HRP960155A2 - 1,3-dihydro-1-(phenylalkyl)-2h-imidazol-2-one derivatives - Google Patents

Info

Publication number

HRP960155A2

HRP960155A2 HR95202898.3A HRP960155A HRP960155A2 HR P960155 A2 HRP960155 A2 HR P960155A2 HR P960155 A HRP960155 A HR P960155A HR P960155 A2 HRP960155 A2 HR P960155A2

Authority

HR

Croatia

Prior art keywords

alkyl

formula

substituted

aryl

amino

Prior art date

1995-04-06

Links

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• 150000001875 compounds Chemical class 0.000 claims description 177
• -1 bicyclo[2.2.1]-2-heptenyl Chemical group 0.000 claims description 124
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 116
• 239000000543 intermediate Substances 0.000 claims description 107
• 239000001257 hydrogen Substances 0.000 claims description 102
• 229910052739 hydrogen Inorganic materials 0.000 claims description 102
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 84
• 125000003118 aryl group Chemical group 0.000 claims description 80
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 70
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 58
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 52
• 229910052757 nitrogen Chemical group 0.000 claims description 45
• 150000002431 hydrogen Chemical class 0.000 claims description 38
• 239000011541 reaction mixture Substances 0.000 claims description 38
• 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 37
• 229920006395 saturated elastomer Polymers 0.000 claims description 37
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 36
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 35
• 229910052736 halogen Inorganic materials 0.000 claims description 35
• 150000002367 halogens Chemical class 0.000 claims description 35
• 229910052760 oxygen Inorganic materials 0.000 claims description 35
• 239000001301 oxygen Substances 0.000 claims description 35
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 34
• 125000005842 heteroatom Chemical group 0.000 claims description 34
• 229910052717 sulfur Inorganic materials 0.000 claims description 34
• 239000011593 sulfur Chemical group 0.000 claims description 34
• 125000000623 heterocyclic group Chemical group 0.000 claims description 33
• 239000002253 acid Substances 0.000 claims description 28
• 125000004076 pyridyl group Chemical group 0.000 claims description 28
• 125000001544 thienyl group Chemical group 0.000 claims description 28
• 150000003839 salts Chemical class 0.000 claims description 27
• 238000006243 chemical reaction Methods 0.000 claims description 26
• 125000001424 substituent group Chemical group 0.000 claims description 25
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 25
• 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 23
• 125000003386 piperidinyl group Chemical group 0.000 claims description 23
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 22
• 125000002541 furyl group Chemical group 0.000 claims description 22
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 22
• 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 21
• 125000003830 C1- C4 alkylcarbonylamino group Chemical group 0.000 claims description 21
• 238000000034 method Methods 0.000 claims description 21
• 239000002585 base Substances 0.000 claims description 16
• 239000012442 inert solvent Substances 0.000 claims description 15
• 208000012657 Atopic disease Diseases 0.000 claims description 14
• 102000004127 Cytokines Human genes 0.000 claims description 14
• 108090000695 Cytokines Proteins 0.000 claims description 14
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
• 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 claims description 13
• 208000026935 allergic disease Diseases 0.000 claims description 13
• 201000010099 disease Diseases 0.000 claims description 13
• 239000003814 drug Substances 0.000 claims description 13
• 125000004193 piperazinyl group Chemical group 0.000 claims description 13
• 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 12
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
• 150000001204 N-oxides Chemical class 0.000 claims description 11
• 230000000172 allergic effect Effects 0.000 claims description 10
• BVCRERJDOOBZOH-UHFFFAOYSA-N bicyclo[2.2.1]heptanyl Chemical group C1C[C+]2CC[C-]1C2 BVCRERJDOOBZOH-UHFFFAOYSA-N 0.000 claims description 10
• 125000004432 carbon atom Chemical group C* 0.000 claims description 10
• 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 10
• 208000027866 inflammatory disease Diseases 0.000 claims description 10
• 125000006239 protecting group Chemical group 0.000 claims description 10
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 9
• 238000007363 ring formation reaction Methods 0.000 claims description 9
• TWJFOISWLZFDAW-UHFFFAOYSA-N 3-[2-(3,4-dimethoxyphenyl)ethyl]-1h-imidazol-2-one Chemical compound C1=C(OC)C(OC)=CC=C1CCN1C(=O)NC=C1 TWJFOISWLZFDAW-UHFFFAOYSA-N 0.000 claims description 8
• 239000008194 pharmaceutical composition Substances 0.000 claims description 8
• 229940079593 drug Drugs 0.000 claims description 7
• LVOSINGOUMKNAD-UHFFFAOYSA-N 1-[2-(3,4-dimethoxyphenyl)ethyl]imidazolidin-2-one Chemical compound C1=C(OC)C(OC)=CC=C1CCN1C(=O)NCC1 LVOSINGOUMKNAD-UHFFFAOYSA-N 0.000 claims description 6
• 241000124008 Mammalia Species 0.000 claims description 6
• 238000007126 N-alkylation reaction Methods 0.000 claims description 6
• 238000005984 hydrogenation reaction Methods 0.000 claims description 6
• 125000002883 imidazolyl group Chemical group 0.000 claims description 6
• 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 6
• 238000004519 manufacturing process Methods 0.000 claims description 6
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
• 125000002757 morpholinyl group Chemical group 0.000 claims description 6
• 125000002971 oxazolyl group Chemical group 0.000 claims description 6
• 125000000335 thiazolyl group Chemical group 0.000 claims description 6
• NLDMLICTXNFISF-UHFFFAOYSA-N 1-[2-(3,4-dimethoxyphenyl)propyl]imidazolidin-2-one Chemical compound C1=C(OC)C(OC)=CC=C1C(C)CN1C(=O)NCC1 NLDMLICTXNFISF-UHFFFAOYSA-N 0.000 claims description 5
• 230000002159 abnormal effect Effects 0.000 claims description 5
• 239000004480 active ingredient Substances 0.000 claims description 5
• 230000003197 catalytic effect Effects 0.000 claims description 5
• 239000003937 drug carrier Substances 0.000 claims description 5
• JFSPBVWPKOEZCB-UHFFFAOYSA-N fenfuram Chemical group O1C=CC(C(=O)NC=2C=CC=CC=2)=C1C JFSPBVWPKOEZCB-UHFFFAOYSA-N 0.000 claims description 5
• 229910021645 metal ion Inorganic materials 0.000 claims description 5
• AICIYIDUYNFPRY-UHFFFAOYSA-N 1,3-dihydro-2H-imidazol-2-one Chemical class O=C1NC=CN1 AICIYIDUYNFPRY-UHFFFAOYSA-N 0.000 claims description 4
• LIGFHIQINFKZOA-UHFFFAOYSA-N 3-[2-(3,4-dimethoxyphenyl)propyl]-1h-imidazol-2-one Chemical group C1=C(OC)C(OC)=CC=C1C(C)CN1C(=O)NC=C1 LIGFHIQINFKZOA-UHFFFAOYSA-N 0.000 claims description 4
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
• 102000011017 Type 4 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 claims description 4
• 108010037584 Type 4 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 claims description 4
• 239000003153 chemical reaction reagent Substances 0.000 claims description 4
• 238000010511 deprotection reaction Methods 0.000 claims description 4
• 230000002255 enzymatic effect Effects 0.000 claims description 4
• 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 3
• GHULUXIPXFWITC-UHFFFAOYSA-N 1,3-bis[2-(3,4-dimethoxyphenyl)ethyl]imidazolidin-2-one Chemical compound C1=C(OC)C(OC)=CC=C1CCN1C(=O)N(CCC=2C=C(OC)C(OC)=CC=2)CC1 GHULUXIPXFWITC-UHFFFAOYSA-N 0.000 claims description 3
• AMJQZQWXTPVXAS-UHFFFAOYSA-N 1-benzyl-3-[2-(3,4-dimethoxyphenyl)ethyl]imidazolidin-2-one Chemical compound C1=C(OC)C(OC)=CC=C1CCN1C(=O)N(CC=2C=CC=CC=2)CC1 AMJQZQWXTPVXAS-UHFFFAOYSA-N 0.000 claims description 3
• VCGJMGSCXRICGA-UHFFFAOYSA-N 3-[2-(3-cyclopentyloxy-4-methoxyphenyl)propyl]-1h-imidazol-2-one Chemical compound COC1=CC=C(C(C)CN2C(NC=C2)=O)C=C1OC1CCCC1 VCGJMGSCXRICGA-UHFFFAOYSA-N 0.000 claims description 3
• 206010012438 Dermatitis atopic Diseases 0.000 claims description 3
• XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 3
• 239000003513 alkali Substances 0.000 claims description 3
• 125000000217 alkyl group Chemical group 0.000 claims description 3
• 201000008937 atopic dermatitis Diseases 0.000 claims description 3
• PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 3
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
• 239000000126 substance Substances 0.000 claims description 3
• BWXQWXIYTNDSLQ-UHFFFAOYSA-N 3-[2-(3,4-diethoxyphenyl)ethyl]-1h-imidazol-2-one Chemical compound C1=C(OCC)C(OCC)=CC=C1CCN1C(=O)NC=C1 BWXQWXIYTNDSLQ-UHFFFAOYSA-N 0.000 claims description 2
• UHHRQVCUEFYSNI-UHFFFAOYSA-N 3-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-methylpropyl]-1h-imidazol-2-one Chemical compound COC1=CC=C(C(C)(C)CN2C(NC=C2)=O)C=C1OC1CCCC1 UHHRQVCUEFYSNI-UHFFFAOYSA-N 0.000 claims description 2
• ACBYRQONKZKIIY-UHFFFAOYSA-N 3-[2-[3-(cyclopropylmethoxy)-4-methoxyphenyl]propyl]-1h-imidazol-2-one Chemical compound COC1=CC=C(C(C)CN2C(NC=C2)=O)C=C1OCC1CC1 ACBYRQONKZKIIY-UHFFFAOYSA-N 0.000 claims description 2
• XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims description 2
• YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 2
• 238000007259 addition reaction Methods 0.000 claims description 2
• 239000004202 carbamide Substances 0.000 claims description 2
• 239000012458 free base Substances 0.000 claims description 2
• 239000012948 isocyanate Substances 0.000 claims description 2
• 150000002513 isocyanates Chemical class 0.000 claims description 2
• 150000003672 ureas Chemical class 0.000 claims description 2
• 238000010306 acid treatment Methods 0.000 claims 1
• 230000007062 hydrolysis Effects 0.000 claims 1
• 238000006460 hydrolysis reaction Methods 0.000 claims 1
• 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 1
• 230000007935 neutral effect Effects 0.000 claims 1
• 150000002902 organometallic compounds Chemical class 0.000 claims 1
• 239000000203 mixture Substances 0.000 description 106
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 90
• 239000002904 solvent Substances 0.000 description 64
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 62
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 56
• 239000000243 solution Substances 0.000 description 46
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 44
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
• 150000003254 radicals Chemical group 0.000 description 34
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 30
• 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 30
• 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 30
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 28
• 239000003480 eluent Substances 0.000 description 27
• ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 26
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 26
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 23
• 108010037444 diisopropylglutathione ester Proteins 0.000 description 23
• 239000012044 organic layer Substances 0.000 description 23
• 239000002244 precipitate Substances 0.000 description 23
• 238000003756 stirring Methods 0.000 description 23
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
• 239000000741 silica gel Substances 0.000 description 22
• 229910002027 silica gel Inorganic materials 0.000 description 22
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
• 239000003054 catalyst Substances 0.000 description 20
• VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 20
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
• 230000000694 effects Effects 0.000 description 14
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 14
• 235000019341 magnesium sulphate Nutrition 0.000 description 14
• 238000002360 preparation method Methods 0.000 description 14
• 230000005764 inhibitory process Effects 0.000 description 13
• 238000004440 column chromatography Methods 0.000 description 12
• 235000019441 ethanol Nutrition 0.000 description 12
• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 12
• 238000012360 testing method Methods 0.000 description 12
• 229910000069 nitrogen hydride Inorganic materials 0.000 description 11
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
• 210000004027 cell Anatomy 0.000 description 10
• 239000000706 filtrate Substances 0.000 description 10
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
• PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 9
• 239000000460 chlorine Substances 0.000 description 9
• PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
• 239000007983 Tris buffer Substances 0.000 description 8
• 238000004587 chromatography analysis Methods 0.000 description 8
• 230000002401 inhibitory effect Effects 0.000 description 8
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• 230000008018 melting Effects 0.000 description 8
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• 239000003826 tablet Substances 0.000 description 8
• 150000007513 acids Chemical class 0.000 description 7
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
• 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 7
• LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 7
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
• 229920000858 Cyclodextrin Polymers 0.000 description 6
• 229920002307 Dextran Polymers 0.000 description 6
• QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 6
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• 239000003795 chemical substances by application Substances 0.000 description 6
• 238000002156 mixing Methods 0.000 description 6
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
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• 238000004128 high performance liquid chromatography Methods 0.000 description 5
• 238000000338 in vitro Methods 0.000 description 5
• 238000001727 in vivo Methods 0.000 description 5
• 229910052763 palladium Inorganic materials 0.000 description 5
• 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
• 208000030507 AIDS Diseases 0.000 description 4
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• 241000699670 Mus sp. Species 0.000 description 4
• 239000007832 Na2SO4 Substances 0.000 description 4
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
• YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 4
• 150000001412 amines Chemical class 0.000 description 4
• 229910021529 ammonia Inorganic materials 0.000 description 4
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• 238000004811 liquid chromatography Methods 0.000 description 4
• DBYQHFPBWKKZAT-UHFFFAOYSA-N lithium;benzene Chemical compound [Li+].C1=CC=[C-]C=C1 DBYQHFPBWKKZAT-UHFFFAOYSA-N 0.000 description 4
• 210000004698 lymphocyte Anatomy 0.000 description 4
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• 229910052759 nickel Inorganic materials 0.000 description 3
• 150000002825 nitriles Chemical group 0.000 description 3
• 125000004433 nitrogen atom Chemical group N* 0.000 description 3
• 239000002674 ointment Substances 0.000 description 3
• 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 3
• BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 3
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