claimed in one or more of claims 1 to 4, wherein Ais a covalent bond or —CH>-CHo-, B, D and E are identical or different and are, independently of each other, -(Co-C4)-alkylene or the radicaal -B1-B2-B3- in which B1is -(CH2),-, in which n is the integer zero, 1 or 2, B3is -(CH2)m- in which m is the imteger zero, 1 or 2, with the proviso that the sum of n an d m amounts to zero, 1 or 2, and B2is : 1) -C(O)- 2) -(C2-C4)-alkynylene, 3) -S(0)o-, where o is the integgers zero or 1, 4) -N(R6)-C(Y)-, in which Y is oxygen atom and R6 is hydrogen atom, 5) -C(Y)-N(R6)-, in which Y is oxygen atom and R6 is hydrogen atom, or 6) -O-, ring1, ring2 and ring3 are identical or different and are, independently of each other, 1) covalent bond, 2) phenyl and are unsubstituted or substituted, independently of each other, once or twice, bey G, or 3) Het ring, in which the Het ring is a radical from the series furanyl, pyridinyl, pyrimidinyl or thiophenyl, and are unsubstituted or substituteed, independently of each other, once or twice, by G, ring is 1) phenyl and is unsubstituted or substituted, independently of each other, once or twice, bey G, 2) Het ring, in which the Het ring is a radical from the series benzofuranyl, dibenzofuran yl, furanyl, 2’-methylbiphenyl-2-ol, morpholinyl, piperazinyl, ppiperidinyl, pyridinyl, pyrimidinyl, pyridothiophenyl, pyrrolyl, pyrrolidinyl, thiazolyl or thiophenyl and is unsubstituted or substituted, independently of each other, once or twice, by G, or3) the following radical ° Eye 0 N Oo and this radical is unsubstituted or substituted once by G, Gis 1) hydrogen atom,2) Br, ClorF,3) -(C1-Cy4)-alkyl, in which alkyl is unsubstituted or substituted once, twice or three times, by Br, CI, F, -Cs- cycloalkyl, phenyl or Het ring, where Het ring is defined as above,4) phenyl,5) Hetring, where Het ring is defined as above,
- 6) -C(0)-0-R10, in which R10 is a) -(C4+-Ce)-alkyl, in vwhich alkyl is unsubstituted or substituted, once or twice, by cyclopropyl, phenyl or Het ring, where Het ring is defined as above,b) phenyl, or c) Hetring, where He tring is defined as above,
- 7) -C(0)-NH-R11, in which R11 is a) -(C+-Ce)-alkyl, in vwhich alkyl is unsubstituted or substituted, once or twice, by cyclopropyl, phenyl or Het ring, where Het ring is defined as above,b) phenyl, or c) Hetring, where ie tring is defined as above,
- 8) -0-R12, in which R12 is a) hydrogen atom,b) -(C+-Cs)-alkyl, in vvhich alkyl is unsubstituted or substituted, once, twice or three times, by halogen, cyclopropyl, phenyl or Het ring, whereHet ring is defined as above,c) phenyl,d) Hetring, where He tring is defined as above,e) -C(0)-0-R13, in which R13 is e)1) -(C+-Ce)-al kyl, in which alkyl is unsubstituted or substituted, once or twice, by cyclopropyl, phenyl or Het ring, where Het ring is defined as above, or e)2) phenyl or Het rings, where Het ring is defined as above, ® f) -C(S)}-0-R13, in which R13 is defined as above, or g) -C(O)-NH-R14, in which R14 is gy) -(C1-Ce)-alkyl, in which alkyl is unsubstituted or substituted, once or twice, by phenyl or Het ring, where Het ring is defined as above, or g)2) phenyl or Het ring, where Het ring is defined as above, 9) -C(O)-R10, in which R10 is defined as above, 10) -S(0),-R12, in which R12 is defined as above and p is : the integers zero, 1 or 2, 11) -NO,, 12) -CN, or 13) -N(R15)-R12, in which R15 is 13)1) hydrogen atom, or 13)2) -(C4-Cg)-alkyl and R12 is defined as above, Xis -NH-OH, n1is the integer 2, n2is the integer 3, and R1, R2, R3, R4 and R5 are in each case hydrosgen atom.6. A compound of the formula | as claimed in orme or more of claims 1 to 5, which is a compound from the series 2-(4’-nitrobiphenyl-4-sulfonyl)decahydroisoquiroline-1-(N- hydroxy)carboxamide, 2-(4'-chlorobiphenyl-4-sulfonyl)decahydroisoquiinoline-1-carboxylic acid, 2-(4'-chlorobiphenyl-4-sulfonyl)decahydroisogquiinoline-1-(N- hydroxy )carboxamide, 2-(6-phenoxypyridine-3-sulfonyl)decahydroisoquinoline-1-carboxylic acid; trifluoroacetate, 2-(6-phenoxypyridine-3-sulifonyl)decahydroisocqquinoline-1-(N- hydroxy)carboxamide; trifluoroacetate, 2-[2-(4'-chlorobiphenyl-4-yl)ethanesulfonyllJdeccahydroisoquinoline-1- carboxylic acid, /2-[2-¢4'-chlorobiphenyl-4-yl)ethanesulfonylldecahydroisoquineline-1- (N-hy/droxy)carboxamide,C 2-[4-(pyridin-4-yloxy)benzenesulfonylldecahydroisoquinoline- 1- carboxylic acid; trifluoroacetate,2-[4-(pyridin-4-yloxy)benzenesulfonyljdecahydroisoquinoline—1-(N- hydroxy)carboxamide; trifluoroacetate, 2-[4-q4-methoxyphenoxy)benzenesulfonylldecahydroisoquinoline-1- carboxylic acid, 2-[4-(4-methoxyphenoxy)benzenesulfonyl]decahydroisoquincline-1-(N-hwdroxy)carboxamide,2-{4- [4-(2,2,2-trifluoroethoxy)phenoxy]benzenesulfonyl}decatydro- isoquiinoline-1-carboxylic acid, 2-{4-[4-(2,2,2-trifluoroethoxy)phenoxy]benzenesulfonyl}decatydro- isoquiinoline-1-(N-hydroxy)carboxamide,2-[4'=(2,2,2-trifluoroethoxy)biphenyl-4-sulfonylldecahydroiso- quinoline-1-carboxylic acid, 2-(4'-isopropoxycarbonylaminobiphenyl-4-sulfonyl)decahydroiso- quinoline-1- carboxylic acid,[4'-(1 -hydroxycarbamoyloctahydroisoquinoline-2-sulfonyl)biphhenyl-4-yl]ca rboxamide isopropyl! ester, 2-[4'-(2,2,2-trifluoroethoxy)biphenyl-4-sulfonyl]decahydroiso- quinoline-1-(N-hydroxy)carboxamide,2-(4' -trifluoromethoxybiphenyl-4-sulfonyl)decahydroisoquinol ine-1- (N-hydroxy)carboxamide,2-[4—(4-fluorophenoxy)benzenesulfonylldecahydroisoquinolirme-1-(N- hydroxy)carboxamide, 2-[4—(4-trifluoromethoxyphenoxy)benzenesulfonylldecahydro iso- quin oline-1-(N-hydroxy)carboxamide, 2-[4—(4-trifluoromethoxyphenoxy)benzenesulfonylldecahydrosiso-quin oline-1- carboxylic acid, 2-(biiphenyl-4-sulfonyl)decahydroisoquinoline-1 -(N-hydroxy)car- boxamide, 2-(biiphenyl-4-sulfonyl)decahydroisoquinoline-1-carboxylic acid, 2-[4~(4-cyanophenoxy)benzenesulfonylldecahydroisoquinolirie-1-(N-hydroxy)carboxamide,2-(d ibenzofuran-2-sulfonyl)decahydroisoquinoline-1-carboxy-lic acid, 2-(d ibenzofuran-2-sulfonyl)decahydroisoquinoline-1-(N-hydreoxy)car- boxamide, or A2-[4-(4-fluorophenoxy)beanzenesulfonyl]-6-methoxydecahydroiso- quinoline-1-(N-hydroxy)carboxamide, and also all the isomeric forms ( of the abovementioned compounds.7. A process for preparing the compound of the formula | as claimed in one or more of claims 1 &o 6, which comprises a) reacting a compowund of the formula IV, 0) n2\R2 Re 0) SE (Iv) R5 R3 in which Re is a hydroge=n atom or an ester-protecting group, with a compound of the ®ormula V, 2 Rz—S— A —Ting,——B—ring;~D—rings~E ring, (V) @) in which A, B, D, E and rring1, ring2, ring3 and ring4 are defined as in formula |, and in which Rz is chlorine atom, imidazoyl or OH, in the presence of a base or following silylation with a suitable silylating agent, or usin g a suitable dehydrating agent when Rz = OH, to give a compound of the formula VI, n2 'e) R2 \ Re oO R4 N 0 ' . R5R3 $— A ——ring,—B—ring;—D——ring;"E—ring, (V1) oO in which A, B, D, E, Re and ring1, ring2, ring3 and ring4 are defined as above, or b) when Re = ester reacting a compound of the formula Vi prepared as described in a) with a solution of alkali such as NaOH or ( LiOH, and then treating the prod uct with acid, to give the carboxylic acid according to the invention of the formula |, in which X = OH (corresponding to VII), with modifications in one of the side chains of the rings ring1-ringd also having previously been made, where appropriate; or converting said ester, by treating it with a mineral acid, such as hydrochloric acid, into the free carboxylic acid VII n2 0 - ry ~OH R4 : N, 0 . . R5R3 8— A—ring,— BB—ring;-D—ring;-E—ring, (vi) O and then converting this into the hydroxamic acid according to the invention, in which X = NH-OH, of the formula |, or c) using salt formation wit h enantiomerically pure acids or bases, chromatography on chiral stationary phases, or derivatization with chiral, enantiomerically pure compounds such as amino acids, separation of the resulting diastereomers and elimination of the chiral auxiliary groups, to separate a compound of formula prepared as described in procedure a), or a suitable precursor of the formula |, which arises in enantiomeric forms due to its chemical structure, into the pure enantiomeers, or d) either isolating the comp ound of the formula | prepared as described in procedures b) or c) in free form, or, when acid or basic groups are present, converting it into physiologically tolerated salts.8. A pharmaceutical, which comprises an effective content of at least one compound of the formula | a s claimed in one or more of claims 1 to 6 together with a pharmaceutically suitable and physiologically tolerated carrier substance, additive and/or other active compounds and auxiliary substances.
- 9. The use of the compound of formula | as claimed in one or more of ® claims 1 to 6 for producing a pharmaceutical for the prophylaxis and therapy of degenerative joint diseases such &s osteoarthroses, spondyloses and chondrolysis following joint traurma or a relatively long period of joint immobilization following meniscus injuries or patella injuries or ligament ruptures, diseases of the connective tissue such as collagenoses, periodontal diseases, wound healing disturbances and chronic diseases of the locomoteory apparatus such as inflammatory, immunologically determined or metabolism- determined acute and chronic arthritides, arthropathies, myalgias and disturbances of bone metabolism, for the treatment of ulceration, atherosclerosis and stenoses, for the treatment of : inflammations, cancer diseases, tumor metastases formation, cachexia, anorexia, heart failure and septic shock, or for the prophylaxis of myocardial and cerebral infarctions -
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10344936A DE10344936A1 (en) | 2003-09-27 | 2003-09-27 | Bicyclic imino acid derivatives as inhibitors of matrix metalloproteinases |
Publications (1)
Publication Number | Publication Date |
---|---|
ZA200601501B true ZA200601501B (en) | 2007-04-25 |
Family
ID=34353126
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ZA200601501A ZA200601501B (en) | 2003-09-27 | 2006-02-21 | Bicyclic imino acid derivatives used as inhibitors of matrixmetalloproteinases |
Country Status (24)
Country | Link |
---|---|
EP (1) | EP1670766B1 (en) |
JP (1) | JP4861179B2 (en) |
KR (1) | KR20060086367A (en) |
CN (1) | CN1856478B (en) |
AR (1) | AR046165A1 (en) |
AT (1) | ATE550327T1 (en) |
AU (1) | AU2004275937A1 (en) |
BR (1) | BRPI0414594A (en) |
CA (1) | CA2539731A1 (en) |
DE (1) | DE10344936A1 (en) |
IL (1) | IL174040A0 (en) |
MA (1) | MA28075A1 (en) |
ME (1) | MEP33008A (en) |
MX (1) | MXPA06002927A (en) |
MY (1) | MY139830A (en) |
NO (1) | NO20061837L (en) |
NZ (1) | NZ546158A (en) |
PE (1) | PE20050432A1 (en) |
RS (1) | RS20060194A (en) |
RU (1) | RU2335494C2 (en) |
TW (1) | TW200520755A (en) |
UY (1) | UY28539A1 (en) |
WO (1) | WO2005030728A1 (en) |
ZA (1) | ZA200601501B (en) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE102004031850A1 (en) * | 2004-06-30 | 2006-01-26 | Sanofi-Aventis Deutschland Gmbh | Substituted tetrahydroisoquinolines as MMP inhibitors, process for their preparation and their use as medicaments |
DE102004031620A1 (en) * | 2004-06-30 | 2006-02-02 | Sanofi-Aventis Deutschland Gmbh | 4-trifluoromethoxyphenoxybenzene-4'-sulphonic acids, process for their preparation and use in medicaments |
DE102005002500A1 (en) * | 2005-01-19 | 2006-07-27 | Sanofi-Aventis Deutschland Gmbh | Tetrahydrofuran derivatives as inhibitors of matrix metalloproteinases |
DE102005015040A1 (en) * | 2005-03-31 | 2006-10-05 | Sanofi-Aventis Deutschland Gmbh | Substituted tetrahydroisoquinolines as MMP inhibitors, process for their preparation and their use as medicament |
US8790714B2 (en) | 2007-08-03 | 2014-07-29 | Nucitec, S.A. De C.V. | Compositions and methods for treatment and prevention of osteoarthritis |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW201303B (en) * | 1990-07-05 | 1993-03-01 | Hoffmann La Roche | |
US5455258A (en) * | 1993-01-06 | 1995-10-03 | Ciba-Geigy Corporation | Arylsulfonamido-substituted hydroxamic acids |
FR2701480B1 (en) * | 1993-02-15 | 1995-05-24 | Sanofi Elf | Compounds with a sulfamoyl and amidino group, process for their preparation and pharmaceutical compositions containing them. |
DE59608740D1 (en) * | 1995-11-13 | 2002-03-21 | Hoechst Ag | CYCLIC AND HETEROCYCLIC N-SUBSTITUTED ALPHA-IMINOHYDROXAMIC AND CARBONIC ACIDS |
HUP0000505A3 (en) * | 1996-08-28 | 2001-12-28 | Procter & Gamble | Saturated 7-9 membered heterocyclic n-hydroxycarboxamide derivatives and pharmaceutical compositions containing them |
YU34599A (en) * | 1997-01-23 | 2002-03-18 | F. Hoffmann-La Roche Ag. | Sulfamide-metalloprotease inhibitors |
DE10300015A1 (en) * | 2003-01-03 | 2004-07-15 | Aventis Pharma Deutschland Gmbh | Imino acid derivatives as inhibitors of matrix metal proteinases |
DE102004031620A1 (en) * | 2004-06-30 | 2006-02-02 | Sanofi-Aventis Deutschland Gmbh | 4-trifluoromethoxyphenoxybenzene-4'-sulphonic acids, process for their preparation and use in medicaments |
-
2003
- 2003-09-27 DE DE10344936A patent/DE10344936A1/en not_active Withdrawn
-
2004
- 2004-09-14 AU AU2004275937A patent/AU2004275937A1/en not_active Abandoned
- 2004-09-14 KR KR1020067005981A patent/KR20060086367A/en not_active Application Discontinuation
- 2004-09-14 WO PCT/EP2004/010248 patent/WO2005030728A1/en active Application Filing
- 2004-09-14 AT AT04786944T patent/ATE550327T1/en active
- 2004-09-14 CA CA002539731A patent/CA2539731A1/en not_active Abandoned
- 2004-09-14 BR BRPI0414594-1A patent/BRPI0414594A/en not_active IP Right Cessation
- 2004-09-14 NZ NZ546158A patent/NZ546158A/en unknown
- 2004-09-14 JP JP2006527308A patent/JP4861179B2/en not_active Expired - Fee Related
- 2004-09-14 CN CN2004800279029A patent/CN1856478B/en not_active Expired - Fee Related
- 2004-09-14 RU RU2006114352/04A patent/RU2335494C2/en not_active IP Right Cessation
- 2004-09-14 EP EP04786944A patent/EP1670766B1/en active Active
- 2004-09-14 MX MXPA06002927A patent/MXPA06002927A/en active IP Right Grant
- 2004-09-14 ME MEP-330/08A patent/MEP33008A/en unknown
- 2004-09-14 RS YUP-2006/0194A patent/RS20060194A/en unknown
- 2004-09-21 PE PE2004000918A patent/PE20050432A1/en not_active Application Discontinuation
- 2004-09-23 TW TW093128791A patent/TW200520755A/en unknown
- 2004-09-23 AR ARP040103437A patent/AR046165A1/en not_active Application Discontinuation
- 2004-09-25 MY MYPI20043935A patent/MY139830A/en unknown
- 2004-09-27 UY UY28539A patent/UY28539A1/en unknown
-
2006
- 2006-02-21 ZA ZA200601501A patent/ZA200601501B/en unknown
- 2006-03-01 IL IL174040A patent/IL174040A0/en unknown
- 2006-03-27 MA MA28892A patent/MA28075A1/en unknown
- 2006-04-26 NO NO20061837A patent/NO20061837L/en not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
MA28075A1 (en) | 2006-08-01 |
KR20060086367A (en) | 2006-07-31 |
IL174040A0 (en) | 2006-08-01 |
MEP33008A (en) | 2010-10-10 |
EP1670766B1 (en) | 2012-03-21 |
JP2007506690A (en) | 2007-03-22 |
EP1670766A1 (en) | 2006-06-21 |
NO20061837L (en) | 2006-06-01 |
PE20050432A1 (en) | 2005-07-21 |
AU2004275937A1 (en) | 2005-04-07 |
BRPI0414594A (en) | 2006-11-07 |
CA2539731A1 (en) | 2005-04-07 |
AR046165A1 (en) | 2005-11-30 |
UY28539A1 (en) | 2005-04-29 |
RS20060194A (en) | 2008-08-07 |
WO2005030728A1 (en) | 2005-04-07 |
CN1856478A (en) | 2006-11-01 |
JP4861179B2 (en) | 2012-01-25 |
TW200520755A (en) | 2005-07-01 |
RU2006114352A (en) | 2006-08-27 |
MXPA06002927A (en) | 2006-06-14 |
ATE550327T1 (en) | 2012-04-15 |
CN1856478B (en) | 2010-05-26 |
RU2335494C2 (en) | 2008-10-10 |
NZ546158A (en) | 2008-11-28 |
MY139830A (en) | 2009-10-30 |
DE10344936A1 (en) | 2005-04-21 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP4733648B2 (en) | Thieno-imino acid derivatives for use as matrix metalloproteinase inhibitors | |
ZA200601501B (en) | Bicyclic imino acid derivatives used as inhibitors of matrixmetalloproteinases | |
AU2007297013B2 (en) | Isoserine derivatives for use as coagulation factor IXa inhibitors | |
CN103864793A (en) | Substituted purin-9-acetamino isohydroxamic acid histone deacetylase inhibitor and preparation method and application thereof | |
CN115304583B (en) | 5-pyridine-1H-indazole compound for targeted inhibition of CLK2 and application thereof | |
CN107056755A (en) | Five-ring heterocycles amide-type WNT pathway inhibitors | |
CN103102352A (en) | Tyrosine kinase inhibitor indolinone derivative | |
CN104529933B (en) | Replace o-benzoic sulfimide histone deacetylases inhibitor and preparation method and application | |
US20060252752A1 (en) | Imino acid derivatives as inhibitors of matrix metalloproteinases | |
CN1393446A (en) | Fused pyrazole compound | |
CN105153163B (en) | 2,9-disubstituted purine-6-amino hydroxamic acid HDAC (histone deacetylase) inhibitor, preparation method and application | |
US7205315B2 (en) | Bicyclic imino acid derivatives as inhibitors of matrix metalloproteinases | |
CN108997230A (en) | Quinoxaline derivant and its preparation method and application with matrix metalloproteinase inhibitory activity | |
KR20070026662A (en) | 4-trifluoromethoxyphenoxybenzol-4'-sulfonic acids, method for the production and use thereof in medicaments | |
KR101315788B1 (en) | Tetrahydrofuran derivatives for use as inhibitors of matrix metalloproteinases | |
Kosareva et al. | Sepsis-Induced Inhibition of Contractile Function of Lymphatic Nodes | |
CN115785071A (en) | 3-ethynyl-5- (1H-1,2,3-triazole-4-yl) -1H-indazole compound and application thereof | |
JPS6212753A (en) | Novel anthranilic acid derivative |