ES2324669T3 - Derivados de bencimidazol, composiciones que los contienen, su preparacion y sus usos. - Google Patents
Derivados de bencimidazol, composiciones que los contienen, su preparacion y sus usos. Download PDFInfo
- Publication number
- ES2324669T3 ES2324669T3 ES04768667T ES04768667T ES2324669T3 ES 2324669 T3 ES2324669 T3 ES 2324669T3 ES 04768667 T ES04768667 T ES 04768667T ES 04768667 T ES04768667 T ES 04768667T ES 2324669 T3 ES2324669 T3 ES 2324669T3
- Authority
- ES
- Spain
- Prior art keywords
- alkyl
- cycloalkyl
- methyl
- butyl
- heterocyclyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- 239000000203 mixture Substances 0.000 title description 20
- 238000002360 preparation method Methods 0.000 title description 8
- -1 cyclohexylethyl Chemical group 0.000 claims abstract description 114
- 150000001875 compounds Chemical class 0.000 claims abstract description 88
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 84
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 54
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 35
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 27
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 25
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 19
- 150000002367 halogens Chemical class 0.000 claims abstract description 19
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims abstract description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 15
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims abstract description 14
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims abstract description 14
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 125000000392 cycloalkenyl group Chemical group 0.000 claims abstract description 11
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 8
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims abstract description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 8
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 6
- 125000006002 1,1-difluoroethyl group Chemical group 0.000 claims abstract description 5
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims abstract description 5
- 125000004398 2-methyl-2-butyl group Chemical group CC(C)(CC)* 0.000 claims abstract description 5
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 claims abstract description 5
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 claims abstract description 5
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims abstract description 5
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims abstract description 5
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims abstract description 5
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims abstract description 5
- 125000006223 tetrahydrofuranylmethyl group Chemical group 0.000 claims abstract description 5
- 125000006173 tetrahydropyranylmethyl group Chemical group 0.000 claims abstract description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims abstract description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 32
- 125000003118 aryl group Chemical group 0.000 claims description 26
- 208000002193 Pain Diseases 0.000 claims description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 17
- 230000036407 pain Effects 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 14
- 238000002560 therapeutic procedure Methods 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 11
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- 208000035475 disorder Diseases 0.000 claims description 9
- 238000011282 treatment Methods 0.000 claims description 9
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 8
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 125000006413 ring segment Chemical group 0.000 claims description 5
- 208000019901 Anxiety disease Diseases 0.000 claims description 4
- 208000018737 Parkinson disease Diseases 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- KBLBICJACVRVPX-UHFFFAOYSA-N 2-tert-butyl-1-(cyclohexylmethyl)-n-(dimethylsulfamoyl)-n-methylbenzimidazol-5-amine Chemical compound CC(C)(C)C1=NC2=CC(N(C)S(=O)(=O)N(C)C)=CC=C2N1CC1CCCCC1 KBLBICJACVRVPX-UHFFFAOYSA-N 0.000 claims description 3
- 208000024827 Alzheimer disease Diseases 0.000 claims description 3
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- 208000023105 Huntington disease Diseases 0.000 claims description 3
- 206010028980 Neoplasm Diseases 0.000 claims description 3
- 201000011510 cancer Diseases 0.000 claims description 3
- 230000008878 coupling Effects 0.000 claims description 3
- 238000010168 coupling process Methods 0.000 claims description 3
- 238000005859 coupling reaction Methods 0.000 claims description 3
- 201000006417 multiple sclerosis Diseases 0.000 claims description 3
- VAQJTZCSQQRNFJ-UHFFFAOYSA-N n-[2-tert-butyl-1-(oxan-4-ylmethyl)benzimidazol-5-yl]-n-methylbutane-1-sulfonamide Chemical compound CC(C)(C)C1=NC2=CC(N(C)S(=O)(=O)CCCC)=CC=C2N1CC1CCOCC1 VAQJTZCSQQRNFJ-UHFFFAOYSA-N 0.000 claims description 3
- SKKPMWNRLILWKU-UHFFFAOYSA-N n-[2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]benzimidazol-5-yl]-n-methylbutane-1-sulfonamide Chemical compound CC(C)(C)C1=NC2=CC(N(C)S(=O)(=O)CCCC)=CC=C2N1CC1CCC(F)(F)CC1 SKKPMWNRLILWKU-UHFFFAOYSA-N 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- 230000002526 effect on cardiovascular system Effects 0.000 claims description 2
- QACIHMKLLVUOTD-UHFFFAOYSA-N n-[2-tert-butyl-1-(oxan-4-ylmethyl)benzimidazol-5-yl]-2-methoxy-n-methylethanesulfonamide Chemical compound CC(C)(C)C1=NC2=CC(N(C)S(=O)(=O)CCOC)=CC=C2N1CC1CCOCC1 QACIHMKLLVUOTD-UHFFFAOYSA-N 0.000 claims description 2
- 125000006542 morpholinylalkyl group Chemical group 0.000 claims 2
- 239000000376 reactant Substances 0.000 claims 1
- 125000000041 C6-C10 aryl group Chemical group 0.000 abstract 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 1
- 125000006719 (C6-C10) aryl (C1-C6) alkyl group Chemical group 0.000 abstract 1
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 54
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 41
- 239000000047 product Substances 0.000 description 25
- 239000002904 solvent Substances 0.000 description 25
- 235000019439 ethyl acetate Nutrition 0.000 description 20
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 125000004429 atom Chemical group 0.000 description 17
- 239000012267 brine Substances 0.000 description 17
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 229930195733 hydrocarbon Natural products 0.000 description 15
- 239000004215 Carbon black (E152) Substances 0.000 description 14
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 239000007864 aqueous solution Substances 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 11
- 102000009132 CB1 Cannabinoid Receptor Human genes 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 125000004432 carbon atom Chemical group C* 0.000 description 11
- 125000001072 heteroaryl group Chemical group 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 10
- 150000001721 carbon Chemical class 0.000 description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Substances ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 150000003254 radicals Chemical class 0.000 description 10
- 238000004007 reversed phase HPLC Methods 0.000 description 10
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 9
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 9
- 108010073366 CB1 Cannabinoid Receptor Proteins 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 9
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
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- 239000000556 agonist Substances 0.000 description 8
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 8
- AYXNGYVQUMYYKQ-UHFFFAOYSA-N 2-tert-butyl-n-methyl-1-(oxan-4-ylmethyl)benzimidazol-5-amine Chemical compound CC(C)(C)C1=NC2=CC(NC)=CC=C2N1CC1CCOCC1 AYXNGYVQUMYYKQ-UHFFFAOYSA-N 0.000 description 7
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
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- 238000003818 flash chromatography Methods 0.000 description 7
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- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- 235000019341 magnesium sulphate Nutrition 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- 102100036214 Cannabinoid receptor 2 Human genes 0.000 description 6
- 101000875075 Homo sapiens Cannabinoid receptor 2 Proteins 0.000 description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 6
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- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- ZVJHJDDKYZXRJI-UHFFFAOYSA-N pyrroline Natural products C1CC=NC1 ZVJHJDDKYZXRJI-UHFFFAOYSA-N 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- LJPZHJUSICYOIX-UHFFFAOYSA-N quinolizidine Chemical compound C1CCCC2CCCCN21 LJPZHJUSICYOIX-UHFFFAOYSA-N 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- SBYHFKPVCBCYGV-UHFFFAOYSA-N quinuclidine Chemical compound C1CC2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 210000002820 sympathetic nervous system Anatomy 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- DJCMTZUQWODNFQ-UHFFFAOYSA-N tert-butyl n-[(4,4-difluorocyclohexyl)methyl]carbamate Chemical compound CC(C)(C)OC(=O)NCC1CCC(F)(F)CC1 DJCMTZUQWODNFQ-UHFFFAOYSA-N 0.000 description 1
- KYOXDOGUXCYNAW-UHFFFAOYSA-N tert-butyl n-[(4-oxocyclohexyl)methyl]carbamate Chemical compound CC(C)(C)OC(=O)NCC1CCC(=O)CC1 KYOXDOGUXCYNAW-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- XSROQCDVUIHRSI-UHFFFAOYSA-N thietane Chemical compound C1CSC1 XSROQCDVUIHRSI-UHFFFAOYSA-N 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- IBBLKSWSCDAPIF-UHFFFAOYSA-N thiopyran Chemical compound S1C=CC=C=C1 IBBLKSWSCDAPIF-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000009529 traumatic brain injury Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
- 230000009278 visceral effect Effects 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
- HQVHOQAKMCMIIM-UHFFFAOYSA-N win 55,212-2 Chemical compound C=12N3C(C)=C(C(=O)C=4C5=CC=CC=C5C=CC=4)C2=CC=CC=1OCC3CN1CCOCC1 HQVHOQAKMCMIIM-UHFFFAOYSA-N 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
- C07D215/18—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/08—Radicals containing only hydrogen and carbon atoms
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
- A61P35/00—Antineoplastic agents
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
- C07D215/38—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/14—Radicals substituted by nitrogen atoms
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Psychology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
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| SE0302573A SE0302573D0 (sv) | 2003-09-26 | 2003-09-26 | Benzimidazole derivatives, compositions containing them, preparation thereof and uses thereof |
| SE2003102573 | 2003-09-26 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2324669T3 true ES2324669T3 (es) | 2009-08-12 |
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| Application Number | Title | Priority Date | Filing Date |
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| ES04768667T Expired - Lifetime ES2324669T3 (es) | 2003-09-26 | 2004-09-24 | Derivados de bencimidazol, composiciones que los contienen, su preparacion y sus usos. |
Country Status (33)
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| EP (1) | EP1670769B1 (https=) |
| JP (1) | JP4896721B2 (https=) |
| KR (1) | KR101170184B1 (https=) |
| CN (2) | CN102010373A (https=) |
| AR (1) | AR045819A1 (https=) |
| AT (1) | ATE430135T1 (https=) |
| AU (1) | AU2004276062B2 (https=) |
| BR (1) | BRPI0414780B8 (https=) |
| CA (1) | CA2539738C (https=) |
| CO (1) | CO5680443A2 (https=) |
| CY (1) | CY1110332T1 (https=) |
| DE (1) | DE602004020907D1 (https=) |
| DK (1) | DK1670769T3 (https=) |
| ES (1) | ES2324669T3 (https=) |
| HR (1) | HRP20090388T1 (https=) |
| IL (1) | IL174215A0 (https=) |
| IS (1) | IS8422A (https=) |
| MX (1) | MXPA06003197A (https=) |
| MY (1) | MY140630A (https=) |
| NO (1) | NO20061839L (https=) |
| NZ (1) | NZ545736A (https=) |
| PL (1) | PL1670769T3 (https=) |
| PT (1) | PT1670769E (https=) |
| RU (1) | RU2346938C2 (https=) |
| SA (1) | SA04250310B1 (https=) |
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| SI (1) | SI1670769T1 (https=) |
| TW (1) | TW200521117A (https=) |
| UA (1) | UA86776C2 (https=) |
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| EP1558252B1 (en) | 2002-08-02 | 2007-10-10 | Merck & Co., Inc. | Substituted furo [2,3-b]pyridine derivatives |
| SE0302573D0 (sv) | 2003-09-26 | 2003-09-26 | Astrazeneca Ab | Benzimidazole derivatives, compositions containing them, preparation thereof and uses thereof |
| WO2006033631A1 (en) * | 2004-09-24 | 2006-03-30 | Astrazeneca Ab | Benzimidazole derivatives, compositions containing them, preparation thereof and uses thereof i |
| UA87327C2 (ru) * | 2004-09-24 | 2009-07-10 | Астразенека Аб | Производные бензимидазола, композиция, которая их содержит, их получение и применение |
| MX2007003105A (es) | 2004-09-24 | 2007-06-07 | Aztrazeneca Ab | Derivados de bencimidazol, composiciones que los contienen, sus preparaciones y sus usos i. |
| WO2006033630A1 (en) * | 2004-09-24 | 2006-03-30 | Astrazeneca Ab | Compounds, compositions containing them, preparation thereof and uses thereof iii |
| MX2007005290A (es) | 2004-11-02 | 2007-07-09 | Pfizer | Derivados de sulfonilbencimidazol. |
| CN101233098A (zh) * | 2005-07-29 | 2008-07-30 | 阿斯利康(瑞典)有限公司 | 成对((二氟环烷基)甲基)胺的制备方法 |
| TW200745049A (en) | 2006-03-23 | 2007-12-16 | Astrazeneca Ab | New crystalline forms |
| TW200808769A (en) | 2006-04-18 | 2008-02-16 | Astrazeneca Ab | Therapeutic compounds |
| US20080139846A1 (en) * | 2006-09-01 | 2008-06-12 | Astrazeneca Ab | New Process 298 |
| EP2070927A4 (en) * | 2006-09-13 | 2010-10-13 | Kyowa Hakko Kirin Co Ltd | CONDENSED HETEROCYCLIC DERIVATIVE |
| US20110086853A1 (en) * | 2009-10-08 | 2011-04-14 | William Brown | Therapeutic Compounds |
| RU2414899C1 (ru) * | 2009-12-29 | 2011-03-27 | Аверин Константин Михайлович | Средства для лечения рассеянного склероза |
| RU2454234C1 (ru) * | 2011-03-16 | 2012-06-27 | Константин Михайлович Аверин | Соли 1,3-диэтилбензимидазолия - иммуностимулирующие средства и фармацевтические композиции на их основе |
| UA119740C2 (uk) * | 2012-06-13 | 2019-08-12 | Сайтек Текнолоджи Корп. | Композиції стабілізатора, що містять заміщені хроманові сполуки, і способи застосування |
| SI2864291T1 (sl) | 2012-06-26 | 2017-01-31 | Bayer Pharma Aktiengesellschaft | N-(4-(kinolin-4-iloksi)cikloheksil(metil))(hetero)arilkarboksamidi kot antagonisti receptorja androgena, njihova izdelava in uporaba kot medicinski izdelki |
| JP2021515767A (ja) | 2018-03-07 | 2021-06-24 | バイエル・アクチエンゲゼルシヤフト | Ｅｒｋ５阻害剤の同定及び使用 |
| WO2020234103A1 (en) | 2019-05-21 | 2020-11-26 | Bayer Aktiengesellschaft | Identification and use of kras inhibitors |
| CN112010789A (zh) * | 2019-05-31 | 2020-12-01 | 中国科学院上海药物研究所 | 乙烯基磺酰胺或乙烯基酰胺类化合物及其制备方法和用途 |
| GB202019335D0 (en) * | 2020-12-08 | 2021-01-20 | Artelo Biosciences Ltd | Pharmaceutical compositions |
| WO2023166450A1 (ko) * | 2022-03-04 | 2023-09-07 | 삼진제약주식회사 | 신규한 헤테로 고리 화합물 및 이를 포함하는 약학적 조성물 |
Family Cites Families (48)
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| FR1604908A (en) | 1965-06-24 | 1971-05-15 | Substd benzimidazoles - with anthelmintic,fungicidal activity and some with antiviral and antibacterial activity | |
| FR5354M (https=) | 1965-09-10 | 1967-09-11 | ||
| US5387600A (en) | 1992-07-30 | 1995-02-07 | Fuji Photo Film Co., Ltd. | Treating arteriosclerosis using benzimidazole compositions |
| DE4237617A1 (de) * | 1992-11-06 | 1994-05-11 | Bayer Ag | Verwendung von substituierten Benzimidazolen |
| DE4237597A1 (de) | 1992-11-06 | 1994-05-11 | Bayer Ag | Substituierte Benzimidazole |
| DE4237557A1 (de) | 1992-11-06 | 1994-05-11 | Bayer Ag | Substituierte Benzimidazole |
| AU722514B2 (en) | 1995-12-28 | 2000-08-03 | Fujisawa Pharmaceutical Co., Ltd. | Benzimidazole derivatives |
| TW453999B (en) * | 1997-06-27 | 2001-09-11 | Fujisawa Pharmaceutical Co | Benzimidazole derivatives |
| US6348032B1 (en) * | 1998-11-23 | 2002-02-19 | Cell Pathways, Inc. | Method of inhibiting neoplastic cells with benzimidazole derivatives |
| AU6762400A (en) | 1999-08-12 | 2001-03-13 | Cor Therapeutics, Inc. | Inhibitors of factor xa |
| US6844367B1 (en) * | 1999-09-17 | 2005-01-18 | Millennium Pharmaceuticals, Inc. | Benzamides and related inhibitors of factor Xa |
| US6632815B2 (en) * | 1999-09-17 | 2003-10-14 | Millennium Pharmaceuticals, Inc. | Inhibitors of factor Xa |
| US6720317B1 (en) * | 1999-09-17 | 2004-04-13 | Millennium Pharmaceuticals, Inc. | Inhibitors of factor Xa |
| JP2003509412A (ja) | 1999-09-17 | 2003-03-11 | シーオーアール セラピューティクス インコーポレイテッド | Ｘａ因子阻害剤 |
| SK287527B6 (sk) * | 2000-01-14 | 2011-01-04 | Bayer Schering Pharma Aktiengesellschaft | 1,2-Diarylbenzimidazoly a ich farmaceutické použitie |
| US7115645B2 (en) * | 2000-01-14 | 2006-10-03 | Schering Aktiengesellschaft | 1,2 diarylbenzimidazoles and their pharmaceutical use |
| US7329679B2 (en) * | 2000-01-27 | 2008-02-12 | Schering Aktiengesellschaft | 1,2 Diarylbenzimidazoles and their pharmaceutical use |
| AU2001250783A1 (en) * | 2000-02-29 | 2001-09-12 | Cor Therapeutics, Inc. | Benzamides and related inhibitors of factor xa |
| WO2002000651A2 (en) | 2000-06-27 | 2002-01-03 | Bristol-Myers Squibb Pharma Company | Factor xa inhibitors |
| US20070004713A1 (en) | 2000-12-07 | 2007-01-04 | Bernard Barlaam | Therapeutic benimidazole compounds |
| SE0101387D0 (sv) * | 2001-04-20 | 2001-04-20 | Astrazeneca Ab | Novel compounds |
| JPWO2002100833A1 (ja) | 2001-06-12 | 2004-09-24 | 住友製薬株式会社 | Ｒｈｏキナーゼ阻害剤 |
| TW200505902A (en) | 2003-03-20 | 2005-02-16 | Schering Corp | Cannabinoid receptor ligands |
| SE0301699D0 (sv) | 2003-06-10 | 2003-06-10 | Astrazeneca Ab | Benzimidazole derivatives, compositions containing them, preparation thereof and uses thereof |
| SE0301701D0 (sv) | 2003-06-10 | 2003-06-10 | Astrazeneca Ab | Benzimidazole derivatives, compositions containing them, preparation thereof and uses thereof |
| US20050026968A1 (en) | 2003-07-14 | 2005-02-03 | University Of Tennessee Research Foundation | Heterocyclic amides with anti-tuberculosis activity |
| WO2005021547A2 (en) | 2003-08-28 | 2005-03-10 | Pharmaxis Pty Ltd. | Heterocyclic cannabinoid cb2 receptor antagonists |
| SE0302572D0 (sv) | 2003-09-26 | 2003-09-26 | Astrazeneca Ab | Benzimidazole derivatives, compositions containing them, preparation thereof and uses thereof |
| SE0302573D0 (sv) | 2003-09-26 | 2003-09-26 | Astrazeneca Ab | Benzimidazole derivatives, compositions containing them, preparation thereof and uses thereof |
| SE0302571D0 (sv) | 2003-09-26 | 2003-09-26 | Astrazeneca Ab | Benzimidazole derivatives, compositions containing them, preparation thereof and uses thereof |
| SE0302570D0 (sv) | 2003-09-26 | 2003-09-26 | Astrazeneca Ab | Benzimidazole derivatives, compositions containing them, preparation thereof and uses thereof |
| CA2567343A1 (en) | 2004-05-20 | 2005-12-01 | Elan Pharmaceuticals, Inc. | N-cyclic sulfonamido inhibitors of gamma secretase |
| EP1765332A2 (en) | 2004-06-17 | 2007-03-28 | Cengent Therapeutics, Inc. | Trisubstituted nitrogen modulators of tyrosine phosphatases |
| SG155188A1 (en) | 2004-07-30 | 2009-09-30 | Exelixis Inc | Pyrrole derivatives as pharmaceutical agents |
| US20060052421A1 (en) * | 2004-09-09 | 2006-03-09 | Eastman Kodak Company | Conjugation agent |
| WO2006033629A1 (en) | 2004-09-24 | 2006-03-30 | Astrazeneca Ab | Benzimidazole derivatives and their use as cannabinoid receptor ligands |
| EP1797076A1 (en) | 2004-09-24 | 2007-06-20 | AstraZeneca AB | Benzimidazole derivatives, compositions containing them, preparation thereof and uses thereof |
| MX2007003105A (es) * | 2004-09-24 | 2007-06-07 | Aztrazeneca Ab | Derivados de bencimidazol, composiciones que los contienen, sus preparaciones y sus usos i. |
| WO2006033632A1 (en) | 2004-09-24 | 2006-03-30 | Astrazeneca Ab | Benzimidazole derivatives and their use as cannabinoid receptor ligands I |
| WO2006033630A1 (en) | 2004-09-24 | 2006-03-30 | Astrazeneca Ab | Compounds, compositions containing them, preparation thereof and uses thereof iii |
| WO2006033631A1 (en) | 2004-09-24 | 2006-03-30 | Astrazeneca Ab | Benzimidazole derivatives, compositions containing them, preparation thereof and uses thereof i |
| EP1797070A1 (en) | 2004-09-24 | 2007-06-20 | AstraZeneca AB | Compounds, compositions containing them, preparations thereof and uses thereof ii |
| WO2006033627A1 (en) | 2004-09-24 | 2006-03-30 | Astrazeneca Ab | Compounds, compositions containing them, preparation thereof and uses thereof iiii |
| MX2007005290A (es) * | 2004-11-02 | 2007-07-09 | Pfizer | Derivados de sulfonilbencimidazol. |
| WO2006078941A2 (en) | 2005-01-20 | 2006-07-27 | Sirtris Pharmaceuticals, Inc. | Novel sirtuin activating compounds and methods of use thereof |
| TW200745049A (en) * | 2006-03-23 | 2007-12-16 | Astrazeneca Ab | New crystalline forms |
| TW200808769A (en) * | 2006-04-18 | 2008-02-16 | Astrazeneca Ab | Therapeutic compounds |
| TW200808772A (en) * | 2006-06-13 | 2008-02-16 | Astrazeneca Ab | Therapeutic compounds |
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