SK284377B6 - Päťčlenné heterocyklické zlúčeniny ako inhibítory adhézie leukocytov, antagonisty VLA-4 a farmaceutický prostriedok, ktorý ich obsahuje - Google Patents

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Publication number

SK284377B6

SK284377B6 SK1526-97A SK152697A SK284377B6 SK 284377 B6 SK284377 B6 SK 284377B6 SK 152697 A SK152697 A SK 152697A SK 284377 B6 SK284377 B6 SK 284377B6

Authority

SK

Slovakia

Prior art keywords

carbon atoms

alkyl

group

moiety

aryl

Prior art date

1996-11-15

Links

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• 108010008212 Integrin alpha4beta1 Proteins 0.000 title claims abstract description 77
• 230000023404 leukocyte cell-cell adhesion Effects 0.000 title claims abstract description 24
• 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 7
• 239000005557 antagonist Substances 0.000 title abstract description 9
• 239000003112 inhibitor Substances 0.000 title abstract description 6
• 150000000565 5-membered heterocyclic compounds Chemical class 0.000 title description 2
• 210000000265 leukocyte Anatomy 0.000 claims abstract description 41
• 239000003814 drug Substances 0.000 claims abstract description 34
• 230000005012 migration Effects 0.000 claims abstract description 32
• 238000013508 migration Methods 0.000 claims abstract description 32
• 238000011321 prophylaxis Methods 0.000 claims abstract description 20
• 201000010099 disease Diseases 0.000 claims abstract description 15
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 15
• 230000004054 inflammatory process Effects 0.000 claims abstract description 11
• 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 8
• 229910052727 yttrium Inorganic materials 0.000 claims abstract description 8
• 125000004432 carbon atom Chemical group C* 0.000 claims description 1404
• 125000000217 alkyl group Chemical group 0.000 claims description 833
• 125000003118 aryl group Chemical group 0.000 claims description 502
• -1 phenylene, phenylene Chemical group 0.000 claims description 355
• 125000003545 alkoxy group Chemical group 0.000 claims description 238
• 150000003254 radicals Chemical class 0.000 claims description 184
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 180
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 119
• 125000003107 substituted aryl group Chemical group 0.000 claims description 103
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 96
• 239000000203 mixture Substances 0.000 claims description 84
• 150000003839 salts Chemical class 0.000 claims description 73
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 66
• 239000002253 acid Substances 0.000 claims description 65
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 63
• 229910052799 carbon Inorganic materials 0.000 claims description 56
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 54
• 125000002947 alkylene group Chemical group 0.000 claims description 53
• 229910052717 sulfur Inorganic materials 0.000 claims description 51
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 49
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 49
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 49
• 229910052760 oxygen Inorganic materials 0.000 claims description 49
• 239000001301 oxygen Substances 0.000 claims description 49
• 239000011593 sulfur Substances 0.000 claims description 49
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 46
• 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 claims description 44
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 42
• 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 40
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 38
• 229910052757 nitrogen Inorganic materials 0.000 claims description 38
• 229910052736 halogen Inorganic materials 0.000 claims description 37
• 125000003277 amino group Chemical group 0.000 claims description 36
• 125000005842 heteroatom Chemical group 0.000 claims description 36
• 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 36
• 150000001602 bicycloalkyls Chemical group 0.000 claims description 35
• 150000002367 halogens Chemical class 0.000 claims description 35
• 125000001072 heteroaryl group Chemical group 0.000 claims description 35
• PIGFYZPCRLYGLF-UHFFFAOYSA-N Aluminum nitride Chemical compound [Al]#N PIGFYZPCRLYGLF-UHFFFAOYSA-N 0.000 claims description 34
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 34
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 34
• 125000002619 bicyclic group Chemical group 0.000 claims description 33
• 230000002401 inhibitory effect Effects 0.000 claims description 33
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 33
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 31
• 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 31
• 238000002360 preparation method Methods 0.000 claims description 31
• 229920006395 saturated elastomer Polymers 0.000 claims description 31
• 125000003342 alkenyl group Chemical group 0.000 claims description 30
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 30
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 30
• 125000001841 imino group Chemical group [H]N=* 0.000 claims description 30
• 108010016626 Dipeptides Proteins 0.000 claims description 29
• 125000000524 functional group Chemical group 0.000 claims description 29
• 125000001424 substituent group Chemical group 0.000 claims description 29
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 28
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 26
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 25
• 238000011282 treatment Methods 0.000 claims description 25
• 125000005914 C6-C14 aryloxy group Chemical group 0.000 claims description 24
• 150000005840 aryl radicals Chemical class 0.000 claims description 24
• 125000000623 heterocyclic group Chemical group 0.000 claims description 24
• 125000005974 C6-C14 arylcarbonyl group Chemical group 0.000 claims description 23
• 125000005096 aminoalkylaminocarbonyl group Chemical group 0.000 claims description 22
• UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims description 22
• 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 21
• 229910052739 hydrogen Inorganic materials 0.000 claims description 21
• 125000006239 protecting group Chemical group 0.000 claims description 21
• 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 20
• 125000000539 amino acid group Chemical group 0.000 claims description 20
• 150000001413 amino acids Chemical group 0.000 claims description 20
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 19
• 150000002148 esters Chemical class 0.000 claims description 19
• 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 18
• 125000004429 atom Chemical group 0.000 claims description 18
• 125000005843 halogen group Chemical group 0.000 claims description 18
• 150000001408 amides Chemical class 0.000 claims description 17
• 125000004076 pyridyl group Chemical group 0.000 claims description 17
• 125000003831 tetrazolyl group Chemical group 0.000 claims description 17
• 125000000304 alkynyl group Chemical group 0.000 claims description 16
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 16
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
• 108090000765 processed proteins & peptides Proteins 0.000 claims description 16
• 235000001014 amino acid Nutrition 0.000 claims description 15
• 125000002950 monocyclic group Chemical group 0.000 claims description 15
• CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 15
• 125000005915 C6-C14 aryl group Chemical group 0.000 claims description 14
• 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 14
• HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical class [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 14
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 14
• VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 13
• 125000002993 cycloalkylene group Chemical group 0.000 claims description 13
• 125000004956 cyclohexylene group Chemical group 0.000 claims description 13
• 239000001257 hydrogen Substances 0.000 claims description 13
• 125000005090 alkenylcarbonyl group Chemical group 0.000 claims description 12
• 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 12
• 125000005100 aryl amino carbonyl group Chemical group 0.000 claims description 12
• 125000004104 aryloxy group Chemical group 0.000 claims description 12
• 125000005167 cycloalkylaminocarbonyl group Chemical group 0.000 claims description 12
• 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 12
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 12
• 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 claims description 12
• 125000003275 alpha amino acid group Chemical group 0.000 claims description 11
• 125000005129 aryl carbonyl group Chemical group 0.000 claims description 11
• 238000000034 method Methods 0.000 claims description 11
• 125000004450 alkenylene group Chemical group 0.000 claims description 10
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 9
• 125000005037 alkyl phenyl group Chemical group 0.000 claims description 9
• 150000001721 carbon Chemical group 0.000 claims description 9
• 239000003937 drug carrier Substances 0.000 claims description 9
• 125000006254 cycloalkyl carbonyl group Chemical group 0.000 claims description 8
• 125000005223 heteroarylcarbonyl group Chemical group 0.000 claims description 8
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 7
• 206010020751 Hypersensitivity Diseases 0.000 claims description 7
• 125000005087 alkynylcarbonyl group Chemical group 0.000 claims description 7
• 230000007815 allergy Effects 0.000 claims description 7
• 125000005099 aryl alkyl carbonyl group Chemical group 0.000 claims description 7
• 125000001624 naphthyl group Chemical group 0.000 claims description 7
• 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 6
• 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 6
• 206010061218 Inflammation Diseases 0.000 claims description 5
• KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 5
• KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 5
• 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 5
• 208000006673 asthma Diseases 0.000 claims description 5
• 230000001419 dependent effect Effects 0.000 claims description 5
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• 230000008569 process Effects 0.000 claims description 5
• HHAVGBXLGVYXFF-AWEZNQCLSA-N (2r)-n-[3-(heptylamino)-3-oxopropyl]-2,4-dihydroxy-3,3-dimethylbutanamide Chemical compound CCCCCCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)CO HHAVGBXLGVYXFF-AWEZNQCLSA-N 0.000 claims description 4
• 206010003210 Arteriosclerosis Diseases 0.000 claims description 4
• 206010027476 Metastases Diseases 0.000 claims description 4
• 125000005907 alkyl ester group Chemical group 0.000 claims description 4
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• 206010012601 diabetes mellitus Diseases 0.000 claims description 4
• 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims description 4
• 201000004792 malaria Diseases 0.000 claims description 4
• 230000009401 metastasis Effects 0.000 claims description 4
• 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 claims description 4
• 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 4
• 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 4
• 208000024172 Cardiovascular disease Diseases 0.000 claims description 3
• COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 3
• 206010028980 Neoplasm Diseases 0.000 claims description 3
• QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 claims description 3
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• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 2
• 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 2
• 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 2
• ZGUNAGUHMKGQNY-ZETCQYMHSA-N L-alpha-phenylglycine zwitterion Chemical compound OC(=O)[C@@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-ZETCQYMHSA-N 0.000 claims description 2
• QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 claims description 2
• KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims description 2
• 239000004472 Lysine Substances 0.000 claims description 2
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• 210000003954 umbilical cord Anatomy 0.000 description 1
• 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
• JOYRKODLDBILNP-UHFFFAOYSA-N urethane group Chemical group NC(=O)OCC JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
• 229960004295 valine Drugs 0.000 description 1
• 210000003556 vascular endothelial cell Anatomy 0.000 description 1
• 235000015112 vegetable and seed oil Nutrition 0.000 description 1
• 239000008158 vegetable oil Substances 0.000 description 1
• 239000003643 water by type Substances 0.000 description 1
• 239000001993 wax Substances 0.000 description 1
• 239000000080 wetting agent Substances 0.000 description 1
• 238000010626 work up procedure Methods 0.000 description 1